(Cornell Hmuersity Hibrarij Jtljaca, Neui fork SOUGHT WITH THE INCOME OF THE SAGE ENDOWMENT FUND THE GIFT OF HENRY W. SAGE 1891 Cornell University Library QP 190.V77 1922 Internal secretion and the ductless glan 3 1924 024 795 068 Cornell University Library The original of tiiis 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/cu31924024795068 INTERNAL SECRETION AND THE DUCTLESS GLANDS INTERNAL SECRETION AND THE DUCTLESS GLANDS BY SWALE VINCENT LL.D,, D.Sc, jM,D., M.R.C.S., L.R.C.P,, F.R.S. (IIdin,), F.R.S. (Can.), F.Z.S. PROFESSOR OF PHYSIOLOGY IN THE UNIVERSITY OF LONDON; FORMERLY PROFESSOR OF PHYSIOLOGY IN THE UNIVERSITY OF MANITOBA ; ASSISTANT PROFESSOR OF PHYSIOLOGY UNIVERSITY COLLEGE, LONDON ; INGLEBY LECTURER (UNIVERSITY OF BIRMINCHAmJ , I9::i ; arkis an'd gai.e lecturer (royal college of surglon^s), I9::2 ILLUSTRATED SECOND EDITION LONDON EDWARD ARNOLD & CO. 1922 [All rights reserved^ PREFACE The first edition, issued in 1912, has been out of print since 1914, but for various reasons the pubhcation of the second edition has been delayed. During this time many aspects of the subject of internal secretion have undergone material changes, Tliese I hope will find adequate expression in the new version of the book. If I have not been so optimistic and expansive in the treatment of certain topics as other ^^Titers on the same subjects, it is because I am convinced that a surer road to sound knowledge lies in the direction of rigid criticism and a reasoned scejiticism. After much doid^t and hesitation I have decided to omit the bibliography. The objections to such a course are obvious, but I found that to review the whole of the literature has become impossible, and to make a selection involves a task so invidious and delicate and at the same time laborious that I have not had the courage to attempt it. The omission of the references to literature will, however, have the advantage of making the book easier to read, and for a large number of students and practitioners will, I hope, not constitute a serious drawback. Investigators who have access to the first edition will find no difficulty in completing a survey of the literature up to the present time. The papers since 1917 are abstracted in Endocrinology, and since 1915 in Physiological Abstracts. Names are still mentioned freely in the text for the reasons that this arrangement involves less re-writing, and that it leaves the respons'.bi'ity in the hands of the original author on numerous topics in which I have had no opportunity of gaining first- hand information. The present edition contains much new matter, but, by re-arrangement and some curtailment of historical and con- troversial sections, it has been possible to avoid increasing the size of the book. The number of illustrations has been increased from 93 to 105. The portions dealing with chnical vi PREFACE subjects have been increased very considerably and tliis, it is hoped, will make the book more useful to students and practitioners. Many of the new illustrations are photographs of patients suffering from diseases of the organs of internal secretion. The nucleus of the book was an article in the Ergebnisse der Physiologie, and I have to tliank the Editor, Professor Asher, of Bern, and the pulalisher, for their courtesy in allowing me to use the material as the basis of the present work. Many of the illustrations are derived from papers contributed to various journals from time to time, either by myself, or by or in conjunction with pupils and others working under my direction. A large number have been drawn for me )3y the late Mrs. F. D. Thompson, of the University of Manitoba. The figures sjjeciaUy drawn by her for the present work are Nos. 13, 13a, 29, 56, 91, 92, 93, 95, 104 and 105, while Nos. 9, 10, 11, 57, 77, 79, 80 and 81 were drawn by her to illustrate her paper in the Phil. Trans., 1910. Most of the tracings have been taken from papers b_y myself or conjointly jiroduoed in the Jourual of Physiology and Endocrinology, and I have to thank Professor Langley for supjjlying cliches of blocks of many of those pubhshed in the former journal. Some of the tracings have, however, been taken from the records of class demonstrations (Figs. 39-43) or from unpublished work in my laboratory (Fig. 46). Figs. 58 and 59 were drawn by Mr. Carmichael from sketches kindly furnished by Professor Evatt. Diagrams A and B of Figs. 82 and 90 are taken from a paper by Dr. Kohn, of Prag. Figs. 20, 23, 24 and 26 are taken from papers by Giacomini, Fig. 21 from Diamare, and Fig. 22 from Kohn. Figs. 83-86 are borrowed from Murray {Diseases of the Thyroid Gland. London, H. K. Lewis, 1900). Fig. 87 from Adami (Text-book of Pathology. Lea and Febiger). Figs. 88 and 89 are taken from a paj^er by Sutherland Simpson. Fig. 98 is a photograph kindly supplied by Dr. Harvey Gushing, while Figs. 99, 100, 101, 102 and 103 are taken from Cushhig's book on the Pituitary. ^ F'or all these I beg to express my best thanks, to both author and publisher. I have to thank Professors A. T. Gameron and Charles H. O'Donoghue of the University of Manitoba for much assistance, ' The Pituitary Body and its Disorders, 1912. Lippiuoott Pliila. PREFACE vii Dr. Cramer, of the Imperial Cancer Research Laboratory, for criticism in the chemical portions of the book, and Dr. Leonard Kidd for references to literature. To IMr. Samson Wright I am deeply indebted for his services in the revision of the whole book, and to Mr. J. W. Brown for assistance in the preparation of the index. I owe a debt of gratitude to Sir Edward Sharpey Schafer for his kindly encouragement and advice on various matters extending over a period of many years. From the time when I had the privilege of acting as his assistant in University CoUege, London, he has always been ready to place the services of his laboratory at my disposal and to assist me in numerous other ways. SWALE VINCENT. Middlesex Hospital Medic.\l School, Fehruary, 1922. CONTENTS CHAPTER I Introductory — Secretion and Internal Secretion Definition of secretion Dnctless glands Internal secretion Organotherapy Nature of internal secretion Limitation of the term " internal secretion " Internal secretion and pathology PACES 1—11 1 4 5 7 9 9 CHAPTER II DEEINrTTON AND LIMITATION OF THK TeRII " INTERNAL SECRETION " 12 19 " Negative internal seci'etion " ...... IG " Hormones " . . . . . . . . . .16 CHAPTER III General Methods of Investigation and the Value op the Rest'lts which may bf. obtained by such methods . . 20 34 Pathological methods ........ 20 Experimental pathology . . . . . . . .21 Extirpation experiments . . . . . . . .21 Grafting 22 Feeding ........... 22 Subcutaneovis injections ........ 22 Intravenous injections ........ 22 Depressor substances ........ 25 Pressor substances ......... 25 Observations upon frog's mesentery . . . . . .31 Cytotoxic sera ......... 33 *' Vividiffusion "......... 33 CHAPTER IV The Nature, Mode of Action, and Ortcin of Hormones Augmentory and inhibitory hormones 3.5—37 35 X CONTENTS CHAPTER V The Internal Secketion op the Liver Glycogenic function of the liver Negative internal secretion Toxicity of liver extracts 'PAGES 38—39 38 38 39 CHAPTER VI The Tnternai, Secretion of the Pancreas Extirpation of the pancreas The islets of Langerhans A and B cells of islets Glycosuria Diabetes inellitiis Polyglandular theories Acidosis .... Medicinal use of pancreatic extracts 40— .51 40 41 47 48 48 49 50 51 CHAPTER VII The Internal Secretion of the Kidney Effects of kidney extracts Extirpation of kidneys .... Urccmia and Cheyne-Stokes respiration Treatment of nephritis with kidney extracts CEdenia in nephritis .... Influence of the kidney on metabolism Therapeutic uses of kidney extracts 52—50 52 50 50 CHAPTER VIII The Internal Secretion of the Intestinal Mucous Meimbrane and the Normal Mechanism of the Secretion of the Pancreatic Juice ....... 57 — 04 State of knowledge in 1889 ....... 57 Theory of nervous action ....... 58 Chemical mechanism ........ 59 Secretion .......... 00 Excitants of the pancreatic juice ...... 02 Secretion in disease. . . . . . . . .02 CHAPTER IX The Internal Secretion of the G.astric Mucous Membr.-vne and the Normal Mechanism of the SECRETroN of the Gastric Juice 05—00 Nervous influences ......... 05 " Gastric secretin " or " Gastric Hormone " . . . . 00 " Progastrine " ......... 00 Extracts of gastric mucous membrane in treatment of disease . 00 CONTENTS CHAPTER X The Internal Secretion of the Keproductive Organ; A. The internal secretioti of tlie testis Subcutaneous injections of extracts of testis Poehl's " spermin " . . . . Effects of castration .... Male sopranos ..... Effects of tying the vasa rlefer.-^ntia Interstitial cells ..... Transplantation of the testis Therapeutic uses of extracts of testis B. The Internal secretion of the prostate gland Extirpation of the prostate .... Administration of extracts of prostate . C. The internal secretion of the ovary and the corpus luteum Structure of the ovary Cyclical changes in the ovary and in the uterus Extirpation of the ovaries befoi'e puberty. Extirpation after puberty Effects of ovariotomy .... Ovarian transplantation Classification of sex characters Structure of the corpus luteum Mode of formation of the corpus luteum . Chemistry of the corpus luteum . Effects of corpus luteiun exti-acts . Ovarian extracts ..... Changes in the uterine niucosa produced Uy the luteum ...... Function of tiic corpus luteum Interstitial cells ..... " Femininity " . D. Ovarian medication ..... E. Osteoinalaoia ...... r.\OES r.-— 92 87—74 67 67 68 68 70 70 71 74 corpus 76 76 77 78 80 81 81 83 84 85 86 88 88 89 -91 92 CHAPTER XI The Internal Secretion of the Adrenal Bodies (the Cortex of THE Adrenal and the Chromaphil Tissues) . . . 93 — 249 A. Introductory ......... 93 Early history of tlie subject. ..... 93 B. Comparative anatomy of the adrenal bodies . . . .9.5 1. Introductory ....... 95 2. Invertebrata ........ 96 3. Anamnia ........ 98 Cyclostomata ....... 98 Elasmobranchii ...... 98 Teleostei 99 Ganoidei ........ 106 Dipnoi . . . . . . .107 Amphibia ........ 109 Anura . . . . . . .110 Urodela 110 xii CONTENTS PAGES 112 112 112 112 114 110 4. Amniota .... Reptilia . Aves Mamnialia 5. Aeces.sory adrenal bodies . Accessory cortical bodies Accessory " medullary " bodies (cliromaphil bodies) . . . . . . . .110 (i. Tabular statement of chief facts in the comparative anatoiny of the adrenal bodies . . . .120 C. Developnaent of the adrenal bodies. ..... 123 D. Addison's disease and the patholog3' of Uie odreu.al liodies. . 127 1. Introductory and historical . . . . .127 2. Sj^mptoms . . . . . . . .129 (1) Pigmentation . . . . . .129 (2) Asthenia 129 {'i) Other symptoms ...... 130 The "white line" of Sergcnt . . .131 3. .Etiology and onset . . . . . . .131 4. Metabolism in Addison's disease .... 132 5. Morbid anaton:iy of Addison's disease . . .132 0. Pathogeny of Addison's disease . . . .134 7. Course and event of the disease — diagnosis, prognosis, and treatment . . . . . .137 8. Other conditions involving adrenal insufliciency . .138 9. Excessive adrenal fvurction . ■. . . .138 10. Adrenal tumours . . . . . . .139 A. Tumours of the adi'enal medulla (rln omajiliii tissue) 139 B. Tumours of the adrenal coi'lex . . .140 E. Extirpation exjierirnents in mammals . . . . .140 F. Tlie question as to accessory adrenal l)odies in relation to extir- pation experiments in mammals . . . . .147 (i. Extirpation of the adrenal bodies in the lower vertebrata . . 149 H. Tire question as to the relative impiortance to life of cortex and medulla . . . . . . . . . .152 I. Changes found ^jost-nioifsm after extirpation of the adrenal Ijodies .......... 1.54 •J. Compensatory hypertrophy of the adrenal bodies . . . 1.54 K. Transplantation of the adrenal bodies . . . . .156 L. The pharmacodynamics of extracts of adrenal medulla (chroma- phil tissues) and of adrenin . . . . . .158 1. The general iihysiological effects of chroraaphil tissue e.xtracts and adrenin ...... 158 2. The special physiological effects of cliromaphil tissue extracts and of adrenin . . . . .105 (1) The effects upon the heart and arteries . . 105 (2) The effects on other structures, and the mode and seat of action of adrenin . . .177 M. Tlio cliemical nature of the active substance of tlie adrenal medulla and other cliromaphil tissues . . . . .185 E.xternal secretion of adrenin ..... 199 N. T)io origin of adrenin in the body ...... 200 O. Tlie mode of disposal of adrenin in the body . . . 201 CONTENTS Xlll P. The proteins, lipoids, etc., of the adrenal bodies . Q. The medical and surgical employment of adrenal preparations Surgical employment of adrenin alone or combined with other drugs ....... Application of adrenal preparations to the conjunctiva and mucous surfaces ...... Use of adrenal preparations in diseases of the bladder . Use of adrenal preparation and of adrenin in hfemorrhages Adrenin in cardio-vascular conditions Adrenal preparations in Addison's disease Various applications of adrenal preparations and of adrenin Mode of administration of adrenal preparations R. Theories as to the function or fimctions of the adrenal Ijodies Introductory ..... 