(a) Before operation (b) Three years after subtotal adrenalectomy

(lint J Surg. September 1957. P- *47-)

Clinical Endocrinology
for Surgeons

BY

D. A. D. MONTGOMERY-

M.D., M.R.C.P.

Plysklan, Pojal llctorla Hospital and Dyiklan-ln-chargc,

Sir George t. C/arJi Metabolic Unit, Royal Victoria Hospital, Belfast

AND

R. B. WELBOURN

M.A., M.D., F.R.C.S. *

Projcssct of Surgery, Postgraduate Medical School of London *■
and Surgeon, Hammersmith Hospital. F ormcrly
Professor of Surgical Science, Queen’s Unlrerslty of Belfast
and Surgeon, Royal Victoria Hospital and City Hospital, Belfast

LONDON

EDWARD ARNOLD (PUBLISHERS) LTD

3311

<£j D. A. D. Montgomery and ft. 11. IVelboum 1963
First published 1963

RTn.t ? c

'.LEGE,,

3341

L ‘ ■ Xyy/ \2r\t-iS

Printed tn Great Jlntmn b\ JheharJ Chi) and Company, I. id.,
fturtga) , Suffolk

CONTENTS

PAGE

Preface vi

Introduction 1

Part 1. The Anterior Pituitary and its Target Glands

CHAPTER

1 The Anterior Pituitary 9

2 The Steroid Hormones 51

3 The Adrenal Cortex 63

4 The Testis 129

5 The Ovary 166

6 Steroid Hormone Therapy * • 202

7 The Thyroid Gland 218

Part II. Other Major Endocrine Glands

8 The Neurohypophysis 333

9 The Adrenal Medulla 342

10 The Parathyroid Glands {by Mary G. McGeozm) 358

11 Islet Cells of the Pancreas 384

Part III. Endocrine Aspects of General Surgery

12 Surgical Stress 415

13 The Breast 427

14 Carcinoma of the Prostate 449

15 The Skeleton 454

16 The Alimentary Tract 473

1 7 Anomalies of Sexual Development 495

Index 533

PREFACE

Clinical Endocrinology has made astonishing progress in the past two
decades, and surgeons are becoming involved increasingly in all its aspects.
It is one of the many fields of medicine in which physicians and surgeons
are drawing close together and making their own contributions to the joint
management of individual patients. This unity of the medical and surgical
aspects of endocrinology has not received proper acknowledgement in the
standard textbooks. Those on surgery discuss the endocrine glands at
length, but do not treat them as parts of an integrated system or supply the
surgeon with an adequate account of the medical features. Medical and
endocrinological works, on the other hand, tend to dismiss the surgical
aspects or to deal with them in a cursor}' fashion. We have attempted to
provide here a systematic account of clinical endocrinology in which the
essential unity of the endocrine system is emphasized and in which both
medical and surgical aspects are treated together.

We hope that the book will be of use to young surgeons who are studying
for higher degrees and diplomas, to established surgeons who encounter
unfamiliar problems in endocrinology and to physicians who wish to know
more about the surgical aspects of their clinical problems.

We make no apology for introducing much elementary chemistry,
physiology and pathology, for patients cannot be investigated and treated
in a rational manner unless these aspects of the subject are understood, at
least in principle.

The amount of space which we have devoted to each subject depends
not only on its clinical importance but also on the adequacy with which it
is treated elsewhere and on the urgency with which practical guidance may
be required. Thus, diseases of the thyroid, which concern the surgeon
very frequently, are discussed at considerable length, while anomalies of
sexual development, which are rare, are also described in some detail
because knowledge of the subject has developed rapidly in recent years
and has not yet been synthesized and incorporated in the surgical litera-
ture. Again, the general account of diabetes mellitus is very' brief, but
the treatment of diabetes (and particularly of diabetic coma) in relation to
surgical operations is described in detail, for a competent physician may
not alwa)s be available in an emergency. Short descriptions of most
surgical operations on the endocrine glands are provided, but detailed
accounts of operative technique must be sought elsewhere.

The book is divided into three parts. Part 1 deals with the anterior

PREFACE

vii

pituitary and its target glands and contains two chapters which are in-
tended to help the understanding of the great interdependence of these
parts of the endocrine system. Chapter 2 on the steroid hormones serves
as an introduction to the adrenal cortex and the gonads, while Chapter 6
on steroid hormone therapy provides a link between these glands, on the
one hand, and general surgery, on the other. Part II deals with the other
major endocrine glands which are not, so far as is known, dependent on
the anterior pituitary or on any other gland. Part III is unusual in that
it provides a discussion of the endocrine aspects of many problems in
general surgery. It presupposes a working knowledge of the material in
the first two parts of the book.

The “ further reading and references ” listed at the end of each chapter
represents the papers and books which we have found most helpful in our
own practice and in the preparation of this book and gives the sources of
the numerical and other data which we have quoted. The lists are selective
rather than comprehensive.

Wherever possible we have referred to our own experience and to that
of our colleagues, who have been very generous in providing us with
analyses of their material and in criticizing our early typescript. To a
large extent, therefore, the book represents the work and views of the
Belfast medical school as a whole, although we accept responsibility for all
that we have written.

We are particularly grateful to three colleagues who have helped with
the actual writing of the book. Dr. Mary McGeown wrote Chapter 10 and
graciously accepted our editing to bring the arrangement into line with
that of the rest of the text. Dr. M. T. Harrison (now lecturer in medicine
in the University of Glasgow) and Dr. E. B. Dowdle (now senior lecturer in
the Department of Medicine in the University of Capetown) wrote the
first drafts of parts of Chapters 15 and 17 respectively and allowed us to
expand them.

Many others have helped in different ways, and we are very grateful
to all of them. Professor J. H. Biggart allowed us to draw on the patho-
logical material in his department, and members of his staff (whose help
is acknowledged below and in the text) analysed some of it for us. Mr.
D. W. Neill and Dr. R. Chenneour gave much valuable advice about
clinical biochemistry and allotted us to quote data from their laboratories.
The elegant diagrams and illustrations of our artist, Mr. G. A. Smith, form
an important part of the book. Mr. R. Wood and his assistants provided
prints of these and most of the clinical photographs, and were most co-
operative and patient. Mr. ]. H. Restrick, Mr. G. Mcllhagger, Mr. W.
Black and their staff gave advice on pharmaceutical matters. Miss J.
Webster and her staff helped us greatly with the bibliography. We have
received skilful secretarial assistance throughout the preparation of the

PREFACE

viii

book from Mrs. H. N. Head and Miss M. M. Scott. The latter has under-
taken the major share with devotion and untiring C3re. Mr. K. F. Kyle
kindly assisted us in reading the proofs. Several colleagues and authors
have generously loaned us clinical photographs or allowed us to reproduce
figures. They are all acknowledged in the text.

The following have helped us in various ways ■with individual (speci-
fied) chapters and we appreciate their generous assistance; (1) Mr. C. A.
Gleadhili, Mr. A. R. Taylor and Dr. J. Willis; (3) Professor G. M. Bull;
Dr. J. B. Gibson and Dr. D. C. Porter; (4) Mr. J. Mcl. Megaw and Dr.
J. B. Gibson; (5) Professor C. H. G. Macafec, Mr. G. Millar and Dr.
Graham Harley; (7) Mr. T. K. Bell, Mr. D. S. Gordon, Mr. T. L.
Kennedy, Mr. R. H. Livingston, Dr. A. R. Lyons, Mr. E. Morrison, Dr.
M. G. Nelson, Dr. G. K. Rastogi, Dr. J. A. Weaver, Dr. J. Willis and
Mr. W. Wilson; (9) Dr. J. W. Dundee and Dr. D. Eakins; (10) Mr. E.
Morrison; (11) Dr. J. B. Gibson and Mr. R. H. Livingston; (12) Mr.
1. D. A. Johnston and Mr. A. McCalister; (13) Dr. G. J. A. Edelstyn,
Dr. A. R. Lyons and Mr. A. McCalister; (14) Mr. R. H. Livingston and
Mr. J. Mcl. Megaw; (16) Dr. J. W. Dundee, Dr. D. Eakins, Dr. J. E.
Morison and Dr. J. T. Ward; and (17) Dr. W. R. M. Morton.

We are especially grateful to Professor H. \V. Rodgers and Dr. J. A.
Weaver, both of whom cheerfully shouldered disproportionate shares of
the routine work of the departments of surgery and metabolism respectively
in order to free us for writing. We thank Mr. H. C. Edwards for sug-
gesting, nearly six years ago, that we should write this book and hope that
he will not be unduly disappointed in the result.

INTRODUCTION

One of the most remarkable things about the animal body is the way in
which it maintains its integrity in a hostile world. It does so by means of a
highly delicate and complex organization which is controlled mainly
through the nervous and endocrine systems. The integrative action of the
nervous system was recognized long ago by Sherrington. That of the
endocrine system has become apparent only recently.

Endocrinology is a young branch of biological science and has, until
recently, been concerned with classification rather than measurement and
with biological rather than biochemical description. Now, however, it is
approaching maturity and narrow hypotheses are giving place to broad
conceptions. Most of the secretions of the endocrine glands have been
identified, many can be estimated by chemical methods and some of them
have been synthesized. The chemical processes involved in their biological
effects are still, however, largely unknown. Formerly the individual endo-
crine glands and their disorders were considered in water-tight compart-
ments. Today they are seen to be closely integrated and to influence most
of the metabolic processes of the body in health and disease. The endocrine
glands are involved not only in the diseases which we commonly regard as
endocrine in nature but also in such common events as the response of the
body to infection and trauma and the development of cancers of the breast
and prostate. A few years ago the role of the surgeon in clinical endocrino-
logy was that of performing a few standard operations, such as thyroidec-
tomy, for the relief of endocrine disorders. Today the scope of such
procedures is much greater, and surgeons are learning that endocrinological
problems may arise when least expected in any of their patients.

ANATOMY OF THE ENDOCRINE SYSTEM

The endocrine system has three main divisions. The first consists of the
anterior pituitary (the adenohypophysis) and the glands which it controls
by means of its trophic hormones. These are the adrenal cortex, the gonads
and the thyroid. The second comprises a group of glands which secrete in
response to various stimuli, but which are not, apparently, under the direct
control of the anterior pituitary or of any other gland. These are the
posterior lobe of the pituitary (the neurohypophysis) and the adrenal
medulla, both of which are in part under the direct control of the nervous
system, the parathyroids and the islet cells of the pancreas. The third
division is not usually considered to be part of the endocrine system proper.

2

INTRODUCTION

It includes 3 number of organs which secrete hormones but which also have
other specialized functions. Parts of the alimentary tract, for instance,
elaborate hormones w hich help to control alimentary function, and most of
the tissues of the body produce histamine.

Most endocrine glands, the adrenal cortex and the thyroid, for instance,
are composed of secretory cellular epithelium, but two, the neurohypo-
physis and the adrenal medulla, are made up of neural tissue. Within the
glands hormones are synthesized, stored and finally released. Facilities for
storage are not great, however, except in the thyroid gland.

PHYSIOLOGY OF THE ENDOCRINE SYSTEM

The endocrine glands produce their effects by elaborating “internal
secretions” (the term used by Claude Bernard) or "hormones” (so named
by Starling from a Greek word meaning “to stimulate”), which are released
into the circulation. Some glands, such as the thyroid, secrete one hormone
only (or hormones with similar actions), while others, notably the adrenal
cortex, secrete several with quite distinct functions.

Hormones vary greatly in the complexity of their chemical structures.
Some, such as insulin and the trophic hormones of the anterior pituitary,
have complex protein or polypeptide molecules, others, such as the steroids,
are of intermediate complexity and some, such as adrenaline and thyroxine,
are relatively simple.

The secretions of most, if not all, the endocrine glands are controlled by
delicate “feed back” mechanisms whereby the production of a hormone is
stimulated when its action is required and inhibited when the effect has
been achieved. These mechanisms are of two main types. (1) The secre-
tion of the trophic hormones of the anterior pituitary is governed by the
hormones produced by their target glands. For example, a low concentra-
tion of cortisol in the blood stimulates the secretion of ACTH, while a high
concentration inhibits it, (2) The secretions of the other glands are
governed directly by the physical or chemical processes which they regu-
late. Thus, the secretion of antidiuretic hormone is controlled by the
osmotic pressure of the blood, and the secretion of insulin is regulated by
the blood glucose let el. The first form of control has important clinical
implications. It may be interfered with deliberately when, for instance,
testicular function is depressed by the administration of oestrogen for the
control of prostatic cancer, or inadvertently when adrenal failure is induced
by the administration and subsequent withdrawal of cortisone.

Some hormones, such as adrenaline, circulate in the blood in a free state,
while others, such as thyroxine, arc bound to specific plasma proteins. Some
again, such as cortisol, are partly bound and partly free. The hormones
permeate most of the tissues of the body but influence only those which arc

INTRODUCTION

3

capable of responding to them. The glands and organs which are in-
fluenced by hormones are called target glands and target organs or end-
organs. The ability of the end-organ to respond to its specific stimulus and
not to any other hormone is an essential feature of the endocrine system.
Some hormones, such as the trophic hormones of the anterior pituitary,
act only on one target gland or end-organ. Others have both specialized
functions and more general actions. The sex hormones, for instance, in-
fluence specialized tissues such as the sex organs, but also have important
actions on metabolic processes. Still others, such as growth hormone,
thyroxine, insulin and cortisol, exert important effects on all the tissues of
the body without subserving any specialized local functions.

Many hormones enhance or antagonize the effects of others, and much
of the stability of the body is due to the physiological balancing of their
synergistic or opposing actions. Thus, insulin, growth hormone, thyroxine,
adrenaline, cortisol and glucagon all influence the metabolism of carbo-
hydrate in different ways. In disease the effect of hormonal antagonism is
seen in the development of diabetes mellitus as a complication of acro-
megaly or Cushing's syndrome and in the deterioration of diabetes if it is
complicated by thyrotoxicosis. Conversely, destruction of the pituitary by
disease, or its removal by hypophysectomy, leads to amelioration of the
diabetic state.

The actions of some hormones, adrenaline, for instance, are immediately
obvious, while others, such as insulin and vasopressin, exert their effects
within minutes or hours. Some, thyroxine, for example, require some days
before they produce measurable effects, and others, such as the sex hor-
mones, influence processes which are measured in weeks. Growth hormone
and the sex hormones exert a controlling influence over the growth and
development of the body over a period of many years.

The fates of hormones after they have exerted their physiological effects
differ considerably. Some are metabolized completely in the liver or
other tissues, tvhile others are partly metabolized and partly excreted in
the urine, often in conjugated forms, together with their breakdown
products.

For years the importance assigned to the anterior pituitary — "the leader
of the endocrine orchestra” — has obscured the close relationship between
the endocrine and the nervous systems. It is appreciated now that the
hypothalamus, which is itself influenced by the higher nervous centres,
exerts a close control over the anterior pituitary and therefore an indirect
control over its target glands. The neurohypophysis and adrenal medulla
are, as we have seen, under the direct control of the nervous system.
Two glands only — the parathyroid and the islet cells of the pancreas —
are not apparently under nervous control. Conversely, many hormones
influence the functions of the nervous system. The feed-back control

4

INTRODUCTION

systems of the target glands of the anterior pituitary are operated partly by
the actions of hormones on the hypothalamus. Thyroxine, cortisol and
insulin influence profoundly the function of the nervous system as a whole.

DISORDERS OF THE ENDOCRINE GLANDS

Diseases of the endocrine system often cause dysfunction of one or more
of its parts. Hormones may be secreted in excess, causing syndromes of
glandular hyperfunction, or in deficient amounts, causing syndromes of
hypofuncuon. The overactivity or underactivity of one gland may affect
adversely the function of another gland. For instance, hyperfunctioning
lesions of the adrenal cortex may cause amenorrhoea through its influence
on the anterior pituitary, or diabetes mellitus because of the antagonism
between cortisol and insulin. Long-standing thyroid failure may be
followed by atrophy of the adrenal cortex and relam e adrenal insufficiency.

Whereas most diseases of the endocrine glands result from too much or
too little hormone production, some disorders may be due to a disorder in
the metabolism or breakdown of a hormone. The gynaecomastia and hypo-
gonadism found in hepatic cirrhosis is an example of this mechanism.
Finally, endocrine glands are sometimes affected by disorders, such as
tumours, which have no recognizable effect on their endocrine activity.

Hyperfunction of a gland is usually associated with hypertrophy, hyper-
plasia or neoplasia. The tumours may be benign adenomas or malignant
carcinomas. It is uncertain whether these lesions constitute varying
degrees of a continuous process or whether they are essentially different.
Lesions in glands which are under the control of trophic hormones may
reflect primary' changes and activity in the anterior pituitary or even higher
in the hypothalamus. Sometimes there is hyperfunction without any
recognizable histological lesion. Occasionally signs of hyperfunction are
present (hirsutism, for example) without there being any direct evidence of
increased secretion of a gland. It is assumed, without much direct evi-
dence, that in such cases there is an increased sensitivity of the target organ
to a normal level of circulating hormone.

Hypofunction is usually caused by destruction of a gland by some patho-
logical process such as haemorrhage, infarction or neoplasia, or by its
surgical remora). More recently genetically determined enzyme defici-
encies, resulting in defective hormone synthesis, have been recognized as
causes of glandular failure. Such defects may cause goitres or congenital
virilizing adrenal hyperplasia. Sometimes a gland is congenitally absent or
hypoplastic and sometimes hypofunction is physiological. The gonads, for
instance, function naturally only during the reproductive period. Di-
minished secretion by the anterior pituitary causes secondary hypofunction
of the glands which depend on it. Occasionally glandular hypofunction

INTRODUCTION

5

may be apparent without there being any evidence of diminished secretion
by the gland. Such a condition is believed to be due to end-organ insensi-
tivity, as occurs in pseudohypoparathyroidism and possibly primordial
dwarfism.

Abnormal function of the endocrine glands can be recognized clinically
and by various radiographic and laboratory methods. The concentration of
many hormones in body fluids can be determined by precise chemical
methods, and new methods are being developed constantly. Doubtless
effective methods will be developed eventually for them all. These are of
great potential value, but much work remains to be done before the in-
formation which they yield can always be interpreted correctly.

ENDOCRINE THERAPY

Many endocrine disorders can be treated effectively. Hyperfunction can
be abolished by surgical removal of tumours of overactive glands, or
by the administration of hormones or other chemical substances which
modify or depress their secretions. The effects of hypofunction can
often be overcome by substitution therapy or by the injection of trophic
hormones.

There are other diseases of the body, such as carcinoma of the breast or
prostate, which are not primarily disorders of the endocrine glands, but in
which hormones play an important role. These can be influenced pro-
foundly by the administration of hormones or by the ablation of endocrine
glands.

Hormones may be used therapeutically and for diagnostic purposes in a
bewildering number of ways. The following list summarizes the most im-
portant applications.

1. The stimulation of a poorly functioning gland (e.g. the use of
chorionic gonadotrophin for hypogonadism).

2. Replacement therapy for deficient endogenous hormone production
(e.g. thyroxine in hypothyroidism).

3. Inhibition of the production of a hormone from another gland (e.g.
cortisone inhibition of pituitary ACTH in the adrenogenital syndrome or
stilboestrol inhibition of pituitary gonadotrophin in cancer of the pros-
tate).

4. Diagnostic purposes (e.g. the use of ACTH in distinguishing be-
tween primary and secondary adrenocortical failure, or thyroxine in a
therapeutic trial in suspected hypothyroidism).

5. Antagonism of the harmful effects of another hormone (e.g. the use
of testosterone to counteract the catabolic effects of cortisone, or of
glucagon in the treatment of insulin hypoglycaemia).

6

INTRODUCTION

6. Specific pharmacological effect of the hormone (c.g, the use of
cortisone in inflammatory and allergic diseases).

The following chapters deal systematically with all the aspects of clinical
endocrinology which have been discussed briefly in this introduction.

FURTHER READINC
General Articles

UUbble, d, (1961). The endocrine orchestra. Brit. tried. J., 1, 523.

MEAN'S, J. It. (1954). The integrative action of the endocrine system fn Lectures
on the Thyrotd, p. 1. Harvard University Press, Cambridge, Mass.

NABuiro, f, d. n (1960). The pituitary and adrenal cortex in general medicine.
Bnt. tned. J , 2, 553,625.

Books (All relevant to Chapters 1-1 1 . They v, ill not be referred to again
specifically)

ASTWOOD, C. B (1960). Clinical Endocrinology I. Grune and Stratton, New York.
dvnowski, t. s. (1962). Clinical Endocrinology. Baillifcre, Tindall and Cox,
London.

duncan, c. c. (1959) Diseases of Metabolism. 4th Ed. Saunders, Philadelphia.
PAScilKis, k. £., RAkOFF, A. e. and cantarow, a. (1958) Clinical Endocrinology,
2nd Ed. Cassell, London

rolleston, it. D. (1936). The Endocrine Organs in Health and Disease. Oxford
UnKersity Press, London

Simpson, s. l (1959) Major Endocrine Disorders. Oxford University Press,
London.

softer, L ] (1956). Diseases of the Endomne Glands. 2nd Ed. Kimpton, London.
spence, A. vv. (1953), Clinical Endocrinology. Cassell, London.

WILKISS, L. (1957) The Diagnosis and Treatment of Endocrine Disorders in Child-
hood and Adolescence 2nd Ed. Blacks ell Scientific Publications, Oxford-
WILLIAMS, R. it. (1955) and (1962). Textbook of Endocrinology. 2nd and 3rd Eds.
Saunders, Philadelphia.

WILLIS, R. a. (I960). The Pathology of Tumours. 3rd Ed. Uuuerworth, London.

PART I

THE ANTERIOR PITUITARY AND ITS
TARGET GLANDS

CHAPTER 1

THE ANTERIOR PITUITARY

The pituitary gland has two main divisions, an anterior or glandular part
(the adenohypophysis) and a posterior or neural part (the neurohypophysis).
Both are connected directly to the hypothalamus (although in different
ways) and are controlled by it. The anterior pituitary is of central im-
portance in the endocrine system as a whole, for its trophic hormones
control the functions of the adrenal cortices, the gonads and the thyroid
gland, and its secretions also exert other widespread effects. The posterior
pituitary has quite different functions and will be considered in Chapter 8.

The pituitary lies below the hypothalamus in the sella turcica or
pituitary fossa of the sphenoidal bone. Its two divisions differ in develop-
ment and structure as well as in function. The anterior pituitary arises
from Rathke’s pouch, an epithelial outgrowth from the oral cavity, and
retains its epithelial structure. The posterior part is formed from a
diverticulum in the floor of the third ventricle and is composed of nervous
tissue. The two parts combine and, in the adult, are joined to the hypo-
thalamus by the infundibulum or pituitary stalk. The anterior pituitary
has two main divisions, the anterior lobe proper and the intermediate lobe.
An extension of the anterior lobe (the tuberal part) passes upwards and
envelops the stalk.

The stalk has two components, one vascular, connected with the
adenohypophysis, the other neural, joined to the neurohypophysis. The
vascular part, or hypophyseal portal system, arises as a plexus of capillaries
within the median eminence of the hypothalamus. These coalesce into
larger vessels which pass down the stalk and then divide again to form large
sinusoids around the secretory cells of the gland.

HISTOLOGY OF ANTERIOR LOBE

Histologically the anterior lobe consists mainly of solid cords of secretory
epithelial cells, surrounded by connective tissue and sinusoids. Three
main morphological types can be distinguished with conventional stains,
but with more refined methods such as the iron-periodic-acid Schtff
(Iron-PAS) stain further subdivisions are possible. The cell types, their
staining reactions, their approximate relative numbers and their probable
functions are shown in Table 1.1. The proportions vary with sex, age and
9

THE ANTERIOR PITUITARY

10

the state of health. The different staining reactions probably represent not
only different types of cell but also different phases of activity of the same
cells. Some at least of the chromophobes, for instance, are probably
chromophil cells in a resting phase.

Table 1 . 1 . Cell types of anterior lobe of pituitary

Comentional stains 1

Iron-PAS stain '

Possible secretion

Colour

pm-

Colour

P'o- .

Cel) type

i of

portion

| Cell t>pe

of !

portion

Granules

(approx

sranulesj

(approx. I

°0>t

“.)• 1

Chromophobe

Chromophil

Acidophil

1 N ‘*

so

Chromophobe

Nit

20 i

Resting phase

Pink '

40

Orange

so 1

GH J ProUcun

Basophil

Blue ,

10

0

Red

14

ACTH TSH

Light

8

? actively secreting

blue

form of 0 and &

S

Blue

8

FSH LII(ICSII)

• Rasmussen (1938) t Eznn et al. (1958 and 19S9).

Ectopic anterior pituitary tissue is found regularly in man, as an embryo-
logical vestige, along the original course of Rathke’s pouch, that is in the
posterior wall of the pharynx and in the sphenoid bone. This “accessory
pituitary” consists mainly of chromophobe cells, but chromophils are
sometimes found. It has no direct connection with the hypothalamus and
is unlikely to be functional.

FUNCTIONS OF ANTERIOR PITUITARY
The anterior pituitary secretes six principal hormones:

l. Acting mainly on body tissues in general —

1. Growth hormone (GH)

II. Acting mainly on target-glands —

2. Adrcnocorticotrophin (ACT1I)

Gonadotrophins —

3. Follicle stimulating hormone (FSH) (Testis and Ovary')

I /Interstitial cell stimulating hormone (ICSH) (Testis)

' /Luteinizing hormone (Lll) (Ovary)

5. Thyroid stimulating hormone (TSII)

III. Acting on specific body tissues and glands —

6. Prolactin (Breast and Ovary)

There is also evidence tliat it may secrete two other hormones:

FUNCTIONS OF ANTERIOR PITUITARY

11

IV. Acting on specific body tissues —

7. Haemopoietm (Haemopoietic tissue)

8. Exophthalmos producing substance (EPS) (Orbital tissues)

The sites at which the hormones are produced are not yet certain, but
it is likely that each type of cell will be found to have a specific secretion.
A tentative scheme, based on the available evidence, is shown in Table 1.1.

CONTROL OF HORMONAL SECRETION
The hypothalamus controls the function of the anterior pituitary,
probably by means of “neurohumours” which are secreted by the hypo-
thalamic nuclei and carried in the blood, via the hypophyseal portal system,
to the gland. The neurohumours have not yet been isolated, but are
probably polypeptides. The hypothalamus itself is controlled by nervous
influences from the higher centres of the brain, which may stimulate or
depress it. The hormones of the target glands of the anterior pituitary also
inhibit, by means of a sensitive mechanism, the secretion of trophic
hormones when adequate stimulation of the glands has been achieved, but
it is not certain whether their inhibitory effects are exerted on the
hypothalamus or on the pituitary. Thus, a humoral stimulus from the
hypothalamus causes the anterior pituitary to secrete TSH, and this in
turn stimulates the production of thyroxine by the thyroid. When
sufficient thyroxine has been secreted its concentration in the blood
inhibits the hypothalamus (or the anterior pituitary) and the release of
TSH, Conversely, when the concentration of thyroxine in the blood is
low the hypothalamus is stimulated and TSH is liberated. There are
similar “feed-back” relationships between the other trophic hormones
and the products of their target glands.

ANTERIOR PITUITARY HORMONES
The anterior pituitary hormones are all proteins or polypeptides, and
the structures of some, but not all, are known in detail. The physiological
activity seems to reside in certain groupings of amino acids rather than in
the whofe molecules. These groupings may well be the same in a if species,
although the complete proteins from different animals vary considerably.
1. Growth hormone (GH, somatotrophin)

GH acts in various ways to promote the growth of the body. It stimulates
the growth of the epiphyses, causing an increase in length of the cartilage
bones. The closure of the epiphyses is controlled by’ other influences,
some of them hormonal, and GH has no effect on the length of bones once
the epiphyses have closed. GH causes all other tissues and organs of the
body, including the other endocrine glands, to enlarge along with the bones.
There is evidence that it stimulates the growth of some hormone-dependent

12

THE ANTERIOR PITUITARY

tumours of the breast. The secretion of GH may be partially inhibited by
the sex hormones.

GH influences several metabolic processes in the body. It promotes
the anabolism of protein and the retention of nitrogen, potassium and
phosphorus. These actions clearly facilitate growth. In addition, it
mobilizes fat from the peripheral depots, promotes gluconeogenesis in the
lher, inhibits the utilization of carbohydrate and causes the retention of
sodium and water. GH antagonizes the actions of insulin on the tissues but
is ineffective when insulin is totally absent.

GH is, to some extent, species-specific, and preparations from animals
other than monkeys are ineffectiv e in man. It is not yet generally available
for therapeutic use.

2, Adrenocorttcotrophic hormone ( corticotrophin , ACTU)

ACTH promotes the growth of the adrenal cortices and stimulates the
production of their hormones. It is a polypeptide, containing 39 amino
acids, but shorter sequences have been shown to possess ACTH activity.
Recently a polypeptide of 23 amino acids, with ACTH activity, has been
synthesized.

ACTH has some unimportant actions other than those on the adrenal.
These include slight melanocyte-stimulating activity and general effects
on metabolism Commercial preparations vary considerably in their
activity. Refractoriness to potent batches may develop after a time when
they are given subcutaneously or intramuscularly. This may be the
result of local destruction in the tissues, for it does not occur when ACTH
is injected intravenously. ACTH will be discussed more fully in Chapter 3.
3 and 4. Gonadotrophins

The gonadotrophins, which govern the growth and function of the
ovaries and testes, arc the same in both sexes. Their molecules are com-
plex glycoproteins It is usual and convenient to describe two principal
gonadotrophins, but there is evidence that there may be only one human
pituitary gonadotrophin (HPG) with two types of action. The first
(follicle stimulating hormone, FSH) acts mainly on the ovarian follicle in
the female and on the germinal epithelium in the male. The second has
different names in the two sexes. It acts mainly on the corpus luteum in
the female (luteinizing hormone, LH) and on the Lcydig or interstitial cells
in the male (interstitial cell stimulating hormone, ICS! I). Prolactin is a
subsidiary gonadotrophin in the female.

Jn the female the secretion of gonadotrophins starts shortly before
puberty and continues into old age. Their secretion varies with the phases
of the menstrual ejele and with pregnancy and lactation. In genera!, FSH
and LH bear a reciprocal relationship to each other, so that when the
secretion of one waxes that of the other wanes. After the menopause, when

FUNCTIONS OF ANTERIOR PITUITARY

13

the ovaries are no longer capable of responding and no oestrogens are
released to inhibit pituitary secretion, high levels of FSH are found in the
blood and in the urine. At the same time the level of LH falls.

Hormones with actions similar to these are formed in the placenta.
“Serum gonadotrophin” from the pregnant mare resembles FSH and
“chorionic gonadotrophin” from the urine of pregnant women resembles
LH. The latter is possibly concerned in the descent of the testes during
the last month of intra-utertne life.

In the male the gonadotrophins appear at puberty, are secreted con-
stantly and do not exhibit the cyclical pattern found in the female. In old
age there is usually some decline in testicular function and an increase in
the production of gonadotrophin.

The actions of the gonadotrophins will be considered in more detail in
Chapters 4 and 5.

5. Thyroid stimulating hormone ( thyrotrophic hormone, thyrotrophin , TSH)
TSH stimulates the growth of the thyroid and regulates the production

and release of the thyroid hormones. It will be considered further in
Chapter 7.

6. Prolactin ( mammotrophin , luteotrophic hormone, LTH)

Prolactin is quite distinct from luteinizing hormone (LH) and must not
be confused with it. It is a subsidiary gonadotrophin in the female and also
Controls the development and function of the breast. It is secreted by the
male pituitary, but its function is not known. Prolactin will be considered
further in Chapters 5 and 13.

7. Haetnopoietin

There is evidence, mainly from animal work, that the anterior pituitary
may secrete a factor which is concerned with haemopoiesis and especially
with erythropoiesis. Its absence may play a part in the hypochromic
anaemia which develops in hypopituitarism.

8. Exophthalmos producing substance ( EPS)

This hypothetical factor is secreted only in exophthalmic goitre and is
probably distinct from TSH. It will be discussed again in Chapter 7,

THE INTERMEDIATE LOBE

The intermediate lobe of the pituitary is small and lies between the
anterior lobe and the neural part of the gland. Various types of cell are
found, including some granular basophils which are similar to those in the
anterior lobe. The intermediate lobe probably secretes the melanocyte
stimulating hormone (MSH, intermedin) which controls the formation of

1 +

THE ANTERIOR PITUITARY

melanin and consequently the pigmentation of the skin. The same
hormone causes expansion of the melanophores in amphibia, and this
property forms the basis of a test for its bio-assay. Part of its molecule is
identical vv ith part of that of the larger ACTH molecule. Perhaps for this
reason ACTH may have some pigmentary activity, but pure MSH has no
corticotrophic action. The secretion of MSH, like that of ACTH, is
inhibited by cortisol MSH is probably responsible for the increased
pigmentation found in patients with Addison’s disease.

INVESTIGATION OF ANTERIOR PITUITARY DISORDERS
The special investigations that arc of help in the diagnosis of disorders
of the anterior pituitary are as follows:

I. X-rays of the pituitary fossa

Lateral and antero-posterior films are taken routinely (fig. 1.1). In cases
of pituitary tumour they may reveal enlargement of the sella turcica

Fig. 1.1 Lateral X-ray of normal pmntarv fossa.

(fig. 1.2) and erosion of the clinoid processes or the walls of the fossa.
These findings are common with chromophobe tumours, less common

INVESTIGATION Of ANTERIOR PITUITARY DISORDERS

15

with acidophil adenomas and very rare with basophil growths. Cranio-
pharyngiomas (fig, 1.3) commonly destroy or distort the walls of the fossa
and cause calcification in (fig. 1.3) or above it. In some cases of Cushing’s
syndrome osteoporosis causes a “cotton-wool” appearance of the bone

Fig. 1.2. Lateral X-ray of pituitary fossa enlarged by basophil adenoma
(Cushing’s syndrome).

surrounding the fossa, and this may give an impression of enlargement
(fig. 3.7). Treatment of the syndrome by adrenalectomy restores the
normal appearance. Arteriograms are of value for defining the size and
extent of a tumour and for excluding other lesions, such as aneurysms,

2 . Assays of anterior pituitary hormones

Gonadotrophins are estimated routinely in some general laboratories,
but not in all. The method is non-specific and measures the total gonado-
trophic activity of FSH and LH (ICSH) in a fresh 24-hour specimen of
urine. An extract of the urine is injected into immature mice and the
increase in weight of the uterus is measured. The results are expressed as

THE ANTERIOR PITUITARY

“mouse uterine units*’ (MUU) or as mg. per 24 hours (Table 1.2). The
standard for comparison is “human menopausal gonadotrophin” (HMG)
from the urine of post-menopausal women. LH (ICSH) activity alone
can be assayed in special centres. Gonadotrophins cannot be detected in
normal children until puberty*. Tests for the diagnosis of pregnancy

Infants

Children, 10-12 jn
Females ,
r rom puberty
After menopause
Males (adult)

• After Millar, G (1961).

INVESTIGATION OF ANTERIOR PITUITARY DISORDERS 17

GH, TSH, ACTH and MSH can also be estimated by bio-assay, but
the methods are used only as research tools at present.

3. Functions of target glands

Indirect evidence of anterior pituitary' function may be obtained by
measurement of the functions of the adrenal cortex, the gonads and the
thyroid. It may be possible to distinguish between primary failure of the
pituitary and primary' failure of the target gland by stimulation with the
appropriate trophic hormone. In the case of the adrenal cortex, for
instance, a low excretion of cortisol may indicate hypofunction of either
gland. The level of cortisol may be increased by the injection of ACTH if
the pituitary is at fault, but not if the adrenal itself is diseased. These tests
will be discussed in greater detail in the sections devoted to the target
glands.

The metyrapone test of pituitary function measures indirectly the pro-
duction of ACTH in response to a low concentration of cortisol in the blood.
It may be carried out after stimulation with ACTH has demonstrated
that the adrenal cortex is responsive. Metyrapone inhibits 11-hydroxy-
lation in the biosynthesis of cortisol (p. 57). Consequently the produc-
tion of cortisol falls, that of ACTH rises {its brake having been removed)
and the adrenal cortex is stimulated to form large quantities of 11 -deoxy-
cortisol (the immediate precursor of cortisol) and other related com-
pounds (none of which inhibit the pituitary). These are excreted in the
urine, causing an increase in the total 17-hydroxysteroids. The basal
excretion of 17-hydroxysteroids is measured for two days and metyrapone
is then given for 24 hours in a dose of 750 mg. every 4 hours (6 doses).
Smaller doses may be used in children, the minimum being 250 mg. every
4 hours. Urine is collected during the administration and for the next
24 hours also. A normal response, which indicates that the pituitary and the
adrenal are intact, is shown by a two- to four-fold increase above basal
levels of the urinary 1 7-hydroxysteroids. This is seen usually on the day
after the metyrapone has been given. A diminished response, which indicates
that the pituitary or the adrenal is defective, is shown by little or no rise in
the 17-hydroxysteroids. If the adrenal has already responded satisfactorily
to exogenous ACTH the defeat can be localized to the ACTH-producing
function of the pituitary.

4 . Visual fields

Accurate measurements of the visual fields (for w’hite light and for
colour) are made in any patient who is suspected of having a tumour in the
pituitary. A perimeter is adequate for the peripheral limits, but a Bjerrum
screen is necessary for the accurate definition of central scotomata.

18

THE ANTERIOR PITUITARY

DISORDERS OF THE ANTERIOR PITUITARY

Hyperjunction of the anterior pituitary is caused by tumours or by
hyperplasia of its secretory cells, by various lesions of the hypothalamus
which presumably stimulate the pituitary to excessive activity or by
unknown factors which are sometimes called “constitutional”. The
clinical syndromes which result depend upon the hormones which are
produced:

Hormone Secreted Clinical Syndrome

in Exeeu

GH Gigantism or acromegaly

ACTH Cushing’* syndrome

rSH and LU Precocious puberty

MSH Pigmentation

TSH Goitre

EPS Exophthalmos

Some of these relationships are complicated, and they w ill be discussed later.

Hypo/unction of the anterior pituitary is brought about by pathological
destruction or surgical removal of the gland or by mechanisms which are
not fully understood. Usually all the hormones are deficient, but in rare
cases the deficiency may involve one hormone only. Selective inhibition
of one function may, however, be caused by the administration or the
pathological secretion of certain hormones.

Hormone deficient Clinical nndrome

All hormone* Hypopituitarism

GH Dwarhsm

ACTH Ilypoadrenahsm

FSll and LH Hypogonadism

TSH Hypothyroidism

Prolactin Defective I jctation

PATHOLOGY AND GENERAL FEATURES OF PITUITARY
TUMOURS

Primary tumours of the anterior pituitary arc usually benign adenomas,
but rare cases of carcinoma have been described. They are usually solid at
first, but undergo cystic degeneration as they enlarge. Small tumours,
which do not cause clinical effects, may be found, if looked for, in up to
25 per cent of subjects in routine post mortem examinations. Those of
dtn'tca) importance fa’ll into two groups:

1 . Non-functioning tumours
Chromophobe adenoma
Craniopharyngioma

These tend to grow slowly and to remain silent for a long time, but they
usually become large eventually, expand the pituitary fossa and cause
hypopituitarism by destroying normal tissue.

PITUITARY TUMOURS

19

2. Functioning tumours

Chromophobe adenoma — Cushing’s syndrome
Acidophil adenoma — gigantism or acromegaly
Basophil adenoma — Cushing’s syndrome
These usually cause symptoms early because of their hormonal effects.
The acidophil adenoma may enlarge the pituitary fossa, but the basophil
adenoma very rarely does so.

Rarely the chromophobe or acidophil tumours are associated with
adenoma or hyperplasia of other endocrine glands (islet cells, parathyroid
and adrenal cortices) in a syndrome of “multiple endocrine adenopathy”.

Other primary tumours are very rare and need no special description.
Secondary tumours are relatively common, but are hardly ever recognized
during life unless they destroy the posterior lobe and cause diabetes insipidus.

Various tumours or other lesions of the suprasellar and hypothalamic
regions may interfere with pituitary function. They include meningiomas,
rarely large aneurysms and, very rarely, gliomas of the optic chiasma.
Belfast series

The relative frequency of pituitary tumours is shown by an analysis of
the Belfast material (J. Willis).

In the 20 years up to 1960 the following 328 primary tumours of the
anterior pituitary were found post mortem on routine examination:

No. causing
effects clinically

Chromophobe

Adenoma

Male

61

Female

Total

35

96

7

Carcinoma

Male

remote

Totat

0

1

1

1

Acidophil

Adenoma

Male

5

Total

6

n

2

Basophil

Adenoma

Male

9

Female

Total

3

12

1

Carcinoma

Male

Female

Total

0

1

1

1

Craniopharynzio ma

Male

2

Total

5

7

7

Total

J2S

19(15%)

20

THE ANTERIOR PITUITARY

In the same period tumour material was examined histologically (after
removal or biopsy in the Department of Neurological Surgery) from 51
patients, with the following findings:

Chromophobe adenoma Male 22
Female 20

Total 42

Aetdophtl adenoma Male 5

Female 0
Total 5

Basophil adenoma Male 0

remale . 2
Total 2

Craniopharyngioma Male 2

Female 0
Total 2

Total 51

It is clear that tumours are usually silent clinically, that chromophobe
lesions are much the commonest and that carcinoma is extremely rare.

Symptoms and signs

The clinical features depend on the nature and size of the tumour, and
on the patient’s sex and age. They include endocrine features and pressure
effects.

1. Endocrine features

Hyperfunction will be described later. Hypo function is caused by
large tumours which compress the normal pituitary tissue. One or more
endocrine symptoms may be present for months or years before more
serious features develop. In adults the gonadotrophic function usually
suffers first, the thyrotrophic next and the corticotrophic last. In women
amenorrhoea is usual and in men poor growth of facial hair, fine texture
of the skin, loss of libido and impotence are common. Children and
adolescents usually remain sexually infantile and may suffer disturbances
of growth. Most arc dwarfed as a result of failure of GH production, while
a few, in whom secondary hypogonadism predominates, may be abnormally
tall.

2. Pressure effects

As the tumour grows it enlarges the pituitary fossa, especially in a back-
ward direction, and erodes the clinoid processes. It may eventually burst
through the diaphragms sellae, especially if the sella is shallow, and extend
in all directions within the cranial cavity. It compresses the structures in
its neighbourhood and may cause a rise of intracranial pressure.

Headache occurs in over half the cases, especially in those with acidophil
adenomas; it is usually occipital or fronto-temporal, but may be

PITUITARY TUMOURS 21

generalized. It may be caused by increased pressure within the sella and
often precedes a general rise of intracranial pressure.

Impairment of vision may be serious. The tumour lies close beneath the
optic chiasma and compresses it as it expands. Colour vision is often
impaired first. The visual defects depend on the direction in which the
tumour expands and on the position of the optic chiasma. The lesions are
usually asymmetrical so that one side is affected earlier and more exten-
sively than the other. Bitemporal hemianopia, involving the peripheral
areas first, is the characteristic finding. Optic atrophy is common and may
become complete, causing total blindness, first of one eye and then of both.
When the chiasma is pre-fixed (about 5 per cent of people) hemicentral
scotomata develop first.

Pressure on nerves in the cavernous sinus, especially the oculomotor,
may cause inequalities of the pupils and ocular palsies. Direct involvement
of the olfactory tracts may cause anosmia.

Pressure on the hypothalamus may cause obesity, drowsiness, polydipsia,
polyuria and disturbances of temperature. Pressure on the uncinate gyrus
may give rise to hallucinations and fits. These features tend to develop
early with suprasellar craniopharyngiomas.

Increased intracranial pressure may follow extension far outside the sella
and causes aggravation of headache and nausea, but rarely vomiting.
Optic atrophy usually prevents the development of papilloedema, except in
cases, such as suprasellar craniopharyngioma, where the tumour extends
backwards and upwards at an early stage, obstructs the third ventricle and
causes internal hydrocephalus.

Treatment

Treatment can rarely be relied upon to cure pituitary tumours, but it
may afford relief of symptoms. The available methods are as follows:

Surgery. Most operations are undertaken for the saving of eyesight
when defects have appeared in the visual fields. However, large tumours
which have extended beyond the pituitary fossa may be difficult and
dangerous to remove and tend to recur locally after operation. On the
other hand, small adenomas, confined to the sella, may be removed more
easily and with greater safety, and postoperative irradiation of the fossa
(preferably from within) should reduce the recurrence rate. It may be
that operation can be undertaken earlier now that surgeons have wide
experience of hypophysectomy in the treatment of other conditions.
Occasionally operation for cerebral decompression is all that can be
attempted.

External irradiation. The normal pituitary is highly resistant to irradia-
tion, although complete destruction can be achieved by external irradiation
with a 340-MeV proton beam. Chromophil adenomas are relatively

22

THE ANTERIOR PITUITARY

radio-sensitive, chromophobe tumours are of doubtful sensitivity and
craniopharyngiomas, like the normal gland, are resistant. Radiotherapy
has a place, therefore, in the primary treatment of gigantism and acro-
megaly, but is of questionable value for other syndromes, except as a
postoperative measure. Small field beam-directed or rotational X-ray
therapy is best and, when it is used as primary therapy, a dose of 4,000 rads

Tig. 1.4 Lateral X-ray of skull, shotting jttrium-90 in pituitary fossa.
Same patient os in fig. 1 .2.

should be delivered in a period of four weeks. Occasionally it causes
oedema or bleeding in the tumour, with sudden deterioration clinically,
and aw urgent. craniotomy may be required. For this reason the daily
tumour dose should be increased gradually, and during treatment the
clinical state, the visual fields and the retinae should be observed closely.
Improvement in the clinical state may not he apparent for weeks or months
after the completion of treatment, and less than half the patients in whom
radiotherapy is used primarily obtain permanent benefit from it.

Intrasellar irradiation. The pituitary' fossa may be irradiated by means
of yttrium-90 inserted through the nose. This method has been used with

PITUITARY TUMOURS

23

good results in a few cases of acidophil tumours. The same radioactive
material, suspended in wax, may be packed into the fossa after surgical
removal of a tumour for the destruction of any remaining tumour cells
(fig. 1.4). The method has been used in Belfast for the treatment of various
types of tumour.

Replacement therapy (p. 37). Cortisone and thyroid hormone are
required for adrenocortical and thyroid deficiency. Special precautions
must be taken during the period of an operation or of irradiation (p. 38).
Sex hormones may be given also, but are not essential. Many patients with
slowly growing chromophobe adenomas or craniopharyngiomas can be
maintained for years on this form of treatment alone.

Non-functioning tumours

Chromophobe adenoma. This is the commonest tumour of the anterior
pituitary and nearly always grows slowly. It is equally common in the two
sexes and occurs most often between the ages of 30 and 50 years, although
no age is exempt. Hypopituitarism is usually the earliest feature, while
disturbance of vision is the commonest complaint. Vision is eventually
disturbed in 80 per cent of patients. The sella turcica is almost invariably
enlarged.

Rarely there may be signs of overactivity of the pituitary. Cushing's
syndrome, acromegaly and galactorrhoea (Chiari-Frommel syndrome) have
been described. The cause of these features is not known.

Replacement therapy alone is required at first. Surgery is needed if the
eyesight is affected or when other signs of pressure develop. If headache
is the only complaint irradiation may be tried.

The patient may survive for many years, but the ultimate prognosis is
poor.

Craniopharyiigioma. The craniopharyngioma is relatively common m
both sexes and arises from rests of the squamous epithelium of Rathkc’s
pouch. It develops usually in the pituitary stalk (suprasellar) and less
commonly within the pituitary fossa (intrasellar). The tumours vary
greatly in size and are often cystic. The cysts are usually filled with fluid
containing cholesterol crystals and may undergo calcification. Malignant
change is very rare.

Suprasellar tumours involve the optic chiasma and hypothalamus, and
often compress the third ventricle before they produce any endocrine
effects. Those within the sella behave like chromophobe adenomas. Half
the cases occur in childhood, so that dwarfism and sexual infantilism are
common. Rarely signs of pituitary hyperfunction, such as mild acromegaly,
may develop.

Calcification is seen on X-ray in the suprasellar region, or more rarely
within the fossa itself, in over half the cases. This sign is characteristic, but

THE ANTERIOR PITUITARY

24

may be simulated by calcification in an aneurysm of the internal caroti
artery or by calcification of the pctroclinoid ligament.

Surgery offers the only hope of cure, but is often impracticable. 4
suprasellar tumour is usually so close to the hypothalamus and other \ it:
structures that operation is justified only when there is clinical evidence t
rapid expansion with impairment of vision or other serious pressure effect:
When possible, the tumour or cyst wall is remoted, but the procedure i
often difficult and dangerous. Palliative measures include aspiration an
the injection of sclerosing fluid, the introduction of radioactive gold and
by-pass operation for the relief of hydrocephalus. An intrasellar ttnnou
should be removed surgically while it is small. If treatment is dclaye
expansion of the tumour may render operation hazardous. Rcplacemer
therapy must be given when required.

HYPERPITUITARISM (GROWTH HORMONE)

Growth hormone m3y be secreted in excessive amounts by an acidoph
(a-cell) adenoma of the anterior pituitary or by hyperplasia of the acidoph
cells. The effects on the body depend mainly on whether or not th
epiphyses have closed. Thus, in childhood and adolescence the result i
gigantism and in adult life it is acromegaly. Normal amounts of Gil ma
cause growth to continue longer than normal in puberal hypogonadisr
because the closure of the epiphyses is delayed by the deficiency' c
sex hormones. It is possible also that GH may be secreted in excess i
such cases, since the sex hormones normally exert some inhibitory cffc<
on its production.

GIGANTISM {GIANTISM)

Gigantism is a very rare condition, characterized by’ excessive growt,
of the skeleton and soft tissues of the body. The bodily proportions, how
ever, remain normal. There is no sharp distinction between maxima
normal height and gigantism, but the condition is suspected if the adul
height exceeds 6 ft. 6 in. In childhood and adolescence the diagnosi
depends on the amount by which the height exceeds the average for th
sex and age. Gigantism must be distinguished from other causes of ex
cessive growth, namely precocious puberty and pscudopuberty, am
hypogonadism.

Clinical features

Rapid growth in childhood and adolescence is the main feature. Thi
may he very striking at puberty. Acromegalic features, which are presen
in about a third of the cases, may appear early or late. Skeletal deformities
such as kyphosis and scoliosis, arc common. The large size cause

GIGANTISM

25

awkwardness and embarrassment, and the patients are often regarded as
freaks. Sexual development and libido may be normal at first, but hypo-
gonadism and amenorrhoea often develop later in life. At first giants may
be exceptionally strong and vigorous, but later most of them tend to tire
easily and to become weak. This may be the result of secondary hypo-
gonadism and adrenocortical insufficiency. Diabetes is rare.

Apart from the endocrine features, gigantism is not often associated
with signs or symptoms of a pituitary tumour. The sella turcica may be
enlarged, but acidophil adenomas rarely cause visual impairment or other
local signs.

The prognosis was previously poor, and many patients succumbed to
intercurrent infections. Now, with adequate replacement therapy for
pituitary insufficiency, patients can enjoy relatively good health in spite of
the disability caused by their size.

Treatment

Treatment is difficult because much damage has usually been done before
the condition is diagnosed. The aim is to prevent excessive growth and
deformity, and effective therapy is dependent on early suspicion and
intelligent supervision by the clinician. The patient must usually be
observed for a few months so that the rate of growth may be determined
before treatment is started.

External irradiation of the pituitary is the method of choice initially, and
an attempt should be made, by trial and error, to find a dose which will
pre\ent excessive growth without depressing the other aspects of pituitary
function. If this fails, or if there are other indications for surgery, operation
should not be delayed.

Androgens (in boys) or oestrogens (in girls) may be used alone, in mild
cases, or together with radiotherapy. They may depress pituitary function
and accelerate closure of the epiphyses.

Replacement therapy must be used if signs of hypopituitarism develop.

ACROMEGALY

Acromegaly, which means “large extremities”, was first described by
Marie in 1886. It is rare and affects males and females equally. Very rarely
it develops in childhood or adolescence in association with gigantism.
Occasionally the condition begins during pregnancy, and in some women
the coarsening of the features observed at this time may be the result of
transient excess of growth hormone. It starts usually between the ages of
20 and 40, and is sometimes preceded by very rapid growth at puberty.

Acromegaty is familial in nearly a third of cases. In most the onset is so
insidious that it cannot be dated exactly, and the disease is often well
advanced before the patient seeks advice.

26 TJIE ANTERIOR PITUITARY

Endocrine features

Most of the clinical features are the result of the excessive secretion of
growth hormone, but some may be caused by excessive or reduced
secretion of other hormones of the anterior pituitary.

General appearance

Acromegalics, like patients with many other endocrine diseases (c.g.
myxoedema and Cushing’s syndrome), bear a striking resemblance to each
other, and those with the fully developed disease show features which are
not easily forgotten (figs. 1.5 and 1.6). The extremities are large and the

Fig. 1.5. Acromegaly in a man aged 49.

face is massi\e and coarse, with bulging supra-orbital ridges, protruding
jaw and widely spaced teeth. Motements are slow and ponderous and,
when the back is bent, the large hands hang near the knees. All these
features combine to impart a grotesque apelike appearance.

Changes in the skeleton, which arc striking, arc of three main types.
Abnormal formation of bone takes place in two ways. Endochondral
ossification at the condyles of the mandibles causes enlargement of the jaw*,

ACROMEGALY

27

prognathism and separation and malocclusion of the teeth; the same
process in the costochondral junctions leads to elongation of the ribs and
an increase in the antero-posterior diameter of the chest. Appositional
formation of bone from periosteum is widespread, and in the skull it causes
general thickening and prominence of the bony ridges. The frontal
sinuses enlarge also, and these together with the large supraorbital ridges
increase the slope of the forehead. Hyperostosis frontalis interna is com-
mon and, in the male, is almost diagnostic of the disease. New bone is

Fig. 1.6. Acromegaly. The feet of the patient shown in fig. 1.5.

also laid down under the periosteum on the anterior surfaces of the
vertebrae and restricts anterior flexion of the spine. The process is most
extensive at about the Sib to tOth thoracic vertebrae, which may become
larger than those in the lumbar region. The muscular and ligamentous
attachments of all bones become prominent and exostoses may develop.
Enlargement of the bones of the hands and feet is accompanied by
thickening of the soft tissues (see later), and the terminal phalanges of the
hands and feet often become “tufted”, although this change is not specific.
The hands are thick and broad, like spades, and the ends of the fingers are
blunt. The patient may notice that he is growing out of his gloves and
shoes. He complains that his hands feel stiff and hard, and he may find
difficulty in clenching them.

28 THE ANTERIOR PITUITARY

Bone resorption, due to osteoporosis, may be diffuse or localized. The
cause of the osteoporosis is unknown, but in the active phase of the disease
hypercalciuria is often present and the calcium balance is negative.
Parathyroid overactivity may be responsible, for recent work suggests that
growth hormone has some parathyrotrophic action. Protein deficiency
(because of demands on the available supplies for growth), increased
adrenocortical activity and hypogonadism have also been suggested as
possible causes. Osteoporosis of the spine may lead to backache and
kyphosis.

Proliferation of cartilage and growth of soft tissues around joints
frequently cause pain and swelling and increase the disability. X-rays may
reveal wide joint spaces, osteophytes and periarticular exostoses.

In the early stages the muscles may enlarge and increase in strength, but
later there is often profound weakness.

The skin is thickened and throw n into folds which, in the face, accentuate
the norma! lines of expression The sweat and sebaceous glands enlarge
and the skin may become damp and greasy. The subcutaneous tissues
increase in bulk and also develop a peculiar oedematous swelling. En-
largement of the nose, lips and ears may aid the diagnosis if comparison
can be made with prer ious photographs. The hair becomes coarse, and
mild hirsutism may be observed in some women.

The tongue hypertrophies and the papillae become prominent. The
larynx is enlarged and the mucous membrane is swollen and oedematous.
The changes in the larynx and tongue, together with enlargement of the
nasal sinuses, impart a peculiar resonance or booming quality to the voice.

Swelling of the soft tissues in the hands and wrists may be followed by
paracsthesiac in the fingers, probably as a result of compression of the
median nene in the carpal tunnel. Obesity is characteristically absent,
since growth hormone mobilizes fat from the peripheral depots.

Effects on the viscera. The lungs, heart, lirer, kidneys and spleen and all
the endocrine glands enlarge. The cardiac hypertrophy may be associated
with h)pertension.

Carbohydrate metabolism. Frank diabetes mcllitus occurs in about a
third of the cases as a result of the failure of the pancreas to o\crcome the
diabetogenic effect of GH. Treatment of the acromegaly may cure or
ameliorate the diabetes. In the Belfast cases diabetic ketosis has been
uncommon and the diabetes has been controlled without difficulty.

Nervous symptoms. Growth of new hone in the spine may encroach on
the inter, ertebral foramina and press on nerve roots, causing pain and
muscle weakness in the limbs. Depression, irritability and apathy are
common m patients with progressi\e disease, but the mom! may be normal
in others. Other neurological features of the disease arc related to the local
effects of the pituitary tumour.

ACROMEGALY

29

Effects on other endocrine glands

The gonads may be stimulated in the early stages, especially in late
adolescence, and libido may be increased. Later they usually undergo
atrophy, causing loss of libido and amenorrhoea or impotence. Occasion'
ally a woman with advanced and progressive acromegaly may conceive and
bear a child. Lactation may occur rarely in the absence of pregnancy.
The excretion of total gonadotrophins may be normal or low.

The thyroid gland is enlarged in about a quarter of patients, but hyper-
thyroidism is very rare. The goitres are diffusely nodular. The BMR is
raised in about half the patients owing to an increased need for oxygen by
actively growing tissues. Occasionally hypothyroidism develops in the late
stages of the disease in association with hypopituitarism.

The adrenal cortices are frequently hypertrophied, and discrete adeno-
mas may be seen. In females hirsutism and an enlarged clitoris may
resemble some of the features of adrenal virilism, but the corticosteroid
excretion is usually normal. Very rarely Cushing's syndrome develops in
association with acromegaly. In long-standing cases adrenocortical in-
sufficiency may develop.

The parathyroid glands are often enlarged, and adenomas have been
reported. The serum phosphorus level is frequently raised (to 4-5 to
5*5 mg. per 100 ml.) during the active phase of the disease, probably as a
direct result of the action of GH on bone This may be the cause of the
parathyroid hypertrophy, but GH in excess may itself be parathyrotrophic.
The serum calcium level is usually normal, but hyperparathyroidism may
develop in association with acromegaly.

Local and neighbourhood pressure effects

Eosinophil tumours are rarely as large as chromophobe ones, and
pressure effects are correspondingly less frequent and troublesome.
However, the sella turcica is usually enlarged and extrasellar extension with
invasion of the surrounding structures may occur. Visual disturbances
occur in about half the cases, but hypothalamic effects are very rare.

Headache may be severe, but has not been troublesome in the Belfast cases.

Increased intracranial pressure and papilloedema are most unusual.

Investigations

X-rays of skull, face, hands and feet, and spine reveal the changes
which have been described.

Laboratory, It is not yet possible to determine the level of GH in the
blood routinely, and other laboratory findings are non-specific and of little
diagnostic value. They may be useful in providing confirmatory evidence
and for assessing the activity of the disease and its response to treatment.
The results of estimations of serum phosphorus and calcium, urinary

30

T1IC ANTERIOR PITUITARY

gonadotrophins, corticosteroids and calcium, 8MR and thyroid function,
and carbohydrate metabolism have been described already.

Differential diagnosis

Occasionally myxocdema, chromophobe adenoma, Paget’s disease of
bone with involvement of the skull, leontiasis ossea and pachydermo-
periostosis (idiopathic osteoarthropathy) may simulate acromegaly. In
women the hirsutism which occasionally accompanies acromegaly may
suggest adrenal virilism.

Course and prognosis

Acromegaly is generally a slowly progressive disease which may take
years to develop fully and may never affect the patient's way of life
seriously. It may pursue a fluctuating course, or it may become inactive at
any stage. Sometimes, however, acromegaly develops rapidly and results
in serious incapacity in a few years. Death may follow the extension of the
tumour into the brain or haemorrhage into the growth. Occasionally death
results from the effects of diabetes, hypertension or hypopituitarism.

Acromegalics arc, on the whole, poor surgical risks and they require
treatment with cortisone before operation if pituitary function is impaired.
Treatment

Treatment includes measures to abolish the secretion of grow th hormone
and to relieve the effects of pressure and headache, replacement therapy for
diabetes and hypopituitarism, and the relief of symptoms caused by goitre.

External irradiation of the pituitary is indicated when the disease is
active, when headache is severe and when there is no evidence of visual
disturbance or great enlargement of the pituitary fossa. The results,
however, are seldom striking. Encouraging results have been obtained
recently from intrasellar irradiation.

Surgical treatment is usually reserved for patients whose headache has
not been relieved by radiotherapy, for those with visual impairment
or for those whose vision deteriorates in spite of irradiation. It may well
be that surgery should be undertaken earlier than in the past and that it
should be considered seriously in all patients who fail to respond well to
radiotherapy.

Oestfogetu and androgens have been recommended for their inhibitory
effect on the pituitary, and they may be given in conjunction with radio-
therapy. They are chiefly of value, however, for replacement thcrap).
Ocstrogens in moderate dosage are useful in women and may be given in a
cyclical manner (p. 184). Hypogonadism in males is treated with testo-
sterone (p. 146). Ocstrogens should not be used in men, foT they aggravate
the impotence.

yy/ed/rtie/rrmust receive standard treatment v\ith diet alone or with insulin.

PITUITARY INSUrriCICNCY 31

Other aspects of hypopituitarism, if present, require treatment (p. 36).
Occasionally a large goitre must be removed.

Results of treatment

Acromegaly does not regress completely, because the changes in bone
and cartilage are irreversible. Improvement may be seen within weeks or
months of treatment, but it may be extremely difficult to assess. In
favourable cases the headache improves, the effects of local pressure
regress and the soft tissues may decrease in bulk to such a degree that the
features are much improved. Strength may increase, the sense of wellbeing
and the mood may improve, the quality of the voice may be partially
restored and the hirsutism, greasiness and sweating of the skin may be
diminished. Other evidence of improvement is provided by a fall in the
serum phosphorus level and the BMU, a decrease in the hypercalcmria
and amelioration of the diabetes.

PITUITARY INSUFFICIENCY (HYPOPITUITARISM)
Pituitary insufficiency or hypopituitarism results from failure or destruc-
tion of the anterior pituitary. Other names for the syndrome are
panhypopituitarism, Simmonds' disease, hypophyseal cachexia and (for
the post-partum variety) Sheehan’s syndrome. Posterior pituitary failure,
or diabetes insipidus, is a separate disorder. Simmonds, a German
pathologist, described hypopituitarism in 1914. Unfortunately his
description caused confusion, since his cases showed extreme cachexia, a
rare terminal manifestation of the disease, and for years its absence in the
majority of patients prevented physicians from recognizing the condition.
Sheehan, in 1937, emphasized the importance of post-partum haemorrhage
and obstetrical shock as a cause of pituitary insufficiency, and described
the syndrome accurately.

AETIOLOGY AND PATHOLOGY
Pituitary insufficiency is usually caused by one of the following condi-
tions:

1. Pituitary destruction
Common

(a) Necrosis. (6) Tumour.

Rare

(c) Inflammation — acute with abscess, (f) Atrophy.

chronic — tuber- (f) Trauma,
culosis, syphilis.

{d.) Infiltration — leukaemia, amyloid, (i?) Carotid aneurysm,
sarcoidosis, etc.

2. Surgical hypophysectomy

32 THE ANTERIOR PITUITARY

Necrosis of the gland associated with shock is the commonest cause.
The pituitary undergoes rapid involution after parturition, and there is a
concomitant reduction in the blood supply. If hypotension occurs as the
result of shock or blood loss the vascular supply to the pituitary may be
seriously embarrassed and infarction and necrosis way follow. Necrosis
may also follow sev ere diabetic coma or vascular catastrophes.

Pituitary tumours and aneurysms compress the normal pituitary tissue
and interfere with the blood supply to the unaffected portions of the gland.
Tumours m the hypothalamic region may cause atrophy by interference
with the control of the gland. Tumours are the commonest cause q{
hypopituitarism in men. Bacterial infection may be blood borne or
may extend from the meninges. Atrophy may be observed without any
recognizable pathological cause. In such cases the primary defect may
reside within the hypothalamus or even in higher centres. Trauma to
the skull which is severe enough to damage the anterior pituitary is usually
fatal and does not cause hypopituitarism. On the other hand, trauma is
a fairly frequent cause of diabetes insipidus. Hypopbysectomy is discussed
later. Three-quarters or more of the functioning tissue of the pituitary
must be destroyed before the clinical syndrome of pituitary insufficiency
develops.

At autopsy there is general atrophy of the viscera even when wasting
of the body is absent. The major changes are found in the endocrine
glands and particularly the target glands of the anterior pituitary. The
thyroid is small and atrophied and lymphoid infiltration may be observed.
Occasionally there may be extensive fibrosis similar to that of primary’
hypothyroidism. The adrenal cortex is thin and atrophied, but the
medulla is normal. The gonads and secondary’ sex organs are atrophied.
The testes show* hyaline thickening of the basement membrane of the
tubules, absence of spermatogenesis and loss of Lcydig cells. In the
ovary there are no developing follicles or corpora lutea and the gland is
shrunken.

In slowly progressive destruction of the anterior pituitary the production
of trophic hormones usually fails in a sequential manner. First the gonado-
trophic function, then the thyrotrophic and finally the corticotrophic
function is lost. Occasionally this sequence may be altered or the produc-
tion of one or tw o hormones may persist normally.

Selectiv c inhibition of pituitary’ function may be caused by the therapeutic
administration of trophic hormones or of the secretions of their target
glands. Clinically this is important in relation to ACTH and to cortisone
and its analogues.

ADULT HYPOPITUITARISM

33

CLINICAL FEATURES

The clinical features are dependent, to some extent, on the nature of the
pathological process and on the age of the patient. The following are the
commonest clinical categories :

1. In adults

(rt) Acute pituitary necrosis associated with parturition, diabetes mellitus
or vascular disorders.

(6) Chronic hypopituitarism with pituitary and hypothalamic tumours
and other slowly progressive lesions.

(c) Hypopituitarism after surgical hypophysectomy.

( d ) Selective hypopituitarism, most commonly associated with the
prolonged administration of cortisone or ACTH.

2. In children and adolescents

(а) Chronic hypopituitarism with infantilism.

(б) Chronic hypopituitarism with hypothalamic features (Frohlich’s
syndrome).

(c) Gonadotrophin deficiency without dwarfism.

ADULT HYPOPITUITARISM

Women are affected more often than men, usually in the childbearing
age (20 to 40 years). In most women the disease follows a complicated
delivery, and a history of post-partum haemorrhage and obstetrical shock
may be obtained. During the first few weeks symptoms of hypopituitarism
may be slight, and the slowness of the patient’s recovery is often attributed
to the obstetrical complications or to anaemia. In moderate or severe cases
specific features include failure of lactation, rapid involution of the breasts,
failure of regrowth of the pubic hair (after its removal prior to delivery),
amenorrhoea and occasionally hypoglycaemia. The complete syndrome
then develops slowly over a period of months or years. In mild post-partum
cases and in those resulting from tumours or other slowly progressive
lesions the whole process is insidious and the syndrome may take many
years to develop.

General clinical features

Most patients are apathetic, depressed and indifferent to their illness.
They lack energy and drive, tire easily and are unable to cope with home
duties or business affairs. They are intolerant of cold and spend much
time by the fire. The skin is like alabaster; it is pale, dry, atrophic, often
finely wrinkled and slightly puffy, and its pigment disappears. The hair
becomes dry and brittle and falls out, particularly in the axillary and pubic
regions. In men the facial hair softens and grows slowly, so that shaving is

34 T1IC ANTERIOR PITUITARY

required less often than formerly. The body temperature, pulse rate and
blood pressure all tend to be subnormal. Nutrition is usually normal and,
if hypothyroidism is severe, there may be moderate obesity. Cachexia
develops only' in sex ere cases, when apathy and lack of care lead to
starvation. Constipation is usual, and half tbe patients have achlorhydria.
There may be mild, hypochromic anaemia, xvhich responds only to
treatment xvith cortisone and thyroid hormone, and eosinophilia. The
anaemia accounts for only a little of the pallor.

Mental symptoms apart from apathy and depression are uncommon, but
may develop, particularly in patients xvith tumours. They include con-
fusional states with hallucinations and psychotic features. Hypoglycaemia
may sometimes cause bizarre mental symptoms, and oxertreatment with
cortisone may induce temporary psychosis.

Failure of the target organs

Some of the features which have been described are clearly the result of
hypogonadism and of thyroid and adrenocortical failure. There arc,
however, other specific effects.

Gonads. In women amenorrhoea is the commonest feature, but there are
sometimes a few irregular periods. There is atrophy of the uterus and
genital tract, and most xvomen lose all sexual desire. In men the testes
atrophy, libido is absent and potency fails. The urinary excretion of total
gonadotrophins is low (<4 MUU per 24 hours).

Thyroid gland. Hypothyroidism is usual, but is sometimes relath cly
mild. Normal thyroid function has been found rarely after hypophysec-
tomy. The clinical features differ in some respects from those of primary
thyroid failure: the skin changes, for instance, are dissimilar and the
xoice does not alter. In hypopituitarism the plasma cholesterol rarely
exceeds 300 mg. per 100 ml. The BMR is usually low (—25 per cent or
less) and the protein bound iodine below 3-4 fig. per 100 ml. As in primary
thyroid failure, radioactive iodine tests usually show impaired thyroid
uptake and an increase in the urinary excretion of iodide. The gland can,
how ever, be stimulated by the administration of TSH unless it has under-
gone fibrosis.

Adrenal glands. Adrenocortical insufficiency is rarely as acute or severe
as in primary adrenal failure (Addison’s disease), since the secretion of
aldosterone is usually undisturbed and the metabolism of water and salt is
relatively normal. Nevertheless, patients withstand stress poorly and must
be protected by replacement therapy. The urinary’ excretion of corti-
costeroids (other than aldosterone) is low (p. 74), but stimulation by
ACTH will increase the output and so help to distinguish secondary’ from
primary’ adrenal failure. There is impaired excretion of water (p. 72),
xx’hich may be corrected by the administration of cortisone. The scrum

ADULT HYPOPITUITARISM

35

sodium and chloride values are generally normal, but are occasionally low
as a result of overhydration. The serum potassium level is normal in
contrast to the high level found in Addison’s disease. Adrenal failure and
deficiency of GH usually lower the fasting blood sugar and cause marked
sensitivity to insulin. Necrosis of the pituitary in diabetic coma may result
in amelioration of the diabetes, the so-called “Houssay phenomenon”.

Hypopituitary crisis

An acute exacerbation of the disease results in hypopituitary crisis,
which may proceed to coma and death. Precipitating causes include all
forms of stress, such as infections, trauma and exposure to cold. Other
forms of stress, which are avoidable, include the excessu e use of sedatives
(such as morphia and barbiturates), to which these patients are very
sensitive; a surgical operation for some unrelated lesion; water intoxication
from excessive intravenous therapy or from the forcing of fluids in a
water-loading test; the administration of insulin (for the assessment of
sensitivity), which is an unjustifiable procedure; and therapy with thyroid
hormone without previous replacement with cortisone.

The principal disorders underlying the clinical features of the crisis
include hypothermia (from hypothyroidism), hypoglycaemia and hypo-
tension (from adrenocortical insufficiency). These combine to cause
cerebral anoxia and other serious disturbances of cellular metabolism.

The early clinical features are anorexia, vomiting, clouding of con-
sciousness, hypotension, loss of reflexes and coldness of the extremities.
Sometimes there are hallucinations and other psychotic features. The
patient lapses into coma and the temperature of the body falls profoundly
as it does in myxoedema coma. Unless the condition is relieved within a
few hours it becomes irreversible and the patient dies.

Investigations

X-rays. Enlargement of the pituitary fossa may be caused by tumours.

Laboratory. Pituitary function can be assessed directly by measurement
of gonadotrophins and indirectly by the metyrapone test and by investiga-
tion of thyroid and adrenocortical function. The blood sugar, serum
electrolytes and serum cholesterol levels may also be helpful. The findings
have all been described.

Differential diagnosis

The fully developed syndrome can be recognized easily. The main
difficulties which arise are : (1) the distinction between hypopituitarism and
primary failure of the target glands (Addison’s disease, myxoedema and
Klinefelter’s syndrome); (2) the detection of mild or incomplete hypo-
pituitarism; (3) the failure to recognize the condition preoperatively in

36

THE ANTERIOR PITUITARY

patients who develop surgical emergencies; and (4) the distinction from
other chrome diseases such as anaemia, nephritis and anorexia nervosa.

In Addison's disease there is usually pigmentation, the hair and menses
are normal, the electrolyte changes arc characteristic and the adrenals
do not respond to ACT! I. In myxoedema hair is usually retained in the
axillary and pubic regions, the scrum cholesterol level is high, the excretion
of gonadotrophins is normal and the thyroid does not respond to TSH.
In longstanding myxoedema the function of the pituitary may be depressed
so that the two conditions cannot be distinguished. When in doubt it is
wise to assume that the pituitary is diseased and to give cortisone before
administering thyroid hormone. In Klinefelter's syndrome the excretion
of gonadotrophins is high and, on testicular biopsy, Leydig cells are
found.

Hypopituitarism should be considered in any anaemic patient who has
mote pallor than can be explained by the blood picture or whose blood
fails to respond to haematinics. The similarity between chronic nephritis
and hypopituitarism is only superficial. Anorexia nervosa is a mental
disturbance and has no connection with hypopituitarism. The patient
refuses to eat from the onset and becomes cachectic, but she retains her
energy' and hair. Amenorrhoca is usual, but thyroid and adrenocortical
function are usually preserved, at least until the late stages.

Course and prognosis

Variations in the course of the disorder depend on the extent and
rapidity of the pituitary destruction and on the nature of the underlying
lesion. Many patients, especially women, exist in misery’ for years before
seeking medical advice. The average length of time between the onset of
the illness and its recognition was 12 years in patients with post-partum
pituitary' necrosis studied by us in Belfast. Hypopituitarism due to
tumours may be present for even longer before more serious symptoms
develop. In very exceptional cases of post-partum pituitary necrosis men-
struation may be resumed and a further pregnancy may be achiev cd.

If the condition is not treated death usually supervenes from intcr-
currcnt infection or from some other form of stress which precipitates a
crisis. Unless the undcrly mg cause carries a serious prognosis, replacement
therapy restores health and gives the patient a normal expectation of life.

Treatment

Two aspects of treatment must be considered: the cause of the hypo*
pituitarism and replacement therapy. The only causative lesions which
can be treated effectively are tumours and infections. The latter may
require chemotherapy or surgery. Treatment may cure the lesion, but

ADULT HYPOPITUITARISM 37

it rarely preserves or restores pituitary function. Replacement therapy is
required for chronic hypopituitarism or for a crisis.

Chronic hypopituitarism

Treatment with hormones must be continued indefinitely to replace the
lost function of the target glands. If adrenal and thyroid replacement is
given, together with testosterone or oestrogens when necessary, the patient
can be maintained in good health. Direct replacement of the target gland
hormone is preferable to treatment with trophic hormones of the pituitary.
Cortisone should be given first and then thyroid hormone.

Cortisone. Cortisone acetate is given by mouth in an initial dose of
12-5 mg. per day. This should be increased with caution over a period of
two to three weeks, especially in patients with tumours, since an acute
mental disturbance can be caused by as little as 25 mg. The maximum dose
which may be required is 37-5 mg. per day (25 mg. on rising and 12*5 mg.
in the late afternoon). Additional salt or steroids with stronger mineral-
ocorticoid action are not usually required, as they may be in Addison’s
disease, because aldosterone secretion is relatively undisturbed. The usual
precautions for steroid therapy must be taken (p. 117).

Cortisone causes a rapid improvement in health and wellbeing. Strength
and energy are restored, the appetite improves, weight is gained, the blood
pressure is increased, the blood sugar is raised and the patient is protected
from the dangers of minor stress. In the event of major stress, such as a
surgical operation, the dose must be increased to about 100 mg. per day.

Thyroid. Thyroid hormone must not be given until cortisone replace-
ment is complete. It will improve the memory and mood, make the skin
more supple, restore the texture of the hair and diminish intolerance to
cold. Initially 0-05 mg. of /-thyroxine sodium is administered daily; an
increment of 0-05 mg. is then given every two weeks until 0-2 or 0-3 mg. of
thyroxine are being taken in a single daily dose.

Sex hormones. The treatment of gonadal deficiency depends on the sex,
age, emotional and sexual needs of the patient. In young women the
maintenance or development of sexual characteristics and genital structure
and regular withdrawal bleeding may be achieved by moderate doses of
oestrogen by mouth, given in a cyclical manner (p. 184). The re-establish-
ment of apparently normal menstruation in young women is good
psychologically, but they should, of course, be told that they are unable to
Conceive. In older tvornen and in those who have borne several children
oestrogens are unnecessary’ unless genital atrophy is sufficiently severe to
interfere with sexual intercourse. Libido is generally restored by cortisone
and thyroxine, but small doses of testosterone may be required also. In
males testosterone is required to restore libido and potency (p. 146). The
dose should be small initially. Testosterone is not advised in the aged.

38

THE ANTERIOR PITUITARY

Management of hypopituitarism during surgical procedures or irradiation

This problem arises when a patient undergoes a craniotomy or is treated
by irradiation for a pituitary tumour, or when some other condition requires
surgical treatment. If time permits untreated patients should be given
regular replacement therapy with cortisone and thyroid hormone before-
hand. The dose of cortisone must be increased to 50 to 100 mg. per day,
depending on the magnitude of the trauma, over the period of operation
(p. 47). If time is short cortisone alone should be given intramuscularly
(25 to 50 mg. 6-hourly) for two days before operation. In an emergency
cortisol hcmisuccinate (100 mg.) may be given intravenously. In these
events the dose is reduced to a regular maintenance level soon after
the operation. If time does not permit regular replacement with thyroid
hormone before operation it should be withheld until afterwards. It is
hazardous to give triiodothyronine rapidly.

Treatment of hypopituitary crisis

Treatment of adrenocortical failure is of first importance, and this should
be undertaken in the same way as that of an adrenal crisis (p. 1 18). Tin's
involves the rapid administration of cortisol, the prevention of hypo-
glycacmia and the prevention or treatment of infections. The disturbance
of electrolytes is not usually severe. Intravenous fluids must be ad-
ministered sparingly and with great caution.

Treatment of the thyroid insufficiency is similar to that of myxoedema
coma (p. 291) and involves the nursing of the patient in warm blankets.
Energetic heating is not advisable. When the adrenal insufficiency has
been corrected a small daily dose of /-thyroxine sodium (0-1 mg. daily) or
of triiodothyronine combined with thyroxine should be given (“Dio-
troxin”, Glaxo, 0-1 mg. per day).

HYPOPITUITARISM IN CHILDHOOD AND ADOLESCENCE
In children and adolescents hypopituitarism causes disturbance of
growth and sexual development and, in some cases, thyroid and adreno-
cortical insufficiency also. The terms “infantilism 0 and “dwarfism" are
often used loosely to describe the results of pituitary' failure. Properly, they
are defined as follows. Infantilism is a condition in which somatic growth
and sexual development correspond with those of a normal individual several
years younger than the patient. Adult stature and sexual development arc
not attained. Dwarfism, on the other hand, implies greatly diminished
somatic growth but not necessarily sexual immaturity. Thus, while a
person with infantilism is dwarfed, a dwarf is not necessarily infantile.
Hypopituitarism is an uncommon cause of these conditions.

HYPOPITUITARISM IN CHILDHOOD AND ADOLESCENCE 39

Hypopituitarism in childhood and adolescence usually presents in one
of the following four ways:

i. Chronic hypopituitarism with infantilism

Hypopituitarism of this type may result from an intrasellar or suprasellar
tumour, or rarely from xanthomatosis of the pituitary (Hand-Schuller-
Christian type). Usually there is no evidence of a destructive lesion of the
pituitary {idiopathic hypopituitarism), and it may be difficult or impossible
to differentiate these cases from those of simple delayed puberty or
primordial dwarfism. When the pituitary is at fault, however, infantilism
persists into adult life and results in an immature appearance and men-
tality. In childhood pituitary insufficiency may be suspected if there is
evidence of thyroid and adrenal failure. Clinical signs of these are often
lacking, however, and evidence should be sought by laboratory investiga-
tions.

Growth is usually deficient and epiphyseal closure is delayed (fig. 1.7).

Fig. 1,7. Long-standing hypopituitarism due to craniopharyngioma. Failure
of closure of epiphyses at 29 years of age.

THE ANTERIOR PITUITARY

40

Occasionally, if the production of GH is impaired less than that of
gonadotrophins growth may reach the normal or exceed it, as it does in
other forms of puberal hypogonadism. Patients with craniopharyngiomas
or other tumours often grow fairly normally until they approach puberty,
so that their final stature, although small, exceeds that of patients with other
forms of hypopituitarism (fig. 1.8).

Fig. 1 .8. Same patient os in Tig. 1 .7,

Note small stature, immature appearance and absence of development of breast* *"4
sexual hair.

In girls the breasts, nipples, areolae and external genitalia remain under-
developed and sexual hair does not grow. In males the testes remain
immature and there may be cryptorchidism. Testicular biopsy repeals
absence of spermatogenesis and Lcydig cells, while secondary sc<ual
changes do not occur. In both sexes there is a low output of 17-oto*
steroids (at or below 2 mg. per 24 hours) and of total gonadotrophin*
(4 MUU or less in the 24 hours). Unfortunately the gonadotrophin
estimation is valueless before the onset of puberty, when a reliable test of
pituitary function is needed most. Consequently the diagnosis of hypo*

HYPOPITUITARISM IN CHILDHOOD AND ADOLESCENCE 41

pituitarism cannot always be made with confidence until childhood and
early adolescence have passed.

2. Constitutional delayed puberty (Delayed growth and adolescent

development)

This condition affects girls more often than boys and is often familial.
The hypopituitarism is probably “functional” and analogous to the
hyperpituitarism which causes precocious puberty. Growth and sexual
development are retarded, but eventually take place normally at the age of
16 to 18 years or even later. If, as sometimes happens, the patient has been
small during childhood the absence of sexual development and of a spurt in
growth at the usual age of puberty cause concern. The appearance and
outlook remain childish. The patient may be embarrassed and is apt to be
teased by adolescents of the same age who are developing normally.
Parental worry may also cause psychological difficulties. When puberty
eventually starts growth is often very rapid and the final height may be
normal.

Delayed osseous development during childhood may lead to confusion
with pituitary dwarfism, but thyroid and adrenal function are normal.

The main importance of this constitutional variation in development is
that it should be recognized and that treatment should be avoided. The
premature use of sex hormones will maintain the dwarfism and prevent
spontaneous growth from taking place.

In one variety of the syndrome obesity is associated with the delayed
puberty. The condition may be familial and is then called constitutional (or
familial) obesity of puberty or constitutional familial adiposity. Slipping of
the femoral epiphyses is not uncommon. A reducing diet usually causes
loss of weight, and sexual development is eventually normal. The condi-
tion must not be confused with Frohlich’s syndrome, which is very rare.

3. Chronic hypopituitarism with hypothalamic features (Frohlich's

syndrome, adiposo-gemtal dystrophy)

This condition is probably more often misdiagnosed than any other
endocrinological disorder. The term is often applied loosely to obese boys
with real or apparent retardation in sexual development and perhaps some
feminine traits. For this reason it is important to define the condition
clearly.

In 1901 Frohlich described the case of a boy of 14 years with a cranio-
pharyngioma in the hypothalamic region. He was sexually immature,
moderately obese, slightly dwarfed and had diabetes insipidus. The
syndrome is therefore characterized by some features of hypopituitarism
and hypothalamic disturbance, including failure of sexual development,
stunted growth and moderate obesity.

THE ANTERIOR PITUITARY

42

Pathology

Usually the syndrome results from a pituitary or parapituitarv tumour,
which involves the hypothalamic region, and rarely from a primary
disorder of the hypothalamus itself. The commonest lesion is a cranio-
pharyngioma; less common are a chromophobe adenoma, a tumour of the
third ventricle, chronic hydrocephalus and chronic inflammatory disorders
of the basal meninges.

Clinical features

The syndrome is very’ rare and cannot be diagnosed before puberty,
since failure of sexual development is one of the main features. Impairment
of genital development may be suspected before puberty in boys but not in
girls. The obesity' is moderate and is mainly confined to the face, trunk and
thighs. In immature boys this imparts a feminine appearance. Growth is
defective and the height is subnormal, although the epiphyses remain open.
Various hypothalamic disturbances, such as somnolence, may occur, and
diabetes insipidus may be a prominent feature. There may be neurological
signs and impairment of vision.

Differential diagnosis

Frdhlich’s syndrome must be distinguished from other conditions which
bear a superficial resemblance to it. Many boys tend to put on weight in
the prepubcral years and, because the penis tends to be buried in pubic fat,
are thought to be sexually immature. In both boys and girls obesity may be
associated with delay in puberty (constitutional obesity of puberty). Other
conditions which occasionally cause confusion arc Cushing’s syndrome ana
the Laurencc-Moon-Biedl syndrome.

4 . Gonadotrophin deficiency without dwarfism (pituitary hypo-
gonadotrophinism)

In this relatively common condition there is idiopathic deficiency of
pituitary gonadotrophins without other evidence of hypopituitarism. In
mild cases the only manifestations may be azoospermia in the male and
primary amenorrhoea in the female. Both, of course, arc associated with
infertility

The excretion of total gonadotrophins is low or absent (4 MUU or less),
while in primary hypogonadism it is high. Adrenocortical and thyroid
functions are normal.

Treatment of hypopituitarism in childhood and adolescence
The causative lerion must be treated whenever possible. Pituitary
tumours cause hypopituitarism more commonly in children than in adults.

OPERATIONS ON THE PITUITARY

43

Human growth hormone will cause linear growth of the long bones, but
it is not yet generally available. When it can be used it would seem wise to
withhold testosterone and oestrogen until adequate growth has been
obtained, otherwise they would tend to close the epiphyses too soon.
Sexual infantilism can be corrected by replacement therapy with testo-
sterone or oestrogen at the appropriate time.

Treatment of the adrenal and thyroid failure is similar to that required
for adults. The doses for very young children are about a third to a half of
those for adults. Cortisone and thyroxine replacement should be started as
soon as the diagnosis of pituitary insufficiency is confirmed.

OPERATIONS ON THE PITUITARY

“Hypophysectomy” implies the removal, in whole or in part, of a
tumour of the pituitary or of the normal gland. Operations are also under-
taken for the destruction of normal or tumorous tissue. When the gland is
diseased these procedures often, but not invariably, cause complete
functional ablation. When it is normal complete removal or destruction is
usually the surgical objective. Operation therefore often results in hypo-
pituitarism which must be anticipated and prevented by replacement
therapy.

INDICATIONS

Operations are performed for the following conditions:

I. Tumours of anterior pituitary (Common)

II. Other diseases —

1. Advanced carcinoma:

Breast (Common)

Prostate (Rare)

2. Visual complications of diabetes mellitus

3. Severe exophthalmos

Jt may well be that the wide experience recently gained in removal of the
normal gland will enable surgeons to enlarge the scope of operations for
pituitary tumours.

OPERATIONS
The main operations are:

1. Transfrontal hypophysectomy.

2. Transsphenoidal hypophysectomy.

3. Transethmosphenoidai hypophysectomy.

4. Transnasal insertion of radioactive material.

44

THE ANTERIOR PITUITARY

Transfrontal hypophysectomy

This is the standard operation and is suitable for all patients except those
with prefixed optic chiasmas (about 5 per cent of people). It is only possible
to recognize this condition preoperatively in patients with tumours who
have hemicentral scotomata in their visual fields. In such cases another
operation may be preferred.

The supine position is used. General anaesthesia, with an endotracheal
tube, is essential and an inhalation anaesthetic with oxygen is satisfactory.
Hypotension by such drugs as trimetophan and dehydration by means of
urea (90 G. intravenously as the dura is opened) ate helpful. In cases of
tumour hypothermia and drainage of the cerebrospinal fluid, by the
ventricular or lumbar route, have a place. Hypothermia may also be useful
in patients with widespread malignant metastases in the lungs. Fluids
must usually be given intravenously for about two days.

A horizontal incision, starting in a skin crease on the forehead and
curving down to the zygomatic arch, is used and a small bone flap is
turned. This pro\ ides adequate access to the normal gland and to most
pituitary' tumours. It has the advantage over the classical frontotemporal
flap that only an inch or so of the scalp need be shaved — an important
point, especially in women. The scar is barely noticeable after a few
months.

Other things being equal, the operation is done from the right side.
This is convenient for a right-handed surgeon and avoids retraction of the
dominant left hemisphere (in a right-handed patient). The side of incision
may be \aried in cases of tumour. Some surgeons always make their
approach on the side of better vision so that the better optic nene can be
seen and preserved, some make it on the side of tcorse vision so that if the
nerve is damaged inadvertently little harm will be done, while others prefer
always to operate on the right side. The results of all these methods are
similar, and the surgeon's own preference is the deciding factor.

The dural incision is made in the shape of a shallow’ U and the frontal
lobe is raised. If the optic chiasma is found to be greatly pre-fixed removal
of the tubcrculum scllae will improve the access, but may result in serious
bleeding. This manoeuvre is rarely needed.

The first step in removal of the normal gland is division of the pituitary
stalk. If this is done at a low level functioning cells of the tubcral part of
the anterior pituitary may lie left behind. If it is done close to the brain
these cells are removed, but the hypothalamus may be damaged and diabetes
insipidus is likely to follow the operation. This complication can I*
controlled and must be accepted if a thorough hypophysectomy is to be
performed. The aperture in the diaphragma scllae is then widened with
fine forceps and the gland is removed piecemeal by means of curettes.

OPERATIONS ON THE PITUITARY 45

Haemostasis is secured with pressure. It is sometimes possible, by means
of special dissectors, to remove the gland whole.

Tumours of the pituitary expand the capsule of the whole gland, and it
is not possible, at operation, to distinguish clearly a tumour from the
surrounding tissue or to shell it out in its own capsule. The steps in an
operation for tumour are: (1) the capsule is pierced with a needle and any
fluid contents are aspirated with a syringe; (2) the capsule is incised;
(3) its contents are removed by curettage and suction ; (4) the capsule is
removed as completely as possible; (5) radioactive material is introduced if
desired.

Insertion of radioactive material

After removal of a normal gland a rim of viable pituitary cells is often
left around the periphery of the sella and, after operation for tumour,
recurrence occurs locally in up to 50 per cent of cases. The operation can
probably be rendered more complete by the insertion of radioactive
material into the fossa at the end of the operation. Yttrium-^O oxide
(Y 2 0 3 ), suspended in wax, is suitable and has been used extensively in
Belfast. Radioactive gold ( m Au), which emits {3-particles and y- rays, has
been used in some other centres. ®°Y has a short half life (62 hours) and
emits [3-particles only. These do not penetrate farther than 1 cm. in soft
tissues and if adequately shielded are less liable than y-rays (e.g. radon) to
damage adjacent neural structures. About 1 ml. of the yttrium-wax
mixture, containing 7*5 to 10 millicuries, is extruded from a special syringe
into the fossa and is then packed in tightly with a spatula. Finally, it is
covered with a shield of muscle and some gelatin foam. In a few patients
the fossa is too shallow to allow the radioactive material to be inserted
without risk of its spilling out.

In patients with cancer of the breast the insertion of t0 Y renders the
operation more complete and may improve the clinical result. In patients
with tumour intrasellar M Y would seem preferable to postoperative
external irradiation.

Complications of hypophysectomy

The operative mortality following hypophysectomy for advanced
mammary cancer varies from nil to 20 per cent in different series. In Belfast
it fell progressively with increasing experience and with the rejection of
poor-risk patients:

Series Operations Deaths

1 10 5 (50%)

2 53 10 (19%)

3 42 2 (S%)

105 1 17 (16%)

Total

46

THE ANTERIOR PITUITARY

In patients with pituitary tumours the mortality varies with the extent of
the lesion. With small adenomas, confined to the sella, it is about 2 per
cent, while with lesions extending into the hypothalamic, temporal or
frontal regions it may be 30 per cent. The operative mortality was appre-
ciably higher before the introduction of cortisone. The main causes of
death are meningitis, extra-dural haemorrhage, coma and hypotension (of
uncertain aetiology), and pulmonary and cardiac lesions.

A few patients de\e!op fits temporarily in the immediate postoperative
period. Damage to the optic and oculomotor nerves are uncommon and
cerebrospinal rhinorrhoea is rare, while anosmia is an occasional complica-
tion. There arc often slight personality changes, consisting of an improve-
ment in mood and decreased aggressiveness and libido.

Hypopituitarism follows if replacement therapy is not given, and sterility
is invariable. Diabetes insipidus is usual, if the pituitary stalk is div ided at
a high level, and requires treatment.

Transsphenoidal hypophysectomy

The transsphenoidal approach is of value in patients with intrasellar
tumours, particularly when the optic chiasma is prc-fi\ed. It is relatively
easy and safe w hen the tumour has expanded and depressed the floor of the
pituitary fossa and obliterated the sphenoidal air sinus. The approach
should not be used w hen the fossa is of normal size, if the bones of the
skull are very thick (as in some acromegalics) or when there is sepsis in the
nasal region.

The operation is essentially one of decompression. The best results are
obtained with cystic tumours and the worst with hard ones. A little of the
tumour tissue and its capsule may be removed by curettage and suction,
but a complete removal cannot be undertaken without danger to the
overlying structures and serious risk of cerebrospinal rhinorrhoea and
infection. Radioactive material cannot be placed accurately nor kept in
position.

Transcthmosphenoidal hypophysectomy
The transethmosphenoidal approach has been developed recently by
James for the removal of normal glands and is likely to prove simple and
effective in the hands of those experienced in nasal and microsurgical
techniques. The operation involves a small incision beside the nose just
below the inner canthus of the eye. It is probably the least traumatic form
of surgical hypophysectomy.

Transnasal insertion of radioactive material

The pituitary fossa can be irradiated from within by means of rods of
*°Y or seeds of ,M Au inserted via the nose. The method docs not involve

OPERATIONS ON THE PITUITARY

47

an open operation and may be used on very ill patients who would not be
considered for craniotomy. It is more precise than external irradiation. It
may be used for destruction of the norma! gland or of intrasellar adenomas,
but is not applicable to tumours which have extended bej ond the fossa.

The safest and most effective technique is that devised by Forrest.
Under light general anaesthesia two rods of W Y, with stainless steel screw-
threaded bases, are introduced up the nostrils. With the help of an image
intensifier they are screwed into the floor of the sella so that each is held
firmly in the centre of one half of the fossa. The accurate placing of the
screws and the plugging of the holes between the fossa and the nose allow a
maximum radiation effect on the gland with minimum risk of damage to
the diaphragma sellae and optic and oculomotor nerves. The optimum
total dose for destruction of the normal gland is 9 to 10 millicuries. In
patients with tumours the dose is increased to 15 to 30 millicuries,
depending on the size of the fossa.

In Forrest’s hands the operative mortality was under 4 per cent in a large
series which included many very ill patients. Destruction of the normal
gland was virtually complete in every case, and visual disturbances,
rhinorrhoea and diabetes insipidus were uncommon. These results are
better than those obtained by other methods of intrasellar irradiation.

Other operations

Section of the pituitary stalk and transantra! hypophysectomy are
alternative procedures which are favoured in some centres.

Replacement therapy

Hypophysectomy causes hypopituitarism and atrophy of all the target
glands. The thyroid, adrenocortical and gonadal hormones can be
replaced and health can be maintained, but the patient remains sterile. A
few women experience vasomotor flushes, like those of the menopause, but
their cause is unknown. Tests of pituitary function provide results similar
to those in other types of hypopituitarism. The excretion of oestrogens
occasionally remains high, in spite of amenorrhoea. Rarely thyroid
function is impaired very’ little, and thyrotoxicosis has been reported after
hypophysectomy.

The replacement therapy for patients with pituitary tumours and
hypopituitarism has been described. In those with normal pituitary
function cortisone acetate should be given as follows:

Before operation

24 hours 100 mg. by intramuscular injection

12 hours tOQ mg. by intramuscular injection

48

THE ANTERIOR PITUITARY

After operation
Day 1-2
3-4
S-6
7-10

II onwards

23 mg. 4-houtly by intramuscular injection

25 mg. 6- hourly by mouth

25 me. 8-hourly by mouth

25 mg. 12-hourIy by mouth

25 mg. morning by mouth

12 5 mg. evening by mouth

Much larger doses are required for those undergoing hypophysectomv for
Cushing’s syndrome. The dose may be varied to meet individual require-
ments. Rarely a profound fall in blood pressure requires cortisol hemi-
succinate intravenously as for the treatment of an adrenocortical crisis.
"Pure” glucocorticoids, such as prednisone, are not suitable because a few
patients develop acute salt deficiency if they are maintained on them. This
does not occur with cortisone. The usual precautions must be taken to
ensure that the patient understands the vital necessity for continued
therapy.

Thyroid deficiency de\ clops very slowly, and thyroxine, 0-2 to 0-3 mg.
per day, should be given from about one month after operation.

Replacement of sex hormones depends on the patient’s age and sexual
requirements. Their possible effect on the tumour should be considered
before they are given to patients with carcinoma.

Diabetes insipidus frequently requires treatment with vasopressin, but
it is wise to withhold therapy for a week or so after operation to avoid over-
hydration of the brain. Frequently, in those who subsequently develop
diabetes insipidus, polyuria starts immediately after operation, probably
because the local operative trauma prevents the release of antidiurctic
hormone. The polyuria may then cease for a few days, possibly as a result
of the release of pre-formed hormone from the remaining neurohypo-
physeal tissue. When this supply is exhausted the polyuria returns. Injec-
tions are usually required, for few patients can be controlled with snuff. A
dose of 2-5 to 10 pressor units of vasopressin tannate in oil (0-5 to 2 ml.) »
needed twice daily to twice weekly, depending on the severity. Diabetes
insipidus usually stops spontaneously after a few months, but may some-
times be permanent.

FURTHER READING AND REFERENCES

General

cl SUING, H. (1912). The Pituitary Body and itt Disorders. Lippincott, Philadrlph^-
RisSFiFxn, a. B. (1957). The adenohypophysis. In Analytical Pathology, p. 2 fi-
I'd. Melton, It. C., McGraw-Hill, New York.

Histology

EZRIN, C., SWANSON, It. E., HUMPHREY, J. G., DAWSON, J. W. and WILSON, W. P. (19581

'Hie delta cell of the human adenohypophysis. J. clin. Enelocr., IS, 917.

EZRIN, C., SWANSON, II. £., HUMPHREY, J. C., DAWSON, J. W. and IIIU, V. M. ( 1 v J /#•
lieta and delta cells of the human adenohypophysis, their response to adreno-
cortical disorders. J. clin. Endocr., 19, 621.

FURTHER READING

49

Rasmussen, A. T. (1938). The proportions of various subdivisions of normal adult
hypophysis cerebri and relative number of different types of celfs in pars
distalis. In The Pituitary Gland. Ass. Res. nerv. Dis. Proc., 17, 118.

SWANSON, H. E. and EZRIN, c. (1960). The natural history of the delta cell of the
human adenohypophysis in childhood, adulthood and pregnancy. J. dm.
Endocr., 20, 952.

Functions of Anterior Pituitary

albert, a. (1956). Human urinary gonadotrophin. Recent Progr. Hormone Res.,
12, 227.

ALBERT, A. (1960). Human pituitary gonadotrophin. In Clinical Endocrinology I,
p. 605. Ed. Astvvood, E. B. Grune and Stratton, New York.

greer, M. A. (1957). Studies on the influence of the central nervous system on
anterior pituitary function. Recent Progr. Hormone Res., 13, 67.

HARRIS, c. vv. (1955). Neural Control of the Pituitary Gland. Arnold, London

ilarris, c. W. (I960). Central nervous control of gonadotrophic and thyrotrophic
secretion. Acta endocr. (Kbit), 34, Suppl. 50, p. 15.

IKKos, D. and LUTT, r. (I960). Aspects of the metabolic action of human growth
hormone. In Ciba Found. Coll. Endocrinol., 13, 106.

LEE, T. h., LOWER, A. D. and BUETLENER-JANL’SCH (I960) Adrenocorticotrophic
hormone and melanocyte-stimulating hormone from human pituitary glands.
In Ctba Found. Coll. Endocrinol., 13, 251.

McArthur, j. w., Worcester, ]. and ingersol, F. M. (1958). The urinary excretion
of interstitial cell and follicle-stimulating hormone during the normal menstrual
cycle. J. din. Endocr 18, 1186.

raben, m. 8. (1960). Action of growth hormone in man. In Clinical Endocrinology I,
p. 11. Ed. Astwood, E. B. Grune and Stratton, New York.

Investigation

LtODLE, G. \V., ESTEP, H. L., KENDALL, J. \V. f JR., WILLIAMS, W. C., JR. and TOWNES,

a. w. (1959). Clinical application of a new test of pituitary reserve, J. din.
Endocr., 19, 875.

lojlawe, j. a. (1958). Pituitary gonadotrophins, p. 15; Growth hormone, p. 125;
Prolactin, p. 133. In Clinical Application of Hormone Assay. Livingstone,
Edinburgh.

millar, g. (1961). Personal Communication.

Pituitary Tumours

Jackson, H., Richmond, j. j. and simpson, s. l. (1958). Discussion on pituitary
tumours. Proc. roy. Soc. Med., 51, 907.

Jefferson, sir Geoffrey (1955). Invasive Adenomas of the Anterior Pituitary. Uni-
versity Press, Liverpool.

Ker.vohan, j. w. and sayre, c. p. (1956). Tumours of the pituitary gland and in-
fundibulum, In Atlas of Tumour Pathology. Section X, Fascicle 36. National
Research Council, Washington D.C.

lyle, t. K., clover, p ., pennybacker, j., ross, e. j. and treip, c. (1961). Pituitary
tumours (ocular symptoms and signs; treatment of pituitary tumours: endo-
crinology of pituitary tumours: pathology of human and experimental pituitary
tumours). Proc. roy. Soc. Med., 54, 611.

Morcensen, e. f. (1957). Chromophobe adenoma of the pituitary gland: a follow-
up study on 60 surgical patients with special reference to endocrine disturb-
ances. Acta endocr. (Kbit.), 24, 135.

Willis, j. (1961). Personal Communication.

Hyperpituitarism (Growth Hormone)

DA vi DOFF, L. M. (1926). Studies in acromegaly. The anamnesis and sympto-
matology in one hundred cases. Endocrinology, 10, 461 .

50 THE ANTERIOR PITUITARY

JOPUN, G. f., Fraser, R., STEINER, R., laws, J. and JONts, E. {1961). Partial pituitary
ablation by needle implantation of gold-19S seeds for acromegaly and Cushing'*
disease. Lancet , 2, 1277.

KELLGREN, J. II., BALL, J. and TlTTOV, c. K. (1952). The articular and other limb
changes in acromegaly. Quart. J. Med., 21, 405.

siMPiON, s. l. (1950). Physiology of gross th. Postgrad. med.J,, 26, 417.

Pituitary Insufficiency

beck, R. N. and Montgomery, D. a. d. (1957). Treatment of hypopituitarism. Brit,
med. J., 1, 441.

ntbiiLtcji, A. (1901). Ein Fall von Tumor der Hypophysis cerebri ohne Acro-
megalie. \Vtert. Min. Rdsch., 15 , 883, 906.

martin, M M. and wjlkins, L. (1958). Pituitary dwarfism; diagnosis and treat-
ment. J. clin. Endacr., 18 , 875.

sheeican, H. l. and summers, v. K. (1949). The syndrome of hypopituitarism.
Quart. J. Med., 18, 319.

SIMMONOS, M. (1914). Ueber Embolische Pro 2 esse in der Hypophysis. Viuhtnt
Arch. path. Anat., 217, 226.

wilkins, l. (1957). Variations in the pattern of adolescent development. In T ht
Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence.
p. 183. Blackwell Scientific Publications, Oxford.

Operations on the Pituitary

EOELSTYN, a. A., CLEADHILL, C. A., LYONS, A. It., RODCERS, II. YV., TAYLOR, A. R. and
welbourn, r. b. (1958). Hypophysectonty combined vdth intrasellar irradia-
tion with yttrium-90. Lancet, 1, 460

torhest, a. P. M-, BLAIR, D. w. and VALENTINE, J. M. (1958). Screw-implantation of
the pituitary with yttnum-90. Lancet , 2, 192.

FORREST, A. P. M , BLAIR, V. YV., PEEBLES BROWN, D. A., STEWART, Jt. J., SYNDICS
A. T., HARRINGTON, R. w,, VALENTINE, J. M. and carter, P. T. (1959). Radio-
active implantation of the pituitary. Brit.J. Surg., 47, 61.

James, j a. (1962). Surgery of the hypophysis cerebri (Jobson Home McmOtul
Lecture — abstract). Brtt. med. J., 2, 332.

jffferson, sir Geoffrey (1956), Operations on the skull and brain (pituitary
gland). In Modern Operatic e Surgery. Ed. Turner, E. G, and Rogers, L. C.,
2. 1464.

tutton, g. k. (1957). Exposure of the Pituitary* Region by the frontal approach.
In Operative Surgery, Part VIII, p. 39. Ed. Rob, C. and Smith, R, Rutter-
worth, London.

CHAPTER 2

the steroid hormones

The adrenal cortices and the gonads have a common origin in the
embryonic coelomic epithelium and, in the adult, they 0 ^°"'

which have very similar structures and many common functions. During
pregnancy the placenta is an additional site of hormone ptt.duc.mn. . The
homtones belong to the group of cyclic chemical “mPOun* known «
steroids. Some dozens of them have been isolated from the body but ™‘ y
a few have endocrine activity. Most of the others are “ bre £

down products of hormones. A few, chote.erol and .he btta « *, for
instance, arc not hormones, but have other important functions,
steroid hormones may be divided into four main groups.

1. Corticosteroids .

These are elaborated in the adrenal cortex and possibly in the placenta.
There are two sub-groups;

(а) Glucocorticoids. Cortisol (hydrocortisone) is the
essential to life. It is concerned with the regulation

processes and enables the body to withstand stress. Cort.co.t'rom
subsidiary one with similar, but weaker, actions. . r

(б) Mineralocorticoids. AMosttrone is the most active m

group and controls the mineral balance of the body by regulating
excretion of sodium, chloride and potassium in t e urine.

These are the male sex hormones and are f°™ ed p ™^ 1 ^ s “ C ular
interstitial or Leydig cells of the testis. Tes os ero . ens j n the
androgen. The adrenal cortex is a subsi tary geveral different

male and the mam source in the female. a ndrostenedione and

compounds, of which dehydroepumdrosterone (DH-A). amoun ts of

ll-hydroxyandrostenedione have been tdeni 1 ' ovarv also secretes
testosterone may be secreted also. It ,s P 11 * 3 e a androgens control the
small quantities of androgens. In the male g annearance

normal development and function of the sexua organ concern ed with
of the secondary sexual characters. In the female they are concerned
51

52

THE STEROID HORMONES

the growth of axillary and pubic hair. In both sexes they have some genera!
metabolic actions.

3. Oestrogen:

These arc the most important of the female sex hormones. They are
formed principally in the graafian follicles and corpora Iutea of the ovary,
but also in the placenta. Oestradiol is the main compound. The adrenal
cortex, which b a subsidiary source in the female and the main source in
the male, secretes oestrone and oestradiol. The testis also secretes small
quantities of oestrogens. In the female oestrogens are concerned with the
development and function of the sexual organs and the appearance of the
secondary sex characters. They also influence general metabolic processes.
The function of oestrogens in the male is not known.

4. Progestogeits

These are also female sex hormones. They are formed mainly in the
corpus luteum of the ovary but also in the adrenal cortex, the testis and
the placenta. Progesterone is the chief hormone. Its main function is the
preparation of the uterus for the fertilized ovum and the maintenance of
the decidua during pregnancy. It also influences metabolic processes.

The inter-relationships of the steroid hormones are very' close. There is,
for instance, considerable overlap in functional activity. Cortisol and all
the sex hormones have definite mincralocorticoid effects, and aldosterone
has a slight glucocorticoid action. Cortisol and progesterone arc mildly
androgenic in certain circumstances. The hormones arc closely related
also in the pathways by which they are synthesized in the glands and
metabolized in the tissues. In the adrenal cortex of both sexes, for
example, cholesterol, which has no endocrine activity, is converted »nto
progesterone (a progestogen); this in turn is changed to 17 -hydroxypro-
gestcrone, which is androgenic, and from this cortisol (a glucocorticoid) »
synthesized. To confuse the issue still further cortisol is metabolized in
part into weak androgens, and testosterone into both weak androgens and
oestrogens.

THE STRUCTURE OF THE STEROIDS

The parent hydrocarbon is pcrhydrcicyclo-pentcnophertanthrene I,

which for convenience is usually represented by formula II. Each angle

THE STRUCTURE OF THE STEROIDS

S3

represents a carbon atom together with sufficient hydrogen atoms to
saturate it. (The valency of Carbon is 4.) The rings are lettered A to D,
and the C atoms are numbered 1 to 17. Many thousands of compounds can
be formed from the introduction of unsaturated (double) bonds between
adjacent C atoms (and loss of H atoms) and from the substitution of
chemical groupings and side chains for one or more of the H atoms. Some
of the C atoms are asymmetrical, and stereo-isomeric forms are common.
Groups lying below and above the plane of the ring are referred to as a and
P respectively, a groups are linked by a dotted line, while (3 groups have a
solid line, thus:

f XO‘

OH

a

This elementary account of steroid chemistry is intended to pro\ ide a
basis for the understanding of normal and pathological metabolic pathways
and of the biochemical tests which are of clinical value. AH the steroids
have systematic chemical names, and many have trivial or semi-triual
names also. The latter are used whenever possible, but sometimes, to
avoid confusion, a longer name is given in brackets. Stcreo-isomeric
configurations are often ignored in the structural formulae.

Ci8 compounds

The simplest hormonal steroids are oestrogens, which have 18 carbon
atoms. Oestradiol is an example. Each double line in the formula
indicates that 2H atoms have been eliminated. The vertical line attached
at the C13 position indicates that a -CH 3 group has replaced the H atom
This C atom is numbered 18.

C19 compounds

Next in complexity are the androgens, which have 19C atoms, fn the
formula for testosterone there is a second ~CH 3 group at the CIO position
This C atom is numbered 19.

Oe stradicl T*»fco»terone

compounds

Progesterone and the corticosteroids have 21C atoms in their molecule.
The two methyl groups are retained at the CIO and C13 positions and, in

54

THE STEROID HORMONES

addition, there is a side chain containing 2C atoms at the C17 position.
These compounds and testosterone ha\e a characteristic structure in the
A ring of the nucleus.

ProqeiW'tns Cwtlio!

Aldosterone may be represented by two tautomeric structural formulae:

AWo*t«rone(*etm«cetal) AWosterone(aldehydi)

Its structure is probably intermediate between these two forms.

STEROID BIOSYNTHESIS

All the steroid-forming glands and the placenta employ simple C2 units,
such as the acetate radical, as their raw materials. The early stages of
synthesis arc common to all these sites and to all the steroid hormones, and
can be represented thus;

Simple C2 unit*

Muij inter jmedntc cont^Mivii

Cholesterol

„ ^ ANDROGENS

PreRnenokmc - Com 7^ AND O ESTROGENS

AO jfUnds

PROGESTERONE

Mjny irJfr|meJj,,f ,twp*Kindi

AM- STEROID HORMONES

STEROID BIOSYNTHESIS 55

End products, which are secreted by any of the glands, are represented in
capitals in this and in the three following diagrams.

The biosynthesis of the C19 compounds in the adrenal cortex and in the
testis can be represented thus:

TESTOSTERONE

56

THE STEROID HORMONES

The synthetic pathways of the CIS o estrogens in the ovary and in the
adrenal cortex have not been elucidated fully, but oestrogens maybe formed
from the CI9 androgens, androstenedione and testosterone, as follows:

PROGESTERONE
17- hydroxyprogesterone

TESTOSTERONE

The synthesis of corticosteroids in the adrenal cortex can he repre-
sented by the scheme on page 57. Most, but not all, of the pathway
have been confirmed. Specific enzymes are probably responsible for
hydroxylation at the different positions. Cortisol, aldosterone and corti-
costerone are the main products. Cortisol is in chemical equilibrium with
cortisone.

CATABOLISM AND EXCRETION OF STEROIDS

The steroid hormones arc partly metabolized in the liver and possibly
in other tissues. Many breakdown products arc formed, but only a few
of them are important. These., together with proportions of the hor-
mones themselves, are excreted in the urine and in the bile, many of
them in conjugated forms. The estimation of urinary steroids is extremely
important in the investigation of diseases of the adrenal cortices, the testes
and the ovaries. The estimations 3rc all performed on fresh 24-hour
specimens of urine.

Pro°ateronf is catabolizcd into several inactive compounds, the most
important of which Is [iregnanediol, which can be estimated chemical!)

CATABOLISM AND EXCRETION OF STEROIDS

57

c

58

THE STEROID HORMO.VES

(fig. 2.1). Like the ocstrogcns, it is derived from the ovary and from the
adrenal cortex. Progesterone itself is not excreted in the urine.

CLASS OF STEROIDS

-

PROGESTOGEN

CESTltOGENS

SECRETIONS Of GLANDS

PROGESTERONE

(ESTRADIOL =*=(EST

SHE

J

URINARY

STEROIDS

MtEGNJ

NEDIOL

/ CST

a

GROUP

PROGESTOGEN

METABOLITES

I'ig. 2 1. Simplified diagram shoeing metabolic pathways and excretion products
of progestogen* and oestrogen*.

The oestrogen s, oestradiol and oestronc, arc converted partly into weakly
oestrogenic compounds, the most important of which is oestriol (fig. 2.1).
The main urinary ocstrogens are oestriol (about half) oestronc (one-third)
and oestradiol (one-sixth). The ovary is the main source, and the adrenal
cortex a subsidiary source in women during the reproductive period. In
men and post-mcnop3usal women the adrenal cortex is the main source.
Ocstrogens can be estimated chemically, but the methods are time-con-
suming and not available in all laboratories.

The metabolites of cortisol and its precursors and of the androgens hate
close inter-relationship3 (fig. 2.2). The main metabolites of testosterone —
androsterone and actiocholanolonc — and all the adrenal androgens and
their metabolites have an “oxo” (= O) group at the C17 position and are
called " I7-ovosteroids". They were formerly named “17-kctostcroids''.
Appreciable quantities of these, but not of testosterone itself, arc excreted
«v wjwfc. The wdverak cortex, vs thew only important IWKCe wv the
female (the ovaries may produce a very small amount) and accounts for
about two-thirds of those winch arc excreted in the male. The testis
provides the remaining one-third. It should be noted that metabolites of
cortisol and cortisone and of their precursors make small contributions to
the 17-oxosteroids, so that, although the Utter provide a useful index of
adrenocortical and of testicular function, they do not represent androgen
production exclusively (fig. 2.2). Oestronc and some of its mctalmlitcs

CLASS OF STEROIDS

60

TJIF STEROID HORMONES

also have the C17 “oxo” configuration, but their phenolic character enables
them to be removed during the estimation of 17-oxosteroids. Estimation of
17-oxosteroids is done in most hospital laboratories.

Cortisol and cortisone are metabolized mainly to their "tetrahydro”
derivatives (so-called because they represent reductions of the molecules of
their parent compounds by the addition of 4 extra II atoms). The
tetrahydro compounds and small amounts of the hormones themselves are
excreted in the urine. Corticosterone is similarly metabolized and excreted
as its tetrahydro derivatives. 17-Hydroxyprogcsterone is metabolized in
part and excreted as pregnanetriol (not to be confused with pregnanediol
derived from progesterone). The estimation of these compounds forms a
very valuable method of estimating adrenocortical function specifically.
Many methods have been described, but two, which arc performed in most
laboratories, are of special value. (1) The 17-oxogcnic steroids are cortisol,
cortisone, their tetrahydro derivatives and pregnanetriol, but not cortico-
sterone and its metabolites. The term “17-oxogcnic steroids” implies that
these compounds can all be converted by chemical (bismuthate) oxidation
into 17-oxosteroids. After preliminary measurement of the 17-oxosteroids
already present, the urine is suitably treated and the estimation is repeated.
The difference between the two results represents the value for the
17-oxogcnic steroids. (2) The total 1 7-hydroxy steroids include atl those
compounds which arc estimated as 17-oxogenic steroids and also the
tetrahydro derivatives of corticosterone.

All the steroids which are included in the 17-oxostcroid and total
17-hydroxystcroid groups can be estimated individually. The methods for
deh)droepiandrostcronc and pregnanetriol can be carried out routinely in
most laboratories and may be very useful. Those for the other steroids
involve chromatographic fractionation and ate both time-consuming and
technically difficult. Estimations of cortisol, actiocholanolone and andro-
sterone, however, may sometimes be very helpful.

Aldosterone is excreted in the urine partly unchanged and partly in the
form of its tetrahydro derivatives. Its estimation is tedious and is not
undertaken in many hospital laboratories.

SYNDROMES OF DEFICIENCY AND EXCESS
Each of the main groups of steroid hormones— corticosteroids (cortisol
and aldosterone), androgens and oestrogens — is formed mainly in one tvpe
of gland, and dejiciency syndromes arise only when the main source is
defective. 17ms, deficient secretion by the adrenal cortex causes deficiency
of corticosteroids (adrenocortical failure), and deficient secretion by the
gonads causes deficiency of sex hormones (hypogonadism). The other
glands cannot make good the deficiency.

SYNDROMES OF DEFICIENCY AND EXCESS 61

Syndromes of hormonal excess, however, may arise from several causes,
and the clinical features depend more on the age and sex of the patient than
on the source of the steroid.

Excess of cortisol may be caused by:

1. Excessive secretion by the adrenal cortex.

2. Excessive secretion by adrenal-like cells in the testis or ovary (very
rare).

3. Exogenous cortisol (or one of its analogues} in excessive dosage.
Cushing’s syndrome results in both sexes and at all ages.

Excess of aldosterone is caused only by hypersecretion by the adrenal
cortex (or, theoretically, by the administration of aldosterone) and the
result is aldosteronism.

Excess of androgens may be caused by:

1. Excessive secretion by the testis.

2. Excessive secretion by the adrenal cortex.

3. Excessive secretion by the ovary.

4. Exogenous androgens in excessive dosage (including administration
during pregnancy with an effect on the foetus).

Virilism of one sort or another always develops. In the male child this takes
the form of precocious development of the secondary sexual characters. In
the female foetus it causes pseudohermaphroditism, in the girl precocious
development of masculine secondary sexual characters, and in the adult
woman regression of some female characters and the development of some
masculine ones.

Excess of oestrogens may be caused by:

1. Excessive secretion by the ovary.

2. Excessive secretion by the testis.

3. Excessive secretion by the adrenal cortex.

4. Defective catabolism of oestrogens (hepatic cirrhosis).

5. Exogenous oestrogens in excessive dosage (therapeutic, including
skin creams, and by inhalation from industrial processes).

The result may be called loosely “feminization”. Girls develop precocious
secondary sexual characters, and both girls and adult women suffer various
disorders of endometrial function. Men lose some of their male characters
and develop some feminine ones, such as gynaecomastia.

The influence of both the androgens and the oestrogens on general
metabolic processes may contribute to the clinical syndromes in both sexes.

The interactions between the trophic hormones of the anterior pituitary
and the secretions of the target glands play an important part in all these
syndromes. Hypersecretion by the pituitary may cause a normal target
gland to secrete excessively, as in Cushing’s syndrome (ACTH), or

62

T11E STEROID HORMONES

precociously, as in precocious puberty (gonadotrophins). On the other
hand, deficient secretion by the target glands may cause hypersecretion of
the trophic hormones as in adrenocortical failure or hypogonadism.
Autonomous hypersecretion by tumours of the target glands causes
inhibition of trophic hormones, and consequent atrophy and secretory
failure of the non-tumorous parts of the glands. Excessive quantities of
androgens or oestrogens from any source inhibit the production of
gonadotrophins and cause atrophy of the gonads.

FURTHER READING

CIO A FOUNDATION COLLOQUIA ON ENDOCRINOLOGY (1955). Vol. 8. The Human
Adrenal Cortex. Churchill, London.

DORFMAN, R. I. (1961). Metabolism of adrenocortical hormones. In The Adrenal
Cortex, p 108. Ed. Moon, H. D. Hoeber, New York.
fieSer, i, f. and ficser, m. (1959). Steroids. Reinhold Pub. Corp-, New York.
GRAY, C II. and BACilARACH, A. L. (1961). Hormones in Blood. Academic Press, New
York.

klyne, W. (1957). The Chemistry of the Steroids. Methuen, London.
loraine, J. a (1958). Corticosteroids, p. 244; 17-ketosteroids and androgens, p.

287. In Clinical Application of Hormone Assay. Livingstone, Edinburgh.
MASON, n. L. (1948). Steroid nomenclature. J. elm. Endocr., 8, 190.

*5*s , £jiT«bN.

, \ ubbabv. )g jj

LN.<* \_ -A '

CHAPTER 3

THE ADRENAL CORTEX

The adrenal (suprarenal) glands consist of two parts, an outer cortex and
an inner medulla. The former tissue is derived from the embryonic
coelomic epithelium, is controlled by ACTH from the anterior pituitary
and is essential to life. The latter develops from the neural ectoderm and
is a specialized part of the sympathetic nervous system. Thus, although
the cortex and medulla of the adrenal form an anatomical entity, they are
distinct from each other in their origin, structure and function. The
medulla is described in Chapter 9.

ANATOMY

There are two adrenal glands, one situated immediately above and close
to the upper pole of each kidney. In congenital absence or ectopia of a
kidney the corresponding adrenal develops in the normal position, and may
thus be some distance away from the kidney. The right adrenal is roughly
pyramidal in shape and the left is crescentic. The normal weight of each
gland is about 4-5 to 5-5 g.

The right adrenal is in contact with the inferior vena cava anteriorly and
medially and with the liver laterally. It lies on the crus of the diaphragm,
while its base rests on the medial and anterior surfaces of the upper pole of
the right kidney. The concavity of the left adrenal is in contact with the
medial border of the upper part of the left kidney. The upper part of the
anterior surface is separated from the cardiac end of the stomach by the
peritoneum of the lesser sac, while the lower portion is crossed by the tail
of the pancreas and the splenic artery. The posterior surface is partly in
contact with the kidney and partly related to the left crus of the diaphragm.
Externally the glands are coloured orange-yellow by the lipid within the
cells of the cortex. They are enclosed in a connective-tissue capsule and
embedded in the perirenal adipose tissue.

The adrenals have a rich blood supply and receive small arterial branches
from the abdominal aorta, and from the phrenic and renal arteries. The
adrenal vein is usually single and emerges from the hilus of the gland.
On the right side it is short and opens directly into the inferior vena cava,
while on the left it drains into the left renal win.

The cut surface consists of the outer cortex and inner medullary zone.

63

THE ADRENAL CORTEX

64

The cortex is firm while the medulla is softer, reddish brown in colour and
more friable. The capsule of the gland contains a rich plexus of arterioles
from which branches pass into the substance of the gland.

Ectopic collections of adrenocortical cells, up to 3 or 4 mm. in diameter,
are present in. about 30 per cent of people near the main glands, elsewhere
in the retro-peritoneal tissues, and in the broad ligament of the uterus or
the spermatic cords.

Histology

The cortex consists of three zones of cells. The outer, or zona
glomerulosa, is the thinnest and consists of columnar-shaped cells arranged
m groups or curved columns. The middle zone is the broadest and is
called the zona fascicuhta. It contains large polyhedral cells, arranged in
parallel strands or columns, which are rich in lipid droplets and ascorbic
acid. The innermost layer, the zona reticularis , consists of cells which are
arranged irregularly. They possess few lipid droplets, but some contain
pigmented granules of lipofusem which may result from cellular degenera-
tion. Sinusoids, connected with the adrenal vessels, lie between the celts
of the cortex and probably receive the hormones as they are secreted.

The histological structure of the adrenal cortex varies with age. In foetal
life the glands are large and at birth the cortex consists of two parts, a large
inner foetal zone consisting of eosinophilic cells and a thin outer layer of
small basophil cells from which the adult cortex de\e!ops. The foetal
cortex regresses and disappears within a few weeks of birth, leaving behind
the true cortex, which continues to grow throughout childhood. At
puberty the reticularis matures and the adrenal as a whole enlarges rapidly.
Thereafter the pace of growth diminishes until middle adult life, after
which the size of the gland diminishes gradually. The nature and function
of the foetal cortex is not understood clearly, but there is no evidence that it
is involved in any of the pathological lesions of the gland which are
described later.

PHYSIOLOGY

The adrenal cortex is essential to life and plays a major part in inter-
mediate metabolism, homeostasis and the resistance of the body to stress.
It plays a subsidiary role in sexual development and function. Total
destruction or removal of both glands is rapidly fatal, but life can be
maintained by substitution therapy with cortisol, cortisone or their
analogues. Aldosterone and the adrenal sex hormones cannot maintain life
in these circumstances.

The principal cortical hormones, and their probable sites of origin, are
as follows:

PHYSIOLOGY 65

Type Main hormone Zone of origin

Mineralocorticoid Aldosterone Glomerulosa (outer)

Glucocorticoid, etc. Cortisol

Sex — Androgenic Dehydroepiandrosterone

Androstenedione Fasiculata (middle) and

1 1 -Hydroxyandrostenedione Reticularis (inner)

Oestrogenic Oestrone

Progestogenic Progesterone

Symington believes that the zona reticularis and zona fasciculata are
functionally a single unit, the inner zone producing all steroids except
aldosterone, while the fasciculata acts as a storehouse for steroid precursors.
It should be noted that both androgens and oestrogens are formed in the
adrenals of both sexes.

Adrenocorticotrophin (ACTH) controls the growth of the adrenal cortex
and the secretion of both cortisol and the sex hormones, but has little
influence on the secretion of aldosterone. There is some evidence that it
may contain two substances, one of which causes adrenal growth and
sensitizes the gland to the action of the other, which stimulates the
secretion of hormones. ACTH also decreases the amount of ascorbic acid
in the adrenal cortex. This action provides a valuable method of bioassay,
but its significance is unknown. Various stimuli, including "stress”, fear,
pain and other emotions, promote the secretion of ACTH. The regulating
centre appears to be in the anterior part of the median eminence of the
hypothalamus, and the neurohumour is named the "corticotrophin
releasing factor” (CRF). The concentration of cortisol in the blood, which
influences the secretion of CRF, is, however, the principal controlling
influence over the secretion of ACTH, and hence of all the cortical steroids
except aldosterone. The sex hormones may therefore be regarded as by-
products of the secretion of cortisol.

The secretion of hormones, in particular cortisol and aldosterone,
changes continually in response to the needs of the organism. In addition,
there is a rhythmic variation in the production of these two steroids which
is highest in the morning and lowest late at night. This variation is not
ietStteaced by light, food, sleep or setmty. It is probably important, but
its cause and function are unknown. The secretion of cortisol, judged by
its excretion in the urine, increases steadily from infancy to adult life and
is related to the surface area of the body. Secretion is maximal at about
30 years and wanes markedly after the age of 60. Its concentration in the
blood remains relatively constant throughout life. The secretion of adrenal
androgens, judged by the excretion of 17-oxosteroids, follows a different
pattern. Negligible amounts are produced in the first 7 years of life. In
both sexes secretion starts to increase regularly at about the age of 8 (the
so-called "adrenarche”) and reaches the maximal adult level about JO years
later. Secretion wanes markedly after the age of 40.

66

THE ADRENAL CORTEX

The cortical hormones are discharged directly into the circulation,
probably in a free state. Cortisol combines rapidly in the blood with
“transcortin”, part of the globulin moiety, and normally about 90 per cent
of it is carried in this bound form, which may be physiologically inactive.
When cortisol is formed in excess (as in Cushing's syndrome) there may be
insufficient transcortin to bind it, and a much higher proportion of the
active form may be found free in the blood or attached to plasma albumin.
The other steroids arc probably associated in some way with plasma albumin.
During their passage through the liver, and possibly other tissues, the
steroids are metabolized in part and their breakdown products arc
conjugated with glucuronic and sulphuric acids. The steroids are excreted
in the urine mainly in these conjugated forms.

Aldosterone

Aldosterone was isolated in 19S2 by Simpson, Tait and Bush, and our
knowledge about it is limited. It is the most powerful natural mineral-
ocorticoid and controls the excretion of sodium and potassium. It also
shares, in a weak manner, many of the activities of cortisol.

The most important action of aldosterone is the control of electrolytic
exchanges in the distal renal tubules. It promotes the reabsorption of
sodium (and chloride) and, secondarily, the excretion of potassium and
hydrogen ions, probably by means of a cation-exchange system (fig. 3.1).
Under its influence sodium ions are reabsorbed from the urine in the distal
tubules in exchange for hydrogen and potassium ions, which are excreted
by the tubular cells. The proportions of hydrogen or potassium ions which
are exchanged depend on their relative availability. The action of
aldosterone on the tubular reabsorption of sodium can be blocked by
drugs of the spironolactone series.

When aldosterone is deficient the reabsorption of sodium ions is impaired
and potassium and hydrogen ions cannot be secreted in its place. This
inability to reabsorb sodium is probably the cause of the striking hyper-
kalaemia observed in aldosterone insufficiency (e.g. Addison’s disease).
When aldosterone is present in excess potassium is lost from the kidney in
exchange for sodium, and hypokalaemia develops. This is accompanied by
a metabolic alkalosis because hydrogen ions migrate from the extracellular
fluid into the tissue cells in place of the potassium ions which have been
lost. Conversely, a metabolic acidosis results from the hyperkalaemia of
aldosterone insufficiency, since potassium ions enter the cells and displace
hydrogen ions into the extracellular fluid. Sodium ions accompany the
hydrogen ions in and out of the cells.

Aldosterone also influences the exchange of electrolytes in other parts of
the body. Thus, it reduces the quantity of sodium and increases that of
potassium in the sweat, the saliva and the succus entcricus. It has a

ALDOSTERONE

67

Fig. 3.1. Diagram showing action of aldosterone on electrolytes in distal renal
tubule.

secondary effect on body water, which tends to follow the sodium and
chloride ions, but, unlike cortisol, it does not have a direct effect on the
urinary excretion of a water load.

Control of aldosterone secretion

The secretion of aldosterone is influenced by several stimuli which
appear to operate independently. Five are recognized. (1) ACTH has a
slight but definite influence on aldosterone secretion, but it is not the mam
controlling mechanism, and aldosterone in excess does not inhibit the
production and release of ACTH. (2) A potassium load increases the
secretion of aldosterone, while potassium depletion diminishes it; these
changes are probably independent of any change in the volume of body
fluid, (3) Diminution of the blood volume increases the secretion of
aldosterone, while elevation of the blood volume reduces it. These effects
arc probably mediated via volume receptors situated in the walls of the
atria, vena cava and carotid vessels. This mechanism may account for the
excessive secretion of aldosterone (secondary aldosteronism) in the
nephrotic syndrome and in hepatic cirrhosis with ascites (in both of which
the blood volume is reduced) and in heart failure (in which the intra-
carotid pulse pressure is reduced). (4) There is some evidence that a
humoral agent (already named “adrenoglomerulotrophm”), secreted from

68

THE ADRENAL CORTEX

either the pineal gland or the sub-commissural body of the mid brain, plays
a part in the regulation of aldosterone secretion. This centre may respond
to the volume receptors in much the same way as the neurohypophysis
responds to the osmoreceptors. (5) The kidney probably plays an impor-
tant role, for injection of angiotensin increases the excretion of aldosterone
in the urine.

Cortisol

Cortisol (hydrocortisone), which was first isolated by Reichstein in 1937,
is the only steroid hormone which is essential to life. Its main physiological
actions are as follow:

Stress

Cortisol plays a vital role in the response of the body to stress such as
that caused by infection, trauma, irradiation with X-rays or a surgical
operation. It is not known how cortisol protects the body against these
noxious stimuli, but it may do so through all the metabolic actions which
are to be described. The concept of the effects of repeated stress on the
body and of the "general adaptation syndrome” of Selye are beyond the
scope of this book.

Carbohydrate and protein metabolism

The dose link between the adrenal cortex and the metabolism of
carbohydrate was recognized long ago in the hypoglycaemia of Addison’s
disease. More recently the development of steroid diabetes in Cushing’s
syndrome and the amelioration of diabetes melhtus by adrenalectomy have
provided further evidence of the association. Cortisol promotes the
breakdown (catabolism) of protein throughout the body and the formation
of glucose from the resulting amino acids (gluconeogenesis). At the same
time it raises the blood sugar, inhibits the utilization of glucose by the
tissues and causes the deposition of glycogen in the liver. The name
"glucocorticoid” is derived from these "diabetogenic effects” on carbo-
hydrate metabolism. There is evidence that cortisol antagonizes insulin
and diminishes the peripheral utilization of glucose. Cortisol is one of
several hormones whose balanced actions control intermediate metabolism.
Thus, its catabolic activity is antagonized by the androgenic steroids and
its "diabetogenic” effect is kept in check by insulin.

Fat metabolism

Cortisol encourages the deposition of fat in the body, and is also needed
for the mobilization of fat from the depots, but its mode of action is not
clear. In excess it causes a redistribution of depot fat so that adipose tissue
is laid down in the cheeks, on the upper part of the trunk and shoulders,
and in the abdomen, while the fat in the arms and legs is diminished.

CORTISOL AND SEX HORMONES

69

Water and electrolyte metabolism

Cortisol exerts an effect on the metabolism of electrolytes (sodium and
potassium in particular) similar to, but much weaker than, that of
aldosterone. Unlike aldosterone, however, it facilitates the excretion of
water, possibly by increasing its filtration by the glomeruli and diminishing
its reabsorption by the tubules.

Blood cells

Cortisol tends to increase the numbers of red cells and of neutrophil
polymorphs and to decrease the numbers of lymphocytes and eosinophils
in the blood. Its effect on the eosinophils forms the basis of a simple though
not very reliable test of adrenocortical insufficiency. In addition, cortisol
reduces the fixed mass of lymphatic tissue throughout the body in contrast
to thyroid hormone, which promotes lymphoid hyperplasia.

Miscellaneous effects

Cortisol is needed for the proper functioning of the nervous system and
increases its excitability. Both excess and deficiency of cortisol may cause
mental depression and psychosis. The catabolic action of cortisol on
muscle has been mentioned, but it improves muscular efficiency when given
to patients with Addison’s disease. Cortisol is concerned in the main-
tenance of the blood pressure , possibly by facilitating the action of nora-
drenaline on the arterioles, and in the secretion of hydrochloric acid by the
stomach. Three further actions , which may be pharmacological rather than
physiological and which are made use of therapeutically, are the inhibition
of inflammatory reactions, the suppression of allergic responses and the
reduction of fibroblastic activity.

Sex hormones

The adrenal androgens are aU weak, compared with testosterone. In the
male they may play a minor part in puberal development and sexual
function. In the female they probably cause the growth of axillary and
pubic hair and skeletal growth at puberty. In both sexes they may
encourage the anabolism of protein and exert other metabolic effects.

The adrenal oestrogens are also weak, compared with oestradiok In the
female they may play a minor role in puberal development and sexual
function, but their function in the male is not known.

The adrenal progestagens provide essential steps in the synthetic pathway
of cortisol and other adrenal steroids, but are probably unimportant
otherwise.

70

THE ADRENAL CORTEX

INVESTIGATION OF ADRENOCORTICAL DISORDERS
The special investigations that are of help in the diagnosis of adreno-
cortical disorders are as follows:

X-rays of the adrenals

X-rays, though often disappointing, are sometimes helpful in the
detection of adrenal tumours or gross hyperplasia. Direct films may reveal
large tumours. Intravenous pyelography is more helpful and may show

Fig. 3.2. Tomogram of normal adrenal glands, after presacral insufflation with
carbon dioxide, combined with intravenous pyelograrn.

displacement or distortion of a ludney. Pyelography, combined with
tomography and presacral insufflation with carbon dioxide, is the best
method. (Other gases, such as air or oxygen, give better pictures, but may
cause death from embolism.) About 1,500 ml., when injected through a
polythene tube between the rectum and the sacrum, pass up between the
layers of the renal fascia and outline the kidneys and adrenals (fig. 3.2).
Gross hyperplasia and many tumours can be recognized by this method
(fig. 3.3), but false positive and false negative results are not uncommon.

INVESTIGATION OF ADRENOCORTICAL DISORDERS

71

Fie. 3.3. Tumour of right adrenal gland.

Antero-posterior X-ray afar pr.aacra. — ™«

(Professor C. A. Wells’ case )

Aortography is sometimes helpful, but its possibilities have not been
explored fully.

Indirect tests of adrenocortical function

Serum electroly tes f , •

Estimations of serum sodium and po.ass.um
adrenocortical disease may interfere unth in ^,do-

SS.T5 changes are often

found in hypoadrenalism.

THF ADRENAL CORTEX

72

Water bad test

A simple test, derived from that of Robinson, Kepler and Power,
depends on the diuretic effect of cortisol. Water (20 ml. per kg. of body
weight) is taken by mouth within 15 to 20 minutes after an 8-hour fast, and
the urine is collected for 4 hours. In normal people 90 per cent or more of
the water is excreted in this time, whereas in those with adrenocortical
insufficiency (primary or secondary) less than 55 per cent is excreted.
Diuresis is also delayed or impaired in renal and hepatic disease, thyroid
insufficiency and dehydration. The administration of cortisone (50 to
100 mg. by mouth) 2 hours before the test improves the diuresis in those
with adrenocortical insufficiency, but not in those with other lesions.

Eosinophil count (Thorn test)

In adrenocortical failure the eosinophil count in the blood rises and may
provide partial information about adrenal function when it is required
quickly. In less urgent cases the Thorn test, or observation of the fall in
the eosinophil count 4 hours after stimulation with intramuscular cortico-
trophin (25 mg.), provides a better estimate. In normal people the fall
exceeds 50 per cent of the initial figure. This test is less helpful than direct
measurement of the adrenal steroids, and is rarely used now.

Direct measurement of adrenocortical steroids and their meta-
bolites

There is no available method for direct measurement of the secretion of
steroids by the adrenal glands. The daily output of the steroids and their
metabolites in the urine and the concentrations of some of them in the
blood can, however, be estimated. The following tests are of most use at
the present time, but others may well prove more valuable in the future.
None of them is sufficiently reliable to replace evidence obtained by
clinical and other methods.

Urinary steroids (Table 3.1)

For practical clinical purposes the 17-oxosteroids can be assumed to
reflect the output of androgenic steroids. It should be remembered that in
the female they are derived almost entirely from the adrenal cortices, while
in the male the testes contribute about one-third. High levels arc found in
association with virilizing syndromes and in some patients w ith Cushing’s
syndrome. Very high levels usually indicate the presence of a tumour.
The 17-oxogenic steroids and the total 17-hydroxysteroids similarly reflect
mainly the output of glucocorticoids and are derived almost entirely from
the adrenal cortices in both sexes. These fractions are usually high in
Cushing’s syndrome and very high in those with functioning tumours.

MEASUREMENT OF ADRENOCORTICAL STEROIDS

73

Table 3.1. Excretion of groups of steroids in normal children, men and
women at different ages . [Ranges { and means) in mg. per 24 hours)

Age

17-oxosteroid* *

Total 17-h>droxy-

steroidst

17-oxogentc
steroids J

Children

-2

0- 1 (05)

0- 3 (1)

(M. and F.)

3- 6 1
7-10 |
11-15 i

0- 2 (10) !

0-5- 3 (I S) |

2-8 (3-5) ,

0-5- 4 (2)

1- 9 (3)

2- 14 (6)

2-4 (3)

Men

16-20 1
21-40 |

4-18 (9)

7-20 (13)

4- 19 (8)

5- 21 (11)

)

41-60

61-

4-18 (9)

2-11 (S)

4-20 (9)

3-16 (7)

j 10-19(13)

Women

16-20 1
21-40 ,

4-10 (6-5)
4-15 (7)

4-15 (7)

4-17 (8)

i)

41-60 !
61-

2- 9 (5)

1-7 (3)

3-16 (7)

2-12 (5)

lj 5-13 (9)

• Hamburger (1948) (Ranges include about 95% of normal subjects),
t Borth el at. (1957) (Ranges include about 95% of normal subjects),
j Norymberaki et at. (1953) (Total ranges).

Measurements are made on fresh 24-hour specimens of urine, and can be
done in three ways.

(1) Basal (t.e, without stimulation or inhibition of the glands). Two or
more specimens, collected consecutively or on different occasions, are more
informative than one.

(2) Stimulation of the adrenal cortex with exogenous ACTH (Table 3.2).
The batch of ACTH must be of proved potency'. Urine is collected for six
consecutive days, the first two of which represent basal secretion. From
the third to the sixth day 20 clinical units of ACTH gel are injected
intramuscularly twice daily, and the last four specimens show the effect of
stimulation. The test may also be done more quickly by the intravenous
infusion of ACTH. ACTH (25 units) is added to 500 ml. of normal saline
solution and infused over 8 hours. Twenty-four-hour urine collections are
made the day before and during the day of the test (the infusion taking
place during the first 8 hours of the collection). Stimulation tests are of
value in distinguishing between primary hypoadrenalism (disease of the
adrenals themselves), in which the response is slight or absent, and
secondary hypoadrenalism (primary disease of the anterior pituitary), in
which the response may be normal or slightly reduced. It also helps in the
recognition of Cushing’s syndrome, in which the response is often
exaggerated. Adrenal tumours do not usually respond to ACTH.

(3) Suppression of the pituitary by exogenous steroids (Table 3,2).
Cortisone and its analogues inhibit the secretion of ACTH, and hence
prevent the endogenous production of cortisol and sex hormones by the
adrenal cortex. They do not (over a short period) inhibit the testicular

74 THE ADRENAL CORTEX

secretion. Dexamethasone (2 mg. per day) and fludrocortisone (2 to 4 mg.

per day), in divided doses 6-hourly, produce almost complete inhibition

Table 3.2. Urinary excretion of adrenal corticosteroids

Representative levels in normal and pathological states (alt values in nig / 24 hours)

| 17-oxosteroids

| 1 7-hydro tysteroids

Basal |

Cortico-

trophin

stimulation*

Basal

Cortiai-

trophtn

kiimulation*

Normal

Men

Women

Children (0-2 years)

7 0-18 0

3 0-14 0

0- 1 0

} 8 0-30 0 ,

7 0-18 0

3 0-14 0
0-3 0

} 18 0-36 0

Cushing’s syndrome
Hyperplasia or hyper-
function

Carcinoma

15 0- 30 0

15 0-150 0

20 0-55 0 j
No rise |

10 0- 30 0

35 0-150 0

! 30 0-85 0

No rise

Addison's disease

0-40

No rise

0-4 0

No nse

Hypopituitarism

0-60

2-10 0

0-40

4 0-10 0

Adrenogenital syndrome

Hyperplasia

Children (0-2 years)
Carcinoma

20 0- 60 0
20- 90
20 0-100 0

Dexa-
methasone
suppression t

5 0-25 0
0-30

5 0-60 0

5 0-15 0 1
05- 20 1

No fall

• Urine is collected for sue successive days The first two days give the basal secretion.
From the third to the sixth day 20 clinical units of corticotrophin-ge! arc given intra-
muscularly twice daily. The last two davs give the '‘stimulated” secretion.

t Unne is collected for four successive 24-hour periods. The first two daj sgn e the basal
secretion During the "hole of the third and fourth days 0 5 mg. of dexamethasone is given
at 6-hourly intervals. The third and fourth days give the “suppressed” secretion.

without themselves contributing appreciably to the steroid content of the
urine. Urine is collected for four consecutive days, the first two of which
provide the basal readings. The steroid (in the above dosage) is given on
the third and fourth days and the urine, collected at this time, provides the
“suppressed” readings. Normal people and those with hyperplastic glands
usually show a brisk fall in secretion, while patients with adrenal tumours,
which secrete autonomously, rarely do so. A gap of two days should be
allowed between the end of a stimulation test and the start of a suppression
test. In testing patients with suspected Cushing’s syndrome larger doses
of dexamethasone (2 mg. 6-hourly) should be used and continued for 5 to 7
days. When tested in this way patients with bilateral adrenal hyperplasia
show a decrease in urinary 17-hydroxysteroid levels, whereas those with
adrenal cortical tumours do not.

MEASUREMENT OF ADRENOCORTICAL STEROIDS 75

Tests which are not generally available, but which may be very helpful
on occasion, are fractionation of the urinary steroids (for the elucidation of
some obscure cases), measurement of urinary aldosterone (for the investiga-
tion of primary and secondary aldosteronism) (Table 3.3) and estimation of
urinary oestrogen* (in feminizing syndromes) (Table 5.2). All require fresh
24-hour specimens of urine. The adrenal secretion rate or daily output of
cortisol may be a more precise estimation of adrenocortical activity than the
measurement of adrenal steroid metabolites m the urine. If w C-labeIled
cortisol is administered it is possible to calculate the adrenal secretion rate
by measuring the M C content of a representative metabolite (e.g. tetra-
hydrocortisol). Normal values are about 4 to 24 (mean 1 1) mg. per day.
It is believed that the cortisol secretion rate provides a more reliable
method of biochemical confirmation of the diagnosis of Cushing’s syndrome
than the urinary steroid excretion, which frequently shows a poor correla-
tion with the clinical findings.

Table 3.3. Excretion of individual urinary steroids in normal adult
men and women [ranges ( and means)]

Steroid

Males

Females

Units

Cortisol*

10-155 (75)

jig /24 hours

Androsterone *

1 0-4 8 (2-2) l 0-2-4(0 9)

mg./24 hours

Actiocholanolone •

0-* 8 (2 2) |

0-3 2 (1 2)

mg. (24 hours

Dehydroepiandrosterone •
Actiocholanolone n . .

0-6-2 (1-4) ]

1:

| 0-1-7(0 5) ,

1

1 1

mg 12 4 hours

Aldosterone f

S-1S (10)

pg./24 hours

Vregnannrio] l

| 0-1-4(06) )

0-1 6 (0-7) ,

mg./24 hours

• Chenneour (1962) (Ranges include about 95% of normal subjects),
t Neill (1962) (Approximate total range and mean).

X Cox (1962) (Ranges include about 95% of normal subjects).

Steroids in the blood

Blood cortisol and. its immediate metabolites (17- bydcoxycor ticosteco ids)
are estimated routinely in some laboratories. Twenty millilitres of blood
are required, and must reach the laboratory within an hour. The free and
the bound forms are measured together, but the conjugated forms are not
usually included. The method is of limited value, chiefly because of the
rhythmic variation in the production of cortisol. The normal concentration
in our laboratory is about 5 to 15 pg. per 100 ml. Low levels are found in
hypoadrenalism and high levels in Cushing’s syndrome and during or
shortly after acute stress.

It is possible that the measurement of androgens in the blood may in the
future be of use in the investigation of virilizing states.

76

THE ADRENAL CORTEX

DISORDERS OF THE ADRENAL CORTEX
Lesions of the adrenal cortex frequently cause disturbance of endocrine
function. Various clinical syndromes may result, depending on whether the
secretion Is increased or diminished and, when it is increased, which
hormones predominate. The lesions and syndromes may be classified as
follows:

(A) WITH DISTURBANCE OF ENDOCRINE FUNCTION

1. Increased secretion
Lesions

(i) Hyperplasia.

(ii) Adenoma.

(iii) Carcinoma.

Syndromes

Excess of mineralocorticoids causes aldosteronism.

Excess of glucocorticoids causes Cushing’s syndrome.

Excess of androgens causes virilism.

Excess of oestrogens causes feminization.

Mixed types of syndrome are also found, since some of the steroids have
overlapping actions and diseased glands may secrete more than one type
of steroid.

2. Decreased, secretion
Lesions

(i) Atrophy.

(ii) Destruction by haemorrhage, infarct, tuberculosis, metastatic
carcinoma, etc.

(iii) Surgical removal.

Syndromes

Chronic deficiency causes Addison’s disease.

Acute deficiency causes acute adrenal failure (adrenal crisis).

(B) WITHOUT DISTURBANCE OF FUNCTION
Lesions

(i) Adenoma.

(ii) Carcinoma.

(iii) Rare tumours, cysts, etc.

General pathology

Hyperplasia is usually bilateral. The number of cells is increased, the
cortex as a whole is enlarged and the production of hormones is increased.

DISORDERS Or THE ADRENAL CORTEX 77

Hyperplasia may be caused by the prolonged therapeutic administration of
corticotrophin and may also be found in Cushing’s syndrome, adrenal
virilism and very rarely in aldosteronism. It is recognized by the size of the
glands, which may be greatly enlarged and, in infants, may be as large as
the kidneys. The pathogenesis and histological features of these types of
hyperplasia will be discussed later.

Atrophy Is also usually bilateral. The number of cells is decreased, the
gland is diminished in size and there is reduced function. Atrophy is found
in the following conditions:

(1) Hypopituitarism and hypophysectomy, which cause a failure of
corticotrophin production.

(2) Prolonged therapeutic administration of cortisone or its analogues,
which inhibit the production of corticotrophin.

(3) Adrenocortical tumours (adenoma and carcinoma) which form
cortisol or related substances. These inhibit the pituitary, with the result
that the adrenal cortex (on the same and on the opposite side), which is
not involved by tumour, undergoes atrophy. Non-functioning tumours
and those which secrete mainly androgens or aldosterone do not cause
atrophy.

The atrophied glands may be half the size of the normal adrenals or even
smaller. There are no special histological features.

Tumours. Cortical nodules, 2 to 3 mm. in diameter, are very common in
normal glands. Benign adenomas are not uncommon and are usually
found at autopsy without having given rise to symptoms during life.
They are circumscribed, roughly circular, orange in colour, usually not
more than 2 to 3 cm. in diameter and rarely multiple. Their structure is
similar to that of the normal adrenal cortex. Carcinoma is rare, but may
occur at any age, and is commonest in women between the ages of 25 and
45. The size of these tumours varies enormously, the largest weighing
between 1 and 2 kg. Their colour is similar to that of the normal cortex.
Some are well differentiated and circumscribed and are barely distinguish-
able from adenomas, while others are anaplastic, pleomorphic and invasive,
and metastasize early to the lungs, the liver and elsewhere. Haemorrhage
and necrosis are common in the larger tumours.

Both adenomas and carcinomas (and their metastases) may or may not
be functionally active, and their activity bears no relation to their size.
They may cause any of the syndromes of hyperadrenocorticism, depending
on the hormones which they secrete. The secretions of adenomas are often
partly under corticotrophin control, but those of carcinomas are usually
autonomous. In Cushing’s syndrome the non-tumorous cortical tissue
undergoes atrophy. In cases of virilism the tumour cells usually give a
positive Vines reaction.

78

TIIE ADRENAL CORTEX

TUMOURS WITHOUT ENDOCRINE ACTIVITY

Adenomas are not recognized in life unless they are found incidentally
during operations.

Carcinomas may cause pyrexia, local pain or swelling, fatigue and loss of
weight, and their secondary deposits may give rise to symptoms. They
may be demonstrable radiologically, but cause no disturbance of steroid
metabolism. A few large tumours have been reported associated with
hypoglycaemia. They do not, apparently, secrete insulin, but may
metabolize large amounts of glucose. Malignant tumours should be
remoted surgically, if possible, but the prognosis is bad.

PRIMARY ALDOSTERONISM (CONN’S SYNDROME)

In 1955, shortly after the isolation of aldosterone, Conn described a
patient suffering from intermittent attacks of paralysis, and from polyuria,
hypertension and hypokalaemia, who excreted large amounts of a salt-
retaining substance in the urine. She was found to have an adenoma of the
adrenal cortex and was cured by its removal. Since then more than
100 cases have been described and the salt-retaining substance has been
identified as aldosterone. The condition is called primary aldosteronism or
Conn’s syndrome and it is a well-established, though rare, clinical entity.
It must be distinguished from secondary aldosteronism, in which the
secretion of aldosterone is increased as a compensatory mechanism in other
diseases.

Causative lesions

In more than two-thirds of the cases a single, small, benign and well-
encapsulated cortical adenoma, weighing between I and 3 g., is the cause.
Occasionally there are multiple adenomas. Bilateral adrenal hyperplasia
has been found in a few' cases, and in a very few the glands have been
morphologically normal. Cortical carcinoma has been described.

The histology of the tumours is variable. In some the cellular structure
resembles that of the zona glomerulosa and in others the zona fasciculata.
Occasionally it resembles both. Hyperplasia is also variable. In a case of
our own the combined weight of the glands was 25 g.

