a^atmll InittetBitg ffiibratg BOUC3HT WITH THE INCOME OF THE SAGE ENDOWMENT FUND THE GIFT OF HENRY W. SAGE 1891 Cornell University Library arV18482 The organs of internal secretion 3 1924 031 256 559 olin.anx Cornell University Library The original of tliis book is in tine Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31924031256559 THE ORGANS OF INTERNAL SECRETION THE ORGANS OF INTERNAL SECRETION THEIR DISEASES AND THERAPEUTIC APPLICATION A BOOK FOR GENERAL PRACTITIONERS BY IVO GEIKIE COBB, M.D., M.R.C.S. LATH ASSISTANT TO OUT-PATIBNT FHTSICIAN, THE MIDDLESEX HOS- PITAL ; TEMPORARY CAPTAIN^ R.A.M.C. ; NEUROLOGIST BBINNINQTON SECTION SECOND WESTERN GENERAL HOSPITAL NEW YORK WILLIAM WOOD AND COMPANY MDCCCCXIX MY FATHEE IN TOKEN OF LOVE AND RESPECT PREFACE TO SECOND EDITION The fact that a Second Edition of this book has been called for a little over a year after publication appears to indicate that it has fulfilled a want. The need of a small work dealing with the Internal Secretions has apparently been felt, not only in this country, but in others, as was shown by a demand for an edition in Spanish and another in Italian. The entire- book has been carefully revised and brought up to date. Numerous references have been added, and a chapter dealing with the Eelation of the Internal Secretions to Functional Nervous Disease has been inserted. The desirability of a chapter discussing this relation had previously been brought home to the author; but the large increase in these disorders in the last year or two has made such an addition imperative. Chapter XI. contains a brief review of this subject. Chapter XII. is devoted to a survey of the whole subject, and, except for several additions to the viii PEEPACE TO SECOND EDITION Bibliography, remains unchanged. A list of some books dealing with the subject of Functional Nervous Disorders has been added. The author desires to express his thanks to Dr. Bernard Hart for much help in the classification and nomenclature of these disorders. Beinnington War. Hospital, Stookpoet, September, 1918. PREFACE TO FIRST EDITION This book is founded upon articles which appeared in the Medical Press and Circular during the summer and autumn of 1916. The author's object in writing these articles was to lay before the busy practitioner the important points in the study of the Endocrine Glands. At the same time he was anxious to make them as complete as possible, and yet keep them within the limits of such publications. After the appearance of these articles, he received requests for reprints, and as they had not been re- printed, and the interest in them appeared to warrant it, he decided to publish them in book form. The present volume comprises these articles, with slight alterations. Hormone-therapy is already established as a recog- nized therapeutic agent, yet as the books which deal with the ductless glands and their secretions are exhaustive studies including the results of laboratory research in detail, and require far more time to read than the general practitioner has at his disposal, it is difficult for him to glean the saMent facts from these lengthy works. It seemed, therefore, to the author that a small book which contained an account of the X PEEFACE TO FIEST EDITION diseases and therapeutic application of extracts of these glands might prove useful. In publishing this small volume, however, the author wishes to state that it makes no claim to be considered an exhaustive and complete account of the endocrine glands, neither can it be considered as a comprehensive therapeutic guide to the adminis- tration of the organic extracts. Eather does it aim at being a guide to other practitioners as to the role which the ductless glands play in promoting bodily health; while it endeavours to point out these morbid states of health in which organic extracts may be utilized with success. Among the glands possessing an internal secretion, the thyroid is perhaps the one which has attracted most attention, partly on account of the well-recognized disorders which arise in connection with it, and partly because, of all the endocrine glands, the thyroid has been most utilized therapeutically. In order to emphasize the signs and symptoms associated with morbid conditions of this gland, the author has devoted three chapters to the consideration of Ex- ophthalmic Goitre and Thyroid Deficiency. The last of these three chapters contains references to the administration of thyroid extract; while this subject is again referred to in Chapter X. A chapter has been devoted to the Pituitary Gland' and the subject of pituitary- therapy has been briefly reviewed. In Chapter VI. the Adrenal Glands are described, and the clinical conditions of hyperadrenia PEEPAOE TO PIEST EDITION xi and hypoadrenia are discussed. Chapter VII. deals with the Pancreas, and describes its structure, physio- logical functions, and relation to glycosuria, and concludes by referring to the therapeutic possibilities of preparations of this gland. The subject of the Internal Secretions of the Sexual Organs, dealt with in Chapter VIII., has been com- pressed into as small a space as was possible; a full account would have filled a large volume. Neverthe- less, this chapter reviews the outstanding features, suggests ways of administering extracts of the genital glands, and describes morbid conditions in which they may be helpful. The Internal Secretions of Digestion form the subject of Chapter IX.; and here the author has endeavoured to lay emphasis upon the therapeutic aspect, as he believes that in the near future this branch of organo-therapy wiU find a very wide field of utility, and will succeed in alleviating many morbid conditions which have hitherto proved resistant to treatment. The Therapeutic AppHcation of Hormones is sum- marized in Chapter X. This chapter has been enlarged since its appearance in the Medical Press and Circular, and it endeavours to epitomize the subject for those readers who are mainly concerned with the therapeutic aspect of this subject. It necessarily summarizes the conclusion of each chapter, but in addition references will be found to preparations and doses not included in the previous chapters. xii PEEFACE TO EIEST EDITION Chapter XI. is devoted to a survey of the whole subject, and deals with the present position of hormone- therapy. As the therapeutic aspect of this subject was dealt with at the end of each article, it has been decided to leave this arrangement unaltered. Likewise, the references have been left in their original positions; but a bibhography has been included at the end of Chapter XI., so that those desirous of a fuller account of the ductless glands and organo-therapy wiU be able to refer to the works enumerated there. In conclusion, the author desires to thank the editor and proprietors of the Medical Press and Circular for permission to reproduce these articles in book form. rVO GEIKIE COBB. Seymotje Street, W., November, 1916. CONTENTS CHAPTER PAOE PEBFAOB TO SECOND EDITION - vii PEBFACE TO FIRST EDITION - ix INTEODTJOTION - - . . 1 I. THE THYEOID AND PAEATHYROID GLANDS - - 16 11. BXOPHTHALMIO GOITEE (HYPBETHYEOIDISM) - 32 in. THYEOID DBFICIBNCY - 56 IV. THYROID DBFioiBNGY (continued) - . 72 V. THE PITUITARY BODY - - - 96 VI. THB ADRENAL GLANDS • - 116 Vn. THE PANOEEAS - - - 134 VIII. THB SEXUAL OEGANS AND THEIR INTERNAL SEOEE- TIONS ..... 150 IX. THB INTEENAL SECRETIONS OF DIGESTION - 166 X. THE THBEAPBUTIO APPLICATION OF HORMONES - 187 XI. THE ENDOCRINE GLANDS AND NERVOUS DISORDERS - 221 Xn. CONCLUSIONS AND BIBLIOGRAPHY - . - 257 INDEX ..... 269 THE ORGANS OF INTERNAL SECRETION INTEODUCTION The place wMeh those glands possessing internal secretions now occupy in the practice of medicine cannot be over-estimated. Although it is only in recent years that their importance has been under- stood, every day brings to our knowledge fresh evidence of their vital influences upon the general bodily and mental health. When it was discovered that ex- ophthalmic goitre owed its existence to an over-action, associated with hypersecretion, of the thyroid gland, the first milestone had been passed in the path which led us to the discovery of the important part which the hormones play in our lives. What we may call the grosser lesions due to disturb- ances in the normal ratio between the various internal secretory glands are nowadays matters of almost popular knowledge. What we desire to emphasize in this book are the smaller signs and symptoms which, to the eye trained to observe, show minor disturbances, either of one or more glands or of the 1 2 THE OEGANS OF INTERNAL SECRETION balance between these glands. Many of these details, trifling in themselves, have been proved to be suffi- ciently characteristic to justify medical science in in- cluding them among the constant features which owe their origin to the ductless glands. "When the pioneer work was being done on this subject, the evidences of the sUghter disturbances of the endocrine glands were regarded by many observers as too fanciful to merit serious consideration. Thus, when Levi and Rothschild first pointed to the " eyebrow " sign as indicative of deficient thyroidism, it was hard for many students of these subjects to convince themselves that this sign was of any value whatsoever. Nevertheless, this and other manifestations of equally slight nature are now admitted to be of the greatest value in diagnosing deficient thyroid secretion. Many of the signs of kindred nature are so slender as to require the most minute study and the most careful observation before we can say, with any degree of probability, which particular gland is at fault. The importance of this lies in the fact that many cases of " functional disturbances," which we have been content previously to cosset with various preparations, and to class as neurotic or neurasthenic according to the depths of our ignorance, are now irecognized as originating in abnormal functioning of the endo- crinic glands. This much is now generally known and universally admitted. Only relatively few observers recognize that this is not the jons el wigo mali, but only one stage on the journey. INTRODUCTION 3 To take a concrete instance, let us suppose that a patient exhibits signs that the thyroid is not function- ing adequately. The patient exhibits many of the well-known signs pointing to this deficiency. Most of us are well content to leave it at that, and even to spend time (which should be occupied in delving still farther and asking ourselves why such a deficiency is present) on self-adulation at our extraordinary deductive powers. It is certainly true that we can benefit our patients by the exhibition of one or other of the organo-therapeutio products, but we shall do so to a much larger extent if we realize one or two simple facts. When advising a patient to take, let us say, thyroid extract for a time, we are constantly asked by the patient the rationale of such a prescription. Having explained that we have reason to beheve that this gland is not supplying an adequate amount of secretion, on more than one occasion we have been asked by the logical patient, " Have I got to continue this medicine for the rest of my life ?" or, " WiU the need for its administration be overcome in due time?" This is an important matter, because it makes us think for ourselves, and not blindly prescribe drugs for indefinite times without reasoning as to their method and length of administration. I think that we are justified in considering for a few moments what underlies the deficiency in secretion. It is highly improbable that one or other of the ^ndo- crinic glands would suddenly and without any stimulus 4 THE OEGANS OF INTERNAL SECRETION refrain from supplying, or deterimne to over-supply, its valuable contents to the blood-stream. It is much more probable that some cause, be it mental or bodily, has determined this upset, and it behoves us to realize that this is the case, and not to consider our diagnosis completed when we have made up our mind that such and such a gland is defective or over-active. In his book on " Intestinal Stasis," Lane states that one of the effects of intestinal intoxication is atrophy of the thyroid. Here we have a definite attempt to go to the root of the trouble, although, unfortunately, there is httle evidence at present for this statement. For the present, at any rate, let us assume that this is one of the causes which imderUe submyxoedema. What others may there possibly be ? Among the causes of diabetes which find their place in most current textbooks on medicine is worry and anxiety. Now, this is at once assuming that mental causes may upset a bodily function or func- tions, and thereby disorganize metabolism. And the writer would be the last to wish to deny this. If, therefore, we may assent to this detail of etiology with regard to diabetes, why should we not include such a cause when we are discussing disorganization of the endocrinio glands ? Many cases which we can call to mind at the moment afford us the strongest possible support for such a theory. Prolonged anxiety, business worry, a sudden shock, are said to be capable of producing diabetes, just as puncture of the floor of the fourth ventricle is, experimentally, capable INTEODUCTION 5 of doing the same. It would seem at least equally probable that the same causes can, and do, upset the mechanism which governs the balance between the ductless glands. In the severe cases of this nature {e.g., Graves' disease), this fact is sufficiently recognized. But is it, has it been, when we come to consider slighter derangements of these important glands ? It is obvious that the entire study- of this subject is of too recent a date to have made the minute cUnical study of the ultimate cause a feasible proposition. Never- theless, we now come to the time when our patients ask us the why and the wherefore of such prescribing. We have suggested two possible causes which may underlie the disorganization of the endocrinic system — namely, intestinal toxaemia (as suggested by Lane); and mental causes, such as worry, anxiety, and mental strain of any kind. But are these the sole causes which may be held responsible ? We are all familiar with the damaged health which may result from a long illness, or, alternatively, from a sudden short attack, such as influenza. The patient recovers but slowly, the strength returns not, the mind is clouded, and in countless other ways the individual shows the effects of the illness. Hitherto we have referred to such cases as post-influenzal debility, when this disease has been at the root of the trouble; or as "neuras- thenia," when we could not find a cause even as tangible as influenza. Our remedies have been confined, certainly in many instances, to a change 6 THE OEGANS OF INTEENAL SECEETION to the sea or spa, and a generous addition to the diet. But we have rarely asked ourselves what factor under- lies these " delayed recoveries." Why should not the toxins of influenza, in like manner to the toxins generated by the inhabitants of the bowel, or the adverse mental influences which exert their harmful action where mental strain is present, be capable of producing an endocrinic dis- organization ? Hypothetically, at any rate, such an occurrence is at least probable, and it would give us a reason for the sudden or gradual withdrawal of the internal secretion which happens to be deficient ia the particular case.* From the practical standpoint, moreover, we must advance some such hypothesis as this in order to ac- count for the train of symptoms, which, certainly in many cases, owes its origin to a disturbance of the normal ratio which exists in health between the various endocrinic glands. Again, most of us are familiar with the cases of delayed convalescence following an operation. The patient invariably presents a similar picture to that designated " post-influenzal debility." In theory, at any rate, he ought to respond to the administration of one or other of the preparations of the hormones, and in many cases he does. On more than one occasion I have had the oppor- * It has recently been reported in the Archives of Inter- national Medicine, that a series of experiments have led some American investigators to the belief that progressive muscular dystrophy may originate in a disturbed functioning of the endocrine glands. INTEODUCTION 7 tunity of putting this theory into practice. One lady consulted me some years ago for neurasthenia following a severe abdominal operation. This condi- tion had resisted a wealth of treatment; many and diverse remedies had been tried without relief. I hoped that I might be enabled to afford relief by the administration of an organo-therapeutic preparation. On considering her sjmdrome, I came to the conclusion that she might derive benefit from the exhibition of pituitary extract. In spite of the laboratory evidence, which should convince us that it is useless to give an extract of this gland by the mouth, I took my courage in both hands and prescribed it. The result surpassed even my optimistic expectations. The lady recovered her strength and health; her digestion righted itself I her functions became normal, and she regained perfect health. This result is striking, for it followed many other remedies, and the patient herself always refers to this medicine as the " magic mixture." I mention this case as it exemplifies our hypothesis tha"^ many and diverse causes may produce a change in the normal functioning of these glands. Whether, in this particular case, it was the shock of the operation, the anaesthetic, or the changes in diet necessitated by these procedures, it is impossible to say. An example of a similar attack of " thyroid deficiency ' ' is the case of a lady who, having nursed her husband through a long and trying illness, which resulted fatally, consulted me for symptoms which, upon investigation, were shown to be due to deficient 8 THE OBGANS OF INTEENAL SECEETION thyroid secretion. Upon the administration of thyroid extract, she made a capital recovery and was restored to health. These cases both help us to answer the question so often put to us when we recommend an extract of one or other of these ductless glands. It would seem that, certainly in many instances, the administration ox the extract either by the mouth or hypodermically serves to act as a stimulus to the normal secretion, so that it is unnecessary to continue artificially its administration for lengthy periods. And, again, the prescribing of the requisite extract at the right time is the " shortest cut " to health which exists. It is even possible that many of the benefits which we all recognize to accrue from a change of chmate, from a course of spa treatment, or from a sea-voyage, are really largely efficacious because they stimulate into activity the gland (or glands) which has been temporarily inhibited by the iUness, operation, or other cause. In this connection reference may be made to another instance where " post-influenzal debihty " has yielded to organo-therapy. A lady consulted me for this condition, which had been in existence for five years, and which had resisted all treatment. It had commenced after a bad attack of influenza five years before. Her condition was much improved from the first by the administration of thyroid extract, and she made a most satisfactory recovery. The point which seems to need emphasizing is this : that prolonged illness, shock, mental anxiety, and INTEODUCTION 9 many other causes, produce effects which owe their origin to a disturbance of the relation between the hormones. The indications are rarely broad. Some- times they require the eye of a medical " detective " before their significance is reaUzed. But the signs and symptoms are rarely wanting if they are looked or. Neurasthenia has been likened to influenza (inas- much as any intangible condition has received this label), and has been dubbed the " dustbin of the neurologist." Nevertheless it is a real and concrete disease — concrete in the sense that it is not a hotch- potch of other diseases. Doubtless some of the diagnoses which have been made under this name would in reality have received another title did we but realize what was the underlying pathology. Some patients who have been called neurasthenics are in reality neurasthenics, but they are neurasthenics because they are suffering from a deficiency of hor- mones. I may perhaps be allowed to mention one other case as illustrating the relation between neurasthenia and the endocrinic glands. During the course of last year I was consulted by a doctor who informed me that he was a neurasthenic, and brought me a typewritten account of his symptoms, in support of this statement. I need not describe the case in detail, as the few points I mention will serve our purpose. The patient complained that he was slow mentally, became extremely tired after comparatively small 10 THE OEGANS OF INTEENAL SECEETION exertion, was exhausted after sexual conneotion, unable to concentrate for any length of time, and so on. On examination, I discovered a very slow pulse (barely fifty to the minute), a dry and rough skin, prematurely grey hair, especially over the temples (the patient was in the thirties), trophic changes in the skin appendages, and many other minor signs which I will not waste time by enumerating. Suffice it to say that the patient presented a typical picture of submyxcedema, and I advised small doses of thyroid. Some months later he advised me that he had suffered from some " extraordinary sinking feelings " when he had taken the thyroid, and in consequence had been forced to abandon it. I explained that these were most certainly due to the stimulating effect which the thyroid would produce upon the circulation, and I encouraged him to persevere with it. The interest of this case Ues in the fact that all the symptoms had gradually supervened after an attack of influenza, and that their real nature had never been diagnosed. Such a case as this will serve to show how a certain proportion of patients who have been treated, and only too frequently dismissed as incurable under some such name as neurasthenia, may be helped by the judicious administration of these extracts. I need not offer an account of the symptoms which make up these diseases, nor is there need for me to describe in detail what is so well known about indi- vidual symptoms of deficiency in thyroid, in pituitary, or in adrenals. But one or two points have come to INTEODUCTION 11 my notice about these conditions that I should like to mention in passing. There can be little doubt that deficiency in thyroid secretion comes on more or less suddenly in some cases. I recall the case of a young male subject who developed this complaint after a hazardous season on the Stock Exchange. His condition, when he came under my observation, was typical, and he made speedy progress under thyroid medication. Again, I have seen a typical attack of submyxoedema develop after one of the exanthemata; likewise excessive thyroid secretion ensue after such a disease as rheu- matism. It may be of interest to note at this place the extraordinary intolerance to tobacco which develops when the thyroid secretion is deficient. I have on several occasions observed that the patient, a heavy smoker previously, has had to abandon the fragrant weed at or about the time when his illness commenced. I have been told that even one cigarette is followed by unpleasant sensations, and I have ascertained that blood-pressure has been lowered as much as ten points after one cigarette. These occurrences all point to the fact that, given suitable conditions, it is not a difficult matter to upset the normal ratio between the various hormones. It is necessary in these cases to study the antecedent conditions with as much care as we should when taking the previous history of, let us say, a case of tuber- culosis. For in these patients we can often discover 12 THE OEGANS OP INTERNAL SECRETION some occurrence which may well have some bearing upon the etiology, and may give us valuable informa- tion both as to the actual cause and as to the particular gland at fault. Unfortunately, the therapeutics of the other glands are scarcely in such a satisfactory state as that of the thyroid gland, and we do not, in practice, obtain results as striking as those which so often ensue from the administration of thyroid. But, before leaving the subject, we may say a few words as to the pre- scribing of the adrenals. The extract of the adrenals may be given in the form of dry extract, and it is often of great benefit to those patients who are weakly, debihtated, with a low blood-pressure and constant fatigue. These are the cases of neurasthenia in which this extract should be tried. Again, the preparations of one or other part of the pituitary gland are in some of these cases more beneficial; while it is sometimes of service to use what Leonard Williams calls a " mitrailleuse " — i.e., a preparation containing the extracts of many glands. Such a one is Hormotone, and it is claimed that its exhibition is followed by marked benefit in many indefinite conditions. The method of treating disease by means of extracts of the endocrinic glands is, relatively, still in its infancy, so we must not be hypercritical at that part of this medication which works without the support of the laboratory. But, as has been admitted elsewhere by a physiological chemist, clinical experience often INTEODUCTION 18 is at variance with laboratory results, and clinical results are not always in the wrong. However much we may condemn the indiscriminate and speculative use of these extracts without adequate reasoning, il we abide by laboratory results, and never test these by practical endeavour, we are liable to remain with little added knowledge on these subjects as the years roll on. The practitioner must perforce use his eyes before he prescribes thyroid extract ; he must be familiar with the small signs which go to make up the picture of deficient or excessive action of this gland ; and he must not hesitate to prescribe this substance, although the signs are slight. He must be familiar with the diagnostic features, and he must be equally au jait with what is now known about treatment. He must choose a carefully standardized preparation; be careful that his preparation is new, and not several months older than when the local chemist purchased it from the wholesale house; and, finally, he must understand that the dose is a matter deserving the closest atten- tion. Thyroid, to quote one example, is not a drug to use from 3 to 10 grains, but in fractions of a grain — certainly to commence with. Had it not been for the fact that it has been utiUzed to reduce weight, the probability is that it would not have obtained that popularity which it now possesses in the lay mind. This has made its administration a matter of danger, especially when we consider that the dose, or rather the initial dose, is often far too large. 