1. Theories as to the function of the jnedulla Stimulation of the splanchnic nerve . Discharge of adrenin into the circulation Histological evidence. .... Emotional discharge of adrenin . 2. Theories as to the fimction of the adrenal cortex . Tumours of adrenal cortex Adrenal hypernephroiriata Functional variations .... Effects of achninistration of adienal pieparation, upon growth of body and testes S. Summary of views as to tlie iiroba})le functions of the adi'enal bodies ......... PAGES 202 204 204 205 206 206 208 209 211 211 212 212 210 224 2.S.3 235 236 238 241 242 243 245 248 CHAPTER XIT The Carotid and Coocyheal Budth.s A. Tlie carotid body .... Historical ..... Comparative anatomy and embryology Microscopical sti'ucture B. The coccygeal body .... 250- 254 2.50 250 251 2.52 2.54 CHAPTER XIII The Functions oii' the Thyhoid and Parathyroids A. Introductory : The organs derived from the region pharynx and gill-clefts ..... B, The comparative anatomy and liistolopy of the thyr parathyroid bodies ...... 1. Cephalochorda and cylostomnla 2. Elasmobranchs . ..... 3. Teleosts 4. Urodela. ....... 5. Anura ....... 6. Reptilia ....... 25.5- -324 of the 255 old and 255 255 256 250 257 258 260 XIV CONTENTS 7. Aves .... 8. Mammalia (a) General (6) Man . (c) Monkejr (d) Dog . (e) Cat . (/) Rabbit (.'/) Guinea-pig . (/( ) Rat . (i) Wolf and badger. (.7) Pig . [k) Horse (Z) Sheep and goat . C. Histology of the thyroid in man and mammals D. The iiitervesicular cellular tissue of the thyroic E. Structure of the parathyroids F. Development of the thyroid G. Development of the parathjnoids and some other branchial cleft organs ..... H. Diseases of the thyroid gland 1. Goitre .... 2. Endemic cretinism . 3. Myxcedema (a) Symptomology (6) Morbid anatomy . [c] Pathogeny . 4. Cachexia strumipri\'a .5. Graves' disease Symptoms Pathogeny Treatment C. Other conditions due to thyroi 38(i 388 388 389 3911 3911 391 301 392 CHAPTER XVII The INTERKEL.4.TION.S OF THE ORGANS OF InTERN.AI, SECRETION 39.J— 4t)9 Introductory .......... 395 A. Interrelationships involving the thyroid gland . . . 398 Action of the thyroid ujjon the adrenal bodies . . . 398 Relations between the thyroid and pituitarj' bodies . . 399 Relations between the thyroid and the reproductive organs 400 Action of the thjToid on the thymus .... 401 Action of the thyroid on the pancreas .... 401 B. Interrelationships involving the pituitary body . . . 402 Action of the pituitary body upon the thyroid . . . 402 Action of the pituitary body upon the reproductive organs . 402 Action of the pituitary body upon the adrenal bodies. . 404 Action of the pituitary body upon the pancreas, . . 404 CONTENTS xvu C. Interrelationships involving the adrenal bodies (cliromaphil tissues and the adrenal cortex) .... Action of the adrenal bodies upon the gonads Action of the adrenal bodies upon the thymus Action of the adrenal bodies upon the pituitary Action of the adrenal bodies upon the thyroid Action of the adrenal bodies upon the pancreas D. Interrelationshijjs involving the organs of reproduction Action of the reproductive oigans upon the pituit body ....... Action of the reproductive organs on the thymus Action of the reproductive organs on the adrenal bodie Action of the reproductive organs upon the thyroid E. Interrelationships involving the thymus. V. Other interrelationships ..... The " pluriglandular synch-ome " . Pubertas prajcox ...... Dercum's disease (adiposis doloro.sa) Arachnodactj-ly ...... 40.3 40,3 405 405 405 405 4 OH 400 40G 407 407 407 407 407 408 408 409 LIST OF ILLUSTRATIONS FIG. PAGE 1. Tracing showing the effect of inti-avenona injection of brain extract . 26 2. Tracing showing the effect of intravenous injection of an exti'act oi spinal cord .......... 27 3. Tracing showing the effect of intravenous injection of an extract of brain as compared with that of injection of choline in a dog after administration of atropine ....... 28 4. Tracing showing the effect of intravenous injection of an extract of brain as compared with that of injection of choline in a cat after atropine .......... 28 5. Tracing showing the effect of brain extract and choline in a labbit after atropine ......... 28 6. Tracing showing the effect of injectifin of a " protein ^' extract of striped muscle ......... 29 7. Tracing showing the effect of an injection of a saline decoction of striped muscle ......... 29 8. Tracing sho^^'ing tlie effect of injection of an alcoholic extract of brain ........... 30 9. Islet of Langerhans from the splenic end of the pancreas of a dog . 43 10. Section through the splenic end of the pancreas of a norn:ial pigeon. 44 11. Section through the splenic end of the pancreas of a 2:>igeon after a few days' inanition . . . . . . . .4.5 12. Photograph of a series of uteri showing the effect of ovariotomy on the uterus .......... 78 13. Section through the ovary of Da.s-yurus viverrinus, showing Graafian follicles and corpus luteum ....... 82 13a. Portion of corpus lutermi of Dasyurns viverrinus, showing the glandular nature of the cells ...... 83 14. Dissection of Scyllium canicvla, giving a ventral view of "paired suprarenals " (chroniaphil bodies) and the interrenal (cortical body) 10(1 15. Ventral view of kidneys and adrenal representatives of Raja batix . 101 16. Tracing showing the effect of injection of an extract made from the " paired suprarenal bodies " of (Scj/HJitm ctmira^a . . .102 17. Tracing showing the effect of injection of extract of interrenal Ijody of Scyllium canicula . . . . . . . .103 18. Kidneys and posterior cortical adrenal bodies (" corpuscles of Stannius ") of Pagellvs centrodonins ..... 104 19. Kidneys and posterior cortical adrenal bodies (" coipuscles of Stannius ") of (Ta(iM.s morrtoa . . . . . .104 20. Semi-diagrammatic figure showing the kidneys and their relations with the cardinal veins and the cortical and chroma|)hil tissues in Ganger vulgaris ........ 10.5 21. Transverse section of the interrenal body of TWf/oyi. ('(o/acen.s-. . 106 22. Transverse section through one of the paired bodies of Tori:)edo . 107 23. Transverse section of a "corpuscle of Stannius" ("posterior interrenal ") of Salino fario ....... 108 24. Section of " head-kidney " of Salmo fario, showing an islet of cortical adrenal tissue (" anterior interrenal "). . . . 109 LIST OF ILLUSTRATIONS xix FIG. I'AGE 25. Section through a cortical body (" corpuscle of Stannius ") of the sturgeon {Acipenser sturw) . . . . . . .110 26. Section through suprarenal body of iJi(/o fttZg'am. . . .111 27. Small portion of the adrenal body of C/roma.solism in the body generally. When this occurs, urea is formed l)y the liver in larger amount, and stinndates the kidneys to increased activity. in a certain sense, and in the direction just indicated, it is evident that all the tissues and organs of the body form internal secretions, for they all pass into the blood materials which have l)een formed as products of their metabolism. Everything which an organ or tissue absorbs from the blood and lymph it gives out to them again in some form or other, except in so far as it forms or separates a secretion which passes away by special ducts. It is oljvious that in this, the Ijroadest sense of the expression "internal secretion," nothing further is implied than that the blood which leaves by the veins coming from an organ or tissue contains different chemical substances from that which enters by the arteries. A distinction might x^ossibly be made in some cases between lutabolic products such as are formed by all tissues, and synthetic x^roducts which are only formed by some, and the term " internal secretion " might lie reserved for the latter. But this distinction could not be maintained systematicallj'', for it is cpiite conceivable that a definite specific and powerful internal secretion might be formed hy a katabolic process. Some authors have included intracellular enzymes among the internal secretions. These are still more " internal "" than the secretions usually so-called, for they are not ])assed out of the cell in which they are pro- duced. They dift'er from the exo-enzymes such as are found in the secretions by reason of the fact that they are bound up in the protoplasm of the cells, and, so long as the cells are alive, can only exert their action intracellularlj'. When the cells die the protoplasm breaks up, and the enzymes may pass into solution. It is supposed that these enzymes are elaborated by and used during the life of the protoplasm. It is possible that in starvation they may bring about the solution of the tissue proteins, and that the autolj'tic processes which take place INTRODUCTORY 9 after death are due to their activitj^ It lias been suggested that life is nothing more than the sum-total of tlae activities of the enzymes contained within the living matter. A theory related to this has been suggested in a tentative form liy Bayliss and Starhng. In a paper on the mechanism of pancreatic secretion (a subject which will be referred to again later on, vide infra, p. 59), these authors tested the hypothesis that the products of metabolism of certain tissues would be found to act as vasodilators only for certain tissues in. functional relation to those in which they arise, or, at all events, would act to a greater degree on these tissues than on the rest of the body in general. Results were oljtained which tended to confirm their view. Vincent and iSlieen, however, obtained dill'erent results, and suggested that the subject may be complicated by the existence not only of specific vasodilators, but also of specific vasoconstrictor substances, whose effects might be looked for on those occasions when the injection of a tissue extract pro- duces a rise of blood-pressure. This line of work has, however, not led to any definite conclusions. In some modern textbooks the conception of internal secre- tion is extended beyond the limits which appear reasonable. Thus, it is stated that the lymphatic glands " form an internal secretion which consists of lymph cells, and these furnish the blood with a supply of certain kinds of colourless corpuscles." It has already been mentioned {su2>ra, p. ;>) that definite morphological elements should l)e excluded from the categorj' of the secretions. Thus, the ova and spermatozoa are not included among the external secretions, and tlie cells manu- factured by the spleen, Ijnnph glands, and bone-marrow must be excluded from the group of internal secretions. The conception of internal secretion has had far-reaching effects in the realms of both physiology and pathology. Patho- logists are now able to recognize the existence of new forms of stimuli which influence growth and metabohsm, and this either in a positive or in a negative direction — that is to say, either in the direction of augmentation or inhibition. Thus, to mention one example, dwarfism and gigantism may be explained by reference to certain internal secretions, or, at any rate, a plaus- ible hypothesis may be furnished by such reference. It is further to be noted that the function of each particular internally secreting gland may be conceived as varying, or capable of 10 INTERNAL SECRETION varying, from the normal in the sense either of hj'persecretion or hyposecretion. In the former case the amount of augmentation or inhibition may be greater than the normal ; in the latter case the amount of augmentation or inhibition will be less than the normal. Various older ])athological conceptions are now expressed in terms of the modern "internal secretion." The "consensus ])artium " of the early writers may be regarded as the prime function of the internal secretions. Tlie " formative stimuli "" controlling the "vegetative processes" of the body and the " sympathetic " relationships betweeii different parts of tlie organism arc now frecpiently regarded as depending upon the integrity of the ductless glands or " correlative organs." An interesting pathological development may be mentioned in this place. Not only in various forms of physiological hypertrophy are we to suppose there is a hypersecretion of a ductless gland, but the same may haj^pen in definite patho- logical overgrowth ; so that it is even believed that in tumours of the internally secreting organs — thyroid, pituitary, pan- creas, adrenal — there may be actuallj? a hypersecretion — that is to say, that the tumour cells may secrete in a specific manner. Some evidence lias been put forward for the existence of what is described as " endocrinopathic inheritance," and the rela- tion of such to the Mendelian theory has been consideied. But there is not sufficient evidence before us to lead to any very definite conclusions. There is a gradually increasing tendency to attribute many cases of mental disease and many kinds of neuroses to changes in the ductless glands. Certain writers have attached con- siderable importance to a relation between