The kidneys show vacuolation and distortion of the distal (and occasion-
ally of the proximal) tubular cells. This appearance is attributed to the loss
of potassium, for similar changes have been described in hypokalaemia
from other causes. An associated chronic pyelonephritis is common, and
hypertensh e changes in the arterioles are usual.

Clinical features

The condition appears to be more common in women than in men, and
is very rare in childhood. The clinical features are caused by the metabolic

PRIMARY ALDOSTERONISM 79

effects of aldosterone, and vary widely in their severity. The common
findings are as follows:

Deficiency of potassium causes episodes of generalized or localized
muscular weakness which may proceed to a flaccid paralysis of the lower
limbs and occasionally of the whole body. The muscular weakness is
similar to that observed in familial periodic paralysis. Indeed, intermittent
excessive secretion of aldosterone is a possible cause of the paralysis in this
condition.

The renal lesions may cause polydipsia and polyuria, with nocturia.
Urine of low specific gravity is passed, and the kidney is unable to elaborate
a concentrated urine when deprived of water. The polyuria is resistant to
vasopressin and to deprivation of water. Some cases of apparent nephro-
genic diabetes insipidus may be examples of primary aldosteronism.

Hypakalaemic alkalosis , which is similar to, but more severe than that in
Cushing’s syndrome, tends to reduce the amount of ionized calcium in the
blood but not the total serum calcium. This may cause tetany and
paraesthesiae. The tetany does not usually respond to calcium intra-
venously.

Retention of sodium is the probable cause of the cardiovascular lesions,
which are common. Hypertension is constant, and varies from mild to
malignant. Headaches are frequent. Oedema has been reported but is
uncommon, possibly because much of the excess sodium is retained within
the cells and does not cause retention of extracellular water. Oedema is
always present in secondary aldosteronism.

It is important to remember that primary aldosteronism may be the
cause of such conditions as hypertension, intermittent muscular paralysis,
the so-called "potassium losing nephritis", tetany, thirst, polyuria and the
syndrome of nephrogenic diabetes insipidus.

Investigation

The characteristic findings are as follows:

Blood chemistry. The serum potassium concentration is usually very low
(c.g. 2-0 mEq./litre) and the serum sodium is often raised slightly (e.g.
145 mEq./litre). The C0 2 -combining power and the blood pH are raised.
The blood urea and NPN are usually high.

The urine is persistently alkaline (or rarely neutral) and of low specific
gravity. Mild proteinuria is common.

Urinary steroids. The excretion of aldosterone is usually high, but
normal levels may be found on some days. For this reason the estimation
should be repeated several times. It is essentia! for the patient to have a
normal sodium intake (5 G. or more daily for 5 to 7 clays). Normal patients
on a restricted sodium diet show increased levels of aldosterone, and this

THE ADRENAL CORTEX

factor must be eliminated before determining the urinary level. The other
urinary steroids are excreted in normal amounts except in very tare cases
of carcinoma.

The ECG shows changes typical of hypokalaemia. The ratio of
sodium/potassium in the saliva may be 1 : 3 instead of the normal 1:1.

X-rays of the adrenals often fail to reveal tumours because of their small
size. Surgical exploration should be undertaken if there is good evidence
of primary aldosteronism.

Treatment

Hypertension is the most serious feature of the disease, and death may
result from cardiac failure or vascular complications. Long-continued
over-secretion of aldosterone may lead to permanent renal damage, so that
early diagnosis and treatment are important. Impaired renal function is an
indication for early treatment, since tubular function may recover remark-
ably once the metabolic disturbance has been corrected.

Removal of the source of the excessive aldosterone causes dramatic
disappearance of the symptoms in the majority of cases. This entails the
removal of an adrenal tumour or bilateral subtotal adrenalectomy (as in
Cushing's syndrome) for those with apparently normal or hyperplastic
glands.

Two complications in the immediate postoperative period can be
expected. First, renal function may become worse temporarily because the
fall in blood pressure may reduce the glomerular filtration rate. Renal
function improves as the blood pressure is restored and as the hypokalaemic
nephropathy recovers. Secondly’, temporary Aypoaldosteronism may
follow the removal of an aldosterone-secreting tumour. This may respond
to dietary supplements of sodium, or it can be corrected by aldosterone
0-5 mg. intramuscularly, or fludrocortisone 0 1 or 0-5 mg. by mouth, twice
or three times daily. Cortisone is not essential postoperatively, since the
secretion of cortisol is not usually affected, but, as partial atrophy of the
remaining adrenal tissue has been reported in a few cases with adrenal
tumours, its use to cover the operative and immediate postoperative periods
may be advisable. It is required for bilateral adrenalectomy. Potassium
supplements do not correct the hypokalaemia of primary aldosteronism,
but they are necessary’ and helpful during the pre- and postoperative
periods, and should be given as potassium chloride in a dose of 2 G. every
4 or 6 hours. Spironolactone (Aldactone-A, 25 to 50 mg. 6-hourly) may
be used to correct the hypokalaemia in the preoperative period.

After the successful removal of an aldosterone-secreting tumour there is
a prompt diuresis of sodium, retention of potassium and correction of the
metabolic alkalosis. The polyuria and polydipsia disappear rapidly.

The blood pressure falls in most patients and returns to normal within

CUSHING’S SYNtJROMC 81

three months in about two-thirds. In a few the hypertension persists,
probably as a result of secondary renal factors. No long-term results of
treatment have yet been reported.

Secondary aldosteronism

Excessive amounts of aldosterone may be secreted as a compensatory
mechanism in various conditions. Such secondary aldosteronism is found
in association with oedematous states (cardiac failure, the nephrotic
syndrome and cirrhosis), when excessive fluid is lost, as in diabetes insipidus
and “salt-losing nephritis”, and during long-continued diuretic therapy
with dietary restriction of sodium. An increase of aldosterone is found
physiologically in the urine in the later stages of pregnancy, but the
mechanism is not known.

CUSHING’S SYNDROME

This is a rather uncommon disorder described by Harvey Cushing in
1912 and 1932. A small basophil adenoma was found in all but one of the
patients in whom the pituitary had been examined adequately, and this
finding led Cushing to describe the condition as "pituitary basophilism”.
He regarded it as a pluriglandular syndrome in which the pituitary' adenoma
played the main part, though he realized that a similar clinical state might
arise from disease of the adrenal cortex.

“Cushing’s syndrome”, as the clinical condition is now called, has been
universally recognized, and striking advances have been made in our
knowledge of its aetiology and of the pathogenesis of its clinical and
metabolic features. Whereas formerly the disease progressed rapidly to a
fatal termination, many patients can now be treated effectively and
supported in good health for years. In the past it was customary to refer to
“Cushing’s disease” when the pituitary gland contained a basophil
adenoma. Such a distinction is not always possible on clinical grounds and,
since a pituitary tumour may develop after the successful treatment of
Cushing’s syndrome, the distinction seems artificial. It is simpler to retain
the term “Cushing’s syndrome” and to apply it to all patients who exhibit
the clinical features described by Cushing.

Causative lesions

Since the isolation of ACTH and cortisol, much has been learned of
their physiology and of the effects of their administration to man. It was
soon discovered that if they were given in excess for long periods all the
features of Cushing’s syndrome might develop. It is now clear that the
naturally occurring syndrome is the result of an excessive endogenous
production of cortisol and possibly, to a smaller extent, of other adrenal
steroids. Theoretically this might arise from lesions in the hypothalamus.

82

THE ADRENAL CORTEX

which stimulate the pituitary to secrete an excess of ACTH, from disorders
of the pituitary itself, from tumours or functional disturbances of the
adrenal cortex or from tumours of ectopic adrenal tissue, particularly in
the ov ary.

Hypothalamus

Tumours and other lesions in the region of the hypothalamus have been
described in association with the condition, but there is no evidence that
lesions in this region are usual.

Anterior pituitary

The pituitary lesions in Cushing’s syndrome have been studied inten-
sively. Adenomas are present in half the cases and two-thirds of them are
basophil m type, but similar lesions may be found in patients without
clinical evidence of endocrine disorder. An almost constant finding in
Cushing's syndrome i9 hyalmization of the basophil cells (Crooke change),
but recent work suggests that this is the result, and not the cause, of
adrenocortical hyperfunction. A carcinoma of the pituitary has been
observed on rare occasions and, although direct evidence is lacking, it is
hard to escape the conclusion that in these cases it is the causative lesion.
Recent experience with the development of pituitary tumours after
adrenalectomy has underlined the importance of the pituitary in Cushing’s
syndrome but has not yet elucidated the nature of the pituitary dysfunction
in patients without tumours.

The role of the pituitary would be clearer if there were a simple and
reliable method for estimation of ACTH and if it were certain that it was
a single substance. There is conflicting evidence about the level of ACTH
in the blood of patients with bilateral adrenal hyperplasia, but increased
amounts of ACTH have been detected in some cases with pituitary
tumours, particularly those developing after adrenalectomy. Tests of
adrenal function in patients with Cushing’s syndrome due to bilateral
adrenal hyperplasia have shown that much larger doses of dexamethasone
are required to suppress cortisol production than in normal subjects. This
suggests that pituitary function is altered in such a way that ACTH
secretion is not suppressed by normal levels of cortisol. Jailer and his
colleagues have postulated the presence of a corticotrophin-potentiating
substance of pituitary origin in Cushing’s syndrome in order to resolve
some of the conflicting findings. It would account for the remissions that
may follow hypophysectomy or pituitary irradiation, which arc difficult to
explain on a purely adrenal basis. It would also explain why patients with
Cushing’s syndrome show an exaggerated response to injected cortico-
trophin, and why the response may return to normal after irradiation of the
pituitary.

cushing’s syndrome

83

Adrenal cortex

The commonest finding is bilateral hyperplasia with excessive formation
of cortical nodules. The average combined weight in the Mayo Clinic
series was 18*6 g. and that in our own 16-2 g. (normal 9 to 11 g.). Hyper-
plasia is not, however, invariable, nor is it always bilateral. The largest
single gland in our series weighed 15-6 g. and the smallest T9 g. Histo-
logically, according to Landing, there are differences between the sexes.
In the male all the cortical zones are increased in thickness and the cells of
the glomerulosa are large. In the female only the fasciculata is thick and
the cells of the fasciculata and reticularis are large. In both sexes the
amount of lipid in the fasciculata is reduced. In our series Gibson found
the reticularis was the most easily recognized zone. In some cases (with or
without virilism) the fuehsinophil staining reaction of Vines is positive.

Tumours have been found in about 20 to 40 per cent of some series. In
our own they were present in only 15 per cent. They are relatively
commoner in women than in men and almost invariable in children. The
majority are benign adenomas and a minority malignant carcinomas.

Other lesions

Patients have been described with some features of Cushing’s syndrome
associated with tumours of adrenal-like cells in the ovary. The syndrome
has occasionally been encountered in association with carcinoma of the
bronchus, thymus or pancreas, and with certain forms of liver disease.
The mechanism in these cases is obscure, but corticotrophic activity has
been found in extracts from some bronchial carcinomas.

Causative lesions in the Belfast series

Our series included 27 patients. The findings in the adrenals were as
follows:

Hyperplasia or hjperfunction 21

Tumour 4

Adenoma 2
Carcinoma 2

Unknow n 2

Examination of the pituitaries revealed the following:

Uasophil adenoma 4

Small (sella not enlarged) 1
Large (sella expanded) 1
Tumours developing after adrenalectomy:

Carcinoma 1
Adenoma 1

Choristoma (large posterior lobe tumour, probably incidental) 1
No tumour (autopsy) 3

Unknown (no histology, but sella not expanded) 19

84 THE ADRENAL CORTEX

Clinical and metabolic features

The syndrome is reported to be three to four times as common in women
as in men, although in our own series the proportion was little more than
two to one (F, 19; M, 8). The average age at diagnosis is about 30 years,

Fig. 3.5. Cushing's syndrome m 0 girl of 19.

Note the obesitj of the trunk, the buffalo hump and the striae airophicae.
Fig. 3.6 Cushing's syndrome in a man of 3D, causing extreme muscular
Masting in the limbs.

but patients of any age may be affected. The average in our patients was
37 and the range 10 months to 68 years. The prognosis is bad, and without
treatment half the patients die within five years from the effects of hyper-
tension, diabetes and infections. Occasionally there are spontaneous re-
missions, which may be cyclical, temporary or permanent.

cushing’s syndrome

85

Because of the widespread effects of cortisol, patients with Cushing's
syndrome may present a variety of symptoms. Usually they complain of
tiredness, alteration in their appearance, obesity, menstrual disturbances
and symptoms referable to the accompanying hypertension. Others may
complain specifically of one symptom, such as the pain arising from a
spontaneous fracture, and it is only on further questioning that other
symptoms are revealed. It is convenient to describe the manifestations of
the condition, as far as possible, in relation to the metabolic and other
effects of cortisol.

Fat metabolism

Deposition of fat causes a characteristic obesity that involves the face,
neck, and trunk but spares the limbs (fig. 3.5). The face becomes full and
rounded (moonface), and the heavy cheeks cause narrowing and drooping
of the mouth (fishmouth). Pads of fat develop in the supraclavicular and
ccrvicodorsal regions (buffalo hump). The latter finding tends to be
overstressed as a special feature of Cushing’s syndrome, for it is commonly
seen in all forms of obesity. Body weight usually increases, sometimes with
considerable rapidity, but the obesity is rarely gross (fig. 3.4). Sometimes
there is little or no gain in weight, so that the obesity of the face and trunk
appears to be due to a redistribution of fat rather than to an overall in-
crease.

Protein metabolism

Catabolism of protein affects mainly the muscles, the skin and the bone
matrix. In the more florid cases muscle wasting (fig. 3.6) is obvious in the
limbs, and lethargy and weakness are frequent complaints. Atrophy of the
skin causes livid striae atrophicae (present in two-thirds of our patients) on
the trunk and proximal parts of the limbs and contributes to the florid
complexion, which is a striking feature (Frontispiece). Loss of protein
from the bone matrix gives rise to osteoporosis , which is present in half the
cases and leads to backache, spinal deformities and pathological fractures
(fig. 3.7), especially of the ribs, pubic rami and vertebrae. They are
remarkable for being painless. Fractures were found in 50 per cent of our
patients and fractures of the spine in 30 per cent. Cushing’s syndrome in
childhood causes stunting of growth and delay' in the appearance and union
of the epiphyses. The liberation of the calcium from the softened bones
may cause hypercalciuria and sometimes urinary calculi. Purpura and
bruising are common features and result from atrophy of the capillary
walls. Balance data may reveal a daily loss of as much as 7 g. of nitrogen
per day, and creatinuria is common.

86

THE ADRENAL CORTEX

Fig, 3.7. Cushing’s syndrome.
Osteoporosis and pjthological fracture of spine.

Carbohydrate metabolism

The antagonism between cortisol and insulin may combine with the
increased catabolism of protein to impair sugar tolerance. Although an
elevated fasting blood-sugar level or frank diabetes mellitus is uncommon,
a diabetic type of glucose tolerance curve is a fairly common finding. In
our patients disturbances of sugar tolerance were infrequent and mild.
About one-third had glycosuria and one-quarter diabetes. The latter has
the features of steroid diabetes, is usually mild and can often be controlled
without insulin.

Cushing’s synbrome

87

Electrolyte metabolism

In most patients the blood electrolytes are normal, but disturbances may
be found. The most frequent abnormality is a reduction in the level of
potassium and chloride in the serum, an associated alkalosis (hypokalaemic
alkalosis) and a normal or slightly raised level of sodium. This abnormality
was present in 25 per cent of our patients. It is perhaps commonest in
those with bronchial or other types of carcinoma. Balance studies show
that loss of potassium is the earliest change. This leads to a depletion of
intracellular base, and the alkalosis that follows is the result of hydrogen
ions migrating into the cells to make good the potassium loss. The changes
can be caused by an excess of cortisol and are most marked m those whose
plasma cortisol levels are very high. It is not clear what part, if any, the
electrolyte disturbances play in the production of hypertension and oedema.

Inhibition of inflammatory reactions

Inflammatory lesions are relatively common. In our own patients one
had septic arthritis, another pulmonary tuberculosis and a third a super-
ficial abscess.

Hypertension and oedema

Hypertension is usual, though not invariable, and may even be malignant.
It was present in all our patients. It is liable to all the complications of
essential hypertension, which may be extensive even in young subjects.
Its cause is uncertain. Salt and fluid retention may play a part, but cortisol
may also enhance the action of noradrenaline on the arterioles. Oedema of
the ankles is occasionally seen and may be related to fluid retention.

Haematological changes

Polycythaemia develops in half the patients and, together with atrophy of
the skin, is responsible for the florid complexion. Of our cases 60 per cent
had a haemoglobin concentration greater than norma!. The total white cell
count is usually raised and there may be an eosinopenia and lymphopenia.
These findings, however, are very variable and of little diagnostic help.

Gastric secretion

Secretion is often greater than normal, but peptic ulceration appears to
be no commoner than it is in the general population. In mo of our
patients, however, dyspepsia from duodenal ulcer was the presenting
feature.

Mental changes

Frank psychosis is not uncommon and, paradoxically, the symptoms may
be similar to those that sometimes develop in adrenal insufficiency. The
patient may even reach a mental hospital before the correct diagnosis is

88

THE ADRENAL CORTEX

made. One of our patients developed an acute confusional state, with
depression and feelings of persecution, shortly after receiving adrenal
stimulation with ACTH. These symptoms cleared up satisfactorily after
surgery. Another behaved similarly for a few weeks while receiving large
doses of cortisone and ACTH after the removal of an adrenal adenoma.
Other patients may be depressed and exhibit suicidal tendencies.

Eye changes

Chcmosis was observed in two of our patients, but its cause is not
known. Exophthalmos may rarely occur without hyperthyroidism and
may be due to a pituitaty disturbance.

Disturbed sexual function

In women amcnorrhoea and sterility are usual. Rarely menstruation is
present but scanty, and very rarely it is apparently normal. Occasionally
there is menorrhagia. Frequently the ovaries are atrophic or show cystic
degeneration. In men impotence is common and the testes may be
atrophied. The hypogonadism in both sexes is probably the result of
suppression of pituitary gonadotrophin by cortisol.

Belfast series. The findings in our own series of adults were as follows:

Females (18)

Amtnotthoea — Primary t

Secondary 8

Oligomenorrhota 2

Menorrhagia 1

No disturbance 6

Menopause 4
Hjsterectomy 2
Mates (6)

Impotence 3

No apparent disturbance 3

Changes in the skin and hair

Striking alterations may be observed in the skin and hair. The livid
striae atrophicae, thinness and ready bruising have been mentioned, but
other changes include hirsutism, patchy cyanosis, increased greasiness of
the skin, acne, telangiectases and pigmentation.

Hirsutism in women is very common and sometimes severe, and it may
affect the body as well as the face. It was present in 90 per cent of our
series. Cortisone in high dosage may cause a little hair to grow on the face
but not on the trunk and limbs, so it is probable that adrenal androgens arc
responsible in many cases. The hair on the scalp may darken, and some-
times becomes lighter again after successful surgery. An infant in our series
had well-developed hair on the vulva. Acne may be caused by cortisol, but
it is generally more pronounced in patients with androgenic excess.

cushing’s syndrome

89

Pigmentation of the skin may occur and must be attributed to an excess
of circulating ACTH or of MSH, Preoperatively it is rare and suggests the
presence of a pituitary lesion. After adrenalectomy widespread pigmenta-
tion indicates the presence of a pituitary tumour.

Polyuria and thirst

Thirst and polyuria are not uncommon symptoms, and may be caused by
diabetes mellitus or hypercalciuria.

Investigation

The diagnosis of Cushing’s syndrome is made primarily on clinical
grounds, and great reliance should be placed on a careful appraisal of the
physical signs. In the last resort the diagnosis may depend on the successful
response to adrenalectomy. Special investigations are helpful for the
elucidation of doubtful cases and for the recognition of the causative lesion,
but it is unusual for them to be decisive where the clinical features are in
doubt.

Radiography

Radiographs of the spine, ribs and pelvis may reveal osteoporosis and
pathological fractures, and those of the renal tract occasionally show calculi.

Fig. 3.8. Cushing's syndrome.

Osteoporosis causing apparent enlargement of pituitary fossa.

90

THE ADRENAL CORTEX

The vertebral bodies may be biconcave (codfish vertebrae) or show lines of
cortical or subcortical sclerosis along the upper and lower borders. This
sign is rare in other forms of osteoporosis. ‘'Callus” around healing
fractures is often dense and irregular and probably represents calcified
proliferated cartilage. Views of the pituitary fossa show enlargement of the
sella in about 10 per cent of patients. Osteoporosis sometimes causes
apparent enlargement of the sella (fig. 3.8), but the appearance returns to
normal after adrenalectomy. The condition of the adrenal glands them-
selves can rarely be determined accurately by radiography, but presacral
insufflation, which may reveal a tumour, may be undertaken.

Adrenal steroids

The increased secretion of cortisol causes, characteristically, a raised
level of cortisol in the blood and an excess of 17-o\ogenic steroids and of
total 17-hydroxysteroids in the urine. In patients with hyperfunctioning or
hyperplastic glands the increase is usually moderate, the response to ACTH
is exaggerated and pituitary suppression ineffective unless very large doses
of dexamethasone are used. In those with adrenal carcinomas the increases
are great but there is no response to ACTH nor fall after suppression, even
with large doses. The excretion of 17-oxosteroids is raised in about half the
patients only, but it is nearly always very high in those with carcinoma. In
a few patients who unquestionably have Cushing’s syndrome (and who
respond favourably to adrenalectomy) the results of group steroid estima-
tions are equivocal. It is in these that the adrenal secretion rate and
fractionation of the urinary steroids may be most helpful. In particular,
the excretion of cortisol itself is nearly always increased, even when that of
its main metabolites is normal; and the ratio of aetiocholanolone (derived
from precursors of cortisol and from androgens) to androsterone (derived
from androgens only) is usually more than 3:1, compared with the
normal 1:1. The urinary excretion of aldosterone is normal, even in those
with hypokalaemic alkalosis.

Miscellaneous laboratory findings

Hypokalaemia with metabolic alkalosis has been mentioned. When it is
present the possibility of a bronchial neoplasm should be considered. The
blood-sugar curve may be of the diabetic type. The serum calcium and
phosphorus are usually normal, but the alkaline phosphatase may be
increased. Polycythaemia, leucocytosis, eosinopenia and lymphopenia
have been mentioned.

Surgical exploration

If an adrenal tumour cannot be excluded after full investigation the
adrenals must be explored surgically.

cushing’s syndrome

91

Differentiation of causative lesions

During the clinical examination associated lesions in the central nervous
system, bronchus, pancreas, thymus, liver or ovaries should be considered
and appropriate investigations undertaken. The distinction between
adrenal hyperplasia, adenoma or carcinoma must be attempted. A short
history (months or weeks) or a palpable adrenal tumour usually indicates an
adrenal carcinoma. An enlarged pituitary fossa indicates a pituitary
adenoma with associated adrenal hyperplasia. The clinical finding of
pigmentation or exophthalmos suggests a primary pituitary cause for the
disorder, and care should be taken to exclude enlargement of the sella
turcica. Radiographs may reveal, but cannot exclude, an adrenal tumour.
The results of steroid determinations may be helpful.

Differential diagnosis

The commonest conditions to be excluded are simple obesity, essential
hypertension, diabetes mellitus and hirsutism, all of which may be found
in a single patient. The urinary excretion of group steroids (particularly
the 17-oxosteroids) may be slightly increased in such cases, and fractiona-
tion may reveal an increase of individual androgens and even of metabolites
of cortisol. The excretion of cortisol itself, however, is normal, and the
aetiocholanolone/androsterone ratio is 1:1.

Red lineae atrophicae occur in several other conditions, but they are
rarely as extensive, wide, irregular in shape and livid in colour as in
Cushing's syndrome. They occur in association with obesity, especially at
puberty, with infections (particularly tuberculosis) and with pregnancy.

The adrenogenital syndrome, particularly the postpuberal variety, may
cause confusion, since some features of Cushing's syndrome are often
present. A nitrogen balance, which is positive in the adrenogenital
syndrome and negative in Cushing’s syndrome, may be helpful, while a
short therapeutic trial with cortisone will restore the menstrual periods in
the adrenogenital syndrome and aggravate the clinical features in Cushing’s
syndrome.

Treatment

The poor prognosis in untreated Cushing’s syndrome renders early
diagnosis and treatment essential. The object of treatment is to reduce or to
abolish the production of cortisol by the adrenals. In the rare cases in
which a pituitary tumour is demonstrable it should be removed by formal
hypophy scctomy. If an adrenal tumour is present it must be removed. If
the adrenals are hyperplastic or overactive an attack may be made either on
the pituitary, by surgery or radiotherapy, or on the adrenals themselves.
We believe that adrenalectomy remains, for the present, the treatment of
choice. Pituitary' irradiation is neither so reliable as adrenalectomy nor

92

THE ADRENAL CORTEX

without danger. Hypophysectomy causes remission but at the same time
abolishes the activity of the thyroid and gonads. Selective hypophysec-
tomy, in which an attempt is made to destroy the basophil tissue by means
of radioactive material inserted into the pituitary fossa, is undergoing
investigation, but the results are not always predictable. Adrenalectomy
does not affect thyroid function and cures the hypogonadism. Adrenal
tumours, which are relatively common, often cannot be excluded without
surgical exploration and, since their secretions are not under pituitary con-
trol, hypophysectomy in such circumstances would be fruitless. Unless,
therefore, there 3s clear e\ idence of a pituitary tumour, we believe that the
best treatment of Cushing’s syndrome is a direct attack on the adrenal
glands themselves. The surgical methods adopted in our series were as
follows:

Adrenal tumour:

Removal A

H> perplasia or hyperfunction of adrenals :

Subtotal adrenalectomy 19

Total adrenalectomy 1

Pituitary tumour.

Hypophysectomy 1

No operation.

Carcinoma of bronchus 1

Spontaneous remission 1

27

Medical measures

These have proted of little value. Testosterone therapy was introduced
by Albright w ith the object of inhibiting the acti\ ity of the anterior pituitary
and of promoting anabolism of protein, but it usually failed to influence the
disease. Potassium salts are useful to correct potassium deficiency.
Adrenal inhibitors have been tried in a few patients, but they are too toxic
for general use. One compound, "O.p'DDD”, has proved of value in
patients with inoperable adrenocortical carcinoma and in those with benign
lesions who refuse operation or fail to respond to irradiation of the pituitary.
However, less-toxic and more effective compounds may in the future
render surgery unnecessary except in patients with tumours.

Adrenalectomy

If permanent remission is to be achieved in a high proportion of cases at
least 90 per cent of the adrenal tissue must be remo\ed. General agreement
has not been reached as to whether subtotal or total adrenalectomy is the
better procedure. Total adrenalectomy has the adtantage of a permanent
cure and a guarantee against recurrence. On the other hand, it necessitates
lifelong replacement therapy. Subtotal resection attempts to o\ ercotne

CUSHING’S SYNDROME

93

such difficulties by leaving a small fragment of adrenal tissue and, if
successful, enables the patient to regard himself as cured in a way that
would not be possible if he had to take tablets for the rest of his life. On
the other hand, the adrenal remnant may prove inadequate (50 per cent of
our patients) and substitution therapy is then unavoidable. Furthermore,
the adrenal tissue may regenerate and cause a recurrence of the Cushing’s
syndrome. Provided the whole of one gland and 95 per cent of the other is
removed, the recurrence rate is not likely to be high ; there has been one
temporary recurrence only among our patients. It seems wise always to
remove the whole of one gland, since if there is a recurrence the side to be
re-explored is known. A good case can be made for total adrenalectomy in
patients under 25 years of age, because the relapse rate in this age group is
relatively high.

Our usual practice is as follows. If a tumour can be located before
operation the gland on that side is explored and the tumour removed. Any
adrenal tissue which is not involved is also resected (at least subtotally),
since the tumour itself may not be functionally active. The other gland
need only be explored if a remission does not ensue. It is worthwhile
attempting to remove a carcinoma, even in the presence of metastases,
since a temporary remission may follow.

If no tumour has been located the left gland is explored first, since it is

Fig. 3.9. The adrenal glands in Cushing’s syndrome.

The left adrenal has been removed subtotally and the right totally together with an
ectopic nodule.

94

TIIE ADRENAL CORTEX

the more accessible and the easier to resect subtotally. When it has been
exposed three courses are possible:

(1) If a tumour is found it is removed.

(2) If the gland is atrophic it is probable (but not certain) that there is
a tumour on the opposite side. A biopsy is taken and the other gland
explored later.

(3) If the gland is normal or hyperplastic it is resected suhtotally and
the whole of the other gland is removed later (fig. 3.9).

Replacement therapy

To prevent death from adrenal insufficiency, cortisone must be given
over the period of the operation and for as long afterwards as necessary.
The recommended dosage is as follows:

/ Dosage of cortisone acetate used in replacement therapy

Time Dose Route

2 day* before operation 50 mg. 4 times a day Intramuscularly

I day before operation 50 mg 4 times a day Intramuscularly

Day of operation tOO mg. 3 tunes a day Intramuscularly

1-2 days after operation 100 mg.'3 times a day Intramuscularly

3-5 days after operation 75 mg. 3 times a day By mouth or mttamuscuUtly

6 days after operation 50 mg. 3 times a day By mouth

7-8 days after operation SO mg. 2 times a da v By mouth

9-10 days after operation 25 mg. 3 times a day By mouth

II days after operation 25 mg. 2 times a day By mouth

12 days after operation 12 5 mg. 2 or 3 times a day

and onwards or less as required

In addition, aldosterone (0-5 mg.) or deoxycortone acetate (5 to 10 mg.)
may be given intramuscularly on the day of operation and for two or three
days afterwards. Replacement therapy is required for both the first and
second stages of adrenalectomy. An adrenal crisis may develop after the
first operation if on unsuspected adrenal tumour is removed, and it may
even follow the removal of the first gland in bilateral adrenal hyperplasia.
This schedule is also indicated for patients undergoing hypophysectomy as
the primary form of treatment.

Those who are accustomed to the smooth postoperative course after
adrenalectomy in patients with metastatic cancer (and the much smaller
dose of cortisone employed) rarely appreciate the serious nature of the
adrenal crisis that may develop with alarming swiftness after operation for
Cushing’s syndrome. Three precautions are advised to ensure the im-
mediate diagnosis of a crisis and to allow it to be treated rapidly. These
are: (1) an efficient apparatus for intravenous therapy (preferably a
polythene tube in the vena cava) should be in place before the operation
commences; (2) the pulse and blood pressure should be recorded every
15 minutes until they hav e been stable for two days after the operation ; and

CUSHING’S SYNDROME 95

(3) cortisol hemisuccinate and noradrenaline (or metaraminol) should be on
hand for immediate infusion if a crisis develops.

After the immediate postoperative period the dose of cortisone depends
on the patient’s requirements, and these can be gauged only by trial and
error. An oral maintenance dose of 25 to 50 mg. per day in three or four
divided doses is necessary after total adrenalectomy, whereas after subtotal
removal cortisone can often be withdrawn altogether in a few weeks or
months. Replacement therapy for patients requiring cortisone per-
manently is similar to that for patients with Addison’s disease (p. 1 1 7). ft
is probably unnecessary to inject ACTH after the removal of an adrenal
tumour.

Postoperative complications

The postoperative course may be stormy. The commonest complication
is adrenal failure, which may be acute or subacute.

Acute adrenal crisis is a serious emergency which takes the form of acute
peripheral circulatory failure. Collapse, hypotension and tachycardia may
develop with dramatic suddenness, often about 24 hours after operation.
It may, as already indicated, follow operation on the first side, even though
the other adrenal is present and hyperplastic. It is treated by the immediate
infusion of 100 mg. of cortisol hemisuccinate. This is usually effective
within 15 to 30 minutes, but if it is not noradrenaline (4 mg. in 500 ml. of
physiological saline) or metaraminol (15 to 100 mg. in 500 ml. of saline) is
added to the drip at whatever speed is required to maintain the blood
pressure at or above 100 mm. of mercury. At the same time the dosage of
cortisone is increased. The treatment of adrenal crisis is described more
fully later.

Acute salt deficiency may also be a manifestation of acute adrenal in-
sufficiency, but is less common than an adrenal crisis. Its danger lies in its
being mistaken for pure cortisone deficiency. The symptoms of weakness,
apathy, nausea and vomiting are common to both states. The early
recognition of salt deficiency is therefore important, and this may be
achieved by the daily estimation of the serum electrolytes during the early
postoperative phase. Minor degrees of deficiency can be corrected by the
administration of salt by mouth and by the use of more potent sodium-
retaining substances such as aldosterone or fludrocortisone in addition to
cortisone. If serious depletion is present, immediate correction by sodium
chloride intravenously is necessary.

Subacute adrenal insufficiency is also known as the “cortisone withdrawal
syndrome” and develops if the dose of cortisone is reduced too rapidly.
It may be seen as soon as a week after operation or at any time in the remote
postoperative period. It may be expected in a mild degree in most patients,
since the correct dose of cortisone can be determined only by trial and

96 THE ADRENAL CORTEX

error. The earliest symptoms are anorexia and nausea, first experienced in
the morning and aggravated by exercise. Later they become persistent,
and vomiting, weakness, lethargy, abdominal discomfort, low-grade fever

Cushing's syndrome

97

and tachycardia follow (fig. 3.10). A characteristic sign is a scaly desquama-
tion of the skin of the face or even of the whole body (fig. 3.11). The
condition, including the skin lesion, responds rapidly to an increase in the
dose of cortisone. If treatment is delayed hypotension, anuria, mental
changes and death may follow.

Other postoperative complications may be troublesome. They include
wound infection or dehiscence, pulmonary collapse and infection,
temporary psychosis, persistent tachycardia and, later, rheumatic-like
pains in the muscles and joints.

The operative mortality rate was 10 per cent in a series of 52 cases
collected from various sources by Mason.

Belfast series. In our own series of 24 cases treated by adrenalectomy
there were 44 operations (3 with tumour had only one operation each, and
in one child both adrenals were removed at the same time). We en-
countered the Following complications:

Death (no cause found) 2

Adrenal failure
Acute:

Adrenal ensis S

Salt deficiency 1

Subacute 10

Miseellanemu

Wound infection 7

Chest complication Frequent

Psychosis {temporary) 1

Tachycardia (persistent) 1

Effects of operation

Remission of the disease. The first sign of improvement is the scaly
desquamation of the skin of the face, which usually starts within two or
three weeks of operation. As mentioned already, the condition is aggra-
vated if cortisone is withdrawn too rapidly. This skin change is an index of
adequate and successful surgery, and it continues until the remtssion is
complete, S-igm of adrenal deficiency always develop if cortisone is with-
drawn completely before desquamation has stopped.

Within a few weeks the Facial and bodily appearances start to improve
and excessive weight is lost. At about 6 months the normal appearance
and bodily configuration are regained (fig. 3.12). Cutaneous striae fade and
leave pale scars. The hair becomes softer and fairer in those in whom it
had darkened. Facial hair usually diminishes, but may not be lost com-
pletely. The menstrual periods return, normal sexual function is restored
and pregnancy with normal childbirth may follow. The blood pressure
falls significantly in nearly all, but returns to normal in only a few. It may
continue to fall slowly for some years. All the metabolic disorders are

THE ADRENAL CORTEX

corrected. Recalcification of bone occurs slowly, but fractures heal and
deformities become stabilized in time. Recalcification of the spine may
lead to the “rugger jersey” sign of Dent, seen also in secondary hyperpara-
thyroidism.

Late deaths. Irreversible cardiovascular changes continue to endanger
life, and patients may die from the effects of associated hypertension (car-
diac failure and cardiac infarction) or from atheroma. One of our patients

Fig. 3.12. Cushing's syndrome.

Patient shown iti fig. 3.5 six months after bilateral adrenalectomy.

(a boj of 1 3 years) died from atheroma and thrombosis of the basilar artery
two months after operation.

Recurrence of disease. Recurrence in Cushing’s syndrome, after initial
remission, has been reported many times after partial adrenalectomy. It
occurred in about 10 per cent of cases in the Mayo Clinic series. Mason
found that recurrence varied directly with the amount of adrenal tissue left
behind and that it was commonest in those under the age of 25 years. In

CUSHING'S SYNDROME

99

these patients the adrenal remnant enlarges and a farther remission may be
induced by its removal. Recurrence does not follow total adrenalectomy.
In our own cases there was one temporary recurrence after subtotal adrena-
lectomy. One patient, with a large adrenal carcinoma, had a recurrence
when functioning metastases appeared.

Postoperative adrenal function. The aim of subtotal adrenalectomy is to
restore normal adrenal function, but this cannot be achieved easily, and too
much or too little tissue may be removed. In the former case adrenal in-
sufficiency results, whereas in the latter the disease is uncontrolled. Since
it is difficult to strike a nice balance, it is probably better to err on the side
of removing too much. We find that half our patients are in good health
without cortisone. The others have failed to achieve independence of corti-
sone or have had to return to it after being without it for a time. Measure-
ment of the postoperative adrenal steroid excretion has shown a low basal
output with little or no response to corticotrophin. In other words,
adrenocortical functional reserve is impaired, and patients not receiving
cortisone replacement may develop adrenal insufficiency in the event of
stress. In order to protect these patients certain precautions are advised.
They are: (1) The patient should be informed of the early symptoms of
adrenal failure and instructed to consult his doctor at once if he experiences
them. He must understand that intercurrent disease or trauma may neces-
sitate his taking cortisone temporarily, or increasing the dose if he is on
permanent replacement. In such circumstances he must inform his medical
attendants that he has undergone an adrenalectomy. Printed cards should
be given to patients in which this information is embodied (p. ! 18). (2) The
patient’s physician should be kept fully informed and advised of the appro-
priate action in face of actual or potential adrenal failure. (3) An accurate
biochemical assessment of adrenocortical function should be performed
soon after cortisone replacement has been stopped. (4) The patient should
be seen and examined at regular intervals.

Belfast series

The late results of operation in our series were as follow:

Late deaths (after partial or complete remission)

Thrombosis of basilar artery
Other cardiovascular accidents
Recurrence of adrenal carcinoma
Encephalitis

Bleeding pituitary carcinoma
Meningococcal meningitis

1 (2 months after operation)

3 (within J year after operation)

1 (1 year after operation)

1 (1 year after operation)

] (3 years after operation)

1 (4 years after adrenalectomy and 1 year after
hypophj sectom y for pituitary tumour)
Remission (complete and lasting 6 months to 10 years) 14

Recurrence of syndrome 2

Adrenal carcinoma 1

Adrenal hyperplasia

1 (temporary)

ioo

THE ADRENAL CORTES

The pituitary

As mentioned previously, the pituitary is belic\ed to play an important
role in the pathogenesis of Cushing’s syndrome. If so it is pertinent to ask
what happens to the pituitary when the overt and lethal features of the
disease are mitigated by adrenalectomy. It is not unreasonable to suppose
that an increase in pituitary activity follows the sudden withdrawal, by
operation, from inhibition by cortisol. There is, in fact, some indirect
evidence that such is the case. Definite, but temporary, brown pigmenta-
tion of the Addisonian type may be seen in the adrenalectomy scars (fig.
3.13), and occasionally it may be more widespread. Treatment with corti-

Fir. 3.13. Brown pigmentation in Scar after adrenalectomy for Cushing’s
syndrome.

sane causes it to fade, and it is probably the result of increased secretion

ofACTHorMSH.

A recent and unexpected observation, made by several workers, has been
the development of a pituitary' adenoma after both total and subtotal
bilateral adrenalectomy for Cushing’s syndrome due to bilateral adrenal
hyperplasia. Only further experience vv HI show how often this occurs and
whether we should attack the pituitary, rather than the adrenals, in patients
who do not have an adrenal tumour. For the present it would seem ad-
visable to keep an open mind on the question. As a precaution, the pituitary

THE ADRENOGENITAL SYNDROME 101

fossa should be X-rayed regularly after operation in order that enlargement
of the fossa may be detected. In reported cases, and in two of our own,
pigmentation has been pronounced, and it has not lessened with cortisone
therapy as it does usually in Addison’s disease. Consequently, the de-
velopment of widespread pigmentation, which does not fade under treat-
ment with cortisone, should be regarded seriously.

Patients with clearly demonstrable pituitary tumours, whether present
initially or arising after adrenalectomy, should have them removed without
delay, for they may become malignant. One of our patients died from the
effects of haemorrhage into a transitional basophil carcinoma three years
after subtotal adrenalectomy. Another, in whom a pituitary tumour was
recognized after operation, responded well to hypophysectomy and lost her
pigmentation. The large doses of cortisone which are advised for primary
hypophysectomy are unnecessary for the removal of a pituitary' tumour
once the Cushing’s syndrome has been cured by adrenalectomy.

THE ADRENOGENITAL SYNDROME

The adrenogenital syndrome results from an excess of adrenal androgens
and causes virilism in women and girls and precocious isosexual develop-
ment (pseudopuberty) in boys. It does not, apparently, affect adult men.

Bulloch and Sequeira first described the condition adequately in 1905,
and Apert, in 1912, published a report in which the effects of adrenal
hyperfunction were classified according to the age of onset. The term
“adrenogenital syndrome” (“le syndrome genito-surrenal”) was first used
in 1912 by Gallais to describe the post-puberal variety in the female. It is
now generally used to include adrenal virilism in both sexes and at all
periods of life.

Pathology

The adrenal may be the site of a tumour or of hyperplasia (fig. 3.14).
Very rarely these lesions are found in ectopic sites, such as the spermatic
cord. A tumour secretes large amounts of androgens, while the secretion
of cortisol by the healthy gland remains normal. In virilizing hyperplasia
the essential lesion is a biochemical defect which causes the adrenal cortex
to form excessive amounts of androgens at the expense of cortisol. The
inhibitory effect of cortisol on the production of ACTH is therefore di-
minished and the adrenal is stimulated to secrete large amounts of steroids
with androgenic properties and to enlarge in the process. In the congenital
variety the adrenals may be as large as the kidneys. I listologically the zona
reticularis increases in size at the expense of the fasciculata and the fuchsino-
phil staining reaction of Vines is usually positi\e.

102

THE ADRENAL CORTEX

VIRILIZING ADRENAL LESIONS

TUMOUR ]

HYPERPLASIA

WU IBB \ f" 1 1 1 1

PD

Itt-railtfMMl

1

K

I

IEE2SIHIEM3

Fig. 3.14. Diagram of pituitary-adrenal relationships in virilizing adrenal lesions.

A tumour secretes excessive quantities of androgens without interfering with the
function of the non-tumorous gland. In virilizing hyperplasia the adrenals secrete
androgens at the expense of cortisol, the pituitary is not inhibited and secretes excessive
ACTH, and consequently the adrenals undergo hyperplasia. Treatment with cortisone
inhibits the pituitary, the secretion of ACTH falls and the adrenals shrink. The cortisone
replaces the deficient endogenous cortisol.

Dejects in biosynthesis

Cortisol is synthesized in the adrenal gland from its precursor proges-
terone, which differs from cortisol in not possessing hydroxyl groups at the
Cll, C17 and C21 positions (Chapter 2). Cortisol is probably formed by
enzymatic hydroxylatton (i.e. the introduction of —OH groups) at the C17,
C21 and Cll positions successively. In congenital virilizing hyperplasia
this process may be disturbed in one of three ways (fig. 3.15). (I) In the
common variety there appears to be a partial failure of C2I hydroxy lation
so that the synthesis of cortisol is impaired. Stimulation by ACTH then
causes a “build up” of 17-hydroxyprogesterone which is metabolized to
pregnanetriol and various androgens (androstcronc, aetiocholanolone and
less frequently dehydroepiandrosterone). These substances have andro-
genic properties and cause virilization, but they are unable to inhibit the
pituitary'. They are excreted in excess in the urine and pregnanetriol can
be estimated simply. (II) In the second variety C2I hydroxylation is prob-
ably inhibited more completely than in the first and there is evidence of
excessive loss of sodium in the urine. Aldosterone secretion is normal in
some but not in others. In the former the presence of an adrenal steroid

THE ADRENOGENITAL SYNDROME

i&n

fpROGESTiaOMi 1

PROGESTERONE

T T

17 noun- AmSHSemPh, IT HYOR.OXY-
rnomMt wwggw f HwwwyE

(AftdrctUront fl

tt-KWMXUMWN JtuxhoWlcfc [I TI-HVOXOttUTlON
L mu and ON A. ) |

CORTEXONI 1VK0XY-

(OOCI CORTISOL

(Cer-pjund 6)

fl-OEOXY- TORT EX ONE

CORTISOL {OOCJ

(Compound S| Ilf

Fig. 3.15. Congenital virilizing adrenal hyperplasia.

Diagram of three mam defects in biosynthesis of cortisol.

** indicates a "block" in the synthetic pathway due to an enzymatic defect

which promotes the excretion of sodium has been postulated. In the latter
it is believed that the progesterone-like compounds which are produced in
excess inhibit the action of aldosterone at the renal tubule level. The result
is virilization associated with adrenocortical (cortisol) insufficiency and ex-
cessive loss of salt in the urine, (III) In the third variety the defect appears
to be in Cll hydroxylation, the last step in the formation of cortisol and
corticosterone. As a result, increased amounts of 11-deoxycortisol (com-
pound S) and cortexone are formed and the mineralocorticoid properties
of the latter cause hypertension. There is also a “build-up” of 17-hydroxy'
progesterone which, together with its metabolites, cause virilization.

VARIETIES OF THE ADRENOGENITAL SYNDROME
The effects of androgens on the tissues vary with the age and sex of the
patient, and hence different varieties of the syndrome are encountered:

Precocious isosesual pseudopuberty
(macrogenitosomia prnecox “Infant
Hercules")

Female syndrome J Female pseudo-

| hcnnapbrodhisir

10 +

THE ADRENAL CORTEX

Congenital virilizing hyperplasia

This condition is often familial and is inherited as an autosomal recessive
trait. It may affect members of both sexes in the same family.

In the female

The earliest signs of virilism, which are present at birth, are enlargement
of the clitoris (which is invariable) and varying degrees of fusion of the
genital folds (which is common). Girls suffering from this condition are
called ‘female pseudohermaphrodites ” and may be mistaken for boys with
hypospadias and undescended testicles. The abnormalities of the external
genitalia will be described in detail in Chapter 17. The internal genitalia
are normal, but remain infantile in form, and the ovaries may develop
atretic follicles. An o\ arian disgerminoma sometimes develops during
childhood or adolescence (Chapter 5). As the child develops, other signs of
virilism appear, causing heterosexual precocious pseudopuberty. The
breasts fail to develop and there is primary amenorrhoea. A \ery few
patients have been described in whom oestrogens, as well as androgens, are
formed in excess and cause precocious uterine bleeding.

In the male

No abnormality is seen at birth, but within a few weeks or months the
penis starts to enlarge, and later all the signs of isosexual precocious
pscudopuberty appear. The testes and scrotum remain small because the
adrenal androgens inhibit the production of gonadotrophin by the pituitary.
The condition is called “ macrogenitosomia praecox " and the child is often
described as an “Infant Hercules”.

In both sexes

There are striking abnormalities of skeletal development in both sexes.
Bony growth is unusually rapid at first and the ossification centres appear
precociously. The epiphyses, however, fuse earlier than normal so that the
final height rarely exceeds 5 ft. Virilism is manifested by hirsutism,
excessive muscular growth, masculine proportions, enlargement of the
larynx, with deepening of the voice, greasiness of the skin and often acne.
Erections of the clitoris or penis occur very early. Mental development
accords with the patient’s true age. Sexual orientation is usually normal
except in the case of girls who have been mistakenly reared as boys. They
may be attracted to other girls.

There may be serious metabolic disturbances which are related to the
biochemical defects in the adrenal and \\ hich may o\ ershado vv the effects of
virilization, On the basis of these, three clinical types of the syndrome may
be recognized in both sexes:

THE ADRENOGENITAL SYNDROME

105

1. Virilization alone — commonest.

2. Virilization and adrenocortical insufficiency.

3. Virilization and hypertension — least common.

Adrenocortical insufficiency. In about a third of the patients there are
features of adrenal insufficiency with excessive loss of sodium and chloride
in the urine, in addition to virilization. These features may be observed in
the first week of life in some, and appear within a few weeks of birth in all.
The child is weak and apathetic, feeding difficulties arise and \omiting,
diarrhoea and dehydration develop. Death may result from circulatory'
collapse, which develops swiftly in acute cases, and an adrenal crisis may be
precipitated by infection or by other forms of stress. Sudden death from
cardiac arrest due to hyperkalaemia has also been reported. The condition
is recognized more easily in female babies than in males because of the
associated genital abnormality. In most boys the penis is of normal size at
birth and does not enlarge until later, so that an adrenal cause for the
metabolic disturbances is not considered and they are attributed to feeding
difficulties, pyloric stenosis or gastrointestinal infections. Prompt diag-
nosis and treatment are essential, for death generally occurs during the
first year of life in those not receiving specific replacement therapy.

Hypertension. A small number of patients have hypertension as well as
virilization. It may be severe enough to cause cardiomegaly and cardiac
failure, even in early childhood.

Adrenogenital syndrome in the child

A congenital virilizing lesion may continue to exert its influence as
described already. If the syndrome appears for the first time in childhood
the cause is almost invariably a tumour. Symptoms and signs develop
rapidly and are similar to those of the congenital form, except that the pre-
natal development of the genital tract is normal.

Adrenogenital syndrome in the adult female

After puberty a pre-existing lesion may continue its activity or a new
lesion may develop. Hyperplasia, apparently similar to the congenital
variety, arises fairly commonly about the age of 18 to 20 years. Tumours
develop less commonly and usually at a later age. They may cause a severe
syndrome of rapid onset.

The clinical Features vary in their intensity and none is constant. They
may be considered under three headings:

(1) Defeminization results from inhibition of the pituitary. Sexual and
somatic development is normal and the menses have usually been regular
for a few years. The periods then become irregular and scanty, ovulation

106

THE ADRENAL CORTEX

stops, the patient becomes sterile and absolute secondary amenorrhoea may
supervene. Occasionally the patient regards her (anovulatory) periods as
normal, but complains of infertility. In severe cases there may be atrophy
of the breasts, loss of subcutaneous fat and of feminine contours, and
atrophy of the external genitals (except the clitoris).

Tig 3.16 ng 3.17

Fig. 3 16. Adrenogenital syndrome (post-puberal virilizing hyperplasia) in
woman aged 28 years.

Fig. 3 17. Hypertrophy of clitoris in untreated congenital virilizing hyperplasia.
Woman aged 24 years.

(2) Virilization of the tissues is a direct androgenic effect. Hirsutism is
the commonest feature, and greasincss of the skin and acne are frequent
(fig. 3.16). In severe cases there may be deepening of the voice, muscular
development and enlargement of the clitoris (fig. 3.17).

(3) Metabolic disturbances are uncommon. There may be retention of
salt and fluid, which causes hypertension. Adrenocortical deficiency does
not seem to occur in those in whom lesions develop for the first time in
adult life.

THE ADRENOGENITAL SYNDROME 107

Hirsutism

Hirsutism is an important feature of the adrenogenital syndrome, but
most hirsute women do not have any serious adrenal disorder. The amount
and the distribution of hair vary greatly and depend on racial and familial
factors and on the distribution and sensitivity of the hair follicles, as well as
on hormonal influences.

In some women with the adrenogenital syndrome hair is practically con-
fined to the sides of the face, the chin and the upper lip as in the adolescent
male. In more severely affected women the growth resembles that found
in adult men, and shaving becomes necessary. On the trunk there may be
a few hairs around the nipples, between the breasts and along the linea alba,
or there may be a more definite masculine type of pubic hair growth with
a general overall increase in hairiness. A few patients have as much hair
on the trunk and limbs as really hirsute males. The scalp hair may become
thickened and greasy and its colour may darken, while in severe cases it is
lost from the frontotemporal regions and vertex as in the normal male.

Mild degrees of hirsutism may be found in patients who do not appear
to have menstrual disturbances or other clinical evidence of adrenal over-
activity. This is sometimes called idiopathic or constitutional hirsutism,
and it is often familial. The distinction, however, is not always clear cut,
and idiopathic hirsutism may be associated with minor abnormalities of
adrenal steroid metabolism. The biochemical findings in these patients
will be discussed later.

Mixed Cushing's and adrenogenital syndrome

It is not uncommon to find some features of both Cushing's and the
adrenogenital syndromes in the same patient. For example, virilism may be
accompanied by hypertension or associated with diabetes, as in the "dta-
betes of bearded women” described by Achard and Thiers.

Diagnosis and differential diagnosis

The diagnosis of these hyperfunctioning adrenal disorders is not easy.
A full investigation is elaborate, time consuming and sometimes incon-
clusive; but without it accurate diagnosis and rational treatment are im-
possible. The first problem is to decide which patients require full
investigation. Generally speaking, it is required when there are serious
clinical grounds for suspecting an adrenal disorder, and when treatment
seems desirable. It is certainly needed if there is likelihood of a tumour
being present; and a tumour should be suspected if symptoms appear
during childhood or if they develop rapidly in an adult. The surgeon has
to answer four main questions:

1. Is there an adrenal disorder?

2. If so, is it hyperplasia or a tumour?

108

THE ADRENAL CORTEX

3. If a tumour, on which side is it?

4. Can an underlying lesion in the pituitary or CNS be excluded?
Congenital virilizing hyperplasia

Female pseudohermaphroditism can now be diagnosed by several tests, 3nd
biopsy of the gonads is no longer necessary:

1 . Microscopy of the cell nuclei shows that they are chromatin positive.

2. Inspection of the urogenital sinus with a urethroscope reveals the
vaginal orifice opening into its posterior wall and may allow the uterine
cervix to be seen and catheterized. Radio-opaque material, injected
through the catheter, demonstrates the uterus and tubes.

3. Biochemical tests (see later) show an abnormal excretion of andro-
gens.

Female pseudohermaphroditism may also develop as a result of the
placental transfer of substances with an androgenic action during preg-
nancy. These may be derived from a virilizing ovarian tumour or from
androgens or synthetic progestational compounds administered thera-
peutically to the mother.

At birth the condition must also be distinguished from other forms of
anomalous sexual development (Chapter 17).

The presence of hypertension or sodium deficiency serves to differentiate
the different forms of congenital adrenal hyperplasia and should be looked
for specifically, since they are of importance in determining the correct
method of treatment.

Adrenogenital syndrome in childhood

In girls adrenal virilism must be distinguished from constitutional
hirsutism or from simple premature de\elopment of pubic hair. Though
sexual hair growth is premature and may be related to an unusually early
"adrenache”, there is no virilization in these cases and no evidence of
adrenal androgen excess. An arrhenoblastoma is extremely rare in child-
hood and can be excluded by a careful pelvic examination.

In boys isosexual precocious pseudopuberty may also be caused by a
Leydig cell tumour of the testis. In the adrenal variety both testes remain
smaYi. A testicular tumour causes enlargement of one organ on'iy. Vn Wfc
precocious puberty, caused by disorders of the pituitary or central nen ous
system, both testicles develop precociously. The urinary steroid findings
are described below.

Adrenogenital syndrome in adults

The diagnosis of the adrenogenital syndrome is made on clinical
grounds, on the characteristic biochemical findings (described below)

Tile ADRENOGENITAL SYNDROME 109

and on the response to treatment. The following disorders should be
considered:

1. Idiopathic hirsutism.

2. Cushing’s syndrome.

3. Stein-Lcventhal syndrome.

4. Adrenal virilism associated with acromegaly.

5. Arrhenoblastoma.

Steroid excretion in the adrenogenital syndrome
The principal findings in the urine in the various forms of the adreno-
genital syndrome are as follows:

Adrenal hyperplasia i

Adenoma

Carcinoma

17-oxogenic steroids
ortotal 17-hydroxy-
steroids

Normal or diminished

Normal

Norma) or raised

17-oxosteroids

Increased

Increased

Increased— very high
levels (->100 mg/
24 hr) suggestive of
carcinoma

Special finding with
steroid fractionation

Increased amounts of
androsterone
aetiocholanolone
dehydro epiandrosterone*

Excess of specific
steroid

Pregnanetriol*

Excessive excretion of
debydroepiandro-
sterone* suggestive
of adrenal carcinoma

Effect on steroid excre-
tion of;

1. ACTH

J, Increased or un- ,
changed

2. Diminished

J. Unchanged

1. Unchanged

2. Dexamethasone

2. Unchanged

2. Unchanged

* It should be noted that the estimation of pregnanetriol and of dehydroepiandro-
sterone, but not that of the other individual steroids, is relatively simple.

Women with idiopathic hirsutism often have slightly increased amounts
of 17-oxosteroids in the urine and are found, on fractionation, to excrete
increased amounts of androsterone and aetiocholanolone, but not of preg-
nanetriol. Those who are both hirsute and obese also excrete increased
quantities of cortisol metabolites, but not of cortisol itself.

Differentiation between adrenal tumour and hyperplasia
The distinction is not always easy. A large tumour may be palpable, and
both hyperplastic glands may occasionally be felt at birth. Suppression of

110

THE ADRENAL CORTEX

the pituitary with dexamethasone and X-rays of the adrenal glands may be
helpful. If a tumour cannot be excluded after full investigation the adrenal
must be explored surgically.

Treatment of the adrenogenital syndrome
The treatment of the adrenogenital syndrome concerns the surgeon less
often than that of Cushing’s syndrome. An adrenal tumour is the only
indication for adrenalectomy in this condition. It should be removed, if
possible, by the thoraco-abdominal route.

Virili 2 ing hyperplasia, whether congenital or acquired, can be managed
satisfactorily by the administration of cortisone, which inhibits the forma-
tion of ACTH and consequently the increased secretion of androgens,
while at the same time providing an adequate substitute for the cortisol
which is deficient (fig. 3.14). Steroid therapy must not be embarked on
lightly in patients with mild hirsutism and minor disorders of steroid
metabolism, for it is potentially dangerous and rarely influences the
growth of hair appreciably. It is, however, of very great value in the treat-
ment of congenital hyperplasia in children and of disturbed sexual function
in adults. The method of treatment is to give relatively large doses of
cortisone initially in order to cause maximum adrenal suppression and
then, by trial and error, to determine the smallest dose necessary to main-
tain the suppression. In growing children it is important to regulate treat-
ment m terms of the rate of growth and bone development. If suppression
is inadequate growth is rapid and the final stature is diminished, while
excessive treatment will retard growth and development unnecessarily.

Cortisone may be given by mouth or injection. We prefer oral treat-
ment, because we believe that injections are unpleasant for babies and
young children and inconvenient for adults. Cortisone must be taken by
mouth in three or four doses, spaced through the day, because its action is
short lived. The oral dose is two or three times greater than the intra-
muscular. Suppression treatment is started with 100 mg. of cortisone
acetate each day for adults and with 25 to 30 mg. per day for infants under
the age of 2 years. Satisfactory adrenal suppression occurs within 3 few
days and is assessed by measurement of the urinary 17-oxosteroids. The
aim is to achieve outputs of the following order :

Adults 8-12 mg /24 hours

Children 6-14 years 4-6 mg./24 hours

2-6 years 2-4 mg./24 hours

Infants under 2 yenrs 0 5-1 mg,/24 hours

The maintenance dose of cortisone varies from one patient to another; we
have found that, for adults, it is usually between 37-5 and 50 mg. daily and,
for young children, between 10 and 25 mg. Correspondingly smaller doses

THE ADRENOGENITAL SYNDROME 111

are required for synthetic steroids, but we prefer to use cortisone itself.
Adjustments are required in the dose from time to time, especially m
growing children, and the physical dc\elopment and 17-oxosteroid output
should be reviewed at regular intervals. Treatment is probably necessary
for life.

Infants with a mild degree of the sodium-losing form of congenital
adrenal hyperplasia may sometimes be maintained in normal electrolyte
balance with cortisone alone, but more often they require 2 to 5 G. of
additional salt each day. More severe cases require 0-1 mg. of fludro-
cortisone daily in addition. Other salt-retaining hormones may be used,
and Wilkins recommends the implantation of two to five 125-mg. pellets of
deoxycortone acetate (DCA), which is effective for nine to twehe months
Surprisingly it is usually unnecessary to repeat the implantation provided
cortisone and salt are continued.

The adrenals of patients receiving long-term steroid suppression are
unable to respond normally to meet the requirements of stress. Such
children may therefore suffer from acute adrenocortical insufficiency unless
additional amounts of cortisone are given to carry them over the illness or
operation. Even untreated patients who reach adult life without overt
adrenal insufficiency may develop a severe crisis after a minor surgical
operation.

The results of treatment are most satisfactory in those treated before the
age of 2. If adequate suppression is achieved and maintained normal
growth and development should result. After the age of 2 therapy will
Check the rapid epiphyseal development, but the ultimate height reached
will depend on the bone age at the time treatment is started. Treatment
also diminishes and halts the progressive virilization.

Feminization occurs rapidly in girls; the breasts develop and normal
menstruation is established. When treatment is started after the age of
puberty further growth will not take place. Hirsutism may decline slowly,
but if it is severe before treatment it continues to be a real problem. It
must be treated by cosmetic methods. In adults normal sexual function
returns and the breasts enlarge, but hirsutism persists and the voice re-
mains deep. Patients who marry may achieve successful pregnancies.

In boys early treatment will halt the genital development and improve
the prospects of growth. The testes will mature at the proper time and
puberty will occur normally. Cortisone should, however, be continued to
maintain fertility and to guard against adrenal insufficiency.

Female pseudohermaphrodites require plastic surgical procedures to
correct the genital abnormalities, and these should be undertaken as early
as possible. Special problems may arise over the treatment of female
pseudohermaphrodites who have been raised as boys. These matters will
be discussed in Chapter 17.

THE ADRENAL CORTFX

Our own cases include the following:

Female pseudohermaphroditism (hjperplasij)

Infants 8

Adults (sisters) 2

Postpuberal vinlism S

(Hyperplasia— 1 7 ; carcinoma — 1)

FEMINIZING ADRENAL TUMOURS (ADRENAL
FEMINIZATION)

This is an exceptionally rare condition caused by an oestrogen-secreting
tumour of the adrenal gland or of ectopic adrenal tissue in males and
characterized by dcmasculimzation and feminization. The tumour is
usually malignant and large and can often be palpated. It develops most
frequently in adult life. Histological examination of the tissue does not
reveal any differences from other hormone-secreting adrenal tumours, but
other features of adrenocortical excess such as Cushing’s syndrome are
very unusual.

The clinical features result from the overproduction of oestrogen by the
growth. This causes inhibition of pituitary gonadotrophin secretion and
leads to testicular atrophy, loss of libido and impotence. Gynaecomastia is
a major symptom and may cause pain and tenderness. Secretion from the
breasts is rare. The facial skin may develop a fine feminine texture and,
in a few cases, facial hair growth diminishes. There may be some obesity,
and muscular development generally declines.

There may be increased excretion of oestrogens, adrenal androgens and
even of gonadotrophins (apparently secreted by the tumour) in the urine.

The condition must be distinguished from other causes of gynac-
comastia.

Treatment consists in the surgical removal of the growth, if that is
possible. Cortisone cover is not required, for the remaining adrenal tissue
functions normally. The prognosis is poor, since in most cases malignancy
is advanced by the time the tumour is discovered.

Removal of an adenoma, however, may relieve all the symptoms, al-
though some degree of gynaecomastia may persist.

ADRENOCORTICAL INSUFFICIENCY

When insufficient amounts of cortisol and aldosterone are produced to
meet the body’s needs the syndrome of adrenal failure develops. This may
be acute if the output of adrenocortical hormones falls abruptly and sub-
acute or chronic if impairment of function is gradual and incomplete.
Chronic insufficiency may suddenly become acute in the face of stress,
such as that provided by infection, trauma or a surgical operation.

112

Belfast series.

Addison’s diseasc

113

CHRONIC ADRENOCORTICAL INSUFFICIENCY

Chronic adrenocortical insufficiency is of mo main types, (A) that in
which the adrenal gland is involved primarily and (B) that in which impair-
ment results from dysfunction of the anterior pituitary. The following
conditions are seen most commonly in clinical practice:

(.4) Primary adrenocortical failure

1. Addison’s disease.

2. Congenital adrenal hyperplasia.

3. Adrenal exhaustion.

4. Failure of adrenal remnant after subtotal adrenalectomy
(B) Secondary adrenocortical (primary pituitary) failure

1. Pituitary destruction.

2. Hypophysectomy.

3. Pituitary’ inhibition.

The last, which is caused by therapy with ACTH or corticosteroids, has
become very common in the past few years.

Addison’s disease

This condition was first described by Thomas Addison, physician to
Guy’s Hospital, in 1849 and again in 1855. Addison’s book On the Con-
stitutional and Local Effects of Disease of the Supra-renal Capsules was one
of the first milestones in the development of endocrinology.

Addison’s disease is a condition of adrenocortical insufficiency resulting
from primary disease or destruction of the adrenal cortices, and is
characterized by asthenia, hypotension, a tendency to hypoglycaemia, pig-
mentation, loss of sodium in the urine, loss of weight, anorexia and gastro-
intestinal symptoms, and a tendency to develop acute crises, which may
endanger life, as the result of any form of stress. Formerly the disease was
fatal, but today, by the use of cortisone, patients can be maintained in good
health for many years.

Causative lesions

Destruction of the adrenal cortices may be caused by the following
lesions. The figures refer to the presumptive diagnoses in our own series
of cases, seen in 10 years. Confirmation was obtained post mortem in one
patient only (carcinoma), for the rest are in good health as the result of
treatment.

Tuberculosis 11 (58%)

Idiopathic necrosis 7 (37%)

Infiltration:

Carcinoma 1

Amy load, etc. 0

19

Total

114

THE ADRENAL CORTEX

Tuberculous destruction of the adrenals is less common now than it was
formerly, but it is still the most frequent cause of the disease.

In tuberculous cases the adrenals may be large and caseous; more rarely
they are small and fibrous. The medulla as well as the cortex is destroyed.
Areas of calcification may be seen and foci of tuberculosis may be found
elsewhere, often in the kidneys or lungs. In idiopathic adrenal necrosis the
glands are small and there is almost complete loss of cortex with preserva-
tion of the medulla. The cause of the necrosis is unknown, but it may
well be an auto-immune phenomenon. It is probably necessary for at
least 90 per cent of the adrenal tissue to be destroyed (by any lesion) before
adrenal failure results.

At autopsy, alterations are found in the pituitary and thyroid, but not in
other endocrine glands. In the pituitary an increase in the percentage of
the chromophobe cells may be found, together with a reduction in the
number of basophil cells. These changes are difficult to correlate with the
increase in secretion of ACTH which follows the reduction in secretion of
cortisol. Lymphoid infiltration of the thyroid is sometimes observed in
idiopathic adrenal necrosis and the gland may appear atrophic. These
findings are similar to, but less pronounced than, those observed in auto-
immune thyroiditis.

Clinical features

The disease may occur in both sexes and at all ages, although it is very
rare in childhood. In our ow n series there were 8 men and 1 1 women. The
youngest was 26 years of age and the oldest 72, while the average age at
onset was 49 years. The disease appears to develop later than it did
formerly,

Presentation and onset. The onset is often so insidious that the patient
finds it hard to remember when he first became ill, but in about a third the
first indication of disease may be an acute crisis. Of our 19 cases, 13 pre-
sented with signs and symptoms which pointed directly to their Addison’s
disease, but in 6 the presentation was atypical and adrenal insufficiency
was discovered only after admission to hospital for other complaints. In
tw'o patients adrenal crises were precipitated by surgical operations and in
another an operation was performed (fortunately without serious con-
sequences) before the condition was recognized. The early complaints arc
usually of tiring easily, loss of weight, distaste for food and malaise, and
these symptoms increase gradually until the patient is constantly tired and
unable to work.

The other symptoms and signs are conveniently described in relation to
the metabolic disturbances caused by deficiency of cortisol.

Pigmentation. This is an important and usual sign, though rarely it may
be slight or even absent. It is caused by increased deposition of melanin

addison’s disease

115

formed by the melanocytes in the skin under the influence of increased
secretion of MSH and ACTH by the anterior pituitary. Pigmentation
develops in areas subjected to pressure, light and irritation, and is usually
also present in the mouth, where it is seen as brown or blue-black patches
on the tongue, lips, gums and buccal mucous membrane. Diffuse brown or
brownish-black pigmentation is also observed around scars, in the peri-
neum, on the penis and scrotum, the folds of the axillae, the knuckles, the
creases of the palms and around the eyes. The areolae of the breasts and
the hair may darken. Many patients develop brown or black freckles on the
face and trunk. In a few patients areas of depigmentation or leukodermia
may be observed in association with areas of pigmentation. The degree
and extent of the pigmentation are not related to the severity of the
disease, but its rapid increase may suggest impending deterioration.
Pigmentation gradually disappears with cortisone treatment if the dose is
adequate.

Electrolytes and plasma volume. The loss of aldosterone secretion causes
disturbances in electrolyte and fluid balance. Sodium is excreted and the
body fluid diminishes. For a time the osmolarity of the plasma is main-
tained, but eventually the level of the plasma sodium falls. Loss of
sodium and water leads in turn to dehydration, hypotension and muscle
cramps, and the plasma specific gravity and the haematocrit rise. The
serum potassium increases and there is a metabolic acidosis. These changes
are greatest during a crisis.

Carbohydrate metabolism. The absorption of glucose from the intestines
is delayed and an oral glucose tolerance test may show a “flat” curve. The
formation of glycogen in the liver is impaired and hypersensitivity to
insulin develops. Consequently an intravenous glucose tolerance test
shows a normal rise in blood sugar but an accentuated and prolonged
hypoglycaemic phase 2 to 3 hours later. Hypoglycaemia is an im-
portant cause of death in an adrenal crisis. Rarely diabetes mellitus is
associated with Addison’s disease and is aggravated by treatment with
cortisone.

Gastrointestinal symptoms. Anorexia is one of the earliest symptoms, but
nausea, vomiting and sometimes diarrhoea are associated with deteriora-
tion or the onset of a crisis. Gastric secretion tends to be diminished, but
patients with Addison's disease do not have complete protection against
duodenal ulceration.

Nervous system. Many patients complain of inertia, lassitude and
depression. Rarely a confusional state may develop and there may be
delusions. These disturbances may be caused in part by electrolyte
changes, dehydration and hypoglycaemia, but lack of cortisol probably has
a direct effect on nervous function.

Muscular system. Muscle weakness and fatigu ability are common

116

THE ADRENAL CORTFX

symptoms and are relieved by cortisone. These may be the result of
impaired protein anabolism from loss of adrenal androgen (especially in
females), hypoglycaemia and disturbances in potassium metabolism. Salt
deficiency sometimes causes cramps.

Sexual disturbances. In women menstruation may continue normally or
there may be amenorrhoea. Before cortisone became available conception
was rare, but in treated patients normal pregnancy and delivery can be
achieved readily. During pregnancy the requirements for cortisone may
diminish, but, on the other hand, the stress of pregnancy may be sufficient
to cause an adrenal crisis. Each patient requires careful supervision until
term. Libido may be deficient in both sexes, and impotence may occur in
men. These features are due partly to the weakening effects of the illness
and partly to lack of adrenal androgens.

Adrenal Crisis. This term is applied to the acute phase of the disorder in
which all features of the disease are intensified and the patient is seriously
ill, collapsed and in danger of dying. A crisis may follow all forms of stress
or may appear to develop spontaneously.

Investigations

Laboratory tests are helpful in the diagnosis and management of severe
cases. Electrolyte disturbances are uncommon in mild cases, but in severe
cases and in those with an adrenal crisis the plasma sodium is low, the
plasma potassium and blood urea are high and the urine contains large
amounts of sodium. The urinary excretion of all adrenal steroids is low
(table 3.2) and there is no significant increase after stimulation with ACTH.
The water-load test reveals impaired diuresis, and this is corrected after the
administration of cortisone.

Radiology is usually of little help. Calcification of the adrenals is not
common, and was seen in only 2 of our 10 tuberculous cases. Convcr-
sely, extensive calcification of the adrenals may be seen without evidence
of adrenocortical insufficiency.

Differential diagnosis

Addison’s disease may be suspected on clinical grounds and evidence of
active or healed tuberculosis provides supporting (but by no means con-
clusive) evidence.

Other forms of pigmentation of the skin may be mistaken for that of
Addison’s disease. Among the diseases which cause it arc hyperthyroidism,
pernicious anaemia, haemochromatosis, intra-abdominal malignancy (acan-
thosis nigrans), steatorrhoea, sclerodema, Cushing’s syndrome with baso-
phil pituitary tumour and poisoning with heavy metals. Darkening of the
skin may take place during the early months of pregnancy. Certain racial

Addison’s disease 117

groups or those in whom there is a strain of Negro, Indian, Levantine or
other Oriental blood may have dark skin, frequently with patches of oral
pigmentation. Labial and oral pigmentation is also seen in the Peutz-
Jeghers syndrome. With these exceptions pigmentation within the mouth
nearly always indicates Addison’s disease.

An attempt should be made to discover the cause of the adrenal destruc-
tion, since it may have a bearing on treatment.

Treatment of chronic adrenocortical insufficiency

Before 1949 patients with Addison’s disease led a precarious existence,
despite treatment with deoxycortone acetate (DCA). Since the introduc-
tion of cortisone rational treatment has been possible.

Nearly all patients can be restored to full health, maintained in satis-
factory salt and water balance and enabled to withstand stress with
cortisone and a normal or increased sodium intake. The synthetic gluco-
corticoids are not satisfactory. The usual dose, which must be discovered
by trial and error, is 25 to 50 mg. of cortisone acetate daily by mouth. The
dose is divided, the larger part (say 25 mg.) being taken in the morning and
the smaller (say 12*5 mg.) in the afternoon or early evening. If the patient
does not improve in general health, and if the pigmentation does not fade
gradually, the dose must be increased.

A few patients lose salt excessively as a result of their disease or from
sweating during heavy work at high temperatures. These patients require
additional salt or a compound such as fludrocortisone (0- 1 mg. daily or more
often as required) in addition to cortisone. Alternatively, deoxycortone
acetate (DCA) may be used, the most satisfactory method being a depot
injection of 50 mg. of the trimethylacetate every two to three weeks.
When an effective oral preparation of aldosterone becomes available for
treatment it may supplant other forms of mineralocorticoid therapy, but
the present preparation (aldosterone 21-monoacetate) is much weaker
than fludrocortisone when given by mouth.

Reactivation of the tuberculous process is a rare complication of treat-
ment, but we consider that a routine course of antituberculous therapy is
advisable when the disease is thought to be tuberculous in origin. We
recommend streptomycin for six weeks combined with PAS and INH
for three to six months.

Avoidance of adrenal crisis . Replacement therapy must be thorough and
lifelong, and the patient must be made to understand the nature of his
disability. He should be warned of the dangers of stopping cortisone, of
the need for increased dosage in illness and of the early symptoms of
adrenal failure. We find it helpful to give two copies of the card (p. 1 18)
to every patient with impaired adrenal function from whatever cause.

118

THE ADRENAL CORTEX

IMPORTANT

MEDICAL CARD FOR PATIENTS WITH IMPAIRED ADRENAL FUNCTION

Medici Condition; 1 Adduon'l ducue.

2 llypopiraitanmn.

3 Tot»l or eubtotel edrmelcctomy

•4 Adrenal suppression following prolonged corticosteroid therepy

1 You are suffering from the condition described above You will remain in good health
provided you take Cortuone tablets every day and such additional treatment as moy be
prescribed You still get your prescription for the tablets from your family doctor Sour

dose is ..tablets! ....mg) of • •• • daily

2 It u essential for you to take the treatment regularly Make sure you hate an adequate
supply if you go avtiy from home

3 The dose may have to be increased temporarily if you develop an illnras (e g a had cold or
bronchitis), hate an accident or have to undergo an operation <e g for appendicitis) Show
this card lo your doctor or to the doctor in hospital at she time

* If you feel weak or lose your appetite It msy mean that you are not taking enough Cortisone
Try taking an eatra half tablet twice a day and tee if you feel better If you don’t, eontart

your family doctor at once or get ut touch with . . ....

at . , . .... Telephone No

S You have been given two of these cards Catty one with you always and keep the other at

ACUTE ADRENAL CRISIS

The causes of acute adrenal crisis are:

1. Adrenalectomy.

2. Acute destruction of the adrenals.

3. Stress associated with diminished adrenal reserve.

These are described more fully in relation to surgical practice (Chapter 12).

The early symptoms are weakness, nausea, vomiting, apathy and con-
fusion, and these are followed rapidly by signs of circulatory collapse with
hypotension and tachycardia. If untreated, coma and death may’ follow
swiftly.

Treatment

An adrenal crisis is an acute emergency and must be treated promptly if
life is to be saved. The principles of treatment are:

1. Provision of adrenocortical hormone.

2. Correction of fluid and electrolyte imbalance.

3. Prevention of hypoglycaemia.

4. Treatment of infection.

ADDISON’S DISEASE

119

Blood is taken immediately for estimation of the serum electrolytes and
the blood glucose and for determination of the blood group. An intravenous
injection of cortisol hemisuccinate (100 mg.) or prednisolone-disodium-21 ~
phosphate (20 mg.) is given either directly into a vein or via a “two-way”
drip set. At the same time an intramuscular injection of cortisone acetate
(100 mg.) is given to provide a depot for absorption. The pulse rate and
blood pressure are recorded every 15 minutes, and a competent nurse
should be present to provide special care until the patient is out of
danger.

The infusion of 5 per cent glucose, containing 100 mg. cortisol hemi-
succinate (or, if this is not available, 100 mg. of hydrocortisone free
alcohol or 20 mg. of prednisolone-disodium-21-phosphate) is continued, or
else commenced after the initial intravenous steroid injection, and run in
during the first 2 to 4 hours. This may be repeated if the response is incom-
plete, or continued more slowly if the patient’s condition improves. If the
fall in blood pressure is profound, or if it fails to reach 100 mm. Hg after
cortisol has been started, aldosterone (Aldocorten, Ciba) 0-5 mg. can be
added to the infusion fluid or injected intramuscularly several times daily.
Noradrenaline or metaraminol may be given as well (p. 354). Cortisone
acetate is continued, at the rate of 25 mg. intramuscularly every 6 hours,
after the initial dose until the patient is able to swallow, when it is given by
mouth. The amount is then gradually diminished to a maintenance dose of
37*5 or 25 mg. daily, as in the treatment of Addison’s disease. Aldosterone,
0-5 mg. intramuscularly, is given at the start of treatment and twice daily
thereafter for the first two or three days. It may then be omitted if there is
no sodium deficiency.

During the first 24 hours 2 to 3 litres of fluid are required, but the exact
volume and composition of the infusion depend on the electrolyte levels
and plasma specific gravity. Additional glucose may be required in patients
with severe hypoglycaemia, but glucose is also required to meet caloric
needs until the patient is able to take nourishment by mouth.

When patients are seen in extremis immediate emergency treatment with
concentrated glucose solution should be given before any other therapy is
attempted. The correction of hypoglycaemia may prolong life sufficiently
for other therapeutic measures to be used successfully. Patients who are
too ill to be moved from home to hospital should be given at once con-
centrated glucose (50 ml. of 50 percent solution) and cortisol hemisuccinate
(100 mg. dissolved in a vial of 2 ml. of sterile water) by intravenous injection.
This should be followed by 100 mg. of cortisone acetate intramuscularly.

Patients in acute adrenal insufficiency are particularly susceptible to
morphia and barbiturates, and if these are essential they should not be
given before specific replacement therapy has been started. Penicillin or
other appropriate antibiotics are given when infection is present.

120

THE ADRENAL CORTEX

ADRENALECTOMY

Indications

Adrenalectomy is performed for the following conditions:

I. Tumours of the adrenal cortex or medulla {whether functionally
active or not). Excision of the tumour may involve removal of all or
most of the gland.

II. Cushing's syndrome with hyperplastic or hyperfunctioning adrenal
glands.

III. Primary aldosteronism with hyperplastic glands.

Both glands are removed totally or subtotally.

IV. Other diseases:

Advanced carcinoma —

Breast (Common).

Prostate (Rare).

Both glands are removed completely.

Bilateral total adrenalectomy, with or without sympathectomy, had a
vogue a few years ago for the treatment of malignant hypertension, The
results were usually bad, and other methods of treatment are now generally
preferred. The operation has also been used for treatment of the visual
complications of diabetes mellitus, but it is probably inferior to hypo-
physectomy. In a few cases it has been undertaken as a method of en-
couraging loss of sodium and fluid in patients w ith ascites.

Surgical approach

The main problem in the surgery' of the adrenal glands is that, while
it is frequently desirable to inspect both glands before removing one, there
is no incision which always gives adequate access to both glands at the
same time. Various approaches may be employed:

(i) An oblique thoraco-abdominal inciston, with resection of a nb, gives
excellent exposure of one adrenal. The opposite gland, the o\arics and
ectopic adrenal swellings can be palpated via the peritoneal cavity', but they
cannot be seen or removed. In thin patients (e.g. with metastatic car-
cinoma) resection of the 12th rib gives adequate access on each side. In
those who are fat (c.g. Cushing’s syndrome) or who have a large adrenal
tumour the left gland is best approached extrapleural ly through the bed of
the 11th rib, while on the right a transpleural, transdiaphragmatic incision
through the bed of the 10th rib gives the best exposure.

(ii) An anterior abdominal incision allows both glands to be palpated and
inspected, and in a thin patient they can he removed. Great difficulty may
be experienced, especially on the right side, if the patient is fat or deep-
chestcd, or if a large tumour is present.

ADRENALECTOMY

221

(Hi) Bilateral posterior incisions through the beds of the 11th or 12th ribs,
with the patient prone, allow both glands to be inspected at the same time,
and resected if necessary- This approach is satisfactory only in experienced
hands.

We prefer the thoraco-abdominal approach except for cases of phaeo-
chromocytoma (unless a large tumour has been located), children and thin
patients with metastatic carcinoma, for whom an anterior incision is
usually better. When two explorations are necessary for examination or
resection of the adrenals it is generally safer to operate in two stages. It
may be justifiable to turn the patient after completion of one operation and
proceed immediately with the other, but this should not be done if the
pleural cavity has been opened, if the patient’s condition causes any
anxiety or if the surgeon is inexperienced in adrenal surgery. If adrenalec-
tomy and odphorectomy are being performed for malignant disease it is
reasonable to remove the left gland and the ovaries at one operation, and
the right adrenal at another. However, we have several times done the
three operations under one anaesthetic without complication.

Preoperative and postoperative care
General measures

The patient is kept ambulant up to the day of operation and breathing
exercises are started. A “broad-spectrum" antibiotic is given from the
time of operation, since cortisone suppresses inflammatory reactions. If
acne or other infections are present the appropriate antibiotic is started a
few days before operation. As already emphasized for the treatment of
Cushing’s syndrome, an intravenous infusion is started before operation
and continued until a normal blood pressure has been maintained for two
days without remedial measures. During this time the puke rate and blood
pressure are recorded every 15 minutes. The patient’s blood is cross-
matched and blood transfusion, cortisol hemisuccinate or noradrenaline
are given if necessary.

Substitution therapy

The effects of removing adrenal tissue without adequate substitution
therapy can be disastrous, and many deaths from adrenal failure occurred
before cortisone became available. An adrenal crisis may follow removal of
one gland only, even in the absence of tumour. It is essential to give adrenal
cortical hormones over the period of operation when bilateral adrenalec-
tomy is proposed or a tumour is to be removed from a patient with
Cushing’s syndrome. It is seise to provide substitution therapy when
exploring or removing adrenal tissue for any cause.

The following scheme of dosage for cortisone is satisfactory, except for

1 22

THE ADRENAL CORTEX

patients with Cushing’s syndrome who require larger doses (p. 94).
Deoxycortone (DCA) need not be given routinely.

Day Cortisone acetate

2 da>s before operation 50 nig 12-hourIy, intramuscularly
1 day before operation 50 mg. 12-hourly, intramuscularly
Day of operation 100 mg. 3 hours before operation, by mouth

25 mg 6-hourIy, intramuscularly

I day after operation 25 mg. 6-hourIy, by mouth jf possible, otherwise intra-

muscularly

2-5 days after operation 25 mg. 6-hourly, by mouth if possible, otherwise intra-

muscularly

6-10 days after operation 12 5 mg. 6 hourly, by mouth

II + days after operation 12‘5 mg. (8 or 12-hourly) by mouth

If, for any reason, preoperative preparation has not been given the
above schedule is started at the time of operation and cortisol hemi-
succinate (200 mg. intravenously) is given rapidly instead of the pre-
operative cortisone.

Cortisone in similar dosage is advised for any patient with adreno-
cortical insufficiency (known or presumed) who requires a major surgical
operation. For minor procedures the dose3 may be halved. Childbirth
(either natural or by Caesarian section) should be regarded as a major
operation.

Subsequent replacement therapy is the same as that in patients with
Addison’s disease, and the same precautions are necessary.

Complications of adrenalectomy

The complications have been described already (p. 95). Provided
adequate substitution therapy js given, adrenal insufficiency' is trouble-
some only in patients with Cushing’s syndrome.

The published mortality after operations for advanced cancer varies
from 2 to 10 per cent. In Northern Ireland there were 21 operations by
various surgeons without a death. The mortality from operations for
adrenal carcinoma may well be fairly high, because the operation can be
technically difficult.

Surgical technique
General considerations

General anaesthesia is used with a culled tndo-trachea’i tube. OiwA fate
should be taken to adjust the patient’s position on the operating table so
that the exposure is as good as possible. The upper pole of the kidney is
the best guide to the adrenal on each side, and the gland is recognized by its
orange colour. The adrenals are friable, and if cells are spilled they may
regenerate. To avoid this they are handled as little as possible with the
forceps and are removed with a thin covering of fat. They may be mo-
bilized by blunt and sharp dissection with scissors. In the absence of a

ADRENALECTOMY

123

tumour bleeding is rarely troublesome, and usually the vein on each side is
the only vessel which requires ligation. The small vessels can be sealed
with diathermy. Tumours, particularly carcinomas, may have many
additional vessels which must be ligated as they are encountered before the
tumour is removed. Gross invasion of the surrounding tissues may make
their removal impossible, but removal of the kidney (and the spleen) may
enable the whole tumour to be excised. A careful search should always be
made for ectopic adrenal tissue near the main glands.

Left adrenalectomy

The patient is placed in the lateral position with the left side uppermost,
and the table is well ‘‘broken" with its apex under the line of the incision

Fig. 3. IS. /to’rtnmVcAjntr Aunro - trMmtatsI incfshn.

The position of the patient on the operating table.

(fig. 3.18). It must be remembered that the ribs and vertebrae may be
fragile in Cushing’s syndrome. A straight incision is started over the outer
border of the sacrospinalis muscle and extended along the line of the lltb
or 12th rib (whichever is chosen) well into the abdominal wall. The rib and
abdominal muscles are exposed and the rib resected subperiosteally as far
back as its angle. The abdominal muscles and lumbar fascia are incised
and the intercostal or subcostal nerve and vessels are preserved carefully.
The bed of the rib is incised, the diaphragm is divided and the pleura is

124

THE ADRENAL CORTEX

avoided with care. If the pleural cavity is opened inadvertently the lung
must be inflated before the incision is closed. Retractors are inserted, the
kidney found by palpation and the renal fascia incised. The kidney is
retracted downwards and the adrenal identified at its upper pole. 'The in-
experienced may easily mistake the tail of the pancreas for the adrenal.
The peritoneal cavity is opened in front of the colon and the ovaries and
opposite gland are palpated. If subtotal removal is proposed the lateral
and anterior aspects are cleared without disturbance of the gland pos-
teriorly or injury to the small vessels which enter its periphery, and a small

The upper pole of the gland has been severed from the mam portion. Timken line*
indicate position of resected 11th nb.

corner — not more than one-tenth of the whole — is selected to be left in the
body. The upper pole is usually suitable and is severed from the main
portion of the gland with scissors (fig. 3.19). If it is viable its colour
remains unchanged and blood oozes from its cut surface. If it becomes
blue the process is repeated with another corner. The remainder of the
gland is then removed and the vein, which usually passes down from its
medial aspect to the renal vein, is ligated and divided. If total adrenalec-
tomy is proposed the gland is removed in one piece. After haemostasis has
been secured the tabic is straightened and the incision closed with inter-
rupted sutures. The main layer is the rib bed behind and the lumbar
fascia in front. The superficial muscles are sutured and the skin closed.
Drainage is not usually required.

ADRENALECTOMY

125

Right adrenalectomy

The lateral position is again used. If the 1 1th or 12th rib incision is used
the procedure is the same as that on the left side. With the higher incision
the 10th rib is resected from its angle to the costal margin and the pleural
cavity is opened. The ribs are held apart with a self -retaining retractor, the
right kidney is palpated and the diaphragm is incised over it in the line of
the skin incision. The liver is held forwards with a retractor, the renal
fascia is incised and the adrenal located at its upper pole. The gland is
cleared on its anterior aspect and the vein (or veins), which enter the vena
cava directly, are found, ligated with the aid of an aneurysm needle and
divided (fig, 3.20). If this step is not undertaken early in the operation

A ligature has been placed on the divided adrenal vein and the gland (shown by dotted
line) has been remoted. Insert shows the adrenal, its vein and the inferior tena cava.

there may be serious bleeding. The gland is then removed, haemostasis
secured and the diaphragm sutured. The incision is closed in the same way
as that on the left, the lung is inflated and an intercostal, under-water drain
is left in place for one or two days.

Bilateral adrenalectomy by the abdominal route
The patient is placed supine and the table is "broken” under the 1 2th
thoracic tertebra. If the subcostal angle is wide a long transverse epigastric
incision, curved upwards in the middle, provides the best access. Other-
wise a long mid-line upper abdominal incision is made and, if necessary, is

126

THE ADRENAL CORTEX

extended laterally to either or both sides. Lateral tilting of the table first
to one side and then to the other assists the exposure of the glands. The
right adrenal is approached by retraction of the liver upwards and mobiliza-
tion of the duodenum towards the left and of the hepatic flexure of the
colon downwards. The left adrenal is exposed by mobilization of the
splenic flexure of the colon downwards and mobilization and retraction of
the spleen, stomach and tail of the pancreas upwards and to the right. On
each side the kidney is retracted gently downwards and the fascia incised
just above its upper pole. The adrenals are exposed fully and examined by
inspection and palpation. Finally, a careful search is made throughout the
para-aortic region and pelvis for ectopic tissue. When the adrenal tissue has
been removed the incision is closed in layers. Drainage is usually un-
necessary.

FURTHER READING AND REFERENCES
General

The adrenal cortex (1962). Brit. vied. Bull., Vo! 18, No. 2.

jones, i. c. (1957). The Adrenal Cortex. Cambridge University Press.

softer, l. J., DORTMAN, R. t. and cabrilove, j l. (1961). The Human Adrenal Gland.
Lea and Febiger, Philadelphia.

Symington, T. (1959). The human adrenal cortex in disease. In Modern Trends in
Pathology, p. 248. Ed. Collins, D. H. Buttcrworth, London.

Histology

landing, B. H (1955). Studies on the anatomy of the human adrenal cortex in
various functional states. In Ciba Foundation Coll. Ertdocr., Vol. VIII, p. 52.
Churchill, London.

SYMINGTON, T. (1962). The morphology and zoning of the human adrenal cortex.
In The Human Adrenal Cortrx, p. 3. Ed. Currie, A. R., Symington, T. and
Grant, J- K. Livingstone, Edinburgh.

Physiology

bayliss, r. i, s (1955). Factors influencing adrenocortical activity in health and
disease. Bril, tried. J., 1, 495.

Farrell, c., rRATT, a. d. and MELLiNCER, J. P. (1962). Adrcnoglomerulotrophin, a
diencephalic factor specific for aldosterone secretion. In The Human Adrenal
Cortex, p. 196. Ed. Currie, A. R., Symington, T. and Grant, J. K. Living-
stone Ltd , Edinburgh.

boss, E. J. (1959). Aldosterone in Clinical and Experimental Mediant. Blackwell
Scientific Publications, Oxford.

savers, c. (1962). Control and inhibition of adrenocortical secretion. In The
Human Adrenal Cortex, p. 181. Ed. Currie, A. R., Symington, T. and Grant,
J. K. Livingstone, Edinburgh.

Simpson, s. a., tmt, j. F. and bush, i. e. (1952). Secretion of a salt-retaining
hormone by the mammalian adrenal cortex. Lancet, 2, 226.

Jmestigalion

BORTit, R., Linder, a. ami RiONDtL, A. (1957). Urinary excretion of 17-hydrox>-
corticostcroids and 17-kctostc raids in healthy subjects in relation to sex, age,
body weight and height. Act a endocr. (Kbh.), 25, 33.

ciiennloi'r, R. (1962). Personal Communication.

rORTIICR READING 127

cope, c. L. and black, l\ c. (1958). The behaviour of J, C-Cortisol and estimation
of cortisol production rate in man. Clin. Set., 17, 147.

cope, c. L. and BLACK, E. G. (1959). The reliability of some adrenal function tests.
Brit, med J., 2, 1117.

cox, ft. l. (1962), The Hitman Adrenal Cortex, p. 383. Ed. Currie, A R., Syming-
ton, T. and Grant, J. K. Livingstone, Edinburgh.

hamburger, c. (1948). Norma! urinary excretion of neutral 17-ketosteroids with
special reference to age and sex variations. Acta endoer. (Kbh.), 1, 19.

/ONES, JC. AT., LLOYD-JONES, R., RIONDEL, A., TAIT, J r., TAIT, S. A. S., BULDROOK,
B. D. and greenwood, F. c. (1959). Aldosterone secretion and metabolism in
normal men and women in pregnancy. Acta Endoer. {Kbh.), 30, 321.

loraine, j. A. (1958). Adrenocorticotrophin. In Chmcnl Application of Hormone
Assay, p. 110. Livingstone, Edinburgh.

neill, D. W. (1962) Personal Communication

NOrymberski, J. K., STUBBS, R. D. and west, H. f. (1953), Assessment of adreno*
cortical activity by assay of 17-ketogenic steroids in urine. Lancet, 1, 1276.

Disorders of the Adrenal Cortex

HARDY,/, d. and Mcphail, j. l. (1960). Management of functioning tumours of the
adrenal cortex. Amer. J. Surg., 99, 433.

WEUiOURN, r. b, (1958). The surgical aspects of adrenocortical disorder Ann. roy.
Coll. Surg. Engl., 23, 292.

WOOD, K. F., LEES, f. and roscntiial, f. D. (1957). Carcinoma of the adrenal cortex
without endocrine effects. Brit.J. Surg., 45, 41.

Primary Aldosteronism

CONN, j. w, (1961). Aldosteronism and hypertension Arch, intern. Med , 107, 813

LUETSCher, j. a. (1962). Aldosteronism: review. In The Human Adrenal Cortex,
p. 479. Ed. Currie, A. R., Symington, T. and Grant, J. K Livingstone,
Edinburgh.

Smethwick, r. IL, kinsey, d. and wniTELAW, c. P. (1962). Surgical treatment of
hypertension— primary aldosteronism Netc Engl J. Med., 266, 160.

Cushing’s Syndrome

ALLOTT, E. n. and SKELTON, M. o. (1960). Increased adrenocortical activity associ-
ated with malignant disease. Lancet, 2, 278.

COHEN, r. b., chapman, w. b. and castlcman, B. (1959). Hyperadrenocorticism
(Cushing’s disease) : a study of surgically resected adrenal glands. Amer. J
Path., 35, 537.

Cope, R. and raker, j. w. (1955). Cushing’s disease, the surgical experience in the
care of 46 cases. Nevt Engl. J. Med., 253, 119, 165.

Crooke, a. c. (1935). Change in the basophil cells of the pituitary gland common to
conditions which exhibit sjTtdrome attributed to basophil adenoma, J. Path.
Sac!., 4i, 33P.

cushjnc, H. (1932). The basophil adenomas of the pituitary body and their clinica)
manifestations (pituitary basophilism). Bull. Johns Hopk. Hosp., 50, 137.

Mason, a. s., rjchardson, /. e. and KIND, c. E, (1958). Adrenalectomy in Cushing’s
syndrome. Lancet, 2, 649.

maunix, ir., karl, r. and GLENN, f. (I960). Adrenalectomy in Cushing’s syndrome.
Amer. J, Surg., 99, 449.

Montgomery, D. A. d. and wt.lbourn, r. B. (1957). Cushing’s syndrome. A report
of thirteen cases and their surgical treatment. Brit.J. Surg., 45, 137.

Montgomery, ». A. D. and weuiourn, r. u. (1959). Cushing’s syndrome: a review.
Quart. Rev. Surg. Obstet. Gynec., 16, 201.

MONTGOMERY, D. A. n., WELBOURN, R. B., MCCAUCHEY, W. T. E. and CLEADHILL, C. A.
(1959). Pituitary tumours manifested after adrenalectomy for Cushing’s
syndrome. Lancet, 2, 707.

128 THE ADRENAL CORTEX

plotz, c. M., KNOWLTON, A. I. and ragan, c. (1952). The natural history of Cush-
ing's syndrome. Amer.J. Med., 13, 597.

Rices, B. L. and sprague, R. c. (196t). Association of Cushing's syndrome and
neoplastic disease. Arch, intern. Med., 108, 841 .

SALAS3A, R. M., KEARNS, T. P., KERNOHAN, J. W., SPRAGUE, R. C. and MACCARTV, C. 8.
(1959), Pituitary tumours in patients with Cushing’s syndrome. J. dm.
Endocr., 19, 1523.

Sprague, R. g., AVEEKS, r. E., Priestley, j. T. and salassa, R. m. (1961). Treatment
of Cushing’s syndrome by adrenalectomy. In Modern Trends m Endocrinology,
p, 84. 2nd Series. Ed. Gardiner-Hdl, H. Butterw orth, London.

T7;e Adrenogenital Syndrome

BONGIOVANNI, a. M. and EBOtLEiN, w. R. (1961). Defects in steroidal metabolism of
subjects with adrenogenital syndrome. Metabolism, 10, 917.

BROOKS, R. V., MATTINCLY, D., MILLS, I. H. and PRUNTY, F. T. C. (1 960) Postpubertal
adrenal virilism with biochemical disturbance of the congenital type of adrenal
hyperplasia. Brit. mcd.J., 1, 1294.

eberllin, tv. R. and bongiovanni, A. M. (1960). Pathophysiology of congenital
adrenal hyperplasia. Metabolism, 9, 326.

CALLACHER, T F., KAPP.AS, A., HELLMAN, L., LirSETT, M. B., PEARSON, O. H. and
west, c. d. (1958). Adrenocortical hyperfunction in idiopathic hirsutism and
the Stcin-Lcventhal syndrome. J. chn. Invest., 37, 794.

PERLOFF, w. II., IIADD, II E., CHANNICK, B. J. Ond NODINE, J. II. (1957). Hirsutism.
Arch, intern. Med., 100, 981.

Tomkins, G. and Mcclmre, j. s. (1960). The adrenogenital syndrome. In The Meta-
bolic Basis of Inherited Disease, p. 637. Ed Stanbury, J. B., Wyngaardcn,
J B. and Fredrickson, D. S. McGraw-Hill, New York.

Feminising Tumours

Armstrong, c. N. and Simpson, j. (1948). Adrenal feminism due to carcinoma of
the adrenal cortex. A case report and review of the literature. Brit, tried. J., I,
782.

wilkins, L. (1948). Feminizing adrenal tumour. J. dm. Endocr,, 8, 111.

Adrenocortical Insufficiency

beck, R. N. and Montgomery, d. a. d. (1956). Treatment of Addison’s disease.
Brit. med. J., 2, 921.

buzzard, n. m., chandler, r. %v., kyle, m. a. and hunc, w. (1962). Adrenal anti-
bodies in Addison’s disease Lancet, 2, 901.

hart, f. D. (1957). Treatment of adrenocortical deficiency states. Brit. med.J., I,
417.

Adrenalectomy

Ellison, E. Ii. (1960). Anterior trnnsabdomtnal ndrcnalcitomy for endocrine
disease. Amer. J. Surg., 99, 497.

PRINGLE, j. s. (1957). Adrenalectomy. In Operable Surgery, Tart VIII, p. 51.
Ed. Rob., C. and Smith* R. Buttcrworth* London.

CHAPTER 4

THE TESTIS

The testes are the primary organs of sex in the male. The gonadotrophins
of the anterior pituitary control their maturation at puberty and maintain
their structure and function in adult life. The testes have two main parts
with separate, but related, functions. The seminiferous tubules, which
produce spermatozoa, are under the control of follicle stimulating hormone
(FSH), while the interstitial or Leydig ceils, which secrete testosterone,
are under the influence of interstitial cell stimulating hormone (ICSH).

DEVELOPMENT

Towards the end of the second month of embryonic life the testis
appears on the gonadal ridge, dose to the developing kidney and adrenal
cortex. At this stage it is relatively large and its lower end lies close to the
anterior abdominal wall, where it is anchored by the ligamentum testis
(which later forms the gubernaculum). As the body develops the spinal
column straightens and the kidney, adrenal cortex and the origins of the
testicular vessels, which remain close to the spine, become separated from
the testis. By this differential growth, and not by "descent”, the testis
comes to lie at the internal inguinal ring by the eighth month of foetal life.
In the next part of its development, however, the testis does descend
through the inguinal canal and into the scrotum. It is preceded by the
processus vaginalis of the peritoneum and by the gubernaculum testis, and
it takes with it coverings from the muscles of the abdominal wall. One
derivative of these is the cremaster muscle, which is responsible for the
retraction of the testis. The testis normally reaches the scrotum just before
birth and the processus vaginalis becomes obliterated soon afterwards.
Whether or not hormonal factors influence any of these processes is un-
certain, but there is evidence that the final descent into the scrotum is
controlled partly by chorionic gonadotrophin (ICSH) from the placenta,
which stimulates the production of testosterone by the interstitial cells of
the foetus.

Primitive germ cells arc recognizable histologically after about six
weeks of gestation and the primary sex cords, which eventually form the
seminiferous tubules, can be seen a week or two later. Central lumina
129

130

THE TESTIS

develop in some of these towards the end of pregnancy. For the first
few years of life the testis remains in a "resting phase" and no further
change is seen. Around the age of 6, however, it enters a "growth phase"
which lasts until puberty. The seminiferous tubules enlarge, all of them
derelop lumina and the nuclei of the germinal syncytium form two distinct
layers. The final “maturation phase” starts with the onset of puberty at
about the age of 10 and is controlled by FSH. The tubules enlarge and
become tortuous. The syncytium differentiates into a germinal epithelium,
Sertoli cells become evident and spermatogenesis commences. When the
process is complete mature spermatozoa are produced.

Interstitial cells appear in large numbers by the fourth month of intra-
uterine life, possibly under the stimulus of chorionic gonadotrophin or of
the foetal pituitary They regress later and disappear soon after birth.
They reappear at the onset of puberty, under the influence of ICSII, and
assume their adult form. The embryology of the testis and of the genital
ducts is considered further in Chapter 17.

ADULT STRUCTURE AND FUNCTION

The adult testes are paired organs which lie in the scrotum. The average
dimensions of each are 4 to 5 cm. by 2*5 to 3 cm. and the weight is about
20 to 30 g. Normal organs, however, vary considerably in size. Each organ
is contained in a tough fibrous sheath, the tunica albuginea. Occasionally a
nodule of ectopic adrenocortical tissue is found in one or both testes or
spermatic cords.

Blood supply

The testicular arteries, which arise from the aorta just below the renal
\csscls, supply the testes with blood. Their communications with other
vessels and their distribution within the testes have important surgical
implications. In the spermatic cords the testicular arteries anastomose
freely with branches from the artery to the vas and, less commonly, with
branches from the cremasteric artery'. Consequently, division of the
testicular artery within the abdomen is comparatively harmless, while
division or injury low in the spermatic cord almost always causes atrophy of
the testis. As it approaches the testis the artery gives off branches to the
epididymis and then usually divides into two or more branches. These
enter the organ at variable points on its posterior border and are distributed
in an inconstant pattern over the surface beneath the tunica albuginea,
where they are usually visible. When they reach the front of the testis they
give off branches, which are end arteries and which therefore receive no
further anastomotic branches. These follow the fibrous septa towards the
mediastinum and finally turn outwards again to supply the substance of the
organ. Clearly, incisions or sutures into the tunica albuginea may damage

AI1ULT STRUCTURE AND TUNCTJON

131

the main vessels lying beneath it and cause atrophy. The veins which
drain the body of the testis converge towards the mediastinum to form the
pampiniform plexus, which anastomoses with the cremasteric vein. At the
top of the scrotum the plexus gives place to three or four large veins, which
in turn unite to form two testicular veins. Within the abdomen these unite
into one testicular vein on each side of the body. That on the right enters
the inferior vena cava close to the origin of the testicular arteries and that
on the left joins the left renal vein. The veins are much less liable to serious
damage than the arteries.

Spermatogenesis

Spermatogenesis is controlled by FSH and 3lso requires the presence of
testosterone.

The seminiferous tubules, which are long, convoluted structures about

Fig. 4.1. Diagram showing portions of two seminiferous tubules, the stages of
spermatogenesis and a group of interstitial (Leydig) cells.

200 (I in diameter, are responsible for the main bulk of the organs. There
are several hundreds of them in each testis. The tubule is surrounded by a
thin basement membrane and lined by two types of cell, the spermato-
genetic cells and the supporting or Sertoli cells (fig. 4.1). Spermatogenesis
proceeds by stages. The earliest cells, which lie on the basement mem-
brane, are the spherical spermatogonia. They produce, by repeated mitotic
division, the primary spermatocytes, which are pushed out towards the

132

THE TESTIS

lumen. Each of these then divides by meiosis, or reduction division, to
form the smaller secondary spermatocytes, and these divide once again to
form the spermatids, which are eventually converted into spermatozoa.
The behaviour of the chromosomes during these processes is described in
Chapter 17. The Sertoli cells are larger than the spermatogonia and rest
on the basement membrane. They project towards the lumen of the tubule,
tapering as they do so. As the spermatids are formed they become attached
in clusters to the Sertoli cells and actually penetrate into their cytoplasm,
where they develop into spermatozoa. The fully formed germ cells arc then
displaced into the lumen by the immature cells pressing behind them. The
Sertoli cells not only aid the development of the spermatozoa but, as will be
mentioned later, may also have an endocrine function.

Each spermatozoon has a pointed head, about 2-5 fi in length, and a Jong
tail which extends for 35 fi or more. Many details of the fine structure have
been revealed recently by the electron microscope. The spermatozoa pass
down the seminiferous tubules, through the network of the rcte testis,
along the efferent ductules and into the duct of the epididymis. Thus far
their passage is probably passive, induced by the pressure of the new
spermatozoa behind and possibly by the actions of the cilia and smooth
muscle in the walls of the efferent ductules. During their passage through
the epididymis, however, they become actively motile and attain their
maximum capacity for the fertilization of ova. When they enter the vas
deferens they are ready for ejaculation. The fluid part of the semen is con-
tributed by the seminal vesicles, prostate and bulbo-urethral glands.

The temperature within the scrotum is 1-5° to 2° C below that in the
abdomen, and normal development and function of the seminiferous
tubules can take place only at this lower temperature.

The interstitial or Leydig cells

The Leydig cells are arranged in groups in the connective tissue sur-
rounding the seminiferous tubules. They have large nuclei and their cyto-
plasm contains lipid droplets and pigment. They are richly supplied with
blood vessels. Similar cells can also be recognized commonly in the tunica
albuginea and rete testis and occasionally in the more remote coverings of
the testis or in the epididymis. Under the influence of 1CSH they secrete
testosterone. The Leydig cells are less dependent than the tubules on a
cool environment.

Physiological actions of testosterone

Testosterone is the most potent natural androgen. It controls the normal
development and function of the male sexual organs, causes the appearance
of the secondary sex characters and has other widespread metabolic effects.
The weaker adrenal androgens may participate in these functions, but they

ADULT STRUCTURE AND FUNCTION 133

are not essential. Testosterone is secreted actively from puberty until late
middle age, but its production is usually decreased in old age. In excess it
inhibits the production of its trophic hormone, ICSH, but there is no
diurnal or periodic change in the levels of secretion of the two hormones.

Sexual organs

Testosterone controls the development of the penis, scrotum, prostate
and seminal vesicles at puberty. Later it maintains their adult structure and
controls the erection of the penis and the volume of the ejaculate. The
presence of testosterone is required for FSH to exert its full influence on
the development of the seminiferous tubules and spermatogenesis.

Secondary sex characters

Testosterone causes the growth of hair on the face, in the axillae, on the
chest and in the pubic region at puberty, and is responsible for the upward
growth of hair towards the umbilicus in the midline (the so-called “male
escutcheon": A). In middle age (or sometimes earlier) it causes the bi-
temporal recession of hair and baldness of the crown which are charac-
teristic of the male. At puberty it causes the larynx to enlarge and the voice
to deepen, and makes the skin relatively coarse and greasy.

Metabolic effects

Testosterone is a powerful stimulant of protein anabolism. It increases
the bulk of the muscles and stimulates growth of the bone matrix, thus
causing a spurt in growth at puberty. Finally, it causes the epiphyses to
close when growth is complete. Testosterone supports the growth of
carcinoma of the prostate and of the male breast.

Metabolism of testosterone (Chapter 2)

Testosterone is metabolized rapidly in the liver and is mainly excreted in
the urine in the form of conjugated 17-oxosteroids. The principal meta-
bolites are androsterone and aetiocholanolone. A small proportion is
secreted into the bile and appears in the faeces. Testosterone is apparently
also metabolized in part to oestrogens. There is evidence that the prostate,
an end organ influenced by testosterone, is also capable of metabolizing it.

The metabolic activity of the liver renders salts of testosterone ineffective
when swallowed. They must be given by the buccal route (as sublingual
tablets) or parenterally, so that they avoid the portal circulation.

Testicular oestrogen

The Leydig or Sertoli cells (it is uncertain which) secrete small quan-
tities of oestrogen. Its function is not known, but it may inhibit the
pituitary and limit the production of FSH as it does in the female. This

134

THE TrSTIS

function has also been attributed to a hypothetical "X hormone” or
“inhibin” which may be formed by the Sertoli cells.

Puberty

Puberty is the stage at which a person becomes functionally capable of
procreation. Legally (in Britain) this occurs at the age of 1+ in boys, but
puberty is a process which has many physical and mental aspects and which
extends over several years.

Clinically it is important to know whether puberty is progressing nor-
mally or whether it is premature or delayed. The following table, compiled
by Seckel, is a useful guide. It should be compared with the similar one for
girls (p. 174).

Average approximate age and sequence of appearances of sexual characteristics in boys
Age 10-11 First growth of testes and penis.

11- 12 Prostatic activity.

12- 13 Pubic hair.

13- 14 Rapid growth of testes and penis. Subareolar node of nipples.

14- 15 Axillary hair. Down on upper lip. Voice change.

15- 16 Mature spermatozoa.

16- 17 Facial and body hair. Acne.

21 Arrest of skeletal growth.

These figures represent the normal average times, but the normal ranger are very wide.

It should be noted that palpable enlargement of the breasts is very
common in normal puberty and should not be regarded as pathological.

Coitus

Coitus, by which the sperms arc introduced into the vagina, depends on
the presence of testosterone and on the integrity of many parts of the
nervous system. The higher centres normally initiate the act, but may also
inhibit it. Erection and ejaculation, however, can be induced rcflcxly in a
paraplegic man. Afferent stimuli pass from the glans penis, via the pu-
dendal nerve (S2-4), and from other areas to the spinal cord. A centre for
erection in the lumbosacral part of the cord sends impulses, via the nervi
crigentes (S2-3), which cause the arterioles of the corpora cavernosa and
spongiosa of the penis to relax. As the erectile tissue fills with blood the
dorsal vein of the penis is compressed and the outflow is reduced. The
centre for ejaculation 13 in the upper lumbar region of the cord. It sends
impulses, via the lumbar sympathetic trunks (Ll-2), which cause the
muscles of the vasa deferentia, the seminal vesicles and the prostate to con-
tract rhythmically and eject the semen into the urethra. At the same time
sympathetic impulses relax the detrusor muscle and cause the internal
sphincter to contract, thus inhibiting micturition and preventing the reflux
of semen into the bladder. Ejaculation from the urethra is effected by

INVESTIGATION OF TESTICULAR DISORDERS 135

rhythmic contractions of the perineal muscles, which are supplied by the
perineal branch of the pudendal nerve (S2-4).

INVESTIGATION OF TESTICULAR DISORDERS

The following methods are used routinely in the investigation of
testicular disorders:

1. Clinical

The testes are inspected and palpated. The position (intra- or extra-
scrotal), size, shape, consistency and sensibility of each is noted. The body
as a whole is examined and the secondary' sexual characters are assessed.

2. Excretion of 17 -oxasieroids (table 3.1)

Estimation of the excretion of 17-oxosteroids is of limited value in
diseases of the testes because about two-thirds of the total amount in the
urine are derived from the adrenal cortex. Complete elimination of the
testes as a source of androgens results only in low normal figures. Very' high
levels, however, may be found in patients with virilizing testicular tumours.

3. Excretion of gonadotrophins (table 1.2)

Estimation of total gonadotrophins (FSH -f- ICSH) in the urine is of
great help in distinguishing between true and false puberty and between
primary and secondary types of hypogonadism. Very high values for total
gonadotrophins and for ICSH may be found with certain testicular
tumours, although estimation of the latter cannot be done routinely.

4. Seminal analysis

Examination of the semen is of great value in the investigation of tubular
function. The specimen is obtained by stimulation of the penis after three
to five days’ abstinence from intercourse. A clean, dry, vvide-moutbed
container (of glass or plastic material), warmed to body temperature, is
used. The specimen must be as fresh as possible when it is examined and,
for this reason, it is preferable for it to be collected in the laboratory. A
condom specimen is useless because chemicals in the sheath reduce
motility and lead to clumping of the spermatozoa. The following observa-
tions are made:

(a) Volume. Normal 3-6 ml.

(b) Sperm count. Normal 40-200 million per ml. Some authorities
accept 20 million as an adequate figure, and pregnancy has been achieved
by men with counts lower than 10 million per ml.

(e) Motility is difficult to assess accurately, but if more than 40 per
cent of the spermatozoa are actively motile, and remain so for 12 hours or
more in vitro, they are probably normal.

136

THE TESTIS

(d) Morphology too is difficult to assess, hut is certainly less impor-
tant than the total count and the motility. In normal semen at least 60 per
cent of the spermatozoa are morphologically normal.

(e) Miscellaneous. The colour, turbidity and viscosity of the semen are
noted with the naked eye and the presence or absence of red blood cells,
pus cells, bacteria and trichomonads is observed microscopically.

If the analysis is normal tubular function is adequate. If it is abnormal it
must be repeated two or three times, at intervals, before it can be accepted
as evidence of disturbed function. If, for any reason, a sperm analysis is
impossible an examination may be made of the cervical mucus from the
patient’s wife, within a day of intercourse, preferably neaT the time of
ovulation. This will indicate whether or not reasonable numbers of motile
sperm are being produced and reaching the cervix.

5. Testicular biopsy

This investigation is of very great value, particularly in the diagnosis of
hypogonadism and of precocious puberty. However, it must not be
assumed that a small piece of tissue taken from the periphery of the testis
is necessarily representative of the whole organ. Atrophic changes may be
seen there while the centre of the testis is relatively normal ; and the con-
verse is also true. It is best to have the patient fully anaesthetized, although
the biopsy can be done under local anaesthesia as an out-patient procedure.
A transverse scrotal incision gives good access to both testes. A piece of
scrotal skin may be removed for chromosomal analysis. The scrotal con-
tents — the testes, epididymes and vasa — are examined carefully and their
dimensions and relationships are noted. The tunica vaginalis is incised and
a small incision is made in the testis. It is essential that the blood supply to
the organ should not be damaged, or atrophy may result. The main
vessels can usually be seen beneath the tunica albuginea, but, for safety's
sake, the incision should be transverse to the long axis of the testis and on its
lateral surface. A little parenchymatous tissue herniates through the in-
cision and is removed with the knife and placed in fixative. It is better to
apply pressure until the oozing stops than to introduce sutures.

6. Chromosomal analysis

This is helpful in the recognition of Klinefelter’s syndrome and other
types of anomalous sexual development (Chapter 17).

7. Other methods

Two other methods, which provide information about the seminal con-
ducting mechanism (and not about the testicles themselves), are cathe-
terization of the ejaculatory ducts at urethroscopy and injection of the vasa

PRECOCIOUS PUBERTY

13?

deferentia with radio-opaque material at open operation. The estimation
of oestrogens in the urine is helpful in the rare cases of feminizing testicular
tumours (table 5.2).

TESTICULAR LESIONS AND DISORDERED FUNCTION
The testes may be affected by a large variety of pathological processes—
congenital, traumatic, inflammatory, degenerative, neoplastic, etc. — all of
which may influence either or both of their two main functions. Further-
more, they may either be stimulated earlier than normal by the pituitary
gonadotrophins or not stimulated at all. The ways in which hypergonadism
and hypogonadism may be produced are as follows:

Functional

Nature of disorder

Clinical syndromes resulting from
affections of.

disturbance

Leydig cells |

Seminiferous

tubules

Hypergonadism

Precocious stimulation I

j Precocious puberty

Tumour

j Pseudopuberty I

Hypogonadism

Lack of stimulation

Intrinsic lesions

Some testicular lesions have diverse and unsuspected endocrinological
significance. Thus, certain intrinsic lesions of the tubules, while not ob-
viously associated with hormonal deficiency, can be treated effectively with
androgens. Cryptorchidism may cause hypogonadism and may be in-
fluenced by gonadotrophins. Lastly, testicular tumours may secrete a
variety of hormones, including gonadotrophins (which have no clinical
effects), androgens (which cause pseudopuberty) and oestrogens (which
cause feminization).

In the following pages precocious puberty and hypogonadism are treated
as clinical entities, but the other aspects of disordered function are dis-
cussed under pathological headings.

PRECOCIOUS PUBERTY

When puberty starts early it is described as "precocious”. The term
cannot be defined precisely because of the wide normal limits, but obvious
sexual characters appearing before the age of 10 should be regarded
seriously. The problem is much less common in boys than it is in girls, but
the cause is more often serious and should always be sought.

Precocious puberty in boys is practically always “isosexual”; that is to
say the secondary sexual characters are masculine. In "true" precocious

138

TIIE TESTIS

puberty the pituitary secretes gonadotrophins which stimulate the develop-
ment of the testes and the production of testosterone. The testes assume
the adult size, and spermatogenesis and Teydig cells arc usually seen
histologically. In "false” or pseudopuberty androgens arc formed elsewhere
in the body and cause the development of secondary sex characters. They
inhibit the secretion of gonadotrophins and the testicles remain small.
“Heterosexual” pscudopuberty (in which the female characters arc caused
by an oestrogen-secreting tumour) is so rare in boys that it can be ignored.

Causes

The causes of precocious puberty, and the numbers of each type which
have been reported, are as follows (after Wilkins):

(A) True puberty (Testes developed)

1. Constitutional (idiopathic)

2. Intracranial lesions

Hypothalamic lesions
Pineal tumours
Uncertain

3. Albright's syndrome

(B) Pseudopuberly (Testes immature)

1. Testis — Leydig cell tumour 18 76 (32%)

2. Adrenal cortex — virilizing hyperplasia 42

\inhzrng tumour 16

Total 240 (100%)

This table should be compared with the similar one for girls (p. 177).

The cause of constitutional precocious puberty (fig. 4.2) is unknown, but a
few cases are familial. For some reason the hypothalamic-pituitary
mechanism starts to operate too soon. Extensive investigations fail to
reveal any other abnormality. Puberty may start as early as 2 years of age
and develop rapidly. The skeletal changes are the same as those seen in
congenital virilizing adrenal hyperplasia. Growth is rapid but stops early,
and the final height is usually less than 5 feet. Dentition usually proceeds
normally. Mental development is essentially normal, but there is often an
abundance of physical energy and strength. Psychosexual development is
not usually precocious, but the boys often masturbate from an early age.
Precocious intercourse is tare. Few patients have been followed for long*
but most of them probably grow up into adults who are normal apart from
their small stature.

Intracranial lesions presumably cause the hypothalamus to stimulate the
anterior pituitary to produce gonadotrophins. They include tumours of
the posterior hypothalamic area, many of which originate in the pineal
gbnd. Other causative lesions are encephalitis, tuberose sclerosis, tuber-
culous meningitis and congenital brain defects. All these conditions give

PRECOCIOUS PUBERTY

139

rise to other clinical features, such as signs of hypothalamic damage,
internal hydrocephalus and compression of the optic chiasma, in addition
to sexual precocity. The prognosis is usually poor.

Fig. 4.2. Constitutional precocious puberty in a boy aged 2J years.

Testicular biopsy showed active spermatogenesis.

Albright's syndrome very rarely causes precocious puberty in boys. The
lesions which cause pseudopuberty are described elsewhere.

Diagnosis

Diagnosis of the cause of precocious puberty depends on clinical
examination and on the results of special investigations. It should be
remembered particularly that there is an intracranial lesion in about one-
third of the cases of true precocious puberty. Examination should be
repeated at regular intervals if no lesion is detected. Inspection and palpa-
tion of the testicles helps to distinguish true puberty from pseudopuberty.
The immature testis is usually less than 2*5 cm. in length. In doubtful cases,
biopsy is helpful. The usual findings in true puberty are spermatogenesis
and an abundance of Leydig cells, and in pseudopuberty, immature semini-
ferous tubules and absence of Leydig cells. A nodule or firm enlargement
of one testis raises the suspicion of a Leydig cell tumour or of a nodule of
virilizing adrenal tissue (tumour or hyperplasia). Very rarely hyperplastic

140

THE TESTIS

adrenal tissue is found on both sides. Biopsy is indicated in these cases.
Measurement of the I7-oxostcroids is of great value. In true puberty the
level is that found in normal adolescents or adults (2 to 18 mg. per 24
hours) Higher le\els arc usually found in the \irilizing lesions associated
with pseudopuberty. Estimations of total gonadotrophins in the urine have
not proved entirely reliable. A high level of excretion is often, but not
always, found in true puberty. They are absent in pseudopuberty. Special
neurological or other investigations must be undertaken in cases of true
precocious puberty if the clinical findings warrant them. The other find-
ings in virilizing adrenal lesions and of Leydig cell tumours of the testis arc
described elsewhere.

Treatment

Treatment of constitutional precocious puberty involves an explanation
to the parents and to the child, when appropriate, of the nature of the

Fig. 4.3. Growth curve rn constitutional precocious pubert) (patient shown
in 4.2).

Sttlboestrol odmin'ulered from »ge jears |o control behaviour.

HYPOGONADISM

141

disorder and an assurance that final sexual development will be normal. It
is important that the child’s true age should be remembered and that he
should not be treated as if he were older. It is very easy, because of his
physical maturity, to make demands on him with which, because of his
mental age, he is unable to comply. Most authorities advise against any
form of endocrine therapy, but oestrogens, given to one boy of 4, made him
much easier to manage, cured his acne and stopped him masturbating. Its
effect on his growth is shown in fig. 4.3. Treatment of other types de-
pends on the underlying lesion. The prognosis in patients with intracranial
lesions is generally poor. Adrenal lesions (except malignant tumours) and
testicular tumours can usually be treated very effectively.

HYPOGONADISM

Hypogonadism implies defective function of both testicles. This may
involve the Leydig cells or the tubules or both. Deficient secretion of
androgens causes eunuchoidism, while deficient spermatogenesis causes
sterility. A ’’eunuch” is a male who has been castrated before puberty. A
’’eunuchoid” is a man who has the physical characteristics of a eunuch
from some other cause. Infantilism implies diminished somatic growth
associated with sexual immaturity.

Clinical features of hypogonadism (androgen deficiency)

Since the testes do not normally function until puberty, hypogonadism
cannot arise until adolescence. Even then, because of the great variation in
the time at which normal puberty occurs, the condition cannot be diagnosed
before the age of 16 or 17 years. It may, of course, be possible to recognize
at an early age a lesion which will inevitably cause hypogonadism later.
The clinical features depend on whether the deficiency appears before or
after the age of puberty.

Puberal hypogonadism (fig. 4.4)

The testes never secrete androgens in normal amounts. The severity of
the clinical picture depends on the degree of the deficiency, and the
description which follows applies to cases in which testosterone is absent.
As in most clinical syndromes, individual variation is great, and some of the
features which are described are found in otherwise normal men.

The testes themselves are nearly always smaller than normal and in-
sensitive, and they may be minute or absent. The scrotum is usually small
also, the penis is small or even infantile and the prostate is impalpable.

Hair is scanty on the body, in the pubic region, and on the face. Axillary
hair is often sparse, but may be normal. Hair grows freely on the scalp and
fails to recede at the temples or to disappear from the crown as it does in the

142

THE TESTIS

normal male. The skin tends to be thin and soft and the face often looks
pale. Acne does not develop. True gynaecomastia (Chapter 13) is some-
times present, but the cause of it is unknown. It tends to be commoner in
partial hypogonadism than in complete testicular failure.

Fig. 4 4. Untreated puberal hypogonadism in a man aged 23.

Note height, long arms, sparse hair and smalt genitalia.

The muscles are poorly developed and flabby, so that heavy and pro-
longed work is impossible. The heart tends to be small, the pulse rate may
be slow and the blood pressure is sometimes low. There are often localized
deposits of fat over the symphysis pubis, behind the breasts, over the
abdomen and on the buttocks, and some patients develop generalized
obesity.

Abnormalities of skeletal growth arc usually obvious. The rapid growth
that is often associated with puberty does not take place and the epiphyses
are very slow to unite. Hence the “bone age" during adolescence is re-
tarded. Provided the production of growth hormone by the pituitary is
normal, growth of the long bones, hands and feet proceeds slowly, but
uninterruptedly, until the age of 25 or 30, and the final stature is often
unusually great. (Absence of growth hormone and gonadotrophins, as
in hypopituitarism, causes infantilism.) The hands and feet are long, so
that the span exceeds the height, while the distance from the symphysis

HYPOGONADISM

143

pubis to the soles exceeds that from the vertex to the symphysis. The
pelvis often becomes gynaecoid, and its width exceeds that of the shoulders,
as it does normally in women. There is sometimes osteoporosis, but its
mechanism is not understood. Slipping of the femoral epiphysis, which is
sometimes loosely attributed to “endocrine" causes, may occur in “con-
stitutional familial obesity”. Dentition is often poor and delayed. The
larynx usually fails to enlarge and the voice remains high-pitched, although
this may be obvious only when the patient is excited.

Libido is absent, and erections and emissions do not occur. Those who
secrete small amounts of androgens may be capable of intercourse, but
their sexual potency is low and they are sterile. Intelligence is unimpaired
and may even be great. The temperament tends to be more like that of a
woman than of a man. Feelings of inferiority about the lack of physical
development often lead to introspection, secretiv eness, shyness and de-
pression. There may be inertia and actual somnolence. Usually no in-
terest is taken in the opposite sex.

Postpuberal hypogonadism

The clinical picture is different from that of puberal hypogonadism,
since a normal puberty has already occurred and the primary and secondary
sexual characteristics have been established. The epiphyses have closed
and skeletal growth has stopped.

The condition of the testicles depends on the cause of the disorder, but
they often become small, soft and insensitive. The penis diminishes in size
and becomes flaccid, but it does not revert to its infantile dimensions. The
prostate involutes. The hair on the body and face tends to diminish, and
shaving usually becomes unnecessary after a time. Muscular mass and
strength diminish. There may be loss of appetite and of weight, but some-
times fat is deposited in the sites already mentioned. The voice is usually
unaffected in pitch, but may deteriorate in quality.

Libido and sexual functions are seriously impaired and often disappear
completely. Cases are on record, however, of men who have retained their
libido and remained fully potent for many years after bilateral castration.
Intelligence is unimpaired, but the mentality usually changes towards that
which is found in the puberal type of hypogonadism.

Hot flushes, similar to those of women at the climacteric, are sometimes
experienced.

VARIETIES OF HYPOGONADISM

There are numerous types of hypogonadism, and the causes of many of
them are not known. The following classification is based, first, on the
main clinical manifestations (androgen deficiency, tubular deficiency or
both), and secondly, on the aetiological factors so far as they are known.

144 THE TESTIS

i. Deficient function of Leydig cells and of tubules

A. Primary {Testicular)

(i) Congenital:

(a) Anorchia (testicular agenesis).

(ft) Cryptorchidism (undescended abdominal testes).

(e) Gonadal dysgenesis (Turner’s syndrome in the male and some cases of Kline-
felter's syndrome).

(d) CNS lesions

(m) Castration.

(а) Surgical.

(б) Traumatic.

(in) Ischaemia.

(<i) Damage to testicular arteries.

(ft) Thrombosis of testicular arteries.

(iv) Infective — orchitis:

(a) Mumps.

(ft) Syphilis, tuberculosis, leprosy, etc.

(v) Traumatic paraplegia.

(vj) Degenerative:

(a) Functional prepuberal castration.

(ft) Male climacteric.

D. Secondary (Pituitary)

(i) Constitutional.

(n) Hypopituitarism.

(hi) Hypogonadotrophimsm :

(a) Idiopathic.

(ft) Inhibition by oestrogen*, androgens or corticosteroids.

(e) Associated with chronic general disease or starvation
Primary

In the primary types the defect lies in the testes themselves. Absence of
both organs is extremely rare, and in some cases the vas and epididymis
(which are derived from the wolffian duct) develop normally and enter the
scrotum. Cryptorchidism rarely causes loss of Leydig cell function unless
the testes are intra-abdominal, and even then the function may be retained
for many years. Its effect on tubular function is described later. Gonadal
dysgenesis is discussed in Chapter 17. Hypogonadism is a common feature
of various CNS lesions, including dystrophia myotonicn, Friedreich's
ataxia and syringomelia, all of which are associated with testicular lesions
similar to those found in Klinefelter’s syndrome. Castration requires no
special discussion. Ischaemic damage is caused more frequently than is
commonly recognized during operations for hernia, cryptorchidism and
other affections of the testis, epididymis and cord. Spontaneous thrombosis
of the testicular artery, possibly due to thrombo-angiitis obliterans, is rare.
Mumps is the only common infection of temperate climates which damages
the testes. Mumps orchitis develops very rarely in children, but quite
commonly in those affected after puberty. Orchitis may precede the
parotid swelling. It is bilateral in about one-third of cases and causes
hypogonadism in about 10 per cent of those so affected. It has been

HYPOGONADISM

145

suggested that early surgical decompression (incision of the tunica al-
buginea) or treatment with oestrogens may reduce the damage, but the
evidence is inconclusive. It would be rational to give prophylactic treat-
ment with oestrogens (to inhibit gonadotrophins) during an attack of
mumps. Cortisone is ineffective. The testicular lesions following mumps,
leprosy and traumatic paraplegia are similar to those found in Klinefelter’s
syndrome. In functional prepuberal castration the testes apparently de-
velop normally, but degenerate during childhood. The condition may be
difficult to differentiate from congenital anorchia. The male climacteric
will be discussed later.

Secondary

In the secondary types the defect lies in the anterior pituitary' or in the
hypothalamus. Constitutional delayed puberty or “delayed growth and
adolescent development” is not very common in boys. Constitutional or
familial obesity of puberty is quite common, and must not be confused
with Frohlich’s syndrome (which is very rare). These have been discussed
in Chapter 1. In hypopituitarism the hypogonadism is usually over-
shadowed by the other features and is of little practical importance.
Frohlich’s syndrome and the Laurence-Moon-Biedl syndrome should
probably be included in this group. Idiopathic hypogonadotrophinim is the
commonest form of uncomplicated eunuchoidism, but its cause is un-
known. The secretion of gonadotrophins may be inhibited by an excess of
oestrogens, and for this reason it usually develops during oestrogen
therapy for carcinoma of the prostate and often in patients with cirrhosis
of the liver. In the latter the liver is apparently unable to metabolize endo-
genous oestrogens adequately. Excess of androgens has the same effect,
except that the secondary sexual characters are, of course, retained or
exaggerated. Corticosteroids may similarly cause hypogonadism, as in
Cushing’s syndrome. Chronic forms of general disease, which may inhibit
the production of gonadotrophins, include malnutrition (especially de-
ficiency of protein), chronic infections, hyper- and hypothyroidism and
uncontrolled diabetes.

Diagnosis

A careful history and general clinical examination are, of course, essential
and may yield valuable clues. The testes in all types are either absent or
small and soft. Estimation of the urinary total gonadotrophins helps to
distinguish the primary from the secondary group. In the former they are
high (100 MUU or more), because of the lack of testosterone, which
normally has an inhibitory effect. In the latter they are absent (4 MUU
or less) because the pituitary does not produce them. The 17-oxosteroid
excretion is usually in the low normal range because the adrenal secretion is

146

THU TESTIS

unaffected. An exception is provided by hypopituitarism, in which the 17-
oxostcroid excretion is very low or absent. Examination of the semen
reveals azoospermia or oligospermia, poor motility’ and many abnormal
forms. Testicular biopsy' shows deficiency’ of Leydig cells and of spermato-
genesis. The skin biopsy or buccal smear is chromatin negative.
Treatment

In the primary type replacement therapy with androgens is all that is
possible. The secondary sex characters can be developed normally, but
tubular function cannot be restored. Treatment should be started at the
normal time of puberty, and must be continued indefinitely.

Testosterone or mcthyltestosterone, by the sublingual route, is usually

r«s.4.S Tib. 4 6

Fig. 4.5. Small genitalia m untreated puberal hypogonadism in a man aged 23.
Fig. 4 6 Same patient after 1 year's treatment with testosterone.

given first (10 mg. three times a day) and the effect observed. After three
or four weeks the dose may need to be adjusted to suit the patient’s require-
ments. Once development has started, and the effective dose is known, a
longer-acting preparation may be used (see Chapter 6).

Treatment causes the voice to deepen, pubic and axillary hair to develop
and. ’.he pewis. axvi scecu.uot. va cwUegfi 4 A a.o/i 4 &y Facial. Imc g,tow s,

but not very vigorously. The body musculature develops, vigour increases
and weight improves. A spurt in growth of several inches may be observed
in those whose growth is stunted, but normal height is rarely attained be-
fore the epiphyses close. Over-treatment with testosterone induces fre-
quent erections and emissions and undesirable psychological effects.
Occasionally gynaccomastia develops as a result of treatment, but the
mechanism is unknown.

HYPOGONADISM

147

Testosterone replacement leads to improvement in morale and causes
youths to lose their embarrassment in the company of other bays. They
mature emotionally and become heterosexual in outlook. Sympathy
and understanding are required to assist these patients in responding
satisfactorily to treatment. With wise guidance their personalities can
be transformed and they become normally adjusted adult members of
society.

In the secondary type the ideal treatment, theoretically, is a combination
of the two main gonadotrophins, FSH and ICSH, Unfortunately no pre-
paration Df human FSH is available commercially, and ICSH (in the form
of chorionic gonadotrophin) must be given indefinitely by frequent
intramuscular injections (500 1U three times a week). The latter alone,
however, may be effective in promoting development not only of the Leydig
cells but also of the tubules. In a young patient with idiopathic hypo-
gonadotrophinism, therefore, it is probably the treatment of choice. If the
patient is older, and if fertility is unimportant, replacement therapy with
androgens may be given as in the primary' type. It seems possible that even
this may stimulate normal tubutar function and fertility in some patients.

Male climacteric

Gonadal function usually wanes gradually with advancing age without
causing any untoward symptoms. Sometimes it persists unabated into old
age. In some men, however, it ceases abruptly at about the age of 55 to
65 years (or rarely younger). It is thus comparable with the normal female
climacteric. The symptoms are loss of libido and impotence, irritability,
depression, loss of memory and an inability to concentrate. Hot flushes
may occur, but are much less common than they are in women. The
clinical features are, therefore, rather vague and may easily be attributed to
psychoneurosis. The diagnosis can be confirmed, how ever, by the finding
of a high level of excretion of gonadotrophins (100 MUU or more in 24
hours), similar to that found in menopausal women. Treatment with
androgens is highly effective.

z. Deficient function of tubules alone

(l) Increased temperature:

(o) Cryptorchidism (most cases).

(b) Varicocele.

(c) Scrotal supports and tight underclothing.

(u) Tubular lesions of unknown aetiology:

(а) Germinal aplasia.

(б) Maturation nn-est.

(e) Distuthed spermatogenesis.

(rf) Progressive peritubular fibrosis.

(iii) Klinefelter's syndrome.

(iv) Radiation damage.

(v) Associated with acute general disease.

148

THE TESTIS

Cryptorchidism nearly always causes irreversible tubular degeneration
unless the testes are in the scrotum at puberty. Varicocele (and possibly
hydrocele) sometimes causes impaired tub ular function and infertility, p re-
sumably because the. jemperature of the testis is raised . Scrotal supports
and tight underpants are said to be quite common causes of impaired,
s permatogenesis. The defect is remedied when they are left off. The
various tubular lesions can be recognized histologically. Little is known of
their causes or of their relationship to the different varieties of gonadal
dysgenesis (Chapter 17). In germinal aplasia the Sertoli cells are normal,
but spermatogenesis and the cells which are derived from them are absent.
The condition sometimes accompanies cryptorchidism. In maturation
arrest spermatogenesis proceeds to the stage of primary spermatocytes, but
reduction-division does not occur. In disturbed spermatogenesis there are
aberrations of cellular division and of the chromosomal pqttern, and im-
mature germ cells arc sloughed off into the lumina of the tubules. In
progressive peritubular fibrosis the connective tissue thickens, at first in
patches and later throughout the testis, obliterating the tubules. This
condition is probably distinct from Klinefelter’s syndrome (Chapter 17), in
which there is hyaline fibrosis of the tubules themselves. The seminiferous
tubules are very sensitive to ionizing radiation, and the resulting lesion is
similar to that of germinal aplasia. Spermatogenesis is depressed tem-
porarily by many acute general diseases. In fever the increased temperature
is probably an adequate cause, and in all acute forms of stress there is
probably impairment of gonadotrophin production.

Diagnosis

The history and clinical examination should reveal cryptorchidism and
varicocele or suggest the possibility of radiation damage. Many of the
patients with tubular lesions of unknown aetiology do not reveal any
physical abnormality and have testes of normal size and consistency.
Examination of the semen shows defective spermatogenesis or azoospermia.
The excretion of 17-oxosteroids is normal and that of gonadotrophins is
normal or high. High levels are found in the majority of patients with
Klinefelter’s syndrome. Histological examination of a testicular biopsy is
the only sure way of differentiating the various tubular lesions. The skin
biopsy is chromatin positive in most patients with Klinefelter's syndrome,
but negative in the others.

Treatment

The treatment of cryptorchidism will be discussed later. Operative
repair of a varicocele by ligation of the cremasteric veins via a scrotal in-
cision may restore tubular function and fertility. Fertility cannot lie in-
duced (by any known form of treatment) in patients with germinal aplasia.

HYPOGONADISM

149

progressive tubular fibrosis or Klinefelter’s syndrome. Recovery from
acute general disease is associated with restoration of normal spermato-
genesis.

In the remaining types — maturation arrest and disturbed spermato-
genesis — treatment with FSH is desirable theoretically. No suitable pre-
paration is available, but serum gonadotrophin, closely resembling FSH,
can be used in a dose of 1,000 IU intramuscularly daily for several weeks.
Testosterone therapy, however, is sometimes effective although there is no
evidence of androgen deficiency. Large doses (e.g. 100 mg. of testosterone
phenyl propionate weekly or 1 ml. of Sustanon 250 monthly) tend to
inhibit the production of gonadotrophins and to depress spermatogenesis.
However, if the injections are stopped after three to four months a "re-
bound phase” may follow, during which the production of gonadotrophins
is increased, spermatogenesis is improved and fertility is augmented.
Treatment is successful in about one-third of cases, and pregnancy results
within one to three years. It is remarkable that fertili ty is im piflycdjnore-
co nsistently than the res ul ts of the semen analysis, an d it may be that the
main effect of the androgen is to render e jaculation m ore efficient.

3. Deficient function of Leydig cells alone

A few patients have been described who exhibit features of eunuchoidism
(including impotence) and in whom testicular biopsies revealed abnor-
malities of the Leydig cells, but normal spermatogenesis. The Leydig
cells are few in number and appear inactive. The cause of the disorder is
unknown, but it is said to respond to treatment with ICSH (chorionic
gonadotrophin). The clinical disturbances should also, theoretically, re-
spond to treatment with androgens.

DIFFERENTIAL DIAGNOSIS OF MALE INFERTILITY
About 12 per cent of marriages in Great Britain are associated with
involuntary infertility. It has been estimated that the cause lies in the
husband in about one-third of cases, in the wife in about one-third and in
both husband and wife in the remaining third.

Infertility may be caused by defective production of spermatozoa or by
defective transference of sperm from the testes to the vagina. A full dis-
cussion of infertility is beyond the scope of this book, but the following
classification provides a basis for the differential diagnosis of its causes.

Causes of infertility in the male
t. Deficient production of spermatozoa:

Hypogonadism

150

THE TESTIS

2 Deficient transference of spermatozoa:

(o) Abnormalities of the conducting ay stem —

(i) Lesion of epididymis:

(a) Congenital defects,

(A) Infections (TB, gonococcal, nonspecific, etc.).

(c) Surgical trauma,

(li) Lesions of vas deferens:

(a) Congenital defects.

(A) Infections (TB, gonococcal, nonspecific, etc.).

(r) Surgical trauma.

(in) Lesions of ejaculatory ducts:

(a) Infections (prostatitis, etc.).

(A) Surgical trauma (prostatectomy, etc.).

(it) Urethral lesions.

(a) Failure of contraction of internal sphincter (lumbar tympa*
thectomy, prostatectomy, etc.).

(A) Stricture, fistula, etc.

(e) Hypospadias.

(A) Impotence (failure of election and ejaculation) —

(0 Psychological,

( 11 ) Lesions of CNS.

(in) Lesions of neni engenti (excision of rectum, etc.).

(iv) Androgen deficiency (hypogonadism).

It should be noted that obstruction of the duct system docs not interfere
with spermatogenesis. A testicular biopsy will reveal a normal structure ,
whilc^semen analy sis w ill show azoosperrm aT ~

CRYPTORCHIDISM

The descent of the testis may be arrested anywhere in its course, or the
organ may take an aberrant path once it has passed through the external
inguinal ring. The types of testicular descent may be classified as follows:
Normal

Migratory (retractile):

Low

High
Unite* cended:

Cxtemal inguinal

Inguinal

Abdominal

Ectopic:

Superficial inguinal

Pubic

Femoral

The terms “cryptorchidism” and “maldcsccnt” imply failure of descent
into the scrotum. The condition may be unilateral or bilateral.

CRYPTORCHIDISM

151

Varieties of normal descent

The normal testis, as has been said, enters the scrotum just before birth.
The migratory (retractile) testis completes its descent later and often at
puberty. It should be regarded as a variant of normal (fig. 4.7). In its
simplest and commonest form it is described by Browne as the “low
retractile" type. Contraction of the cremaster muscle holds the testis at
the top of the scrotum or in a “superficial inguinal pouch” which lies above

Normal testes lie in the scrotum or can be manipulated into it. Undescended testes do
not enter the scrotum.

the pubis, lateral to the external ring and between the fascia of the external
oblique and the deeper layer of the superficial fascia. The patient may say
that the testis sometimes enters the scrotum. If the atmosphere and the
surgeon’s fingers are warm, and if the patient is lying at ease, the testis can
be manipulated to the bottom of the scrotum. The more advanced form is
described as the 41 high retractile ” type. Shortness of the spermatic cord, as
well as retraction, holds the testis in the superficial inguinal pouch, and
manipulation will bring it down to the upper part of the scrotum, but no
farther.

Abnormal descent

Undescended testes lie along the line of normal descent but rarely, if ever,
reach the bottom of the scrotum of their own accord (fig. 4.7). In the

152

THE TESTIS

external inguinal position the testis is accompanied by a hernial sac along
which it slips in and out of the inguinal canal, either spontaneously or with
manipulation. The testis is an elongated soft structure and is impalpable
when it lies in the inguinal canal because it is entered by the firm apon-
eurosis of the external oblique muscle. If a testis is palpable in the region
of the canal it is almost certainly in the inguinal pouch which is superficial
to the aponeurosis (migratory or ectopic). An inguinal undescended testis,
which is less common, lies within the inguinal canal. Like the external
inguinal type, it is associated with a hernial sac along which it motes freely.
It does not, however, emerge from the external ring and is neter palpable.
The abdominal type, which is very rare, lies just inside the internal inguinal
ring or even on the posterior abdominal wall. It is rarely associated with a
hernial sac and (unless a sac is recognizable clinically) can be distinguished
from the inguinal type only at operation.

Ectopic testes leave the external inguinal ring normally, but then, instead
of descending into the scrotum, become deflected into abnormal positions
and do not complete their descent spontaneously. The commonest variety
is the superficial inguinal. The testis lies in the superficial inguinal pouch,
but, unlike the migrator}* (retractile) tesus, it cannot be made to enter the
upper end of the scrotum. It can occasionally be manipulated back into the
inguinal canal. The other types of ectopia— perineal, pubic and femoral—
require no special description.

The clinical differentiation of all these types may not be easy, especially
if the boy is obese, but increasing experience leads to greater accuracy in
diagnosis. The types which cause the greatest confusion are those in which
the testis is felt near the external inguinal ring, namely the high migrator}',
the external inguinal (undescended) and the superficial inguinal (ectopic).
In doubtful cases it is wise to make several examinations on different
occasions under optimal conditions.

Incidence

The incidence of cryptorchidism is hard to discover because of differ-
ences in interpretation of the significance of the empty scrotum. Some
observers, for instance, have included in their figures normal testes which
are temporarily retracted, while others have not. An extensive survey
among school children has been made recently in East Anglia. The follow-
ing figures, derived from this and other sources, grie an indication of the
frequency of the condition:

At birth:

Premature babies 25%

Full-term babies 10%

Before puberty (5-11 yean) 5%

After puberty (14+ years) 0 5%

CRYPTORCHIDISM

153

In about one-quarter to one-third of cases the condition is bilateral. Uni-
lateral cryptorchidism is about twice as common on the right side as on the
left. It is likely that the high figures in infancy and childhood are caused by
the relative frequency of migratory types at this period. Browne considers
that they account for 80 per cent of the cases of maldescent which are seen
in consultant practice. These testes enter the scrotum either shortly after
birth or at puberty. The hard core of those in w hom the condition persists
after puberty suffer from true undescent or from ectopia.

Causes

Little is known of the causes of cryptorchidism. Prematurity is clearly
responsible in some cases, but in these the condition rights itself. True
hermaphroditism and male pseudohermaphroditism are very rare causes,
but should always be considered. Female pseudohermaphroditism is
commoner, and may suggest cryptorchidism in a child who is in fact a girl
(Chapter 17). Germinal aplasia is not uncommon, and may account for
many of the cases in which the testes fail to descend at puberty.

Complications

Sterility is much the commonest complication of cryptorchidism, and is
probably caused by the relatively warm environment of the maldescended
testes. Retarded development has been observed histologically after the
age of 6, when the testis enters the growth phase. This finding has been
used as an argument for early operation, but there is little evidence that the
damage is irrevocable provided the testis is in the scrotum soon after the
beginning of puberty. If it is not there by this time, however, the tubules
nearly always degenerate irreversibly. In some cases, perhaps in half of
those whose testes do not descend by puberty, cryptorchidism is the result
of a failure in development (germinal aplasia) which also prevents the testis
from developing normally even if it is in the scrotum. The scrotal testis,
for instance, may remain undeveloped in patients with unilateral mal-
descent, and surgical correction of the deformity may fail to influence
development.

Unilateral maldescent does not cause sterility (except in the cases of
hypogonadism which have just been mentioned), because the normal testis
is fully functional.

The Leydig cells are not so dependent on temperature as the semini-
ferous tubules, and they usually function normally unless the testis is
within the abdomen.

Inguinal hernia, as has been mentioned, is a common complication,
especially in patients with inguinal and external inguinal undescended
testes. They are commoner in bilateral than in unilateral cases. Many of
them are not recognizable clinically, but arc found at operation. On the

154

THE TESTIS

other hand, the hernia, rather than the maldescent, may be the presenting
feature.

The abnormally placed testis is particularly liable to suffer trauma, and a
hydrocele may form around it. Torsion is said to be commoner than in the
normal organ, J Malignancy (especially seminoma) is at least ten times as
common in mal descended testes as in norma! ones, and is even commoner
in those which are retained within the abdomen. It is worth noting that
malignancy may develop after late normal descent, after orchiopexy, and
also in the scrotal testis in patients with unilateral cryptorchidism.

Treatment

There is little agreement about the treatment of cryptorchidism, and
discussions of the subject are often characterized by dogmatism and in-
vective. Surgical methods usually succeed in placing the testes in the
scrotum, but they do not necessarily result in fertile gonads. Indeed, by
damaging the blood supply, they may cause the Leydig cells to degenerate
so that a patient who would otherwise have been sterile, but normally de-
veloped, becomes both sterile and eunuchoid. Hormonal treatment, while
apparently producing good results, may do so most often in those with
migratory testes which would have descended spontaneously. It may,
moreover, cause the seminiferous tubules to degenerate if it is continued
too long.

Unilateral cases

Unilateral and bilateral cases must be considered separately because they
pose different problems. Provided one normal testis is in the scrotum,
there is no danger of sterility. Early operation is necessary only if there is a
troublesome inguinal hernia. Otherwise the decision about treatment can
be left until the onset of puberty (about 10). At this time some adv ise that
nothing need be done if the testis is impalpable and painless. We consider
it better to operate on all patients because of the high incidence of com-
plications (particularly malignancy) in the undescended testis. Orchiopexy
is undertaken, if it is possible, otherwise the testis is excised. A co-cxistent
hernia must, of course, be repaired.

Bilateral cases

In bilateral cases the problem is more difficult. Migratory testes, that is
those which can be manipulated into the scrotum, require no treatment
because they will complete their descent and function normally at puberty.
Ectopic testes, on the other hand, will not enter the scrotum and must be
treated surgically. Operation should not be postponed beyond the
beginning of puberty and may’ be performed earlier. The spermatic cord is

CRYPTORCHIDISM 155

always long enough to allow the testis to be placed in the scrotum without
difficulty.

Bilateral undescended testes, and those in which the diagnosis cannot be
made with confidence, require very careful consideration. Treatment is
certainly required at the age of 9 or 10, and an accompanying inguinal
hernia may necessitate earlier operation. Two methods are available:
(1) injections of chorionic gonadotrophin, and (2) surgical orchiopexy.
Chorionic gonadotrophin (500 IU twice weekly for twelve weeks) induces
some testes to descend promptly and causes others to enlarge so that they
may be operated on more easily. Larger doses or longer periods of ad-
ministration may cause precocious puberty and should therefore be avoided
at this age. If descent does not occur most authorities agree that operation
should be undertaken without delay.

Orchiopexy

Operation demands patience and great delicacy in the handling of the
tissues. For this reason it is best, in bilateral cases, to do the two operations
on separate occasions. The principles of an operation to correct mal-
desccnt are:

1. To secure a sufficient length of spermatic cord to allow the testis to reach
the scrotum. The vas deferens and its accompanying artery and vein are
usually long enough, but the testicular vessels may be too short. The
operation may be very difficult, or even impossible, in the inguinal and
abdominal types of undescent. The inguinal canal is opened, the testis is
mobilized and the cord is detached from its surroundings up to the level of
the internal ring. In many cases this results in an adequate length. If it
does not, the transversalis fascia is incised, the inferior epigastric vessels are
divided, the peritoneum is displaced medially and the vas is mobilized to
the base of the bladder. At this stage, as pointed out by Fowler and
Stephens, advantage may be taken of the anastomotic channels between the
testicular artery and the artery to the vas deferens (fig. 4.8). The testicular
artery is damped lightly at the lex el of the internal ring and an incision is
made into the body of the testis, care being taken to avoid damage to a
major vessel. If there is free bleeding the testicular artery and vein are
divided and the testis is thereby freed considerably. If further mobilization
is required the upper anastomotic channels may be similarly clamped and
divided after it lias been established that their occlusion does not prevent
bleeding from the distal end of the divided testicular artery. A new internal
ring, which allows the cord to run a shorter course, is constructed just
above the pubic spine.

2. 7o place and retain the testis in the scrotum. A suitable pocket can
usually be prepared by blunt dissection. Many methods have been devised

156

THE TESTIS

for preventing the testis from slipping up out of the scrotum. Those which
involve excessive traction or the placing of sutures in the testis are liable to
damage the blood supply. The simple method of Ombredanne, in which
the testis is passed through a small hole in the septum to the opposite side
of the scrotum, like a button through a buttonhole, is applicable to uni-
lateral or to bilateral cases and anchors the testis to a yielding structure
without the insertion of sutures. In the method of Gross, which is used by
many surgeons, gentle traction is applied to the testis by means of a silk
suture inserted into the tunica albuginea at the lower pole, passed through

Fjg. 4.8. Operation for undeseended testicle which lies at the internal ring.