14 THE OEGANS OP INTEENAL SECBETION Convalescence is frequently accompanied by defici- ency in the thyroid gland, and its administration in minimal doses is of very real help. During the months which follow a serious illness, such as pneumonia, the administration of a " mitrailleuse " is frequently indicated. The tendency to obesity, or alternatively to undue loss of flesh, which is usual after severe ill- nesses, would point to an upset in the hormone balance ; and this may be remedied by a careful study of the symptom-complex and the prescription of a suitable organo-therapeutic extract. To all those who treat neurasthenia, who have to lighten the lot of those unfortunate sufferers from what are known as " the functional neuroses," the impor- tance of organo-therapy caimot well be over-estimated • When administered with intelligence, with the patient under observation, there need be no risk in such prescribing. Bather is there a risk in prolonging a morbid condition owing to neglect in the faculty of observation or an oversight as to the underlying causation. Again, what a difScult matter i' is to " fatten up " some patients. Best cures, hyperalimentation, malt extracts, digestive ferments — all seem to be of no avail. But the extracts of the ductless glands will often be found of service, when taken with regularity. It should, however, be remembered that thyroid must be prescribed with great care in such cases as these. Extracts of the brain and spinal cord, of the . pancreas and liver, of the testes and seminal vesicles, INTEODUCTION 16 are of much help. I have recently had under my care a man suffering from advanced neurasthenia, whose weight had dropped from eleven stone to between eight and nine. Under the administration of a mixed extract his weight is now (one month after the commencement of treatment) nearly ten and a half stone, although nothing had previously been able to stop the loss of weight. In the Practitioner for January and February, 1915, will be found many able articles from the pens of experts on the subject of the endocrine glands. These articles discuss fully the available material both from the standpoint of the laboratory and the bedside. A perusal of these numbers wiU well repay the time occupied. With these introductory remarks, we will leave the general survey of the possibilities of opotherapy, and wiU pass on to a consideration of the thyroid and parathyroid glands. In the next chapter we shall deal briefly with the histology and physiology of these glands, and offer a short account of the functions which have been attributed by different observers to these bodies. The grosser disorders of these glands are discussed in subsequent chapters. CHAPTER I THE THYEOm AND PARATHYROID GLANDS In the Introduction we briefly reviewed the present place of the endocrine glands ia mediciae, and sug- gested some practical points in connection with hormone-therapy. We now propose to discuss in a little more detail the more important of the ductless glands, laying emphasis upon the known results of administration of the extract of these glands, and^the signs pointing to deficiency or excess of secretion. Naturally, the thjToid gland first deserves our attention, and for several reasons. More is known of its characteristics, secretion, functions, and dis- orders; it takes a particularly important place in medicine on account of the frequency with which disorders of its functions are encountered ; and, finally, of all the ductless glands whose secretions have been utilized in the form of extracts for oral or hypodermic injections, the thyroid gland has given the best and most astonishing results. Prom *he moment when G. R. Murray first published the results achieved by administering thyroid extract to a patient suffering from myxcedema (October 10, 1891), great interest has been aroused in the practice of organo-therapy, 16 THYEOID AND PAEATHYEOID GLANDS 17 an interest which Brown-S6quard'3 previous state- ments on the results of feeding with testicular extract had failed to arouse. In 1890, Vassale in Italy and Gley in France experi- mented with injections of thyroid extract to animals who had been deprived of their thyroids, and demon- strated that these animals could be kept ahve by such injections. This was followed shortly afterwards by the application of this discovery to therapeutics, when Murray treated his case of myxcedema by thyroid extracts and established that this condition could be cured by these means. Previous to this date. Gull and Ord in England had investigated myxcedema, and Kocher had described a condition following the removal of the thyroid, which, from the similarity of its symptom-complex, was shown to be identical with the spontaneous condition already named myxcedema. As far back as 1859, Schiff discovered the fatal result which accrued from the total removal of this gland, and later, when Kocher described " cachexia strumipriva," or the condition of post-operative myxcedema which followed so many of his early operations for goitre, this fact attracted wide attention. Schiff and subsequent observers also discovered that transplanting the gland beneath the skin reUeved the Symptoms. Unfortunately, it has now been shown that an implanted gland is very liable to absorption, and thus to lose its utility. These researches had established the fact that 2 Missing Page Missing Page 20 THE OEGANS OF INTEENAL SECEETION at first rather bewildered by the apparent contradiction which faces us. Early observations upon the effects which followed the removal of the gland in animals showed that in camivora the effects were very severe, and often fatal, tetany supervening and the animal dying from cachexia. In herbivora, however, the results of such an operation where often exceedingly sUght, and were confined to a slight cachexia, but sometimes a rapidly fatal result ensued. The first inference to be drawn from this was that a meat diet was the important factor which accounted for the difference between the effects in carnivorous and her- bivorous animals. Gley, however, showed that the explanation was quite different, and he proved that the parathyroids (one pair, now usually known as the " external parathyroids ") were responsible for the wide difference in the results. He demonstrated that these small glands were so situated in carnivora that, when the thyroid was removed, the parathyroids were also removed; whereas in herbivora they were as habitually left behind. When the operations were made identical the results were approximated. This originated the view now widely held, which regards the nervous symptoms following removal as attributable to the loss of the parathyroids — ^the effects of thyroid removal alone being, in the young a condition analogous to cretinism, in the adult a cachectic condition. Indeed, in the young animal the effects of thyroid extirpation are much more marked than in the adult animal. A few of the changes THYEOID AND PAEATHYROID GLANDS 21 produced are striking. As we have akeady said, a cretinoid condition results, with delayed ossification of epiphyses, diminished development of the bones of the skull, protuberant abdomen, relaxation of the ligaments of the spinal column, and sexual infantiUsm. Alterations in the growth of the hair are observed in some species, and, most interesting of all, an extensive atheromatous degeneration of the aorta is found, which bears out the hypothesis that the function of this gland is concerned with calcium metaboUsm. Previous to this discovery Horsley had surmised that many of the features of thyroid inadequacy resembled those which characterize senile decay. Where thyroid secretion is excessive, we know that ttere is increased calcium leaving the body; and, in those patients exhibiting deficiency of thyroid, we may assume that increase of the calcium salts at the disposal of the metabolism results in an atheroma — a laying down of this substance in the walls of the arteries. After thyroid extirpation there are several changes which deserve special mention. There is a marked retardation in metabohsm in general, nitrogenous metabolism is greatly reduced, fat metabolism is likewise diminished, as the tendency to the deposition of fat in myxcedema shows. The animal without a thyroid exhibits excessive tolerance to carbohydrates; it can take abnormally large amounts without suffer- ing from glycosuria. The reduction in the metabolic exchanges naturally diminishes heat production, and this point is of interest from the practical standpoint, 22 THE OEGANS OP INTEENAL SECRETION human beings with deficient thyroid secretion being more susceptible to cold, and suffering increased discomfort in the winter months. As opposed to this, patients with Graves' disease rarely suffer any inconvenience from cold, but feel the heat of the Summer months to be almost insupportable. As is well known, they are nervous and restless, and the increased tissue wastage produces a rapid loss of flesh, and in some cases actual emaciation. The Parathyroid Glands. Turning now to the parathyroids, whose existence, it wiU be remembered, is of more recent discovery, we find that there are two pairs of these glands, situated, as we have abeady said, in close proximity to the lateral lobes of the thyroid gland itself. In structure they bear some resemblance to this latter gland, resembling it, however, more in its embryonic charac- teristics. They are formed of columns of granular epithelium cells, and show a very vascular connective tissue between these. It has been stated that, if these glands are left when the thyroid has been re- moved, they undergo a marked hjrpertrophy. To Sandstrom belongs the credit of first accurately describing these httle glands. His view was that they were in reality embryonic rests of thyroid tissue proper. At the present time, although our knowledge of their functions has advanced somewhat, much of the knowledge we possess may be described as more speculative than proven. MacCuUum came to the THYEOID AND PAEATHYEOID GLANDS 23 conclusion that they controlled in some way the calcium metabolism of the body. Calcium moderates the activity of nerve cells; therefore, when the secretion of the parathyroids is deficient, and calcium is lost from the nerve cells, the patient will suffer from an exaggeration of nervous excitability. This corre- sponds to the surmises as to the causation of the nervous symptoms which are manifest when the thyroid has been extirpated. In support of this view, the administration of extracts of the parathyroid glands in cases of tetany has been proved to be ef&cacious in controlling the convulsions. It will be remembered that tetany is a prominent symptom after extirpation operations in animals. Likewise the administration of calcium salts will control the symptoms of tetany. Opposed to the views just quoted, some observers believe that the parathyroids are portions of the true thyroid gland; that they have become separated from the gland itself, or that they secrete the same colloid, although they have not as yet formed vesicles; or that they develop into normal thyroid tissue, inter- mediate types having been noticed. It is stated that if all four parathyroids are removed the animal succumbs rapidly, no matter whether the thyroid is left intact or not. If one parathyroid be left, death does not usually ensue, although tetany may be brought on. It has also been said that changes in these glands are very common in cases of tetany in children, in pregnant women, and in osteomalacia (a disease associated with defective 24 THE OEGANS OP INTEENAL SECRETION calcium metabolism). This would seem to be sup- ported by the beneficial effects of calcium administered by the mouth as it would tend to replace the excessive loss of calcium due to the defective parathyroid secretion. With the few facts at our disposal, and the many speculative theories based thereon, it is natural that, many diseases should have been attributed to an abnormaUty of these glands. To take one example, it has been suggested that paralysis agitans may be due to disease of the parathyroid glands, but, un- fortunately, it does not appear to benefit by the exhibition of extracts of these glands.* This is, of course, not tantamount to a refutation of this theory, as it may mean that the extract undergoes changes during its passage through the body which rob it of its natural properties, so that it is unable to replace the normal secretion which should be deUvered into the blood-stream. The only instance which, so far as I am aware, has been published in which para- thyroid extract appears to have been absolutely successful, and to have been, if one may use the expression, specific, is described by Hurst in the Practitioner for January, 1915, in an article on the parathyroids. Briefly, this case was a man of middle age, who had suffered from an enlargement of the thyroid gland, and had undergone an operation in • An inteieeting case of paralysis agitans, in which pro- gressive atrophy of the globus pallidus was found, is described in the Medical Annual, 1918, p. 404. THYEOID AND PAEATHYEOID GLANDS 25 which the greater part of it was removed. He re- mained well for two years, and then suddenly became very restless, tremulous, and developed fibrillary tremors and other signs which closely resembled Graves' disease. His hair ceased to grow, he became impotent, his bowels were loose, and his weight decreased very rapidly. No treatment was of much avail, and the administra- tion of dry thyroid gland aggravated the symptoms. He was given dry ox parathyroid by the mouth, and from that day he began to improve, became stronger, increased very markedly in weight, and returned to work. Not until he had been taking the parathyroid gland for six months did his sexual powers return. Hurst thus concludes the account of this very interest- mg case: " His weight in February, 1914, had risen to 189 pounds; he felt perfectly well and strong, and no trace of nervousness remained, although he was working very hard." Here, apparently, was a, case in which the secretion of the parathyroids was deficient, and where its administration by the mouth was able to replace the normal secretion. If this latter surmise be correct, it would seem that it is possible for an analogous treatment to that of myxcedema to be initiated, if only we could arrive at an accurate diagnosis. It would support the school which believes in the separate functioning of the thyroid and parathyroid, and might eventually show us where we are lacking in the treatment of 26 THE OEGANS OF INTEENAL SECEETION exophthalmic goitre. It is certain that the removal of part of the thyroid does not cure this disease, although it may amehorate the symptoms for a variable time. If the nervous symptoms are due to excess of thyroid secretion, then removal of part of the gland should counteract the excess. But if this group of the many symptoms of Graves' disease owes its exist- ence to an abnormaUty of the parathyroids, we must alter our surgical treatment of this disease. On the other hand, we have yet to study the views of that school which has returned to Gley's original belief: that the parathyroids are part of the thyroid gland; that they are an embryonic and partly developed thyroid tissue. In support of this view, it is stated that post-operative tetany is greatly benefited by administering thyroid gland by the mouth, and that pure parathyroid, even in larger amounts, has not given the same results. It would appear from this that tetany owes its origin to deficient th3rroid, and not necessarily deficient parathyroid, although the ordinary sheep's thyroid gland contains parathyroid substance. This school, therefore, regards the parathyroids as part of the thyroid, and not separate structures; their function would be similar, and it follows from this hypothesis that the diseases which have been tentatively attributed to the parathyroids (mainly on account of the similarity which their symptom- complexes bear to those produced experimentally) must in reality owe their origin to thej^thyroid — THYEOID AND PAEATHYEOID GLANDS 27 assuming that they are in any way connected with this gland. This is comforting, as it narrows the field of inquiry: it leaves us one set of riddles to solve instead of two. But we must admit that this view is not widely accepted, mainly on account of the many small facts which have been collecting, albeit slowly, to show us that the parathyroids are undeserving of neglect. Functions ol the Thyroid Gland. We must now leave the subject of the parathyroid glands, and, before concluding this chapter, briefly review the theories which endeavour to account for the work of the normal thyroid gland. What is the function of the thyroid ? Does it govern metabol- ism ? Is it a " vital antiseptic " ? Or is it concerned with girowth alone ? The only way in which we can attempt an answer to these questions is to give some few facts and more theories deahng with the function of this gland. Firstly, then, the thyroid gland possesses the pecuUar property — ^peculiar in the sense that it is not shared, so far as we know, by the other endocrinic glands — of being able to store its secretion. This is proven by the fact that, in cases where the gland has atrophied or been removed, its secretion can be replaced by artificial ingestion. We quite naturally turn to the colloid as being the stored-up secretion, and, indeed, we are justified in so doing, as there is evidence to show that this substance arises as droplets in the 28 THE OEGANS OF INTBENAL SECRETION epithelial cells lining the vesicles (Dale). Again, this secretion contains a relatively large percentage of iodine (0-2 per cent.), and on this fact, or partly on this fact, has arisen the theory that the thyroid has a phagocytic or antitoxic action. In young animals, however, the iodine content is very small, and in adult animals it appears to bear a direct ratio to the iodine-content of the food. On the other hand, there is no reason to suppose that the power of the body to resist intoxication is raised when iodine or the iodides are given by the mouth; although Hunt found that young thyroids had some power to raise the resistance to a particular substance (acetonitrile), and that this power ran more or less roughly parallel to the iodine- content. In this connection, the action of iodides upon gum- mata is of interest; and, as pointed out by Eendle Short, the beneficial action of these drugs is in reality due to the increased action of the thyroid which is engendered by the administration. He says: " I have found thjTToid extract quite as effectual as iodide Of potassium in healing tertiary syphilitic ulcers." In speaking of the action of iodides on gummata and atheroma, he says: "In cases of myxoedema arterio- sclerosis is early and intense. The same is true in animals after removal of the thyroid."^ Eiselsberg gives a number of very convincing photographs of intense atheroma of the aorta in his cretin lambs in which the thyroid had been removed in early life. THYEOID AND PAEATHYEOID GLANDS 29 In the second place, thyroid extract has a wonderful power over young connective tissue, as is seen by the way in which it absorbs the subcutaneous thickening of myxcedema and cretinism. It is not surprising, therefore, that it should be able to deal also with gummata and atheroma. The theory of toxin-neutraUzation states that the secretion of the thyroid has the power to neutralize toxins which find their way into the blood-stream. It goes on to maintain that these toxins (of albuminoid nature) are absorbed from the alimentary canal, and undergo iodization in the thyroid by means of its secretion. It will be remembered that Lane maintains that atrophy of the thyroid gland is one of the features of chronic intestinal stasis. Is this the result of over- work? Hardly, for overwork produces hypertrophy not atrophy, and yet, if the symptoms and signs attributed to intestinal stasis owe their origin to toxaemia, and the thyroid is the neutralizer, then (to reconcile the two theories) the thyroid should be enlarged, not atrophied. In othei words, it should be overworked, not idle. We know, however, several facts of importance about the thyroid to balance this tangle of theories. Firstly, we know that a train of symptoms follows its deficiency or absence, whether produced experimentally or arising spontaneously, and that these symptoms will yield to thyroid feeding. The results of an extirpation operation in young animals differ only 80 THE OEGANS OF INTEENAL SECEETION slightly from the condition which we know as cretinism, while the adult analogy of this we encounter as myxoedema. Thyroid is therefore concerned with the growth of bone, with the development of the body, and with a normal circulation. It has been suggested that the reason why the coUoid is scanty in the young is that it is used as rapidly as it can be manufactured by the gland. As we shall see when discussing thyroid deficiency, the clinical pictures of the slighter forms of inadequacy require discrimination to discover, and are as yet not sufficiently definite for their wide acceptance. But the above facts lend themselves to further investigation. Again, in the adult, there can now be Uttle doubt that absence or diminution of the secretion produces, or helps to produce, a condition of secondary anaemia. Whether this argues any direct connection with the haematopoietic system, we are unable at present to say. That the thyroid is a direct circulatory stimulant there can be httle doubt; for the slow pulse, cold extremities, sluggish circulation, and deficient action of the sweat glands in submyxoedema, are very well recognized. The iateraction of the thyroid with the other duct- less glands is at present unknown, but the future will probably show that the relation between the thyroid and some of the other endocrinic glands, notably the spleen, is a close one. We must here leave the discussion of the thyroid THYEOID AND PAEATHYEOID GLANDS 31 and its small neighbours, realizing only too well that many blanks stiU remain to be filled up, which further light on this most difi&cult subject can alone do.