endocrine dis- turbances and the dental apparatus. It must be confessed that we do not know the functions of any one of the ductless glands in the same definite Avay in "which we know the functions of, for example, the lungs or tlie pan- creas. Owing to the lack of bomidaries and the absenc? of precise exploration in many regions, the territory of internal secretion has been invaded by some irresponsible exploiters. The time has arrived for us to take our bearings and ascertain our precise position Avith regard to the subject. In doing this, every effort will l)e made to avoid dogmatism, even at the risk INTRODUCTORY 11 of losing, or hesitating to accept, some tempting and plausiljle theories. In the following pages, after a chapter upon the definition and limitation of the term "internal secretion," it will be desirable to treat first of the general methods of investigation of the subject of internal secretion and the validity of the con- clusions which may be drawn from results obtained by such methods. Afterwards the internal secretion of glands which have also an external secretion will Ije dealt with. These are the liver, the pancreas, the kidney, the intestinal glands, and the gastric glands. Following these, the internal secretion of the testis and ovary (with its corpus luteum ') will be described. Then will follow in due order treatment of the function of the " ductless glands " — namely, the adrenal body, consisting of "cortex" and "medulla"; the thyroid body; the para- thyroid bodies ; the pituitary body, consisting of the " infundi- bular " or " nervous " portion and the " glandular ' portion ; the thjanus gland ; and the pineal body. Finally will be found a chapter dealing with the relation- ships which exist between the various internally secreting organs. ^ The corpus luteum may he looked upon as a " cUu-lless gland,'" but it will obviously be convenient to treat of it along with tlie ovai'y (see p. 75). CHAPTER II DEFINITION AND LIMITATION OF THE TERM " INTERNAL SECRI'^TION " It is obvious at the outset that the term " internal secretion " ought to be employed in such a way that it corresponds as far as possible to the term " external secretion,"" or secretion by means of ducts. Secretion, as we have seen, is the prepara- tion and setting free of certain substances, the raw material for which is supplied by the circulating blood. iSuch secretion is the function of certain specially differentiated cells — the secretory cells. It has already been mentioned that several authors, relying upon the fact that the different organs and tissues of the bodj? have different functions, and therefore pour out into the blood different metal)olic ])roclucts, have insisted that all these have an internal secretion, and that this secretion is in each case a specific one. But this, as pointed out by Kohn, is simply a misuse of the term " secretion.'" Just as we have certain tissues — namely muscle and nerve — highly specialized and set apart for the functions of motility and conduction of irritability, so we have certain other tissues also higlily differ- entiated and set apart for the purjioses of secretion, and it is only to these that we can with ])ropriety ascribe the function. Such are secretory cells and their accumulations, called " glands." The secretory cells are in their origin and in their character einthelial. Secretory cells are highly 8'pecializccl epithelial cells. It is not necessary to insist on this criterion in the case of externally secreting glands, because here it is generally recognized ; but it is just as important in regard to internal secretion if the term is to be defined with anything approaching accuracy. The morphological sign of special differentiation in gland cells is the presence of granules which undergo periodical changes in number and position, according 12 DEFINITION OF "INTERNAL SECRETION" 13 to the stage of activity of the gland. It is not, perhaps, possible to insist on the recognition of granules as definite as those in the pancreatic cells 1:»efore we admit a structure into the category of internally secreting glands, but it is essential that the constituent cells should have the general character of glandular — i.e., secretory — cells. This is in some instances not altogether an easy matter to determine, and, as we shall see later on, there is still some discussion as to whether such a tissue as the chromaphil may reasonably be supposed to have a secretory function. That a discussion of this kind should arise in connection with a structure generally supposed to be internally secretory shows how little we know about the actual act of secretion in such a case (see p. 216 et jf.). We conclude, then, that secretion (internal or external) represents a highly specialized grade of metabolic activity, and should be distinguished as rigorously from general meta- bolism as the contraction of muscle from general motility (Kohn). Kohn gives a very excellent illustration of the two processes, external secretion and internal secretion. The manufacture of the bile and its conveyance into the duodenum is a secretion in the ordinary sense of the word — an "external" secretion. When we obstruct the bile ducts, the secretion goes on just the same ; but now the bile is conducted into the blood-stream, and we get an " internal secretion " of bile. This shows that the products of secretion can, under certain cu'cumstances, pass into the circulation. And we can be tolerably certain that this process can in some tissues occur normally. As we have seen, it is sometimes difficult to decide whether a given tissue is glandular or not, and therefore whether we ought to ascribe to it a secretory function. Thus, Kohn admits the "cortex" only of the adrenal among the glands, while he insists that the "medulla" consists of "chromaphil cells," which are not secretory, not epithelial, and therefore cannot secrete. This point will be referred to later and more fully under the head of the adrenal body (see p. 216 etjf.). It may be well, however, to remark in passing that it is from the medulla, and not the cortex, that the active principle is obtained. We are now in a position to define internal secretion. The process consists in the freiiaration and setting free of certain 14 INTERNAL .SECRETION substances of i^hyslological utility {the raw materials for which are supjMed by the circulating blood), by certain cells of a glandular type ; the substances set free are not passed out on to a free surface, but into the blood-stream. According to this definition, the products of ordinary meta- bolism, and even the special products of metabolism arising in such kinds of highly specialized tissues as muscle and nerve, are excluded from the internal secretions. We Iiave seen that externally secreting glands sometimes manufacture and pour out substances which are waste products, and are no longer of any use in the economy. These are " excretions." It is possible that some of the substances elaborated liy the internally secreting glands may also have to be ]ilaced in the category of "excretions." They would then lie "internal excretions" (see p. 38). The terms "ductless gland" and " Blutgefassdruse " were originally applied to a very varied group of structures, including the thyroids and parathyroids, the adrenal bodies, the thymus gland, the ]iituitary body, the spleen, and the lymphatic glands. But some of these — the spleen and the lymphatic glands — jiave not a "glandular" structure; that is to say, they do not consist of epithelial " secreting " cells, and belong to quite a different category of organs, namely, the " h»molymph " scries. The struct lu-es usually included at the present time under tlie title of "ductless glands" are the thyroid gland ; the ]iarathyroid glands ; the adrenal body, consisting of "cortex" and "medulla"; chromaphil cells and bodies in different regions, the pituitary body, consisting of the " in- fundibidar " or "nervous" and the "glandular" portion; the thj'mus gland ; and the corpus luteum.^ The thymus originates as an epithehal structure, but subsequently appears to become largely converted into a lymphoid organ.- Its morpholfigical characters are therefore unique. It is believed that these " ductless glands " manufacture and pour, directly or indirectlj', into the blood-stream some suljstance or substances which are of service in the economy, either by supplying a need or by destroying other substances which are needless or positively harmful. This last function 1 It is possible that wc may luive to add to tlie li.st the " Glaiidula insularia cervica,lis " of N. Pendo. 2 See, howevoi-, discussion on p. 329. DEFINITION OF "INTERNAL 8E0RETION " 15 — that of " Entgiftung," an " antitoxic " function — is fre- quently ascribed to the thyroid, tliough in this, as in otiier cases, the two conceptions are not necessarily antagonistic. We can readily imagine that a gland may manufacture a definite internal secretion whose active ])rinciple maj^ be competent to destroy poisonous products in the blood-stream or in some part of the bodj^ It is, perhaps, desirable to point out at tliis stage that the term " internal secretion "' has been used too generally and too confidently in many cases. Oiu' knowledge of internal secretion is not to be compared in accuracy and definiteness with our knowledge of " external " or ordinary glandular secretion. Thus, in the case of the suljmaxillary glands, we can oljserve the various conditions, loaded or luiloaded, of the gland cells. We can watch the flow of the secretion, and regulate it by stimulation of nerves. We can note changes in the volume and blood-supply of the gland concomitantly with the act of secretion. Finalty, we can recognize an "enzyme' in the fluid secreted, and are familiar with its chemical action on the food as a jjrocess of digestion. Very different is the case, for example, of the medulla of the adrenaf bod}' and of the chromaphil tissues generally. Here com- paratively little is known of changes in the cells indicative of the act of secretion,! and the very fact that any secretion is l^oirred into the blood-stream can only be shown, if shown at all, by laborious and indirect methods. It must be confessed, as a matter of fact, that some of our conceptions in regard to internal secretion are worthy to rank little higher than plausible hypotheses. But a typical gland having a duct and performing ' ' external secretion" may possess also, according to modern views, the function of "internal secretion." This applies to the liver, the pancreas, the kidney, as well as the intestinal and gastric glands. The liver has, besides the formation of the bile and the gly- cogenic function (which, owing to its highly special character, is usually not treated along with the internal secretions), the still further duty to render innocuous the end-products of protein metabolism. One of these end-products is ammonia ; this is converted in the liver into urea. So that the distinctly poisonous ammonia is transformed in the liver into the com- '■ See, however, pp. 23.5, 2J7. 