The vas deferens is of normal length.

The artery to the vas (V.A.) runs a long recurrent course with several anastomotic
branches (1 and 2) (the accompany mg \ ems are omitted from the diagram). The testicular
artery (T.A.) with veins is compressed with a bulldog clamp cranial to the testis. Tunica
albuginea is incised, continued Weeding from this incision indicates adequate auxiliary
blood supply and that high ligation of testicular vessels is safe. Leave cut caudal end of
artery to bleed for further teste tf greater length te needed, damp branches 1 and 2 In
turn If Weeding from artery continues the branches may be div ided with safety, (from
Fowler and Stephens, 1959 )

the scrotum and connected by an elastic band to a piece of adhesive
strapping on the thigh. Gross recommends a pull of 200 to 300 g. It is
clearly possible to damage the blood supply to the organ by this method
and if it is used great care must be taken to a\ oid vessels w hen the testicular
suture is inserted.

TESTICULAR TUMOURS 157

3. To repair any co-existing hernia. This, of course, vs ill be done before
the testis is anchored in the scrotum.

Results of treatment

Agreement about the best methods of treatment will not be reached until
there is more precise information about the results and, in particular, about
the effects of surgical operations on fertility in patients with bilateral
cryptorchidism. Some studies suggest that operation is only occasionally
successful in producing spermatogenesis, while others indicate that fertility
is achieved in about 60 to 80 per cent of patients who are treated by surgery,
by hormones or by a combination of the two.

TESTICULAR TUMOURS

Tumours of the testis are usually malignant and account for between 1
and 2 per cent of all malignant growths in men. They develop most com-
monly in those between 25 and 35 years of age and account for about
12 per cent of malignant tumours in this age group.

Classification

The most satisfactory classification is that proposed by Dixon and Moore
in 1953, based on a detailed clinical and pathological review of nearly
1,000 cases (of men aged 18 to 44) in the files of the United States Armed
Forces Institute of Pathology. They recognized two main divisions:

I. Germinal tumours 96 5%

II. Non-germmal lumours 3-5%

100 0 %

(I) The germinal tumours, much the commoner type, presented four
morphological patterns — seminoma, embryonal carcinoma, teratoma and
chorioepithelioma* (Dixon and Moore use the term “choriocarcinoma”) —
which occurred alone or in any combination. These could be arranged in
five groups on the basis of biological behaviour and apparent morpho-
genesis. These were:

1. Seminoma (pure) 41%

2. Embryonal carcinoma (pure or with 1) 30%

3. Teratoma:

(o) Pure (or with 1) 9%

(6) Complex (with 2 and/or 4 and with or without I) 19%

4. Choriocptthchoma (pure or with 1 and/or 2) 1%

100%

* We use the term chorio«epithetioma for tumours arising from the true chorion only.

158

TIIE TESTIS

(II) The nan-germinal tumours were:

1. Leydig cell tumours 34%

2 Adrenal rest tumours 6%

3. Miscellaneous 60%

100 %

A review by Jones of the Belfast material (at all ages) included 85 cases
which were examined histologically between 1933 and 1952. They were

distributed as follows:

Germinal tumours

Nan-germinal tumours

Seminoma

3? (51%)

Leydig cell tumour 1

Embryonal carcinoma

12 (16%)

Adrenal rest tumour 1

Teratoma

10 (14%)

Miscellaneous 10

Chorioepuhelioma

14 (19%)

Total

73 (100%)

Total 12

The relatively high proportion of chorioepitheliomas to embryonal car-
cinomas, compared with Dixon and Moore’s series, is probably the result
of differences in interpretation of the histological features of these two
tumours.

GERMINAL TUMOURS

Pathology

All germinal tumours are malignant, but some types are more malignant
than others. Thus the seminoma carries a good prognosis with proper
treatment, while the chorioepithelioma is usually rapidly fatal.

The germinal tumours probably arise from totipotent germ cells. The
four distinct morphological patterns, which form the basis of their sub-
division, are as follows. The seminoma consists of cells which resemble
spermatogonia. Groups of such cells may be found in association with any
of the other histological types. The cells of embryonal carcinoma remain
undifferentiated or differentiate at best with roughly glandular structures.
Teratomas contain cells of all three germ layers, usually composing re-
cognizable tissues such as glia and bone marrow and sometimes poorly
formed organs such as bronchus. In the pure teratomas (group 3a) these
elements occur alone or with seminomatous areas. In the complex group
(3b) areas of embryonal carcinoma or of chorioepithelioma (or areas of both)
are mingled with teratoma and the prognosis is worse. The co-existence of
teratoma, however, appears to modify somewhat the rapidly malignant
character of the other two components. The chorioepithelioma consists of
two elements, one resembling cytotrophoblast and the other syncytiotro*
phoblast.

GERMINAL TUMOURS

159

Macroscopicalty the tumour destroys the testis partly or totally and
distends the capsule to give a smooth or nodular outline. The size varies
considerably. The largest tumours arc the seminomas and teratomas,
averaging about 5 cm. in diameter, but the more malignant ones are often
much smaller. Teratomas vary in consistency because of the variety of
their constituent tissues, and they are usually honeycombed with cystic
spaces containing fluid or gelatinous material. The cut surfaces of semino-
mas and embryonal carcinomas are grey-white and glistening. Areas of
necrosis and haemorrhage are common in these two tumours and very
extensive in chorioepitheliomas. The tumours may infiltrate the epidi-
dymis or spermatic cord, but operation is often performed before this takes
place. Metastasis occurs widely, however, via the lymphatics and the
blood stream. In fatal cases the iliac and para-aortic glands, the lungs and
the liver are nearly always invaded and other sites, such as the vertebral
column, are frequently affected. Metastases are demonstrable at rhe time
of diagnosis of the tumour in about 10 per cent of seminomas, 20 per cent
of teratomas, 30 per cent of embryonal carcinomas and 100 per cent of
chorioepitheliomas.

Clinical features

The commonest age-group affected is 25 to 35 years. Teratomas, how-
ever, tend to develop in the third decade and sometimes in childhood or
even before birth. One-fifth of the teratomas in the Belfast series developed
before the age of 10. Seminomas are commonest in the fourth decade, and
a few develop in much older men. A history of direct trauma to the testis is
obtained in some cases, but is of doubtful aetiological importance. The
commonest symptom is swelling of the testis, which usually develops
gradually. Pain, which is experienced by about half the patients, has a bad
prognostic significance. Secondary deposits may cause a variety of symp-
toms. Examination of the testis reveals a hard mass, which is usually
smooth and heavy. A small tumour may be difficult to detect, but if it is
suspected on clinical grounds the testis should be explored surgically
without delay. The iliac or para-aortic lymph glands and the liver may be
palpable. X-rays of the lung fields and of the skeleton should always be
taken to reveal metastases. The diagnosis of malignancy in a testis which is
retained within the abdomen is rarely made before there are widespread
metastases.

Endocrinological features

Many patients with germinal tumours excrete very large quantities of
total gonadotrophins in the urine, and those with teratoma or chorio-
cpithelioma often excrete ICSII. In fact, a high titre of ICSH in the male
ia found only with a germinal testicular tumour. The prognosis tends to be

160

THE TrSTlS

worse for patients who excrete gonadotrophins than for those who do not.
In some patients the hormones disappear from the urine within a week or
so of surgical removal of the tumour and return if the growth recurs, but in
others there is no such helpful correlation. The source of the gonado-
trophins is probably the tumour itself. There seems no reason to doubt
that a chorioepithelioma can secrete chorionic gonadotrophin. In other
types of tumour the origin of the hormones is less certain, and it is possible
that the pituitary is concerned. We may conclude that the estimation of
gonadotrophins is often of diagnostic and prognostic value, but that the
significance of its excretion is uncertain.

The excretion of oestrogens is sometimes increased, especially in chorio-
epitheliomas, and an excess of oestrogen may occasionally cause gynaeco-
mastia. This sometimes occurs with other germinal tumours, however,
and its cause is not known. Teratomas occasionally contain a sufficient
number of functioning Leydig cells to cause an increase in the excretion of
17-oxosteroids in the urine.

The Leydig cells of the non-tumorous part of an amputated testis often
show hyperplasia, and this, together with an increased excretion of gonado-
trophins, is a bad prognostic sign. It is possible that the hyperplasia is
caused by gonadotrophin formed in the tumour.

Treatment

Simple surgery, radical surgery and radiotherapy are all valuable in
treatment, and different methods arc indicated for different types of
tumour. The whole of the affected testis must be removed for histological
examination, and the operation should include removal of the spermatic
cord up to the level of the internal ring. Seminomas are highly sensible to
irradiation, A dose of 1,000 to 1,200 rads, delivered to the iliac and para-
aortic glands and to any recognizable secondary deposits, is usual, but
Rains and Kunkler have found 2,500 to 3,000 rads more effective. The other
tumours (particularly the pure teratomas) are much less radiosensitive and,
unless there are distinct metastases, should be treated by block dissection
of the glands up to the level of the renal pedicle. This radical excision may
perhaps be preceded by irradiation in cases of complex teratoma and
embryonal carcinoma. The only large series in which the results of the
radical operation (often combined with irradiation) have been compared
with those of simple orchiectomy (similarly irradiated) is that of Lewis,
whose results are reported by Dixon and Moore. The radical operation
appears to improve the surv Ival rate for teratomas and for embryonal carci-
nomas. Distant metastases from chorioepithelioma occur so early that
conventional surgery is of no avail. It is unlikely that hypophysectomy
would be of benefit, since it does not influence chorionepUhelioms tn
women. Chemotherapeutic agents sometimes cause temporary remissions.

NON-GERMINAL TUMOURS 161

Chorioepithelioma of the testis does not respond to folic acid antagonists
in the way that chorionepithelioma does in the female.

Prognosis

In Dixon’s and Moore’s series 95 per cent of the patients underwent
orchiectomy, and mast of these received radiotherapy also. The mortality
rates within two and five years of operation were as follows :

° 0 Dead within

Type of tumour 2 jeare 5 ) ears

[, Seminoma (pure) 6 10

II. Embryonal carcinoma 59 64

III. (a) Teratoma (pure) 26 29

(6) Teratoma (complex) 48 52

IV, Chorioepithelioma 83 100

Thus, most of the deaths occurred within two years of operation. These
survival figures are appreciably better than many others which ha\e been
reported. In the Belfast cases of seminoma, for instance, 6 out of 15
(40 per cent) died within two years of treatment. The better results in the
American Army were possibly achieved by regular medical examination,
which permitted early diagnosis and treatment. Features which indicate a
relatively poor prognosis are a painful tumour, excessive gonadotrophins
in the urine and hyperplasia of the Leydig cells in the non-tumorous part
of the testis.

The outlook for patients with clinically demonstrable metastases at the
time of diagnosis is very poor except in seminoma. With intensive radio-
therapy to the metastases more than half of the patients with seminoma in
Dixon’s and Moore’s series were alive five years after treatment.

NON-GERMINAL TUMOURS

This small group contains several tumours of great endocrinological
interest. They are all rare and are usually benign.

Leydig cell tumours
Pathology

Up to I960 less than 100 tumours derived from the Leydig cells had been
reported. The ages ranged from 1 to 82 years, and 26 of the tumours
developed in children. These growths are usually small and roughly
spherical and may be difficult to palpate. The cut surface is homogeneous
and yellow to brown. They are not capsulated, but are rarely malignant, and
are composed of cells resembling normal interstitial cells. Anaplasia may
be found in the rare metastasizing tumours.

162 THE TESTIS

Clinical endocrinological features

In children Leydig cell tumours secrete androgen (presumably testo-
sterone) and cause precocious pseudopuberty, sometimes associated with
gynaecomastia. The somatic manifestations are identical w ith those caused
by a \inlizing adrenocortical tumour. The excretion of 17-oxosteroids is
often increased and may exceed normal adult levels. A malignant Leydig
cell tumour has not been reported in a child.

In adult men the tumours behave differently. There are usually no
clinical endocrine features, although the excretion of 17-oxosteroids is
sometimes very high ; more than 1 g. in 24 hours has been recorded in some
patients. About one patient in 10 develops gynaecomastia, and this may be
associated v ith pigmentation of the areolae, loss of sexual hair, diminished
libido and a change in the texture of the skin. These features are similar to
those caused by feminizing tumours of the adrenal cortex, but their cause is
not known. They may possibly be due to oestrogen excess, for high levels
of oestrogen have been found in the mine of a few patients, but it is not
known whether the oestrogens are secreted directly by the tumours or
whether they are derived from the metabolism of androgens. In a patient
observed by us, who had all these clinical features at the age of 63, the
excretion of oestrogens was high and that of androgens was low. After
removal of a benign tumour the androgens rose to a normal level. In
malignant cases with widespread metastases the patients may maintain
their muscular strength and development to the end, presumably because
of the anabolic effect of the androgen.

Treatment

Because malignancy is rare, treatment by orchiectomy is usually effective.
In prepuberal patients sexual characters regress and puberty eventually
takes place normally, but the skeletal changes remain. Gynaecomastia m3y
diminish, but did not do so in our patient. The abnormal excretion of
steroids is usually corrected shortly after operation, but sometimes persists
in spite of clinical improv ement.

Adrenal test tumour

The nodules of adrenal tissue, which arc occasionally found in the testis,
epididymis or cord, are sometimes adenomatous. They are usually
symptomless.

Miscellaneous

The miscellaneous group contains two extremely rare tumours which
may cause feminization. The androblastoma is derived from primitive
testicular cells and is analogous to the arrhenoblastoma of the ovary. The
Sertoli cell tumour is thought by some to be an atypical Leydig cell tumour.

163

ORCIIIECTOMV

“. peculiar to the testis and requ.re no desenptton.

ORCHIECTOMY

Indications

Orchiectomy may be needed for:

(1) Testicular disorder or disease
Tumours.

H^TOaphroditisnt^male^seudohertnaphroditism (some cases)

Traumatic injury (including surgical).

“fneightuLg structures (haematoce.e, carcinoma of
the scrotum, etc.).

Usually one testis only need be removed. tatCf breast.

(2) Palliation of carcinoma elsewhere in > •

Both testes must be removed.

Method . . , .Ua scrotal route.

The testis may be approached by ,h "2” nce a ; d part ly on other
The choice depends partly on turo0 ur the inguinal route is

factors. Thus, in the treatment of a testic while ln bilateral

obligatory because the whole cor sinele scrotal incision gives

orchiectomy for the palliation o car ‘ . 0 f t he scrotum is a simple
convenient access to both organs. D^age^tr

insurance against postoperative f (3 or tvithnut the cord) is a
Total removal of the testis and p y A procedure which is

simple operation which requires " 0 . d ““'P bilatera I enucleation of the
often used for the palliation of _ carcin . um ; ca albuginea and the
testes. A longitudinal incision » maa ' m A(ih „ cnt tissu e can be scraped
parenchyma U scooped out with a and becomes filled

away with dry gauze. The tunica alb 8 , f ee l s ute a small testis,

with a blood clot which organizes and event ly^ ^ ^ patient than
This result renders the procedure more arSantage that Mtratesticular
ordinary castration. It has the theore cont j nu e to secrete significant
Leydig cells may he left beh.nd and may contmue

amounts of testosterone. t ;„ n ts Adolescents and young

Orchiectomy causes distress to pros ,heses. They are

men sometimes welcome the insertion of v.tallmm p

THE TESTIS

164

best inserted via inguinal incisions, /or the scrotal shin may fail to heal
satisfactorily.

Replacement therapy

Remotal of both testes (though not of one) causes hypogonadism, whose
effects are severe in joung patients, but less troublesome in the aged.
Androgen replacement therapy should be given if it is required. It must
not, of course, be used for patients with carcinoma of the prostate or breast.

FURTHER READING AND REFERENCES
General

JONES, H. W. and SCOTT, W. w. (1958). Hermaphroditism, Genital Anomalies and Re-
lated Endocrine Disorders. Williams and Wilkins, Baltimore.

Development

>1 ANm.-rCJN , ny, 1 ., ROTO, J.D. and mobsman, n. w. Unman E nforytAug?. InA

Ed. Heffer, Cambridge.

HARRISON, r. c. (1959). A Textbook of Human Embryology. Blackwell Scientific
Publications, Oxford.

SCIIONFELD, w. A. (1943). Primary and secondary sexual characteristics. Amer.J.
Dit. Child., 65, 535.

Adult Structure and Function

ALBERT, A., UNDERDAHL, t. o., Greene, l. f. and lorenz, N. (1953). Male hypo-
gonadism: 1. The normal testis. Proc. Mayo Clin-, 28, 409.
dorfman, R I, and SHIPLEY, r. A. (1956). Androgens: Biochemistry, Physiology and
Clinical Significance. Chapman and Hall, London.

HARRISON, r u, (1949). Distribution of vasal and cremasteric arteries to testis and
their functional importance. J. Anal. ( Land .), 83, 267.
harrison, R. o. and Barclay, a, E. (1948). The distribution of the testicular artery
to the human testis. Brit. J. Urol., 20, 57.

Investigation

CHARNY, C. w, (1940). Testicular biopsy; its value in male sterility. J. Amer. mtd.
Ass., 115, 1429.

MACLEOD, j. and cold, r. Z. (1953). The male factor in fertility and infertility.
Fertil. and Steril., 4, 10, 194.

Precocious Puberty

CROSS, R. E. (1940). Neoplasms producing endocrine disturbances in childhood.
Amer. J. Dis. Child., 59, 579.

jolly, h. (1955). Sexual Precocity Blackwell Scientific Publications, Oxford.
seckel, H. p. g. (1946). Precocious sexual development in children- Med. Clin. A.
Amer., 30, 183.

WEINBERGER, l. M. and grant, f, c. (1941). Precocious puberty and tumours of the
hypothalamus. Report of case and review of literature, with pathophysiologic
explanation of precocious sexual syndrome. Arch, intern. Med., 67, 762.
Wilkins, L. (1957). Precocious sexual development. In The Diagnosis and treat-
ment of Endocrine Disorders in Childhood and Adolescence, p. 1 98. 2nd Ed.
Blackwell Scientific Publications, Oxford.

FURTHER READING

165

Hypogonadism

ALBERT, A., UNDERDAHL, I,. O., GREEN, L. F. and LORENZ, M. (1953-1 955). Male hypo.

gonadism II-VII. Proc. Mayo Clin., 28, 557, 698; 29, 131, 317, 368; 30, 31.
bodhe, Y. o. (1959). Condition of testicle after division of cord in treatment of
hernia. Brit. med. J., 3, 1507.

HANLEY, h. c. (1955). The surgery of male sub-fertility. *4««. toy, Co//. Swrg.
Engl, 17, 159.

Hanley, H. g. and HARRISON, R. c. (1962). The nature and surgical treatment of
varicocele. Brit. J. Surg., 50, 64.

IIECKEL, N, J., Rosso, w, a. and kestel, l. (1951). Spermatogemc rebound pheno-
menon after testosterone therapy. J. elm. Endocr., 31, 235.

HELLER, C. G., NELSON, W. O., HILL, 2. B., HENDERSON, E., MADDOCK, IV. O , JUSGCK,
E. C., paglsen, C. A. and MORTIMER, c. e. (1950). Improvement in spermato-
genesis following depression of the human testis with testosterone. Fertil. and

SterU , 1, 415.

Klinefelter, h. F., rtifenstein, E. c. and Albright, F. (1942). Syndrome character-
ised by gynaecomastia and aspermatogenesis without A-leydigism and increased
excretion of follicle-stimulating hormone, y. clin. Endocr., 2, 615.
McctiLLAGH, e. P-, beck, J. c. and scin ffenburc, c. a. (1953). A syndrome of
eunuchoidism with spermatogenesis normal urinary FSH and low or normal
ICSH (fertile “eunuchs”), y. din. Endocr., 13, 489.

MACK, l. s., HANLEY, it. c., Tulloch, w. s. and scott, L. s. (1962). Male Infertility.
Proc. roy. Soc. Med., 55, 1042.

macleod, j. and gold, R. z. (1953). The male factor in fertility and infertility.
Fertil. and Steril, 4 , 10, 194.

MONRO, i>., HORNE, H. w. and PAULL, d. p. (1958). The effect of injury to the spinal
cord and cauda equina on the sexual potency of men. Neu Engl.J. Med., 239,

soirvAL, A. n. and softer, l. j. (1953). Congenital familial testicular deficiency.
Amer.y. Med., 14. 328.

spence, A. w. (1954). The male climacteric: js it an entity?. Brit, rned.y., J, 1353
werner, s. c. (1947). Clinical syndrome associated with gonadal failure in men.
Amer.y. Med., 3, 52.

Cryptorchidism

browne, d. (1938). The diagnosis of undescended testicle. lint. med. y., 2, 168.
brunet, j., de Mowbray, r. r. and BtsHOP, P. M. F. (1958). Management of the un-
descended testis. Brit. med. J., 1, 1367.

CHArny, c. vv. and wolgin, w. (1957). Cryptorchism. Cassell, London.

FOWLER, k. and STEPHENS, f. (1959). The role of testicular vascular anatomy in
the salvage of high undescended testes. Austr. N.Z. y. Surg., 29, 92.
kark, w. (1962). The problem of cryptorchidism and malignancy. Med Proc., 8, 83.
society of medical officers or irEALTH (1958). The significance of the empty
scrotum. Report on a survey amongst school boys in East Anglia. Med. Ojfr.,
m, ST9.

Testicular Tumours

Btsiior, p. m. i\, van meurs, D. P., wilcox, D. R. c. and ARNOLD, D. (1960). Inter-
stitial-cell tumour of the testis in a child. Report of a case and a review of the
literature. Brit. med. J., t, 238.

oixoN, f. j. and moore, r. a. (1953). Testicular tumours ; cJinicopathological study.
Cancer, 6, 427.

JOves, a. (1955). Testicular tumours: a chnico-pathological survey. Ulster Med.
7., 24, 27.

patto.v, j.f., sutzman, d. n. and ZONE, R. A. (1960). Diagnosis and treatment of
testicular tumours. Amer. y. Surg , 99, 525. _
bains, A. j. ii. and kunkler, p. B. (1959). The testis and retroperitoneal region. In
Treatment of Cancer in Clinical Practice, p. 574. Livingstone, Edinburgh.

CHAPTER 5

THE OVARY

The ovaries are the primary organs of sex in the female. They are con-
cerned with the formation of the ovum, and they secrete important
hormones which, are essential for sexual development, the preparation of
the uterus for the fertilized ovum and the maintenance of pregnancy. The
gonadotrophins of the anterior pituitary initiate the maturation of the
ovaries at puberty and influence the cyclical function of the organs through-
out reproductive life.

STRUCTURE AND FUNCTION

Anatomy

The development of the ovaries and genital ducts is described in
Chapter 17.

The ovaries are paired organs which lie in the pelvic cavity. They, and
the fimbriae of the fallopian tube, are the only intra-abdominal organs which
are not covered by peritoneum. In the adult each gland is a solid ovoid
structure, measuring about 3*5 x 2-0 X 1*5 cm. and weighing 4 to 5 g.
The hilum serves as the point of attachment of the mesovarium, which
anchors the ovary to the bach of the broad ligament, and of the ovarian
ligament, which suspends it from the cornu of the uterus. Nerves and
vessels enter and leave the organ at the same point. Small clusters of “hilus
cells”, which may be homologous to the Leydig cells of the testis, are found
in the region of the hilum and mesovarium.

The ovary consists of two parts: (1) the stroma of supporting connective
tissues, blood vessels, lymphatics and nerves, and (2) the ovarian (graafian)
follicles. Both are enclosed by a dense capsule of connective tissue, the
tunica albuginea, and this is covered by a layer of Battened epithelium.
Some interstitial cells may be seen in the stroma. At birth the ovary con-
tains all the primordial follicles (or oogonia) vv hich it v\ ill possess. Many of
them degenerate gradually during childhood and at puberty there are
about 40,000 in the two ovaries. Less than 500 of these are destined to
mature. During infancy and childhood the ovary is small and has a smooth
surface. It cnlacges as it matures and ripening ova and degenerating
corpora lutea render its surface irregular. After the menopause the ovary
166

STRUCTURE AND FUNCTION 16?

shrinks and has a shrivelled appearance, but in old age it becomes smooth
once again. All follicles have disappeared at this stage.

The ovary receives its blood supply from the ovarian and uterine
arteries. Occasionally a large branch of the uterine artery provides the
main arterial supply. The division of this vessel may account for the
ovarian atrophy which rarely follows hysterectomy. The veins of the ovary
join to fonn the pampiniform plexus in the mesovarium, and this drains
into the ovarian and uterine veins.

The ovarian cycle (fig. 5.1)

The first ovum is probably shed at about the time of the first menstrual
period, but regular ovulation is not normally established until the age of
16 or 17 years. The adult ovary goes through a recurrent cyclical process
which results in ovulation and menstruation and occupies about 28 days.
The cycle starts on the first day of menstruation and consists of two phases :
(I) the follicular phase, during which the ovum ripens and discharges; this
lasts for about 14 days and is followed by (2) the luteal phase. Ovulation
occurs at about the 14th day of the cycle and separates the two phases. The
regularity of the cycle is normally controlled by the time of ovulation.
Menstrual bleeding occurs fourteen days after this event unless fertilization
takes place.

Fig. 5.1. Diagram of ovarian and menstrual cycles.

168

THE OVARY

Follicular phase

At puberty, under the influence of pituitary gonadotrophins, the follicles
start to develop regularly and to form ova and corpora lutea. During each
cycle several follicles in each ovary start to grow, but one outstrips the
others. Rarely two or more reach maturity at the same time and may
result in multiple pregnancy. The follicles which fail to mature generally
disappear but sometimes form small atretic cysts. As the main follicle
develops there is proliferation of the follicular (granulosa) cells, enlarge-
ment of the ovum and formation of a capsule. This develops from the
differentiation of stroma cells into a vascular layer of connective tissue cells,
the theca interna, and the compression of external stromal cells to form a
false capsule, the theca externa.

As the follicle grows a cavity develops within it and becomes filled with
the secretion of the granulosa cells which contains the oestrogenic hormone,
oestradiol. The ovum is displaced to one side of the cavity and remains
attached by a disc of granulosa cells, the discus proligerus. When mature,
the follicle first forms a bulge on the surface of the ovary and finally rup-
tures, discharging the ovum into the peritoneal cavity.

Luteal phase

After ovulation the ruptured follicle changes rapidly into the corpus
luteum. During the process of “luteinization” the follicular cells swell and
become filled with a lipoid pigment, lutein, which is yellow in colour.
These cells now elaborate progesterone, while those of the theca interna
maintain and enhance the secretion of oestradiol. Within a few days of
ovulation new blood vessels grow into the corpus luteum and the tissue
becomes functionally active. If conception does not take place the cells
degenerate about five days before the next menstrual period and eventually
become converted into avascular hyaline tissue, the corpus albicans. When
the discharged ovum is fertilized the corpus luteum, instead of regressing,
becomes much larger and may attain a diameter of 2 to 3 cm. The activity
of this “corpus luteum of pregnancy'” begins to wane by about the tenth to
twelfth week and is inactive during the second half of gestation.

Control of the ovarian cycle

The gonadotrophic hormones of the anterior pituitary control ovulation
and menstruation directly. Gonadotrophins initiate the ovarian cycle and
the ovarian hormones, in turn, play an important part in the regulation of
gonadotrophin secretion. Follicle stimulating hormone (FSH) causes the
follicle to ripen and FSH, together with luteinizing hormone (LH),
stimulates the secretion of oestradiol. As the lev el of oestrogen increases,
FSH is inhibited and a greater output of LH and of luteotrophic hormone
(prolactin, LTH) is encouraged. When the amounts of circulating FSH

STRUCTURE AND FUNCTION

169

and LH reach the necessary proportion (which is unknown) ovulation
occurs. LH stimulates the corpus luteum to develop and to secrete
oestradiol and LTH probably causes it to secrete progesterone. The excre-
tion of oestrogens in the urine is high at two periods in the menstrual
cycle. An “ovulatory’ peak” (which is usually the highest level of excretion)
occurs at about the thirteenth day and the “luteal maximum” lasts from
about the twentieth to the twenty-fifth day. As the level of progesterone
rises in the luteal phase, it in turn inhibits the production of LH and LTH.
As their influence wanes the corpus luteum degenerates and the secretion
of oestradiol and progesterone diminishes rapidly. With the removal of
this brake on its production, FSH is secreted once more, a fresh follicle
ripens and a new cycle begins. The gonadotrophic and ovarian cycles are
thus closely interlocked and, once initiated, they continue regularly until
the ovaries become refractory at the time of the menopause.

When the ovum is fertilized the integrity of the corpus luteum is main-
tained by the trophoblastic gonadotrophin. Pituitary LH may play a sub-
sidiary part.

Hormones of the ovary

Oestradiol and progesterone are the only important hormones secreted
by the human ovary. A small amount of androgen is probably formed also,
but its significance is not known.

Oestradiol

Oestradiol is the most potent natural oestrogen. Appreciable quantities
of oestrogens, derived from the mother or from the placenta, are excreted
in the urine in the first few days of life and may account for the uterine
bleeding and mammary secretion which are occasionally observed in the
neonate. Small amounts, probably derived from the adrenals, are excreted
during childhood and increasing quantities, possibly from the ovaries, from
about the age of S years. From the onset of puberty r (about 11) oestradiol is
secreted in a cyclical manner, under the influence of FSH, by the graafian
follicles and the corpora lutea. During pregnancy oestradiol and other
oestrogens are produced in increasing amounts by the placenta, which
becomes the main source after two or three months. At term the secretion
of oestrogens and their excretion in the urine are higher than at any other
time. The levels fall abruptlyafter delivery. After the menopause the secre-
tion falls again to a very low level, and most of the oestrogens in the urine
at this time are derived from the adrenal. Oestradiol is concerned with the
development and function of the sexual organs and causes the appearance
of the secondary sex characters, Like the androgens, it also has widespread
metabolic effects.

170

THE OVARY

Sexual organs

Oestradiol controls the development of the accessory organs of reproduce
tion (the uterus and fallopian tubes, the vagina and the vulva) from their
infantile size and form to their adult proportions. The changes which occur
in these organs during menstruation and pregnancy are caused partly by
oestradiol and partly by progesterone and are described Jater. After the
menopause the deficiency of oestrogen results in atrophy of the sexual organs.

Oestradiol has striking and important effects on the vaginal epithelium.
In the infant this is a delicate structure, consisting of one or two rows of
basal cells, and it is readily injured by trauma or infection. As puberty
approaches oestradiol causes the basal cells to multiply and the epithelium
to become thicker until, in the adult, it is of the robust stratified squamous
type. The thickness of the epithelium and the degree of cornification of the
superficial layer vary with the level of oestradiol secretion, being greatest
when oestrogenic activity is at its height. The cells which are shed from
the surface can be obtained on a vaginal swab and examined by the method
of exfoliative cytology. The degree of cornification provides a useful index
of oestrogenic activity. A biochemical effect of oestradiol, which is readily
recognizable histologically, is the deposition of glycogen in the cells of the
vaginal epithelium. The glycogen is apparently broken down to lactic
acid, which renders the reaction of the vagina acid (pH 4 to 5). This
favours the growth of the lactobacillus vaginalis, which tends to inhibit
infection by other organisms. After the menopause the epithelium atro-
phies and becomes less resistant, though an appreciable degree of cornifica-
tion persists, even in old age, as a result of the action of adrenal oestrogens.

Secondary sex characters

Oestradiol, aided by the adrenal androgens, brings about the growth of
axillary and pubic hair at puberty. The pubic hair appears to be dependent
mainly on oestrogenic stimulation and the axillary’ hair on stimulation by
androgens. The “female escutcheon” forms a triangle with the base across
the symphysis pubis ('\7), A male type of distribution, with the apex-
pointing to the umbilicus, is not uncommon and does not necessarily
indicate virilism. Oestradiol influences the distribution of the subcutaneous
fat and causes the characteristic female contours. It is responsible for the
smooth skin and clear complexion of the female. In the breast it stimulates
proliferation of the ducts, development of the connective tissue and nipples
and pigmentation of the areolae. Its role in lactation w ill be discussed in
Chapter 13.

Metabolic effects

Oestradiol causes retention of salt and water, but its effect is less than
that of the synthetic progestogens or testosterone. Its physiological action

HORMONES OF THE OVARY

171

on bone is uncertain. It is probably mainly responsible for the closure of
the epiphyses in the female, and it tends to preserve calcium in the body.
In large amounts it has an effect similar to that of the androgens. Oestradiol
probably influences the metabolism of cholesterol and lipoproteins in such
a way as to reduce the likelihood of atheroma developing in the coronary
arteries.

Effects on anterior pituitary

The production and release of FSH are stimulated by lack of oestrogen,
and the release is inhibited by an excess. LH and LTH are probably
stimulated by small amounts of oestrogen and inhibited by larger quan-
tities. There is evidence that oestrogens in excess tend to inhibit the
production or release of growth hormone.

Metabolism and excretion

Oestradiol is metabolized by the liver and converted, in part, into the
much weaker oestrogens, oestrone and oestriol (Chapter 2). These are con-
jugated with glycuronic and sulphuric acids and are excreted in the urine
and In the bile. The natural oestrogens, like the androgens, are inactivated
when swallowed because they are carried by the portal circulation to the
liver. Cirrhosis and other extensive diseases of the liver may cause impair-
ment of its capacity to metabolize them.

Progesterone

Progesterone is the most potent natural progestogen and is secreted by
the granulosa cells of the corpus luteum, probably under the influence of
LTH. Its blood level rises rapidly after ovulation and declines sharply
when the corpus luteum degenerates. There are insignificant amounts in
the blood during the follicular phase of the cycle. During pregnancy large
quantities of progesterone are probably synthesized in the placenta. It is
Formed in the adrenal cortex as an intermediate step in the synthesis of
cortisol and other hormones.

Progesterone prepares the uterus for the fertilized ovum and maintains
the decidua during pregnancy. It influences the secondary sexual organs
only when they have been prepared by oestradiol. Its effects on the uterus
are described later. The action of progesterone on salt and water meta-
bolism is uncertain. In most animals it causes strong retention of sodium,
but in man it has been said to promote its excretion. Progesterone relaxes
smooth muscle in many organs, including the blood vessels, the ureters and
the alimentary tract, and may be partly responsible for the frequency of
■varicose veins, piles, hydro-ureter and constipation in pregnancy. It con-
gests and relaxes the ligaments of the pelvis, allowing them to be stretched
during labour. Progesterone raises the basal temperature of the body. Its
effect on the breast is described in Chapter 13.

172

THE OVARY

Progesterone inhibits the production and release of LH, LTH and FSII.

Like the other sex hormones, progesterone is metabolized in the liter,
partly to the inactive pregnanediol (Chapter 2), which is conjugated and
excreted in the urine and bile. It is inactive when given by mouth.

The menstrual cycle (fig. 5.1)

The changes in the uterus during the menstrual cycle are entirely de-
pendent on the secretion of the ovarian hormones. The first 4 or 5 days
of the cycle, during which bleeding occurs, leave the endometrium denuded
of its surface epithelium. Oestradiol causes it to regenerate from the glands
and basal layers, a process which occupies 2 or 3 days, and then to pro-
liferate. By the 14th day of the cycle (9 or 10 days after bleeding has
stopped) it is 2 to 3 mm. in thickness. From then on progesterone causes
further thickening of the endometrium, to 5 or 7 mm., the appearance and
growth of glands and, finally, glandular secretion. At this stage the uterus
is prepared to receive and nourish a fertilized ovum. If it does so the
changes characteristic of pregnancy ensue. Otherwise the endometrium
ceases to grow at about the 23rd day (5 days before menstruation starts) and
then begins to shrink. Infiltration with leucocytes and some red cells
follows and menstruation starts when blood is extravasated into the endo-
metrial tissue. Degenerated fragments of tissue and altered blood comprise
the menstrual loss, which usually lasts for 4 to 5 days. In an adult woman,
who has a normal uterus but whose ovaries are functionless (e.g. after
oophorectomy or the menopause), the administration of oestrogen causes
the changes characteristic of the follicular phase of the cycle, and its sudden
withdrawal causes breakdown of the endometrium and “oestrogen-with-
drawal bleeding”. If progestogen is given when the oestrogen is with-
drawn it causes the changes of the luteal phase and prevents the bleeding.
When this is discontinued “progestogen-withdrawal bleeding” occurs.
The normal menstrual flow is caused by the sudden withdrawal of both
oestrogen and progestogen

Pregnancy

The ovum is normally fertilized in a fallopian tube, probably within a
day or two of ovulation, and undergoes its early development as it passes
down to the cavity of the uterus. It becomes embedded in the
metrium, usually by the 21st or 22nd day of the cycle. The implantation of
the ovum and the presence of progesterone together cause the stromal cells
of the endometrium to undergo a decidual reaction. They imbibe water and
their cytoplasm swells, so that histologically the loose stromal network is
replaced by large polyhedral cells with small nuclei. The corpus luteunt
enlarges and continues to secrete oestradiol and progesterone, mainly under
the influence of gonadotrophin secreted by the Langhans cells of the

HORMONES OF THE OVARY

173

chorion. The secretion of chorionic gonadotrophin (which resembles LH)
reaches its maximum after about 7 to 8 weeks and then declines gradually.
After about the 12th week the placenta takes over the formation of oestro-
gens and progestogens, as well as the secretion of gonadotrophin, and from
then on pregnancy is independent of ovarian control and is uninfluenced by
bilateral oophorectomy. The levels of oestrogen and of progesterone in the
blood and in the urine continue to rise until term.

Progesterone is essential for the successful embedding of the ovum and
for the maintenance of the decidua. Oestrogens cause hypertrophy of the
myometrium and an increase in its vascularity and enable the fibres to
contract regularly and forcefully. They render the myometrium sensitive
to oxytocin. Progesterone causes hypertrophy and hyperplasia of the
myometrium and lowers its tone. It reduces the frequency, but increases
the amplitude, of the uterine contractions.

Endocrine diagnosis of pregnancy

Changes in the breast can be recognized very early in pregnancy,
especially in primigravida and brunettes, and are the result of hormonal
influences (Chapter 13).

All biological tests for the diagnosis of pregnancy depend on the pre-
sence of chorionic gonadotrophin in the urine and its effect on the gonads
when injected into animals. Strictly they reveal only the presence of living
chorion and not of pregnancy, so that positive tests may be obtained when
the foetus is dead. Positive tests are also obtained in hydatidiform mole and
chorionepithelioma when no foetus is present. The tests are performed
with fresh early morning urine, and great accuracy is obtained by skilled
workers. False negative results are quite common if the urine is not fresh
(e.g. if it has to be sent by post for testing). The tests are positive within
1 or 2 weeks of the first missed period, that is 3 to 4 weeks after conception.
The tests performed for the diagnosis of pregnancy are qualitative. They
may be made quantitative by the serial dilution of 24-hour specimens of
urine. The result is expressed in international units. One IU is the
activity contained in 0-1 mg. of a standard preparation.

The following table shows the main tests which are used :

Test

Animals

Duration 1
of test |

Criterion for positive result

Ascheim-Zondek (AZ)
Friedman

IJogben

Male frog or toad

Immature female

Mature female
rabbit

Adult female

Xe nopus toads
| Adult males

4 days

2 days

l day

6 hours

Haemorrhagic follicles or cor-
pora lutea in ovaries
Haemorrhagic follicles or cor*
pora lutea in ovaries

Ovulation

Spermatozoa in urine

174

THE OVARY

The Ascheim-Zondek test is the most reliable, but it takes longer than the
others and involves many injections,

Zondek’s “medical curettage” is a clinical test which is fairly reliable.
Ainenorrhoea may result from deficiency of ovarian hormones or from
pregnancy. In the former case the administration of oestrogen and pro-
gestogen together cause the endometrium to develop. When the hormones
are stopped withdrawal bleeding follows in about 3 dajs. In pregnancy the
hormones do not cause bleeding because the endometrium is being main-
tained naturally. Ethinyloestradiol (0-05 mg.) and allylestrenol (a synthetic
progestogen) (20 mg.) are given together, by the sublingual route, once
daily for 3 days.

Puberty

The process of puberty has many physical and mental aspects and
extends o\er several years. Legally (in Britain) a girl is capable of pro-
creation at the age of 12, but in fact the earliest normal pregnancies occur
2 to 3 years later. The first sign of puberty is usually the budding of the
nipples at the age of 9 or 10, but even in early childhood a girl’s nipples arc
often more prominent than those of a boy. The date of the first appearance
of menstrual bleeding is called the “menarche”. It occurs usually at 13 or
14 years, but there is much variation, and the extremes of 11 and 18 may
still be regarded as normal.

Clinically it is important to know whether puberty is progressing nor-
mally or whether it is premature or delayed. The following table, compiled
by Sechcl, is a useful guide. It should be compared with the similar one for
boys (p. 134).

Average approximate age and sequence of appearance of sexual characteristics in g‘rh

9-lOjears Growth of bony pehu. Budilin# of nipples.

10- 11 Budding of breasts. Pubic hair. .

1 1- 12 Changes in vaginal epithelium and smear. Growth of external and internal

genitalia

12- 13 Pigmentation of nipples. Breasts filling m.

13- 14 Axillary hair. Menstruation, which may be anovular for the first few jear*

14- 15 Earliest normal pregnancies.

15- 16 Acne. Deepening of voice.

16- 17 Arrest of skeletal growth.

These figures represent the normal average times, hut the normal ranges are very
and the sequence of events is not slwavs the same.

INVESTIGATION OF OVARIAN DISORDERS
The following methods are used in the investigation of ovarian dis-
orders:

1. Clinical

The patient is examined and secondary sexual development is assessed.
Pelvic examination is carried out, and an attempt is made to palpate the

INVESTIGATION 0 T OVARIAN DISORDERS 175

adnexae and to estimate the size of the uterus. In some patients a bimanual
examination under anaesthesia is required.

2. Vaginal smears

Examination of a smear of the vaginal epithelium reveals the presence or
absence of oestrogenic activity. The appearances alter during the men-
strual cycle and, with experience, the changes found in the early follicular
phase, late follicular phase (ovulatory peak) and luteal phase can be
recognized. The appearances in childhood and old age are also charac-
teristic.

3. Temperature changes

The temperature of the body is raised by progesterone and, when
measured accurately, is found to be highest during the luteal phase of the
cycle. Ovulation is marked by a low dip, followed by a sharp increase with-
in 24 hours. After this the temperature continues about half to one degree
higher than in the preovulatory phase. This biphasic change at the mid
point of the cycle is characteristic of ovular menstruation, but does not
occur with anovular periods.

4. Operative

Curettage and endometrial biopsy may be used to obtain endometrial
tissue for histological examination. From the appearance of the endo-
metrium information about the presence or absence of ovulation and of
oestrogenic and progestogenic stimulation may be obtained.

Tubal insufflation is used for the investigation of tubal patency in cases of
infertility.

tiysterosaipingography is useful in the diagnosis of tubal obstruction,
uterine malformation and other disorders associated with infertility.

Culdoscopy is a form of endoscopy by which the ovaries (and other pelvic
viscera) may be seen through an instrument passed into the pelvis via the
posterior vaginal fornix. It may be helpful in the diagnosis of the Stein-
Leventhal syndrome, gonadal dysgenesis, infertility and ovarian tumours.

Pneumoperitoneum, followed by X-rays, is of value for the detection of
enlargement of the ovaries.

Laparotomy may be justified in special cases if the diagnosis is in doubt.
Formerly it was undertaken in cases of gonadal dysgenesis but, with
modern methods of diagnosis, it is no longer necessary.

5. Urinary hormone assays

Gonadotrophins. Estimation of total gonadotrophins (FSH and LH)
(Table 1.2) in the urine is of great help in distinguishing between true and
false puberty and between primary and secondary- forms of hypogonadism.
Very high levels of chorionic gonadotrophin (pregnancy tests performed

176

THE OVARY

quantitative!}) (Table 5.1) may be found with hydatidiform mole and
chorionepithelioma.

Tadle 5.1. Chorionic gonadotrophin excreted in urine *

Approximate normal values (IU per 24 hours)

Pregnanes :

60th day (maximum) 30,000

Later 5.000-10,000

• From Loraine (1958).

Oestrogens (Table 5.2). Determination of the urinary oestrogens is ter)'
time-consuming, but will probably be undertaken more frequently in the
future than in the past. It is likely to prove valuable in the investigation of

Table 5.2. Oestrogen excretion in the urine *

Approximate normal ranges (and means)

1 Oestnol I

Oestrone 1

1 O estradiol 1

I Total

>ig. per 24 hours

Children under 7 (male
and female)

Mates (adult)

Females

Onset of menstruation
Ovulation peak

Luteal maximum

After menopause

1-11 (3 5)

0-15 (6)
13-54 (27)
8-72 (22)

0 5-9 (3)

3- 8 (5) 1

4- 7 (5) i

11-31(20) ,

10-23 (14)

1-7 (2-5)

0-6 Cl 5) |

0-3 (2)
4-14 (9)
4-10 (7)

CM (0 5)

(D

(10)

(13)

(56)

(43)

(6)

mg per 24 hours

Full-term pregnancy

| (30) |

a> |

(01) 1

(JS)f

• From Loraine (1958)

f Includes significant amounts of other oestrogens.

abnormal uterine bleeding and of amenorrhoea. Very low levels are found
in cases of gonadal dysgenesis. In patients with granulosa cell tumours of
the ovary a continuous high normal excretion (on a par with ovulatory
levels) is found.

Pregnanediol (Table 5.3). This metabolite of progesterone is found in
Table 5.3. Pregnanediol excretion in the urine *

Approximate normal mean \»tues (mg. per 24 hours)

Children (prepuhetal, male and female) 0 7

Malts (adult) 1

Females — .Menstrual cycle, follicular phase 1

luteal phase 2-5

After menopause 1

Pregnancy, 32 meek* to term 40

• From Loraine (1958).

the second half of the menstrual cycle and is evidence of normal luteal
formation and previous ovulation. It must not be confused with pregnane-

PRECOCIOUS PUBERTY 177

trial, a metabolite of 17-hydroxyprogesterone (Chapter 2), which is ex-
creted in excess in patients with congenital adrenal virilism.

Yl-Oxosteroids (Table 3.1). The estimation of 17-ovosteroids is usually
of little value in the investigation of ovarian disorders. High levels, how-
ever, may be found in women with virilizing lesions of the ovaries or of the
adrenal cortices.

Chromosomal analysis. This is helpful in the diagnosis of Turner’s syn-
drome and of other types of anomalous sexual development (Chapter 17).

PRECOCIOUS PUBERTY

When puberty starts early it is described as “precocious”. An exact
definition is difficult because of the wide variation of normality, but obvious
sexual characteristics appearing before the age of 8 years should be regarded
with concern. The problem is much commoner in girls than it is in boys.

In “true” precocious puberty the pituitary secretes gonadotrophins which
stimulate the ovary to develop and to ovulate normally. Sexual develop-
ment is “isosexual” (feminine). In “false” or pseudopuberty secondary
sexual development may be isosexual or heterosexual (masculine). The
isosexual type is caused by an ovarian tumour which secretes oestrogens.
Ovulation does not occur, and pregnancy is therefore impossible. The
heterosexual type is associated with congenital virilizing hyperplasia of the
adrenals, or with androgen-secreting tumours of the adrenal cortex or ovary.

Causes

The causative lesions of isosexual precocious puberty, which have been
reported, are as follows (after Wilkins):

A. True puberty (ovaries mature)

1. Constitutional (idiopathic)

2. Intracranial lesions

Hypothalmic
Pineal tumour
Uncertain

3. Albright's syndrome

B. False puberty (ovaries immature)

Otarian tumours
Granulosa cell
Uncertain (I granulosa cell)

Teratoma (? granulosa cell)

Thecoma
Choriocpithehoma
Adrenocortical tumours*

Total 530 (100%)

• A single case has been reported elsewhere.

This table should be compared with the similar one for boys (p. 138).

401 (76%)
18 (3%)

10

33 (6%)

78 (15%)
33
30
6
5

178

THE OVARY

Constitutional precocious puberty

This is much the most frequent cause of premature sexual development
in girls and is about four times as common as in boys. The cause is un-
known, and it may be familial. For some reason the hypothalamic-pituitary
mechanism starts to operate too soon, and extensive investigations fail to
reveal any other abnormality. Sexual development may be present at an
exceptionally early age, and breast development, menstrual bleeding and
the presence of sexual hair have been recorded in infancy. Ovular periods
render pregnancy possible, and it has been reported several times under the
age of 10. The most famous case is that of the Peruvian girl, Lina Medina,
who menstruated at 8 months and who was delivered of a 61-lb baby by
Caesarian section at the age of 5^ years.

The skeletal changes are the same as those seen in congenital virilizing
adrenal hyperplasia. Skeletal development occurs early and growth is
rapid initially, but the epiphyses close prematurely and the final height
rarely exceeds 5 feet. Adult skeletal proportions are not attained by the
time growth stops, so that the low-er limbs are shorter than the trunk, and
the patient may bear a superficial resemblance to an achondroplastic dwarf.

Mental and psychosexual development lag behind the somatic and
sexual transformation, but the majority of patients grow into normal
(though stunted) adults who marry and have children.

Intracranial lesions

These are responsible for sexual precocity less commonly in girls than in
boys. Presumably the hypothalamus and the anterior pituitary are stimu-
lated to secrete gonadotrophins.

Albright's syndrome

This consists of sexual precocity, pigmentation of the skin and polyo-
stotic fibrous dysplasia of bone. It occurs predominantly in girls, but its
cause is not known. The bone lesions, which may lead to spontaneous
fractures, are not associated with any detectable disturbances in calcium
and phosphorus metabolism. Pseudocysts and patchy rarefaction arc seen
in the long bones, but the skull is rarely affected. The skin shows patches
of yellow-brown pigmentation which may be present at birth or develop
shortly afterwards. It is frequently distributed irregularly and sometimes
unilaterally. Occasionally the syndrome is incomplete and only the bony
disorder is present.

Ovarian neoplasms

These growths secrete large quantities of oestrogens, but they are not
under the control of gonadotrophins, so that the secretion is not cyclical.
Menstrual bleeding is capricious and may be absent, irregular or prolonged

PRECOCIOUS PUBERTY 179

(menorrhagia). Skeletal growth and secondary sexual characters are similar
to those seen in constitutional precocious puberty.

Granulosa cell tumour. About 10 per cent of these tumours are found in
childhood. They are usually benign at this age and are often palpable
abdominally.

Ovarian teratomas are rare and usually highly malignant. When they
produce hormonal effects they may resemble granulosa cell tumours
clinically. Chorioepitheliomas of the ovary are also rare (fig. 5.2). They are

Fig* 5.2. Precocious pscudopuberty, due to chorioepithelioma of ovary, in
girl aged 9 years.

(Professor C. II. G. Macafre’s case.)

malignant, and signs of sexual precocity may be seen in the presence of
emaciation. Thecoma is another very rare cause of sexual precocity.

Diagnosis

The diagnosis of the cause of precocious puberty depends on detailed
clinical examination and on the results of special investigations. Seventy-

ISO

THE OVARY

five per cent of the cases are of the constitutional type. An intracranial
lesion must not be forgotten as a possible cause, although it is rare in girls,
and examination should be repeated at intervals if no lesion is found
Granulosa cell tumours are usually palpable abdominally by the time
symptoms have developed, and the other ovarian tumours may be felt on
bi-manual examination.

Estimation of the urinary levels of gonadotrophins, ocstrogens and preg-
nanediol may afford assistance in differentiating true from false puberty.
In the former gonadotrophins may be found in the urine, while in the latter
they are absent. However, the test is by no means infallible, and gonado-
trophin excretion may not be raised in patients with true constitutional
precocious puberty. The excretion of oestrogens is often increased with
granulosa cell tumours. Very high levels of urinary chorionic gonadotro-
phin may be suggestive of a chorioepithelioma, while pregnanediol excess
has been reported with thecoma.

Precocious sexual development must be distinguished from vaginal
bleeding due to trauma and foreign bodies, premature development of
sexual hair (premature pubarche), premature breast development without
other features of sexual maturation and the accidental ingestion of oestro-
genic preparations.

Treatment

In constitutional precocious puberty the parents should have the nature
of the disorder explained to them and be reassured that the final sexual
development will be normal. The child should also be told about the
condition in simple terms and be warned of menstruation. It is important
to remember the chronological age of the child, and the parents should not
make demands in advance of her capabilities. Girls need special protection,
since they are advanced for their age, and advantage may be taken of their
immaturity. The risks of pregnancy should be considered and safeguards
adopted by the parents. Most girls adjust themselves normally and do not
become sexually promiscuous. Operative and hormonal treatment have no
place; an attempt to inhibit pituitary function with oestrogens simply
accelerates epiphyseal closure.

A gmnu/osn cell tumour may be removed with a good prospect of cure.
Other ovarian rumours should also lie removed, but the results arc less
certain; recurrence with metastases and death is to be expected in chorio-
cpithelioma.

The prognosis in patients with intracranial tumours is generally poor.
Adrenal lesions causing heterosexual precocity can often be treated
effectively (Chapter 3).

HYPOGONADISM

181

hypogonadism

the secretion of the ovarian hormones inv * lverae nt of the other,

rare for one function to be to S ; ed while that of the other
Sometimes the secretion of one hotmoncB ^ whiU . deficient secre-

is diminished. Absence of ora a ^ (hc body , analogous to those in

tion of hormones causes general , ities infantilism is a condi-

the eunuchoid male, and menstrua d ith exua l immaturity,

tion of diminished somatic growth associated

Clinical features of hypogonadism hypogonadism cannot

Since the ovaries do not fu " ct,0 | " “” ' , he great variation in the time

arise until adolescence. Even then, ca nnot be diagnosed with

at which normal puberty occurs, of course, be possible to

certainty before the age of 18 ^i .,, in „ to bly cause hypogonadism
recognize at an early age a lesion w h h (he deficiency appears

later! The clinical features depend on whetne
before or after the age of puberty.

Fuberal hypogonadism oestradiol in normal

In puberal hypogonadism the oyanes dj on the degree of the

amounts. The severity of the clinical find g « P^ Dn patie „ts in whom
deficiency; the description winch fo «°« . conside rable variation

ovarian oestrogen formation is absent.

between different individuals 0 f menstruation (pn-

The patients usually compla.n ei.h r of absen ^ xhe ex-

mary amenorrhoea) or of lack of"®*'^ utcnl5 fails to develop
ternal genitals remain infantile in . eo j t helium are absent. The breas
and oestrogenic effects on the P , bido an d show little or

do not develop. Patients - is immature and the features and

interest in the opposite sex. in .

actions remain childish. of , he hypogonadism. Hyp P

Skeletal changes depend on the ca and gonado ,rophins are

tuitarism, In which growth homo*. * stature as well as sexual I n
deficient, causes infantilism with dim b with skeletal deformities,

maturity (fig. 1.8). Diminished sumu ^ d B . 0 f pituitary gonadotrophirr
is also found in gonadal dysgenesis. eunucboid proportions, since ep'P >

varieties, but is most evident in hypop

182

THE OVARY

sex hormones as welt as oestradiol arc deficient. Osteoporosis is not un-
common.

Hair growth varies considerably. In hypopituitarism growth of hair in
the pubic and axillary regions is absent or scanty. In gonadal dysgenesis it
is usually present, though rarely normal. It is often more advanced in the
axillae than in the pubic region on account of the normal adrenal function.

In partial hypogonadism the secondary sexual characters may develop
fairly well, but ovulation, and menstruation are not established.

Postpuberal hypogonadism

This is less common than the puberal variety. The clinical picture is
different, since a normal puberty has occurred already and the primary and
secondary sexual characteristics have been established. The epiphyses
have closed and skeletal growth has stopped.

Amenorrhoea follows immediately if the lack of stimulation, destruction
or removal of the ovaries is complete. Castration does not destroy the
capacity for sexual activity, and most women retain normal libido and
sexual function. Libido is lost when the hypogonadism is secondary to
pituitary insufficiency. Loss of oestradiol leads to atrophy and inactivity of
the whole of the genital tract and of the breasts. The changes are usually
more rapid and severe than those which develop during the course of the
natural climacteric. Hair usually diminishes in the pubic and axillary
regions, but it does not disappear unless there is pituitary (adrenal) in-
sufficiency also.

Palpitations, cardiac irregularity and vasomotor instability (hot flushes),
identical with those of the normal climacteric, may be found and are often
severe after surgical castration. Hot flushes are believed to be due to
increased gonadotrophin secretion, but we have observed them after total
hypophysectomy. Psychological features may be severe after surgical
castration, particularly in women who are unable to adjust themselves to
the loss of their ovaries.

Emotional factors may cause some patients to increase their consumption
of food and to put on weight, but hypogonadism itself does not cause
obesity.

There is evidence that coronary occlusion occurs more often and that
carcinoma of the breast develops less often in those who have undergone
oophorectomy than in women with intact ovaries.

Varieties of hypogonadism

There are many types of hypogonadism, and the causes of some of them
are not known. The following classification is based, so far as possible, on
aetiological factors.

HYPOGONADISM

183

04) Primary ( Olarion )

(i) Congenital (gonadal dysgenesis).

(li) Acquired:

(а) Castration.

(б) Inflammation (mumps, salpmgo-oSphoritis, pelvic peritonitis, etc )

(r) Radiation damage.

(B) Secondary ( Pituitary )

(i) Constitutional (delayed puberty)

(ii) Hypopituitarism.

(hi) Hypogonadotrophimsm:

(a) Psychological.

(b) Idiopathic.

(r) Inhibition by oestrogen s, androgens or corticosteroids.

(d) Associated with chronic general disease, surgical stress or starvation.

Primary hypogonadism

In the primary type the defect lies in the ovaries, which fail to respond
to gonadotrophic stimulation. Gonadal dysgenesis is described in Chapter
17. Castration requires no special description. Mumps oophoritis is less
easily recognized than mumps orchitis because the ovaries are hidden in
the abdomen, but it may be the cause of some unexplained cases of hypo-
gonadism. Mumps very rarely, if ever, affects the ovary before puberty.
The administration of oestrogens (to inhibit gonadotrophin) during an
attack of mumps may reduce the risk to the ovaries. Pelvic infections
commonly cause peri-oophoritis, which prevents ovulation and encourages
the development of cysts. It comm only interferes with the cyclical produc-
tion of hormones, but rarely causes signs of oestrogen deficiency. The
ovaries are extremely sensitive to ionizing radiation.

Secondary hypogonadism

In the secondary type the secretion of gonadotrophins is deficient and
the ovaries are normal (though infantile or atrophic). Constitutional de-
layed puberty or “delayed growth and adolescent development" is fairly
common in girls. "Constitutional or familial obesity of puberty” is
quite common also and must not be confused with Frohlich's syndrome
(which is very rare). Hypopituitarism results from disease of the pituitary
itself, or of the hypothalamus or higher centres, and influences other
glands and tissues as well as the ovaries. Frohlich’s syndrome and the
Laurence-Moon-Biedl syndrome probably belong in this group. The
secretion of gonadotrophins is frequently suspended temporarily by
psychological factors such as excitement or worry and the patient develops
amenorrhoca. Idiopathic hypogonadotrophimsm is a relatively common
cause of puberal hypogonadism, as it is in the male. The secretion of
gonadotrophins may be inhibited by oestrogens, androgens or cortico-
steroids produced endogenously or administered therapeutically. Thus,
hypogonadism develops commonly in patients with cirrhosis of the liver

184

THE OVARY

(failure to inactivate oestrogens), in those receiving testosterone for ad-
vanced cancer of the breast and in patients with Cushing’s syndrome. As
m the male, gonadal function is frequently disturbed by any chronic
debilitating disease, such as tuberculosis, thyrotoxicosis or uncontrolled
diabetes mellitus, and by starvation and surgical stress, but the precise
mechanisms are unknown.

Diagnosis

A careful history and general clinical examination arc, of course, essential
and may yield valuable clues. This must include a pelvic examination
Measurement of the basal temperature shows absence of the ovulatory
trough. Estimation of the total gonadotrophins helps to distinguish the
primary from the secondary group. In the former they are high (100 Ml)U
or more) because of the lack of ovarian hormones which normally ha\e an
inhibitory effect. In the latter they are absent (4 MUU or less) because the
pituitary does not produce them. The excretion of oestrogens and of
pregnanediol is usually low and that of 17-oxosteroida normal, except in
hypopituitarism when it is low also. Biopsy of the endometrium usually
shows absence of oestrogenic stimulation. The buccal smear or skin biopsy
is chromatin positive except in gonadal dysgenesis, when it is usually
chromatin negative.

Treatment

In the primary type replacement therapy with sex hormones is all that is
possible, and in the secondary type it is usually preferable to the use of
gonadotrophins. Oestrogens promote the development of secondary sexual
characters and, when given in a cyclical manner, induce regular uterine
bleeding. This is, of course, “oestrogen withdrawal bleeding” and not
menstruation.

Ethinyl-oestradiol (0-15 mg. daily by mouth) is suitable in most cases.
It is given for 21 days and then withheld for 10 day s. If no bleeding occurs
after the first withdrawal the cycles 3re continued regularly until a “period”
occurs. Thereafter treatment is started on the 5th day of each episode of
bleeding and continued for 21 days. The patient may find it easier to take
oestrogens for the first 21 days of every calendar month. The possibility of
normal menstruation being established in patients w ith hypopituitarism is
remote, but there is a slight chance in those with idiopathic deficiency' of
gonadotrophin. In such cases treatment can be stopped after a few months
and then restarted if spontaneous menstruation does not develop. Treat-
ment is usually continued until the age of the normal menopause (45 to 50).
Intramuscular injections may be necessary' if the oral rate causes toxic
symptoms.

Sometimes a progestogen is given in combination with an oestrogen-

HYPOGONADISM

185

Dimcthisterone (5 to 15 mg. daily by mouth) or allylestrenol (10 mg. daily
by mouth) is administered during the second half of the 21 -day course. It
is unnecessary in obvious cases of chronic hypopituitarism.

In hypopituitarism the administration of a small dose of testosterone
causes growth of pubic and axillary hair, assists in the growth spurt caused
by oestrogen treatment and improves muscular growth, wellbeing and
libido. Testosterone (5 to 10 mg. daily, sublingually) is usually adequate
and free from virilizing effects. If, as occasionally happens, it causes acne
the dose must be reduced.

The response of young girls with hypogonadism to therapy with oestro-
gens and testosterone is gratifying, and sexual characteristics develop
adequately. The personality matures and normal heterosexual interests
follow. The psychological effects of hypogonadism are less intense in girls
than in boys, because of the hidden nature of the disability, but the promo-
tion of regular artificial “periods” is a source of satisfaction to them. The
patients should be left in no doubt that they are incapable of bearing
children.

The climacteric

The climacteric is the time when ovarian function wanes and the ovary
becomes refractory to stimulation by pituitary gonadotrophin. It is, there-
fore, a physiological form of primary postpuberal hypogonadism. The
climacteric process may occupy months or years, while the menopause , or
cessation of menstruation, is a single event.

Several follicles are lost in each ovarian cycle and, as they near exhaus-
tion, anovular cycles become frequent. When all have gone ovulation stops
and the ovary is unable to secrete hormones. Loss of ovarian oestrogen is
the principal cause of the clinical features of the climacteric.

Clinical features

The climacteric usually occurs between the ages of 45 and 50 years, but
is sometimes earlier or later. Its duration is variable. Menstruation itself
may stop abruptly or may occur irregularly and in diminishing amounts for
some months. Occasionally disturbances in ovarian hormone production
lead to prolonged and excessive bleeding. In the British Isles the meno-
pause takes place cm the average at 48 years of age. Amenorrhoea in a
woman under 40 is unlikely to be menopausal, while uterine bleeding after
55 should be regarded as pathological.

The genital organs and breasts atrophy and the skin loses its elasticity.
In some women the changes are slight and delayed, probably because of the
activity of the adrenals. In most the uterus decreases progressively in size
and undergoes fibrous replacement. The vagina atrophies and the loss of
glycogen from the cells results in loss of acid from the vaginal secretion.

G

186

THE OVARY

This may be the cause of post-menopausal pruritus vulvac. Some women
tend to gain weight and to develop fat about the abdomen and hips, but this
tendency cannot be attributed directly to loss of oestrogen.

Secondary effects may be observed in the endocrine system as a whole.
Loss of the inhibitory effect of oestrogen allows increased amounts of FSH
to be secreted, and this may be accompanied by temporary excess of other
pituitary trophic hormones. Coarsening of the features, for instance, is
observed in some women and may be due to a temporary excess of growth
hormone.

Subjective symptoms may prove troublesome for variable periods. The
commonest are vasomotor symptoms (hot flushes), nerv ous tension, irrit-
ability, vertigo, depression and insomnia.

Management of the climacteric

Explanation and reassurance are all that is required in most people.
Those who require further aid are best treated with small doses of seda-
tives. Endocrine therapy is rarely necessary, and should be given only to
those with disabling symptoms.

Oestrogens help to control the vasomotor and other subjective symp-
toms. Ethinyl-oestradiol (0-01 mg. daily by mouth) is given for 2 to 4
weeks, and its effect on the frequency of the hot flushes is observed by the
patient. It is advisable to reduce their frequency, but not to abolish them
completely. The dose may have to be increased initially, but after trial
stoppages and progressive reduction in dosage it is usually possible to stop
all treatment after 2 to 3 months.

DISORDERS OF MENSTRUATION

The menstrual cycle provides a very sensitive index of gonadotrophic
and ovarian function in woman. There is nothing comparable in man.
Disorders of the “pituitary-ovarian axis”, which may arise in many ways,
frequently disturb menstruation. The function of the axis may be altered
by other endocrine glands, and menstrual disorders are often early and
important features of endocrine disease. Intrinsic lesions of the uterus,
which modify its response to hormonal stimulation, are also important
causes of menstrual irregularities.

The following brief account of menstrua! disorders is concerned mainly
with their hormonal aspects and with their significance in major endocrine
disease. The purely gynaecological aspects are not considered.

Definitions

Amenorrhoea means the absence of menstrual bleeding. In fahe amcnor-
rhoea (cryptomcnorrhoea) bleeding occurs, but the pathway is obstructed
and the discharge does not reach the outside. This may occur in some

DISORDERS OF MENSTRUATION

187

types of anomalous sexual development associated with absence or atresia
of the vagina. True amenorrhoea, in which the uterus does not bleed, may
be physiological (as in childhood, during pregnancy and lactation, and after
the menopause) or pathological. It is called “primary" if the patient has
never menstruated and “secondary'” if it occurs after a period of normal
menstruation. Scanty menstruation (in which the flow lasts for 2 days or
less) and infrequent menstruation (in which the cycle lasts more than 35
days) may be constitutional and associated with normal fertility or may
represent incomplete or early forms of conditions which may also cause
amenorrhoea.

Menorrhagia implies that the menstrual loss is excessive in amount or
duration, but that it occurs at normal intervals. The cause usually lies in
the uterus. In ephnenorrhoea a normal loss occurs at short intervals.
Epimenorrhagia is excessive loss at short intervals, and is usually caused by
ovarian and uterine disorders. Disturbance of the pituitary-ovarian axis is
the usual cause. Metrostaxis is irregular or continuous bleeding of any
amount, usually caused by a uterine lesion. Ovulation haemorrhage is
bleeding, usually slight in amount, which occurs at about the time of
ovulation. It is very common and of no pathological significance.

Pathological effects of oestrogens and progestogens on the endo-
metrium

Normally ocstradiol causes proliferation of the endometrium and the
formation of glands and progesterone subsequently causes the glands to
develop completely and to secrete. Menstruation is the result of the sudden
withdrawal of both hormones from the circulation. This cycle may be
disturbed in various ways.

1. If the hormones are absent, as in hypogonadism, the endometrium
does not proliferate and there is amenorrhoea.

2. Sometimes oestrogens are produced in normal or excessive amounts
while the secretion of progesterone is absent or deficient (urinary preg-
nanediol less than 1 mg. per 24 hours in second half of cycle).

(fl) The oestrogen level may be fairly constant, in which case the state of
the endometrium can be correlated with the amount of “total oestrogens”
in the urine as follow's:

Urinary oestrogen*

(wj-j24 hr.) Endometrium Symptoms

0-10 Atrophic Amenorrhoea

7-18 Early proliferation Amenorrhoea or scanty or infre-

quent menstruation

15-30 Proliferation Often none

25-40+ Cystic glandular hypertrophy Metrostaxis

A proliferative endometrium may break down and bleed at fairly regular
intervals, and the loss may simulate normal menstruation. The cycles,

188

THE OVARY

however, are anovulatory, secretory changes are not found on endometrial
biopsy and the temperature of the body does not change.

(A) Sometimes the oestrogen level fluctuates, but the excretory peaks tend
to be higher and to persist for longer than in normal cycles. The endo-
metrium may either break down at regular intervals as a result of oestrogen
withdrawal (anovular menstruation) or undergo cystic glandular hyper-
trophy with episodes of bleeding (metrostaxis) at any stage in the cycle.
The precise mechanism of uterine bleeding in many of these states is not
known.

3. Sometimes progesterone is produced excessively or for long periods,
and may then be withdrawn more slowly than normal. The result is
exaggeration or prolongation of the secretory phase with amenorrhoea,
which may be followed by metrostaxis.

Various combinations of abnormal patterns of secretion, which have not
been fully elucidated, may occur and influence menstruation in complex
ways.

Causative lesions
Disturbance of anterior pituitary

Hypopituitarism causes hypogonadism because the production of gonado-
trophins is deficient. The commonest form is probably psychogenic hypo-
gonadotrophinism which causes temporaty amenorrhoea. Hypopituitarism
accounts for the amenorrhoea which is usual with pituitary tumours, in-
cluding those causing acromegaly. Gonadotrophin secretion is probably
inhibited by androgens and by large amounts of corticosteroids. Con-
sequently, amenorrhoea is usually observed when large doses of these
hormones are administered therapeutically or when they are produced
endogenously by lesions of the adrenals (adrenogenital and Cushing's syn-
dromes) or ovaries (virilizing tumours and possibly the Stcirt-Lcventhal
syndrome). Oestrogens (from endogenous or exogenous sources) inhibit
the secretion of FSH and prerent normal menstruation, but may cause
uterine bleeding in the ways described already.

Little is known of the role of hyperpituitarism in causing menstrual dis-
orders. Prolactin (LTH), which is secreted throughout the period of
lactation, inhibits ovulation and thus causes amenorrhoea. Precocious
secretion of gonadotrophins causes precocious puberty. It has been sug-
gested that over-secretion of one or more of the gonadotrophins may inter-
fere with ovarian function and cause the menorrhagia that is occasionally
seen in acromegaly or in Cushing's syndrome.

Oxarian lesions

Anovular ovarian cycles occur normally at the onset of puberty and be-
fore the menopause, and pathologically 3t other times. It is postulated

DISORDERS OF MENSTRUATION 189

that the graaffian follicles ripen and degenerate in a cyclical manner with-
out forming corpora lutea.

Follicular cysts are graafian follicles which have failed to rupture. The
ova degenerate, but the granulosa cells persist and liquor accumulates.
Finally, they undergo atrophy. A cyst may form as an isolated event, or
many cysts may form in succession in place of normal ovulation. Oestradiol
is often secreted for prolonged periods in either constant or fluctuating
amounts.

Lutein cysts are corpora lutea which have become cystic, often as a result
of bleeding within them. They may secrete progesterone for long periods.

Ovarian cysts and tumours, even when bilateral, rarely interfere with the
endocrine function of the ovary unless they secrete sex hormones or cortico-
steroids. Those which do so will be described later.

Uterine lesions

Absence of the uterus (congenital or acquired) causes amenorrhoea.
Neoplasia or inflammation of the uterus or inflammation of the pelvic
organs may cause abnormal bleeding of various types.

General disease

Several other disease states often influence menstruation, but the precise
mechanisms by which they do so are unknown. Thus, amenorrhoea may
accompany malnutrition, severe anaemia, chronic sepsis, tuberculosis and
chronic diseases of the heart and kidneys. Certain endocrine diseases
belong in this category. Thyrotoxicosis commonly causes oligomenorrhoea,
and is sometimes associated with amenorrhoea. Hypothyroidism usually
causes menorrhagia or epimenorrhoea and rarely amenorrhoea. Un-
controlled diabetes mellitus may cause amenorrhoea.

The Stein-Leventhal syndrome (Polycystic ovaries)

In this uncommon syndrome multiple small cysts of the ovaries are
associated with infertility, some disturbance of menstrual function and
often mild virilism. The condition has been recognized for more than a
hundred years, but very little was known about it until 1935, when Stein
and Leventhal reported a series of patients in whom fertility and normal
menstruation had been restored by resection of wedges of ovarian tissue.
Pathology

Both ovaries are involved and are usually enlarged from two to five times
by the presence of multiple cysts, whose sizes vary from about 2 mm. to
2 cm. in diameter. The tunica albuginea is often thickened and tough so
that the cysts are not always visible to the naked eye. Microscopically the
tunica is sclerosed and thickened. The cysts are lined by granulosa and
theca interna cells, and atretic follicles are often conspicuous. The ovarian

190

THC OVARY

stroma may be hypertrophied and contain scattered collections of large cells
filled w ith lipoid material. Hyperplasia of the cells of the theca interna with
luteinization may be prominent in some cases. Corpora lutea 3re usually
absent.

Pathogenesis

Little is known of the pathogenesis of the condition. Analysis of the
fluid from the ovarian cysts reveals a deficiency of oestradiol and an excess
of its androgenic precursor, androstenedione (Chapter 2). This suggests
that the synthesis of oestradiol is defective and that the excess of androgen
is responsible for the virilism. The condition may therefore be analogous
with virilizing adrenal hyperplasia. Oestrogens, however, are found in the
urine, usually in amounts comparable with those of the first half of the
menstrual cycle, and endometrial biopsy and studies of vaginal cytology
reveal oestrogenic activity. Occasionally cystic glandular hypertrophy is
found, indicating a high level of oestrogen secretion. The oestrogens may
be derived from unaffected parts of the ovaries or from the adrenal cortices.
The significance of other occasional findings (high excretion of pregnane-
diot, high normal levels of 17-oxostcroids and variable amounts of gonado-
trophins) is not clear.

Clinical features

Infertility is invariable, although the patient may have had a child before
the onset of symptoms.

Menstrual irregularities are usual. The commonest complaint is of
secondary amenorrhoea, developing in the late ’teens or early twenties.
Menstruation, usually normal at first, becomes scanty and infrequent.
Some patients suffer metrostaxis and other clinical features suggestive of
metropathia haemorrhagica. The bleeding is nearly always anovular, but
ovulation and formation of a corpus luteum may occur occasionally.

Virilism of some degree is present in half the patients. Hirsutism is the
commonest Feature, and acne is frequent. Hypertrophy of the clitoris,
atrophy of the breasts and lowering of the voice are rare.

Enlargement of the ovaries is almost invariable, but may not he apparent
clinically, especially in fat patients.

Obesity is seen in about 30 per cent of patients.

Investigation

The enlargement of the ovaries, if not obvious clinically, may be detected
by bi-manual examination under an anaesthetic, by X-rays after the induc-
tion of a pneumoperitoneum or by culdoscopy.

Measurement of body temperature reveals absence of ovulation.

Vaginal smears and endometrial biopsy usually show evidence of oestro-
genic activity.

OVARIAN TUMOURS WITH ENDOCRINE MANIFESTATIONS 191

The excretion of 17-oxosteroids in the urine is often in the high normal
range. Oestrogens are usually present in moderate amounts, and the excre-
tion of pregnanediol may be high. The total gonadotrophins are usually
normal, but sometimes high or low.

Differential diagnosis

The Stein-Leventhal syndrome must be distinguished from idiopathic
hirsutism, the adrenogenital syndrome, Cushing’s syndrome and a virilizing
tumour of the ovary. Bilateral cystic enlargement of the ovaries is the most
characteristic finding.

Treatment

Resection of a wedge of tissue from each ovary restores normal menstrua-
tion and fertility in about 80 per cent of cases. Usually about half the ovary
is removed and the defect is repaired by sutures. How this procedure
confers benefit is not known.

OVARIAN TUMOURS WITH ENDOCRINE MANIFESTATIONS

Certain tumours of the ovary secrete hormones which exert general
effects on the body. Those which do so are uncommon and account for
about 2 per cent of all ovarian tumours. Most of them arise from the sex
cords or mesenchyme of the primitive gonad, and their cells are capable of
differentiating into (ovarian) granulosa or theca cells or into (testicular)
tubular, Sertoli or Leydig cells. Their histogenesis is not understood well
and their classification is controversial. They may be considered in three
groups: (1) oestrogen-producing or feminizing tumours; (2) androgen-
producing or masculinizing tumours; and (3) a miscellaneous group.

Oestrogen-producing tumours

These include: (1) granulosa cell tumours; (2) thecomas; and (3) Brenner
tumours.

Pathology

Granulosa cell tumours occur at all periods from childhood to old age,
but are commonest in the fifth decade. They are round, smooth, firm,
yellowish -white tumours, which vary greatly in size, but are rarely more
than 10 cm. in diameter. The centres of the larger ones may be cystic and
haemorrhagic. Histologically they show great cellular activity and up to
25 per cent are malignant. The cells are cubical and have deeply staining
nuclei. Their arrangement differs greatly, but three main types — diffuse,
trabecular, and folliculoid— are recognized. Thecal cells are often present
as well and may be so prominent as to justify the term “granulosa- theca cell
tumour”. Luteiniz3tion is sometimes conspicuous, and a tumour showing

192

THE OVARY

this feature is called a luteoma. The so-called “tubular androblastoma”,
which was formerly thought to be an oestrogen-secreting arrhenoblastoma,
is probably a form of granulosa cell tumour.

Thecomas occur in middle and old age and are commonest after the age
of 50. Grossly they are similar to the granulosa cell tumours, but are
usually smaller in size. They contain bright yellow streaks of fatty material.
Histologically the tumour is composed of interlacing bands of spindle-
shaped cells. Their cytoplasm is more copious than that of fibiocytes and
often contains vacuoles in which steroid crystals (possibly oestrogens) may
be seen. Luteinization is rare. Fine fibrils of reticulum often invest the
cells, and sometimes broad bands of hyaline connective tissue form between
the cells and may eventually replace them. The tumour at this stage is in-
distinguishable from a fibroma. Indeed, many so-called fibromas may, on
extensive sectioning, be found to contain theca cells. The thecoma is rarely
malignant.

The Brenner tumours occur only in adults, and arc commonest after the
age of 40. They are occasionally bilateral. Grossly they resemble granulosa
cell tumours or thecomas, but sometimes they arc found in the walls of
pseudomucinous cysts. Histologically there are islands of epithelium (of
uncertain origin) surrounded by a stroma of fibrous, hyaline or cellular
tissue. In tumours with oestrogenic activity the stromal cells may contain
steroids, similar histologically to those of thecomas. The Brenner tumour
is benign.

Belfast series

In a review of tumours of the ovarian mesenchyme in Belfast, Biggaxt
and Macafee found:

Granulosa cell tumours 18

Thecoma* 25

Fibromas 69

Brenner tumours 15

Total 127

The proportion of thecomas is relatively high compared with other scries.
Many had been regarded as fibromas at first, but after it had been found
that the patients had shown evidence of oestrogenic activity in the endo-
metrium further blocks of tissue were cut and they vvtie reclassified as
thecomas (or fibro-thecomas).

Clinical features

Oestrogenic features, which usually take the form of menstrual distur-
bances or of abnormal uterine bleeding, arc seen in nearly all cases of
granulosa cell tumours (89 per cent in the Belfast scries), in many thecomas
(68 per cent) and in a few Brenner cell tumours (13 per cent).

ANDROGEN-PRODUCING TUMOURS 193

An oestrogen-secreting tumour in childhood may cause precocious iso-
sexual pseudopuberty. The secondary sex characters develop and the
endometrium bleeds. The breasts undergo hypertrophy and may secrete
colostrum. Ovarian function is depressed and ovulation and regular men-
struation do not occur. In the young adult the menstrual cycle is disturbed
in various ways, depending on the amount of oestrogen produced and on
whether or not its production fluctuates, Post-menopausal women may
become “rejuvenated". Uterine bleeding returns and the breasts may re-
develop and even secrete milk.

Most of the tumours are palpable on bi-manual examination, and some
may present as abdominal swellings or undergo torsion. Malignant tu-
mours may cause ascites and symptoms associated with metastatic spread.

Endometrial changes

The endometrium frequently shows evidence of oestrogenic stimulation,
even after the menopause. Proliferation and cystic hypertrophy are com-
mon. Tumours which show luteinization may secrete progestogens as well
as oestrogens, and cause secretory changes in the endometrium.

Carcinoma of the body of the uterus (adenocarcinoma) occurs quite fre-
quently in association with granulosa cell tumours and thecomas and may
be the result of prolonged stimulation with oestrogen. It was present in
18*5 per cent (8 cases) in the Belfast series. Its incidence is highest after the
menopause.

Androgen-producing tumours

These are rare, compared with the previous group, and include:
(1) arrhenoblastomas; (2) lipoid cell tumours (adrenal rest tumours,
masculinovoblastomas) ; and (3) hilus cell tumours.

Pathology

Arrhenoblastomas are the commonest tumours of this group and occur
mainly in young adults. Grossly they resemble granulosa cell tumours, but
histologically they are quite different. The structure is very variable. The
tumour may be well differentiated and resemble the normal testis, with
seminiferous tubules and lipoid-containing interstitial cells, or it may be
highly anaplastic and resemble a sarcoma. The commonest variety is inter-
mediate between these extremes, and consists of cords of cells with darkly
staining nuclei, whose axes run at right angles to those of the cords, and
with occasional poorly formed tubules. The tumour may be locally malig-
nant, but it rarely metastasizes.

Lipoid cell tumours are very rare. They are possibly derived from adreno-
cortical rests, for they contain liptd and resemble the cells of the adrenal
cortex. Similar tumours may cause Cushing’s syndrome.

194

THE OVARY

Htlus (Leydig) cell tumours are small and consist of clumps of cells re*
sembhng normal hilus or Leydig cells.

Belfast series . In a review of virilizing ovarian tumours in Belfast (1933-
61) Harley (1962) found:

Arrhenobtastoma 4

Lipoid cell tumour 0

Hilus cell tumour 0

Total 4

Clinical features

Androgenic features are usual. The commonest symptom is secondary
amenorrhoea. Defeminization (atrophy of breasts and genitalia) and viri-
lization (hirsutism, acne, lowering of the voice and hypertrophy of the
clitoris) are not uncommon. In one reported case an arrhenoblastoma in
childhood caused heterosexual precocious pseudopuberty. The tumours
are usually palpable.

Miscellaneous tumours

Some of these rare tumours are of endocrinological interest.

The chorioepithelioma* may be a variety of teratoma and is highly malig-
nant. It secretes chorionic gonadotrophin in large amounts and stimulates
the secretion of oestrogens (and progestogens) and the formation of cystic
corpora lutea in the opposite ovary. The oestrogens may cause effects
similar to those produced by a granulosa cell tumour.

The struma ovarii is a teratoma in which thyroid tissue predominates.
About 10 per cent of cases show signs of hyperthyroidism.

The disgermimma resembles histologically the seminoma of the testis. It
does not secrete hormones, but it occurs not uncommonly in female
pseudo hermaphrodites (virilizing adrenal hyperplasia), often in childhood
or adolescence.

Investigation

In patients with feminizing tumours evidence of oestrogen excess may be
seen in vagina] smears and in endometrial biopsies. The excretion of
oestrogens in the urine is frequently high, but few detailed studies have
been made. In those with virilizing lesions the 17-o\ostcroids should be
measured. With arrhenoblastoma they are often normal or only slightly
raised, and it may be that the androgen is not excreted in the 17-o\ostcroid
fraction. With lipoid cell tumours the 17-oxostcroids tend to be higher.

The excretion of gonadotrophins may be low with tumours secreting
oestrogens or androgens, but arc very high with chorioepitheliomas.

Thyroid function may be increased in patients with struma ovarii,
though the neck uptake of iodine is not, of course, raised.

• We use the term chortomrpithelioma for tumours arising from the true chonon only.

ANDROGEN-PRODUCINC TUMOURS 195

Most of the ovarian tumours are palpable clinically or visible by culdo-
scopy. Laparotomy, however, is usually necessary for precise diagnosis.

Differential diagnosis

Oestrogen-secreting tumours must be distinguished from other causes
of oestrogen excess. In children the other causes of precocious puberty
must be considered. In adults oestrogen therapy, accidental assimilation of
oestrogens from shin creams or industrial processes, follicular cysts of the
ovary and cirrhosis of the liver must be excluded.

Androgen-secreting tumours must be distinguished from other causes of
defeminization and virilization. Androgen therapy, virilizing lesions of
the adrenals, Cushing’s syndrome, the Stein-Leventhal syndrome and
idiopathic hirsutism must be excluded.

Treatment

Surgical removal of the tumour is usually indicated. Excision of the
affected ovary and tube is adequate in young patients with unilateral lesions
which are well encapsulated and free from adhesion to adjacent structures.
Total hysterectomy and removal of both ovaries and tubes are required
when the tumour is evidently malignant and for women past the age of
about 45. The radical procedure is more likely to eradicate a malignant
ovarian growth and removes a potentially or actually malignant uterus in
patients with oestrogen-secreting lesions. If examination of a tumour,
after simple removal, shows it to be malignant a second, radical operation
may be required. Irradiation with X-rays has little place in the treatment
of these lesions.

The prognosis is good except in malignant cases where the lesion has
spread beyond the ovary. Recurrence, howe\er, has been reported as late
as 20 years after removal of a granulosa cell tumour.

The endocrinopathy is cured rapidly by removal of a tumour. Normal
menstruation and fertility' are restored (provided the uterus and one ovary
remain) and feminizing or virilizing features are reversed.

Cftonbepithefibma requires special mention. Radical* surgery ana’ ir-
radiation are required as soon as the diagnosis is established. The prog-
nosis, however, is bad.

MISCELLANEOUS LESIONS OF THE UTERUS
Carcinoma of the endometrium

Adenocarcinoma of the body of the uterus occurs most commonly after
the menopause, and often in nulliparae or in women who have had few
pregnancies. There is evidence that overstimulation of the uterus bv
oestrogens may contribute to its development, for endometrial carcinoma

196

THE OVARY

often occurs in patients with oestrogen-secreting tumours of the ovary and
may occasionally follow prolonged oestrogen therapy. Endometrial
glandular or cystic hypertrophy is sometimes associated with it. The
tumour tissue retains the capacity of normal endometrium to respond to
progesterone, but the response is slow and incomplete. There is a signifi-
cant association between endometrial carcinoma and diabetes mellitus.

Advanced cases of endometrial carcinoma have been treated with pro-
gesterone and related steroids (in doses of 150 to 1,000 mg. per week) with
gratifying results. One-third of cases show objective remission, lasting
months or years, and many more benefit subjectively. The progesterone
probably has a direct action on the tumour.

Hydatidiform mole and chorionepithelioma

Both these lesions are neoplasms of the chorion. Benign hydatidiform
moles are particularly liable to develop into malignant chorionepitheliomas
in women over the age of 40, that is when ovarian function is waning. It
may be, therefore, that oestrogens have some protective action.

Chorionepithelioma metastasies locally to the vagina and vuha, and
distantly to the lungs, brain, liver or kidneys. Occasionally deposits arc
found in the alimentary’ tract and cause bleeding.

Both tumours secrete large amounts of chorionic gonadotrophin which
may be measured in the urine and which causes the development of
multiple cysts in both ovaries. Some cysts may be follicular, but the
majority are luteal. They may enlarge the ovaries greatly, but they regress
after removal of the tumour and should not be removed.

The measurement of chorionic gonadotrophin in the urine is helpful
diagnostically, but not entirely reliable. In most cases the readings arc
abo\e 300,000 IU per litre, but a few normal pregnant women, especially
those with multiple pregnancy, secrete similar amounts in the early months.
After removal of a mole the excretion of gonadotrophin usually falls to
zero within one month. Serial determinations are valuable after treatment,
and a level of 30,000 IU or more after one month is highly suggestive of
retention of molar fragments or of the development of chorionepithelioma,
provided a new pregnancy' can be excluded. Similarly, the completeness of
removal of a chorionepithelioma, or its recurrence after treatment, can be
‘Ksessied b’j wwzsukwk?& vs? gwpadvAtvspbvw.

Hydatidiform mole is treated by hysterectomy, but the ovaries should
not be removed. Chorionepithelioma may be treated with oestrogens, hut
the prognosis is very bad and there is little evidence that any endocrine
measures are of value. I ly pophysectomy has been tried several times
without success. Remissions, lasting for months or years, have been
reported after treatment with folic-acid antagonists such as methotrexate.
It is possible that more success will attend the recognition that the tumour

ENDOMETRIOSIS

197

is a homograft (half of its genic material being derived from the father) and
that the patient exhibits a state of acquired tolerance. Immunization of the
mother against tissue from the father is a method of treatment that is being
explored.

Endometriosis

Endometriosis is the presence of endometrial tissue in abnormal sites. It
may occur anywhere in the body, but is commonest in the ovaries 3nd in
the organs and tissues of the abdomen and pelvis at or below the level of the
umbilicus. Its cause is unknown, but it is thought to arise by retrograde
menstruation, by serosal cell metaplasia or by lymphatic or vascular em-
bolism from the uterus.

The ectopic tissue is identical with normal endometrium histologically,
and it is subject to the same hormonal control. It proliferates, breaks down
and bleeds with every menstrual period. The discharge, being unable to
leave the body, remains within the tissues and forms a collection which
increases in size with each period. Some of the fluid is absorbed, however,
and the blood becomes thick and dark, producing “chocolate” or “tarry”
cysts. These are usually small, but may reach the size of a foetal head. In
time the endometrial lining may be destroyed, and this may render histo-
logical diagnosis difficult. The cysts frequently rupture and scatter their
contents, which include endometrium, within the abdominal cavity. The
peritoneum reacts strongly with the formation of dense fibrous adhesions.
It is important that these cysts and adhesions should be recognized at
laparotomy and that they should not be mistaken for malignant disease.
During pregnancy the endometrial tissue shows a decidual reaction and
becomes quiescent, often permanently. After the menopause or after
castration endometriosis nearly always undergoes atrophy, although fibrous
adhesions may remain. Sometimes the lesions become inactive after a time
without any obvious change in the endocrine environment.

Endometriosis is a common condition. It is most frequently active
between the ages of 30 and 40 years, but it can arise at any time in the re-
productive period. The most characteristic clinical feature is that it causes
or aggravates symptoms only at the time of the menstrual period.

There are special sites at which endometriosis may confront the general
surgeon. It is frequently not recognized because it is not considered as a
possible cause of symptoms.

Intestinal endometriosis

The ileum, colon, rectum (recto-vaginal septum) or appendix may be
involved. The lesions are usually confined to the peritoneal surface, but
may occasionally penetrate to the mucosa. This may be congested and
puckered, but it is rarely ulcerated. The cysts and fibrous tissue tend to be

198

THE OVARY

localized to small areas on the surface and not to encircle the bowel, and
the lymphatic glands are not enlarged.

The symptoms (which coincide with the menstrual periods) depend on
the site of involvement. Ileal or colonic lesions may cause recurrent
diarrhoea or intestinal obstruction, which may become complete. Rectal
lesions may cause rectal pain on the passage of faeces or flatus. Rarety a
lesion at any of these sites causes rectal bleeding. Endometriosis in the
appendix, (or the rupture of a cyst anywhere in the pelvis) can mimic acute
appendicitis. Associated lesions of the genitalia may cause dysmenorrhoea,
dyspareunia or vague lower abdominal pain. Pyrexia is sometimes caused
by material absorbed from the cysts at the time of menstruation. General
ill-health and malaise are common, but weight is usually maintained.

Clinical examination should include a careful search for accessible endo-
metrial deposits. These may be seen or felt in the posterior wall of the
vagina (where they form multiple blue-domed cysts, which feel hard and
may ulcerate), in the recto-vaginal septum or in the ovaries. Sigmoido-
scopy may reveal a stricture of the rectum or pelvic colon, usually without
involvement of the whole circumference or ulceration of the mucosa.
Examination both during menstruation and in between two periods may
show that the lesions vary in size and tenderness. Barium enemas, per-
formed at these two times, may provide similar information.

Treatment of intestinal obstruction should be sufficient to relieve it and
usually involves resection of bowel. Castration alone rarely halts the pro-
gression of an obstructiv e lesion. It is important that the condition should
not be mistaken for carcinoma, otherwise the patient may be submitted to
an unnecessarily mutilating operation. Appendicular lesions arc treated by
appendicectomy.

Belfast series. Endometriosis was found in the intestines in 3 per cent
(29 out of 803 cases) of a series reviewed by Macafcc and Greer in Belfast.
They were divided into 4 groups:

1. Bowel involvement without obstruction 11

2. Bowel involvement with obstruction 8 (acute in 6)

3. TnvoUement of recto-vaginal septum 5

4 Im oh ement of appendix S

Total 29

Other sites

Endometriosis of the bladder may cause haem3tuna, frequency or
strangury at the menses. Lesions may rarely obstruct the ureters.

Superficial tumours may be formed by endometrial tissue at the um-
bilicus, in the inguinal canal, in the perineum or in abdominal scars. They
enlarge and become painful at the menses and may rarely burst on to the
surface.

THE OVARIES AT LAPAROTOMY

399

Treatment

It should be remembered that lesions regress, often permanently, during
pregnancy and occasionally at other times, and that the menopause nearly
always brings relief. Expectant treatment and the use of analgesics is the
treatment of choice for young married women.

If symptoms are severe and pregnancy is unlikely surgery may be
necessary. Localized lesions in the ovaries and elsewhere can be excised.
Widespread deposits, associated with much fibrosis, are difficult to treat.
In young women, in whom fertility must be preserved, as much as possible
of the diseased tissue is excised and the rest is destroyed by diathermy.
Incomplete operations often yield good results. In women over 40 years of
age bilateral obphorectomy and hysterectomy is often the best course.

Radiotherapy can be used for the destruction of ovarian function, but it
should not be employed when the diagnosis is in doubt.

The administration of hormones may have a place in treatment. Andro-
gens (testosterone 10 mg. per day, sublingually) will relieve symptoms
temporarily, and may be helpful as a diagnostic test, but they suppress
ovarian function. Attempts to reproduce the effect of pregnancy with
oestrogen and progestogen together (e.g. “enavid”) for 6 to 9 months con-
tinuously have been reported, and the preliminary results have been en-
couraging.

THE OVARIES AT LAPAROTOMY
The general surgeon frequently sees or feels “cysts” or other lesions in
one or both ovaries during the course of laparotomy. Often he cannot
recognize what he finds and is at a loss to know what he should do. As
Jeffcoate points out, many ovaries have been removed in the course of
appendicectomy because they contained normal corpora lutea. Such a
tragedy is particularly common when the appendix has been found to be
normal and the "cyst” has been mistakenly blamed for the patient's pain.
It cannot be stressed too strongly that, with few exceptions, an ovary should
be removed only for malignant disease.

The following cystic and neoplastic lesions may be found:

1 . Cystic ovaries

A cyst of one of the normal ovarian structures is very common indeed in
women of childbearing age, and usually has no pathological significance.
There are four types:

(tr) Corpus luteum (sometimes more than one).

(b) Follicular cyst (single or multiple).

(c) Lutein cyst (single or multiple).

(d) Atretic cysts (single or multiple).

200

THE OVARY

These ha%e been mentioned already. They are often bilateral, but always
small (up to 3 cm. in diameter). When multiple they may enlarge the o\ ary
considerably. It is very doubtful if they ever cause pain. They may be
punctured if found at laparotomy, but should otherwise be left alone.

2. Ovarian cysts

“Ovarian cysts”, as distinct from “cystic ovaries", are neoplasms.
About 80 per cent of primary' ovarian tumours are mainly cystic. The
following types are recognized :

(«r) Pseudomucinous cystadenoma (30 to 40 per cent of all o\arian
tumours).

(A) Serous cystadenoma (10 per cent)

(c) Papilliferous cyst.

(<f) Cystic teratoma.

(e) Endometrial cyst.

(J) Cystic degeneration in a solid tumour.

All are larger than the “cysts” of cystic ovaries, and some may be enormous.
They are frequently multilocular and often bilateral. Many are malignant.
Evidence of malignancy is suggested by the presence of: (1) solid areas;
(2) fungation; (3) large vessels on the surface; (4) internal bleeding; (5) free
peritoneal fluid, especially if bloodstained; (6) adhesions to adjacent struc-
tures; (7) bilateral lesions; and (8) peritoneal metastases (JefFcoate).

Most benign tumours of the ovary', however large, can be enucleated
from the organ and the normal functioning tissue preserved and re-
modelled by sutures. This should always be done in young women. If
there is a suspicion of malignancy the whole ovary and tube should be
removed. In older women (over 45 years) in whom malignancy is sus-
pected, both ovaries and tubes should be removed because of the risk of a
lesion developing later in the other organ.

3. Solid ovarian tumours

These include all types of tumour, both primary’ and secondary’, in-
cluding those described earlier. Solid primary tumours should be removed
by oophorectomy according to the principles just described.

1TXTHFR READtNC AND lUTERCNCES
General

ALLEN, g. s. (I960). Tests for pregnancy. C/in. Med., 7, 977.

BISHOP, P. »!. r. (1951). Gynaecological Endocrinology. 2nd Ed. Livingstone,
Edinburgh.

brown', J. B., kellar, R. and MAmrEW, c. D. (1959). Preliminary observations on
urinary oestrogen excretion in certain gynaecological disorders J- Qbstet.
Gynaec. Bnt. Emf>„ 66, 177.

TURTHER READING

201

jiamblen, e. c. (1947), Endocrinology of Woman. Thomas, Springfield, 111.

) EFFCOATE, T. N. A. ( 1962). Principles of Gynaecology. 2ndEd. Butterworth, London.

lloyd, c. \v. (1959), Recent Progress in the Endocrinology of Reproduction Academic
Press, New York.

loraine, j. a. (1958). Human chorionic gonadotrophin, p. 65 , Oestrogcns, p. 154;
Progesterone and its metabolites, p. 205; In Clinical Application of Hormone
Assay. Livingstone, Edinburgh.

novak, e, R. and JONES, g. s. (1961). Novak’s Textbook of Gynecology . 6th Ed.
Baillicre, Tindall & Cox, London.

NOVAK, e, and novak, e. R. (1958). Gynecologic and Obstetric Pathology. Saunders,
Philadelphia.

Precocious Puberty

Benedict, P. H. (1962). Endocrine features of Albright’s syndrome (fibrous
dysplasia of bone). Metabolism, II, 30.

JOLLY, tt. (1955), Sexual Precocity. Blackwell Scientific Publications, Oxford.

SECkel, H. P. G. (1946). Precocious sexual development in children Med. Clin. N.
America, 30, 183.

WILKINS, L. (1957). Precocious sexual development. In The Diagnosis and Treat-
ment of Endocrine Disorders in Childhood and Adolescence. 2nd Ed. Blackwell
Scientific Publications, Oxford.

S tein-heveniha] Syndrome

short, r. v. and London, d. r. (1961). Defective biosynthesis of ovarian steroids in
the Stein-Leventhal syndrome. Brit, ttted. J., I, 1724.

STEIN, i. F., COHEN, M. r. and ELSO.V, r. (1949). Results of bilateral wedge resection
in 47 cases of sterility. Amer. J. Obslet. Gynec., 58, 267.

STEIN, i. f. and LEVENTHAL, M, l. (1935). Amenorrhoea associated with bilateral
polycystic ovaries. Amer.J. Obstet. Gynec., 29, 181.

Tumours tcith Endocrine Manifestations

BICCART, j, it. and MACAFEE, c. H. G. (1955). Tumours of the ovarian mesenchyme.
y. Obstet. Gynaec. Brit. Emp., 62, 829.

Harley, g. (1962). Personal communication.

morris, j. M. and SCULLY, R. e. (1958). Endocrine Pathology of the Ovary. Kimpton,
London.

Hokes, j, m. and claibone, h. a. (1956), A clinical evaluation of masculinizing
tumours of the ovary. Ann. Surg., 143, 729.

ullery, j. c. (I960). A review of endocrine tumours of the ovary, Amer.ff. Surg.,
99, 519,

Chorionepithelioma

chan, D, p. c. (1962). Chorionepithelioma — a study of 41 cases. Brit. vied. J., 2,
953.

chan, d. p. c. (1962). Treatment of chorionepithelioma with methotrexate. Brit.
med.J., 2, 957.

Endometriosis

macafee, c. !J. c. and greer, h, l. ix. (I960). Intestinal endometriosis. J. Obstet.
Gynaec. Brit. Emp., 67, 539.

PRATT, j. h. (1961). Difficulties in diagnosis and surgical treatment of endo-
metriosis. S. Clin. N. America, 41, 1007.

CHAPTER 6

STEROID HORMONE THERAPY

Steroid hormones and many synthetic drugs, which have similar or
modified actions, are used in the treatment of endocrine disorders and also
in the management of many other diseases within the provinces of general
medicine and surgery. The following general account describes their uses,
the ways in which they may be administered and the complications which
they may cause.

CORTICOSTEROIDS

Corticosteroids are used therapeutically for three main purposes:

(1) Substitution therapy in adrenal insufficiency.

(2) Suppression of the production of ACTH in virilizing adrenal
hyperplasia.

In these two categories physiological doses are generally used (25 to
50 mg. per day of cortisone or equivalent doses of other steroids).

(3) Treatment of various diseases, not associated with adrenal disorder,
in which it is desirable to suppress inflammation, allergic reactions or
antibody production, or to cause lymphatic tissue to shrink. The doses
are pharmacological (50 to several hundred mg. of cortisone per day).
Injections of ACTH into patients with intact adrenal glands have many
similar actions, since their main effect is to stimulate the secretion of
cortisol.

The following list includes many diseases which surgeons may be called
upon to treat. The anti-inflammatory, anti -allergic and antifibroblastic
actions are made use of principally except where other actions are
indicated.

Allergic conditions — allergic, rhinitis, angioneurotic oedema, drug rashes
(including penicillin), serum sickness, status asthmaticus, urticaria.
Arthritic conditions — ankylosing spondylitis, Felly’s syndrome, osteo-
arthritis, periarthritis and rheumatoid arthritis.

Blood diseases — idiopathic acquired haemolytic anaemia, leukaemia, pur-
pura, reticuloses.

Collagett diseases — dermatomyositis, disseminated lupus erythematosus,
polyarteritis nodosa, rheumatic fever, scleroderma, temporal arteritis.

202

CORTICOSTEROIDS 203

Eye diseases — acute inflammations, allergic conjunctivitis, sympathetic
ophthalmia.

Gastrointestinal diseases — chronic virus hepatitis, cirrhosis, idiopathic
steatorrhoea, pancreatitis, regional ileitis, ulcerative colitis.

Metabolic diseases — acute gout, organic hyperinsulinism (antagonism of
insulin).

Neoplasia — carcinoma of breast and prostate (inhibition of ACTH and
hence of adrenal sex hormones).

Neurological diseases — acute febrile polyneuritis, Bell’s palsy, polymyo-
sitis.

Renal diseases — nephritis, nephrosis.

''Shock" (Chapter 12).

Skin diseases — ano-genital pruritus, drug rashes, exfoliative dermatitis,
pemphigus.

Soft tissue lesions — acute bursitis, acute plantar fasciitis, Dupuytren’s
contracture, Peyronie’s disease, tennis elbow, tenosynovitis, trigger
finger.

Thyroid disease — subacute thyroiditis.

Urological condition — Hunner’s ulcer.

The following corticosteroids are available:

Cortisol

Cortisol hemisuccinate given by rapid intravenous injection is very
valuable for the treatment of acute adrenocortical insufficiency. The usual
dose is 100 mg. Preparations are also available for topical application to the
rectum and colon, the eye and the skin. It can be injected into joint cavities.

Cortisone and its analogues

Cortisone was the first potent glucocorticoid to be isolated from the
adrenal cortex and the first to become available for clinical use. Much of
the well-deserved credit for its isolation, production and early clinical
investigation in the treatment of rheumatoid arthritis (in 1949) belong to
Kendal and Hench. Its use enabled patients with adrenocortical in-
sufficiency to be treated effectively, and it rendered the operation of
bilateral adrenalectomy feasible and safe.

Cortisone is now prepared synthetically. Its actions are very similar to
those of cortisol, but its activity is about one-fifth less. It remains the
standard glucocorticoid for replacement therapy and for the inhibition of
ACTH. In the form of cortisone acetate it may be given by mouth or in-
jected intramuscularly in the same dose. It is absorbed and excreted more
rapidly by the oral route.

One of the disadvantages of corticosteroid therapy, especially in high
dosage, is retention of salt and water. To overcome this drawback, a

20+

STEROID HORMONE THERAPY

number of synthetic analogues of cortisol and cortisone have been de-
veloped in which the desirable properties (which are related to gluco-
corticoid activity) have been enhanced out of proportion to the mincralo-
corticoid actions. Weight for weight they are more potent than cortisone
and are therefore given in smaller doses (Table 6.1). The therapeutic

Table 6.1. Oral corticosteroid preparations

Preparation

Therapeutic
potency com-
pared tilth '
cortisone (

Mmeralo-

corticate!

activity

Relative cost
of equivalent
dose

Cortisone

* i

Moderate 1

Expensive

Prednisone (A'-Cortisone*)

x S

Slight

Cheap

Prednisolone (A ’-Cortisol*)

x 5

Methyl Prednisolone (6 ethyl-
prednisolone)

Triamcinolone (16*- Hydroxy-9*-

x 6

None

Very expensive

x 6

None

Expensive

fluoropredjnosolone)

Paramethasone (16a-Meth>I-6*-

xlO

Very slight

Expensive

fluoropredmsolone)

Dexamethasonc (16*-Meth)]-9a-

x35

Very slight

Expensive

fluoropredmsolone)

Betamethasone (16j8-McthyI-9*-

X3S

Very slight

Expensive

fluoropredmsolone)

"Replacement" doses are not given because cortisone is the only preparation which «
suitable for use atone in patients w ith adrenocortical insufficiency.

• A 1 «= a double bond between carbon atoms 1 and 2.

effects of these analogues differ little in general from those of cortisone,
although some patients do best on one corticosteroid and some on another.
Prednisone is relatively cheap and is probably the best all-purpose com-
pound except for replacement therapy. Prednisolone-disodium-2l-phos-
phate (20 mg.) may be injected intravenously in the same circumstances
as cortisol hemisuccinate. Several long-acting intramuscular preparations
are available, one of which is methylprcdnisolone acetate (+0-120 mg.
per week).

When corticosteroids are being used for replacement therapy salt
deficiency sometimes develops because, in physiological doses, the mineralo-
corticoid action of cortisone is comparatively slight. For this reason also
the synthetic glucocorticoids, which ba\c still less mineralocorticoid acti-
vity, are unsuitable. In these circumstances a stronger mineralocorticoid
must be used in addition. In an emergency aldosterone (0-5 mg.) may be
given intramuscularly. It is not yet available for use by mouth, but
cortexone, which has been in use for over 20 years, is \ery effective. On a
molar basis it has about one-twenty-fifth of the mineralocorticoid potency
of aldosterone and much less glucocorticoid effect than cortisol. It is ghen
in the form of deoxycortone acetate (DCA). For a short action linguets
(2 to 10 mg. per day) or intramuscular injections (2 to 5 mg. on alternate

CORTICOSTEROIDS

205

days) may be used. For prolonged action the trimethylacetate (25 to
50 mg.) may be given by deep intramuscular injection and will last for 2 to
3 weeks. This preparation has largely replaced the pellets which are im-
planted subcutaneously and last for 5 to 6 months. A synthetic cortico-
steroid, in which the mineralocorticoid effect has been enhanced out of
proportion to the glucocorticoid activity, is fludrocortisone (9x~fluoro-
hydrocortisone). Its mineralocorticoid action is 50 times greater than that
of cortisol, while its glucocorticoid effect is very much less. It is given by
mouth, usually in a dose of 01 to 0-5 mg. per day. It must be administered
with care, for even in these doses oedema and hypertension may result.

Complications of corticosteroid therapy

Corticosteroids in pharmacological doses are often of very great benefit,
but they are fraught with danger, and patients receiving them must be
supervised very carefully. In general, the higher the dose and the longer
the period of administration, the greater is the risk of serious effects. Most
of the complications are reversible if the treatment is stopped in time.
Corticosteroids applied topically or injected into joints are not absorbed to
any great extent and do not usually cause systemic upsets or adrenal sup-
pression, unless large and repeated doses are used.

The most serious complication is Cushing’s syndrome, in which all the
metabolic disturbances and clinical features of the naturally occurring
disease are reproduced (fig. 6.1). One feature of this is the retention of salt
and water which has been mentioned already. Others are of particular
importance in surgery:

1. Liability to infections. Infection is the commonest cause of death
attributable to corticosteroid therapy. Minor lesions tend to spread and to
become serious. Healed tuberculous lesions may become reactivated.
Diagnosis may be difficult because the signs of inflammation are often
masked. All infections must be treated vigorously and surgical procedures
should be covered by antibiotics.

2. Poor wound healing. Surgical wounds tend to break down, partly
because of defective fibroblastic activity and partly as a result of infection.
The problem is not as serious as it was once thought to be, but it is still a
real one. Great care should be taken with the suturing of wounds, and
ascorbic acid should be given before and after operation. Bruising of the
skin is a prominent side-effect of long-term therapy, and a haematoma may
develop as the result of trivial injury.

3. Osteoporosis is caused by the breakdown of protein in the bony matrix.
Pathological fractures, especially of the ribs and vertebrae, may occur.

There are other complications which are not usually associated with
Cushing’s syndrome.

STEROID HORMONE THERAPY

206

4. Inhibition of ACTH. Cortisol and its analogues, even in physiological
doses, inhibit the production of ACTH by the anterior pituitary, and thus
cause atrophy of the adrenal cortices. As a result, the endogenous produc-
tion of cortisol ceases. Serious inhibition is usual after 12 to 18 months’

Fig. 6.1. Cushing’s syndrome caused by over-treatment of psoriasis with
synthetic glucocorticoid.

Male aged 36 years.

continuous treatment, but in some patients it occurs much sooner. It may
be many months before normal function is restored completely after
corticosteroid therapy has been stopped, and during this time the patient
suffers from relatixc adrenocortical insufficiency. This has two important
implications :

(i) Corticosteroids must ncxer be stopped abruptly, but must be with-
drawn slowly in steadily decreasing doses, oxer a period of sex-cral xxcchs
or more, to allow time for the endogenous secretion of cortisol to
recox er.

(ii) If a patient suffers the stress of infection, an accident or a surgical
operation while he is rcceixing corticosteroid therapy, or if he has com-
pleted a course within the previous 12 months, he may be unable to respond
in the usual xvay by the secretion of cortisol. Consequently, he may
dexelop acute adrenal insufficiency, xxhich may proxc fatal. The same

ANDROGENS

207

applies to pregnant women during childbirth. In all such circumstances

adequate amounts of corticosteroid must be given for as long as they are

required. The dosage over a period of operation should be the same as

that advised for adrenalectomy (p. 122).

5. Peptic ulceration is discussed in Chapter 16.

6. Aggravation of ulcerative colitis. Some patients with this disease
respond well to corticosteroid therapy, but those who do not do so may
become worse. The wall of the colon tends to disintegrate, and free per-
foration may occur. These complications may render surgical treatment
unduly difficult and hazardous. For this reason systemic corticosteroid
therapy should not be continued for more than 2 to 3 weeks unless there is
definite and sustained improvement.

7. Destructive arthropathy of the weight-bearing joints, similar to
Charcot joints, may develop in patients with rheumatoid or other forms of
arthritis, treated with steroids. It is believed to be largely due to the
increased mobility and weight bearing afforded by the relief of pain.

8. Myopathy. A troublesome myopathy, affecting principally the proxi*
mal muscles of the legs, occurs in some patients on long-term treatment.
It is seen most commonly in those taking a synthetic steroid with a fluorine
radical, but can occur with any preparation.

Corticotrophin

Corticotrophin (ACTH) can be used effectively in place of oral cortico-
steroids, but its extra cost and the need to give it parenterally limit its use-
fulness. Injections of ACTH have many similar actions to the cortico-
steroids, but differences are seen during long-term administration. ACTH
leads to a higher incidence of hypertension, acne and hirsutism, whereas
dyspesta, peptic ulceration and bruising are commoner with corticosteroids.
ACTH used for long periods causes less pituitary inhibition than corti-
costeroids, and this is probably responsible for the greater ease with which
it can be withdrawn. Indeed therapy with ACTH may help to restore
adrenal function during the withdrawal of corticosteroids.

ANDROGENS

Androgens are used therapeutically for three main purposes:

2. Substitution therapy in androgen deficiency —

Mate— hypogonadism, hypopituitarism.

Female — hypopituitarism.

2. Suppression of the production of gonadotrophins in the female
(menstrual and mammary disorders, etc.).

3. Metabolic effects in both sexes (anabolism of protein).

These are all discussed elsewhere.

208

STEROID HORMONE THERAPY

Preparations and administration

Testosterone and its derivatives are used for most therapeutic purposes.
Testosterone and its esters (proprionate, etc.) are metabolized and in-
activated in the liver and appear in the urine as 17-oxosteroids. For this
reason they are ineffective when swallowed, and must he given sublingually,
by intramuscular or subcutaneous injection or by subcutaneous implanta-
tion. Long-acting intramuscular preparations have now largely replaced
subcutaneous implants. Some esters are absorbed from their depots more
slowly than others, and mixtures of esters are available which provide both
rapid and prolonged effects. Methyl testosterone is only partly inactivated
by the liver and is not excreted as a 17-oxosteroid. It is therefore active
when swallowed, but is more effective when taken sublingually. ffiu-
oxymesterone, a synthetic preparation, is said to be active when swallowed,
but we have not found it very effective.

The doses given in the accompanying table arc those required to provide
full replacement in adult males (complete hypogonadism or hypopitui*
VmVswv). dts** -ait often vn nvbev cowAftvw* tiw male

Table 6.2. Androgenic preparations

Route

Preparation

Replacement dose
(adult male)

Relative cost
of equivalent
dose

Short-acting preparations

Sublingual

Testosterone BP

20-50 mg. daily

Cheap

Sublingual or
oral

Oral

Methjjtestostrrone BP

25-50 mg daily (

Cheap

riuoro-hj droxj -methj Itestostcrone

|0-15 mg. daily ,

Expensive

Intramuscular
injection j

Testosterone proprionate BP

25-50 mg. three i
times a week

Cheap

Ijmg-acUng preparation*

Subcutaneous |

Testosterone phenylproprionate j

50-100 mg. weekly j

Cheap

Intramuscular .

Sustanon "100” (Organon). Com- 1

1 ml every 1 or 2

Cheap

injection 1

binotion of testosterone esters, 1
containing proprionate 20 mg ,
phenj 1 proprionate 40 mg., iso- i
caproate 40 mg, per ml

Sustanon "250” (Organon). Com-

weeks

Cheap

Intramuscular

1 ml. every 3 or 4

injection

binatmn of testosterone esters, |
containing proprionate 60 mg.,
isoepproate 60 mg , decanoate

weeks

| Cheap

Intramuscular

injection

Testosterone isobutyratr crvxtulcs

50 mg. every 2or3
weeks

Intramuscular

Testosterone oenanlhatc

100-2S0 rog. every

Cheap

injection

propnonnfe

Cheap

400-800 mg every

m,|*m

1

4-6 month s

ANDROGENS 209

and are always used in the female, except in the treatment of advanced
cancer of the breast.

The preparations of most general use are shown in Table 6.2.

The main disadvantage of androgen therapy in women and children is
the development of virilism. To overcome this drawback several synthetic
“non-virilizing androgens" or “anabolic steroids” have been developed
recently. They retain the protein-anabolic property of the androgens (and
some of them may inhibit the pituitary), but they have far less effect on the
primary and secondary sex characters. They are discussed in the next
Section.

Toxic effects

Toxic effects are quite common in women and children, but are rare in
men. Sensitivity to androgens varies greatly. Some women may show
marked effects after small doses for a few days, while others tolerate large
quantities for long periods. The effects are of three main types: (1) those
due to inhibition of the pituitary; (2) those caused by direct action on the
end organs; and (3) those resulting from metabolic disturbances. The
clinical features are very similar to those of the adrenogenital syndrome and
vary with the sex and age of the patient.

In both sexes androgens tend to produce euphoria and to increase libido.
They encourage the anabolism of protein and increase the muscle mass.
They cause retention of salt and water in much the same way as aldosterone
docs except that they promote the retention (instead of the excretion) of
potassium by encouraging its deposition with protein in the cells. They
should be used with caution in patients with cardiac failure, nephritis or
cirrhosis of the liver. They tend to reduce the secretion of ACTH or to
increase the body’s requirements of corticosteroids, so that they may cause
acute adrenal failure in patients with partial adrenocortical insufficiency.
If androgens are indicated in such patients the dose of cortisone should be
increased.

Mcthykestosterane may cause jaundice which subsides when treatment
is stopped. There is no evidence that liver function is affected permanently
(Chapter 16).

In the adult female inhibition of the pituitary causes amenorrhoea and
atrophy of the breasts, and virilization of the tissues causes hirsutism,
greasincss of the skin, acne, deepening of the voice and enlargement of the
clitoris. Administration of androgens during pregnancy' may cause viriliza-
tion of the foetus. In the female child androgens cause virilization (pre-
cocious heterosexual pseudopuberty).

In the adult male excessive amounts of androgens may cause testicular
atrophy and premature balding. In rare cases gynaecomastia may

210 STEROID HORMONE THERAPY

complicate the administration of androgens. It is probable that this is an

indirect effect and results from their conversion to oestrogens within the

body.

ANABOLIC STEROIDS

Testosterone and the synthetic “non-virilizing androgens” have a
marked anabolic effect on protein metabolism, and the latter arc often
referred to as ‘'anabolic steroids”. Their mode of action is not jet clear,
but they appear to render fat readily available for the provision of cnergj’
and either to stimulate the synthesis of protein or to inhibit its breakdown.
Consequent!} - , when the intake of food is adequate they cause an increase in
the muscle mass of the body and, when there is a deficiency of calories (as
in acute illness), they spare the muscle mass at the expense of tissue fat.

The activity of the anabolic steroids in patients can be assessed most
readily by metabolic balance techniques. Their effect is to reduce the
amount of nitrogen lost in the urine, so that in favourable circumstances
a negative nitrogen balance is converted into a positive one. A positive
nitrogen balance, however, is an intangible state of affairs and not readily
appreciated clinically. The clinical effects of anabolic steroids are, un-
fortunately, difficult to assess and still await full investigation. In general,
though, they include gain in weight, improvement in appetite and an in-
creased sense of wellbeing. The weight gain cannot be accounted for by
retention of fluid alone.

Clinical application

No general indications can be given for their use, since their poten-
tialities are only now being explored. The anabolic steroids are preferable
to testosterone, especially in women, and the latter should be used for
anabolic purposes only if an androgenic effect is required also, as in the
treatment of hypogonadism in the male or of carcinoma of the breast in
the female.

Their toxic effects, in general, arc the same as those of androgens, and
the same precautions are necessary. Virilism, however, is rare, but may
develop in some patients. If it does so the dose should be reduced or treat-
ment stopped. Jaundice has been observed with norcthandrolone and
methandienone therapy (Chapter 16).

The preparations and adult doses of the anabolic steroids arc shown in
Table 6.3. Their relative therapeutic merits have not been assessed
adequatclj - . High doses may be given at first and smaller ones for main-
tenance. Treatment is usually continued for 4 to 6 weeks at a time, with
intervals of 2 to 4 weeks between courses. The dosage in children should
be calculated in terms of body weight. For methandienone, for instance,
0*1 to 0 - 3 mg./kg./day is adequate.

ANABOLIC STEROIDS

211

Table 6.3. Anabolic steroids

Route

Preparation

Dose i

Relative cost
of equivalent
dose

Oral

I Androatanolone •

50-75 mg. daily

Cheap

Oral

1 Methylandrostenediol *

50-150 mg. dailv

Expensive

Oral

Ethylestrenol

2-4 mg daily

Cheap

Ora!

! Mcthandienone

5-20 mg. daily

Cheap

Oral

Methylstanazole

1 0 mg. daily

Cheap

Oral

Norcthandrolone

30-50 mg. daily

Expensive

Oral

Oxymesterone

10-40 mg. dailv

Cheap

Oral

Oxymetholone

5-15 mg. dailv

Cheap

Intramuscular

Norcthandrolone

25-50 mg dailv

Expensive

Intramuscular,

Jong acting

Nsndrolone pheny lproprionate

(BNF)

25-50 mg. weekly

Cheap

Intramuscular,
long acting

Nandrolone decanoate

25-50 mg. every’

3 \veek4

Cheap

• These preparations are possibly more prone to cause virilization in the recommended
dosage than the others.

The following are some of the conditions in which the anabolic steroids
have been used with apparent benefit.

Prolonged debilitating and wasting diseases
These include extensive burns, bedsores, major fractures in the elderly,
sepsis and fistulae, tuberculosis, anorexia nervosa, malignant disease, mal-
absorption after operations on the stomach and alimentary’ tract, and the
effects of radiotherapy. Adequate nourishment, including protein, must of
course be given as well. A gain in weight of a kilogram or more per week
may be observed in some cases, and recovery and convalescence may be
hastened.

Catabolism of endocrine origin

The muscular wasting and osteoporosis which accompany thyrotoxicosis
and Cushing’s syndrome may be reversed by the administration of anabolic
steroids. They should be used only as adjuncts to specific therapy. They
may have a place in the prevention of catabolism during corticosteroid
therapy. Androgens stimulate protein anabolism in hypogonadism.

Renal failure

The uraemic state is associated with failure to excrete the waste products
of protein metabolism and the benefits of denying protein to patients in
acute renal failure are well known. Further benefit may be derived,
especially in those with renal failure of obstetric origin, from the use of
anabolic steroids which reduce the catabolism of tissue protein. Nore-
thandrolonc (25 to 100 mg. per day) reduces the rate of production of urea

212

STEROID HORMONE THERAPY

by 65 to 70 per cent and probably renders dialysis unnecessary In some
patients who would otherwise require it.

Retarded growth in children

Growth of the long bones accompanies the use of anabolic steroids in
children and is apparently related to the anabolism of protein. Retardation
of growth from many causes may be treated effectively. Testosterone,
used in similar circumstances, induces growth but also stimulates early
closure of the epiphyses so that the ultimate height is not increased. There
is some evidence that the anabolic steroids do not ha\c this drawback.

Other indications

The use of anabolic steroids in the treatment of osteoporosis, advanced
cancer of the breast and in the reduction of nitrogen catabolism after
operations is discussed elsewhere.

OESTROGENS

Oestrogens are used therapeutically for three main purposes:

(1) Substitution therapy in oestrogen deficiency in the female (hypo-
gonadism, menopausal symptoms, vaginitis in childhood and old age),

(2) Suppression of production of:

(i) Gonadotrophins —

in the female (postponement of menstruation, dysmenor-
rhoea, advanced mammary carcinoma after the meno-
pause);

in the male (prostatic and advanced mammary' carcinoma)

(ii) Prolactin —

in the female (inhibition of lactation, advanced mammary
carcinoma after the menopause);
in the male (advanced mammary carcinoma),
pi) Growth hormone —

in the female (gigantism and acromegaly),

(3) Metabolic effects in either sex (osteoporosis).

(4) Treatment of advanced mammary carcinoma in post-menopausal
women and men.

Most of these are discussed elsewhere.

Preparations and administration

The natural oestrogens are inactive when given by mouth because, like
the natural androgens, they arc metabolized by the liver. They arc also
expensive. However, synthetic and partially synthetic compounds have
been developed which hav e overcome both these draw bucks. The synthetic

OESTROGENS

213

oestrogens are interesting because, although they have oestrogenic pro*
perties, they do not have steroid structures. Stilboestrol (diethylstilboes-
trol), for instance, is

and dienoestrol is similar. Oestradiol itself has been modified by the inser-
tion of an ethinyl (-C>=CH) group at the C-17 position to form the
partially synthetic ethinyloestradiol, which possesses oestrogenic potency
and is active when given by mouth. Oestrogens by mouth sometimes cause
unpleasant symptoms in women, but these can be avoided by the use of
intramuscular preparations.

Of the many preparations on the market those of most general value are
shown in Table 6.4.

Table 6.4. Oestrogenic preparations

Route

Preparation

“Replacement"
dose (adult
female)

1

Toxicity ^

Relative cost
of equivalent
dose

Oral

Stilboestrol

3 0 mg. daily 1

Cheap

Oral

Ethinyloestradiol
“Conjugated equine
oestrogens”

0-15 mg. daily

Cheap

Oral

7*5 mg. daily

~ i

Expensive

Intramuscular 1

Oestradiol monoben2oate

5—1 5 mg. twice
weekly

15-30 mg. every
3 weeks

-

Expensive

Intramuscular

Oestradiol valerianate

~

Expensne

Oestrogens start to exert an effect in 12 to 24 hours, but their full in*
fluence is not exerted for 3 to 4 days. After withdrawal the effect starts to
wane after 2 days. Frequent small doses or “depot” injections are more
effective than infrequent large doses. In women the following dose ranges
of stilboestrol (and equivalent ones of other oestrogens) are usually used;

mg. per day

Low 0 t to 1-0

Moderate 1 -0 to 3 0

High S to IS

Very high Up to 100

Full replacement therapy requires about 3 mg. per day. The very high
doses are used only in the treatment of cancer. Similar doses are sometimes
also used in men. Oestrogens are often administered cyclically, 3nd some-
times in association with progestogens or androgens. The details are dis-
cussed elsewhere.

Three other preparations require special mention. Chlorotrianhene is
a non-steroid oestrogenic substance which, after oral administration, is

214 STEROID HORMONE THrRAPY

thought to be stored in the fat depots and then released slowly. This
sustained action makes it unsuitable for normal replacement therapy, but
it can be used in the treatment of the menopausal syndrome in which the
"depot-effect” is advantageous. The usual dose is 12-24 mg. daily for
30 days. Clomiphene citrate ( MRLjdl ), an analogue of chlorotrianisenc,
induces ovulation in some women with amenorrhoca. Its mode of action
and full potentialities have not been, elucidated. Stilboestrol diphosphate is
activated by phosphatase 3ftcr administration. Its advantage is that it is
very soluble and can be given intravenously when a rapid action is required,
as in prostatic carcinoma (Chapter 14).

Toxic effects

Oestrogens often cause toxic effects, especially when stilboestrol and, to a
lesser extent, ethinyloestradiol are used. The commonest are nausea and
vomiting; less common are headaches, malaise and depression. Their
severity is related to the dosage, but they tend to wear off if the patient
persists with treatment. They are not experienced during pregnancy nor
in the puerperium, and men seldom notice them.

In women direct effects on the sexual organs may be observed, and
patients should be warned to expect them. They include profuse vaginal
discharge of cervical mucus, amenorrhoca for variable periods and uterine
bleeding. The latter is described as "break-through bleeding" if it occurs
during the course of treatment, and as "withdrawal bleeding" if it occurs
after treatment has been stopped. The breasts are affected directly, be-
coming swollen and tender, and the nipples and areolae may become
pigmented. Metabolic effects include retention of salt and fluid, which
may cause a bloated feeling and a gain in weight. Large quantities of
oestrogens in children may, like androgens, cause early formation and
closure of the epiphyses, but they do not cause much linear grow tb. There
is a possibility that excessive oestrogens may encourage the development
of carcinoma of the breast or of the body of the uterus.

Men may become partially "feminized”. Pigmentation of the nipples,
gynaccomastia and testicular atrophy arc common. Carcinoma of the breast
has been reported. The metabolic effects are similar to those in women.

PROGESTOGENS

Progestogens are used therapeutically in women for the following main
purposes:

(1) Action on endometrium —

(i) Induction or prolongation of secretory changes after stimu-
lation with oestrogen (hypogonadism, menstrual dis-
orders associated with luteal deficiency, postponement
of menstruation).

PROGESTOGENS 215

(ii) Maintenance of pregnancy (threatened or habitual abor-

tion).

(iii) Atrophy of deposits of endometriosis (with oestrogen).

(tv) Diagnosis of pregnancy (with oestrogen).

(v) Control of advanced adenocarcinoma of uterus.

(2) Suppression of gonadotrophin production (with oestrogen) —

(i) Contraception.

(ii) Dysmenorrhoea.

Preparations and administration
Progesterone itself is inactivated by the liver, but it is effective, tran-
siently, when given intramuscularly. The long-acting preparations tend to
be painful. Many synthetic progestational agents, which are active orally,
are available now and have largely replaced progesterone. Some of the
earlier ones, such as ethisterone (which has been largely superseded) and
norethisterone, are mildly androgenic as well as progestational. The most
effective and safe are shown in Table 6.5. The first five are purely pro-

Table 6.5. Progestational preparations

Route j

Preparation

1 “Replacement” dose ,
' (adult female)

Retative cost of
equivalent dose

Oral |

Norethisterone acetate

i S mg. daily

| Cheap

Oral !

1 15 mg. daily

Expensive

Ora? i

Allylcstrennl

| ?0 mg. daily

Moderately cheap

Oral

Dydrogesterone

10 mg. dailv

Moderately cheap

Intro-

17-Ilydroxyprogesteronc

, 125 mg weekly

| Moderately cheap

muscular i

caproate

Oral

Norethynodrel

5 mg. daily

| Cheap

gestational. The last (norethynodrcl) is also weakly oestrogenic. The doses
are the average ones required to produce full secretory endometrial response
in castrated women primed by oestrogens. The equivalent dose of
progesterone is about 20 to 30 mg. per day, which is the amount produced
by' the cotpus luteum during the luteal phase of the menstrual cycle. In
pregnancy the output may be 100 to 400 mg. daily, so that in the treatment
of threatened abortion due to progesterone deficiency' a daily dose of less
than 100 to 200 mg. would not be sufficient. Such a dose is difficult to
achieve with the older preparations and, even with the newer preparations,
the efficacy of progestogens in the prevention and treatment of abortion is
undecided.

Progestogens affect the endometrium only when it has been prepared by
oestrogens (either endogenous or exogenous), so that progestogens and
oestrogens are often given alternately or together. A corn enient and potent
preparation is “Enavid", which combines norethynodrcl (9*85 mg.) with

216

STEROID HORMONE THERAPY

cthinyIoestradioI-3-methyl ether (0-15 mg.) in one tablet. A dose of 10 to
20 mg. per day, from the fifth day of the cycle, causes secretory changes in
the endometrium within 5 days. These are followed in two weeks by
atrophy and early decidual changes. Cessation of treatment is followed by
withdrawal bleeding. If treatment is continued endometrial changes
similar to those of advanced pregnancy arc produced, and menstruation can
be delayed, apparently indefinitely. Enavid also inhibits gonadotrophin
production and prevents ovulation. Early reports indicate that the cyclical
administration of this preparation or “Conovid” (norethynodrel 5 mg. and
ethiny Iocs t rad iol-3-methyI ether 0-075 mg.) for three weeks from the fifth
day after the start of bleeding is an effective method of preventing con-
ception. Similarly, the regular inhibition of ovulation may be used for the
treatment of severe spasmodic dysmenorrhoea. There is a greater tendency
for , ‘break-through‘ > bleeding to occur with the progestational steroids
than with oestrogens, and the dose must be increased gradually if suppres-
sion of menstruation is desired, e.g. in the treatment of endometriosis.

Toxic effects

Toxic effects are less common and less troublesome than they arc with
other sex hormones. The oral preparations, however, may cause nausea,
vomiting, malaise, dizziness, breast discomfort and headaches in up to
20 per cent of patients. These effects sometimes wear off and tend to be
minimal if the tablets arc taken at night. Prolonged administration of
progestogens without oestrogens may produce signs of oestrogen de-
ficiency'. Virilization of the foetus (female pseudohermaphroditism) may
be caused by the administration of progesterone, the earlier oral agents and
norethistcrone. The other recommended preparations do not appear to
have this disadvantage, although the c\idcnce is not yet complete. At
present the safest preparation appears to be 17 -hydroxyprogcstcrone
caproate. Norethisteionc may cause (non-sensitivity) cholestatic jaundice,
and norethynodrel has been reported to cause bromsulphthalcin retention
(Chapter 16).

TOVnitR READING
Corticosteroids

allAVBY, k. D. (1957). Deaths associated with steroid hormone therapy. Lancet,
1104.

brown, J. and PEARSON, c. M. (1962). Clinical Uses of Adrenal Steroids. McGraw-
Hill, New York.

niRMMONDo, v. c. and forsiiam, p. m. (1958). Pharmacophysiolojjie principles tn
the use of corticoids and adrenocorticotropm. Metabolism, 7, 5.

HEN on, p. s„ kendall, £. c., SLOCUMn, c. it. and pout, it. r. (1949). Effect of a
hormone of the adrenal cortex (17-h>droxy-l l-dehydrocortieosterone: Cpd I.)
and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Ptoc-
Mayo Clin., 24, 181.

FURTHER READING 217

PARIS, J. (1961). Pituitary-adrenal suppression after protracted administration of
adrenal cortical hormones. Proc. Mayo din., 36, 305.

robinson, n. h. b,, Mattingly, d, and cope, c. l. (1962). Adrenal function after
prolonged corticosteroid therapy. Brit. med. J., t, 1579.

spence, A. W. (1958). Cortisone and hydrocortisone. Practitioner, 180, 22.

Sex Hormones — - General

AARO, l. a. (I960). Endocrine therapy in obstetrics and gynecology. Proc. Mayo
Clin., 35, 555.

bishop, p. m. F. (1958). Endocrine treatment of gynaecological disorders. In
Modern Trends in Endocrinology, p. 231. Ed. Gardiner-Hdl, H. Butterworth,
London.

jeftcoate, t. n. a. (1962) Principles of Gynaecology, p. 749. 2nd Ed. Butterworth,
London.

Androgens

bishop, P. St. r. (1 960). Mate sex hormones. Brit. med. J., 1 , 1 84.

crooks:, a. c. (1958). The androgens. Practitioner , 180, 13.

Anabolic Steroids (see also Chapter 12)

BRADSHAW, j. s., ABBOT, W. E. and LEVEY, S. (3960). The use of anabolic steroids in
surgical patients. Amer. J. Surg., 99, 600.

McchAcken, 8. 11. and parsons, F. .\J. (1958). Nilevar (17-erhyl-19-nonesjosterone)
to suppress protein catabolism in acute renal failure. Lancet, 2, 885.

Oestrogens

bishop, p. m, F, (1958). The oestrogens. Practitioner, 180, 5.

Charles, n. (1962). MRL 41 in the treatment of secondary amenorThoea and
endometrial hyperplasia. Lancet , 2, 278.

Progestagens

ROCK, j., CARC1A, c. and PINCUS, c. (1960). Use of some progestational 19-nor-
steroids in gynecology. Amer. f. Obstet. Gynec., 79, 758.

swyer, c. I. M. (I960). Progestogens and their clinical uses. Brit. med. J-, 1, 48,
121 .

WILKINS, l., JONES, w. h., holman, c. ii. and stempfel, R. s (1958). Masculmiza-
tion of female foetus associated with administration of oral and intramuscular
progestins during gestation: nonadrenal female pseudohermaphroditism. J.
clin. Endocr., 18, 559.

CHAPTER 7

THE THYROID GLAND

The thyroid gland is not essential to life, but it plays an important part in
growth and in most or all of the metabolic processes of the body. Altera-
tions of its secretory activity result in profound and widespread distur-
bances of bodily function.

The thyroid originates as an invagination of the primitive pharynx in the
region of the 1st and 2nd branchial arches. The point of origin persists
as a small dimple, known as the foramen caecum, on the posterior aspect of
the tongue. As the primitive gland develops it descends caudally until it
takes up its final position in the anterior part of the neck.

ANATOMY

The thyroid, which weighs between 20 and 25 g., consists of two lateral
lobes joined by an isthmus. This crosses the trachea just below the level of
the cricoid cartilage and overlies the 2nd, 3rd and 4th tracheal rings. Doth
lobes invest the trachea closely and cover its anterior and lateral aspects.
In 40 per cent of subjects a small pyramidal lobe extends upwards from the
isthmus. The right lobe is a little larger than its fellow, and each terminates
in a sharp superior pole and a blunt inferior pole.

The gland is covered by a thin adherent capsule which enters the tissue,
dividing it into poorly defined lobules. The pretracheal fascia provides an
additional covering by dividing to enclose the thyroid and to bind it to the
trachea and larynx. This is sometimes called the “surgical capsule

The carotid sheaths and sternomastoid muscles lie lateral to the thyroid,
while the infrahyoid muscles cover it anteriorly. Medially the lower poles
arc closely related to the recurrent laryngeal nerves as they lie in the lateral
grooves between the trachea and the oesophagus. The parathyroid glands
lie behind.

The thyroid is a highly vascular organ and each lobe receives its blood
supply from a superior and an inferior thyroid artery. The former is a
branch of the external carotid vessel and supplies the superior pole, while
the inferior thyroid artery’, which is a branch of the subclavian, penetrates
the gland at the junction of the middle and lower thirds to supply the lower
pole. Additional vessels, derived from the laryngeal, tracheal and ocso-
2)8

PHYSIOLOGY 219

phageal arteries, supply the medial aspects of both lobes. All these vessels
anastomose freely.

The venous drainage consists of three pairs of veins. The superior and
middle thyroid veins join the internal jugulars, while the lower pair, the
inferior thyroid veins, drain into the innominate. The two upper pairs
originate from a venous plexus on the surface of the gland, while the in-
ferior thyroid veins are formed from the downward extension of the plexus
on the front of the trachea. When the gland enlarges many accessory' veins
develop.

Lymph vessels drain to the deep cervical lymph glands, while a few
descend in front of the trachea to the pretracheal and innominate lymph
glands.

Non-medullated postganglionic fibres from the superior and middle cer-
vical sympathetic ganglia enter the thyroid via the cardiac nerves, the
superior and recurrent laryngeal nerves and the periarterial plexuses.
Some fibres are vasomotor, but the function of others, which are closely
related to the epithelial cells, is unknown.

The thyroid tissue is made up of a mass of minute vesicles, about 200 to
300 ft in diameter, which are known as acini. The wall of an acinus con-
sists of a single layer of cubicle cells resting on a rich network of capillaries.
Filling the acini is a clear mucoid fluid, the colloid, which stains deeply with
acid dyes. Groups of twenty to forty acini are bound together loosely with
connective tissue to form the thyroid lobules, each of which is supplied by a
single arteriole and probably forms the functioning unit of thyroid tissue.
The histological appearance varies with the functional state of the gland.
Activity is associated with “evolution”, when the acinar cells are relatively
high and there is little colloid. Periods of relative inactivity are accom-
panied by “involution”, when the cells are low and the acini store con-
siderable amounts of colloid.

PHYSIOLOGY

Synthesis and release of the thyroid hormones
The biosynthesis of thyroid hormones requires not only the proper
function of the thyroid gland and its trophic hormone (TSH) but also an
adequate supply of the main chemical constituents of thyroxine, namely
iodine and the amino acid tyrosine.

Iodine is obtained from water and food, mainly as inorganic iodide,
through the gastrointestinal tract. It circulates in the blood stream and, by
means of an unknown mechanism, is trapped and concentrated in the
thyroid gland. Here the iodide is converted to iodine by oxidation and is
then bound organically to tyrosine with the formation of monoiodotyrosine

220

THE THYROID CLAMD

(MIT) and diiodotyrosine (DIT). Subsequently the coupling of the iodo-
tyrosines results in the formation of tetraiodothyronine (thyroxine, T4} and
also, to a lesser extent, of triiodothyronine (T3), both of which (together
with some MIT and DIT) are bound to thyroglobulin and stored in the
colloid. Thyroglobulin, which is the main constituent of the colloid, may
be considered as thyroid hormone in storage (figs. 7.1 and 7.2).

■'tfesSr 1 ♦ “Os-Li" 1 "

i T >"”“

“05-5*-“°" v

Vtenoiodotyrosir'c (MIT) '

(C OufJmij Zr\ryr*n)

yc-c-eooH >

£myn'«)

Trlw«ot>yron.n»(T,) Alanine

Diiodolyroj n« (OITj

2 molecules
(Coupfinq Enzyme)

no ^~^ -o^~^c-c-c

4 (f CM, Cm (nhj)COOhJ

t 1

Thyrox'o* (X,) Alanine

Fig. 7.1. Simplified diagram of chemical pathways in synthesis of thjroid
hormones.

Thyroxine and triiodothyronine are liberated into the blood stream by the
proteolytic hydrolysis of thyroglobulin, which does not itself enter the
circulation. At the same time any remaining iodoty cosines arc reconverted,
by dciodtnase, into iodine and become available once more for synthesis.

Thyroxine and triiodothyronine arc probably the only iodine compounds
which arc hormonally active in m3n, and thyroxine is the principal
todinated amino acid in the plasma (forming 60 to 90 per cent of the cir-
culating organically hound iodine). Once the thjroid hormones enter the
circulation they arc for the most part bound firmly to specific proteins,
namely thyroid binding protein (TBP), which is found between the rr-l
and a-2 globulins on the electrophoretic strip, thjroid binding pre-
albumin (TBPA) and serum albumin. TBP and TBP A base strong affinity

PHYSIOLOGY

221

Fig. 7.2. Simplified diagram of synthesis, storage and discharge of thyroid
hormones.

Names of enzymes are ln itahet. Arrows indicate chemical reactions or pathways of
substances. “TSH" indicates that thyrotrophin stimulates activity in the direction of the
arrow beside which it lies. — *- f indicates that the pathway is blocked by the agents
named alongside. The numbers in circles correspond to those in Table 7 3 and show the
sites at which thyroxine synthesis may be impaired in sporadic cretinism Other s>mboU
as in fig. 7.1.

for thyroxine and, to a lesser degree, for triiodothyronine. Small amounts
of the thyroid hormones are "free" in the plasma and probably enter the
tissues in this form. Triiodothyronine appears to be more active physio-
logically than thyroxine, for, being attached more loosely to TBP and
TBPA, it may enter the tissues more readily. However, at the cellular
level there is little difference between the actions of the two hormones.
Thyroid hormones are partly broken down by the tissues and partly
excreted in the bile.

Factors which influence the production of thyroid hormone

The orderly synthesis of thyroid hormone depends on a number of
closely inter- related factors.

(1) State of the thyroid gland. The thyroid must be healthy, possess the
requisite enzymes for thyroxine synthesis and have sufficient tissue to meet
the body’s requirements for hormone. The average gland contains about
20 g. of active tissue, but as little as 3 g. of healthy tissue are capable of
maintaining the body in a euthyroid state.

(2) Thyrotrophic hormone ( thyrotrophin , thyroid~slimulating hormone ,
TSH). Thyrotrophic hormone is secreted by the basophil (0) cells of the
anterior pituitary and controls the activity of the thyroid gland. It is a
glycoprotein containing glucosamine and galactosamine with a molecular

222

THE THYROID GLAND

weight of about 28,000. The amino-acid composition and sequence in this
protein moiety have not been fully elucidated, but cystine is present in
large quantities and tryptophan is absent.

TSH stimulates the uptake of iodine and the synthesis of thyroxine, en-
hances the breakdown of thyroglobulin and raises the level of circulating
thyroxine. It combines with the thyroid tissue and is inactivated by it.
Excessive and prolonged stimulation by TSH causes an increase in the
size and number of the acini and may result in a goitre. In the absence
of TSH, as in hypopituitarism, the thyroid undergoes involution and
atrophy and its output of hormones is greatly reduced. Usually, however,
it possesses a little autonomous function. The BMU is reduced more
by thyroidectomy than by hypophyscctomy. After hypophysectomy the
tissue remains responsive to parenteral thyrotrophin for a long time, and
this property can be used to distinguish primary failure of the thyroid from
that resulting from lack of stimulation by TSH. Eventually, however,
secondary atrophy may occur so that the gland becomes unresponsive.

(3) Central nervous system and hypothalamus. The secretion of TSH is
controlled by the central nervous system, by the temperature of the en-
vironment and by the concentrations of thyroid hormones circulating in the
blood. The anterior basal part of the hypothalamus forms a relay station
between the higher nervous centres and the anterior pituitary. The nature
of the higher nervous control is unknown, but it is likely that stress of
various types, emotion and other factors can either stimulate or inhibit
thyroid function. The hypothalamus itself secretes a polypeptide neuro-
humour which passes down the hypophyseal portal system to the pituitary
and stimulates the secretion of TSH (fig. 7.3). If the hypothalamus is
destroyed or the pituitary removed the production of TSH ceases. If the
pituitary’ stalk is divided the output of TSH is greatly reduced, possibly
because the ncurohumour reaches the pituitary only in a diluted form
through the general circulation. The temperature of the environment in-
fluences the production of TSH, probably via the hypothalamus. Cold
stimulates its release and heat inhibits it.

(4) Circulating thyroid hormones. The thyroid hormones themselves in-
fluence thyroid function in various ways. When they arc present in the
circulation in adequate or excessive quantities the production of TSH is
diminished and thyroid function is depressed. The inhibitory effect is
probably exerted directly on the pituitary’ and not on the hypothalamus.
When thyroid hormones arc deficient, however, the hypothalamus is
stimulated and TSH is again released. Thyroxine and triiodothyronine
apparently also inhibit the activity’ of the thyroid gland itself, but do not
prevent it from responding to exogenous TSH.

(5) Availability of iodine. The synthesis of the thyroid hormones requires
a regular and adequate supply of iodine. The daily requirement is about

PHYSIOLOGY

223

10 0 .0 150 ,g.. but

pregnancy or stress “f ed if th e food contains naturally occurring

Antithyroid stfbstances^ 2 Deficiency of iodine leads to hyperplasia of the

^IodintAis present in *be blcKH^ur Ipgj^Thdlatter^orrndthe major
protein-bound (or prec.p.tab ^odmc (PB ). 1 h 3 . 5 and 7 . 5 per

fraction, and values m normal individuals a ary □ ThePBI

lOOml. The total serum iodine level is about 1-0 to 1 a /*g

rises after the ingestion of iodine-con g e ® sed f or X-rays of the gall

organic iodine compounds, many o ' drugs used for pyelo-

bladder, the kidneys and the bronchial tr. ^ those employed in
graphy raise ,hePBIforafewtoun«r^™y. months ^
bronchography and cholecystography derate

• triiodothyronine

The physiological effects of thyroxine Bses within the cells

Thyroid hormones tend to stimulate m -

of the body, but their mode of action a*. dinlinished by the experr-
MetaboUsm. The rate of cellular oxi t ^ jn complete thyroid

mental removal or inhibition oft e ^ y ;1 n 3 to about —40 per cen .

deficiency in man the basal meta 01 considerably. The incrcas

hyperthyroidism the BMR ma - v e . , , te is accompanied by mere

production of heat in the hyperthyroid state

224 THE THYROID GLAND

in the consumption of oxygen and in the formation of carbon dioxide and
may be measured directly by calorimetry.

Triiodothyronine is three to four times more potent than thyroxine and
increases the oxygen consumption more rapidly. It is therefore of greater
therapeutic value when thyroid hormone is required urgently.

Thy roid hormone is essential for normal growth. Cretins arc retarded in
their mental, sexual and skeletal development, and hyperthyroid children
are abnormally tall.

Cardiovascular system. In hyperthyroidism the pulse rate is rapid and
the peripheral blood flow is increased, while in myxoedema the pulse is
slow and the peripheral circulation (particularly in the brain, kidneys and
skin) is decreased. These circulatory changes arc dependent on the state of
metabolism. Thus, a raised metabolic rate requires an augmented blood
flow, and this in turn demands an increase in the cardiac output. In addi-
tion, thyroxine stimulates the heart itself, probably by increasing the sensi-
tivity of the cardiac muscle to adrenaline and to the effects of sympathetic
nervous stimulation.

Nert oiii system and muscles. Thyroid hormones influence the levels of
activity of the central, peripheral and autonomic nervous systems and of
the voluntary muscles. Thus, hyperthyroid patients arc nervous and
irritable and exhibit muscular tremors. Catabolism of muscles may cause
wasting, weakness and sometimes frank myasthenia. Creatinuria is com-
mon. Autonomic stimulation causes sweating, gastrointestinal hyper-
peristalsis and vasomotor instability. The hypothyroid patient is apathetic
and mentally retarded and the electroencephalogram may show' slow waxes
of diminished amplitude and sometimes absence of a waxes. The xoluntary
muscles may exhibit delayed contraction and relaxation and the gut may
be sluggish.

Metabolism of carbohydrate, fat, protein and t itamins. Thyroid hormones
have little effect on carbohydrate metabolism. However, they tend to in-
crease the rate of absorption of glucose from the intestinal tract and to
stimulate glycogcnolysis, so that in hyperthyroidism the blood sugar may
rise and glycosuria may result. An oral glucose tolerance test is often of the
oxyhypcrglycaemic type, but an intraxenous test provides a normal ctirxe.
In myxoedema a flat curve is obtained if the sugar is given by mouth.

An excess of thyroid hormones may cause 3n increase in the urinary
excretion of nitrogen, largely as a result of increased protein consumption
to meet metabolic needs. Excessive destruction of protein may aggravate
this condition and also cause crc3tinuria.

The excretion of cholesterol in the bile is diminished in hypothyroidism,
and the level of cholesterol in the hlood is consequently raised. In hyper-
thyroidism the blood cholesterol lex cl may be loxxcrcd.

Thyroxine influences the metabolism of vitamins in various ways. In

LABORATORY INVESTIGATION' OF THYROID DISEASE 225
particular, hyperthyroidism increases the body’s requirements for members
of the B complex.

Metabolism of minerals and water. Thyroid hormones increase the excre-
tion of calcium and phosphorus. In hyperthyroidism the concentration of
these substances in the blood is usually normal, but occasionally the serum
calcium may be elevated. Thyroxine often causes a brisk diuresis, when
given to myxo edematous patients, by increasing the excretion of extra-
cellular fluid.

The thyroid and the hormones of the adrenal medulla

There is a dose relationship between thyroid hormone and the sym-
pathetic catechol amines (noradrenaline and adrenaline). The metabolic,
circulatory and neuromuscular actions of the catechol amines are enhanced
by the administration of thyroxine, while many of the clinical features of
thyrotoxicosis can be explained largely by the augmentation of the action of
the catechol amines by excess thyroid hormone. If the effects of the cate-
chol amines are eliminated, either by depleting the body stores with reser-
pine or by using a sympathetic blocking agent such as guanethidine,
significant improvement in the peripheral symptoms and signs of thyro-
toxicosis can be achieved. Among these are a loitering of the pulse rate and
pressure, a reduction in lid retraction and digital tremor, and a fall in the
BMR. There is no alteration, however, in the intrinsic thyroid gland
abnormality, for the size and activity of the goitre and the level of the PBI
remain unchanged. Drugs that inhibit the action of the catechol amines can
thus be used as adjuncts to treatment directed specifically against the
thyroid gland itself.

LABORATORY INVESTIGATION OF THYROID DISEASE

The first essentials in the recognition of thyroid disease are a careful
history and a detailed clinical examination. Laboratory tests may give con-
flicting results. Several tests are available, but none is sufficiently compre-
hensive or reliable to be used atone. The best results are obtained when a
few selected investigations are made and interpreted in the light of the
clinical findings.

Basal metabolic rate (BMR)

The BMR is an expression of the caloric output of the body and is
estimated from the oxygen consumption after a period of rest and fasting.
In these circumstances the oxygen uptake provides an index of the caloric
requirements for the basal metabolic processes of the body. The result is
expressed as a percentage of a standard previously determined for sex and
age. If it is to be reliable the test must be performed carefully under
standard conditions. Anything which increases the oxygen uptake above

226

THE THYROID GLAND

the basal level will jeopardize its validity, and all possible steps must be
taken to ensure complete relaxation, to eliminate nervous movement and
to encourage normal regular breathing. An experienced nurse or tech-
nician will generally be able to control these factors. The test should be
repeated if the patient’s co-operation is in question.

The majority of patients with hyperthyroidism have a BMR greater
than -*-I5 per cent. Other conditions, unrelated to thyroid disease, which
increase it arc fever, anaemia, breathlessness from cardiac or pulmonary
disease, hypertension, coarctation of the aorta, arteriovenous aneurysms,
leukaemia, polycythaemia, various reticuloses, acromegaly, phacoclvro-
mocytoma, diabetes insipidus, Paget’s disease and the later months of
pregnancy.

In hypothyroidism the estimation of the BMR is more consistent and
less liable to error. In myxoedema it usually falls to between —25 and —45
per cent. Minor reductions in the BMR are difficult to interpret and arc
probably not important unless they are accompanied by suggestive signs
and symptoms.

Plasma cholesterol

Determination of the plasma cholesterol level (normal 140-260 mg. per
100 ml.) is helpful in the diagnosis of myxoedema and values above 300 mg.
per 100 ml. arc found in nearly 80 per cent of patients. Serial observations
are of help in assessment of the response to therapy with thyroxine. The
test is an unreliable method for the recognition of increased thyroid func-
tion.