* Reference. * The Newer Physiology in Surgical and General Practice, by A. Rendle Short, third edition, pp. 82, 83. * For a fuller account of the thyroid gland, the reader is referred to MoCarrison's work (see Bibliography on pp. 265- 267). CHAPTEE II EZOPHTHALUIC GOITRE Synonyms: Graves' Disease; Basedow's Disease; Hyperthyroidism. With increasing knowledge, the conception of this disease has become a much more difficult matter than when it was regarded as being solely due to an over-action of the thyroid gland. Modem views as to the pathology of Graves' disease would have us beheve that, although derangement of this gland is present in this malady, the thyroid is not the sole organ at fault, neither is a hyperseciion of this gland alone responsible for the symptoms. Definition. Let us for a moment refer to some definitions of this condition which have been current, and then compare these with modem views as to the etiology and pathology. In one textbook of medicine we meet the foUowiag definition : "A disease characterized by enlargement of the thyroid, exophthalmos, in- creased action of the heart, tremor, and nervous instability."^ Again: "The four classical symptoms A9 EXOPHTHALMIC GOITRE 33 of Graves' disease are — ^A staring appearance of the eyes, generally spoken of as exophthalmos, though there need be no actual protrusion of the eyeballs; moderate and almost symmetrical enlargement of the thyroid gland; a pulse-rate between 120 and 180 per minute — ^usually about 140 when the attack is moderately severe; and extreme nervousness, with fine tremor of the outstretched fingers. When all these symptoms are present at the same time, there can be little doubt as to the diagnosis, but very often some of them are absent, and it is possible for tachy- cardia to be the only sjTnptom of the disease."" " There are three prominent symptoms : Protrusion of the eyeballs, enlargement of the thyroid gland, and frequent action of the heart." ^ " We are accustomed to recognize three cardinal symptoms in this disease — namely, (1) tachycardia, (2) goitre, and (3) exophthal- mos; but we must remember that these are not the only symptoms."* These definitions represent the general views which have been held on the nature of the disease and on the most constant symptoms. The condition was first recognized by the celebrated Dublin physician whose name it now bears about the year 1835, although Von Basedow in 1840 pubhshed a paper on the subject. Consequently the disease is in Germany and some other parts of the Continent still referred to as " Basedowsche Krankheit," or " Von Basedow's disease." However, as early as 1825 Caleb Parry, of Bath, drew attention to the 3 34 THE OEGANS OF INTEENAL SECEBTION condition, and, according to Osier, to him belongs the credit of first describing the disease. Many of the early conceptions of the malady have, in the fulness of time, given place to views which have been promul- gated from the results of the extensive practical physiological research which has been imdertaken in order to establish the causation of the disease. But it was recognized then, and it is believed now, that emotional strain can precipitate the disease. Thus Trousseau refers to a lady who was suffering great grief at the death of her father, and had been crying for a long time; she " suddenly felt her eyes swell and Uft up her eyehds." This was accompanied by copious epistaxis, violent palpitation, and throbbing and enlargement of the thyroid. A few days later the nature of the disease was recognized. Again, Stokes describes the case of a man who developed the disease from long-continued bleeding from piles; and many other records show that the etiology of the disease was universally regarded as a wide one. From the early thirties of the last century the nature of the condition was recognized, but it is only com- paratively recently that the diagnosis has been narrowed. Thus, it wiH be seen, from the definitions quoted above, that it is not necessary, as used to be thought, for all the classical symptoms to be present in any given case. Nevertheless, there is one symp- tom without which, as Mackenzie rightly insists, the condition cannot be diagnosed, and that is persistent tachycardia. EXOPHTHALMIC GOITEE 35 So we come down to this : that exophthalmic goitre may, and in the opinion of many observers does, exist without the exophthalmic symptom. It is, there- fore, somewhat unfortunate that the name of the disease should be inseparably connected with a symp- tom which is by no means constant. But we carmot at the moment, at any rate, suggest any other name which is free from objection. As we shall see later the modern nomenclature which is sometimes used — namely, " hyperthyroidism " — is open to an equally serious objection, as it implies that it is always an over-action of the thyroid alone which is responsible for the features of the disease, of which we must reckon proptosis, when present, as one. Again, it has been pointed out by one observer that this latter symp- tom is significant of over-action, not of the thyroid, but of the adrenals.^ Therefore, hyperthyroidism is a no more suitable label for the disease than is exophthalmic goitre. Although there seems to be an objection to utihzing the name of the discoverer of a disease to designate that disease,* in the present * It may be affirmed that this mode of naming a disease after its discoverer is to be deprecated, partly on account of the difference of opinion as to whom the credit of the discovery really belongs, and partly because it is, perhaps, an unfortunate reward for the happy pioneer in the particular disease. Again, if a disease is discovered more or less synchronously by different observers in different countries, a nomenclature is adopted which varies with the different countries, and this all leads to confusion. If a disease is called by its most distinctive feature, this will probably be similar in different languages, so where such a course is possible it is certainly to be preferred. 36 THE OEGANS OF INTEENAL SECEETION instance it would seem, for the moment at any rate, to be the most satisfactory way to designate this malady. " Graves' disease " has the merit of being non-committal as to symptoms, and less unwieldy than many of the other names by which the disease has been known. In the majority of textbooks, the malady under discussion is referred to as " exophthalmic goitre," in contradistinction to ordinary goitre. When the swelling in the neck, if present, is accompanied by the other well-recognized signs of Graves' disease, such as persistent tachycardia, exophthalmos, tremor, and other symptoms and signs to be described anon, then we diagnose the presence of this disease as opposed to simple goitre. Etiology and Symptoms. Graves' disease (as we shall call the malady in this book) is seen more commonly in the female sex than in the male, and more commonly in young people than in elderly. It has been seen, however, ia an infant only two and a half years of age, and several cases are on record of the disease occurring in children of both sexes. Von Graefe stated that the proportion of females to males was 6 to 1, while Eulenburg said that the ratio was at least 2 to 1. Trousseau's cases show a ratio of 50 to 8, Henoch's 23 to 4, and Prael's 28 to 1. Whatever figures we study there is plainly a vast preponderance of females over males. The EXOPHTHALMIC GOITEB 37 commonest time for the disease to develop is in the decades twenty to forty, and its features are often made manifest at critical times in the history of the patient, such as puberty, the catamenia, and the menopause. Indeed, it is said that in normal persons of the female sex the thyroid is liable to swell and to exhibit increased vascularity at these times and during sexual excitement. As we have already indicated, there can be little doubt that, certainly in individuals prone to the disease (by this I mean persons who exhibit signs indicative of thyroid instability), a mental strain or a sudden anxiety seems to be capable of precipitating the disease. Again, there is a sufficiency of evidence to show that a parenchymatous goitre can develop into an exophthalmic goitre, given suitable opportuni- ties. The symptom-complex which is produced by thyroid feeding on a large scale differs in many details from the symptom-complex of this disease, so, as Biedl says, we must regard the similiarity of the two pictures, not as conclusive evidence that the thyroid is the organ responsible for the disease, but as very strong presumptive evidence. When we come to study the symptoms of Graves' disease, we see three or four definite and fairly con- stant features, and a multitude of smaller and some, what vaguer signs. There can be little doubt that tachycardia deserves the first mention, as it is very constant, and may be looked upon as a fundamental sign of this disease. Indeed, it is one of the symptoms 38 THE OEGANS OF INTEENAL SECEETION which can always be produced by the ingestion of thyroid extract; and there must be very few cases of undoubted exophthalmic goitre which do not show this sign. The pulse is usually rapid, ranging from 100 to 140 or more per minute. The pulse-wave is not always thin; indeed, in many cases a full and bounding pulse is observed. Again, it is usually regular, but the rate increases upon very slight exertion. In this connection it is interesting to refer to the theory which Bppinger and Hess brought forward. They consider that the symptoms seen in Graves' disease enable us to divide these cases into two groups. In the first the symptoms of sympathetic excitement predominate, and these they describe as sympathetico- tonic; while the second group is described as vago- tonic, from the fact that the symptoms seem to proceed from disorganization of the autonomous system. " Palta, Eppinger, and Eudinger, assume a polyvalency of the thyroid secretion, and they regard the hyperthyroidism of Graves' disease as the out- come of a simultaneous though probably independent stimulation of both the sjnnpathetic and autonomous nervous systems."" There seems to be little doubt that tachycardia is only one of the many symptoms seen in this disorder which can be justly attributed to the sympathetic nervous system. We shall refer to these later. The symptom which merits consideration next is the local enlargement of the thyroid gland. Although not so constant as tachycardia, it is nevertheless EXOPHTHALMIC GOITEE 39 present in the majority of cases of this disease. The thyroid is generally moderately enlarged, the right side being perhaps more so than the left. In some cases, however, the enlargement is scarcely perceptible, while, on the other hand, it may be very great. In the early stages the gland is soft and elastic from vascular engorgement, but later it becomes harder from fibrous hyperplasia. Histologically the gland presents a picture of diffuse enlargement, with a great increase in the vascular supply. There is definite new formation of tissue, which runs hand in hand with certain retrogressive processes, notably cell desquamation. Young folUcles are seen associated with older cells, and in the latter may be seen breaking-down processes. As a rule a thrill can be detected, certainly in the larger tumours, and as the disease progresses the thyroid may alter in size, diminishing in favourable cases. It is said that the histological appearance in Graves' disease is typical, and Erdheim maintains that the young cell formations with fat granules are characteristic of Graves' disease. For a long time the proptosis was looked upon as an essential feature of this disease, and it is only recently that we have come to realize that it is by no means always present. Its origin or, rather, the changes which underlie the exophthalmos are still unknown. It has been suggested that it is due to a deposit of fact behind the eyeballs; to a venous con- gestion in the posterior part of the orbit ; to dilatation 40 THE OEGANS OF INTEENAL SECEETION of the retrobulbar arteries; or to contraction of Miiller's muscle. It is pointed out that the sympathetic system is largely connected with the symptoms of this disease, and that a disorganization of this system wiU account for many, indeed for most, of the features, always excepting the changes in the gland itself. On this theory it is much more probable that the proptosis is due to circulatory changes than to either a contraction of Miiller's muscle or a deposit of fat in the orbit. There are certain classical signs which one is ac- customed to look for in association with the ex- ophthalmos, and we must briefly refer to these. The widening of the palpebral fissure gives an appearance of great protrusion to the eyeball, and this is partly due to the retraction of the upper Ud. This is known as Stellwag's sign. Although the eyeball in many cases appears to be prominent, it is in reality less so than it appears, on account of the uncovering of the eyeball due to the retraction of the upper lid. There is also a diminution of the reflex excitability of the eye, so that there is less irritation of the globe than would otherwise be the case. Another sign in con- nection with the lid is known as Von Graefe's sign, and consists in a lagging of the upper Hd behind the globe during the downward descent of the eye. Sometimes there is an insufficiency of the internal recti muscles of the eye, as a result of which con- vergence of the eyes in near vision is imperfect Mobius). Occasionally blepharo-clonus is present. Tremor is another constant sign of Graves' disease. EXOPHTHALMIC GOITEE 41 and is quite characteristic. It is usually very fine, and confined to the hands, although occasionally it is seen in the muscles of the trunk, so that by laying a hand on the shoulder or trunk the observer can feel a quiver of the whole body (Oppenheim). The tremor of this disease is usually excited by movement or by nervousness, but is also present during rest. The rate of movement is somewhere about nine per second, and can best be seen when the patient extends the hands with the palms downwards. Before turning to the discussion of the mental changes present in Graves' disease, there remain a few less constant symptoms and signs which we have to mention. These may be classed under the headings vasomotor, secretory, and trophic. The subject of Graves' disease is very liable to suffer from profuse perspiration; indeed, in some cases this amounts to a definite hyperidrosis. As we stated in the previous chapter, these patients feel the heat greatly, and naturally this symptom is worse in hot weather. The sweating may be more or less local, or it may be general. One point of interest in this connection is with regard to the electrical resistance of the skin in cases of Graves' disease. Vigoroux first discovered that in patients suffering from exophthalmic goitre the electric resistance of the skin was diminished. This is now generally beheved to be due to the undue moisture of the skin owing to the increased sweating. Flushing of the skin, quite irregular in distribu- tion, erythemata of a patchy nature, pigmentation — 42 THE OEGANS OP INTEENAL SECEETION particularly of the margins of the lids of the eyes, and sometimes as marked as that seen in Addison's disease — are all phenomena of this condition. As is well known, there is a tendency to loose evacuations of the bowels, sometimes of actual diarrhoea; while the secretion of urine is also increased. The digestive system is often upset, and attacks oi sickness, with bulimia, or, alternatively, loss of appetite, are about equally common. The reflexes are often altered — ^more usually in- creased, although they may be diminished, or even, in rare cases, absent. Cases are occasionally encountered in which the symptoms present a strange combination of those seen in exophthalmic goitre and those characteristic of thyroid deficiency. Thus, patches of lipomatosis are sometimes met with in a typical case of Graves' disease; while occasionally the condition of the skin approximates much more nearly to that typical of submyxcedema. Leonard Williams believes that there is often, if not always, a combination of excess and deficiency in this disease. Again, some of the symp- toms which we are accustomed to regard as indicative of disease in the chromaffin system, such as pigmenta- tion, would suggest the presence of a combination of thyroid and adrenal disturbance. But as important, or nearly as important, as the physical symptoms of this complaint is the mental change which characterizes exophthalmic goitre. The main features of the sufferer from this disease are well EXOPHTHALMIC GOITEE 43 known, but perhaps a brief sketch of the mental make-up of the patient may be useful. Whatever s the agent at work in these cases, whether the dis- turbance is originally in the sympathetic system, or to be attributed to an excess of thyroid secretion due to a cause or causes unknown, it is one fraught with evil for the peace of mind both of the patient and her relatives. Prom being gentle and docile, it may be, she changes to an intractable, selfish, restless, and inconsiderate being. The medical attendant as a rule receives the full benefit of this, and Httle he can do is right. He is either old-fashioned when he explains that the reason for rest in bed, for example, is to avoid straining an already weakened heart; or an ignoramus if he insists that rest combined with hygienic principles offers the best hope for alleviating the disease. If he suggests trying a new remedy, he is experimenting with her; if he persists with the old, he is a " stick-in-the-mud." Perhaps the saddest of the changes wrought by this disease are the changes for the worse in the psyche, and it behoves the medical man to be very tactful with such patients, and to remember that the mind is the victim of a disordered bodily fimctioning and is no more to blame for its vagaries than the victim of, let us say, puerperal mania.* The mental symptoms are, like the physical, capable of entirely clearing up ; but even so, Leonard Williams * For a fuller discussion of the psyoho-physioal disturbances of Graves' disease see Chapter XI., p. 221. 44 THE 0EGAN8 OF INTEENAL SECEETION doubts whether the individual is ever quite the same again. There can be little doubt that this disease plays havoc with the patient's character. It changes the quiet to the restless, the unselfish to the self- centred, and the amiable to the perverse. That these patients are notoriously difficult to treat is well known; that they make the treatment of their condition doubly difficult by their attitude to what is being done for them is almost equally well realized by every- one cormected with the case except the patient herself. Apart from the changes in character which we have outlined, more serious symptoms are seen in coimec- tion with Graves' disease. Apart from actual insanity, such as melanchoMa, mania, hallucinatory confusion, and obsessions, there are the minor changes which are apt to lead to these more serious psychoses. Thus, the patient is excitable, wildly restless, sleepless, and confused. She is incapable of organized thought, of successful memory, or of attentive control; while her general mental habits have been well spoken of by Eeynolds as " mental chorea." It is quite obvious that it is but a short step from this stage to that of insanity. Needless to say, fortunately only a relatively small percentage passes from the mentaUty characteristic of Graves' disease to that typical of insanity. Never- theless, the picture we have drawn of the mental condition of these sufferers is not exaggerated. It is true that in many diseases which the physician is called upon to treat to-day the patient's worst enemy EXOPHTHALMIC GOITEE 45 is himself; and in no disease is this more true than in exophthalmic goitre. Consequently, it is no rare occurrence for such a patient to pass from one doctor to another, giving no one a fair chance to improve the patient's condition. This is the analogue in the mental apparatus of the restlessness in the physical system which prohibits the patient from resting, which is the one thing most to be desired. Thus is her tempera- ment at the time her worst enemy, and it is this which needs treatment quite as much as the syndrome of symptoms which we have been discussiag. Such, then, is the bare outUne of what constitutes Graves' disease. What is the , prognosis, and what can we do to benefit that part of suffering humanity afflicted with Graves' disease ? Prognosis. First as to prognosis. The course of the disease is very variable; it may in rare cases be rapidly fatal, or it may linger for many years, sometimes showing improvement, at other times retrogressing. Mackenzie gives the mortality at approximately 25 per cent. In patients who eventually recover, there is often a period when no improvement seems to take place and the disease seems to be stationary. Even in these cases there is a prolonged convalescence, and sometimes years afterwards some sUght trace of the disturbance can be found. In the early stages the malady is very liable to be 46 THE OEGANS OP INTEENAL SECEETION diagnosed wrongly, some such diagnosis as neurasthenia being made. This probably partly accounts for the advances which this disease makes in the early stages, owing to a misconception of the nature of the trouble. Also the prognosis must be based upon the length of duration of the disease, the prominence of individual symptoms, the means of the patient, and, last but by no means least, the degree of mental abnormahty which exists. But, speaking generally, p,atients who have had the disease for a long time, especially where treatment has been of little avail, are not the most hopeful of subjects, and there seems httle reason upon which to base hopes of complete recovery. Indeed, in such cases as these it is doubtful whether they are ever entirely restored to the sfaiws quo ante. Although it is usual to see ameUoration of the symptoms, even a vanishing of the proptosis, or at least a diminution of the amount of protrusion, under successful treatment, such patients are extremely liable to relapse. Their nervous symptoms recur from time to time; indeed, it would seem that it is very difficult for them to return to the successful functioning of this system once Graves' disease has developed. There have, however, been many reports of recovery of long duration. Cheadle reports recovery lasting twenty years; while Oppenheim says that, in one case of his, recovery lasted " for twenty-seven years, in another for eighteen, in four for six to eight years." ^ The chief difficulty lies in keeping up the faith of the EXOPHTHALMIC GOITEB 47 patients, in exacting obedience, and in counteracting individual symptoms. Sudden death has taken place during the course of this disease, and when we remember the strain upon the circulation, the dilatation of the heart, and the disorganization of the neuro-musculature of this organ, it is not to be wondered at. Occasionally, as a sequel to this malady, atrophy of the thyroid may take place, with resulting myxcedema. Treatment. We shall have to refer at some length to the treat- ment of this malady, for it necessitates a discussion of methods which have been utilized for many years, as well as those which have found favour recently. Modem physiological research has enhghtened us upon many points in this connection, and some of these have pointed to different methods of treatment, a few of which, at any rate, have shown signs of success. But whatever treatment we may initiate — ^whether we incline to the old practice of counteracting the symptoms by controUing the exuberance of the heart's action, by producing adequate sleep, by anointing the thyroid glands, or by countless other small attentions — one factor remains constant, and that is the insist- ence upon sufficient rest, even complete rest in bed in bad cases. The apphcation of the principles of general hygiene cannot be insisted upon too firmly, for this should be the bed-rock upon which all subsequent 48 THE OEGANS OF INTEENAL SECEETION treatment is based. The difficidty is that the restless- ness which these patients so often ekhibit makes this stipulation a difficult matter to enforce. Nevertheless, it is not so much a matter of the practice of medicine as of the practice of common sense which suggests this; for it must be obvious that exertion, particularly undue exertion, which is always followed, as it is in this disease, by an increase in the symptoms, must be wrong, and therefore in no circumstances to be con- sidered. When tachycardia is present, as it invariably is, our first aim must be to reduce the work of the heart to a minimum, and in doing this to reduce the tachycardia. Even if the rate of the heart's action is not excessive, the patient must be made to take periodic rests in the course of the day. She should rise late and retire to bed early, resting after meals, and avoiding hurry and perturbation. Where tachy- cardia is a marked feature, and more especially where the signs of general debility with marked loss of flesh are evident, complete rest in bed is essential. There can be httle doubt, moreover, that these patients require every hygienic advantage which can be given them. Thus, where possible, they should reside in the country or by the sea, but not in too bracing a place. They should rest in the open air, lie in the sun for the greater part of the day, and at- tempt no exercise of a strenuous nature. I have on several occasions had occasion to emphasize the harmful effects which absence of rest has produced; but it is often extremely difficult to make the patient under- EXOPHTHALMIC GOITEE 49 stand this. Again, the diet must be regulated to the individual case, and with some thought to the nature of the disease. Thus, we must bear in mind what underlies this malady, especially what has been discovered in recent years. Firstly, the condition of the gastro-intestinal tract must be considered: if the digestion is good, and there is little tendency to diarrhoea, vegetables may be permitted, but this item of diet must remain under the control of the medical attendant. Again, in this connection we should bear in mind another important fact — ^namely, that iodine is ex- cessive in the colloid in Graves' disease, and is also contained in most vegetables. Therefore we do not want to add to the amount already present in the body. In this connection Eendle Short says: " We see also that exophthalmic goitre is due to hypersecretion of the iodothyrin, as is proved by the artificial imitation of the disease by excessive thyroid feeding, by the excess of iodine present in the colloid in Graves' disease, and by the character of the histological changes. Thus, we have reason to expect good from partial removal, which has been very successful in the hands of Kocher, the Mayos, and others. It would be reasonable also to try the effect of iodine starvation by eliminating vegetables and ordinary tap-water from the dietary, and substituting for the latter the water of a goitre well. It is well known that exophthalmic goitre and parenchymatous goitre show a sort of geographical antagonism, and the effect 4 ' 50 THE OEGANS OF INTEENAL SECEETION of the water in reducing the amount of iodine for conversion into iodothyxin would be valuable."