16 INTERNAL SECRETION paratively harmless urea. This is an example of what Biedl calls " negative internal secretion." Since the process is a stage in the elimination of waste material, it might be called '' internal excretion " {vide supra, p. 38). Recently discovered and extremely interesting examples of internal secretion are furnished l^y the mechanisms of pan- creatic and gastric secretions [vide infra, pp. 59 and 65). There is considerable reason for ascribing an internally secreting function to the testis and to the ovary [vide infra, pp. 66 and 75). Though these are not glands in the usual acceptation of the term, yet many of their constituent cells are of the "glandular," "secretory" type. Lane-Claypon and Starling reported that injections of extract of fostus into a virgin rabbit causes growth of the mammary glands. Starling suggested the name " Hormone " (from op/xuoi — I excite or arouse) for these various substances which act as chemical messengers, and the name has in recent years become generally adopted. Eoa finds that injection of extract of foetal calf causes some mammary growth in rabbits. It is concluded, therefore, that the effects described by Lane- Claypon and Starling are not specific for only one kind of animal. Heape points out that it is well known that virgin animals sometimes produce milk. So that it seems clear that the beginning of the development of the gland dates from some point of time prior to or during pro-cestrum or cestrus, and occurs normally quite apart from pregnancj^ and that since the full functional development of the gland may be experienced by virgin animals, this must occur without any stimulus from a fcetus. Heape believes that the source of the stimulus which excites the development of the mammary glands is to be found in what he calls " gonadin," secreted by the ovary at that time, if not in the "generative ferment," which, he holds, governs the activity of the generative glands. There is now some considerable evidence that the stimulus to growth of the mammary gland arises from the corpus luteum. This will be referred to again and more fully under the head of "The Internal Secretion of the Ovary and the Corpus Luteum " {vide infra. Chapter IX., Sect. C, p. 75). Arguing from the mammary gland experiments, and from those upon the inechanism of pancreatic secretion {ride infra, DEFINITION OF "INTERNAL SECRETION" 17 p. 59) performed in conjunction with Bayliss, Starling has made some interesting generalizations upon this type of mechanism. He points out that in the normal life of the higher animals, looked at as a series of reactions to environmental change, the nervous system plays such a predominant part that we are in danger of overlooking more primitive means of co-ordination between different parts of the body. Starling further points out that in the lowest animals, before the appear- ance of a central nervous system, it is by chemical means that co-adaptation of function is achieved. As examples he mentions the movement of phagocytic cells towards an irritant, the chase for food, the escape from noxious environment, or the approach of sexual cells. In these cases the mechanism is chemotaxis. The process of action of these stimuli must be slow, and the development of a blood-circulation is necessary in order to quicken it. But before this development occurs, the need for cpiick reactions has determined the setting apart of special reactive cells ; we see, in fact, the rudiments of the nervous system. The whole history of the evolution of man and the higher animals centres about this nervous system. But in some cases still, where there is no necessity^ for a specially rapid reaction, as, for example, in the adaptation of the activities of the digestive glands to the presence of food in the alimentary canal, one might expect to find, as Bayliss and Starling actually found, that chemical means of stimula- tion are employed. Among the various hormones Starling- enumerates the gastric and pancreatic hormones, as well as similar bodies which determine the secretory activity both of the liver and the intestinal glands, adrenin, thyroiodin, and the substance secreted by the foetus during pregnancy. He prophesies that with increasing knowledge the list of these messenger substances will be largely extended, he points out that they are comparable in many respects to the alkaloids, and he intimates that the practice of drugging would therefore seem to be not an unnatural device of man, but the normal method by which a number of the ordinary physiological processes of the organism are carried out. How far this attitude may be justified by future discoveries must at present remain doubtful, but it certainly represents the view of a large number of modern workers upon the subject of internal secretion. The nervous system is no longer the 2 18 INTERNAL SECRETION only controlling influence to Ije reckoned with in explaining the bodily functions, and ewpecially is this the case with the co-ordination and interactions of many of the chief functions of the bodj^ It is even possible that the nervous system itself may be controlled l)j' chemical stimuli. Leyton has performed some experiments to test the lior- monc theory of the causation of new growths. The work of Starling and f'laypon upon the internal secretion of the fcetus in relation to the mammary gland suggested that perversion of internal secretion might have some relation to the formation of new growths. Such a hypothesis presupposes tlie existence within the organism of separate substances wliich stimulate the normal growtli and repair of the several organs and tissiies, and tJiat eacli substance is secreted eitlier by its own special organ, or by another organ or tissue. Under the former supposition, so the authors imagine, malignant growtli of such tissue would ho very unlikely. Ihider the latter the rcsidt might 1)0 brought about either liy hypersecretion of the substance or by insufficient absorj^tion thereof, whereby in either case the still absorbing tissues would receive an excess. Given an excess of hormone in the organism, together with a lesion or irritation of the tissue complemcntarj' to the hormone, unlimited growth might result. It is further conceivable that a real hj^persecretion acting on otherwise normal tissue might lead to the formation of a cpiickly increasing growth, while the relative hypersecretion resulting from diminished absorption from an atrophied senile mendirane might account for slow-growing tumours. The author inoculated previously refractorj' rats ^yith pieces of glandular organs from known susceptible animals, along with sarcoma. The results in two experiments seemed to show that parotid gland is able to assist sarcoma growth in rats otherwise insusceptible. He further excised the parotid along with inoculation with, sarcoma to see if the growth of the tumour was inhibited. The results wei'e not very definite. Ehrlich thiidvs that there may be substances circulating in the organism M'liich may stimidate tlie body cells to resist the athreptic influence of cancer cells. Askanazy believes that certain hyperplasias in the genital organs subsequently to the f(jrmation of tumours in the ovary, testis, or ])ineal body, may DEFINITION OP "INTERNAL SECRETION" 19 be due to the influence of embryonic tissue formed by the tumour. The object of the present chapter has been to define as accurately as possible what we mean by internal secretion. The point of greatest importance is to limit our conception of internal secretion so as to include only those processes which are comparable to ordinary or external secretion. We must only allow of the hypothesis of internal secretion in cells which are of a glandular type, and we must diligently search for all signs of cellular activity indicative of secretion. We must further strive to study the process of secretion itself, to discover the products of secretion, to trace them out into the blood- stream, to follow them to their place of activity, and to find their ultimate destination. In the next chapter we shall study some of the methods of such investigations. CHAPTER III GENERAL METHOIJS OF INVESTIGATION AND THE A'ALUE OE TI-IE RESULTS WHICH MAY BE OBTAINED BY SUCH METHODS In the investigation of a subject of such wide physiological import as internal secretion, it is natural that all methods employed in general jihysiological research should be utilized as occasion demands. The usual methods of exijeriinental physiology, recording devices, and all the appurtenances belonging to the graphic method, are in regular requisition. Physiological chemistry is no longer a mere handmaiden, but is rapidly becoming mistress of the situation. No attempt will be made to pass in review all these details of scientific biological technicpie. A few of the more important methods which have been of especial service in the development of the subject of internal secretion will be briefly referred to, and an opportunity will at the same time be seized to deal with a few side issues which could not conveniently be treated in any other chapter. The subject of internal secretion is, of course, a physiological one, but we shall again and again have occasion to make reference to pathological methods and pathological data. This is perhaps more emphatically the case than in any other chapter in physiology, because such a large proportion of our knowledge of internal secretion is derived from the realm of pathology, not only from Imman -patliology, but also from experimental pathology, tlie result of experiments upon animals. The fact discovered by Addison in 1855 that the symptoms of what is now known as Addison's disease are due to a lesion of the adrenal liodies is still one of the most imjiortant pieces of information we possess about these structures. The association of defective tliyroid development or atrophy with cretinoid and myxcedematous conditions is still the sheet anchor of our 20 METHODS OF INVESTIGATION 21 knowledge of the thyroid a|)paratiLS. The same may be said of the pituitary body and acroniegaly, and doubtful as may be the connection between enlarged thymus and sudden death in infants, yet this is almost the only allegation which points to the organ having any definite function. Exferimental patliology in the form of extirj^ation ex'peri- ments has been largely emploj'cd in the attempt to elucidate the functions of the glands with an internal secretion. The method has undoubtedly brought to liglit many important new facts. It has revealed, for example, the fact that certain of these glands, such as the adrenal and the pituitary, are essential for life, and that removal of the thyroid apparatus entails in most animals very serious results. It has taught us, further, that extirpation of the thymus is without obvious effects. But the results obtained by different observers have often been very contradictorjr, and the method of complete extirijation has several drawbacks. In the first place the technical difficulties are always very considerable, and are often wellnigh insurmountable. This applies especially to the pituitary body, though modern surgical skill seems at last to have triumphed (see p. 361). It is very frequently impossible to remove just the organ one wishes to remove without doing considerable damage to other tissues. Thus the extirpation of the adrenal bodies and the thyroids must always involve considerable injury to nervous structures and bloodvessels. This consideration must largely account for the contradictory results obtained by different observers. The difficulty of removing the parathj'roids without considerable injury to the thyroids can scarcely be overcome, and the successful removal of the pituitary cannot have been ]>erformed l>y more than a very few observers. Again, we must remendjer that complete removal of an organ, even if successful from a surgical standpoint, is, owing to its suddenness, an event which can never hajjpen in nature, and can never happen in pathology, and we must be cautious in interpreting the residts. The method, however, under modern surgical conditions, is capable of fruitful results, for animals do not appear to suffer to any considerable degree from surgical shock. Extirpation experiments performed in a series of steps at successive operations are more valuable than when the whole 22 INTERNAL SECRETION of an organ (or both organs in the case of bilateral structures) is removed at once. Better still and more fruitful of results are operations in which the organs are crushed, damaged, or infected artificially with the germs of disease, or inoculated with toxins, or partially destroyed by chemical poisons, or in which the blood-supply is interfered with to a more or less complete degree. Further, extirpation experiments, as usually performed, are only likely to give us useful information in cases where the organ or tissue extirpated normally provides an internal secretion which is needful for the body as a whole. If we remove the submaxillary glands, for example, we find that the animal is apparently unaffected, and the same applies to the mannnary and gastric glands. But we are not justified in concluding from these experiments that the glands in question have no internal secretion, but merely that if there be such a secretion, it cannot be regarded as essential to the body as a whole. As a matter of fact, it is now believed that the gastric mucous menibrane secretes a specific hormone (vide infra, p. 65), and the same has been alleged to be the case with the salivary glands. Proceedings of a reverse character, such as grafting, feeding, and subcutaneous and intravenous injections, have also been extensively employed in the search for the functions of the ductless and other glands supposed to possess an internal secretion. Experiments in grafting have been chiefly carried out in connection with the thyroid and parathyroid glands, and the reproductive organs. Some work in the same direction has also been done with the adrenals. The object of these experiments has been to replace the extirpated tissue by freshly implanted tissue of the same kind, either in the original situation or in some other part of the body. The earlier attempts were not very successful, and the effects were of a temporary character. The graft became absorbed, and so the final result was no more than that of the administration of a certain dose of the substance of the gland. Some recent experiments, however, have been more successful, and have yielded interesting and important results. An account of these grafting experiments will be given in their appropriate place under the heads of Thyroid, Adrenal, and Reproductive Organs. METHODS OF INVESTIGATION 23 Feeding with fresli tissues, or with tissue extracts prejiared in various ways, has been very extensively emploj'cd. The therapeutic metliod called " oijotherapy " is based upon the principle that the active substance, the " hormone," or the " internal