Protein-bound iodine

Measurement of the protein-bound iodine (PB1) level in the plasma gives
an approximate estimate of circulating thyroid hormone. The estimation is
technically difficult and is prone to error from contamination of the glass-
ware by minute traces of iodine. When performed carefully it is a useful
index of thyroid activity. The normal range of PBl is 3-5 to 7-5 /ig. per
100 ml. This level is generally exceeded in thyrotoxicosis, hut high normal
or slightly elevated levels may also be found (without clinical evidence of
hyperthyroidism) in pregnane)', in thyroiditis and after irradiation of the
thyroid. The FBI falls below 3'5 tig. per 100 ml. in myxoedema, in mal-
nutrition and in the nephrotic syndrome. The PBI may be increased by
the administration of drugs containing iodine, and this possibility should be
considered when unexpectedly high results are obtained.

The Butanol extractable iodine (BEI) test is a modification of the PBI
test and depends on the solubility of thyroxine in alkaline butanol. This
method does not extract inorganic iodide, mono* and diiodotyrosinc or
thyroglobulin (released as a result of thyroiditis or irradiation of the

LABORATORY INVESTIGATION OF THYROID DISEASE 227
thyroid), so that when contamination is caused by one of these, the BEI is a
more accurate measure of the circulating thyroxine level. Normally the
BEI is about 0-5 /tg. less than the PBI. Unfortunately the BEI test does not
eliminate iodine contamination from iodinated drugs and dyes and it has
not come into general use.

Radioactive iodine tests of thyroid function

Radioactive isotopes of iodine ( m I and 132 I) Have been used increasingly
in the quantitative estimation of thyroid activity. These isotopes, with half
lives of 8 days and 2-26 hours respectively, can be administered and
measured in minute amounts so that there is negligible danger of significant
radiation to the body in general or to the thyroid in particular. J3l I, how-
ever, should not be used in children or in pregnant women. If such tests
are essential in these patients 132 I should be employed, since the total
irradiation delivered to the thyroid (from the same initial microcurie dose)
is only one-fortieth of that resulting from ,M I. 132 I is more difficult to
prepare and to handle than m I, but its short life enables it to be used
repeatedly at short (even daily) intervals for the estimation of thyroid
function. The usual doses are 10 to 20 pc. of I31 I and 25 pc. of 1S2 I

The radioactive iodine can be measured in various stages of its meta-
bolism and several different facets of thyroid function can be examined.
Eight main types of test are available for diagnostic purposes.

1 . Thyroid uptake tests

The rate at which iodine is taken up by the thyroid and the final con-
centration achieved there depend on the functional activity of the gland.
Small amounts of an administered dose are removed by the salivary glands
and the gastric mucosa, but these can be ignored for most purposes. The
remainder is excreted in the urine. The amount of radioactive iodine taken
up by the thyroid can be measured by means of a Geiger-Miiller tube or a
scintillation counter. 131 I may be measured "early" (i.e. up to 6 hours after
administration of the dose) or “late" (24 or 48 hours). ^I, because of its
short life, can only be measured early.

Early uptake tests are particularly valuable for the detection of hyper-
thyroid states, but less so for the recognition of hypothyroidism. I32 I is
particularly suitable; it may be given intravenously and counted over the
thyroid 10 minutes later or by mouth and counted 2 hours later. 191 I is
usually counted half an hour after intravenous injection or 4 hours after
oral administration, but frequent counts during the first 24 hours allow the
determination of the “thyroid accumulation rate”, and this improves the
accuracy of the test.

Late uptake tests are of most value in the detection of hypothyroidism,
but arc less satisfactory' for the recognition of hyperthyroid states. They

226

THE THYROID GLAND

the basal level will jeopardize its validity, and all possible steps must be
taken to ensure complete relaxation, to eliminate nervous mo\ement and
to encourage normal regular breathing. An experienced nurse or tech-
nician will generally be able to control these factors. The test should be
repeated if the patient’s co-operation is in question.

The majority' of patients with hyperthyroidism have a BMR greater
than +15 per cent. Other conditions, unrelated to thyroid disease, which
increase it are fever, anaemia, breathlessness from cardiac or pulmonary
disease, hypertension, coarctation of the aorta, arteriovenous aneurysms,
leukaemia, polycythaemia, various reticuloses, acromegaly, phaeochro-
mocytoma, diabetes insipidus, Paget’s disease and the later months of
pregnancy.

In hypothyroidism the estimation of the BMR is more consistent and
less liable to error. In myxoedema it usually falls to betw een —25 and —45
per cent. Minor reductions in the BMR are difficult to interpret and are
probably not important unless they are accompanied by suggestive signs
and symptoms.

Plasma cholesterol

Determination of the plasma cholesterol level (normal 140-260 mg. per
100 ml.) is helpful in the diagnosis of myxoedema and values above 300 mg.
per 100 ml. are found in nearly 80 per cent of patients. Serial observations
are of help in assessment of the response to therapy with thyroxine. The
test is an unreliable method for the recognition of increased thyroid func-
tion.

Protein-bound iodine

Measurement of the protein-bound iodine (PBI) level in the plasma gives
an approximate estimate of circulating thyioid hormone. The estimation is
technically difficult and is prone to error from contamination of the glass-
ware by minute traces of iodine. When performed carefully it is a useful
index of thyroid activity. The normal range of PBI is 3 "5 to 7-5 /ig. per
100 ml. This level is generally exceeded in thyrotoxicosis, but high normal
or slightly elevated levels may also be found (without clinical evidence of
hyperthyroidism) in pregnancy, in thyroiditis and after irradiation of the
thyroid. The PBI falls below 3*5 /xg. per 100 ml. in myxoedema, in mal-
nutrition and in the nephrotic syndrome. The PBI may be increased by
the administration of drugs containing iodine, and this possibility should be
considered when unexpectedly high results are obtained.

The Butanol extractable iodine (BEI) test is a modification of the PBI
test and depends on the solubility of thyroxine in alkaline butanol. This
method does not extract inorganic iodide, mono- and diiodotyrosine or
thyrogjobulm (released as a result of thyroiditis or irradiation of the

LABORATORY INVESTIGATION Or THYROID DISEASE 227
thyroid), so that when contamination is caused by one of these, the BEI is a
more accurate measure of the circulating thyroxine level. Normally the
BEI is about 0-5 fig. less than the PBI. Unfortunately the BEI test does not
eliminate iodine contamination from iodinated drugs and dyes and it has
not come into general use.

Radioactive iodine tests of thyroid function

Radioactive isotopes of iodine ( ,3, I and 132 I) have been used increasingly
in the quantitative estimation of thyroid activity. These isotopes, with half
lives of 8 days and 2-26 hours respectively, can be administered and
measured in minute amounts so that there is negligible danger of significant
radiation to the body in general or to the thyroid in particular. 131 I, how-
ever, should not be used in children or in pregnant women. If such tests
are essential in these patients M2 I should be employed, since the total
irradiation delivered to the thyroid (from the same initial microcurie dose)
is only one-fortieth of that resulting from m I. m I is more difficult to
prepare and to handle than 13, I, but its short life enables it to be used
repeatedly at short (even daily) intervals for the estimation of thyroid
function. The usual doses are 10 to 20 fic. of 13I 1 and 25 fic. of 182 I.

The radioactive iodine can be measured in various stages of its meta-
bolism and several different facets of thyroid function can be examined.
Eight main types of test are available for diagnostic purposes.

1. Thyroid uptake tests

The rate at which iodine is taken up by the thyroid and the final con-
centration achieved there depend on the functional activity of the gland.
Small amounts of an administered dose are removed by the salivary glands
and the gastric mucosa, but these can be ignored for most purposes. The
remainder is excreted in the urine. The amount of radioactive iodine taken
up by the thyroid can be measured by means of a Geiger-Muller tube or a
scintillation counter. m I may be measured "early” (i.e. up to 6 hours after
administration of the dose) or "late” (24 or 48 hours). 132 I, because of its
short life, can only be measured early.

Early uptake tests are particularly valuable for the detection of hyper-
thyroid states, but less so for the recognition of hypothyroidism. 133 I is
particularly suitable; it may be given intravenously and counted over the
thyroid 10 minutes later or by mouth and counted 2 hours later. m I is
usually counted half an hour after intravenous injection or 4 hours after
oral administration, but frequent counts during the first 24 hours allow the
determination of the “thyroid accumulation rate”, and this improves the
accuracy of the test.

Late uptake tests arc of most value in the detection of hypothyroidism,
but are less satisfactory for the recognition of hyperthyroid states. They

228

TIIC THYROID GLAND

are, however, sufficiently sensitive for most purposes and are used as
standard tests in many clinics. The counts are usually made 24 and 48
hours after the administration of an oral dose of ul I. Most normal glands
take up 20 to 50 per cent of the ingested dose within these times, while
hyperactive glands take up more. Values below 20 per cent arc suggests e
of hypothyroidism and those below 15 per cent are diagnostic. Com-
parable figures for 13S I given by mouth at 2 hours are as follows: normal
glands take up between 5 and 23 per cent of the ingested dose, while
hyperactive glands take up more than 25 per cent; inactive glands take up
less than 7 per cent and the majority less than 5 per cent.

Combination of the early and late m I tests, with counts taken at 2, 4, 6,
24 and 48 hours, is more accurate than either alone, but is rarely worth the
extra time and trouble in which the patient is involved.

Compensatory thyroid overactivity may cause a high uptake of 13, I in the
absence of hyperthyroidism. Such a condition may be found in patients
with iodine deficiency (endemic) goitres and in those who have undergone
partial thyroidectomy. Conversely, treatment with thyroxine may depress
the uptake. If a high uptake is found without clinical evidence of thyro-
toxocosis, it is useful to give iodine for 2 weeks (10 mg. of potassium iodide
daily) and then to repeat the test 4 weeks later. The effect of triiodo-
thyronine suppression may also be tried. In thyrotoxic patients and in those
with endemic goitre no suppression is obtained, whereas in normal subjects
the uptake falls to a low level. The test is repeated after the administration
of 100 pg. of triiodothyronine (in divided doses) daily for 4 to 7 days.

2. Thyroid clearance rate

The thyroid clearance rate, which is the volume of plasma cleared of
radioactive iodine per minute, varies with the functional activity of the
gland. Its accurate determination entails fairly complex measurements,
but an approximation may be obtained from the ratio between the neck
count and the thigh count after 2 hours. The advantage of this test is that
the result is independent of the dose and does not require measurement of a
standard. For the patient the test is satisfactory hccausc it may be per-
formed during a single visit to the clinic.

3. Urinary excretion tests

Measurement of the urinary excretion of JS1 I is another useful method of
estimating thyroid function. The thyroid and the kidneys compete for
circulating iodine, so that relatively more is found in the urine in states of
diminished thyroid function and relatively less when the gland is over-
active. The urine is collected for 24 or 48 hours after administration of the
isotope and its radioactiv ity is measured. Various refinements of the test
(such as the “T index” of Fraser and co- workers) have been made to im-

LABORATORY INVESTIGATION OF THYROID DISEASE

229

prove its accuracy, but unfortunately they tend to introduce opportunities
for error in the collection of samples of urine. The test is more helpful in
the diagnosis of thyrotoxicosis than of myxoedema, but with intelligent and
co-operative patients it is usually sensitive enough to distinguish both.

4. Radioactive protein-bound iodine

After radioactive iodine has been taken up by the thyroid it becomes in-
corporated in the thyroid hormones and is discharged as such into the cir-
culation. The proportion of the PBI which is radioactive increases steadily
for about 48 hours after the administration of a dose of 131 I. A “conversion
ratio” expressing this change may be calculated as a percentage, thus:

Serum PB m I
Total serum PBI

Normal values at 24 hours after the administration of the isotope are
between 10 and 45 per cent. Higher values are found in hyperthyroidism
and lower ones in hypothyroidism. The test may be invalidated in several
ways. Renal and cardiac failure tend to increase the level of inorganic m I
and thus to alter the conversion ratio, and the separation of the PBI from
the total serum iodine is liable to technical errors. For these reasons it is
more usual to measure the PB 131 I after 48 hours, by which time most of the
PBI is radioactive, and to express it as a percentage of the total dose ad-
ministered, thus:

Serum PB 1 * 1 ! per litre
Total ®1 administered

X 100

The test is of more help in the detection of hyperthyroidism than of hypo-
thyroidism, because the range in the latter tends to overlap that of normal
subjects. High values may be found in auto-immune thyroiditis and in
thytotoxic patients after effective treatment with surgery or radioactive
iodine. On the other hand, values are usually normal in goitres when high
values for the uptake of m I show that the gland is avid for iodine.

J. Direct mapping of the thyroid xcith radioactive iodine
The thyroid uptake test may be modified to provide information about
the relative activity of different parts of the gland. By means of a scintilla-
tion counter, which is moved about over the gland, “contours” of counts
may be prepared which locate and delineate areas of increased or decreased
activity. “Hot nodules” (showing increased activity) may be found in
thyrotoxicosis. “Cold nodules” (decreased activity) may be provided by
cysts, solitary' nodules and areas of malignancy. The same method may be
used to discover the positions of ectopic functional thyroid tissue and of
functional metastases from thyroid cancer.

230

THE THYROID GLAND

6 . Thyroid stimulation test

This test may be useful in distinguishing between primary and secondary
thyroid failure. Exogenous TSH causes a response in the Jatter, but not in
the former. The uptake of 13i I (or W2 I) by the thyroid gland and the plasma
PBI are measured before and after stimulation in the following way:

First day.

(1) a tracer dose of lsl I is given orally to the fasting patient and a
sample of blood is taken for the estimation of PBI ;

(2) the neck uptake of m I is measured 4 hours later (or 2 hours later
with ^I); then

(3) TSH (“Thytropar” — Armour) is injected intramuscularly in a dose
of JO IU.

Second day .

(1) twenty-four hours after the first tracer dose the residual thyroid
radioactivity of I3l I is measured (with ,33 I it is virtually nil) and a sample
of blood is taken for estimation of PBI;

(2) a second tracer dose is given to the fasting patient;

(3) the neck uptake of 7 * * * * * 13, I is measured 4 hours later (or 2 hours later
with U2 I) and the result is corrected for the residual radioactivity de-
tected in the earlier test.

In primary hypothyroidism there is no increase in the uptake of ,3, I nor
any rise in the PBI. A rise of about 20 per cent, which is observed both in
normal subjects and in patients with secondary hypothyroidism, con-
stitutes a significant response. A rise of 1-0 p g. per ml. in the PBI probably
also represents an adequate response and confirms the presence of active
thyroid tissue.

7. Perchlorate test of impaired hormone synthesis

In sporadic goitrous cretinism and iodide goitre iodide accumulates

abnormally at the iodide trap because its incorporation into thyroid hor-

mone is defective. Perchlorate, which inhibits the iodide trapping mechan-

ism, also possesses the ability to release from the thyroid iodide which has

not been bound organically. When perchlorate is administered to these

patients iodide is discharged rapidly from the gland. The test is performed
as follows. A dose of m I is given and the uptake is measured after I, 2 and
4 hours. Potassium perchlorate (400 mg.) is then given by mouth, and the
uptake is measured ev cry 1 5 minutes for 2 hours. In normal subjects there
is no discharge of iodide, but in patients with sporadic goitrous cretinism
and iodide goitre the counts over the thyroid fall considerably, sometimes

LABORATORY INVESTIGATION OF THYROID DISEASE 231
to 20 per cent of the initial reading. A similar discharge of iodide is seen in
auto-immune thyroiditis.

8. The red blood cell or resin uptake of m f labelled triiodothyronine

This test, in which labelled triiodothyronine is added to a sample of the
patient’s blood in vitro , depends on the freedom of thyroid binding
protein to take up the radioactive hormone. If TBP is saturated because of
a high level of circulating thyroxine (as in thyrotoxicosis) the radioactive
triiodothyronine is free to be taken up by the red cells or resin. The test is
carried out by mixing a tracer dose of m I labelled triiodothyronine with a
small volume of the patient’s whole blood or the patient’s serum and a
resin. The sample is incubated and centrifuged, after which the red cells or
resin are washed and their radioactivity measured.

The test possesses the advantage that no radioactivity is given to the
patient, but its place in clinical thyroid disease has not been established.

Conclusions

Radioactive iodine tests are safe and have added much useful knowledge
to our understanding of the thyroid gland, but none of them yet provides
the perfect diagnostic tool. The main problems are the fairly wide overlap
between normal and abnormal activity and the errors which may arise either
from the inherent nature of the tests or from failure of co-operation by the
patients. The accuracy is increased if two or more tests, which measure
different aspects of thyroid function, are combined. The measurement of
the neck uptake at 4 hours and 48 hours, combined with a urinary excretion
test and measurement of the concentration of 131 I in the plasma after 48
hours, will afford sufficient accuracy to meet the needs of the majority of
cases. Table 7.1 shoivs the results obtained in 273 patients, studied by us,

Table 7.1. m J and 132 1 studies in 273 patients

Hypothyroid

Euthyroid

‘•‘I neck uptake:

4 hours

24 hours

48 hours
,S, I neck uptake :

2 hours

T-lndex (Fraser *t at)

Protein bound m I (as proportion
of do»e/l. of plasma)
m I-T3 Red cell uptake

2-20%

1-33%

0-33%

0-7%

0-8-2-9

0-0*32%

11-5-17*5%

10-25%

20-53%

20-52%

S-23%

20-14*2

0-0*44%

14*5-22-5%

who received a tracer dose of 20 fie. of ,3J I and 25 pc. of 132 I. Ninety per
cent of cases in each of the three clinical categories fell within the ranges
detailed.

232 THE THYROID GEAND

Creatinuria and the creatine tolerance test
The observation that creatinuria is common in hyperthyroidism has led
to the creatine tolerance test as an indirect estimate of thyroid function.
When normal subjects on a low creatine diet ingest 1-329 g. of creatine
(equivalent to 1 g. creatinine) they excrete less than 30 per cent of it in the
urine In hyperthyroidism more is excreted. The test is rarely performed.

Therapeutic trial of iodine or antithyroid drugs as a test for hyper-
thyroidism

When clinical findings and laboratory’ tests continue to gi\e equivocal
results in patients with suspected thyroid overactivity, a therapeutic trial
with carbimazole (45 mg. daily by mouth in divided doses) may be necessary
before a definite diagnosis can be reached. It produces objective and sub-
jective improvement in 10 to 14 days in the majority of patients with
thyroid overactivity; iodine (for 2 to 3 weeks) may be used similarly, but it
interferes with subsequent medical treatment.

DISEASES OF THE THYROID GLAND
Disease of the thyroid may involve disturbance of structure alone or of
structure and function. Extensive anatomical changes may be found with
normal function (euthyroidism), while considerable alteration in function
may be present with only slight changes in structure. The different clinical
syndromes which result depend on whether the secretion of the gland is
increased (hyperthyroidism or thyrotoxicosis) or diminished (hypothy-
roidism). The lesions and syndromes may be classified in the following
way:

(A) Without disturbance of endocrine function

Lesions

(i) Hyperplasia w ith or without goitre (iii) Adenoma

formation (iv) Carcinoma

(ii) Nodular goitre

(B) With disturbance of endocrine function
1. Increased secretion

Lesions

(i) Hyperplasia (iii) Carcinoma

(ii) Adenoma (i\) Inflammation

Syndrome

Excess of thyroid hormones causes hyperthyroidism

DISEASES Or THE THYROID GLAND 233

2. Decreased secretion
Lesions

(i) Hyperplasia
(it) Aplasia and hypoplasia
(iii) Atrophy
Syndromes

Deficiency of thyroid hormones causes
Myxoedema in adults and children,

Cretinism in infants.

GENERAL PATHOLOGY

Hyperplasia of the thyroid is usually a compensatory process, dependent
on stimulation by TSH, which increases the output of thyroid hormones
in response to physiological requirements or maintains it at a normal level
in the face of adverse circumstances. If the compensation is adequate the
patient remains euthyroid, if it is inadequate he becomes hypothyroid and
if, as sometimes happens, it is excessive hyperthyroidism develops. Hyper-
thyroid hyperplasia, however, does not always (or even often) develop in
this way, and it is uncertain whether, in this condition, the primary fault
lies in the thyroid or in the pituitary.

Hyperplastic glands may be associated with various histological changes,
several of which may be found in one gland at the same time. These repre-
sent different stages of pathological development rather than separate
processes.

If the hyperplasia is great enough the gland enlarges to form a "goitre”,
which is detectable clinically.

Atrophy may follow involution of the thyroid, when it has reached an
irreversible stage, or may overtake a gland which has previously functioned
actively. In an atrophic thyroid the functioning tissue is decreased in
amount, the gland is diminished in size, the colloid is scanty, there may
be fibrous tissue replacement and infiltration with lymphocytes, and there
is reduced function. Atrophy is found in the following circumstances:

(1) hypopituitarism and hypophysectomy cause a failure of thyrotro-
phin secretion;

(2) prolonged therapeutic administration of thyroxine inhibits the
secretion of thyrotrophin;

(3) in toxic adenoma of the thyroid the tissue which is not involved in
the adenomatous growth undergoes atrophy because of pituitary inhibi-
tion;

(4) auto-immune thyroiditis may cause destruction of thyroid tissue.
This causes idiopathic hypothyroidism (myxoedema) of adults.

(iv) Destruction

(v) Inflammation

(vi) Surgical removal

hypothyroidism:

234 Tim THYROID GLAND

Aplasia and hypoplasia are due to developmental defects which result
in absence or great reduction of thyroid tissue and cause sporadic cretin-
ism. Some cases of congenital hypoplasia may be due to the placental
transmission of maternal thyroid antibodies or cytotoxic agents.

Tumours rarely cause alteration in total thyroid function. Some forms
of carcinoma (the papillary growths) are partially or wholly under the
control of TSH.

Destructive lesions. Hypothyroidism rarely follows extensive destruction
of thyroid tissue by haemorrhage, tuberculosis, syphilis, actinomycosis,
cancer (primary or metastatic), amyloidosis, reticuloses or excessive
ionizing radiation.

Inflammation. The thyroid may be affected by acute, subacute or chronic
thyroiditis. Sometimes hyperthyroidism results temporarily from the
rapid liberation of thyroglobulin during the early phase of subacute
thyroiditis or in the acute form of auto-immune thyroiditis. More often
hypothyroidism follows destruction of thyroid tissue in longstanding
disease.

GOITRE

Goitre formation is one of the commonest features of thyroid disorder.
The pathogenesis and special characteristics of the different types will be
described later. The word “goitre" may be used to describe any type of
swelling of the thyroid gland, and we shall use the following terms here.
A "simple goitre" is one associated with normal thyroid function. It may
be “ endemic ’’ when it occurs commonly in one geographical region or
“ sporadic ” when it occurs elsewhere. A "nodular goitre " is an enlarged
gland with palpable nodules in its substance. A "toxic goitre" is associated
with hyperthyroidism. If there is also exophthalmos the patient is said
to have "exophthalmic goitre". A “ nodular toxic goitre " is a gland with
nodular enlargement associated with hyperthyroidism. A “ hypothyroid
goitre" is an enlarged thyroid associated with hypothyroidism and a
"malignant goitre" is one containing a malignant tumour. When un-
qualified, the term “goitre” usually refers to the simple (endemic or
sporadic) type.

Gross anatomy

Goitres vary in size from barely detectable enlargements to enormous
swellings which occupy the whole neck and hang down over the chest (fig.
7.4) The thyroid may enlarge diffusely or in one part only. When diffuse,
the enlargement may be uniform or may involve one lobe more than the
other. The gland usually has a uniform consistency and a smooth surface
at first, but becomes progressively nodular and irregular w ith the passage of
time. The swelling commonly remains in the neck, but a nodular enlarge*

ment at the lower pole of one lobe may extend behind the sternum into the
mediastinum.

The thyroid, being invested by the pre-tracheal fascia, moves upwards
with the larynx and trachea on swallowing. This property may be lost if it
becomes fixed to the surrounding tissues by an acute inflammatory process,
by fibrosis or by malignant invasion, or if it becomes wedged behind the
sternum. Occasionally an early retrosternal goitre may jerk up into the

.a#''

Fig. 7.4. Enormous simple goitre in woman aged 71, which had been present for
many years without causing obstruction. (Mr. W. Wilson’s patient.)

neck on swallowing and plunge down again into the mediastinum after-
wards (goitre plongeant).

The enlarged gland may press on adjacent structures and interfere with
their functions. Compression of the trachea causes respiratory obstruction.
An asymmetrical goitre often displaces the trachea to one side and a
localized nodule may kink it laterally. Bilateral enlargement sometimes
causes a “scabbard” deformity. The deep veins of the neck may be ob-
structed by a large goitre, and the superficial ones may enlarge in a com-
pensatory manner. The oesophagus and one, or rarely both, of the recurrent
laryngeal nerves are sometimes compressed by goitres which extend round
the back of the trachea. Such swellings are usually, but not invariably,
malignant.

236

THE THYROID GLAND

Retrosternal goitres cause compression at an earlier stage and to a
greater degree than those in the neck. Sudden enlargement of the gland
may follow haemorrhage into a cyst and cause acute (and sometimes fatal)
respiratory obstruction.

Symptoms

The throat is a sensitise structure and any swelling in this region may
cause symptoms out of proportion to its size. Women, for example, may
complain of “choking” before any swelling is visible. Conversely, enor-
mous swellings may cause no symptoms at all (fig. 7.4). The patient may
notice that his neck is increasing in size or become aware of a localized or
diffuse swelling. Dyspnoea is not uncommon when the trachea is com-
pressed and is often noticed first on exertion. A lateral nodule, which
kinks the trachea, may cause attacks of dyspnoea in bed when the head is
flexed to one side, and a retrosternal goitre may obstruct the airway when
the head is flexed on to the chest. Dysphagia, which is rarely severe, may
follow oesophageal obstruction, and dysphonia may result from com-
pression of the laryngeal nerves. Pain usually indicates haemorrhage into a
cyst, acute or subacute inflammation or malignancy.

Physical signs

The thyroid gland is examined by inspection, palpation and auscultation.
Inspection from the front and sides will usually reveal a swelling in the
position of the thyroid, which moves upwards when the patient swallows.
In those with fat or thick necks it may be helpful to have the neck extended,
but supported from behind so that the sternomastoids are relaxed. The
whole gland may be seen to be enlarged uniformly or in a nodular manner
or a localized nodule may be visible. Distension of veins, dyspnoea, stridor
or deviation of the trachea may be obvious. With severe venous obstruction
the head and neck may be cyanosed. Measurement of the circumference of
the neck at regular intervals may be of help in assessing the progression or
regression of a goitre.

Palpation may be carried out comeniently either from the front or from
the back. The outlines of the lobes and the isthmus are defined, and the
movement of the gland on swallowing is confirmed. When examining the
gland from in front each lobe can be felt in turn after it has been dislocated
laterally by firm inward pressure on the opposite lobe. The isthmus cannot
always be felt directly, but the absence of the tracheal rings which it over-
lies can usually be appreciated. Occasionally an enlarged pyramidal lobe
can be detected. If the lower pole of one of the lateral lobes cannot be
defined during swallowing with the neck extended the possibility of a
retrosternal goitre should be considered. Occasionally a retrosternal goitre,
which cannot be detected clinically by any other method, may become

GOITRE

237

apparent when the patient expires forcibly with the glottis closed (fig. 7.5),
The surface of the whole gland is palpated carefully to discover whether
the swelling is regular or nodular. The commonest site for a single nodule
is the junction of the isthmus with one of the lateral lobes. The position of
the trachea, which may be far from the midline, is defined, if possible, by
palpation. The consistency of the gland is estimated. Simple goitres are

(a) <*)

Fig. 7.S. (a) Masked goitre. (6) Goitre revealed by forced expiration with closed
glottis.

usually firmer than normal glands, and cysts may feel tense or solid. Hard-
ness usually indicates malignancy, dense fibrosis or calcification. Many
malignant goitres, however, do not feel hard. A thrill may be felt in about
one-third of toxic goitres and must be distinguished from transmitted
carotid pulsation. Tenderness, like pain, usually indicates haemorrhage
into a cyst, inflammation or malignancy. The lymph glands should always
he sought. They are often hard in malignant disease, but are rarely en-
larged in other conditions.

Auscultation may be helpful in two ways. The position of the trachea
can be defined accurately, and a bruit may often be heard in toxic goitres.
A bruit is rarely audible in other types of hyperplastic gland.

238

THE THYROID GLAND

Investigation

The surgeon must answer three questions about every goitre. (I) Is it
simple? (2) Is it toxic? (3) Is it malignant? The assessment of thyroid
function has been described already. The following investigations are of
value in assessing the other characteristics.

Radiographs of the neck and of the thoracic inlet in the anteroposterior
plane may show the soft-tissue shadow of the goitre or patches of calcifica-
tion, but do not distinguish between retrosternal goitre and other types of
mediastinal swelling. They will also reveal displacement and compression
of the trachea (fig. 7.6). A lateral view of the neck and supraclavicular

(a) (b)

Fig. 7.6. (a) Narrowing of trachea by simple goitre ("scabbard deformity”).
(6) forward displacement of larynx and trachea in same patient.

region may rarely show the larynx and trachea displaced forwards by a
goitre which has enlarged behind them. This usually, hut not always,
indicates malignancy, A retrosternal goitre often displaces the tracheal
shadow backwards. A barium swallow may reveal displacement and
narrowing of the oesophagus. Laryngoscopy, which should always be done
on patients with djsphooia and on those about to undergo thyroidectomy,
may show paralysis of one or both of the vocal cords. The detection of hot
and cold nodules with radioactive iodine studies has been described already.
Biopsy of suspected malignant lesions by needle or drill aspiration or by
open operation will be discussed later.

ENDEMIC AND SPORADIC GOITRE 239

SIMPLE {ENDEMIC AND SPORADIC) GOITRE

Compensatory hyperplasia and diffuse enlargement of the thyroid may
develop in the following circumstances :

t. Increased need for thyroid hormones. Puberty, pregnancy and lactation.

2. Impaired formation of thyroid hormones.

(it) Iodine deficiency.

(b) Ingestion of antithyroid substances —

(i) goitrogens in diet;

(ii) antithyroid drugs.

(c) Defective enzyme systems (goitrous cretinism).

It is not always possible to separate these groups, for more than one factor
may operate at the same time. An increased need for thyroid hormones, for
instance, may unmask a relative deficiency of iodine. Diffuse hyperplasia
of unknown cause, associated with hyperthyroidism, will be discussed
later.

Aetiology

An increased need for thyroid hormones is apparent most often during
puberty (especially in girls), pregnancy and lactation, and in pregnancy
the kidneys also excrete larger amounts of iodide than usual. Normally
plenty of iodine is available in the food and water and the thyroid is able to
meet the extra demand without difficulty. However, if the supply is only
just adequate at other times the gland may undergo compensatory hyper-
plasia and form a goitre when increased demands are made upon it.

The commonest cause of goitre is a low intake of iodine as a result of a
deficiency of iodine in the water supply. This type is known as " iodine-
deficiency goitre" or “ endemic goitre ” and has a world-wide distribution.
The areas most affected are the Alps, the Pyrenees, the Himalayas and
Northern India, South-West China and the Andes. There are less severely
affected regions around the Great Lakes of North America, in New Zea-
land, many parts of Africa, South-West Britain, Derbyshire, the Pennine
Chain and Eire. The disease, which is largely preventable, causes much ill
health and economic hardship. The magnitude of the problem in Great
Britain atone, where it affects about 1 per cent of the population, is rarely
appreciated.

In some of the areas of endemic goitre, such as the Himalayas, the de-
ficiency of iodine in the water is not great, and here other factors must play
a part. Chronic gastrointestinal infection may interfere with the absorption
of iodide from the bowel, and naturally occurring antithyroid substances or
goitrogens may contribute to the formation of goitres. It is probable that a
really adequate supply of iodine can mitigate the effects of both. Anti-
thyroid substances have been isolated from certain vegetables and from the

240

TJIE THYROID GLAND

milk of cows which have been fed on them. If they are consumed in exces-
sive amounts thyroid function may be impaired. A substance named pro-
goitrin, whose derivative goitrin interferes with the synthesis of thyroxine,
has been isolated from plants of the genus Brassica (which includes cab-
bage, kale, rape and turnip). Progoitrin is probably destroyed by cooking.
Thiocyanates, which prevent the trapping of iodide by the thyroid, have
been found in all the Cruciferae (the family which includes the genus
Brassica). Such antithyroid substances have been held responsible for
endemic goitre in some countries, notably parts of Australia and Finland,
but their importance in general is uncertain.

Several drugs are known to inhibit the formation of thyroid hormones
and to cause compensatory hyperplasia. The process is usually reversible
l'n the early stages, and drug-induced goitres are not seen often in clinical
practice. There are three main groups of goitrogenic drugs, whose actions
are different. First are those which interfere with the trapping of iodide by
the thyroid. Thiocyanates, which we have met already as goitrogens in
food, are included in this gToup. More important, however, because of
their greater therapeutic value, arc perchlorates. Second, and most active
of all, are dnigs which interfere w'ith the synthesis of thyroxine, probably
by inhibiting the oxidation of iodide and thus preventing its organic
binding. The group includes the thiocarbamides (thiourea and thiouracil)
and the imidiazoles (carbimazole). Iodides themselves may, paradoxically,
cause goitres when given in excess for long periods, possibly by a similar
mechanism (see later). In the third group are drugs w hich interfere with
thyroxine synthesis in another way, probably by competing with thyroxine
for iodine. These are aniline derivatives (paraminosalicylic acid, sul-
phonamides and amphenone), aromatic phenols (resorcinol) and phenyl-
butazone. Finally, cobalt is goitrogenic and reduces the uptake of iodine
by the thy roid, but its mode of action is not known.

Some individuals and some families suffer from congenital defects in the
enzyme systems which are necessary for the synthesis of thyroid hormones.
Severe defects give rise to goitrous cretinism (which will be discussed
later), but minor disturbances may well be responsible, in whole or in part,
for some cases of endemic or sporadic goitre.

Pathogenesis

The first reaction of the thyroid to an increased need for thyroid hor-
mones or to impairment of their formation (or to both) is an increase in
vascularity and diffuse hyperplasia. Under the influence of TSH the acinar
cells increase in height, sometimes being throw n into folds, and the colloid
becomes greatly' reduced in quantity. By these means the output of
thyroid hormones is usually maintained at an adequate level. This evolu-
tionary phase is followed by involution, in which the cells decrease in

ENDEMIC AND SPORADIC GOITRE 241

height and the acini become filled with colloid. The reason for this is not
dear, but possibly the demand for thyroid hormones decreases after a time
— at the end of puberty, for example — or a goitrogenic agent is removed so
that the hyperplastic gland then stores its secretion. The colloid, however,
is fixed and cannot be mobilized on demand as it can from the normal gland.
Up to this time the gland as a whole is uniformly and smoothly enlarged.
Later, however, the acini may become so enormously distended that their
walls break down, forming large pools of colloid which may give rise to
localized palpable nodules or cysts within the substance of the gland. The
further course of the goitre is characterized by cycles of evolution and in-
volution, probably brought about by periods of increased or decreased
demands for thyroid hormones, relative sufficiency or deficiency of iodine,
and the presence or absence of other goitrogenic factors The processes
tend to become irregular, affecting different parts of the gland in different
ways. A few' zones or nodules of hyperplasia may be interspersed among
much more numerous colloid cysts, and some hyperplastic areas may
undergo atrophy instead of involution. Fibrous tissue tends to form around
the nodules, investing them with capsules. Haemorrhage may occur into
cysts, and the blood eventually becomes organized and sometimes partially
calcified. Carcinoma of the thyroid develops in a very few nodular goitres,
but is found in about 7 per cent of those removed surgically (Table 7.4).

Studies with radioactive iodine have throwm much light on the func-
tional aspects of these goitres. Total thyroid function is usually normal, so
that the patient is maintained in a euthyroid state. The gland, however, is
avid for iodine, and the uptake may be as rapid as that in a toxic goitre.
Autoradiography (the exposure of a slice of thyroid tissue, treated with 131 I,
to a photographic plate) shows that the hyperplastic areas are functionally
active, while the parts filled with colloid are inactive. Sometimes all the
functioning tissue is concentrated in one or several zones of hyperplasia,
which form “hot nodules” in a “cold thyroid”. Rarely, if the nodules are
sufficiently large and active, and if iodine is in adequate supply, thyro-
toxicosis may develop. In other cases the thyroid may be unable to produce
sufficient thyroid hormones for the body’s needs and hypothyroidism
develops.

The administration of iodine in the early hyperplastic phase may reverse
the pathological process and restore normal structure and function. Later,
if iodine is administered in the hope of diminishing the size of the gland,
thyroxine may be produced in excess. The resulting thyrotoxicosis has
been called “Jod-Dasedow” by the Swiss.

Clinical features

Goitres which are caused principally by increased need for thyroid
hormones are seen most often in girls at about the time of puberty, less

242

THE THYROID GLAND

frequently in boys and sometimes in several members of the same family.
They often subside spontaneously during adolescence, but may recur
during pregnancy and lactation, subsiding again afterwards. Sometimes
they develop for the first time during pregnancy. In some patients the
goitres regress only partially, becoming larger with each menstrual period,
during successive pregnancies and at the menopause. The enlargement of
the thyroid is usually soft and diffuse at first, but tends to become firm and
nodular when it has been present for some years. Rarely, in very vascular
glands, a bruit or a thrill may be detected, but these signs are much more
common in toxic goitres.

Endemic goitres are also commoner in females than in males and vary
considerably in their severity. In areas of severe iodine deficiency they
tend to develop in early childhood or even before birth in the children of
goitrous mothers. The ultimate size and nodularity may be very great and
myxoedema and cretinism are relatively common. Normal thyroid function
may, however, be preserved in patients with enormous diseased glands. In
areas where iodine deficiency is not so severe the goitres tend to develop
later in life, are usually smaller and less nodular and rarely cause hypo-
thyroidism. The course of endemic goitre may be influenced by events in
the reproductive life in the same way as those which are caused primarily by
increased demands for thyroid hormones. Sporadic goitres develop in
areas where goitre is not particularly common, but are otherwise indis-
tinguishable from endemic goitres.

The complications of haemorrhage into cysts, thyrotoxicosis and malig-
nant change should always be borne in mind, especially with nodular
goitres. Haemorrhage may cause a sudden increase in size of the gland,
pain and acute dyspnoea or even fata! respiratory obstruction. The blood-
filled cyst may be tender.

The symptoms and signs of thyrotoxicosis will be described later. The
condition may be simulated when a nervous or a pregnant patient has a
simple goitre, especially if she fears that the swelling is a cancer. Women
at or near the menopause may have symptoms such as tachycardia, sweating
and flushes, and it may be difficult to exclude toxicity without investigation
of thyroid function.

Malignant disease must always be considered if the voice is hoarse or
absent, if the gland is painful or increases rapidly in size, or if examination
shows it to be tender, hard, fixed or associated with enlarged lymph glands.
A nodule which takes up radioactive iodine is unlikely to be malignant.

Treatment

The treatment of simple goitre may be divided into prophylaxis, drug
therapy and surgery.

Prophylaxis, Endemic goitre with all its morbidity and complications—

ENDEMIC AND SPORADIC GOITRE 243

cretinism, carcinoma, thyrotoxicosis — can be prevented almost completely
by the administration of iodides in very small amounts. This may be done
quite simply in areas of iodine deficiency by the addition of iodide to table
salt or, less easily, by prescribing iodine for individual subjects. Unfor-
tunately this knowledge is not applied as it should be by many authorities.

Drug therapy. In the very early stages of goitre, especially when the
gland is hyperplastic and has not undergone involution, the administration
of iodine may cause the gland to diminish in size. Potassium iodide (Pot.
iod. 0-03 g., distilled water, 20-0 ml.; 4 to 6 drops daily in water) may be
given and is more effective in treating endemic goitre than sporadic goitre.
If the enlargement is more than slight in degree inhibition of pituitary TSH
by the administration of thyroxine, triiodothyronine or of both is usually
more effective. Thyroxine (/-thyroxine sodium) is the method of choice.
The dose is 0T mg. per day initially, increasing by 0*1 mg. increments
weekly to 0*3 or 0*4 mg. daily in a single dose. Treatment should be given
for a trial period of four to six months and then continued for a year or
more if the response is good. Children and adolescents should be given
iodide in addition. When the optimum effect has been achieved the dose
should be reduced by steps for about four weeks and then stopped. In
endemic areas regular iodine therapy should be given after thyroxine has
been stopped unless adequate prophylactic measures are established.
There is no point in continuing treatment beyond the trial period if it does
not cause benefit. The results are best in diffuse goitres but a reduction in
size is sometimes obtained in multinodular glands. Thyroxine must, of
course, be given if there is evidence of hypothyroidism. Relapse is fairly
common in patients with sporadic goitre, and in these thyroxine should be
continued for the remainder of the patient’s life.

Surgery. Partial thyroidectomy is the treatment of choice for very large
goitres (to relieve pressure or for cosmetic reasons), for goitres of recent
onset, for those with single nodules and for all other cases in which
malignancy is suspected. Some surgeons advise thyroidectomy for all
nodular glands because of the risk of complications and because of the im-
possibility of excluding malignancy for certain by any other method.
However, medical measures can be given a trial with some chance of
success. If they are unsuccessful surgery should certainly be advised.

Operation involves the partial resection of both lobes and removal of the
isthmus (see later). Enucleation of a single nodule, which was often under-
taken, is likely to be followed by recurrence of nodules elsewhere in the
gland. Thyroid insufficiency may follow temporarily and cause increase in
weight, fatigue, intolerance of cold and so on. If any hypothyroidism was
present before operation it is aggravated. For this reason it is wise to give
replacement therapy (/-thyroxine sodium, 0*2 to 0*4 mg. per day) routinely
for 6 to 12 months after operation and then to withdraw it slowly. Most

244

THE THYROID GLAND

patients can then manage without it, but a few require thyroxine indefi-
nitely.

Iodide goitre

A special variety of drug-induced goitre may follow the prolonged in-
gestion of iodides by patients with bronchitis and asthma. It is believed to
develop in those who are unduly sensitive to the inhibitory effect of excess
iodide on the organic binding of iodide. Parenchymal hyperplasia is pro-
nounced, and some patients may become hypothyroid. Other biochemical
features include a high PBI, tow BMR, a release of iodide from the thyroid
after perchlorate and an increased uptake of m I when iodides are stopped.
Clinically the condition resembles auto-immune thyroiditis, but the history
of iodide ingestion and lack of thyroid auto-antibodies helps to distinguish
it. Treatment consists in withdrawing the iodide-containing medicines.

TOXIC GOITRE

Hyperthyroidism is the commonest disturbance of the endocrine glands
which the surgeon is required to treat. The first clinical description was
made by Pany in 1786. Graves, after whom the disease is often called,
described three cases in 1835, while von Basedow gave a very complete
description in 1S40.

Iodine was first used by von Basedow in 1840 and later by Stokes for the
treatment of toxic goitre. Its beneficial effects were recognized by some,
but it was generally held to be harmful because of the occasional occurrence
of hyperthyroidism after its administration in cases of severe endemic goitre
(Jod-Basedow). Full appreciation of its effectiveness had to wait for the
work of Plummer in 1922.

The first partial thyroidectomy for toxic goitre was performed in 1872 by
Watson and the operation was later popularized by the work of Billroth and
Kocher in Europe and of Halsted and C. H. Mayo in America. However,
the brilliant work of Dunhill, published in 1909, established the operation
of subtotal thyroidectomy as it is known and practised today. The pre-
operative preparation, which has done so much to render surgery safe, owes
most to Plummer, who re-introduced iodine therapy, and to Astwood, who
added thiovitacil in 1943.

Nomenclature

The condition of thyroid enlargement with hyperfunction has been given
many names, chiefly because of the various symptoms and signs encoun-
tered clinically.

“ Thyrotoxicosis " and ** hyperthyroidism ” are synonymous and refer to the
effects of increased secretion of thyroid hormone. The terms "Graves’

TOXIC GOITRE

245

disease” and “von Basedow’s disease” are properly used for the syndrome
originally described by these authors, namely thyrotoxicosis, goitre and
exophthalmos. Neither term is exact, and both are often used to describe
thyrotoxicosis, whether accompanied by eye signs or not. The terms
'‘exophthalmic goitre”, ‘‘toxic goitre” and ‘‘toxic nodular goitre” have been
defined already. "Toxic adenoma" describes the rather unusual condition
of a single "hot” nodule of the thyroid associated with hyperthyroidism.

There are two principal types of thyrotoxicosis, both of which are
characterized by oversecretion of thyroid hormones by the thyroid gland.
They are not so much distinct diseases, as different manifestations of the
same disease process, conditioned by differences in the age of onset, the
functional state of the thyroid gland and the susceptibility of the tissues to
thyroxine.

Primary thyrotoxicosis ( exophthalmic goitre , primary Graves' disease, diffuse
toxic goitre) usually occurs in young adults (mainly females) m whom there
has been no previous goitre. The onset is often sudden, the goitre is sym-
metrically enlarged and smooth, and nervousness, exophthalmos, in-
creased metabolism and tachycardia are the main clinical features.

Secondary thyrotoxicosis ( toxic nodular goitre, Plummer's disease, secondary
Graves' disease) is usually found in older patients, and the onset is often
insidious. A goitre may have been present for many years, and the gland is
asymmetrical and frequently nodular. Nervous manifestations are less pro-
nounced and exophthalmos is generally absent or slight. The cardio-
vascular system bears the main brunt of the hyperthyroidism and, because
of the frequent association of ischaemic and hypertensive heart disease in
this age group, cardiac failure and auricular fibrillation are common.

The terms “primary” and “secondary” thyrotoxicosis may be convenient
to indicate the presence or absence of a pre-existing goitre, but they are
also confusing because they imply that the aetiology of the two conditions
is in some way different. We therefore prefer not to use them. Similarly,
the distinction between diffuse and nodular goitre is not exact because
thyroids which are thought to be smooth on palpation may contain nodules.
It thus seems best to retain the term toxic goitre and to use it for all types of
goitre with symptoms and signs of thyrotoxicosis.

Aetiological factors

The precise aetiology of toxic goitre is not known. Genetic factors may
he involved in some cases because a family history of thyroid disease is
often obtained. Clinical evidence suggests that nervous and emotional
factors play a large part in the initiation of thyrotoxicosis. In women, who
are affected more frequently than men, the sexual disturbance and mental
Stress which may be associated with puberty, pregnancy and the meno-
pause appear to be of particular importance. For these reasons it seems

246

TJIC THYROID GLAND

likely that the higher nervous centres and the hypothalamus are involved
primarily.

The essential endocrine disturbance is a loss of the normal reciprocal
relationship between the anterior pituitary and the thyroid gland. The
enlargement and hyperplasia of the thyroid in toxic goitre are similar to
the changes induced by injections of TSH in experimental animals and
suggest the presence of a humoral thyroid stimulating agent. Such a sub-
stance has in fact been found in the serum of a high proportion of patients
with toxic goitre. It differs from TSH in that it exerts a more prolonged
action on the thyroid of the guinea-pig and that its secretion is uninfluenced
by thyroxine or triiodothyronine, even when they are given in large doses.
For these reasons the substance has been called "long-acting thyroid
stimulator" (LA.TS). The thyroid retains its sensitivity to thyrotrophin, for
the administration of TSH to patients with toxic goitre increases thyroid
function and the progressive enlargement of the thyroid which follows the
induction of hypothyroidism by antithyroid drugs can be explained only on
the assumption that an excess of TSH is released in response to the fall in
the thyroxine level. The nature of the abnormal thyroid stimulator has not
been determined nor has the site of its production been located. It is
possible that it is closely related to the exophthalmos-producing substance
(to which we shall refer later) and that both arise in the pituitary'.

The evidence for an abnormal thyroid stimulator is not universally
accepted, and some argue that the response of a toxic goitre to exogenous
TSH and its lack of inhibition by administered thyroxine indicate the pre-
sence of an autonomous thyroid disorder which suppresses the endogenous
production of TSH, Further support for this view comes from the occa-
sional persistence of thyroid function and the very occasional development
of thyrotoxicosis in patients who have undergone hypophysectomy. These
observations, however, can be explained by the finding in such thyroids of
areas of adenomatous hyperplasia (or “hot nodules”) which may well be
autonomous, and by the frequency of incomplete removal of the pituitary
gland.

Pathology

1. Diffuse toxic goitre. The thyroid is enlarged, but there is no constant
relationship between the size of the gland and the degree of clinical
activity. The tissue is firmer in consistency than that of the normal
thyroid and very vascular, owing to the dilatation and proliferation of the
blood vessels. The tissue is generally of a uniform reddish-brown colour,
on section, but the shade varies with the degrees of vascularity, hyper-
plasia and colloid content. The cut surface loses its normal glistening
appearance, owing to the lack of colloid, and becomes granular and friable.

TOXIC GOITRE 247

An increase in fibrous tissue is common in long-standing cases and im-
parts an abnormal toughness to the tissue.

Microscopically the epithelial cells lining the acini are diffusely hyper-
plastic, and the amount of colloid is reduced. The cells are of the high
columnar type and active mitotic division may be observed. The colloid
contains many vacuoles and stains poorly with eosin. Most of the acini are
enlarged, but when hyperplasia is intense they may be smaller than normal.
Papilliferous infolding of the epithelium may be seen in the larger acini and,
when extreme, may be suggestive of a papillary carcinoma. Occasionally
lymphocytic infiltration with follicular aggregations may be observed,
possibly associated with the presenceof thyroid antibodies in the circulation.

The appearance of the thyroid in thyrotoxicosis varies with the clinical
course of the disease. When it is progressive the gland shows only the
features of hyperplasia, but when the course is characterized by exacerba-
tions and remissions areas of involution are interspersed among regions of
hyperplasia. Where involution occurs the acini fill with colloid and the
epithelium becomes flat and inactive. Frequently these areas of quiescence
coalesce and form adenomatous or nodular masses of varying size.

2. Toxic nodular goitre. Nodules in toxic goitres may be of two types:
(a) Areas of intense hyperplasia or involution associated with longstanding
and remittent thyrotoxicosis, and (6) Areas of hyperplasia or involution
arising in a pre-existent simple goitre (endemic or sporadic). The former
type has just been described. It should be noted that nodules tend to en-
large both during episodes of activity (when hyperplasia occurs) and during
periods of quiescence (when the acini undergo involution). The latter type
was discussed in the section on simple goitre. The presence or absence of
hyperthyroidism in such nodules cannot be decided on histological grounds
alone.

3. The single toxic adenoma ( the (, hot nodule ” tcith thyrotoxicosis). A single
adenoma is a rare cause of hyperthyroidism. It is composed of a large
number of acini showing intense microfollicular hyperplasia, and is thus a
localized adenomatous goitre and not a true adenoma. The lesion functions
autonomously and the rest of the gland is inactive because the secretion of
TSH is inhibited by the excess of circulating thyroid hormone. The acti-
vity of the nodule is confirmed by the high uptake of radioactive iodine by
the tissue and by the relief of thyrotoxicosis by local surgical excision of the
lesion. It is almost certain that the single toxic nodule represents a spon-
taneous variety of thyrotoxicosis, which is not controlled by TSH or by an
abnormal thyroid stimulator.

4. Auto-immune thyroiditis. Infiltration of the toxic gland with lym-
phocytes and plasma cells may occur in a focal manner or rarely in a diffuse
fashion. This process may eventually destroy the parenchyma and lead to
hypothyroidism.

248

THE THYROID GLAND

5. Carcinoma. Carcinoma is found in about 1 per cent of toxic goitres
removed surgically (Table 7.4).

Effects of therapeutic agents on the thyroid in toxic goitre

1 . Iodine increases the storage of colloid in thyrotoxic glands and reduces
the height of the epithelial cells. It thus induces the changes characteristic
of involution and reduces the vascularity of the gland. Clinical impro\c-
ment usually follows, but the relief is only temporary.

2. Thiouracil and its derivatives and carbimazole block the sjnthesis of
thyroid hormone. The secretion of TSH increases as the level of cir-
culating thyroid hormone falls, and causes an increase in epithelial hyper-
plasia, a reduction in the amount of colloid in the follicles and an increase
in the vascularity of the gland. Thyroid function diminishes steadily and
may reach a subnormal level. The hyperplasia and thyroid enlargement
which result may cause pressure symptoms, especially if the patient
becomes hypothyroid. The simultaneous administration of thyroxine
diminishes the pituitary response. The gland remains responsive to iodine
therapy, so that involution of the gland, with reduced vascularity, may be
induced,

3. Perchlorate inhibits the uptake of iodide by the thyroid. It may render
the gland hyperplastic and vascular if the patient is made hypothyroid.
Pathological findings in other organs

Most descriptions of the morbid anatomical findings in patients dying
from thyrotoxicosis are found in the older literature, for with modern
treatment the disease is rarely fatal. The findings are largely non-specific.
There are no characteristic thyrotoxic lesions in the heart, but hypertrophy,
due to the increased cardiac output, is usually seen. Cardiac failure usually
develops when there is an underlying pathological lesion, such as ischaemic
heart disease or rheumatic fever, but occasionally it may supervene in the
absence of any detectable form of heart disease. Hyperplasia of the thymus
and lymph nodes, particularly those in the region of the neck and medi-
astinum, is fairly common, and splenomegaly is found in a small proportion
of cases. The liver may show acute degenerative changes in patients djing
from thyroid crisis. The skeletal tnuscles may undergo non-specific de-
generative changes and may contain lymphorrhages. The latter arc most
ywroimwA w. xfeit x v AvVr&vt w&Ik vrwscSsa. Mw wi rgrifiaant. ohaMg m have
been found in the pituitary gland in toxic goitre.

Incidence and age of onset

Toxic goitre is of world-wide distribution. In general, it is about fi'c
times commoner in females than in males, but in endemic goitre areas the
sex distribution is more nearly equal. The incidence in the general popula-
tion has not been established accurately, but it is generally believed to be

SYMPTOMS OF TOXIC COITR!*.

249

closely related to that of simple goitre. In endemic goitre regions sudden
access to large amounts of iodine may precipitate the onset of hyper-
thyroidism. The relative incidence of diffuse and nodular toxic goitres
varies widely in different localities.

The disease may occur at any time from infancy to old age, but most
cases arc seen in the third, fourth and fifth decades. It is much less common
in children than in adults, and is rare before the age of 5 years. Recently
the average age of onset seems to have increased, but whether this is a true
increase, or the result Df better diagnosis and clinical awareness of the
occurrence of thyrotoxicosis among older people, is not certain.

Clinical and metabolic features
There are three main types of disturbance in toxic goitre :

(1) increased metabolism, the result of the excessive secretion of
thyroid hormones;

(2) the goitre, which may be caused by an abnormal thyroid stimu-
lator; and

(3) the ocular changes, which are probably caused by an exoph-
thalmos-producing substance.

These disturbances may be present together, but one may precede the
others or develop independently.

Toxic goitre produces a wide variety of symptoms, and those of one
patient may be quite different from those of another. As mentioned
already, two main clinical types may be recognized, which are dependent
on the severity of the condition, the age of onset, the state of the thyroid
gland and the presence or absence of pre-existing heart disease. But even
within these two broad groupings considerable individual differences are
seen.

The onset may be abrupt and follow, within a few days, some severe
emotional shock; but usually the disease increases gradually over several
weeks or months. The natural history is unpredictable. Relapses and re-
missions occur, and a severe relapse may take the form of a thyroid crisis or
storm which threatens the patient's fife. Such episodes are not observed
when antithyroid drugs are applied correctly in treatment. Jn elderly
patients the disease may be so mild, apart from cardiac complications, that
it has been referred to as “masked hyperthyroidism”.

Symptoms

The chief complaints are nervousness, fatigue, palpitations and loss of
weight. Other symptoms commonly mentioned by patients are intolerance
of heat, sweating, trembling of the limbs, prominence of the eyes or stare,
and fullness or swelling of the neck. Other symptoms may often be elicited

i

250

THE THYROID GLAND

if sought specially. Among these are increase in appetite, emotional in-
stability, such as frequent crying or irritability without adequate cause,
sleeplessness, restlessness, tremor, loose motions or frank diarrhoea,
menstrual irregularities, dyspnoea of effort and generalized pruritus. In
early cases patients may not be aware of anything amiss until their attention
is drawn, by relatives or friends, to some feature of the disease such as
prominence of the eyes or goitre. Occasionally some complain of one
symptom only, such as loss of weight, tiredness, diarrhoea or unaccountable
nervousness.

General appearance

The usual features of toxic goitre are well known, and the experienced
observer can recognize the frank condition from a brief glance at the patient.
The early signs in the eyes are brightness and widening of the palpebral
fissures which impart an eager and attentiv e appearance to the features.
When exophthalmos is more pronounced the face takes on an anxious,
unblinking appearance. The skin is usually flushed, and many patients
have a nervous and breathless manner. This is heightened by motor
restlessness, fidgeting and rapid, jerky movements. A fine tremor of the
hands is noticeable when the fingers are held outstretched in front of the
body. The skin is soft, clammy and unusually fine and has a characteristic
velvety feel. The hands are warm and moist, and the grip, particularly in
women, may be noticeably limp. Premature greyness of the hair, together
with the loss of weight, makes some women look older than their years.

Thyroid gland

A goitre is almost invariably present, although there are rare cases in
which hyperfunction of the gland occurs without anatomical enlargement.
A goitre may escape detection if it is retrosternal or set low in the neck, and
minor enlargements may be unrecognizable in subjects with thick necks-

In diffuse enlargement of the thyroid both lobes and the isthmus arc en-
larged, often symmetrically, but sometimes one lobe is larger than the other.
The surface is smooth and the gland is firmer than normal. Because of the
increased vascularity, a bruit is heard over the gland in more than 70 per
cent of cases, and in half of these a thrill may be felt also. The latter
finding, particularly, provides confirmatory evidence of increased thyroid
activity, for it h very rare in simple goitre.

In toxic nodular goitre the gland is irregular in shape and tends to be
both firmer and larger than the diffuse gland, but the clinical distinction
between the two types is not always easy. Enlargement of the pyramidal
lobe may suggest nodularity in a diffusely hyperplastic gland. Conversely,
some nodular goitres may feel quite smooth. Local pressure symptoms in
toxic goitre occur more commonly in association with nodular than with

SYMPTOMS Or TOXIC GOITRE 251

diffuse glands. Such symptoms, however, are less frequent in toxic than in
simple goitres.

Ocular signs

Eye changes are found in the majority of patients with diffuse thyroid en-
largement, but are rare in those with nodular goitres. They usually develop
fairly rapidly for the first few months, but then often remain relatively
static for years. Eye signs, indistinguishable from those of toxic goitre,
occasionally develop in the absence of any recognizable endocrine disease.

Fig. 7,7. Lid retraction and exophthalmos in thyrotoxic male aged 55. (a) The
condition is marked, but (6) gentle closure of the lids is still possible.

There are three main clinical features, which are usually, but not always,
bilateral and often asymmetrical.

1, Lid retraction (figs. 7.7 and 7.9) is usually the earliest and the most
striking change. It is caused by elevation of the upper lid and results in
widening of the palpebral fissure. When the eyes are directed forwards in
the neutral position part of the sclera, which is normally covered by the
upper lid, may be seen exposed above the edge of the cornea. The lower lid
may be slightly raised so that it covers the edge of the cornea. Lid retrac-
tion reduces the capacity to blink. “Lid lag” may be seen when the patient’s
eyes follow the examiner’s finger vertically from above downwards.
Normally the upper lid and the eye move synchronously and the sclera

252

THE THYROID GLAND

above the cornea remains covered. When the ltd is retracted the rim of
sclera becomes progressively wider. This sign may be elicited before any
evidence of retraction is seen with the eve at rest.

2. Exophthalmos (fig. 7.7) is true forward displacement of the eyeball
(proptosis) and should be distinguished from the apparent displacement
caused by lid retraction. The earliest sign is often a band of sclera, more
than 2 mm. in width, visible between the limbus and the edge of the lower
lid when the eye is looking straight forwards. The proptosis can be
measured by means of an exophthalmometer. Normally the apex of the
cornea lies in a plane 10 to 23 mm. anterior to the lateral margin of the
orbit, and the readings for the two eyes do not differ by more than I mm.

Fig. 7.8. Ophthalmoplegia (right side) in thyrotoxic female aged 72.
Weakness of elevation and abduction.

The wide normal range of protrusion may prevent the detection of early
exophthalmos by a single observation. However, since the proptosis is
often asymmetrical (or even unilateral) in thyrotoxicosis, measurements
which differ by more than 1 mm. are significant. Serial readings, made at
monthly intervals, may reveal progressive exophthalmos.

3. Ophthalmoplegia (fig. 7.8), or weakness of the external ocular muscles,
is the least common of the ocular signs. It may he comparatively harmless,
but more often it is associated with oedema Df the orbit and chemosis, and
indicates advanced disease. One or more muscles may be paralysed com-
pletely, The superior rectus is usually involved first, so that the eye cannot
be raised. The lesions arc usually bilateral and symmetrical. Weakness of
abduction and of adduction follow in that order, but inability to lower the
eye is rare. Patients may complain of diplopia, and an obvious squint >s
sometimes present.

SYMPTOMS OF TOXIC GOITRE

253

In the majority of patients the ocular changes are relatively mild and con-
sist of lid retraction and moderate exophthalmos only The condition is
called "simple (benign) exophthalmos”. In a minority (less than 5 per
cent), however, they are much more severe and threaten vision or even life
itself. This variety has many names, including “hyperophthalmopathic
Graves* disease”, "exophthalmic ophthalmoplegia”, "malignant exoph-
thalmos” and "infiltrative ophthalmopathy”. The difference between
the two types is probably one of degree only, for both form an integral
part of the syndrome of toxic goitre, and the milder form may develop
slowly or rapidly into the more severe.

Fig. 7.9. Female aged 44 years with thyrotoxicosis.

Note implement in upper lid retraction after 7 days’ treatment with guancthidme
(100 mg. daily). No antithyroid treatment was given during this period.

Hyperophthalmopathic Graves' disease tends to be more serious in men
than in women. It is characterized by severe exophthalmos, oedematous
thickening of the lids, chemosis, ophthalmoplegia, deterioration of visual
acuity, papilloedema and (eventually) optic atrophy. The earliest com-
plaints are usually of a "gritty*' or “sandy** sensation in the eyes, a feeling
of tension and increased lachrimation. The proptosis may be so great that
the litis cannot close. Conjunctivitis, corneal ulceration and ophthalmitis
may follow. In extreme cases, when the intra-orbital pressure is very great,
the whole eye may become dislocated.

The pathogenesis of the ocular changes is not understood fully. Lid re-
traction is probably due to excessive sympathetic tone in M tiller’s superior

254

THE THYROID GLAND

palpebral muscle, brought about by the effect of catechol amines on tissues
sensitized by increased amounts of thyroxine. This can be abolished by sym-
patholytic agents such as guanethidine (fig. 7.9) or phentol amine, and lid
retraction usually subsides when the thyrotoxicosis is brought under control.

The characteristic pathological lesion is an increase in the fat which lies
between the bundles of the extrinsic ocular muscles and in the tissues
behind the globe of the eye. In the hyperophthalmopathic form the
tissues become oedematous and infiltrated with leucocytes as well. These
processes aggravate the exophthalmos and probably cause the ophthalmo-
plegia. In longstanding cases the oedematous tissues undergo irreversible
fibrosis and cause permanent ocular palsies.

It was thought at one time that TSH was directly responsible for the
ocular changes, for crude extracts caused exophthalmos in experimental
animals. However, pure extracts do not do so, and patients with hypo-
thyroidism, who secrete TSH excessively, do not show eye signs. Recent
evidence suggests that, in toxic goitre, the anterior pituitary secretes an
abnormal “exophthalmos-producing substance” (KPS). Several species of
fish are sensitive to the action of EPS and form convenient preparations for
its assay. High litres can be detected in the sera of patient9 with progressive
exophthalmos. EPS probably influences fatty tissue throughout the body,
but its effects are manifested clinically in the orbits only.

Other features
The skin

The temperature of the smooth, velvety shin increases as a result of
vasodilation, so that the exposed areas are {lushed and feel hot. An
increase in moisture accompanies the rise in temperature, owing partly to
the normal mechanism of heat elimination and partly to overactivity of
the autonomic nervous system. Palmar erythema is fairly common, and
some women show dilated veins on the dorsal aspects of their hands. The
latter is an unusual finding when the metabolic rate is normal. Multiple
angiomata (spider naev i) are sometimes seen in young women with diffuse
toxic goitre and resemble those of hepatic disease.

Disturbances in pigmentation may be seen sometimes. Ilypcrpig-
mentation, due to excessive deposition of melanin, may be diffuse and
Addisonian in type, but the oral mucous membranes are not affected.
More rarely pigmentation is reduced and v itihgo may occur initially or may
follow hyperpigmentation. The mechanism of these pigmentary changes is
not understood. The hair often becomes soft, fine and prematurely grey
and may fall out. Onycholysis or “Plummer nails” may be seen in patients
of either sex with diffuse toxic goitre. The distal part of the nail becomes
separated from its bed in such a way that the curved line, where the nail
joins the shin, becomes concave instead of convex.

SYMPTOMS OF TOXIC GOITRE

255

Localized pretibial tnyxoedema {myxoedema circumscriptum thyrotoxi-
cum) occurs in about 1 to 3 per cent of patients with active thyrotoxicosis,
but may not develop until after correction of the toxic goitre by surgical or
other means (fig. 7.10). It is not found in spontaneous hypothyroidism, but
may develop in patients who have been rendered hypothyroid as a result
of treatment. The connective tissues of the cutis become infiltrated by

Fiy. 7,10. Pre-tibia! myxoedema following subtotal thyroidectomy for toxic goitre.

mucinous material, which causes bilateral cutaneous thickening on the
anterolateral aspect of the lower part of the leg. The lesions are firm and
raised, pinkish or brownish in colour and may have a translucent waxy
appearance. They vary' in size from small nodules or plaques to extensive
irregular swellings. The affected areas may be very hairy, and the large,
coarse hair follicles may give the appearance of pig skin.

Pretibial myxoedema is commonly associated \\ ith severe exophthalmos
and may have a similar cause. The constancy with which the localized
lesion is confined to the lower leg, however, suggests that some local tissue

TIIC THYROID GLAND

256

factor is involved also. The condition is unsightly, but it causes little dis-
ability. It may disappear spontaneously, but more often it diminishes
slowly over a number of years. No effective treatment is known. Clubbing
of the fingers and toes (thyroid achropachy) may be observed in association
with pretibiat myxoedema, and a few patients may also show the bony
changes of pulmonary' hypertrophic osteoarthropathy.

Cardiovascular manifestations

The effects of hyperthyroidism on the heart and circulation depend
largely on the severity of the condition and on the age of the patient. The
increase in metabolism imposes a load on the heart which may cause it to
undergo hypertrophy. Thyroxine in excess may also cause ahnormat
cardiac rhythms which further embarrass the circulation. The heart rate
is rapid and the cardiac output is consequently raised. There are in-
significant changes in the stroke volume and in the difference in oxygen
saturation between the arterial and the venous blood. The increased
cardiac output is accompanied by an elevation in the systolic blood pres-
sure, while peripheral vasodilation causes a fall in the diastolic pressure.
These changes increase the pulse pressure. The vasomotor responses arc
often hyperexcitablc.

These circulatory changes may cause patients to complain of palpita-
tions and shortness of breath on exertion. Many complain of frequent
flushing of the face, neck and chest when excited or when entering a warm
atmosphere. The pulse rate is nearly always increased to about 100 to
120 beats per minute and is occasionally very rapid (140 to 160 per
minute). During sleep the pulse usually falls somewhat but remains above
the normal level. Excitement such as that caused by a visit to the doctor,
or even a trivial incident, may raise the pulse still further, but it usually
falls with rest in bed or during the course of the clinical examination. The
pulse is usually full and bounding and may occasionally be collapsing in
quality.

The cardiac impulse is forceful and diffuse and, in severe or long-
standing cases, it may be displaced outwards as a result of cardiac enlarge-
ment. The heart sounds arc loud, and a systolic murmur is usually heard
at the apex or base, with the point of maximum intensity over the pul-
monary artery. The murmur is due to the rapidity and force of the blood
stream. Radiological examination of the heart may show prominence of the
pulmonary artery and right ventricular outflow tract. The electrocardio-
gram reveals sinus tachycardia, but is otherwise within normal limits in the
majority. In a few live 1’ waves ami QRS complexes arc augmented, but
these changes are of little clinical or diagnostic significance.

Among older patients cardiac manifestations may be severe, and distur-
bances of rhythm arc common. At first these are paroxysmal in nature,

SYMPTOMS Of TOXIC COITRC

257

with either paroxysmal tachycardia or atrial fibrillation, but the latter soon
becomes established, and cardiac failure may follow. In many elderly
patients the metabolic features of the thyrotoxicosis are mild and the
cardiac features assume major prominence. Age makes the heart so sensi-
tive to the effects of thyroxine that changes of rhythm may occur with
increases in thyroid function which are insufficient to alter the metabolic
rate significantly. The frequent association of hjpertension and m>o-
cardial ischaemia increases the liability to heart failure. Cardiac failure
with normal rhythm is rare in hyperthyroidism.

Metabolic changes

Hyperthyroidism increases the oxygen consumption of the tissues, and
is therefore accompanied by increased production of heat. The accelerated
metabolism may be assessed by measurement of the basal metabolic rate
This is elevated in all cases, although in a few the level may be no higher
than that of some normal people.

The increase in metabolism is accompanied by a negative nitrogen
balance, loss of w eight, increase in appetite and occasional!)- by disturbance
in carbohydrate tolerance. Creatinuria, due to the breakdown of muscle, is
sometimes found. In spite of the increase in appetite, patients generally
continue to lose weight, but occasionally a positive nitrogen balance with
gain in weight is found if the calorie intake is considerably in excess of the
basal requirement. A minority of patients deny any increase in appetite.
The increased need for fuel causes the withdrawal of fat from the depots
and sometimes an increase of fat in the liver.

Elevation of the blood sugar with glycosuria may be found, and the oral
glucose tolerance test frequently reveals a curve which begins at a slightly
high level, rises very high at £ to 1 hour, and returns to normal or to a
slightly hypoglycaemic level at 2 hours.

The increased heat production enables the patient to withstand cold and
leads to intolerance of heat, while the peripheral vasodilatation and in-
creased sweating tend to prevent the body temperature from rising. A few
patients, however, have slight fever, and hyperpyrexia occurs in a thyroid

crisis.

Gastrointestinal tract

Symptoms related to the alimentary tract are common and are occa-
sionally so severe that the possibility of hyperthyroidism as the underlying
cause is overlooked. A choking sensation or a feeling of fullness in the
throat is a frequent complaint, but true dysphagia is unusual, even when the
goitre displaces the oesophagus.

The appetite is generally increased, and the combination of weight loss
with a good appetite is common in toxic goitre, as it is in diabetes mellitus.

258

THE THYROID GLAND

As mentioned already, a few patients experience no change in appetite;
some may even have anorexia.

Diarrhoea, when severe, may suggest some organic lesion of the bowel.
A few patients with longstanding constipation obtain partial or complete
amelioration with the onset of thyrotoxicosis.

Localized abdominal pain may resemble that of peptic ulceration, but
ulcers are found less commonly than in the general population. Achlor-
hydria is common, and secretion may return after successful treatment.
Nausea and vomiting may develop in severe hyperthyroidism, especially at
the onset of a crisis.

Structural and functional disturbances of the liter have been found,
mainly in patients dying from the disease. The most frequent finding is
depletion of hepatic glycogen with increased fatty infiltration of the liter
cells. Occasionally alteration in routine liter function tests may demon-
strate these derangements in patients with toxic goitre. Clinical c\ idence of
altered liter function is exceptional.

Neuromuscular disorders

In addition to the muscular atrophy and weakness, which accompany the
breakdown of tissues in general, a number of distinct myopathic syn-
dromes (of unknown pathogenesis) hate been observed in association with
thyrotoxicosis.

Chronic thyrotoxic myopathy. Very rarely muscular atrophy and weak-
ness may be so set ere as to resemble those of progressive muscular atrophy.
In most of these the other evidence of thyrotoxicosis is slight, so that the
clinical picture is that of "masked” hyperthyroidism. Recovery is usual
after treatment of the thyrotoxicosis.

Myasthenia gravis may accompany thyrotoxicosis and is seen only in
those with diffuse goitres. Patients respond to neostigmine, but probably
less well than those with the uncomplicated disease. Treatment of the
thyrotoxicosis usually causes some improvement in the myasthenia, but
rarely cures it.

Periodic paralysis is occasionally related directly to thyrotoxicosis, and is
usually relieved completely by treatment of the thyroid disorder, Like
myasthenia gratis, it is seen only in those with diffuse goitres.

Exophthalmic ophthalmoplegia has been discussed already.

Acute thyrotoxic myopathy. Muscular weakness and wasting with bulbar
palsy develop acutely in thyrotoxic crisis. It is not clear whether the myo-
pathy is a specific entity or simply an acute manifestation of tissue break-
down.

Emotional and nervous features

The nervous symptoms are very variable, and depend largely on the
severity of the disease and on the underlying personality. The patient is

SYMPTOMS Or TOXIC GOITRE 259

usually tense and restless. She feels anxious, is unable to relax and cannot
allow others to do so either. The mood is labile, and tears are induced by
trivialities. Some become irritable and flare up or snap without reason at
their children or neighbours. Insomnia may add to the worry and appre-
hension. Acute toxic confusional psychoses may develop in severe cases,
especially in the presence of infection.

Sexual function

Disturbance of menstruation is rare in thyrotoxicosis, but when present
amenorrhoea or oligomennrrhoea is usual. Treatment of the hyper-
thyroidism restores the menses to their customary rhythm.

In men there is little change in sexual function. Gynaecomastia occurs in
a few patients, but the cause is obscure. The breast enlargement is usually
slight and often passes unnoticed, but in some the breasts may be tender.
Regression follows treatment.

Skeletal changes

Rarefaction of the skeleton is common in severe thyrotoxicosis and,
while often silent, it may advance rapidly and produce se\ere symptoms.
Backache, loss of height and kyphosis are not uncommon, particularly in
the elderly. Pathological fractures occur, while pain in the long bones, due
to decalcification, may lead to reluctance to use the arms and the develop-
ment of a “ frozen shoulder”. X-rays commonly show generalized rare-
faction of the skeleton. The vertebrae are affected most severely, and one
or more may be collapsed.

Biopsies of bone reveal osteoporosis, and metabolic studies show that the
patients are in chronic negative calcium balance. As in other forms of
osteoporosis, the balance may be rendered positive by a high consumption
of calcium. The pathogenesis is uncertain, but it is generally believed that
thyroxine has a direct catabolic action on bone.

Thyrotoxic crisis

A crisis or storm may occur in severe toxic goitre and represents an acute
exacerbation of all the features of hyperthyroidism. Since the advent of
antithyroid drugs crises have been much less frequent than formerly, but
are still liable to occur as a result of intercurrent infection, after thyroidec-
tomy in patients still actively hyperthyroid, after emergency operations of
any type performed on patients with uncontrolled thyrotoxicosis and on
withdrawal of iodine therapy before sufficient control has been achieved in
se\erc cases. There is some evidence that adrenocortical failure or "ex-
haustion” may play a part in the crisis, especially when the thyrotoxic
patient is subjected to the stress of infection or of a surgical operation, and
cortisol may be of value therapeutically. The usual clinical features are
hyperpyrexia, restlessness, delirium, severe mental confusion, tachycardia

260

THE THYROID GLAND

or atria! fibrillation, weakness and marked flushing and sweating of the
skin- There may be peripheral circulator}' failure. In some patients vomit*
ing, abdominal pain and diarrhoea dominate the clinical picture.

Much more rarely the crisis is “apathetic” in type, the patient exhibiting
profound prostration, weakness, clouding of consciousness and eventually
coma. The thyrotoxic nature of this syndrome and the critical illness of the
patient may easily be overlooked. Both forms are dangerous and poten-
tially lethal. If untreated, a crisis terminates in coma and death, usually
within 36 to 48 hours of its onset.

Thyrotoxicosis in pregnancy

Thyrotoxicosis is not unusual in pregnancy, but unless it is recognized
early and treated effectively, the consequences for the mother and the
child may be serious. Thyrotoxic crisis may occur at term or in the
puerperium, and the double load of hyperthyroidism and pregnancy may be
particularly serious in a patient with cardiac disease. A few patients under-
go spontaneous remission as pregnancy advances. The foetus may abort at
about the 12th week or later. Thyroxine and EPS may pass through the
placenta and cause thyrotoxicosis and exophthalmos in babies bom at full
term.

Unfortunately the diagnosis may be very difficult, for many of the
symptoms and signs of thyrotoxicosis arc similar to those of a normal
pregnancy. Reliance must be placed chiefly on the severity of the clinical
features. Loss of weight (or failure to gain weight normally), a high sleep-
ing pulse rate and a large gland with a bruit and a thrill arc highly sugges-
tive, while exophthalmos (when present) is almost diagnostic. Special
investigations arc of little help, for thyroid activity is normally increased in
pregnane) - and the BMR, the uptake of iodine by the gland, the PBI and
the BEI are all raised. If radioactive iodine studies are considered essential
1M I, and not 13, I, must be used.

“ Masked ” hyperthyroidism

In a few atypical patients one symptom predominates to the exclusion of
others, while evidence of the underlying thyrotoxicosis is readily over-
looked. The commonest form is cardiac failure or atrial fibrillation, which
proves resistant to treatment, in an elderly subject with nodular goitre.
The thyroid swelling is often small or impalpable because it lies in an un-
usual position. Other occasional manifestations arc an obscure myopathy,
unexplained diarrhoea or dyspeptic symptoms and vomiting.

Thyrotoxicosis in children

The symptoms do not differ from those in adults, except that children do
not complain so often of subjective sv mptoms. Usually the child is brought

DIAGNOSIS or TOXIC GOITRE 261

for advice because the parents have noticed increased nervousness, swelling
in the neck or an increase in appetite. One distinctive feature of juvenile
hyperthyroidism is acceleration of growth and osseous deielopment (fig.
15.4(c)).

Diagnosis of toxic goitre

The diagnosis of toxic goitre is based firmly on the clinical examination,
supplemented where necessary hy suitable investigations, and is confirmed
by the response to treatment.

1. Clinical diagnosis

The experienced clinician finds little difficulty in the diagnosis of the
majority of patients. The main problems arise in the recognition of mild
cases and in the detection of masked hyperthyroidism. The commonest
problem is the differentiation of simple nervous tension and anxiety from
thyrotoxicosis in a patient with a goitre. This may be particularly difficult
in a woman at the time of the menopause. In an anxiety state the tachy-
cardia is often variable, but the sleeping pulse rate is usually normal ; loss of
weight is uncommon and the appetite is not increased. The patient may
have moist palms, but the peripheral circulation is not increased and the
hands are cool. The digital tremor is coarse and irregular in contrast with
the fine tremor of thyrotoxicosis. Careful appraisal is necessary before any
operative procedure is contemplated, and a period of rest and observation,
preferably away from home, is advisable before a decision is reached
Thyroidectomy in the wrong patient gives a poor result, increases the
anxiety and tends to cause chronic invalidism. Laboratory tests, properly
used and interpreted, are of the greatest help in such patients.

The patients with masked hyperthyroidism whom surgeons are most
likely to encounter are those with obscure intestinal symptoms, such as
diarrhoea, dyspepsia and loss of weight, in whom the possibility of intra-
abdominal malignancy has been raised.

Very rarely true hyperthyroidism is caused by ectopic thyroid tissue at
the back of the tongue (lingual thyroid) or in an ovarian teratoma (struma
ovarii).

Other conditions may simulate hyperthyroidism, especially those which
cause a hyperkinetic circulation and increase the basal metabolic rate.
Among these are disorders of the blood, including the leukaemias and
anaemia, extensive Paget’s disease of bone, arterio-venous aneurysm, free
aortic regurgitation, fever with wasting, and phaeochromocytoma.

The pigmented form of thyrotoxicosis may be mistaken for Addison's
disease. Patients with either condition may show wasting, fatigue and
diarrhoea, but the absence of buccal pigmentation, the presence of a goitre

262

THE THYROID GLAND

and the other features of hypermetabolism should distinguish those with
hyperthyroidism.

Thyrotoxicosis jactitia, resulting from the self-administration of cxcesshe
quantities of thyroxine or thyroid extract, may lead to the clinical state of
hyperthyroidism. The drug is usually taken by neurotics or by those who
are trying to lose weight. Clinically eye signs are absent and there is no
goitre (unless one was present before), for the exogenous thyroxine causes
atrophy of the thyroid gland. Biochemical tests reveal an elevated BMR
and protein-bound iodine, but the uptake of radioactive iodine is low or
negligible because of the thyroid atrophy.

2- Laboratory diagnosis

Laboratory investigations (which ha\e been described already) in toxic
goitre usually confirm the clinical diagnosis, but they are also of help in
distinguishing between toxic and non-toxic goitres when there is clinical
doubt. In thyrotoxicosis the BMR, chemical FBI and the uptake and re-
lease of radioactive iodine are increased. The plasma cholesterol level is
rarely helpful, but a low normal level is usually found. Thyroid auto-
antibodies (using the tanned rcd-cell technique) may he detected in the
blood in about 60 per cent of cases, but the precipitin test is usually
negative. Slight anaemia and leucopenia are common. Other changes
include creatinuria with impaired creatine tolerance, a diminished glucose
tolerance and a raised erythrocyte sedimentation rate.

When there is difficult)' in distinguishing between a mild toxic goitre and
a simple goitre (with or w ithout iodine deficiency) the effect of thyroxine or
triiodothyronine suppression of thyroid uptake should be investigated. The
uptake of m l is depressed by the administration of thyroid hormone in
normal subjects and in those with simple goitre (without iodine deficiency),
but not in those with thyrotoxicosis or iodine-deficient goitre. The two
latter m3y be distinguished by the effect of iodine.

3. Radiological diagnosis

X-rays should be taken in all cases. They may reveal a retrosternal
goitre and will delineate any tracheal distortion. A barium swallow' should
be done in the presence of dysphagia, but usually there is no objective
evidence of oesophageal obstruction. X-ray examination of the chest may
reveal changes in the size and shape of the heart.

Course and prognosis

The natural history of the disease is unpredictable. Spontaneous re-
mission may occur, especially in young patients with mild symptoms and a
short history, and perhaps a quarter of these recover without treatment
within a year or two of the onset of the disease. More severe cases rarely

TREATMENT 0T TOXIC GOITRE 263

recover, and the course is prolonged and subject to partial remission and
exacerbations. Before the era of surgery about 10 per cent of patients died
from the effects of hyperthyroidism, especially cardiac failure, wasting or
crisis.

Occasionally in longstanding and untreated cases the disease seems to
subside gradually over a number of months or years and the patient returns
to a euthyroid state eventually. In a few, hypothyroidism follows, possibly
because the intense hyperplasia terminates in exhaustion atrophy. Recent
work suggests that a more likely cause is auto-immune thyroiditis, which
may be severe in about 10 per cent of cases of thyrotoxicosis. This will be
discussed later.

Modem treatment produces a satisfactory remission in the vast majority
of patients. Many, however, although relieved of their symptoms, exhibit
residual signs of disease, such as atria! fibrillation or exophthalmos, and so
Cannot be regarded as completely cured. A few never achieve a satisfactory'
remission and relapse after each spell of treatment.

Treatment

The aim of treatment is to reduce the secretion of the thyroid gland to a
level which supports normal metabolic function, to prevent the onset of
complications and to correct those already present. Specific antithyroid
therapy and non-specific general measures are available. The latter include
limitation of activity for all, and complete mental and physical rest for those
who are seriously ill. Patients who are wasted require extra calories and an
adequate supply of protein, while all benefit from added vitamins, especially
those of the B group. Sedatives are useful for the relief of nervous symp-
toms. Reserpine and guanethidine are also of value and will dimmish
anxiety, nervousness and tachycardia, and will lower the BMR, without
affecting the thyroid overactivity. Reserpine, with its central sedative
effect, is of particular value for those in whom nervous symptoms pre-
dominate. It is given in a dose of 0-5 or 1*0 mg. daily, and in a larger dose
for a thyroid storm. Guanethidine is administered in a single daily dose of
50 to 150 mg. Since these drugs act by diminishing the circulating cate-
cholamines, they should be prescribed only in conjunction with a standard
method of antithyroid treatment. When combined with antithyroid drugs
before surgery they should be discontinued one iveek before the operation
to avoid the anaesthetic hazard which may result from depletion of the
body’s stores of catechol amines.

There arc three specific measures which reduce the secretion of the toxic
gland effectively, named antithyroid drugs, subtotal thyroidectomy and
radioactive iodine. Opinions differ about the indications for each, and no
well-controlled comparisons of the different methods appear to have been
made.

264

TJIE TIIVROID GLAND

Treatment could be arranged more rationally if it was possible to predict
which patients would undergo spontaneous remission without therapy and
which would suffer protracted illness. Unfortunately this is impossible at
present. However, each method has advantages and drawbacks which
limit the range of choice in each patient and which may render one method
imperative.

Antithyroid drugs

Antithyroid drugs are of two main types: (I) those which interfere with
the synthesis of thyroid hormones (methyl thiouracil, propyl thiouracil,
methimazole and carbimazole), and (2) those which inhibit the trapping of
iodide by the thyroid gland (perchlorate). All inhibit thyroid function and
thereby increase the secretion of TSH by the anterior pituitary. As a con-
sequence, the thyroid undergoes hyperplasia and the goitre usually in*
creases in size, sometimes with serious consequences. Overdosage results
in hypothyroidism. Both these disadvantages can be minimized by the
simultaneous administration of thyroxine, which inhibits the production of
TSH and replaces the endogenous secretion of the thyroid.

Several factors determine the response of a patient to an antithyroid
drug. The activity of the drug increases with rising dosage until a critical
point is reached at which thyroid function ceases. This optimum dose is
about the same for most patients. A few, however, require larger doses and
a very few seem to be completely resistant. The amount of hormone stored
within the gland and the rate at which it is being synthesized are also im-
portant. Thus, if a large store is present in a big gland (c.g. as a result of
previous treatment with iodine) a clinical response to treatment may be
delayed for a long time. Conversely, a modest store in a small gland is soon
exhausted and improvement may follow rapidly. In the average case im-
provement is noticeable in 2 to 4 weeks, and eutliyroidism is established in
2 to 4 months.

All the antithyroid drugs are liable to cause toxic reactions, which may be
serious (Table 7.2). The toxicity is usually related to the dosage, and some
drugs are more toxic than others. When used in their optimum doses two
drugs, carbimazole and perchlorate, seem to be leas toxic than the rest and
arc employed frequently. Carbimazole has been used more extensively and
Vs the drug which \xe employ. Tout casta of aplastic anaemia haxe htew
reported recently from the use of perchlorate and, in our opinion, this
hazard prohibits its routine administration. It should Ire reserved for
special circumstances. Perchlorate also has the disadvantage that its action
is inhibited by iodide so that the two remedies cannot be combined (e.g. in
preparation for thyroidectomy). AH medicines which contain iodine in any
form (c.g. cough mixtures) must be withheld during perchlorate therapy.

TREATMENT OF TOXIC GOITRE

265

Table 1.1. Comparison between commonly used antithyroid drugs

[ Maintenance

j Toxic reactions§

I>rug

| (mg./day)

1 dose

| (mg. /day)* |

Major! !
(%) !

MinorJ

(%)

Total

<%)

Methyl thkniracil

1 300- 600

50-200

92

38

13 0

Propyl thiouracij

I ISO- 300

50-150

09

2-2

3 1

Methimazoic

| 15- 40

5- 20

1-4

4-5

59

Cwbimazole

| 30- 60

15- 45

05

1-5

20

Potassium perchlorate

800-1,000

200-400

0 7i*
00<Ji

23

2 o<2

30

2 GCJ

• The smaller maintenance doses should be used in patients who are not receiv ing
regular thyroxine replacement.

f Major toxic reactions ** agranulocytosis, fever, te\ er and arthralgia, and purpura.

j Minor toxic reactions = skin rashes, etc.

§ Tram Burrell el al (1956) Figures obtained from various reported senes in the litera-
ture. They are open to the objection that neither dose let els nor criteria of toxicity
were standardized. They ore to be taken as a guide only.

|( Four cases of aplastic anaemia reported recently .

<3 From Crooks and Wayne (1960). Toxic side-effects seen in 200 patients treated
with perchlorate in a dose of 1,000 mg. daily or Jess.

The antithyroid drugs are used in four main ways:

(1) as the definitive form of treatment;

(2) in preparation for thyroidectomy (see later);

(3) in association with radioactive iodine (see later); and

(4) as a therapeutic test in the diagnosis of obscure cases; this has been

discussed already.

Antithyroid drugs as definitive treatment. Definitive treatment of toxic
goitre with antithyroid drugs is undertaken in the hope that the disease will
have undergone spontaneous remission by the time the therapy is stopped
and that it will not then recur. Remission cannot, of course, be recognized
while the disease is being controlled by an antithyroid drug, and the out-
come of therapy can be assessed only by prolonged observation after the
drug has been withdrawn.

Treatment can usually be undertaken without admission of the patient to
hospital, although those who are seriously ill must be admitted until some
degree of control has been achieved. Continuous specialist supervision for
up to three years is usually necessary, for few family doctors can obtain
sufficient experience in the handling of antithyroid drugs. If, for any
reason, regular attendance at hospital is impracticable this form of treat-
ment should not be used.

Treatment is most effective in patients up to 40 years of age with diffuse
goitres and disease of mild or moderate severity, and least effectives older
patients with nodular glands. Definitive treatment with antithyroid drugs
should not be attempted in those with obstructive features (particularly

266

THE TIIYBOID GLAND

narrowing or displacement of the trachea) or in patients with retrosternal
goitres, for enlargement of the gland may ha\ c serious consequences.

Administration of antithyroid drugs. The drugs which are used most fre-
quently, their initial and maintenance doses and the frequency with which
they cause toxic reactions are summarized in Table 7.2. As we have said,
we prefer carbimazole and use it routinely.

All are given in divided doses by mouth. Methyl and propyl thiouraci!
are taken three times daily, but methimazole and carbimazole, which are
broken down and eliminated more rapidly, are more effective when given
four times daily. In mild cases, however, they may be taken 8-hourly with
satisfactory results. Perchlorate is administered in three or four divided
doses throughout the day, the method depending largely on the total
amount selected and the strengths of the tablets or capsules.

The principle of therapy is to give the drug in a dose which will control
the hyperthyroidism effectively without inducing hypothyroidism or caus-
ing serious toxic effects. Many schemes of therapy have been described,
but that which we prefer and use routinely is as follows. Carbimazole is
given at first in a daily dose of 60 mg. After 2 to 3 weeks, when the patient
begins to notice some improvement, /-thyroxine is given also, in doses of
()•! mg. per day at first and 0-2-0-3 mg. per day after 2 weeks. When the
hyperthyroidism is coming under control, usually in about 6 to 12 weeks,
the dose of carbimazole is reduced to 45 or 30 mg. per day and maintained
at this level until the drug is withdrawn.

If control is not achieved within three months the reason should be
sought. The commonest cause is the failure of the patient to take the drugs
as directed. Some do not take them at all. Previous iodide therapy may
delay the response owing to storage and subsequent slow release of hor-
mones by the gland. Control will, however, be achieved eventually. A few
patients, who are relatively resistant to antithyroid drugs, require up to
twice the usual doses, and these should be given if the other causes have
been eliminated. A very few are completely refractory and 3 per cent of
our patients failed to respond to carbimazole.

The response to treatment is assessed primarily on clinical grounds, the
most useful objective measurements being the body weight and the pulse
rate. Measurement of the BMR may be helpful w hen clinical assessment is
difficult. If signs of hyperthyroidism recur during treatment the dose of
carbimazole must be raised. It is very rare for hypothyroidism to develop
when throxinc is being given. If the gland increases in size rapidly, or if ob-
structive features develop during the course of treatment, antithyroid drugs
must be stopped and another form of treatment employed.

Carbimazole and thyroxine are continued for at least 12 months after the
patient has become euthyroid, that is usually about 18 months after the
start of therapy. The drugs arc then withdrawn gradually over the next

TREATMENT Or TOXIC GOITRE

267

3 months. If thyrotoxic features return full therapy is re instituted for
several months more. Reassessment is made at intervals of 1, 6 and 12
months after treatment has been stopped, by which time two-thirds of
those who are going to relapse will haw done so. Thereafter the super-
vision of the patient can be left in the hands of the family doctor. Those
who relapse after two courses of treatment should usually be treated by
thyroidectomy or radioactive iodine.

Toxic reactions. The toxic effects of the antithyroid drugs are sensitivity
reactions of the delayed type, similar to those caused by sulphonamides.

Fig. 7.11. Arthropathy due to treatment of toxic goitre with carbimazole (45
mg. for 3 weeks). Note clinical similarity to rheumatoid arthritis.

They usually occur within two months of the start of treatment, and are
rare after prolonged therapy (Table 7*2.).

The skin is affected most frequently, and may be the site of maculo-
papular rashes, or occasionally of widespread dermatitis. Other reactions
include fever, headache, arthralgia and swelling of joints, especially those
of the hands (fig. 7.11), lymphadenopathy, nausea and vomiting and, most
serious of all, leukopenia, agranulocytosis and thrombocytopenia. Aplastic
anaemia is exceptional. Hepatocellular jaundice and polyarteritis nodosa
have also been reported. Usually granulocytopenia, thrombocytopenia and
aplastic anaemia are the only reactions for which treatment need be stopped.

Careful watch must be kept for toxic effects, especially during the first
few weeks of treatment, and patients should be reviewed at fortnightly (or
at the most monthly) intervals for the first three months. Should any be

268

THE THYROID GLAND

noticed, a blood count must be done immediately. If the white cells are
below 3,000 per cu. mm. or the platelets below 120,000 per cu. mm. the
antithyroid drug must be stopped. If there is no fall in the white cells or
platelets treatment can usually be continued, for the fever, arthralgia, skin
rashes and other toxic reactions usually diminish or disappear. If the
rash does continue an antihistamine drug or a reduction in the dose of the
antithyroid drug may bring relief. If the rash persists in spite of these
measures the drug must be changed or, preferably, another form of therapy
substituted.

If agranulocytosis (with feier and mouth ulcers) develops the drug must
be stopped and appropriate antibiotic therapy started forthwith. In the
majority the bone marrow recovers quickly and no harm results. Thrombo-
cytopenia may require transfusions of fresh blood to control purpura
until the platelet count returns to normal. Once either of these manifesta-
tions appears, the patient should never be treated with antithyroid drugs
again. Agranulocytosis usually develops with dramatic swiftness, and
routine blood counts give no advance warning of its imminence. Patients
should therefore be warned to report immediately any toxic reactions,
particularly sore throats, and (in the event of the latter) not to take any
further tablets until they have sought medical advice.

Results of definitive treatment. Prolonged remissions have been reported
in about 60 per cent of all patients treated after one course of therapy and in
another 10 per cent after a second course. Further anatysis shows that
about 75 per cent of patients up to the age of 40 years with small diffuse
goitres of mild or moderate severity are relieved of hyperthyroidism by
one course of treatment, while only about 33 per cent of older patients with
nodular glands obtain relief.

The goitre usually increases in size, especially if large initially, when
antithyroid drugs are used alone. When thyroxine is given as well about
one- third of the glands becomefwo//<T during therapy and onlyaboutone in
lQenlarges. The remainder a re unchanged. Sustained remissions are rarely
achieved in those whose goitres enlarge. It must he stressed that a goitre
persists after the completion of treatment in the great majority of patients.

The eye signs are influenced by antithyroid drugs in much the same way
as the goitre. Signs, particularly lid retraction, improve in about 33 per
cent of cases and deteriorate in about 10 per cent. They are unchanged in
the remainder. Progressiv e severe exophthalmos has been reported, but wc
have not observed it. There is little evidence that the administration of
thyroxine has any beneficial effect on the eyes.

Subtotal thyroidectomy

The operation of subtotal thyroidectomy in one stage was developed
after much trial and error, but is now established as a standard surgical

TREATMENT OF TOXIC GOITRE

269

procedure which is safe and highly effective in the hands of those who are
experienced in the pre- and post operative management and skilled in the
surgical technique. The operation usually restores normal thyroid func-
tion and causes remission, but it is difficult to understand how it does so,
for the amount and the functional activity of the remnant must vary con-
siderably from case to case. It is surprising that hyperfunction or hypo-
function does not follow more commonly, as in the case of subtotal
adrenalectomy for Cushing’s syndrome.

Operation is immediately effective in all cases (after suitable prepara-
tion) and controls the hyperthyroidism swiftly and predictably. It is the
only procedure which is guaranteed to remove the goitre, and is therefore
mandatory in those with obstructive features or retrosternal glands. It is
the treatment of choice, at least in younger patients, when definitive
therapy with antithyroid drugs has to be abandoned. The patient can be
told the probable course of e\ents at the outset and can make suitable
arrangements in advance for her admission to hospital for a period which
need rarely exceed three to four weeks. She is able to approach the opera-
tion with the disease well controlled and in a tranquil state of mind.

Preparation for operation

Preliminary medical treatment with antithyroid drugs and iodine, or
with iodine alone, is essential. Antithyroid drugs are of very’ great value,
but should be given only when they are required, because of the dangers of
toxic reactions and of enlargement of the goitre. The patient should be
admitted to hospital several days, at least, before operation, so that it can
he undertaken at the optimal time.

When the thyrotoxicosis is of mild or moderate severity preparation with
iodine alone is nearly always satisfactory. It is easier for the experienced
clinician to recognize patients who are suitable for this form of preparation
than for him to define their characteristics. In general, though, the goitre is
small, the weight loss moderate, the pulse rate less than 100 beats per
minute during sleep or after rest and the BMR not higher than -f~35 per
cent. Iodine is given in the form of Lugol's iodine (5 drops daily in milk) or
potassium iodide (pot, iod. 0-03 G., distilled water 20-0 ml.; 4 to 6 drops
daily in water). Larger doses are not necessary. Treatment may be started
at home or in hospital. Improvement, which is assessed on clinical grounds,
is usually evident in 7 to 10 days and maximal in 2 to 3 weeks. Thereafter
the patient’s condition often deteriorates somewhat. Operation is carried
out as soon as it is judged that the optimal response has been achieved, and
usually when the resting pulse rate has fallen by 10 to 20 beats per minute
and has been steady for 2 to 3 days. Young patients with small, diffuse
goitres are usually ready for operation sooner than older ones with large

270

THE THYROID GLAND

nodular glands. Iodine therapy is given up to the day of operation and
continued for 3 or 4 days afterwards.

In set ere cases the disease must be controlled with antithyroid drugs
before operation. These can usually be given at home in the manner
described already for definitive treatment. The simultaneous administra-
tion of thyroxine minimizes the risk of enlargement of the goitre. Hie
disease should be brought under control as rapidly as possible and the
patient rendered euthyroid or nearly so. Overdosage increases the risks of
operation and must be avoided. Operation on a patient who has been pre-
pared with antithyroid drugs alone is technically difficult and haemorrhagic
because of the effect of the drugs on the gland. For this reason iodine,
which induces the storage of colloid and reduces the friability and vascu-
larity, must be given (in the manner described already) together with the
antithyroid drug (but not with perchlorate) for the last 2 to 3 weeks before
operation. The antithyroid drug is continued until the day of operation
and the iodine for 3 or 4 days afterwards. Control of the disease may be
lost if the antithyroid drug is stopped when the iodine is started. The
action of perchlorate is inhibited by iodine, and it cannot therefore be used
in this way. Some surgeons, however, maintain that its use does not in-
crease the technical difficulties of operation and that iodine is therefore un-
necessary. We have no experience of it.

The operation and its possible complications will be discussed later.
Most patients can leave hospital 7 to 10 days after operation and then make
a rapid convalescence. A few require substitution therapy with /-thyroxine
(0 2 mg. daily) for several months (see later).

Complications of subtotal thyroidectomy

The operatite mortality has fallen, since the introduction of antithyroid
drugs, to under 1 per cent in experienced hands, and in some large scries
has been as low as 0-2 per cent. These low figures arc obtained only by
great care at all stages, and appreciably higher rates (which have not
been published) probably obtain in non-specializcd clinics. Most deaths
occur in elderly patients with cardiac complications, who arc best treated
with radioactive iodine. The mortality varied from about 3 to 12 per cent
when iodine alone was available for preoperative preparation.

A postoperative thyrotoxic crisis was at one time the major cause of
death, but is now very rare. Wc have not seen a case in many hundreds of
thyroidectomies since w e started to use the antithyroid drugs. A crisis may,
however, follow inadequate preparation in severely toxic patients. The
clinical features, which develop within a few hours of operation and are
rapidly progressive, have been described already. The mortality varies
from 25 to 50 percent. The treatment will be described later.

Cardiac arrhythmias, especially atrial fibrillation, may develop after

TREATMENT Or TOXIC GOITRE 271

operation, but are often transient. If they persist qutnidinc therapy should
be instituted after about two weeks.

The other complications, in particular hypoparathyroidism and injur}' to
the recurrent laryngeal nerves, are probably commoner after thyroidectomy
for toxic goitre than after operation for simple goitre. They will be dis-
cussed later.

Effects of thyroidectomy on thyrotoxicosis

Permanent relief of hyperthyroidism is achieved in about 95 per cent of
patients after one operation. The proportion is higher in some series and
lower in others, probably as a result of inadequate removal of thyroid tissue
or of failure to ligate the inferior thyroid arteries In the remainder toxicity
either persists or recurs, sometimes after many years. In these the goitre
usually recurs, either diffusely or in a nodular fashion, and a residual
pyramidal lobe may enlarge. The diagnosis of recurrence should not be
made on clinical grounds alone, for an anxiety state associated with per-
sisting exophthalmos can mimic the condition. Thyroid function must be
investigated fully. A second operation should not be undertaken lightly, for
the chance of permanent cure falls to about 50 per cent and the risk of
complications rises appreciably. In these circumstances radioactive iodine
is usually the best form of treatment, although antithyroid drugs may be
preferable in young patients. Surgery should he reserved for large recur-
rent goitres with obstructive features, and should then be undertaken only
if both recurrent laryngeal nerves are intact.

Hypothyroidism may follow operation (fig. 7.12), and the incidence may
be as high as 20 to 25 per cent of cases. In most, however, normal function
returns after some months and hypothyroidism persists in only about
5 per cent. After a second operation the incidence increases to about
10 per cent. Clinical features are seen most frequently 2 to 3 months after
operation and rarely sooner. When apparent, they should be treated with
thyroxine (/-thyroxine 0-2 mg. daily). Hypothyroidism is most common in
patients with large glands but only slight hyperthyroidism, m those with
concomitant auto-immune thyroiditis, in cases where the surgeon is obliged
(for technical reasons) to remove unusually large amounts of thyroid tissue
and in those with solitary' toxic adenomas. In such cases thyroxine should
be given prophylactically after operation. It is impossible to predict which
patients will require permanent treatment with thyroxine, and therapy
should be withdrawn slowly after 4 to 6 months. The clinical features and
thyroid function are then assessed and treatment is either stopped com-
pletely or reinstituted as a permanent measure in whatever dose is found
to be necessary (0T to 0-3 mg. daily).

The appearance of the eyes nearly always improves after operation, but
in a few (perhaps 5 per cent) it deteriorates. Improvement is due mainly to

272

THE THYROID GLAND

diminution or complete disappearance of lid retraction. The exophthalmos
usually remains unchanged, but is less noticeable because of the improve-
ment in lid retraction. If the degree of proptosis does change it is more
likely to increase than to decrease. If the ocular changes are severe initially
(extreme exophthalmos, chemosis and ophthalmoplegia) operation may

Tjg 7.12, Hypothyroidism (myx oedema) following thyroidectomy for toxic goitre-
Ltd retraction and exophthalmos have persisted.

cause acute exacerbation, especially in men, and surgery should be avoided
if possible. Ophthalmoplegia without other serious signs is usually un-
affected. Rarely eye signs develop for the first time after thyroidectomy,
and may then be accompanied by pretibial myvoedema.

Radioactive iodine therapy

The avidity of the hyperplastic thyroid gland for iodine provides a
method, first introduced in 1D42 by Hamilton and Law rence and by Hertz
and Roberts, whereby a large dose of radiation can he delivered selec-
tively to the secretory cells. An effective therapeutic dose of l5 'I, much
larger than the tracer doses used for diagnostic purposes, can be given
simply and safely by mouth with no inconvenience to the p3ticnt. As the
isotope disintegrates within the gland it emits mainly ^-particles, which
destroy the acinar cells to an extent which depends on the dose of radiation
which they receive. The ^-particles penetrate the other tissues for a dis-

TREATMENT OF TOXIC GOITRE

273

tance of a few millimetres only, and consequently do not harm adjacent
structures, such as the parathyroid glands, the recurrent laryngeal nerves
and the cartilage of the larynx and trachea. About 10 per cent only of the
radiation takes the form of y-rays, which penetrate farther but whose dose
is too small to cause damage.

Many thousands of patients have been treated with radioactive iodine,
and facilities for its use are now available generally. If its complete safety
could be assured it would be employed much more commonly. There are
three possible dangers. (1) There is a risk that irradiation might cause
carcinoma to develop in the thyroid after a latent period of about 20 years.
No case has yet been reported in which the radioactive iodine could be in-
criminated, but there is good evidence that external irradiation of the neck
in childhood may cause thyroid cancer to develop later. (2) Despite the
rapid concentration of the iodine in the thyroid, there is a danger that
leukaemia may be induced. The incidence of this disease in patients with
carcinoma of the thyroid, who have been treated with radioactive iodine, is
considerably higher than that in the general population, but the incidence
in those with thyrotoxicosis, treated by this method, does not seem to be
increased. (3) Harmful mutations may be caused by damage to the germ
cells in the gonads, but the risk is probably small. These considerations,
however, have led most workers to restrict the use of radioactive iodine to
patients over the age of 45 years and to younger ones whose expectation of
life does not (because of some complicating disease) exceed 20 years. It is
not used in pregnant women. It is possible that before long this age limit
may be reduced with safety.

Radioactive iodine, then, is of value in alt older patients without serious
obstructive features. Minor degrees of obstruction may be relieved by
therapy. It provides a safe alternative to thyroidectomy in those for whom
operation might be hazardous (e.g. patients with cardiac complications, the
aged and the infirm) or who refuse surgery, and it is the treatment of choice
for most older patients with recurrent thyrotoxicosis after thyroidectomy.

Administration of radioactive iodine

Treatment is usually undertaken by a radiotherapist. Its object is to
relieve the thyrotoxicosis as rapidly as possible and to restore normal
thyroid function. Calculation of the effective dose is not easy. Inadequate
irradiation fails to control the disease, but can be followed by a further dose
of isotope. Over-irradiation destroys too much tissue and causes hypo-
thyroidism. Most therapists aim to deliver a dose of 6,000 to 8,000 rads to
the gland. Larger doses may be needed for patients with severe hyperthy-
roidism or nodular glands and smaller ones for those with small diffuse
glands or recurrent toxic goitres. The dosage in terms of millicuries may
be calculated in several ways. We administer 150 microcuries (/re.) per

274

THE THYROID GLAND

estimated gramme of thyroid tissue. Thus, a patient with a toxic goitre
would be treated in the following manner:

Tracer dose of “‘I = 75% uptake in thyroid at 48 hours

Estimated n eight of thyroid by palpation => 45 j».

Therapeutic dose of m l *=» = 9,000 pc or 9 0 me.

Preliminary control of hyperthyroidism with antithyroid drugs for a few
weeks may be required in very severe cases. The drug must be withdrawn
3 to 7 days before the tracer and therapeutic doses of J3, l arc given, and
need rarely be restarted. An alternative plan for those who are seriously ill
is to give the radioactive iodine at once, and to follow it with an antithyroid
drug until the disease shows signs of remission.

The isotope is administered in a glass of water, and it is not essential for
the patient to be admitted to hospital. There are not usually any im-
mediate side-effects, but sometimes slight swelling of the gland and local
pain may occur about 10 days later. Transient exacerbation of the hyper-
thyroidism is seen rarely and thyrotoxic crisis has been reported.

After treatment the patient is seen at monthly intervals for at least a year
and until the final response is determined. Clinical assessment (including
regular weighing) and chemical measurement of the PBl provide the best
evidence of progress. Signs of impro\ement are usually obvious in 6 to S
weeks, and remission is generally complete in 3 to 6 months. If a full re-
mission is not obtained within this period, and if improvement has ceased,
a second dose of radioactive iodine may be necessary, but it should be given
only after prolonged and careful observation. Occasionally a third dose
(or even more) may be needed. Observation must be continued for 6 to
12 months after cuthyroidism has been achieved, so that any hypo-
thyroidism or recurrence of hyperthyroidism may be detected. The former
often develops temporarily 3 to (i months after treatment, and should not
be treated with thyroxine until it is clear that it is permanent. The latter is
uncommon, but requires further treatment with radioactive iodine.

Result! of radioactive iodine therapy

About 60 per cent of patients become euthyroid after a single dose of
M, I, while 25 per cent require two or more doses. Permanent hypothy-
roidism develops in up to 30 per cent of patients. It is usually apparent
within a year, but may not appear until much later. It is commonest in
patients with small glands and in those who have previously undergone
thyroidectomy. Permanent replacement therapy (/-thyroxine, 0-1 to 0 - 3
mg. per day) is necessary.

The goitre usually shrinks, and minor degrees of tracheal compression or
deviation may be corrected.

The eye signs arc affected much 3s they are by thyroidectomy, except
that there is less tendency for malignant exophthalmos to be aggravated.

TREATMENT OT TOXIC GOITRE

Belfast series. Our own experience in the first 50 patients treated with
radioactive iodine in our clinic has been analysed by Rastogi (1962). The
dose range was 4 to 15 me. and the follow-up period ranged from 9 to 21
months. The results were as follows :

Euthyroid 40 (SG%)

Single treatment 35 (70%)

Two treatments 5 (10» o )

Hypothyroid and on permanent replacement treatment (all re-
ceived single dose) 6 (12%)

StiH toxic and awaiting further treatment 3 (6%)

Died from unrelated cause (thyroid status uncertain before death I i (2% )

Choice of treatment

Effective treatment can nearly always be provided by one of the three
methods which we have described. The adv antages and disadvantages of
each are summarized and compared in the following table:

Subtotal thyroidectomy Radioactive iodine

Less than 1% I Nil

Few weeks

j 5-6 months

95% after first opera- 95% or better after
tion (50% after one or more treat-
second operation) ments

Goitre

Remains and may enlarge.

1 Regression may aecom- ,
pany remission

Removed (scar mtrtins)

Hypo-

thyroidism

i Occasional but temporary

1 only, reverting when
j drug therapy is reduced

5% after first operation
(10% after second
operation)

I Usually improved

Not visually necessary

Usually improved.
Rarely aggravated
seriously

j Severe for 1-2 day*

2-3% with carbimazole
or perchlorate

Only if patient receives
antithyroid drug also j

276

THE THYROID GLAND

These facts must always be considered in relation to the age and clinical
state of the patient and the special features of the goitre. Our general policy
may be summarized as follows:

Type of goitre ami clinical features

Treatment recommended

I Diffuse goitre

1 Under 45% ears

(a) Small gland and mild or moderate
toxicity

(4) Large gland and moderate or sc % ere
toxicity

2 Cher 45 years'

Antithyroid drugs

Subtotal thyroidectomy

Radioactive iodine

1 1 Modular goitre

1 Under 45 years

2. Over 45 years

(а) Small gland without obstruction

(б) Large gland with obstruction

Subtotal thyroidcctomv

Radioactive iodine

Subtotal th) roidectnmv

1 1 1 Recurrent lh} roto xicout

\ After antithyroid drugs
(a) Under 45 years
(ft) Cher 45 years

2. After operation

(a) Under 45 seats
(ft) (her 45 vents

(e) Large obstructive goitre at anv age

3 After radioactive iodine

Subtotal thyroidectomy

Radioactive iodine

Antithyroid drugs

Radioactive iodine

Subtotal thyroidectomy

Radioactive iodine

IV. Special circumstances

1. Childhood

2. Pregnancy

3 Infirmity (heart failure, old age, inter-
cun-ent disease, etc.)

4. Hyperophthalmopathic Graves’ disease

5. Solitary toxic adenoma

6. Thy roloxic crisis

Antithyroid drugs

Antithyroid drugs or subtotal
thyroidectomy

Radioactive iodine

Antithyroid drugs until eyes sta-
bilized and special measures
Partial thyroidectomy

Special measures

There are clearly many patients in whom the choice of treatment is not
easy. Difficulties arise, for instance, when the gland is of moderate size or
causing minimal compression and when the patient is approaching the age
of 45 years. In such circumstances especially weight must be given to the
patient’s emotional makeup and responsibilities. Surgery', for instance,
should be a\ Didcd in those w ho are averse to it and cannot readily spare the
time to enter hospital, or in those, such as actors and barristers, whose live-
lihoods depend on their voices. On the other hand, thyroidectomy should
be preferred for those who travel much or who live in Temote parts and
cannot visit hospital regularly, and for those who favour swift and decisive
action.

It must be emphasized that the quality of thyroid surgery is very variable
and that, unless he is a good thy roidectomist, the surgeon should not advise

TREATMENT OF TOXIC GOITRE

277

operation if another satisfactory method of treatment is available. The best
results are obtained by physicians and surgeons, with a common interest in
thyroid disease, collaborating in the choice of treatment and in all stages of
its execution.

The special circumstances mentioned in the table require further dis-
cussion.

(1) Childhood. Children should be treated by medical measures in pre-
ference to surgery, for the influence of subtotal thyroidectomy is less pre-
dictable than it is in adults. Antithyroid drugs and thyroxine should be
given continuously for 12 to 18 months in the following doses:

Age Proportion of adult dose

- 5 years J-J

6-10 years i-f

11-15 years f-1

The optimal dose for each child must be found by trial and error. Opera-
tion should be reserved for those who show progressive thyroid enlarge-
ment during treatment, who fail to co-operate, who relapse after several
courses of therapy extending over not less than two to three years, or who
develop toxic reactions to the drugs. Radioactive iodine is never used
therapeutically.

(2) Pregnancy. Treatment of thyrotoxicosis during pregnancy needs
special care because both the disease (see earlier) and the treatment carry'
special risks. The choice of treatment between antithyroid drugs and
thyroidectomy may be made on several grounds and need not be influenced
by the pregnancy. Radioactive iodine must not, of course, be used. Iodine
and antithyroid drugs pass through the placenta and, if given in excess,
may result in abortion or cause hypothyroidism and a goitre in the foetus.
For these reasons they must be given with care and should always be com-
bined with thyroxine. The control of the disease should be assessed on
clinical features rather than on laboratory tests, all of which may be in the
thyrotoxic range in normal pregnancy. If good control is obtained with
antithyroid drugs in the first half of pregnancy the dosage can usually be
reduced with safety in the second half. Antithyroid drugs are excreted in
milk, so that babies born to mothers who are receiving them must not be
breast fed. If surgical treatment is indicated for any reason, and good
facilities are available, pregnancy should not be regarded as a contra-
indication. Some, indeed, advocate it in preference to antithyroid drugs.
If thyroidectomy is postponed until after the 12th week, the risk of abortion
is small and may be minimized by the use of thyroxine replacement therapy
until after delivery.

(3) Infirmity. Severe physical disability in thyrotoxicosis may be caused or
aggravated by the disease (e.g. cardiac failure or neuromuscular disorders)

278

THE THYROID GLAXO

or be independent of it (e.g. old age or intercurrent disease). Physical in-
firmity increases the risks of operation more than those of other methods of
treatment, so that thyroidectomy should be avoided. Radioactive iodine,
combined with antithyroid drugs if the toxicity is severe, prov ides the best
method of treatment. In a few, permanent treatment with an antithyroid
drug is satisfactory.

(4) Hyperophthalmopathic Grates' disease. Simple exophthalmos does
not require any treatment other than that of the hyperthyroidism. Lid re-
traction nearly always diminishes and often disappears after any form of
treatment, while the exophthalmos tends to remain.

Hyperophthalmopathic Graves’ disease requires very special care and
the co-operation of an ophthalmic surgeon and a neurological surgeon.
The earliest features — chemosis, oedema of the lids and diplopia— must
always be excluded before exophthalmic goitre is treated, for sudden re-
duction of thyroid function by thyroidectomy may c3use severe aggravation
of the condition. In these circumstances it is best to use antithyroid drugs,
whose effects are reversible, until the state of the eyes has become stabilized.

Management must include regular exophthalmometry, measurement of
visual acuity and ophthalmoscopy in order that progress may be assessed
objectively. The patient must be reassured about the alarming changes in
the eyes but must also be made to understand that extreme care is necessary.

Hormonal therapy with testosterone, stilboestrol or cortisone has been
used at various times, with the object of depressing pituitary function, hut
without obvious benefit. Thyroxine (/-thyroxine, 0-3 to 0-6 mg. per day)
is usually used for the same purpose once the hyperthyroidism has been
controlled. Its effect on the pituitary' is questionable, but its regular use is
valuable in the prevention of hypothyroidism.

Treatment is designed primarily to protect the cornea and to presen c
vision. Simple measures include the use of dark glasses with side flaps by
day and of padded eyeshields by night. The eyes should be kept moist by
the application of mineral oil or a solution of methyl cellulose (0-5 per cent
in physiological saline). Chemosis may he reduced by the local injection of
hyaluronidasc (04 ml. of a I per cent solution of procaine IIC1, containing
1,000 Bengcr units of hyalase) under local anaesthesia (2 per cent ametho-
caine HC1) two or three times a week. Diuretics may be helpful.

If the condition continues to deteriorate surgical measures must he used
in good time. They are rarely needed, but they should not he postponed
until the cornea has become ulcerated. The simplest procedure is lateral
tarsorrhaphy, and this is often effective alone. It may be aided, if neces-
sary’, by decompression of the orbit by fasciotomy, division of the lateral
canthal ligament and excision of the herniating orbital fat. A tarsorrhaphy
may be undone quite simply if and when it is no longer required.

If these procedures arc impossible (because of the severity of the prop-

TREATMENT Of TOXIC GOITRE 279

tosis) or ineffective in protecting the cornea, or if papilloedema increases,
the orbit must be decompressed by the Naffziger procedure, or a modifica-
tion of it, in which the bony roof and lateral wall of the orbit are removed
at craniotomy. This relieves the pressure and usually reduces the ex-
ophthalmos. If tarsorrhaphy was impossible before, because of the degree
of proptosis, the eye can be pushed back sufficiently after the decompression
to allow the lids to be approximated. For some unknown reason decom-
pression of one orbit sometimes causes improvement m both.

The other measures, which may be used as alternate es to decompression,
are irradiation of the orbital tissues and destruction of the pituitary' by
X-rays or by surgical hypophysectomy. Irradiation of the orbits is effective
in some cases and may be worthwhile, but valuable time may be lost if it
does not cause improvement. It is rational to destroy the pituitary because
it is the probable source of EPS. External irradiation is disappointing,
although it has been argued that the beneficial effects of X-rays directed at
the orbits result from the inadvertent inclusion of the pituitary in the field.
Hypophysectomy and section of the pituitary stalk are drastic procedures,
but are said to be very effective. They have not yet been assessed ade-
quately.

Diplopia and ophthalmoplegia may respond to treatment with neo-
stigmine at any early stage, but become resistant later. Surgical correction
of squint may be possible and desirable after some years when the eyes are
well stabilized.

Hyperophthalmopathic Graves’ disease usually stops advancing after
some months and may undergo spontaneous regression at any stage. Pro-
vided effective treatment is given in time, the eyes and the vision can
usually be preserved.

(5) Toxic adenoma. A single toxic adenoma is a rare cause of thyro-
toxicosis, but, like other solitary nodules in the thyroid, it may be the seat
of a carcinoma. For this reason it should be excised. Operation involves
removal of the nodule together with most of the lobe in which it lies. Since
the remainder of the gland is usually hypoplastic, partial replacement
therapy (/-thyroxine, 0-2 mg. per day) may be necessary' until it recovers its
function.

(6) Thyrotoxic crisis. Treatment must be immediate and energetic. Its
chief aims are to reduce the metabolic rate, to lower the temperature, to
correct the fluid and electrolytic disturbances, and to prevent hypoxia.

Iodine should be given at once, by mouth if possible (Lugol’s iodine in
milk, 60 minims Followed by 30 minims 6-hourly for 24 to 48 hours) or
intravenously (sodium iodide, 0-5 G. in 2 ml. of distilled water 12-hourly).
This may cause great improvement in those who have not had iodine pre-
viously. Antithyroid drugs should also be started, although their action is
slow (carbimazole, 80 to 100 mg., followed by 20 mg. 6-hourly until the

280 THE THYROID GLAND

crisis is under control). Reserpine and guanethidinc may he helpful in
reducing the severity of the thyrotoxic symptoms.

Restlessness and delirium, which involve the useless expenditure of
energy, must he combated by sedation with morphia, barbiturates or
paraldehyde intramuscularly or by thiopentone intravenously.

Hyperpyrexia is treated by ice-packs, tepid sponging and fans or, in
addition, by controlled hypothermia with pethidine, promethazine and
chlorpromazine. Loss of fluid and electrolytes by sweating, and occasion-
ally by vomiting and diarrhoea, must he corrected quantitatively by mouth,
if possible, or by intravenous infusion. Plenty of glucose should be given at
the same time. An oxygen tent is usually preferable to a mask for the pre-
vention of hypoxia.

If these measures do not bring the crisis under control within a fen-
hours, and especially if there are signs of peripheral circulatory failure,
adrenocortical steroids (cortisol hemisuccinatc and cortisone acetate) should
be given as in the treatment of an adrenal crisis. Any infection must be
treated by appropriate antibiotics.

HYPOTHYROIDISM

Hypothyroidism is of importance to the surgeon because it is often
associated with goitre and may follow surgical thyroidectomy. It must he
recognized at an early stage in its development, because prolonged ill-
health can be avoided by effective treatment. Some forms of hypothyroid
goitre diminish or disappear under thyroxine therapy and do not require
thyroidectomy.

The association between cretinism and goitre has been known since
Roman times. In 1874 Gull described the adult form of hypothyroidism,
and in 1891 thyroid extract was introduced for its treatment.

“ Hypothyroidism " means deficiency or absence of thyroid hormone. The
term "myxoedema" should he reserved for patients with hypothyroidism in
whom there are obvious myxoedematous deposits in the tissues. Thyroid
deficiency' due to disease or destruction of the thyroid gland itself is called
"primary hypothyroidism", w hile that due to failure of the anterior pituitary
is known as "secondary” or “ pituitary hypothyroidism

The lesions of the thyroid which arc associated with depressed function
have been described already. It is clear that the size of the gland may vary
enormously from case to case, depending on the cause of the hypothy-
roidism. At one extreme it may be completely absent, w hile at the other it
may form an enormous goitre.

The common causes and the clinical manifestations of hypothyroidism
differ at different ages, and the disease may be considered conveniently at

CRETINISM 2S1

three distinct periods, namely; (1) during foetal and neonatal develop-
ment; (2) in childhood and adolescence; and (3) in adult life.

Congenital hypothyroidism (cretinism)

The lesions and aetiological factors which may cause hypothyroidism
during foetal and neonatal development may be classified as follows:

1. Aplasia or hypoplasia — defective thyroid development.

2. Hyperplasia or atrophy (if the hyperplastic process fails) —

(a) lack of iodine (endemic cretinism);

(b) inborn enzymatic defects in synthesis of thyroxine;

(c) maternal factors (ingestion of antithyroid substances during

pregnancy or lactation).

Endemic cretinism occurs in areas where iodine deficiency is severe and
endemic goitre is common. Thyroid function probably deteriorates pro-
gressively through successive generations until a cretin is bom. The
mother is usually, but not always, goitrous, and some cretins have goitres
also. The incidence of endemic cretinism has declined in areas where
iodized salt has been introduced. Other factors, such as those responsible
for sporadic cretinism, may be involved also, and genetic influences,
aggravated by dose intermarriage, may be important.

Sporadic cretinism occurs in areas where iodine is not deficient and may
be caused by thyroid aplasia or by the transmission of antithyroid sub-
stances from the mother. Aplasia of the thyroid (athyreotic cretinism) may
sometimes result from the placental transmission of maternal thyroid auto-
antibodies or cytotoxic agents. The features of hypothyroidism develop
early and in a severe form. Hypoplastic glands may sustain adequate
thyroid function for a time so that the infant escapes cretinism but develops
juvenile hypothyroidism later. Iodides and antithyroid substances from
the mother (taken therapeutically or ingested in food) may be transmitted
across the placenta or in the milk and cause congenital goitre with or with-
out hypothyroidism. The effects are reversible and often disappear
spontaneously.

Sporadic goitrous cretinism is caused by an inherited defect in the syn-
thesis of thyroid hormones. The gland undergoes compensatory hyper-
plasia and forms a goitre, which may be present at birth but usually appears
in infancy or childhood. Goitres of this type were sometimes treated, by
partial thyroidectomy and showed a great tendency to recur. Clinical
hypothyroidism is not inevitable, but if severe it may be present at birth.
In some cases (Pendred’s syndrome) congenital deafness accompanies the
goitre. Five distinct biochemical abnormalities in the synthesis of thyroid
hormones have been recognized, any one of which may be present (Table
7.3. and fig. 7.2).

282

THE THYROID GLAND

Table 7.3. Inborn errors of thyroid hormone synthesis resulting in
goitrous cretinism

1 failure of iodide trapping mechanism (? enzyme)

2 Failure of organic binding of iodine (? lack of peroxidase)

3 Failure of coupling of diiodotyrosme to form tmodoth) ranine and thj roxlne (f lade of
coupling enzj me)

4 Failure of deiodtnatton of lodothyromnea l? lack of dciodinasc)

5. Presence of abnormal lodmated polypeptide in serum (? enzyme)

Clinical features

Congenital hypothyroidism varies in severity and three classes of cre-
tinism are recognized. 1. Cretins have vegetative faculties only. They
have no intellectual or reproductive capacity and cannot speak, 2. Semi -
cretins have vegetative and reproductive faculties and are capable of rudi-
mentary' speech, but their intellectual powers are very limited. 3. Cretinous
persons are capable, in addition, of limited conversation by word and ges-
ture. They are intellectually subnormal, but can pursue some unskilled
manual occupations.

Endemic and athyreotic cretins usually show clear evidence of hypo-
thyroidism at birth and their brains may be so seriously afflicted during
development that they are incapable of normal intellectual function, even if
treated at once. Sporadic goitrous cretins, on the other hand, may be
apparently norma! at birth and develop signs of hypothyroidism only after
some months. If treated adequately, they are capable of normal develop-
ment.

The clinical appearance of the typical cretin is striking and well known.
The bridge of the nose is broad, the nostrils arc wide and flared and the
thick tongue protrudes through the open mouth. The muscles are poorly
developed and flabby, the lumbar spine lordotic and the abdomen pro-
tuberant. Umbilical and other types of hernia are common. The skin is
dry, scaling and of a yellowish tinge, and in severe cases myxoedematous
deposits occur in the skin and subcutaneous tissues, especially above the
clavicles. The hair is coarse and scanty, dentition is delayed and the
peripheral circulation is poor.

Defects of growth and general development may not be apparent for the
first few months of life, but thereafter cretins lag behind normal children in
linear growth (dwarfism) and in behaviour. They arc unusually slow in
passing the usual milestones of development. The epiphyses fail to develop
normally and show stippling on X-rays (epiphyseal dysgenesis, fig. 7.13).
Sexual development is retarded or fails completely, depending on ihe
severity of the hypothyroidism.

The prognosis for untreated cretins is variable. Some die of mtercurrent
infections, while others remain in reasonable health, being cared for at

7.13. X-rays of pelvis and ^^J^trcTeVnou^pcrson aged 66 years
treated cretin aged 4 years, W

28+

THE THYROID GLAND

home or in institutions for the mentally defective. Recently we observed
myxoedema coma in an untreated cretinous person aged 66 years (fig. 7,14).

Fig. 7.14. Previously untreated cretinous person aged 66 years, after recovery
from hypothyroid coma.

Diagnosis

The diagnosis of established cretinism is not difficult, but by then
effective treatment may be impossible. It is therefore important to re-
cognize the condition early. Cretinism should be considered in any infant
who has a relevant family history or a goitre, or who is deaf. It should be
suspected in a baby who is unduly lethargic, constipated or slow' to feed and
gain weight, or who has a poor peripheral circulation.

Cretinism is most likely to be confused with Langdon-Down’ssjndmmc
(mongolism), achondroplasia, hypertelorism, osteochondrodystrophy and
other forms of dwarfism (Chapter IS).

laboratory tests in infancy and childhood are usually confined to the
estimation of the pLisma 1’IJI and cholesterol levels. The PHI is usually less
than 2-0 ft g. per 100 ml. in athyrcotic cretins and between 2 0 and 3*5 /ig.

CRETINISM

ier 100 ml. in those with less “^^‘y^bm'thlterfL a level in

::«’l7lof:;;'Voo:iis a ,u ^ ,hyro,d

unction. . unnecessary for the recognition of

Radioactive iodine tests (with I) . M bettveen the athyreotic

hypothyroidism, but are usefu . d impairment of hormone

sSe, °u ^ °ne band, undendemm^CTetnustn an ^ telen ap

available for the recognition of ^““'ms'Cvith sporadic goitrous

valuable for the control of treatment of patients

cretinism. . . ■ : n f 3n ts and is unreliable in young

The BMR cannot be determine f show changes simitar to

children. The ECG may be of some help an ^ <how delayed

those of adult myxoedema (see later). . } ^ they have started to

development of the ossification ce 3. This ^ most marked

ossify) the signs of epiphyseal dysgenesis (fig. 7.13).
in the femoral and humeral heads.

Treatment the euthyroid state by

The object of treatment is to e5 ‘ abl ‘ s sl)0uW be started as early as
replacement therapy. In infants treat fi . may be prevented. The
possible in order that permanent menu ^ ^ resp0 nse of the

dosage of thyroxine depends on the g ^ of |_ thyr0 xine sodium (in

child. The initial and usual maintenance
mg. per day) arc as follows:

Age (years)
0- 1
1- 3
3-10

Initial dose
0 0125
0 025
0 05

Maintenance dose

0 05-0 l

01 -02
02 -03

1 _r infants for instance.

The Increases must be made g radu! ^ d J„' de a , intervals of two to three
an increase of 0 0125 mg. per day should be ma

weeks. . _r t h e excretion of water an t c

The weight usually falls at first berau Th=rt;after development pro-
disappearance of myxoedematous 1 / d b con tinulng loss of weig .

cecds normally. Overdosage is characterae y ^ ^ of course> be con-

irritability, tachycardia and diarrhoea the dosage must be

tinued throughout life and, as the child grows p.

increased to adult levels. , vn thesis of hormones without

Goitrous cretins and those with <Mec > o|d hormones for life-
clinical hypothyroidism require trea m . inhibited and the goitre

Under their influence the secretion of ™ Undertaken, is likely to be
shrinks. Thyroidectomy is unnecessary and,

THE THYROID GLAND

2S6

followed by recurrence. The best guide to dosage in euthyroid patients is
the uptake of 13S I by the thyroid. The uptake is measured before treatment
is started and one month after the dose of thyroxine has reached 0*1 mg.
daily. If iodine is still concentrated in the gland the dose is increased in
steps (of 0-1 mg. per month) until the uptake is inhibited. The test must be
repeated and the dose increased periodically as the child grows up.

Cretins who are treated early and adequately have excellent prospects of
normal physical and sexual development. If replacement therapy is de-
layed until middle childhood or later there may be permanent dwarfism.
Mental development is much less certain, and its extent depends largely on
the stage of foetal or post-natal life at which thyroid insufficiency occurs and
on the speed with which treatment is instituted. Development is most
likely to be adequate when treatment is started at birth, or, at the latest,
within the first 6 months of life. However, individual patients vary greatly,
and the possible benefits of treatment should not be denied to those in
whom the diagnosis is made at a later date. Full replacement therapy may
cause irritability and lead to difficulties in management of those who remain
mentally deficient. In such cases it is best to reduce the dose to a level
which allows reasonable somatic development without undue stimulation.

Juvenile hypothyroidism

The lesions and actiological factors which may cause hypothyroidism
during childhood and adolescence may be classified as follows:

1. Atrophy-

fa) Idiopathic in previously (?) normal thyroid;

( b ) Hypopituitarism.

2. Surgical removal (excessive) of thyroid tissue for hyperthyroidism

or lingual thyroid.

3. Inflammation — auto-immunc thyroiditis (rare in childhood).

4. Hyperplasia — due to inborn errors of thyroid hormone synthesis

(of mild degree) becoming apparent in childhood.

Acquired juvenile hypothyroidism is rare, the commonest causes being
idiopathic thyroid atrophy and hypopituitarism. Untreated cretinism may,
of course, persist. The clinical features depend on the age at which it
occurs. Within the first year of life it is barely distinguishable from cre-
tinism, except that the mental impairment is less severe and is more likely
to respond fully to treatment. In later childhood and early adolescence the
condition resembles adult myxoedema, except that sexual development and
skeletal growth are defective (fig. 15.4). Delay in ossification and dysgenesis
of the epiphyses are widespread, painless and common.

ADULT HYPOTHYROIDISM

287

The distinction between primary and secondary hypothyroidism de-
pends on the presence or absence of other signs of pituitary disease and, jf
necessary, on the uptake of 132 I by the thyroid.

The condition must be distinguished from other types of dwarfism, in
which epiphyseal dysgenesis does not occur. The X-ray appearances of the
epiphyses may be mistaken for those of osteochondritis deformans (e.g,
Perthe's disease), but in this condition it is unusual for more than one joint
to be affected and the lesions are painful.

Treatment depends on the child’s age and is similar to that of cretinism
or of adult hypothyroidism.

Adult hypothyroidism

The lesions and aetiologica! factors which cause hypothyroidism in the
adult may be classified as follow's:

(а) Inflammation —

(i) auto-immune thyroiditis (Hashimoto’s disease, primary

adult hypothyroidism or myxoedema);

(ii) subacute viral thyroiditis (temporary only);

(hi) chronic (Riedel’s thyroiditis, etc.).

(б) Surgical removal (excessive) for goitre, etc.

(c) Destruction (radioactive iodine, etc.)

(d) Atrophy —

(i) hypopituitarism (secondary hypothyroidism);

(ii) idiopathic;

(iii) (?) exhaustion in longstanding toxic goitre.

(e) Hyperplasia, resulting from ingestion of goitrogens or antithyroid

drugs.

Auto-immune thyroiditis is the commonest cause of hypothyroidism de-
veloping for the first time in the adult. It accounts for the thyroid atrophy
which is associated with many cases of primary adult hypothyroidism or
myxoedema. The term "idiopathic hypothyroidism” must still be re-
tained for patients in whom thyroid auto-antibodies cannot be detected.
Auto-immunity is also the cause of hypothyroidism in Hashimoto’s
disease and may well be responsible for that which sometimes supervenes
in toxic goitre or which occasionally follows subtotal thyroidectomy for
this disease.

Destruction of the thyroid with radioactive iodine or inhibition by over-
treatment with antithyroid drugs are increasingly common causes of hypo-
thyroidism. Any of the antithyroid drugs which may cause goitre (e.g.
paraminosalicylic acid and iodides) may also give rise to hypothyroidism.

288

THE THYROID GLAND

Secondary hypothyroidism, due to pituitary insufficiency, is not uo»
common. Thyroid failure is rarely’ as severe as in primary hypothyroidism
and is accompanied by other signs of hypopituitarism.

Pathology

The pathological findings in the thyroid are very variable and depend on
the cause of the disorder. The shin shows characteristic changes. The
sweat glands and sebaceous glands atrophy’, and the corium and sub-
cutaneous tissues become infiltrated with myxoedematous tissue which, on
section, stains like mucin and is probably a muco-protcin containing
hyaluronic acid. The heart may be dilated and the myocardium thickened
as a result of myxoedematous infiltration. Sometimes a pericardial effusion
is found without underlying pericarditis. Advanced coronary athero-
sclerosis is common, probably as a result of hypercholesterolaemia, and
sometimes there is evidence of previous myocardial infarction. The
pituitary may be slightly enlarged and the basophil (£) cells may be
vacuolated.

Clinical features

Hypothyroidism, like all thyroid diseases, is commoner in women than in
men. It develops usually between the ages of 40 and 50 years, that is at
about the time of the female climacteric. However, no age is exempt and
the condition is not uncommon in the elderly.

The clinical picture of hypothyroidism is the antithesis of that of thyro-
toxicosis and the features of the advanced disease are unmistakable. The
onset is often so insidious that the patient is only vaguely aware that any-
thing is amiss, and mental apathy leaves her indifferent to her physical
discomfort and appearance. Symptoms develop more rapidly after thy-
roidectomy or during treatment with antithyroid drugs, and the patient is
usually more conscious of them. Early complaints include tiredness, cold-
ness, drowsiness, aching in the limbs, loss of hair, defective memory, in-
ability to concentrate, deafness and constipation.

General appearance and demeanour. The hypothyroid patient moves and
thinks slowly. The face is impassive and prematurely aged. Its tissues arc
coarse and the eyes are narrowed by ptosis of the upper lid and oedematous
pouches in the lower lids. The features arc usually pale owing to thickening
of the skin and anaemia, and may be yellowish as a result of carotinacmia.
The malar regions sometimes have a purple flush. The hair is lifeless, dry
and coarse, and bare patches may develop. Loss of hair in the outer thirds
of the eyebrows is not a specific feature of myxoedema. Hair in the
axillary and pubic regions may become scanty, but disappears completely
in secondary hypothyroidism only. The back becomes rounded, the
abdomen protuberant and the ankles oedematous, sometimes scicrcly.

adult hypothyroidism

Sensitivity ,o cold is

villingness to undress or f hought causes the patient to i pause

ibout the temperature. . Slo " ne f to „_ th ., r „ ith deafness, may render the
aefore replying to questions and, g al at „ tu de is

scnse of

hU & is dry, rough scaly “

makes it feel thickened and spongy, myxoe dema may develop

form in the supraclavicular region ' . n0 , fou ^ in spontaneous hypo-

after thyroidectomy for toxic got , d row over the pulps of the

thyroidism. The nails are thick an f oun d i n association with

fingers. Clubbing (thyroid achropadty) TOY occasiona l complaint as
pretibial myxoedema. Generalized pruritus is

it is in thyrotoxicosis. gutteral as a result of myxoede-

The voice becomes hoarse or anl j 0 f thickening of the

matous tissue in the larynx and nasopharynx

tongue and lips. . variable and may be slow, nor-

Cardiovascular system. The p ha lf the patients with longstanding

malor fast. The heart is enlarged Ht over halft P flat or

hypothyroidism. The ECG sho diminished Angina of effort may

imrertedT waves and the cardiac output Hd,mimshed.^^^.^. on ^ Thesc

be present and myocardial infarc Stated by replacement therapy,

serious features may be aggravated p P and some patients have
Alimentary system. The appe 0 f tcn depressed. Alimentary’

dyspeptic symptoms. Gastric secre . , is a constant finding. The

motility is usually reduced and con P and subacute

colon frequently becomes distended with faeces

intestinal obstruction may supervene. r . § fmmd in less than

Haemopoielic system. Anaemia of modem shou l d always be

half the patients, and a full haema “ lo B . . The fi rs t, which is never

made. Three types of f mtt T “fCothyroidism on haemopoiesis-

severe, results directly from the effe . V. and of vitamin B„.

The other two are caused by deficiencies °j a ‘u ’ “rLon and may be the
Sexual function. In women menorrta p ion occurs, abortion »

presenting feature. Sterility “ “^ nld lsm. Libido is diminished in

likely. In men there may be mild nypog

both sexes. . , tiredness and stiffness in t e

Musculoskeletal system. Muscular p , ^ fclt in ,h e weightbearing

arms, thighs and legs are common. Hypothyroidism m

joints, especially by obese women 3t ' he ” ton %„ d the bones are normal
the adult has no obvious effects on
on X-ray.

ADULT HYPOTHYROIDISM 289

Sensitivity to cold is shown by excessive clothing or bedclothes, by un-
willingness to undress for examination and by unreasonable complaints
about the temperature. Slowness of thought causes the patient to pause
before replying to questions and, together with deafness, may render the
taking of a history very tedious. However, the patient’s general attitude is
pleasant and uncomplaining and she often has a dry and pan ky sense of
humour.

The skin is dry, rough, scaly and cold. Myxoedematous infiltration
makes it feel thickened and spongy, and occasionally, in severe cases, pads
form in the supraclavicular regions. Pretibial myxoedema may develop
after thyroidectomy for toxic goitre, but is not found in spontaneous hypo-
thyroidism. The nails are thick and brittle and grow over the pulps of the
fingers. Clubbing (thyroid achropachy) may be found in association with
pretibial myxoedema. Generalized pruritus is an occasional complaint as
it is in thyrotoxicosis.

The voice becomes hoarse or thick and gutteral as a result of myxoede-
matous tissue in the larynx and nasopharynx and of thickening of the
tongue and lips.

Cardiovascular system. The pulse rate is variable and may be slow, nor-
mal or fast. The heart is enlarged in over half the patients with longstanding
hypothyroidism. The ECG shows low- voltage complexes with flat or
inverted T waves and the cardiacoutput is diminished. Angina of effort may
be present and myocardial infarction is a common complication. These
serious features may be aggravated or precipitated by replacement therapy.

Alimentary system. The appetite is poor, and some patients have
dyspeptic symptoms. Gastric secretion is often depressed. Alimentary
motility is usually reduced and constipation is a constant finding. The
colon frequently becomes distended with faeces and gas, and subacute
intestinal obstruction may supervene.

Haemopoietic system. Anaemia of moderate severity is found in less than
half the patients, and a full haematological examination should always be
made. Three types of anaemia are recognized. The first, which is never
severe, results directly from the effect of hypothyroidism on haemopoiesis.
The other two are caused by deficiencies of iron and of vitamin B I2 .

Sexual function. In women menorrhagia is common and may be the
presenting feature. Sterility is usual and, if conception occurs, abortion is
likely. In men there may be mild hypogonadism. Libido is diminished in
both sexes.

Musculo- skeletal system. Muscular pains, tiredness and stiffness in the
arms, thighs and legs are common. Rarely pain is felt in the weightbearing
joints, especially by obese women at the menopause. Hypothyroidism in
the adult has no obvious effects on the skeleton, and the bones are normal
on X-ray.

290

THE THYROID GLAND

Nervous system. The reflexes are altered in a characteristic way. Ordi-
nary clinical examination of the ankle jerk, for instance, reveals prolonga-
tion of the relaxation phase — the so-called "hung-up jerk”. Investigation
by electrical methods with graphic recording confirms the delayed relaxa-
tion quantitatively and shows that the contraction phase is prolonged also,
though to a lesser degree. This test provides a simple, reliable and cheap
index of thyroid function in hypothyroidism. Acroparaesthcsiae are not
uncommon and are probably the result of compression of the median nerve
by fluid or by myxoedematous deposits in the carpal tunnel. Ataxia and
clumsiness have been described and are thought to be due to cerebellar
dysfunction.

Mental features. The common manifestations have been described
already. Occasionally, however, an acute confusional state may develop
("myxoedema madness”).

Diagnosis

The diagnosis of hypothyroidism is made primarily on clinical grounds
and on the response to specific therapy. Surgeons see the condition most
frequently in association with Hashimoto’s syndrome and in patients who
have undergone thyroidectomy. They must be on the lookout for the
earliest features so that treatment is not delayed.

Hypothyroidism may be confused with chronic nephritis, the nephrotic
syndrome, pernicious anaemia and early cases of acromegaly.

Laboratory tests are very useful for die diagnosis of mild cases and for
distinguishing between the primary and the secondary disease. The BMR
is usually less than —25 per cent. The plasma cholesterol is raised and is
often higher than 300 mg. per 100 ml. in primary hypothyroidism. In
hypopituitarism it is usually between 200 and 300 mg. per 100 ml. The
plasma PBI is usually below 3-5 fig. per 100 ml. The uptake of radioactive
iodine by the thyroid is not necessarily depressed in hypothyroidism,
since the defect may be one of synthesis of thyroid hormones. Exogen-
ous TSH increases the uptake in secondary, but not in primary hypothy-
roidism.

The changes in the ECG have been described already. The ESR is
often raised, possibly owing to an increase in the plasma globulin level.
Thyroid antibodies can be detected in up to 80 per cent of patients with
spontaneous primary hypothyroidism, and in about 20 per cent they arc
present in the high litres encountered in Hashimoto’s disease.

Treatment

Replacement therapy with thyroxine is highly satisfactory, and most
patients can be restored to normal health and maintained in a euthyroid
state. The initial dose is 0-05 mg. per day of /-thyroxine sodium or of

ADULT HYPOTHYROIDISM

291

Diotroxin. An increase of 0-05 mg. per day is made every 10 to 14 days
until the optimal effect is obtained. The usual maintenance dose of
thyroxine, which must be discovered empirically, is about 0-3 mg. per day.
The patient starts to feel better within a week or two of the commencement
of therapy and often experiences a brisk diuresis and loss of weight
Normal health is usually restored within two to three months. Signs of
overdosage include tachycardia, palpitation, mental irritability and pro-
gressive loss of weight. Most intelligent patients can discover the best
dosage for themselves, but they and their families must be warned of the
need for permanent therapy. Sometimes progression or amelioration of
the disease may necessitate an increase or a reduction in dosage. Serial
estimations of the plasma cholesterol level are very helpful in assessment of
the dosage of thyroxine.

The anaemia may respond to thyroxine therapy alone, but requires the
addition of iron or vitamin B 12 if the haematological findings indicate that
they are deficient.

Patients with angina or cardiac failure must be treated very cautiously
because, although these complications may be improved by thyroxine
therapy, they may also be aggravated. The initial dose of thyroxine should
be \ery low (0 0125 to 0-025 mg. per day) and the increments should be
given more slowly than usual. It may be necessary to withhold thyroxine
therapy temporarily or permanently in the face of cardiac emergencies and
to use other forms of cardiac therapy.

Patients with hypothyroidism secondary to pituitary' failure must be
given adequate cortisone replacement before thyroxine is administered
(Chapter 1).

Myxoedema coma

In severe uncomplicated and untreated hypothyroidism the metabolic
processes eventually run down and are no longer able to maintain the
temperature of the body. Hypothermia, unconsciousness and death super-
vene.

Exposure to cold appears to be a precipitating factor, and profound
mental disturbances and convulsions often precede the onset of coma. The
skin feels cold, but the severity of the hypothermia may be overlooked
unless a low-reading thermometer is used. The pulse may be impalpable
and the blood pressure unrecordable.

Urgent treatment is essential, but the outlook is poor even when it is
provided. Replacement therapy with Diotroxin or /-thyroxine (0*1 to
0-2 mg. per day) by mouth is required. If the patient cannot swallow,
triiodothyronine (20 to 40 pg. per day) may be given by stomach tube.
Cortisone acetate (100 mg. per day) by mouth or intramuscularly and
suitable antibiotic cover, to control any infection, are essential. Fluids and

THE THYROID GLAND

292

nourishment should be given sparingly, and the patient must be disturbed
as little as possible. More vigorous measures, including large doses of
triiodothyronine, active warming and vasopressor agents, are sometimes
effective, but are liable to place a severe strain on the seriously damaged
myocardium.

THYROIDITIS

Several varieties of inflammatory disease affect the thyroid. All except
auto-immune thyroiditis are rare. Thyroiditis may develop in a previously
normal gland or in one already the seat of disease. It may be acute, sub-
acute or chronic and suppurative or non-suppurative. The following
classification, based on that of Doniach, Roitt and Hudson, is convenient:

1. Infectious thyroiditis —

(«) Bacterial:

( 1 ) acute (pyogenic);

(ii) chronic (specific).

(A) Viral—

(I) subacute (de Quervain’s thyroiditis);

(ii) chronic (granulomatous pseudotuberculous thyroid-
itis).

2. Radiation thyroiditis.

3. Auto-immune thyroiditis (Hashimoto’s disease, etc.).

4. Riedel’s thyroiditis.

5. General “pseudogranulomatous” disease, affecting thyroid (sar-

coidosis and amyloid disease).

Acute bacterial thyroiditis

Bacterial infection of the thyroid is rare but may reach it by the blood
stream, via lymphatics from local sources (e.g. the tonsils), or by direct
extension from adjacent structures (e.g. laryngeal carcinoma). If untreated
an abscess may form, the infection may spread beneath the deep fascia of
the neck and into the mediastinum, and the condition may prove fatal.

Clinically there are general signs of acute infection, which may be severe.
The thyroid itself i$ painful, swollen and tender, and the skin over it is red.
Hoarseness, dysphagia and other signs of obstruction may follow.

Thyroid function is rarely disturbed unless extensive suppuration de-
stroys the whole gland and causes hypothyroidism.

With appropriate antibiotic treatment the prognosis is good. The pri-
mary lesion and other aspects of the patient’s illness must receive attention.
Abscesses require drainage. If multiple abscesses form, and fail to respond
to simple measures, partial or even total thyroidectomy may be necessary.

SUBACOTE THYROIDITIS

293

Chronic bacterial thyroiditis Tuhtrculosis may be

Chronic specific infectton of the t juni D disease> or localized and

miliary, and accompany *<= acnte^ ^ ^ invoU - cs th e adjacent
caseous. The latter form u y ma( j e un til the lesion has been

lymph glands. The diagnosis ' an d appropriate surgery

“ -SWS - SS,Tt. l =— - —

spread of the disease.

viral infection'^anddiere isevidence that the mumps virus may sometimes
be responsible.

Pathology aiffn.elv but sometimes the

Usually the whole ^-d 's en'argr^d ^ > ometimes adh cren.
process is more confined. 1 ne

surrounding structures. inflammatory destruction of the acinar

The earliest lesion is probably an in ' ^ act ^ a foreign body,

epithelium which allows the colloid , Ib roa y be flattened or

The acini are often small, and may be highly

necrotic and lying free within' the : lurnir . . ^ often it U infiltrated with
eosinophilic or retracted from t e » g ’^e s t r oma around the acini
nuclei which resemble those of giant j the colloid. It contains
shows evidence of a granu omatous £*“> celUi lymphocytes, histio-

many fibroblasts and is infiltrate «' P . time and the acini re-

cyj and true giant cells. The Occasionally the

generate, but some permanent fib chronic form of granulomatous
histological appearances show . tp1l j n t u h er cuh us thyroiditis’'. .

reaction, known as "granulomatous p ways. Damage to the acini

Thyroid function may be d,s,u ‘) , 'f , , h old hormones in the early

may cause the excessive release of J. f hormon cs in the later

stages of the disease and impair the synthesis

stages before resolution is complete. co u 0 ; d Dr to damaged acinar

A mild auto-immune response to
cells occurs sometimes.

294

THE THYROID GLAND

Clinical features

The disease is reported much more frequently in some parts of the world
(e.g. Minnesota, Ohio and possibly Toronto) than in others. Adult women
are affected most commonly. Usually the thyroid is affected primarily, but
sometimes the thyroiditis accompanies other infections, such as mumps,
measles, tonsillitis and scarlet fever.

The clinical features may be mild or severe. In the former there is little
more than painless enlargement of the thyroid, while in the latter the gland
is painful and the patient shows general signs of an acute febrile illness.
The pain may radiate behind the ears and is aggravated by swallowing and
by movement of the neck. Pressure symptoms may accompany gross en-
largement of the gland.

The thyroid itself is usually enlarged diffusely to about twice its normal
size and is firm and tender. Nodules may be felt if the gland is involved in
a patchy manner or if a nodular goitre was present previously.

Signs of mild hyperthyroidism may be present early in the illness, and
those of hypothyroidism may follow temporarily.

The course is usually subacute and the fever, which is low or moderate,
persists for several weeks. The local signs in the thyroid resolve in two to
four months. Occasionally the course is more chronic, and thyroid en-
largement persists for much longer (granulomatous pseudotuberculous
thyroiditis). Clinically the resolution is complete and no late sequelae have
been observed.

Diagnosis

At the onset of the disease subacute thyroiditis may be confused with
acute bacterial thyroiditis, in which the clinical features are usually more
severe, with haemorrhage into a cyst and with simple pharyngitis or laryn-
gitis. In the later stages subacute thyroiditis must be distinguished from
auto-immune thyroiditis, Riedel’s thyroiditis and cancer of the thyroid, all
of which will be discussed later.

The characteristic early laboratory findings are a normal or slightly
raised PBI and a much diminished uptake of 131 1. This combination is
practically diagnostic of the condition. The ESR is always raised, and
readings of 100 mm. in 1 hour (IVestergrcn) are not uncommon. There is
often a moderate leucocytosis. Lowtitres of thyroid antibodies may befound.