^ It must be borne in mind that parenchymatous goitre is supposed to occur owing to a deficiency of the iodothyrin, so that the thyroid hypertrophies in an endeavour to supply that deficiency. If, therefore, there is little of this element in the thyroid of sufferers from parenchymatous goitres, they may be helped by the ingestion of vegetables. The water of the well-known goitre weUs is supposed to produce paren-. chymatous goitres by containing a substance which deprives the body of the iodine by forming a combina- tion with it. In an effort to counterbalance the diminished output of iodine the gland hypertrophies. On this assumption, then, it is recommended to try the water on patients suffering from exophthalmic goitre, in the hope that the unknown substance in the water wiU utihze some of the excessive secretion of the thyroid. Turning now from the consideration of the general treatment of this disease, we find a host of other remedies which have from time to time been recom- mended. Apart from symptomatic remedies, over the consideration of which we shall spend but little time, we have before us a choice of many drugs, both for internal and external application. Of these, preference seems to He with belladonna, aspirin, the saHcylates, arsenic, and iron salts (where indicated). As we have already said, Graves' disease is often associated with ansemia, and therefore some benefi* EXOPHTHALMIC GOITBE 51 may be expected by the administration of these latter salts. Of cardiac tonics, some authorities prefer strophan- thus, while others recommend digitahs and nux vomica. But the help which the physician may expect from these drugs is strictly limited to their local action upon tachycardia. Leonard Williams has reported good results in several cases from the hypodermic or intramuscular injection of bile salts. The rationale of this treatment lies in the fact that it is well known that these salts circulating in the blood produce a sedative effect on the brain and a slowing of the pulse. Of recent years more and more stress has been laid on the chance of finding an organo-therapeutic com- pound which will help to neutrahze the excessive action of the thyroid. Extracts of the adrenals have been tried, as also the extracts of pituitary, the ovaries, the parathyroids, and the spleen. Unfortunately, these have not given good results, only the para- thyroid holding out any hope in this direction. But there remain several external remedies to mention, some of which have been stated to give really good results in some cases. Of these, the X rays is very well spoken of when applied to the exterior of the gland, and it has been said on many occasions to have limited the exuberant activity of the thyroid. In the Bradshaw Lecture,® Hector MacKenzie describes in some detail the treatment of Graves' disease by the X rays. He relates a case of this disease which, under 62 THE ORGANS OF INTEENAL SECEETION Rontgen therapy was converted into a typical case of myxcedema. In all, thirty-six treatments were given, extending over a period of four years. MacKenzie considers that a possible reason why treatment by the X rays has not up to the present yielded better results is because it has not been persevered with for sufficiently long. In commenting upon this case, he says: " I have never before seen such a complete disappearance of the signs and symptoms of well- marked exophthalmic goitre as has taken place in the above case. I think one is justified in ascribing the cure to the prolonged X-ray treatment. "My present views on X-ray treatment are: It may prove to be far the best means of treatment at our command. It must be applied in no half-hearted way. It must be persevered with, and in many cases continued for a long period. It is most likely to prove beneficial in cases where the thyroid enlargement is moderate and the patient is not so seriously ill as to necessitate confinement to bed. I think it may prove valuable in bringing about a retrogression of the remaining thyroid after hemithyroidectomy. I have not at present sufficient evidence to speak of its usefulness where the goitre is a very large one. It has seemed to fail, as other remedies do, in cases of a severe type and rapid course. The trend of present experience in respect of X-ray treatment is decidedly in favour of its further trial." Again, galvanism and faradism, applied either- to the gland itself or to the sympathetic in the neck, has EXOPHTHALMIC GOITEB 53 been tried, sometimes with success. Or a compress of adrenalin applied to the goitre is a help in some cases. I have had good results in some patients from the application of a mercury ointment to the thyroid. A small portion rubbed in every night, associated with internal treatment, has on more than one occasion resulted in an amelioration of the symptoms. Again, since 1884 preparations have been manu- factured from thyroidectomized animals. Of these, the more important are " antithyroidin " (Mobius), " heemato-^thyroidine," and " thyroidectin." Beebe has evolved a method of treating Graves' disease by an antiserum produced by the inoculation of a thyroid preparation in animals.^° It is too soon to speak of the results of this latter treatment, but its value is said to have been proved in a large number of cases. Some observers, notably H. Campbell,^^ advocate the administration of calcium salts to patients suffer- ing from exophthalmic goitre, and claim better results from treatment in which this medication is included than from any other treatment. Again, preparations of thymus gland have been recommended for this disease, but so far no very encouraging reports have been pubhshed. Many authorities speak very highly of the beneficial effects of X rays, and claim that treatment by this method successfully counteracts the over-action of the thyroid ; while some observers maintain that the X rays 54 THE OEGANS OP INTEENAL SECEETION should always be administered before an operation is finally decided upon. With regard to the question of operative interference, there can be little doubt that it should be reserved for the grave cases only, and that it should only be performed after all other remedies have failed. The medical man must insist upon hygienic principles as a sine qua non, and he, as well as the patient, must regard the disease as one requiring the tacit obedience which is given to the orders of the medical man in a disease such as pneumonia or typhoid. If this is done, the patient is prevented from straining an already overworked organ, and much possible mischief may be prevented. In conclusion, we must emphasize the fact that, of all diseases which the medical man is called upon to treat, probably no one makes such caUs on his per- severance and patience. For he has to treat an irresponsible patient, and one who is not the best judge of her condition. He requires infinite tact and an everlasting patience if he is to see the fruits of his labours. Furthermore, he must perforce try any remedies which hold out a chance of help, and he must discriminate nicely between those which are logically futile and those which are based upon reason. There is some ground for hoping that in the near future, as our knowledge of the disease and its causa- tion widens, we shall evolve a more satisfactory mode of treatment. For the present we must make up by our resourcefulness what we lack in our nicety of knowledge. EXOPHTHALMIC GOITEE 55 Refeeenobs. 1 A Textbook of Medical Practice, edited by Bain, p. 315. " Index of Differential Diagnosis of Main Symptoms, edited by French, p. 772. 3 The Practice of Medicine, by Taylor, p. 860. * A Textbook of Nervous Diseases, Oppenheim, p. 1343. 6 Maurice, Lyon MSdical, quoted by Leonard WiUiams in Practitioner, January, 1915, p. 96. " The Internal Secretory Organs, by Biedl, p. 98. ' Oppenheim, Textbook of Nervous Diseases, p. 1349. ' The Newer Physiology in Surgical and General Practice, by A. Rendle Short, pp. 85, 86. 9 Lancet, 1916, ii. 815. 10 The Diseases of the Ductless Glands, for Practitioners of Medicine and Surgery, by S. P. Beebe. " H. Campbell, Exophthalmic Goitre, Clinical Journal, 1915, xliv. 329. CHAPTER III THYBOm DEFICIENCY In the previous chapter we dealt with the disease variously known as " Graves' disease," " exophthalmic goitre," and " hyperthyroidism," and showed that there is strong evidence to support the view that the symptoms are largely caused by excess of the thyroid secretion. In this chapter we propose to discuss thyroid deficiency, laying emphasis on the lesser degrees. The history of thyroid-therapy has already been given, and we have described the earUer operations of Kocher upon the thyroid, and referred to the condition of " cachexia strumipriva " which was liable to ensue. Likewise we have mentioned the earlier work upon the functions of this gland, and the discovery by Gull and Ord of the disease myxoedema. Reference was also made to the important fact elicited by G. R. Murray, that this condition yielded to the adminis- tration of extract of thyroid gland. The discovery was of the greatest importance, and for two reasons: First, because it proved beyond question that the pecuhar disease to which the name " myxoedema " had been assigned was largely due to 66 THYEOID DEFICIENCY 57 a deficiency or absence of the thyroid secretion; second, and^even more important, it enabled complete rehef to be afforded to the unfortunate sufferers. Since that time a great deal of work has been done on the thyroid, both by laboratory workers and clinicians, with the result that myxcedema has emerged from the nebulae of ignorance, and has taken its place as a curable disease. But quite recently workers in all fields of medicine have been observing cases which, while they were by no means comparable to myxcedema, were sufficiently similar to appear to resemble this condition in certain points. As a countenance reminds one of a more famihar face by reason of a similarity in one feature, so do these eases, sometimes because of an item one can barely specify, make one think of the more marked disorder. In this chapter, then, we wish to include those cases whose vagueness is a defiance to conclusive diagnosis, as well as the more definite disease which has received the name of " myxcedema." As we have already in a previous chapter discussed " cachexia strumipriva," we shall here confine our attention to that variety which arises apparently idiopathically, and not ensuing after operative procedures. Myxcedema. We will briefly review the features of this condition, but will not attempt to describe them in any detail, as they can be found discussed in any textbook of medicine. 58 THE OKGAlsrS OP INTERNAL SECEETION As we have already said, Gull and Ord, G. R. Murray, Kocher, Mayo, and others, are the workers responsible for unearthing the cause of the symptom-complex which is known as myxcedema, and to Murray belongs the credit of discovering that the administration of thyroid extract reheved the symptoms. Myxcedema is one of those interesting clinical con- ditions which are diagnosed rather by the summary of the effects produced by the individual symptoms than by one predominant feature. Thus, we find that a typical instance shows to the observer a slowly- moving, mentally sluggish, and prematurely aged individual, with localized deposits of fat, more marked in certain areas, a dry, rough skin, characteristic facies, and uncertain gait. The patient is altered in most ways ; indeed, the disease, in common with many, if not most, of the serious disturbances of the endo- crinous glands, changes the personality of the patient almost beyond recognition; but this alteration is, in the majority of cases, gradual. The onset of the disease is insidious, and may occupy several years, although in a few instances its onset is more acute. The initial symptoms vary in different cases, but most usually commence with lassitude, debility, disinclination for exertion, and marked susceptibihty to cold and chills. The patient appears a changed man, and, to anyone who has not seen him for a protracted period, almost a different being. He becomes much stouter, and the actual body-weight is increased, but the fat is THYEOID DEFICIENCY 59 deposited in a characteristic manner. Pads of adipose tissue are situated in the clavicular regions, over the cervical spinal area, and in the neighbourhood of the lower ribs and flanks. But perhaps the facies is even more characteristic. The eyelids are thickened, with resilient bags of fluid under the lower lids; the lips, ears, and tongue, are enlarged; and the whole appearance of the face is one of extreme coarseness. At the same time there is an absolute lack of any intelligent expression in the face; the features are immobile, with, in some cases, a shght expression of sur- prise, owing to the eyebrows being somewhat raised.* The skin loses its normal moisture, and becomes harsh, dry, and rough. The teeth are frequently in a state of decay, the nails are ridged, and the hair loses its gloss and shows evidence of trophic change — in fact, the epidermal appendages undergo atrophic degeneration. The individual becomes comparatively lifeless. His extremities change; his hands are carried in a peculiar maimer, which has received the name of " spade-hands," while his feet enlarge (not, however, hi a marked manner, as is seen in gigantism), and are carried in a clumsy manner. Even the fingers show a change, for they are shaped somewhat Hke sausages, and are not narrower between the joints as are the fingers of a normal person. * In " The Expression of the Emotions," Darwin draws attention to the curious fact that cretins never weep. They may cry out or moan, but do not, it appears, shed tears. 60 THE OEGANS OF INTEENAL SECEETION Small warty growths are liable to appear on the surface of the skin; while patches of dry eczema, similar to psoriasis, make their appearance. The changes in the habits are equally characteristic. The speech is slow, and a long time elapses before an answer is given to a question. Co-ordination is interfered with, and the gait is " waddling." The mental attitude is almost exactly antagonistic to that which is typical of exophthalmic goitre. Thus, the patient is slow in every act, whether this act involves mental or bodily exertion. The finer co-ordinations of the muscles are deficient, a greater length of time is required even for simple acts, while the mental hebetude is shown by the set and iminteUigent ex- pression of the face. This disease depends upon an atrophy of the thyroid gland, which can be demonstrated by an examination of the gland in the neck. It will be much harder to localize than in health, and to the examining finger its presence can only be detected by requesting the patient to swallow. That the disease owes its origin to an absence or diminution of the thyroid secretion there can be no doubt; for the administration of an extract of this gland removes, or markedly lessens, the symptoms. Lesser Degrees of Hypothyroidism. Now let us turn for a moment to the study of the lesser degrees of deficiency in thyroid output, and THYEOID DEFICIENCY 61 we will then consider the physiological effects which the thyroid produces upon the body. Needless to say, it is a more difficult matter to deal with these lesser degrees than it is to diagnose those marked instances known as myxcedema. There can hardly be any mistaking a case of myxcedema, unless a particular instance is very atypical. Once a typical instance is seen, the peculiar characteristics cannot well be forgotten. When, however, we come to describe the symptoms and signs which would lead us to arrive at a diagnosis of hypothyroidism, the diffi- culty arises that the various signs are widely divergent (according to modern views), and that their presence at all may be transitory, or, again, the physical signs may be very few. We shall endeavour to describe those signs which are usually present in a case of sub- myxcedema, laying especial emphasis upon those which are characteristic. In this way it is hoped that those cases requiring thyroid medication will be more readily recognized. As is to be expected, on the whole the clinical picture is a modified version of myxosdema, with this difference, that the disease — i.e., the thyroid deficiency — ^is still probably in its youth, and the more advanced changes, which are dependent upon structural alter- ations of the grosser kind, are absent. It is not possible with our present knowledge of this subject to do more than hazard a guess as to the cause of thyroid insufficiency, and this we have already done.^ Whether prolonged illness on the physical side, 62 THE OEGANS OF INTEENAL SECEETION and anxiety on the mental, are capable of initiating a thyroid disturbance we do not know for certain. With the evidence at our disposal, it would seem probable; for, ia the experience of most medical men, hypothyroidism is more liable to ensue after iUness, worry, and similar harmful processes, than it is to arise spontaneously.* Whatever its genesis, it be- hoves the medical man to be on the lookout for its signs, more especially after acute illness. Let us briefly review its features, and outline the signs of thjTToid insufficiency. Before doing this, however, it it better to state that there is a certain difference of opinion as to what constitutes the typical picture of thyroid insufficiency. We shall, therefore, at this place confine our remarks to those signs about which there can be Uttle dispute, and in conclusion we shall * I described a case of submjfxoedema in a young male subject in the British Medical Journal for June 20, 1914. This followed a prolonged period of financial stress on the Stock Exchange, and was quite typical in its features. The patient was a young man, who had been out of sorts for some weeks, and had gone about his usual occupations, although he had noticed that he had been putting on weight rapidly. Briefly, his symptoms con- sisted in dyspnoea on exertion, bradycardia, eczematous rashes, pads of fat in the clavicular region, subnormal temperature, slow pulse, and trophic changes in the hair. Even the " eye- brow " sign was present. This man was first treated with cardiac stimulants, rest, and general hygienic measures, but made no progress. The day after he commenced thyroid medication the temperature ap{)roxLmated to the normal, the pulse-rate increased, he became more comfortable in himself, and after three weeks' treatment his good health was restored, with a reduction of weight. As may be imagined, his tem- perature chart was most instructive. THYEOID DEFICIENCY 68 briefly review the many points in this connection about which opinion is unsettled. Signs of Thyroid Insufficiency. When studying the main features of Graves' disease, we saw that the rate of bodily metabohsm was vastly increased, that the nutritive exchanges were acceler- ated, and that there was a loss of weight in consequence. Again, we noted that the vasomotor system was irritable, that perspiration was easily induced, erythe- mata were frequent, and that the tendency to the production of glycosuria was increased. The general picture of thyroid insufficiency is exactly opposite (I am speaking of the main features) to that seen in exophthalmic goitre. Let us take the salient points one by one: Temperature. — In this condition the bodily tempera- ture is usually subnormal, in extreme cases as low as 96° P., more generally about 97° to 97-5° or 98° P. In any case, if the temperature be taken consistently, it will rarely be found in be normal. In this connection we must remember that these patients feel the cold in a marked manner, and are in a more or less constant state of chiUiness. A patient who constantly com- plains of his " bad circulation " should be suspected of thyroid inadequacy. Pulse. — The pulse-rate in submyxoedema is con- sistently slow, although I am aware that many authori- ties differ from this. I would therefore modify this 64 THE ORGANS OP INTERNAL SECRETION statement by saying that, where other signs of thyroid insufficiency are present, and the pulse-rate is not slower than normal, or even faster, this is a sign that the condition present is not one of simple thyroid inadequacy, but is a condition of complicated endo- crinous disturbance — a condition in which there may be more or less concomitant disturbance of the thyroid and some other internal secretion, or in which there may be a concurrent hypo- and hyper-thyroidism. General Nutrition. — In submyxoedema, just as in the larger disease, there is a storage of products of diges- tion, as is seen by the larger amounts of sugar which can be consumed before glycosuria is produced. The bodily weight is therefore increased, but the deposit of fat is more or less local, as in myxoedema, and certain areas are more affected than others. Thus, the neck and shoulders are thickened, the clavicular regions • contain pads of fat, while the feet and hands, ankles and thighs, are often found to be unaffected. Again, the hypochondrium is another situation which in- creases in size, while the abdominal wall frequently contains masses of fat.