secretion," is absorbed unaltered into the circulation. This is apparently a matter for discussion in some cases, as, for example, in the case of the adrenals {vide iv.fra, p. 211). On the other hand, feeding with thyroid glands or thyroid extracts (or even with the so-called active jjrincijile, iodothj'rin or thyroiodin or thja-oxiu [Kendall]) has proved a most valuable mode of treatment in cases of cretinism and of myxoedema, and has, besides, been used by physiologists for experimental purjioses. But our knowledge of the functions and internal secretions of most of the glands, and especially of their true and intimate relationships to morbid processes and pathological conditions, is still so limited and inexact that it can hardly be expected to furnish guidance in treatment. More especially is this true in regard to the pituitary body, the thymus, and even the pancreas. Among the tissues which have been con- sidered from the standpoint of opotherapy or organotherapy are, in addition to the thyroid apparatus and the adrenals, the glands of the alimentary tract, the ovary, the testis, the pituitary body, the thymus, the spleen, the bone-marrow, the lymphatic glands, muscle, nerve, and the jjlacenta. In feeding experiments the effects produced upon metabolism have been carefully studied in many cases. Thus the addition of thyroid substance to the normal dietary of growing rats causes a great increase of food consumjition, with alteration of growth and retention of nitrogen in the body. At the same time the nitrogenous metabolism is greatly increased. Gudernatsch has carried out a very interesting series of experiments showing that certain mammalian ductless glands, when given as food, can exert a decided influence on the growth and differentiation of amphibian emltryos, the thyroid stnnu- lates differentiation, but it lacks the power to cause growth. The thymus and spleen stimulate growth, but are wanting in power to excite differentiation. A word of caution is necessary in respect to the mode of preparation of commercial gland substances. In order to obtain a clean, easily manipulated product, it is usual to re- move all fatty matters before desiccation. It is possible, 24 INTERNAL SECRETION especially in the case of the adrenal cortex, that some useful principles may thus Ije removed (see under Adrenal Bodies, p. 203). Subcutaneous injections of extracts (either fresh or after various modes of extraction and preparation) was the method which first aroused modern interest in the subject of internal secretion. The work of Brown-Sequard in 1889, upon testi- cular extracts was, perhaps, open to some criticism, but it served to stimulate research in various directions, and led directly or indirectly to very valuable results. Subcutaneous or intraperitoneal injection of all other tissues and glands has since been carried out, and the results will be referred to m their pro])er place. By far the most striking are those obtained by the injection of extracts of the adrenal bodies [vide infra, p. 158). Hypodermic injection of the non-coagulable portion of aqueous extracts of thyroid, parathyroid, thymus, spleen, and liver increases both gastric secretion and the movements of the stomach, while those prepared from the pituitary body and the adrenal inhibit the flow. Pancreatic extract increases the flow of gastric juice. The same kind of extract made from liver causes a marked flow of pancreatic juice. Extracts of thyroid and thymus act less powerfully in the same direction, while those of the pituitary, the parathyroid, spleen, and pancreas are inert. Adrenal extract inhibits the flow. There is not sufficient evidence to warrant us in regarding these effects as manifestations of internal secretion. Intravenous injection does not appear to have been much used in the study of internal secretions until the publication bjr Oliver and Scliafer of tlie extraordinary effects upon the heart and circulation ])roducecl by the injection of adrenal extracts, or in more modern phraseology, by extracts made from the chromaphil tissue included in the adrenal (see p. 105 and Figs. IG, 30, 39-43). Since that time, however, the method has been used perhaps to a greater extent than any other. Numerous observers have tested the effects of every imaginable organ and tissue in the hope of finding some remark- altle substance in the extracts comparable in its effects with adrenin from chrouuxphil tissues. Briefly, the results have been as follows. One other tissue besides the chromaphil — namely, the nervous portion of the pituitary — has been found METHODS OF INVESTIGATION 25 to contain a pressor substance. All other organs and tissues, but especially nervous tissues, contain a depressor substance, or depressor substances (see Eigs. 1-8). The subject of intravenous injection of tissue extracts has played such a large part in connection with internal secretion that it must be dealt with in some detail. ( 'onsideralile naivete has been displaj'ed by many observers, both as to details of method and as to the interpretation of the results obtained. Thus, for example, it has too often been assumed that a slight rise or fall of the blood-pressure obtained after injection of a fluid into the circulation is in reality due to some specific action of the extract, and not due, as it very likely is, to its effects qua fluid, or to its temperature, or to the rate of injection, or to some other adventitious circumstance. Again, it has been rashly concluded in manjr cases that because an extract of a certain tissue or organ produces a certain effect, for example, on the blood-pressure, that this is evidence of an internal secretion on the part of the tissue or organ in cj^uestion. This unjustifiable attitude is being continually maintained. Thus, Livon divides the glands of the body into tM'O groups, "hypertensive" and "hypotensive," according as their extracts when injected into the circulation of an animal cause a rise or a fall of the blood-pressure. The adrenals, the pituitary, the spleen, the kidney, ^ and the parotid, are placed in the former group ; the liver, lung, pancreas, thjanus, ovary, and testis in the latter. As we have seen, the remarkable discovery of Oliver and Schiifer stimidated numerous observations upon the special physiological effects of extracts made from different organs and tissues. These authors noted, in addition to the effects of adrenal extracts, that pituitary prej^arations also produce a rise of blood -pressure. And we may state at the present time, with some degree of certainty, that these are the only two tissues in the body an extract of wliich produces fre.s.sor effects. Professor Schafer also, working in conjunction with the present writer, found that a dej'ressor substance is also present in pituitary extracts, and noted " a certain similarity of physio- ^ It is doubtful in any case whether the sjileen and kidney would be in- cluded in the pressor group. (In regard to tlie kidney, see p. 52.) 26 INTERNAL SECRETION logical action between nervous matter and the infundibular ])art of the ])ituitary." A striking result in some of our experi- ments was the causation of very extensive irregularities in the blood-pressure curve after injection of brain extracts. Schafer and Moore had jireviously noted a lowering of blood-pressure on injection of brain extracts, but they did not lay any stress on the observation. Professor Osborne and the author worked out fully the effects of nervous-tissue extracts, and found that extracts made from all ])arts of the nervous system produce a marked temporary fall of arterial blood-pres- sure, which can be ob- tained after section of Ijotli vagi and after administration of suf- ficient atropin to abol- ish vagus action (see Figs. 1 to 5). We came to the conclusion (con- trary to that of Mott and Halliburton) that, although choline was present in small amounts in the ex- tracts, the de])ressor effect was not due to the presence of that substance. The reason for this view was that, whereas after the ad- Fio. l.~ Dog. A.C.E., inorijliine, eujaie, aili- ficial respiration. Loop of intestine in air plethysmograph. Injection of 1-.5 o.c. de- coction cat's brain (Osiiorne and \^incent). ministration of atropin to an animal, choline always jiroduces a rise of blood-pres- sure, these extracts, on the contrary, always produced a fall (see Figs. 3-5). Figs. 1 and 2 show the effects of extracts of brain and spinal cord upon the blood-pressure, the volume of the intestinal wall, the volume of the hind-limb, and upon the contraction of the avuicle and the ventricle of the heart. Figs. 3, 4, and 5 show the difference in action between nervous-tissue extracts and choline in an atropinized animal. Vincent and Sheen ffjiuid that a depressor substance can be METHODS OF INVESTIGATION 27 extracted, not onty from nervous tii-sues, but also from all kinds of muscular tissue, kidney, liver, spleen, testis, pancreas, ovary, and lung. They note, also, that other observers have extracted a depressor substance from thyroid, thymus, adrenal, and pituitary body. Figs. 6 and 7 show the effect of injection of ex- tracts of muscle. Fig. 8 shows the effect of brain extract for the purpose of comparison. By this time it had become tolerably clear to the present writer that all animal tissues impart to watery or saline extracts a substance or substances which, when injected into the circulation of a living animal, affect the arterial blood-pressure. The effect produced by these sub- stances is depressor, with the exception of the medulla of the adrenal [" paraganglion supra- renale" (Kohn)], other groups of chromaphil cells, and the infundi- bular portion of the pituitary body. It had also been rendered prob- able that these depressor effects of an extract are not to be regarded as an indication of an internal secretion on the part of the tissues in question. This seems now to be generally recognized, and the view is adopted in the majority of textbooks. It is naturally of some interest and importance to ascertain CL,.JU I^;''»w*wiHP'^'^i^^'GS'siil ■yv '■■uji eiU- ~\ / • ' \ VA.A \J \ V/ ySt \ : \^ . S.y.^ cA*^/*.^ ^ er rf«/^#^t*t/^yf,r Fic!. 2. — Dog. A.C.E., morphine, curare, artificial respiration. Hind-limb plethysmograph. Hooks in auricle and ventricle. Injection of 2 c.c. saline decoction spinal cord (Osliorne and Vincent), 28 INTERNAL SECRETION Fig. 3. — Dog. A.C.E., morphine, curare, artificial respiration, atropin. Tlie first injection = choline. The second = saline decoction of brain. (Osborne and Vincent). ■'*™^— , Fig. 4. — Cat. A.C.E., morphine, atropin. First injection = 1 c.c. of 0-2 per cent, choline. The second = 1 c.c. brain decoction (Osl>orne and Vincent). Fig. 5. — Rabbit. A.C.E., morphirie, atropin. First injection = choline. The second = brain decoction (Osborne and "\'incent). METHODS OF INVESTIGATION 29 £18 far as possible how far the active substances are identical in different tissues. The pre- sent writer, working in con- junction with Dr. Cramer, found that there are two groups of substances in watery ex- tracts of nervous tissues, which, when injected into the veins of an animal, lower the blood- pressure. Both of these groups Fig. 7. — Dog. A. C.E., morphine, curare, arti- ficial respiration. Upper curve = intestine ; middle curve = limb ; lower curve = carotid blood-pressure. Injection of .5 c.c. saline decoction striped muscle of rabbit (Vincent and Sheen) . Fio. 6. — Dog. A. C.E., mor- phine. Injection of 5 c.c. "protein" extract of striped muscle (\'incent and Sheen). are soluble in water. One group is easily soluble in absolute alcohol, and the other scarcely soluble in this fluid. The alcoholic solution contains two depressor substances ; one of them has its effect abolished by atropin, the other has not. The latter is the more powerful, but rather the less soluble in alcohol. The alcoholic solution gives an abundant precipitate with plati- nitm chloride. Only a small part of this is readily soluble in water, and on purify- ing gives octahedra and prismatic crys- tals. The greater part of the precijjitate 30 INTERNAL SECRETION consists of the platinum chlorides of potassium and ammonium. The octahedra are the ammonium salt. Since the prisms have a percentage of 32-8 — i.e., 1-2 per cent, higher than would correspond to the platinum salt of choline — and since the free base has a physiological action slightly different from that of choline, it would follow that the base is not choline, but a choline-like body, perhaps a di-choline anhydride. Flg. S. — Dog. A.C.15., iTiorj>hine, curare, artificial respiration. Ujiper curve = limb volume : middle curve ^^ intestine ; lower curve ^ carotid blood- pressi_u'e. Effect of injection of 5 c.c. alcoholic extract of rabbit's brain (Vincent and Sheen). Apart from this choline-like body, we did not find any choline as such in brain extracts, and we fully confirmed the view of Osborne and Vincent, and Vincent and Sheen, that the de- pressor effects of nervous-tissue extracts are not due