Biopsy of the thyroid by needle or by open surgery may be required
occasionally if the diagnosis is in doubt and if cancer cannot be excluded.
Treatment

Steroid therapy is highly effective and leads to resolution within about
two weeks. Cortisone acetate (25 mg. 6-hourly) or other steroid (in
equivalent doses) should be given for two weeks and then withdrawn

AUTO-IMMUNE THYROIDITIS 295

gradually. If symptoms recur the full dose must be restored for a further
Meek or two.

Other methods, which are probably less effective and less desirable, are
radiotherapy (600-800 rads) and antithyroid drugs (carbimazole, 15 mg. 3
times a day for 2 weeks).

Partial thyroidectomy may be required very rarely if obstructive features
do not respond to treatment.

Radiation thyroiditis

Therapeutic irradiation with radioactive iodine or with X-rays causes
patchy cellular necrosis, thrombosis of the blood vessels and oedema of the
stroma. There may be slight pain and tenderness in the gland from 2 to
10 days after treatment. Later the gland becomes fibrotic and the structure
of the acini is severely deranged.

Auto-Immune thyroiditis
Aetiology and pathogenesis

In 1912 Hashimoto described the clinical and pathological features of the
disease which bears his name. His patients \\ ere middle-aged women with
goitres which, on section, showed diffuse infiltration with lymphocytes and
plasma cells, small follicles and fibrosis. In 1956 Doniach and her col-
leagues found that the sera of patients suffering from this condition often
contained thyroid auto-antibodies. This observation has been confirmed
and extended by many workers and has led to the concept of "auto-immune
thyroiditis” as a pathological process, one variant of which is the classical
Hashimoto’s disease. The basic hypothesis is that the body forms anti-
bodies against its own thyroid tissue and destroys it. Similar auto-immune
mechanisms have since been recognized in other diseases such as systemic
lupus erythematosus and rheumatoid arthritis.

Three distinct antibodies have been found in thyroid disease by means
of immunological techniques. The first reacts with thyroglobulin and
can be detected by a precipitin test and by the more sensitive tanned red-
cell haemagglutination test. The second reacts with an unknown con-
stituent of the thyroid cell, which is probably microsomal in origin, and
can be recognized by means of a complement-fixation test. The third
reacts with an antigen of the thyroid colloid which is distinct from thyro-
globulin. It is revealed by means of the immuno-fluorcscence technique.
The antibodies are true m/to-antibodies, for they react not only with homo-
logous thyroid extracts hut also with extracts from the patients’ own glands.
They arc probably formed by the immunologically competent lymphocytes
and plasma cells which invade the gland and, in established cases, by the
reticuloendothelial system as a whole.

Damage to the thyroid cell, which causes it to release its contents, seems

THE THYROID GLAND

296

to be the essential stimulus to antibody formation. We have seen already
that this may occur temporarily in subacute viral thyroiditis, and it is also
found sometimes in toxic goitre and in carcinoma of the thyroid. The
cause of the initial cellular damage in auto-immune thyroiditis is unknown,
but it has been suggested that it is a viral infection. The auto-antibodies arc
harmless to intact cells, but they can destroy those whose membranes ha\e
been damaged. It is possible that sensitized lymphocytes are the agents
responsible for damaging the membranes and allowing the antibodies to
enter the cells. As a result, the cells atrophy and at the same time release
antigens which provoke the formation of further antibodies.

Stimulation of the thyroid by TSH apparently plays a part in the
pathogenesis of the disease. Gradual destruction of the gland by the
disease process probably tends to reduce the let el of circulating thyroid
hormones and to stimulate the production of TSH, w ith consequent hyper-
trophy of the gland and goitre formation. This process is analogous to that
in simple goitre. When the secretion of TSH is inhibited by exogenous
thyroxin* the Vesiwv undergoes resolution, the goitre diminishes and the
antibody litres fall.

Pathology

The essential histological feature of auto-immune thyroiditis is infiltra-
tion of the gland by lymphocytes and plasma cells. Such infiltration is
found in the following conditions, all of which are varieties of auto-immune
thyroiditis:

1. Diffuse (struma lymphomatosa)—

(а) Hasbimoto’s disease (lymphadenoid goitre);

(б) Lymphocytic thyroiditis;

(c) Atypical forms;

(rf) Primary adult hypothyroidism (myxoedema).

2. Focal.

In typical Hashimoto's disease the thyroid is diffusely enlarged, firm and
smooth. Adhesions to surrounding structures are rare. Histologically
there is widespread oxyphilic degeneration of the acinar epithelium and
scanty colloid. Lymphocytes and plasma cells infiltrate the stroma diffusely
and extensively, forming lymph follicles with prominent germinal centres
which may be visible to the naked eye in a stained section. There are
occasional giant cells, similar to those of subacute viral thyroiditis. Fibrous
tissue is increased somewhat throughout the gland and may impart a
lobulated appearance on section. The process is usually slow ly progressive
and eventually destroys the greater part of the acinar epithelium.

Lymphocytic thyroiditis is a variety of autoimmune thyroiditis which
affects girls and young women and which develops fairly rapidly.

auto-immune thyroiditis

297

Various atypical forms of typical pathological (and

cognized. Occasionally it » (the fibrous variant)

clinical) features of i thyrotoxrcc '“^'Jm and, except for the

absenw^of^extension beyond the gland, may be indistinguishable fronr

and on section shows a few atrophic ve > ■ ^ P nd either beC omes in-

increased fibrosis. In this variety, app 7> ] the goitre is small and

filtrated and destroyed without regenerating or g

transient and passes unnoticed. fowl d ^ uncomra only in

Small foci of auto-immune * h 7 r01 “ ff d by simple goitre, toxic
otherwise normal glands or in those already affected ny l

goitre or carcinoma.

“Sir, r «

30 and 60 years, but we have «'“ un,er “ d h . finn . u is not painful, but

The thyroid is uniformly enlarged, sm lymph glands are

may cause pressure symptoms B«dy ^ „ Snt but

enlarged and firm. Thyroid function vcarsmd frank myxoedema
hypothyroidism often develops after y ^ occasions hyper-

frequently accompanies longstanding B • disease, and very rarely it
thyroidism occurs transiently at the onset of the oise

persists. , „™,ntered In one the disease has

Three other clinical variants may be mi vira l thyroiditis. In

a painful subacute onset, not unlike that d it re formation

another (the remittent form) episodes of acmny ^ i Acl iv.ty

alternate with periods of quiescence and shnnkag Thc third is

may be stimulatea oy inieeuu.u, - ■

primary adult hypothyroidism or ' d

and impalpable. This has been deserr ^ au to-immune basis.

Other diseases, some of which may . ne thyroiditis. They m-

occasionally found in association wit au non _tuberculous Addison s

elude rheumatoid arthritis, permcous anaemi > temic lupus etythe-

disease, hepatic cirrhosis, Sjogren s sy
tnatosus and possibly Paget’s disease ot bone.

Diagnosis . . .. at ; ents with goitre

Auto-immune thyroiditis should be c0 *** 1 , exhibit both these

or hypothyroidism and suspected strongly in those

298

THE THYROID GLAND

features. The gland is firmer than that in most simple or toxic goitres,
which it otherwise resembles, but not so hard as that in Riedel’s thyroiditis
or some carcinomas. The rare variety with a subacute onset must be dis-
tinguished from acute bacterial thyroiditis and from subacute viral thy-
roiditis. It differs from both in that the disease is usually less acute and
that it persists in a chronic form while the others resolve completely. How-
ever, the differentiation may not be easy on clinical grounds in the early
stages. Enlarged glands may be present rarely, but should always raise the
suspicion of cancer.

Immunological reactions provide specific tests for the recognition of
auto-immune thyroiditis. A positive precipitin test (the least sensitive
method) indicates a high litre of antibody, is found in about 70 per cent of
cases and is practically diagnostic. The tanned red-cell test is more sensi-
tive and is positive in about 80 per cent. However, high titres may also be
found in toxic goitre (60 per cent of cases) and in cancer of the thyroid
(30 per cent of cases). The complement-fixation test is more sensitive still,
and is positive in some 90 per cent of patients. It has the disadvantages of
the tanned red-cell method and also gives positive reactions in some cases
of simple goitre and in a few elderly females without clinical evidence of
thyroid disease.

Antibodies arc found in the y-globulin fraction of the plasma proteins,
and high titres may be associated with increased amounts of y-globulin on
electrophoresis and with positive non-specific flocculation tests (thymol
turbidity, thymol flocculation, colloidal gold and zinc sulphate). The ESR is
often raised, though rarely to such an extent as in subacute viral thyroiditis.

Tests of thyroid function yield results which vary with the stage of the
disease. In euthyroid and hypothyroid subjects the uptake of 131 I is usually
normal or low and the PB m I is slightly raised at 48 hours. The uptake may
be increased at first in those in whom the onset is subacute, whereas in sub-
acute viral thyroiditis the uptake is reduced. In some clinically euthyroid
patients isotope studies suggest hyperthyroidism. However, the uptake is
depressed by triiodothyronine or thyroxine as in normal subjects. In toxic
goitre it remains elevated. Potassium perchlorate causes the rapid dis-
charge of radioactive iodine from the glands of patients with auto-immune
thyroiditis, but not from normal glands or from simple goitres.

Biopsy of the gland, by needle or by open operation, may be needed
before a final diagnosis can be reached.

Treatment

Thyroxine is the mainstay of treatment, whether or not thyroid function
is depressed, and the results arc highly satisfactory. Thyroxine inhibits the
production of TSH, the thyroid becomes inactive and the auto-immune
reaction diminishes or disappears completely, /-thyroxine sodium is given,

RIEDEL’S THYROIDITIS 299

as m the treatment of myxoedcma, until the daily dose is 0-2 to 0-3 mg. If
the patient is euthyroid initially the dose can be increased rapidly. The
gland shrinks quite fast, and any pressure effects are relieved. The titres of
circulating antibodies diminish gradually, but low titres may be detectable
for a long time after the disease comes under control. It is not yet known
how long thyroxine treatment is required in euthyroid patients, but until
evidence to the contrary is available it would seem wise to continue it in-
definitely. If the thyroid continues to enlarge under treatment with
thyroxine the presence of cancer should be suspected.

Surgical treatment is very rarely required, but it should be considered:
(1) when there are severe pressure effects, particularly from a retrosternal
goitre, and (2) when carcinoma cannot be excluded. Partial thyroidectomy
(including removal of the isthmus) is the operation of choice for most cases.
If the disease affects one region only, local excision may be adequate.

It sometimes happens that the disease is recognized for the first time at
operation. In these circumstances a small goitre should be biopsied and
then left alone. A large gland should be removed by partial thyroidectomy.

Thyroxine treatment must, of course, be continued after operation.

Riedel's thyroiditis (Riedel’s struma, chronic fibrous or ligneous
thyroiditis, struma fibrosa, invasive fibrous thyroiditis)

This condition, which is a very rare form of thyroiditis, was first de-
scribed by Riedel in 1896 and again in 1910. Its aetiology is unknown.
There is no dear evidence that it is related to other forms of thyroiditis.
Pathology

The thyroid is large and extremely hard, and is fixed to the surrounding
structures. In about one-third of cases the disease is localized to one part
of the gland when the condition is first seen.

Histologically the acinar tissue is almost completely destroyed and
replaced by dense fibrous tissue, which extends into adjacent structures and
fixes the thyroid to them. Some fairly noimal acini may be compressed by
adjacent fibrous tissue, and some are invaded by acute and chronic in-
flammatory cells. Giant cells, however, are not seen. The fibrous tissue
may be invaded by a low-grade inflammatory exudate, or it may be hyaline
and acellular. Cuffing of the vessels with inflammatory cells and peri-
vascular fibrosis may render the tissue relatively ischaemic. The condition
is slowly progresshe.

Clinical features

Riedel’s thyroiditis occurs most commonly in women between the ages
of 30 and 60 years. The first complaint is usually of painless unilateral or
bilateral swelling in the neck, which has been present for months or years.

300

THE THYROID GLAND

The gland feels woody hard in one or both lobes and is fixed to the sur-
rounding structures. It is not tender. Pressure symptoms develop at a late
stage tn the disease and may be related to involvement of the trachea,
larynx, oesophagus and recurrent laryngeal nerves.

Thyroid function is retained for a surprisingly long time, but myxoe-
dema develops eventually in those with extensive bilateral disease.

Diagnosis

Riedel’s thyroiditis is most likely to be mistaken for carcinoma, which is a
far commoner condition, and the distinction cannot be made for certain
without biopsy. The hardness and fixity of the gland usually distinguish it
from auto-immune thyroiditis.

Laboratory investigations are mostly negative. The ESR is normal or
slightly raised, and antibodies may be present occasionally in low titres.

Treatment

If the condition is suspected the thyroid should be explored surgically so
that the diagnosis may be confirmed, the presence of cancer excluded and
obstruction of the trachea prevented or relieved.

At operation the dense white fibrous tissue in and around the gland is
obvious immediately. A generous biopsy should be taken and examined at
once by frozen section.

Definitive treatment involves a wedge resection of the isthmus and
inner portions of both lobes, which may be very difficult technically. If the
disease is localized to one lobe the affected region should be removed as
extensively as circumstances permit. It is wise to forestall trouble by re-
moval of the isthmus, even when it is not obviously involved.

The results of surgery are surprisingly good, and the disease often seems
to become quiescent after operation. Results are best when operation is
performed early, and once the trachea has been freed serious obstructive
features are uncommon.

Replacement therapy is needed for those who are myxoedematouS, and
should also be given prophylactically after extensive resection of thyroid
tissue.

BENIGN TUMOURS OF THE THYROID

True adenomas w hich arise from the glandular epithelium of the thyroid
are much less common than other types of benign nodule.

Pathology

Several types of adenoma are recognized.

A follicular adenoma is usually a single, solid, well-encapsulated tumour.
It is liable to the complications of degeneration, haemorrhage and sub-
sequently of cyst formation, and it may undergo malignant transformation.

BENIGN TUMOURS OF THE THYROID 301

The growth is composed of cubical or spheroidal cells with large deeply
staining nuclei, surrounded by a small faintly staining rim of cytoplasm.
Five distinct histological types are recognized. (1) The embryonal adenoma
is poorly differentiated and the cells are arranged in sheets or columns.

(2) The foetal adenoma shows a little differentiation and contains miniature
follicles containing small amounts of colloid (micro-follicular adenoma).

(3) The simple adenoma is well differentiated and consists of colloid-filled
follicles which appear fairly normal. The capsule, however, separates it
clearly from the remainder of the gland. (4) The colloid adenoma (macro-
follicular adenoma) contains large colloid-filled follicles of varying size,
which are usually quite distinct from the adjacent normal gland. (5) The
Ifurthle cell adenoma is composed of large, finely granular, acidophilic cells,
arranged in sheets or clumped around small acini. The origin of the cells
is not known for certain.

The papillary adenoma is much less common than the follicular type,
whereas papillary carcinoma is the commonest form of malignant tumour.
The adenoma is usually cystic, with papillary processes growing into the
spaces, and is poorly encapsulated.

Clinical features

Thyroid adenomas occur at all ages, but are commoner in females than in
males. They usually present as firm or cystic solitary thyroid nodules,
which may follow one of five courses. (1) The nodule does nor change in
size, but remains as a palpable mass in the thyroid. (2) It increases in size,
eventually causing pressure effects or disfigurement. (3) Degenerative
changes, particularly haemorrhage, may occur abruptly with alarming and
serious consequences. Pain, swelling and pressure effects then demand
immediate treatment. (4) Toxicity may supervene, but is exceptional.
The so-called "toxic adenoma” is not a true tumour, but a localized area of
hyperplasia. (5) Malignancy may develop.

The varieties of adenoma can only be distinguished from each other and
from other types of solitary nodule (in particular carcinoma) after they
have been excised and examined histologically.

Treatment

AH solitary nodules in the thyroid must be excised surgically by partial
lobectomy. Simple enucleation is inadequate. This policy establishes the
nature of the lesion and forestalls the development of complications. An
emergency operation may be needed if haemorrhage occurs into an ade-
noma.

MALIGNANT TUMOURS OF THE THYROID

Carcinoma of the thyroid is responsible for less than 1 per cent of all
deaths from cancer, but it b a dbease of great interest and attracts the

302

THE THYROID GLAND

attention of many workers. It has many singular features. The experi-
mental conditions under which it can be induced in animals have been
partly defined, and there is good evidence that it is largely under the control
of TSH. Irradiation of the thyroid gland in childhood often causes cancer
to develop later. The lesions are diverse in their morphology and tery
variable in their malignancy. Some, which are well differentiated and
almost indistinguishable from normal tissues, behave in a relatively benign
manner, while others are highly anaplastic and rapidly fatal. Unlike most
neoplasms, cancer of the thyroid attacks children and adults of all ages.
Some lesions concentrate radioactive iodine, which may be used thera-
peutically. Zn many ways, in fact, more is known about this tumour than
about any other, but much still remains to be learned.

Incidence

The incidence of thyroid cancer may be estimated, from the Registrar
General's reports, from autopsy material or from histological examination
of thyroids removed surgically. All methods are open to objections. The
Registrar General’s reports can only be as accurate as the certified causes
of death, and the}- obscure the fact that patients who die from other causes
may have had thyroid cancer treated successfully. Autopsy material is un-
representative and, like surgical material, depends very largely on the
criteria of malignancy accepted by individual pathologists. These criteria,
as we shall see, differ widely.

In Northern Ireland (according to the Registrar General) about one
person per 100,000 of the population dies from cancer of the thyroid each
year. These deaths represent about 0 6 per cent of those due to cancer in
all sites. The corresponding figure for England and Wales and for the
United States is about 0-4 per cent. The autopsy and surgical material
from Northern Ireland (1934-58) has been analysed by Willis, who found
thyroid cancer in 0-1 per cent of 15,000 patients examined post mortem and
in about 4 per cent of thyroids removed at operation (Table 7.4). The

Table 7.4. Incidence of primary carcinoma in surgical thyroid specimens

Type of goitre

Number of surgical ,

Number (and %) in which

specimens

carcinoma found

Non-toxic solitary nodular

Non-toxic multinodular

Hashimoto’s disease

2 (3 2%)

Toxic nodular goitre

Toxic diffuse goitre

222

f> » gS}« 0,1 >

Miscellaneous

279

4 (14%)

Total

3,590

149 (4 1%)

(From Willis, I960.)

MALIGNANT TUMOURS OF THE THYROID 303

number of cancers recognized in thyroids removed surgically has in-
creased greatly (about fivefold in Northern Ireland) in the past 20 to 30
years, but there has been an almost parallel (fourfold) increase m the
number of thyroidectomies performed. These figures are similar to many
others which have been published. The overall incidence throughout the
world has been estimated by Sokal to be about 25 patients per year with
thyroid cancer per one million of the population. The disease is about
twice as common in women as in men (four times as common in Northern
Ireland).

Several important points arise from Willis’ analysis of the surgical
material. Carcinoma is commoner in nodular and simple goitres than in
diffuse and toxic ones. It is most common (10 per cent) in solitary non-
toxic nodules and least common (0-7 per cent) in diffuse toxic goitres. On
the other hand, 0 per cent of the patients with thyroid cancer who had
undergone thyroidectomy had had thyrotoxicosis.

Aetiology

There is considerable evidence that overstimulation of the thyroid by
TSH is an aetiological factor. In rats any procedure which reduces the
level of circulating thyroid hormones, and consequently increases the secre-
tion of TSH, causes hyperplasia, nodularity and finally neoplasia of the
thyroid. The procedures include the deprivation of iodine, the administra-
tion of antithyroid drugs or radioactive iodine, and subtotal thyroidectomy.
In man cancer of the thyroid is commoner in simple (hyperplastic) goitres
than in normal glands, and the administration of thyroxine, which inhibits
the production of TSH, controls many well-differentiated (papillary')
growths.

The aetiological importance of simple goitre is hard to define. Cancer of
the thyroid is commoner in regions of endemic goitre than elsewhere, and
Burn and Taylor found that half their patients with differentiated growths,
and a quarter of those with anaplastic lesions, had had goitres for more than
a year before the cancer was diagnosed. About one-fifth of each group had
bad goitres for more than 10 years. On the other hand, hundreds of
nodular goitres have been followed carefully for many years without any
cancer being recognized. A simple nodular goitre certainly has some
tendency to become malignant, but the risk of it doing so is probably small.

Irradiation of the neck (for thymus enlargement, etc.) in childhood pre-
disposes to the development of cancer after 10 years or so, and many such
cases have been reported. Although cancer of the thyroid has been reported
after irradiation with radioactive iodine, there is no evidence that the
irradiation was responsible. If it does cause cancer the latent period is
probably at least 20 years, and isotopes have been used only since 1942.

Antithyroid drugs cause cancer to develop in rats, but only' after they

THC THYROID GLAND

304

have been administered for half the normal life span. There is no evidence
that they are of aetiological importance in man.

Pathology

Pathologists differ greatly in their interpretations of thyroid tumours and
about the criteria of malignancy. Attention must be paid to all the histo-
logical aspects, including the structure and arrangement of the cells, to
signs of invasion of the capsule, of blood vessels and of lymphatics, and to
the presence of metastases in lymph glands or distant organs, particularly
the lungs and bones. The main problem concerns the distinction between
a benign lesion and one which shows early malignant change. Some patho-
logists regard invasion of blood vessels as an essential feature, but most
consider this criterion too rigid, because it excludes some tumours (par-
ticularly papillary ones) which spread predominantly via the lymphatics.

As pointed out by Dunhill m 1931, a clear distinction must be drawn
between, differentiated lesions (papillary and follicular) and anaplastic
growths, because their behaviour and response to treatment arc quite
different.

The best of many classifications of thyroid carcinoma is that of Warren
and Meissner, and most recent reports (including that of Willis) are based
on it. The histological types and their relative frequencies are as follows:

Histological type

No. (and %) in surgical
material from N. Ireland
(Willis, I960)

Average percentage
in 5 recent series
(Burn & Tajlor, 1962)

Differentiated

Papillary

48 (32%) 1

46%

Grade I

22

Grade II

26

ToUicular

49 (33%)

28%

Grade I

23

Grade II

26

Anaplastic

52 (35%)

23%

Round-cell

21

Spindle-cell

15

Pleomorphic

16

Miscellaneous

3%

Total

149 (100%)

100%

It will be seen that the three main types of growth were found with about
equal frequency in the Northern Ireland material, but that other scries
showed a relath ely higher incidence of differentiated lesions. It is probable
that papillary growths are being recognized more commonly than they
were some years ago.

MALIGNANT TUMOURS OF THE THYROID

305

Papillary carcinoma

This is the commonest and most highly differentiated type of growth,
and it carries the best prognosis. It may develop at any age, but is the
commonest tumour in young subjects. The average age of onset in the
Northern Ireland series was 44 years.

Grade I tumours are small, soft, reddish in colour, often encapsulated and
unilateral. Grade II tumours are larger, firmer, greyish in appearance and
frequently uncncapsulated. They are multicentric in origin in at least
20 per cent of cases, and involve both lobes of the gland in 10 per
cent.

Histologically a Grade I papillary carcinoma consists of a single layer of
uniform cuboidal or columnar cells, which are arranged in papillary pro-
cesses and show few mitotic figures. The distinction from a papillary
adenoma may be difficult. Grade II tumours have a papillary architecture,
but their processes are covered by more than one layer of epithelial cells.
The cellular structure is varied, and mitoses are relatively frequent. Ail
stages of gradation between Grades I and II may be found, and mixed
papillary and follicular types are not uncommon. The classification de-
pends on the predominant type. Calcospherites are found in nearly half the
papillary tumours and are commoner in Grade II than in Grade I types.
The u unencapsulated sclerosing tumour" is included in Grade II. It consists
mainly of fibrous tissue in which small groups of cells, arranged in a
papillary pattern, are seen.

Invasion of the lymphatics occurs in two-thirds of the tumours, while
invasion of the capsule or of the veins is much less common. Occasionally
metastases in the adjacent lymph glands so overshadow the parent lesion
that they were at one time believed to be primary growths in ‘'lateral
aberrant thyroid” tissue. A careful search of the thyroid by the pathologist
will reveal the primary thyroid lesion.

Follicular carcinoma

This type of growth is less common than the papillary in most series and
less well differentiated, and it carries a less favourable prognosis. All ages
may be affected, but most tumours develop between the ages of 40 and
60 years. The average age of onset in the Northern Ireland scries was
49 years.

Grade I tumours are solitary, firm and usually well encapsulated. The
cut surface is often uniform and greyish in colour, but haemorrhage, cyst
formation and fibrosis are not uncommon. These tumours may be in-
distinguishable from adenomas to the naked eye. Grade JJ tumours are
much less uniform in appearance. They arc unencapsulated, solitary or
multiple, sometimes small, but often widespread and involving the whole

306 THE THYROID GLAND

of one or both lobes. Section often reveals haemorrhage, necrosis and
cysts.

Histologically Grade I follicular carcinomas include all follicular
“adenomas” of any type (including those of the Hurthle cell type), which
show evidence of malignant change, and carcinomas whose origin from pre-
existing adenomas cannot be established. The latter show well-developed
acini, filled with colloid and lined by single layers of epithelium. Occa-
sionally the epithelium is invaginated. Grade II lesions show a variety of
histological features, but usually the cells are arranged in an acinar pattern.
Occasionally the cells are seen in groups or sheets, separated by fibrous
septa, and have an alveolar arrangement. The acinar epithelium is often
distorted, and its cells are unmistakably malignant, even in the absence of
invasive features. A rare type of tumour included in Grade II is one whose
structure is like that of an adenocarcinoma of the kidney and whose cells
resemble the water-clear cells of parathyroid adenomas. They are thought
to arise from pluripotential ectodermal cells.

Two-thirds of the follicular carcinomas metastasize via the bloodstream,
and comparatively few spread along the lymphatics or invade the local
tissues.

Anaplastic carcinoma

This is the least common of the three main groups in most reported
series. It is undifferentiated and (with the possible exception of the
malignant lymphoma) has a very poor prognosis. It is commoner in older
patients. In the Northern Ireland series the average age of onset was 64
years, and there was no patient under the age of 40 years.

The tumours infiltrate one or both lobes of the thyroid and the sur-
rounding tissues and are not encapsulated. They are usually firm, greyish-
white to yellow in colour and necrotic in places. The histological appear-
ances vary greatly from one tumour to another and also within the same
tumour, but three main groups are recognizable.

The round-cell carcinoma has round or oval cells with hyperchromatic
nuclei and variable amounts of cytoplasm. The cells are arranged in strands
or dumps, surrounded by connective-tissue septa. The tissue may have
an alveolar arrangement, but sometimes the appearance resembles that of a
malignant lymphoma (immature lymphosarcoma). The latter may well be a
distinct sub-group, for it apparently carries a better prognosis than the
other types. The spindle-cell carcinomas are similar to round-cell car-
cinomas except for the shape of the cells. The remaining anaplastic growths
are called pleomorphic-cell carcinomas. Their cells vary greatly in size, shape,
structure and staining qualities. Mitotic figures and multinucleated cells
(giant-cell carcinoma) are common.

MALIGNANT TUMOURS OF THE THYROID 307

Anaplastic tumours spread by local invasion in two-thirds of cases and by
the blood and lymphatics less commonly.

Miscellaneous tumours

A small proportion of rare primary tumours, including squamous
carcinomas, cannot readily be placed in any of the three main groups.
Secondary deposits, especially from primary lesions in the breast, lung or
kidney, are rare.

Clinical features

The early symptoms and signs of thyroid cancer are rarely specific, and
the late features often indicate that treatment is unlikely to be effective.
When he examines patients with thyroid disease the surgeon must con-
stantly be on the lookout for suggestive features which will enable him to
make a firm or, at least, a presumptive preoperative diagnosis of cancer.

The commonest symptom is of a swelling in the neck, and this was the
presenting feature in 71 per cent of Willis’ series (Table 7.5). The sig-
nificant points which suggest a malignant goitre are: (l) rapid development

Table 7.5. Symptoms on admission to hospital of 129* patients who
underscent thyroidectomy (or biopsy) for carcinoma of thyroid (Willis, 1960)

Swelling in neck

92 (71%)

Without pre-existing goitre

55(43%)

Recent enlargement of pre-existing goitre

37 (29%)

Dyspnoea )

f 19 (15%)

Dysphagia V (Mostly anaplastic)

18(14%)

Hoarseness!

U9 (15%)

Thyrotoxic symptoms

13 00%)

Pain in neck

8 (6%)

No neck s>rnptoms

15(12%)

• Adequate clinical records v, ere available in only 129 of the 149 cases of thyroid cancer.

of a thyroid swelling, and (2) acceleration in the rate of growth of a long-
standing goitre.

Dj'spno ca, dysphagia and hoarseness are usually late symptoms, but they
are often the presenting features of anaplastic growths. Thyrotoxic
symptoms arc not uncommon, and were present in 10 per cent of Willis’
patients. Pain in the neck, which may be referred to the ear, is an occa-
sional symptom. Metastases to local lymph glands are noticed occasionally
by the patient, and distant deposits in the chest, the skeleton, the brain or
other viscera may occasionally produce a variety of symptoms.

The commonest physical sign is a goitre, and this was present in 86 per
cent of Willis’ series (Table 7.6), but the thyroid may feel normal, especially
when a papillary growth is present. The goitre is usually nodular and in a
large majority (Table 7.4) consists of a single nodule. Diffuse enlargement

308

THE THYROID GLAND

Table 7.6. Physical signs on admission to hospital in 129 patients to ho
underwent thyroidectomy {or biopsy) for carcinoma of thyroid (Willis, 1960)

Goitre

Nodular

Diffuse (mostly anaplastic)

No goitre (mostly papillary)

Characters of 111 goitres
F«ed} (mostly anaplastic)

Regional lymph glands palpable (mostly papilhry)
Signs of thyrotoxicosis (mostly differentiated)

MI (66%)

90 (70%)

21 (16%)

IS (14%)

( 56 (50%)
X 18(16%)
31 (24%)
13(10%)

often indicates an anaplastic lesion. It is important to note that only about
one-half of the goitres (i e less than half of all the cancers) feel hard and
that most of these are anaplastic. The growth may even feel cystic.
Irregularity, however, may be a feature that arouses suspicion. Fixity is
uncommon and is often a late sign of an anaplastic tumour. The dyspnoea
and hoarseness which often accompany it may be obvious on examination,
and Homer’s syndrome, due to involvement of the cervical sympathetic
chain, may be seen occasionally. The regional lymph glands in the neck,
and sometimes in the axilla, are palpable in about one-quarter of the
patients, especially those with papillary lesions. In a few cases the secon-
dary deposits are palpable, while the thyroid feels normal. Signs of
thyrotoxicosis are present in about 10 per cent of cases. There may be
physical signs related to distant metastases. In three published cases
functioning metastases have produced thyrotoxicosis.

Diagnosis of thyroid cancer

The diagnosis of cancer may be suspected or presumed on clinical
grounds, but should always be confirmed by special investigations and by
histological examination.

Clinical diagnosis

The main problem is the recognition of the early case which does not
show characteristic signs. The only safe course is to remain suspicious and
vigilant in every patient with thyroid disease and to consider the possibility
of malignancy in every goitre. The ways in which thyroid cancer commonly
presents are :

1. A nodule, which is apparently single, develops fairly quickly. This
type of onset is most common in young females and usually denotes a
papillary growth. It is often indistinguishable from a simple nodule, but,
being single, must be regarded with suspicion. Hardness, as we have said,
is not constant and may also be caused by a simple cyst or by calcification.

2. A pre-existing goitre, which is usually nodular and either unilateral or
bilateral, increases in size rapidly. The change in the rate of growth, any

MALIGNANT TUMOURS OF TICE THYROID 309

hardness, irregularity or fixity, or the presence of enlarged lymph glands
should at once suggest the presence of a cancer. Cancer should also be
suspected in Hashimoto’s disease if the goitre continues to enlarge during
thyroxine therapy.

3. A goitre develops diffusely from the start and causes obstructive
symptoms at an early stage. This is the common finding with anaplastic
lesions. It must be distinguished from auto-immune thyroiditis and from
Riedel’s thyroiditis.

4. A mass of malignant glands appears in the neck. The thyroid should
always be examined carefully in such cases and, even if it feels normal, must
be considered as the possible primary source. Other sites which must be
examined include the para-nasal sinuses, the pharynx and larynx, the
bronchial tree, the oesophagus and the upper abdomen.

5. Secondary deposits, especially in the lungs or bones, may cause symp-
toms or be found on X-ray examination. The bronchus, breast, kidney and
adrenal cortex are the other common primary sites of such lesions.

Laboratory diagnosis

Thyroid function is usually normal, but it should be remembered that
1 per cent of toxic goitres contain malignancy. Differentiated lesions
usually take up radioactive iodine, but they do not do so as efficiently as the
adjacent normal thyroid tissue. Tests of uptake are of most value in plan-
ning therapy with radioactive iodine and will be described later. The up-
take of radioactive iodine with direct mapping of the thyroid may be of
diagnostic help. A cold nodule may be simple (colloid) or malignant, while
a hot one is most unlikely to be malignant.

Some workers have found the use of radioactive phosphorus, together
with mapping of the neck, valuable in the diagnosis of cancer. As in other
sites, the isotope tends to be concentrated in the cellular malignant lesion
more than in the adjacent tissue.

The blood should be examined for antibodies, and these will be found in
about one-third of cases. A high titrc is far commoner with auto-iinmune
thyroiditis than with carcinoma, but carcinoma may occasionally com-
plicate Hashimoto’s disease (Table 7.4).

Radiological diagnosis

Routine X-rays of the neck, thoracic inlet and oesophagus should be
taken, as described for any goitre, and the chest, skull, spine and pelvis
should also be examined. Calcification in the thyroid is most common in
benign lesions, but sometimes occurs in malignant ones. Forward dis-
placement of the larynx and trachea and oesophageal obstruction arc very
suggestive of malignancy'. Secondary deposits in the lungs often produce a

310

THE TI1YROIP GLAND

snow-storm appearance, very like that of miliary tuberculosis or sarcoi-
dosis (fig. 7.15). Those in the bones are usually osteolytic and have no
specific characteristics.

Fig. 7.15. X-ray of chest, showing pulmonary dissemination of thyroid carcinoma.
Special investigations

Laryngoscopy should be performed routinely. Invasion of one or both
recurrent laryngeal nerves may produce paralysis of the vocal cords before
symptoms are apparent. This information is essential before any operation,
and the patient should be told of any impairment of function. The trachea
should be evamined by bronchoscopy in any patient whose grow th is fixed,
since invasion may influence the choice of treatment.

Biopsy examination of the lesion is essential, and may be done either at
open operation or by needle. If an enlarged lymph gland is present it may
be removed simply through a small incision directly over it. Otherwise the
thyroid must be exposed formally. If glands, which had not been palpable

MALIGNANT TUMOURS OF THE THYROID

311

clinically, are found to be involved one or more are taken for histological
examination. IF there are no obvious metastases, and the suspected lesion
is unilateral, the whole lobe and the closely adjacent glands are removed.
In total removal of one lobe there is no need to take special steps to pre-
serve the parathyroid glands, but the recurrent laryngeal nerve should be
avoided whenever possible. If the lesion involves both lobes or infiltrates
the surrounding tissues a biopsy is taken from its growing edge. When
adequate facilities for immediate frozen sections are available (and the
report is positive for cancer) a definitive operation may he done at once.
Otherwise the wound is closed and the pathological report awaited.

Needle biopsy is not performed by many surgeons, but Burn and Taylor
report favourably on its use and have not encountered any serious com-
plications. They emphasize that it should be attempted only when the
disease process appears to involve a large part or most of the thyroid gland.
A split needle, of the Vim-Silverman type, is introduced under local
anaesthesia and usually provides enough material for the diagnosis to be
made. A biopsy can also be taken with a mechanical drill.

Accuracy of diagnosis

In the Northern Ireland material the following diagnoses were made
before biopsy or definitive operation in 129 cases:

Carcinoma S3 (41 ® u )

Suspected carcinoma 27 (21 %)

Benign lesion 40 (38%)

In more than one-third, therefore, malignancy was not suspected before
operation. These figures are fairly typical of many others, although much
greater accuracy has been recorded by a few workers. Anaplastic lesions
were recognized most easily (78 per cent diagnosed or suspected) and
papillary lesions with the greatest difficulty (49 per cent diagnosed or
suspected).

Prophylaxis

Every effort should be made to prevent the development of cancer of the
thyroid by methods which we have indicated already. These include the
administration of iodine to prevent or treat endemic goitre and the ad-
ministration of thyroxine, when indicated, in established cases. The use of
radioactiv'e iodine tests in children and in adults during pregnancy must be
avoided, and the neck should not be irradiated during childhood except for
compelling reasons. If all nodular glands were removed completely the
incidence of cancer would be reduced, but very many unnecessary opera-
tions would be performed. However, all suspicious glands should be
biopsied and all solitary nodules in the thyroid should be excised.

THE THYROID GLAND

312

Treatment

Before undertaking treatment the surgeon must decide :

I. Is the growth unilateral or bilateral?

2 Is it operable?

3. What is the histological structure?

4. Are there metastases in the local lymph glands? and

5. Are there distant metastases?

Four main methods are available for the treatment of thyroid cancer. They
must be considered in relation to the principal characteristics of the three
main types of growth (Table 7.7). (1) Surgery is used for the removal of the

Table 7.7. Comparison of principal characteristics of three main types
of thyroid cancer

Anaplistic

Principal age group

20-60

40-60

50-80

Predominant method of spread
Response to surgery together with.

Lymphatics

Bloodstream

Local invasion

1. Radioactive iodine

Rad

2. Thyroxin*

Good 1

Poor

, Bad

3. External irradiation

Poor |

Fair

Prognosis

Good

Fair

Bad

primary growth and adjacent lymph glands, for the removal of normal
thyroid tissue so that the malignant cells may take up radioactive iodine,
and for the palliative relief of obstruction, especially of the trachea.
(2) Thyroxine is used for suppression of TSH production by the anterior
pituitary and is particularly useful in the treatment of highly differentiated
(papillary) growths. Thyroxine replacement therapy is required for those
whose thyroid tissue has been removed or destroyed completely. (3) Radio-
actiie iodine is taken up by follicular lesions particularly, but effective con-
centrations cannot be achieved until the normal thyroid tissue has been
removed surgically or destroyed (by preliminary treatment with radio-
active iodine). (4) External irradiation is of most value for the palliative
treatment of inoperable anaplastic lesions and for the relief of pain in
secondary deposits in bone.

Surgery

Surgery remains the single most important therapeutic measure, and
(unless the growth is inoperable) thyroxine and radioactive iodine should
be used only to supplement an adequate operation.

MALIGNANT TUMOURS OF THE THYROID 313

Unilateral operable lesiotu. In unilateral cancer of all types the affected
lobe should be removed totally, together with the isthmus, the pyramidal
lobe, the adjacent lymph glands and any other glands which are involved.
Removal of the isthmus and pyramidal lobe should ensure that any recur-
rence will not constrict the trachea. Some advocate a formal block dissect-
ion of the lymph glands on the side of the lesion, especially for papillary
growths, but this is not necessary and does not alter the prognosis. The
management of the opposite lobe depends on the pathological report. If the
growth is papillary there is a 10 per cent chance that small contralateral
lesions are present and a good case can be made for removing it totally.
However, excellent results may be obtained by the use of thyroxine without
further resection. If the growth is follicular the opposite lobe should be re-
moved completely in preparation for treatment with radioactive iodine. If
it is anaplastic nothing will be gained from further surgery.

When a goitre (or one lobe), which had been considered benign and re-
moved partially, is reported to be malignant the problem of a second opera-
tion arises. The decision must be made on the histology of the growth and
on the extent of the local disease. If the lesion is papillary and well circum-
scribed by a layer of normal thyroid tissue, and if no obviously imolved
glands were seen at operation, it is unnecessary to proceed further. If
these criteria cannot be satisfied a second operation for the removal of the
stump of the lobe and the adjacent lymph glands should be undertaken, for
these are the commonest sites of recurrence. If the lesion is follicular both
lobes, together with adjacent or other involved lymph glands on the side of
the lesion, should be removed completely. Anaplastic lesions are rarely
missed at operation, so that the problem of the remaining stump does not
arise.

Bilateral operable lesions . Bilateral growths of all types should be re-
moved completely by total thyroidectomy, and adjacent and involved
lymph glands should be excised. Care should be taken to identify and pre-
serve at least one parathyroid gland if possible. The recurrent laryngeal
nerves should be saved unless they are involved by the growth. One may
he removed if essential, but if both are damaged the patient is left with a
serious disability.

Inoperable lesions. Fixation of the growth to the trachea or carotid sheath
is the main cause of inoperability, and is found most frequently with ana-
plastic lesions. The trachea may be freed of growth, at least partially, at
the time of biopsy. Subsequent treatment depends on the histological
findings.

Thyroxine

The value of thyroxine suppression was first reported by Dunhill in
1937. His first patient had had two operations for thyroid cancer before the

L

314

THE THYROID GLAND

age of 13 and was then treated for recurrence with thyroxine. According
to Burn and Taylor, the patient was still alive 25 years later.

Thvroxtne is most effective in the treatment of papillary growths. It may
be used after surgical removal of the primary lesion or as the sole method of
treatment m those whose growths arc inoperable. Crite reports one death
only in 74 patients, treated by conservative surgery (total or subtotal
lobectomy), who were followed for an average of nine years. Distant
metastases, including those in the lungs, are usually arrested and may
regress. Follicular growths do not respond so well, hut should be treated
with thyroxine, whether or not other forms of therapy are used. Anaplastic
lesions are quite insensitive, and treatment is without benefit.

Thyroxine (0-3 to 0-4 mg. per day), triiodothyronine (100 fig. per day
individed doses) or Diotroxin (0 - 3 to 0-4 mg. per day) may be used. These
maintenance doses are achieved in three to four weeks and are then given
for the remainder of the patients’ lives.

Radioactive iodine

Radioactive iodine is most effective in follicular and mixed follicular and
papillary growths. Anaplastic and pure papillary lesions and follicular
growths of the Hurthle cell variety respond very rarely. Treatment is
worthwhile in only about 15 per cent of growths. The suitability of a
tumour for treatment is assessed on histological grounds and then by
measurement of its uptake of ,3, I after the normal thyroid tissue has been
removed. If the growth is inoperable, if one vocal cord is paralysed or if the
patient is too ill for operation the normal tissue is destroyed by radioactive
iodine (80 me.). Destruction by this method is slow and surgery is pre-
ferable whenever it is feasible. Thereafter the following procedure, based
on that of Pochin, is followed:

1. Two to four weeks after total thyroidectomy, or six to eight weeks
after thyroid ablation with radioactive iodine, a tracer dose of 131 1 is given.
The neck uptake is measured to discover whether or not functioning
thyroid tissue remains. Residual tissue is often found after an apparently
total thyroidectomy. If present it must be destroyed by radioactive
iodine. The ability of the tumour to concentrate the isotope is deter-
mined by measurement of the urinary excretion of 13I I and by direct
counts over accessible tumour deposits. Pochin considers that treatment
is worthwhile if a concentration of 0-1 per cent of a test dose per g. of
estimated tumour mass is achieved.

2. When the patient is fully myxoedematous (and if uptake of the iso-
tope is found) a therapeutic dose of ,3, I is administered. The initial
therapeutic dose should be large (100 to 200 me.), because therapy may
impair the capacity of the cells to concentrate iodine a second time.

MALIGNANT TUMOURS OF THE THYROID 315

3. Uptake is measured every three months and, if it is significant,
further therapeutic doses are given until no further iodine-concentrating
tissue can be detected or else a satisfactory clinical response has been
achieved.

4. Thyroxine replacement is given between the treatments to prevent
clinical hypothyroidism and to abolish the stimulation of the growth by
TSH. It is withheld for three to four weeks before tests or therapy with
151 1 because it impairs the uptake of iodine by the tumour.

5. When the initial treatment is complete the patient is followed up
regularly. Further tracer doses of I3, I (20 to 25 jxc.) are given at yearly
intervals, or whenever clinical or radiographic signs of recurrence
appear, and appropriate therapy is undertaken.

The results of treatment are spectacular in some patients, but disappoint-
ing on the whole, because so few respond. The bone marrow may be
depressed as a result of irradiation, especially if it is the site of secondary
deposits. Leukaemia develops in a significant proportion of cases, but the
risk must be accepted in a patient who already has malignant disease.
Secondary deposits in the lungs may heal with extensive fibrosis, causing
severe respiratory disability, and in those with widespread pulmonary
lesions radiotherapy should be used only as a last resort.

External irradiation

External irradiation is of most value in anaplastic lesions, and should be
applied to the neck in inoperable cases and also after thyroidectomy. In the
malignant lymphoma group the prognosis is quite good. In all others
palliation may be obtained, but the outlook is hopeless. Radiotherapy may
be of value for the relief of pain in distant metastases. It has little, if any-
thing, to offer to those with differentiated tumours.

Treatment policy

Our policy for the treatment of thyroid cancer can be summarize d as
follows :

Papillary lesions are treated by removal of the affected lobe or lobes and
lymph glands. Thyroxine therapy is given thereafter. In inoperable cases
thyroxine is given alone.

Follicular lesions are treated by total thyroidectomy and removal of
affected lymph glands. Radioactive iodine is used For those which con-
centrate it. In inoperable cases radioactive iodine is used for initial de-
struction of the normal thyroid tissue. Thyroxine therapy is given.

Anaplastic lesions are treated by removal of the affected lobe or lobes and
lymph glands. External irradiation is given thereafter. In inoperable cases
irradiation is used as the sole method of treatment.

316

THE THYROID GLAND

Prognosis

The crude survival rate in the Northern Ireland series, which extends
back to 1934, was as follows:

5 > ears 10 years
Papillary 71% 50%

ToHicular 33% 25%

Anaplastic 10% 0%

It is seen that the prognosis is good for patients with papillary lesions, fair
for those with follicular growths and practically hopeless in the anaplastic
cases. Other comparable figures have been reported, but in recent years
the widespread use of thyroxine for patients with papillary lesions has
improved their outlook considerably. Radioactive iodine has had some
benefit on those with follicular growths, but nothing has been found to
alter appreciably the gloomy prognosis for those with anaplastic lesions.

DEVELOPMENTAL ANOMALIES OF THE THYROID GLAND

The development of the thyroid or its descent into the neck may be
arrested at any stage. On the other hand, it may descend excessively and
enter the superior mediastinum. The following developmental anomalies
may be encountered.

Aplasia and hypoplasia are common causes of sporadic cretinism, which
has been described already.

A lingual thyroid is a mass of thyroid tissue near the foramen caecum at
the back of the tongue. It may represent all the thyroid tissue in the body
or accompany a normal cervical gland. The swelling may be noticed in
childhood, but is usually silent until puberty or pregnancy, when it en-
larges and causes symptoms. Dysphagia, respirator)' obstruction or
haemorrhage from large vessels on its surface are usually the presenting
features. It is liable to any of the disease processes which affect the normal
thyroid, including cancer. Hypothyroidism is not uncommon, and thyro-
toxicosis has been described. Tracer studies with radioactive iodine are
very helpful in diagnosis. The neck should always be scanned to discover
whether or not it contains functioning thyroid tissue. Symptoms may
sometimes be relieved by suppression of TSH with thyroxine (0-2 to
0-4 mg. per day). If bleeding or obstructive symptoms persist in spite of
this treatment the lingual thyroid must be excised. If it is the only site of
thyroid tissue in the body an attempt should be made to conserve the
deeper part of it. If this is impossible permanent replacement therapy will
be required.

Incomplete descent of the thyroid or of a part of it may result in persisting
nodules of thyroid tissues along the line of the pyramidal process. Treat-
ment is only necessary if the tissue becomes diseased.

THYROIDECTOMY

317

Excessive descent results in a retrosternal thyroid, v hich may be the site of
a goitre- It may or may not be accompanied by thyroid tissue in the neck.
Treatment is only needed in the event of disease.

Tltyroglossal cysts and fistulae, unless accompanied by nodules of in-
completely descended thyroid tissue, are not of endocrinological impor-
tance. They must be excised thoroughly.

THYROIDECTOMY

The main types of thyroidectomy and the diseases for which they are
performed are as follows:

1. Subtotal thyroidectomy —

Toxic goitre

2. Partial thyroidectomy —

One lobe:

Benign solitary nodule
Both lobes :

Non-toxic nodular or diffuse goitre
Auto-immune (and other types of) thyroiditis

3. Total lobectomy or total thyroidectomy —

Carcinoma

4. Retrosternal thyroidectomy —

Retrosternal goitre

5. Palliative decompression of trachea —

Carcinoma
Riedel’s thyroiditis

Thyroidectomy is no longer used for the treatment of cardiac failure.

Special preoperative measures include the examination of the vocal
cords in all cases by a laryngologist and the control of thyrotoxicosis when
indicated. If there is evidence of paralysis of one or both cords the patient
should be told about it before operation.

Anaesthesia

General anaesthesia with an unkinkable (flcxometailic) cuffed endo-
tracheal tube is used. The anaesthetist should examine the vocal cords
before he passes the tube and again after he has withdrawn it at the end of
the operation. Special care is needed if there are any signs of respiratory
obstruction. If the neck is to be infiltrated with adrenaline neither haio-
thanc nor cyclopropane should be used, because of the danger of cardiac
complications, and if diathermy is to be employed an explosive anaesthetic

318 THE THYROID GLAND

should be avoided. These problems must be discussed with the an-
aesthetist before operation.

The operative technique is described fully in many standard books. The
principles and a few important details only will be outlined here. Surgeons
differ considerably in the ways in which they perform the operations, and
particularly in the order in which they take the various steps.

Exposure of the thyroid gland

The patient is placed on his back with a small pillow between the
shoulder blades to extend the neck. The end of the table is adjusted to
support the head without over-extension, and the whole table is tilted so
that the head is about 1 ft. higher than the feet. These steps prevent venous
engorgement and the development of an occipital headache after operation.

The whole operation must be done gently, and haemostasis must be
secured completely. Small vessels may be sealed with diathermy forceps,
but larger ones must be caught with haemostats, preferably before they arc
cut, and ligated.

The line of the incision is marked with thread, preferably in a skin crease
about 1 in. above the manubrium stemi. The region of the skin flaps is in-
filtrated with a solution of adrenaline in physiological saline (or added to a
0’S per cent solution of procaine or xylocaine), the total dose of adrenaline
not exceeding 0-5 mg. (100 ml. of 1 : 200,000). The incision is made
through the skin and platysma muscle and the flaps are dissected up to the
notch of the thyroid cartilage and down to the sternum. The dissection
must be made superficial to the anterior jugular veins.

The anterior borders of the sternomastoid muscles arc defined, dissected
free from their deep fascial attachments and mobilized laterally. The
fascia co\ering the strap muscles and the pretracheal fascia arc divided in
the midline from the thyroid cartilage above to the sternum below, and the
muscles are separated w ith the finger from the surface of the thyroid gland
and from the trachea. Suitable mobilization and retraction of these
muscles provides adequate exposure of the thyroid in many cases, but if the
gland is very large, firm, vascular or adherent, if there is a retrosternal ex-
tension, if the gland is malignant or if the surgeon is inexperienced they
should be divided on one or both sides. The anterior jugular veins are
divided between ligatures and the muscles are cut between clamps at their
upper ends, to avoid injury to their nerves. The thyroid is now exposed and
must be inspected and palpated carefully. Nodularity is often found to be
much more extensive than was appreciated clinically. Enlarged lymph
glands (suggestive of carcinoma) are sought along the internal jugular vein
and around the trachea. A finger is passed down behind the sternum to
locate any ectopic thyroid nodules in that region.

THYROIDECTOMY

319

Subtotal thyroidectomy

The purpose of the operation is to remove the greater part of the gland in
order to cure the disease (usually thyrotoxicosis) and to relieve any ob-
struction. Sufficient tissue must be left behind at the back to preserve
normal thyroid function and to protect the parathyroid glands and re-
current laryngeal nerves. The amount of gland to be left cannot be defined
precisely, and surgeons vary greatly in their practice. Fortunately, as we
have said, normal function is usually restored. About 3 g. of normal
thyroid tissue are probably adequate for the body’s needs (the normal
gland w eighs about 20 to 25 g.), and if 2 to 3 g. of diffuse goitrous tissue are
left on each side the result will usually be satisfactory'. Rather more should
be left in the case of a nodular goitre. The size of the remnant can, of
course, be estimated only roughly. The vascularity of the gland and the
possibility of recurrence of toxicity are reduced by division of the superior
thyroid artery and by ligation of the inferior artery, but the remnant is still
supplied adequately with blood by additional small vessels.

Each lobe is mobilized in turn and its vessels are ligated and divided
before any tissue is resected. The lobe is retracted medially and the middle
thyroid veins are dissected, ligated and divided singly, well lateral to the
thyroid, as they enter the internal jugular \ein. The upper pole of the gland
is then mobilized and the superior thyroid artery and \ein are divided be-
tween ligatures. It is important not to include any deeper tissue in this
ligature, otherwise the superior laryngeal or recurrent laryngeal nene may
be injured. The inferior thyroid veins are ligated and div ided similarly just
below the gland. There are usually several on each side, and they must not
be taken in a mass ligature for fear of injury to the recurrent laryngeal
nerve. The whole lobe is then rotated medially, while the carotid sheath is
retracted laterally, and the inferior thyroid artery' is located at the point
where it emerges from behind the common carotid artery'. If it is not seen
at once it may sometimes be palpated. Occasionally it is very small or even
absent. The recurrent laryngeal nerve lies immediately behind the lateral
lobe of the thyroid and passes either in front of or behind the artery. The
course of the right nerve is more oblique than that of the left. If the nerve
is to be identified (see later) it is located by palpation and exposed through-
out the whole or most of its retrothyroid course at this stage. It should not
be dissected and mobilized, for this procedure may cause temporary
paralysis. The inferior thyroid artery is then ligated in continuity as far
laterally as possible.

When these procedures are complete on both sides the lobes may be
resected. An attempt is made to identify' and preserve the parathyroid
glands, but they arc often very difficult to find in the presence of a diseased
thyroid, and the search should not be prolonged. The lateral line of

320

THE THYROID GLAND

division of the gland is chosen (on the posterior surface) and haemostats are
applied along it to the capsule and vessels which run over the surface. The
line may be very difficult to determine in cases where nodules project bach-
wards into the neck. The tissue is divided from without inwards, and the
lobe, which is still attached by its isthmus, is dissected off the trachea. It
may then be necessary to enucleate or dissect one or two nodules from the
stump of the gland. Haemostasis is secured and the thyroid stump is o\er-
sewn with catgut. It is usually simplest and safest to insert some or all of
the sutures on the medial side into the fascia on the surface of the trachea.
Great care is taken to avoid picking up the recurrent laryngeal nerve
with the sutures. The procedure is then repeated on the opposite side.
If a pyramidal lobe is present it must be dissected off the front of the
larynx and trachea. The whole of the resected part of the gland is now
removed.

When the operative field is quite dry the incision is closed. Drainage is
necessary whenever there is doubt about the haemostasis, and no harm is
done by drainage in ev ery case. Two corrugated rubber strips may be used.
One is placed down to each thyroid stump, passed through the strap
muscles and fascia just anterior to the sternomastoid muscle, and brought
out through the lateral end of the incision. The strap muscles are repaired
and approximated in the midlrne. The platysma muscle is sutured with
fine catgut and with great care to ensure a neat scar. The skin edges are
approximated with Michel clips.

Partial thyroidectomy

The purpose of the operation is to remove diseased tissue from one or
both lobes and to relieve obstruction. The operation is essentially the same
as subtotal thyroidectomy, except that it is not usually necessary to remove
so much tissue. A solitary nodule, which is thought to be benign, is re-
moved with a good margin of healthy tissue around it. This usually in-
volves the resection of the whole of one pole and half to three-quarters of
the other. Simple enucleation is quite inadequate. Nodules must often
be left in the thyroid stumps of multinodular goitres. The isthmus and
pyramidal lobe should always be rcmo\ed, whether or not a bilateral opera-
tion is necessary, to forestall tracheal obstruction.

Total lobectomy or total thyroidectomy

The purpose of the operation is to remove tissue which is suspected of
being malignant or which is known to be so. Adjacent and enlarged lymph
glands are remo\ed at the same time. Block dissection, as wc have said, is
unnecessary'. The indications for removal of one or both lobes ha\e been
discussed already.

THYROIDECTOMY

321

The incision is made to curve upwards at one or both ends to assist the
removal of high glands. The strap muscles should always be divided and
if there is any suspicion of anterior attachment of the lesion the stemo-
thyroids (and stemohyoids if necessary) on one or both sides are divided
close to their upper and lower insertions and left attached to the gland.
Thyroidectomy proceeds in the usual way, except that the whole lobe is
removed. The recurrent laryngeal nerves must be identified all along the
back of the thyroid. No great harm is done by removal of one nerve, but if
total thyroidectomy will involve the removal of both nerves it is best to be
content with a subtotal resection on one side. Great care should be taken
to identify and preserve at least one parathyroid gland if at all possible.
The isthmus and pyramidal lobe should be removed in all cases, whether or
not both lobes are resected. Lymph glands should be sought around the
trachea and along the internal jugular chain and removed. If enlarged
glands are found above or below the level of the thyroid they should
be pursued and removed as well. Occasionally it may be necessary to
split the upper end of the sternum to remove glands from the superior
mediastinum.

Retrosternal thyroidectomy

Most retrosternal goitres are downward extensions of cervical goitres.
A large nodule at one lower pole lies behind the upper end of the sternum
and may become impacted. The operation follows the usual lines until all
the vessels have been dealt with. The superficial veins may be very dis-
tended, and care must be taken not to damage them. The inferior thyroid
veins usually pass downwards in front of the retrosternal nodule, and must
be divided and ligated firmly. The nodule can usually be freed from the
surrounding tissues with the finger and delivered into the neck by upward
traction on the thyroid. The operation is then completed in the usual way.
Occasionally the mass cannot be delivered, either because it is too large or
because it is a true aberrant intrathoracic goitre and does not arise from the
main gland. If it feels cystic it should be aspirated and may then be
delivered. Otherwise the incision must be extended downwards in the
midline and the sternum split, in the line of the incision, as far as the third
intercostal space. Suitable retraction then allows the goitre to be removed.
This procedure is very rarely required.

Palliative decompression of trachea

In advanced cancer and in Riedel’s thyroiditis palliative operation may
be needed to free an obstructed trachea. The strap muscles may be in-
volved in the disease process and obscure the normal anatomy. However,
with the thyroid cartilage and the trachea as landmarks, it is usually

THE THYROID GLAND

322

possible to define the region of the isthmus, to divide it down to the
trachea and then to resect sufficient diseased tissue on either side of it to
relieve the obstruction. If the trachea is invaded by growth the operation
can be very difficult, and it may be necessary to make a tracheostomy.

Postoperative care

The patient is returned to bed and observed carefully for the first two
dajs, during which time the pulse rate is recorded every hour. Careful
watch is kept for signs of haemorrhage, dyspnoea or tetany, and if they
appear appropriate measures (see later) must be taken urgently.

The drains may be removed after 24 hours. Alternate clips arc taken out
after two days and the remainder on the next day. About one week after
operation the vocal cords should be examined again by a laryngologist.

In the majority of cases the patient may return home about one week
after operation. He should be reviewed at increasing intervals for a year
and then, in simple cases, returned to the care of his family doctor.
Patients with cancer or those who require special and prolonged care (e.g.
for hypothyroidism, hypoparathyroidism, auto-immune thyroiditis, etc.)
must, of course, continue to attend hospital indefinitely.

Complications of thyroidectomy

The special complications of thyroidectomy for toxic goitre have been
described already.

The operative mortality for thyroidectomy of all types is under 1 per cent.
In Belfast there was one death in 400 cases.

Early complications

Sore throat, hoarseness and dysphagia are common during the first two or
three days after operation, but subside rapidly.

Haemorrhage, from an artery or a vein in the wound, within a few hours
of operation, can be serious. Minor oozing is relieved by the drains (if
present), but major loss of blood causes a large haematoma, which may be
deep to the strap muscles, local swelling, stridor, apprehension and general
signs of haemorrhage. The wound must be reopened immediately, the clot
evacuated and the bleeding point found and ligated. Local or genera!
anaesthesia may or may not he required. The wound is packed lightly with
gauze, left open for about two days and then closed by secondary suture-
If severe respiratory obstruction develops the wound must be reopened and
packed in bed and the patient then taken to the theatre. Minor oozing may
cause a haematoma which disfigures the neck permanently. If it is re-
cognized the clot should be evacuated early and the wound resutured a day
or two later.

THYROIDECTOMY

323

Serosanguinom effusions beneath the skin flaps develop fairly commonly a
few days after operation. If left untreated they may become infected and
cause distortion of the scar. If large they should be aspirated.

Wound infection of a serious nature is rare.

Injury to recurrent laryngeal nerves

The nerves are most likely to be damaged during partial or subtotal
thyroidectomy for nodular goitre (simple or toxic), total lobectomy or total
thyroidectomyfor cancer, and operations on recurrent goitres. Haemorrhage
in the wound obscures them, and they may be damaged with forceps during
attempts to stop the bleeding. The nerves are also at risk when any of the
thyroid vessels (except perhaps the middle veins) are being ligated, when
deeply placed nodules are being dissected and when the thyroid stumps are
being sutured.

Injury has been reported in from T5 to 6 per cent of nen es at risk during
bilateral subtotal thyroidectomy, when it has been sought specifically by
laryngoscopy. Since most patients have two nerves at risk (a few have a
nerve palsy already at the time of operation) and since the injury is usually
unilateral, the proportion of patients who suffer injury to one nerve
probably varies between about 2 and 10 per cent. The higher injury rates
are mostly in series in which the nerves were not identified routinely. In
Riddell's hands identification halved the risk of injury (identified: 1-5 per
cent; not identified: 3*1 percent). For these reasons we believe that identi-
fication should be practised routinely, as advocated by Lahcy. In two-
thirds or more of cases the injury is temporary and function returns in a few
weeks. In these it is probably caused by temporary ischaemia, bruising,
traction or oedema and not by division or ligation. On rare occasions
injury to the nerve develops some weeks after operation, presumably as a
result of its involvement in scar tissue.

Unilateral injury causes an abduction paralysis of the vocal cord on the
affected side. Complete paralysis of all movement is rare. Clinically there
is surprisingly little disability, and the patient and surgeon may be un-
aware of any damage unless laryngoscopy is undertaken routinely. How-
ever, the voice may be weakened, and a singer or public speaker may be
seriously handicapped.

Bilateral injury is very serious, but fortunately rare. Bilateral paraljsis of
abduction causes complete closure of the glottis, and stridor is apparent as
soon as the endotracheal tube is removed. The tube should be reinserted
immediately and a tracheostomy performed. This may be closed some time
later if the patient is able to breathe adequately without it. However,
speech will be difficult and dyspnoea will develop on exercise. An opera-
tion in which one arytenoid cartilage is rotated to allow the cord to swing
away from the midline may be of benefit.

324

THE THYROID GLAND

The superior laryngeal nerve is injured occasionally during ligation of the
superior thyroid vessels. The injury' causes little disability.

Hypoparathyroidism

Hypoparathyroidism may follow the inadvertent removal of parathyroid
tissue or interference with the blood supply to the glands. It is not common,
but it is very difficult to control satisfactorily and is subject to serious com*
plications. Most cases develop after total or subtotal thyroidectomy, hut
the condition may follow removal of one lobe only. For some reason
women are much more \ulnerable than men.

The reported incidence after thyroidectomy of all types varies from
under 1 per cent to over 5 per cent. The hypoparathyroidism is often
temporary only, but the reported ratio of permanent to temporary cases
varies greatly.

The commonest clinical feature is tetany', which usually appears within
48 hours of operation. Rarely it develops some weeks later. The sooner the
tetany appears, the more likely is the hypoparathyroidism to be permanent.
Mild symptoms include a vague feeling of discomfort, tingling in the
fingers and toes, numbness and stiffness in the face and limbs, and nausea
and vomiting. The serum calcium level is reduced, usually to between 6
and 8 mg. per 100 ml. It is a wise precaution to measure the serum calcium
in any patient who fails to make satisfactory progress after thyroidectomy.
Tetany requires urgent treatment with calcium gluconate intravenously
(10 to 20 ml. of a 10 per cent solution).

The clinical features and treatment of hypoparathyroidism are discussed
more fully in Chapter 10.

Hypothyroidism

The de\elopment of hypothyroidism after thyroidectomy for different
types of goitre (simple, toxic, auto-immune and malignant) and the
indications for replacement therapy have been discussed already. It
must be emphasized that the surgeon should be on the lookout for
early signs of thyroid insufficiency and must investigate and treat them
appropriately.

Unsatisfactory scar

In the great majority of patients the scar heals well by first intention, and
becomes supple, mobile and practically invisible after some months. In a
small minority, especially after operation for toxic goitre, the scar becomes
puckered, adherent and unsightly, and may de\clop keloid. Appropriate
plastic reconstruction may be necessary \\hen the situation has become
stabilized.

THYROIDECTOMY

325

Belfast series

The following analysis concerns two series of thyroidectomies per-
formed in Belfast. The first includes 300 consecutive operations by
Morrison between 1948 and 1954. The second consists of 100 consecutive
operations by various surgeons on patients in the Metabolic Unit of the
Royal Victoria Hospital between 1958 and 1962,

Metabolic

unit

Total

Thyroid Lesions

Simple nodular goitre

95

38

135 (34%)

Toxic goitre

180

53

233 (5S%)

Thyroiditis

n

2

13 (3%)

Adenoma

0

5 (1%)

Carcinoma

12

2

14 (4%)

Total

300

100 ,

400

Operative Mortality

1

0 ]

I (0 25%)

Complications of Operation

Haemorrhage (severe, requiring
surgery)

Haemorrhage (extensive bruising)

■ s

2 1

4 (1%)

>191

3

Serosanguinous effusions (requiring
aspiration)

Wound infection (serious)

?

4

i

O

1 (0 25%)

Injury to recurrent laryngeal nerves:

Temporary

Permanent

hb

6 (1-5%)

Bilateral

0

0

Hypoparathyroidism (tetany) :
Temporary

Permanent

■i

$ *

'? ( M H«W

Hypothyroidism

Unsatisfactory scar:

■JE

71

Fibrosis and puckering

Keloid

m

lb

* 1 in total thyroidectomy for cancer, 1 in subtotal thyroidectomy for toxic goitre which
had recurred twice after operations elsewhere, and 1 in operation for retrosternal goitre.

+ 4 in 97 operations for simple nodular goitre. Several other cases in patients with
thyroiditis and cancer. Follow-up too short for final assessment.

1 2 (1 deliberate) in total thyroidectomy for cancer.

§ Includes 2 cases after total thyroidectomy for cancer. Follow -up too short for final
assessment.

The following analysis compares the incidence of various complications
after operations for simple goitre (including thyroiditis and adenoma)
with that after operations for toxic goitre (in the Metabolic Unit
series);

326

THE THYROID GLAND

Simple goitre
(45 operations)

Toxic goitre
(53 operations)

Haemorrhage (set ere)

1 (2%)

1

(2%)

Haemorrhage (bruising)

1 (2%)

1

(2%)

Effusions

I (2%)

3

(6%)

Nerve injury (unilateral):
Temporary

0

1

(2%)

Permanent

0

0

Tetany .

Temporary

1 (2%)

5

(10%)

Permanent

0

2

(4%)

Hypothyroidism

I * (2%)

4*

(8%)

Unsatisfactory scar

0

3

(6%)

Thyrotoxic crisis

1 o

Recurrence of thyrotoxicosis

l*f

(2%)

Aggraiation of exophthalmos

0!

Paroxysmal tachycardia

1 (2%)

0

• To] low -lip too short for final assessment,
t 2 of 180 cases ui Monism's senes, but follow-up too short.

X 3 of 63 with exophthalmos in Morrison’s series. None serious.

These analyses underline many of the points which we have made
already.

THYROID HORMONE THERAPY
Four principal preparations of thyroid hormones are available. The
dried extract of the gland (Thyroid BP) has been in use for many years,
but has the disadvantage that the potencies of different batches tend to
vary. Thyroxine (/-thyroxine sodium) is much more reliable and very little
more expensive. Both require at least 24 hours to exert their actions, and
can therefore be given once daily. A proprietary preparation (Dioxtrin,
Glaxo) combines /-thyroxine sodium with the more rapidly effective
/-triiodothyronine in the proportions of 9 : 1. When it is administered once
daily it provides both rapid and sustained actions and is convenient at the
start of treatment. It is unnecessary for maintenance therapy and is rather
more expensive than the other preparations. Triiodothyronine is also
available for use alone.

The equivalent doses are as follows:

Thyroid (BP)

/- Th) roxlne sodium

"Diotroxin"

Tri iod othyronine

Rr.

i

8

00125

i

16

0025

St

i*

32*

0 05*

1*

65*

01*

01 *t

20 1

130

02

195

03

4

260

04

* Scored tablets are supplied in these strengths. For the smallest doses (c g. in Infants)
syrups can be prepared.

t 1 tablet contains /-thyroxine sodium 0 09 mg. and /-triiodotbj ronine 0 01 mg.
j Tablets supplied In these strength*. The 20 /tg. tablet i* scored.

THYROID HORMONE THERAPY

327

Full replacement therapy In an adult is provided by 0-3 to 04 mg- of
thyroxine dailyor by equivalent doses of other preparations. In general,
a low dose (0-05 to 04 mg. per day) is given at first in order to avoid
complications. Myocardial damage is common in hypothyroidism and a
high initial dose, or a rapid increase in dosage, is liable to cause cardiac
irregularities which may prove fatal. The dose is increased at intervals
of one to three weeks by 0-05 to 04 mg. per day until the optimal clinical
effect is obtained and until biochemical measurements return to normal.
The correct dose can be discovered only by trial and error. It is con-
tinued, with suitable adjustments, for as long as it is needed. Full details
are given in the appropriate sections.

FURTHER READING AND REFERENCES
General

advances in thyroid RESEAncn (1961). Transactions of the Fourth International
Goitre Conference, London, July, I960. Ed. Put-Rivers, R. Pergamon Press,
London.

JOLL, c. A. (1951). Diseases of the Thyroid Gland. 2nd Ed. Ed. Rundle, F. F
Heinemann, London.

Mccarrison, R. (1917). The Thyroid Gland in Health and Disease. Batlherc, Tindall
and Cox, London.

MEANS, J. ii. (1954). Lectures on the Thyroid. Harvard University Press, Cambridge.

Modem Concepts of Thyroid Physiology (1960). Ann N.Y. Acad. Sa., 86, 311

Werner, S. C. (1955). The Thyroid. A Fundamental and Clinical Text, Cassell,
London.

The Thyroid Gland (I960). Brit. med. Bull., s6, 1.

WAYNE, e. I. (1960). Clinical and metabolic studies of thyroid disease. Brit. med. J.,
1, 1,78.

Physiology

brewster, w. R., Isaacs, J. r. t oscood, p. F. and kinc, t. L. (1956). The haemo-
dynamic and metabolic interrelationships in the activity of epinephrine,
norepinephrine and the thyroid hormones. Circulation, 31, 1.

lef , w. y ., dro.vsky, d. and waldstein, s, s. (1962). Studies of thyroid and sym-
pathetic nervous interrelationships. II, Effects of guanethidine on the mani-
festations of hyperthyroidism. J. clin. Endocr., 22, 879.

LORAINE, j. A. (1958). Thyrotrophin. In Clinical Application of Hormone Assay, p.
99. Livingstone, Edinburgh.

pitt-rivers, r. and TATA, J. r. (1959). The Thyroid Hormones. Pergamon Press,
London.

FURVE3, II. d. (1960). On the mechanism of hypothalamic control of thyrotrophin
secretion. Acta endocr, (Kbit.), 34, Suppl. SO, 21.

Imestigat/on

Fraser, t. R. (I960). The diagnostic use of radio-iodine in thyroid disease. Post-
grad. tned.y ., 36, 418. „„„„ .

ERASER, t. R-, iiobSon, Q- J. c., ARNOTT, D, c,, and EMERY, E. N. (19a3). Urinary
excretion of radio-iodine as clinical test of thyroid function. Quart, j, Med.,
22, 99.

328 THE THYROID GLAND

COOLDEN, a, w, c. (1960). Use of radioactive iodine in the diagnosis of thyroid dis-
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nouCRTSON*, j. d. and reid, D. D. (1952). Standards for basal metabolism of normal
people in Britain. Lancet, 1, 940.

Simple Goitre

endemic cornu: (1960). II'J/.O. Monograph series. No. 44, Geneva.

SPENCE, a. w. (1960). The aetiology, prevention and treatment of simple goitre.
Postgrad- med. J., 36, 430.

taylor, s (I960). Genesis of the thyroid nodule. Brit. med. Bull , 16, 102.

Toxic Goitre

asper, s p. (1960). The treatment of hyperthyroidism. Arch, intern. Med., 106,
878

BLOOMFIELD, C. W., ECKERT, H , FISHER, M„ MILLER, II., MUNRO, D. S. and WILSON,
C. M. (1959). Treatment of thyrotoxicosis with ,S, I — a review of 500 cases.
Brit. med.J., 1, 64.

boyd, m. w. J. (1959). Carbimazole in thyrotoxicosis. A review of 60 patients.
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brain, R. (1959). Pathogenesis and treatment of endocrine exophthalmos. Lancet,

I, 109.

BURRELL, c. d., fraser, t. R. and DONIACii, d. (1956). The low toxicity of carbi-
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CANARY, J. j., schaaf, M., duffy, b. J. and Kyle, L. H. (1957). Effects of oral and
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CROOKS, j. and wayne, e. J. (1960). Comparison of potassium perchlorate, methyl-
thiouracil and carbimazole in treatment of thyrotoxicosis. Lancet, 1, 401.
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J. din. Endocr., 21, 648.

CSMLETTE, t. M. D. (I960). Thyroid acropathy. Lancet. 1, 22.

HAMILTON, j. c. and LAWRENCE, J. H. (1942). Recent clinical development* in the
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IIAWE, p. and FRANCIS, II. H. (1962). Pregnancy and thyrotoxicosis. Brit, med.J.,
2, 817.

HERTZ, S. and ROBERTS, A. (1942). Application of radioactive iodine in therapy of
Graves’ disease. J. din. Iniest., 21, 31.

HUNC, w., WILKINS, L. and BLI2ZARD, R. M. (1962). Medical therapy of thyrotoxi-
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mcCULLAcii, e. p., clamen, M. and GARDNER, w. j, (1957). Clinical progress in the
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MCGILL, D. A. and ASPER, s. P. (1962). Endocrine exophthalmos. Netc Engl.J. Med.,
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McKenzie, j. M. (1961). Studies on the thyroid activator of hyperthyroidism, j.
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macell, j. (1962). Thyroid crisis. Brit. J. Surg., 49, 594.

MONTGOMERY, D. A. D. (1957). Toxic goitre. In IVhitla’s Dictionary of Treatment,
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pociiin, E. E. (1960). Leukaemia following radio-iodine treatment of thyrotoxi-
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rastoci, c. k. (1962). Personal Communication.

riddell, v. (1962). Thyrotoxicosis and the surgeon. Brit. J. Surg., 49, 465.

FURTHER READING 329

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tion with toxic goitre. Quart. J. Med., 11, 229.

Hypothyrouhsm

ASHER, R. (1960). The diagnosis and treatment of myxoedema. Postgrad, tiled. 1.,
36, 4 7 1.

buzzard, R. M. (1960). Inherited defects of thyroid hormone synthesis and meta-
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ROMFORD, r, (1938), Anaemia in myxoedema: and the role of the thyroid gland in
erythropoiesis. Quart. J. Med., 7, 495.

CHANDLER, r. w., dlizzard, r. M., HDNC, vv. and kyle, M. (1962). Incidence of
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DtLVHtLL, T. p. (1909). Remarks on partial thyroidectomy with special reference to
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jer.Lt.VEK, E. It. and Kelly, r. e. (1960). Cerebellar syndrome in myxoedema.
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lawsov, I. D. (1958). The free achilies reflex in hypothyroidism and hyper-
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lovell, T. W. I. (1962). Myxoedema coma. Lancet, 1, 823.

McCirr, e. M. (1960). Sporadic goitre due to dyshormonogenesis. In Clinical
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sheilman, L., goldberg, m. and larson, f. c. (1963). The Achilles reflex. A
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stanbury, J. B. (1960). Familial goitre. In The Metabolic Basis of Inherited Disease,
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tudhope, c. r. and Wilson, g. M. (1962). Deficiency of Vitamin B12 m Hypo-
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Thyroiditis

dfquervain, f. and GIORDA.VENGO, G. (1936). Die Akute und Subakute Nichteitrige
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doniach, d., roitt, i. m. and Hudson, r. V. (1961). Thyroiditis. In Progress in
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Fraser, t. R. and harrisov, r. j. (1952). Subacute thyroiditis. Lancet, 1, 382.

HASlHMoro, H. (1912). Zur Kenntniss der lymphoma toser VerSnderung der
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Riedel, b. (1897). Vorsteliung eines Kranken mit Chronischer Strumitis. Verb,
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WOOLNER, L. b., MCCONAGHEY, w. m. and beahrs, o. H. (1959). Struma lympho-
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Tumours

BURN, j. i. and TAYLOR, s. f. (1962). Natural history of thyroid carcinoma, Brit.
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CRILE, c. (1960). Papillary carcinoma of the Thyroid. In Clinical Endocrinology l,
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DUNHILL, T. (1937). Surgery of the thyroid gland (Lettsomian Lectures, Abstract).
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330 THE THYROID GLAND

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willis, J (I960). Studies on Carcinoma of the Thyroid Gland, M.D. Thesis,
Queen's University of Belfast.

willis, J, (1961). Incidence and aetiology of thyroid carcinoma. Brit, med.J., 1,
1646.

Thyroidectomy

FOUR MAN, P., DAVIS, R. !!., JONES, D. b. and smith, j. W. c. (1963). Parathyroid
insufficiency’ after thyroidectomy. Brit.J. Surg., 50, 608.

HAWF, p. and LOTHIAN, k. R. (1960). Recurrent laryngeal nerve injury during
thyroidectomy. Surg. Gynec. Obstet., 110, 488.

lahey, F. it. (1938). Routine dissection and demonstration of recurrent laryngeal
nerve in subtotal thyroidectomy. Surg. Gynec. Obstet., 66, 775.

-MORRISON, E. \\9S3). Observations on "Mi consecutive Thyroidectomies. USstw
med.J., 24,41.

piercy, j. E. (1962). Surgery’ of the thyroid gland. In Operatise Surgery, Service
Volume, Part VIII, p. 9. Ed. Rob, C. and Smith, R- Buttcnvorth. London.

ROB, c (1957). Thyroid gland. In Operative Surgery, \ ; o\. 4, Part VI II: Endocrine
Glands, Section I. Ed. Rob, C. and Smith, R. Butterworth, London.

wade, j. s. It. (1960). The morbidity of subtotal thyroidectomy. Brit.J. Surg., 48,

PART II

OTHER MAJOR ENDOCRINE GLANDS

CHAPTER 8

THE NEUROHYPOPHYSIS
(POSTERIOR PITUITARY GLAND)

v The neurohypophysis consists of the following essential parts (fig. 8.1):
(1) the nerve cells of the supraoptic and paraventricular nuclei of the hypo-
thalamus, from which nerve fibres originate and pass by (2) the hypo-
thalamo-hypophyseal tract to end in (3) the nervous tissue of the median

eminence of the hypothalamus, the stalk and the posterior lobe of the
pituitary gland. Similar connections join the tuber cinereum and infundi-
bulum to the posterior lobe. Collectively these structures form the secre-
tory and storage unit for the neurohypophyseal hormones. The cells in the
hypothalamic nuclei probably secrete the hormones, which are transmitted
along the neurohypophyseal tract until they reach the posterior lobe. Here
they arc stored and released in response to physiological needs.

NEUROHYPOPHYSEAL HORMONES
Extracts from the posterior pituitary glands of mammals were found by
du Vigneaud and his colleagues to contain tuo active principles, oxytocin
333

334 THE NEUROHYPOPJIYSIS

and vasopressin. Both are cyclic octapeptides of very similar composition:

Oxytocin

Cy — -Tyr — L<ru — Gla(NH,) — Asp<NH t ) — Cy — Pro— Leu — Glj(NH t )
123 4 5 678 9

Vasopressin

s s

Cy — Tyr — Phe — Glu{N’H,> — Asp(NH,) — Cy — Pro — Arg — GI>(NH,)
123 4 5 6789

There is only one mammalian form of oxytocin, but, so far, two vaso-
pressins ha\e been isolated. That represented is “arginine vasopressin",
which has been found in man, the horse and the ox. Vasopressin is almost
entirely responsible for the pressor and antidiuretic effect of posterior
pituitary lobe extract, while oxytocin acts principally on the uterus and the
lactating breast. However, their actions overlap to a slight extent.

Physiological effects of the neurohypophyseal hormones
Vasopressin (Antidiuretic hormone, ADH)

ADH plays a major role in fluid homeostasis by regulating the reabsorp-
tion of water from the distal renal tubules. Its partial or complete absence
leads to uncontrolled loss of water by the kidneys and the syndrome of
diabetes insipidus.

The release of ADH from the neurohypophysis is controlled mainly by
changes in the osmotic pressure of the plasma, and this is determined
largely by the concentrations of sodium and chloride. The primary "osmo-
receptors" arc in the xvalls of the carotid arteries and are connected to the
neurohypophysis by autonomic nerves; secondary' ones may be present in
the hypothalamic nuclei themselves. A rise in the osmotic pressure of the
plasma causes the release of ADH, which increases the reabsorption of
water by the tubules and thus diminishes the flow of urine. By this means
fluid is retained in the body and the hypcrosmolarity of the plasma is
corrected. Conversely, a fall in osmotic pressure (such as follows the in-
gestion of a large quantity of water) inhibits the release of AD1I, permits
the diuresis of water and corrects the osmolarity of the plasma. An increase
in the volume of the plasma (without any change in its osmolarity) also
causes diuresis, probably by inhibiting reflexly the production of ADH-
There is evidence that the “volume receptors" are located in the walls of
the atria and great veins. Nervous impulses, mediated through the hypo-
thalamus, also play a part in controlling the release of ADH. Strong

NEUROHYPOPHYSEAL HORMONES 335

emotions, surgical stress, morphia and nicotine (by injection or inhalation)
stimulate its release, while alcohol inhibits it.

The precise mechanism by which ADH influences the distal renal
tubules is unknown. Possibly it enlarges the aqueous channels in the
resorptiv e surface of the tubules so that more water may flow through them
under the influence of an osmotic gradient.

Effect of other hormones on the action of vasopressin (ADH). The renal
effect of ADH is modified by the action of the adrenocortical and thyroid
hormones, whose presence is necessary for the development of diabetes
insipidus. Destruction of the anterior pituitary alleviates the condition by
eliminating the diuretic effects of cortisol and thyroxine. Simultaneous
destruction of both lobes of the pituitary, as in post-partum pituitary
necrosis, is rarely associated with diabetes insipidus because of the con-
comitant failure of adrenal and thyroid function. The kidney probably
possesses an inherent concentrating mechanism which is brought into play
when both lobes of the pituitary are destroyed. The mechanism is upset
when cortisone is administered, and diabetes insipidus may be aggravated
or brought to light by corticosteroid therapy. The diuretic action of corti-
sone may depend on its ability to increase glomerular filtration and to
diminish tubular reabsorption of water.

Additional effects of vasopressin (ADH). Apart from its antidiuretic
action, ADH stimulates smooth muscle to contract. In large (pharmaco-
logical) doses it causes vasoconstriction and a rise of blood pressure, but
the blood pressure does not fall after destruction of the neurohypophysis.
In portal hypertension it decreases the splanchnic venous pressure, ap-
parently by constricting the intrahepatic arterio-portal communications.

Oxytocin

The physiological role of this hormone is less clearly defined than that of
vasopressin. Oxytocin is believed to be responsible for the initiation and
maintenance of uterine contractions at parturition, and at term the uterus
is highly sensitive to it. The drug is used extensively in the practice of
obstetrics. Oxytocin is also essential for the ejection of milk from the
breast in lactation, and is probably released by means of a nervous reflex,
initiated by the act of suckling.

J DISEASE OF THE NEUROHYPOPHYSEAL SYSTEM

The only clinical disorder of note results from partial or complete failure
of formation of ADH and is known as diabetes jnsipidus. No comparable
disorder, in which oxytocin formation is deficient, has been recognized and
normal childbirth may occur in patients with diabetes insipidus. No
clinical diseases caused by hypersecretion of ADH or oxytocin are known.

336 THE NEUROHYPO PIIYSJS

^Primary tumours without endocrine function are recognized very rarely
during life.

Diabetes insipidus

This uncommon condition is the result of partial or complete deficiency
of the secretion of vasopressin (ADH) and is characterized by copious and
persistent diuresis of large quantities of dilute urine and intense thirst.
The patient is unable to diminish the flow of urine or to increase its con-
centration in response to rising osmolarity of the plasma. Consequently,
polyuria and thirst develop and large quantities of fluid arc consumed to
make good the deficit. When ADH is injected the concentration of the
urine rises and the output diminishes.

Causative lesions

Any condition which damages the integrity of the neurohypophyseal
system causes diabetes insipidus. The following are seen most frequently
in clinical practice:

I. No recognizable lesion

Familial diabetes insipidus
Idiopathic diabetes insipidus

II. Organic disease

Surgical hypophysectomy

Primary pituitary and parapituitary tumours

Metastatic tumours (usually from cancer of the breast)

Trauma (fracture of the skull)

Inflammatory lesions (encephalitis, basal meningitis, sjphilis and tuberculosis)
Vascular or infiltrative lesions (sarcoid, leukaemia, lymphosarcoma and Hodgkin t
disease)

Xanthomatosis (Hand-SchtOlcr-Christian sj ndrome)

Developmental defect (Laurence-Moon-Biedl syndrome)

Clinical features

Diabetes insipidus occurs at all ages, but about one-third of cases arc
seen in children. It is slightly commoner in males than in females and is
sometimes familial. The principal symptoms are polyuria and intense
thirst. The volume of urine passed is usually between 5 and 10 litres in
24 hours, but may be much more. It is pale in colour and of low specific
gra\ ity (less than 1 ,006). It is difficult to increase the specific gravity abo\ c
1,008 or 1,010, even when fluid is withheld for a long period.

The tissues are not dehydrated, unless fluids arc restricted, but the con-
stant necessity to drink and to urinate interferes with normal activity and
with sleep and leads to fatigue and irritability. I-oss of weight and other
nutritional disorders may develop because the appetite is impaired by the
consumption of large amounts of water, and in children this may result in

DIABETES INSIPIDUS 337

infantilism if the condition is not checked. Constipation is common, the
tongue is dry and parched and sweating is diminished or absent.

The condition often escapes recognition in infants and in unconscious
patients (e.g. those with recent traumatic injury to the neurohypophysis).
Such patients cannot drink unaided and may become seriously dehydrated.
A record of the urinary volume and of the serum electrolyte concentrations
should always be kept during prolonged periods of unconsciousness.
Young children are often irritable and may develop pyrexia and circulatory
collapse. They require frequent drinks of water or glucose solution be-
tween their main feeds.

If the causative lesion involves the hypothalamus other features of hypo-
thalamic disorder may accompany the diabetes insipidus.

Investigations

Two findings are essential to the diagnosis of diabetes insipidus. They
are: (1) the inability of the patient to reduce the flow of urine and to in-
crease its specific gravity in response to a rise in the osmolarity of the
plasma, and (2) the correction of these factors by the injection of vaso-
pressin. The integrity of the neurohypophyseal system and its ability to
secrete ADH may be tested in the following ways:

1. Fluid deprivation test . This requires strict supervision to prevent sur-
reptitious drinking or serious dehydration. The patient is weighed and the
bladder emptied. Fluid is then withheld to the limit of endurance and, if
possible, for 24 hours or until 3 per cent of the body weight has been tost.
Dry meals may be taken. The weight is recorded at 2-hourly intervals and
the volume and specific gravity of the urine are measured hourly.

Interpretation. No completely reliable criteria have been established.
Patients with severe diabetes insipidus experience great thirst and lose
3 per cent of the body weight within a few hours. The volume and specific
gravity of the urine change very little. Those with less severe disease may
tolerate the procedure for longer, and rarely the specific gravity may rise
above 1,010.

2. The hypertonic saline infusion test (fig, 8.2). This test establishes the
ability of the neurohypophysis to secrete antfdiuretfc hormone in response
to an increase in the osmolarity of the plasma. Fluid and tobacco are with-
held for 8 hours before the test. Water (20 ml. per kg. of body weight) is
then administered during 1 hour, the fluid being taken in three or four
equal draughts at regular times throughout the period. Thirty minutes
after the first drink a catheter is introduced into the bladder and specimens
of urine are collected at intervals of 15 minutes. The rate of flow of urine
(in ml. per minute) is calculated. After measurement for 60 minutes (pro-
vided the flow exceeds 5 ml. per minute) an intravenous infusion of 2*5 per

THE NEUROHYPOPHYSIS

338

cent sodium chloride is given, at a rate of 0-25 ml. per kg. of body weight
per minute, for 45 minutes. If there is no decrease in the rate of flow of
urine during the period of infusion, or during the next 30 minutes, ADH
(0 1 unit of an aqueous solution of vasopressin) is given intravenously and
its effect on the flow observed.

Interpretation. Normal subjects show a marked decrease in the volume
of urine (antidiuresis) because antidiuretic hormone is released promptly.

Tig. 8 2. The hypertonic saline infusion test.

In patients with diabetes insipidus the volume does not diminish until
vasopressin is injected.

3. Nicotine test. The patient is deprived of fluid and tobacco for 4 hours,
after which fluid is administered in the same way as in the saline infusion
test. The patient is catheterized and the urine output is measured at in-
tervals of 15 minutes. After 1 hour, if the rate of flow exceeds 5 ml. per
minute, nicotine is given intravenously and urine collected every 10 minutes
thereafter. If the rate of flow diminishes, collections are continued until the
maximum rate is re-established. It is advisable to measure the specific
gravity of the urine, as w ell as the flow, for nicotine may cause syncope and
a reduction in glomerular filtration. The consequent reduction in the
urinary volume is not accompanied by an increase in concentration.

Nicotine is administered as the pure alkaloid in a few ml. of physiological
saline. Non-smokers receive l mg. and those who do not respond are re-
tested with a dose of 2 mg. Habitual smokers are given 3 mg. The nicotine

DIABETES INSIPIDUS 339

may cause dizziness, paraesthesiae, palpitations, a feeling of constriction in
the chest, blurred vision, nausea and vomiting.

Interpretation. In normal subjects nicotine stops diuresis by stimulating
the production of ADH, whereas in diabetes insipidus the volume of urine
does not fall. A disadvantage of the test is that nicotine is probably effective
only when given in a dose large enough to cause unpleasant side effects.

Patients who fail to respond to both the nicotine and hypertonic saline
tests probably have complete los3 of neurohypophyseal function. A few
respond normally to nicotine but not to hypertonic saline, and it is possible
that these have defective osmoreceptor mechanisms, but intact neuro-
hypophyses.

Differential diagnosis

Diabetes insipidus must be distinguished from other causes of polyuria
and polydipsia. The Conditions most likely to be confused are : ( 1 ) diabetes
mellitus; (2) chronic renal disease; (3) primary aldosteronism; (4) hyper-
calcaemia; (5) nephrogenic diabetes insipidus; and (6) compulshe water
drinking (hysterical polydipsia).

Diabetes mellitus can be differentiated readily by the glycosuria and high
specific gravity of the urine. Chronic renal failure gives rise to polyuria and
thirst of moderate degree, a constant specific gravity of the urine (about
1,010), raised blood urea and albuminuria.

In primary aldosteronism the defective tubular reabsorption of water is
resistant to ADH. However, the associated features of muscle weakness,
hypertension, tetany, hypokalaemia and increased excretion of aldosterone
will enable a correct diagnosis to be made. Hypercalcaemia from any cause
may cause polyuria and polydipsia and impairment of the renal concen-
trating mechanism. The serum calcium level should be measured in all
cases of obscure polyuria and polydipsia.

Nephrogenic diabetes insipidus (water-losing nephritis or vasopressin-
resistant diabetes insipidus) is a rare congenital or acquired disorder in
which the renal tubules are insensitive to ADH but the neurohypophyseal
mechanism is intact. The acquired variety is often associated with hyper-
calcaemia and nephrocaleinosis and may thus complicate hyperpara-
thyroidism or multiple myelomatosis. It may also be caused by obstructive
hydronephrosis. Both varieties can be distinguished from true diabetes
insipidus by their unresponsivencss to endogenous or exogenous ADH.
Removal of the cause may restore the sensitivity of the renal tubules to ADH
and cure the condition. Otherwise symptomatic relief may he given by the
use of chlorothiazide or related drugs.

Compulsive renter drinking (hysterica! or psychogenic polydipsia) is the
condition most often confused with diabetes insipidus. It is four times

THE NEUROHYPOPHYSIS

340

commoner in women than in men, may be intermittent in nature, and is fre-
quently associated with a previous history of other hysterical symptoms or
neurotic illness. It can usually be distinguished from true diabetes in-
sipidus by means of the tests described abo\e, which will demonstrate an
intact neurohypophyseal system. The patients are often unco-operative
and unreliable in their behaviour (even drinking water from flower vases),
so that rigid supervision of the tests is necessary. When there is doubt
about the diagnosis, a long-acting injection of ADH (5 units of vasopressin
tannate in oil) may be given. Patients with diabetes insipidus lose their
thirst and reduce their intake of fluid, but those with compulsive water
drinking continue to drink. They may become ill and vomit from the
effects of overhydration. Some patients with long-standing compulsive
water drinking revpal impairment of neurohypophyseal function when
special tests are carf|ed out, while others with true diabetes insipidus drink
more than they need to quench their thirst. These facts are not always
appreciated and may account for some of the difficulties in differentiating
between the two conditions.

Treatment

The causative lesion should be treated if possible. Otherwise replace-
ment therapy with ADH should be given in a dose sufficient to control the
symptoms.

Vasopressin tannate in oil (5 units per ml.) is convenient and is given by
deep intramuscular injection. The dose and frequency of administration
depend on the severity of the condition. The dose varies from 2*5 to
10 units and the frequency from twice daily to once every 3 days. The dose
should be adjusted sq that the patient excretes between 1,200 and 1,800 ml-
of urine in 24 hours. When daily injections arc required it is preferable to
give them in the late gftemoon or evening to ensure an undisturbed night's
rest. The oily solution should be w'armed and shaken vigorously before
injection. ADH may plso be administered by nasal insufflation in the form
of powdered posterior lobe (snuff) or nasal spray of the recently introduced
synthetic lysine vasopressin. The dose of the former is 25 to 50 mg. three
or four times daily, and the patient soon learns to estimate the correct dose.
This method is suitable in mild cases only.

Treatment w ith AD H is very effective in most patients. Appetite, energy
and body weight increase, while excessive thirst and frequency disappear.
Various toxic effects may be encountered:

(o) Overdosage with ADH leads to overhydration and water intoxication,
which is characterized by headache, confusion, epileptiform fits, nausea,
vomiting and rarely death. It can be prevented by periodical measurement
of the daily output of urine and by reduction of the dose if the volume falls
below 750 ml. Most patients can do this for themselves.

CITORI STOMA

341

(6) Side-effects on smooth muscle may be caused by excessive dosage.
They consist of nausea, abdominal cramps, diarrhoea and palpitations.

(c) Allergic reactions, due to local sensitivity, may cause painful swelling
and urticaria at the site of injection. A different batch of vasopressin may
be tolerated, and antihistaminic drugs may be useful. In severe cases de-
sensitization may be necessary. Asthmatic wheezing may follow the inhala-
tion of pituitary snuff and necessitate the use of injections. Anaphylactoid
reactions to vasopressin are very rare.

Patients who become intolerant of (or refractory to) vasopressin may be
tried on chlorothiazide (0-5 G. twice daily) or related drugs, together with
potassium salts (3 G. of potassium chloride daily). The results are en-
couraging.

^horistoma

Tumours of the posterior lobe and stalk are rarely recognized. However,
small nodules of large granular acidophilic cells, named chorisromas, may
be found in up to 6 per cent of glands if looked for carefully post mortem.
They are probably not of clinical significance. On three occasions large
tumours of this type have been recognized during life, and we have ob-
served one in association with Cushing’s syndrome.

FURTHER READING

BARLOW, e. n. and DE wardener, it. E. (1959). Compulsive water drinking. Quart,
y. Med., 28, 235.

BERLINER, R. W., LEVINSKY, \V. C., DWIDSON, D. G. and EDEN, M. (1958). Dilution
and concentration of urine and action of antidiuretic hormone. Amer. J Med.,
24, 7 30.

BLOTNER, ir. (1958). Primary or idiopathic diabetes insipidus, a system disease,
Metabolism, 7, 191.

carter, a. c. and ROBBINS, j. (1947). The use of hypertonic saline infusions in the
differential diagnosis of diabetes insipidus and psychogenic polydipsia. J. clin.
Endocr., 7, 753.

cates, j. e. and carrod, o (1951). The effect of nicotine on urinary flow in
diabetes insipidus. Clin. Sd., 10, 145.

du Vigneaud, v. (1954). Hormones of the Posterior Pituitary Gland ; Oxytocin and
Vasopressin. Harvey Lect., Ser. L, 1.

Kennedy, c. c. and Crawford, j. D. (1959). Treatment of diabetes insipidus with
hydrochlorothiazide. Lancet, 1, 866.

Leaf, a. (1960). Diabetes insipidus. In Cltnical Endocrinology, I, p. 73, Ed.
Astwood, E. B. Grune and Stratton, New York.

lewis, a. a. c. and chalmers, t. m. (1951). A nicotine test for the investigation of
diabetes insipidus. Clin. Sci., 10, 137.

LVse, s. a. and kernohan, j. \v. (1955). Granular-cell tumours of the stalk and
posterior lobe of the pituitary' gland. Cancer, 8, 61 6.

Martin, f. i. R. (1959). Familial diabetes insipidus. Quart. J. Med., 28, 573.

vernry, E. B. (1946). Absorption and excretion of water. The antidiuretic hormone.
Lancet, 2, 739, 781.

CHAPTER 9

THE ADRENAL MEDULLA

The adrenal medulla is a specialized part of the sympathetic nervous
system and is composed of chromaffin cells and sympathetic ganglion cells.
It is richly supplied with non-medullated nerve fibres, derived from the
splanchnic nertes. Additional small islands of extra-adrenal chromaffin
tissue, the paraganglia and organ of Zuckerkandl, are found elsewhere in
the abdominal cavity and are derived from primitive sympathetic ner\c
cells. Little is known of their function, and normally they degenerate
before adult life is reached.

PHYSIOLOGY

The hormones of the adrenal medulla and the amines of the sympathetic
nervous tissue arc known collectively as) 1 ‘catechol amines*', owing to the

catechol grouping which is common to their molecules. The active secre-
tions arc adrenaline and noradrenaline, which are formed in the neural
tissue from the amino-add tyrosine. The biosynthetic pathway is shown
in fig. 9.1.

The adrenal medulla secretes the two principal catechol amines, adrena-
line and noradrenaline, together with traces of dopamine, in response to
acute stress and nervous stimuli. The first two exert widespread and im-
portant effects on metabolic processes. The adrenal medulla, howc\er, is
not essential to life, and replacement of its secretions is not required after
adrenalectomy.

Adrenaline is the main amine secreted in adult life and is concerned
chiefly with the emergency reactions of “fight or flight”. It causes tachy-
cardia, increases the metabolic rate, accelerates glycogcnolysis in the fiver
and causes mental excitement and anxiety. The other catechol amine,
noradrenaline, is the adrenergic nene transmitter. It causes peripheral
vasoconstriction and is concerned mainly with the regulation of the blood
pressure. It slows the heart and has much less marked metabolic and ner-
342

PHYSIOLOGY

343

Excretion

Products

(*Methory'

Derivatives]

3'Methoxy- Normeta-

tryplamme adrenalin*

l N

Horneraml lie

Acid (HVA)

Adrenaline

I

Meta-

Fig. 94 . Metabolic pathways of catechol amines.

vous actions than adrenaline. These differences account in part for the
variable symptoms of hyperfunctioning lesions of the medulla and render
noradrenaline a much more satisfactory therapeutic agent for the correction
of hypotension.

The catechol amines are probably stored within the chromaffin granules
of the cells of the adrenal medulla, and there is histochemical evidence to
suggest the presence of separate cells for the storage of adrenaline and of
noradrenaline.

The catechol amines are metabolized mainly in the liver and then ex-
creted in the urine, where they can be measured. High levels are often
found in hyperfunctioning lesions of the medulla. The principal metabolic
pathway (fig. 9.1) involves methylation to metaadrenaline and normeta-
adrenalinc and then deamination to vanillyl mandelic acid (VMA). The
quantities (total ranges) of these substances which are normally excreted tn
24 hours (by an adult) are as follows:

Caltehol amines •
Adrenaline
Noradrenaline

0-25 pjM
5-50 pg. '

S-75pg. (3-6%)

"Afethnxy'' derivoth.es
MtindrcmBnet

Normeraadrcnnlmef 1 00-300 pg.i

Vanillyl mandelic acid t 700-6.400 hr.

• Neill (1962).
f Yoshenaga el of. (1961).

J Mahler and HumoJJer (1962).

3+4

THE ADRENAL MEDULLA

It will be seen that only very small quantities of adrenaline and noradrena-
line are excreted unchanged.

DISEASES OF THE ADRENAL MEDULLA
The following tumours, which may or may not cause increased secretion,
are the only important lesions of the adrenal medulla:

Increased secretion

1. Phaeochromocytoma Usual

2. Ganglioneuroma (benign) Common

3. Neuroblastoma (sympathieoblastoma) (malignant) Common

Very rarely simple hyperplasia is associated with increased secretion.

Phaeochromocytoma (chromaffin tumour)

The first complete study of a typical patient, in whom the diagnosis was
made post mortem, was published in 192 2 by Labe, Tinel and Doumer.
Four years later Vaquez, Douzelot and Gerandel recognized the condition
during life, and Laubry treated the patient with success (at least for six
months) by irradiation of the adrenals. The first successful surgical re-
moval of a phaeochromocytoma (which had not, however, been diagnosed
preoperatively), was recorded by C. H. Mayo in 1927. Pincoffs and
Shipley, in 1929, were the first to recognize the condition and then to treat
it successfully by removal of the tumour. Beer, King and Prinzmetal, in
1939, first isolated a pressor substance from the blood from such a patient
and found that operation abolished the pressor effect. Hundreds of phaeo-
chromocytomas have now been reported, and 71 have been treated success-
fully at the Mayo Clinic.

In the past, tumours of chromaffin tissue have been referred to as chro-
maffin cell tumours, phaeochromocytomas or paragangliomas, the latter
term being used for tumours arising in the paraganglia. The term phaco-
chromocytoma is now used for all tumours of chromaffin tissue irrespective
of their adrenal or extra-adren3l origin.

Pathology

This is a rare tumour, usually benign, occurring at all 3gcs, but most
often between 20 and 50 years. It is equally common in the two sexes and
occasionally familial. Two-thirds of the growths arise in the right adrenal,
and bilateral tumours are found in about 10 per cent of cases. Tumours
arising in extraadrenal chromaffin tissue may be found in the retroperi-
toneal space, the thorax, the neck and very rarely w ithin the capsule of the
kidney or in the female bladder. The grow ths are round or ov oid in shape
and, although well circumscribed, are rarely encapsulated. They arc
usually under 5 cm. in diameter, but may be larger. Their structure is

PHAEOCHROMOCYTOMA

omogeneous, but Urge tumours ^ "ik W—m

rey or brownish and the tumours are in „ hich

i^— (von « u, the

multiple, andvacuoUnonoftheqtop m whjch me tastasize

is always present, but variable in V behave in a benign

are indistinguishable histologically from those vth.cn

manner. .. I.™- amounts of noradrenaline

Many phaeMhromocytomas secrete .^ ^ ^ (he former usu3 u y
or a mixture of noradrenaline and a (ion 0 f adrenaline greatly

predominates. Tumours in vvhic Th , increased secretion of catechol

exceeds that of noradrenalme are rare. 1 t b e ir metabolic

amines is responsible for the clinical features, and they ^ , umours
products may be detected in the urin , P be functionally

themselves. Metastases from ™ lg . ; n some phaeochromocytomas
active. Surprisingly, cortisolhasbeen f . ; t h the foregoing but which
Tumours, which are identical histologically w«h th< iftu g 8 ,

do not secrete catechol amines or cause systemic effects, are
found.

Clinical features . ropcirt ions of

The symptoms are variable, depen ,n g , and on w hether their

adrenaline and noradrenaline which are P main syndromes are re-
secretion is intermittent or continuous. exhibit mixed

cognized (1 and 2 below), but patients may be t«nv
forms and whose presenting features are qui . • b t not the com-

1. Paroxysmal hypertension is the m ^' -fabouriOto 45 years,
monest, manifestation. The average ag ,. * oCCUr at intervals, the

Paroxysms of hypertension (systolic an 1 always greater than 200/
blood pressure during an attack being ne y . or precipitated

100 mm. Hg. The paroxysms may ansesponun ^ Remind palpa tion.

by emotion, exercise, preprandial hyp g y ent intervals only. They

They may come on several times a day ora The accompanying

may last for about a minute or for as ong 33 headache, tachycardia and
symptoms and signs, in order of frequency, a J. ’ -n nervousness and
palpitations, sweating, pallor (which -J • a _„ oea , pain in the chest
tremor. Less common features include . oarae sthesiae, nausea,

or abdomen, anxiety, coldness of the extremities, p

346 THE ADRENAL MEDULLA

vomiting, dilatation of the pupils, blurring of vision, and pain and tender-
ness in the right hypochondrium. Occasionally bradycardia is found and
sometimes the face is flushed. Weakness, exhaustion and hypotension fre-
quently follow an attack. In prolonged attacks the fingers and toes may
become gangrenous, and in one patient we observed gangrene of the colon.
In severe cases the systolic blood pressure rises to 300 mm. Hg or more,
and death from cerebral haemorrhage, pulmonary oedema, heart failure or
circulatory collapse may follow.

Examination between attacks may reveal a normal blood pressure or, in
longstanding cases, some degree of hypertension. Mild retinal changes
are present in half the patients, and the BMR is raised in a similar pro-
portion.

The condition must be distinguished from anxiety neurosis, hyper-
insulinism, the hyperventilation syndrome, paroxysmal tachycardia, mi-
graine and periodic cerebrovascular insufficiency.

2. Sustained hypertension is the commonest manifestation. The patients
are, on the average, 10 to 15 years younger than those who develop par-
oxysmal hypertension. The blood pressure may rise progressively from
the beginning or become raised permanently only after rising inter-
mittently for a period. The clinical features and complications are the
same as those of essential or, in very severe cases, of malignant hyper-
tension, and the prognosis is bad. Moderate or severe retinopathy is found
in over half the patients. The fasting blood sugar is high in 70 per cent,
and glycosuria is common. The BMR is raised in 90 per cent of patients,
but thyroid function is normal.

The condition must be distinguished from hypertension of other types
(including prc-eclampsia in pregnant women), thyrotoxicosis and diabetes.
Ganglion blocking agents (e.g. hexamethonium bromide) have the unusual
property of raising the blood pressure in patients with phaeochromo-
cytomas (at least when recumbent). If such an effect is observed as a result
of therapy in a hypertensive subject an adrenal medullary tumour should
be suspected.

3. Unusual manifestations. In some patients the metabolic effects of
adrenaline outweigh the circulatory changes, and symptoms similar to
those of thyrotoxicosis dominate the clinical picture. The hypertension in
this “ metabolic syndrome ” is mild but, unlike that in thyrotoxicosis, it in-
volves the diastolic as well as the systolic pressure. Several patients have
been described recently in whom paroxysmal hypotension has been the
presenting feature, and we have observed one such case. The tumour
apparently secretes a high proportion of adrenaline, which in certain cir-
cumstances may cause a fail, instead of the usual rise, of blood pressure.
I/aematuria, in association with other features, should suggest the presence
of a vesical tumour. Polycyihaemia (possibly due to hacmoconccntration)

PHAEOC1IROMOCYTOMA

347

is an occasional finding, and we have observed it in one case. Hypertension
in a patient with von Recklinghausen’s disease (multiple neurofibromatosis
and patchy pigmentation of the skin) should raise the suspicion of phaeo-
chromocytoma. A phaeochromocytoma may de\elop or be awakened to
activity during pregnancy. If it remains undiagnosed it may cause maternal
or foetal death.

4. Circulatory collapse at operation. Patients with unsuspected phaeo-
chromocytomas, who undergo surgery for other conditions, arc poor opera-
tive risks, and a number of deaths have been reported from cardiac arrest or
peripheral circulatory failure. In exceptional cases induction of anaesthesia
may provoke a hypertensive attack, so that the condition may be suspected
and the operation abandoned until it has been investigated fully.

Patients with phacochromocytomas are usually thin, and the tumours
can be felt in about one-third of cases. Pressure on a tumour may prov oke a
hypertensive attack, and must be avoided in a patient with sustained hyper-
tension. Palpation of the neck and pelvis, which are rare sites for tumours,
should be undertaken routinely.

Investigation

Many tests are available for the investigation of patients suspected of
having phaeochromocytomas, but none is completely reliable. As many as
possible should be performed, and any which yield equivocal results should
be repeated. Surgical exploration of the abdomen should be undertaken as
the final step in a doubtful case.

Investigation is called for particularly in those with suggestive symp-
toms and in all hypertensive subjects who are thin or young, who have a
fluctuating blood pressure or a short history, or who show rapid progression
of the disease.

The following investigations are available:

1. Provocative tests. These are designed to precipitate a paroxysm of
hypertension in a patient whose blood pressure is normal or only slightly
raised (less than 170/110 mm. Hg). The blood pressure should be
measured in both arms throughout. Sev'eral drugs have been used, but the
best is histamine , which causes the tumour to release its secretions. Before
the test the patient should have no sedative for 48 hours and no antihyper-
tensive drugs for 2 weeks beforehand. Failure to take these precautions
may yield false negative results. The blood pressure is observed at rest for
30 minutes and a cold pressor test is then performed, the blood pressure
being recorded before, and 10 minutes after, immersion of the hands in
iced water. After the pressure has returned to normal an intravenous in-
jection of histamine in 0*5 ml. of saline is given rapidly. The adult dose is
0 025 mg. of histamine base; that for a child is proportionally less. This

348

THE ADRENAL MEDULLA

usually causes flushing, headache and a slight fall in blood pressure within
30 seconds. The result is positive, and highly suggestive of phaeochromo-
cytoma, if the systolic pressure rises 20 mm. Hg or more above the highest
reading recorded in the cold pressor test within 2 minutes of the injection.
If the pressure rises alarmingly phentolamine (5 mg.) should be injected
intravenously. A smaller rise occurring later may be encountered in a sub-
ject with a labile blood pressure.

2, Pressor-inhibiting tests. These are designed to lower the blood pres-
sure during paroxysms or when the hypertension is sustained (blood pres-
sure more than 170/110 mm. Hg). The best drug is phentolamine, which
antagonizes the actions of circulating adrenaline and noradrenaline. Drugs

TIME IN MINUTES

Fig 9.2. The phentolamine (pressor-inhibiting) test for phaeochromocytoma.

arc withheld beforehand and the blood pressure is measured (in both arms)
for 30 minutes at rest, as in the histamine test. An intravenous injection of
5 mg. of phentolamine is given rapidly. In phaeochromocytoma the
systolic pressure usually falls ax least S3 mm. llg and the diastolic 25 mm.
for 3 to 5 minutes (fig. 9.2) Normal people and other hypertensit es usually
sustain a much smaller fall, but false positive results may occur.

The histamine and phentolamine tests may be combined by injection of
the latter at the height of the pressor response.

3. Estimation of urinary catechol amines and their metabolites. The cate-
chol amines and their metabolites are usually excreted in the urine in in-

PHAEOCHROMOCYTOMA

349

creased amounts, and can be estimated in various ways. The tests require
fresh 24 -hour specimens of urine, collected in bottles containing 50 mg. of
ascorbic acid. The collection should, whenever possible, be started im-
mediately after a hypertensive attack or a histamine test, when excretion is
likely to be maximal. Several samples of urine should be tested, since in-
creased excretion may only be demonstrable intermittently. High levels
may be found in patients receiving certain drugs, especially methyldopa
(Aldomet), tetracyclines and adrenaline drops or sprays, so that all medica-
tion should be stopped at least t«o days before the collection is started.
Renal failure, jaundice, raised intracranial pressure and lymphoma may
also provide high readings.

The following methods are available:

(i) Catechol amines (adrenaline, noradrenaline, dopamine, etc.) may be
estimated as a group by qualitative and quantitative chemical methods.
The former (Hingerty test) is designed to detect more than ISO fig. of
“noradrenaline equivalents” in a 24-hour specimen. This is the highest
level which is likely to be found in normal subjects or in those suffering
from other types of hypertension. The test is available in most laboratories,
but may be misleading. Quantitative estimations are done in many labora-
tories. Levels well in excess of 180 fig. of “noradrenaline equivalent”, and
sometimes as high as 3 mg. in the 24-hour specimen, are frequently found
in phaeochromocytomas.

(ii) Pressor substances (adrenaline and noradrenaline) may be estimated by
bioassay. The effect of a purified extract of urine on the blood pressure of
an anaesthetized cat is used commonly in some laboratories. The levels
found in phaeochromocytomas are similar to those obtained by chemical
methods.

(iii) Catechol amines and their “methoxy-amino” derivatives (adrenaline,
noradrenaline, dopamine, etc.; metaadrenaline, nonnetaadrenaline, 3-
methoxytryptamine) can be estimated separately and semi-quantitatively
by paper chromatography. The detection of dopamine and its catabolites
may suggest the presence of a malignant phaeochromocytoma.

(iv) Vanillyl mandelic acid, the main excretion product of both adrenaline
and noradrenaline, can be estimated by a quantitative chemical method.
VMA is not estimated by the previous method (iii), since it does not con-
tain an amino group.

The last two tests (iii and iv) have been developed only recently, and
their value is not yet known. However, since the methoxy derivatives of
adrenaline and noradrenaline are excreted in much greater quantities than
the catechol amines themselves, it is likely that they will prove increasingly
useful. In particular, the chromatographic method is capable of dis-
tinguishing between adrenaline and noradrenaline.

350

THE ADRENAL MEDULLA

Catechol amines may also he estimated in the blood, and high levels may
be found in patients with phaeochromocytoma. The method, however, is
difficult and is probably less reliable than those described.

4. Radiography by the methods which are used for detecting adreno-
cortical tumours may be helpful (fig. 3.3). Insufflation of gas may precipi-
tate a hypertensive attack, and phentolamine should be available for its

Fig. 9.3. Itccord of blood pressure and its management during and after
surgical removal of phaeochromocytoma.

control. Radiographic examination of the chest is essential, since tumours
are occasionally found there.

5. Adrenocortical function should be assessed by measurement of the
urinary steroids. Stimulation w ith ACTII should not be given, since it may
precipitate a fatal paroxysm of hypertension.

Treatment

Surgical removal of a phaeochromocytoma is the only effective form of
treatment. Medical measures may, however, be required for the treatment
of emergencies prior to operation or for the preoperative preparation of
the patient.

Severe hypertension, either sustained or paroxysmal, requires treatment
with phentolamine (50 mg. by mouth or 5 mg. intramuscularly, every' 3-fi
hours). Other hypotensive drugs, especially ganglion-blocking agents,
must be avoided because they may aggravate the hypertension.

PHAEOCHROMOCYTOMA

351

Hypotension, occurring primarily or after a severe paroxysm of hyper-
tension, may require treatment with noradrenaline or metaraminol (see
later).

Tumours should be sought and removed without delay, since the prog-
nosis without surgery is bad. This applies particularly to phaeochromo-
cytoma in pregnancy.

Before operation an intravenous drip (preferably a polythene catheter
passed into the inferior vena cava) should be set up. Cortisone need be
given preoperatively only if bilateral tumours arc known to be present or if
adrenocortical function is depressed. The blood pressure must be mea-
sured at frequent intervals throughout the operation (fig. 9 3). It may rise
to a very high level during induction of anaesthesia or w hile a tumour is
being manipulated, and can be controlled with phentolamine (up to 5 mg.
intravenously). It may fall precipitously after remoial, and must then be
controlled with noradrenaline or metaraminol (see later). If it does not fall
the presence of a second tumour should be suspected.

If a large tumour has been demonstrated in one adrenal it is best to
approach it by the thoraco-abdominal route (pp. 123-5). Otherwise, since
the patients are usually thin, the transabdominal route is best. The whole
abdomen is explored with the hand and the aortic region and pelvis as well
as the adrenal glands are palpated. The adrenal areas and any suspicious
masses within the abdomen are squeezed gently and the effect on the blood
pressure is noted. Squeezing of a phaeochromocytoma characteristically
causes the pressure to rise sharply. If a positive response is obtained the
tumour must then be handled as gently as possible until it has been
removed. Both adrenal glands must be exposed, inspected and palpated
carefully. The vessels supplying a tumour should be ligated as early as
convenient during its removal. As much adrenocortical tissue as possible
should be preserved. After removal of a tumour both adrenal areas and any
suspicious masses should be squeezed again and the cfTect on the blood
pressure noted.

After operation a noradrenaline (or metaraminol) drip is required to
maintain the blood pressure at !00 to 110/70 to 80 mm. Hg, but the dose
can usually be reduced and the drip stopped w'ithin two days. Difficulty is
sometimes encountered in weaning the patient off the drip, and in these
circumstances cortisone therapy (or, in an emergency, cortisol hemi-
succinate) for a few' days can be very helpful. Rarely, even in the absence
of severe loss of blood, neither noradrenaline nor cortisone will control the
blood pressure, and transfusion with blood plasma may be life-saving.

Paralytic ileus (possibly caused by the action of catechol amines on the
bowel) may be troublesome after operation.

When the patient has recovered from the operation tests for pkaco-
chromocytoma should be repeated. If they arc still positive the presence of

352

THE ADRENAL MEDULLA

a further tumour should be considered seriously. In particular, if a tumour
has been removed by the thoraco-abdominal route (through which
thorough examination of the opposite adrenal is impossible) a further
operation is advisable.

Results of surgical therapy

Provided the blood pressure is controlled carefully, the operathe mor-
tality is low. In the Mayo Clinic series 71 patients were treated surgically
without a death. The results of surgery are good. Paroxysms stop, the
metabolic disorders disappear and sustained hypertension is greatly re-
duced in most cases. Secondary effects on the cardiovascular system may,
of course, persist.

Malignant tumours, which are unrecognizable histologically, may recur
locally or metastasize as long as 10 years after operation and cause a return
of symptoms and signs. The skeleton and chest should always be X-rayed
for evidence of secondary deposits before the abdomen is re-explorcd.
Operations for recurrent tumours may be difficult because of their great
vascularity. If they cannot be removed radiotherapy is worthwhile and is
sometimes effective.

Belfast series

The findings in 12 cases of phaeochromocytoma observed in Belfast
during the years 1950 to 1962 are recorded below (Eakins, 1962).

Lesions

Benign tumours 12

Carcinoma 0

Situation
Right adrenal
Left adrenal

Bilateral (one in light adrenal medulla, one ectopic above left adrenal)
Ectopic sites in abdominal cavity
Clinical features
Males
Females

Mean age in tumours causing symptoms: 46 years (range 16-66 years)
Hypertension and other classical symptoms
Hypotension
Incidental finding in:

Cardiac failure

Cerebral tumour with von Recklinghausen's disease
Abdominal mass
Fractured skull

Cardiac arrest during appendicectomy

The treatment and results were as follows:

Death before operation
Malignant hypertension
Acute pulmonary oedema

NEUROBLASTOMA AND GANGLIONEUROMA 353

Ofieratne deaths 2

H>potcnsion (wrong side explored) 1

Cardiac arrest (emergency operation during uncontrolled paroxysm — gangrene
of colon) 1

Successful surgery 3

Removal of bilateral tumours (2 operations) 1

Right adrenal tumour 1

Left adrenal tumour 1

Neuroblastoma and ganglioneuroma

Pathology

A typical neuroblastoma consists of immature undifferentiated neuro-
blasts and is highly malignant, while a ganglioneuroma is formed from
well- differentiated nerve cells and fibres, and is benign. There are, how-
ever, many intermediate forms. Neuroblastoma, although rare, is one of
the commonest malignant tumours of infancy and early childhood, and may
be present at birth. It is rare in adults. Ganglioneuroma is, on the other
hand, commoner in older children and young adults. The tumours
probably occur with equal frequency in the two sexes. About one-third
arise in one or other adrenal medulla, one-third in sympathetic tissue else-
where in the abdomen and the remainder in the thoracic or cervical parts of
the sympathetic chains. Multiple primary tumours have been described.

Neuroblastomas metastasise early and widely, and the secondary deposits
may be much larger than the primary lesions. Metastasis to bone is
frequent, and new bone formation in the lesion may lead to confusion with
Ewing’s tumour or osteogenic sarcoma. The name “Hutchinson’s syn-
drome" was formerly given to cases with extensive metastases to the skull.
The term “Pepper’s syndrome” was applied to those with prominent hepatic
secondaries. The lungs and other organs are also involved, and lymphatic
spread to the para-aortic glands is common.

Clinical features

The symptoms are usually non-specific. Intermittent abdominal pain or
pyrexia may develop early, but a growth is rarely suspected until a tumour
is found on palpation. Secondary deposits cause symptoms and signs
locally.

Recently increased excretion of catechol amines and their metabolites has
been reported in a high proportion of patients, especially in infants with
neuroblastomas. Occasionally there have been clinical features similar to
those of phaeochromocytoma and chronic diarrhoea, which have been
cured by the removal of tumours.

Investigation

Radiography of the adrenals and the skeleton, biopsy of accessible
lesions, aspiration biopsy of the bone marrow and surgical exploration are

354

THE ADRFNAt MEDULLA

all valuable. Calcification of the abdominal mass, which is seen in nearly a
third of cases, is a useful finding. Estimation of catechol amines should be
made routinely.

Treatment

The primary tumour should be removed if possible. Irradiation of the
operation site and of secondary deposits may cause some regression, and
temporary remission may be induced by nitrogen mustards and folic acid
antagonists. The results following the removal of benign tumours are good.
Malignant tumours may undergo partial remissions spontaneously or as a
result of therapy, but the ultimate prognosis is hopeless.

NORADRENALINE THERAPY

When noradrenaline is administered intravenously it stimulates the
adrenergic nerve endings and causes constriction of most of the vessels
in the body, including those of the muscles. Consequently it raises the
systolic and diastolic blood pressures. This is the basis of its therapeutic
use in hypotensive states.

Hypotension has many causes. Deficiency of noradrenaline is rare, but
in this type of case therapy with noradrenaline is specific and highly
effective. Loss of blood, cardiac insufficiency, toxaemia or adrenocortical
failure are much commoner causes of hypotension in surgical patients. In
such cases noradrenaline may be a useful adjunct to specific treatment, but
cannot replace it. No hormone or drug, for instance, can provide an ade-
quate substitute for blood in oligaemic shock.

There are certain actions of noradrenaline w hich may be undesirable and
which may limit its clinical usefulness. Vasoconstriction in the kidneys,
liver and uterus reduces the blood flow in these organs. It would therefore
seem wise to use noradrenaline cautiously, if at all, in patients with im-
paired renal or hepatic function or in women who are pregnant. There is
also evidence that the blood flow in the brain is reduced, but the clinical
significance of this observation is uncertain. Noradrenaline (like adrena-
line) may provoke ventricular extrasystoles if used in excessive doses during
anaesthesia with cyclopropane, trichlorethylene, chloroform or halothane-
Constriction of arterioles anywhere in the body causes ischaemia of the
tissues which they supply and, if the constriction is prolonged, the tissues
will die. For this reason therapy with noradrenaline may, in the long run,
defeat its own object. One further disadvantage is that, when given for a
long time, noradrenaline may exert a ganglion-blocking action which per-
sists after the drug is withdraw n.

Several synthetic vasopressor drugs which have been introduced recently
are preferable to noradrenaline in some way’s and m3y come to replace it.

NORADRENALINE THERAPY 355

Foremost among these is metaraminol, a sympathetico mimetic drug,
whose rate and duration of effect can be varied and controlled easily by
alteration of the route of administration.

Indications

The specific indications for noradrenaline therapy are as follows;

(1) Removal of phaeochromocytoma has been discussed already.

(2) Thoraeo-hmbor sympathectomy for hypertension is occasional ly fol-
lowed by severe hypotension in the immediate postoperath e period, pre-
sumably because the sympathetic nerve endings suddenly stop secreting
noradrenaline. The blood pressure can be controlled effectively by nora-
drenaline. It is, however, simpler (and often adequate) to use methyl-
amphetamine intramuscularly.

(3) Spinal anaesthesia paralyzes the sympathetic roots as well as those of
the somatic nerves. This sometimes causes hypotension, which can be
controlled with noradrenaline.

Noradrenaline may be of value as an adjunct to specific treatment in the
following conditions:

(4) Adrenocortical insufficiency. Noradrenaline is highly effective as an
immediate measure in the treatment of an adrenal crisis, and will maintain
the blood pressure until cortisone, administered intramuscularly or by
mouth, becomes effective. It has often been life-saving in the past, but is
very rarely necessary now that the rapidly acting cortisol hemisuccinate is
available for intravenous therapy.

(5) Oligaemic shock. Noradrenaline may sometimes be of use as a tem-
porary measure until the loss of blood has been replenished.

(6) Coronary thrombosis. Noradrenaline increases the blood pressure,
slows the heart reflexly and may increase the coronary’ blood flow. It is
sometimes of value in patients whose blood pressure remains low despite
the relief of pain by morphia.

(?) Peripheral circulatory failure. Hypotension is often caused by the
severe toxaemia, dehydration and metabolic disturbances which occur in
the terminal phases of many acute and chronic diseases. In these circum-
stances it is a contributory cause of death, for life can often be prolonged
(sometimes for two or three days) by the administration of noradrenaline.
As a rule, progressively larger doses are required to maintain the blood
pressure until, at last, there is no response and death supervenes. Rarely,
however, it is possible to tide the patient over a critical phase until specific
measures can take effect. The use of noradrenaline for the treatment of
peripheral circulator)’ failure in diabetic ketosis is described elsewhere.

(8) Cardiac Resuscitation. Adrenaline or calcium chloride arc preferable
to noradrenaline for intracardiac injection, but noradrenaline is useful for

356

THE ADRENAL MEDULLA

maintenance of the blood pressure once cardiac action has been re-
established. Ampoules of a dilute solution are available for rapid injection
intravenously or into the canty of the left ventricle.

Administration

Noradrenaline is administered by intravenous drip in a 5 per cent solu-
tion of glucose or in physiological saline. It is given on its own and should
not be mixed with blood, plasma or dextran. If these arc required as well
two drips must be set up. It should be introduced, if possible, via a long
polythene tube passed up into the vena cava. If this is impracticable a
needle can be introduced into a large vein. Both these methods enable the
noradrenaline to he diluted quickly by blood and are preferable to the use
of a tied-in cannula. The usual initial dose is 4 mg. Df noradrenaline in
500 ml. of glucose solution. The rate at which it is given is determined by
the response, and the blood pressure must be recorded every 1 to 2 minutes
until it has been stabilized. If the solution is introduced too fast the pres-
sure may rise to a dangerously high level. If a rate of CO drops per minute
fails to control the pressure the strength of the solution must be doubled.
Trial reductions of the rate should be made periodically and the infusion
stopped as soon as possibte. If the dose has to be increased to maintain
the response, or if the noradrenaline is required for more than 24 hours,
the patient is unlikely to recover. Sometimes, however, a patient may he
"weaned" off noradrenaline by a change to another vasopressor drug.
Metaraminol (2-10 mg.), ephedrine (10-20 mg.) or methylamphctammc
(5-10 mg.) by intramuscular injection are of value.

An occasional complication of noradrenaline therapy is superficial
gangrene, which may be extensive, near the site at which the solution enters
the vein. It is probably the result of intense vasoconstriction, and it some-
times occurs when the infusion has been given for only a few minutes.
The first sign is local pallor of the skin. The site of injection should be in-
spected frequently and, if pallor is seen, gangrene can be prevented by
multiple local injections of acetyl choline (106-200 mg.), or phentolamine
(5 mg.) plus hyaluronidase (125 units), dissolved in 10 ml. of physiological
saline. The general benefit of the noradrenaline must be weighed against
the severity of the local complication in deciding whether or not to con-
tinue the infusion. Metaraminol docs not, apparently, cause superficial
gangrene.

rVHTllFR READING AND REFERENCES
Physiology

hagcn, P. (I960). The adrenal medulla and its secretions. In Clinical Endo-
crinology /, p. 397. Ivd. Astwood, E. B. Grune and Stratton, New York.
von fl'ler, it. s. (1955), Noradrenaline in hypotensive states and shock; physio-
logical aspects. Lancet, 2, 151.

FURTHER READING

357

Investigations

cifford, R. w.» roth, c. M. and kvale, \v. f. (1952). Evaluation of anew adrenolytic
drug (Regitine) as a test for phaeochromocytoma. J. Amer. tned. Ass., 149,
1628.

jjjncerty, D. (1957). Thirty' minute screening test for phaeochromocytoma.
Lancet, 1, 766.

mauler, d. j. and iiumoller, F. L. (1962). A comparison of methods for deter-
mining catechol amines and 3- me thoxy-4 - h yd ro.vy mandehc acid in urine.

Clin. Ghent., 8, 47.

manger, w. M., wakim, K. G. and boLlman, j. l. (1959). Chemical Quantitation of
Epinephrine and Norepinephrine in Plasma. Thomas, Springfield, IU.

Neill, z>. tv. (1962). Personal communication.

roth, c. M. and kvale, w. F. (1945). A tentative test for phaeochromocytoma.
Amer. J. mtd. Set"., 210, 653.

ROTH, C. M. (1958). Laboratory diagnosis of phaeochromocytoma. Minn. Med., 41,
297.

yoshenaca, K., 1TOH, c., isiiiDi, N., sato, t. and wada, y. (1961) Quantitative
determination of metaadrenaline and normetaadrenahne in normal human
urine. Nature {Load.), 191, 599.

Phaeochromocytoma

BOLLMAN, J. L., FLOCK, E. V., roth, G. M. and kvale, w. f. (1960). Catecholamines
in patients with phaeochromocytoma. J. Lab. din. Mtd., 56, 506.

Bakins, d. (1962). Persona] communication.

cemmell, A. A. (1955). Phaeochromocytoma and the obstetrician. J. Obstet.
Gynaec. Brit. Emp., 62, 195.

ctmmo, R. w., kvale, w. f., maicer, f. t., roth, g. m. and priestuzy, j. t. (1961).
Clinical experiences with phaeochromocytoma. A review of 71 cases. In
Hypertension. Recent Advances. ( Second Hahnemann Symposium on Hyper-
tensive Diseases), p. 586. Ed. Best, A. N. and Mayer, J. H. Lea and Febtger,
Philadelphia.

hughes, L. e., bolt, d. e. and hobson, q. j. c. (1962). Phaeochromocytoma. pre-
senting as resistant intestinal ileus. Proc. roy. Soc. Med., 55, 998.

HUME, D. M. (1960). Phaeochromocytoma m the adult and child. Amer. J. Surg.,
99, 458.

LEATHER, H. M., SHAW, D. B., CATES, J. E. and WALKER, R. M. (1962). Sl\ cases of
phaeochromocytoma with unusual clinical manifestations. Brit, med J , J,
1373.

RAMSAY, i. d. and LANGLANDS, j. II. m. (1962). Phaeochromocytoma with hypo-
tension and polycythaemia. Lancet, 2, 126.

Ganglioneuroma and Neuroblastoma

Isaacs, it., UCDAUC, m. and polctzcr, w. si. (1959). Naradcenaline-sececting neara-
hlastomata. Brit. tned. J., 1, 401.

KINCAID, o. w., hodcson, j. R. and DOCKERTY, m. B. (1957). Neuroblastoma: A
roentgenologic and pathologic study. Amer. f. Roentgenol., 78, 420.

PUiLLtrs, r. (1953). Neuroblastoma. Ann. roy. Coll. Surg. Engl., 12, 29.

Willis, R. a. (I960). Neuroblastoma and ganglioneuroma, fn Pathology of Tumours,
3rd Ed., p. 847. Buttenvorth, London.

CHAPTER 10

THE PARATHYROID GLANDS

By Mary G. McGemcn, M.D., Ph.D.

Medical Urologist, Royal Victoria Hospital and City Hospital, Belfast

ANATOMY

The parathyroid glands are situated in the neck, in relation to the upper and
lower poles of the thyroid gland. There are usually four, but occasionally
five or six may be present. They vary from fawn to reddish brown in
colour and may easily be mistaken for lobules of fat. They are often flat-
tened and oval in shape but, being soft, are moulded readily by adjacent
tissues. The average dimensions of each arc 6 x 4 X 1*5 mm., and the
average weight is 30 to 40 mg.

The anatomy of the glands is very variable, but the arrangement is
usually symmetrical. The parathyroids are often partially surrounded by
small pads of fat through which their vascular pedicles run. The superior
glands are situated behind the thyroid gland, at or above the junctions of
the upper and middle thirds of its lobes. They may cither be closely
applied to the thyroid and lie within its capsule, or lie in small depressions
in its posterior border, or be found in loose areolar tissue a little distance
away. The position of the inferior parathyroids is less constant. They may
lie lateral and posterior to the loner thirds of the lobes of the thyroid, just
below the lower poles, posteriorly between the trachea and oesophagus, or
even within the substance of the thyroid gland. They may lie at or within
the upper pole of the thymus, but are still accessible from the neck. Rarely
they are situated elsew here in the mediastinum, anterior or posterior to the
thymus, or even as far down as the arch of the aorta.

The blood supply of the superior glands usually arises from the an-
astomosing channels between the superior and inferior thyroid arteries.
When the lower parathyroids are situated in the neck or at the entrance to
the thorax they arc supplied by the inferior thyroid arteries. Glands within
the mediastinum proper may be supplied by branches of the inferior
thyroid arteries, or by the intercostal or pleural vessels.

Histology

Under low magnification normal parathyroid tissue from the adult looks
358

ANATOMY AND PHYSIOLOGY

359

not unlike bone marrow, with islands of secretory cells interspersed with
fat cells. Fat cells do not appear in the stroma until after puberty; they
then increase in number until about the age of 40. The stroma consists of a
rich sinusoidal capillary network. The glandular cells are of two types.
The “chief” or *' principal ” cells are small, with vesicular nuclei and poorly
staining cytoplasm which contains vacuoles. “Water-clear" cells, which
are derived from the chief cells, are found in hyperplastic and neoplastic
glands, but probably not in norma! ones. The “ oxyphil ” cells are less
numerous and larger and have a granular cytoplasm which stains with
eosin. Their nuclei stain more deeply. The cells are not arranged in a
regular pattern and their proportions vary in different glands.

PHYSIOLOGY

Active extracts of the parathyroid glands were first prepared by Hanson
in 1924 and by Collip in 1925, but the parathyroid hormone (parathor-
mone, PTH) has not yet been isolated in a pure form. The purest extracts
have a molecular weight of about 9,000 and are polypeptide in nature.

The function of PTH appears to be that of maintaining the blood calcium
and phosphorus at constant levels. A low level of calcium in the blood
stimulates, and a high level inhibits, its production. The serum calcium
(which is the form in which the blood calcium is measured) is normally
about 10 0 mg. per 100 ml., the range for most laboratories being 9*5 to
11*0 mg. per 100 ml. The serum calcium is composed of two fractions, one
ultrafiltrable and the other non-filtrable. The latter is almost entirely
protein-bound. A small proportion of the ultrafiltrable fraction is bound to
citrate and the rest, which is in an ionized form, is the only fraction which
is under the control of the parathyroid glands. The normal concentrations
of the various fractions of serum calcium (in mg./lOO ml.) are as follows:

Ultrafiltrable

Ionized

Bound to derate
Non-filtrable

Total

6 0 (5 9-6 S)
5-5
OS

40

10 0(9 5-11 0)

The serum inorganic phosphorus normally has a concentration of 3*0 to
4‘0 mg. per 100 ml.

If the parathyroid glands are removed experimentally from an animal, or
accidently during thyroidectomy in man, four metabolic changes occur:
(1) the scrum calcium falls; (2) the serum inorganic phosphorus rises
simultaneously; (3) the urinary excretion of calcium rises at first and then
falls; and (4) the urinary excretion of inorganic phosphorus falls at first and

360

THE PARATHYROID GLANDS

rises later to a level a little below normal. There are two main views about
the cause of these changes. The older one, proposed by Collip, is that
PTH acts directly on bone to cause the solution of calcium salt. Albright
and his co-workers suggested later that PTH acted on the electrolytic
equilibria of the body fluids and that the bone changes, u hen they occurred,
were secondary to the chemical ones. They proposed the following se-
quence of events. PTH increases the excretion of phosphate by the kid-
neys and lowers the blood phosphorus. The product of the concentrations
of calcium and phosphorus tends to be constant, so that as one falls, the
other rises. As a consequence of the lowered phosphorus level, calcium is
mobilized from bone until its concentration in the blood is higher than
normal and the calcium-phosphorus product is restored. The raised con-
centration of calcium in the blood in turn increases its excretion in the
urine and causes the continued resorption of bone. The phosphorus, which
is resorbed at the same time, is excreted even more readily than the calcium
and the blood phosphorus remains low. This hypothesis explains the low
serum phosphorus which is^often'found in hyperparathyroidism, but it does
not account for all the observations. Thus, in ncphrectomized animals,
PTH increases the concentration of calcium in the blood, despite a rise in
phosphorus which, in other circumstances, is associated with a fall in the
calcium. Furthermore, parathyroid glands transplanted into hone cause
local erosion. In man the time relationships of the changes in the serum
and urine after parathyroidectomy, and after injection of PTH, do not
support the view that the primary effect is on the excretion of phosphate.

It is probable that, as Collip suggested, the most important action of
PTH is that of facilitating the resorption of calcium from bone and that its
effect on the renal excretion of phosphorus, at least under physiological
conditions, is of minor importance. Recent work, in fact, indicates that
PTH stimulates the total metabolism of calcium in bone and increases the
rate at which it is deposited as well as that of its resorption. Resorption
maybe accelerated by an increase in the concentration of citrate around the
bone trabeculae. There is now evidence that PTIl causes a reduction in
calcium clearance for any given filtered load, thus conserving the body’s
calcium at the same time as withdrawing it from bone.

It has been suggested, although the evidence is inconclusive, that more
thaw owe parathyroid hormowe is respowsihle for these various effects and
for the different guises in which clinical hyperparathyroidism may appear.
It is not certain whether a parathyrotrophic hormone is produced by the
pituitary. Hyperparathyroidism may be associated with other endocrine
diseases in the syndrome of multiple endocrine adenopathy, hut in the
most common type of hj perparathj roidism one parathyroid gland only is
overactive and the condition does not usually recur after its removal.
Ilypophysectomy docs not cause hypoparathyroidism.

INVESTIGATION OP PARATHYROID DISORDERS

361

INVESTIGATION OF PARATHYROID DISORDERS

Direct measurement of the circulating level of PTH is not possible, so
that it is necessary to assess alterations in parathyroid function by changes
in blood chemistry and by other tests. The special investigations that are of
help in the diagnosis of parathyroid disorders are as follow:

Serum calcium and phosphorus

These are essential biochemical investigations in parathyroid disease.
The calcium is high and the phosphorus is usually low in hyperpara-
thyroidism, while the opposite changes are found in hypoparathyroidism.
As small elevations of the serum calcium may be significant, it is essential
that the estimation. should be made accurately. The upper limit of normality
varies in different laboratories, depending on the method used and on
minor variations in technique. In our laboratory, in which the oxalate-
permanganate method is used, the upper limit is 1 1 ‘0 mg. per 100 ml. It is
best to use samples of blood obtained in the fasting state and important to
avoid prolonged stasis before entering the vein. A casual specimen of
blood is, however, satisfactory, provided the patient has not drunk milk
within a few hours of the test. With care each individual estimation of
the serum calcium can be made reliable.

Estimation of the serum phosphorus (as phosphate) is technically easier
and is usually done on the same sample of blood. Its level does not
necessarily vary inversely with that of the serum calcium. The lower limit
of scrum phosphorus is usually 3-0 mg. per 100 ml., but occasionally values
as low as 2-5 mg. per 100 ml. may be encountered in patients without para-
thyroid disease.

Alkaline phosphatase

The alkaline phosphatase is elevated in hyperparathyroidism only if bone
disease is present. The increase usually parallels the radiological changes.

Urinary calcium excretion

The excretion of calcium in the urine may be increased in hyperpara-
thyroidism. The increase can often be detected on an ordinary diet (about
800 mg. of calcium per day), but more precise information is obtained by
the use of a diet low in calcium. On a standard diet containing 150 mg. of
calcium per day we have found that the upper limit of excretion for normal
subjects is 154 mg. per 24 hours. Patients with normal excretion on an
ordinary diet continue to excrete normally on this diet. However, the test
is useful for the detection of patients with small elevations of the urinary
calcium and for the exclusion of some who appear to have hypercalciuria on
an ordinary diet. It can be performed on outpatients, provided they are

362 TUB parathyroid glands

intelligent, are carefully instructed and are given diet sheets and scales for
weighing the food. The diet is eaten for four days and 24-hour collections
of urine are made on the third and fourth days. In hypoparathyroidism the
urinary excretion of calcium is negligible in amount. Sulkow itch's reagent
can be used as a qualitative test of urinary calcium, but is valueless without
knowledge of the 24-hour volume of urine. If a 24-hour urine collection is
available it is easy and much more informative to use a quantitative test.

Urinary phosphate excretion

An increase is found in about 60 per cent of patients w ith hyperpara-
thyroidism, and also in some patients with renal stones who do not have
hyperparathyroidism and in patients with hypercalcaemia from other
causes.

Tests of bone metabolism

A tracer test of bone metabolism, in which stable strontium is used, has
been developed recently and enables the rate of new bone formation to be
measured. Hyperparathyroidism is the only disease associated w ith hyper-
calcaemia in which the rate is increased. In hypoparathyroidism the rate of
bone deposition is slow.

Miscellaneous tests of parathyroid function

Many other special tests of parathyroid function have been devised, but
are less reliable than those described.

Radiological examination of the skeleton
The most useful X-rays in patients suspected of hyperparathyroidism
are those of the skull and hands. Radiographic changes may also be present
in hypoparathyroidism and in pseudohypoparathyroidism.

DISORDERS OF THE PARATHYROID GLANDS
Lesions of the parathyroid glands usually cause disturbance of endocrine
function. One of two clinical syndromes results, depending on whether
secretion of PTI1 is increased or diminished. The lesions and syndromes
are classified as follows:

A. With disturbance of endocrine function
1 . Increased secretion

lesions

(i) Hyperplasia:

(fi) Primary.

( b ) Secondary.

(ii) Adenoma,

(iii) Carcinoma.

DISORDERS OF THE PARATHYROID GLANDS

363

Syndrome

Excess of PTH causes hyperparathyroidism. The primary disease is
caused by hyperplasia, adenoma or carcinoma, all of which produce the
same clinical and biochemical features. Although there are several clinical
variants of hyperparathyroidism, they are not related to any special type of
pathological lesion. Secondary hyperparathyroidism is associated with
chronic renal failure and metabolic bone disease.

2. Decreased secretion

Lesions

(i) Congenital absence or hypoplasia.

(ii) Surgical removal.

(iti) Destruction by haemorrhage, infarction, tuberculosis, secondary
carcinoma (rare and usually symptomless unless all glands are destroyed).

(iv) Infarction of adenoma (previously causing hyperparathyroidism).

Syndromes

Chronic deficiency causes hypoparathyroidism.

Acute deficiency causes tetany.

Temporary' deficiency causes hypoparathyroidism in newborn babies of
mothers with hyperparathyroidism.

B. Without disturbance of endocrine function

Lesions

(i) Adenoma.

(ii) Carcinoma.

General pathology
Hyperplasia

Hyperplasia affects all four glands more or less equally. The fat globules
which occupy a third to a half of the normal gland are reduced and may
almost disappear. They are replaced by chief cells arranged in sheets, cords
or acini. These cells stain poorly and, when large and vacuolated, are
known as “water-clear” cells. The oxyphil cells may also be increased in
number but are rarely prominent. The histological features of secondary
hyperplasia resemble closely those of the primary variety.

Hypoplasia and congenital absence

In idiopathic hypoparathyroidism all the parathyroid tissue may be
absent or atrophied.

364 THE PARATHYROID GLANDS

Tumours

A typical adenoma contains a rim of compressed normal parathyroid
tissue, which may not always be identified readily. If only one gland is
enlarged it is usually regarded as an adenoma even when the compressed
rim is not seen. In other respects the histological appearance is the same as
that of primary hyperplasia. The predominant cell type varies from the
dark chief cell to the water-dear cell, and the arrangement of the cells
shows a similar variation. It is doubtful whether oxyphil cells form func-
tioning tumours.

Multiple adenomas are found in 20 per cent of cases of primary hyper-
parathyroidism, and may affect two or even three glands. If the rim of
normal parathyroid tissue cannot be identified the distinction from primary
hyperplasia can be difficult, and may depend on the finding of normal-
sized glands at the operation. There are no special histological features.

Carcinoma of the parathyroid is very rare. The cells invade and grow
through the capsule of the gland and infiltrate the surrounding tissues.
The tumour appears to have little tendency to metastasize.

Multiple endocrine adenopathy

Rarely hyperparathyroidism is one feature of the syndrome of multiple
endocrine adenopathy. Lesions of the anterior pituitary or the islet cell
tissue of the pancreas usually dominate the clinical picture.

Primary hyperparathyroidism

This is a relatively common disorder, but one which frequently passes
unrecognized. The first known clinical descriptions were those of Bcvan in
1743 and Cadwalader in 1745. In 1891 von Recklinghausen described
three patients whose bones were deformed by a condition which he called
“osteitis fibrosa cystica”, one of whom probably suffered from hyperpara-
thyroidism. In 1903 Askanazy found a parathyroid tumour in 3 patient
with this condition, and in 1925 Aland! removed one from a similar patient
and observed that the bony lesions healed. For many years osteitis fibros3
cystica was regarded as the chief form of hyperparathyroidism.

Pathological effects of hyperparathyroidism

Most of the pathological effects of the disease can be related to the dis-
turbance of calcium metabolism. Resorption of calcium salts from the
bones leads to decalcification and its sequelae. The raised blood calcium
causes increased excretion of calcium in the urine and the formation of
renal stones, it reduces the excitability of nerve fibres and lowers the tone of
muscles, and it may tead to the deposition of calcium salts in the paren-
chyma of the kidneys, in the corneae of the eyes and elsewhere. Finally,

PRIMARY HYPERPARATHYROIDISM 365

the raised blood calcium is probably responsible in some way for duodenal
ulceration and various alimentary symptoms.

Clinical features

Hyperparathyroidism is rather commoner in women than in men. It
may develop at any age, but is recognized most commonly between the ages
of 20 and 60 years. The clinical features are very variable, but the following
main varieties of the disease are recognized. Patients may exhibit more
than one of the main features.

Renal stones

The formation of renal stones is much the commonest clinical manifesta-
tion. The symptoms and signs are the same as those caused by any type
of urinary calculus. The stones are usually composed of mixtures of
calcium salts, but sometimes consist of pure calcium phosphate or oxalate.
X-rays of the kidneys may show not only calculi and their effects but also
fine scattered calcification of the renal parenchyma. The diagnosis of
hyperparathyroidism is rarely made before bilateral or recurrent calculi
have formed, but surgeons should look for the condition in every patient
with a calcareous renal stone. In Belfast we (McGeown and Morrison)
have found hyperparathyroidism in 20 per cent of patients with renal
calculi attending a specialized renal stone clinic. In ordinary surgical out-
patients the incidence is unknown.

Renal function may be impaired by the stones and by their complications,
and also by deposits of calcium salts in the renal parenchyma. Polyuria and
polydipsia may result, although these symptoms are rare in our experience.
Hypertension is fairly common but not invariable, even at a late stage of
the disease. Azotaemia may cause dryness and scaliness of the skin.

Patients with renal stones often have alimentary symptoms and lack of
energy, but do not usually suffer from bone pain.

Rone disease

The skeletal changes of primary hyperparathyroidism are well known
but rate. They consist of generated decafcificatibn (osteoporosis and
osteitis fibrosa) sometimes accompanied by bone cysts (osteitis fibrosa
cystica), deformities and giant cell pseudo-tumours (“osteoclastomas").
The presenting clinical feature may be a giant cell tumour which may be
removed without the decalcification being recognized. Other clinical
features include pain in the bones and joints, loss of height due to collapse
of the vertebral bodies, pathological fractures and clubbing of the fingers.

On radiological examination of the bone two characteristic features arc
seen: (1) an alteration in the texture of the bones, and (2) the presence of
subperiosteal erosions. The changes can be appreciated first in the skull,
hands and the distal ends of the clavicles. In early cases there may be only

366

THE PARATHYROID GLANDS

slight loss of density of the mandible and maxilla and loss of definition of
the lamina dura of the teeth. In severe cases the tables of the skull show a
ground-glass appearance, which is quite characteristic, and the inner table
of the skull becomes indefinite (fig. 10.1). Occasional!)’ there may be large

Fig. 10.1* The skull in hyperparathyroidism.

Note loss of definition of inner table and ground-glass appearance of the bone of the
vault.

clear areas in the skull. In long bones coarse, wavy trabeculae, which have
been likened to basket work, are seen along the inner aspect of the cortex.
These changes arc often marked at the lower end of the radius and ulna
and in the middle of the femoral shaft. The distal ends of the clavicles
become decalcified. Tiny areas of resorption appear beneath the perio-
steum of the bone cortex (subperiosteal erosions) and are seen most often
in the phalanges (fig. 10.2). Rarely they develop in the long bones and on
the articular surfaces of the patellae.

“Osteoclastomas" may affect any bones, but occur most commonly in the
jaws, ribs and lower ends of the tibiae and fibulae (fig. 10.3). They ate
composed of masses of connective tissue containing osteoclasts and osteo-
blasts and resemble primary’ osteoclastomas histologically. They are not,

PRIMARY HYPERPARATHYROIDISM

however, true tumours and regress after parathyroidectomy. On X-ray
examination they resemble bone cysts in their absence of structure, but
clinically they cause local expansion of the bone. Early symptoms from the

368

THE PARATHYROID CT.ANDS

Patients with bone disease often have alimentary symptoms. Some have
renal stones, but others do not suffer renal symptoms until diffuse cal-
cification of the kidneys causes renal failure.

Alimentary symptoms

Alimentary’ symptoms often accompany other features of the disease and
occasionally dominate the clinical picture. Adesola, reviewing 70 of our
patients, found that symptoms were of three main types and that they were
present as follows:

Mates (31) Female* (30)

(l) Major djspepsia

(at) Peptic ulcer (usually duodenal) 7 (23%) 1 (3%)

(4) Ulcer-like symptoms, but ulcer not demonstrated 3 (10%) 5(13%)

(u) Other alimentary symptoms

(а) Anorexia, nausea and vomiting 14 (20%)

(б) Constipation 6 (9%)

Total haling alimentary sy mptomi 36 (51%)

In many cases the ulcers (including two stomal ulcers) were cured and
alimentary symptoms were relieved by parathyroidectomy (see Chap. 16).

Acute hyperparathyroidism ( parathyroid crisis)

This conditions had been reported only 22 times up to 195S. It has been
recognized twice in Belfast and may not be as rare as was belieted pre-
viously. In more than half the patients the diagnosis is made after death.
Acute hypercalcaemia may supervene in a patient with renal stones or bone
disease, and these features may provide clues to the diagnosis. Other
patients complain of the recent onset of non-specific symptoms, such as
malaise and headache, pcihaps associated with abdominal pain, loss of
appetite and weight, and constipation. They then become acutely ill with
severe vomiting, usually accompanied by oliguria, dehydration and cloud-
ing of consciousness, w hich progresses rapidly to coma and death unless the
condition is recognized and treated. The serum calcium is \ery high,
usually over 17 mg. per 100 ml. Similar symptoms may accompany hyper-
calcaemia from other causes, such as carcinoma of the breast with extensive
metastases in bone. Acute hyperparathyroidism is a true emergency and
requires rapid correction of dehydration and electrolytic imbalance, fol-
lowed by emergency exploration of the parathyroids.

Other varieties

Muscular iceakness is a very common symptom and may be the pre-
dominant feature. Anaemia often develops late as a result of either renal
impairment or fibrous replacement of the bone marrow. Its failure to
respond to therapy may provide a clue to the diagnosis. Mental changes may
be present and vary from impairment of memory 3nd mild confusion to

PRIMARY HYPERPARATHYROIDISM

369

delusional psychosis. Some patients may be admitted to mental hospitals.
Very rarely a tumour may be palpable in the neck and is then usually mis-
taken for a thyroid nodule. Pancreatitis sometimes complicates hyperpara-
thyroidism. Tetany in the newborn is a rare manifestation of hyperpara-
thyroidism in the mother. One such case has been seen in Belfast. Finally,
the condition may be asymptomatic and discovered incidentally during in-
vestigation of other complaints.