* A sudden increase of weight, without obvious cause, phould make us at once suspect some thyroid disturbance. * The condition known as "chronic subcutaneous fibrosis," about which Stockman of Glasgow has written, although not attributed to deficient thyroid secretion, nevertheless yields to the ingestion of thyroid extract. This condition is characterized by the increase of fat, but in the subcutaxaeous tissue are also found masses of fibrous tissue, and the latter tissue in this complaint is very tender to the touch. THYEOID DEFICIENCY 65 Skin. — The skin is dry, rough, patchy in places, and may be in an eczematous condition. The internal surfaces of the tibiae, the sternum, the forearm, and the back, are the main situations where ichthyotic rashes are seen. There is usually present in thyroid insufficiency an itching, which is sometimes so intoler- able as to make the patient wish to scratch every part of his body at the same time. There may, on the other hand, be little or nothing to see, but the proof that the skin irritation is due to the diminution of thsnroid secretion is that it gradually yields when thyroid feeding is instituted, although not until some time after the beginning of the treatment. If the hair be examined, it will be found to be dull and without its usual lustre, sparse in places, prematurely grey (in cases where the condition has persisted for some time), with patches of alopecia. L^opold-Levi and H. de Eothschild draw attention to the " eyebrow sign " — i.e., the scarcity of hair in the eyebrows, with a marked diminution of the outer third of each eyebrow. This sign the present writer believes to be fairly constant, as he has observed it in many patients showing other signs of thyroid deficiency. Constipation. — The subjects of this condition are nearly always constipated. As in thyroid excess the reverse is the case and the motions are on the loose side and frequent, so in submyxoedema are the bowels costive. Other Characteristic Features. — ^If we can describe a type of " thyroid deficients " — ^that is to say, sub- 5 66 THE OEGANS OF INTEENAL SEOEETION jects of long-standing submyxcedema — we must lay emphasis on one or two points. The individuals are usually small, with deepset eyes, scanty hair, dry skin, and with the appearance of premature senility. They require abundant sleep, and are particularly liable to somnolence after meals. They are inclined to obesity, with the deposits of fat which characterize this condition, thickset, with an expressionless face, possibly carious teeth, and gingivitis or actual pyorrhoea. Again, the subjects of thyroid deficiency are very prone to fatigue, which develops without an undue expenditure of energy. In this way they resemble the neurasthenic, just as in their somnolence after food they remind the observer of the hthaemic subject. As we pointed out in a previous chapter, these patients frequently exhibit signs of premature senility, the arteries may be thickened, the skin wrinkled, the joints have lost their suppleness, as they are wont to do in old age. We may refer in passing to the supposed relationship between the parathjrroid glands and calcium metabolism, as it is assumed by many observers that derangements of these small glands permit the retention in the body of the lime salts, which are deposited in various parts of the body- It may be that thyroid deficiency is related in many of these patients with a parathyroid deficiency, and that it is the diminution in the latter secretion and not in the former which causes the symptoms of premature senility. THYEOID DEFICIENCY 67 It may be helpful at this stage of our study to refer to the work of L6opold-Levi and H. de Eothschild on this subject. These observers combine physio- logical research with cUnical utility, so that the two aspects of thyroid deficiency are, so to speak, brought into focus." These authors refer to " thyroid in- stability " — i.e., to the habiUty to disturbance in the normal working of this gland, whether in the direc- tion of excess or that of deficiency. They assert that a simple excess (slight hyperthyroidism) is very Uable to be succeeded by a deficiency, and that the two conditions — ^hyperthyroidism and subthyroidism — are frequently associated in the same individual. Thus, when these two conditions are present in the same patient, the prominent features of both might equally well be noticed. Those pointing to excess of the secretion of the gland, such as palpitation, nervous- ness, exophthalmos, and tremors, are combined with those indicating deficiency, such as constipation, chilliness, sclerodermia, scanty hair, etc. In another place ^ L6opold-Levi refers to the "hyperthyroidism associated with thyroid deficiency," which he says may be classified as follows: (o) Paroxysmal derangements of a hyperthyroidic nature, which appear as simple reactions and may be classed as symptoms. (6) Eeactions of a more complex nature, the mani- festation of which includes other symptoms, and which may be classed as syndromes. 68 THE OEGANS OP INTEENAL SECRETION (c) Eeactions affecting the thyroid gland itself (endogenous goitre). To emphasize the characteristics which we have already discussed as being present in thyroid deficiency, we wUl quote from this same article what this author gives as being the symptoms of a " slight degree of hyperthyroidism," as by this means we shall serve to impress the two different clinical pictures. " 1. Hypertrichosis, more particularly of the eye- brow. " 2. Hyperthermia, flushings, febricula of thyroid origin. " 3. Acro-erythrosis, with cutaneous humidity. " 4. Tendency to diarrhoea, the stools being soft and frequent. " 5. Great physical restlessness, with a sensation of being hurried. " 6. Insomnia. " 7. Emaciation. " 8. Excessive height. " 9. Developmental precocity. " 10. The syndrome which I have named ' syn- drome of persistent juvenility.' "11. Extreme nervous irritabihty, with cardiac and cutaneous excitability, etc. " 12. Large brilliant protruding eyes, with nystagmi- form movements. " 13. The reactions are generally excessive, and there is exaggeration of the nutritional exchanges. " 14. Hyperplasia of the entire thyroid gland."^ THYEOID DEFICIENCY 69 It is, however, quite obvious that many of these symptoms can only be present in those patients where the condition has been congenital, has commenced during adolescence, or has been in existence for a very long time; for, to take only one example, the stature could scarcely be altered in an adult patient who develops the condition after, let us say, a severe illness. But, on the other hand, there can be little doubt that many of the symptoms are quite constant, and can be observed in a large proportion of cases. At the present time the writer of this book has under his observation a lady who is undoubtedly suffering from deficiency of the thyroid, but has also the syn- drome which points to excessive action of this gland. Thus, while she has typical deposits of fat, ichthyotic skin, characteristic hair, somnolence, and mental turpitude, she also has slight tachycardia, rather prominent eyes, an almost unnoticeable tremor, some degree of nervousness, and transitory restlessness. In fact, in this case the picture changes from time to time — sometimes the signs of excess in the thyroid secretion being uppermost, at other times the signs of deficiency being more noticeable. There can be little doubt that in many cases both conditions are present, but not necessarily at the same time. It is quite possible that a hyperthyroidism succeeds a transitory deficiency, that while this condition is present the signs of its presence are marked, but that the reaction brings with it exactly opposite symptoms. The view expressed by Leopold-Levi — ^namely, that 70 THE OEGANS OF INTEENAL SECEETION the thyroid can be in an unstable condition, so that both these two opposite syndromes can be combined — ^is one which is supported by many observers. He believes, however, that the two conditions are rarely combined at the same time, but that the fundamental state is one of " thyroid instability." This, however, may constitute a condition in which the thyroid wobbles, so to speak, between outbursts of hard work and spasms of idleness. About such a state he says : " Associated with thyroid insufficiency is a large number of syndromes, the characteristic features of which are that they are precipitated suddenly in the form of thyroid crises, and that they yield to treatment with thyroid extract. " Although associated with thyroid inadequacy, these syndromes are the clinical expression of a hyper- thyroidism which is, in itself, the reactionary mani- festation of the fundamental subthyroidic condition. " They are — ^migraine, ophthalmic migraine, asthma, nasal asthma, attacks of chronic rheumatism and gout, mucous enteritis, urticaria and other skin affections (acne, eczema), mental symptoms."^ From this quotation the reader will see that the alteration in the thyroid is behoved, by this authority at least, to present many features which are sufficiently capable of recognition to enable the diagnostician to arrive at an accurate judgment. Before closing this chapter, however, it may be well to remember that not all these symptoms can be expected to be present in the same patient. Eather must the physi- THYEOID DEFICIENCY 71 cian be on the lookout for any of them, remembering that, so far as the endocrinous glands are concerned, diagnosis must be aided by ingenious detection. RBrEEENCBS. * See Introduction, pp. 3-6. " See " La Petite Insuffisance Thyroidienne et son Traite- ment," by L6opold-Levi and H. de Rothschild, published by 0. Doin et Fils, Paris, 1913. 3 Practitioner, vol. xciv.. No. 2, p. 211. * Ibid., vol. xciv.. No. 2, p. 212. 6 Ibid., p. 213. CHAPTBE IV THYROID DEFICIENCY (ContmueS) We have now discussed the broad outlines of thyroid excess and thyroid deficiency. But this latter subject is of such Importance, if we are to use to the full the powers which a knowledge of organo-therapy gives us, that we propose to devote this chapter to a more detailed study of the signs and symptoms of hypo- thyroidism. Owing to the importance of this subject, which, indeed, increases from day to day in vital importance as our knowledge of the lesions which may be attributed to disturbances in the hormonic system becomes wider, it is necessary for us to discuss at some length this aspect af the endocrinous glands. For thyroid defici- ency is of the most vital interest to all students of medicine, if only that, when recognized early, many aberrations from normal health may be remedied, or even averted, by the administration of extract of the thyroid gland. For this reason alone it behoves us to make our- selves au fait with the more marked symptoms of this disorder, for many of these will yield to rational therapy. Again, as in every other treatment, there 72 THYEOID DEHCIENCY 73 is a right and a wrong way to proceed with thyroid administration, but, unfortunately, this fact is not widely appreciated. Probably from the erroneous impression as to the dosage which is given in text- books of medicine, and iu posological tables the dose of thyroid extract is usually far too high. In any case it is necessary to proceed cautiously when prescribing this drug, for the personal factor is never more important than in thyroid therapy. We shall discuss this in more detail at the end of this chapter. In the last chapter we reviewed the opinions which are held as to the symptomatology of thyroid defici- ency, and quoted the views of Leopold-Levi and H. de Eothsohild. We referred to " thyroid instability," to the syndromes which these authors beheve to be characteristic of thyroid excess and thyroid deficiency, and to their behef that the two conditions may be present successively or even concurrently in the same patient. The opinions expressed by these observers are important, for they have made a careful study of the thyroid gland and its disorders, and their conclusions are of the greatest help to anyone wishing to familiarize himself with thyroid dosage. narrower quotes in his book on " Practical Hormone- Therapy " from L6opold-Levi and H. de Eothschild's book on " La Petite Insuffisance Thyroidienne." ^ These authors say: " Considerable importance attaches to minor thyroid insufficiency, for, unhke myxcedema, it is very frequent. It should be also especially interesting to the physician because of its usually 74 THE OEGANS OP INTEENAL SECEETION rapid response to treatment. Clinical experience is the basis of these deductions, just as it was the original basis of the present knowledge of the stigmata of hypothyroidism." Now, let us spend some time in studying those points which are generally considered to be typical of thyroidic insufficiency. We have already studied the main symptoms, and the manner in which normal physiological processes are altered in the absence or perversion of thyroid secretion. Our object now is to study the type which makes one look for symptoms rather than the symptoms themselves. The following may be said to be points in bodily construction which suggest faulty thyroid secretion. As we have already said, these patients are small. Their stature is frequently diminutive, while the development of their soft structures is excessive in proportion. There is also present, according to Hertoghe, a relaxed condition of the articular hga- ments, which permits of over-extension of the joints. Thus, we shall look for what is known in popular language as " double-jointed " people. The patient to whom we referred in the last chapter (in whom symptoms suggestive both of excess and insufficiency were present) showed this symptom remarkably well. She was able to bend her fingers back until the nails almost touched the back of the hand. In this con- nection, Hertoghe refers to a man who had been under his care for a number of years suffering from thyroid insufficiency, in whom there was spontaneous painless THYEOID DEFICIENCY 75 dislocation of the patella. So impressed is Hertoghe ■with the changes in this respect that he says "it is possible, with very little practice, to judge of the degree of thyroid inadequacy merely by squeezing the patient's hand." 2 He says that these hands give the impression, when squeezed, of a " glove filled with clay." The present writer is certainly of the opinion that the relaxation of the hgamentous structures in sub- myxcedema is something more than an artificial symptom. He has noticed it in a number of patients affected with this disease, in which the diagnosis was confirmed by treatment. In children certain signs of thyroid deficiency have to be added to those for which one must look in an adult. Thus, while growth is impaired and stature infantile, we have learned to expect a protuberant abdomen, a lumbar lordosis, due to relaxation of the spinal liga- rrients, sometimes abnormahties of development, such aa umbilical hernia, undescended testes, and so on. Again, as such children grow up, they continue to show these and similar signs, which are more noticeable owing to adolescence. The sexual development is delayed, immature sexual organs only being present in many cases, the stature remains stunted, and there is faulty mental development. The exhibition of thyroid extract serves to increase stature, remedy faulty development in other directions, and even to abolish symptoms such as umbilical hernia. If omitted too soon, or if given in insufficient doses, the improve- ment is apt to cease and the growth to stop. 76 THE OEGANS OF INTEENAL SECEETION This, then, is what to expect in subthyroidic children; if exaggerated, we meet cretinism. Such children are deficient in hair, and may even show more or less generalized alopecia. This, when combined with the infantile expression of the face, should at once make one suspect thyroid deficiency. The child may be small for his age; he may present one or more of the stigmata referred to above; and, finally, the diagnosis is clinched by the exhibition of thyroid extract and the resulting improvement. So much, then, for thyroid deficiency in a child. What produces this is a more difficult question. There can be little doubt Jjhat in many cases the tendency is an inherited one. These children often come from stock which can be shown, on careful examination and questioning, to be subthyroidic. Hertoghe quotes a case of infantilism of the Lorain type, the mother of the child being a myxoedematous subject of a benign type. Like many other diseases, prenatal conditions must be blamed for many of these cases, and it wiU have already been noticed how some of the defects, due to imperfect development, are more or less directly traceable to the thyroid gland, as they are remedied after birth by the administration of the extract of this gland. In support of this, witness the umbilical hernia in one of Hertoghe's cases, and note how it cleared up when the child had been taking thyroid for some time. Again, it will be remembered that such stigmata as imperfect development of the bones are among the THYEOID DEFICIENCY 77 signs of inherited syphilis; while it has been stated that the administration' of thyroid extract is as effica- cious as iodide of potassium in healing tertiary syphilitic lesions. ^ Two other functions of the thyroid are pertinent to our study. First, we have to remember the theory which deals with the " antitoxic " power of this gland, and to bear in mind that, if this is true, the subjects of any kind of thyroid delBiciency must needs be more open to bodily infection, either from so-caUed auto- genetic or heterogenetic sources. Second, as pointed out by Hertoghe, the hfe of each cell of the body, considered as an individual, is relatively a short one. It serves its purpose, degenerates, and is excreted from the body by one of the normal channels. For this to be performed, however, in a normal maimer, the presence of thyroid secretion is necessary; for in its absence such cell elimination does not follow its usual course. Hence the vast increase in the subcutaneous tissue which is present in myxoedema, and to a less degree in submyxcedema. As is so well known, this gives rise to oedema, or, to be accurate, to increased subcutaneous tissue, which pits on pressure. Extract of thyroid gland diminishes this abnormal subcutaneous tissue, and in so doing lessens the bodily weight. The excretion of nitrogen is increased by this extract, so that the ehmination of broken-down cells is restored to normal — another reason for the reduction in weight under thyroid feeding. As we have said already, the submyxcedematous 78 THE OEGANS OF INTEENAL SECRETION patient is habitually constipated, and this may have an effect to which we drew attention in a former chapter. These patients show many of the signs upon which Lane lays emphasis as indicative of intestinal stasis; in fact, one of these signs is atrophy of the thyroid. The question to be answered is this: Is the thyroid primarily responsible for the inertia of the intestine, or does this latter factor produce atrophy of the thyroid ? I have seen cases which would argue that Lane's view is the correct one; on the other hand, many patients impress one more in favour of the theory that the thyroid atrophy is responsible for the signs to which both the supportei^s of the alimentary theory and those who uphold the " primary thyroid defici- ency " theory lay claim. A short time ago I saw a lady who was complaining of vague pains in the extremities, dry and itching skin, languor and lack of mental alertness, and constipation. On examination I found a sweUing of the thyroid gland, a slow pulse and an ichthyotic condition of the epidermis. Purtherr more, there was a good deal of evidence of intestinal stasis, such as meteorism, offensive flatus, insufficient motions even after a purge, and digestive disturbances. To many of those students who have read Sir Arbuthnot Lane's latest work upon the subject of intestinal stasis, the signs indicative of intestinal stasis were all (I refej to the main signs, and not to the smaller indications) present. At the same time the student of opotherapy would find mogt of the signs which he THYEOID DEFICIENCY 79 had learnt to regard as pathognomonic of thyroid deficiency present in this case. The stature was small, the hair atrophic, the skin dry, the pulse slow, the bowels costive. I need hardly enumerate the other well-known signs. There I must leave the discussion of the primary cause, as there is insufficient evidence to warrant us in dogmatizing further on the why and the wherefore of thyroid atrophy. In reading the mass of literature which has accumu- lated of recent years on this subject, the reader is struck with the many different signs which are beheved by the majority of observers of organo-therapy to be caused by thyroid insufficiency. Even if at first glance one is inclined to believe that the chnical picture of submyxcedema has been exaggerated, yet, if one reaUzes the signs which a severe degree of thyroid deficiency produces, one can scarcely doubt that a minor degree might very well alter the individual, although in a sUghter degree; indeed, in the very mild cases to so small a degree as to make the change all but im- perceptible. The main object of this chapter is to bring the practical points in connection with hypothyroidism before the notice of those whose time does not permit of the perusal of the latest physiological and chnical research, so that a greater percentage of patients who might be helped by organo-therapy (and who will in all probabihty be helped by no other means) 80 THE ORGANS OF INTERNAL SECRETION shall benefit by our knowledge, which has increased every year since Murray's original discovery. The study of the changes wrought in the various parts of the body by an absence or diminution in the secretion of the thyroid are so numerous that it will be best to deal with them separately, classing them under the different bodily systems. We will therefore study them in this way. The Influence of the Thyroid Secretion upon the CeU. Throughout hfe the Hving cell requires certain hormones if it is to follow the normal cycle of life. Thus, if starved of thyroid its growth is impaired; administer to the individual organism the extract of this gland, and growth is resumed. This is shown by the behaviour of cretins to thyroid feeding; they, improve in every way under such treatment, but relapse if it is stopped or diminished. We have already pointed out that broken-down cells which should be eliminated are retained and stored (in a form that originally was thought to be mucinous) if the thyroid secretion is diminished. Thus, the cycle of growth and decay are both interfered with, if the endocrinous system is disturbed. In association with this, we must explain one or two important facts. The subject of thyroid deficiency is never "fit "; he is generally tired, he finds work a burden, and, whether his employ- ment is physical or mental, he requires a "push" before he can make himself take up his tools. Again, THYEOID DEFICIENCY 81 his mental apparatus fails bim^ his memory is un- rehable, he camiot recall either recent or past events; his attention wanders; his concentration is never at its brightest when he wishes to solve a problem; and, in a word, he is sluggish mentally as he is languid physically. He is neurasthenoid. The muscular system, in association with the sub- cutaneous, ligamentous, and fascial systems, undergoes infiltration; while ihe nerve cell " suffers derangement of nutrition." It becomes " infiltrated, and it also imdergoes compression, as the result of the infiltration of the connective tissue surrounding it. Hence, the transmission of motor and sensory impulses, both voluntary and involuntary, though delayed, is in no sense abolished. The reflexes are tardy, but they are present." Therefore the cells of the nervous system are em- barrassed in a double manner — ^from within and with- out. The infiltration of fascia, of 'muscle, and of sheath, must of necessity exaggerate the difficulty of exertion. This would apply both to physical and mental exertion. Symptoms Beierable to Nervous Tissue. Apart from the mental sluggishness, which we have already described, these patients suffer from a variety of ailments more or less directly referable to the nervous system. Thus, they are very hable to headache, which is usually frontal, but occasionally occipital. The two forms, however, are rarely merged. The 6 82 THE OEGANS OP INTEENAL SECEETION headache of thyroid insufficiency is, in nearly every case, worse in the morning, improving as the day wears on. Giddiness is another constant symptom, with which is associated, in some cases, a " swimming " sensation. Tinnitus aurium, either in the fprm of buzzing, roaring, whistling, or shrieking noises, is common, while these patients sometimes experience even more serious sensory disturbances, such as hearing voices, the ringing of bells, etc.