to choline. We stated that the chemical and physiological tests recom- mended for this substance in pathological blood cannot be relied upon ; indeed, normal blood gives both the octahedral crystals and the depressor effect on the blood-pressure. METHODS OF INVESTIGATION 31 In regard to the cliemical nature of the depressor substance in tissue extracts, nothing positive has yet been discovered. It has been suggested that it may be histamine (/5 — Iminazol- yletliyhimine) but more recent investigations have rendered this hypothesis untenable. It is doubtful whether the presence of these depressor sub- stances in tissue extracts has any physiological significance. Recent literature supplies many contributions from authors who become impressed by the fact that some organ (such as a Ij'mphatic gland) yields a depressor substance to extracts, and therefrom rashly assume that it is the function or one of the functions of the oi'gan in cpiestion to pour out this depressor substance as an internal secretion to minister to the needs of the economj'. Abelous and Bardier find in normal urine a substance which raises the blood-pressure. This substance they call " uro- hypertensin," but it is satisfactory that so far there has been no suggestion that this is any kind of " hormone " or evidence of an "internal secretion." The physiological activity of the amines which are formed when carbon dioxide is split off from amino-acids, as, for example, by putrefaction, ought perhaps to be referred to here. Abelous first noted the presence of pressor principles in putrid meat. These have since been identified by Barger and Walpole as isoamylamine, phenyl-ethylamine, and p. hydroxy- phenylethjdamine. But, of course, the effects upon the blood-pressure are not the only actions of tissue extracts which have been studied. The influences which such extracts exert upon the heart are studied by recording directly the heart movements either in the body or isolated in the lower vertebrata, and in mammals, and various forms of tonometers and plethysmographs have been employed for registering changes in the volume of the heart. The muscle-nerve preparation may be used to demon- strate the action of the extracts upon muscle and upon nerve. The volume of organs, the rate of flow of secretions, and the movements of muscular tissues, are also observed. In fact, all the modern methods of observing and recording changes in phj'siological conditions are constantly employed for the study of the action of tissue extracts. An interesting method of studying the action of animal 32 INTERNAL SECRETION extracts on the perijiheral vessels was employed by Oliver. The vessels of the frog's mesentery were observed before and after the application of a drop of normal saline (as a control) and of normal saline containing 1 per cent, of the organ dried at 38° C. — the simple saline and the saline extract being exactly of the same temperature (16° C). Throughout each observa- tion the micrometer scale was kept iu situ over exactly the same portion of an artery and its companion vein ; and when any change of calibre was observed to follow the application of the saline extract its duration and degree were noted until the calibre was restored, and it was accepted as the effect of the extract when it exceeded the normal variations and when it was practically immediate, was invariable, and when it lasted a certain uniform time, and was succeeded by restoration of the calibre. There was not much effect except in the case of adrenal extracts. This constricting effect of adrenal extract on the peripheral vessels may likewise be observed by the unaided eye by setting uj) inflammation of the conjunctiva in a rabbit (as by touching the eyeljall with a glass rod di]i]3ed in acetic acid) and then drop])ing tlie extract on the injected surface, when the redness quickly vanishes, and remains absent for about lialf an hour. But even if, on injection of an extract of an organ, we get several different effects on the organism, it is olivious that we have no right to assume on these grounds alone that the organ yields an "internal secretion." This may be suspected when the extract yields a siibstancc having very special physiological actions, but can be definitely stated only when the organ con- sists of glandular " secreting "' cells which show histological signs of activity (granules, etc.), and when the blood which leaves the organs by its veins can be found to contain the same active princii^le as the organ itself. To make the evidence for internal secretion com])lete, it ought to be possible to recognize in the symptoms produced by extirpation of the organ the direct and reasonable effects of absence of the active principle, the internal secretion, and to remove these symptoms by re- placing the organ in some other part of the body or by admin- istering the active principle in some form or other. Isolated organs and tissues are now employed frec^uently in order to test the effects upon them of extracts of the various organs. Tlius a strip of uterine wall or of different portions of METHODS OF INVESTIGATION 33 the intestine may be suspended from the short arm of a writing lever in a cyHnder containing Locke's fluid at the proper temperature. Then the fluid may be rejilaced by any other (such as an organ extract) whose action it is desired to record. Various organs yield extracts which will produce distinct effects upon such muscle preparations. Many of these have been shown not to be specific. The more important of them will be referred to again under adrenal bodies, pituitary, etc. This method is one of extreme dehcaey, and great care should be taken that proper control experiments are carried out. The preparations are very susceptible to -slight changes of tem- perature, slight accidental mechanical stimuli, and in all probability the rate of change of dosage of the active substance makes a great difference to the result. Distinct effects are reported to be noticed by this method when adrenin in dilutions of 1 : 500 millions is employed. The electrical res])on,se as an index of glandular activity has been employed to study the activity of the thyroid gland. By preliminarjr experiments with the submaxillary it appeared that the electrical change is a manifestation of the secretory process and not of anything else. The results of these experiments will be described in the chapter on the thyroid (p. 308). Abel has recently introduced a method which he calls " vividiffusion," which seems likely to be of great service in the study of the internal secretions. An artery or vein is connected by a cannula to an apparatus made of celloidin in the form of tubes immersed in a saline solution, and providing for the retirrn of the blood to the animal's body by another cannula attached to a vein. The tubes and cannulas are filled with sahne solution. This is displaced into the body by the inflow of blood when the circulation in the apparatus is estab- lished. The blood leaving the artery flows through a perfectly closed system and returns to the body within a minute or two, while the diffusible substances which it contains can pass out through the walls of the tubes. Coagulation of the blood is prevented by means of hirudin. If, then, the hormones are diffusible substances they may be separated from the circulating blood by this method. The employment of cytotoxic sera as a means of investigating the tissues concerned in internal secretion has so far not yielded 3 34 INTERNAL .SECRETION any results of importance. The antibodies obl;ained are not specific for any particular organ or tissue. It seems to the present writer that one of the methods which will yield the most valuable results in the near future is the oldest of all — namely, careful study of clinical conditions and a patient investigation of pathological anatomical findings. Now that the microscopical structure and the comparative anatomy has been worked out with some completeness, and the results of extirpation experiments and the action of organ extracts fairly well known, pathologists ma}' return to the problems with a better foundation of knowledge and fresh hopes for future discovery. CHAPTER IV THE NATURE, MODE OF ACTION, AND ORIGIN OF HORMONES Hormones may conceivably be of two kinds — namely, auginentcry and inhibifori; — analogous in their action to the two well-known kinds of nerve fibres. But it would seem probable that the inhibitory is in many cases the only active influence exerted. This may be regarded as a putting on of the brake, while the augmentary influence is simply a case of removing the brake. In other words, the organs have a superabundance of stored energy, and are constantly tending to over-activity. The normal degree of activity is determined by inhibitory influences. These influences may be nervous, or, as we have seen, they may be chemical. But there seem to be some definite examples of augmentary hormones, as, for example, secretin and adrenin. The two groups are sometimes called " assimilation " and " dissimila- tion " hormones. Sir E. Sharpey Schafer suggests the name " autocoid sub- stance " instead of "hormone," and restricts the term " hor- mones " to the excitatory autocoid substances, while those whose actions are inhibitory are called " ohalones." Matthews has recently introduced the term " cryptorhetic tissues " as applied to those furnishing an internal secretion. These organs and tissues are also often referred to as " endocrine " or " endocrinous," and the subject as " endocrinology." Nothing definite can be stated about the origin of hormones in general. In the case of some of the individual hormones, the matter may be discussed in its proper place. The hormones which have so far been described are secretin, the gastric hormone, the hormones of the liver, pancreas, kidney, testis, ovary, and corpus luteum, as well as adrenin and the active substances of the thyroid apparatus and the pituitary body. 35 36 INTERNAL SECRETION Zuelzer, Dorlin and Marxer (in a series of communications dating from the year 1908) have described the firopertj^ which extracts of certain tissues (gastric and duodenal mucous membrane, and the spleen) have of exciting intestinal peri- stalsis. This property they refer to "peristaltic hormone." A substance called " hormonal," said to contain a solution of the hormone, has been recently put upon the market. If used for therapeutic purposes, the peristaltic hormone must be introduced intravenously or intramuscularly. It has been strongly recommended for atonic constipation. The hormone is probably developed in the gastric mucous mem- brane and stored in the spleen. It is pointed out by Starling that the hormones must not be of such a character as to pro- duce antibodies, that if they are to pass easily through the walls of the blood-vessels, they must have a comparatively low molecular weight, and that they should be susceptible of easy destruction in the fluids of the body. It is said that they are destroyed by ultra-violet rays. Our knowledge of the chemical nature of the hormones is at l^resent confined to adrenin and possibly to the recently dis- covered thyroxin of Kendall. (See Chap. XI.) In 1911 Eppinger and Hess enunciated a complicated theory that not only is the whole symj^athetic controlled by adrenin, iDut that the autonomic fibres other than those of the sjunpa- thetic proper are dependent on the beneficent influence of a hypothetical hormone — autonomm. This is sometimes called " Hormone X." There are no soimd reasons for believing that any such hormone exists. Gley has recently suggested a classification of endocrine substances based upon their general physiological actions. Substances which regulate chemical processes and functions he calls " Harmozone.s " ['ipiJ.o^«\ I regulate). Under this head he includes the substance Avhicli controls the production of sugar, adrenin (in so far as it is concerned in the mobilization of sugar), and aiitithrombin. Starling's term " hormone " Gley proposes to restrict to sjjecific functional excitants such as secretin, thyroid substance, and adrenin, while he introduces the term " Pnrhorinone.s " to include products of metabolic activity which have a physiological role such as carlion dioxide. When we consider how little we know about the internal secretions, we are tempted to regret that the nomenclature NATURE AND ORIGIN OF HORiMONES 37 has already become so abstruse and complicated. In the opinion of the present writer the term " internal secretion" is sufficient to satisfj' all the working requirements of tlie subject. CHAPTER V THE INTERNAL SECRETION OF THE LIVER As stated in a preliminary manner above, the liver has, in addition to the formation of the bile, several important meta- bolic duties. The chief of these, the glycogenic function, has already been alluded to, and although to it was first applied the name " internal secretion," we shall not treat of the subject any further, for the reasons that the process is a highly special one, and that it