Physical signs

There are few physical signs except in the presence of severe bone
disease, and most of those which may be found ha\e been mentioned
already. In advanced cases yellow-white plaques, associated with increased
vascularity, may be seen in the conjunctiva. Calcium salts may be deposited
in the superficial layers of the periphery' of the come a (“band keratitis”)
and may be seen on slit-lamp examination. Occasionally similar deposits
may be seen in the ear drums.

Belfast series

The presenting features in 96 cases were as follows :

Renal stone 79 (82%)

Rone disease 9 (10%)

Gastrointestinal symptoms 5 (5%)

Acute hyperp arat hyraidism 2 (2%)

Asymptomatic (tetany m the newborn) 1 (1%)

Refractory anaemia 0

Tumour m neck 0

Biochemical aspects

The classical changes associated with hyperparathyroidism are: (1) ele-
vation of the serum calcium; (2) depression of the serum phosphorus;
(3) increased excretion of calcium and phosphorus in the urine; and (4)
elevation of the serum alkaline phosphatase when bone disease is present.
The elevation of the serum calcium is the most important single finding.
It may, however, be modest and intermittent (fig. 10.4), and it is therefore
important that accurate readings should be obtained on at least four occa-
sions, over a period of months, in patients suspected of hyperparathy-
roidism. If there is considerable elevation of the serum calcium at the first
estimation the diagnosis may never be in doubt, but this is uncommon in
those who present with renal stones. The highest values tend to occur in
patients with bone disease, but when the skeleton is grossly decalcified the
serum calcium falls again towards normal.

It has been reported that the ionized calcium may be elevated out of
proportion to the protein-bound calcium, but this has not been the general
experience.

SERUM C4LC/UM my per cent

370

THE PARATHYROID GLANDS

The urinary excretion of calcium is high in 60 per cent of patients with
primary hyperparathyroidism at the time of investigation, but a calcium
balance may be necessary for the detection of a small increase. The

13

12

11

10

2 4 6 8 10 12 14 15 IS M

MONTHS

Fig 10.4. .Serum calcium levels observed at intervals before and after para-
thyroidectomy.

urinary excretion of calcium in 88 of our patients with hyperparathyroidism
(on a daily intake of 150 mg.) was as follow:

Urinary calcium

(mg./24 hr.) No. of patients

<154 34

154-200 17

>200 37

Total 88

The urinary calcium is usually normal in patients with impaired renal
function and is occasionally normal in those in whom renal function is un-
impaired. An increased excretion of calcium in the urine is found not un-
commonly in patients with renal stones who do not otherwise appear to
hare hyperparathyroidism.

The reabsorptinn of phosphate by the renal tubules is decreased in 60 to
70 per cent of patients with hyperparathyroidism. The same abnormality,

PRIMARY HYPERPARATHYROIDISM 371

however, is often found in other patients with renal stones, in those with
hypercalcaemia from other causes {see later), and in patients with osteo-
malacia, Cushing’s syndrome and Sjogren’s syndrome.

The scrum phosphorus is often less than 3-0 mg. per 100 ml. When
renal function is poor, however, normal or raised levels may be found be-
cause the excretion of phosphate by the kidneys is impaired. However,
some patients with hyperparathyroidism are never observed to have a low
serum phosphorus, even when renal function is normal.

Differential diagnosis

The main difficulties in the diagnosis of hyperparathyroidism are that
the condition must be considered in all patients with calcareous renal
calculi and that, since both the serum calcium and the serum phosphorus
tend to fluctuate, tests may have to be done repeatedly over a period of
months. If any abnormality of either the serum calcium or the serum
phosphorus is detected the urinary excretion of calcium should be
measured.

When the serum calcium is raised or the serum phosphorus lowered
other causes of these abnormalities must be excluded. The commonest are :

1. High scrum calcium and normal or occasionally late serum phosphorus

(i) Secondary carcinoma »n bone (breast, prostate, bronchus, kidney, thyroid)

(n) Multiple myeloma
(iii) Sarcoidosis
(hr) Vitamin D intoxication

2. High serum calcium only

Mdk-alkah syndrome

3. Lon, serum phosphorus only

(i) Osteomalacia
00 Hodgkin’s disease
On) Cushing’s syndrome
(it) Sjogren’s syndrome

The X-ray appearances of secondary carcinoma, multiple myeloma and
sarcoidosis may be characteristic, but may also resemble those of osteitis
fibrosa cystica. Electrophoresis of the serum proteins may be diagnostic in
multiple myeloma and in sarcoidosis. Cortisone (150 mg. of cortisone
acetate daily for up to 10 days) restores the serum calcium to normal in
vitamin D intoxication and in sarcoidosis but not (with very rare excep-
tions) in hyperparathyroidism. Its effect on the hypercalcaemia of se-
condary carcinoma and multiple myeloma is variable.

The milk-alkali syndrome is rare and is caused by the prolonged con-
sumption of milk and alkali for the relief of peptic ulceration. Its clinical
features are very like those of hyperparathyroidism (especially the type
associated with ulceration), and it may similarly cause hypercalcaemia,
renal damage and urinary calculi. However, bone changes do not occur,
the serum alkaline phosphatase and serum phosphorus are normal and the

372

THE PARATHYROID GLANDS

excretion of calcium in the urine is not increased. The hypercalcacmia
disappears after a period on a low calcium intake but impairment of renal
function may remain. The distinction between the two conditions may be
very difficult, and some even doubt whether the milk-alkali syndrome
exists.

When bone disease is present the diagnosis is usually easy. The level of
the serum alkaline phosphatase tends to follow the severity of radiological
changes. Paget’s disease may co-exist with hyperparathyroidism; the
latter should be suspected strongly if the serum calcium is elevated and
must be excluded in all cases of Paget’s disease.

Secondary hyperparathyroidism (see later) may cause confusion. The
patients are azotaemic, have a high serum phosphorus and tend to have a
low serum calcium. The radiological changes show a mixture of osteitis
fibrosa and osteosclerosis. Occasionally a patient is seen w ith azotaemia, a
high serum phosphorus and a serum calcium within the upper normal
range. We have explored three such and have found parathyroid adenomas
in two.

Treatment

In the absence of treatment the course of hyperparathyroidism may be
protracted and sometimes lasts for 30 years. The disease, however, is pro-
gressive, leads eventually to death from renal failure in the majority, and to
weakness, deformity of the skeleton, fractures, immobilization and eventual
death from mtercurrent infections in a few. The poor prognosis in un-
treated cases makes early diagnosis and treatment essential. The condition
cannot be controlled medically, and the object of treatment is the removal
of the overactive gland or glands. In the early stages of the disease opera-
tion is safe and effective. Even patients with considerable impairment of
renal function should not be denied surgery, for some with a blood urea of
over 100 mg. per 100 ml. have remained clinically well and capable of
normal activity for up to six years after operation.

Parathyroidectomy. It is difficult for surgeons to obtain adequate ex-
perience of parathyroid smgery unless one surgeon in each region lakes a
special interest in the subject and performs all the operations. The best
preparation for this work is a wide experience of thyroid surgery.

Preoperatire treatment is not usually required. When there is severe
impairment of renal function or acute hyperparathyroidism (parathyroid
crisis) it may be necessary to correct dehydration and electrolytic imbalance
before operation can be carried out.

Surgical technique

The following account is based on the practice of Morrison of Belfast.
The purpose of the operation is to find and examine all the parathyroid

PRIMARY HYPERPARATHYROIDISM 373

glands and to deal appropriately with those which are diseased. This is
much easier at a first operation than at a second, when the field is obscured
by scar tissue. General anaesthesia with a cuffed endotracheal tube is
essential. Hypotension may aid haemostasis, but is unnecessary in ex-
perienced hands, A collar incision is made, the strap muscles are separated

Fig. 10.5. Location of 76 parathyroid adenomas in Belfast series.

in the midline, but not divided, and the anterior surface of the thyroid is
exposed. The parathyroids may now be sought.

Certain general principles must be borne in mind. The glands are very
variable in position, and they will not be found unless their possible sites
(uhich have been described already) are explored systematically. The loca-
tion of the tumours in our series is shown in fig. 10.5. A gentle, unhurried

374 THE PARATHYROID GLANDS

technique, dissection with blunt forceps rather than gauze and complete
haemostasis are essential. Roughness and bleeding vv ill not only obscure the
glands but will also remove or damage them irreparably. The parathyroids
vary in colour from fawn to reddish brown, and each is enclosed in a smooth
shining capsule, often partially covered with a small pad of fat. It may be
difficult, on the one hand, to distinguish parathyroids from lobules of fat,
lymph glands, thyroid nodules and thymic rests and, on the other, to deter-
mine whether a gland is hypoplastic, normal, hyperplastic or adenomatous.
For these reasons facilities for making frozen sections should always be
available. The vascular pedicles are very narrow, and their branches can be
seen running beneath the capsules of the glands. Their origins arc more
constant than the sites of the glands themselves. The pedicles are of great
help in the recognition of the parathyroids, but they are easily damaged.
A spreading subcapsular haematoma may obscure the gland completely and
lead subsequently to atrophy. All the glands must, however, be mobilized
on their pedicles and inspected thoroughly.

The search for the parathyroids follows the same lines on each side of the
neck. The first step is to ligate and divide the middle thyroid vein or veins
and to rotate the lobe of the thyroid medially. The upper gland is sought
first and is usually found in the plane of the inferior thyroid artery and just
above the point of entry of its upper branches into the thyroid. If the para-
thyroid is not seen at once the superior thyroid vessels arc ligated and
divided and a wider field is explored. This must extend backwards behind
the trachea and the oesophagus. Quite large tumours may lie unrecognized
in these sites unless they are sought deliberately. Upwards the search must
extend to the upper pole of the thyroid, laterally to the carotid sheath and
downwards to the region behind the inferior thyroid artery.

The inferior gland is usually found close tD the low er pole of the thyroid,
anterolateral to the trachea. As a rule it lies in front of the inferior thyroid
artery and recurrent laryngeal nerve, so that the latter structure should
rarely be at risk. If the parathyroid is not found here the tissues along the
inferior thyroid veins are inspected as far down as the thymus. A vascular
pedicle, running from the inferior thyroid artery, may lead to the gland.
Finally, the spaces in front of and behind the thymus arc examined and the
upper pole of the thymus itself (which may contain a parathyroid gland) is
resected.

If four parathyroid glands have not been found by now attention is
directed again to the thyroid gland. Its whole surface is inspected and
palpated carefully, and any part of it which contains a suspicious nodule is
resected, for on rare occasions a parathyroid gland may lie within its sub-
stance. The search may also lie continued in the neck lateral to the carotid
sheaths, for glands have very rarely been found there. If any glands still
escape detection the operation is completed and the patient is reinv cstigaled.

PRIMARY HYPERPARATHYROIDISM

375

If clinical and biochemical evidence of hyperparathyroidism persists the
sternum must be split and the whole superior mediastinum, down to the
arch of the aorta, explored. This procedure is very rarely needed.

When as many of the glands as possible have been found any which con-
tain adenomas are removed. If their nature is in doubt frozen sections are
examined immediately. It is important to remember that adenomas are
multiple in 20 per cent of cases. When all four glands are hyperplastic it is
probably best to remove three and to ensure that the remaining gland and
its vascular pedicle are intact. If four apparently normal or hypoplastic
glands are found it is advisable to search for a fifth, which may contain an
adenoma. If histological examination shows a gland to be malignant (a very
rare occurrence) a block dissection of that side of the neck and hemithy-
roidectomy are probably advisable.

Postoperative complications

Convalescence is usually smooth except in patients with advanced renal
damage or severe decalcification of the skeleton. In the latter tetany usually
occurs on about the third day after operation, although it can occur as early
as 6 hours after surgery. It is treated by slow intravenous injections of cal-
cium gluconate (10 to 20 ml. of a 10 per cent solution), which are repeated
as often as necessary and may be needed for several weeks. Calciferol and
oral calcium therapy are given also, as in the treatment of hypoparathy-
roidism (sec later), and must be continued until the bones are completely
recalcified. This process may take a year or more. The serum calcium
level must be checked every few months to ensure that the dose of calciferol
is not causing hypercalcacmia. Tetany does not occur after parathyroidec-
tomy in patients without bone disease unless all the parathyroids have been
removed or destroyed.

Effects of operation

The immediate effects of operation in patients with bone disease are
rapid disappearance of bone pain, increase in strength and loss of gastro-
intestinal symptoms. Recalcification of the bones takes many months, and
bone cysts may persist. "Osteoclastomas’', however, regress. Deformities
are permanent, but can often be corrected by orthopaedic measures when
the bones have recalcified.

Progressive impairment of renal function maybe halted, and when renal
damage is slight the function may be restored completely. The tendency to
form stones is reduced greatly. Irreversible renal damage may endanger
life and patients may die from uraemia or the associated cardiovascular
complications of chronic renal disease.

376

THE PARATHYROID CLANDS

Belfast series. The following operations were performed:

Patients with primary hyperparathyroidism 96

No. undergoing operation 95

No. undergoing re-exploration 5

No. undergoing second re- exploration ]

Patients explored without hyperparathyroidism being prosed 20

(a) Still hypereajcaemio, probably requiring re-exploration 14
lb) Now thought not to hast had hyperparathyroidism 6

The patient who did not undergo operation had acute disease which was
only recognized post mortem. The five re-explorations were required be-
cause removal of single adenomas had failed to restore the serum calcium
to normal. In three patients a second tumour was found, but in one three
operations (including splitting of the sternum) failed to reveal another
tumour. In all other cases the tumours were removed via the neck.

The operative findings in the 95 cases of hyperparathyroidism were as
follow:

Adenoma:

Single

Multiple

Hyperplasia

Carcinoma

Indefinite, but good clinical and biochemical results

No. of patients

46

21

16

0

12

(4S%)

(22%)

( 17 %)

Total

95 (100%)

The postoperative complications were as follow:

Death (renal failure, one with tetany)

Hypoparathj roidum :

Acute
Subacute
Wound infection
Chest infection:

Minor

Severe

No. of patients
4

9

1

4

frequent

The late results (one to six years) in the 91 patients surviving operation

were as follow:

Late deaths 6*

Alive and well 72

Clinically well, but azotaemic 11

Unt raced 2

Total 91

• 3 from unrelated cause*.

Of the 80 patients with renal calculi there was:

No recurrence in 71 (89%)

Recurrence or increase in size 9(11%)

The biochemical abnormalities recurred in two.

SECONDARY HYPERPARATHYROIDISM

377

Secondary hyperparathyroidism

A reduction in the concentration of calcium in the blood acts as a
stimulus to the parathyroid glands and causes them to hypertrophy. This
so-called “secondary hyperparathyroidism” can be classified according to
the cause of the low blood calcium:

1. Azotaemic renal failure.

2. Diminished absorption of calcium —

(а) Malabsorption syndrome;

(б) Simple vitamin D deficiency.

3. Renal tubular acidosis.

In patients with severe and long-continued renal impairment, failure to
excrete phosphate leads to an increase in its concentration in the blood and
to a reduction in the blood calcium. The parathyroid hypertrophy which
results is a compensatory process and does not usually require treatment.
In a few patients, however, the hypertrophy seems to overreach the physio-
logical need and causes severe hyperparathyroid bone disease, which may
be more disabling than the primary renal disorder. This view of the causa-
tion of azotaemic renal osteodystrophy has been accepted until very
recently. However the bone changes of osteitis fibrosa are sometimes
mixed with sclerosis and with the uncalcified osteoid of osteomalacia. The
serum phosphorus is not raised in all patients with azotaemic osteodys-
trophy. Vitamin D induces healing of the bone lesions and it may be that
renal dysfunction causes an acquired resistance to, or increased need for,
vitamin D.

The bony changes are similar to those of the primary form of the disease
except that cysts are less common and are confined to the small bones, and
that osteoclastomas probably do not occur. The spine characteristically
shows sclerosis of the upper and lower parts of the vertebral bodies and
decalcification of the centres of the bones. (This “rugger jersey” sign of
Dent occurs also in primary hyperparathyroidism with severe renal im-
pairment and in Cushing’s syndrome.) There is frequently marked calci-
fication of the arteries and sometimes of other soft tissues.

In most patients withazotaemic renal osteodystrophy the serum calcium is
low, and healing takes place when the serum calcium is raised by treatment
with vitamin D. In a few patients, however, the serum calcium is main-
tained at a normal, or even slightly elevated, level by the excessive hyper-
trophy of the parathyroids. In these patients treatment with vitamin D is
dangerous. Subtotal parathyroidectomy, followed by vitamin D therapy,
relieves bone pain and is followed by healing of the skeleton and sometimes
by improvement in general health. Two such patients have been treated
in this way in Belfast.

378 THE PARATHYROID CLANDS

The hypocalcacmia of the malabsorption syndrome, of simple vitamin D
deficiency or vitamin D malabsorption, and that of renal tubular acidosis
leads to parathyroid hypertrophy and to a reduction in the blood phos-
phorus level. The treatment is that of the primary condition, and para-
thyroidectomy is not indicated. This subject is considered in more detail
on page 469.

Hypoparathyroidism

Clinical features

The clinical features of hypoparathyroidism btc similar, whatever the
cause, and are mainly the result of hypocalcaemia. The most striking
feature is tetany , which is caused by neuromuscular hyperexcitability. It
is usually intermittent even in the absence of treatment. An attack usually
starts with numbness or tingling in the extremities and progresses to tonic
and painful contractions involving the hands and, less commonly, the feet.
The tetany may be precipitated by a voluntary' action such as writing or
walking. In carpal spasm the hands assume a characteristic position in
which the thumb is adducted, the fingers are compressed tightly together
and flexed towards the thumb at the metacarpal-phalangeal joints and the
wrist is strongly flexed ("wain d' accoucheur"). When the feet are involved
the toes are plantar flexed and the medial and lateral borders of the foot are
drawn together. There may be forcible extension at the ankle, knee and
hip joints. Spasm of the diaphragm, the other muscles of respiration and of
the glottis (which produces laryngeal stridor) are less common. There may
be convulsions in infancy and fits, resembling epilepsy but without loss of
consciousness, in later childhood.

In the absence of characteristic carpopedal spasms the neuromuscular
excitability or latent tetany may be demonstrated by r three signs:

(1) Chvostek’s sign is obtained by tapping over the branches of the facial
nerve at the angle of the jaw. Twitching occurs at the corner of the mouth,
the ala of the nose and the eyelids.

(2) Trousseau's sign is the development of carpal spasm when a sphygmo-
manometer cuff is applied to the arm and inflated abov e the systolic blood
pressure for not more than 2 minutes.

(3) Erb's sign. The muscles are hypcrevcitablc on electrical stimulation.

A few patients develop extrapyramidal rigidity and an ataxic gait,

associated with choreiform movements. Papillocdema of uncertain cause
may’ be present and has led to confusion with brain tumour.

Mental abnormalities may occur if the disease is not treated. In children
development may be retarded and in adults features ranging from irrita-
bility', forgetfulness and minor anxiety to major delusional psychosis may
appear. Some patients may be admitted to mental hospitals.

HYPOPARATHYROIDISM

379

The ectodermal structures in general are often affected. The skin tends
to be dry, coarse and scaly, as in long-continued Ay/vrparathyroidism, and
eczema may develop. The nails may be brittle and atrophic and are some-
times infected with monilia. The hair on the scalp may be thin, and bald
patches may appear. Axillary and pubic hair may be scanty or absent.
Many of the patients have cataracts in one or both eyes.

There are sometimes abnormalities of bowel function, including con-
stipation, cramps and occasionally steatorrhoea. The latter can also, of
course, cause hypocalcaemia.

When the disease occurs in childhood bodily and skeletal development
are retarded and the normal stature may never be attained. Severe genu
valgum is common. The teeth erupt late and have blunted roots. The
dentine and enamel are poorly developed and caries is common. Skeletal
changes are not found when the disease develops in adult life.

Varieties of hypoparathyroidism

Idiopathic hypoparathyroidism

This is a rare condition, caused by congenital absence or hypoplasia of
the glands. Only about one hundred cases have been reported, and we
have observed one. The diagnosis is usually made in childhood, but
occasionally the onset is in middle age. It may be familial, and sometimes
there is a family history of diabetes mellitus. Any of the symptoms and
signs described above may be present. The following special investigations
are helpful:

X-ray changes. Calcification in the basal ganglia (and sometimes else-
where) is common and is often symptomless. The calcium is deposited
mainly in the adventitia and media of the vessels. The skeletal changes,
which are found in childhood, include thickening of the calvaria and of the
lamina dura of the teeth, osteosclerosis and coarse trabeculation of the
bones.

Electrocardiogram. Prolongation o£ the Q-T interval is commonly
associated with hypocalcaemia.

Electroencephalogram. Changes resembling those of epilepsy are some-
times present, even in the absence of fits. They disappear very slowly after
the return of the serum calcium to normal.

Surgical removal

The glands may be removed, or their blood supply interrupted, accident-
ally during operations on the neck, especially thyroidectomy. Their re-
moval may be inevitable during operations for cancer. Tetany usually
occurs within a few days of the operation, but rarely its onset is delayed.
Numbness, tingling and carpopedal spasm occur, but fits and spasm of the

380 THE PARATHYROID GLANDS

respiratory muscles and glottis are unusual. Mental symptoms arc com-
mon, and the patients are often suspected of being hysterical, especially as
the reduction in the serum calcium is sometimes inconstant. Occasionally
the tetany disappears and the serum calcium returns to normal spon-
taneously. Such patients are relatively deficient in PTH, however, and the
serum calcium continues to fall, probably when there is little absorbable
calcium in the diet. Changes in the skin are rare, and mondial infections do
not occur in postoperative hypoparathyroidism. Cataracts may be formed
after many years. The condition is found almost invariably in adult women.

As mentioned earlier, tetany may occur after the removal of a para-
thyroid adenoma, especially if marked bone changes are present. It is
caused partly by depression of the remaining glands by the o\cractivc
adenoma and partly by the deposition of calcium in the depleted bones.
Recovery usually occurs after weeks or months. Destruction or removal of
all parathyroid tissue during parathyroid exploration causes permanent
hypoparathyroidism.

Neonatal hypoparathyroidism

Tetany may appear in the first w eek of life, usually as twitciting and con-
vulsions or as laryngeal stridor. It is most common in premature infants
and in those fed on cow’s milk. The high ratio of phosphate to calcium in
cow’s milk may play some part in the production of the tetany, but it is
more likely that the parathyroid glands are immature. A curious feature of
the condition is that the tetany is made worse by small doses of vitamin D,
although it is cured by large doses.

Tetany may occur in the newborn as a result of suppression of the infant s
parathyroids by maternal hyperparathyroidism. Only seven such cases
have been reported. In one, whom we observed, the mother was well
except for asymptomatic hypcrcalcaemia. In this infant, and in most of the
others, the hypoparathyroidism was transient.

Biochemical aspects

The serum calcium is lower than 9-0 mg. per 100 ml., and tetany is usual
when the level falls below 8 0 mg. per 100 ml. However, the sensitivity of
patients to a lowered serum calcium varies and there is no constant level
at which tetany always appears. The serum phosphorus is raised, and
levels above 7-0 mg. per 100 ml. may be found. Little or no calcium is
excreted in the urine.

After thyroidectomy a state of partial hypoparathjroidism can some-
times be demonstrated in patients with tetany and a normal serum calcium
level. When they arc given a low calcium diet and sodium phytate by
mouth the serum calcium falls and tetany becomes marked. These measures

HYPOPARATHYROIDISM

381

do not lower the serum calcium in normal subjects. Complete recovery is
unusual, even if the tetany disappears, but such patients benefit both men-
tally and physically from replacement therapy.

Differential diagnosis

Tetany or the history of an operation on the neck should immediately
arouse the suspicion of hypoparathyroidism. In the absence of these the
diagnosis may be very difficult because of the non-specificity of the
symptoms and signs. Once the serum calcium has been found to be
low other causes of hypocalcaemia must be excluded. The commonest
are:

1. Malabsorption syndrome: gastrectomy, gastro-jejuno-colic fistula,

pancreatic insufficiency', idiopathic steatorrhoea, coeliac disease, ulcera-
tive colitis.

2. Renal insufficiency.

In the malabsorption syndrome the serum phosphorus is usually low, as
well as the serum calcium. In chronic renal failure a low serum calcium
and high serum phosphorus are associated with a high blood urea.

Other metabolic disturbances may cause tetany without influencing the
level of the serum calcium. They include over-breathing and metabolic
alkalosis associated with potassium deficiency. The latter may result from
excessive vomiting (pyloric stenosis), aldosteronism or a potassium-
secreting tumour of the intestine.

Pseudohypoparathyroidism closely resembles true hypoparathyroidism
both clinically and biochemically. Patients with this rare disorder are short
in stature, have round faces and short, wide metacarpal and metatarsal bones.
Treatment with PTH does not correct the biochemical abnormalities, and
exploration of the parathyroids reveals normal or hyperplastic glands.
Possibly the tissues are resistant to the action of PTH.

Treatment

The treatment of hypoparathyroidism is directed to relief of the acute
symptoms of tetany and to the maintenance of the serum calcium at a level
at which tetany does not occur. An acute attack of tetany is relieved by the
slow intravenous injection of calcium gluconate (10 to 20 ml. of a 10 per
cent solution). This is repeated as often as is required to keep the patient
comfortable.

Absorption of calcium from the bowel is encouraged by the administra-
tion of calciferol (vitamin Dj). It is used for long-term treatment and the
dose is adjusted to suit each patient's needs. Calciferol is available as Tab.
calciferol, BP (1*25 mg., 50,000 units). The initial dose is 400,000 units
(10 mg.) orally, followed by 150,000 units (3-75 mg.) daily for two to three

382

THE PARATHYROID GLANDS

weeks. After this it is reduced to about 50,000 units (1-25 mg.) daily. The
only reliable guide to dosage is the level of the serum calcium, which should
be estimated frequently and maintained at about 9 0 mg. per 100 ml. Doses
which raise the serum calcium above this level are liable to cause serious
impairment of renal function. Hypercalciuria may occur earlier than the
elevation of the serum calcium 3nd is also harmful. For this reason it is
important that those who are receiving calciferol should be seen and hate
their serum 3nd urinary calcium let els estimated regularly etcry three
months for as long as therapy continues. Some patients, as already men-
tioned, require therapy even when the serum calcium is normal.

Dihydrotachystero! (AT10) may be used instead of calciferol. It is
more expensive than calciferol, and oilincss of the solution makes precise
measurement of the dose difficult. Nevertheless, it is useful for some
patients who become refractory to calciferol. ATI0 is given in an initial
dose of 1 to 2 ml. ttto or three times a day; 1 ml. daily or on alternate days
is usually sufficient for maintenance therapy.

Additional calcium is useful and can best be given as cffenesccnt tablets
of calcium glucono-galacto-gluconate (4 G. three or four times daily).
Since the serum phosphorus is high, the administration of aluminium
hydroxide, which diminishes the absorption of phosphate, is helpful. Milk
contains much phosphate as well as calcium, and should not be given in
excess.

It is said PTH cannot be used for long-term treatment of hypoparnthy-
roidism because it loses its effect after a few weeks.

Prognosis

Hypoparathyroidism is a chronic condition which causes considerable
disability but is not lethal. If treatment is inadequate cataracts may form.
Patients with idiopathic hypoparathyroidism must he treated indefinitely.
Some patients « ith postoperative hypoparathyroidism appear to be able to
manage without treatment after a few weeks, while others require per-
manent replacement therapy.

FURTHER Rf ADI.NO AND KFFUIKMTS
General

Foirvian, i*. (I960). Calcium Metabolism and the Hone. JlJjckwcll, Oxford.
MlfNSON, !•. l. (I960). Recent advances in parathyroid hormone research. Fed.
Proc., 19, 593.

llyperfwrathyeoiditm

ADESOW, A. O , WARD, J. T., Mil.EOWV, M. O, and Ull IKH'RN, R. fl. (1961) Hjper*
parathyrnidism and the alimentary tract, lint. J. Surg., 49, 112.

AUiRlGirr, r., AI-II. j. c. and nvmi. w. (1934). II $ perparathv roidism. J. Amer. mra.
An.. 102. 1276.

FURTHER READING 383

Albright, r, (1948). A page out of the history of hyperparathyroidism. J. cltrt.
Endocr., 8, 637.

BLACK, b. M. (1961). Problems in the treatment of hyperparathyroidism. S. Clin.
A'. America , 41, 1061.

cope, O. (1960). Hyperparathyroidism: diagnosis and management. Amer. J.
Surg., 99, 394.

dent, c. E. (1962). Some problems of hyperparathyroidism. Brit. med. J., 2, 1419,
1495.

McCEOWN, M. C. and morrison, £. (1959). Hyperparathyroidism. Postgrad, med.y.,
35, 330.

Mcceown, M. D. (1961). The value of special tests of parathyroid function. Proc.
Ass. Clin. Biochem., I, 46.

Hypoparathyroidism

bronsky, i>., kushner, D. s., DUB1N, a. and snapper, i. (1958). Idiopathic hypo-
parathyroidism and pseudohypoparathyroidism. Medicine, 37, 317.
four. man, p., DAVIS, R. it., jones, d. b. and SMITH, j. w. c. (1963). Parathyroid
insufficiency after thyroidectomy. Bnt. J. Surg., 50, 608.
wade, j. s. ii. (1960). The morbidity of sub-total thyroidectomy. Bnt. J. Surg., 48,

CHAPTER 11

ISLET CELLS OF THE PANCREAS

The islet cells of the pancreas were first described in 1869 by Langerhans,
and diabetes was induced in animals by pancreatectomy 20 years later by
von Mehring and Minkowski. Evidence that diabetes was caused by the
lack of an internal secretion from the pancreas, controlling carbohydrate
metabolism, had accumulated by 1922, when Banting and Best isolated the
hypoglycaemic factor, insulin, and found that it was effecthe in the treat-
ment of the disease. Soon after this it was noted that some pancreatic
extracts produced a transient rise in the blood sugar before the charac-
teristic fall, and the name “glucagon” was gi\en to the hypothetical hyper*
glycaemic factor. The molecular structures of insulin and of glucagon arc
now known.

ANATOMY

The islets of Langerhans are distributed throughout the pancreas, being
perhaps more common in the body and tail than in the head. The number
of islets in the normal pancreas varies from about one-half to one and a half
million. They vary greatly in size, but most of them stc between 120 and
240/t in diameter. They have a rich blood supply. Four types of cell, a, p,
y and 8, can be distinguished by special staining techniques. The p cells
arc the most numerous and secrete insulin, which can be seen as granules
in the cytoplasm. The * cells, which are fewer in number, probably secrete
glucagon. The S cells do not take specific stains, and their function is un-
known, while the y cells, which are present in some species, are not found
in man.

PHYSIOLOGY

The secretions of the islet cells arc intimately concerned with the meta-
bolism of carbohydrate.

Intulin, which is secreted by the p cells, is a protein, containing 51 amino-
acids which are arranged in two cross-linked chains. Its release is stimu-
lated by a high concentration of glucose in the blood, and the result of it*
actions is the lowering of the blood glucose to normal. It does so by in-
creasing the rate at which glucose is deposited as glycogen in the liver and
in the muscles and as fat in the adipose tissue, by stimulating the rate of
glucose metabolism and by depressing gluconeogenesis (the formation of
glucose from sources other than carbohvdrntes). (Fig. ILL) Insulin is,
384 '

PHYSIOLOGY

385

Fig. 11,1. Simplified illustration of main actions of hormones on carbohydrate
metabolism.

See centre of diagram for key to symbols. Some hormones assist insulin in some actions
and inhibit it in others. Their overall effects on the blood glucose lei el are shown in the
centr e of th e diagram. indicates reversible pathways of transport or of metabolism.
—IS indicates that the pathway is blocked by C and GH. "Glycogenolysis” is the
breakdown of glycogen to form glucose. “Gluconeogenesis" is the formation of glucose
from non-carbohydrate sources.

therefore, antagonistic in some respects to growth hormone, cortisol,
thyroxine and adrenaline. The suggested modes of action of insulin on
glucose metabolism are shown in fig. 11.2.

HOOP III INTERSTITIAL RUtD CELL

CMlLAHY MEMfctUHE
AUDW5 fUFE miWH

OF SOLUTES

Fig. 11.2, Mode of action of insulin.

Predominant action is probably that of facilitating transport of glucose through cell

membrane which normally prevents diffusion of lipoid-insoluble substances.

Possible subsidiary action in actuating enzyme systems concerned with gljcogen
formation

386

ISLET CELLS OF THE PANCREAS

Glucagon, which is probably secreted by the a cells, is a polypeptide con-
sisting of 29 amino acids. It is released in response to a loro concentration
of glucose in the blood and has the effect of restoring it to normal. It does
so principally by stimulating glycogen olysis (the breakdown of glycogen to
glucose), an action in which it antagonizes insulin. On the other hand, like
insulin, it promotes the peripheral utilization of glucose.

INVESTIGATION OF DISORDERS OF THE ISLET CELLS

Insulin in the blood can be estimated by bioassay and by immunological
techniques, but the methods arc not available generally. The most useful
tests are concerned with the metabolism of glucose.

Glycosuria

The urine may be tested for the presence of sugar by the use of Bene-
dict’s reagent. A positive result usually means that glucose is present, but
lactose (in lactating women) and rarely other sugars may be found.

Glycosuria may be caused by:

(i) A low- renal "threshold”.

(ii) Rapid absorption of glucose from the bowel (functional hypo-

glycaemia, after gastric operations, thyrotoxicosis).

(iii) Diabetes mellitus.

(iv) Disease of the renal tubules (Fanconi’s syndrome).

The first two are not of pathological significance and the last is rare. If
there is doubt about the nature of the sugar further specific tests arc
necessary.

Fasting blood glucose

The older methods for measurement of "blood sugar" include reducing
substances other than glucose and give higher readings than the methods
for "blood glucose” which have largely superseded them. In general, the
discrepancy is about 10 to 20 mg. per 100 ml.

The normal blood glucose level, after 12 hours’ fasting, is 60 to 90 mg.
per 100 ml. (The equivalent range for "blood sugar" is SO to 110 mg. per
100 ml.) Fasting hypcrglycacmia is suggestive of diabetes mellitus and
fasting bypoglycaemia of hyperinsutinism.

Glucose tolerance lest

The ability of the body to handle carbohjdrate is tested by an oral load
of 50 G. of glucose in water (TO G. per kg. of body w eight in children). The
venous blood glucose is measured immediately before and at 30 -mmute
intervals after its administration, usually for 2 or 3 hours. Normally the
blood glucose reaches a peak of 130 to 150 mg. per 100 ml. ("Mood sugar"
150 to 180 mg. per 100 ml.) after about 1 hour and returns to the resting

DISORDERS OF THE ISLET CELLS 387

level within 2 hours. The urine may be tested for sugar at the beginning of
the test and again after 2 hours. Normally sugar is absent. The blood
glucose curve is altered significantly in various disease states. Sometimes it
is helpful to prolong the test for 4 or 6 hours, and sometimes it is necessary
to take samples of blood every 15 minutes in order to detect a transient
hyperglycaemic peak or hypoglycaemic trough.

Other special methods of investigation apply only to specific disorders
and will be described later.

DISORDERS OF THE ISLET CELLS
Hyperfunction of the islets of Langerhans may be associated with one or
more of the following lesions of the islet cells :

(i) generalized hyperplasia;

(ii) discrete adenoma (single or multiple);

(iii) generalized adenomatosis;

(tv) carcinoma.

Discrete adenomas are the commonest finding. Rarely there is no re-
cognizable morphological change, even when there is clinical evidence of
hyperfunction. Conversely, neoplastic lesions sometimes cause no obvious
disturbance of function. The lesions may consist of either a or 0 cells or,
occasionally, of both types. The (3 cell lesions, which are the most fre-
quent, may secrete insulin and cause organic hyperinsulinism. This property
is shared by the merastases of carcinomas. An insulin-secreting tumour is
often called an “insulinoma”. The a cell lesions, which are less common,
might be expected to secrete glucagon, but there is little evidence that they
do so. They may, however, secrete gastrin or a closely related gastric
secretogogue, and be associated with peptic ulceration, which is sometimes
fulminating (Chapter 16). In some cases the islet cell lesions (either a or {3)
form part of a syndrome of multiple endocrine adenopathy, with hyperplasia
or tumours of the anterior pituitary, the parathyroids, the adrenal cortex
and, occasional [y, the thyroid. This syndrome is often familial and shows
itself clinically by such features as hyperinsulinism, hyperparathyroidism,
acromegaly and peptic ulcer.

Hypofunction of the islet cells is associated with:

(i) a decrease in the number of islets;

(ii) hyalinization and fibrosis of the islets;

(iii) destruction of the pancreas by inflammation, secondary’ to ob-
struction of the pancreatic duct, etc. ; or

(iv) total pancreatectomy.

All these conditions cause diabetes mellitus. Occasionally in this condition,
however, the number of islets is within the normal range and their histology
appears normal.

388 ISLET CELLS OF THE PANCREAS

Pathology of islet cell tumours

Silent tumours, which do not cause any clinical features, are relatively
common, but are usually so small that they pass unnoticed on routine post-
mortem examination. In a review of the Belfast material Gibson found
that tumours had been discovered in IS patients only during a period of
20 years, an incidence of 0-015 per cent. When a special search is made
tumours may be found in 1 to 2 per cent of cases.

In clinically significant cases about two-thirds of the tumours arc found
in the body or tail of the pancreas, one-quarter in the head and one-tenth
in ectopic sites, particularly at the hilum of the spleen and around the
duodenum or pyloric antrum (fig. 1 1.3). In about one-third of patients the

• MALIGNANT (lOW GRADE) 33 %

•NOT RECOGNIZED AT EXPLORATION 15*

Fig. 11.3. Location of islet cell tumours of the pancreas.

tumours are multiple and in one-third they are histologically malignant.
Few of the tumours are large enough to be recognized easily at laparotomy
and 1 in 7 (15 per cent) escapes detection, even when the pancreas is
mobilized and palpated carefully.

Adenomas vary considerably in structure. The best differentiated arc
composed of ribbons or trabeculae of islet cells, closely related to small
blood-vessels. They arc surrounded by fibrous capsules, vi hich distinguish
them from hyperplastic islets. A solid form of architecture, with poor en-
capsulation and without any well-marked arrangement, is also common in
less differentiated growths. Degenerative changes occur frequently, but do
not alter the endocrine activity. Bleeding may take place in the solid type
of adenoma, and diffuse hyaline sclerosis is often present in the trabecular
form. The hyaline tissue may eventually calcify and may rarely be seen on
X- raj-s.

Carcinomas usually display the solid form of architecture which is seen
in some of the benign tumours. Thcj' invade the surrounding tissues,
permeate the blood vessels and metastasize to lymph glands and to the

ORGANIC HYPERINSULINISM

3S9

liver. Some tumours with histological features suggesting malignancy be-
have in a relatively benign fashion. Among the frankly malignant cases
there are reports of patients with proved metastases surviving in reasonable
health for several years.

Special stains, designed to demonstrate a or p granules in the cells,
frequently yield positive results in well-differentiated tumours, but are
rarely helpful in the poorly differentiated ones.

Belfast series

The following islet cell tumours were found in about 100,000 routine
biopsies and necropsies between 1939 and 1958:

Islet cell lesions only 8

Hyperinsulinism (0-cell adenoma) 2

Incidental finding at autopsy (adenoma) 6

Islet cell lesions in multiple endocrine adenopathy 7

Simple peptic ulceration 3

Fulminating peptic ulcer (\\ ith islet cell carcinoma) 1
No peptic ulcer 3

Total IS

ORGANIC HYPER1NSULINISM

In 1924 (two years after the discovery of insulin) Harris postulated that
excessive secretion of insulin might sometimes cause spontaneous hypo-
glycaemia. In 1927 W. J. Mayo explored the abdomen of a patient who had
been studied by Wilder and his associates and found an islet cell carcinoma
with metastases in the liver. An extract of the tumour contained a hypo-
glycaemic factor indistinguishable from insulin. Two years later Graham
removed a benign adenoma from a patient studied by Howland and his
colleagues and cured the organic hypennsulinism.

Incidence

Hyperinsulinism associated with a lesion of the islet cells is well known
but rare. Many hundreds of cases have been reported, but few surgeons
ever see more than one or two. Insulinomas are commonest in middle age,
but have been found in. infants and in the aged. The sexes are affected
equally. Occasionally there is a family history of diabetes, and very rarely
hyperinsulinism develops in a diabetic. In these circumstances the first
sign is that the patient’s insulin requirements become progressively smaller.

Clinical features

The clinical features are caused by attacks of hypoglycaemia, which
occur particularly during periods of fasting. They are therefore commonest
in the early morning and in the late afternoon. They are aggravated by
exercise and relieved by the consumption of sugar. The attacks are often

390

ISLET CELLS OF THE PANCREAS

mild and infrequent in the early stages and become severe and frequent
later. The disease usually runs a course of several years, but occasionally
it is fulminating in onset and rapidly fatal.

The symptoms and signs arc very’ variable and may be considered under
the following headings:

(a) Those related to the nervous system.

1. Mental disturbance.

2. Sympathetic stimulation.

3. Organic nervous disease.

( b ) Hunger and epigastric discomfort.

The mental features range from mild neurotic symptoms, such as tired-
ness, anxiety, restlessness, confusion and emotional instability, to those of
frank psychosis. Sympathetic stimulation may be caused in part by the re-
flex release of adrenaline in response to the hypoglycaemia. The features
are similar to those of phaeochromocytomas and include flushing, sweating,
pallor, tremor, palpitation and transient hypertension. Signs of organic
nervous disease include disturbances of speech and vision, vertigo, con-
vulsions (especially in infants), hemiparcsis, loss of consciousness and coma.
When an attack has passed the patient frequently has no recollection of it.
In the final stages irreversible anoxic changes occur in the cerebral cortcv,
basal ganglia and cerebellum, and the patient passes into a state of decere-
brate rigidity and dies.

The hunger and epigastric discomfort, which arc common symptoms,
may lead patients to eat excessively and to put on weight. They may dis-
cover for themselves that sugar brings relief and may develop a craving for
it.

Investigation

High levels of insulin in the blood have been found in the few patients
with organic hypcrinsulinism who have been studied. Several simple tests,
designed to detect hypoglycaemia and to establish its temporal relationship
to the symptoms, are available.

The blood glucose should be measured at once if (as rarely happens)
symptoms are present when the patient is seen or if he is admitted to
hospital in coma. It will often be found to be lower than 30 mg. per 100ml.
(50 mg. per 100 ml. “blood sugar"). Subsequently the e/Tect of glucose
(50 G.) by mouth, or intravenously, should be observed.

A glucose tolerance test may be of help if it is extended for 4 or 6 hours
instead of the usual 2) hours. Typically the resting let cl is low, the h)per-
glycacmie rise is slight and does not cause glycosuria, and the subsequent
hypoglycaemia is profound. The blood glucose level does not rise again
spontaneously.

ORGANIC HYTEMNSULINISM

393

Fasting for 4 to 6 hours, while the patient is ambulant, will usually induce
an attack, but the diagnosis can only be excluded with reasonable cer-
tainty if a fast of 3 days (with nothing but water by mouth) fails to do so.
The blood glucose falls and usually reaches a le\el well below 30 mg. per
100 ml. (50 mg. per 100 ml. "blood sugar"); very rarely in pro\ed cases it
fails to do so.

Either of these tests may induce symptoms, and glucose should be avail-
able for administration (by mouth or intravenously). Its effect is striking
and helps to confirm the diagnosis.

Other tests of carbohydrate metabolism , which have been introduced re-
cently, are of less certain value than those described above. They include
the administration of glucagon or of the hypoglycaemic agent tolbutamide,
both of which are said to cause severe hypoglycaemia in certain circum-
stances in patients with organic hyperinsulinism. The amino-acid l-
leucine also causes profound hypoglycaemia in some patients with insulin-
secreting tumours, probably by stimulating release of insulin.

Encephalography. During an attack of hypoglycaemia the EEG record
shows 8 waves, but the a rhythm does not disappear entirely. Anoxia
aggravates the changes and glucose abolishes them rapidly. An EEG is of
no help between attacks.

Differential diagnosis

The single most important step in making the diagnosis of organic
hyperinsulinism is to think of it. Very often the condition is mistaken at
first for epilepsy, neurosis, psychosis, drunkenness or organic nervous
disease. Whipple has proposed a triad of features which are rarely found
except in organic hyperinsulinism. These are:

(i) attacks of nervous or gastrointestinal disturbances coming on in the

fasting state, associated with

(ii) hypoglycaemia with blood glucose readings below 30 mg. per

100 ml. (“blood sugar” levels below 50 mg. per 100 ml.), which is

(iii) relieved quickly by the ingestion of glucose.

When it has been established that hypoglycaemia is responsible for the
patient’s symptoms, other causes must be excluded. They may be classified
as follows:

(a) Excess of insulin . Exogenous — overdosage in diabetics or in others

with access to insulin.

(b) Idiopathic (? functional hyperinsulinism).

1. Functional.

2. After gastric surgery.

3. Infantile.

392 ISLET CELLS OF TltE PANCREAS

(c) Hypersensitivity to insulin (absence of insulin antagonists).

1. Adrenocortical failure.

2. Anterior pituitary failure.

(d) Disturbance of glycogen storage in liter.

1, Von Gierke’s disease.

2. Cirrhosis, acute yellow atrophy, etc.

(e) ? Increased utilisation of glucose.

1. Mesenchymal tumours of abdomen and thorax.

2. Adrenocortical tumours.

The commonest type in general surgical practice is that which follows a
gastric operation, and a history of this should arouse suspicion (see later).

Functional hypoglycaemia is common in medical practice and is associated
with rapid absorption of sugar from the bowel. In this variety hypo-
glycaemic symptoms appear 1^ to 3 hours after a meal, especially one rich
in carbohydrate, and pass away spontaneously after half an hour or so.
A glucose tolerance test (with readings every 15 minutes) shows an o\y*
hyperglycaemic or “Jag-storage” type of curv c— that is a rapid rise to a high
sharp peak (often associated with glycosuria), and an abrupt fall to a hypo-
glycaemic level. Finally, the curve rises again to the normal resting level.
The hypoglycaemia is thought to be caused by the temporary overproduc-
tion of insulin. Attacks can be terminated by the consumption of sugar and
prevented by a diet low in carbohydrate but rich in protein (which forms
sugar slowly by gluconeogenesis).

The infantile type of idiopathic hypoglycaemia is sometimes, apparently,
caused by sensitivity to Mcucine in the food and can be controlled by a diet
rich in carbohydrate. It should not be forgotten that insulinomas can
occur in infancy and that some of them, as well as those in adults, are also
/-leucine sensitive.

Interest has centred recently round a group of large mesodermal tumours
which cause hypoglycaemia. They include mesotheliomas, fibromas and
fibrosarcomas, and they develop in the mediastinal, diaphragmatic or retro-
peritoneal regions. They tend to be encapsulated and rarely metastasize.
The clinical features are often identical with those of organic hyperin-
sulinism and Whipple’s triad is fulfilled. Removal of the tumours brings
relief, but the cause of the hypoglycaemia is not known. The tumours may
possibly compete with other tissues for carbohydrate; they do not,
apparently, secrete insulin. Large tumours of the adrenal cortex (usually
carcinomas) rarely behave similarly without causing any other metabolic
disturbance.

Other varieties of hypoglycaemia can usually be recognized by appro-
priate tests. When a firm diagnosis cannot be made, and an insulin-

ORGANIC HYPERINSUL1K1SM 393

secreting islet cell tumour cannot be excluded, the pancreas should be
explored.

Treatment

When the diagnosis of organic hyperinsulinism has been made (or when
it cannot be excluded) surgical exploration of the pancreas should be under-
taken and the responsible lesion or lesions excised (see later). The pre-
operative period of Fasting may induce a hypoglycaemic attack, and it is
wise to set up a slow' intravenous glucose drip before operation. Reactive
hyperglycaemia is common after operation, but it does not last for more than
two weeks, and treatment with insulin is not necessary.

The results are excellent, and three-quarters of the patients are cured by
one operation. If operation does not stop the attacks of hypoglycaemia
there is probably hyperfunctioning islet cell tissue in the head of the pan-
creas and a further operation is necessary. An interesting 25-year follow-up
of six patients treated surgically by^WhippIe has been published recently.
Four were still alive, and hypoglycaemia had recurred in only one, who had
moderate generalized adenomatosis and multiple endocrine adenopathy.
Unforeseen sequelae included duodenal ulcer in two and gastric ulcer in
one; diabetes mellitus in two; and severe neuropsychiatric disturbance in
three. Only one could be regarded as thoroughly healthy.

Carcinomas which cannot be resected because of local spread or meta-
stasis are incurable surgically and the problem of controlling the hj-po-
giycaemia becomes increasingly difficult. Sugar must be given frequently
and in large doses. Glucagon (which must be given by injection) may be
effective in raising the blood glucose and cortisone (in large doses), which
antagonizes insulin, is helpful.

Hypoglycaemia after gastric operations

Attacks of hypoglycaemia develop in about 5 per cent of patients after all
types of gastrectomy and after vagotomy. The symptoms arc similar to
those of organic hyperinsulinism. They are usually mild, but the patient
may lose consciousness. The attacks develop II to 3 hours after a meal
(i.c. "late postcibal"), and must not be confused with the rather similar
"early postcibal” dumping symptoms, which appear immediately after
eating. Attacks are precipitated by meals with a high carbohydrate content
and by exercise. On examination during an attack the tremor and sweating
are obvious and the patient is usually pale. Tachycardia and a low' blood
pressure may be found. The blood glucose is often less than 50 mg. per
100 ml. (blood sugar 75 mg. per 100 ml.). Symptoms are usually noticed
for the first time within a few weeks or months of operation. They tend to
diminish with time, but may persist intermittently. Occasionally they do
not develop until much later. Attacks are relieved immediately by sugar.

394

ISLET CELLS OF THE PANCREAS

The precise mechanism is uncertain, but certain facts have been
established. After gastric operations the blood glucose cun e {like that of
functional hypoglycaemia) is usually of the oxyhyperglycaemic or lag-
storage type and glycosuria is common (fig. 11.4), The ftypcrglycacnua is

HOURS

0 12 3 4

HOURS

Fir. 1 1.4. Glucose tolerance curve ("blood sugar curve") in relation to
postcibal symptoms after gastric operation.

not caused solely by rapid emptying of the stomach, for vagotomy, which
reduces the rate of gastric emptying, accentuates the abnormality. The
M/>oglycaemia may be caused partly by excessive secretion of insulin and
partly by increased sensitivity to insulin which has been observed to de-
velop within about a month of gastric operations. Its cause is unknown.

The diagnosis can usually be made on clinical grounds and by the im-
mediate relief of symptoms by sugar. When there is doubt a glucose
tolerance test (with readings every IS minutes) should he performed while
the patient is ambulant so that the correlation betw cen the symptoms and
the blood glucose level can be tested.

The finding of glycosuria associated with loss of weight (which is com-

SURGERY 1 OF ISLET CELL LESION’S 395

mon after gastrectomy) sometimes leads to an erroneous diagnosis of
diabetes. The condition has sometimes been mistaken for drunkenness.

Treatment consists of reassurance and an explanation of the nature of
the disorder. A diet containing plenty of protein and fat, but little carbo-
hydrate, may prevent gross hyperglycaemia and so reduce the frequency
and severity of the hypoglycaemic attacks. Snacks between meals should
be advised, and the patient should always carry lumps of sugar or sweets
which can be taken at once if an attack is imminent.

SURGERY OF ISLET CELL LESIONS

The indications for surgical exploration of the pancreas in suspected
disease of the islet cells are:

(i) Organic hyperinsulinism.

(ii) The fulminating peptic ulcer (Zollinger-EUison) syndrome

(Chapter 16).

It is important to remember that tumours are often small and multiple,
sometimes in ectopic sites (at the hilum of the spleen or close to the
duodenum or pyloric antrum) and sometimes very difficult to find. For
these reasons the whole pancreas must be mobilized, inspected and palpated
in every case.

A transverse epigastric incision, curved upwards, gives good access to the
whole organ. Wide division of the gastrocolic and gastrosplenic omenta
allows the front of the pancreas to be seen and felt. Division of the peri-
toneal attachment along the inferior border of the pancreas and of the
peritoneal attachments between the spleen and the diaphragm permit the
spleen to be drawn forward into the wound and the body and tail of the
pancreas to be mobilized by blunt dissection. The whole of these parts and
the hilum of the spleen can now be seen and palpated carefully between the
finger and thumb. The rest of the gland is mobilized by division of the
peritoneal attachment on the right side of the duodenum. By this man-
oeuvre the head and neck of the pancreas, the duodenum and the pyloric
antrum can be freed and examined.

Tumours are often pinker and firmer than normal pancreatic tissue, and
sometimes have a network of tiny vessels leading to them. When benign
they can be shelled out easily with little bleeding. Any such nodules should
be removed and examined histologically. Immediate frozen sections should
be made unless the nature of a nodule is obvious.

When the examination of the pancreas is complete, and any suspicious
nodules have been removed for biopsy, a decision must be taken about what
further tissue should be resected. The following policy is recommended;

(1) The body and tail of the pancreas (together with the spleen) should
he removed in every ease, whether or not a tumour has been found. This

396

ISLET CELLS OF THE PANCRfAS

involves ligation of the splenic artery and \ ein, division of the gland {« ith a
V-shaped incision) at the point where it is crossed hy the superior mesen-
teric vessels, ligation of the pancreatic duct and oversewing of the bare area
with nonabsorbable material. The reasons for this arc: (i) it is a com-
paratively simple and safe procedure, and it interferes little with pancreatic
function; (ii) this portion of the gland contains two-thirds of all tumours
and, even if none is recognized at operation, one or more may be found
later by the pathologist; (hi) if there is islet cell hyperplasia the amount of
secreting tissue will be reduced considerably.

(2) Tumours in the head or neck of the pancreas should be enucleated if
possible. The tumour bed is closed with mattress sutures of non-absorb-
able material. If the lesions cannot be removed in this way a formal pan-
creatico-duodenectomy must be undertaken, for the head of the pancreas
cannot be removed without destroying the blood supply to the duodenum.
Thfe is, of course, a formidable and serious procedure, and it should not be
undertaken lightly. It is occasionally necessary’ at a second operation if
hyperinsulinism persists after resection of the body and tail.

When tumours or pancreatic tissue arc removed a drain should be in-
serted and the abdominal wall closed with nonabsorbable material. For-
tunately leakage of pancreatic juice is rare.

Removal of the body and tail of the pancreas rarely causes any permanent
adverse effects. Total pancreatectomy, however, causes diabetes mellitus
and impairs digestion. The diabetes is always mild, presumably because
the secretion of glucagon, as well as of insulin, is abolished. Treatment b)
diet and by 15 to 30 units of insulin per day is usually sufficient. The
digestion of fat is affected more than that of protein or carbohydrate, and
stcatorrhoca develops in most cases. The intake of fat should he reduced
to 50 or 70 g. per day, and pancreatic extract, in the form of panercalin,
BP or whole extract of hog pancreas (Cotazym, Organon), should be given
regularly.

DIABETES MELLITUS AND THE SURGEON
Surgeons frequently encounter diabetic patients in the course of their
practice and need a working understanding of the disorder. Diabetics may
be seen for one of tw o reasons :

(1) because of surgical conditions developing in diabetic patients; or

(2) because of complications of diabetes requiring surgical treatment.

Nature of diabetes mellitus and the diabetic syndrome

Diabetes mellitus is a disorder of metabolism characterized, at least in
its fully developed form, by hyperglycacmia. It results from deficiency of
the production or utilization of insulin, from inactivation of insulin by un-
known factors or from increased secretion by tbc pituitary, adrenal or

DIABETES MELLITUS AND THE SURGEON 397

thyroid of hormones which normally balance and control its action. The
deficiency of available insulin depresses the formation of glycogen m the
liver and muscles, reduces the rate at which carbohydrate is utilized in the
tissues and promotes gluconeogenesis (the formation of glucose from
amino acids). These factors combine to raise the blood sugar, and the
hypergtycaemia in turn causes glycosuria. The lack of carbohydrate for the
provision of energy and the diminished amount of insulin cause increased
mobilization of fat from the depots, and the liver is presented with more
neutral fat than it can handle. The result is the excessive formation of
ketone bodies and ketosis.

There are several causes of the diabetic syndrome. Total pancreatec-
tomy, for instance, removes completely the source of insulin and haemo-
chromatosis, chronic pancreatitis or carcinoma of the pancreas may destroy
sufficient islet cell tissue to cause the disease. In all these conditions there
is a dear relationship between the absence or deficiency of insulin-secreting
tissue and the development of diabetes.

In most cases, however, there is no such obvious connection. Moreover,
a primary deficiency of insulin is unlikely to be the usual cause of diabetes,
for many patients require doses of insulin far greater than do those who
are known to have primary' pancreatic insufficiency. The increased require-
ment of insulin has been explained by the actions of physiological insulin
antagonists such as cortisol and growth hormone. Thus, adrenal hyper-
function may increase the severity of diabetes during periods of stress and
cause diabetes to develop in Cushing’s syndrome. Pituitary overactivity
may account for the diabetes of acromegaly and for the development or
aggravation of the disease during adolescence or pregnancy. The role of
glucagon in the pathogenesis of diabetes is unknown. As already men-
tioned, some patients with a cell tumours of the islets have impaired glucose
tolerance. Other insulin antagonists have been found in the plasma of
diabetics who require insulin, and although little is known of them, they
appear to depend on pituitary and adrenal activity and can be diminished
or eliminated by surgical hypophysectomy. It may be that diabetes occurs
when the p cells of the pancreas are no longer able to provide sufficient
insulin to overcome their effects.

There are probably, then, two factors concerned in the development of
diabetes. One is the tendency for insulin antagonists to appear in the body;
the other is the efficiency of the pancreas in meeting the challenge. Their
relative roles are probably different in the two major varieties of diabetes
which have been recognized for many years. In the “juvenile-onset" or
“thin” variety, which is the more severe, the disease develops during
growth or sometimes later and is associated with loss of weight, a tendency
to ketosis, sensitivity to insulin and a lack of response to oral sufphonyfurea
drugs. Insulin activity in the plasma and in extracts from pancreatic tissue,

398 ISLET CELLS OF THE PANCREAS

obtained post mortem, is low or absent. It seems likely that the islet cells
are ovens helmed by the demands that arc made upon them. In the
“ maturity onset " or "obese" variety, sshich is usually milder, the diabetes
manifests itself in adult life, usually after the age of 40 years. It is associated
with obesity, absence of ketosis, insensitiv ity to insulin and responsiveness
to oral sulphonyiurea drugs. Insulin activity in the plasma and in pan-
creatic tissue is normal or nearly so. In this variety, apparently, the two
factors are fairly well balanced and may well base been in opposition for
years before the syndrome manifests itself clinically.

Although there are clinical and biochemical differences between the two
groups, there are also many similarities. First, they are similar genetically,
and may therefore have a common aetiology. Secondly, the major diabetic
complications, which are probably caused by the insulin antagonists, are
similar except in so far as they are influenced by the ages of the patients.
The obesity which is commonly seen in maturity-onset diabetics may be the
result of the prolonged overproduction of insulin by the pancreas, for the
antagonists of insulin do not, apparently, inhibit its action on adipose tissue.

Clinical features

Diabetes is common in both sexes and may develop at any time from
infancy to old age. In childhood the sex incidence is about equal, but in
those over the age of 40 women are affected more often than men. It is a
familial disease and is probably inherited as a simple recessive character
with incomplete penetrance.

The hypcrglycacmia causes osmotic diuresis and the characteristic
features of thirst and polyuria. The mobilization of fat from the tissues
causes loss of weight, ev en though the appetite remains normal or increases.
Loss of fluid is followed by dehydration and depletion of sodium, and th«,
in tum, may cause muscle cramps. Ketosis is commonest in the juvenile
onset variety and may be followed by coma which may prove fatal. Ketosis
and coma sometimes result from the rapid progression of untreated
diabetes, but may be precipitated by infection, the stress of surgery and
anaesthesia or the failure of the patient to take insulin. Other complica-
tions of diabetes, many of which may require surgical treatment, arc dis-
cussed later.

Investigation

The characteristic findings are glycosuria, hypcrglycacmia in the fasting
state and impaired glucose tolerance. 'Hie glucose tolerance test reveals a
curve w hich starts higher than normal, reaches a v cry high peak and fails to
return to its resting level in 2 hours. 'Hie nitroprusside and ferric chloride
tests usually reveal ketone bodies (acetone and aceto-acctic acid) in the
urine if ketosis is present. Other laboratory findings w ill he mentioned later.

DIABETES J1ELLITUS AND THE SURGEON 399

Principles of treatment

Diabetes can be controlled by means of diet and the use of oral hypo-
glycaemic agents or insulin. Diet alone is adequate in mild cases. The
patient roust receive sufficient food to provide energy for his normal
activities and enough protein to supply the tissues of the body. The intake
of carbohydrate is determined by two conflicting considerations. If too
much is given it cannot be utilized and if too little is given protein and fat
cannot be metabolized. In either case ketosis results. If a balance cannot
be struck other forms of treatment must be used. The oral hypoglycaemic
agents (sulphonylureas and biguanides) are convenient and adequate in
many patients, particularly the older ones. Insulin, which must be given by
injection because of its protein nature, is needed for the rest. Most patients
can be taught to inject themselves. Soluble insulin must be injected twice
daily, and is the best preparation for patients undergoing surgical opera-
tions. Various long-acting preparations, which need be given only once
daily, are preferable for routine management. In our own practice we find
that about one-third can be treated by diet alone and one-third by oral
hypoglycaemic agents while insulin is needed for the remainder. All
diabetic patients must be instructed carefully about the control of their
disease and must be seen regularly by their physicians.

Types of insulin and oral hypoglycaemic drugs in common use

Several preparations of insulin are available:

(1) Soluble insulin (unmodified or regular), which is an improved version
of the original preparation. It acts more quickly and intensely than the
others and is the insulin of choice for the treatment of surgical emergencies
and diabetic ketosis.

(2) Modified insulins, which are altered chemically so that their actions
are delayed and prolonged. The different types are as follows:

Type of insulin

Duration of action |
(hours)

Maximum effect
(hours after injection)

Short acting

Soluble insulin

Insulin line suspension (semilente)

6-10 |

3- 6

Intermediate

Glnbin zinc insulin

fsophanc insulin

6-18

Insulm line suspension (lentc)

8-20

6-10

Long acting

Protamine zinc insulin

16-24

Insulin zinc suspension (ultralente)

18-24

12-20

The duration of action and the time at which the maximum effect is exerted
depend on the size of the dose employed and on many other variable

400

ISLET CELLS OT THE PANCREAS

factors. The figures given provide an approximate guide. In general,
hypoglycaemia tends to occur 2 to 4 hours after injection with a short-
acting insulin, in the late afternoon or evening with an intermediate type
(injected in the morning) and during the night with a long-acting prepara-
tion. Insulin is standardized in units so that it is possible to ensure that the
dose remains constant. The strength is expressed in units of insulin per ml.
Soluble insulin is supplied in strengths of 20, 40 and 80 units per ml., white
the modified insulins are supplied in 40 and 80 units per ml.

There are two groups of oral hypoglycaemic agents — the sulphonjlureas,
which liberate pre-formed insulin from the pancreas, and the biguanidcs,
which probably facilitate the peripheral utilization of glucose. The main
preparations are as follows:

Drug

At crape d-itl) dose

SuIphon>Iureas:

Tolbutamide (Rastinon, Orinase)
Chlorpropamide {Diabmese)
Acetohexamide (Dimclor)

Biguanidcs:

PhtnfoTmin (ThcnMh>lbiRuaTiide)
Metformin (Dimeth)Ibiguanide)

05 G.

025 G.

0 5 G.

0 05 G.

05 G.

1-5-3 G.

0 2S-05 G.

0 5-1 0 G.

0 05-0 3 O.

1-2 G.

Insulin hypoglycaemia may develop while a diabetic patient is receiving
surgical treatment. The clinical features of hypoglycaemia ha\c been
described already, but it is important to remember that the syndrome
varies with the type of insulin used. With soluble insulin symptoms dc-
\clop rapidly and vegetative features arc prominent. The onset is more
insidious with the long-acting preparations, and cerebral disturbances arc
common. The patient may be flushed or pale, the skin is usually moist, the
pulse is full and hounding and the plantar responses arc extensor. Danger
signals are profound coma, shallow respirations, unresponsive pupils, loss
of comeal and other peripheral reflexes and subnormal temperature. The
diagnosis is confirmed by a blood glucose level of 30 mg. per 100 ml. of
less. The urine specimen may be misleading. The condition is treated »n
the following manner:

If the patient is conscious give sugar (4 to 6 lumps) or sugary drinks im-
mediately. Orange j'uicc or lemon juice containing 30 to 60 G. of glucose or
sucrose in 240 ml. is normally sufficient to revive the patient.

If the patient is unconscious do not attempt oral feeding. Give glucose
intravenously in a dose of 20 ml. of 50 per cent solution. This is frequently
sufficient, but larger amounts may be necessary. As soon as the patient
recovers carbohydrate should be given by mouth. Severe eases not re-
sponding to 40 or 60 ml. of glucose intravenously should he infused with
20 per cent glucose solution.

DIABETES MELMTUS AND THE SURGEON 401

Hypoglycaemia may recur after its successful treatment in patients taking
long-acting insulins. To prevent this, additional amounts of carbohydrate
should be continued for the next 12 hours until the risk has passed. Re-
current hypoglycaemia in a patient who has shown initial improvement
must be treated vigorously again.

A marked diuresis follows the intravenous administration of large
quantities of glucose, so that a watch must be kept on the patient’s bladder.
Adrenaline 0*5 ml. (1 : 1,000 solution) subcutaneously or glucagon 0*5 to
1 mg. subcutaneously or intravenously may be used in unconscious patients
if intravenous glucose is not available. Both may raise the blood sugar and
bring the patient round sufficiently to allow oral feeding with glucose.

Management of diabetic patients undergoing surgical operations
In the pre-insulin era operations on diabetics were major hazards and
frequently led to severe ketosis, coma and death. Today diabetics can
undergo any form of surgery provided they receive proper supervision and
care. Operations on diabetics can be divided into three categories:

1. Operations for surgical emergencies which threaten life.

2. Non-urgent operations in which the patient’s diabetes will be con-
sidered with all other aspects of the case. In some, the added factor of
diabetes may persuade the surgeon not to operate, while in others the
presence of diabetes may hasten his decision in order that he may fore-
stall complications which may later render the control of the diabetes
very difficult. If the surgical indications for operation are sound (e g. the
presence of gall stones) and the patient is stable and fit for surgery the
operation should be undertaken electively and not when complications
(e.g, acute cholecystitis) make surgical treatment hazardous.

3. Surgical conditions, such as sepsis and gangrene, which develop
largely as a result of the diabetes and maintain and intensify its severity.

Choice of the best time to operate

If the patient is known to have diabetes the treatment will depend on the
urgency of the surgical condition, the effectiveness of the diabetic control
and the form of anaesthesia required. In acute abdominal emergencies or
other conditions requiring an immediate operation the presence of sugar in
the urine can be ignored provided ketosis is absent. If the ferric chloride test
is negative it is probably safe to operate in accordance with the surgical
indications. It is usually necessary' to give the patient 20 to 30 units of
insulin, or more if the medical needs warrant it, before operation and to
infuse glucose (5 per cent solution) during the procedure. Patients who
have had an injection oflong-acting insulin {protamine zinc, isophane, lente
or ultralente) previously that day may not need more insulin. However, if

402 ISLET CELLS OF THE PANCREAS

there is considerable glycosuria preopcratively a small dose of soluble in-
sulin(10 to 15 units) may be advisable. If the ferric chloride test is positive
and there are other indications of Ketosis and incipient coma it is wise to
postpone operation for a few hours until the diabetes has received adequate
emergency treatment.

Occasionally a local collection of pus requires urgent treatment, because
its presence makes diabetic control difficult or impossible. In these cir-
cumstances it may be advisable to undertake surgical treatment even if
severe ketosis is present (see later).

Preoperative management

General anaesthesia alone is liable to cause ketosis, and infection,
stanation and vomiting increase the risk. Accordingly, all patients, except
the mildest and those in whom the surgical procedure is trivial, requite
insulin to cover the operative period. Elective operations on diabetics should
always be done as early as possible in the day. This allows time for the patient
to be wide awake in the afternoon, when further feeding with carbohydrate
and more insulin will be required.

Trivial operations in mild diabetics. Special measures are not usually
necessary in this group, but a careful watch must be kept for signs of
ketosis. The patient should, if time permits, be controlled carefully before
operation. In many mild diabetics stabilization can be achieved by diet,
alone or in combination with an oral hypoglycacmic drug. If the blood
sugar rises and ketosis develops insulin will be needed temporarily.
Patients on oral treatment can omit the tablets safely for a few hours until
they are again able to swallow. If insulin is being vised it can be omitted
on the morning of the operation, but a small dose of soluble insulin is given
at 5.30 p.m. to cover the evening meal of carbohydrate, which can usually
be taken after a minor procedure. The usual diet and insulin arc then re-
started the next day.

Routine major operations for diabetics on insulin. A properly stabilized
diabetic should he brought into hospital a few days before operation. We
prefer to change from a long-acting insulin, injected once daily, to soluble
insulin, given twice daily, so that there is no risk of hypoglycacmia as a
result of preoperativc starvation. Soluble insulin is more flexible in use,
and frequent injections can be given postopera lively if Ketosis is severr.
The total daily amount of soluble insulin should be equivalent to the dose
of long-acting insulin which it replaces. Three-fifths (60 per cent) of 0“
total dose should be given in the morning and two-fifths (-40 per cent) in the
evening.

No food or glucose is given via the stomach on the morning of operation,
but before the patient goes to the theatre the blood glucose is estimated and
| an intrav cnous drip of glucose (5 per cent) is sta rted and con tinued through*

DIABETES MBLLITUS AND THE SURGEON 403

out the operation and for as long as it is needed afterwards. Veins are
precious in diabetics, and we prefer not to cut down on them unless intra-
venous therapy is likely to beprolonged. When the drip is running smoothly
half to two-thirds of the usual morning dose of soluble insulin (or less if the
initial blood glucose was low) is injected subcutaneously. It is rarely
necessary to exceed 30 units except in the severest cases. At the end of the
operation the blood glucose estimation is repeated to ensure that it is neither
too high nor too tow.

Postoperative management

Serious ketosis must be anticipated after operation. If it develops it
must be treated with repeated doses of insulin and with carbohydrate
feeds. After short operations, and whenever oral feeding can be started
early, light fluid feeds with adequate carbohydrate (milk and lactose feeds —
sec below) can be given in the afternoon. Regular testing of the urine and
administration of insulin, according to the degree of glycosuria (see below),
is a practical method of management until normal meals and insulin twice
daily can be restarted. After longer operations, when oral feeds cannot be
given (as In gastrointestinal surgery) or when postoperative nausea or
vomiting make administration of carbohydrate difficult, it is wise to keep
the infusion running until normal feeding can be resumed. During the first
24 hours 500 ml. of the 5 per cent glucose solution (plus electrolytes as re-
quired) are run in every 6 to 8 hours.

The urine must be tested for sugar and acetone at 2- or 4-hourly inter-
vals (depending on the severity of the diabetes), and the patient must be
catheterized if necessary. Soluble insulin is given every 4 or 6 hours
(again depending on the severity) according to the following scheme. The
aim is to keep the urine free of acetone but to allow a trace or plus ( +) of
sugar.

Urinary sugar (clinitest scale) + + + + +++ ++ + B * ue

Dose of soluble insulin 30 unit 3 20 units 12 units — —

When the patient can swallow, oral feeds may be given. Milk (1,120 ml.)
plus lactose (60 G.) is a suitable allowance for the first 24 hours and supplies
1,000 Calories. The lactose is dissolved in 140 ml. of boiling water and
added to the milk, making a total volume of 1,260 ml. This is given as nine
2-hourly feeds, each of 140 ml. (6 a.m. to 10 p.m.).

When the danger of ketosis has passed and the patient is able to take food
normally a light diet of 1,000 to 1,200 Calories is given and soluble insulin is
continued twice or three times daily in accordance with the results of the
urine tests. When possible, the preoperative diet and insulin should be
resumed, but it is often found that the dose of insulin has to be increased
temporarily after an operation.

404

ISLET CELLS OF THE PANCREAS

Diabetic ketosis (precoma) and coma
Diabetic ketosis may be precipitated by a surgical emergency, infection,
starvation or vomiting, and the surgeon must be familiar with it and under-
stand its emergency treatment.

Symptoms

Increasing thirst and polyuria with weakness, malaise and impairment of
appetite are the earliest features. Complete anorexia, followed by nausea,
vomiting and dehydration, may develop. Acetone may be detected on the
breath Rapid infiltration of the liver with fat sometimes causes abdominal
pain, which is occasionally severe and associated with muscle guarding.
This “diabetic acute abdomen’’ is readily mistaken for a surgical emer-
gency. Musclecramps, air hunger and drowsiness develop and are followed,
if treatment is delayed, by coma, peripheral circulatory failure and death.

The severity of diabetic ketosis depends on the degree of metabolic
acidosis and not on the level of the Wood glucose. If the carbon dioxide
combining power (CO,CP) of the blood (normal 24 to 32 mEq. per litre)
is below 10 severe acidosis is present; if it is between 10 and 18 there is
moderate acidosis; and if it is above 18 the condition is mild.

Principles of treatment of ketosis
The principles of treatment are:

1. Immediate and adequate treatment with insulin.

2. Correction of the metabolic acidosis, dehydration and shock by
parenteral fluid and replacement of electrolytes.

3. The treatment of any complicating infection.

4. Prevention of pulmonary’ complications by gastric aspiration and
nursing procedures.

5. The operative treatment of surgical emergencies when the patient *
condition permits.

6. The re-establishment of normal diet and control with insulin as
soon as possible.

Management of ketosis

(1) Immediate action. On admission blood is taken immediately fot the
rapid estimation of blood glucose, COjCP, plasma specific gravity' and
electrolytes, while the urine is tested for sugar and ketone bodies. It may
be necessary to cathetcrue the patient, and an indwelling catheter w ad-
visable for those likely to require operation so that samples can be obtained
readily’ when the patient is in the theatre. A detailed clinical examination
is made to determine whether infection or other surgical complications arc
present. Special attention is paid to the state of the stomach, bladder and
chest and to the presence or absence of signs of circulatory failure.

DIABETIC KETOSIS AND COMA 405

Insulin is given in a dose of 60 to 100 units (of soluble insulin) as soon as
the diagnosis of diabetic precoma or coma is made. In severe cases,
especially those with signs of peripheral failure, half or even all the insulin
is given intravenously. As soon as the laboratory findings are known the
situation is reviewed. If the blood glucose exceeds 500 mg. per 100 ml., or
the COjCP is below 10 mEq. per litre, an additional 50 to 100 units of
insulin are given at once. The subcutaneous route may be used if the
original dose was given intravenously; otherwise at least half of the second
dose should be given by vein. When the initial blood glucose is between 600
and 1,000 mg. per 100 ml. the second dose of insulin should be 100 units.
It must be stressed that these large doses of insulin must be given only to
diabetics with ketosis; if they are given for a high blood glucose alone they
will cause hypoglycaemia.

Gastric lavage is advisable to prevent the aspiration of the gastric contents ;
it is essential in the preparation of the patient for surgery. The stomach
is aspirated completely and washed out gently with physiological salme.

Intravenous therapy is estimated from the specific gravity and the electro-
lyte content of the plasma. In the average case the fluid deficit is at least
2 litres and may be between 3 and 5 litres. For each rise of 0,001 over the
normal plasma specific gravity (1,027) an adult requires not less than
200 ml. of fluid. This amount can be replaced as fast as it can be run in
without any risk of overloading the circulation. Thereafter the plasma
specific gravity can be estimated or more fluid infused at a slower rate in
accordance with the clinical requirements. In elderly subjects a careful
watch must be kept on the jugular venous pressure and on the bases of the
lungs in order that overloading of the circulation may be detected. Insulin
alone will correct the acidosis in time, but its correction may be speeded by
the administration of sodium lactate in moderate amounts. If 2,000 ml. of
fluid are required it may be given in the following manner: 500 ml. of M/6
sodium lactate is given first and is followed by 500 ml. of physiological
saline and 1,000 ml. of 5 per cent dextrose (the latter provides water to
overcome the cellular dehydration). Once the initial correction has been
carried out alternate bottles of saline and dextrose may be given.

Occasionally patients with severe ketosis may die from circulatory
failure before fluid and electrolyte replacement can raise the blood pressure.
When the initial systolic blood pressure is below 80 mm. Hg, noradrenaline
(4 ml. per 500 ml. of physiological saline) or metaraminol should be infused
at a rate sufficient to maintain the blood pressure between 100 and 120 mm.

(2) Second to sixth hours of treatment. In severe cases the blood glucose
and electrolytes should be redetermined at about 4 hours after the start of
treatment, or earlier in those who fail to respond. If the blood glucose is
rising, or failing to fall, another 60 to 120 units of insulin should be given.

406 ISLET CELLS OF THE PANCREAS

Further electrolyte correction will depend on the biochemical findings.
Potassium depletion usually develops as the fluid deficiency is made good,
and once the urine output exceeds 1 ml. per minute, and the result of the
second potassium level is known, it is safe to infuse potassium chloride in a
strength of 1 G. per litre of fluid.

(3) Sixth to twenty-fourth hours of treatment. If the blood glucose is falling
satisfactorily soluble insulin is continued every 4 to 6 hours according to
the results of the urine tests. When the patient is conscious and able to
swallow, the milk-lactose mixture described above is given until a semi-
fluid light diet of 1,000 to 1,200 Calories can be tolerated.

Surgery and diabetic ketosis

An emergency surgical operation must be delayed long enough to allow
preliminary correction of the ketosis. In serious cases the surgeon and
physician must decide on the relative risks of surgical delay and operation
on a patient with incompletely treated ketosis. A few hours’ respite, how-
ever, will accomplish a great deal and improv e the patient’s chances con-
siderably. Frequent laboratory estimations of the blood glucose and CO,CP
and the clinical response to treatment will enable a decision to lie made on
the most opportune moment for action. A further 30 to 40 units of insulin
will be necessary to cover the actual operation. Blood should be taken for
estimation of the blood glucose and COjCP before the patient leaves the
theatre so that the effects of the surgical procedure can be assessed rapidly.

Complications of diabetes

There are three major complications, namely infections, peripheral
neuropathy and vascular disease. All arc commonest in those in whom the
disease is untreated or controlled inadequately. Rigid control, however,
docs not eliminate the complications completely. A minor condition, which
may be commoner in diabetics than in others, is Dupuytrcn’s contracture.

Infections

Infections are common in diabetics, and may themselves aggravate the
diabetic state.

Staphylococcal and fungal infections of the skin and vulva were formerly
frequent and severe. If they develop they usually aggravate the diabetes
temporarily and increase the need for insulin. They can now be treated
cffcctiv cly w ith specific antibiotics and fungicidal drugs. Ihtlmanary tuber-
culosis is fairly common in younger patients. l*ythnephrUh is a very' fre-
quent complication and is often symptomlcss. It may, however, cause
serious renal impairment and hypertension. The urine should be examined
regularly for the presence of pus cells and organisms. If they are found,
specific treatment should be given.

COMPLICATIONS OF DIABETES

407

Peripheral neuropathy

Peripheral neuropathy is fairly common, hut may not be apparent unless
sensation and tendon reflexes are examined routinely. Its chief importance
is that it contributes to the development of lesions in the feet (see later).
In the early stages it tends to regress when the diabetes is brought under
control.

Vascular disease

The blood vessels may be affected in three ways, only one of which (the
capillary lesion) is specific to diabetes. Atheroma is far commoner, and
develops earlier, in diabetics than in other subjects. It presents the usual
morphological appearances and is associated with raised lipoprotein and
cholesterol levels in the plasma. The distribution of the lesions is unusual,
however, for they tend to affect the smaller and more distant vessels. The
feet are affected most often. Lesions in the hands and in the coronary and
cerebral vessels are only slightly commoner in diabetics than they are in
non-diabetic subjects. Hypertensive arteriolar disease may follow pye-
lonephritis or specific renal lesions.

The specific capillary lesions of diabetes affect primarily the basement
membranes of the retinal and glomerular vessels. Microaneurysms of the
retinal capillaries, seen as red spots on retinoscopy, are the first signs of a
retinopathy which may lead eventually to blindness. The glomerular
lesions cause albuminuria, the excretion in the urine of cells containing
doubly refractile lipid, and severe renal damage which contributes to the
hypertension. It is possible that these lesions are related to insulin an-
tagonists, for they may be reversed by hypophysectomy (see later).

Surgical lesions of the feet

Three factors, either separately or together, commonly cause serious
lesions of the feet.

1. Atheroma causes lesions which are primarily ischaemic. Intermittent
claudication may develop in the small muscles of the feet as well as in the
larger muscles of the calves. Affected feet are cold and pulseless, although
the pulses at the knees and ankles may be strong. They are blue or red in
colour, and trophic changes are usually pronounced. Rest pain (erythral-
gia) is often severe, and is aggravated by warmth or dependency’. Gangrene
supervenes commonly, starts usually in one or more toes and is “dry” m
type* In the presence of infection it may be “wet” and associated with
severe toxaemia. Ischaemic ulcers often develop as a result of trauma, and
are liable to become infected.

2. Diabetic neuropathy may cause severe pain in the legs and feet, even
when the circulation is intact. Unlike vascular pain, it tends to be eased by

■408

ISLET CELLS OF TIIE PAXCRFAS

dependency. Sometimes it impairs the peripheral sensation so that lesions
develop on the feet as the result of trauma to insensitive tissues. Blisters art
neglected because of the freedom from pain and may form large superficial
ulcers. Some of these penetrate deeply into the tissues and cany infection
into the joints and bones (fig. 11.5).

Tip. 11.5. X-ray of foot in diabetic neuropathy with associated atheroma and
ojtMwnjrhtn.

3. Infection. Septic lesions on the feet may be primary or may complicate
vascular of neuropathic disorders.

I *r event ion of foot lesions. Careful management can do much to prevent
the development of serious lesions, and patients with arterial disease f>*

COMPLICATIONS Of DIABETES

409

neuropathy must be instructed in detail about the care of their feet.
Trauma and cold must be avoided by the use of thick dry socks and wide,
well-fitting shoes. The feet should be washed, dried carefully and dusted
with fungicidal powder daily. The toenails should be cut square. Direct
heat to an ischaemic or insensitive limb must be forbidden, and hot-water
bottles and electric pads in bed must be avoided. Corns and callosities
require treatment by a skilled chiropodist. Local abrasions should be
covered, to prevent infection, and the foot rested until healing is complete.
The control of diabetes in these patients should be as rigid as possible.

Treatment of foot lesions. Before treatment is started it is essential to
discover, if possible, the extent to which arterial insufficiency, neuropathy
and infection have each contributed to the lesions. Clinical examination of
the pulses, capillary circulation, sensation and tendon reflexes must be
carried out. X-rays should be taken of the bones for evidence of osteo-
myelitis and sequestra, and the discharges from ulcers and sinuses should
be cultured.

The diabetes must be brought under rigorous control, and any infection
must be treated by specific antibiotics and by the drainage of pus. Control
of infection will often reduce the severity of the diabetes and will reveal the
extent of underlying lesions.

Treatment of painful ischaemic and ulcerated feet is the same in diabetics
as in non-diabetic subjects, and consists of rest, the relief of pain and the
use of anticoagulants and vasodilators. It is usually best to expose the feet
to the atmosphere to reduee the temperature (and hence the oxygen re-
quirement) and to prevent lesions from becoming wet. Small dressings
may be needed to absorb pus, but maceration of healthy tissue must be
avoided. Wet dressings, containing antiseptics or trypsin, are sometimes
necessary for the removal of crusts or sloughs, but they must be used with
caution.

Surgical measures include sympathectomy, the local removal of dead
tissue, formal amputations and occasionally skin grafting. Lumbar sym-
pathectomy may be used to prevent the onset of gangrene, to limit its
spread or to encourage an amputation to heal. In this case it is best to do
the sympathectomy at the same time as the amputation, for vasodilation is
maximal in the first few days after operation.

The removal of necrotic tissue should always be as conservative as
possible, and high amputations are rarely needed. Atheromatous lesions
are usually peripheral, and neuropathy alone does not impair healing
seriously. The tissues must be handled very gently in all operations, for-
ceps must not be used on the skin, and amputation stumps should be sewn
in two layers— one for the fascia and one for the skin. Gangrene, confined
to one or more toes, is best treated by local amputation, provided the cir-
culation is adequate in the rest of the^foot. A guillotine amputation, with

410 ISLET CELLS OF THE FANCRFAS

coring-out of the hone of the proximal phalanx and approximation of the
skin edges with one or two sutures, is usually satisfactory. When more
extensive amputation js needed for necrosis or pain it can usually be less
radical than that required for non-diabctic subjects. 'Hie transmctataml,
Syme’s and below-knee amputations can often be used. lesions com-
plicated by osteomyelitis respond to wide local excision of infected bone
and hardly c\er require amputation. Healing may take many months and
leave the patient with a distorted foot, but the limb will be useful and much
better than a prosthesis.

Disease of the coronary and cerebral arteries may render impractical the
definitive surgical treatment of peripheral lesions On the other hand, the
prolonged recumbency (which is needed for the healing of ulcers and septic
lesions of the feet) may encourage thrombosis in these vessels. If the risks
of prolonged rest seem greater than those of surgery it may occasionally be
wise to amputate a limb which, in other circumstances, could he saved.

Hypophysectomy for diabetic retinopathy and nephropathy

The specific capillary lesions of diabetes cause retinopathy and nephro-
pathy. The first (retinitis proliferans) may progress to detachment of the
retina, vitreous haemorrhage and blindness. The second may cause hj per*
tension, hypoproteinaemia, renal failure and death. They are found most
often in comparatit ely young patients w ho hat e had diabetes for 20 years or
longer. The pathogenesis of the lesions is not understood, but they maybe
caused in part by the direct actions of insulin antagonists. Good control of
the diabetes is the best method of preventing them, but it does not do so
completely. Once they arc established their progress cannot be halted by
simple means.

In 1953 Poulsen observed that post-partum necrosis of the anterior
pituitary in a patient n ith diabetic retinopathy was followed by a reduction
in the insulin requirement and also by remarkable regression of the retinal
lesions. Tuft and Olivecrona were the first to attempt to arrest the de-
velopment or progression of vascular complications by elimination of the
diabetogenic factors of the anterior pituitary' by surgical hypophvJrctom).
Xo large scries has been published yet, and preliminary reports only
available. The patients arc poor subjects for surgery, postoperative
management is difficult and the marked insulin sensitivity which follows
hypophv scctomy necessitates v cry careful diabetic control. The operative
mortality may l*c as high as 20 per cent. ! low ever, in at least half of those
who survive, severe retinopathy regresses and the ability to read improves.
'The blood pressure usually falls and progression of the renal lesion* »*
halted. 'JTicsc encouraging results might be improv cd if patient* were sub-
mitted to operation at an earlier stage of their disease.

FURTHER READING

431

FURTHER READING AND REFERENCES
General and Diabetes

DANowsfcr, r. s. (1957). Diabetes MeUitus. Williams and Wilkins, Baltimore

ROYAL COLLEGE OF Physicians OF LONDON (1962). Disorders of Carbohydrate
Metabolism . Pitman Medical, London.

JOSLIN, B. F., ROOT, h. f., white, p. and marble, a. (1 959). The Treatment of Diabetes
Melhtus. 10th Ed. Kimpton, London.

ren old, a. e. and CAHILL, c. F. (1960). Diabetes melhtus. In The Metabolic Basis
of Inherited Disease, p, 65. Ed. Stanbury, J. B., Wyngaarden, J. B. and
Fredrickson, D. S. McGraw-Hill Book Company, New York, Toronto,
London.

Williams, n. ii, (1962). The pancreas. In Textbook of Endocrinology, 3rd Ed., p.
559. Ed. Williams, R. H. Saunders, Philadelphia.

Investigations

FAJANS, S. S., SCHNEIDER, J. RL, SCHTEINGART, D. E. and CONN, J, W. (1961). The
diagnostic value of sodium tolbutamide in hypoglycaermc states. J. elm.
Endocr., 21, 371.

marble, a. (1959). Applied physiology in diabetes and The examination of urine and
blood in diabetes. In The Treatment of Diabetes Mellilus 10th Ed , pp. 138,
192. Joslin, E.P., Root, H. F., White, P. and Marble, A. Kimpton, London

Hyp trtnsu lim'sm

Cochrane, w,, payne, \v. w., simpkiss, m. j. and woolf, l I. (1956) Familial
hypoglycaemia precipitated by ammo acids. J. din. Invest . , 35, 411.

Conn.j.w. and seltzer, H.s. (1955). Spontaneous hypoglycaemia. Amer.J Med.,
19, 460.

OCNCAN, g. c. (1959). Spontaneous hypoglycaemia. In Diseases of Metabolism,
4th Ed., p. 712. Saunders, Philadelphia.

cidson, j. b. and weldourn, n. o. (1960). Islet cell tumours and peptic ulceration.
Postgrad, med.y., 36, 154.

HOWARD, j. M., MOSS, m. h. and RHOADS, j. E. (1950). Hypennsulimsm and islet-
cell tumors of pancreas: with 398 recorded tumors. Int. Abstr. Surg., 90, 417.

Markowitz, A. rl, slanetz, c. a, and frantz, v. k. (1961). Functioning islet-cell
tumors of the pancreas. 25 -year follow up. Ann. Surg., 154, 877.

REmine, w. ii., scholz, d. a. and priestley, ]. t. (1960). Hyperinsulinism: clinical
and surgical aspects. Amer. J. Surg., 99, 41 3.

RtCHARDSON, J. E. and russell, D. s. (1952) Cerebral disease due to functioning
islet-cell tumours. Lancet, 2, 1054

seracue, h. c. (1960). Severe hypoglycaemia associated with large non-pancreatic
tumours of the abdomen and thorax. In Clinical Endocrinology I, p. 315.
Ed. Astwood, E. B. Grune and Stratton, New York.

Schwartz, t. b., flannacan, g. c., stuppy, g. w. and tarum, n w. (1959) The
hypoglycaemic effect of /-leucine m organic hyperinsulinism. 3. Lab. clitt.
Med., 54, 944.

WrttlPPti, a. o. (1938). The surgical therapy of hyperinsulinism. J. int. C/ur., 3,
Diabetes MeUitus and the Surgeon

hernbero, c. a., bjOrkesten, g. and vannas, s. (1959). Hypophysectomy in the
treatment of retinopathy and nephropathy in severe juvenile diabetes. Ada
endocr. (FCb/i.), 31, 241. . , _

JOpLtv, c, r. (1962). Pituitary' ablation in the treatment of diabetic retinopathy. In
Disorders of carbohydrate metabolism. Ed.Pyke, D-A. Pieman Medical, London.

wjieelock, r. c. and root, h. f. (1959). Surgery and diabetes. In The Treatment of
Diabetes Melhtus. 1 0th Ed , p. 584. Joslin, E. P-. Root, H. F„ White, P. and
Marble, A, Kimpton, London.

PART III

ENDOCRINE ASPECTS OF
GENERAL SURGERY

CHAPTER 12

SURGICAL STRESS

the metabolic response to trauma

As long ago a, 1872 Bauer obsenxd thatlo^sonilood^rau^d an ^increased
excretion of nitrogen in the urine, n without the withdrawal

same phenomenon after simple punc ure increased excretion of

of blood. Benedict, in 1915, observe, 0 f1hcse observe-
nitrogen during prolonged s “ r ™ ,lon ' rece ntly The present era

tions has not been appreciated by surg Cuthbertson on the cata-

started thirty years ago with the ° bs ' rva j w ith t i, osc 0 f Wilson

bolic effects of immobilization and of •f**^™*™ S oo„ after

and Stewart on the changes in electro ytem^ ^ of nOTtous stimuli

this Selye expounded the view that g boU / clian ge and that the
elicited a common non-specific pattern nti During the past

endocrine system played a vital role in nIn i«Moote have worked out

decade very many workers, foremost among vvhomis Moore, na ^^

in great detail the implications of this concept for the careo! surg P

Stress and the metabolic response i t u e i ene th

Moore has pointed out that the and duration of the

of time during which it lasts vary \ , cause on ly a minor

trauma. Minor operations, such as henuontap^. such ,,

disturbance of metabolism, white more ex striking response,

gastrectomy or pneumonectomy, “ ™ ration5 , an d serious injuries,

Very severe operations, such as pelvic disturbances. Traumatic

such as extensive burns, cause gross meta or ^ effective stimuli.

injury and surgical operations are not, owe , . j rrac liation with

The stress of parturition and the dam ge a J Wi fatigue, drugs,

X-rays are, for instance, equally potent, *n ^? on all contribute to it.
general anaesthesia, immobilization • a the site of injury or in the
Other factors, such as accumulation flu,d a * ^ £ d. in the

body as a whole, deficiency of oxygen or h k d sprc adlng

blood, provide relatively strong strmuh. Ohgaemic
sepsis are the most potent factors of a . known and need no

The clinical aspects of these problems ^ '' C “^ t hem arc well
description here. The metabolic changes \v meta bolic response has

documented, but not yet generally appreciated. The metaboi
413

416

SURGICAL STRFSS

two main phases, the catabolic, in which the body tissues are broken down
and provide energy, and the anabolic, during which the tissues are replaced.

The catabolic phase, “phase of injury” (Moore) or “alarm reaction”
(Selye), starts as soon as the stress is inflicted and lasts for 1 to 10 daw, or
even longer in exceptional circumstances. Its most transient feature is
extracellular retention of water, which reduces the excretion of urine for
24 to 36 hours. Its characteristic and most important aspects concern the
metabolism of protein, fat and carbohydrate and of the electrolyte ions.
The protein of the skeletal muscles and other tissues throughout the body is
broken down (catabolized). A patient undergoing gastrectomy, for in*
stance, loses about 10 g. of nitrogen in the urine daily for 5 to 7 dap. This
loss represents the catabolism of about 300 g. of tissue pci day. It «
obligator}' and cannot be prevented by the administration of protein; loss
of weight is therefore inevitable. Energy is provided mainly bv oxidation
of fat from the body’s stores, by the catabolized protein and to a small
extent by carbohydrate. The latter source is consumed entirely within
24 hours. Potassium is excreted in excess in the urine. It is derived both
from the muscle cells which have been broken down and from the genera!
cell mass of the body, in which potassium is replaced partly by sodium and
hydrogen ions from the extracellular fluid. At the same time sodium and
chloride are retained in the body and their excretion in the urine is
diminished, both ions accumulate in oedema fluid, and the sodium, a*
already mentioned, tends to replace potassium in the cells. The significance
of all these changes, which appear to be very wasteful of body tissue, is not
clear, but they seem to be inseparable from a satisfactory response to
noxious stimuli. The)' may, however (os will be mentioned later), l>c
modified by the administration of androgens or of anabolic steroids. It
may be that the mobilization of protein provides amino acids for the reput
of damaged tissues and that the retention of sodium helps to preserve
homeostasis during a period of relative dehydration.

The catabolic phase usually finishes at the time the acute postoperative
illness gives place to the period of convalescence. This may occur in 4 to
5 days after a simple hernial repair, in 7 to 9 davs after gastrectomy and not
until 30 days or so after severe burning. The first sign of metabolic change
is a sudden reduction in the excretion of potassium (fig. 12.1). A day or
two later the loss of nitrogen falls abruptly, even if food «s not supplied,
and synthesis or anabolism of protein begins if sufficient protein and
calorics are provided. The excretion of sodium and chloride increases
rapidly at about the same time (sodium diuresis). Thereafter, prov ided the
patient consumes enough food, he enters the anabolic phase, which con-
tinues throughout the period of convalescence. Svnthesis of protein
proceeds until the muscle mass and strength arc restored and finally the
fat, which bad been mobilized for the provision of cncTgy, is replaced.

THE METABOLIC RESPONSE TO TRAUMA

417

DAYS

Fig. 12.1. Metabolic balance in male patient undergoing inguinal herniorrhaphy.

Joule is plotted upwards from rero and output downwards from intake. Days of
po>iti\e balance are shown in black columns above aero and days of negative balance in
shaded columns below zero. The nitrogen and potassium changes are straightforward.
The study has not been continued long enough to show the completion of the sodium
diuresis. (Mr. I. D. A. Johnston’s data.)

These reparative processes continue for a week or two or for many months,
depending on the severity of the catabolic phase and on the patient’s pre-
operative state of nutrition.

The changes which have just been described may be modified by many
factors. Thus, postoperative complications, such as infection of the wound
or chest, venous thrombosis or paralytic ileus prolong or aggravate the
catabolic phase and delay the onset of anabolism. Complications which
de\elop after anabolism has started may stimulate a second catabolic phase.

418

SURGICAL STRESS

Undernourished patients lose little nitrogen, but othervv isc exhibit a nomu!
metabolic response to surgical trauma. Hypothermia delays the onset of
metabolic changes, but does not otherwise influence them.

The endocrine glands

Marked changes in function of the endocrine glands accompany the
metabolic processes and may be partly responsible for them. The ini*
mediate postoperative oliguria is caused by increased production of anti-
diuretic hormone from the posterior pituitary. The adrenal medulla and
adrenergic nerve endings secrete excessive amounts of catechol amines for
a day or two after severe injury, and these substances can l>c detected in
increased amounts in the urine. Tear, pain and oligacmic shock are the
main stimuli to their production. They are probably concerned in mobiliz-
ing sugar, in maintaining blood pressure and in causing tachycardia.

The adrenal cortex responds to stress by the increased production of
cortisol and possibly of aldosterone. The concentration of cortisol in the
blood increases two- to five-fold within 4 to 6 hours, but returns to normal
within 10 to 12 hours. The excretion of cortisol and its metabolites in the
urine (measured as 17-o\ogcnic steroids or as total 17-h\dro\ystcroi(b)
increases two- to tlircc-fotd during the first pan of the catabolic phase,
while the rate of utilization of cortisol by the tissues is reduced. There is
indirect evidence of an increased excretion of aldosterone in the urine at the
same time. There is no consistent increase in the excretion of androgens
(measured as 17-oxosteroids). Histological changes in the adrenal cortex
follow the biochemical ones. Lipid (which represents the precursors of the
corticosteroids) disappears from the cells of the zona fasciculata, at first in a
patchy manner and later, if the stress is severe and prolonged, from the
whole zone. It returns w hen the stress has passed. It is supposed, without
direct cv idence, that the adrenocortical response is induced by increased
secretion of ACTl l . If this is so, it is surprising that increased exaction of
androgens docs not accompany that of cortisol and its metabolites. If may
be that the role of ACTl I is permissive (see later).

The changes in the metabolism of protein and electrolytes arc similar to
those found in Cushing’s syndrome and during the administration of
cortisone. For these reasons it was formerly thought that the adreno-
cortical response was mainly, if not entirely, responsible for the metabolic
changes associated with trauma. This view was strengthened by the oh*
servation that patients with adrenocortical insufficiency, who are unable to
produce corticosteroids, succumb to triv lal injuncA instead of responding to
them in the usual way. There arc, however, serious objections to this
hypothesis. First, there is no close correlation between the reduction in
corticosteroid excretion and the other mculwlic changes which occur at the
end of the catabolic phase. Secondly (and more significantly), the charac-

THE METABOLIC RESPONSE TO TRAUMA 4,9

fgSlltB

cortisol (and possibly aldosterone) OTrttosterords do not

SStalS the metabolic changes. They play, to use Ingle's term, a
permissive role and not a causative one. simply and

The eosinophil count in the blood ' hases d „ f ,he metabolic

quickly, shows characteristic changes d g P ' manner by the

response to surgery. It is also influence >•> P norm al count is

adrenal cortex, but is affected by other factors . ]0n , _

usually 100 to 300 cells per cu. mm. Immediately b P ^

sibly under the influence of adrenaline) it c .ten U. ' to B * M or ^
again soon after induction of anaesthesia, u . .u | tve ] through-

morc by the end ofthe operation.

out the catabolic phase and rises again at the 1 excretion and the

not always) a correlation between the fall in cor i . characlenstic

rise in the number of eosinophils. A c ™ < ‘ n “' I ’ 8 o£ adrcnocort ical failure
of a complicated convalescence and a high h cone*

Little information is available about the. effects td mju.y <he £

There is presumptive evidence of decreasedendocr me function , tor^ ^

men lose their libido and women experience ^ sec0 nd half

valescence is nearly complete. If trauma is m c e j M a rcsu i t 0 f

of the menstrual cycle bleeding may fo How q b y. is unknown.

possible role of the sex hormones and of growth hoi™on . t j ate( j
the synthesis of protein) in the anabolic phase

but skeletal growth in children continues norma y forms of stress

Cold stimulates the secretion of thyro^, bo o te & « ^ ^
probably do not do so. Indeed, surgical opera i . . trauma on the

the uptake of >»I by the thyroid. The influence of su rg trau

parathyroids and on the islets of Langerhans is uncer

Oligaemic shock and the adrenal glands v m ic shock

It has been mentioned already that the syn ro medulla and

stimulates the production of catechol amines y _ Pta bolic response
constitutes a severe stimulus to the development of a metabolic

SURGICAL STRESS

420

an d to the secretion of corticosteroids bv the adrenal cortex. The medullary
secretions (together with those of the adrenergic nerv cs) augment vaso-
motor tone and tend to preserve the blood pressure. It is probable that
corticosteroids do so too, since an optimal vasomotor efTect on the peri-
pheral vascular system cannot occur without them.

The clinical features of oligaemic shock and of acute adrenocortical
failure (adrenal crisis) arc strikingly similar, and both are characterized by
collapse, hypotension and tachycardia. It is not surprising, therefore, that
adrenal insufficiency has at times been thought to play a part in the shock
syndrome and that some people Ime used corticosteroids in its treatment.
The evidence, however, is against this view. Shock stimulates the adrenal
cortex and is accompanied by a high level of cortisol in the blood and by a
low eosinophil count. There are, however, situations in which surgical
stress can cause adrenal failure and where its early recognition is of vital
importance. These will be considered later.

Severe infections and shock-states threatening life

Shock associated with bacterial invasion of the blood stream, obstetrical
shock, endotoxin shock, Mendelsohn’s syndrome (aspiration pneumonitis)
with obstruction of the airway and anaphylactic shock may he countered by
massive doses of corticosteroids. In these conditions there is no direct
evidence of adrenocortical insufficiency and use is made of the ability of
corticosteroids to suppress inflammation (Mendelsohn’s syndrome) or to
protect against cellular injurv (shock states), when given in pharmacological
doses. Cortisol hcmisuccinate is given in doses of 500 1,000 mg over a
few hours or prcdnbolonc-disodnim-Zl-phosphatc (1(H) mg.) is injected
intravenously every four hours. If the clinical condition improves these
doses arc curtailed rapidly. If there is no response within 24 hours treat-
ment is abandoned. Appropriate antibiotics must of course, be given for
the control of infection.

Anabolic steroids

The analiohc steroids and testosterone arc capable of reducing appre-
ciably the nitrogen deficit which develops during the catabolic phase after
surgical operations. Johnston in Belfast has observed that mctliandienonc
(50 mg. per day int ramuscularly) exerts this efTect after herniorrhaphy or
vagotomy plus gastroenterostomy when it is given for 5 days from the time
of operation. It 3lso increases slightly the normal retention of sodium and
reduces the excretion of potassium. If melhandienone 11 given for a week
before operation as well it does not have these ctlccts in the postoperative
phase. Mctliandienonc docs not appear to interfere with the adreno-
cortical response to operation. It is not yet clear whether analiolic steroids
confer any clinical Inmcfit in these circumstances and. until the matter has
been investigated further, they cannot be recommended for routine me.

THE METABOLIC RESPONSE TO TRAUMA

421

Patients who are unable to consume, digest or absorb sufficient food,
whose diet is deficient in protein, or who lose much protein from sinuses,
fistulae or infected wounds, may remain in negative nitrogen balance for
months or years. The first line of supportive therapy is the provision of
adequate calories and protein. Anabolic steroids may, however, be of great
value in enabling a patient to make the best use of the protein. Johnston
has investigated the effects of testosterone and of methandienone in patients
who are seriously underweight after gastrectomy. The following table
shows that the best results are obtained by a combination of dietary super-
vision and methandienone. Gain in weight is usually associated with an
increase in appetite and in wellbeing.

Mean gam in weight

Treatment No. of patients Sex in 8 v eeks (!b.)

Diet alone tO M & F 4-3

Methyliestosteronc 7 M 3 7

(25 mff./day)

Diet + merh) ltes tos t crane 9 M 6-2

Diet + methandienone 7 F 7-2

(20 mg./day)

Diet + methandienone 6 M 9 7

(50 mg./day)

The nitrogen balance becomes strongly positive after a few days of treat-
ment (fig. 12.2)

■DAYS

Fig. 12.2. Nitrogen balance in male patient 50 lb. under standard weight 9 years
after gastrectomy for peptic ulcer.

The nitrogen intake was constant throughout the period of study. Comenlion* a* in
fig. 12.1. The anabolic steroid was methandienone. The weight increased by 3f lb. mil
da>s and by 6 lb. in 2 months. (Mr. I. D. A. Johnston’s data.)

422

Sl'RGICAL STRESS

ADRENOCORTICAL FAILURE IN SURGERY

Adrenocortical failure, which develops whenever the supply of cortisol
is inadequate to meet the needs of the body, has been discussed in Chapter
3. In surgical practice it is encountered most often as a complication of
operation and may prose fatal. It develops more frequently than is com-
monly realised and is not confined to patients who ha\e undergone
adrenalectomy. Precautions must be taken to present its onset. If it does
appear it must be recognized at once and treated urgently.

Clinical features

The onset may be acute if corticosteroids arc absent and the stress
severe, or subacute if the deficiency is partial or the stress mild The
clinical features of the acute form arc those of an adrenal crisis, which is
indistinguishable clinically from oligacmic shock. Those of the tuhocutt
form arc less striking and similar to the "cortisone withdrawal sjndromc"
seen after adrenalectomy for Cushing's syndrome. The blood pressure
falls slow Jyo\ era period of days, the pulse rate rises and there is often slight
pyrexia. The patient usually feels weak. Abdominal discomfort, anorexia,
nausea and vomiting arc inconstant features and sometimes there arc
mental changes. Pigmentation is present only when there has been
chronic deficiency (Addison’s disease) previously. 'Hie subacute form of
deficiency usually becomes acute in the terminal stages. I .aboratory tests
may be helpful in subacute failure. 'Hie eosinophil count tends to be high,
the serum sodium concentration may be low despite normally adequate
replacement of salt and the blood glucose may be low. I’cw observations
have been made on the concentration of cortisol in the blood, hut low levels
have been reported. The estimation takes too long, however, to be of help
in the immediate management of the patient.

Causes of adrenal failure

There arc many causes of primary and secondary adrenal failure in
surgical patients. They may be classified as follows:

Primary Aitrrmil Failure

Removal Adrenalectomy
Dctlrurtitm Chmnic, AdJnnn'* drvraw
Acvitr adrenal apopleav
Iicharmia Clamping of aorta
Dyafondion Vmlirms h'T^ml-oia
T-ih»u«ion tevrrr nr repeated afrrti

Sttimjary A hrnal (Primary Pituitary) Failure
Ren**'*! llyTv>ph>aectnm»

l>e»trUC1ion Hyjvipiluitarifm iS'nmondt’ «!>«eat< or Nhrehan’a lyrKJmrne)
Inhibition Therapv » ith o>iurwirfi«l» or AC"! 1 1
Atfrrmlrrttmv

An acute adrenal crisis may follow aJrcnalectcmvv or the removal of an
adrenal tumour in Cushing’* syndrome, but is much trs* common when

ADRENOCORTICAL FAILURE IN SURGERY 423

adrenalectomy is performed for other reasons. It must be emphasized that
patients whose adrenals have been removed completely (and many who
have undergone subtotal adrenalectomy) require corticosteroid replace-
ment therapy for the rest of their lives. If stress increases the requirement
of corticosteroids, and if the need is not met, adrenal failure results.

Addison's disease

It is important that the presence of Addison’s disease should be re-
cognized in surgical patients, otherwise minor trauma or infection may
precipitate an adrenal crisis. A low blood pressure, patches of pigmenta-
tion and thinning of axillary or pubic hair should arouse suspicion.

Adrenal apoplexy

Traumatic injury, especially to the chest or abdomen, sometimes causes
bleeding into the adrenals. Patients with this type of injury have been
encountered in whom shock was “irreversible” in that it failed to respond
to blood transfusion. It seems likely that the oligaemic shock merges into
an adrenal crisis. Adrenal apoplexy may account for 1 per cent of deaths
in the newborn and is usually the result of prolonged and difficult labour.
Similar haemorrhagic destruction of the adrenals occurs in septicaemia
(which is frequently meningococcal) and may play a part in the “Water-
house-Friderichsen syndrome”.

Clamping of the aorta

Operations which involve prolonged occlusion of the aorta above the
level of the adrenals are associated with adrenal ischaemia. This may cause
adrenal failure postoperatively.

Virilizing hyperplasia

The relative deficiency of cortisol in patients with virilizing hyperplasia
of the adrenals renders them very liable to adrenal insufficiency. This may
be spontaneous in infancy or induced by a surgical operation at any time.
It must be remembered particularly when the adrenal glands or gonads are
being explored or when plastic surgical procedures are being undertaken.

“ Adrenal exhaustion"

Adrenal insufficiency sometimes develops in patients who have suffered a
long illness, are under-nourished, develop a fulminating infection, undergo
a very lengthy operation or require a second operation before they have
recovered fully from the first. It may also follow prolonged and difficult
labour or operations on patients with argentaffinomatosis. The deficiency
tends to be acute immediately after operation or subacute if it dev elops some
time afterwards. These patients respond dramatically to the administration,
of cortisol intravenously and of cortisone intramuscularly or by mouth.

424

SURGICAL STRESS

After a week or two the corticosteroids can be withdrawn and norma!
function is restored. The term “adrenal exhaustion" 1m been applied to
such cases. It implies that the adrenal response lias been o\erw helmed by
the demands which has e been made upon it, but that normal adrenal func-
tion can he restored when the body recovers with the help of replacement
therapy. It must be emphasized, though, that little exact information is
available about the pathology of the pituitary or of the adrenal in this condi-
tion. Details of a typical case are given in fig. 12.3.

Fig. 12.3. “Adrenal exhaustion” in female patient ngetl M>

The Wood prewure fell juddetilr 14 day» after a »econd operation (compttcated Iwr
itmt wound infection) and retponded ranull) ti» I0O mg. of corttvd hemnuccmilf mtn*
venouvly. (Mr. 1. U A. Jolmvton's data.)

llypophyseetomy and pituitary destruction

Primary pituitary failure is rarely so sudden in onset nr so sex ere as
primary adrenal failure, possibly because the secretion of aldosterone is
unimpaired. However, such patients withstand stress poorly and are
particularly intolerant of cold. Adrenal crisis docs develop rarch tn patients
nho ore maintained on jsynthettc Rhscvcvrtim'uif. n)»ch have weak
mincralocorticnid activity, hut it docs not occur in those who arc main-
tained on cortisone.

Pituitary inhibition by corticosteroid i or ACTU
The dangers of therapy with corticosteroids and with ACTII base been
stressed in Chapter 6. This is bv far the commonest form of aditno*
corticd failure in surgery and one which should Iwr avoidable

ADRENOCORTICAL TAILURE IN SURGERY 425

Diagnosis

The immediate diagnosis of adrenal insufficiency depends on the re-
cognition of possible underlying causes, on the clinical features, on the
exclusion of other pathological conditions and on the response to specific
treatment. Confirmatory evidence maj’ be provided later from estimation
of cortisol in a sample of blood taken before treatment is given. An adrenal
crisis is most likely to be confused with oligaemic shock and with other
acute lesions, such as coronary thrombosis or pulmonary infarction. Sub-
acute failure may be confused with salt deficiency, and with severe infec-
tions such as peritonitis. Adrenal insufficiency should be suspected at once
if the blood pressure fails to respond to adequate replacement of blood in
“shock” or to the administration of saline in salt deficiency.

Treatment

Treatment is required urgently, especially in acute failure. If the condi-
tion is suspected 100 mg. of cortisol hemisuccinate or 20 mg. of predniso-
lone-disodium-21 phosphate should be given intravenously at once. If the
diagnosis is correct there is a striking rise in the blood pressure within an
hour and usually within a few minutes. Cortisone is continued thereafter
by intramuscular injection or by mouth. If the intravenous preparation is
not available an infusion of noradrenaline or of metaraminol may tide the
patient over until cortisone by another route becomes effective. The other
measures which are needed for the treatment of an acute adrenal crisis have
been described in Chapter 3. It is important not to give too much cortisone
(or other corticosteroids) because of the dangers of infection and of wound
dehiscence, both of which may be real problems in these patients. If there
is an established infection it must be treated vigorously with antibiotics.
If the blood pressure does not rise when the cortisol is given the diagnosis
of adrenal insufficiency can be excluded. No harm is done, provided corti-
sone is continued in diminishing dosage for a few days.

Prevention

Every effort must be made to prevent adrenocortical failure in surgical
practice. This can be largely achieved if attention is paid to the following
points:

(1) The conditions which predispose to adrenal failure should be re-
membered. All patients undergoing surgical operations should be asked if
they have received steroid therapy.

(2} Any patient who requires surgery and is suspected of suffering from
chronic adrenal or pituitary insufficiency should, if time permits, have his
adrenal function investigated before operation. Brooke has found good
correlation between the stimulating effect of an infusion of ACTH {25 IU

426

SURGICAL STRESS

in 500 ml. of physiological saline, given in 6 hours) on the plasma cortisol
(measured at the start and again 3 and 6 hours later) and that of surgical
stress. An inadequate response indicates potential adrenal failure.

(3) Patients who are known to run the risk of adrenal insufficiency if they
undergo stress should be made to understand the urgent need for replace-
ment therapy at such times. The card which we give to such patients is
illustrated on p. 118.

(4) AH patients with potential adrenal insufficiency should be given re-
placement therapy routinely if they require surgical operations. The dosage
of cortisone is the same as that for patients undergoing adrenalectomy. If
adequate substitution therapy is given anaesthesia and surgery will offer
no special problems.

FURTHER READING AND REFERENCES
The Metabolic Response to Stress

Bradshaw, J. s., ABBOTT, w. e. and levey, s (1960). The use of anabolic steroids in
surgical patients. Amer. J. Surg., 99, 600.

CUTHBERTSON, D. v. (1930). The disturbance of metabolism produced by bony and
non-bony injury with notes on certain abnormalities of bone. Biochem. J., 24,
1244.

COODALL, M., stone, c., and haynes, b. w. (1957). Urinary output of adrenaline
and noradrenaline in severe thermal bums. Arm. Surg., 145, 479.

INCLE, o. J. (1954). The permissw e action of hormones. J. rim. Endoer., 14, 1272.

Jamieson, r. A. and KAY, A. «. (1959). Metabolic response to trauma. In Tettbaok
of Surgical Physiology, p. 49. Jamieson, R. A. and Kay, A. W. Livingstone,
Edinburgh.

Johnston, J. D. A. and chenneour, R (1963) The effect of methandicnone upon
the metabolic response to surgical operation. Brit. J. Surg. In Press.

LE QUESNE, L. p. (1954). Fluid Balance in Surgical Practice. Lloyd Luke, London.

LEVenson, S. M. and watki.n, d. M. (1959). Protein requirements in injury and
certain acute and chronic diseases. Fed. Proc., 18, 1155.

Moore, f. D. (1959). Metabolic Care of the Surgical Patient. Saunders, Phila-
delphia.

MOORE, F, d. and ball, M. R. (1952). The Metabolic Response to Surgery. American
Lecture Series, Thomas, Springfield, III.

MOORE, F. D„ STEENBURG, R. W., BALL, M. R., WILSON, G. M. and MYRDEN, J. A. (1955),
The urinary excretion of 17-hydroxycorticoids and associated metabolic
changes in cases of soft tissue trauma of varying seventy and bone trauma.
Ann . Surg., 141, 145.

PEOEN, J. c., MAXWELL, M. c. and ohin, a (1957). Anabolic effect of a new synthetic
steroid on nitrogen metabolism after operation. Arch. Surg., 75, 625.

Symington, T., CURRIE, A. R., CURRAN, R. c. and davidson, t. n. (1955). The re-
action of the adrenal cortex in conditions of stress. In Ctba Foundation Coll
Endoer., 8, 70.

Adrenocortical Failure in Surgery

Sampson, p. A., Winstone, N. F and broorf, B N. (1962). Adrenal function in
surgical patients after steroid therapy. Lancet , 2, 322.

SlaneY, c. and brooke, B. n. (1957). Postoperative collapse due to adrenal in-
sufficiency following cortisone therapy. Lancet , I, 1167

welbourn, R b.( 1957). Adrenocortical failure in surgery. Irish J. tried Set , 6th
Series, No. 381, 401.

CHAPTER 13

THE BREAST

The normal development and function of the breasts is very largely under
the control of the endocrine system. At least seven hormones are known
to exert an influence at one stage or another (fig. 13.1). It is hardly sur-

Fig. 13.1. The main hormones which control the development and function of
the breast.

prising, therefore, that endocrine factors are concerned in diseases of the
breasts and that the organs are often affected in disorders of the endocrine
glands. Our knowledge of the hormonal control of the breasts is derived
largely from animal experiments, but the main findings are probably
applicable to man.

427

42 S

THE BREAST

DEVELOPMENT AND LACTATION

The breast undergoes characteristic changes at different stages. In child-
hood the areola is flat, the nipple is small and there is no palpable breast
tissue. At the onset of puberty the areola becomes raised, the nipple en-
larges and a palpable disc of breast tissue appears beneath them. The
breast as a whole then enlarges as a result of the growth of glandular tissue
and the deposition of fat. The fat is mainly responsible for the final size
and shape of the breast, but the firm breast tissue is palpable within it In
the adult the areola sinks back to the general level of the breast and only the
nipple protrudes.

In early pregnancy the breasts tend to become painful and tender, in-
creased vascularity causes engorgement of the superficial \eins, the organs
enlarge and the areolae become brown and develop Montgomery’s tubercles
(whose nature is uncertain). At about the middle of pregnancy secondary
areolae develop; later small quantities of colostrum can be expressed, the
nipples become increasingly erectile and the breasts become nodular. The
early changes are especially noticeable in primigravidae and in brunettes.

Oestradiol alone is capable of stimulating growth of the mammary ducts
and of the nipples. The further development of lobules and alveolae is
dependent on four hormones — oestradiol, progesterone, growth hormone
and prolactin. The greatly increased production of oestradiol and pro-
gesterone by the placenta is probably responsible for the final full develop-
ment of the secretory system towards the end of pregnancy. Lactation,
that is the formation of milk, is apparently initiated in two ways. First, the
act of suckling evokes, by a nervous reflex, the secretion of prolactin,
growth hormone and ACTH by the anterior pituitary (and hence of cortisol
by the adrenal cortex). These are all essential to lactation. Secondly,
delivery of the placenta causes a sudden fall in the concentration of
oestrogen in the blood, and this allows the release of prolactin. The ex-
pulsion of milk from the alveoli is also controlled reflexly. Suckling causes
the secretion of oxytocin by the ncurohypophysis, and this stimulates the
myoepithelial cells of the alveoli to contract. It is probable that thyroxine
plays a part in the maintenance of an optimum yield of milk. Prolactin
normally inhibits ovulation throughout the period of lactation.

After the menopause the parenchyma of the breasts undergoes atrophy,
although evidence of epithelial activity can often be found histologically.
These changes may reflect the influence of hormonal secretion by the
adrenal cortices or of residual activity in the ovaries.

Suppression of lactation

Lactation can be suppressed by the administration of ocstrogens, which
inhibit the secretion of prolactin, provided treatment is started within

DEVELOPMENT AND LACTATION 429

24 hours of the delivery of the placenta. Stilboestrol, in the following
dosage, is usually adequate:

S mg. 3 times a day for 2 da> s
S mg. 2 times a day for 2 days
S mg. daily for 3 dajs

Sometimes the dose may have to be increased greatly and the administra-
tion prolonged to achieve suppression. Alternatively, a single injection of a
long-acting oestrogen (in equivalent dosage) may achieve the desired result.
It is much more difficult to suppress lactation once it has become estab-
lished. Androgens are undesirable and unnecessary.

Acute mastitis

The decision to suppress lactation should not be taken lightly. Acute
cellulitis usually responds rapidly to appropriate antibiotic therapy without
interruption of breast feeding. The infant suckles the healthy breast and
receives complementary feeds, while the infected breast is emptied with a
pump until the inflammation has subsided. Normal feeding is then re-
sumed. Lactation must usually be suppressed if pus forms, if the lesions
are causing severe pain or if both breasts are affected.

Abnormal lactation

Persistent lactation. Lactation usually persists as long as the child is
allowed to continue to suckle. Rarely, however, it persists for years in the
absence of suckling and is accompanied by amenorrhoea (Chiari-Frommel
syndrome). The condition is associated with diminished excretion of
gonadotrophins and of oestrogens, increased excretion of prolactin and an
atrophic uterus. Sometimes there is a chromophobe adenoma in the
anterior pituitary. Attempts to stop the lactation and to start uterine
bleeding should be made with oestrogens, progestogens and possibly with
androgens. If, as is often the case, they are ineffective, deep X-ray to the
pituitary may be tried or an adenoma may be removed surgically. This
will stop the lactation, but is likely to render the amenorrhoea permanent.

Spontaneous Jactation. Lactation can occur only in breasts whose lobules
and alveoli are developed, and hypertrophy of the breasts therefore pre-
cedes the secretion of milk. The breasts of the newborn infant sometimes
secrete milk for a few days as a result of stimulation by the maternal
hormones. Other types of lactation without preceding pregnancy are
extremely rare. Acromegaly is occasionally associated with lactation in
both w'omen and men. Presumably growth hormone stimulates the breast
directly. Chromophobe adenomas of the pituitary may cause lactation, but
the mechanism is obscure. Oestrogen-secreting tumours of the ovary may
cause spontaneous lactation even in children and in elderly women.

Non-endocrine causes of spontaneous lactation include persistent

430

THE BREAST

sucking and manipulation of the nipples, a habit sometimes indulged in by
psychotics, and the use of drugs. Phenothiazine derivatives (chloro-
promazine) and reserpine have been reported to cause lactation, amcnor-
rhoea and reduction of the excretion of oestrogens in some female patients.

Failure of lactation. The commonest cause of failure of lactation is in-
adequate suckling or failure to persist with nursing. Endocrine deficiency
is a rare cause. However, failure of lactation in a patient who has suffered
postpartum shock is often the first sign that the pituitary has been damaged
and that hypopituitarism will develop. Substitution therapy should be
instituted at once, but it will not, of course, initiate lactation. Prolactin and
growth hormone are not yet generally available, but it is possible that they
will prove of value in this condition and in other types of lactational failure.

Gynaecomastia

Gynaecomastia is abnormal enlargement of the breast tissue in the male.
Histologically the ducts and periductal fibrous tissue are increased. Some-
times the changes resemble those of fibroadenosis in women. Alveoli and
acini develop only in the very rare cases of lactation in acromegaly. The
areola may be prominent, and the breast tissue is palpable as a firm disc
beneath it. Deposits of fat in the pectoral regions often accompany simple
obesity, but these bear no relation to gynaecomastia. The distinction be-
tween breast tissue and fat can usually be made by palpation, but if there is
doubt about the matter (and if it is important) a biopsy should be taken.

"Gynaecomastia” is an unfortunate term, for it suggests feminization.
“Hypertrophy of the male breast” would be a better description, for the
condition may develop in virile men and can be caused by androgens.

The cause of most cases of gynaecomastia is unknown. An excess of
oestrogens causes proliferation of the ducts in the male breast just as it docs
in the female, and there is evidence that androgens may do so too, at least
in the absence of normal testicular function. The breast tissue is probably
most sensitive to these influences at puberty, A local abnormality or sensi-
tiv ity of the breast tissue must be postulated in many cases, since the condi-
tion may be unilateral.

The following classification, which is partly aetiological, includes all the
types of gynaecomastia which are likely to be encountered:

“ Physiological Neonatal
Puberal

Idiopathic in adults

Oestrogen excess'.

Exogenous Therapeutic administration

Industrial hazard

Endogenous Adrenocortical tumour

Testicular tumour (fig. 13.2)

Hepatic cirrhosis

GYNAECOMASTIA

431

Testicular dysfunction:

Hypogonadism

Hypogonadism with androgen therapy
Klinefelter's syndrome

0//ier endocrine causes:

Acromegaly

Thyrotoxicosis

Malnutrition

Diseases of the central nenous system:
Traumatic paraplegia
Syringomyelia
Friedreich’s afaxra
Dystrophia myotonica

Fig. 13.2. Dilateral gynaecomastia due to oestrogen-secreting Leydig cell
tumour of testis.

The commonest of these are the puberal and idiopathic types, those due to
oestrogen therapy (in prostatic carcinoma) and those associated with
testicular dysfunction.

"Physiological" gynaecomastia

Some hypertrophy of the breast is probably normal in puberty, and the
hypertrophied tissue is often palpable when puberal development is rapid.
Less commonly it is visible and the breasts become sore. The condition
often affects one breast much more than the other. Local trauma may

432

THE BREAST

aggravate the condition and may possibly account for its unilateral distribu-
tion. In most cases gynaecomastia regresses completely before the end of
puberty.

Treatment consists in allaying the fears which the patient and his parents
have about his apparent abnormality. Possible sources of trauma must be
sought and removed. If the breasts are sore a temporary gauze dressing,
attached with adhesive strapping, will prevent the friction of clothes and
remove the discomfort. Hormones should not be used. If resolution fails
to occur within a reasonable period surgical excision may be necessary.
The incision should be made in the submammary area, and the nipple must
be preserved.

Similar hypertrophy is sometimes seen during the waning of testicular
function in old age. It is transient and requires no active treatment.

Idiopathic gynaecomastia

A clinically similar type of hypertrophy, nearly always confined to one
breast, is not uncommon in virile fertile men (fig. 13.3). Occasionally there

Fig. 13.3. Unilateral idiopathic gynaecomastia.

is cyst formation. It is not a precanccrous lesion, although clinically it
cannot always be distinguished confidently from carcinoma. If simple
measures do not afford relief, or if malignancy cannot be excluded, the
breast should be excised.

ATROPHY AND HYPERTROPHY

43 3

Other types of gynaecomastia

Gynaecomastia is not uncommon in hypogonadism, especially when the
testicular defect is incomplete, and it may develop when the condition is
treated with androgens. It is a characteristic feature of Klinefelter’s syn-
drome. Severe malnutrition, caused by starvation, is sometimes accom-
panied by hypertrophy of the breasts, especially when normal feeding is
resumed.

Atrophy and hypertrophy of the breasts

The size of the normal female breast varies greatly from person to person,
owing mainly to differences in the amount of fat in the stroma, and some
asymmetry is not uncommon.

Atrophy of the breasts results from deficiency of oestrogens. The causes
may be classified as follows:

Physiological: Prepuberal

Postmenopausal
Hypogonadism: Primary

Secondary

Lesions which are present in childhood prevent normal mammary de-
velopment at puberty, while those which appear later cause the mature
breasts to regress.

Atrophy usually affects the two breasts symmetrically, unlike hyper-
trophy, which often involves one only. It must be distinguished from
congenital absence of one or both organs and from loss of fat caused by
under-nutrition. (Severe starvation may lead eventually to secondary
hypogonadism and true atrophy.)

Secondary hypogonadism may be caused by androgens which are either
administered therapeutically or secreted by lesions of the ovaries or
adrenals. The breasts of some women are much more sensitive to the
action of androgens than those of others.

Development or redevelopment of the breasts may be induced by re-
moval of the cause of the atrophy and, if necessary, by the administration of
oestrogens.

Bilateral hypertrophy of the breasts associated with spontaneous lactation
has been considered already. Occasionally one or both breasts enlarge
greatly, usually from the time of puberty. The cause is unknown and is
probably unrelated to any endocrine disorder.

Fibroadenosis

The aetiology of fibroadenosis is not understood, but the condition is
probably related to oestrogen activity. Thus, it does not develop until after

434

THE BREAST

puberty and it usually regresses after the menopause. Pain, u hen present,
is usually maximal premenstrually. Pregnancy affords some protection, for
fibroadenosis is most common in women who have not borne children and
least common in those who have borne many. Hormone therapy has been
tried often, and benefit has been claimed from the use of androgens. The
results, however, are not so striking as those of reassurance that the patient
does not suffer from cancer and aspiration or remo\al of palpable cysts.

CARCINOMA

Deatson of Glasgow first propounded the idea that the ovaries were con-
cerned in the development of cancer of the breast, and in 1896 he reported
that obphorectamy sometimes benefited patients suffering from advanced
forms of the disease. Androgen therapy was introduced by Loeser in 1938,
and oestrogen therapy by Haddow and his colleagues in 1944. Adrenalec-
tomy and hypophysectomy were first reported in 1952 by Huggins and
Olivecrona respectively.

We know now that the development and progression of two-thirds or
more of all cases of mammary cancer are supported by hormones, especially
oestrogens, prolactin and growth hormone. Progesterone (and possibly
other hormones too) may also play a part. The course of the disease may
often be altered profoundly by the administration of hormones or by the
removal of endocrine glands, and growths which can be influenced in this
way are termed "hormone dependent”. It is not yet known whether these
procedures act primarily on the tumour cells or on the environment in
which they grow, and the choice of treatment is still largely empirical.
However, the benefits which treatment confers and the situations in
which the different forms may best be applied have been assessed fairly
accurately.

Evidence of hormone-dependence comes from four main sources.
(1) Oophorectomy affords some protection against the development of
breast cancer in women. (2) The administration of oestrogens, growth
hormone or prolactin to those with bony metastases may stimulate the rate
of growth of the lesions and increase the excretion of calcium (derived from
the eroded bone) in the urine. (3) The administration of certain hormones
and the removal of the ovaries, the adrenals or the pituitary may halt the
disease and cause it to regress. (4) The disease may be influenced by
natural events which are associated with endocrine changes. Thus, growth
may be accelerated during the premenstrual phase of the monthly periods
and during pregnancy and lactation. On rare occasions a temporary re-
mission may coincide with the menopause. Honnonc-dependcncc is
probably not a permanent feature of any growth for no method of endo-

CARCINOMA

435

crme therapy causes more than a temporary remission in the disease, at
least when it has reached an advanced stage. After a variable time the
growth becomes autonomous or hormone-independent and can no longer
be halted by hormonal measures.

Response to treatment

Endocrine methods of treatment are usually reserved for those whose
lesions have passed beyond the bounds of conventional surgery (simple and
radical mastectomy) and radiotherapy. Most of those who have been
treated have been in clinical stage IV and some in stage III.

The response to treatment can be described in one of the follow mg ways :

1. Objective remission. Objective evidence of regression of major lesions.
No progression. No new' lesions.

2. Subjective improvement. Relief of pain, etc. The disease may be
arrested, but there is no objective evidence of regression.

3. No response. The disease continues to progress at the previous rate.

4. Acceleration. The disease progresses more rapidly than before treat-
ment.

The assessment of the response is made on clinical grounds, on X-ray
changes and on laboratory data. The patients are usually seen at monthly
intervals. It may be clear within a few days of the start of treatment that
there is subjective improvement or deterioration, but objective evidence of
change in the growth is rarely obvious for two to three months.

Subjective improvement alone is not usually associated with prolonga-
tion oflife, but it is valued highly by the patient, and may render treatment
well worthwhile. The first indication of improvement is usually relief from
the pain of bony metastases, which is often immediate after operations on
the endocrine glands. A patient who required frequent injections of
morphia may need no analgesics at all. This is followed by an improve-
ment in general health, a sense of wellbeing, improved appetite and in-
crease in weight, renewed capacity for work and a return to normal life.
Some forms of treatment, particularly cortisone and testosterone, may
cause subjective improvement without having any specific effect on the
disease.

Objective improvement is recognized by regression of lesions which can
be observed and measured. Some may vanish completely. Those on the
surface of the body can be charted and photographed. Changes in osseous
lesions occur slowly and can rarely be detected at intervals of less than
three months. It is usual for all the lesions in one patient to behave in the
same way as a result of therapy. Occasionally, however, some may regress
while others remain stationary or even advance. Illustrations of typical

CARCINOMA

437

objective signs of remission are shown in fig 13.4 (a) and (b) and fig. 13.5
(a) and (b).

(«) ( 6 )

Fig. 13.5. Metastatic deposit of breast cancer in greater trochanter: (a) before
treatment ; (6) one year after hypophysectomy.

Progression or acceleration of the growth may cause hypercalcaemia in
patients with osseous metastases. It is characterized by nausea, vomiting,
diarrhoea, apathy, weakness, renal damage and peripheral circulatory
failure. It is a relatively common cause of death in advanced cancer of the
breast.

Laboratory data are usually less helpful than clinical and radiographic
findings, but they should be taken into account. A favourable response
may improve the blood picture (fig. 13.6). The concentration of calcium in
the blood and its excretion in the urine may return to normal levels. The
serum alkaline phosphatase level may rise while reosstfication is taking
place and fall again when it is complete. The erythrocyte sedimentation
rate may fall, but it often remains high throughout the period of remission.
Hormone assays provide information about the effects of treatment on the
function of the endocrine glands, but give no indication of the clinical
response.

438

THE BREAST

Fig. 13.6. Effects of hypophyscctomy anti eventual relapse on haemoglobin
concentration in patient with widespread osseous metastases

Five pints of blood were transfused before operation, but no other anti-anaemic treat*
ment was given.

Duration of response

The effects of treatment arc temporary only. The most effective
methods cause remissions which last, os a rule, for 18 months to 2 }cars.
Sometimes they arc shorter, and occasionally they persist for years. Those
who respond to treatment survive, on the aterage, from two to four times
as long as those who do not.

Factors which influence the response

Several factors are known to influence the response and must be taken
into account when deciding which form of treatment is to he used. They
will be discussed in detail later.

1. The menopause. Some forms of treatment are more effective before the
menopause (e.g. oophorectomy) and others after (e.g. oestrogens).

2. Sites of lesions. No site ensures or precludes a remission, but lesions In
some sites are more responsive than those in others. In general, all the
lesions in patients who have osseous metastases (demonstrable on X-ray)
arc more likely to respond to ablative operations than those in patients with
lesions of the soft tissues only. The latter (especially those with \isccral
metastases) rarely respond to operation. A group of patients who require

HORMONAL TREATMENT OF CARCINOMA 439

special consideration are those with extensive local disease, involving the
breast, chest wall (and underlying pleura) and the regional lymph glands,
but without evidence of bloodbome metastases. They respond well to
hormonal therapy, but not to surgery.

3. Time of treatment. The earlier treatment is undertaken the more likely
it is to be effective.

4. Rate of progression of disease. Those in whom recurrent or metastatic
lesions develop slowly (more than two or three years after treatment of the
primary lesion) are more likely to respond to endocrine therapy than those
in whom they develop quickly.

5. Previous response to endocrine therapy. Those who respond favourably
to hormonal therapy and then relapse are more likely to undergo remission
after operation than those who do not respond. This point will be ela-
borated later.

The following factors do not appear to influence the response:

1. Histological structure of the tumour;

2. Presence or absence of primary breast lesion;

3. Age (except in so far as it influences the menopause).

Tests for predicting response

It may be possible in the future to assess, by means of hormone assays or
other tests, the form of treatment which is most likely to be effective. Three
such tests have given encouraging results, but none can yet be used
routinely:

Analysis of urinary steroids. Bulbrook, Greenwood and Hayward have
found that a mathematical function, calculated from the levels of 17-
hydroxysteroids and of aetiocholanalone in the urine, allows them to pre-
dict the probable response to adrenalectomy or hypophysectomy.

Influence of prolactin on urinary calcium. McCalister in Belfast has
observed that, in patients with osseous metastases, injections of prolactin
increase the urinary excretion of calcium more in those who respond
favourably to hypophysectomy than in those who do not do so.

Uptake of oestrogen by tumour. Folca, Glascock and Irvine have found
that, when a dose of tritium ( 3 H) labelled hexoestrol is injected intra-
venously, it is taken up avidly by tumour tissue in patients who subse-
quently respond favourably to adrenalectomy, but not in those who fail to
respond.

Hormonal methods of treatment
Androgens

Rationale. Androgens may have two actions: (1) Inhibition of the pro-
duction of gonadotrophins by the pituitary, and hence of oestrogens by the
ovary; (2) antagonism of the action of the ovarian hormones. They may

440

THE BREAST

also cause subjective improvement by increasing the appetite and en-
couraging the formation of protein.

Administration. The dosage should be high. Twenty-five to 100 mg. of
testosterone proprionate intramuscularly three times a week (or equivalent
amounts of other androgens) are usually required. Non-virilizing andro-
gens (anabolic steroids) maybe used, but it is doubtfulif they are as effective
as the other preparations.

Results. Objective remissions follow in about a quarter of patients, the
results being best in those who are well past the menopause (sec Table
13.1). Subjective improvement alone is found in a similar proportion. The
Table 13.1. Objective remission following androgen and oestrogen
therapy in relation to menopause

Androgens (“!,)

Oeslrogens (°i)

Premenopausal

Postmenopausal

20

0-4 j cars

} 16

12

5-8 years

} 37

9 -f years

(After Council on Drugs, American Medical Association, 1960.)

sites of the lesions have little effect on the results. The average survival
period is about 20 months for those who respond favourably and about
10 months for those who do not. Testosterone is the best form of hor-
monal therapy in menstruating women, but less effective than oestrogens in
those who have passed the menopause.

Disadvantages. In addition to causing virilism and fluid retention,
androgens may rarely accelerate the growth of the tumour, possibly by
being converted in part into oestrogens in the body.

Oestrogens

Rationale. It seems irrational to use oestrogens, which arc known to
stimulate tumour growth, to treat the disease. They may, however, have
three favourable actions: (1) inhibition of the production or release of
gonadotrophins, prolactin and growth hormone by the pituitary, par-
ticularly when given in massive doses; (2) an antimitotic action which
affects the tumour directly; (3) encouragement of hyperplasia and sclerosis
of elastic tissue, which may enhance the reparative action of the stroma
surrounding the tumour celts.

Administration. The initial dose of stilhoestrol is 5 mg. three times a day.
This may be increased up to 100 mg. per day if it is tolerated.

Results. Objective remissions follow in at least one-third of patients who
arc five years or more past the menopause, and subjective improvement is
experienced by some others. Earlier than this the results arc poor, while in

SURGICAL TREATMENT OF CARCINOMA

441

those who are still menstruating the growth is likely to be accelerated by
oestrogens. The results are best in those with extensive local disease who do
not have obvious blood borne metastases. Edelstyn in Belfast has observed
remissions in 50 per cent of this group. The average survival period isabout
27 monthsfor those who respond and about 10 months for those who do not,

Disadvantages. The growth may be accelerated, and oestrogens should
not be given to those who are menstruating.

Corticosteroids

Rationale. Cortisol and its analogues, in large doses, inhibit the produc-
tion of ACTH, and thus of adrenal oestrogens, and corticosteroid therapy
may thus be regarded as a “medical adrenalectomy”. The ovaries also
secrete oestrogens, even after the menopause, and their production may
even be increased by corticosteroids. It is important therefore that this
form of therapy should be employed only after (or in conjunction with)
oophorectomy.

Administration. Cortisone acetate is given in a total daily dose of 100 mg.
If there is no response the daily dose may be increased to 300 mg. Other
glucocorticoids, in equivalent doses, are equally effective.

Results. A sense of wellbeing follows commonly, and inhibition of in-
flammatory reactions may cause the resolution of oedema and apparent
shrinkage of tumours. Objective remissions occur in from 30 to 50 per cent
of patients. The improvement, however, is rarely so striking or lasting as
that which follows the use of sex hormones or of glandular ablation.

Disadvantages. The high doses which are required are very liable to
cause serious complications. A Cushingoid appearance, hypertension and
pathological fractures are not uncommon.

Surgical methods of treatment
Oophorectomy

Rationale. The ovaries are the main source of oestrogens and of pro-
gestogens in women of childbearing age and a subsidiary source in those
past the menopause. Since many tumours are oestrogen-dependent, and
some possibly progestogen-dependent, removal of the ovaries should be of
benefit, at least in younger women.

Method. Surgical excision is the method of choice. The operative
mortality is extremely low, except in those who are acutely ill. The whole
uterine adnexa should be removed, and not the ovaries alone, since they
contain ovarian hilus cells which possibly secrete oestrogens. Irradiation is
an unreliable method of destroying the ovaries and is not advised.

Effects. As a therapeutic measure oophorectomy causes objective re-
mission in 40 to 50 per cent of women before the menopause, but in only
10 to 15 per cent after. Rarely it causes acceleration of the growth.

442

THE BREAST

Oophorectomy is sometimes undertaken as a prophylactic measure at the
time of mastectomy. Preliminary reports suggest that the procedure almost
halves the recurrence rate at all periods after operation, especially in those
with axillary metastases. The effect is not, apparently, confined to pre-
menopausal women.

Adrenalectomy plus oophorectomy

Rationale. The adrenal cortices are the main source of sex hormones in
women whose ovaries have been removed or in those who have passed the
menopause. It is irrational to remove the adrenals without the ovaries,
since even in older women the latter often continue to secrete hormones.

Method. The surgical approach is largely a matter of personal choice on
the part of the surgeon (p. 120). If the patient is thin both adrenals and the
ovaries can be removed through one long midline anterior incision.

Results. The operative mortality varies from about 2 to 10 per cent. If
the procedure is undertaken in staged operations a variable number of
patients die before it is completed. Objective remissions are found in 30 to
50 per cent of all patients and subjective improvement in another 20 per
cent. In a small series in Northern Ireland there were no operative deaths;
32 per cent of the patients (7 out of 22) had objective remissions and sur-
vived, on the average, nearly two years after operation. Those who did not
respond survived only 10 months. Improvement rarely follows removal of
one adrenal. Very occasionally adrenalectomy causes acceleration of the
growth. The factors influencing the response are probably similar to those
which affect the result of hypophysectomy (see below).

Disadvantages. The operation is formidable and involves two or three
incisions, if not two or three stages. The operative mortality is not
negligible. Life after operation is entirely dependent on cortisone substitu-
tion therapy and is relatively precarious (p. 117).

Hypophysectomy and pituitary destruction

Rationale. The anterior pituitary produces gonadotrophins (which con-
trol the secretions of the ovary), ACTTH (which regulates the adrenal cor-
tex), prolactin and growth hormone. ACTH also controls the activity of
ectopic adrenal tissue, although there is little evidence of significant
adrenocortical secretion after adrenalectomy. Hypophysectomy should
therefore, at one operation, prev ent the secretion of all the hormones which
are known to promote tumour growth.

Methods. The techniques for removal or destruction of the pituitary
have been described in Chapter 1. It is probable that complete ablation is
necessary both for complete functional depression and for an optimal
therapeutic effect. ! lowcvcr, remissions may follow incomplete destruction,
and failure may follow complete removal. The problem is complicated by

SURGICAL TREATMENT OF CARCINOMA 443

the presence of the “pharyngeal pituitary”. It is not known whether this
has any function, and no method has been devised for its destruction.

Results. The operative mortality from surgical hypophysectomy varies in
different series from nil to 2D per cent. In Belfast it fell to 5 per cent with
increasing experience. Objective remission follows in from 30 to 50 per
cent of patients, and subjective improvement or arrest of the disease in a
further 10 to 25 per cent. In the Belfast series (see Table 13.2) 43 per cent
of patients had objective remissions and a further 23 per cent had subjec-
tive improvement after hypophysectomy (plus, in many, irradiation with
yttrium-90). Those who had objective remissions survived, on the average,
about 18 months after operation, those who had only subjective improve-
ment survived 5 months, while those who showed no response lived only
2 to 3 months.

Following transnasal implantations of yttrium-00 the operative mortality
is under 4 per cent in Forrest’s series, but probably much higher in the
hands of those who have not made a special study of the technique. The
objective remission rate is about 25 per cent. The procedure is com-
paratively trivial and can be used with safety in poor-risk patients.

Factors influencing the response. In the Belfast series three factors, which
were assessable before operation, had a favourable influence on the result of
hypophysectomy (see Table 13.2). (1) Those patients who showed X-ray
evidence of osseous metastases, either alone or combined with other lesions,
responded better than those who had soft-tissue lesions only (local disease
and/or visceral metastases). (2) Premenopausal patients dtd better than
those who had passed the natural menopause or whose ovaries had been
removed. (3) Those who underwent operation early, that is within six
months of the disease passing out of control by simpler methods (surgery,
radiotherapy, hormones or oophorectomy), responded more favourably
than those who had their operations later. A combination of the premeno-
pausal state and osseous metastases produced the best results, while soft-
tissue lesions, also in premenopausal patients, produced the worst. The
influence of previous endocrine therapy on the result of hypophysectomy
varied with the type of lesion. In those with osseous metastases the out-
come was appreciably better in those who had not received any hormones
previously than in those who bad, while in the patients with soft-tissue
lesions only the best results were obtained in those who had previously had
a good response to hormones.

Disadvantages. The operative mortality is not negligible. Partial blind-
ness, damage to the Ilnd and Illrd cranial nerves, cerebrospinal rhinor-
rhoeaand meningitis are the main complications, but are uncommon. Those
who suffer visual defects, and undergo remission of their disease, usually
regard them as a small price to pay for the benefits of operation. Replace-
ment therapy is essential, but the ill-effects of stopping corticosteroids for

444

THE BREAST

Table 13,2. Factors influencing response to hypophysectomy for
advanced cancer in patients surviting operation (Belfast series)

Oterall results

Objective remission

32 (43%)

Subjective improvement

17 (23%)

No response

26 (35%)

Total

75

Total

Objective remission

Sites of lesions

Osseous metastases

Alone

291

15 (52%)1

With local disease

15 V 52

9 (60%)

* 27 (52%)

With visceral metastases

«J

3 (37%)J

Soft-Ussue lesions only

Advanced local disease alone

161

4 (25%)1

Visceral metastases alone

3 > 23

0 (0%)}

• 5(22%)

Local and visceral

1 (25%)J

Total

75

32

Menopausal status

Premenopausal

21

13 (62%)

Postmenopausal (natural or artificial)

54

19 (35%)

Total

75

32

Time of operation

Early (within 6 months of disease becoming

45

23 (51%)

uncontrolled)

Late (more than 6 months)

30

J> (30%)

Total

75

32

Combinations of factors

Osseous and premenopausal

17

13 (76%)

Osseous and postmenopausal

35

14 (40%)

Soft tissue and premenopausal

4

0 (0%)

Soft tissue and postmenopausal

19

5 (26%)

Total

75

32

Influence of previous endocrine therapy •

Osseous metastases

Good response to hormnmes

11

5 (45%)

Poor response to hormones

20

8 (40%)

Hormones not used

20

14 (70%)

Total

SI

27

Soft-tissue lesions only

Good response to hormone*

3

3 (100%)

Poor response to hormones

14

2 (14%)

Hormones not used

5

J> (0?.)

Total

22

5

Total

73*

32

(• Excluding 2 patients who had undergone adrenalectomy.)

SURGICAL TREATMENT OF CARCINOMA 445

short periods are less serious than they are after adrenalectomy. The in'
jections which may be required for the control of diabetes insipidus are an
inconvenience.

Comparison between adrenalectomy phis oophorectomy and hypophysectomy

It is not yet certain which of the two procedures has the more to offer.
Two large pairs of series have been compared in detail. In a retrospective
study of over 800 patients, collected from many centres in the U.S.A. (by
the Committee on Endocrine Ablative Procedures in Disseminated Mam-
mary Carcinoma), the results of adrenalectomy plus oophorectomy and of
hypophysectomy were almost identical. The operative mortalities were
9 per cent, the objective remission rate 31 to 32 per cent and the mean
lengths of survival of those who responded favourably was 20 to 22 months.
Those who did not respond to either survived on the average 6 to 8 months.

In a smaller prospective study, undertaken as a statistically controlled
therapeutic trial, by Atkins, Falconer and their colleagues in England the
results were slightly in favour of hypophysectomy. The operative mor-
tality was lower (4 per cent, compared with 9 per cent for adrenalectomy)
the clinical results were superior and the mean postoperative period of
survival longer.

Our experience is that hypophysectomy carries a higher operative
mortality than adrenalectomy, but that it produces a greater proportion of
objective remissions in those who survive. Hypophysectomy requires one
operation and one incision and is less painful than adrenalectomy. In our
experience the long-term postoperative state is less precarious after hypo-
physectomy. For these reasons, if a skilled neurosurgical team is able to
undertake the treatment, we prefer hypophysectomy. If these facilities are
not available we regard adrenalectomy plus oophorectomy as an alternative
which can be undertaken by any competent general surgeon.

Excretion of oestrogens and response to operation

If removal of oestrogens from the body is the sole means by which these
surgical procedures cause benefit it should be possible to correlate the
excretion of oestrogens in the urine after operation with the clinical re-
sponse. Attempts to do so have met with little success in patients who have
undergone oophorectomy and adrenalectomy, but the results are more
promising after hypophysectomy. The effects of the operations on oestro-
gen excretion are variable. Oophorectomy regularly reduces it in pre-
menopausal women, but in those past the menopause the operation has no
consistent effect. Subsequent adrenalectomy reduces it still further.
Hypophysectomy usually abolishes the excretion of oestrogens, but some
patients continue to excrete small, or even large, quantities intermittently
or continuously. Remissions may proceed in those who continue to excrete
oestrogens, and the disease may advance in those who excrete none.

446 THE BREAST

A policy for the treatment of patients with advanced cancer of the
breast

The surgeon must remember that half the patients, at the most, will
receive real benefit from any procedure, that the average duration of re-
mission is 18 months to 2 years and that only a very few patients will sur-
vive for as long as 3 or 4 years. The most drastic measures are usually the
most effective, and delay in applying them may result in a tumour de-
veloping independence of hormonal control or in the patient becoming too
ill to withstand a major operation.

Chemotherapeutic agents (particularly thiotepa) provide alternative
methods of treatment. The experience of Lyons and Edelstyn in Uclfast is
that thiotepa and hypophysectomy arc effective in the same types of
patients, but that hypophysectomy is the more effective and the less
hazardous procedure.

The following scheme is that which we follow at present. It may well
require modification in the light of future experience. It is essential first to
discover the extent of the disease by means of a full clinical examination and
of X-rays of the chest and skeleton and, secondly, to determine the men-
strual or menopausal status of the patient. These factors influence the
choice of treatment primarily.

I. Patients with osseous metastases

1. Premenopausal. If the disease is progressing slowly and there are few
metastases oophorectomy is the initial treatment of choice. If progression is
rapid, if there are many lesions or if there has been no response to oopho-
rectomy hypophysectomy (or adrenalectomy plus oophorectomy) should be
advised at once.

If operation is not feasible (because the patient refuses it or is too ill)
androgens are used until four years after the menopause. Those who relapse
after oophorectomy and who cannot withstand operation are treated with
corticosteroids.

2. Postmenopausal ( natural or induced). Hypophysectomy (or adrenalec-
tomy plus oophorectomy) is the treatment of choice. If it is not feasible
androgens are used in the first four years after the menopause and oestrogens
thereafter. Those who have already undergone oophorectomy and who are
not fit for another operation m3y be treated with corticosteroids,

//. Patients with soft-tissue lesions only

Most of these patients are postmenopausal and arc best treated with
oestrogens. The response is often very good in those with extensive local
lesions only. Androgens are used for patients who are still menstruating or
who are not more than four years past the menopause. Hypophysectomy (or
adrenalectomy plus otiphoreciomy) is worthwhile only in those who relapse
after an initial response to hormone therapy.

CARCINOMA OF MALE BREAST* 447

III. Patients who fail to respond to 1 or II

The outlook is practically hopeless, and the problem is very difficult.
After hypophysectomy androgens may be tried in patients up to the age of
52 (average age of natural menopause +4) and oestrogens in older women.
If oestrogen therapy fails, androgens may be tried. Corticosteroids are
worthwhile in patients treated previously by oophorectomy. Thiotepa
(with androgens) occasionally causes regression. Radiotherapy often re-
lieves the pain of osseous lesions. Strong analgesics and tranquillizers are
helpful in the terminal stages.

Carcinoma of the breast and pregnancy

Carcinoma of the breast usually runs a highly malignant course if it
coincides with pregnancy or lactation, and it is often recognized only at a
late stage of the disease. Treatment should be undertaken as early as
possible. Therapeutic abortion does not confer any benefit. If the disease
is advanced the problem is difficult. Oophorectomy causes abortion in the
first trimester but not later. Androgens may cause virilization of the foetus.
Hypophysectomy, followed by normal labour and regression of metastases,
has been described. Pregnancy' following the primary treatment of breast
cancer does not appear to affect the prognosis adversely.