^ In practice, many such cases have been benefited by the administration of thyroid extract. So far as I am aware, there is no evidence that true vertigo is seen, although I have prescribed this extract for one or two patients in whom the giddiness and dizziness were very similar to true vertigo. We have already referred to the functional nervous changes which are seen in thyroid deficiency, of which Bonmolency is, perhaps, one of the most marked. These patients seem to be able to sleep very soundly at night, after every meal, and at any other time when the opportunity offers. Most subthyroidics complain of their marked tendency to slumber at all times, and the more intelligent find that it is sufficiently marked to be abnormal. In spite of this, these patients do not wake up refreshed, and they feel worse in the morning than they do at night. Hertoghe suggests that in all probability the thyroid neutralizes the toxins generated during the hours of activity during the night — ^that is, under normal physiological THYEOID DEFICIENCY 83 conditions — but that this does not happen in the subject of thyroid deficiency."' We have already dealt with the changes in the mental apparatus which must be looked for in sub- myxcedema; to the confusion of mind and the lack of mental initiative we must attribute the slowness of thought, as well as the lack of confidence, which these patients show. To these facts also we must attribute the undue exertion which any work demands from these patients. The Subcutaneous and Muscular Tissue. The thickening seen in thyroid inadequacy is characteristic. It involves aU tissue, according to most observers, but in certain areas it is laid down more or 1%S3 in " heaps." Thus, the nape of the neck down to the last cervical vertebra shows a thickening, while in the last-named area is almost always seen a mass of fat which resembles a lipoma. Particularly is this so in adult patients, more especially in the female sex. The head is held somewhat forward (" cassowary neck "), so that the cervical deposit appears more prominent than is reaUy the case. The shoulders of such patients are broad, while the clavicular regions contain pads of fat. Such deposits of fat as these are more or less de- pendent on sluggish circulation, and therefore regions such as the abdominal wall are apt to suffer. The flanks and back are, in adult patients, enlarged by 84 THE 0EGAN8 OF INTBENAL SEOEETION rolls of fat, while the bones of the extremities are sunken Ln an envelope of adipose tissue. This deposit is not solely fatty, nevertheless it adds to the body- weight considerably and hampers bodily activity. The entire subcutaneous integument appears to be thickened, and this thickening can be made to pit on pressure, although the pitting disappears as soon as the pressure is relaxed. As regards the changes in the muscular system, we can by reason of these changes explain several symp- toms from which these patients suffer. The muscles are burdened with fat and mucinous infiltration, so that their size is increased and their drainage insufficient. Muscular movement is hampered, so that the metabolic exchanges are even more restricted. Hence the disHke of active exercise which these patients invariably show. Again, the increase in the volume of the musculature leads to discomfort, if not actual pain, which latter may be vastly relieved by the exhibition of thyroid extract. It is well known that children who are the subjects of thyroid inadequacy are very prone to the develop- ment of adenoids, and that this is one of the charac- teristic stigmata of this condition. Again, in such subjects the enlargement of lymphatic glands is common, and some thickening of these structures is frequently observed. Sweating is practically unknown In submyxcedema, per se, and in consequence there is some increase in the secretion of the kidneys, with a tendency to nocturnal THYEOID DEFICIENCY 85 enuresis. The solids of the urine are, of course, diminished, but increase enormously when the patient is taking thyroid. The nocturnal enuresis from which these patients suffer is in part, at any rate, due to the extreme heaviness with which they sleep; and for some years now thyroid extract has been prescribed empirically for this condition, although the under- lying causation was not understood in the same way as it now is. This medication has given very good results in many cases, but it is almost infallible where the underlying condition is one of thyroid inadequacy. The absence of adequate secretion from the skin — and these subjects rarely sweat — ^results in a stagnant condition of the liver; and, according to Hertoghe, this results in itching of the skin, the icturus of myx- oedema. It may also assist in the intense drowsiness, if not also in the slow pulse; but even if so, it would only be a contributory factor. It is, however, quite conceivable that the constipation is partly due to diminution of the normal bihary secretion in the intestine, the natural laxative. The Osseous and Cartilaginous Systems. The delayed growth resulting from a deficient thyroid secretion is too well known to demand lengthy description. So long as the epiphyses are not ossified, there remains the possibility of renewal of growth under thyroid feeding. This can be ascertained by the Eontgen rays. 86 THE OEGANS OF INTBENAL SECEETION Again, myxcedema produces its characteristic in- filtration in the joints and their ligamentous structures. This causes crackling in the joints, and gives the impression of a rheumatoid condition. When this sign is present, therefore, a careful search should be made for either symptoms pointing to thyroid defici- ency. It has been said that delayed union after fracture is very common in subthyroidic subjects, and that the bone unites on the exhibition of thyroid extract. Epidermal Symptoms. The dry, rough, and ichthyotic skin which character- izes these subjects has already been described. Prom their point of view, this is probably one of the most troublesome features, as the inconvenience of a generalized itching cannot well be exaggerated. There is httle to be seen on examining the skin of these patients beyond what we have already described. The hair suffers in common with other epidermal appendages. The nails are brittle and grooved, or they may be actually cracked. As we have already said, the " eyebrow " sign, first described by L6opold- Levi and H. de Eothschild, is of considerable diagnostic significance. There is a sparseness of the outer third of each eyebrow, with a scarceness and partial falUng out of the whole eyebrow. This feature can be seen in many subthyroidics, and should always be remem- bered when looking for confirmatory evidence of a suspected inadequacy of this secretion; THYEOID DEFICIENCY 87 Pigmentation of the skin, perhaps more commonly seen on the forehead, and raising of the eyebrows, are both characteristic; while the lips are usually thickened, and the mouth tends to open. The changes in the facial characteristics give an unusually stupid appearance to the patient, but this changes under thyroid feeding. The more marked cases of thyroid insufficiency develope countenances which resemble nothing so much as a porker; and the change which is brought about in the expression as treatment proceeds is most gratifying to the patient himself, as well as his relatives and friends. In adult subthyroidics the hair is prematurely grey, and this change in colour is usually more marked over the temples. In the case which I published in the British Medical Journal of June 20, 1914, this feature was well shown, although the patient was a young man about twenty-eight years of age. If the hair is a normal colour, it is frequently without gloss, and is brittle and " Ufeless." Patches of alopecia are common, and the scalp as a whole is dry and scaly. It must be remembered that pigmentation of the skin is seen in thyroid excess as well as in thyroid deficiency, and that it is a characteristic feature of Addison's disease.* As a diagnostic symptom, therefore, it is not of great value. * See a case of marked facial pigmentation which is descrihed in Chapter X., pp. 203-205. 88 THE OEGANS OF INTEENAL SECEETION Sexual Symptoms. During childhood the diminution or absence of the thyroid secretion prevents the normal development of the genital organs at puberty. In fact, such patients grow up to adult years without any change from the infantile character of these organs. Indeed, in some cases more serious defects are seen; for cryptorchidism, either complete or unilateral, may be present. In cretinism, of course, there is no development of any sexual characteristics, and the child remains in this respect unchanged. Graves' disease produces a diminution of the periods, either with scanty menstruation or amenorrhoea. The reverse is true in submyxcedema, for here there is a tendency towards menorrhagia, although the periods do not as a rule develope until the patient is well past the usual time. The uterus remains undeveloped, or at all events partially so, while the ovaries are likewise immature. There is sometimes a marked retroversion. The changes brought about in thyroid inadequacy by pregnancy are for the best; while the patient is pregnant the thyroid secretion is increased. But, unfortimately, this improvement is not permanent, and she retrogresses, so far as this is concerned, after delivery. Immediately after delivery there is too much secretion, but later this ceases, and the former condition of subthyroidism is reverted to. According to Hertoghe, some of the increased thyroid secretion THYKOID DEFICIENCY 89 is directed towards establishing uterine involution, while another function of this important secretion at such times is to estabhsh lactation. Gastro-Intestinal Symptoms. In considering the gastro-intestinal symptoms of thyroid inadequacy, we must refer again to the syn- drome, which Lane attributes to intestinal stasis, but which observers in organo-therapy claim to be caused by the thyroid. " The symptoms are hypo- thermia, uncontrollable headache, rheumatoid pain and neuralgia, mental depression, dyspnoea, asthmatic attacks, premature greyness and baldness, dental caries, choleHthiasis, and brownish pigmentation of the skin." Thus Hertoghe refers to this syndrome, and he attributes the gastro-intestinal symptoms of thyroid insufi&ciency to infiltration of the muscular tissue of the intestines, causing partial paresis. This in turn leads to ptosis, or partial ptosis, and then we have kink formation and the other features so carefully described in Lane's book.' We must emphasize, in passing, what we believe to be a very important aspect of this condition — ^namely, weakening of the abdominal wall, which fails to give that support upon which- the intestines have come to rely. This may be due to degenerative processes of an infiltrative nature, or to some other cause, but in any case the weakening helps the intestinal derange- ments. This in turn affects the digestive functions; 90 THE 0EGAN8 OP INTEENAL SECEETION appetite, which is notoriously capricious in sub- thjTToidics, is poor; digestion is imperfect, and assimila- tion lessened. These patients are always weak and incapable of sustained effort. This is probably due in part to the causes already enumerated, and partly to deficient assimilation of food. The association between subthyroidie conditions and septic affections of the alimentary tract, such as appendicitis, has often been commented upon, while it is said that the relation between tonsillitis and appendicitis is a close one. Eectal haemorrhage is said to be common in this condition, and, according to Hertoghe, it is due to premature thickening of the rectal veins and to the deficient coagulation of the blood. Just as the monthly period is apt to be excessive, so is the haemorrhage due to piles, etc., liable to be copious. Treatment. We have now outlined the main changes which may be observed in subthyroidie patients, and the chief signs by which the condition may be recognized. All that now remains to be done is to svmimarize our conclusions in a few words, and to outline the treat- ment. Whether the condition is in evidence during child- hood or not until after adolescence, the main features are characteristic. The change in the bodily temper- ature is constant (a subnormal temperature is nearly THYEOID DEFICIENCY 91 always present), likewise the pulse is slow. These two points should always be investigated. Having deter- mined the condition of the temperature and pulse, the skin and hair should be examined, and a careful investigation undertaken to determine the bodily weight and the characteristics of the subcutaneous tissue. The deposits of fat, if present, should be locahzed. On the other hand, the patient may not necessarily be obese if the degree of thyroid deficiency is slight. In such cases careful observation must be made to ascertain whether other signs are in evidence, and, if so, whether the sum of the signs and symp- toms point to submyxoedema. The condition of the digestion and the bowels, the nature of the monthly period in women, the presence or absence of sensations of chilliness, of flushings, and of pains in the limbs, should be ascertained. Having reached this stage in the investigation, the further points which suggest themselves for examina- tion deal with the minor changes which are character- istic of this disease. Any change in the voice, in the expression, or in the mental outlook, which either the patient or her relatives have noticed, is of importance. The functional efficiency of the patient should be studied, bodily weakness and fatigabihty examined, and the patient questioned as to the length of time these changes have been noticed. All the minor points are important, as the question of treatment depends upon these. We caimot empha- size too strongly the fact that, so far as submyxosdema 92 THE OEGANS OF INTEENAL SBGEBTION is concerned, the initial dose should be small. Even if this should be so small as to appear to the inexperi- enced prescriber to be useless, it is infinitely preferable to order a small dose, and to continue this over a lengthy period, than to commence with a big dose and have to suspend treatment on account of un- toward reaction. In severe cases — i.e., where definite myxoedema is present — the initial dose may be larger;. but such oases do not nowadays form the majority of patients, as they are usually far outnumbered by the patients who show the signs of minor degrees of hypothyroidism. Where myxoedema is present, the patient may be given one, two, or three 5-grain tablets of thyroid substance in a day; or, if it is preferred, a liquid preparation may be prescribed, such as Elixir Colloid (Squire) or the Liquor Thyroidei (B.P.). The dose of EHxir Colloid is from 1 to 2 drachms, but even smaller quantities may be given (1 drachm represents 1^ grains of the dry extract) ; while the Liquor Thyroidei is given in doses ranging from 5 to 15 drops. Needless to say, these doses must be given entirely according to the individual case, as under no circumstances should thyroid medication be undertaken by rule of thumb. Each case must be treated on its individual characteristics, the length of time during which the disease has been manifest, the degree of thyroid deficiency, and the alterations in the patient which this has produced. Kendall, of the Mayo Foundation, Eochester, Miim. THYEOID DEFICIENCY 93 has isolated a crystalline substance from the thyroid gland containing 60 per cent, of iodine. This he designates alpha-iodine compound. The results fol- lowing the treatment of myxoedema by this prepara- tion are reported to be extraordinarily good. When we come to the treatment of the lesser degrees we cannot speak so definitely. The initial dose should always, as we have already indicated, be small. The drug should be increased after some days or weeks, and it should be regarded as a failure of technique if the prescriber ever has to reduce the dose owing to commencing with too large a quantity. He should, so to speak, feel his way, looking carefully for the changes which wiU show that the drug is doing its work. The temperature will approximate to normal almost from the first, certainly as the circulation feels the result of the additional thyroid extract. The pulse will increase in rate, and, if charted, will show a steady approximation to the normal. It must be remembered that these patients are often smaU, and that small people have, under normal conditions, a more rapid pulse than large individuals. When we find, therefore, that a small patient has a slow pulse, we should seek for the reason. Again, the subjective symptoms wiU improve under thyroid medication; the feelings of languor, the extreme chiUiness, the depression, and the general discomfort, will diminish in severity. Provided that such changes are looked for and noted as they appear, it will be safe to increase the dose 94 THE 0EGAN8 OF INTEENAL SECEETION should they be delayed or incomplete. The adminis- tration of thyroid is both an art and a science: an art, because of the skill required to apply correctly the knowledge gained of thyroid-therapy; and a science, because of the exactitude of such application, which is essential if we wish to achieve the best results. In cases of submyxcedema, it is far better to err on the side of caution — i.e., of too small doses — ^than of rashness. The former can be remedied as the reaction of the patient indicates ; while the latter may not only lose the faith of the patient in this remedy (which is, if the diagnosis be correct, the only remedy), but may even make the prescriber doubt his own judg- ment. One-tenth to one-quarter of a grain should form an initial dose, certainly in the majority of cases, which, when all is said and done, are in the main minor degrees of deficiency. This may be given two or three times a day, and increased to J grain, 1 grain, or even 2 grains, three times a day. Generally speaking, this is quite a sufficiently large dose. There are cases of submyxcedema which require larger doses, but they should only attain to these after a long administration. One other word of warning, and we may conclude. The prescriber must be able to rely upon his prepara- tion. He must know that the percentage composition is constant, that it contains a due proportion of iodine, and that it is fresh and has not reposed on a shelf in a local chemist's shop for many moons. Thyroid extract degenerates, and when this happens it becomes inert; and it does not take long for this THYEOID DEFICIENCY 95 to happen. If the patient fails to react, we must remember that the quahty of the drug may be at fault, and not the diagnosis. So long as the drug is fresh, it matters little whether it be given in the form of dry extract, Uquid extract, or one of the many prettier preparations on the market. The prescriber must know what he is prescribing, or he will be unable properly to check progress. Finally, as the treatment proceeds, a careful watch must be kept upon the temperature, pulse, and weight, for mainly on these points can the supply of thyroid extract be regulated. Befebenoes. I Chapter XIII., p. 192. ' Practitioner, vol. xoiv., No. 1, p. 30. ' The Newer Physiology in Surgical and General Practice, by Rendle Short, p. 85. * Practitioner, vol. xciv.. No. 1, pp. 40, 41. * Hertoghe quotes Murray in saying that these patients show a marked disinclination to discuss these symptoms, and asks whether this is due to the fact that such hallucinations show a marked resemblance to those associated with alcoholism. They are due, Hertoghe believes, to infiltration of the nervous centres, or to more local infiltration, such as thickening of the aural mucosa, Eustachian tubes, and the naso-pharynx. * In myxoedema Brun and Mott have shown the presence of subacute general ohromatolysis of nerve cells. ' Chronic Intestinal Stasis. CHAPTER V THE PITUITARY BODY The existence of this body has been known for centuries, but until recently it has been regarded as of no functional importance — as a vestigial relic. Now, however, the very reverse has been shown to be the case, and since 1895 it has been known that this small gland exerts an active influence upon the general bodily metabolism. Its intimate functions are still far from clear, and experiments have not infrequently led to contrary results. However, the light is beginning to dawn, and clinicians are now reaping the benefits which laboratory workers have made possible by their investigations of the structure and functions of this gland. These investigations have been made largely with a view to ascertain the results of extirpation experi- ments, and the conclusion arrived at is this, that, far from being a vestigial remnant and unnecessary to life, its influence upon the health is of prime impor- tance, and that its normal functioning is essential to health. Its full relation to bodily efficiency has still to be explained, as there are aspects and features about 96 THE PITUITAEY BODY 97 which we should Uke more enlightenment. The French were wont to refer to the pituitary as " I'organ enigmatique," and its mysteries more than justify such a name. The ancients, while cognizant of its existence, regarded it from a different standpoint. Thus, Galen and VesaUus believed that it was con- cerned in the formation of the nasal secretion; hence the name " pituitary." Vieussens and Sylvius con- sidered that it was concerned with the manufacture of the cerebro-spinal fluid. The first hint as to its real functions — ^namely, the manufacture of an internal secretion — ^is conveyed in a paper to which Gushing calls attention. This was written by Lower, and was called " Dissertatio de Origine Catarrhi," 1672, and contained the statement: "For whatever serum is separated into the ventricles of the brain and tissues out of them through the infundibulum to the glandula pituitaria distills not upon the palate, but is poured again into the blood and mixed with it." Here, then, we have the precursor of our knowledge of hormone-therapy. As the space at our disposal is hmited, we must confine our remarks to the more important and sub- stantiated facts about the pituitary body; and these we will study from the standpoints of structure, physiological functions, effects of excess or deficiency of the secretion of the pituitary, and therapeutic considerations. 98 THE OEGANS OF INTEENAL SECEETION Structure of the Pituitary Body. The pituitary body consists of three parts: an anterior part (glandular), an intermediate portion, and a posterior or nervous part. The anterior part is composed of a network of epithelial cells, between which run many wide bloodvessels with thin walls. This part of the gland is derived from the buccal invagination (that portion known as " Eathke's pouch "). As Swale Vincent points out, the structure is similar to the adrenal cortex, the islets of Langerhans, the thyroid, the thymus (in its epithelial stage), and ttie interstitial tissue of the ovary and testis,^ Next to this anterior part comes the pars intermedia, which, while it is derived from Eathke's pouch, and resembles the pars glandularis in structure, differs from it in that " its cells are less glandular and its bloodvessels much less numerous." ^ This portion of the gland is separated from the pars anterior by a well-defined cleft; but it is not always markedly separate from the pars posterior. This latter portion of the gland is derived from the infundibulum, or stalk of the pituitary. This is attached by its terminal portion to the floor of the third ventricle; while its other extremity expands and forms the posterior part of the pituitary body. This is known as the pars nervosa, and consists of neuroghal fibres and cells. Histologically the anterior part of the gland consists, as already stated, of " trabecular masses of epithelium- like cells between which are|very numerous sinus-like THE PITUITAEY BODY 99 blood-capillaries lying in intimate relation to the cells, which are, indeed, sometimes set closely round the blood-spaces."^ The pars intermedia resembles the pars anterior in general formation, but its cells are less granular and it is not so vascular. The pars posterior is formed almost entirely of neuroglial fibres, vfitla neuroglial cells scattered between the fibres. Between these fibres is found a hyaline matter, which is more abundant in the neighbourhood of the stalk. Schafer maintains that there can be little doubt that the activity of extracts of this part of the gland is due to this substance. Herring denies that any nerve cells are present in the pars posterior, and believes that there are very few nerve fibres . Physiological Functions. In studying the physiological action of extracts of the pituitary, we are faced with certain apparent contradictions. If an extract of the whole gland be injected, there is an immediate rise of blood-pressure, associated with a slowing of the heart's action. In this connection the effect of pituitary is similar to that produced by adrenin. The arterial system is affected by this extract, as is aU the involuntary tissue of the body — in other words, vaso-constriction is increased; and it is this property which makes pituitary extract such a valuable remedy in shock. We shall refer to this factor when discussing the therapeutic aspect of extracts of the pituitary body. 100 THE OEGANS OF INTEENAL 6ECEETI0N Certain observerg believe that the substance -which exerts this tonic action exists in the posterior part of the gland only* (which includes in this connection the pars intermedia as well as the pars nervosa), and, in point of fact, it has been shown that this effect is produced by either the pars intermedia or the pars posterior, but more by the latter than by the former. As well as this tonic effect upon the heart and the bloodvessels (which, while it resembles that produced by adrenin, differs from it in that this latter extract causes increase in the rapidity of the heart's beat, whereas pituitary extract causes slowing of the pulse), pituitary extract acts upon other plain muscle, such as the stomach, the intestines, the uterus, and the bladder. As opposed to this general stimulation, there are one or two notable exceptions. The kidney, when stimulated by the administration of extract of the pituitary, reacts in a different manner. Thus, the renal arteries dilate, there is diuresis, and this is partly due "to a selective influence of one of the contained hormones upon the cells of the renal tubules. . . . This action has been supposed to be due to a special diuretic hormone from the pars intermedia, and it is not as yet certain that this is not the case; but it seems more probable that all the effects that it causes are due to the active principles of the posterior lobe."6 Again, the effects produced upon lactation by injections of this gland are interesting. Ott and THE PITUITAEY BODY 101 Scott, in 1910-11, pointed out that it possessed a marked galactagogue action, and since that time many observers have supported this statement. There have, however, been a few dissentients, who maintain that extracts of pituitary have no such effect; these are, however, in the minority.