would occupy too much space to treat of the enormous literature of the subject. It is possible that some of the ductless glands which are usually suiDposed to act only on the pancreas may act on the liver by means of the sympathetic nerves. A word or two ought to be said about the duty of the liver in rendering innocuous the end-products of protein metabolism. There are many facts which point to the significance of the liver in the production of urea. In the dog, when the arterial blood-supply is completely cut ofE from the organ, the ratio of the urea to the total nitrogen of the urine falls considerably. The liver can manufacture urea not onlv out of NH3, but also from other nitrogenous bodies. So far as the production of urea from ammonia compounds is con- cerned, the process involves an antitoxic action, the dis- tinctly ]3oisonous ammonia being transformed into the com- paratively harmless urea. This is what Biedl calls a " negative internal secretion," and what has already been referred to as "internal excretion" (pp. 14, 16). There are, however, l^robably several sources of urea in the body, and several distinct places of origin. The liver is stated to be antitoxic also for other poisons, such as strychnine and nicotine, but not for atrojDine and curare. According to C'liarrin, the protective action of the liver in 3S THE LIVER 39 certain intoxications is probably due to its action on the coagulability of the blood. According to some authors, extracts of the liver are toxic. Mairet and Vires find that injection of a watery extract of rabbit's liver into the veins of another rabbit caiises varioiis severe affections of the respiration, heart's action, and the nervoi;s system, and a close of 60 grammes per kilogramme of body ■weight is fatal. The efficiency disappears on heating the extract. Of course, these are enormous doses. It is probable that in corresponding doses other animal extracts prepared in the same way woiild be ecpuxlly injurious. Liver extracts have been administered therapeutically iii several affections. The value of cod-liver oil has been sup- posed to be clue to its containing some of the internal secretions of the liver. Hepatic opotherapy is recommended in digestive disorders, hepatic insufficiency, hepatic cirrhosis, hsemorrhages due to liver disorders, phlebitis, icterus, hepatic diabetes, gout, antemia, and tuberculosis. It is in cases of hepatic diabetes that liver extracts might be tried with the best prospects of success, but it cannot l^e giiaranteed that any good results will certainly accrue. CHAPTER VI THE INTERNAL WRCRETION OF THE PANCREAS The most usually quoted example of a gland which has both an internal and au external secretion is the j^ancreas. A relation between diseases of the jiancreas and diabetes has long been suspected, but Minkowski and Mehring first definitely showed that comjalete removal of the pancreas in the dog, cat, and pig is followed by diabetes having the usual symptoms of that disease in man. Tliat this is caused by the absence of an internal secretion is proved by the facts that it does not occur if the gland be left in situ and the duct tied, nor does it occur if a portion of the pancreas be grafted in some situation remote from its normal position {e.g., underneath the skin or in the peritoneum ) . It is interesting to note that a dog djdng from pancreatic diabetes eats ravenously because of increased intensity of the gastric hiinger contractions. It lias heen oljserved that complete pancreatectomy in pregnant bitclies near term does not result in diabetes, altliough there is serious general disturljance. How the internal secretion of the pancreas normallj? f)revents glycosuria is not clear. We can only sajf that it exerts some influence upon the carbohydrate metabolism, either by favour- ing the formation of glycogen in the liver from the glucose taken to it ])y the portal vein, or by furthering the oxidation of glucose in the tissues generally. Pfliiger confirmed the observation of Marcuse that extirpa- tion of the pancreas in the frog produces the same symptoms as in mammals. He also makes the further statement that extirpation of the duodenum or separation of the duodenum from the pancreas — the Ijlood-supply of tlie gland being left intact — has the same effect. Pfluger criticizes the ordinary 40 THE PANCREAS 41 internal secretion theory of the pancreas, and substitutes for it a theory according to whicli there exist nerve centres, stimulation of whicli determine the production of sugar, and other centres of an antagonistic nature determining an internal secretion of the pancreas, wliich internal secretion hinders the production of sugar. In removing the pancreas these centres are necessarily damaged, and tlie same happens in extirpation of the duodenum or separation of tlie duodenum from the pancreas. Herlitzka, working with frogs, agrees that the ganglia in the wall of the duodenum are necessary for the normal internal secretion of the pancreas, and agrees with the doctrine of Pfluger that the correlation between duodenum and pancreas is due to the action of these ganglia. Vahlen points out that it is usually believed that there is in the pancreas a material which promotes the destruction of sugar in the organism, and that this unknown substance splits up the sugar in some way and thereby makes oxidation easier. The author referred to has tried to isolate such a substance, with entirely negative results, but he thinks he has obtained a constituent of the pancreas which acts in a purely catalytic manner on the vital destruction of sugar. Pancreatic extracts exercise an inhibitory influence on the production of lactic acid in surviving muscle. The Islets of Langerhans By perhaps the majority of authors the pancreas is considered to consist of two separate and distinct kinds of tissue, the secreting alveoli, and the islets of Langerhans. The question, however, as to the morphology and physiology of the islets of Langerhans needs a little discussion. Modern writers may be divided into two chief groups according to their views as to the morphological significance of the islets. The first of these believe that the islets are essentially of the same embrj^ological and morphological nature as the zymogenous tubules, and are not to be looked upon as, in any sense, organs sui generis. The second group of observers regard the structures in question as definite and distinct organs, analogous to the cortex of the adrenal, the epithelial part of the pituitary body, and the parathyroids, and consider that they have no connection 42 INTERNAL SECRETION (except a community of embryonic origin) witli the secreting tubules of the pancreas. Some among tlie first group of writers even consider there may be no difference in function between the two structures. Thus Harris and Gow thought that the islets might take part in the external secretion, probably forming one of the ferments. Some authors look upon the islets as exhausted secreting cavities, and believe that after a jjeriod of rej^ose they may again take on their secretory function. Others, on the con- trary, look upon the islets as exhausted acini M'hich are unable to return to their former state. In most vertebrates there are no lumina in the islets of Langerhans, but sucli liave been described occasionally in amijhibians and reptiles. Laguesse refuses to admit that the islets are simply exhausted masses of acini, or that they are in their nature simply secreting tubes modified by inanition, and he urges against either of these theories the abundance of the granules of secretion in the islets, the permanent juxtasplenic islet of the Ophidians, and the fact that islets are found in every functional state of the pancreas. The presence of lumina in the islets of reptiles is a strong indi- cation that their origin is from alveoli. Tlie same author, in his numerous contril)utions on the subject, has laid stress on the anatomical details above referred to, and inclines strongly to the view that the islets of Langerhans are portions of the secreting tubules temporarily modified for the purpose of supplying an internal secretion. Dale employed a new method for investigation of the sub- ject, using secretin to exliaust the gland. He concluded that the islets of Langerhans are not independent structures, but are formed by certain changes in the cells of the secreting tissue of the jjancreas. The change from the secreting to the " islet "' condition may hv accelerated bj^ the adnnnistration of secretin and as a result of inanition. The authors belonging to the second chief group all believe in the internal-secretion theory of the islets, and, indeed, so convinced arc many of them that this is the correct theory, that they do not accej^t the statements of the first group, who describe changes in the islet in exhaustion and inanition, and the transition forms from one kind of tissue to tlie other. According to Diamare, the islets are " epithelial bodies '' in THE PANCREAS 43 Kohn's sense. They are constant and invariable, and are a form of " epithelial body " derived from the pancreas (for he admits, of course, the common embryonic origin of pancreas and islets). The adult islets, in his view, have no relation to the surrounding tissue, except that of contiguity, and he denies that the islets ever possess lumina, even in reptiles. He denies the continuity of the islets with the exocrine gland and all bid. c Fig. 9. — Islet of Langerhans, from the splenic end of the pancreas of a normal dog, showing the alveolar form of the islet tissue. The tissue of the islet is seen to consist of solid branching columns of cells, for the most part two deep, separated by wide capjillary bloodvessels (Vincent and Thompson). (Drawn by Mrs. F. D. Thompson.) Lettering common to Figs. 10, 11, and 12. — hld.c, red blood-corpuscles; c.a.c, centro-acinar cells ; cap., blood-capillaries ; i., islet of Langerlaans ; I., lumen ; trans. c, transitional cells ; zym., zymogenous tissue. forms of physiological variation. Rennie, in his work on the teleostean fishes, describes the fairly constant occurrence of an encapsuled islet (" principal islet ") of large size, whose relation to the pancreatic tissue is frequently extremely slight. He considers the islets to be " blood-glands " which have entered into a secondary relation to the pancreas. This author finds no sign of any transitional forms. 44 INTERNAL SECRETION The present writer, as the result of investigations carried out in conjunction with Mrs. Tliompson, considers that the eni- bryological work of Laguesse and the experimental researches of Dale are confirmed in all essential jjoints. Fig. 9 reiDresents an islet of Langerhans from the splenic end of the pancreas of a normal dog, showing the " alveolar " form of the islet tissue. The isk^t is seeir to consist of solid, ))ranching columns of cells, for tlie most jjart two deeji, sepa- rated hy wide capillary Ijlood vessels. In some jjlaces the zymogenous tissiu' shows transitions towards islet. Fig. 10 >iP"^' '^ I.' * * 1 I 4-1 f V (l^ 4^'^' '' \^4. ' ^ NnK;|j6.«* ,3^j V Fig. 10. — Fi-om the splenic end of the pancreas of a normal pigeon. The section sliows the islets and tlie zymogenous tissue. Co7ripare this with tlie ne.xt figure (Vincent and Tliompson). (Drawn hy Mrs. F. D. Thomp- son.) Lettering same as for Fig. 0. is a section taken from the splenic end of the pancreas of a normal pigeon. The section shows the islets and the zjano- genous tissue. Compare this with Fig. 11, which shows the splenic end of the pancreas of a pigeon after a few daj's' inanition. The increase in the amount of islet tissue is very striking. Jf a pancreas from an animal in inanition is examined, a very remarkable increase in islet tissue is noted^ (see Figs. 1 It jnust be admitted tliat tliis does not occur with complete regularity, but probably depends vipon tlie state of n\itrition of tlie animal at the {hue the inanition is begim. THE PANCREAS 45 10 and 11), but if after such a period the animal is restored to its normal state of nutrition, the usual proportion of islet tissue is found. The most obvious explanation of this is that the alveoli are reformed from the islet tissue. There is, however, another possibility — namely, tliat the islet tissue formed from alveoli, as a result of cjianged physiological conditions, is not reconverted into secreting tubules, but, having reached the last stage of its career, degenerates and disappears. If this ^..^J.%^.,-.^. (rail,.?. (■ 1 \ ? -A zyin i — ' M' trans, c. tran.'^. c Fig. 11. — Splenic end of the pancreas of a pigeon after a few days' inanition. The increa.se in the amovint of islet tissue is very marked (Vincent and Thompson). CJ. with Fig. 10. (Drawn by Mrs. F. D. Thompson.) Lettering same as for Fip;- 9. be the case, we must assume that new alveoli are formed from the existing tubules, and occupy the space recently occupied by islets. On this hypothesis the more solid islets might be regarded as nothing more than worn-out alveoli about to disappear. Of the two possible views here put forward, the present writer is inchned to support the former. Feeding dogs upon a purely carbohydrate diet also increases the amount of islet tissue, and removal of the spleen from frogs has a similar effect. 