Carcinoma of the male breast

Carcinoma of the breast is rare in men, and affects mainly those over the
age of 50. The growth has usually spread beyond the limits of the breast
when the patient is first seen, and treatment by local surgery or radio-
therapy is rarely profitable. The endocrine aspects of the disease ha\e been
studied very little, but there is evidence that oestrogens may initiate its
development and that androgens may support its further growth. Both
these groups of hormones are derived from the testes and from the adrenals.

The only method of endocrine therapy which has been assessed
thoroughly is bilateral orchiectomy. Treves has reported on the results m
42 patients. Of these three-quarters obtained subjective improvement and
two-thirds objective evidence of remission, which lasted, on the average,
two and a half years. Adrenalectomy and hypophysectomy have, on occa-
sion, induced further remissions in patients who have relapsed subse-
quently, In Belfast a patient with widespread metastases showed a good
objective response, lasting nine months, after hypophysectomy. Oestro-
gens have been used therapeutically, but few results have been reported.

In those in whom local treatment alone is impracticable bilateral orchiec-
tomy is the treatment of choice. If this does not cause a remission, or if the
patient relapses later, hypophysectomy or adrenalectomy should be under-
taken. Oestrogens in large doses should be reserved for those who fail to
respond or who are unfit for operation.

44S

THE BREAST

FURTHER READLNC AND REFERENCES

Development and Lactation

hall, F. F- (1959). Gynaecomastia. Australian Publishing Co., Sydney.

fqlley, s. J. (1960). T>isorders of mammary development and lactation. In
Clinical Endocrinology J, p. 518. Ed. Astwood, E. B. Grune and Stratton,
New York.

FORBES, A. F., HENNEMAN, P. II., GRISWOLD, C. C. and ALBRIGHT, F. (1954). Syndrome
charactensed by galactorrhoea, amenorrhoea and low urinary FSH; com-
parison vvilh acromegaly and normal lactation. f. din, Eiidoer,, 14, 265.

LYONS, w. R , Lt, C. H. and JOHNSON, r. e. (1958). The hormonal control of mammary
growth and lactation. Recent Prcgr. Hormone Res., 14, 219.

STOKES, j. F. (1962). Unexpected gynaecomastia. Lancet, 2, 911.

TREVES, N. (1956), Gynaecomastia: origins of mammary swelling in male, analysis
of 406 patients with breast hypertrophy, 525 with testicular tumours and 13
with adrenal neoplasms. Cancer, II, 1083.

Carcinoma (see also Chapters 1 and 5)

ATKINS, H. J. B., FALCONER, M. A., HAYWARD, J. L., MACLEAN, K. S., SCHl’RR, P. It. and
ARMITACE, P. (1960). Adrenalectomy and hypophysectomy for advanced
cancer of the breast. Lancet, 1, 1148.

baker, w. it , kelly, r. M. and sotUER, \v. n. (1960). Hormonal treatment of meta*
static carcinoma of the breast. Amer. J. Surg , 99, 538.

beatsov, o. T. (1896). On treatment of inoperable cases of carcinoma of mamma
Lancet, 2, 104, 162.

BULBROOK, R. D., CREENWOOD, f. c. and HAYWARD, J l. (1960). Selection of breast-
cancer patients for adrenalectomy or hypophysectomy by determination of
urinary 17-hydroxy corticosteroids and aetiocholanolone. Lancet, l, 1154.

council ON drugs (1960). Androgens and estrogens m treatment of disseminated
mammary carcinoma. J. Amer. med. Ass., Ill, 1271.

currie, A. R. (1958). Endocrine Aspects of Cancer. Livingstone, Edinburgh.

edelstyn, c. J. A. (1962) Personal communication

folca, p. j., clascock, r. f. and irvine, tv. r. (1961). Studies with tritium-labelled
hexocstrol in advanced breast cancer. Lancet, 2, 796.

JOINT COMMITTEE ON ENDOCRINE ABLATIVE PROCEDURES IN DISSEMINATED MAMMARY
carcinoma (1961). Adrenalectomy and hypophysectomy in disseminated
mammary carcinoma. J. Amer. med. Ass., 175, 787.

LYONS, A. R. and EDELSTYN, c. j. A. (1962), Thiotcpa in treatment of advanced
breast cancer. Bril, med. J., 2, 1280.

McCalister, a. and welbouhn, r b. (1962). Stimulation of mammary cancer by
prolactin and the clinical response to hypophysectomy. Brit, med J., I, 1669.

McCalister, a , welbourn, r. b., edelstyn, c. j. a., lyoss, a. r., taylor, a. r ,
CLEADHILL, c. a., GORDON, d. s. and COLE, j. o. Y. (1961). Factors influencing
response to hypophysectomy for advanced cancer of breast. Brit. mtd. J., 1,
613.

PEARSON, O II. and RAY, B. R. (1960). Hypophysectomy in the treatment of meta-
static mammary cancer. Amer. J. Surg., 99, 544.

Randall, II T. (1960). OOphorectomy and adrenalectomy in patients with in-
operable or recurrent cancer of the breast. Amer. J. Surg., 99, 553,

TREVES, N. (1 959). The treatment of cancer especially inoperable cancer of the male
breast by ablative surgery (orchiectomy, adrenalectomy and hypophysectomy)
and hormone therapy (ocstrogens and corticosteroids). An analysis of 42
patients. Cancer, 12, 820.

TREVES, n. and flNKBSiNER, J. A. (1958). An evaluation of therapeutic surgical
castration in the treatment of metastatic, recurrent and primary inoperable
mammary carcinoma in women. An analysis of 191 patients. Cancer, II, 421.

WCUKHTtv, R. n. (1959). Endocrine aspects of breast cancer. In British Surgical
Progress, p 247. Hutterworth, London.

CHAPTER 14

CARCINOMA OF THE PROSTATE

Growth of the prostate at puberty is controlled mainly by testosterone. In
puberal hypogonadism the prostate remains infantile in form and in post-
puberal hypogonadism it undergoes involution. Benign hypertrophy of the
prostate does not occur in eunuchs, and the condition can be made to
regress in dogs by castration or by the administration of oestrogens.
Although there is no good evidence that benign prostatic hypertrophy in
man can be influenced by hormonal methods, these considerations led
Huggins and his colleagues, twenty years ago, to investigate the influence of
androgens on the growth of human prostatic carcinoma. They found that
castration or treatment with oestrogens often caused clinical remission of
the growth and sometimes radiographic regression of bony metastases.
Conversely, they observed that the administration of androgens might
reactivate the tumour. These findings have been amply confirmed, and it is
clear that carcinoma of the prostate is dependent on androgens in the same
sort of way as carcinoma of the breast is dependent on oestrogens.

Recent observations, however, suggest that the problem is not so simple
as it appeared at one time and that it may be as complex as that of ihe
hormonal aspects of carcinoma of the breast. Testosterone, for instance,
does not activate all tumours, and may even cause some to regress, although
it cannot be recommended as a method of treatment. Moreover, testicular
oestrogens and one or more of the hormones from the anterior pituitary
may possibly iaSaettce the growth of the norms} and of the malignant
prostate, either directly or in a synergistic manner. Furthermore, hormone
sensitivity does not appear to be a property of whole tumours, but only of
parts of them. Thus, some lesions may regress under treatment while
others continue to advance, and active-looking tumour cells may be seen
histologically among others with severe degenerative changes.

RESPONSE TO TREATMENT

It should be remembered that carcinoma of the prostate affects, on the
whole, an older age group than carcinoma of the breast and that, when it
+49

450 CARCINOMA OF PROSTATE

metastasizes, it tends to run a more chronic course. Many who develop the

disease after the age of 70 die from unrelated causes.

Hormonal methods may be used either alone or in conjunction with
surgical or radiotherapeutic procedures designed to relieve urinary ob-
struction or to remove the growth. These latter procedures will not be
discussed here. The response to treatment can be assessed in the same way
as that of carcinoma of the breast and the patient can be classed as showing
(1) objective remission, (2) subjective improvement or (3) no response.
Acceleration of the disease does not seem to result from the methods which
are to be described.

Subjective improvement alone is well worth while, for severe pain is
relieved and there is great improvement in wellbeing and appetite. Ob-
jective remission is recognized by shrinkage or disappearance of the primary
tumour and of soft-tissue metastases. Retention of urine may be overcome
within a week or two, and catheter drainage may be adequate to relieve it
during this period. Many patients, however, require surgical relief of
prostatic obstruction. Bony metastases occasionally show radiographic
evidence of regression, sclerotic lesions becoming less dense and lytic
lesions becoming reossified. Body weight increases, and patients who are
bedridden, or even paraplegic, may sometimes get up and regain the use of
their legs. The haemoglobin concentration may rise, and a raised serum
acid phosphatase level usually falls after treatment. The scrum alkaline
phosphatase, which may also be raised, often rises further for a time, while
new bone is being formed under the influence of hormonal therapy.

About 80 per cent of patients treated at all ages show subjective improve-
ment or objective remission. The response is only temporary', however,
although further improvement may follow the institution of other forms of
endocrine treatment. An increase in the scrum acid phosphatase or in the
ESR may be the first sign of recurrence.

METHODS OF TREATMENT
Oestrogens and orchiectomy

Oestrogens inhibit the production of gonadotrophins by the pituitary, and
hence that of androgens by the testes. They may also antagonize the action
<st iv.dvi'j'iv.s iwd hive a. dv.«ct vatwhitovy w. lb* ivwwviv c*Ui. Sdl-

boestrol in doses of 5 to 15 mg. daily is relatively non-to\ic, causes complete
suppression of testicular function and produces clinical remission in the
majority of cases. Larger doses (e.g. 100 mg. of stilboestrol daily) may be
more effective in ymingeT patients and in those who fail to respond to the
lower doses. These high doses arc usually reserved for resistant cases and
for patients who relapse after responding initially to smaller doses. There
is little evidence that any of the phosphorylatcd or other new oestrogenic

ENDOCRINE TREATMENT 452

preparations are superior to stilboestrol. It is claimed that the phosphory-
lated compounds are taken up from the circulation by prostatic tissue and
that they exert a local cytostatic effect. Any local concentration, however,
appears to be transitory. Stilboestrol diphosphate has the advantage that
it can be given intravenously (500 mg. daily) to produce a rapid effect,
particularly in patients with urinary retention. After 10 days or so oral
stilboestrol is substituted.

Relief of pain is usually experienced within a week or two of the start of
treatment. Objective signs of remission (apart from relief of urinary
retention) do not appear for several weeks or months.

In favourable cases oestrogens cause striking histological changes in the
tumours. The cells and alveoli arc largely destroyed and dense fibrous
tissue forms ultimately, walling off small clumps of inactive tumour cells.

Castration removes the major source of potent androgens from the body.
Enucleation of the testes is the method commonly used, but total orchiec-
tomy may possibly be a more effective procedure. The response to
orchiectomy is more rapid than that which follows the administration of
oestrogens, and pain may be relieved on the day of operation. Operation is
followed by an immediate reduction of about one-third in the excretion of
17-oxosteroids in the urine. Later, however, the excretion tends to rise
again, and may exceed the previous level, as a result of increased secretion
by the adrenals.

Choice of treatment

The effects of oestrogen and of orchiectomy on survival may be seen from
the results of a large series collected by Nesbitt and Baum in the U.S.A.
(fig. 14.1 (g) and (6)). It is clear that, in those without demonstrable
metastases at the beginning of treatment, there is little to choose between
the results of either oestrogen or orchiectomy alone. A combination of the
two, however, gives appreciably better results after the first two years and
nearly half the patients survive five years. In those with obvious metastases
oestrogen alone, although often causing temporary remissions, hardly
affects the five-year survival rate, while orchiectomy does increase it. A
combination of the two again gives the best results, although only one-
fifth of the patients survive five years.

On this evidence, therefore, orchiectomy combined with oestrogen
therapy would seem to be the treatment of choice for all patients. Many
surgeons, however, are impressed by the fact that oestrogens alone often
cause striking temporary' remissions, even in those with metastases, and
prefer to start all patients on this form of therapy. They resene orchiec-
tomy (with continuation of the oestrogen when possible) for those who
cannot or wall not take the drug, and for those who fail to respond to it or
who relapse after an initial remission. Nesbitt and Baum found that 35 per

452

CARCINOMA OF PROSTATE

cent of such patients (with or without metastases) obtained additional
benefit from castration. O’Conor and Sokol, adopting this policy, found
that 36 per cent of their patients survived 5 years and that 7 per cent sur-
vived 10 years. Others have used orchiectomy first and oestrogens later,

Fig. 14.1. Percentages of patients dying from prostatic carcinoma at intervals up
to 5 years: (a) patients without demonstrable metastases on first admission;
(A) patients with metastases.

The control patients did not receive hormonal therapy.

Dieih. = Diethylsulboestrol (Stilboesuol).

Orch. — Orchiectomy.

(From Nesbit and Baum, 1950.)

but the results ha\e been less favourable. We may conclude that oestrogens
and orchiectomy will be required for most patients but that little if any-
thing will be lost by using oestrogens alone in the first instance. Such a
policy is certainly more acceptable to the majority of patients than im-
mediate castration.

Other methods

Androgens from the adrenal cortex can support the growth in the same
sort of way as adrenal oestrogens can support that of mammary cancer.
Measures directed towards inhibiting their production include treatment
with corticosteroids, adrenalectomy and hypo p hy sect o my. The latter
operation may also affect the grow th in other ways. These methods play a
much smaller part in the treatment of cancer of the prostate than they do in
that of cancer of the breast because their results are more often disappoint-
ing and because the simpler measures are relatively more effective. They

FURTHER READING

453

are generally indicated only as a last resort. They often cause temporary
subjective improvement, but only occasionally objective remission.
Adrenalectomy and hypophysectomy (or intrasellar irradiation) are with-
stood well, despite the advanced age of most of the patients, and are worth
consideration. Fergusson has observed survival for two to three years in
about 10 per cent of patients after each procedure. We have observed two
paraplegic patients who walked again after adrenalectomy. In both, how-
ever, the effect was short lived. Corticosteroids are less effective and, in the
large doses which are required, may cause serious complications.

Carcinoma of the “female prostate”

Adenocarcinoma of the periurethral glands in the female (which are
analogous to the prostate in the male) is a rare tumour which develops
usually after the menopause. It would seem reasonable to treat the condi-
tion with oestrogens, although no results appear to have been published.

FURTHER READING

CA LA PINTO, V. and A GERHART, c. (1961). Clinical trial of massive stilboestrol di-
phosphate therapy in advanced carcinoma of the prostate. Brit. J. Urol., 33,

fercusso.v, j. d. (1961). Cancer of the prostate. In Textbook of Gemto-Unnary
Surgery, p. 623. Ed. Winsbury-White, H. P. and Fergusson, J. D. Living-
stone, Edinburgh.

HUGGINS, c. and bercenstal, d. m. (1952). Inhibition of human mammary and
prostatic cancers by adrenalectomy. Cancer Res., 12, 134.
macfahlane, d. A., thomas, L. p. and harrison, j. H. (1960). A survey of total
adrenalectomy in cancer of the prostate. Amer. J. Surg., 99, S62.

NESbit, r. m. and daum, w. C. (1950). Endocrine control of prostatic carcinoma.
J. Amer. med. Ass., 143, 1319.

o'conor, v. j. and sokol, j. K. (1960). Bilateral orchiectomy in the treatment of
carcinoma of the prostate. Amer.J. Surg., 99, 573.

CHAPTER 15

THE SKELETON

The skeleton is the framework on which the rest of the body is built. It is
composed essentially of a protein matrix in which complex salts of calcium,
phosphate and carbonate are incorporated. The major hormones play an
important part m its development and maintenance, and diseases of the
endocrine glands influence it profoundly in many ways. Most of these
effects are described in the appropriate sections, but we will discuss here
two groups of disorders — disturbances of growth and metabolic bone
disease — which may have endocrine causes but which are often dependent
on other factors also.

GROWTH

Growth is a complex process which takes place continuously from the
moment the ovum is fertilized until adult life is reached. It depends on
several factors, the most important of which is genetic. The hereditary
capacity for growth, however, can be expressed fully only when the endo-
crine system guides the metabolic processes of the body correctly and
when adequate supplies of food are available for the construction of new
tissues. The growth of the skeleton is of major importance in the develop-
ment of the body as a whole.

Bone is a dynamic structure which, throughout life, is being removed
and rebuilt continuously. New bone is deposited on the face of older bone,
while the latter is resorbed and its calcium and phosphate ions are liberated
into the body fluids for excretion or rebuilding into fresh hone. In the
normal adult the rates of these two processes arc equal, about 500 mg. of
calcium passing in each direction daily, and there is no net gain or loss of
bone. During growth both processes are more rapid, but deposition ex-
ceeds resorption, while in many diseases affecting bone, resorption pre-
dominates and leads to skeletal rarefaction. Bath formation and resorption
are influenced greatly by the endocrine glands, some hormones stimulating
skeletal growth and others inhibiting it. The growth-stimulating or ana-
bolic hormones 3re growth hormone, thv roxine, insulin and the androgens.
In childhood the importance of each of these hormones in promoting and
maintaining growth of the skeleton is unquestioned, but in adult life their
relative importance is uncertain. The principal growth-inhibiting or anti-
454

GROWTH 455

anabolic hormone is cortisol. The hormonal effects on grow th have been
expressed by Hubble in the form of an equation :

Growth hormone -+■ Thyroxine -f Insulin -f Androgen ^ Cortisol
In adults the two sides of the equation are equal, while in children the left
side is the greater. When there is excess of cortisol or deficiency' of one of
the anabolic hormones the right side becomes greater, skeletal formation
slows down and there is a net loss of bone. This equation helps the under-
standing of some of the endocrine causes of disordered growth.

This integrated system may be disturbed in various ways at different
ages. In foetal life genetic abnormalities may cause the dwarfism associated
with such conditions as Langdon-Down’s syndrome (mongolism) and
gonadal dysgenesis. After birth other diseases may interfere with proper
nutrition and with the supply of calcium and phosphorus. Cyanotic con-
genital heart disease and pulmonary insufficiency cause anoxia and impair
cellular metabolism and growth. Deficiency in the secretion of growth
hormone, thyroxine, insulin or the adrenal steroids affects development,
while the premature and excessive secretion of the hormones of the gonads
stimulates early fusion of the epiphyses and so impairs the final stature.
The influence of hormones on growth

The endocrine system plays a major part in the control of skeletal
growth and bodily development. The anabolic hormones are essential
growth-promoting factors, and each probably plays a distinct role and
exerts its influence during a particular period. Growth hormone is essential,
but it is uncertain when its secretion starts, how long it is active and
whether or not its anabolic effects are important in the adult. During early
life it may play only a small part, for pituitary dwarfs usually grow nor-
mally until they are two to four years old. During the rest of childhood
growth hormone increases linear growth but plays little part in the matura-
tion of bone, so that when it is administered to pituitary dwarfs it increases
the height but does not advance the bone age. At puberty the effect of
growth hormone is overshadowed by that of the sex hormones.

The influence of thyroxine on growth is most evident during the first few
years of life, although its absence at any stage in childhood causes growth
to slow down or stop. Thyroxine stimulates the maturation of bone, but
has less influence on linear growth. In cretinism or juvenile hypothy-
roidism the skeletal age is retarded and the body build remains infantile;
when the epiphyses do develop they are abnormal and appear stippled on
X-ray photographs (epiphyseal dysgenesis).

The rapid spurt of growth, which occurs in puberty and adolescence, is
caused by testicular androgens in the male and probably by adrenal andro-
gens in the female. Oestrogens have only a slight effect on growth in
immature girls.

456

THE SKELETON

Growth is often rapid just before the onset of juvenile diabetes and is
then slower than normal once the disease is established. The explanation
of this dwarfing is uncertain, but insulin is known to be a growth-promoting
factor in animals, and infantilism may be associated with poorly con-
trolled diabetes.

Finally, linear growth stops when the epiphyses fuse with the diaphyses
of the long bones. This process is caused by androgens in the male and by
oestrogens in the female. It is uncertain whether the sex hormones in-
fluence the epiphyses directly or whether they inhibit the action of growth
hormone. Once the epiphyses ha\e closed hormonal influences cannot
increase the length of bones.

Assessment of growth and development

Measurement of the skeleton is important in assessment of the integrity
of the endocrine system in childhood and adolescence. Other aspects of
development— intellectual and sexual — must, of course, be considered as
well. The following methods enable the degree of advancement or re-
tardation from the “normal" growth pattern to be determined. The

GROWTH

457

Fig. 15.1 (a) ami (6). Sample of chart for recording growth and development.
Prepared by J. M. Tanner and R. H. Whitehouse, University of London, Institute of
Child Health, for the Hospital for Sick Children, Great Ormond St., London, W.C.I.
Full notes on the use of the charts are provided. Separate charts are available for the boys
and girls at three age ranges (0-3 years, 2-10 years and 9-18 years). The plotted lines are
‘percentiles”; that marked “50” represents the average normal, 50 per cent of individuals
falling below it and 50 per cent above it. 10 per cent of normal individuals fall below the
10th percentile and 90 per cent above it and so on.

average normal figures must not be given too much emphasis, for the
normal ranges are wide.

Height and weight

Charts, in which the height and weight are plotted against age, are avail-
able (fig. 15.1). When regular measurements are recorded it is possible to
see whether or not the expected changes in growth and weight are taking
place at the proper times.

The "height age" is sometimes used to assess growth. A girl of 50 inches,
for example, is said to have a height age of 8^- years, which corresponds to
the chronological age of an average normal child of the same height.
Determination of weight is probably less important than that of height,

458

THE SKELETON

for we know less about its endocrine control and cannot easily distinguish
between fat and muscle.

Deiclopmental age

The most useful index of the developmental age is the bone or skeletal
age. This is obtained by radiological examination of the skeleton, where
the appearance and union of the various epiphyseal centres oF ossification
normally follow a fairly definite pattern. Ossification of one group of bones
may be ahead or behind that of others, so that it is wise to X-ray several
groups and to determine a composite bone age. The main landmarks are
shown in Table 15.1. The centres tend to appear and to fuse earlier in
girls than in boys.

Table 15.1. Age of appearance and fusion of ossification centres

Age of
appearance
(years)

Centre of ossification

Age of union of
epiphysis with
diaphysis (years)

<1

3

4

5

6

10-12

Wrist amt hand (4 months to 12 years)

Hamate (4 months), capitate (6 months), epiphysis of
radius (1 year)

Triquetrum, epiphyses of metacarpal* and phalanges
Lunate

Trapezium, scaphoid !

Trapezoid, epiphysis of ulna

Pisiform

18

IS

18-20

2

Elhose (1-11 years)

Capitulum

1 S— 18

5

Head of radius

16-19

6

Medial epicondyle

18

10

15-18

Olecntnnn

16-19

11

Estemal cpicondylc

17-18

Ihp (9 months to 10 years)

Head of femur

15

Greater trochanter

15

Union of ischium and puhis

7

10

Lesser trochanter

Delayed epiplijscal development is obvious in hj pothyroidism, but is
also found in pituitary dwarfism and to a slight extent in both gonadal
dysgenesis and malnutrition Acceleration of bone maturation is found in
sexual precocity and in obesity.

Dentition

The progress of dentition may also be used as an index of development.
The teeth arc examined during the two periods of active dental growth,
namely from 6 months to 2 years and from 6 to 13 years. Unfortunately
the times at which the teeth appear vary widely and do not correspond well
with skelctat development.

DISTURBANCE Or NORMAL GROWTH 459

Skeletal proportions

The proportion of the upper to the lower segment of the body (vertex to
symphysis pubis: symphysis pubis to the ground) is important because it
changes as growth proceeds and is influenced by hormonal factors. At
birth the upper segment exceeds the lower in the proportion of 1*7 : 1.
During development the legs grow more rapidly than the trunk, so that by
the age of 10 or 11 the ratio has reached 1:1. Thereafter the upper and
lower segments of the body remain approximately equal. In hypogonadism
the limbs continue to grow so that the lower segment lengthens in pro-
portion to the upper, whereas in hypopituitarism, and even more so in
hypothyroidism, the infantile proportion is retained. In primordial
dwarfism the proportions are normal for the patient’s age. The endocrine
significance of these measurements is lost in dwarfism resulting from bone
disease. In chondrodystrophy, for instance, the limbs are short in com-
parison with the trunk, while in osteochondrodystrophy the trunk is short
because of the developmental abnormality of the vertebrae.

The body span (measured from fingertip to fingertip of the outstretched
arms) is a less useful measurement. During infancy and childhood the span
is less than the height. As growth of the limbs increases the two measure-
ments become approximately equal by the age of 9 or 10, and remain so
until the age of 14 years. Thereafter the span usually exceeds the height,
and in normal adult men it may do so by as much as 24 inches. In women
the span is usually not more than 2 inches greater than the height. In
hypogonadism these figures are often exceeded because the excessive length
of the hands is included in the span while that of the feet is not included in
the height.

DISTURBANCE OF THE NORMAL PATTERN OF GROWTH

The rate of growth and the final height may be affected in various ways
by endocrine or other influences.

Dwarfism

Dwarfism is a condition of greatly diminished somatic growth. It does
not imply sexual immaturity. Infantilism, on the other hand, includes
dwarfism and sexual immaturity. Dwarfism maybe considered under four
main aetiological headings.

1 . Genetic (primordial or constitutional ) dwarfism

In this group failure of skeletal growth occurs without other evidence of
endocrine or developmental abnormality. It often occurs sporadically in
families, but there may be a hereditary predisposition. It is not known
whether the production of growth hormone is impaired or whether the
tissues are unable to respond to it.

460

THE SKELETON

At birth primordial dwarfs are usually of average size or slightly small,
but from then on linear growth is slow. The appearance and union of the
ossification centres, however, proceed normally and sexual maturation
takes place at the usual time. Eventually the child matures and develops
into a normal but diminutive adult (fig. 15.2) Fertility is unimpaired and
the offspring arc usually of normal size.

Tig. 15.2 Fig. 15.3

Fig. 15.2. Pnmordiat dwarfism in woman aged 35 years.

Fig. 15.3. Dwarfism associated with gonadal dysgenesis, age 17.

Note early development of breasts and pigmentation of areolae due to oestrogen
therapy.

Primordial dwarfism is occasionally accompanied by other defects, in-
cluding premature senility (progeria), a bizarre facial appearance and mal-
development of the facial and cranial structures.

The dwarfism associated with gonadal dysgenesis (fig. 15.3) can he ex-
plained most satisfactorily on a genetic basis. This is a specialized variety
of primordial dwarfism in which the associated gonadal dysgenesis results
in sexual infantilism.

Dwarfism is a usual but not invariable feature of the Ijiurence-Moon-
Biedl syndrome. In its complete form this is characterized by obesity,
dwarfism, sexual infantilism, mental defect, retinitis pigmentosa, poly-
dactylism and syndactilism, and diabetes insipidus, but incomplete forms
| may be seen in which some abnormalities are lacking. The disorder is con-

DWARFISM

461

genital and familial and is believed to be due to a genetic factor which is
inherited as a recessive character. The stunted growth may constitute one
aspect of the genetic disturbance or be mediated through a congenital
defect in the hypothalamus which is thought to account for the obesity,
sexual infantilism and diabetes insipidus.

2. Endocrine dwarfism

Pituitary insufficiency results in stunted growth. Pituitary' dwarfs are
usually of average size at birth and grow fairly normally for the first few
years of life. Thereafter growth becomes very slow but does not cease
entirely. The centres of ossification appear very late, epiphyseal union maj
be delayed indefinitely (fig. 1.7) and the normal growth spurt of puberty
does not take place. Other signs of hypopituitarism appear. In Frohhch’s
syndrome a pituitary or hypothalamic disturbance causes endocrine
dwarfism which is usually of mild degree.

Cretinism and juvenile hypothyroidism (fig. 15.4 (a) and (6)) are associated
with great impairment of skeletal growth. The cretinous dwarf, unlike the
pituitary or primordial dwarf, retains the infantile skeletal proportions.

M (/>) M

Fig. 15.4. Disorders of growth associated with thyroid dysfunction

(а) Dwarfism in jus enile hypothyroidism. Age 13.

(б) Same patient 16 months later, after treatment with thy roxtne.
te) Accelerated growth tn hyperthyroidism. Age 8.

462

THE SKELETON

Precocious sexual development causes an initial rapid spurt of growth,
followed by early union of the epiphyses. The ultimate height is below
normal (fig. 15.5).

Fig. 15.5. Dwarfism in woman aged 39 years with congenital virilizing adrenal
hyperplasia.

Both idiopathic hypoparathyroidism and pseudohypoparathyroidism may
be associated with dwarfing, but the skeletal abnormalities in the latter
afford helpful diagnostic clues. Cushing’s syndrome in childhood retards
growth. Constitutional delayed puberty (delayed growth and adolescent
development) causes relative dwarfism, especially during the period of
normal adolescence. When puberty eventually starts growth may be very
rapid and the final height is normal or nearly so.

3. Nutritional, metabolic and general diseases of infancy and childhood
Prolonged undemutrition (deficiency of calories) and malnutrition (de-
ficiency of essential amino acids, vitamins and minerals) may both interfere
with normal growth. Chronic conditions, such as cocliac disease, cystic
fibrosis of the pancreas, renal and hepatic disorders, infections, congenital

DWAnriSM

463

syphilis, congenital heart disease, pulmonary insufficiency, diabetes in-
sipidus, poorly controlled diabetes mellitus and glycogen storage disease,
may all retard growth. They must be excluded in the investigation of
dwarfism. Particular attention should be paid to the elimination of coeliac
disease, for dwarfism may be present in the absence of obvious bowel
disturbance.

4. Disorders of bone

Several bone diseases result in diminished stature. Among these are
chondrodystrophy (achondroplasia), osteochondrodystrophy (Morquio’s
disease), dysostosis multiplex (gargoylism), rickets, osteogenesis imperfecta
and various diseases of the spinal column. Most of these are obvious
clinically, but atypical cases of the chondrodystrophies occur occasionally
in which the skeletal deformity is so mild that the condition may be over-
looked and ascribed to primordial or pituitary dwarfism.

Diagnosis

The types and clinical features of dwarfism are summarized in Table
15.2.

Nutritional factors, general and metabolic disturbances and diseases of
bone can be recognized usually if they are sought. The commonest re-
maining types of dwarfism are those due to genetic factors, endocrine
lesions or constitutional delayed puberty. Two of the endocrine causes,
namely congenital and juvenile hypothyroidism and sexual precoctty, can
be diagnosed usually without difficulty. This leaves primordial and
pituitary dwarfism, gonadal dysgenesis and delayed puberty for differentia-
tion. These disorders are usually clearly discernible in adult life, but their
distinction before puberty and during adolescence may be difficult, or even
impossible, because the degree of sexual development provides important
evidence upon which the diagnosis is based. Gonadal dysgenesis can some-
times be recognized before puberty by some of the characteristic congenital
defects, such as webbing of the neck, coarctation of the aorta and wide
carrying angle of the elbow joint. The relative frequencies of the different
types of dwarfism are as follow (after Wilkins):

Diagnosis

Constitutional retardation of growth and adolescent development
Slow growth and retarded hone age (too young for diagnosis)
Primordial dwarfism

Primordial dwarfism with Craniofacial anomalies
Hypothyroidism (dwarfism conspicuous)

Syndrome of gonadal dysgenesis
Ilvpopituitary or hjpothalamic —

Pituitary deficiency
Tumours

Xo of cases
130 (ZO°J
6? (15 V
} 114 (26%)
S3 (12%)
48 (11%)

',?} 30

Total

442 (100%)

Table 15.2. Differential diagnosis of dscarfism

464

THE SKELETON

ACCELERATED GROWTH 465

Treatment of dwarfism

Any underlying disease or remediable lesion calls for the appropriate
treatment. Human growth hormone (or monkey somatotrophin) has been
used very little, but it is likely to prove useful in pituitary dwarfism. It
deserves trial in primordial dwarfism.

In pituitary dwarfism androgens will produce a growth spurt but, since
this is associated with eventual closure of the epiphyses, the overall effect is
unlikely to exceed 3 or 4 inches. The intermittent use of androgens may
accomplish more than prolonged treatment by postponing epiphyseal union
for some time. The anabolic steroids, in interrupted courses of a month at
a time, have been advocated for increasing growth and may be tried in all
forms of dwarfism with the exception of delayed puberty. They cause
little virilization, and are more suitable than androgens for girls.

Accelerated growth

There are three main types of accelerated growth in childhood.

1. Genetic or constitutional factors

Some normal children have a height and skeletal development well in
advance of their contemporaries. Puberty usually occurs early, however,
so that growth ceases before too great a height is achieved. Height appears
to be a familial characteristic and is presumably determined genetically
Some such children may be thought to have gigantism, but the latter is very
rare in childhood. Coarsening of the features, skeletal deformity, the
finding of a raised serum phosphorus in patients over the age of 12 or an
enlarged sella point to a pituitary lesion.

2. Endocrine causes of excessive and rapid growth

Excessive secretion of growth hormone causes gigantism. In childhood
hyperthyroidism (fig. 15.4 (c)) and obesity are accompanied by accelerated
growth. All form s of sexual precocity , whether true or false, produce an
initial rapid growth spurt akin to that seen during the phase of normal
puberal development. The epiphyses, however, unite early, and the final
height is usually less than 5 feet. Hypogonadism results in a delay in union
of the epiphyses and, since this is associated with a normal secretion of
growth hormone, growth may be excessive and prolonged.

3. Arachnodactyly

This is a congenital disorder, characterized by increased height, long
slender feet and hands (spider fingers), high arched palate, congenital heart
disease, renal disorders and dislocation of the lens. Linear growth may be
much advanced in childhood, but it stops before an excessive height is
attained. The condition is not due to any hormonal disturbance.

466

THE SKELETON

METABOLIC BONE DISEASE

When the skeleton as a whole is altered by biochemical changes in its
environment the result is metabolic bone disease. There are three main
types: (1) osteoporosis; (2) generalized osteitis fibrosa; and (3) osteo-
malacia.

Osteoporosts is a condition in which the amount of bone in the skeleton
is decreased but the bone present appears to be qualitatively normal. It
may be thought of as atrophy of bone.

Generalized osteitis fibrosa is associated with replacement of bone by
fibrous tissue, often with formation of cysts, together with an increase in
the rate of resorption and formation of bone. It is probable that osteitis
fibrosa and osteoporosis represent different degrees of the same process and
that the former dev elops « hen the process of bone resorption is \ cry rapid.

Osteomalacia is characterized by failure of the osteoid matrix of the
skeleton to calcify, so that wide osteoid seams surround the bony trabe-
culae. The total mass of calcified bone is usually, but not necessarily,
decreased. It may be considered as a qualitative defect in bone in which
the mineral salts are reduced more than the organic material. Osteo-
malacia developing in infancy is called “rickets”.

Osteoporosis and osteomalacia produce the same mechanical effect in the
skeleton, for both cause softening and weakening of the affected parts.
The two conditions may coexist, particularly in malabsorption states.

Osteoporosis

This is probably the commonest metabolic disorder of the skeleton. It
may present as a primary disorder or in association with diseases of the
endocrine glands. It is seen more commonly in women than in men and in
the aged more often than in the young. The following arc the commonest
causes:

Generalised Osttoporosu

( Primary

2. Secondary

(a) Acromegaly
(h) Hyperthyroidism
(f) llypcrparathyroidiun
(,/) CuahiPR** svndrome
(e) Corticosteroid therapy
(/) Hypojronadum

iMahsrd Oltenpareiit

1. Immobilization

2. Rheumatoid arthrim

3. Sudecfc’* airophv

Aetiology

The cause of osteoporosts is not yet known. Early writers suggested that
it might be the result of calcium deficiency, but this idea was largely dis-

OSTEOPOROSIS

467

carded when Albright and his colleagues advanced the view that osteo-
porosis represented a reduced rate of new bone formation and that it
resulted from a deficiency of bone matrix due to defective osteoblastic
activity. This hypothesis was based mainly on the association of osteo-
porosis with certain endocrine disorders in which there was a negative
nitrogen balance. In particular, the catabolic effect of cortisol in Cushing’s
syndrome and the therapeutically induced osteoporosis of prolonged
corticosteroid treatment gave the defective protein matrix theory strong
support. Similarly, the frequent onset of osteoporosis in women after the
climacteric, when the output of anabolic hormones was declining, added
confirmatory evidence.

More recent work involving tracer methods, balance studies and animal
experiments has cast doubt on Albright’s views. It is now suggested that
osteoporosis may be due to a long-continued deficiency of calcium, which
eventually leads to its resorption from the skeleton because of the over-
riding need to maintain its concentration in the blood at a normal level.

Evidence for this view comes from several sources. Animals fed on diets
deficient in calcium alone develop osteoporosis, while those deprived of
vitamin D develop osteomalacia (or rickets). Patients with primary osteo-
porosis have been found to consume subnormal amounts of calcium in
their diets and to exhibit a marked and long-continued avidity for calcium
when it is administered in excess. It seems possible that bone disease
reflects poor adaptation to a prolonged deficiency of calcium. The rate of
new bone formation in osteoporosis which, according to Albright’s hypo-
thesis, should be reduced has been found by tracer studies to be normal.
Finally, osteoporosis develops in many conditions characterized by a nega-
tive calcium balance (e.g. steatorrhoea with diminished absorption of
calcium) or by increased resorption of calcium salts from bone (e.g. hyper-
parathyroidism).

Calcium deficiency probably accounts largely for the primary disease.
Defective formation of the bone matrix, however, may contribute also, and
in Cushing’s syndrome, corticosteroid therapy, hypogonadism and post-
menopausal osteoporosis it may well play an important role.

Sex hormones and osteoporosis

The influence of the sex hormones on the skeleton is not fully under-
stood. Albright found osteoporosis frequently in postmenopausal women
and in those w-ho had undergone oophorectomy. In these patients he found
that administration of oestrogen led to retention of calcium and nitrogen
and, believing as he did that the condition resulted from deficiency of sev
hormone, advised oestrogen replacement therapy. More recently it has
been found that oestrogen causes a positive calcium balance only if the
dietary calcium is low, so that it is not likely to be of much value when

46S THE SKELETON

patients are given an adequate amount of calcium. It is possible that the
sex hormones play some part in protecting the organism against the effects
of calcium deficiency and that osteoporosis is more likely to develop when
both calcium and sex hormones are deficient.

Clinical features

The patient may complain of backache, which is intensified by stooping,
or else sustain a fracture from trivial injury. Pain is felt in the lumbar
region and may radiate down the thighs, and there is often local tenderness
of the spine. Fractures usually occur in the neck or shaft of the femur, but
are also seen in other long bones. Crush fractures and simple wedging of
the vertebral bodies may be visible in X-rays (fig. 3.7).

Radiological examination of the skeleton reveals rarefaction of bone.
Loss of bone density in the spine is followed by biconcavity of the vertebrae
due to the pressure exerted by the intervertebral discs. Elsewhere there
may be loss of cortical bone.

Laboratory investigation does not reveal any characteristic biochemical
abnormality. The plasma calcium, phosphorus and alkaline phosphatase
levels are normal. The urinary excretion of calcium may be low, normal or
increased.

Treatment

Calcium replacement is possibly the best form of treatment for all forms
of the disease, but it must be given for a long time (6 to 12 months) before
adequate relief is obtained. Pain is relieved and further fractures are pre-
vented, but radiological healing of bone is unconvincing. Calcium may be
given in the form of effervescent tablets of calcium glucono-galacto*
gluconate (4 G. three or four times daily).

Sex hormones (androgens or oestrogens) should, of course, be given for
hypogonadism. It has been customary' to prescribe them also for primary
osteoporosis, particularly in postmenopausal women, but in this group they
are probably no better than calcium and their other effects (uterine bleeding
from oestrogens or virilization from androgens) may be troublesome.

Anabolic steroids have been advocated reccntty. In the primary disease
they' may add little to the effects of calcium, hut they will not do harm.
They may well be of benefit for patients with Cushing’s syndrome (before
and after adrenalectomy), for those receiving corticosteroid therapy and for
older women with hypogonadism.

Osteomalacia

This is not an endocrine disease, but it may be complicated by secondary
hyperparathyroidism. The main conditions with which it may be as-
sociated are:

OSTEOMALACIA

469

1. Deficiency of vitamin. D

(a) Nutritional

(&) Alimentary

2. Renal diseases

(а) Renal tubular acidosis

(б) Fanconi’a syndrome

(c) Vitamin D-resistant rickets

(d) Ureterocolic anastomosis

The commonest of these is vitamin D deficiency, which, in many parts of
the world, is due to dietary insufficiency and the increased demands of
pregnancy and lactation. In the United Kingdom, however, such causes
are rare, and hypovitaminosis is usually associated with steatorrhoea and
other surgical lesions of the alimentary tract which cause malabsorption.
Osteomalacia is being recognized with increasing frequency in patients
10 years or more after gastrectomy. Osteomalacia associated with renal
disease is relatively uncommon.

Vitamin D promotes the absorption of calcium from the bowel and the
calcification of bone, and is apparently necessary for the maintenance of a
normal level of calcium in the blood. The effects of its deficiency are
variable and unpredictable, but three main consequences are recognized.

1. Impaired absorption of calcium causes a negative calcium balance
and osteoporosis. This is rarely seen alone.

2. Defective calcification of osteoid tissue.

3. Lowering of the blood calcium. This often evokes a compensatory
hypersecretion of parathyroid hormone which tends to restore the blood
calcium at the expense of the bones. The excess of parathormone, how-
ever, diminishes the tubular reabsorption of phosphate and lowers the
serum phosphorus level. Consequently, the product of the calcium and
phosphorus concentrations (Ca x P) falls and if it remains below the
critical level of about 30 osteoid tissue fails to calcify. The longer this
biochemical disorder persists, the more severely does the bone disease
develop. Occasionally, for reasons which are not known, the lowering of
the blood calcium continues without the development of secondary
hyperparathyroidism, and tetany results. Osteomalacia and tetany may
be associated, but more often (in malabsorption states) the patient suffers
from either osteomalacia and secondary hyperparathyroidism or tetany
and hypocalcaemia.

Some renal tubular lesions are associated with a failure to reabsorb
phosphates (and possibly calcium) from the glomerular filtrate, while others
(renal tubular acidosis and ureterocolic anastomosis) cause acidosis. Con-
sequently, the blood phosphorus and calcium-phosphorus products fall and
if the latter reaches the critical level osteomalacia results. These disorders

470

THE SKELETON

are often referred to as “vitamin D-rcsistant osteomalacia” because the
bone lesions are not caused by deficiency of vitamin and do not respond to
treatment with it in ordinary doses. Very large doses, however, may cau«e
regression.

Osteomalacia causes the bones to soften and become painful. De-
formities develop, the stature diminishes and partial cracks, known as
Milkman fractures or Looser zones, appear at the points of stress (fig.

Fig. 15.6 (6). Osteomalacia.

Not. Milkman’, fraciuraa m lateral bonier of scapula.

The distinctive biochemical features of osteomalacia are :

1. Lowered serum calcium and phosphorus, usually "f
product below 30. It should be noted that the ^ctum “d pho^horu
are normal in osteoporosis and that the calcium is ig

phorus often low in primary hyperparathyroidism. condition

2. Raised scrum alkaline phosphatase. This is found in any condition
associated with increased osteoblastic activity.

Treatment is directed, if possible, towards the eause of die osteomata;
The bone lesions are treated with vitamin D an rf secon dary

and with suitable orthopaedic measures. Th
hyperparathyroidism is discussed on pages 3

472

THE SKELETON

FURTHER READ1NC
Grozcth

caffey, J. (1956). Pediatric X-ray Diagnosis. 3rd Ed. Year Book Publishers,
Chicago.

itt’BBix, D. (1957). Hormonal influence on growth. Bril, tned.y., 1, 601.

soasav, a , avcry, h. and cockayne, e. a. (1939). Obesity, hypogenitalism, mental
retardation, polydactyly and retina! pigmentation. The Laurence- Moon-
Biedl syndrome. Quart. J. Med., 8, 51.

TANNER, J. M. (1962). Graft th at Adolescence. With a general consideration of the
effects of hereditary and environmental factors upon groteth and maturation from
birth to maturity. 2nd Ed. Blackwell Scientific Publications, Oxford.

wilkins, l. (1957). Endocrine relationships and their influences upon growth and
development, and Methods of endocrine study and diagnosis: clinical and
developmental studies, and Dwarfism. In The Diagnosis and Treatment of
Endocrine Disorders in Childhood and Adolescence, 2nd Ed., pp. 11, 29, 156.
Blackwell Scientific Publications, Oxford.

wilkins, L. (1962). The influence of the endocrine glands upon growth and
development. In Textbook of Endocrinology, 2nd Ed., p. 908. Ed. Williams,
R. H Saunders, Philadelphia.

Metabolic Bone Disease

ALBRIGHT, T. f smith, r. H. and rjchardso.v, A. M. (1941). Post-menopausal osteo-
porosis: its clinical features. J. Amer. med. Ass., 116, 2465.

FRASER, T. r. and KINO, e. j. (1957). Diseases of bone and the parathyroid gland.
In Biochemical Disorders in Human Disease, p. 352. Ed. Thompson, R. II. S.
and King, E. J. Churchill, London.

HARRISON, m., fraser, t. R. and mullan, u. (1961). Calcium metabolism in osteo-
porosis. Acute and long-term responses to increased calcium intake. Lancet,
1, 1015.

NORDiN, B. E. c. (I960). Hyperparathyroidism, osteomalacia and osteoporosis. In
Clinical Endocrinology J, p. 233. Ed. Astwood, E. B. Grune and Stratton,
New York.

nordin, B. e. c. (1961). The pathogenesis of osteoporosis. Lancet, 1, 1011.

snapper, i. (1949). Medical Clinics on Bone Disease. 2nd Ed. Interscience, New
York.

VAN BL'CHEM, F. S. P. (1959). Osteomalacia. Brit. med. y., 1, 933.

CHAPTER 16

THE ALIMENTARY TRACT

Many endocrine diseases cause symptoms which

mentary tract, and such common conditions as peptic ulceration and
altered bowel function sometimes have an endocnne bas^ Indeed he
predominant clinical features of a cell tumours of the pancreattc t
which apparently secrete the alimentary hormone gastrin, are du' « » I B
hypersecretion of acid gastric juice. It is clearly

underlying cause should he recognized and treated and that unn=«sMri
operations 5 on the stomach or bowel should be avo.deA Argentaffina
tumours arise most frequently in the bowel, and some of their symptm n
which are due to hypersecretion of the local hormone 5 -hydroxytrypt
amine, are those of altered bowel function.

THE STOMACH AND PEPTIC ULCERATION

Peptic ulceration often accompanies some endocrine adenopathiM^a^^

incidence of ulceration is reduced in others. Physio ogi , ’ t or CO urse

with changes in endocrine activity, also influence t e e P gastric

of peptic ulcers. These phenomena may reflect, in P art > c ^j d J denal
secretion, for increased secretion of acid is

ulcer and decreased secretion with gastric ulcer. °' e > a ] ways be
absence of peptic ulceration in abnormal endocrine s^ d ^ we „ be that
correlated with changes in secretion (Table 1 • )» , < muCO sa.

some hormones alter the resistance of the gastric or duodenal

The hour-to-hour regulation of gastric sc “ e .‘“" . Jjj b the act ions
logical needs is accomplished by vagal P.. are sti mulatory and

of alimentary hormones, some of which (U^e g ) ted by the

others (like enterogastrone) !" hibi '°1|'- J he d f °™ hKe mechanisms and
major endocrine glands provide a backgrou . c eCre tion. They

probably assume a permissive role in the contro o g deficient

obtrude themselves only when they are ^^^^"o^times in-
amounts and then either stimulate or inhib different wavs. The

fluencing the various components of gastric juice i studied in

effects of some of these hormones on gastric secretion have been
man and in animals.

473

474

THE ALIMENTARY TRACT

Hormones may influence gastric secretion by varying the stimuli which
reach the secretory cells, by changing the sensitivity of the cells to stimula-
tion or by altering their number. Some hormones probably affect secretion

Table 16.1. Relationship of hormones to secretion of acid and to
incidence of duodenal ulceration ( DU) in man
Secretion increased

DU increased
Hyper pa ra th yroidism
Zollmuer-Ellison syndrome {? gastrin)

Cirrhosis and ? porta-caval anastomosis (? histamine)

DU not increased
Cushing's syndrome (cortisol)

Corticosteroid therapy (gastric ulcer increased)

Ilypennsutuusm
Secretion decreased

DU decreased

Diabetes mellitus
Addison'* disease
Hypopituitarism
Thj roto si costs
Pregnancy (? oestrogen)

? DU increased

Argentaffinoma (S-hydroxytryptamine)

directly, while others do so by altering the concentrations of substances
such as calcium and glucose in the blood.

Adrenal cortex

The adrenal corticosteroids influence gastric secretion in man and many
animals. The endogenous hypersecretion of cortisol in Cushing’s syndrome
is often associated with hypersecretion of acid but not with an increased
incidence of duodenal ulcer; and secretion is restored to normal by
adrenalectomy. Administration of cortisone, aldosterone or synthetic
glucocorticoids likewise increases the secretion of acid, but only after
pharmacological doses have been used for some days. Their action on the
secretory mucosa is probably direct and unrelated to their major metabolic
effects. The secretion of acid in response to maximal stimulation with
histamine is often increased greatly, suggesting that the parietal cell mass is
increased; and there is direct evidence that this is the case. Increases in
plasma and urinary pepsinogen have been observed often, but the concen-
tration of pepsin in gastric juice and the numlier of peptic cells in the
stomach arc, if anything, reduced. The clearance of pepsinogen by the
kidneys may be increased. The secretion of gastric mucus, measured

THE STOMACH AND PEPTIC ULCERATION 475

by the viscosity and total protein content of the juice, appears to be

re t“ons of the adrenal cortex (neoplasia or

more commonly post mortem in patients Bigprt and
duodenal) than in those without gasl I o n.es inal dise^e.^ ^

Willis, reviewing the Belfast material fo ^ The signifionce of
cent of the former and ml P er< *"‘° 7 ‘ is ' ent corre lation has been

atSTS ^X^o^tion and the presence or

lbS ,T“,V,Sr "e^e in acid -e.ion an^a decr«se in that of

mucus might be expected to cause uo ^ ving adrenal steroid therapy,
heard of steroid-induced ulcers in patients receiv ing icostero ; ds cause

Many clinicians have formed the impressro ^ ^ have them already,
peptic ulceration and aggravate ulcers arthritis treated at the

However, in over 2,000 patients with rh = u ™ a “ d t . a ™;“ t e d by steroids
Mayo Clinic peptic ulceration treatcd fey ot J r means,

(even when the dosage was excessive) _ g per cen t and this was

The incidence of ulceration in both groups "^^c “potion. Cor-
threc or four times as great as that in g ,b ree , imes tbe pro-

ticostcriods did, however, appear to increa y steroids

portion of patients who developed ^ilr.rulcec U there „

taken by mouth exert a local ulcerogenic .„ , he

some evidence that they do so. Aspirin 'vhich “Sc erosions and
treatment of rheumatoid arthritis, may ^ Hem in patients

bleeding. Peptic ulceration can certainly b control it by simple

receiving steroid therapy, and it is often i ^ an ,acid with cortico-
measures. It would seem wise always g . . d (combined

steroids when they are being used in Lid such

preparations of corticosteroid and an,3C,d , B in patients who are

therapy, or to use steroids in entenc-co P ‘ becomes necessary

known to have peptic ulceration. Ifsurgica . jodo f operation, and
extra corticosteroid cover should be given ove breakdown of suture

extra care should be taken to prevent infection and th

Addison's disease in man and adrenalectomy *" “JSjlhy'of'the gastric
the secretion of gastric acid, and may a so 033 promptly in adrena-
mucosa. Treatment with cortisone restores se -.1, Addison’s disease,
lectomized animals, but not, apparently, m pa 1 causes irreversible

possibly because long-continued hyp03 *’ e, \ : s believed to be low in
changes. Although the incidence of duodena 1 e Q un( j 4 seV ere cases of
Addison’s disease, this is not our experience,
duodenal ulceration in our IS cases, an incidence of 22 per

476

THE ALIMENTARY TRACT

Anterior pituitary

The anterior pituitary influences gastric secretion through its adreno-
corticotrophic hormone and possibly by other means. ACTH stimulates
the secretion of corticosteroids, u hich in turn act on the stomach. Pituitary
tumours may be associated with peptic ulceration in the syndrome of
multiple endocrine adenopathy. In rats the secretion of acid is reduced more
by hypophysectomy than by adrenalectomy, and may be restored sub*
sequently by corticotrophin or by growth hormone. The effects of hypo-
physectomy on the mucosal structure are uncertain. Some workers have
reported degranulation and a decrease in size of the peptic cells and others a
reduction in the parietal cells mass. In man hypophysectomy and sub-
sequent replacement therapy with cortisone alone reduces gastric acid
secretion by about 50 per cent. The administration of thyroid extract in
addition to cortisone seems to restore the secretion completely. Chronic
hypopituitarism in man has effects on the stomach similar to those of
Addison’s disease, except that there is, if anything, less departure from
normal. Replacement therapy with cortisone and thyroid extract does not,
as a rule, restore structure or secretion, but it may do so occasionally.

Parathyroid

Peptic ulceration and ulcer-like symptoms are common in patients with
hyperparathyroidism. Adesola in Belfast found definite duodenal ulcers in
23 per cent of male patients, but in only 3 per cent of the females. Ulcer-
like symptoms (not confirmed as being due to ulceration) were found in
another 10 per cent of the males and in 13 per cent of the females. In
nearly all cases the ulcers (including two stomal ulcers) were cured by
parathyroidectomy. Reports on the influence of parathyroid hormone on
gastric secretion arc conflicting. Adesola and Ward found that the basal
secretion of acid was above the normal range in 4 out of 8 hyperparathyroid
patients and that it fell in 7 after parathyroidectomy. The mean fall was
32 per cent. They also found that PTH stimulated basal secretion of acid
in the dog. The effect may possibly be secondary' to hypercalcacmkt. The
secretion of pepsin is probably increased also by excess of PTH.

It is probable that between 1 and 2 per cent of all patients with duodenal
ulcer suffer from hyperparathyroidism. Surgeons should be on the lookout
for such cases and should suspect the disease, especially in those with
associated renal stones. Differentiation from the "milk-alkali syndrome”
may be difficult. If hyperparathyroidism is present parathyroidectomy, and
not an operation on the stomach, is indicated. On the other hand, para-
thyroidectomy is unlikely to cure the ulcer found in the rare syndrome of
multiple endocrine adenopathy, c\cn when hyperparathyroidism is present.

THE STOMACH AND PEPTIC ULCERATION

477

Thyroid

Thyrotoxicosis is often associated with achlorhydria. Ulcer-like
symptoms may be encountered, but peptic ulceration is very uncommon.
Gastric secretion returns after treatment of the hyperthyrotdism.

Gonads

Peptic ulceration is less common and secretion of acid is lower m women
of reproductive age than in older vv omen or in men. Prtgiumcy 'affords pr -
tection against ulceration and is associated with a reduct.on ‘" ^“c et on
of acid and of pepsin. Secretion increases greatly during Ration in the
human and in the dog, and quiescent ulcers are liable to recrudesce shortly
after delivery. Stilboestrol may be of benefit in duodenal uloratton ir i mam
The influence of sex hormones on gastric function has been studied ery
little, but stilboestrol appears to reduce secretion of acid m the cat

Islets of Langerhans

The islet cells influence gastric secretion in several ways. Injections o
insulin induce hypoglycaemia, which stimulates the vaga ce
turn causes the secretion of acid and pepsin. The effect is abohshedbv
vagotomy. We have observed that spontaneous hypog jcaemia ^ •

secretion similarly in patients with insulin-secreting tumours o > i ’

but duodenal ulcer is apparently very uncommon in this condition. h
however, develop some years after removal of « tummr. »

is often associated with diminished secretion of acid an s0 ™
achlorhydria, possibly as a result of prolonged yperg y ‘ j
incidence of duodenal ulcer is much lower in diabetics than in g
population, while that of gastric ulcer is the same. n0

Glucagon inhibits acid secretion in man and in the g, ce jj

direct evidence of excessive secretion of glucagon in isease.
tumours, associated with gross gastric hypersecretion and J"" fou P n Jj to

ulceration in the Zollinger-Ellison syndrome, have recen y -phis

secrete large amounts of a substance indistinguishable rom g
subject will be discussed later.

Local hormones

Two local hormones, 5-hydroxytryptamine and histamme, may wuse

:ptic ulceration and influence gastric secretion in .

uastric and duodenal ulcer may be commoner in pa ie " noo ulation,
affinomas which have metastasized widely than m t e 8F increases

altho.rnS LHT n^^nvimllv reduces the secretion of aetd ana in

although 5-HT paradoxically reduces the
that of mucus in the dog.

478 THE ALIMENTARY TRACT

Hepatic cirrhosis is associated with an increased incidence of peptic
ulceration, especially in the duodenum. Women and those with primary
biliary cirrhosis are affected mainly. The influence of porta-coral anasto-
mosis on ulceration in these patients is uncertain. It has been suggested
that spontaneous or surgical portal-systemic venous shunts allow hista-
mine of enteric origin (which is normally conjugated and inactivated in the
liver) to circulate to the stomach and stimulate the secretion of acid. Such
a mechanism probably operates in the dog after porta-caval anastomosis,
but the evidence in man is inconclusive.

ISLET CELL LESIONS AND PEPTIC ULCERATION

An association between multiple endocrine adenopathy (including islet
cell tumours) and peptic ulceration has been recognized for many years
(Tabic 16.2). Underdahl and his associates and Wermer, in 1953 and 1954

Table 16.2. Correlation bettceen islet cell lesions and clinical features

Clinical feature*

Islet cell lesion* only

Multiple endocrine
auenopathy

« cell

0 cell

a cell

P cell

Hyperinsutinism

No

Very common

No

Common

Peptic ulcer

Usually

fulminating;

Very rare

Usually

simple

Hyperpituitarism and/or

hyperparathyroidrim

No

Fairly common

respectively, were however the first to study the syndrome carefully. Ful-
minating peptic ulceration, associated with islet cell tumours which do not
secrete insulin, was noted by Zollinger and Ellison in 1955. The syndrome,
which is now known by their names, has attracted much attention recently
and is seen, in some cases at least, to be a special example of the syndrome
of multiple endocrine adenopathy.

Simple peptic ulceration

Peptic ulceration is a common featureofthe syndrome of multiple endocrine
adenopathy. The associated islet cell lesions may affect a or p cells. Usually
the ulceration has no special features, but it may be of the fulminating
variety. Multiple endocrine adenopathy and associated simple peptic
ulceration appear to he determined genetically. A famitv has been obscr\ ed
in which some of the affected members presented symptoms of peptic ulcer

ISLET CELL LESIONS AND PTPTIC ULCTHATION

479

alone, one had symptoms of endocrine lesions alone and some had symp-
toms of both ulceration and endocrinopathy. Hyperparathyroidism on its
own may, as we have said, cause simple duodenal ulceration, and v cell islet
tumours may cause fulminating peptic ulcers, but there is little evidence
that either lesion is responsible for simple peptic ulceration in the syndrome
of multiple endocrine adenopathy. Occasionally other gastric lesions, such
as gastritis or polyposis, are found. Of the seven patients \\ ith multiple
endocrine adenopathy in the Belfast series the following gastrointestinal
lesions were found:

Duodenal ulcer alone 2

Duodenal and gastric ulcers t

Fulminating peptic ulcer 1

Chronic gastritis with vomiting and diarrhoea 1
Acute colitis 1

Carcinoma of colon 1

Total 7

Peptic ulcers, as we have mentioned already, appear to be extremely rare
in the syndrome of hyperinsulinism when the islet cells alone are affected
In fact, if peptic ulcer develops in a patient with hyperinsulinism it i»
almost certain that there are also lesions in other endocrine glands
The treatment of simple peptic ulceration raises no special problems
Endocrine lesions which are causing trouble must be dealt with appro-
priately.

Fulminating peptic ulcer (Zollinger-EIlison) syndrome
The essential features of the syndrome are:

(1) a diathesis to fulminating peptic ulcer;

(2) gastric hypersecretion; and

(3) an islet cell tumour of the pancreas not composed of {J cells.

Many cases have been described in the past few years. The sexes are
affected equally, most patients are in middle age (30 to 50 years), and the
condition has not so far been reported in childhood.

Peptic ulcer

The ulcers have several characteristic features. They are often multiple
and in unusual sites, particularly in the second, third and fourth parts of
the duodenum and in the jejunum (fig. 16.1). A primary peptic ulcer in the
jejunum is almost pathognomonic of this condition. The course of the
ulceration is fulminant, checkered by serious complications and rapid re-
currence after normally adequate surgical treatment (including vagotomy

480

THE ALIMENTARY TRACT

and high gastric resection), and marked by considerable loss of weight.
Many patients have had more than one operation, several have had five or

Fig. 16.1. Peptic ulceration in the Zollinger-Elhson syndrome.

Sites of 57 ulcers in 34 patients. Tweheof the ulcers were found in one patient (after
Mackenzie tt of,, 1958).

six and most have died e\ entually from the complications of peptic ulcer or
its treatment.

Gastric hypersecretion

Gastric hypersecretion has been noted repeatedly. The volume and
acidity of the juice tends to be greater than, that found with ordinary duo-
denal ulcers. The basal (resting) juice often amounts to 2 to 3 litres in
12 hours, and as much as 6 litres has been recorded. This juice usually
contains 50 to 100 mEq. HCl per litre and sometimes more. The basal
secretion of acid usually approximates to the maximum, so that little or no
increment is obtained after the administration of histamine, even in large
doses. The concentrations of pepsin in the serum and of uropepsin in the
urine are often extremely high.

Another feature, « hich is related to the gastric hypersecretion and which
has been noted in several patients, is gross hypertrophy of the gastric and
duodenal mucosae. It may be recognized during life by X-rays or gastro-
scopy, and it may be found post mortem.

Severe watery diarrhoea, sometimes associated with potassium de-
ficiency and steatorrhoea, is occasionally caused by the gastric hyper-
secretion, and may occur atone or precede the ulceration by several years.

ISLET CELL LfSIONS AND PEPTIC ULCERATION

481

Islet cell lesions

The location and general characteristics of the lesions have been de-
scribed in Chapter 11. Lesions have been reported in other endocrine
glands in about a quarter of the cases, but information on this aspect is
often incomplete, and perhaps the proportion will eventually prove to be
higher. Gibson’s wotk on the Belfast material and on tumours collected
from elsewhere in the British Isles makes it clear that a cells predominate
in well-differentiated tumours, but that specific staining is not obtained in
the poorly differentiated ones, cells (and hyperinsulinism) have been
found in some patients with multiple endocrine adenopathy, but not in
those with islet cell lesions alone. In very rare cases islet cell hyperplasia
without a tumour has been observed, and in at least one case no pancreatic
lesion has been found.

Some patients with the Zollinger-EUison syndrome have impaired
glucose tolerance, possibly caused by increased secretion of glucagon.

Pathogenesis of peptic ulcer

The gastric hypersecretion is the probable cause of the peptic ulceration
for total gastrectomy regularly cures it. The probable connection between
the islet cell lesions and the hypersecretion has been established by Gregory
and his co-workers, who have isolated a potent gastric secretogogue, in-
distinguishable from the antral hormone gastrin, from several tumours.
Furthermore, removal of the tumour, either as a primary procedure or after
the failure of gastric operations, has reduced secretion and cured the
ulceration in a number of patients. There is no evidence that gastrin is
secreted by normal islet cells.

Diagnosis

The Zollinger-EUison syndrome should be suspected in any patient who
has;

(1) primary peptic ulcers, which are multiple or in unusual sites,
especially in the lower duodenum or jejunum;

(2) gross gastric hypersecretion (2 to 3 litres or more of highly acid
basal juice in 12 hours); or

(3) a fulminating peptic ulcer which recurs rapidly after normally ade-
quate surgery.

In any such patient a search should be made for endocrine lesions: a glucose
tolerance curve should be obtained, the pituitary fossa X-rayed, the serum
calcium and phosphorus levels measured, the urinary tract X-rayed, and
the adrenal steroid excretion estimated.

482

THE ALIMENTARY TRACT

Treatment of fulminating peptic ulcer syndrome
Surgical treatment is usually essential, but one patient has been reported
in whom the anti-cholinergic drug poldine methyl methosulphate (4 mg,
increasing to 8 mg. 6-hourly) apparently abolished the secretion of gastric
acid. Such' therapy should therefore be considered preoperathely or as an
alternative measure in patients unsuitable for operation.

Other steps which must be taken before operation include the correction
of any dehydration, alkalosis or hypokalaevnia which may have resulted
from diarrhoea or gastric aspiration. If the nutritional state is poor blood
transfusion and a diet rich in protein and vitamins for a week or so may
improve matters. If the patient is diabetic he may require insulin.

Surgical treatment should be directed in the first place towards the
pancreatic tumour or tumours. If it is reasonably certain that they have
been removed completely no gastric operation is needed. If they cannot be
removed, because of malignancy or because they cannot be found, total
gastrectomy is the operation of choice. Lesser procedures court disaster.
Any other endocrine lesions which are discovered and which are causing
trouble (e.g. pituitary or parathyroid tumours) should receive attention.

ARGENTAFFIN OM A (CARCINOID TUMOUR)
Argentaffinomas are of endocrinological importance because many of
their malignant forms secrete large quantities of the local hormone 5-
hydroxytryptamine, which exerts widespread pathological effects. The
characteristic clinical syndrome was described first by Casstdy in 1930, and
was elucidated more fully by a group of Swedish workers some 20 years
later.

5 -Hydrosytryptamine ( 5 -HT, enteramine, serotonin)

Most of the 5-HT in the body is located in the mucosa of the
alimentary tract. It is synthesized there from dietary tryptophan, mainly
in the argentaffin or Kultschitsky cells, which are found throughout the
stomach and intestines and in the biliary and major pancreatic ducts.
They are particularly common in the depths of the crypts of Lieberkuhn
where they lie singly between the other epithelial cells. Granules of 5-HT
can be recognized in the cells by special silver stains (whence the name
“argentaffin"). 5-HT is transported round the body by the blood plate-
lets and is liberated from them into the serum when blood clots. Small
amounts of 5-HT are found elsewhere, notably (like noradrenaline) in the
sympathetic nerve ganglia and in the brain stem and hypothalamus. It is
probably synthesized jn neural tissue, for it cannot, apparently, penetrate
the btood-brain barrier.

The chemical pathway by which 5-HT is synthesized and metabolized
is as follows:

ARGENTArFINOMA

483

^(tryptoph»nhrdro*;rl*«e)

/Vt ch -^ h_nh '

V/v,/ COOH

5 -Hydroxytr> ptophan (S-HTP)

5-Hydrox>tr>P tarrnne (5-HT)

5-H>droxyuidnlc acetic acid (S-HIAA)

Monoamine oxidase is found pnncipally injhe ' 1 '" these organs

inactive 5-hydroxyindole acet.c acid » of 5-H1AA in

and then excreted in the urine The a , )0ut o ne -tenth of this,
adults is about 2 to 9 mg.; that of 5-H ; capable of stimulat-

The physiological role of 5-HT « ^ conc „ n P 5 d with intestinal

ing most forms of smooth muscle and ^ lumen of th gut

peristalsis. There is evidence th ter f rom the bowel wall

releases 5-HT and that this causes atransfer_ ^ ^ ^ 5 . HT may
to the lumen and stimulates pensta tic a • pro bably pharmaco-

possibly be a nervous stimulant. Itso * . and some of them will be

logical or pathological, rather than p ysia 1 8 ’ , tt | e wasp stings

described later. 5-HT is an active const.tuent of nte V ^

and of itching powder, and causes intense stimulation P
endings.

“Gnomes are derived from

wherever these are found. The >erm "mrc.no, d implies^ ^ ^ ^ mk _

resemble carcinomas, but do not be a\e more ma lignant than was

leading, for argentaffinomas are o

thought formerly. , . ■ „ k,> n ; e n fashion, and their

Two-thirds of argentaffinomas behave in a benign

THE ALIMENTARY TRACT

484

most frequent site is the vermiform appendix, particularly near the tip.
They are most common in the second and third decades of life, and
account for about one in 200 of appendicular lesions found at operation.
The tumour is usually single, rounded, golden yellow in colour and rarely
as large as a cherry. A very' small appendicular growth lies within the wall
of the organ, but a larger one expands it and may occlude the lumen,
causing obstruction, colic or inflammation. Most appendicular argent-
affinomas are remo\ed surgically because they tend to cause symptoms,
often ascribed to appendicitis, at an early stage.

The remaining one-third of argentaffinomas are frankly malignant, but
progress very slowly. They are often multiple and arise anywhere in the
alimentary tract from the stomach to the rectum, hut most commonly in
the small intestine. They tend to develop later in life than the benign
lesions, being most common in middle and old age. Their colour is often
golden yellow, like that of the benign growths. Cases have been described
in the testis and in an ovarian teratoma. They may obstruct the lumen of
the bowel partially or completely, bleed, perforate, invade local structures
and metastasize to the lymph glands, the liver and occasionally to other
parts of the body.

Microscopically an argentaffinoma is composed of groups, columns or
masses of small round cells with prominent nuclei, lying in a fibrous
stroma. There is no capsule and the cells tend to invade local tissues.
Primary tumours which behave in a malignant fashion cannot be distin-
guished histologically from those which run a benign course. Many of the
cells contain lipoids which give the tumour its characteristic colour. Like
normal argentaffin cells, they often contain fine chromatin granules (of
5-HT) which have a strong affinity for silver salts when stained by Masson's
method. This feature is characteristic, but not invariable, and is found
most often in fresh specimens.

Argentaffinomas often secrete large quantities of 5-HT. Much of this
is broken down by monoamine oxidase in the liver and in the lungs and
does no harm. However, large deposits of tumour may secrete sufficient
5-HT to swamp the available enzymes and to cause clinical effects. This
is particularly likely to occur when secondary lesions in the liver sccrctc
directly into the hepatic veins, so by-passing the hepatic cells; and,
indeed, primary lesions in the area drained by the portal vein do not cause
endocrine effects in the absence of hepatic metastascs. Some tumours
drain partly into the retroperitoneal veins, and so tend to by-pass the
liver. The valves of the right side of the heart are frequently damaged
by 5-HT (as will be described), while those of the left side arc protected
by the monoamine oxidase in the lungs.

It has been recognized recently that some metastasizing “adenomas” of
the bronchus secrete excessive amounts of 5-HTP (the precursor of 5-HT)

ARCENTAFFINOMATOSIS

485

and cause the same clinical effects as argentaffinomas. They may resemble
argentaffin tumours on ordinary histological examination, but the argen-
taffin reaction is usually absent or only slight. It is possible that the cells
are of neural origin. All the cases with endocrine features have had large
metastases, usually in the liver.

Argentaffinomatosis (the malignant carcinoid syndrome)

About 20 per cent of malignant argentaffinomas produce clinical endo-
crine features. The remainder cause intestinal obstruction or other non-
specific effects. Argentaffinomatosis is a rare syndrome, but cases are being
reported frequently. The clinical syndrome is the result of excessive
quantities of 5-HT or, more rarely, 5-HTP in the circulation. Any of the
following features may be present, but they vary in incidence and severity
from one patient to another.

Alimentary symptoms. Diarrhoea is the commonest symptom. Hyper-
motility of the bowel causes frequent watery stools, crampy abdominal pain
and borborygmi. Sometimes there is steatorrhoea and malnutrition.
Blood in the motions is unusual.

Peripheral circulatory effects. 5-HT stimulates the myocardium directly
and causes peripheral and pulmonary vasoconstriction (hence the name
“serotonin”). Systemic and pulmonary hypertension and tachycardia fol-
low. Sometimes 5-HT causes hypotension and bradycardia reflexly. The
circulatory changes are usually intermittent, and may arise spontaneously
or be induced by emotion, food (and especially alcohol), palpation of the
abdomen or drugs. They are often accompanied by changes in the vessels
of the skin. A characteristic brick-red flush, superimposed on a mottled
cyanotic background, affects the face at first and then spreads to the trunk
and limbs. In longstanding cases the face may be persistently reddish or
cyanosed and studded with dilated vessels, and the sclera may be reddened.

Cardiac lesions are the most sinister complications of argentaffinomatosis,
but usually take a long time to develop. 5-HT probably damages the endo-
cardium of the right side of the heart directly, causing tricuspid and pul-
monary stenosis (fig. 16.2) or tricuspid incompetence. The left heart is
unaffected, unless there is a right-to-left shunt, because of the protective
effect of the lungs. The symptoms and clinical signs are characteristic and
do not require any description. The right side of the heart may enlarge
and cardiac failure may supervene. Oedema is an occasional feature, which
may be due to cardiac failure, hypoprotemaemia or pressure on deep veins
by tumour tissue.

Respiratory features. 5-HT stimulates the smooth muscle of the bronchi
and causes asthmatic wheezing, which responds to the action of broncho-
dilators. Hyperventilation may follow direct stimulation of the carotid
body.

Fig. 16.2. ArgentafBnomatosis — stenosed pulmonary valve and normal aorta,
viewed from above.

lesions of the limbs and brown pigmentation, resembling pellagrous
dermatitis.

Other occasional features, whose causes are not known, are peptic ulcera-
tion, lesions of small joints like those of rheumatoid arthritis, and sclero-
derma.

Examination of the abdomen may reveal the primary tumour mass or
metastascs in the liver. Occasionally there is the scar of an earlier operation
(for appendicectomy or intestinal obstruction) associated with the tumour.

Investigation

The symptoms and signs which have been described should arouse the
suspicion of argentaffinomatosis. If flushing can be pro\ oked by food or by
alcohol it should he observed carefully and the blood pressure and pulse
rate measured before, and at intervals during, the attack.

Measurement of the excretion of 5-IIIAA in a 24-hour specimen of
urine is the most helpful diagnostic test. If sufficient 5-HT is produced to

ARCENTAFFrNOMATOSrS

487

cause symptoms the excretion of 5-HIAA is usually raised above 20 mg.
and often much higher. Daily excretions of over 500 mg. have been
recorded. The excretion varies from day to day and, in doubtful cases, the
estimation should be repeated several times. Smaller tumours, which do
not cause symptoms, increase the excretion slightly or not at all. Patients
with oat-cell bronchial carcinomas may sometimes excrete an excess (some-
times a great excess ) of 5-HIAA, and normal subjects show a slightly in-
creased excretion after eating bananas (which are rich in 5-HT).

The usual measures should be taken (barium studies, examination of the
stools for occult blood, etc.) for the detection of lesions in the bowel.

Treatment

Treatment is influenced by the fact that malignant tumours tend to grow
very slowly. Patients with known metastascs in the liver have survived in
reasonable health for many years. In this respect argentaffinomas resemble
pancreatic islet cell carcinomas.

If an argentaffinoma is found unexpectedly at operation (e.g. for
“appendicitis” or intestinal obstruction) every effort should be made to
remove the primary and all the metastases. An obviously benign ap-
pendiceal tumour is treated adequately by appendicectomy, but if there is
any suspicion of malignancy a formal right hemicolectomy should be under-
taken. It is worthwhile to remove involved mesenteric lymph glands, even
if the liver contains metastases, since the reduction in the size of the tumour
mass will reduce the secretion of 5-HT.

The same considerations apply to the treatment of patients in whom the
diagnosis has been made preoperatively, and resection of hepatic metastases
may be worthwhile.

The main complications of operation are bronchospasm and hypoten-
sion, both of which may be due to the Hooding of the circulation with 5-HT.
The risk of them developing can be minimized and their treatment can be
facilitated by the avoidance of barbiturates (whose hypnotic effect is po-
tentiated by 5-HT and which tends to cause hypotension in these patients),
chlorpromazine and related drugs (which render noradrenaline ineffective),
and by the preoperative administration of full doses of atropine (which in-
hibits the bronchoconstrictor action of 5-HT). Cyclopropane gives some
protection against the effects of 5-HT (at least in rats) and is suitable for
induction and full anaesthesia. If bronchospasm occurs it should be
treated with atropine intravenously and phenylephidrine by nebulization
into the anaesthetic circuit. Hypotension may develop during or after
operation and must be anticipated. There is some evidence that it may be
caused by adrenal “exhaustion”. It is treated by infusion with noradrena-
line or metaraminol or, if these are ineffective, by cortisol intravenously.

The excretion of 5-HIAA usually falls after the resection of tumour

THE ALIMENTARY TRACT

48S

tissue, and its periodic measurement may give valuable and early informa-
tion about recurrence.

Medical measures include the administration of nicotinamide to treat or
prevent vitamin deficiency, of bronchodilators to relieve asthma and of
drugs to counteract diarrhoea. There are several substances which antago-
nize the actions of 5-HT, but only two of them appear to be of practical help
in the clinical management of symptoms. “UML 491” (descril), in doses
of 2 to 16 mg. 3 times a day, may control diarrhoea and cyanotic flushing,
while “RO 5-1025” may reduce the flushing in doses up to 75 mg. daily.

Belfast series

The following analysis of argentaffinomas was made from the records of
the Pathological Department of the Royal Victoria Hospital (1930-60) by
Eakins (1962) and of the Central Pathological Laboratory (1945 — 61) by
Morison (1962):

Silts of lesions

Appendix SS

Ileum 21

Colon 4

Rectum 3

Meckel's diverticulum 1

Total 87

Metastatic tumours

Primai} in iteum 12

Site of primary uncertain 4

Total 16

Argentaffinomatosu (malignant carcinoid syndrome) 4

THE LIVER

The liver plays an important role in regulating endocrine activity by
modifying some hormones and by converting others into inactive products.
These important metabolic functions may be deranged by disease, and
endocrine changes are seen frequently in chrome hepatocellular failure due
to portal cirrhosis. Corticosteroids are used in the treatment of liver disease
and may be useful for differentiating between intra- and extrahepatic
cholestatic jaundice. Finally, a number of orally active steroids arc hepato-
toxic, and it is important for surgeons to be aware of their effects on the
excretory capacity of the liver. Diseases of the endocrine glands do not,
however, cause specific changes in the liver.

Endocrine features of chronic liver disease

Changes are most evident in patients with chronic portal cirrhosis,
especially that associated with alcoholism, during the reproductive phase

489

THE LIVER

!SSS===ttSS=S~=

rarely virilization. Some features are common to both sexes.

Clinical picture

The following features may be seen:

1. Spider angiomata (naevi).

2. Palmar erythema.

3. Infertility.

s'. KminLhedn-oxosteroid and 17-hydroxys, eroid excretion.

6. Loss of axillary and pubic hair.

7. Fluid retention.

8. Portal hypertension.

Males

1. Testicular atrophy.

3. LmvereSdence of benign prostatic hypertrophy.

4. Loss of facial and bodily hair.

Females

1. Menstrual irregularities or amenorrhoea.

2. Hirsutism and acne (rarely).

Mechanism of endocrine changes .... j„„,, a telv bv the

Oestrogen e.ccess. Oestrogen, are

diseased liver, and high levels are . y ider angiomata and

They cause feminization » spider naevi are found

palmar erythema. It is not clea ' h he V virilization and uterine
almost exclusively in the upper h > expect from enhanced

atrophy in women are the reverse of what one wou P
oestrogen activity, and have not «"exp draj]ating oeat rogen inhibit the
Pituitary inhibition. Increased Ic t ^ e ur i nar y levels of

secretion of gonadotrophins by -ntifreduS pmbably

gonadotrophins are diminished t omenorrhoea „ 0 mcn. Loss of
causes testicular atrophy in hair, loss of libido and

testicular function accounts for J bute t0 the diminished excretion of
impotence in men. It may also b t convert testosterone to

17-o\ostcroids, although an inabilit> ot me

17-oxosteroids may also play a part. levels are found in

Adrenocortical function. Normal plasma

490 THE ALIMENTARY TRACT

patients with cirrhosis, but urinary 17-hydroxysteroids and 17-oxosteroids
are usually low. The rate of cortisol metabolism by the liver is diminished
in cirrhosis, and the maintenance of a normal plasma cortisol level is,
therefore, due to a fall in the rate of adrenocortical synthesis of cortisol.
This relative adrenal insufficiency for both cortisol and adrenal androgen
accounts for loss of libido and body hair in vs omen and for weakness in both
sexes.

In contrast to the decline in cortisol production, aldosterone synthesis is
augmented. Ascites is probably not initiated by adrenal hyperfunction, but
secondary aldosteronism may be an important factor in its perpetuation.
There is no evidence of impaired destruction of aldosterone by the cirrhotic
liver.

Antidiuretic hormone. An excess of ADH has been postulated as a cause
of impaired excretion of water and of ascites in cirrhotic patients. There is,
however, no good evidence that the production of ADH is increased nor
that the diseased liver is incapable of destroying it. It should be noted that
ADH lowers the portal pressure in p3tients with portal hypertension and
that 20 units of vasopressin (diluted in 100 ml. of 5 per cent dextrose),
given intravenously over a 10 minute period, may be effective in the con-
trol of bleeding from oesophageal varices.

Catechol amines. High levels of adrenaline and noradrenaline have been
found in the portal venous blood of patients with portal hypertension. It
is probable that these catechol amines are produced in the portal vascular
territory and metabolized by the liver, since there is little, if any, leakage
into the systemic circulation. It is possible, although direct proof is lacking,
that they may play a part in initiating or sustaining portal hypertension.
This hypothesis receives some support from the experimental observation
that intraportal infusions of adrenaline and noradrenaline raise the portal
pressure without affecting the systemic vascular pressure. The cause of the
increase of catechol amines in the portal venous blood and the role, if any,
played by a diseased liver in the process are unknown.

Liver disease with endocrine features in young women

A special variety of liver disease is found in adolescents and young
women, and is often associated with endocrine features. The patients
are usually well nourished, with acne, amenorrhoea, facial rounding and
occasionally striae and hirsutism. This picture suggests some degree of
adrenocortical overactivity and androgen excess. The reason for the
preponderance of virilizing features in this age group is unknown, but
presumably there must be an imbalance between oestrogens and androgens.
Associated disturbances include fever, polyarthritis, hypcrgammaglo-
hulinaemia and disseminated lupus erythematosus. The liver may be the
seat of an auto-immunc process which causes persisting damage to the liver

THE LIVER 491

cells (lupoid hepatitis). For this reason the condition is treated with
adrenal steroids.

Endocrine treatment in liver disease

This can be considered under two headings:

(1) treatment aimed at correcting the effects of hormonal excess; and

(2) hormonal treatment of the liver disease itself or of symptoms

arising from it.

Treatment of hormonal effects

Aldosterone antagonists (spironolactone, Aldactone-A, 25 mg. four times
a day) may be used alone, or with other diuretics, for the relief of ascites.
Adrenalectomy has been used in the past as a means of combating secondary
aldosteronism, but it is not recommended.

Androgens may be required for the treatment of hypogonadism in males.

Hormone treatment of liver disease

Corticotrophin and the corticosteroids. Corticotrophin and cortisone and
its analogues (preferably prednisone or prednisolone) will cause rapid
symptomatic relief in patients with virus hepatitis and will accelerate the
fall in serum bilirubin. The beneficial results are not sufficiently great,
however, to outweigh the risk of side-effects, and routine corticosteroid
treatment is unwarranted in a condition which is usually benign. In acute
fulminating hepatitis , with or without coma, cortisone may be life-saving
and tide the patient over until hepatic regeneration sets in. Intravenous
cortisol hemisuccinate is given in a dose of 200 mg. or more each day. In
chronic virus hepatitis with prolonged jaundice of obstructive type (chole-
static) corticosteroids frequently cause clinical amelioration and a fall in the
bilirubin level, but liver biopsies reveal continuation of the disease process.
Nevertheless, treatment seems desirable in some of these ill patients with
prolonged jaundice, and treatment should be continued well into the con-
valescent period. The place of corticosteroids in the treatment of cirrhosis
is not clear. Prednisolone will generally improve the appetite and sense of
wellbeing and cause the serum albumin level to rise and the bilirubin to
fall. In some patients a sharp diuresis follows, especially in those with a low
serum sodium level, but in others prednisolone increases ascites and fluid
retention. Occasionally short interrupted courses of prednisolone are use-
ful as adjuncts to other diuretic therapy in those showing a diuretic re-
sponse. Corticosteroids are indicated in the “auto-immune” form of liver
disease. In these patients it is likely that the beneficial effects depend on a
reduction of the antigen-antibody reaction and the arrest of the progressive
liver destruction.

Testosterone , me thy l testosterone and the anabolic steroids. These drugs are

492

THE ALIMENTARY TRACT

valuable in relieving the itching of jaundice and cirrhosis. The rationale is
unknown. Methyhestosterone is commonly used in an initial dose of
25 mg. sublingually daily. The minimal effective dose must be given in
women so that virilization is avoided. Anabolic steroids cause less viriliza-
tion, but are probably less effective. Methyhestosterone and some of the
orally active anabolic steroids increase bromsulphalein retention and may
increase the jaundice and serum bilirubin levels. Testosterone proprionate
(100 mg. on alternate days for 4 weeks and then 300 mg. every 2 weeks
thereafter) has been recommended for the treatment of patients with
cirrhosis of the liver, and a decreased mortality in a group treated with large
doses, compared with a control group, has been reported. The method
must still be regarded as tub judice.

Corticosteroids in the differential diagnosis of jaundice . The distinction
between intrahepatic and extrahepatic cholestasis cannot always be made
on clinical and biochemical grounds, and corticosteroids may be helpful
diagnostically in difficult cases. Prednisolone (40 mg. per day for 4 or
5 days) will cause a pronounced fall in serum bilirubin in patients with
intrahepatic cholestasis due to virus hepatitis. Those with obstructive
jaundice from mechanical causes, or with cholestatic jaundice from
chlorpromazine and other similar drugs, show little if any change in the
bilirubin level; if it does fall it rises again when the drug is stopped. A fall
in the serum bilirubin of 8 per cent (or more) per day in response to pred-
nisolone is strongly suggestive of hepatitis.

Hepatotoxic effects of synthetic steroid hormones

A form of cholestatic drug jaundice may complicate treatment with orally
active steroid hormones. Methyltestosterone and many of the newer
anabolic steroids (norethandrolonc and methandicnone) and progestogens
(norethisterone) sometimes show these hepatotoxic effects. One of the
latter (norethynodrel) has been reported to cause bromsulphalein retention.
AH these substances owe their effectiveness by mouth to the presence of an
alkyl substitution at the C17 position of the steroid nucleus (fig. 16.3).

16 3 (o). Testosterone propnonatc 16 3(6). 17a-meth)Itcstosicronc

( M rt hy 1 1 « t osterone)

Fig. 16 3. Examples of steroids (androgens, anabolic steroids, and progestogens)
which arc: (a) inactive by mouth and innocuous to the liter, and (6) active by
mouth and hepatotoxic. An atkjl group (-CIP as here, -Cfl^CH,
-CHiCHj, etc.) at the C17 position confers these properties on steroids in
group (6).

FURTHER READING

493

Unfortunately this grouping also appears to confer the property of inducing
cholestasis. Testosterone proprionate and nandrolone do not possess this
particular configuration, and are active only when given parenterally.

The jaundice is not (like that caused by chlorpromazine) due to drug
sensitivity, and bromsulphalein retention or frank cholestatic jaundice
occurs in all the patients receiving enough of the drug for a sufficient time.

Clinically the jaundice is an intrahepatic form of cholestasis which de-
velops usually after several months of therapy. Recovery is complete when
the offending drug is stopped, and chronic jaundice, such as may follow
chlorpromazine sensitivity, has not been reported.

FURTHER READ1NC AND REFERENCES

The Stomach and Peptic Ulceration

ADtsoLA, a. O., ward, J. T. McCCOWN, M. c. and WELBOURN, r. b. (1961). Hyper-
parathyroidism and the alimentary tract, Bnl.J. Surg., 49, 112.

bicgart, J. it. and WILLIS, j. (1959). Peptic ulceration and endocrine disease in
necropsy material. Lancet , 2, 938.

BOWEN, R., MAYNE, J. C., CAIN, J. C. and BARTHOLOMEW, L C. (1 960). PcptlC utcer i ft
rheumatoid arthritis and relationship to steroid treatment. Proc. Mayo Clin ,
35. 537.

WELBOURN, R. b. and WARD, j. T. (1962). Hormones, gastric secretion and peptic
ulceration. (Review article, containing many other references.) Gastro-
enterology, 42, 784.

Islet Cell Lesions and Peptic Ulceration

GIBSON, J. B. and WELBOURN, r. B. (1960). Islet cell tumours and peptic ulceration.
(Review article, containing many other references.) Postgrad, tried. J., 36, 154.

CRECORV, r. a., TRACY, H. J., french, j. M. and sjrcus, w. (1960). Extraction of a
gastrin-like substance from a pancreatic tumour in a case of Zollinger-
Ellison syndrome. Lancet , 1, 1045.

Lawhie, r. s., Williamson, a. w . H. and hunt, j . N . (1962) Zollinger-EMison
syndrome treated with poldine methyl methosulphate. Lancet, 1, 1002.

underdahl, l. o., woolner, l. B. and black, b, m. (1953). Multiple endocrine
adenomas; report of eight cases in which the parathyroids, pituitary and
pancreatic islets were involved. J. clin. Endocr., 13, 20.

VERNEn, j. and Morrison, a. (1958). Islet cell tumour and a syndrome of refractory
watery diarrhoea and hypokalaemia. Amer.J. Med , 25, 374.

wermer, p. (1954). Genetic aspects of adenomatosis of endocrine glands. Amer . J.
Med., 16, 363.

Zollinger, R. M. and craig, T. v. (1960). Ulcerogenic tumours of the pancreas.
Amer.J. Surg., 99, 424.

zollinger, r. m. and ellison, E. It. (1955). Primary peptic ulcerations of the
jejunum associated with islet cell tumours of the pancreas. Ann. Surg., 142,
709.

Argentaffinoma

bridges, j. m., cibson, j. b., loughridce, l. w. and Montgomery, d. a. d. (1957).

Carcinoid syndrome with pellagrous dermatitis. Brit.J. Surg., 45, 117.
DUBACH, v. c. and csell, o. R. (1962). Carcinoid syndrome. Alleviation of diar-
rhoea and flushing with “Dcsertl” and Ro 5-1025. Brit. med.J., 1, 1390.
eakins, d. (1962). Personal communication.

494 THE ALIMENTARY TRACT

JONES, w. P. c. (1959). Serotonin and the carcinoid syndrome. Canad. Anaesth.
Soc.J., 6 , 130.

JOSEPH, M. and taylor, R. R. (1960). Argentaffinoma of the lung with carcinoid
syndrome. Brit. med. J 1,2,568.

MACFARLANE, P. S., DALCLIESll, C. E., DUTTON, R. TV., LENNOX, D., NYHl'S, L. and

smith, A. N. (1956). Endocrine aspects of argentaffinoma. Scot. med. J., 1,
148.

MOR1SON, J. E. (1962). Personal communication.

sacer, w. c., dearinc, w. h. and flock, E. v. (1958). Diagnosis and clinical
management of functioning carcinoids. J. Amer. med. Ass., 168, 139.

THORSON, A. H. (1958). Studies on carcinoid disease. Acta, tried, scand , 161, Suppl.
334.

Williams, E. D. and azzopardi, j. c. (1960). Tumours of the lung and the carcinoid
syndrome. Thorax, 15, 30

williams, e. D. and SANDLER, M. (1963). The classification of carcinoid tumours.
Lancet, 1, 233.

The Lner

FOSS, C. L. and SIMPSON, S. L. (1959). Oral methyltestosterone and jaundice. Brit,
med. J., 1, 259.

crossman, m I. (1962). Gastroenterology. Liver diseases. In Chmcal Uses of
Adrenal Steroids, p. 239. Ed. Brown, J. and Pearson, C. M. Blakiston, New
York.

hollb, d. A. and jailer, J. W (1960). Sodium and water diuresis in cirrhotic
patients with intractable ascites following chemical inhibition of aldosterone
synthesis. Ann. intern. Med., 53, 425.

mackay, i. r , TAFT, L. I. and cow'LInc, d. c (1956) Lupoid hepatitis. Lancet, 2,
1323.

peterson, R. E. (1960). Adrenocortical steroid metabolism and adrenal cortical
function in liver disease. J. elm. Invest., 39, 320.

popper, h. and scHAFFNEn, F. (1957). Relation of the liver to the endocrine glands.
In Liter; Structure and Function, p. 635. Blakiston, New York.

SHALDON, C., PEACOCK, J. WALKER, B M., PALMER, D. B., and BADRICK, F. E. (1961).
The portal venous content of adrenaline and noradrenaline in portal hyper-
tension. Lancet, 1, 957.

SHALDON, s. and SHERLOCK, s. (1960) The use of vasopressin (’Titressm") in the
control of bleeding from oesophageal varices. Lancet, 2, 222.

Sherlock, s. (1958). Hepatocellular failure — endocrine changes. In Diseases of the
Liver and Biliary System, 2nd Ed., p 126. Blackwell Scientific Publications,
Oxford.

sherlock, s. (1962). Jaundice. Brit. med. J., I, 1359.

SUMMERSKUX, w. H. J. and jones, f A. (1958). Corticotrophin and steroids in the
diagnosis and management of '‘obstructive’' jaundice. Brit. med. J., 2, 1499.

WELLS, R (1960). Prednisolone and testosterone prop donate in cirrhosis of the
liver — a controlled trial. Lancet, 2, 1416.

CHAPTER 17

ANOMALIES OF SEXUAL
DEVELOPMENT

Surgeons encounter patients with anomalous sexual development much
more commonly than is generally recognized, particularly in paediatric,
urological and gynaecological practice. Anomalous states should always be
considered in children with undescended testicles or hypospadias, in men
or women complaining of infertility and in subjects with a wide variety of
congenital deformities. There are many traps for the unwary. Female
pseudohermaphroditism, for instance, is not uncommon, and may mas-
querade as cryptorchidism with hypospadias. Injudicious attempts at
surgical correction in such a patient would be disastrous and might even
prove fatal.

We shall describe here the various ways in which sexual anomalies may
arise, indicate the signs which should lead to them being suspected and
outline the principles which underlie their treatment. It is essential that,
in patients of doubtful sex, a thorough investigation should be completed
as early in life as possible, that a firm diagnosis should be made and a
definite policy pursued with confidence.

SEXUAL DEVELOPMENT
The sex of an individual is composed of:

I. Genetic sex, chromosomal sex or genotype (XV or XX sex chromo-
somes).

II. Somatic sex or phenotype, which may be considered under three
headings —

(1) gonadal sex (testes or ovaries);

(2) internal genital sex (wolffian or mullerian derivatives);

(3) external genital sex (penis and scrotum or vulva and
vagina).

III. Hormonal sex (androgenic or oestrogenic secondary sexual
characters).

495

496 ANOMALIES OF SEXUAL DEVELOPMENT

IV. Behavioural, social or psychological sex (masculine or feminine
orientation, behaviour, dress, etc.).

In the great majority of people all these elements agree and combine to
make a male or a female, but in a small but important minority one or more
of them are out of keeping with the rest. Such anomalous individuals ate
neither wholly male nor wholly female. We will consider each of the above
elements in turn.

Genetic or chromosomal sex

The role of the X and Y chromosomes in the determination of sex has
been known for many years. Recently, however, two important technical
developments (which we shall discuss later) have permitted \cry great
advances in our understanding of the subject, particularly in anomalous
states. The first was the observation by Barr and Bertram of morpho-
logical differences between the nuclei of genetic males and those of genetic
females. The second (and more fundamental) an as the development by
Tijo and Levan and by others of satisfactory techniques for counting and
characterizing the chromosomes in man.

Human cells contain 23 pairs of chromosomes, that is 46 in all (the
“diploid” number). Twenty-two of these are called “autosomes” and one
pair the “sex chromosomes”. One set of 22 autosomes and one sex chromo-
some (i.e. 23 — the "haploid” number) is derived from each parent. Each
individual thus carries two complete sets of chromosomes consisting of
what are knoNvn as homologous pairs. The two members of each pair
have different genetic constitutions, however, because of their different
ancestry.

Two mechanisms of chromosomal division are known. During growth
or regeneration of tissue, cells divide by mitosis. Each chromosome repro-
duces itself by splitting lengthwise, so that two identical portions (or
chromatids) pass to the daughter cells and grow into mature chromosomes
identical with those in the parent cell.

The formation of germ cells, or sexual reproduction, involves a different
process and is known as niriosis. This occurs during spermatogenesis and
oogenesis, and starts at the stage when the primary spermatocytes and
oQcytes divide to form secondary spermatocytes and oocytes respectiscly.
This involves a “reduction division” in which the cells divide in such a way
that one member of each pair of autosomes passes to each daughter cell,
the paternal and maternal contributions probably being represented at
random, as shown diagrammatically on the next page.

The two sex chromosomes require special consideration because they
determine the sex of the offspring. Female somatic cells contain two

GENETIC SEX

497

MEIOSIS (REDUCTION DIVISION) IN FORMATION OF CERM CEDES
° ^ fhaoloid number)

mother.

Capital letters indicate dominant, and small letters tecessire, genes.
8 e„o, yP =. Mter .reduction ^

contains an X chromosome, ” hll ° ?'?■ and half contain Y

the secondary spermatocytes “". ta " * , ted by the seC ondary sperma-

chromosomes. In the male maosi. » P which the chromosomes
tocytes undergoing one further dtvtsion dunng which ^

split longitudinally as in J1 h spermatozoa .

spermatids, which develop, with < ^ (0 four sp5rmatoZ oa, two

Each primary spermatocyte, thereior , g female the behaviour

bearing X and two bearing Y "°^ J but the cyto-

of the nuclei and chromosomes is th ‘ • 0 5 cy te is unequal,

plasm behaves differently. The dtvtsion <***£?%* fotms q the

most of the cytoplasm passing to one daughter «“■ ™ „ f nuclear
secondary oocyte. The other daug ter ce secon< j ar y oocyte also

material and is called the "first P^^Xcorf-otob^'- The polar
divides unequally, forming an ovum a rnnt , ; n one X chromosome,
bodies usually disappear. All norma m a Sonand a „ 0 vum)

A, fertilization the ™clcti.ftwogam«es(a ^ number (46) ; s

unite to Form a zygote (or <“**“? ua i derives half of his or her genetic

thus reconstituted, and the new mdiv always contains an

material from each parent. Since the normal. ^whettaan X-bearing
X chromosome, the sex of the offspnng dcpr"* 0 " ™ , . C,hCr
or a Y-bearing spermatozoon effects fert.lcrat.on, thus.

49S

ANOMALIES OF SEXUAL DEVELOPMENT

It is thought that equal numbers of X-bearing and Y-bearing spermatozoa
are formed, but for some unknown reason rather more males are conceived
than females.

Chromosomal abnormalities

In recent years many pathological states have been found to be associated
with abnormalities in the number or form of the chromosomes. The auto-
somes are involved in a variety of conditions, including Langdon-Down’s
syndrome (mongolism), some forms of mental deficiency and various con-
genital deformities. The sex chromosomes (with which «c are concerned)
are involved in some types of anomalous sexual development.

The obsened findings can be explained on the hypothesis that "non-
disjunction” occurs either during gametogencsts (in either the father or the
mother) or after fertilization of the ovum. At the first or second division of
meiosis the sex chromosomes may fail to separate, so that both pass to one
daughter cell and none to the other. The possible results of non-disjunc-
tion in the male are as follow:

Division I Division E

Primary 1 Secondary j 5p«rmatoioon

Spermatocyte T Spermatocyte (gametej

Those in th a female arc:

GENETIC SF.X

499

Normal XX

Non- disjunction .

at I

Non -disjunction
at n

A spermatozoon may thus bear normal X or Y chromosomes, two X
chromosomes (XX), an X chromosome and a Y chromosome (XY), two
Y chromosomes (YY) or no sex chromosomes at all (O). An ovum may
carry the normal X or the abnormal XX or O. Five different anomalies may
arise in the zygote from the union of a normal with an abnormal gamete:

X 4- XX — - Super I XXX 47 £

X + O — ► Turner XO 45

Y +- XX Kl.ne- XXY 47 cf

felter

Y + O — ► (Lethal)! YO 45

(Lethal) XYY 47 YY + X

Two of these, Klinefelter’s and Turner’s syndromes, are quite common,
the “superfemale” is probably not uncommon, while the remaining two
have not been described and are probably incompatible with life. With the

500 ANOMALIES OF SEXUAL DEVELOPMENT

XO and YO combinations the total number of chromosomes is, of course,

reduced to 45 and with the other three it is increased to 47.

More complicated mechanisms may be invohed sometimes. For in-
stance, non-disjunction may occur at both the first and the second meiotic
divisions or in both paternal and maternal gametes. Or again, the geno-
types of the parents may be abnormal to start with, for both XO and XXX
individuals may occasionally be fertile. Many further abnormal combina-
tions of sex chromosomes in the zygote are thus theoretically possible, and
as many as 49 chromosomes (XXXXY) have been described. The matter
may be complicated still further by abnormalities in the form as well as in
the number of the X chromosomes. Parts of the arms may be lost (x) or
duplicated (X)* presumably by a process of partial non-disjunction.

Non-disjunction occurring during mitosis in the fertilized zygote may
give rise to “mosaicism”, a condition often found in anomalous individuals,
some of whose cells have one sex chromosome constitution and others
another. If the error occurs at an early stage about half the cells of the body
will have one genotype (e g. XXX or XYY with 47 chromosomes) and half
will have another (c.g. XO with 45 chromosomes). If it occurs at a later
division many cells will be normal (46), while some will contain more, and
others less, chromosomes than normal. Few such triple mosaics have been
described so far. In many of the mosaics which have been studied the
pattern suggests that one or more chromosomes have been lost at the time
of non-disjunction (e.g. XO /XX or XO/XY, both of which have 45/46
chromosomes instead of the expected 45/47). Other rare complicated
patterns (e.g. XXXY/XXXXY) suggest that non-disjunctions may have
occurred both before and after fertilization. Mosaicism could, theo-
retically, account for some anomalous states, such as hermaphroditism, on
the assumption that testicular tissue was derived from cells with a male
genotype and ovarian tissue from those with a female genotype. However,
there is no direct evidence for such a simple explanation. Some of the
mosaics which have been observed will be described later.

Gonadal sex (Table 17.1)

The primordia of the gonads appear first at the age of 4 to 5 weeks.
They are derived from three main sources (fig. 17.1):

(1) the coelomic epithelium, adjacent to the mesonephros, which
thickens to form a genital ridge;

(2) the underlying mesenchyme of the mesonephric ridge;

(3) the primitive germ cells, which probably arise in the endoderm of
the yolk sac and then migrate to the genital ridge.

The coelomic epithelium proliferates inwards and sends fingcr-like pro-
cesses, called primary' sex cords, to meet the rctc cords which are formed

GONADAL SEX

501

CG10M1C EKTHEIWM [ m
MESENCHYME \r

mesonephros — — l =

-PRIMORDIAL GERM CUIS
-MESONEPHRIC TUBULES
-MESONEPHRIC DUCT

tuhica vaginalis^

TUNICA ALBUGINEA—
SEMINIFEROUS TUBULES -
l WITH ttHimiU)

INTERSTITIAL CEILS"
RETE TESTIS ft*d U
VASA EFFERENTIA T
VAS DEFERENS-"^

OVARY PRIMARY ^SEX^CORDS

SECONDARY SEX CORDS
FORMING PRIMORDIAL
■ J.*— OVARIAN FOLLICLES

Q Q n [WITHCtUMCtUil

ft n ri n DEGENERATING RETE

yjLir MESONEPHRIC TUBULES
a«d OUCT

Fig. 17.1. Development of gonads.

differently in the two sexes. cells are

77ie leslis differentiates earlier than the ovmy. . s d and the
carried by the primary sex cords into t e me t jj e mcdu lla.

mesenchyme condenses beneath the awtex^sepa g vaginalis and the

The cortex is represented, in the adult by the tunica^ g^ f thl .

mesenchymal condensation by the turn S nt The sex cords

testis is therefore derived from the me and pro bably provide the

develop eventually into thesemimfcrou establish connections

Sertoli cells. The rete cords am derived from the

development and descent of the

testts have been described in Chapter 4.

502

ANOMALIES OF SEXUAL DEVELOPMENT

In the ovary the cortical elements predominate. The inner ends of the
primary sex cords and the rete cords degenerate and form the medulla,
which becomes separated from the cortex by a fine layer of condensed
mesenchyme. Secondary sex cords de\ elop in the cortex from the germinal
epithelium and break up into masses to surround the germ cells and form
primordial ovarian follicles. These sex cord cells eventually become
granulosa cells, while the underlying mesenchyme provides the theca
interna and the interstitial cells.

Control of gonadal differentiation

The differentiation of the primitive gonads into testes or ovaries is con-
trolled mainly by the sex chromosomes. Normally an XY genotype induces
the formation of testes and an XX the formation of ovaries. Examination
of the chromosome patterns in abnormal states shows that the presence of a
Y chromosome nearly always encourages the formation of testicular tissue,
even when two or three X chromosomes are present also, but that testes
may sometimes be formed in the absence of a Y chromosome.

The interstitial cells of the medulla seem to occupy a key position in the
differentiation of the gonad, for there is evidence that they secrete a “male
organizing substance” which inhibits the differentiation of the cortex into
an ovary and encourages that of the medulla into testicular tissue. This
substance, as we shall see, is also of importance in controlling the develop-
ment of the internal genitalia.

Table 17.1. Development of sex glands and organs

Indifferent

Male

Female

Gonad

Gubernacular cord

Testis

Gubernaculurn

Ovary

Ligament of ovary

Round ligament of uterus

Mesonephric tubules
Mesonephric (uolflian) duct 1

Vasa efferentia

Duct of epididymis

Vas deferens

Ejaculatory duct

Appendix testis

Prustauc utricle

l'poophoron

Duct of epoflphoron

Paramesonephric (mutlenan)
duct

Utennc tubes

Uterus

Vagina

Urogenital sinus:
Vesico-umhral canal

Petvic part

Plinlhc part

Most of bladder 1

Upper prostatic urethra
Median lobe of prostate
Lower prostatic urethra
Most of prustate
Membranous Urethra

Penile urethra

Most of bladder

Whole of urethra

Bulbo-urcthral glands

Vestibule

Genual swellings

Genital folds

Genital tubercle j

Scrotum

Body of penis

Gians penis !

Lahia majora

Labia minora

Clitoris

INTERNAL GENITAL SEX 503

Gonadal abnormalities

Abnormalities of gonadal development are not uncommon and are often
the result of abnormal genotypes. Sometimes there may be some inherent
or acquired defect in the interstitial cells of the medulla or in the gonad as a
whole. The abnormalities may involve the germ cells, the cortical elements
and the medullary elements separately or together. The following main
categories are recognized:

I. Gonadal dysgenesis

1. Gonadal aplasia, hypoplasia and dysplasia. In gonadal aplasia there is
no morphological differentiation, and in hypoplasia there is very little. In
gonadal dysplasia the interstitial cells only are well developed. The geno-
type is usually XO, but normal (XX) or other abnormal patterns are some-
times found. The commonest clinical conditions are Turner’s syndrome
and its variants.

2. Seminiferous tubular dysgenesis ( testicular hypoplasia, germinal aplasia
and tubular fibrosis). Morphologically the gonads are poorly developed
scrotal testes, but the interstitial cells are usually normal. The genotype is
usually XXY, but normal (XY) or other abnormal patterns are sometimes
present. The clinical conditions are Klinefelter’s syndrome and allied
conditions. Germinal aplasia, as a cause of infertility and possibly of
cryptorchidism, has been discussed in Chapter 4. A similar lesion,
associated with a normal male genotype (XY), is found in male pseudo-
hermaphroditism.

II. True hermaphroditism

Morphologically testicular and ovarian tissues are present either in
separate organs or in combined ovotestes. Testes may lie anywhere along
the normal line of descent. The genotype is either XX or a mosaic.

Internal genital sex (Table 17.1)

Every foetus is equipped with the structures which are necessary for the
formation of either male or female internal genital ducts (fig. 17.2). In the
male the mesonephric (wolffian) system persists and the paramesonephric
(mUllerian) system largely degenerates. The reverse occurs in the female.
In the male (fig. 17.3) the mesonephric tubules join with the rete testis to
form the vasa efferentia and the wolffian duct develops into the duct of the
epididymis, the vas deferens, the ejaculatory duct and the seminal vesicle.
The mullerian duct persists at its two ends only to form the functionless
appendix testis and the prostatic utricle. In the female (fig. 17.4) the
mullerian duct forms the uterine tube, and the ducts from the two sides
fuse to form the uterus and upper part of the vagina. Functionless wolffian
relics (the paroophoron and epoophoron) may remain close to the ovary.

504

ANOMALIES OF SEXUAL PEVELOPMENT

Fig. 17.2. The primordia of the interna! genital ducts at the indifferent stage.

Fig. 17.3. Internal genital ducts of the male.

The internal genital organs in both sexes are formed by about the six-
teenth week.

The lower parts of the genital ducts (urethra and vaginal orifice) are
derived from the'urogcnital sinus which, together with the anorectal canal,

Fig. 17.4. Internal genital ducts of the female,
b formed from the primitive cloaca by the ingrowth of the mesodermal
urorectal septum. The urogenital sinus has three parts, which are con-
tinuous (fig. 17.5). From above downwards these are: (1) the vesico-
urethral canal; (2) the pelvic part; and (3) the phallic part. The mesone-
phric (wolffian) ducts open into the sinus at the junction of the first two.

506 ANOMALIES Or SEXUAL DEVELOPMENT

The further development is different in the two sexes. In the male (fig.

17.6) the vesico-urethral canal forms most of the bladder and prostatic

urethra down to the orifices of the ejaculatory ducts (which are derived
from the wolffian ducts). The pelvic part forms the rest of the prostatic
urethra and the whole of the mebranous urethra, while the phallic part
forms the penile urethra. In the female (fig. 17.7) the vesico-urethral canal

EXTERNAL GENITAL SEX

507

forms most of the bladder and the urethra. The bulbovestibular glands are
derived from the pelvic part of the urogenital sinus. The lower part of the
vagina is formed by canalization of a solid mass of cells which is derived
from the fused lower ends of the mullerian ducts and from the wall of the
urogenital sinus. The phallic part of the sinus constitutes the vestibule,
which receives the openings of the urethra and the vagina.

External Genital sex (Table 17.1)

The external genitalia are formed in both sexes from the indifferent
genital swellings, folds and tuberclewhich appear at about the tenth week in
the mesoderm surrounding the lower end of the urogenital sinus (fig, 17.8).
They differentiate later than the internal genitalia. In the male the genital
tubercle forms the glans penis, and the genital folds fuse round the de-
veloping penile urethra to form the body of the penis. The genital swellings
fuse to form the scrotum, which later receives the testes. This process is
complete by about the sixteenth week. In the female the genital tubercle
forms the clitoris, and the folds and swellings form the labia minora and
majora respectively. This process is complete by about the twentieth week.

Control of development of internal and external genitalia
Experimental work in animals, notably by Jost, has thrown much light
on the ways in which the development of the internal and external genitalia
is controlled. Clinical observations, operative findings and the results of
gonadal biopsies suggest that similar mechanisms operate in man. The
interstitial cells of the foetal testis produce a “male organizing substance”
which has three actions: (1) as already mentioned, it controls the dif-
ferentiation of the rest of the gonad; (2) it inhibits female development of
the mullerian ducts and causes them to atrophy; (3) it stimulates male
development of the vvolffian ducts, the urogenital sinus and the external
genitalia. Without this substance development is entirely female and the
wolffian ducts regress. The actions on the mullerian and w'olffian ducts
(which are very close to the gonad) are exerted locally, for unilateral
orchiectomy in the foetus, while the organs are still indifferent, results in
female development on the same side and male development on the side
of the remaining testis. Bilateral orchiectomy results in female development
on both sides. The actions on the urogenital sinus and on the external
genitalia are exerted through the circulation, for they undergo male de-
velopment so long as one testis at least is present. The ovaries do not,
apparently, exert any influence on development during foetal life. Oophor-
ectomy has no obvious effect, and the grafting of a testis into one side in a
female foetus produces the same result as unilateral orchiectomy in the
male. Similar extirpations and graftings performed after differentiation

508

ANOMALIES Of SEXUAL DEVELOPMENT

GENITAL SWELI
GENITAL FOLD

UROGENITAL MEMBRANE
URORECTAL SEPTUM

Fir. 17.S. Development of evtcmal genitalia.

has started result in various types of intersex or states intermediate between
the male and the female forms.

The nature of the male organizing substance is unknown. Its secretion
is apparently controlled by the anterior pituitary for decapitation ("hypo-
physectomy”) of the foetus has the same effect on de\elopment as bilateral
orchiectomy, and this effect can be prevented by the administration of
gonadotrophins. Androgens administered to the mother or to the foetus
stimulate male development of the wolffian duct, urogenital sinus and
external genitalia, but do not inhibit female development of the mullerian

EXTERNAL GENITAL SEX 509

duct. It is possible that two substances are produced by the interstitial
cells, one an androgen and the other an unidentified inhibitor.

Abnormalities of internal and external genitalia

The internal genitalia may resemble those of one sex and the externa!
genitalia those of the other. Sometimes internal organs of both sexes are
present, both being fully developed or one assuming greater prominence
than the other. The external genitalia may be ambiguous in form with an
appearance intermediate between that of either sex. Thus, in the female
the clitoris may enlarge to resemble a penis, and the phallic part of the
urogenital sinus and the genital folds may fuse partly, to obscure the orifice
of the vagina, or even wholly to form a common opening for the urethra and
vagina on the glans clitoris. In the male the testes may fail to descend, the
scrotum may remain bifid to resemble the labia majora and the urethra may
be hypospadic, simulating that in the female. Finally, there may be scrotal
testes and also a vagina in the same individual.

Many, but not all, of the anomalous states in man can be explained by
the actions (or absence) of the male organizing substance of the interstitial
cells. Thus, in gonadal aplasia and hypoplasia the internal and external
genitalia are female in form whatever the genotype. In gonadal dysplasia
the phallus is enlarged, but development is otherwise female. Possibly in
this condition the interstitial cells produce their secretion too late to exert
their full influence. With testicular defects development is usually male,
but may be ambiguous. In true hermaphrodites internal development may
be male on the side of a testis and female on that of an ovary; but an ovo-
testis, which would be expected to cause some degree of male internal
development, does not always do so. Similarly, the external genitalia,
which should always be male in type, are often female.

In female pseudohermaphroditism, caused by virilizing adrenal hyper-
plasia or by the administration of androgenic substances to the mother,
androgens cause enlargement of the clitoris and often partial (or rarely
complete) fusion of the genital folds after the completion of normal
mullerian development. Wolffian development does not occur, presumably
because the stimulus is applied too late. There is no simple explanation of
the findings in other types of pseudohermaphroditism.

Hormonal sex

The development of secondary sex characters at puberty has been de-
scribed in Chapters 4 and 5. Normally the male characters are caused by
testicular androgen and the female characters by ovarian oestrogen. If the
secretion of the gonad is defective secondary sexual characters do not de-
velop and hypogonadism results. An anomalous state may be caused by
virilizing lesions in the female or by feminizing lesions in the male. In true

510 ANOMALIES Or SEXUAL DEVELOPMENT

hermaphroditism the development may be either male or female, and in one
type of male pseudohermaphroditism development is female because the
testis, apparently, secretes considerable amounts of oestrogen as well as
androgen.

Behavioural, social or psychological sex

Sexual behaviour and orientation depend much more on the sexual role
m which a child has been reared (name, dress, hairstyle, toys, etc.) than on
any innate instinct, morphological criterion or hormonal influence. It is
noteworthy that androgens tend to increase the force of the sexual urge in
either sex, but do not influence its direction. This fact is of paramount
importance in the management of patients with anomalous states.

Psychological deviations, such as homosexuality and transvestism, do
not appear to hate any organic bases. The genotype, phenotype and
hormonal sex are in agreement with each other, but conflict with the
psychological orientation.

INVESTIGATION OF ANOMALOUS STATES

Treatment of anomalous sexual states demands accurate assessment of
the structural and functional lesions in each patient. This involves a full
clinical examination and many or all of the following investigations.

1. Excretion of 17-oxosteroids

This estimation is particularly valuable in the recognition or exclusion of
congenital virilizing hyperplasia of the adrenal (female pseudoherma-
phroditism), which is the only condition which causes increased excretion
within the first few weeks of life. The excretion of prcgnanetriol is often
raised also. In later years the I7-oxosteroid excretion is helpful in the
recognition of other virilizing lesions and of hypogonadism.

2. Excretion of gonadotrophins

Estimation of total gonadotrophins (FSH + ICSH or LH) in the urine
is of most value in distinguishing between true and false puberty and be-
tween primary’ and secondary types of hypogonadism.

3. Nuclear (sex) chromatin

This method of examination, devised by Ilarr and his colleagues, is
undertaken in most routine laboratories, but it demands some experience.
It is a useful screening test for the detection of discrepancies between the
genotype and the phenotype.

Normal females ha\c a single aggregation (about 1 /i in diameter) of
deeply staining chromatin material applied to the inside of the nuclear
membrane, which can be identified in a proportion of the cells of most
tissues (fig. 17.9). It will be seen clearly only in the plane of examination

INVESTIGATION OT ANOMALOUS STATES 511

when the disposition of the nucleus brings it to one side. This chromatin
body is thought to represent the XX chromosome mass. Individuals with
more than two X chromosomes have two or more chromatin bodies in their
cells, the maximum number being one less than the number of X chromo-
somes. Thus, XXXX subjects have three chromatin bodies. Similar bodies
are sometimes identified in a few cells in normal males. The most con-
venient material to examine is a smear of the buccal mucosa, which can be
taken easily with a wooden spatula. This is spread evenly on a glass slide,
fixed while wet in equal parts of 95 per cent alcohol and ether, and then
stained, usually by the Feulgen technique. Chromatin bodies are found in

Fig. 17.9. Chromatin positive cell from buccal mucosa.

one- to two-thirds of the cells in normal females and in none (or at the most
12 per cent) of those of normal males. Skin biopsy material, fixed in
Bouin’s fluid, sectioned and stained, may be used similarly.

It is important that the results of these examinations should be reported
as "chromatin positive” or "chromatin negative”, and not as “female
nuclear sex” or "male nuclear sex”, otherwise a patient might be deeply
distressed to read such a report. Moreover, an XXY individual (ivho is not
female) will be chromatin positive and an XO individual (who is not male)
trill be chromatin negative.

The nuclei of the polymorphonuclear leucocytes also show differences
between the sexes. Club-shaped projections (about 1-5 /i in diameter),
called "drumsticks", are found in from 1 to 5 per cent of cells in females,
but not in males.

4. Analysis of chromosomes

Chromosome analyses can be made only in a few special centres.
Leucocytes, bone marrow cells or other tissues are grown in tissue culture
and then colchicine is added to the medium. This stops growth in the
metaphase of mitosis, when the chromosomes are separate and ready for

512

ANOMALIES OP SEXUAL DEVELOPMENT

division. The cells aie then placed in hypotonic solution to allow them to
swell and to disperse the chromosomes throughout the cytoplasm. Finally,
the cells are squashed or dried quickly, fixed, analysed visually and photo-
graphed.

The resulting photographic print (fig. 17.10) is cut up, so that the chro-
mosomes are separated, arranged in pairs in order of size and numbered

zl

'to

■£ 0 '4

4 1 4 n *

1 S»>" *

V^H>

lUHi MiinsMI

I 2 3 4 S 6 * s

it a it is t; »s I

tA fa k 6 fa cr. » <■> “

I '3

; s k

: M At.

20 21

Fig. 17.10. Chromosome analysis (Denser classification) of patient with Kline-
felter’s syndrome, mental deficiency and colour blindness.

INVESTIGATION Or ANOMALOUS STATES 513

according to the Denver classification. They can be counted fairly easily,
but their arrangement in order is not entirely objective, for there may be
difficulty in distinguishing between an X and pairs 6 to 12 and between a
Y and pairs 21 and 22.

5. Endoscopy

Examination of the urethra with a small cysto-urethroscope (after meato-
tomy, if necessary) is very helpful for establishing the presence of an in-
ternal vaginal opening, as in female pseudohermaphroditism. The opening
is always posterior and 2 to 4 cm. from the internal urethral orifice. The
distance depends on the age of the child and on the degree of closure of the
genital folds. It may be large enough to admit the instrument so that the
uterine cervix can be seen and catheterized (for hysterosalpingography), or
it may be so small that it escapes detection until the child is older.

Culdoscopy may be useful for visualization of the internal genitalia and
gonads.

6. Radiographic investigation

Information about the morphology of the internal genitalia and gonads
may be obtained by various radiographic means. (1) Urethrography with a
simple catheter may be used as an alternative to endoscopy and hystero-
salpingography to reveal an internal vaginal orifice. If the opening is
small and not visible by either of these methods radiography under pres-
sure (with general anaesthesia) may be helpful. Jones and Scott recom-
mend the use of a Foley catheter, modified in such a way that the distal
opening is occluded and a new opening made proximal to the balloon. The
balloon is distended in the bladder and traction is applied to occlude the
upper end of the urethra. A rubber olive is threaded on to the catheter to
block the urethral outlet and a few ml. of water-soluble radio-opaque fluid
are injected. By this technique the urethra and vagina, and sometimes the
uterus and tubes, may be outlined. (2) Pneumoperitoneum, followed by
radiography of the pelvis (with the patient in the head-down position), may
reveal the uterus, tubes and gonads.

7. Surgical biopsy and exploration

Biopsy of the gonads is of very great help in the diagnosis of anomalous
states and should be undertaken routinely, in adults and older children,
when the organs are palpable in the scrotum or in the inguinal regions.

In other cases resort must be made to laparotomy through a lower mid-
line incision. This is unnecessary in congenital virilizing hyperplasia of the
adrenals (the commonest cause of female pseudohermaphroditism), which
can be diagnosed adequately by other methods, and is often unnecessary in
gonadal aplasia. In other types of hermaphroditism it should be under-
taken both as the final stage of the investigation and also as a therapeutic

514 ANOMALIES OF SEXUAL DEVELOPMENT

measure. The nature of the internal genitalia should be determined at the
same time, and the surgeon must be prepared to remo\e contradictory
structures (see later). Laparotomy can readily be left until about the age of
2 years for, as we shall see, the sex in which the child is to be reared is
decided primarily on the structure of the external genitalia.

The gross appearance of a gonad is often misleading, and facilities for
immediate histological examination of frozen sections should be available.
A generous biopsy is often helpful, but care should be taken to avoid
damage to the blood supply. It is sometimes difficult to find small gonads,
but they may usually be traced by following the testicular or ovarian
arteries from the aorta. A “streak" gonad may appear as a local thickening
in the broad ligament of the uterus.

CLINICAL SYNDROMES

As we have seen, practically anything can happen in sexual de\elopmcnt,
and the permutations and combinations of genotype, phenotype, hormonal
sex and psychological sex are very numerous. It is important that the
structural and functional characteristics of every patient should be deter-
mined as precisely as possible in order that the best form of treatment may
be given. The clinician should not be content with a diagnosis which
simply relegates the patient to a particular category'. There are, however,
some well-defined syndromes which should be recognized.

Hermaphroditism (intersexuality)

Hermaphrodite (the Greek name) or Hermaphroditus (the Latin), the
bisexual god of Greek mythology, was the child of Hermes and Aphrodite.
In Greek and Roman statues the habitus, face, hair and breasts are de-
picted as feminine, but the external genitalia as masculine.

In the \egetablc and animal kingdoms in general the term herma-
phroditism implies the ability to produce both male and female gametes.
In man it is used to describe a discrepancy' between the gonadal sex and the
internal or external genitalia. Although both types of gonad may some-
times be present and both types of gamete formed, a human hermaphrodite
is nc\er able to function completely in both male and female roles.

Hermaphroditism may be classified as follons:

I 1‘trudoktTmaphrodt turn

1. Female. Genotype femaJe (XX) with o vanes, female internal genital orpins, and
external genitalia which are partly or w hotly masculinized.

2. Male. Genotype male (XV) with teste* (abdominal, inpimal or scrotal), male or
female internal genital orpins and male, female or ambicuous external Renitati*.

//. True Uermaphroditim

Genotype female or mo*aic. Ovoteste* or testis and ovary, mixed internal Renital
organs and male, female or ambiguous external genitalia.

HERMAPHRODITISM

515

Female pseudohermaphroditism

This is one of the commonest types of congenital sexual anomaly, and
is nearly always the result of congenital virilizing hyperplasia of the
adrenals. It is usually inherited and has been estimated to occur once in
every 67,000 births. Occasionally the condition is caused by the admini-
stration of androgens or of progestogens during pregnancy, and a few cases
have been described associated with virilizing ovarian tumours m the
mother. Very rarely no cause can be found.

Fig. 17.11. Masculmization of external genitalia in female pseudo-
hermaphroditism

1. Normal.

2. Enlarged clitoris ( common ).

3. Common opening for urethra and »agina (common).

4. Urethral opening at end of clitoris (rare).

The subjects have female genotypes (hence the term “female” in the name),
ovaries, female internal genital organs and vaginas. The external genitalia,
however, are masculinized to varying degrees. If the adrenal disorder
develops between about the twelfth and twentieth weeks of intrauterine
life the phallic part of the urogenital sinus and the genital folds tend to fuse
* .m the masculine fashion with the result that they cover the vaginal orifice
(fig. 17.11). Thus the vagina opens into the posterior wall of the elongated

516 ANOMALIES Or SEXUAL DEVELOPMENT

urethra. The clitoris enlarges to resemble a penis, but is usually kinked
ventrally by fibrous tissue (fig. 17.12). The urethral opening is usually
behind the base of the clitoris so that the condition resembles that of a boy
with undescended testicles, bifid scrotum and perineal hypospadias. Very'
rarely fusion of the sinus and fold is complete, so that the urethra opens at
the glans clitoris. Suppression of the adrenals with cortisone will cause
menstruation via the urethra if plastic reconstruction is not undertaken
before puberty. If the adrenal disorder develops after about the twentieth

Tig. 17.12. Female pseudohermaphroditc aged 3 months.

Note hypertroplw of clitoris and rugose labia majors which resemble a bifid scrotum.

week of intrauterine life the clitoris enlarges, but the vagina and urethra,
whose de\e!opment is then complete, remain normal. Virilization is pro-
gressne after birth in the patients with adrenal hyperplasia (the majority),
but not in others.

As mentioned already, female pseudohermaphroditism can be dis-
tinguished from all other types of interecx immediately after birth by
analysis of the urinary steroids or by the history of administration of
androgens or progestogens to the mother during pregnancy. Examination
of the nuclear chromatin is helpful, but diagnostic laparatomy is not
necessary. Detailed ins estigation of the vaginal opening can be left until
later.

The children should be reared as girls and treated with cortisone
(Chapter 3). Plastic reconstruction of the genitalia should be undertaken t
as soon as it is practicable (see later).

HERMAPHRODITISM

517

Male pseudohermaphroditism

In this rare condition the genotype is male and the gonads are mor-
phologically testes (hence the use of “male" in the terminology). It occurs
in males, whose testicular interstitial cells fail to function normally during
intrauterine life. The cause of the disorder is unknown, but sometimes it is
inherited. The form of the genitalia depends on the time at which the
testicular failure occurs and on its severity. The testes themselves may he
in the scrotum or labia, in the inguinal canals or within the abdomen. The
Leydig cells function well enough at puberty to cause the development of
secondary sexual characters, but the lining of the seminiferous tubules is
poorly differentiated and consists of little more than Sertoli cells (germinal
aplasia). Malignant germinal tumours are not uncommon.

The internal genitalia are often abnormal and show some persistence of
mullerian structures and deficiency of wolffian development. At one
extreme the fallopian tubes, uterus and vagina are well developed, while
the vasa deferentia are rudimentary or absent. At the other the prostatic
utricle alone is large while the vasa are normal.

The external genitalia are very variable and show one of three main
forms:

( 17 ) male, often with hypospadias;

(b) mixed, with hypospadias, bifid scrotum, etc. ;

(c) female, sometimes with palpable testes.

The hormonal sex, which manifests itself at puberty, may be either
androgenic or oestrogenic in type. It is usually androgenic in those with
male or mixed external genitalia whose internal organs are predominantly
female in form (type 1 — Table 17.2), and always oestogenic in those with
female external genitalia (type 3). It may be of either type in those with
male or mixed external genitalia whose internal organs are predominantly
male in form (type 2).

The association of male gonads with female external genitalia and
oestrogenic secondary sexual characters is called “ the feminising testis
syndrome The testes secrete oestrogens (in normal -adult female amounts)
as well as androgens (sometimes in excessive quantities), and the Leydig
cells are indistinguishable histologically from those of normal testes. The
uterus is usually absent, so that the vagina ends blindly and menstruation
does not occur. Clinically these patients are women with amenorrhoea
and a negative nuclear chromatin. Axillary and pubic hair growth is often
absent or scanty and cannot be induced with androgen therapy. The
reason for this is unknown.

Male pseudohermaphroditism cannot be distinguished from other types
of intersex without full investigation. This should be undertaken as e3fly
as practicable so that the sex of rearing and the programme of management

HERMAPHRODITISM

519

may be decided as soon as possible. The presenting features may be
ambiguous external genitalia or undescended testes at birth, the presence
of unilateral or bilateral labial or inguinal swellings (testes) in children
reared as girls, the development of male secondary sexual characters at
puberty in those with female external genitalia or primary amenorrhoea in
those with the feminizing testis syndrome.

True hermaphroditism

This very rare condition cannot be distinguished from male pseudo-
hermaphroditism without full investigation, including biopsy of the gonads.
The cause is unknown, but it may sometimes be inherited. The genotype is
often XX, but various chromosomal mosaics have been reported (XO/XY ;
XX/XXX; XX/XXx; XX/XY or XX/Xx). There may be a testis on one
side and an ovary on the other, or an ovotestis on one or each side. Ovaries
and ovotestes are probably always intra-abdominal, but a testis may de-
scend partly or wholly into the scrotum or labium.

The internal genital ducts are nearly always of mixed type, but a uterus
(which may be unicornate) and vagina are usually present. Sometimes
there is a vas deferens, but no fallopian tube, on the side of a testis and a
fallopian tube, but no vas, on that of an ovary.

The external genitalia are very varied in their development, but (despite
the presence of a vagina) they usually resemble the male type more closely
than the female, and most true hermaphrodites have been reared as boys.
It is impossible to predict, even after full investigation, whether secondary
sexual development at puberty will be male or female predominantly.
However, most develop breasts and many menstruate (even through a
penile urethra). The beard grows and the voice breaks in others. In some
again there may be breast development and menstruation, with slight
growth of facial hair.

Relative incidence

The following table, compiled in 1955 by Wilkins, shows the number of
patients with each type of disorder collected from the literature together
with those studied by him. Many more have been reported since then, but
the relative incidence is probably much the same.

Type Number

Female pseudohermaphroditism 177 (48%)

Adrenal hyperpt 2 ®' 3 168

Other types • 9

Male pseudohermaphroditism 151 (41%)

True hermaphroditism 40 (11%)

Total 368 (100%)

• Cases caused by therapy with androgens and progestogens in pregnancy had not been
repotted by 1955.

520

ANOMALIES OF SEXUAL DEVELOPMENT

Management of hermaphroditism

The management of female pseudohermaphroditism due to congenita!
virilizing hyperplasia of the adrenals has been described already (Chapter
3) Treatment with cortisone results in normal female development and
sexual function, and the children should always be reared as girls. Surgical
correction of the external genital defects will be described later.

All other cases ( and those with virilizing adrenal hyperplasia in whom
the diagnosis is not made at birth) present five distinct problems. The
patients must be followed up carefully so that any new problems which
arise may be dealt with promptly.

1 . Selection of sex of rearing

The first problem, which presents at birth, is to select the sex to which
the child should be assigned, since the sex of rearing determines the adult
psychological orientation. The most important factor is the appearance oj
the external genitalia, for they must be rendered competent, by surgical pro-
cedures, for normal sexual intercourse in either the male or the female role.
The male sex should be chosen only if the phallus appears large enough to
be capable of functioning as a penis and to allow’ adequate repair of any
hypospadias. If its size is inadequate the patient will be constantly em-
barrassed and humiliated in assuming the male role. Jones and Wilkins
have found that only about one-third of male pseudohermaphrodites are
suitable for rearing as males. The female sex should be chosen for the
majority. A normal vaginal opening can be made quite simply for those with
labial fusion, and an artificial vagina can be constructed for those w ho do not
have one. The enlarged phallus can be reduced in size to serve as a clitoris.

2. Removal of internal genital organs

The internal genital organs should be made to conform, as far as possible,
with the sex to which the child is assigned. Contradictory structures —
fallopian tubes and uterus or vasa deferentia — should be removed, prefer-
ably at the time of the exploratory laparotomy when the gonads have been
biopsied (and examined by frozen section) and the final choice of sex has
been made. This operation is probably best performed by the age of two
or three. Removal of the vagina via the abdomen can be tedious and diffi-
cult, and is probably unnecessary’. Indeed, the vagina may be useful later
for the construction of a penile urethra. If the vagina opens as a diver-
ticulum from the urethra an indwelling catheter should not be used
postoperativ cly, for it may introduce infection which is hard to eradicate.

3. Removal of gonads and hormonal replacement

No hard and fast rules can be given about the removal of gonad9. The
first consideration is the form which the secondary sexual characters are

HERMAPHRODITISM

521

likely to take at puberty. In true hermaphrodites, who have a testis on one
side and an ovary on the other, it is reasonable to remove the contradictory
gonad. It is not possible to separate the ovarian from the testicular parts
of ovotestes. Since feminization is commoner than masculinization at
puberty, the ovotestes may be left in those to be reared as girls and re-
moved from those to be raised as boys. In male pseudohermaphrodites who
are to be reared as girls the testes may be left if the external genitalia are
female in type, for feminization will occur at puberty. If the external
genitalia are mixed or male in type it is probably best to remove the testes
early in infancy. In those to be reared as boys the testes may be left alone
if the internal genital organs are predominantly female (for masculinization
is likely at puberty) and removed if the organs are predominantly male.

The gonads should always be removed if, at puberty, contradictory
secondary sexual characters develop. Some advise waiting until puberty in
all types of intersex and then removing the gonads only if the hormonal sex
fails to correspond with that in which the child has been reared. This
course is probably unsatisfactory, for it may cause psychological dis-
turbance.

There are two other considerations which influence the decision about
the removal of gonads. The first is their site. An inguinal or labial testis,
for instance, is liable to trauma and, in a “girl”, it is probably better to
remove it than to replace it in the abdomen. Similarly, in a boy, if it cannot
be placed in the scrotum, it should be removed. Finally, the gonads of
male pseudohermaphrodites are particularly liable to undergo malignant
change, and it may be best to remove those which cannot be kept under
observation in the scrotum.

At the time of puberty and throughout adult life hormonal replacement
therapy must be given to those who cannot produce androgens or oestro-
gens themselves. The methods are the same as those used in other types of
hypogonadism.

4. Plastic reconstruction of the external genitalia

Operation is undertaken primarily to make the external genitalia look as
normal as possible and to enable the patient to live a normal married life.
It 5s usually much easier to construct female organs than male ones, and
it must be stressed that masculinization should be attempted only if the
phallus is really well developed.

In children reared as girls. Operation should be undertaken as early as
possible and preferably before the development of permanent memory. It
is usually possible at the age of 18 months to 2 years, and must certainly
be completed well before puberty. Thosewithvirilizingadrenal hyperplasia
must receive additional cortisone over the period of operation. Two pro-
cedures, which can be undertaken at the same time, are used commonly.

522

ANOMALIES OF SEXUAL DEVELOPMENT

(a) Reduction in size of the clitoris. Redundant skin and subcutaneous
tissue are excised, as shown in fig. 17. 13. Some surgeons prefer to amputate
the clitoris completely while others remove the major parts of the corpora

Fig. 17.13. Operation for reduction in *ize of clitoris.

ca\ ernosa while preserving the erectile tissue in the glans. The last pro-
cedure may be the best, but it is the most difficult to accomplish for the
glans is liable to slough.

(b) Construction of a new vaginal orifice (fig. 17.14). The vagina! orifice is
identified and cathcterizcd and an incision is made backwards from the

HERMAPHRODITISM

523

urethral orifice to within 2 or 3 cm. of the anus. Very rarely the vaginal
orifice cannot be identified from below. In these circumstances the ab-
domen and the uterine cavity must be opened and a probe passed down the
vagina to the perineum. Deepening of the incision down to the catheter
(or probe) exposes the true orifices of the urethra and of the vagina. A

Fig. 17.14.

1 and 2. The orifice has been catheterized after meatotomy if necessary.

3. The skin has been incised on to the probe.

4. The separate openings of the vagina and of the urethra have been exposed, and the
latter has been catheterized also.

5. The epithelium behind the vaginal orifice is being freed.

6. The skin and perineal epithelium have been sutured together with exposure of the
two onfices. A Foley catheter has been placed in the bladder and a gauze wick in the
vagina.

second catheter is inserted into the urethra and the septum separating the
two orifices is left intact. The lateral and posterior waits of the vagina are
dissected upwards for a short distance to enable their lower margins to be
mobilized and sutured to the surrounding skin. The anterior part of the
incision is repaired in such a way that the two orifices open at the surface.
The dissection must be made with fine instruments and great delicacy, and

524

ANOMALIES OF SEXUAL DEVELOPMENT

very fine chromic catgut must be employed. Finally, a Foley catheter is
left in the bladder and a gauze wick is placed in the vagina. Fortunately
there is little tendency for scar tissue to form.

In children reared as boys. Several operations are usually needed, and they
cannot be undertaken as early as those in girls. However, most of the stages
should be completed before school age.

(a) Straightening of the penis. This is usually needed before anything
else can be done. It involves a transverse incision at the penoperineat
junction, excision of the contracted fibrous tissue and longitudinal closure
of the skin.

(b) Construction of a penile urethra. Urethroplasty is performed as in the
repair of any perineal hypospadias. A vagina, if present, may be excised
via the perineum at the same time, and can sometimes be used as a free
tube graft for the construction of the urethra.

(c) Construction of a scrotum. The two halves of a bifid scrotum or of the
labia majora may be approximated at the time of the urethroplasty or later.

(d) Orchiopexy, if required, may be delayed until puberty, because
sterility is usual (at least in male pseudohermaphrodites) and because opera-
tion is then easier.

(e) Insertion of artificial testes. Vitallium prostheses are satisfactory' and
are best inserted through low inguinal incisions. The operation may well
be left until after puberty.

5. The problem of delayed diagnosis.

All too often full investigation is not undertaken and a complete diagnosis
is not made until late in childhood or even in adult life. The question of a
“change of sex” may then arise. It cannot be emphasized too strongly that,
except in the rare case of an adult who desires to change, alterations after
the age of 18 months to 2 years nearly always result in psychological disas-
ters. The overriding therapeutic principle, therefore, should be to under-
take all steps that are necessary to make the physical features conform with
the sex of rearing. A special problem is presented by an adrenal female
pseudohermaphrodite who has been reared as a boy. Cortisone may be
undesirable, because it will cause feminization at puberty. If cortisone
therapy is thought to be important to prevent early closure of the epiphyses
or to guard against adrenal insufficiency, oophorectomy and hysterectomy
should he considered. Androgen therapy will then be necessary from the
time of puberty.

Gonadal dysgenesis

Gonadal dysgenesis (fig. 17.15) is associated with two main types of
disorder — Turner's syndrome and Klinefelter's syndrome — and a variety
of conditions allied to each. They arc relatively common.

GONADAL DYSGENESIS

525

GONADAL

APLASIA

KTUMER'S $rttOAOM£)

SEMINIFEROUS TUBULAR
DYSGENESIS

{KimttLTEA'S SriYMOM)

■ran

XX

XO

HHTMH

BTi'ISIfinuRlIJl

■HSl

■cm

— vt

IsMHmHHI

mm

Bh

■

6

APUSTIC GONAD

NORMAL

DIFFERENTIATED
SON AD

u

ovary

4

HYPOPLASTIC TESTIS

PKEHOTVPE

MALE

FEMALE

FEMALE

HORMONAL SEX

■njnunsi

Ml

HYPOGONADISM

MASCULINE |

Fig. 17.15. Summary of findings in gonadal dysgenesis compared with the
normal state.

Turner’s syndrome (gonadal aplasia or hypoplasia) and allied conditions

In 1938 Turner described the syndrome, which now bears his name,
consisting of "infantilism, congenital webbed neck and cubitus valgus" in
young women. The typical patient has an XO genotype, negative sex
chromatin, aplastic gonads, female phenotype, infantile genitalia, absence
of secondary sex characters, sterility, short stature (figs. 15.3 and 17.16) and
other characteristic congenital defects. There are, however, many variants
from this pattern.

The gonads are represented by streaks on the broad ligaments in the
normal positions of the ovaries. They are composed of whorls of connec-
tive tissue without follicles. Sometimes (in gonadal dysplasia) they contain
clumps of hilus (or interstitial) cells.

Aetiology and pathogenesis . The commonest genotype is XO, but some-
times Xx, XX or a mosaic (XO/XY, XO/XX, XO/XYY, XO/XXX) is
found. It seems likely that these chromosomal defects cause failure of
gonadal development and that, in consequence, the internal and external
genitalia develop along female lines and remain infantile. A few patients
have apparently normal XX genotypes. In these, presumably, other un-
known factors damage the gonads at an early stage, with the same result.
Occasionally the genotype is XY and the phenotype male. The testes are
perhaps damaged by unknown agents after masculine development of the
genitalia is complete.

The associated dwarfism and other congenital defects are probably
carried by autosomes, for they are not constant features and may be present

526

ANOMALIES OF SEXUAL DEVELOPMENT

(in Ullrich’s syndrome) in patients with normal gonads and sexual develop-
ment. Indeed, 45 (instead of the normal 44) autosomes have been found in
some such patients.

Fig. 17 16. Turner’s syndrome.

Phenotypic female, aged 19, with XO genotype, chromatin negative. Height 4 ft. U>J in.
(Professor C. II G Mac* fee’s patient.)

Clinical features. For practical purposes the clinical variants may be
classified as follows:

(/I) Female Phenotype

1. Gonadal aplasia (or hypoplasia) and sexual infantilism With

(<t) Dwarfism, webbed neck, etc. (“Turner’s syndrome in the female”)

(h) Dwarfism only
(r) Normal stature

2. Normal ovaries and sexual development with dwarfism, v ebbed neck, etc. ("Ullrich'*
syndrome in the female”)

(D) Mate Phenotype

t. Testicular defect and sexual infantilism with dwarfism, webbed neck, etc. (“Turner’*
syndrome tn the male")

2. Normal testes and sexual development with dwarfism. uebbrd neck, etc. (“Ullrich**
syndrome in the male”)

GONADAL DYSGENESIS

527

In one other variant of the female type (A 1), associated with gonadal
dysplasia, there is some degree of masculinization of the external genitalia,
usually consisting of hypertrophy of the clitoris. The interstitial cells pre-
sumably develop and function at a late stage in foetal life.

The congenital abnormalities (other than those of the genitalia) may be
classified as follows:

I. Skeleton

(a) Dtcarftsm
(6) Deformities

(i) Micrognathia

(ii) Scheuermann's disease
(tii) Fusion of spinal rertebrac

(iv) "Shield" or “funnel” chest

(v) Android pelvis
(\i) Cubitus valgus

(vii) Madelung’s deformity

(viii) Brachymetacarpahsm (short fingers, "pseudo-pseudohypoparathyroidism")
(c) Osteoporosis

2. Skin and Face

(n) Webbing of neck

(b) Facial deformity (“Bird face”)

(i) Small mandjble and depressed comers of mouth
(u) Ptosis and antimongolian slant of ejes

(tii) Low-set and deformed ears

(c) Figmented naevi, vitiligo and cafe-au-lait spots

(d) Deformed nails

<c) Syndactyly and webbing of axillae

(/) Tendency to keloid formation after operations

t?) Abnormalities of palmar creases

3. Viscera

(а) Cardiovascular system

(i) Coarctation of aorta

(ii) Hypertension

(iii) Congenital lymphoedema of arms and legs (often disappears after a few
months)

(б) Renal tract

(i) Horseshoe kidney

(ii) Double ureter, etc.

(c) Alimentary tract

Haemangiomas

4. Intelligence

Slight impairment sometimes

Dtcarfism is a cardinal feature of the disease and is present in all but one
group of patients. The birth weight is usually less than 5 J lb. and the height
is below the third percentile at all ages. The epiphyses appear at about the
normal time, but do not fuse with the shafts. Growth does not continue,
however, as it does in simple hypogonadism, and adults rarely exceed
4 ft. 9 in. in height. Webbing of the neck is a very characteristic feature,
and js present in about half the reported patients. It may be obvious at

528 ANOMALIES or SEXUAL DEVELOPMENT

birth, but more commonly the first sign is redundancy' of the skin at the
back of the neck. Some of the other defects are usually present in most
patients, but often pass undetected. Intelligence is usually normal, but
sometimes it is somewhat impaired. In contrast, mental deficiency is com-
monly associated with Klinefelter’s syndrome and allied states.

Diagnosis. Turner’s syndrome is rarely diagnosed in infancy and child-
hood. Dwarfism and the other congenital defects are often the earliest
signs, and should always be investigated appropriately. The typical patient
presents as an apparent female with primary amenorrhoea, poor or absent
breast development, sparse pubic and axillary hair, eunuchoid proportions
and infantile external genitalia. Primary amenorrhoea is often the pre-
senting feature in adolescents and young adults, and gonadal dysgenesis, or
incomplete forms of it,* probably account for 20 per cent of such cases.
Other features of hypogonadism are often, but not necessarily, present.

The most helpful investigations are the total urinary gonadotrophins,
which are high (or sometimes normal), and the nuclear chromatin, which is
negative in 80 per cent of patients. Positive results may be found in those
who have two or more X chromosomes in all or some of their celts. The
17-oxosteroids are often low. Exploratory laparatomy and gonadal biopsy
may be needed for final confirmation.

Treatment. Treatment consists in oestrogen therapy from the age of
puberty, as in other types of hypogonadism. It should he continuous for
the first six months or so and cyclical thereafter. In most cases secondary
sexual development and withdrawal bleeding occur. The patients, of
course, remain sterile. Therapy usually causes the epiphyses to close. The
associated congenital abnormalities may require surgical correction, but the
tendency to keloid formation should be borne in mind.

Klinefelter's syndrome ( Seminiferous tubular dysgenesis )

In 1942 Klinefelter, Reifenstcin and Albright described a syndrome in
man, characterized by small testes, azoospermia, relatively normal external
genitalia, gynaecomastia and high urinary excretion of gonadotrophins.
Mental deficiency is common. The commonest genotype is XXY, and
most patients arc chromatin positive. The phenotype is always male. It
has been estimated that the condition is present in about one in every 400
“males” born alive.

The testes are probably normal up to the time of puberty. From then on,
however, most of the seminiferous tubules undergo characteristic hyaline
fibrosis, while the rest remain small and immature and are lined mainly by
Sertoli cclU. Spermatogenesis, if it occurs, is defective. The Leydig cells
usually develop normally and are arranged in dense clumps.

Aetiology and pathogenesis . The condition U sometimes familial. The
commonest genotype is XXY, but sometimes XXXY, XXYY or a mosaic

GONADAL DYSGENESIS

529

(XX/XXY, XY/XXY, XXXY /XXXXY) is found. These chromosomal
arrangements presumably cause the development of testes and masculine
differentiation, but result in defective maturation of the spermatic tubules.
In general, the more X chromosomes there are, the more severe is the
testicular damage. Some patients are chromatin negative and probably
have a normal XY genotype. It must be assumed that some unknown agent
causes the tubular damage. The Leydig cells in such patients are often

Fig. 17.17. Klinefelter’s syndrome.

Phenotypic male aged 44 w ith hypogonadism, XXY genotype, chromatin positive.

arranged diffusely, rather than in the typical clumps, and the tubular
fibrosis is less marked.

CAwdorf fertenr. The essentia! findings are small, but net necessarily
atrophic, testicles with a characteristic histological structure, and azoo-
spermia or severe oligospermia. The testes are nearly always in the scrotum
and measure about T5 X TO x 0-5 cm. Testicular sensation is normal.
The disorder is rarely recognized before puberty, except by analysis of the
chromosomes. Klinefelter’s syndrome is responsible for some 3 per cent of
cases of infertility in the male.

Gynaecomastia is a frequent, but not essential, feature, and may be the
chief complaint. It develops at puberty or a few years later. Its cause is
uncertain.

Sexual development is usually normal, but may sometimes be defective.

530 ANOMALIES OF SEXUAL DEVELOPMENT

Libido and sexual function are generally satisfactory, and the volume of the

ejaculate is normal.

Somatic development is normal in most patients, but eunuchoid features
are sometimes present in those with severe damage to the Leydig cells.

Intelligence is often impaired, particularly in those with more than two X
chromosomes, and many of the patients may be found in mental institu-
tions. Neurotic manifestations are not uncommon.

Diagnosis. The total urinary’ gonadotrophins are always high, possibly
because of the deficiency of Sertoli cells. These are thought to secrete an
oestrogen or “X hormone” which normally regulates the secretion of FSH
(Chapter 4). The urinary 17-oxosteroids are low or normal, and the
nuclear chromatin is usually positive. Patients with more than two X
chromosomes have two or more chromatin bodies in their cells. A few
patients are chromatin negative. Biopsy of the testes shows the charac-
teristic histological structure.

Postpuberal testicular atrophy, resulting from mumps orchitis, trauma or
other cause, may cause a condition indistinguishable from chromatin-
negative Klinefelter’s syndrome (see Chapter 4). The testicular biopsy may
even fail to differentiate the two, so that the absence of a history of testicular
injury or disease forms an important part of the diagnosis.

Treatment. The testicular defect and sterility cannot be cured. Mastec-
tomy may be needed for gynaecomastia, and replacement therapy with
testosterone will help those with androgen deficiency.

" Super female" ("Meta-female”, XXX syndrome)

Several phenotypic women have been described with three X chro-
mosomes. Most have been mentally defective and have had defccthe
sexual development, menstrual irregularities, including oligomenorrhoea,
and 3n early menopause. Some, however, have borne normal children.
A few cases ha\ c been described of women with four X chromosomes.
They have similar, but more severe, defects.

FURTHER READING
General

CRCMtucll, M. M. (1960), Some considerations of the pathogenesis and classifica-
tion of anomalies of sex in man. In Clinical Endocrinology I. fid. Astwood,
E. B. Grtinc and Stratton, New York.

Human Genetics (1961). lirit. med. Hull., 17, No. 3.

joves, jr. w. and scott, w. w. (1958). Hermaphroditism, Genital Anomalies and
Related Endocrine Disorders. Haiti i£re, Tindall and Cox, London.

ROYAL College Oi Physicians of j ovdon (1961). Cltniretl Aspects of Genetics.
Pitman Medical, London.

YOLNC. ii, H. (1937). Congenital Abnormalities, Hermaphroditism am! selattd
Adrenal Diseases. Bail here, Tindall and Cox, London.

FURTHER READING

531

Chromosomes

bake, M. l.( 1957). ecological tests of chromosomal sex. In Progress in Gynecology,
3,131. Ed. Meigs, J. V. and Sturgis, S. H. Grune and Stratton, New York.
DAVIDSON, w. M. (1960). Sex determination: diagnostic methods. Bril. med. J., 2,
1901.

harnden, D. G. (1961). The chromosomes. In Recent Advances in Human Genetics.

Ed. Penrose, L. S. and Brown, H. L. Churchill, London.
harnden, D. G. and Jacobs, p. A. (1961). Cytogenetics of abnormal sexual develop-
ment in man. Brit. med. Bull., 17, No. 3, 206.
lennox, b. (1961). Indirect assessment of number of X chromosomes m man,
using nuclear sexing and colour vision. Brit. med. Bull., 17, No. 3, 196.
lennox, B. (1961). Chromosomes for beginners Lancet, 1, 1046.

Embryology

HAMILTON, w, J., boyd, J. d. and .MossMAN, ii. w. (1952). Embryological differentia-
tion of sex characters. In Human Embryology, 2nd Ed , p. 244. Hefier,
Cambridge.

Harrison, b. G. (1959). A Textbook of Human Embryology. Blackwell Scientific
Publications, Oxford*

josr, a. (1958). Embryonic sexual differentiation. In Hermaphroditism, Genital
Anomalies and Related Endocrine Disorders, p. 15. Ed. Jones, H. W and
Scott, W. W. Bailliire, Tindall and Cox, London.

Hermaphroditism

ARMSTRONG, c. N. (1955). Diversities of sex. Brit, med J., I, 1173.
cordon, r, n. and devvhurst, c. H. (1962). Ambiguous sex in the newborn
Lancet, 2, 872.

cresham, G. a. and fairgrieve, j. (1960). True hermaphroditism. Brit. J . Surg ,
48, 235.