* One other feature, which at first sight appears rather contradictory, is the effect of pituitary extract upon amenorrhcea. It has been on several occasions utilized to counteract cessation of menstruation, and with marked success. This is, of course, contrary to what we should expect, but can only be explained, as suggested by Harrower, on the assumption that the gland is acting vicariously in carrying on this function. It is known that the pituitary undergoes hypoplasia during pregnancy, and Fromme tried injecting an extract of the gland in amenorrhcea, with some degree of success. Now as regards the active principles of the pituitary. Krst of all in importance, certainly from the thera- peutic standpoint, is the fact that the majority of observers are agreed that the posterior part of the gland contains the active principle. In other words, better and more constant results have been obtained by the use of some preparation of this part of the gland than by the exhibition of extracts of the whole » Sohafer maintains that the effeet of pituitary extract upon lactation is one of the most striking experiments in physiology; but Heaney does not believe in the galactogogic effect of pituitary extract (quoted in Harrower's " Practical Hormone-Therapy "). 102 THE OEGANS OF INTBENAL SECEETION gland or by the attempted isolation of extracts of the other portions. Harrower states that a definite salt has been isolated from the pituitary — hypophysm sulphate — ^which is available for use, and standardized in 1 in 1,000 solutions. This has been utilized by many observers, who report favourably on its use (Hertzberg, Puhner, and Harrower). The Effects Produced by Disease of the Pituitary Body. In discussing the thjnroid gland, we saw that morbid conditions due to its faulty functioning might be classified into those due to hypersecretion (hyper- thyroidism), and those due to deficient secretion (hypothyroidism). In hke maimer, when discussing diseases due to abnormal working of the hypophysis cerebri, we may adopt this division — ^namely, diseases due to excessive action of the pituitary and those due to deficiency. The best recognized disease associated with this gland is that to which Marie gave the name " ac- romegaly" (a/e/3oi;=point; /i,e'ya9=Jarge). It is now beheved that this condition owes its origin to a hyper- secretion of the pituitary, and that part of the symp- toms are directly due to an excess of the hormone elaborated by the anterior part oi this gland.* It is * Schafer says: " That the acromegalic skeletal growth is produced by hypertrophy and over-secretion of the anterior lobe is highly probable, both as the result of partial extirpations in animals and from the effect of operative removal of pituitary tumours in man " {" The Endocrine Glands," p. 113). THE PITUITAEY BODY 103 also now generally believed that a common sequence in the production of this disease is a primary hyper- pituitarism, the cause of which may or may not be clear, followed in some cases by a hypopituitarism. Before proceeding to outUne the features of these two clinical conditions, we will briefly describe the sjrmptoms of acromegaly. This disease usually com- mences with a marked narrowing of the field of vision, so that ocular symptoms are a prominent part of the complaint in its early stages. This feature may be due to the presence of a tumour in the gland pressing upon the region of the optic chiasma. Sooner or later are developed the characteristic features of the complaint which caused Marie to describe it under the name " acromegaly." These consist in a marked overgrowth of the head and extremities. The face enlarges and coarsens in its expression ; while the shape of the head tends to alter, becoming flatter and squarer. The fingers, if viewed by the X rays, show an enlarge- ment of the bones, with a " mushrooming " of the terminal phalanges. The entire skeleton increases in size, so that the individual becomes more or less generally enlarged. Certain other changes are common, and these de- velope concurrently with the skeletal enlargement. There is a tendency to hypertrichosis, with a general in- crease of the hair all over the body. Sexual activity diminishes, as a rule, early in the course of the disease: although, in those cases where hyperpituitarism is succeeded by hypopituitarism, sexual activity may 104 THE OEGANS OF INTEENAL SBOEETION be primarily increased, and subsequently diminished. A tendency to glycosuria is common, which, again, may be followed by a diminished glycogenesis. The integument is also thickened, in a somewhat similar manner to that seen in myxoedema; while if the disease commences before ossification of the epiphyses has taken place, the stature becomes enormous and the individual turns into a giant. It is now generally beheved that acromegaly is due to an overgrowth of the pituitary; indeed, in many cases actual tumours are present, and have been demon- strated post mortem. Sometimes, in these cases, the sella turcica can be shown by a skiagram to be definitely enlarged. On the other hand, after the glandular enlargement, a secondary atrophy may ensue, in which case the symptoms become those of hypo- pituitarism. It is at this stage that symptoms contra- dicting the earher clinical picture may make their appearance, so that, whereas at first there may have been a tendency to undue glycogenesis, there is now increased sugar storage, and whereas at first there had been hypertrichosis, there is now a change in the hair, the distribution often tending towards the feminine type. Again, it does not follow that every case of what Gushing calls dyspituitarism may commence as a hyperpituitarism, and subsequently change to a hypo- pituitarism; for some cases evidence symptoms point- ing to the latter condition from the first. The state described by Frohhch, and named by Bartels THE PITUITAEY BODY 105 " Dystrophia adiposogenitalis," is essentially a typical example of hypopituitarism. The symptoms pointing to this state are, as is to be expected, the opposite of those typical of hyperpituitarism. Thus, the stature is small (if the disease commence before adolescence), adiposity is excessive, sexual development is delayed or deficient, the development of hair is wanting, and there is a tendency to the formation of feministic characteristics. Thus, the hair on the pubes is more locahzed than is the case in man, but the development of the hair on the head is frequently abundant. The sweat is usually deficient, although the sldn exhibits a smooth and even texture. Gushing deals very fully with the production of this state in his book, " The Pituitary Body and its Dis- orders." He beUeves that the tendency to the deposi- tion of fat, which subjects of hypopituitarism show, owes its origin to deficiency of the secretion from the posterior lobe. Likewise the unusually high tolerance for sugar and the increased assimilation of carbo- hydrates are due to the same cause. Again, in hypopituitarism there are other changes which may be expected in the symptoms. The tem- perature is usually subnormal, the pulse slow, the blood-pressure low, and the mental attitude sluggish, with a tendency to somnolence. It will be seen that the chnical picture is not unlike that seen in myx- oedema. The parallel is, in fact, a close one, certainly in many features. It is important to remember that the symptoms of 106 THE OEGANS OP INTBENAL SECEETION hypopituitarism will differ according to whether the deficiency first appears before adolescence, or is only in action after adult hfe has commenced. Once the ossification of the epiphyses has taken place, there is no possibiUty of further increase of stature. But the increase in the integuments, the alteration in the circu- lation, the changes in the mental outlook — ^these all point to the underlying cause. Schafer says that the symptoms differ widely, according to whether the an- terior or posterior lobe of the gland is mainly affected; if the lesion is concerned with the anterior part of the pituitary, the chief effects will be upon the stature, while affections of the posterior lobe produce fat for- mation and deficient sexual development. Needless to say, the two sometimes occur together; the impor- tant point to emphasize is that the anterior lobe in excess produces enlarged stature, in deficiency the reverse; while the posterior lobe concerns itself with the regulation of carbohydrate metabohsm, and, if deficient in secretion, undue fat formation results inter alia. A total deficiency of the pituitary secretion, appearing during childhood, would produce a dwarfed stature,* with the other symptoms which are beheved to be due to deficient posterior secretion. Moreover, it is possible that with one part of the gland functioning adequately, and the other deficient, the clinical picture might correspond to what is expected when the particu- lar part is abnormal. Supposing the anterior part of * Cases have been recorded in which the pituitary gland has been found atrophied in dwarfs, although this is not invariable. THE PITUITAEY BODY 107 the gland to be normal and the posterior deficient, we should expect a fully-grown individual, but with ex- cessive deposits of fat, slow circulation, sluggish mentality, and the other features of hypopituitarism, with the exception of stunted skeletal development. Although much of this particular study leads us into realms of speculation, nevertheless there is strong probability that these suppositions are near the truth. Although the pituitary is by no means always atrophied in dwarfs, this is not tantamoimt to saying that its secretion is normal quaHtatively as well as quantita- tively; for it might be enlarged by tumour formation, or by hypertrophy, without secreting the normal amount. Here we must leave the discussion of abnormalities in the pituitary secretion, and discuss briefly the treat- ment of such disorders. Treatment of Pituitary Disorders. In a brief review of the treatment of pituitary dis- orders, or, rather, of such disorders as come within the scope of this chapter, we must perforce spend some time on the study of both surgical and medical treatment. For, as regards that class of disorder which is caused by a radical change in the structure of the gland or by a tumour interfering with the adequate functioning of the gland either by direct pressure, or by raising the intracranial tension, surgery is not always even a matter of choice, but a matter of necessity. As we have already said, some cases of acromegaly 108 THE OEGANS OF INTEENAL SECRETION haye shown the existence of tumours of the pituitary- gland which have upset its normal secretion. Thus, a cystic growth of the gland, when removed, may pro- duce hypopituitarism, which, again, can be remedied in some cases by pituitary feeding. But previous to the operative measures the symptoms have naturally been those of excessive secretion, sometimes accompanied by locahzing symptoms due to an increase of intracranial tension. Gushing has reviewed the treatment of pituitary disorders very fully in his book,^ and he deals with the question of surgical interference and with the choice of treatment in a thorough manner. Apart from those cases which show the presence of a tumour, where surgical treatment is generally the only hope at the present state of our knowledge — i.e., with the uncertainty of the minutise of the diagnosis — we can scarcely recommend surgical interference for hyper- pituitarism, on the same grounds on which some authorities recommend partial removal of the thyroid gland tor hyperthyroidism. In this connection Gushing " In view of the fact, therefore, that hyperpitui- tarism, so far as glandular secretion is concerned, is a condition which tends to right itself, it must remain lor the time being a matter of uncertainty as to whether or not, in the absence of a degree of hyper- plasia sufficient to cause neighbourhood symptoms, operative measures can hold out any promise of per- manently controlling the disorder. THE PITUITAEY BODY 109 "When, however, neighbourhood symptoms have arisen owing to the extreme enlargement of the gland, due to the formation of an adenomatous struma, whether or not there have been antecedent symptoms of acromegaly, the surgical aspects of the matter stand on firmer ground.'"' Owing to the situation of the pituitary gland, and the difi&culty of operation, we see, therefore, that its partial removal, in the absence of urgent sjonptoms, is not to be considered, even as a possibility, in the hope of benefiting sjrmptoms of hyperpituitarism. Fortu- nately, there seems to be a good deal of evidence to point to the assumption that states of hypersecretion are often transitory, so that we must treat the early stages of such a condition with care and watchfulness. It is opposed to our present knowledge to administer extract of the pituitary gland to patients suffering from acromegaly; for as thyroid extract makes patients suffering from Graves' disease worse, so does pituitary extract affect acromegaUcs.^ The subsequent hypo- pituitarism may well be met by organo-therapy; some- times, indeed, one feels tempted to employ the extracts of other of the endocrine glands in the treatment of hyperpituitarism, in the hope that the hormone balance will be restored. In the present state of our know- ledge, however, this latter form of therapy for this disorder must needs be empirical; nevertheless, much has in the past been achieved by empiricism, and doubtless in the future much more wiU have to be placed to its credit. no THE OBGANS OP INTEENAL SECEETION Turning now to the study of the treatment of hypo- pittdtarism, we find that medicine naturally takes a more prominent place than surgery. The administra- tion of pituitary substance may be carried out in three ways — ^namely, by ingestion, by injection, or by graft- ing. For simplicity of administration, the first is un- doubtedly the method of choice, and consequently is the one mainly rehed upon in actual practice. From the experimental standpoint, Goetsch found that the subcutaneous injection of the extract in dogs was more effective in the ratio of 4 to 1 than the oral administra- tion, while the intravenous injection was even more effective than the subcutaneous in the ratio of 2 to 1. These tests were made with the standard devised by Gushing, from whose book they are quoted. This standard is based upon the increased tolerance for sugar which patients suffering from hypopituitarism exhibit; for in hypopituitarism " the rational dosage of glandular extract to be administered by mouth can possibly be determined by giving the individual daily an amount of glucose or Isevulose sufficient to produce a temporary meUituria in a. normal individual of equal bodily weight; meanwhile an increasing amount of the extract is administered daily, until, under the condi- tions of increased carbohydrate tolerance which the patient exhibits, hyperglycamia occurs, with a trace of sugar in the urine."^ Having arrived, then, at the diagnosis of hypopitui- tarism, we next have to decide upon the treatment, both as to the method to adopt and as to the particular THE PITUITAEY BODY 111 preparation to employ. We are concerned here more with the routine administration of pituitary extract (in one of its many forms) than we are with its employ- ment in urgent conditions, such as shock, obstetrical emergencies, etc. ; so that this account must be under- stood to deal chiefly with the treatment of definite hypopituitarism. If it is decided that pituitary extract is required over a lengthy period, it is far preferable to administer it by the mouth, as there are many disadvantages attached to both the other methods. Where it has to be given repeatedly by injection, the intramuscular method is the one for choice, as subcutaneous injection is un- desirable on account of the local anaemia produced. For a very rapid result, it may be administered by intravenous injection well diluted with normal saline solution. As to the various preparations which are on the market, a wide selection is before the prescriber. Pituitrin may be administered by intramuscular injec- tion or by the mouth. The dose in the latter method is from 10 to 30 minims. This preparation is said to be especially cardio-tonic in action, " and in a less degree hypertensive."^" Again, Hypophysin (Fuhner) is stated to possess, from the physiological standpoint, " the essential properties of the extract of the macerated posterior lobe."^^ These and other hquid preparations are usually put up in ampoules, should it be desired to administer them hypodermically or intramuscularly. The dose of the 112 THE OEGANS OF INTEENAL SEOEETION liquid preparations is usually from 8 to 16 minims. A preparation which ■will be found useful in practice is the EUxir Hypophysis (Squire), which is manufactured from the whole gland, 1 teaspoonful representing ^ grain of the dried and powdered extract. The dose is from 1 to 2 drachms two or three times daily. Again, pituitary extract is manufactured in solid form, either as a separate preparation or in combina- tion with other of the endocrine gland extracts. These products are very numerous, and it would be tedious to mention them in detail; suffice it to say that most of the wholesale chemists manufacture such extracts in tablet or powder form. It is, of course, as important in deaUng with this extract as it is in deahng with thyroid extract that there should be a known standard of strength, and that the prescriber should be sure that his preparation is fresh. As a rule this is easily ascertained, and the dosage regulated with some degree of certainty. Many manufacturers place on the market prepara- tions specified as having been made from the anterior or posterior part solely, and thus another variety of this treatment is introduced. The majority of cases appear to indicate treatment with posterior extract; indeed, the majority of the preparations are expressly stated to have been manufactured from the pars posterior. Now as to small points in the treatment of pituitary disorders, and also in the utilization of this extract in counteracting symptoms. Krst in importance is un- THE PITUITAEY BODY 113 doubtedly its contra-indication. As pituitary extract raises the arte^al tension, it (or any preparation con- taining it) should be carefully avoided in all states indicating hypertension. It should be administered •Vfith caution over long periods, and frequent sphygmo- manometric readings taken to control any undue rise in blood-pressure. The present writer has known it work wonders in some neurasthenic conditions, like- wise in states of weakness following long-continued strain, in impotence and such disorders. Again, in delayed convalescence, in persistent low blood-pressure, in depressive states, and the Hke, a course of pituitary extract, wisely controlled, will frequently be found to be invaluable. The requisite dose varies enormously, and so wide is the range that it appears probable that some at least of the failures are due to the dose being unsuit- able. In speaking of the dosage required in some of these cases, Gushing emphasizes the vast range of dose which is effectual in different cases. Thus, one boy exhibiting the signs of hypopituitarism in a marked manner underwent a " complete mental, moral, and physical awakening " by taking 18 grains of whole gland preparation daily. But another case quoted by the same author required as much as 300 grains daily (a prohibitive dose, as Gushing remarks) to give the same subjective benefits which other patients ex- perienced with far smaller doses. In undertaking the treatment of a patient by means of pituitary extract, it is wise to progress slowly, and 8 114 THE OEGANS OP INTEENAL SECEETION to endeavour to ascertain the dosage required by the individual case, as well as the reaction to the extract. In practice, it is often necessary to rest content -with methods which are, perhaps, not so precise as those which are open to laboratory workers; and it is therefore often only possible to watch care- fully the progress made under the treatment, at the same time looking for any symptoms the ameUoration of which may justifiably be claimed to be due to the drug. Cases are sometimes encountered, however, especiajly in neurasthenic subjects, in which irritabihty is pro- duced by the administration of pituitary extract. Often this appears to be due to the rise in blood- pressure which follows such treatment; but it is well to be carefxil to reduce the dose should this symptom appear, or even to cease its administration altqgether, and after a few days' cessation to recommence the treatment with small doses. This will generally be successful in combating the irritabihty, and will enable the treatment to be persevered with after the rest. In Chapter X. the use of pituitary extract in com- bination with other organic extracts is fully discussed, also the joint administration of this substance and thyroid extract is considered. Refbbencbs. I Swale Vincent, Practitioner, vol. xciv,, No. 1, p. 149. ' Schafer, The Endocrine Glands, p. 77. 8 Ibid, THE PITUITAEY BODY 115 « Howell, Jcmr. Exper. Med., 1898, iii. 245-258. ' narrower. Practical Hormone-Therapy, p. 305. * H. Cuahing, p. 294 et seq. 1 Ibid. ■ Experiments of Renon and Delile, quoted by Cashing, p. 315» 9 Gushing, pp. 317, 318. w narrower, p. 313. " Ibid. CHAPTBE VJ THE ADRENAL GLANDS The study of the chromaffin system involves a careful investigation of its most important member — ^namely, the adrenal or suprarenal glands. These bodies are now known to possess such vital properties in the body physiology, and to perform such an indispensable part in the maintenance of the " tonic " state of all vas- cular and plain muscular structures, that they deserve a foremost place in any study of the endocrine glands. Although as long ago as the sixteenth century the great anatomist Eustachius discovered the existence of the adrenal bodies, their importance remained tm- known until recent years. In 1849 Addison discovered that, in some cases of illness characterized by definite pigmentation ot the skin, the adrenal glands were found to be diseased, often with a tuberculous in- fection. From that day to almost fifty years after, our knowledge of these structures may be said to have increased but httle; but in 1894 the famous discovery by Oliver and Schafer, that extracts of the glands possessed a marked blood-pressure-raising property, inaugurated the interest which has led to the really remarkable discoveries of the properties which the 116 THE ADEBNAL GLANDS 117 chromaffin system in general, and the adrenals in particular, possess. Before commencing the study of the therapeutic value of extracts of the adrenals, we must briefly outline our knowledge of these glands, both from the anatomical and physiological standpoint. Anatomy and Physiology of the Adrenal Glands. The suprarenal glands are two flattened bodies more or less globular in shape, of a yellowish colour, and are situated behind the peritoneum in front of the upper part of each kidney. Their size in normal health varies in different individuals, but as a rule the left is slightly larger than the right, and situated somewhat higher up. The former is semilimar in shape, while the latter is more triangular, and somewhat resembles a " cocked hat." In structure these glands are made up of a central portion, or medulla, and a peripheral part, or cortex. The former is composed of highly vascular cells, em- bedded in a venous plexus, which secrete adrenahn; owing to this property they stain more or less deeply with chromate salts, which has earned for them the name of " chromaffin cells." According to the depth of stain which the cells of the medulla take, the degree of activity of their secretion can be roughly estimated. The medulla of the suprarenal gland has very close nervous relations, which, from a morphological stand- point, would be expected. For early in embryonic 118 THE OEGANS OF INTEENAL SECEETION life neuroblastic cells emigrate, and while some settle in front of the spinal cord, forming the ganglia of the sympathetic chain, others eventually become the visceral ganglia; while another group, not converted into nerve ganglia, remain in close coimection with the kidney, forming the medullary cells of the adrenals, which secrete its active principle. As well as the medulla, which is formed in this manner, certain clumps of cells stray farther afield, forming accessory bodies external to the main gland. The importance of these facts is shown by two characteristics of the gland ; the first is that it is these cells, originally formed from the same embryological tissue as the great ganglia, which secrete adrenalin; the second is that this secretion stimulates only that plain muscle in the body which is supplied by the • sympathetic system. That this is so can be verified by electrical stimulation of the sympathetic nerves, which corresponds exactly with the result of adrenalin stimulation. The exact composition of adrenalin has been dis- covered by Takamine, to whom we owe the isolation of this substance; and he shows that it is ortho-dioxy- phenyl-ethanol-methylamine. Its secretion into the blood-stream is controlled by the splanchnic sym- pathetic nerves. Moreover, the amount of secretion has been shown to depend largely on other factors, both mental and physical. Thus, mental agitation — fright, emotion, hurried exertion, etc. — all exert an influence upon the secretion of this substance. It is THE ADEENAL GLANDS 119 to the cells of the medulla, therefore, that we owe this important hormone — ^in this case a true hormone, as it is an excito-tonic chemical. These cells, it must be remembered, have an extremely intimate connec- tion with the sympathetic nervous system; this is important, as we shall see when we discuss the effects of hypo-adrenia. The other part of the gland is of different structure, and is composed of fatty material; a doubly refractive lipoid is found in the cortex, with which this part of the gland is loaded. The cortex is very much larger than the medulla; in fact, it forms about 90 per cent, of the whole gland. Included in the chromaffin system are the following bodies: the medulla of the suprarenal gland, the carotid gland, and the intercarotid body, the accessory adrenals, and some of the cells of the anterior lobe of the pituitary body which give the same reaction to chromate salts. While the medulla is in reality a part of the nervous system, at all events morphologically, the cortex is not in any way connected or controlled by the sym- pathetic nerves. From an embryological standpoint, its cells are derived from the same neighbourhood as the sexual glands, and as the testes or ovaries descend they carry with them processes from the same area. ElUott maintains that there is reason to beKeve that some buds of this nature are embedded in the sex gland itself, giving rise to the lutein cells of the ovary or the interstitial cells of the testis.^ 120 THE OEGANS OF INTEENAL SECRETION The cortical cells, however, are glandular structures, and appear to supply some secretion which influences the growth and reproductive powers of the individua;l. This has been demonstrated clinically, for cases are on record where tumours of the adrenal cortex have been found in cases where the characteristics of the opposite sex have developed; in one girl, quoted by Elliott, the menses ceased, a beard commenced to grow, and the body took on masculine characters. It is stated, also, that enlargement of the adrenal cortex takes place during breeding and pregnancy: and feeding of young animals with adrenal gland substance seems to stimulate the growth of the testes.* An interesting case, in which an autopsy was per- formed, has been recorded.f The patient was a woman, age unstated, who was bald, but had a dense beard and moustache. There had been amenorrhcea for three years, and there was pigmentation of the face. At the post-mortem examination, the right adrenal gland was found to be hypertrophied, and weighed 141 grammes. Adrenalin. The active principle which is secreted by these glands has been named "adrenalin." It possesses certain very definite characteristics, and is a necessary secre- tion for the continuance of hfe, as loss of both adrenals * Vincent, S., quoted in Endocrinology, October-December, 1917, p. 516. t Ibid., p. 634. THE ADEENAL GLANDS 121 is fatal, although one adrenal can be removed ■without any apparent ill effects. With regard to adrenalin itself, its most striking characteristic is its power of raising blood-pressure, even when injected in small doses. Experimentally, about one-twentieth of a miUigramme when injected into an animal is suf&cient to cause a considerable rise in the sphygmomanometric reading; which, again, is even more noticeable if the vagus is put out of action, as this substance also causes a slowing of the pulse when injected. If this is done, the blood- pressure may rise in quite a remarkable manner. This effect is produced by a vaso-constricting action upon the walls of the peripheral bloodvessels. Ohver and Sohafer showed, by means of oncometric readings, that the volume of the viscera was very markedly reduced by adrenalin, while the volume in the ex- tremities was increased owing to the excess of blood reaching them from the splanchnic area. A full account of the chemistry and physiology of adrenalin will be found in Biedl's book on the internal secretory organs, in Swale Vincent's book, and in many other studies of this subject. Sufficient has now been said to show that this secretion is very im- portant in bodily metabohsm, and exerts a considerable influence upon the cardio-vascular system. The cortex is supposed to have an internal secretory function, which is concerned in neutrah2dng the poisonous products of muscular activity. In other words, the medullary secretion exerts an angio-tonic influence. 122 THE OEGANS OF INTEENAL SBCEETION while the cortical is concerned vdth neutraHzang toxins. There seems to be a good deal of evidence that the adrenal secretion is in some way concerned with mus- cular energy; it is a well-known fact that in Addison's disease, where hypo-adrenia exists, muscular asthenia is a marked symptom; also that muscular power is raised " after adrenal secretion is invoked, or after epinephrin is injected."^ Where the adrenal glands are injured (which sometimes happens during operative procedures in the neighbourhood of the kidney) or diseased, there can be httle doubt that muscular efficiency is diminished. Langlois has shown that the adrenals are concerned in the destruction of muscle poisons.' So we are justified in assuming that one function of the secretion of these glands is to keep up cardio-vascular tone, while another is to neutralize poisons elaborated during muscular energy. It will have been noticed that we have laid stress here upon the intimate relation between the adrenals and the sympathetic system. The present writer has on several occasions laid stress upon the sympathetic symptoms so commonly present in neurasthenia, and has hazarded a theory that in many instances of this condition the underlying cause is sympathetic in- volvement.'* The low blood-pressure, the generalized asthenia, the vasomotor symptoms, are, certainly in the majority of cases of true neurasthenia, the most striking features.* * It has been shown that an intramuscular injection of 1 milligram of adrenalin caused an increase of secretion of THE ADEENAL GLANDS 123 Following up this Une of argument, we should expect to see much improvement in these patients after the administration of a vaso-tonic hormone, such as adrenalin. And in many cases, in the experience of the writer, this has happened. Doubtless some patients suffer from a combined endocrinous derangement, and these would not of necessity benefit from adrenal administration alone. But, nevertheless, the similarity between hypo-adrenia and neurasthenia is sufficiently striking to be noted. The features of a disorganization of the adrenal system are daily receiving more attention, and Sargent " has distinguished three different types of adrenal in- sufficiency — ^the chronic, the subacute, and the acute."^ He maintains that many of the manifestations of acute illnesses are due to adrenal insufficiency. It is obvious that such features might conceivably be due to this cause, and when further Ught has been shed upon the endocrine glands, it is probable that we shall have to revise many of our existing views on the manifestations which accompany febrile disturbances. We shall certainly have a better opportunity of ex- plaining factors hitherto regarded as necessary but inexplicable features of many diseases. hydrochloric acid in the stomach, and augmentation and aocelera. tion of the contractions of the gastro-intestinal tract. The fact that nem'asthenia is so often associated with gastro- intestinal atony, and the possibility that this is due to h3?po- adrenalism is interesting. 124 THE OEGANS OF INTEENAL SECEETION Adrenal InsnfSciency. Now for a little fuller description of the signs and symptoms of adrenal insufficiency. Of prime impor- tance is a low blood-pressure; an asthenic condition, of mind and body; a subnormal temperature; a head- ache of a "vacuum " nature; and the dermographic sign described by Sargent.* This same observer refers to certain compUcations of convalescence, which he regards as due to a subacute inflammation of the adrenals ; while other observers also lay stress upon the exhaustion which may supervene during the course of a fever. This may presumably be due to an fexhaus- tion of the adrenals, produced by their efforts to safe- guard the organism from toxsemia." It is quite possible that these small glands play an important part in all such febrile states, in neutrahzing toxins, and in helping to maintain blood-pressure. In any case, it is stated that their administration in such conditions can be relied upon to counteract these effects. The clinical state of the patient with Addison's disease needs no detailed description here. The flabby atony and muscular weakness, the vasomotor debility, as shown in the coldness of the skin surface, as well as the characteristic pigmentation, are too well known to require minute detaihng. As ElUott points out, all the symptoms, except the pigmentation, can * This consists in a white line which appears on the skin of the abdomen when lightly stroked with the finger. THE ADEENAL GLANDS 125 be explained by the vasomotor derangement and the paralysis of the sympathetic nerves.' There is also in this disease gastro-intestinal dis- turbance, as shown by vomiting and diarrhoea; but the danger undoubtedly lies in the risk of heart-failure. Other symptoms are anorexia with deficient appetite, sometimes constipation, attacks of vertigo, syncopal attacks, subnormal temperature, with coldness of the extremities. There are frequently found a persistent thjmius, an enlarged spleen, more or less generalized hypertrophy of the lymphoid tissue of the body, par- ticularly of the stomach and intestines. There is usually some degree of wasting; indeed, in the more severe cases a considerable degree of emaciation may be present. These constitute the graver form of the disease. As a rule, although muscular strength is very markedly diminished, general nutrition is not affected. Death occurs from asthenia, delirium or convulsions, sudden syncope, or, in some cases, generaHzed mihary tubercle. The main features of Addison's disease are the markedly feeble pulse, the extreme asthem'a, the pigmentation, and the gastro-intestinal disturbance. The milder degrees of hypo-adrenia are those to which we have already referred, and they are fre- quently labelled " neurasthenia." That is to say that the main features are asthenia, vasomotor disturbances, and a low blood-pressure. In speaking of these forms, narrower says: " The disorders of the adrenals, accom- panied by anatomatic changes, are fortunately not very common, while functional hypo-adrenia (sometimes 126 THE OEGANS OP INTEENAL SECRETION termed ' hypo-epinephrinia '), varying very greatly in degree and the consequent manifestations, is of fre- quent occurrence. In general, the evidence of the presence of such conditions is lack of vascular tone, hypotension, myasthenia, and instability of the sym- pathetic nervous system. This class of disorders is BtiU frequently overlooked, and, because of the intimate relations of the endocrinous organs, almost invariably associated with, and complicated by, disturbances in other internal secretory organs."^ It might be expected that the extreme weakness and asthenia which are associated with this condition would be accompanied by great bodily wasting. But this is by no means always so; in fact, the bodily weight usually is not lost in any marked degree. It may be that this is due to an increased storage of fat or carbohydrate in the body, due to tne diminished glycogenesis ; tor we know that an injection of adrenalin increases the conversion of glycogen into glucose, and may produce glycosuria; therefore a diminished adrenaUn content in the blood-stream might prevent a utilization of the stored up glycogen, and produce a diminished combustion. This would be probable, seeing that the bodily heat is lowered, with an extreme degree of subjective feelings of chilliness. Treatment. Having now very briefly reviewed the symptoms of hypo-adrenia, we will turn to the study of the thera- peutics of the adrenals. Opinion is divided as to the THE ADEENAL GLANDS 127 beneficial effects which result from the adroinistration of adrenalin to patients suffering from gross deficiency of this hormone — i.e., Addison's disease. 'Thus, Elliott says: " Neither with animal experiments nor in man has treatment with adrenalin been proved to be of value in prolonging Hfe. I have used hypodermic and intravenous injections of adrenalin without obvious benefit. Still, the substance is worth a trial." On the other hand, Harrower says: "Addison's disease was naturally fijst among the disorders in which this form of treatment was tried; and while the results have been by no means uniform, numerous cases are recorded by such men as OHver, Langlois, Osier, Eobin, and others, in which the general condition was improved, pigmentation was diminished, and nutrition was bene- fited. In most cases the results were temporary, though Beclere obtained a complete and permanent cure in one case. He credits the treatment with causing a compensatory hypertrophy of the un- affected areas of adrenal tissue."® Again, it has been suggested that in some cases the causation is solely referable to the adrenal glands, while in others the sympathetic system is at fault, with or without adrenal disturbance; and that in the first class of case benefit is to be expected from adrenal therapy, while in the second we cannot and do not see improvement from the administration of the hormone. As it is generally beUeved that 80 per cent, of the patients who suffer from this disease are the subjects of tubercle, the general antitubercular treatment should 128 THE OEGANS OP INTERNAL SECRETION be insisted upon, whatever hormonic treatment they receive. In any case, the dose of adrenal substance would have to be large, and Harrower says tliat as much as 2 or 3 grains of desiccated gland substance should be given three times a day. We must beUeve, therefore, from the summation of evidence, that, so far as is at present known, the ad- ministration of adrenalin has not been the success in Addison's disease that it was expected to be. But the explanation probably is that, if the larger part of the gland is destroyed by tubercular or other mischief, the substitution of its secretion is not sufEicient, and the disease progresses in intensity. With regard to the utilization of adrenal extracts for Other conditions, it has been tried and recommended for a variety of diseases. Thus, it has been adminis- tered as a vaso-tonic in cholera, with, according to the particular author, who beUeves that this disease is an " acute hypo-adrenia due to poisoning of the adrenals by toxins of the cholera spirillum," immediate and gratifying success."" It has hkewise been utihzed in the vomiting of pregnancy, in the behef that the adrenals stand between the body and the toxBBmias of pregnancy which arise in the chorionic vilU. Again, in the condition known as " cyclic vomiting " it has been tried with apparent success. It will be seen from these quotations that, so far, the diseases mentioned have been acute, and often present no known etiology. It is, therefore, more than possible THE ADEENAL GLANDS 129 that the chromaffin system is at fault. But there are encountered other conditions of a more chronic nature which appear to yield to adrenalin, and these are more particularly seen in children. Thus, a boy or girl who developes asthenia, in some cases after an acute specific illness, with languor, hypopiesis, and " backwardness " at school, is possibly suffering from hypo-adrenia. And it has been stated that administration of adrenal extract counteracts this condition, renders the patient more active, and banishes the indolence. Again, after acute ilhiesBes in adults, where asthenia and delayed convalescence is a marked feature, the exhibition of adrenaHn should deserve consideration. It is not improbable that a disturbance of the adrenal hormone (which, it must be remembered, is a hormone in the real sense of the word) contributes to the slow recuperation and hintiers recovery. Therefore, an extract of the adrenals seems to be indicated. Or alternatively, a pluriglandular preparation should be selected if it is considered, on all the evidence, to be desirable. Adrenalin, or an adrenal extract, has been tried in exophthalmic goitre, but, so far as the present writer's experience is concerned, the results have not been encouraging. Blair Bell believes that osteomalacia should be treated by means of suprarenal extract — ^not neces- sarily because this extract is antagonistic to the ovarian hormone, but because he believes there is often suprarenal inadequacy in this disease.^^ He 9 130 THE OEGANS OF INTEENAL SECEETION thinks that the secretions of the adrenals are of value during pregnancy in " assisting the absorption and retention of hme." In this connection it is interesting to note that certain observers have experimented upon the action of adrenalin upon the growth of bone, and have found that animals from whose bones rings of tissue have been removed, if subjected to the ingestion of this extract, heal with bony union much more rapidly than the control animals who are not sub- jected to the action of this drug. It would seem, therefore, that adrenalin exerts a helpful influence upon the growth of osseous tissue. Now as to the methods of administrating the adrenal preparations, and the different varieties which may be utilized. The extract of the gland may be given either separately or in combination with other hormones. Thus, Houssay recommends the combination of adrenaUn and hypophysin, and maintains that given together a smaller dose of the former extract is required, which, as it is the more toxic of the two, is a decided advantage. " The combination may be used success- fully in fulminating intoxications associated with hypo- tension, in tachycardia, and in myocarditis toxica, either subcutaneously or by the mouth. The com- bination produces a greater and more persistent local ischaemia than adrenalin alone. The adrenalin neu- tralizes the powerful enterokinetic action of hypo- physin, while the active constituent of the posterior lobe of the hypophysis counteracts the mydriatic effect of the adrenal extract."^* Swann has foimd that THE ADEENAL GLANDS 181 moderate doses of a 1 in 1,000 solution of adrenalin administered hypodermically completely cured, in two doses, urticaria. The extract of this gland may be given either as a liquid preparation or as a solid extract. Adrenalin or adrenalin chloride may be administered by the mouth, hypodermically, or intravenously (the latter in emer- gencies). The first of these methods is the routine for the majority of cases — i.e., where the treatment is required in small doses, probably over a lengthy period. Again, where it is to be utilized, not because there is definite evidence that the adrenal substance is de- ficient, but either as a counteraction to other hormones which may be presumed to be in excess or simply for its therapeutic action, this preparation may be relied on. Orally it may be given in doses ranging from 2 to 3 minims up to J drachm. The dose hypodermically should be about half — that is to say, up to 15 minims. This extract has also been used in the treatment of asthma, with a considerable degree of success. It may be given hypodermically or locally as a spray or douche to the nasal mucous membrane. Preparations of the gland are also made in the form of dry extracts, but the dose appears to vary with different authors. Thus, it is sometimes recommended in doses ranging from J to 3 grains (for mild hypo- adrenia), and it is possible that this variance is to be explained by the fact that different authorities are referring to different preparations. Again, some manu- facturers supply a tablet containing the extract of 182 THE OEGANS OF INTEENAL SECEETION several of the ductless glands, such as thyroid, pitui- tary, and adrenals. If it is desired to give a pluri- glandular preparation, such as this, it is important to know the exact dose of each extract which the tablet contains. We may mention here a possible method of counter- acting hyperadrenia. The patient with over-action of the adrenals is by no means uncommonly met with, but the accurate treatment of such a case is difficult. He is usually thin, nervous, with digestive instabiUty and disturbed sleep. It is always worth while to treat such a patient with pancreatic extracts, as the antag- onism between the adrenals and the pancreas is well proven. It may be assumed that such extracts will help to antagonize the excessive secretion from the suprarenal glands, and thus assist in the maintenance of a normal balance. Finally as to the contra-indications of adrenal therapy. It will be quite obvious, from what has already been said, that hypertension is an absolute contra-indication ; also that it should never be admin- istered in diabetes, as it is well known that the output of sugar is increased by the administration of adrenalin. Again, if it is given at aU in tuberculosis, especially in phthisis, it must be stopped as soon as any pulmonary hemorrhage manifests itself. Provided that it is given under the careful observa- tion of a medical man, who can observe the changes which accrue as the treatment progresses, more par- ticularly with regard to the vascular tension and THE ADEENAL GLANDS 183 pulse, it is not only a safe remedy, but a particularly successful one. We shall refer in a subsequent chapter to the important points in pluriglandular therapy, and to the factors which decide our choice between the prescription of a single hormone or a preparation con- taining the extracts of several of the ductless glands. Befebences. ' Elliott, Practitioner, vol. xoiv., No. 1, p. 126. * Edit. Jour. Amer. Assoc, 1913, Ixi. 123. 3 narrower, Practical Hormone-Therapy, p. 263. * Geikie Cobb, Neurasthenia : Its Causes and Treatment, Practitioner, August, 1915 ; see also article on the Diagnosis of Neurasthenia in Practitioner, April, 1913. " Sargent, quoted in Practical Hormone-Therapy, p. 266. ' Sajous, Hypo-adrenia as a Cause of Death in Infections, and its Treatment, Mo. Oyc. and Med. Bull., 1911, iv. 725. ' Elliott, loc. cit, pp. 127, 128. ' narrower, loc. cit., p. 265. * narrower, loc. cit., p. 264. 1" narrower, loc. cit., quoted from Naame, Ji 5 m -f :S S bO m III b d o S ° s sions t. 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