GROSS, r. e. and meeker, I. A. (1955). Abnormalities of sexual development,
observations from 75 cases. Pediatrics, 16, 303.
jolly, it. (1956). Hermaphroditism, a critical survey. Postgrad, med. J., 32, 58
JONES, h. w. and WILKINS, L. (1961). Gynecological operations in 94 patients with
intersexuality. Amer.J. Obstet. Gynec., 82, 1142.
miller, o. j. (1961). Developmental sex abnormalities. In Recent Advances m
Human Genetics. Ed. Penrose, L. S. and Brown, H. L. Churchill, London.
money, j., hampson, j. g. and Hampson, j. l. (1955). Hermaphroditism: recom-
mendations concerning assignment of sex, change of sex and psychologic
management. Bull. Johns Hopk. Hasp., 97, 284.

WILKINS, L. CKUMBS.cn, M. M., VAN IVYK, J. J., SHEPARD , T. If. and PAPADSTOS, C.
(1955). Hermaphroditism: classification, diagnosis, selection of sex and
treatment. Pediatrics, 16, 287.

Gonadal Dysgenesis

Klinefelter, H. F., REiFENSTEiN, e. c. and ALBRIGHT, f. (1942). Syndrome character-
ised by gynae comas tia, aspermatogenesis without a-Leydigism and increased
excretion of follicle-stimulating hormone. J. Clin. Endocr., 2, 615.
polant, p, e. (1961). Turner’s syndrome and allied conditions. Brit. med. Bun.,
17, No. 3, 200. , .

STEWART, J. S. S., MACK, VC. S., COVAN, A. D. T., rERGL’SON -SMITH, M. A. and LENNOX,
b. (1959). Klinefelter’s syndrome: clinical and hormonal aspects. Quart. J.
Med., 28, 561. ,

TUrnfr, it. h. (1938). A syndrome of infantilism, congenital webbed neck and
cubitus valgus. Endocrinol., 23, 566.

gllrich, O. (1930). l)ber typische Kombinationsbildcr Multipier Abartungen.
Ztschr.f. Kinderh., 49, 271.

INDEX

(Where there are several page references to one heading the most important is usually that
With an inclusive reference of more than two pages, e g. 101-12. Otherwise, when relevant,
it is indicated by italics )

Abdomen, diabetic acute, 404
Acanthosis nigrans, 116
Aceto-acetic acid, 398 (see also “Ketone
bodies”)

Acetohexamide (Dimelor), 400
Acetone, 398 (see also “Ketone bodies")
Achard-Thiers syndrome, 107
Achilles tendon reflex, 290
Achondroptasia

Cretinism, diagnosis from, 284
Dwarfism, caused by, 463
Skeletal proportions in, 459
Achropachy, thyroid, 256, 289
Acidophil adenoma of pituitary, 18-24
in Acromegaly, 25-31
in Gigantism, 24-5
Acidosis (metabolic)
in Adrenocortical insufficiency, 115
in Aldosterone insufficiency, 66
in Diabetic ketosis, 404-6
Acne vulgans

in Adrenal virilism, 104, 106
in Androgen-producing tumours of the
ovary, 194

in Androgen therapy, 209
in Corlicotrophin therapy, 207
in Cushing’s syndrome, 88
in Hypogonadism, absence of, 142
at Puberty, 134, 174
in Stein-Leventhal syndrome, 190
Acromegaly, 25-31
BMR, 226

in Chromophobe adenoma of pituitary, 23
Cushing’s syndrome in, 29
Diabetes in, 28, 397
Differential diagnosis, 30
Eosinophilic tumours in, 29
Hyperparathyroidism in, 29
Lactation in, 29, 429
Osteoporosis in, 28, 466
Response to treatment, 31
ACTH stimulation test, 73, 74, 425-6
in Addison's disease, 116
in Adrenogenital syndrome, 109
in Cushing’s syndrome, 90
in Hypopituitarism, 34
Actinomycosis causing chronic thyroiditis,
293

Addison's disease, 113-18
Adrenocortical failure m surgery, cause
of, 422

Addison’s disease (ron/d )
and Auto-immune thyroiditis, 297
Causative lesions, 1J3
Clinical features, 114-16
Differential diagnosis, 116-17
Hypopituitarism, diagnosis from, 36
Investigation, 116
Toxic goitre, diagnosis from, 261
Treatment, 117-18
Urinary steroids in, 74
Adenohypophysis, 9-50 (see also “Pituit-
ary, anterior”)

Adenoma

Acidophil, of pituitary (g.c.), 18-24
of Adrenal cortex, 76-8
of Adrenal rests, 162
Basophil, of pituitary (5 t.) r 18-24
Chief cell, of parathyroid, 364
Chromophobe, of pituitary (?s.), 18-24
Colloid, of thyroid, 301
Embryonal, of thyroid, 301
Foetal, of thyroid. 301
Follicular, of thyroid, 300-1
Htirthle cell, of thyroid, 301, 314
Islet cell. 387-9
of Leydig cells, 161-2
“Metastasizing” of bronchus, 484
in Multiple endocrine adenopathy, 19,
364, 387, 476, 478
Oxyphil, of parathyroid, 364
Papillary, of thyroid, 301
of Parathyroids, 364
of Pituitary, anterior, 18-24
Simple, of thyroid, 301
of Thyroid, 300- ]

Toxic, 229, 233, 245. 246. 247, 279. 30!
Water-clear, of parathyroid, 364
Adiposity, constitutional familial, 41 (see
also “Obesity”)

Adrenal cortex, 51, 55, 63-128
in Acromegaly, 29
Addison’s disease (q «.), 113
Adrenalectomy, 120-6
in Adrenocortical failure in surgery,
422-6

Adrenogenital syndrome (?.»•), 101-12
Aldosterone (q-v.), 66-8
Aldosteronism, primary (q v.\ 78-81
Aldosteronism, secondary, 8l
Anatomy, 63-4
Atrophy, 77

533

534

INDEX

Adrenal cortex [contd.)

Blood steroids, as test of function, 75
Conn's svndrome, 78-81
in Corticosteroid therapy, 206
Cortisol (q t?.), 68-9
Crisis, acute, 95, 118
Cushing's syndrome {q t\), 81-101
Disorders, 76-8

Electrolytes, as test of function, 71
Eosinophil count, as test of function, 72
Feminizing tumours, 1 12
Foetal zone, 64

Further reading and references, 126-8
Gastric physiology, effect on, 474-5
Histology, 64
Hormones, 65-9
Hyperplasia, 76-7
in Hypogonadism, 185
Hroophysectomy, effect on, 47
in Hypopituitarism, 34
Insufficiency, subacute, 95-7
Investigation, 70-5
Lactation, influenced by, 428
in Management of carcinoma of breast,
442

in Metabolic response to trauma, 418-19
in Multiple endocrine adenopathv, 19,
387

in Oligaemic shock, 419-20
Pathology, 76-7

Peptic ulcer, influenced by, 474-5
in Phoeochromocytoma, 350
Physiology, 64-9
in l’seudopubert) , 138, 177
Radiography of, 70-1
Set hormones (q v.), 69
Thom test of function, 72
Tumours, 77

Tumours without endocrine actitity, 78
Urinary steroids, as test of function, 72-5
Water load, as test of function, 72
Zona fascicubta, 64
Zona glomerulosa. 64
Zona reticularis, 64

Adrenal medulla, 342-54 (see also "Cate-
chol amines")

Adrenalectomy for tumours, 120
Anatomy, 63, 342
Diseases, 344-53
Hormones, 342-4
Ph\ siology, 342—4
in Surgical stress, 418
and Thyroid hormone, 225
Tumours, 344-5, 353-4
Adrenal rests, 64, 442
Ovarian, 193
Testicular, 64, 139, 162
Adrenalectomy, 120-6
for Adrenal tumours, 78, 112
for Adrenogenital syndrome, 110
for Aldoiteronism, 80-1
Anterior route, 120, 125-6
for Ascites, 491

for Carcinoma of breast, female, 442, 446

Adrenalectomy ( contd .)
for Carcinoma of breast, male, 447
for Carcinoma of prostate, 452-3
Complications, 95-7, 122
for Cushing’s syndrome, 92-9
Effects in Cushing’s syndrome, 97-9
for Ganglioneuroma, 354
Indications, 120
Left side, 123-4

Metabolic response following, 418-19
for Neuroblastoma, 354
for Phaeochromoeytotm, 350-2
Posterior route, 121
Pre- and postoperative care, 121-2
Right side, 125
Substitution therapy, 121-2
Surgical approach, 120-1
Technique, 122-6
Thoraco-abdominal route, 120
Total rs. subtotal for Cushing's, 92-3
Adrenaline, 342-4 [tee also “Cstechol
amines")

Biosynthesis, 343
Excretion, normal values, 343
in Phaeochromoeytoma, 345, 349
Phentolamme, effect on. 348
Physiology, 342
in Portal hypertension, 490
Adrenaline therapy

Catechol amine excretion following, 349
for Insulin hypoglycaemu, 401
for Thyroidectomy, 328
Adrenarchc, 65

Adrenocortical insufficiency, 60, 112-19
(ire also “Addison's disease")
in Acromegaly, 29
after Adrenalectomy, 95-7, 122
in Adrenogenital syndrome, 105
in Argcntaflinomatosis, 423
in Corticosteroid therapy, 206-7
Gastric sccreiion, influenced by, 475
after Hypophysectomy, 47-8
in Hypopituitarism, 34-5, 38, 39
Investigation of, 71-5
in Phaeochromoeytoma posto petal ively,
351

Rclativ e, in liver disrate, 490
in Surgery, 422-6
in Thyrotoxic crisis. 259
Adrenocorticotmphic hormone (cortico-
tronhin, ACTI!)
in Addison’s disease. 114, 115
in Adrenogenital syndrome, 101-2, 110
Assay. 17

in Carcinoma of the bresvt. 442
in Cushing’s syndrome, SI-2, 83, 8 A
100

Disorders, 18

Gastric secretion, influence on, 476
Melanocyte stimulating hormone, rela-
tion to, 14

in Metabolic response to trauma, 418
Metyraponc test, 17
Phi siology, 12. 65, 67

INDEX

535

Adrenocorticotrophic hormone (cortico-
trophin, ACTH) (fonlrf.)

Stimulation test, 7J, 1^9, 116, 425-6
Suppression, 32, 73-4, 109, 206, 422, 424
Therapy, 207
in Thom test, 72
Adrenogenital syndrome, 101-12
in Adult female, 105-6
Androgen-secreting tumours of ovary,
diagnosis from, 195
in Childhood, 105

Congenital virilizing hyperplasia. ItH-a,
515-16 (see also “Female pseudo-
hermaphroditism” and “Macrogenito-
somia praecox”)

and Cushing’s syndrome, mixed, 107
Differential diagnosis, 107-10
Hirsutism, 107
Pathology, 101-3
Treatment, 110-11, 520-4
Urinary steroids in, 74, 109
Adrenoglomemlotrophin, 67
Aetiocholanolone, 58

in Adrenogenital syndrome, 102, 103,
109

Excretion, 59

Excretion in carcinoma of breast, 439
Excretion in hirsutism, 109
Excretion, normal values, 75
Aetiocholanolone tandrosterone ratio, 75
in Cushing’s syndrome, 90
Agenesis, testicular, 144
Agranulocytosis, antithyroid drugs causing,
265, 268

Albright's svndrome
remale, 177, 178
Mate, 138, 139
Aldosterone, 51, 66-7

in Adrenogenital syndrome, 102
Biosynthesis, 57
Control of secretion. 67-8
Excess, causes, 61
Physiology, 66-8
Structure, 54
Aldosterone excretion, 59
in Aldosteronism, 79
in Cushing’s syndrome, 90
in Metabolic response to trauma, 418
Normal values, 75
in Pregnancy, 81
Aldosterone therapy, 204
In Adrenal crisis, 119
in Cushing’s syndrome, 94
in Hypoaldosteronism, 80
Aldosteronism, primary (Conn’s syndrome;,
76,78-81

Causative lesions, 78
Clinical features, 78-9 _ n

Diabetes insipidus, diagnosis from, 337
Hypokalaemia in, 66
Investigation, 79-80
Treatment, 80-1
Aldosteronism, secondary, 81
in Liver disease, 490

Alimentary tract, 473-94 (see also “Consti-
pation”, "Diarrhoea", “Gastric secre-
tion”, and "Peptic ulcer")
in Addison’s disease, 115
in Adrenogenital syndrome, 105
Antithyroid drugs, toxic action on, 267
Argentaffinoma, 482-8
Argentaffinomatosis, 485-8
Carcinoid tumour, 482-8
in Carcinoma of thyroid, 307, 309
in Cushing's syndrome, 87
Fulminating peptic ulcer, 479-82
in Goitre, 235-6
m Hyperparathyroidism. 368
,n Hypoparathyroidism, 379
in Hypopituitarism, 34
in Hypothyroidism, 288-9
Infection, cause of goitre, 239
Islet cell lesions and peptic ulcer, 478-83
Liver disease (q. t.), 488-93
Malignant carcinoid syndrome, 485-8
in Phaeochromocytoma, after removal,

351

m Thyroid hormone therapy, over-
in Toxic goitre, 250, 257-8, 260
in Turner’s syndrome. 527

Zolhnger-EHison syndrome, 479-83
Alkalosis. Hypokalaemic (metabolic)

in Aldosteronism, 66, 79, 80
in Cushing’s syndrome, 87, 90
in Zollinger-Elhson syndrome, 480, 482
Allylestrenol, 174, 185, 215
Amenorrhoea, 186-7 (see also Menstrua-
tion’’)

Amphenone causing goitre, 240
Amputation

Below knee, 410
in Diabetes mellitus, 409-10
Guillotine, 409-10
Syme’s, 410
Technique, 409
Transmetatarsal, 410

Anabolic steroids, 209, 210-12
in Carcinoma of breast, 440
Clinical application, 210-12
Dosage, 211
in Dwarfism, 465
in Liver disease, 491-2
in Osteoporosis. 468

Preparations, 211

in Protein catabolism, 4ZO-i

A Amenorrhoea, caused by,189
Basal metabolic rate in, 226
in Carcinoma of breast, effect of treat-

in ^CarciMma of prostate, effect of
CorricoTtero* i ds for haemolytic anaemia,

Haemopoietm, absence causing, ,13
in Hyperparathyroidism, 368, 3t>v

INDEX

Anaemia (could.)
m Hypopituitarism, 34
in Hypothyroidism, 2S8-9
Toxic goitre, diagnosis from, 261
Anaemia, aplastic, 264, 265, 267
Anaemia, pernicious

in Auto-immune thyroiditis, 297
in Hypothyroidism, 289
Pigmentation, cause of, 116
Anaesthesia

for Adrenalectomy, 122, 3S1
for Argentaffinomatosis, 487
in Diabetes, 393, 402
for Hvpophysectomy, 44, 47
Metabolic response induced by, 415
Noradrenaline in relation to, 354
for Parathyroidectomy, 373
for Testicular biopsy , 136
for Thyroidectomy, 317-18
Androblastoma
of Testis, 162
Tubular (of ovary ), 1 92
Androgen therapy, 207-10
in Acromegaly, 30

m Carcinoma of breast, female, 439-40.
446-7

in Cushing’s sj ndrome, 92
Dosage, 20S
in Dwarfism, 465
in Endometriosis, 199
in Fihroadenosis of breast, 434
Further reading and references. 217
in Gigantism, 25
in Hermaphroditism, 521, 524
in Hyperophthalmopathic Grates’ dis-
ease, 278

in Hypogonadism, female. 185
in Hypogonadism, male, 146-7, 149
in Hypopituitarism, 37
in Klinefelter’s svndrome, 530
in Liter disease, 491-2
for Orchiectomy, 164
in Osteoporosis, 468
Preparations, 208
in Protein catabolism, 420-1
Toxic effects, 209-10
Androgens, 51-2 (iff aha “Tesiostcronc”,
etc.)

Adrenal, 69

in Adrenogenital syndrome (iff.), 101-

Atrophy of breast, caused by , 433
Biosynthesis, 54-6
in Carcinoma of breast, male, 447
in Carcinoma of proslate. 449
in Cushing’* syndrome, 88
Deficiency, 141-3 (ice aha “Hypo-
gonadism”)

Excess, causes, 61
Excretion, 58-9

in “Feminizing testis syndrome", 517
Growth, effect on, 455
in Gynaecomastm, 430
Metabolism, 58-9

Adrogcns { conld .)

Non-t inlizing, 210-12 (see afio“Anabohc
steroids’’)

m Sexual development, 503-10
Therapy, 207-10 (tee also "Androgen
therapy")

Tumours secreting, 161-2, 193-4
Androstanolone, 211
Androstenedione, 51, 65
Biosynthesis, 55-6
Excretion, 59
Metabolism, 59
Structure, 55
Androsterone, 58
Excretion, 59

Excretion, in adrenogenital syndrome,
102, 103, 109

Excretion, in hirsutism, 109
Excretion, normal values, 75
Aneurysm, carotid, 24, 31, 32
Angiomata (spider naevi), 254, 489
Angiotensin, 68

Aniline derivatives causing goitre, 240
Anorchia (testicular agenesis), 144
Anorexia nervosa, 36
Anabolic steroid therapy for, 211
Anovular cycle, 188-9
Anterior pituitary, 9-50 (see also “Pituit-
ary, anterior")

Antidiurctic hormone (ADH), 334-5 (see
also “Vasopressin")

Antithyroid drugs

Carcinoma of thyroid, caused by, 303-1
in Childhood, dosage, 277
Dosage, 265, 277

Effects on thyroid in toxic goitre, 248
Goitrogenic properties, 240
Pre-operative, 270
Sites of action, 221

for Subacute thyroiditis, treatment of,
295

as Test for hyperthyroidism, 232
for Toxic goitre, 264-6, 274, 275-80
Toxic reactions, 265, 267-6
Apoplexy, adrenal, 423
Appendix testis, 503. S04
Arachnodactyly, 465
Argentaffin reiction, 482
Argentaffinoma, 4S2-8

5-Hydroxy tryptamine, 482-3
Pathology, 4S3-5

Argentaffinoniatosis (malignant carcinoid
syndrome), 4S5-8
Adrenal exhaustion in. 423
Clinical features, 485-6
Investigation, 486-7
Treatment. 487-8

Aromatic phenols causing goitre, 240
Arrhrnobtajtoma, 103, 109, 193, 194
Arthropathy (see aho “ Joints")
in Acromegaly, 28
in Antithyroid drug therapy, 267
in Corticosteroid therapy. 207
A*chrim-Znndek lest, 173

INDEX

537

Aspiration pneumonitis (Mendelsohn's
syndrome), 420

AT 10 (Dihydrotachysterol). 362
Auto-antibodies, thyroid, 29ar-b
in Carcinoma of thyroid, 3U3
in Hypothyroidism, 290
in Riedel’s thyroiditis, 300
in Subacute thyroiditis, 294
Tests for, 298
in Toxic goitre, 262

Auto-immune thyroiditis, 233, 234, tn.

Hypothyroidism, due to, 286, 287
in Subacute thyroiditis, 293
in Toxic goitre. 247
Autosomes, 496

Basal metabolic rate (BMR). 225-6
in Acromegaly, 29
Antithyroid drugs, effect of, 266
Catechol amines, effect of, 22a
in Cretinism, 285
Guanethidine, effect on, 225, 263
Hypophysectomy, effect of, 222
in Hypopituitarism, 34
in Hypothyroidism, 290

in Phaeochromocytoma, 34b
in Pregnancy. 260
Reserpine, effect on, 225, 263
Thyroid hormones, effect of, 223
Thyroidectomy, effect of, 222

in Thyrotoxicosis factitia, 262

in Toxic goitre, 257, 262, 266, 269
von Basedow’s disease, 245 _

Basophil adenoma of pl tu,t *n f »
in Cushing’s syndrome, 82, lUU-i
Belfast senes, analyses of

Addison’s disease, 113 , .

Adrenalectomy for carcinoma of breast.

Adrenogenital syndrome, 112
Anabolic steroids and post-gastrectomy
loss of weight, 421
Anterior pituitary tumours,
Argentaffinoma, 488

Carcinoma of thyroid, 302, 30 , .

303,311,312, 316

Cushing’s syndrome, 83, 88, 92, 9 ,
99

Endometriosis, intestinal, 198
Hyperparathyroidism, 368—70, 373,
Hypophysectomy for carcinoma ot
breast, 444 .

Hypophysectomy, operative mortality,
45

Islet cell tumours, 389

Multiple endoenne adenopathy, 4/9

Ovarian tumours, 192, 194

Phaeochromocytoma, 352-3

Radioactive iodine for toxic goitre,
275

Testicular tumours, 158, 161
Thyroidectomy, 325-6
Betamethasone, 204

l disorders < see also •‘Agranulocyto-
sis’’, “Anaemia”, “Anaemia, aplastic ,
“Anaemia pernicious”, “Leukaemia
and “Polycythaemia”) ,

BigUJnides, 400 (ree also individual druffO
Blood pressure (see also Hypertension
and “Hypotension”)
in Adrenalectomy, 94, 121

m Adrenal crisis, 119 ,

in Adrenalectomy for Cushing s syn-
drome, 97

in Adrenocortical failure in surgery, 422
Cortisol, influence on, 69
in Diabetic coma, 40a

Bone.” ¥.',S , ol (f» ' "Ep ,ph T<“'^ '■
(choX.^mophv),

284.463

in Acromegaly, 26-8

3 . 7 cro m «3.y.

in 3 Differential diagnosis of cretinism,
m^Differential diagnosis of dwarfism,
m 46 Differential diagnosis of hyper-
m Pa Differentid ’diagnosis of neuro-

Dysostosi^multiplex (gargoylism). 463

Ewing’s tumour, 353 __

in Hyperparathyroidism, 365-8, 377
in Hypoparathyroidism, 379

bone disease”)

Multiple myeloma, 371
Osteitis fibrosa cystica, 36 a
Osteitis fibrosa (generalized), 365, 466

Osteochondrodystrophy (Morquio

««

tumour), 365, 366

Osteogenesis imperfecta, 463
Osteogenic sarcoma, 333

8SpS ( rL£Ln,eU,.u,,40S.

sassssfiiS'iM-^

Rccalcification in Lushing s j

after adrenalectomy, 9b

in Toxic goitre, 259
in Turner’s syndrome. 52/

Bone metabolism, 359-6 ,

Cortisol, catabolic effect ot, oa

538

INDEX

Bone metabolism ( eontd ).

Growth hormone, effect of, ] 1
Ossification centres end epiphyseal
fusion, 458

in Osteomalacia, 469-71
in Osteoporosis, 466-8
Oestrogen, effect of, 171
in Secondary hyperparathyroidism, 377—
8

Strontium, test of, 362
Testosterone, anabolic effect of, 133
Thyroxine, catabolic effect, 259
BMR in, 226

Corticosteroid therapy for, 202
Toxic goitre, diagnosis from, 261
Brachymctacarpalixm (pseudo-pseudo-
hypopanthvroidnm), 527
Breast, 427-48 '

ACTH, effect on, 428
in Adrenogenital syndrome, 104, 106,
til

Androgens, effect on, 209
Atrophy, 433

Carcinoma of (o tt.), 434—47
Development, 42S
Fibroadfnosis, 433-4
Further reading and references, 448
Growth hormone, effect on, 11-12, 428
Gynaecomastia (? c.), 430-3
m Hermaphroditism (true), 519
Hypertrophy. 433
m Hypogonadism, 181, 182, 433
in Hypopituitarism, 40
Lactation 428-30
Lactation, failure of, 430
Lactation, persistent, 429
I dictation, spontaneous, 429-30
Mastitis, acute, 429
Menopause, effect on. 428
Oestrogen, effect on, 170, 214, 428
in Oestrogen-secreting tumours of the
ovary, 193

Oxytocin, effect on. 335, 428
Pigmentation in Addison’s disease, 115
Pigmentation in oestrogen therapy, 214
in Post-partum pituitary necrosis, 33
in Precocious puberty, 178-9
in Pregnancy, 428
Progesterone, effect on, 428
Prolactin, effect on, 13, 428
m Turner’s syndrome, 528
Thyroxine, effect on, 428
Brenner tumour, 192
Bronchus, neoplasm of
in Argentaffinomatosts, 484-5, 487
in Cushing’s syndrome, 83, 90
Butanol extractable iodine (I1CI)

Normal values, 227
in Pregnancy, 260
as Test of thyroid function, 226-7

Calciferol (vitamin D2>. 381-2
for Osteomalacia, 471
m Secondary hyperparathyroidism, 377

Calciferol (Vitamin D2) {eontd.)
for Tetany following removal of para-
thyroid adenoma, 375
Calcium balance
in Acromegaly, 28
in Hyperparathyroidism, 370
Oestrogen, effect on. 171, 467
in Osteoporosis, 467
Test, 361-2, 370
in Thyrotoxicosis, 259
Calcium gluconate, 324, 381 (ree also
"Calcium therapy”)

Calcium glucono-galacto-gluconste, 3S2,
468 {tee alio "Calcium therapy")
Calcium, serum, 359-61
in Acromegaly, 29
in Aldosteronism, 79
in Azotaemic renal osteodystrophy, 377
in Carcinoma of breast with osseous
metastases, 437
in Cushing's syndrome, 90
in Differential diagnosis of hyperpara-
thyroidism, 371
in Hyperparathyroidism, 369
in Hyperparathyroidism, acute, 368
in Hyperparathyroidism, secondiry,
377-8

in Hyperthyroidism, 225
in Hypoparathyroidism, 3S0
in Malabsorption syndrome, 381
Measurement in polyuria, 339
in Osteomalacia, 471
in Osteoporosis, 468
in Parathyroid disease, 361
in Pseudohypoparathyroidism, 381
in Renal failure, 331
Thyroid hormones, effect of, 225
Thyroidectomy, effect of, 324
Vitamin D, effect of, 377, 469
Calcium therapy

for Cardiac resuscitation, 355
for Hypoparathyroidism, 381-2
for Osteomalacia, 471
for Osteoporosis, 468
for Tetany following removal of para-
thyroid adenoma, 375
for Tetany following thy roidectomy, 324
Calcium, urinary, 359-60
in Acromegaly, 28

in Calciferol overdosage and therapy. 382
in Cushing’s syndrome, 85, 89
Excretion, 361-2
in Hyperparathyroidism, 369-70
in Hypoparathyroidism, 380
in Osteoporosis, 468
Prolactin, effect of. in carcinoma of
breast. 439

Thyroid hormones, effect of, 225
Calculi, urinary

Composition in hyperparathyroidism,

365

in Cushing"* »v ndromc, 85, 89
in Hyperparathyroidism. 365
in Milfc-alkalt syndrome, 371

INDEX

539

Carbimazole, 264-8 [see also “Antithyroid

drugs")

Dosage. 265
Goitrogenic effects, 240
Site of action, 221
Toxic reactions, incidence of, 26S
Carbohydrate metabolism
in Acromegaly, 28
in Addison’s disease, 11 S
Cortisol, effect of, 68
in Cushing’s syndrome, 86
in Diabetes meUitus, 396-98
Glucagon, effect of, 385-6
Growth hormone, effect of, 12
Insulin, effect of, 384-5
in Metabolic response to trauma, 416
in Organic hyperimulmism, 389-95
in Phaeochromocytoma, 346
Thyroid hormones, effect of, 224
in Toxic goitre, 257, 262
Carbon dioxide combining post er (CO,CP),
404-6

Carcinoid tumour, 482-8
Malignant carcinoid syndrome, 485-8
Carcinoma

of Adrenal cortex, 76-8
Anaplastic, of thyroid, 306
of Breast (g.t;.), 434-47
of Bronchus, 83, 487
of Endometrium, 195-7
Follicular, of thyroid, 305-6
of Osary, 191-5, 200
of Pancreas, 83, 397
Papillary, of thyroid, 305
of Parathyroid, 362-4
Pituitary, anterior, 18-24
Pfeomorphic-cell, of thyroid, 306
of Prostate [q v.), 449-53
Round-cell, of thyroid, 306
Spindle-cell, of thyroid, 306
of Testis, 157-63
of Thymus, 83
of Thyroid (g.ti.), 301-16
of Uterus, 195-6
Carcinoma of breast, 434—47
Adrenalectomy for, 442
Adrenalectomy versus hypophysectomy,
445

Androgens for, 439-40
Corticosteroids for, 441
Factors influencing response, 438-9
Further reading, 448
Hormonal treatment, 439-41
Hormone dependence, 434-5
in Hypogonadism, 182
Hypophysectomy for, 442-5
in Male, 447

Oestrogen*, excretion after treatment,
445

Oestrogen* for, 440-1
Ofiphormomy for, 441-2
Orchiectomy for, 447
Policy for treatment, 446-7
in Pregnancy, 44 7

Carcinoma of breast (r ontd.)

Response to treatment, 435-8
Surgical treatment, 441-5
Tests for predicting response, 439
Carcinoma of pancreas
Cushing’s syndrome, cause of, S3
Diabetes melhtus, cause of, 397
Carcinoma of prostate, 449-53
Adrenalectomy for, 452-3
Choice of treatment, 451-2
"‘Female prostate” (periurethral glands
in the female), 453
Further reading, 453
Hypophysectomy for, 452-3
Methods of treatment, 450-1
Oestrogens for, 450-2
Orchiectomy for, 450-2
Response to treatment, 449-50
Carcinoma of thyroid, 234, 301-16
Aetiology, 303-4
Anap/asCic, 306-7
Clinical features, 307-8
Diagnosis, 308-9
Follicular, 305-6
in llashimoto’s disease, 302
Incidence, 302-3
Malignant lymphoma, 306
Miscellaneous, 307
in Nodular goitre, 241 , 302

Papillary. 305

Pathology, 304-7
Pleomorphic-cell, 306
Prognosis, 316
Prophylaxis, 311
Round-cell, 306
Spindlc-ccll, 306
in Toxic goitre, 248, 302
Treatment, 312-15

Card for patients with impaired adrenal
function, 118

Cardio\ascular system (ree also “Blood
pressure”, “Hypertension” and
“Hypotension”)
in Acromegaly, 28
in Adrenogenital syndrome, 105
in Aldosteronism, 79, SO
in Argentaffinomatosts, 485
in Cushing’s syndrome, 87
Diseases, BMR in, 226
in Hypogonadism, 142, 182
in Hypoparathyroidism, 379
in Hypothyroidism, 285, 288-9
Thrroid hormones, effect of, 224
in Thyroid hormone therapy, o\cr*
dosage, 285

Thyroidectomy, effect on, 270-1
in Toxic goitre, 245, 248, 256-7,

260

in Turner’s syndrome, 527
Carpal tunnel syndrome
in Acromegaly, 28
in Hypothyroidism, 290
Castration. 144, 183 (ice also "Orchiec-
tomy” and "Oophorectomy")

INDEX

540

Catechol amines, 342-4 (see also ‘'Adren-
aline" and “Noradrenaline**)
Biosynthesis, 343
in Blood, 350

Excretion, normal x slues, 343
Excretion products, 343
Gusncthidme, affecting, 225, 263
Mcthoxy derivatives, 343, 349
in Neuroblastoma and ganglioneuroma,
353

Ocular signs in toxic goitre, influence on,
254

Paralytic ileus, cause of, 351
in Phaeochromocytoma, 348-50
>n Portal hypertension, 490
Rrserpine affecting, 225, 263
in Sex ere injury, 418
Central nervous system disorders
in Cushing's syndrome, 8J-2
in Frbhbch's syndrome, 42
in Hypogonadism, 144
Hypoparathyroidism causing. 378
Hypothyroidism causing, 290
in Insulin hypoglycaemia (therapeutic),
400

Organic hyperinsulimsm causing, 390
Pituitary tumours causing, 20-1
in Precocious puberty, female, 177,
178

in Precocious puberty, male, 138
Charts, ^for recording height ami xxeight,

Chiari-Frommel syndrome, 23, 429
Chief (principal) cells, 359
in Parathyroid adenoma, 364
in Parathyroid hyperplasia, 363
Chlorothiazide, 341

Chlorotnanisene, 213-14 (tee also ''Oestro-
gen therapy”)

Chlorp ro marine
in ArgcntafRnpmatosis, 487
Drug sensitivity jaundice, cause of,
493

Lactation, cause of, 430
in Thyrotoxic crisis, 2S0
Chlorpropamide (Diabinext), 400
Chotcsteiol

Oesirogens, effect of, 171
m Steroid biosynthesis, 54
Thyroid hormones, effect of, 224
Cholesterol, plasma, 226
in Adult hypothyroidism, 290, 291
in Cretinism, 284-5
in Hypopituitarism, 34
in Myx oedema, 290, 291
Normal x-alucs, 226
Test of thyroid function, 226
in Toxic goitre, 262

Chondrodystrophy (achondroplasia). 284,
459, 463

Chonoepithehoma, ovarian. 179. 180, }94
Choriocpilhelioma, testicular, 157-61
Chononepithehoma, 196-7
Chomtoma, 83, 341

Chromaffin cells, 342-3
Staining (Chromaffin) reaction, 345
Tumours of, 344
Chromatin, nuclear, 310-1 l
in Female pseudohermaphroditism,
diagnosis of, 108

in Hypogonadism, diagnosis of, 146, 184
Chromophobe adenoma of pttuttarv, 18-
24

in Chian-Frommel syndrome, 429
in Cushing's syndrome, 82, 100-1
in Hypopituitarism, 32
Chromosomal analysis, 136, 177, 311-13
(tee also "Genetic sex”)

Chromosomal set, 496-500 (i re also
“Genetic sex")

Chromosomes, 496-500
Chxostek’s sign, 378
Climacteric, female, 185-6
Clinical features, 185-6
Management. 186
Climacteric, male, 144, 14 7
Clitoris

jn Acromegaly, 29
in Adrenogenital syndrome, 104, 106
Androgen therapy, effect of, 209
in Androgen-secreting tumours of ovary,
194

Development, 502, 506-8
Enlargement of, 104, 106,5/6
Erections of, 104

in Female pseudohermaphroditism, 104,
509, 516

in Stein-Levcnth.d syndrome, 190
in Turner's syndrome, 527
Clomiphrne citrate (MRL/41), 214 (see also
"Oestrogen therapy")

Clubbing of digits

in Hypothyroidism, 289
in Toxic goitre, 256
Coarctation of the aorta, 463, 527
Cobalt causing goitre, 240
Coeliac disease, 381, 463
Coelomic epithelium, 51, 500, 501
Coitus, 134-5 (see also “Sexual inter-
course”)

Painful in endometriosis, 198
"Cold” nodules. 229
Colloid, thyroid, 219

»n Adenoma of thyroid, 301
Antithyroid drugs, effect of, 248
in Atrophy of ihvroid, 233
in Auto-immune thyroiditis, 295
Cysts, 241

Iodine, effect of, 248, 270
in Simple goitre, 240-1
in Subacute thyroiditis, 293
in Toxic goitre, 246-7
Coma, diabetic, 404-6 (see also “Ketosis,
diabetic”)

Complement -fixation test (for thyroid
auto- antibodies), 29S

Conjugated equine oestrouens, 213 (serai »o
“Oestrogen therapy”)

INDEX

541

Conn’s syndrome, 78-81 (ree also “Aldo-
steronism, primary”)

Conovid, 2! 6
Constipation

in Diabetes insipidus, 337
in Hyperparathyroidism, 368
in Hypopituitarism, 34
in Myxoedema, 2S9

Constitutional delayed puberty, 41 (see
also “Puberty”)

Corpus luteum, 168-9
Cysts (Lutein) of, 189, 199
in Stein-Leventhal syndrome, 190
Cortexone (DOC) (see also “Deoxycortone
acetate”)

in Adrenogenital syndrome, 103
Biosynthesis, 57

Corticosteroid therapy, 202-7 (see also
1 ' Corticosteroid s ”)
in Adrenal crisis, 118-19
Adrenal failure, cause of, 113, 206,
422

for Adrenalectomy, 121-2
for Adrenalectomy (Aldosteronism), 80
for Adrenalectomy (Cushing's syn-
drome), 94-5

for Adrenalectomy (phaeochromocy-
toma), 351

in Adrenocortical failure in surgery,

425

in Adrenocortical insufficiency, 117-18
in Adrenogenital syndrome, 110-11
in Carcinoma of breast, 441, 447
in Carcinoma of prostate, 452-3
Gastric secretion in, 475
in Hyperptcaemia, diagnosis of, 371
in Hypcrinsuhmsm, 393
in Hypcrophthalmopathic Graves' dis-
ease, 278

for Hypophysectomy, 47-8
in Hypopituitarism, 37, 38, 43
in Hypothyroidism, secondary, 291
in Liver disease, 491-2
in Mumps orchitis, 145
in Myxoedema coma, 291
Osteoporosis, caused by, 466
Peptic ulcer in, 475
Preparations, 204
in Severe infections, 420
in Shock-states, 420
in Thyroiditis, subacute, 294-5
in Thyrotoxic crisis, 280
Water load test influenced by. 72
Corticosteroids, 51 (see also “Corticos-
teroid therapy”)

Biosynthesis, 57

Gastric secretion and peptic ulcer, effect
on, 475

Hypogonadism, cause of, 145, 183
in Menstruation, disorders of, 188
Metabolism and excretion, 59-60
Pituitary suppression, test of, 73-4
Structure, chemical, 53-4
Vasopressin, relation to. 335

Corticosterone, 51
in Adrenogenital syndrome, 103
Biosynthesis, 57
Excretion, 59, 60

Corticotrophm releasing factor (CRT), 65
Cortisol (hydrocortisone), 51, 68-9 (see also
“Corticosteroids")
in Adrenal crisis, 119
Adrenal secretion rate, 75
Biosynthesis, 57

Biosynthesis, defects in adrenogenital
syndrome, 103, 103
in Blood, norma! range, 75
Blood cells, affected by, 69
Blood pressure, affected by, 69
in Breast development, 427-8
Carbohydrate metabolism, affected by, 68
tn Cushing's syndrome, 81, 85, 88, 90
Electrolyte metabolism, affected by, 69
Excess, causes, 61
Fat metabolism, affected hj , 68
Gastric secretion, affected by, 69, 474
in Liver disease, 490
Metabolism and excretion, 58, 59, 60, 75
Osteoporosis, cause of. 467
Physiology, 68-9

Protein metabolism, affected by 68
Structure, 54

Skeletal grow tb, effect on, 455
Therapy, 203 (see also "Corticosteroid
Therapy")

Transport in blood. 66
Water metabolism, affected by, 69
Cortisone, 203 (see also “Corticosteroids”)
Biosynthesis, 57
Cortisol, relation to, 56
Therapy, 203 (see also “Corticosteroid
therapy ’’)

Withdrawal syndrome, 95-7, 422
Cortisone suppression test (hypcrcal-
caemic states), 371
Coupling enzyme, 229*/, 282
Craniopharyngioma, 18-20, 23-4
Creatmuria and creatine tolerance
Test of thyroid function, 232
in Toxic goitre, 257, 262
Cretinism (congenital hypothyroidism),
281-6

Aetiology, 281

Biochemical abnormalities, 221, 281-2
Clinical features, 282— ♦

Diagnosis, 284
Differential diagnosis, 284
Dwarfism in, 282, 455, 46} , 463-4
Endemic, 281
in Simple goitre, 242
Skeletal growth, retardation in, 282, 455
Sporadic. 221. 281
Treatment, 285-6
Cretinous person, 282
Crisis, acute adrenal, 118-19
in Addison’s disease, 116
in Adrenocortical failure in surgery,

422-6

INDEX

542

Crisis, acute adrenal (eontJ.)
in H> pophy sect o my end pituitary de-
struction, +24
in Hypopituitarism, 33
Postoperative, 95, 121
Crisis, hypopttuitary, 35
Treatment, 38
Crisis, parathyroid, 368
Crisis, thyrotoxic, 259-60
Apathetic, 260
Postoperative, 270
Radioactive iodine causing, 274
Treatment, 279-80
Cryptorchidism, 144. 147, ISO-7
Causes, 153
Complications, 153-4
Female pseudohermaphroditism, diag-
nosis from. 104. 153
in Germinal aplasia, 148. 153
in llvpopituitansm, 40
Incidence, 152-3

in Male pseudohermaphroditism, 519
Orchiectomy for, 163
Orchiopexy, 155-7

Seminiferous tubular degeneration in,
148

Treatment, 154-7
Varieties, 151-2
Culdoscopy, 175

m Anomalous sexual states, investiga-
tion of, 513

in Ovarian tumours, 195
in Stein-Lev enthal svndrome, 190
Cushing’s disease, 81 (ree also "Cushing’s
syndrome”)

Cushing’s syndrome, 81-101
in Acromegaly, 29
Adrenal crisis in. 95, 422
Adrenogenital *> ndrorne, diagnosis from,
109

Adrenogenital syndrome with, 107
Anabolic steroid therapy for, 468
Androgen-secreting ovarian tumour, di-
agnosis from, 195
Causative lesions, 81—3
Chonstoma in, 341
in Chromophohe adenoma, 23
Cttmcal and melaholic features, 84—9
Corticosteroid induced, 205
Cortisone withdraw al sy ndrome u\,9'-7,
422

Diabetes mellitus in, W. 397
Gastric secretion in, 87, 474
Growth, effect on, 462
Investigation, 89

in Lipoid cell tumour of nvarvr. 193
Medical treatment, 92
Menstrual ion. effect on, 8S, 188
Osteoporosis ill, US, 466-7
Phosphate rcahsorplion in, 371
Pituitary in, 100
“Hugger jersey ” spine in, 377
Siem-I.eventhal svndrome, diagnosis
from. 191

Cushing's syndrome ( contd .)

Substitution therapy for adrenalectomy,
94

Treatment. 91
Urinary steroids in, 74
Cycle, menstrual, 172 (set also “Menstrua-
tion”)

Ureast carcinoma, influenced by, 441
Disorders of, 186-9
Surgical stress, effect on, 419
in Traumatic stress, 419
Cycle, ovarian, 167-9
Anovular, 188-9
Cysts, ovarian, 1S9, 700

Deafness in hypothyroidism, 281, 284, 288
Decidual reaction, 172, 216
Defcmimzation

in Adrenogenital syndrome, 105
in Androgen therapy, 209
in Ovarian tumours, 194
Dehydroepiandrosicrone (DIIA), 51, 65
in Adrenogenital syndrome, 102, 103
Biosynthesis. 55
Structure, 55

Dehydrocpiandrojtcrone excretion, 59
in Adrenogenital syndrome, 109
Normal values. 75
Deiodinase, 220-1, 282
Delayed growth and adolescent develop-
ment, 41, 145, 183, 462 (tee alto
"Growth, retarded")
ll-Deoxycimi<ol (compound S)
in Adrenogenital syndrome, 103
Biosynthesis, 57
Metabolism and excretion, 59
in Metyraponc test, 17
Dcoxvcortone acetate (DCA) therapy, 204
in Adrenalectomy , 1 22
in Adrenalectomy for Cushing's syn-
drome, 94

in Adrenocortical insufficiency, 117
in Adrenogenital syndrome. 111
Developmental age, 458
Dexamethasnne, 204
Suppression lest, 74, 109
Diabetes insipidus, 335-41
Aldosteronism, secondary, resulting
from. SI
BMR in. 226
Causative lesions. 336
Clinical features, 336-7
Differential diagnosis, 339-40
in 1'rOtilich'e svndrome, 41
Further reading, 341
in Hypophy sect omy, 4S, 445
m laiurence-Moon-Hiedl syndrome,

460

Nephrogenic, 79, JJ9
Treatment, 340-1
Diabetes mellitus, 396-410
in Acromegaly , 28, 30
Acute abdomen in. 404
in Addison’s disease, lit

INDEX

543

ibetes mellttus (eontd.) .

Amelioration following adrenalectomy,

68

Amelioration following pituitary ne-
crosis, 35

Complications of, 406-10
in Cushing's syndrome, 86
Diabetes insipidus, diagnosis Irorn,
Duodenal ulcer, incidence m, 477
Family history of, in hypermsulinism,
389

Feet, lesions of, 407-10
Gastric secretion, effect on, 477
in Gigantism, 25
Hyperinsuhnism in, 389
Hypogonadism in, 145. 184
m Hypoparathyroidism, idiopathic, 3/v
Hypophyscctomy for retinopathy and
nephropathy, 410
Infantilism in, 456, 463
Infections in, 406, 408
Insulin hypoglycaetnia, management ot.

Insulin sensitivity following hypo-
ph>sectomy, 410
Insulin therapy for, 399-400
Ketosis and coma, management ot,
404-6

Neuropathy in, 407-8
Oral therapy for, 400
Pancreatectomy, diabetes following, 396
Phaeochromocytoma, diagnosis from,

346

Steroid diabetes, 68, 86
Surgery in (q.v.), 401—3, 406
Vascular disease in, 407 .

Diabetes of bearded women (A chard
Thiers syndrome), 107 . . .

Dialysis, anabolic steroids diminishing,
necessity for, 212
Diarrhoea (tee also "Steatorrhoea )
in Addison’s disease, 115
in Argentaffinomatosis, 485
in Neuroblastoma and ganglioneuroma,

353

in Toxic goitre, 258, 260
in ZoUmger-Ellison syndrome, 48U
Dienoestrol, 213 .

D icthy lstilboestrol , 213 (see also btil-
boestrol”) „

Dihydrotachyxteml (AT 10), 382
Duodotyrosine, 220-1
Dimcthisterone, 185, 215 .. .

Diotroxin. 326-7 free also “Thyroid hor-
mone therapy")

Diploid number, 496, 497

Addison’s, 113-9

Cocbac, 381,463 .. .

Cushing’s, 81 (see also Cushing!
syndrome")

iSmito’,. 287, 290. 292, 29S-9
Hodgkin’s, 336, 371

Disease (eontd.)

Morquio’s (osteochondrodystrophy),

284, 463

Paget’s, 30, 226, 261, 297, 372
Perthe’s, 287
Peyronie’s, 203
Plummer’s, 245
Scheuermann’s, 527
Simmonds*, 31
Von Basedow’s, 245
Von Gierke’s. 392
Von Recklinghausen s, 345, 34/
Disgerminoma, 104, 194
DOPA, 343
Dopamine, 342-3, 34)

Dupuytren s contracture, 203, 40b
Dwarfism, 38, 459-65 (see also Growth,
retarded")

in Bone disorders, 463
Constitutional, 459-60
Diagnosis, 463—4
Endocrine, 461-2
in General disease, 462-3
Genetic. 459-60
Primordial, 459-60
Treatment, 465

ssssrssii. <■» «'»

“Gonadal dysgenesis )

Dysostosis multiplex (gargoy lism). 403
Dystrophy, adiposo-gemtal, 41-2 (see
also ‘Trfihlich s syndrome )

Electrocardiogram (CCG)
in Aldosteronism, 80
in Adult hypothyroidism, 289
in Cretinism, 285
in Hypocalcaemia, 379
in Toxic goitre, 2s6

Electroencephalogram

in Hypoparathyroidism, 37 7

in Organic hyperinsuhnism, 331
Electrolytes, disturbances of 14 j*“ ! £
"Acidosis". “Alkalosis , ,, H >P cr “_
laemia", “Hypemairaemia , Hypo
kalaemia" and “Hyponatraemia )
in Addison’s disease. 115, 116, 119
in Adrenocortical disease, 71
tn Adrenogenital syndrome. 1U3
Aldosterone, effects of, bb-/
in Aldosteronism, 79
in Catabolic phase of stress, 416
Cortisot, effects of. 69
in Cushing’s syndrome, »7
in Diabetic ketosis. 404-6
in Fulminating pcptic u^cer fZoihnsc
Ellison syndrome), 480, 482
in Hyperparathyroidism, acute, 368
in Hypopituitarism. 35

in Hypopituitary ensis. 35
in Thyrotoxic crisis, 279

Embryonal tumours

Adenoma or thyroid, 301
Carcinoma of testis, 157-61

544

INDEX

Ena* id, 199. 215-16
Fndometnosis, 197-9, 215, 216
Endometrium, 172-3
Biopsj, 175
Carcinoma of, 195-6
Curettage, 175

in Menstrual disorders, 187-8
in Ovarian tumours, 193
in Progestogen therapy, 214-16
Enteramine, 482 (tee also “5-Hydroxy-
tryptnmine”)

Entcrogastrone, 473
Eosinophil count and Thom test, 72
in Adrenocortical failure, 72, 422
in Hypopituitarism, 34
in Metabolic response to trauma,
419

in Shack, 420
Eosinophiha

in Adrenocortical failure, 72, 422
in Hypopituitarism, 34
Epimenorrhagia, 187
Epimenorrhoea, 187

Epiphvses (ire also “Bone, disejsc of",
•'Growth" and “Skeleton")
in Adrenogenital syndrome, 104
in Constitutional delated puberty, 41
Dysgenesis in cretinism, 282-3, 455
Dysgenesis in juvenile hypothyroidism.
286. 287

in rrtihlich’s svndrome, 42
in Hypogonadism, 142, 181
in Hypopituitarism, 42
Ossification and fusion, 45.8
in Precocious puberty, 138, 178
in Pickets. 471

Sex hormones, effect on. 133, 146, 171,
456, 465

Slipped femoral, in constitutional
familial obesity. 143
Thyroid, effect on. 485
in Turner’* svndrome, 527
TpoOphoron. 502, 503, 505
Erb’s sign, 378

Erosions, subperiosteal, 365, 366 , 367
Escutcheon
female, 170
Male, 133

Ethinyloestradiol, 213 (ire at so “Oestrogen
therapy”)

Ethisterone, 215
Ethylcstrcnol. 211

I'unuch and Eunuchoid, 137, Ml, 149
Euthvroidism

Radioactive iodine tests, 23!
in Simple goitre, 242
in Thyroiditis, 292, 297. 300
Ewing’s tumour, 353

Exophthalmic goitre, 244-80 (ire also
“Toxic goitre")

Exophthalmos, 252 fire alto "Ocular signs
of toxic goitre”)
in Cushing’s syndrome, 83
in Newborn, 260

Exophthalmos producing substance (EPS),
13. 254, 279
in Pregnancy, 260

External genitalia (ire “Sexual organs")
Eyes

in Argentaffinomatosis, 485
Catecholamines, influence on, in toxic
goitre, 254

in Cushing’s syndrome, 88
in Diabetes methtus, 410
Diseases, corticosteroid treatment for,
203

in Hyperparathyroidism, 369
in Hypoparathyroidism, 379
m Hvpothyroidism, 288
in Pituitary tumours, 21
in Toxic goitre, 251—4 (tee also "Ocular
signs of toxic goitre”)

Tacial deformity (“Bird face”), 527
Pacvcnni’s syndrome, 386, 469
Pat metabolism
in Acromegaly, 28
Cortisol, effect of, 68
in Cushing’s syndrome, 85
in Diabetes mcllitus, 397-8
Growth hormone, elfcct of, 12
in Metabolic response to trauma,

416

Ocstradiol. effect of, 170
Thy roid hormone*, effect of, 224
in Toxic goitre, 257
Tclty’s svndrome, 202
feminizing testis syndrome, S17
Feminization, 61

Adrenal tumours, 112
in Adrenogenital syndrome after treat-
ment, 111

in feminizing testis syndrome, 517
in Liver disease, 489
Oestrogen therapy, 214
Ovarian tumours, 191-3
Sertoli cell tumour in dog, 163
Testicular tumours. 162-3
Feme chloride test, 39S, 401, 402

Antithyroid drugs causing, 267
II Mil increased by. 226
in Diabetes insipidus, 337
Hyperpyrexia in thyrotoxic crisis, 2Sf)
in Li«er disease. 4W
in N eii mbla stoma, 353
in Subacute adrcnjl insufficiency - 96,

422

Toxic goitre, diagnosis from, 26!
fits

in Ilypopsrathvroidiim, 378
in Hypothyroidism. 29 1
m Insulin hvpogtycaeniu (therapeutic),
4tX)

in Organic hypennsulinism, 389-91
in Pituitary tumour*. 21
in Vasopressin merdosage, 340
flocculation tests 294

INDEX

545

Fludrocortisone (9i-fluorohydrocortisone),
205

for Addison’s disease, 117
for Adrenogenital syndrome. 111
for Hypoaldosteronism, 80
Suppression test, 74
Fluid deprivation test, 337
Fluoro-hydroxy-methyltestostcrone (flu*
oxymesterone), 208
Folic acid antagonists

for Chorioepithelioma of testis, 160-1
for Chorionepithelioma, 196
for Neuroblastoma, 354
Follicle stimulating hormone (FSH) (ree
aha “Gonadotrophins”)

Assay, 15

in Female climacteric, 186
in Hypogonadism, treatment of, 147
in Menstruation, disorders of, 188
Oestradiol, relation to, 169, 171
in Ovarian cycle, 168, 169
Physiology, 12. 129-30
Progesterone, influence on FSH, 172
Spermatogenesis, controlled by, 131
Testicular oestrogen, possible effect on
FSH, 133

Testosterone, influence on FSH, 133
"X hormone” (inhibm), possible effect
on FSH, 134

Follicles, ovarian (graafian), 166
Cysts (follicular), 189, 199
Tolhcular (granulosa) cells, 168, 171, 189
in Stein-Leventhal syndrome, 189
Tumour, 179, 191-3
Fried man test, 17 3
Friedreich’s ataxia, 144, 431
FriShl/ch’s syndrome, 41-2, 145, 183, 461

Gamete, 497, 499

Ganglion cells, sympathetic, 342 ( see alto
“Chromaffin cells")

Gangrene

in Diabetes melhtus, 407, 409-10
in Noradrenaline therapy, 356
in Phaeochromocytoma, 346
Gastrin, 387, 473, 477
Gastric secretion, 473-82 (ree also “Peptic
ulcer")

in Hypopituitarism. 34, 476
in Myx oedema, 289
in Zollingcr-Oison syndrome, 480
Gastrointestinal system, 473-94 (tee also
“Alimentary tract”)

Genetic sex (chromosomal sex, or geno-
type) 495, 496-500
Analysis, 511-3

Gonadal differentiation, control of. 502
in Gonadal dysgenesis (Turner’s syn-
drome), 503, 525

in Hermaphroditism (true), 503, 519
Mosaicism, 500
Non-disjunction. 498-500
in Pseudohermaphroditism, female, 514
in Pseudohermaphroditism, male, 514

Genetic set ( contd .)

in Seminiferous tubular dysgenesis
(Klinefelter's syndrome), 503, 528-9
Genital tubercle, 505, 507
Genitalia (see “Sexual organs”)

Genotype, 496-500 (see also “Genetic
sex”)

Genu valgum, 379
Germinal aplasia, 147, 148
in Cryptorchidism, 153
in Gonadal dysgenesis, 503
in Male pseudohermaphroditism, 517
Giant cell pseudo-tumour ("Osteoclas-
toma"), 365

von Gierke’s disease, 392, 463
Gigantism (giantism), 24-5
in Accelerated growth tn childhood,
465

Globin insulin, 399 (ree also “Insulin”)
Glucagon, 384—6
in * cell lesions of pancreas, 387
Gastnc secretion, influence on, 477
Test, in organic hypennsuhmsm, 391
Therapy, 401

m Zollinger-Ellison syndrome, 481
Glucagon test, tn organic hypennsulmi'm,
391

Glucocorticoids, 51 (tee also individual
hormones)

Gluconeogenesis, 384, 385
Cortisol causing, 68
in Diabetes melhtus, 397
Growth hormone causing, 12
High protein diet, effect on, 392
Glucose, blood, 386-7
Cortisol, effect on, 68
m Diabetes mellitus, 397
Gastnc operations, effect on, 393-5
Glucose tolerance test, 386-7
Hormonal control of, 385
Hyperglycaemia (q v ), 396-8
Hypoglycaerma (7 «.), 389-95
Insulin, effect on, 384-5
in Management of ketosis, 404-6
Normal values, 386
Thyroid hormone, effect on, 224
Glucose 6-phosphate, 385
Glucose tolerance lest, 386-7
in Addison’s disease, 115
tn Cushing’s syndrome, 86
in Diabetes mellitus. 398
Gastnc operations, effect on, 394
in Organic hyperinsultnism, 390
in Toxic goitre, 224. 257
Glycogen, 384, 385, 386
Cortisol, effect on, 68
Deficiency in diabetes melhtus, 397
Formation in Addison’s disease, IIS
Storage disease, 392, 463
Vaginal, 170
Gl> cogenoiysis, 385, 386
Adrenaline caustng, 342
Glucagon causing, 386
Thyroid hormone causing, 224

INDEX

546

Glycosuna, 336
in Acromegaly, 28
in Cushing's syndrome, 86
in Diabetes meihtus, 397, 393
in Functional h> poglycaemia, 392
in Phaeochromocy toma, 346
in Toxic goitre, 2S7
Goitre, 232, 234-S
m Acromegaly , 29
Antithyroid drugs, influence of, 240,
26S

Congenital, 281
Definition, 234
Diffuse toxic, 245
Endemic, 234. 239-44
Exophthalmic. 234. 245 (tee alto "Toxic
goitre")

Hypothyroid, 234 (see also "Hypo-
thsroidism”)

Iodide, 244

Iodine deficiency. 239-44
Lvmphadcnoid, 296
Malignant, 301-16
Masked, 237
Nodular, 234

Retrosternal, 235, 236, 237, 317. 321
Simple, 234. 239-44
Sporadic, 234, 239-44
in Thyroiditis. 292-300
Toxic fa. *.), 234, 244-80
Goitnn, 240
Goitrogem, 239. 240

Gonadal aplasia, 525 (ire alto “Tuniet’s
syndrome”)

Gonadal dysgenesis, 503. 324-30
Dwarfism in. 455. 460
Hair growth »n, 528
Klinefelter's syndrome (a i\V 528-30
Ovarian, 18 3
Testicular, 144

Turner’s sxndromc (q.t 525-S
Gonadal dysplasia. 525, 527 (see also
"Turner’s syndrome")

Gonadal hypoplasia, 525 (tee alto "Turner’s
*> ndrome”)

Gonadotrophin therapy
in Cry ptorchidum, 155
in Hypogonadism, 147, 149
Gonads (tee also "Oiary" and "Testis")
Abnormalities, 503
m Acromegaly. 29
Biopsy, 146. 513-14
Decline in function. 147, 185
Dei elopment, 500-2
Dvsccnests, 144, 183. 524-30
in Hypopiluitansm. 32. 34
in Metabolic response to trauma. 419
Peptic ulceration, relation to. 477
Post-puberal atrophy , 530
"Streak". S14. 525

Gonadotrophins (tee also individual hor-
mones)

in Acromegaly . 29

Assay and normal salues, 15, 16

Gonadotrophins (confd.)
in Anomalous sexual states, im estimation
of, 510

in Chiari-Frommel syndrome, 429
in Chonoepithehoma, 194
Chorionic. 16, 129, 130. 172, 173, 175,
180, 196

Chorionic, normal values, 1 76
in Cushing’s syndrome, 88
Deficiency, 42. 145. 161
in Dwarfism, diagnosis of, 464
in Feminizing adrenal tumour, 112
m Foetal dc\ elopment, 503
Hot flushes, possible cause of, 182
in Hypogonadism, 145, 148, 181, 183,
184

in Hypopituitarism, 34, 40
m Klinefelter’* syndrome, 530
in Liter disease, 4S9
in Mate climacteric, 147
in Menstruation, disorders of, 133
in Ovarian cycle, 168, 169
Ovarian function, test of, 175
in Ovarian tumours w ith endocrine

manifestations, 194
Physiology, 12

in Precocious puberty, female, 180
in Precocious puberty, male, 137, 13S,
140

in Stein-Leventhal syndrome, 190-1
Suppression by androgen therapy, 207
Suppression by oestrogen therapy, 212
Suppression by progestogen therapy. 21 5
in Testicular tumours. 159. 160
Testicular function, test nf, 135
in Turner’* syndrome, 528
Granulosa (follicular) cells, 168. 171, 189
Tumour, 179, 191-3

Graves' disease, 244-5 (see also “Toxic
goitre")

Growth, 454-65

Accelerated, 465 (see also "Growth,
accelerated")

Bone metabolism (ft.), 359-60, 454-6
Disorder* of, 4S9-65
Epiphyses far.).

Growth hormone, effects nf. 11-12
Hormonal influences, 133, 224, 433-6
Measurement of, 456-9
Prolonged. 40, 142, 181 (tee alto

"Growth, prolonged")

Retarded, 459-65 (ire alto "Growth,

retarded")

Skeleton fa t .), 454-72
Growth, accelerated, 465
in Adrenogenital syndrome, KM
in Arachnodaetyly, 465
Genetic, 465
in Gigantism, 24
in Hypogonadism. 142. t SI, 465
m Jusmile diabetes, 456
in Obesity , 465

in Precocious puberty, 13S, 178, 465
in Toxic goitre, 261, 465

INDEX

547

Growth hormone (GH, somatotrophin),
11-12

in Acromegaly, 28-9
Assay, 17

in Breast, carcinoma of, 11-12, 434, 440,
442

in Breast, control and development of,
427-8

in Climacteric, female, 186
Disorders, 18
in Hyperpituitarism, 24
in Hypopituitarism, 20, 35, 40
Physiology, 11-12
in Skeletal growth, 11, 455
Growth, prolonged

in Hypogonadism, 142, 181
in Hypopituitarism, 40
Growth, retarded, 459-65 (see also “Dwarf-
tsm '*)

Anabolic steroid, effect of, 212, 465
in Chronic hypopituitarism u ith infanti-
lism, 39

in Cretinism, 282, 461
in Cushing’s syndrome in childhood, 462
in Cyanotic congenital heart disease, 455,
463

Delayed growth and adolescent de-
velopment (7 r.), 41, 462
in Diabetes melfitus, 456, 463
jn FrShlich’s syndrome, 41, 461
in General disease of infancy and child-
. hood, 462-3

in ^Idiopathic hypoparathyroidism, 379,

in Juvenile hypothyroidism, 286, 461
in Laurcnce-Moon-Biedl syndrome, 460
In Pituitary tumours, 20
in Pseudohypoparathyroidism, J38l. 462
in Pulmonary insufficiency, 455, 463
in Turner’* syndrome (gonadal dysgene-
sis), 460, 525-6
in Ullrich’s syndrome, 525-6
in Undemutntion, 462-3
Guanethidine in toxic goitre, 225, 253-4, 263
Gubcmaculum testis, 129, 502
Gy-naecomastia, 430-3
In Adrogen therapy, 209-10
in Feminizing adrenal tumour, 1 12
in Hypogonadism, 142
in Klmefcher’s syndrome, 529
in Leydig cell tumours, 162
In Liver disease, 489
m Oestrogen therapy, 214
in Toxic goitre, 259

Hacmochromatosis

in Addison’s disease, diagnosis from, 116
Diabetes mrllitus, cause of, 397
ilacmopoietin, 13

llatT, body and scalp (tee also “HaiT,
sexual" and "Ilitsutism")
in Acromegaly, 28

Bitemporal recession due to testosterone,

Hair, body and scalp (could.)

Cortisone, effect of, 88
in Cushing’s syndrome, 88
in Hypogonadism, 141
In Hypoparathyroidism, 379
in Hypothyroidism, 282, 288
in Liver disease, 4S9
Localized, in pretibial myxoedema, 255
>n Toxic goitre, 250, 254
Hair, sexual (axillary and pubic) (see also
■’Hirsutism’’)

Adrenal androgens, effect of, 69
Adrenal androgens, effect of in females,
170

Escutcheon, female, 170
Escutcheon, male, 133
in Feminizing testis syndrome, absence
of, 517

in Hypogonadism, 141, 182
in Hypoparathyroidism, 379
in Hypopituitarism, 33, 40
m Hypothyroidism, 288
Ocstrogens, effect of, 170
Testosterone, effect of, 133
Testosterone therapy, effect of, 146, 185
in Turner’s syndrome, 528
Hand-Schuller-Chnstian svndrome, 39
336

Haploid number, 496, 497
Hashimoto’s disease, 287. 290, 292. 295-9
(see also "Aulo-immune thyroiditis")
Heavy metal poisoning, pigmentation m,
116

Height age, 457

Hermaphroditism (mtersex), 514-24
Classification, 514, 518
Cryptorchidism, cause of, 153
Management, 520-4
Oophorectomy in. 520-1
Orchiectomy in, 163, 520-1
Pseudohermaphroditism, female (// 1 >
515-16

Pseudohermaphroditism, male (7 1 ),
517-19

Relative incidence, 519
Selection of sev of rearing, 520
True hermaphroditism. 519
Hernia

in Cretinism. 282
in Cryptorchidism. 153
Hexoestrol (tritium labelled) test, 439
Hilus cells, 166

in Management of carcinoma of breast,
441

Tumour, 193, 194
in Turner’s syndrome, 523, 527
Ilingerty test, 349
Hirsutism, 107
in Acromegaly , 28

in Adrenogenital syndrome, 106-7, til
Adrenogenital syndrome, diagnosis from,
108-9 . , .

in Androgen-producing tumours of the

ovary, 194

INDEX

548

Hirsutism (canid.)
tn Androgen therapy, 209
in Corticotrophin therapy, 207
in Cushing’s syndrome, 88, 97
Idiopathic (constitutional), 107, 109
in I,iur disease, 489
in Stem-Lev entha] syndrome. 190
Histamine
■n Hepatic cirrhosis, effect on gastric
secretion, 477, 478

in Phacochromocytoma (investigation),
347

in Zollmger-Elhson syndrome, 4S0
Hodgkin's disease, 336, 371
Hogbtn test, 173
Homologous pairs, 496
Homovanillic acid (HVA), 343
“Hot” nodule, 241 (r ee aha “Toxic
adenoma")

Houssay phenomenon. 3S, 410
“Hung-up" jerk, 290
HUrthlc cell adenoma, 301, 314
Hutchinson's syndrome, 353
Hydatidifomi mole, 196-7
Hydrocortisone, 51 (»« also “Cortisol")
!1-H)droxyandrostenedione, 51, 65
Metabolism and excretion, 59
5-Hydroxy indole acetic acid (5-HIAA). 483
Excretion, in argentaflinomoiosis, 486-8
Excretion, normal values, 483
17-Hydroxyprogesterone, 52
m Adrenogenital syndrome, 102, 103
Biosynthesis, 55-7
Caproate, 215
Excretion, 59, 60
Metabolism, 59, 60
17-Hydrnxysteroids, total. 59, 60
in Addison’s disease, 74, 116
tn Adrenogenital syndrome, 74
m Aldosteronism, 80
in Carcinoma of breast, 439
in Cushing's syndrome, 74, 90
in Hypopituitarism, 74
in Liver disease. 490
in Metabolic response to trauma, 418
Normal values, 73, 74
Tests of adrenal function, 72, 10*)
5-Hydroxvtrypt amine (5-HT). 482-8
in Argcmafhnuinatnsii, 485-8
Biosynthesis. 483
Effects of. 485-6

Gastric secretion, reduced by, 477
Metabolism, 483-4
Peptic ulcer, caused by, 477
Structure, 483

5-IIydroxvtryptophan (5-1 N’T), 483
m Metastasizing bronchial adenoma,

484

Hypercatcacmu (set also "Catcium.
serum”)

in Calciferol therapy, 375, 382
in Carcinoma of breast w ith osseous
metastases, 437

Diabetes insipidus, diagnosis from, 339

Hypcrcalcacmia (canid.)

Differential diagnosis, 371-2
Gastric secretion, influenced by, 476
in HypcTpara thyroid ism, 369
in Hyperparathyroidism, acute, 36$
in Hvperthyroidtsm, 225
Hypercalduna ( see aha “Calcium,

urinary”)
in Acromegaly, 28
in Calciferol ov erdosage, 382
in Cushing's syndrome, 85, 89
in Hyperparathyroidism, 369-70
in Osteoporosis, 468
Hypergly caemia, 396-8
in Cushing's syndrome, R6
Gastric operations, cause of, 394
Gastric secretion, influenced by, 477
Glucagon causing, 384, 386
in Glucose tolerance test, 387
Hormones raising blood sugar. 3S5
in Ehaeochromocytoma, 346
Ueactive, after pancreatectomy for in-
sulinoma, 393
in Toxic goitre, 257
Hypergonadism, male, 137
Hypennsulinism, organic, 387, 389-93,
478, 479 (tee also "Hypoglv caemia ')
Clinical features, 389-90
Differential diagnosis, 391-3
Investigations, 390-1
Pathological features, 387-9
Treatment, 393
HypcrkataemiJ

in Adrenocortical insufficiency, 66, 105,
115

Hypcmatraemia
in Aldosteronism, 79
in Corticosteroid treatment, 203
tn Cushing's syndrome, 87
Hypcrophthalniopathic Graves' disease.
253-4 (ice also "Ocular signs of toxic
goitre")

Treatment, 278-9
Hyperostosis frontalis interna. 27
Hvperparathyroidism, acute, 368
Hyperparathyroidism, primary, 364-76
Adenoma, 364
Age of onset, 365
Alimentary symptoms, 368
Anaemia in, 368
Asvmptomatic, 369
Biochemical aspects, 369-71
Bone disease in, 365-8
Clinical features, 365-9
Differential diagnosis, 371-2
Eve signs. 369
Menial disorders, 368-9
Multiple endocrine adenopathy in far-).
364, 478-9

Muscular weakness in, 368
Pancreatitis in. 369
Pa rat hv mid crisis. 368
Parathyroidectomy (yr,). 372-6
Peptic ulcers in, 368, 476

INDEX

549

Hyperparathyroidism (contd.)

Physical signs, 369
Renal stones in, 365
Sex incidence, 365
Tetany in the newborn, 369
Treatment, 372-6

Hyperparathyroidism, secondary, 377-8
I lyperphosphatacmia (see aha * ‘Phosphorus,
scrum inorganic”)
in Hypoparathyroidism, 380
Parathyroidectomy causing, 359
in Secondary hyperparathyroidism, 372,

Hyperpituitarism, 24-31
Acromegaly (g.v.), 25-31
Gigantism 24-5
Menstrual disorders in, 188
Hypertension
in Acromegaly, 28
in Adrenogenital syndrome, 105
in Aldosteronism, 79, 80-1
in Argcntaffinomatosis, 485
in Corticosteroid therapy, 441
in Cortirotrophin therapy, 207
in Cushing’s syndrome, 87, 97
in Diabetes mellitus, 406-7
Essential, diagnosis from Cushing’s
syndrome, 91

in Fludrocortisone therapy, 205
Malignant, adrenalectomy for, 120
in Mixed Cushing’s and Adrenogenital
syndrome, 107

in Phaeochromocytoma, 345-7
Portal, in liver disease, 489, 490
Pulmonary, tn Argentaffinomatosis, 485
Systolic in Toxic goitre, 256
in Toxic goitre, 245, 256, 257
in Turner’s syndrome, 527
Hyperthyroidism /thyrotoxicosis), 244-80
(see also “Toxic goitre”)
in Auto-immunc thyroiditis, 297
Juvenile, 260-1
Masked, 258, 260
Radioactive iodine tests, 231
in Subacute thyroiditis, 294
Hypertonic saline infusion test, 337
Hyperventilation
in Argentaffinomatosis, 485
Phaeochromocytoma, diagnosis from.
346

Syndrome, 346
Hypoaldosteronism, 80
Hypocalcaemia (tee also “Calcium, scrum”)
Differential diagnosis, 381
in Hypoparathyroidism, 3S0-1
in Osteomalacia, 469-71
in_Secondary hyperparathyroidism, 372,

Thyroidectomy, cause of, 324
In vitamin O deficiency, 469
Hypoglycaemia, 389-95
in Addison's disease, 115, 119
in Adrenocortical failure m surgery,

Hypoglycaemia (contd )
m Adrenocortical tumour, 78, 392
Differential diagnosis, 392
Drugs causing, 400
Functional, 392

Gastric operations causing, 393-5
Gastric secretion, influenced by, 477
in Glucose tolerance test, 387
in Hypopituitarism, 33, 34, 35, 38
Infantile, 392
Insulin induced, 400-1
I- leucine sensitivity in, 392
Liver diseases causing, 392
in Mesodermal tumours, 392
in Organic hypennsulmism, 389-93
Preoperative starvation causing, 402
in Toxic goitre, 257

Hvpoglycaemic agents, oral, 399, 400 (see
also individual drugs)

Hypogonadotrophimsm, pituitary, 42
Hypogonadism m, 144, 145, 183
Menstrual disorders in, 188

Hypogonadism, female, 181-6
in Adrenogenital syndrome, 104-6, 515-
16

Androgen therapy causing, 209
in Androgen-producing ovarian tumours,
193-4

Climacteric (g.t\), 185-6
Clinical features, 181-2
in Cushing's syndrome, 88
Diagnosis, 184

in Gonadal dysgenesis, 503, 524-S
Growth, excessive, caused by, 465
in Hermaphroditism, 519, 521
in Hypopituitarism, 34, 40. 188
in Liver disease, 490
Postpuberal, 182
Primary, 183
Puberal, 181-2
Secondary, 183—1

in Sexual development, anomalies, 509
Trauma causing, 419
Treatment, 184—5

Hypogonadism, male, 137, 141-50
in Adrenogenital syndrome, 104, 10S
Climacteric, 147
Clinical features, 141-3
in Cushing’s syndrome, 88
Deficiency of Leydig cells alone, 149
Deficiency of tubules alone, 147-8
Diagnosis, 145, 148
in Gonadal dysgenesis, 503, 524-30
Growth, excessive, caused by, 465
in Hermaphroditism, 517, 519, 521
in Hypopituitarism, 34, 40
in Hypothyroidism, 289
in Liver disease, 489
Oestrogen therapy causing, 214
Postpuberal, 143
Primary, 144-5
Prostate in, 449
Puberal, 141-3
Secondary, 145

INDEX

Hypogonadism {contd.)

in Sexual development, anomalies of,
509

Trauma causing, 419
Treatment, 146-7, 148-9
Varieties, 143-9
Hypokalaemia

in Aldosteronism, 66, 79, 80
Causing ECG changes, 80
Causing renal lesions, 78
in Cushing's syndrome, 87, 90
in Diabetic ketosis, 406
■n fulminating peptic ulcer (Zollrnger-
Kllison syndrome), 480
Hvponatraemia
in Addison's disease, 11 S, 116
in Adrenocortical failure in surgery,

422

in Adrenogenital syndrome, 105
in Cushing's syndrome (postoperative!) ),
95

m Hypopituitarism, 35
Hypoparathyroidism, 378-82
jiiochemical aspects, 380-1
Clinical features, 378-9
Differential diagnosis, 381
Electrocardiogram in, 379
Electroencephalogram in, 379
Pseudohypoparathyroidism (q v ), 381
Radiological features, 379
Retarded growth in, 379, 462
Tetany (o o.), 378

after Thyroidectomy, 271, 275, 322, 324,
325, 326, 37Z-80
Treatment, 381-2
Varieties, 379-80

Hypophosphataemia (j tt also "Phosphorus,
serum inorganic")

in Hyperparathyroidism, 361, 369, 371
in Malabsorption syndrome, 381
in Pseudohypoparathyroidism, 381
Hypophysectomy, 43-8
for Acromegaly , 30
Adrenal crisis after, 422, 424
IJ.MK influenced by, 222
for Carcinoma of brtast. female, 442-5,
446

for Carcinoma of breast, male, 447

for Carcinoma of breast in pregnancy , 447

for Cborionepnhehoma, 196

for Carcinoma of prostate. 452

Complications, 45-6

for Cushing's syndrome. 91-2

for Diafvetcs mcllitus, 410

for Exophthalmos, 43, 279

Indications, 43

Metabolic response following, 418-19
for Pituitary tumours, 21
Replacement therapy after, 23, 38, 47
'Phyroid influenced by, 222
Transantral, 47
Transethmosphcnoidal, 46
Transfrontal, 44
Tfamphenoidal, 46

Hypopituitarism, 31-43
Adult, 33

Childhood and adolescence, 38
Course, 36

Differential diagnosis, 35-6
Dwarfism in, 461. 464
Hypogonadism caused by, 144, 183
Hypopituitary crisis, 35
Menstrual disorders in, 1SS
Pathology. 31-2
Target organs, failure of, 34
Thyroid in, 233
Treatment. 36-8, 42-3
Urinary steroids in, 74
Hypospadias

Development of, 509
Pseudohermaphroditism, diagnosis from,
104, 516

in Pseudohermaphroditism, male, 517
Treatment, 524
Hy potension

in Acute adrenal crisis, 95, 118
in Addison’s disease, 115
in Adrenocortical failure in surgery. 422
in Ailien nRcnital syndrome, 105
in Argentaflinontatosis, following sur-
gery, 487

Controlled, in hypophysectomv, 44
tn Diabetic coma, 405
Drugs causing, in phaeochromocytoma,
350

in Hypopituitary crisis, 35
in Phaeochromocv toms, 351
Pituitary necrosis, caused by. 32
in Subacute adrenal insufficiency. 97
Hypothalamus, 9
Anatomy, 9. 333
in Cushing's syndrome, 81-2
in rrOhlich’s syndrome, 41, 461
in I^urcnce-Moon-Hiedl syndrome,
460-1

Physiology, II. 333

Pituitary tumours, pressure effects on.
21

in Puberty, precocious, 138, 178
Thyroid function, control of, 222-3
in Toxic goitre, 246
flipothermu

tn Hypopituitarism, 34
m Hypopituitary crisis, 35
in Hypothyroidism, 289
in Insulin hy pogly cacmia, 400
in Myxoedema coma, 291
in Surgical stress. 418
•o Treatment of thyrotoxic crisis, 280
280-92 (w aha "Myx-

Hypothyroidism
Antithyroid di

Antithyroid drugs causing, 266, 275
tn Auto- immune thyroiditis, 247, 296-8
11MK in, 226
Causative lesions, 286-8
Cholesterol, nUvrru. in, 226
m Childhood (hypolhyroidism. juvenile
qv ), 2S&-7

INDEX

551

Hypothyroidism (coatd.)

Clinical features, 288*90
Congenital (cretinism, gv.), 281-6
Definition hypothyroid goitre, 234
Diagnosis, 290

in Endemic and sporadic goitre, 242
General pathology, 233—4
in Hyperophthalmopathic Graves’ dis-
ease, dangers of, 278
Hypogonadism, due to, 145
Hypophysectomy, following, 48
in Iodide goitre, 244
Lesions and syndromes, 233
Menorrhagia, due to, 189
Myxoedema coma (g.v.), 291-2
PDI in, 226

Physiological disturbances, due to, 223-5
m Pregnancy, dangers of, 277
Radioactive iodine causing, 274-5
Radioactive iodine tests in, 227-31
in Riedel’s thyroiditis, 300
in Subacute thyroiditis, 294
in Thyroid cancer, management of,
314-15

Thyroidectomy causing, 243, 271, 275,
287, 324-6

in Toxic goitre, 247, 263
Treatment, 290-1, 326-7
Hypothyroidism, juvenile, 286-7, 461 (see
alto "Cretinism” and "Hypothyroid-
ism”)

HysterosaJptngography, 175

Imidiazalcs, 240 (see also "Antithyroid
drugs”)

Impotence
in Acromegaly, 29
in Addison's disease, 116
Causes, 150

in Climacteric, male, 147
in Cushing’s syndrome, 88
jn Feminizing adrenal tumour, 112
in Hypogonadism, 143
in Hypopituitarism, 34
Infertility, cause of, 150
m Liver disease, 489

Infantilism, 38, 39, 459 (see also "Dwarf-
ism” and "Sexual development”)
Infections

in Corticosteroid therapy’, 205
in Cushing’s syndrome, 87, 97
Massive, corticosteroid therapy for, 420
Precipitating adrenocortical failure, 117,

Infertility, female (ire also "Hypogonadism,
female”)

in Adrenogenital syndrome, 106
in Stein-Leventhal syndrome. 190
Infertility, male, 137, 149-50 (see also
"Hypogonadism, male”)
in Cryptorchidism, 153
in Klinefelter’s syndrome, 529
Infiltrative opthalmopathy, 253
Inhibin (X-hormonc), 134, 530

Insulin, 384—5

in Acromegaly, treatment of, 30

Cortisol, effect on, 68

in Cushing’s syndrome, treatment of,

86

Gastric secretion, effect on, 477
in Growth, 455, 456
Growth hormone, effect on, 1 2
Hypoglycaemia, 400-1
Hypopituitary crisis, cause of, 35
in Organic hypennsuhmsm, 390
Sensitivity after hypophysectomy, 410
Sensitivity in Addison's disease, 115
Therapeutic preparations, 399-400
Therapy in diabetic ketosis and coma,
405-6

Therapy m diabetes melbtus, 399
Therapy in postoperative management,
403

Therapy in preoperative management,
402-3

in Zolfmger-EHison syndrome, 482
Insulin, protamine 2 inc, 399, 401
Insulin, soluble, 399, 402-3, 405-6
Insulin zinc suspension (lente, semilente
and ultralente), 399, 401
Insulinoma, 387 (see also "Islet cells of
pancreas”)

Intersex, 514—24 (see also "Hermaphrodit-
ism”)

Interstitial cell stimulating hormone
(ICSH) (see also “Luteinizing hor-
mone, LH”)

Assay, 15

m Germinat tumour of testts, 159
Leydig cells, effect on, 1 32
Physiology, 12, 129-30
Testosterone, influence on ICSH, 133
Interstitial cells of ovary, 525 (see also
"Hilus cells")

Interstitial cells of testis, 132 (see also
"Ley dig cells”)

Iodide and iodine (see also "Radioactive
iodine”)

Deficiency, causing cretinism, 281-2
Deficiency, causing goitre, 239-44,
281-2 ‘

Goitrogenic effects, 240, 244
Hypothyroidism, causing, 287
Physiology, 219-23
Protein-bound (g.v.), 223, 226-7
Trapping mechanism {q.v.), 219
Iodide (and iodine) therapy
Prophy laxis of endemic goitre, 243
Prophylaxis of thyroid carcinoma, 311
in Simple goitre, 241, 243, 244
as Test of thyroid function, 232
in Thyrotoxic ensis, 279
in Thyrotoxicosis, 248, 269-70
in Toxic goitre, 248, 269-70
Iodide trapping mechanism, 219, 221, 240
Failure of, 282

Perchlorate test, effect on, 230
Iodine ( m I) conversion ratio, 229

552

INDEX

Islet ccllsof pancreas (islets of Langerhans).
384-96

Anatom), 384

in Diabetes mclhtus (91.), 3S7, 398
Disorders, 3S7

Further reading and references, 4JI
Gastric secretion, influence on, 477
Investigation, 386-7

Multiple endocrine adenopathy (o.r.),
387, 478

Organic hyperinsulinism (q.v.), 389-93
Peptic ulcer, cause of, 478-82
Surgery, 395-6
Tumours, 388-9

Isophane insulin, 399, 401 (tee also “ln-
Jaundice

Alkyl group in steroid nucleus causing,
492-3

in Anabolic steroid therapy, 210
Antithyroid drugs causing, 267
Chlorpromazme, 493
in Liter disease, 491-2
in Meth) ltestosterone therapy, 209
in Progestogen therapy, 216
Jod-Bascdow, 241, 244
Joints (see also "Arthropathy ")
in Acromegaly, 28

Corticosteroid therapy for joint diseases,
202

in Cretinism, untreated, 283
in Liver disease, 490
Painful in hypothyroidism, 2S9

Keloid

after Thyroidectomy, 324
in Turner** syndrome, 528
Keratitis, band, 369
Ketone bodies, 397, 404
Ketosis, diabetic, 397, 398, 399, 401, 402,
403, 404-6

Influence on surgery , 406
Management, 404-6
Principles of treatment, 404
Symptoms, 404

17-ketosteroids, 58 (see alto “17-oxo-
stcroids")

Klinefelter’s syndrome, 144, 147, 148, 52S-
30

Hypopituitarism, diagnosis from, 36
Kultschitsky cell, 482

lactation, 428-30
Abnormal, 429
in Acromegaly, 29, 429
Chtari-Frommel syndrome, 23, 429
in Chromophobe adenoma of pituitary,
23, 429

Drugs causing, 430
Failure of, 33, 430
m Feminizing adrenal tumour, 1 12
Growth hormone, influence on, 428
Lactose in urine, 356

Lactation (confd )

in Oestrogen-secreting tumours of os ary,
193, 429

Oxytocin, influence on, 335, 428
Persistent, 429

in Post-paitum pituitarv necrosis, 33,
430

Prolactin, influence on, 428
Spontaneous, 429
Suppression of, 428-9
Lactose

in Diabetic ketosis, management of, 406
in Posiopcratn c management of diabetes.
403

Lamina dura (ire "Teeth”)

I^ingdon-Dow n's avndrome (mongolism).
455, 498

Cretinism, diagnosis from, 284
Laryngoscopy in thyroid disease, 23S, 310,
32 3

Laurence-Moon-Ihedl syndrome, 145,
183, 460-1
Leontiasis ouea, 30
Leukaemia

Corticosteroid therapy for, 202
Diabetes insipidus caused by, 336
Hypopituitarism caused by, 31
Radi03ciiee iodine causing. 273, 315
Leukodcrmia (vitiligo)
in Addison's disease, 115
in Toxic goitre. 254
Leydig (interstitial) cells, 129, 132, 133
in Cryptorchidism, 153
Deficiency, 40, 137, 141, 144-7, 149
in Feminizing testis syndrome, 517
Foetal testis, function m, 507, 508-9
Gonadotrophin (ICS 1 1) effect on, 12
Hyperplasia, in germinal tumours, 160
in Klinefelter's syndrome, 529-30
Leydig cell tumour (lulus cell) of ovary,
194

in Male pseudohermaphroditism, 517
in Precocious puberty, 138, 139
in Teratoma of testis, 160
Tumours, 161-2

in Acromegaly. 29
in Addison's disease, 116
Androgen therapy, effect on, 209
«n Climacteric, male, 147
lit Feminizing adrenal tumour, 112
in Gigantism, 25

in Hypogonadism, 143, 181, 182. 185
tn Hypopituitarism. 34, 37
in Hvpothyroidism, 289
in Klinefelter’s syndrome, 530
in Leydig cell tumour, 162
in Liver disease. 4S9
in Metabolic response to trauma, 419
in Pituitary tumours, 20
Lid bg and Ik! retraction, 251-2 free also
"Ocular signs of toxic goitre")
LiebcrkUhn, cry P 1 * of, 482
IJpoid cell tumour, 193

Liver disease, 488-93
Adrenocortical function in, 489-90
Antidiuretic hormone in, 490
Antithyroid drugs causing, 267
in Argentaffinomatosis, 484, 486
Auto-immune thyroiditis, associated
with, 297

Catechol amines in, 490
Corticosteroid treatment for, 203, 491
in Cushing’s syndrome, 83
Endocrine features in, 488-9
Further reading, 494
Hepatotoxie effects of steroid hormones,
492-3

Hypogl j caemia in, 392
Oestrogen excess in, 489
Peptic ulcer in, 478
Pituitary inhibition in, 489
Pruritis, treatment of, 491—2
Retarded growth in, 462
Testosterone therapy for cirrhosis, 492
Treatment of hormonal effects, 491
in Toxic goitre, 248, 258
Virilizing features In lupoid hepatitis,
490-1

/-Leucine test, in organic hypennsulimsm.
Looser zones, 470-1

/-Thyroxine sodium, 326-7 (see also
“Thyroid hormone therapy")

Lugol’s iodine (see “Iodide (and iodine)
therapy")

Lupus erythematosus, systemic, 202, 297,
490

Luteinizing hormone (LH) (zee also
“Interstitial cell stimulating hormone,
1CSH”)

Assay, 15

Oest radio], influence on LH, 171
in Ovarian cycle, 168-9
Physiology, 12

Progesterone, influence on LH, 172
Lutcotrophic hormone (ire “Prolactin'')
Lymphatic system

Antithyroid drugs, toxic action on,
267

Cortisol, effect on, 69, 202
Hodgkin's disease, 336, 371
Lymphosarcoma, 336
in Toxic goitre, 248
in Turner’s syndrome, 527

Macrogenitosomia praecox, 103-4 (see also
“Adrenogenital syndrome”)

“Main d'accoucheur”, 378 (see also
“Tetany”)

Malabsorption syndrome
Anabolic steroids in, 21 1
in Differential diagnosis of hypocal-
caemia, 381

Osteomalacia, cause of, 469
in Secondary hyperparathyroidism, 377
Male frog or toad test, 173
Male organizing substance, 502, 507S

ex 553

Malignant carcinoid syndrome, 485-8
(ree also “Argentaffinomatosis”)
Malignant lymphoma, 306
Malignant exophthalmos, 253 (see also
"Ocular signs of toxic goitre”)
Mammotrophin (ree “Prolactin”)
Maturation arrest, 147, 148
Medical curettage (Zondek’s), 174
Meiosis, 496, 497

Melanocyte stimulating hormone (MSH,
intermedin)

m Addison’s disease, 115
Assay, 17

m Cushing’s syndrome, 89, 100
Physiology, 13
Menarche, 174

Menorrhagia, 187 (see also “Menstruation”)
Mendelsohn’s syndrome (aspiration pneu-
monitis), 420
Menopause, 185
in I-ibroadenosis, 434
Gonadotrophins in, 12-13
in Hypothyroidism, 289
in Selection of treatment for carcinoma
of breast, 438

m “Sujwfemale" (XXX syndrome), 530
in Toxic goitre, 245
Mesonephnc duct (wolffian), S01-5
Mesonephros and mesonephnc tubules,
500. 501. 503

Methiniazole (see also ‘ ‘Antithyroid drugs’’)
Dosage, 265

Toxic reactions, incidence of, 265
Menstruation, 172, 174, 185
in Addison’s disease, 116
in Acromegaly, 29
in Adrenogenital syndrome, 106
in Anorexia nervosa, 36
in Castration, 182

in Carcinoma of breast, influence on
therapy, 440-1
in Cushing's syndrome, 88
Disorders of, 186-91
in “Feminizing testis” syndrome, 517
m Gigantism, 25
in Hermaphroditism (true), 519
in Hypopituitarism, 34
in Hypothyroidism, 289
in Liver disease, 489
in Oestrogen therapy. 214
in Ovarian tumours, 192-4
in Pituitary tumours, 20
in Precocious puberty, 178
in Stem-Les enthal syndrome, 190
in ” Superfemale” (XXX syndrome), 530
in Surgical stress. 419
in Toxic goitre, 250, 259
in Turner’s syndrome, lack of, 528
Mental deficiency
in Cretinism, 282, 286
in Klinefelter’s syndrome, 530
in Laurence- A toon-Bied} syndrome, 460
in “Superfemale” (XXX syndrome), 530
in Turner’s syndrome, 528

554

INDFX

Mental disturbance (ree oho "Mental
deficiency ")

m ActwMjjly, 2*5
in Acute adrenal crisis, ] 18
m Acute hyperparathyroidism, 36S
m Addison's disease, 115
in Cushing's syndrome, 87-8
in Hyperparathyroidism, 368-9
in Hypoparathy roidism, 378
in Hypopituitarism, 34, 35
in Hypothyroidism, 290
in Organic hypennsulmism, 390
m Surgical removal of parathyroids, 3S0
m Thyrotoxic crisis, 259-60
Metabolic bone disease, 466-7]

Further reading, 472
Osteitis fibrosa (9 v ), 466
Osteomalacia (f.r.), 468-71
Osteoporosis ( q l.), 466-8
Metabolic syndrome (in phaeoehromo-
cytoma), 346
Mctaadrenahne, 343

Metaraminol, 356 (see alto “Noradrenaline
therapy”)

in Adrenal crisis, 119
in Adrenalectomy for Cushing’s syn-
drome, 95

in Adrenocortical failure in surgery, 425
in Diabetic ketosis end coma, 405
in Phaeochromocytoma, 350-1
Metformin (Dime thy Ibigusnide), 400
Methandienone, 21 1
in Catabolic phase following surgery.
420-1

Methotrexate, 196 (m alio “Folic scid
antagonists”)

3-Methoxytryptamine, 343
Methyl prednisolone, 204
Methyl ihiouracil (ire alto "Antithyroid
drugs”)

Dosage, 265

Toxic reactions, incidence of, 265
Methylamphetamine, 355, 336
Mcthylandrostmedio], 211
Methyldopa (Aldomct), 349
Methylstanaxole, 21 1
Mcthy It Mto»t crone, 20S-9
in Catabolic phase following surgery.
421

Hepatotoxic effects, 492-3
Therapy, 207-10 (r te aho “Androgen
therapy”)

Metrostaxis, 1S7

Mctyrspone testwC pauitirs (unctvvw, 57
Milk-alkiU syndrome, 371-!, 476
Milkman fractures. 470-1
Minerslocorticoids. 51
Excretion, 59, 60
Mitosis, 496

Mongolism («rr “lamgdon-Dovm's syn-
drome”)

Monoiodoryrosine, 219-21

Morquio’s disease (“osreochondrodvt-

ttophy”), 2S4, 459. 463

Mullerian (paramesoncphric) duct, 502,
503-5

Multiple endocrine adenopathy
Islet cell lesions in, 3S7, 478
Parathyroid lesions m, 364
Peptic ulcer in, 476, 478
Pituitary tumours in. 19
Mumps

Oophoritis, 183
Orchitis, 144-5
Thyroiditis, 293
Muscular system
in Acromegaly, 28
in Addison’s disease, 115-16
in Adrenogenital syndrome, 104, 106
m Aldosteronism, 79
in Corticosteroid therapy, 207
in Cushing’s syndrome, 85
in Hyperparathyroidism, 368
in Hypogonadism, 142, 143
in Hypoparathyroidism, 378
in Hypothyroidism, 282, 2S9
in Leydig cell tumours, 162
m Metabolic response to trauma, 416
Testosterone, effect of, 133
Thvroid hormones, effect of, 224
in Toxic goitre, 248, 257, 238
Mutations

Radioactive iodine causing, 273
Myasthenia gravis
in Toxic goitre, 258
Myeloma, multiple, 371
Myopathy

in Corticosteroid therapy, 207
Hypogonadism, associated with, 144
in Toxic goitre, 258, 260
Myxoedema. 225, 280. 287-92. 2% (ree
also "Hypothyroidism'')

Acromegaly, diagnosis from, 30
Coma, 284, 291-2
in Cretinism, 2S2
Definition, 280

Hypopituitarism, diagnosis from. 36
Madness, 290
Menstrual disorders, 189
Pathological features. 288
Pretihial, localised, 255-6. 289

Ntevi, spider (angiomata), 254, 489

Naffiiger procedure, 279

Nails

in Hypoparathyroidism, 379
in Hypothyroidism, 2S9
in Tuxic stmwc (cc.yeW.yvvs, Plummet
nails), 254

in Turner’s syndrome, 527
Nandrolonc decs nos tr. 21 1
Nandrolone pKenylpropnonate, 211
Nephritis, potasnum losing, 79
Nephrogenic duties tv imipidus, 339 (we
aha “Diabetes imipidus”)
Nephropathy

Diabetic. 407, 410
Hypokslarmic, 78, 79

INDEX

555

Nerves, recurrent laryngeal
Anatomy, 218

in Carcinoma of thyroid, 242, 310
Goitre, compression by, 235
Radioactive iodine not injurious, 273,
314

in Thyroidectomy, 271, 275, 276, 313,
319, 321, 323, 325, 326
Nervous system
in Acromegaly, 28
in Addison’s disease, 115
in Diabetes insipidus, 336
in Diabetes meltitus, 407-8
Diseases and gynaecomastia, 431
Diseases and hypogonadism, 144
in Hyperinsulimsm, 390
in Hypoparathyroidism, 378
in Hypothyroidism, 282, 286, 288-90
in Thyroid hoimone therapy, over-
dosage, 285-6, 291
Thyroid hormones, effect of, 224
in Toxic goitre, 245-6, 250, 258-9
Neurohypophyseal hormones, 333-4 (tee
also individual hormones)
Neurohypophysis, 9, 333-41
Diabetes insipidus (90.), 336-41
Further reading, 341
Investigations, 337-9
in Metabolic response to trauma, 416,
418

Tumours, 341
Neuropathy

in Diabetes mellitus, 407-8, 409
Nicotine test, 338-9
Nitrogen mustard therapy
for Neuroblastoma, 354
Nitropru aside test, 398
Non-diyunction, 498-500
Non- virilizing androgens, 209-12 (see also
“Anabohc steroids”)

Noradrenaline, 342-4 (ree also ‘‘Catechol
amines”)

Biosynthesis, 343
Normal values, 343
in Phaeochromocytoma, 345, 349
Phentolamine, effect on noradrenaline,
348

Physiology, 342
in Portal hypertension, 490
Therapy (q.v.), 354-6
Noradrenaline therapy, 354-6
in Adrenal crisis, 119
in Adrenalectomy for Cushing’s syn-
drome, 95

in Adrenocortical failure in surgery,

42S ^

Contraindications, 354
in Diabetic ketosis and coma, 405
Gangrene, superficial, occurring in, 356
Indications for, 355-6
Method, 356

in Phaeochromocytoma, 351
Nomhandrolone, 211
Nomhisterone acetate, 215

Norethynodrel, 215
Normetaadrenaline, 343
Nuclear (sex) chromatin, 510-11 (see also
"Chromatin, nuclear”)

Obesity

in Acromegaly, absence of, 28
Cortisol, effect of, 68
in Cryptorchidism, 1 52
in Cushing’s syndrome, 85, 97
rn Feminizing adrenal tumours, 112
lit Frohhch's syndrome, 41
Growth, influenced by, 465
m Hypogonadism, 142, 182
in Hypopituitarism, 34
Influence on adrenalectomy, 120
in 'Laurence-Moon-Biedl syndrome,
460-1

of Puberty, constitutional (or familial),
41, 143, 145, 183
Simple, 91

in Stem-Lcvcnthal syndrome, 190
Ocular signs of toxic goitre, 245, 251-4
Antithyroid drugs, effect of, 268
in Pregnancy, 260
Prctibial myxoedema with, 255
Radioactive iodine, effect of, 274
Thyroidectomy, effect of, 271-2
Treatment of, 278-9

Ocsttadsol, 169-71 (tee also “ Oestrogens "
and "Oestrogen therapy”)
Biosynthesis, 56
Excretion, normal values, 176
Menstrual cycle, 172
Metabolism and excretion, 58, 171
Monobenzoate, 213
Pregnancy, 172, 173
Structure, 53
Valerianate, 213
Oestriol, 58, 171
Excretion, normal values, 176
Oestrogen excretion, 58, 75
in Abnormal betation, 430
Effect of endocrine ablation, 445
Normal values, 176
m Precocious puberty, ISO
Test of ovanan function, 176
Oestrogen therapy, 212-14
in Acromegaly, 30
in Atrophy of breasts, 433
in Carcinoma of breast, female, 440-1,
446-7

in Carcinoma of breast, mate, 447
in Carcinoma of prostate, 450-2
in Chorionepithelioma, 196
in Climacteric, 186
Dosage, 213
in Duodenal ulcer, 477
in Endometriosis, 199
Further reading, 217
in Gigantism, 25_
in Hermaphroditism, 521
in Hyperophthalmopathic Graves’ dis-
ease, 278

INDEX

Oestrogen therapy (ha id.)
in Hypogonadism, 184
in Hypopituitarism, 37
for Lactation, suppression of, 428-9
m Mastitis, acute, 429
in Osteoporosis, 468
in Precocious puberty, 140-1
as Pregnancy test, 174
Preparations, 212-14
Progestogen therapy, combined with,
199, 215-16
Toxic effects, 214
m_ Turner's syndrome, 528
Withdrawal bleeding caused by, 172
O estrogens, 52 {tee alto individual hor-
mones)

Adrenal, 69
Biosynthesis, 54
Deficiency, 181-6
Excess, causes, 61
Excretion, 58 , 176
Excretion in hypogonadism, 184
Excretion in ovarian tumours, 194
in Liver disease, 489
Pathological effects on endometrium,
187-8

Testicular, 133

Tumours secreting, 112, 162-3, 191-3
Oestrone, 52, 65, 171
liiosynthesis, 56
Excretion, 58

Excretion, normal values, 176
On> cholyiis (Plummer nnilO. 254
OOcyte, 496, 497
Oogenesis, 496, 497
Oophorectomy

for Carcinoma of breast, 434, 441-2,
445-7

for Endometriosis, 199
in Female pseudohermaphroditism, 524
for Hermaphroditism, management of,
520

Hypogonadism, cause of, 183
for Ovarian cy*l»> 200
for Ovarian tumours, 180, 195, 200
bcxual activity, effect on, 182
Simultaneously with adrenalectomy, 121
Oephomis, 183
O.p'DDD, 92

Orbit, decomposition of, 279
Orchiopexy, 155-7

in Hermaphroditism, 524
Orchitis, 144-5

Ophthalmoplegia, 252-3 (ire alto “Ocular
sign* of toxic goitre")

Orchiectomy, 163-4

for Carcinoma of male breast. 447
for Carcinoma of prostate, 4SO-2
in Hermaphroditism, management of,
520-1

Hypogonadism, cause of, 144
for Testicular tumours, 160, 162
Osmoreceptors, 68 , 334
Ossification centres, 458

Osteitis fibrosa cystica, 364, 365, 466
Osteoarthropathy

Idiopathic (pachydermoperiostosis). 30
Pulmonary hypertrophic, 256
Osteochondritis deformans (Perthc's
disease), 287

Osteochondrodj strophy (Morquio 'a dis-
ease), 284, 459, 463
Osteoclastoma, 365, 366, 367, 375
Osteodystrophy, azotarmic renal, 377
Osteogenesis imperfecta, 463
Osteogenic sarcoma, 353
Osteoid (bone) matrix, 377, 466, 467 (ree
also "Osteomalacia”)
in Cushing's syndrome, 85
Defective calcification of, 469
Osteomalacia, 46S-71
Biochemical features, 471
in Secondary hyperparathyroidism, 377
Treatment, 471
Osteomyelitis, 403, 409
Osteoporosis, 466-8
in Acromegaly, 28

Anabolic steroids, treatment with, 212,
468

in Corticosteroid therapy, 205
in Cushing's syndrome, 85, 89
in Hyperparathyroidism, primary, 365
in Hyperparathyroidism, secondary, 377
in Hypogonadism, 143, 182
Sella turcica, affected by, 15, 90
in Toxic goitre, 259
in Turner's syndrome, 527
Ovary, 166-201
Anatomy, 166-7
Cystic, 189, 199

Disorders of menstruation, 186-91
{tee also “Menstruation”)

Further reading, 200-1
Hormones, 167-72
Hypogonadism (ft.), 181— A
Investigation, 174 — 7
at Laparotomy, 199, 200
Menstrual cycle (q r.), 172
Ovarian cycle, 167-9
Polycystic. 189-91
Pregnancy, 172-4
Ihiberty (g v.), 174
Puberty, precocious, 177-80
Radiation damage to, 183
Structure and function, 166-77
Tumours. 200

'I\imour». androgen-producing, 193-4
Tumours, oestrogen-producing, 177,
178, 191-3
Ovulation. 167
Haemorrhage, 187
Ovum, 166-9, 497-9

17-oxo genic (17-Vetogmic) steroids, 59,
60

in Addison’s disease, IJ6
in Aldosteronism. 80
in Cushing’s syndrome, 90
in Metabolic response to traurnt, 4!8

INDEX 557

1 7 -oxogeni c { 1 7-k etogeni c) s t e ro ids (contd.) Paraminosalicyclic acid causing goitre, 240
Normal values, 73 Parathormone (PTH), 359-60

Tests of adrenal [unction. 72, 109 Gastric secretion, effect on. 476

17-oxosteroids (17-ketosteroids), 58, 59, 60
in Addison's disease, 74, 116
in Adrenogenital syndrome, 74, 110
Age, effect on excretion, 65
in Aldosteronism, 80
in Anomalies of sexual development, in-
vestigation of, 510
Castration, effect on, 451
in Cushing's syndrome, 74, 90
in Female pseudohermaphroditism, 109
Formation from testosterone and its
esters, 208

in Hypogonadism, 145, 146, 148, 184
in Hypopituitarism, 40, 74
in Klinefelter’s syndrome, 530
in Liver disease, 489
in Lcydig cell tumours, 162
in Metabolic response to trauma, 418
Normal values, 73, 74
in Ovarian tumours, 194
in Precocious puberty, 140
in Stein-Lev enthal syndrome, 190-1
Test of adrenal function, 72, 109
Test of ovarian function, 177
Test of testicular function, 135
in Testicular teratomas, 160
in Turner’s syndrome, 528
Oxymesterone, 211
Oxymetholone, 211
Oxyphil cells, 359
in Parathyroid adenoma, 363
Oxytocin, 325, 428

Pachydermoperiostosis (idiopathic osteo-
arthropathy), 30
Paget’s disease, of bone
Acromegaly, diagnosis from, 30
in Auto-immune thyroiditis, 297
BMR in, 226

Hyperpara thyroid /sm diagnosis from, 372
Toxic goitre, diagnosis from, 261
Pancreas

in Acromegaly, 28

Carcinoma of, in Cushing's syndrome,
83

Islet ceffs (g.v.), 384-96
Pancreatitis, in hyperparathyroidism, 369
Surgery’ of, 395 h 5
Pancreann (UP), 396
Pancreatitis

Corticosteroids for, 203
Diabetes, cause of, 397
in Hyperparathyroidism, 369
Paraganglia, 342
Tumours (paraganglioma), 344
Paralysis, periodic
Aldosterone, relation to, 79
in Toxic goitre, 258

Paramesoncphric (mullcri 3 n) duct, 502.
503-5

Paramethasone, 204

in Osteomalacia, 469
Physiology, 359-60
in Pseudohypoparathyroidism, 381
Parathyroid glands. 358-83
in Acromegaly, 29
Anatomy, 218, 358
Crisis, 368

Further reading, 382-3
Growth hormone, effect on, 28, 29
Histology, 358-9

Hypoparathyroidism (?.».), 324, 378-82
Investigation of parathyroid disorders,
361-2

Lesions and syndromes, 362-3
m Parathyroidectomy, 372-5
Pathology, 363-4
Physiology, 359-60

Primary hyperparathyroidism ( 9 . 0 .),
364-76

Secondary hyperparathyroidism (q. t,.),
377-8

in Thyroidectomy, 313, 319, 321, 324
Parathyroid hormone. 359-60 (r«e also
"Parathormone PTH”)
Parathyroidectomy, 372-6
in Azotuemic renal osteodystrophy, 377
Complications, 375

in Multiple endocrine adenopathy, 476
Results, 375

Surgicat technique, 372-5
Tetany, 375
Paroophoron, 503
Pendred’s syndrome, 281
Penis (tee also "Sexual organs”)
Development, 502, 507-9
Erection, mechanism of, 134
in Hypogonadism, 141, 143
Plastic operations on. 524
in Selection of sex of rearing, 520
Testosterone, effect on, 133
Pepper’s syndrome, 353
Peptic ulcer, 473-82
in Addison’s disease, 115, 475
Adrenal cortex, influence on, 474-5
in Cushing’s syndrome, 87
in Diabetes meffitus, 477
Futminating peptic ulcer, 479-82
Gastric secretion and hormones, relation
to, 474

Gonads, influence on, 477
Histamine, influence on, 477-8
5-H>droxytryptamme, influence on, 477
in Hyperparathyroidism, 368, 476
and Islet cell lesions, 477, 478-S2
in Liver disease, 478
in Multiple endocrine adenopathy. 476
Pituitary, anterior, influence on, 476
Porta -cava! anastomosis, relation to, 478
Pregnancy, influence on, 477
Steroid ulcers, 475
Stilboestrol, influence on, 477

INDEX

558

Peptic ulcer (eontJ )
in Toxic goitre, 258, 477
Zollinger-O 1 1 son syndrome, 479-82
Perchlorate, potassium, 264-8 ( see also
“Antithyroid drugs")

Dosage, 265
Goitrogenic action, 240
Site of action, 221

Test of impaired hormone synthesis,
230-1. 244, 298

Toxic reactions, incidence of, 265
Peritubular fibrosis, progressive, 147, 14S
Peroxidase. 219, 221, 282
Perthe’s disease (osteochondritis defor-
mans)

Jut ende hi pothy roidism, diagnosis from,
287

Pcutr-Jegher’s sy ndrome, 117
Peyronie's disease, 203
Fhacochromocytoma (chromaffin tumour),

344-52

B.MR in, 226, 346
Clinical features, 345-7
Collapse at operation, caused by, 347
Cortisol secretion in, 345
Cortisone, in postopcrntiv e management,
351

Differential diagnosis, 346
further reading, 357
Ganglion blocking drugs, effect in, 346
Imestigntion of, 347-50
Noradrenaline in surgical management,
351, 35S

Organic hypennsulinism, diagnosis from,
390

Pathology, 344-5

Phentolamine in diagnosis and manage-
ment, 348, 350
«n Pregnancy, 347
Toxic goitre, diagnosis from, 261
Treatment, 350-2

in Von Recklinghausen’s disease, 345,
347

X-ray investigation, 70-1
Phenformin (Phenelhylhiguanide). 400
Phenotype (somatic sex), 500-9
Phentolamine

in Phaeochromocy toma, diagnosis, 348
in Phaeochromocy toma, management.
350-1

for Toxic goitre, 254
Phenylbutazone causing goitre, 240
Phosphatase, serum acid, 450
Phosphatase, scrum alkaline, 361
in Carcinoma of breast, 437
in Carcinoma of prostate, 4S0
in Cushing’s svndrome, 90
in Hyperparathyroidism, 369. 372
m Milk alkali syndrome. 371
in Osteomalacia, 471
in Osteoporosis, 468

Phosphorus, radioactive in diagnosis of
thyroid cancer, 309
Phospliorut, serum inorganic, 359-61

Phosphorus (con Id.)
in Acromegaly, 29
in Cushing's syndrome, 90
in Differential diagnosis of hyperpara-
thyroidism, 371

in ^Hyperparathyroidism, primary, 369,

in Hv perparathy roidism, secondary, 372,
377, 378

in Hypoparathyroidism, 380, 382
in Malabsorption syndrome, 381
in Osteomalacia, 471
in Osteoporosis, 468
in Pseudohypoparathyroidism, 3.81
■n Renal failure, 3.81
Thyroid hormones, effect of, 225
Phosphorus, unniry, 359-60
Excretion, 362

in Hyperparathyroidism, 369, 370-1
in Renal tubular lesions, 469
Phosphorylation, oxidative, 3S5
Pigmentation, 14

in Addison’s disease, 1/4-15, 422, 423
in Albright's syndrome, 178
Buccal. 115. 117

in Cushing's syndrome. 89. 91. 100, 116
Differential diagnosis of, 1 16—17
in Hypopituitarism, loss of, 33
in Pregnancy, 1 1 6
in Toxic goitre, 1 16, 254
in Turner’s syndrome, S27
Pituitary, anterior, 9-50
in Aeromeguly, 25-31
in Addison's disease, 114
Anatomy, 9

in Cushing's syndrome, 82
Disorders, 18
Functions, 10-13
Further reading, 48-50
Gigantism (q t\), 24-5
Histology, 9, 10

Hormones, 11-13 (m oho individual
hormones)

Hyperpituitarism (growth hormone),
24-31

in Hypothyroidism, 2S8
Insufhricncy. 31—43 (i re aho “Hypo-
pituitarism”)

Investigation, 14-17
Irradiation, external, for Acromegaly, 30
for Cushing's svndrome. 91-2
for Hypemphthalmopathic Graves'
disease, 279

for Pituitary tumours. 21
Irradiation, intrasellar, 45, 46
for Cushing's syndrome, 91-2
for Pituitary tumours, 22, 4$
Oestradiol, effect on pituitary' function.

171

Operations, 43-8 (ice alto
phjsectomv")

HiysKilogy, 10-13
Stalk, section of. 47. 279
in Toxic goitre, 248

"Hypo-

INDEX

559

tuitary, intermediate lobe, 13-14
tuitary, posterior, 333-41 (see also
“Neurohypophysis”)
tuitary stalk, section of, 47, 279
ummer's disease, 245
ummer nails (onycholysis), 254
Mumoperitoneum, 175
alar body, 497
alyarteritJs nodosa
Antithyroid drugs causing, 267
Corticosteroid treatment of, 202
olycythaemia
BAIR m, 226

in Cushing’s syndrome, 87
in Phaeochromocytoma, 346
'olyuria

in Aldosteronism, 79
in Computsive water drinking, 33 9
in Cushing’s syndrome. 89
in Diabetes insipidus, 336
in Diabetes melhtus, 398
m Hyperparathyroidism, primary, 365
Hypophysectomy, cause of, 48
in Nephrocalcinosis, 339
in Nephrogenic diabetes insipidus, 339
Potassium iodide (see “Iodide (and iodine)
therapy”)

Potassium therapy
in Aldosteronism, SO
in Cushing’s syndrome, 92
in Diabetic ketosis, 406
Precipitin test (for thyroid auto-antibodies),
298

Prednisolone, 204
Prednisone, 204
Pregnancy, 172-4
in Addison's disease, 116
in Adrenogenital syndrome, after treat-
ment, 111

Adenocarcinoma of uterus, relation to,
195

Androgen therapy in, 209
BE! in, 260
BMR in, 226
Breast, influenced by, 428
in Carcinoma of breast, 447
in Constitutional precocious puberty,
178, 180

Corticosteroid therapy in, 207
in Cushfng’s syndrome, after treatment.

Diagnosis of, endocrine, 173-+
in Endometriosis, 197
Gastric secretion in, 477
Gonadotrophin excretion in, 176
in Hypothy roidism, 2S9
Iodine requirements in, 223, 239
Maternal factors in cretinism, 281
Oestrogen excretion in, 176
PBlin. 260

Phaeochromocytoma in, 347
Pigmentation in, 116
in Post-partum pituitary necrosis, 36
Pregnanediol excretion in, 176

Pregnancy ( contd .)

Progestogen therapy for, 21 5
in Pseudo puberty, 177
Radioiodme tests in. 227
Simple goitre in, 239 , 24
in Thyrotoxicosis, 245, 260, 276, 277
Pregnanrdiol, 56, 58
Pregnanediol excretion
m Hypogonadism, 184
Normal values, 176
in Precocious puberty, 180
in Stem-Leventhal syndrome, 190-1
Test of ova nan function, 1 76
Pregnanetnol, excretion, 59, 60
in Adrenogenital syndrome, 102, 103,
109

Normal values, 75

Pressor-inhibiting (phentolamine) test in
phaeochromocytoma, 34S
Progesterone, 52, 65, J71-2 (see also
“Progestogens")
in Adrenogenital syndrome, 103
Biosynthesis, 54, 55, 56, 57
Breast, effect on, 428
in Menstrual cycle, 172
Metabolism and excretion, 56, 58, 172
in Pregnancy, 172, 173
Structure, 54

Therapy, 214-16 (see also "Progestogen
therapy”)

Progestogen therapy, 214-16

for Abortion, threatened or habitual,
215

Break-through bleeding, 216
for Contraception, 21 5
for Dysmenorrhoea, 215
Dosage, 215

for Endometrial carcinoma, 196
for Endometriosis, 199, 215
Further reading, 217
for Hypogonadism, 184-5
Preparations, 215
for Pregnancy diagnosis, 174
Toxic effects, 216

Virilization of foetus, from, 108, 216
S16

Progestogens, 52
Adrenal, 69
Excretion, 58

Pathological effects on endometrium,
187-8

Progoitrin, 240

Prolactin (mammotrophin, luteotrophic
hormone, LTH)

Breast and lactation, effect on. 427, 428
in Carcinoma of hreast, 434, 439
in Chian-Frommel syndrome, 429
Lactation, secretion during, 188
Oestradioi, influence on LTH, 171
in Ovarian cycle, 168-9
Physwtogy, J3, 163-9, 428
Progesterone, effect on, 171
Progesterone, influence on LTH, 172
Prolactin test in carcinoma of breast, 439

560

INDEX

Prop)! thiouracd {see also "Antithyroid
drugs”)

Dosage, 265

Toxic reactions, incidence of, 265
Prostate gland

development, 133, !34,
449

in Hypogonadism, 141. 143
Prostatic utricle, 503, 504
Protcm-bound iodine (PHI), 223
in Adult hypothyroidism, 290
in Cretinism, 2S4-5
in Iodide goitre, 244
m Myxoedema, 290
Normal values, 226
in Pregnancy , 260
Radioactive, 229. 231, 29S
Itv Subacute thyroiditis, 294
as Test of thyroid function, 226-7, 230
m Thyrotoxicosis. 262
in Toxic goitre, 225, 262, 274
Protein metabolism
in Acromegaly, 28
in Addison’s disease, 116
Anabolic steroids, effect of, 210. 420-1
Corticosteroid therapy, effect of, 205
Cortisol, effect of, 68
in Cushing’s syndrome, 85
Growth hormone, effect of, 1 2
m Malignant Leydig cell tumour of
testis, 162

in Metabolic response to rrauma, 416-18
Testosterone, effect of. 133, 420
Thyroid hormones, el red of, 224
in Toxic goitre, 257
Proteolytic enzyme, 220-1
Provocative test for phaeoehromoevtoma,
347-8
Pruritus

Ano- genital, corticosteroid treatment lor,
203

in Hypothy raid ism, 2S9
in Liver disease, 491-2
in Toxic goitre. 250

Pseudohermaphroditism, female, 61, 103-5.
513-16 (see aho "Adrenogenital aynd-

Cryptorthidum, diagnosis from, 153
Diagnosis. 10S-9
Disgenninoma in, 104. 194
Maternal factors causing 108
Progestogen therapv causing, 216
Treatment. 110-11. 520-4
Pseudohermaphroditism, male, SI 4, 517-
19

Cryptorchidism, cause of, 153
Orchiectomy in, 163
Pscudohypopamthy roiditm, 38 1
Pseudo- pseudoh y po pa rath vtmd i sm (bra-
thymrtacarpabim), 527
Pseudopubertv

1'tmale, 104, 177, 209
Male, 10», 108, 137. IJ9. 162

Puberty (see also ‘‘Pseudopuberty”)
Androgen, causing growth spun at. 455
Breasts at, 423

Delated, constitutional, 41, 145, 183,
462

FcroMe, 174
Male, 134

Precocious, female, 1 77-80
Precocious, male, 137-41
Toxic goitre, relation to, 245
Pulmonary valve, in Antcmaffinomatosis,
435

Pyelonephritis
in Aldosteronism, 78
in Diabetes mellitus, 406

dc Qucrvain’* thyroiditis, 292-5

Radioactive iodine ( ,M I «nd IM l) tests of
thvroid function, 227-31
in Adult hvpothyroidism, 290
in Auto-immune thyroiditis, 298
Avoidance of in childhood and preg-
nancy, 227, 260, 311
in Carcinoma of thyroid, 309, 314-15
in Cretinism. 2SS-6
in Hashimoto’a disease, 298
in Iodide goitre, 244
in Juvenile hypothyroidism, 2S7
in Myxoedema, 290
in Nodular goitre, 242
Normal v alues, 23 1
in Pregnancy, 260
in Subacute thyroiditis. 294
in Thyrotoxicosis, 262
in Toxic goitre, 262
Radioactive iodine ( m I) therapy
Carcinoma of thyroid, causing, 273
Hypothyroidism, causing, 274-5, 237
Leukaemia, causing, 273, 315
Mutations, causing, 273
m Thyroid carcinoma, 312, 314-16
Thvroiditis, causing. 295
in Thyrotoxicosis, 272-6. 278
in Toxic goitre, 272-6, 273
Radiography (diagnostic)
in Acromegaly, 29
in Adrenal disease, 70-1
in Adrenocortical insufficiency", 116
in Adrenogenital syndrome, 104, 108
in ArgentafFuinma, 487
in Bone age. assessment of. 458
in Carcinoma of breast, 435-7, 443
in Carcinoma of prostate, 450
in Carcinoma of thvroid, 309-10
in Cretinism, 282. 285, 455
in Cushing's syndrome, 89-90
in Diabetic lesion* of feet, 409
in Endometriosis, intestinal. 198
in Goitre. 23 S

in I lypcrparatheroidism. 365-7, 371-2.
377

in Hypogonadism. t42. 181
in llypopirjthvmtdism, 379

INDEX

561

Radiography ( contd .)
in Hypopituitarism, 35, 39
in Juvenile hypothyroidism, 287, 455
in Myxoedema, 289

in Neuroblastoma and ganglioneuroma,

353-4

in Osteomalacia, 470-1
in Osteoporosis, 468
in Ovarian disease, 175
m Parathyroid disease, 362
in Phaeochromocytoma, 350
in Pituitary disease, 14-15, 22-4
in Precocious puberty, 138, 178
in Sexual development, anomalies of, 513
in Stein-Leventhal syndrome, 190
in Testicular tumours, 159
in Toxic goitre, 262
in Zollinger-Ellison syndrome, 480
Radiotherapy (external irradiation)
for Acromegaly, 30
Anabolic steroids in, 211
for Carcinoma of thyroid, 312, 315
Carcinoma of thyroid, caused by, 303
for Cushing’s syndrome, 91-2
for Endometriosis, 199
for Exophthalmos, 279
for Gigantism, 25

Hypopituitarism, treatment of during, 38
Metabolic response caused by, 41 S
for Neuroblastoma and ganglioneuroma,
354

for Ovarian tumours, 195
of Pituitary for lactation, persistent, 429
for Pituitary tumours, 21-2
Seminiferous tubular damage, caused by,
147-8

for Subacute thyroiditis, 295
for Testicular tumours, 160
Thyroiditis, caused by, 295
von Recklinghausen's disease, 345, 347
Red blood cell or resin uptake of m I, 231
Reduction division (“mciosis”), 496
Renal deformities, 527
Renal failure

Anabolic steroids in, 211-12
Azotaemic causing osteodystrophy, 377
in Diabetes mellitus, 406, 41 0
in Differential diagnosis of hypocal-
caemia, 381

in Differential diagnosis of polyuria, 339
in Hyperparathyroidism, 365, 372, 375
Menstruation, effect on, 189
in Mdk-alkah syndrome, 37 1-2
in Primary aldosteronism, 80
Secondary hyperparathyroidism in, 377
in. Subacute adrenal insufficiency, 97
Vitamin D, effect on, 377
Renal stones, 365 (see also “Calculi,
urinary”)

Renat tubular acidosis, 377, 378, 469
Reserpinc

lactation, cause of, 430
in Toxic goitre, 225, 263
Resorcinol causing goitre, 240

Respiratory system

m Carcinoma of thyroid, 307, 309
Diseases, DMR in, 226
Diseases, corticosteroid treatment for,
202

Goitre, effect on, 235, 236
Growth, pulmonary insufficiency, effect
on, 463

in Hypothyroidism, 289
in Malignant carcinoid syndrome, 485,
487

in Toxic goitre, 250
Rete cords, 500-1
Rete testis, 501 , 503
Reticuloses
BMR in, 226

Diabetes insipidus caused by, 336
Retinopathy
Diabet,c, 407, 410
in Phaeochromocytoma, 346
Rheumatoid arthritis
in Argcntaffinomatosis, 486
in Auto-immune thyroiditis, 297
Corticosteroid therapy for, 202
Rickets, 463, 466, 467 (iee also ‘‘Osteo-
malacia")
in Dwarfism, 463
Vitamin D-resistant, 469-70
Riedel's struma (thyroiditis), 287, 292,
299-300. 321

Carcinoma, diagnosis from, 300

Salt deficiency (see “Hyponatraemia’*)
Sarcoidosis

Diabetes insipidus, caused by, 336
in Hyperparathyroidism, diagnosis of,

Hypopituitarism, caused by, 31
Scheuermann's disease, 527
Scleroderma

in Argcntaffinomatosis, 486
Corticosteroid therapy for, 202
Pigmentation in, 116
Semicretin, 282
Seminal analysis, 135
Seminoma, 157-61

Serotonin, 482 (see also “5-Hydroxy-
tryptamine")

Sertoli cells, 131, 133, 134
Development, 501
in Klinefelter's syndrome, 528, 530
Tumour, 162
Sex

Behavioural, social or psychological, 510

Chromatin (nuclear) (q.v), 510—1 1

Coitus (q r.), 134-5

External genital, 507-9

Genetic or genotype (q.v.), 496-500

Gonadal, 500-3

Gonads (o v.)

Hormonal, 509-10 (see aha “Oestrogen*”
and “Testosterone")

Internal genital, 503-7

Sex characters, secondary ( 5 1 ',), 133, 170

562

INDEX

Sex (could.)

Somatic or phenotype, 495, 500-9
Sex character*, secondary
Absence in Turner's »vn drome, 525
Androgens, effect on, 5J, 146, 185
1’etnale, 170
Male, 133

Oestrogen*, effect on, 52, _l84-5
in Precocious puberty, 137-8, 177-9
Sex cords, 500-2
Primary, 500-1
Secondary, 501-2

Set hormones (iff also tndmdual hor-
mones)

O estradiol, 169-71
Progesterone, 171-2
Testosterone, 132-3
Sctunl dciclopment, 495-531
m Adrenogenital syndrome, 103-11
Anomalous states, mi estimation of,
510-14

in Assessment of, growth and dciclop-
ment, 456. 463

liehaeioural. influences on, 510
m Differential disgwM.it do.arf.«w,
464

External genital, 507-9
Further reading, 530-1
Cenetic (chromosomal) factors in, 496-
500

in Gigantism, 25
Gonadal, 500-2
Gonadal abnormalities, 503
Gonadal d> genesis (qv.), 524-30
Hermaphroditism (qr.), 514-24
Hormonal factors. 509-10
m Hypopituitarism in childhood end
adolescence, 38—43
in Hypogonadism, 141-3, 181—4
in Hypothyroidism, 282, 286
Inttmal genital, 503-7
in Klinefelter's sindmme. 529-30
in Pituitary tumours. 23
Precocious, 127-8, 177-9
at Puberty, 134, 174
llrtsrded, 38, 39-43. 460-1. 462 (ree oho
“Hypogonadism'')
in Turner’* syndrome, 515. 511 ^
Sexual intercourse (scr alio "Coitus”)
Castration, effect on, 182
in Hypogonadism, 143
in Hypopituitarism, 37
Management of hermaphroditism, in-
fluence on, 529-1

Sexual organs (set alio "Sex characters,
secondary” and "Sexual deirlop-
ment")

in Adrenogenital syndrome. 103-11
Androgens, effect on, 51, 146
m Climacteric, 185-6
Deiclopnirnt, 507-9
Female, 170

in I’emate pieudohertnaphroJiitim. 104.

515-16

Sexual organs (contd.)
in Hermaphroditism (true), 519
m Hypopituitarism, 32, 40, 4t
Influence on management of herma-
phroditism, 520-1

Investigation of anomalous states, 510-
14

Male, 133

in Male pseudohermaphroditism, 517-19
Oestrogen, effect on, 52. 184
Plastic operations on, 521—4
in Postpubcrtal hypogonadism, 143. 182
in Puberal hipogonitdtsm, 141, 181
in Turner's syndrome, 527, 52S
Sheehan’s syndrome, 31
Sign

Chvostel/a, 378
Erb's, 378

Ocular, in toxic goitre, 251-4
Trousseau’s. 378

Simmonds’ disease, 31 (ree also "Hypo-
pituitarism”)

Sjdgren’s svndronie, 297, 371
Skeletal age, 458

SkeVeWti. 454-72 fire olio "Pont, distait
of, "Epiphyses" and "Joint*")
Disturbances of growth, 459-65
Further reading, 472
Growth (7 c.), 454-9
Measurement, 456-8
Metabolic bone disease (q p ), 466-71
Ossification centre*, 458
Osteomalacia (jt.), 468-71
Osteoporosis (<r.t\), 466-8
Proportions. 459

in Turner’s syndrome (deformities),
527

Skin

in Acromegaly, 23
in Addison’* disease, 114-15
in Adrenogenital syndrome, 104, 106
Antithyroid drugs, toxic effect* on, 267
in Argentaffinomatosi* (7 r.). 456
m Cushing’s syndrome, 85-9, 96-7
Diseases treated with corticosteroidi,
202-3

in Hyperparathyroidism, 365
m Hypogonadism. 142
in Ilypopsrathyroidum, 379
in Hypopituitarism, 33
in Hypothv roidism. 282, 2S8-9
Pigmentation (7 1'.)

Testosterone, effect of, 1 33
in Toxic goitre, 230, 254-5
in Turner’s *y ndrome. 527
Snuff, posterior pituitary lohe. 48, 340
Somatic sex (phenols pc), 500-9
SpenuJtnroinii, 1)1-2, 496-7
Disturbed, 147. 148
in Klinefelter’* syndrome, 528, 529
Spermatozoon. 132, 497-9
Spironolactone, 66
for AJdostrromsni, 80
for Ascites, 49 J

INDEX

563

Steoiorrhoea .

in Argentaffinomatosis ,483

Corticosteroid therapy for, ZU5
in Differential diagnosis of hypocat-
caemia, 381

in Hypoparathyroidism, 3/9

in Osteomalacia, 469
Pigmentation in, 116

in Zollmgcr-Elloon .yndrome, 480

Stein-Leventhal syndrome (polycystic
ovaries), 189-91

Sterility (»« "Infertility ) .... ...

Steroid hormones, 51-62 (see also individual
hormones)

Biosynthesis, 54, 55, 56, 57

Blood, as tests of adrenal function, 75

Catabolism and excretion, 56-60

Structure, 52 .

Syndromes of deficiency and excess.

Therapy. 202-17 (see also "AmMk
steroid", “Androgen ,
steroid", "Oestrogen and Vio-

uSSTJWJ adrenal function,

St ilbo estrol ,^2 1 3 (see also "Oestrogen

Stilboestro? diphosphate, 214 (see also
"Oestrogen therapy )
in Carcinoma of prostate, 431
Stress, surgical, 415-26 *

Adrenocortical failure in surgery .

(tee aha "Adrenocortical lnsuffi-

Anabohc phase (“phase of recovery ),
416-17 . _ .

Anaboltc steroids in, 420-1 _

Catabolic phase (“phase of injury ), 410
Cortisol, protective role, 68
Endocrine glands in, 418-17
Further reading, 426

Metabolic response to trauma, .

Oligaemic shock, effect on adrenal
glands, 419—20 . e

Shock-states and severe infections,
treatment of, 420 -

Strontium test of bone metabolism, aoi
Struma fibrosa, 299
Struma lymphomatosa, 296
Struma ovant, 194, 261
Sulkov, itch’s test, 362 _ -

Sulphonamides causing goitre, 24U
Sulphonylureas, 400 (*« also individual

Superfemale (XXX syndrome). 530
Surgery in diabetes mellitus, 401-3
Amputations, 409-10
Choice of time, 401-2
in Diabetic ketosis, 406
Indications, 401 ...

Postoperative management, wJ
Preoperative management. 402-3
Sympathectomy, 409

Sustanon, 208
Sympathectomy

for Diabetic ischaemia, w
Noradrenaline therapy for, 355
Syndromes (see also individual syndromes)
Adrenogenital, 101-11
Albright’s. 178
Carpal tunnel, 28, 290
Chian-Frommel, 23, 429
Conn’s, 78-81
Cushing’s, 81-101
Fanconi’s, 469
Telty’s, 202
Feminizing testis, 31/

Frohlich’s, 41

Hand-Schuller-Chnstian, 39, 336
Hutchinson’s, 353
Hyperventilation, 346
Klinefelter’s, 528-30

Langdon-Down’s, 45 b

Laurence-Moon-Biedl, 460-

Maltgnant carcinoid, 48>-»
Mendelsohn’s, 420
Milk-alkali, 371
Pendred’s, 281
Pepper’s. 353
Peutz-Jegher s, 117
Sheehan’s, 31

!SES2iS s .i«H. 1

Turner’s, 525-8

Waterhouse-Friderichsen, 423

«*rax” 530

^^mger-Elhson, 479-82

S> Ehabetes insipidus, caused by, 336
Dwarfism, caused by, 46Z-J
Hypopituitarism, caused by, 31

Thyroiditis, 293
Syringomyelia, 144, 431

Tanned d“

antibodies), 298
Tarsorrhaphy, 278-9
T «th

in Cretinism, lot _

in Growth and development, 458

in Hypogonadism, 143

in 37V

Lamina dura, 366, 37*

in Precocious puberty, 138 „ „ d

Temperature, body 0« also 1 ever
“Hypothermia )

in Hypothyroidism, 287

in Insulin hypoglycaemia 400
in Mvxoedema coma, its
in Pituitary tunwa . 21

Progesterone, effect of. r7 .
in Thyrotoxic costs, 259. >

in Toxic goitre, 257
Teratoma

Chanan. 179. 19+

Testicular, 15/-61

INDEX

563

Steatorrhoea

in Argentaffin omatosts, 485
Corticosteroid therapy for, 203
in Differential diagnosis of hypocal-
caemia, 381

in Hypoparathyroidism, 379
in Osteomalacia, 469
Pigmentation in, 116
in Zollinger-Ellison syndrome, 480
Stein-Leventhal syndrome (polycystic
ovaries), 189-91
Sterility (see '‘Infertility*’)

Steroid hormones, S 1-62 (see also individual
hormones)

Biosynthesis, 54, 55, 56, 57
Blood, as tests of adrenal function, 75
Catabolism and excretion, 56-60
Structure, 52

Syndromes of deficiency and excess,
60

Therapy, 202-17 ( see also “Anabolic
steroid", "Androgen", "Cortico-
steroid”, "Oestrogen” and “Pro-
gestogen therapy”)

Unnary, as tests of adrenal function,
72~5, 109, 116

Sulboestrol, 213 (see also "Oestrogen
therapy’’)

Stilboestrol diphosphate, 214 (fee also
"Oestrogen therapy”)
in Carcinoma of prostate, 451
Stress, surgical, 415-26
Adrenocortical failure in surgery, 422-6
(tee also "Adrenocortical insuffi-
ciency”)

Anabolic phase (“phase of recovery”).

Anabolic steroids in, 420-1
Catabolic phase ("phase of injury”), 416
Cortisol, protective role, 68
Endocrine glands in, 418-19
Further reading, 426
metabolic response to trauma, 415-18
Uligaemic shock effect on adrenal
glands, 419-20

Shock-states and severe infections,
treatment of. 420

Strontium test of bone metabolism, 362
otruma fibrosa, 299
Struma lymphomatosa, 296
Stroma ovarii, 194, 261
oulkowitch’s test, 362
Su phonamides causing goitre, 240
nuiphonylureas, 400 (see also individual
drugs)

Supcrfemale (XXX syndrome), 530
surgery tn diabetes melbtus, 401-3
imputations, 409-10
r™’** of time, 401-2
I«i • c ketosis, 40G
indications, 401

Postoperative management, 403
sS lvc management, 402-3
•sympathectomy, 409

Sustanon, 208
Sympathectomy
for Diabetic ischaemia, 409
Noradrenaline therapy for, 355
Syndromes (see also individual syndromes)
Adrenogenital, 101-11
Albnght’s, 178
Carpal tunnel, 28, 290
Chian-Frommel, 23, 429
Conn’s, 78-81
Cushing’s, 81-101
Fancom’s, 469
Felly's, 202
Feminizing testis, 517
Frohlich’s, 41

Hand-Schuller-Cbnsfian, 39, 336
Hutchinson’s, 353
Hyperventilation, 346
Klinefelter’s, 528-30
Langdon-Dovvn’s, 455
Laurence-lMoon-Biedl, 460-1
Malignant carcinoid, 485-8
Mendelsohn’s, 420
Milk-alkali, 371
Pcndred's, 281
Pepper’s, 353
Peutz-Jegher’s, 117
Sheehan's, 31
Sjorgren's, 371
Stein-Lev enthal, 189-91
Turner's, S2SS
Ullrich’s, 526

Waterhouse-Friderichsen, 423
“XXX”, 530
Zollinger-Ellison, 479-82
Syphilis

Diabetes insipidus, caused by, 336
Dwarfism, caused by, 462-3
Hypopituitarism, caused by, 31
Thyroiditis, 293
Syringomyelia, 144, 431

Tanned red-cell test (for thyroid auto-
antibodies), 298
Tarsorrhaphy, 278-9
Teeth

in Cretinism, 282
in Growth and development, 458
in Hypogonadism, 143
in Hypoparathyroidism, 379
Lamina dura, 366, 379
in Precocious puberty, 138
Temperature, body (see also "Fever” and
“Hypothermia”)
in Hypothyroidism, 289
in Insulin hypoglycaemia, 400
in Myxoedema coma, 291
in Pituitary tumours, 21
Progesterone, effect of, 171, 175
in Thyrotoxic crisis, 259, 279
in Toxic goitre, 257
Teratoma

Ovarian, 179, 194
Testicular, 157-61

564

INDEX

Testis, 1 29-65
Agenesis (anortlua), ] 44
Btopsv, 136, 513-14
Blood supply, 130-1
Coitus (ft ), 1 34
CoTio r chi(li*ni (f e.), 149-57
Development, 129, 501, 502
Further reading, 164-5
Gonadal abnormalities, 503
in Hermaphroditism, 514-19
Hypogonadism (f.t >, 141-9
Intcmlity, 149-50

Interstitial or !,eydig cells (ft 1, 132
Investigation of disorders, 135-7
in Klinefelter's syndrome, 528-9
Lesions end disordered function, 137
Oestrogen, 133
Orchiectomy (f t .), 1 63-4
Precocious puberty, 137—11
Puberty (f.t ), 134
Spermatogenesis, 131-2
Structure and function, adult, 130-5
Testosterone (f t ). 132-3
Tumours, 157-63 (tee also individual
tumours)

Testosterone, 51, 132-3 (ire also •‘Andro-
gens")

Biosynthesis, 55, 56
Dcconoate, 209
Isobutyrate, 208
fsocaproate, 208
I,c>dig cells, 132, 162
Metabolism and excretion, 59, 133
Oenanthate proprtonatc, 208
Phenylproprionnte, 208
Physiological actions, 132-3
Proprionatr, 208
Spermatogenesis, 131
Structure, 53

Therapy, 207-10 (srr also "Androgen
therapy")

Tests

ACT! I stimulation, 73, 425-6
BMR, 225-6

Calcium balance. 361-2. 370
Complement fixation (for thyroid autn-
antihodirs), 298

Corttsone suppression, in hvprtcalcacinic
states, 371

Creatine tolerance, 232
Dexamethasone suppression, 74
I’cme chloride, 398
Flocculation. 298
VWi dxpxvNMwtv, 111
Glucagon. 391
Glucose tolerance, 386-7
Hesocsttol (tritium lalielled), 439
Hingcrty, 349

Hvpertomc «»lme infusion, 337-8
/-leucine, 391
Mctynpnne, 17
Nicotine, 338-9
Nitropntsside. 398
Perchlorate. 230-1

Tests (eon hi.)

Precipitin (for thyroid auto-antibodics),

29b

Predicting response in carcinoma of
breast, 439
Pregnancy, 173—4

Pressor inhibiting (phentolamme), 348
Prolactin, 439

Provocative (histamine), 347-8
Radioactive iodine, 227-31
Strontium, 362
Sulim witch’s, 362

Tanned red-cell (for thvroid auto-anti-
bodies). 298
Thorn, 72

Thvroid stimulation, 230
Tolbutamide, 391
Triiodothyronine suppression, 228
Water load, 72

Tetanv, 378-82 (tee also "Hvpocalcacmu”
and •‘Hypoparathyroidism")
tn Aldosteronism, primary, 79
Biochemical aspects, 380-1
Clinical features, 378-9
Differential diagnosis, 3SI
Thyroidectomy causing, 324
Treatment, 381-2

Trtraiodothyrontne (T4. thyroxine),
220-1 (tee alto "Thyroid hormones")
Thecoma, 179. 192

Thiocyanate, 240 (tee abo "Antithyroid
drugs")

Goitrogenic elTect. 240
Site of action, 221
Thtotrpa, 447

Thiouracil. 264-8 (see alto “Antithyroid
drugs”)

Goitrogenic effect. 240
Site of action. 221

Thiourea, 240 (tee also "Antithyroid
drug*")

Thom test (eosinophil count), 72
Thvmus

Carcinoma in Cushing's lyndromc. 83
Parathyroids located in, 358, 373-d
Resection tn parathyroidectomy, 374
in Toxic goitre, 248
Thyroglobulin, 220-1
'Diyroglotsal evst and fistula, 317
Thyroid binding pre-albumin (THPA).
220-1

Thvroid binding protein (TBP). 220-1 , 231
Thvroid clearance rate. 228
Ttiyxxwi tM, H&-MU
Aberrant, lateral, 303
in Acromrgaly, 29
in Addison's disease, lt4
Adenoma of, 300-1
Anatomy, 218-19
Aplasia. 3J4. 281, 31 ft
Atrophv, 233. 28 1. 287
Benign tumours, 3tX>-l
Ilinpsv of, 298, 3 IX*. 310-11
Carcinotna (ft.), 301-16

INDEX

565

Thyroid gland (cotitd.)

Descent, excessive, 317
Descent, incomplete, 316
Developmental anomalies, 316-17
Diseases, 232-3
Further reading, 327-30
General pathology, 233-4
Goitre ( q r.). 234-8
Histology, 219

Hormones, 219-25 [see also "Thyroid
hormones'*)

Hyperplasia, 233, 281
Hypophysectomy, effect on, 48, 233
Hypopituitarism, effect on, 34, 233
Hypoplasia, 233, 281, 316
Inflammation, 234, 292-300
Investigation, 225-32
in Lactation, 427-8
Malignant tumours, 301-16
in Multiple endocrine adenopathv, 387
Physiology, 219-25
Pyramidal lobe, 218, 236, 271, 320
Simple goitre, 239—44
Thyroid hormone therapy iq.v.), 326-7
Thyroidectomy (q.v.), 3 J 7-26
Thyroiditis (q i\), 234, 292-300
Toxic goitre 244-SO
Thyroid hormones, 219-2S

Defects in synthesis, 221, 281-2
in Lactation, 427-8
Physiological effects of, 223-5
Production, factors influencing, 221-3
Release (discharge), 220
Storage, 220-1
Synthesis, 219-21
Vasopressin, relation to, 335
Thyroid hormone therapy, 326-7
for Adult hypothyroidism, 290-1
in Antithyroid drug therapy, 264, 266-8,
277

for Auto-immune thyroiditis, 298-9
for Carcinoma of thyroid, 313-15
for Cretinism, 285-6
Dosage, 285, 326
for Hashimoto’s disease, 298-9
for Hyperophthalmopathic Graves’ dis-
ease, 278

for Hypophysectomy, 48
for Hypopituitarism, 37, 38, 43
for Juvenile hypothyroidism, 287
for Myxo edema, 290-1
for Mycoedema coma, 291-2
Overdosagc, signs of, 285-6, 291
Prophylaxis of thyroid
.311

in Radioactive iodine therapy, 274, 315
for Riedel's thyroiditis. 300
Self-administered, 262
for Simple goitre, 243-4
for Thyroidectomy, 243-4,271, 277, 279,
299, 300, 324
Thyroid, lingual, 261. 316
Thyroid nodule, single, 237, 243, 301, 308,
311, 317, 320

carcinoma.

Thyroidectomy, 317-26
for Adenoma, 301
Anaesthesia for, 317-18
for Carcinoma, 312-13, 315
Carcinoma, caused by, in animals, 303
Complications, 270-1, 322— t
Effect on BMR, 222
Exposure of thyroid, 318
Hypothyroidism, causing, 286, 287
Partial, 320

Postoperative care, 322
Preparation for, in toxic goitre, 269-
70

Retrosternal, 321

for Simple (endemic and sporadic) goitre,
243-4

Subtotal, 319-20
Total, 320-1

for Toxic goitre, 268-72, 275-80
for Thyroiditis, 292, 293, 295, 299, 300
Thyroid-stimulating hormone (thyrotro-
phic hormone, thyrotrophin, TSH),
13,219-23

Antithyroid drugs, effect of, 248, 264
Assay, 17

in Auto-immune thyroiditis, 296
Carb/mazole, effect of, 248, 264
in Carcinoma of thyroid, 234, 303, 312
in Exophthalmos, 254
in Hyperplasia of thvroid, 233
Inhibition, 233. 243, 285, 298, 312.
316

in Lingual thyroid. 316
in Ocular signs of toxic goitre, 254
Physiologv, 13, 221-2
in Simple goitre, 240-1
Thiouracil, effect of, 248, 264
Thyroid stimulation test, 230
in Thyrotoxicosis, 246
in Toxic adenoma, 247
m Toxic goitre, 246
Thyroid stimulation test, 230
in Hypopituitarism, 34
rn Hypothyroidism, 290
Thyroid stimulator, long acting (LATS),
246

Thyroid uptake tests, 227-8
Normal values, 231
Thyroiditis, 292-300

Auto-immune ( q t;.), 295-9
Bacterial, acute. 292
Bacterial, chronic, 293
Fibrous, invasive, 299
Giant cell, of de Quervain, 293-5
Granulomatous, 293-5
Granulomatous pseudotuberculous, 292-
4

Hashimoto’s, 29S-9
Ligneous, 299
Lymphocytic, 296
Non-suppumive, scute, 293-5
Radiation, 292. 295
Riedel’s, 287, 292. 299-300
Subacute viral. 287, 292-5

566

INDEX

Thyrotoxicosis (hyperthyroidism), 244-80
(iff alto “Toxic goitre”)

Fsctitia, 262

Thyfotrophic hormone, 2 1 9-23 (ice also
"Thyroid stimulating hormone”)
Thyrotrophm, 219-23 (re< also “Thyroid-
stimulating hormone”) >
Thyroxine, 219-25 {tee also “Thyroid
hormone*”)

Therapy, 326-7 (iff alio “Thyroid
therapy")

Thytropor, 230 (tee alio "Thyroid stimulat-
ing hormone”)

T index, 228-9
Normal values, 231
Tolbutamide (Rastinon), 400
Ten in organic h> pennsulmiim. 391
Toxic adenoma, 229, 233, 245, 246, 247,
279, 301

Toxic goitre (thy rotoxicom), 244-80 {tee
also “Hyperthyroidism”)

Adenoma, 247
Aetiology, 245-6
Age of onset, 248-9
Antithyroid drugs, 264-8
Carcinoma in, 248, 307, 303
Cardiovascular manifestations, 256
in Children, 260, 277
Clinical features, 249
Course, 262-3
Diagnosis, 261-2
Diffuse gland, 246-7
Emotional features, 258-9
Gastrointestinal tract, 257-8
General appearance, 250
Incidence, 248-9
Infirmity, 277-80
Investigation, 225-32, 238, 262
Masked, 260

Metabolic fratures, 249, 257
Myxoedema, localized pretibial, 255-6
Nervous features, 258-9
Neuromuscular disorders, 258
Nodular gland in, 247
NoranKtiiuit, 244-5
Ocular signs (or ), 251-4. 278-9
Pathology of, 246-8
in Pregnancy. 260, 277
Pnmary, 245
Prognosis of, 262-3
Radioactive iodine therapy for. 272-5
Recurrence, treatment of, 271. 276
Secondary, 245
Sexual function in, 259
Skeletal changes in, 259
Subtotal thvroidectomy for, 268-72
Symptoms, 249-50
Treatment, 263-80
Treatment, choice of. 275-80
Treatment, methods compared, 275
'therapeutic agents, effect* on thyroid,
248

Thyroid gland in, 250-1
Thyroiditis, auto-immune in, 247

Toxic goitre (thyrotoxicosis) {(oislJ.)

Thyrotoxic crisis, 259-60
Trachea, decompression, 320, 321-2
Transcortin, 66
Triamcinolone, 204

Tricuspid valve, in Argent a ffinomatovts,
485

Triiodothyronine, 219-25 (ree also "Thy-
roid hormones")

Therapy, 326-7 {see alto "Thyroid hor-
mone therapy”)

Suppression, 228. 262
Trousseau’s sign, 378
T\ibal insufflation, 175
Tuberculosis

Addison's disease, caused by. 113, 114,
117

in Cushing's syndrome, 87
Diabetes insipidus, caused by, 336
Hypopituitarism, caused by, 3(
Pulmonary, in diabetes melhtus, 406
Reactivation in corticosteroid therapy,
205

Thyroiditis caused by, 293
Tubules, seminiferous, 129-32
Deficiency. 144-9
Development, 501
in Klinefelter's syndrome, 528
Tunica albuginea. 130, 136,50/

Tunica vaginalis, 136. 501
Turner's syndrome, 144, 499, 503, 525-41
Aetiology and pathogenesis, 525-6
Clinical features, 526-8
Diagnosis, 528
Dwarfism in. 460. 527-8
Treatment, 528
Tyrosine. 219-20. 342-3

Ulcerative colitis

Corticosteroid therapy for, 207
Clinch's syndrome, 526
Unencapsulatcd sclerosing tumour, 305
Urcterocohc anastomosis. 469 ■
Urogenital membrane, 505, 508
Urogenital sinus, 502. 504-5
Urorectal septum. 505. SOS
Uterus

Adenocarcinnma, 193. 195
Development, 502, 503
Miscellaneous lesions, 195-9
Utnculus rmseulinu* (ire “Prostatic

Vaginal epithelium, 170
Smears, 17S

Vamllyl mandehc acid (VMA1. 343
in Phacochromocytoma, 349
Vancncele. 147, 148

Vasopressin (antidiuretic hormone, ADH).
334-5

in Ijver disease, 490
in Metabolic response to surgery,
418

Therapy, 48, 340 - /

INDEX

567

Vasopressin tannate in oil, 48, 340
Vim-Silvennan needle, 3 1 1 " - * t
Vines, fuchsinophil staining reaction of,
77, 83, 101 ' , •

V/rilum »

in Acromegaly, 29

in Adrenogenital syndrome, 104, 106
Androgen therapy, cause of, 209
Causes of, 61

in Female pseudohermaphroditism (fl.t.),

509, 515-16

in Liver disease, ‘ 489, 490
Ovarian tumours, cause of, 194
Progestogen therapy, cause of, 216
in Stcm-Leventhal syndrome, 190
Virilizing hyperplasia, adrenal free also
"Virilism")

Acquired, 105

Congenital, 104-5, 509, 515-16
Vitamin B complex
Bn in hypothyroidism, 289, 291
Nicotinamide deficiency in argentaffino-
matosis, 486

in Toxic goitre, treatment of, 263
Vitamin D

Cortisone in Vitamin D intoxication, 371
Deficiency, 377-8, 467, 469-71
in Hyperparathyroidism, secondary, 377
Intoxication, 371

Therapy, 381-2, 471 (see also "Calci-
ferol")

Vitamin D-resistant rickets, 469
Vitamins (tee also individual vitamins)
Deficiency in malabsorption, 469
Thyroid hormone, effect of, 224-5
in Toxic goitre, 263
- in Zollinger-Ellison syndrome, 482
Vitiligo (leukodermia), 115, 254
Volume, receptors, 67, 68, 334
Vulva (see also “Sexual organs”)
Development, 502, 507-9
in Female pseudohermaphroditism, 515-

in Hypogonadism, 181, 182
in Hypopituitarism, 34, 37
Infantile in Turner’s syndrome, 52S
Oestradiol, effect of. 170
Plastic operations on, 521-4
m Selection of sex of rearing. 520

Water-dear celts, 359
in Parathyroid adenoma, 364
in Parathyroid hyperplasia, 363
in Thyroid tumour, 306
Water load test, 72
in Addison's disease, 116

Water load tesj (could.)

in Hypopituitarism, 34, 35
Water metabolism

in Addison’s disease, 115
Aldosterone, effect of, 67
Androgens, effect of, 209
Corticosteroid theropv, effect of, 203
Cortisol, effect of, 69
in Diabetes insipidus, 336
Growth hormone, effect of, 12
in Hypopituitarism, 34-5
in Hypothyroidism, 288, 291
in Liver disease, 490
Oestradiol, effect of, 170
Progesterone, effect of, 171 '

Thyroid hormones, effect of 225
Vasopressin (ADII), effect of, 334-5
Water intoxication
in Hypopituiiarv crisis, 35
in Vasopressin overdosage, 340
Waterhouse-Friderichsen syndrome 423
Webbing of neck, 527
Weight loss

in Addison’s disease, 114
Anabolic steroid therapy for. 21!
in Anorexia nervosa, 36
in “Catabolic phase" after trauma 41
in Diabetes insipidus. 336
in Diabetes mellitus, 398
in Hypopituitarism, 34
in Thyroid hormone therapy, overdose
285, 291

in Toxic goitre, 249-50, 257
Whipple’s triad, 391
Wolffian (mesonephric) duct, 501-5
W’ound healing

in Corticosteroid therapv, 20S, 425
in Cushing’s syndrome, 97
Thyroidectomy, 324
in Turner’s syndrome (keloid formation),
527, 52 8

Xanthomatosis, 39, 336
X-hormone (inhibin), 134, 530
XXX syndrome, 530

Zollinger-Ellison syndrome, 479-82
Diagnosis, 481
Diarrhoea in, 480
Gastric hypersecretion in, 480
Hypolcalaemia in, 480
Islet cell lesions in, 481
Peptic ulcer in, 479, 481
Treatment, 482
Zukerkandl, organ of, 342
Zygote (fertilized ovum), 497-9