46 INTERNAL .SECRETION Experiments involving ligature of the pancreatic duct have given contradictory results in the hands of various observers. Manj? writers have alleged that if a portion of the pancreas is separated from the rest of the gland and its duct tied it atrophies and leaves a tissue contaming enlarged islets. Schafer was the first to suggest that the islets of Langer- hans are the part of the pancreatic tissue concerned with carbohydrate metabolism. A number of more recent observers have found in cases of diabetes mellitus that the islets are affected by a hyaline degeneration, atrophy, or inflammatory changes ; Isut others have been \uiable to confirm these results. Not\^'itlistanding the conflicting nature of the evidence upon this point, a large number of pathologists have — at any rate, until cpiite recently — appeared to favour the view that the islets of Langerhans constitute a tissue titi generis, whose function it is to control, by means of some kind of internal secretion, the metabolism of sugar in the body. Diamare has, indeed, put forward some experimental work in support of this definite view as to the function of the islets. He finds that tlie amylolytic ferment occurs only in the ordinary jDancreatic cells, while it is absent in the islets of Langerhans. He states that the islets possess the power of inverting grape- sugar, and is of opinion tliat these structures are intimately concerned in the economy of glucose in the body. The glycolytic action of the islets in vitro is very weak, and he looks upon the tissue as furnishing an endocrine zjmioplastic secretion. H^yperglycfemia and diabetes are in this view the result of functional insufficiency of the islets. This observer fiu'ther records certain modifications occurring in the islets of Moiella iricirratd as the result of the injection of glucose into the abdominal vein. As we have seen, the ju'esent writer was the first to prove experimentally that the islets of Langerhans actually pass tlu'ough a structural cycle, corresponding to a cycle of changes in physiological conditions. We were able to provoke ex- perimentally the formation of new islets at the expejise of the exocrine parenchyma, and then to induce their disappear- ance by a new transformation into acini. Laguesse, working A\ith the pigeon, has Iieen able to confirm our results. He has performed a- very large number of experi-^ THE PANCREAS 47 ments, and his results are carefully tabulated. He gives, moreover, a careful account of the anatomy of the pancreas in the pigeon. He states his conclusions as follows : " Chez les animaux soumis a Tinanition pendant quelques jours, le nombre des ilots double presque, pour retomber a son taux normal chez les pigeons renourris." " Nos observations, completant et elargissant celles de Swale Vincent et Thomp- son, nous j)araissent fournir une preuve experimentale tres demonstrative du balancement." The results of recent investigations have not been very concordant. M. Labbe and P. Thaon have reported an in- crease in amount of islet tissue in guinea-jiigs when fed on animal food. This result may possibly be attributed to inani- tion. Bensley, as the result of very painstaking work, finds himself unable to agree with Vincent and Thompson. He has used Lane's methods for the study of the cell granules and has adopted the classification into A and B cells, according as the granules are fixed resj^ectively by alcoholic or watery solutions. In order to test tlie question as to alterations in islet tissue under different conditions, tliis author emjiloyed the neutral red method for staining the islets and for their enumeration. He has taken lao account of the size of the islets. He believes that the structures in question are con- stant and do not change under different physiological conditions. Von Hansemann confesses that he has been forced to change his opinion as to the significance of the islets of Langerhans. He now regards them as varieties of the j^arenchyma of the organ and 2iot as separate structures. He finds that in dia- betes the changes in the islets correspond exactly to those in the rest of the organ. Pratt and Murphy have observed that pancreatic tissue implanted in tlie spleen and separated from its original vascular and nervous connections can live and fiuictionate for months. A small nodule of pancreas composed of acini without demon- strable islets prevented the development of diabetes. This shows that the islets are not the only portions of the pancreas which furnish an internal secretion. Other experiments of the same nature and with similar results have been recorded. 48 INTERNAL SECRETION Adami affirms that he has encountered appearances in the human subject which would be difficult to explain, except on the hypothesis that the islands are not separate organs ; that they vary in number according to the state of nutrition and activity of the gland, becoming converted into active acini, and vice versa. As Adami justly points out, these observations do not wildly negative the contention tliat the islands bear some intimate relationship to a certain order of cases of diabetes ; tiaey suggest, however, that degenerative changes seen in them are an indication of other changes occurring in the intimately connected jjancreatic tissue proper. Whatever may be subsequently discovered to be tjie true function of the islets of Langerhans, their intimate anatomical relationshij) with the zymogenous tubules, the numerous transition forms in all groups of vertebrates, and the transforma- tion of alveolus into islet, and vice verm, all appear to prove conclusively that the islets are not organs .mi generis, but are an integral part of the pancreatic tissue. As to whether the temporary structiu'al modification of alveolus into islet tissue corresponds to a specialization of fiuiction, the evidence is at present inconclusive. A prolonged discussion of the pathology of' glycosuria and speculations as to the precise manner in which the internal secretion of the pancreas normally prevents such a condition, would serve no useful purpose. It is, however, of supreme importance to bear in mind tliat a certain order of cases of diabetes mellitus are, in all probability, due to insufficienc}' of the internal secretion of the pancreas. But we must bear in mind the possible influence of disturbances in certain others of tlie endocrine glands wliicli are concerned with carbohj'drate metabolism, as, for example, the adrenal and the thj'roid. In disease of the pancreas the limit of assimilation for carbo- hydrate may be greatly lowered even when spontaneous glycosuria docs not occur. The symptoms of diabetes as observed in the human subject are well known, and need only be referred to briefly. The cases are described as acufe and chronic, the former usually occurring in children, the latter usually in older people. There are 'inild and severe cases, and there are the fat or emaciaied cases. Many other subdivisions and classifications have been suggested. Polyuria, thirst, increased appetite, dryness of THE PANCREAS 49 the skin, constipation, loss of sexual power, are among the most prominent symptoms. The diagnosis, when these symp- toms are present, is based upon the finding of sugar in the urine. The percentage varies from 3 to 5 per cent, or over. In the acute cases the course is rapid and the disease is almost inevit- ably fatal. In the chronic cases the condition is not so serious and the patients may live for many years. Among the complications the commonest is pulmonary tuberculosis, the most serious diabetic coma. The presence of /5 — oxybutyric acid or diacetic acid in the urine is relied upon as a sign of approaching coma. The commonest form is the dyn'pnoiic. The condition may be introduced by lassitude, headache, etc., followed by restlessness. iSjDeech becomes incoherent, and the patient lapses into coma. Although jiJiysicians have Ijeen warned repeatedly against confusing glycosuria with diabetes, a clear distinction between the two is by no means generally made. The " polyglandular " theories of the Viennese school take no account of the dis- tinction between, for example, adrenin intoxication and true diabetes. The work of Mehring and Minkowski referred to al)ove led to a great deal of investigation and to much controversy. Many authors stated that diabetes did not always occur when the pancreas was removed. But this was supposed by the sup- porters of Minkowski to be due to incomplete removal. Pan- creatic feeding seemed useless in diabetes and it was not always possible to find any lesion of tlie pancreas in cases of diabetes. Considerable stress was laid, moreover, upon the differences between diabetes in the human suliject and the condition induced in animals by extirpation of the pancreas. But more recently it has been found that diabetes may be induced artificially in a dog if a sufficient portion of the pancreas be removed, leaving the remainder \\ith its nornuil blood sujijjly and its normal connection with the duct. In such cases the progress of the disease is hastened by carljohydrate feeding. Changes in the islets have been described in such cases. The chief differences which are alleged to exist between clinical and experimental diabetes are as follows. The dextrose — nitrogen ratio is said to be 3-65 in severe human diabetes, while in the dog after extirpation of the pancreas it is not more than 2'8. The increase of total metabolism in the dejjan- 4 50 INTERNAL SECRETION creatized clog is said to be greater and more frequent than in human subjects with diabetes. Tlie changes found in the islets of Langerhans in human diabetes are not so striking as in dogs after removal of large portions of the pancreas. Finally, dogs with experimental diabetes rarely die of coma, while this is notoriously a common ending in the case of human beings with diabetes. Allen, who has carried out a great amount of painstaking work on this subject, points out that dogs have much less tendency to ketoniu'ia than man, and believes that experiments upon animals of other species may give a result more nearly ajjproaching human diabetes. He is inclined to believe that explanations may be found for the other differences enumerated. Nothing is certainly known about the natiu'e and origin of the acidosis and the diabetic intoxication which gives rise to coma. It is generally believed, however, that ketones are formed as a result of an incomplete destruction of fat, due to an imperfect consumption of carbohydrates. The ketones Ijecome oxidized to acetoacetic and /? — oxybutyrio acids. The condition is often referred to as I'etosis. The intoxication seems largely due to the increased acidity, an increased H — ion concen- tration. After extirpation of the pancreas in dogs and cats, Loewi produced dilatation of the pupil by the installation of adrenin. He attributes the dilatation to an increased excitability of the sympathetic nervous system. The reaction has been used as a test for pancreatic deficiency in the human subject, but does not appear to be very reliable. Organotherapy — treatment with pancreas or extracts made from it — appears to be useless. The most modern form of treatment and, so far as can Ije judged from the clinical evidence available, the most successful form, is by fasting, combined with vigorous exercise. These measures, at any rate, prolong the life of the patient and render him useful and comfortable, even if they do not cure. As Allen points out, what is required is some means of strengthening the weakened function as well as giving it a rest. There can, however, be little hope for this till we are quite clear about the pathogenesis of the condition. A functional relationship between the islets of Langerhans and the reproductive organs is claimed by some observers THE PANCREAS 51 and a similar relationship between the spleen and the pancreas has been suggested by certain authors. An important function of the pancreas ajipears to be to increase the resistance of the body towards bacterial in- fection. Extracts of pancreas are employed medicinally in gangrene and tuberculosis, as well as in pancreatic diabetes. The use of such extracts with the object of increasing the resistance to infection is of recent date, but is deserving of further practical study. CHAPTER VII THE INTERNAL SECRETION OF THE KIDNEY A BELIEF ill Home kind of internal secretion on the part of the kidney has existed since the period when interest in the subject was stirred by tlie researches of Brown-Seqnard. We have already seen (p. 25) that some writers have described pressor effects as the residt of the injection into animals of extracts made from the kidney. Lewandowsky, however, found that with 5 to (J centimetres of the blood from the renal vein no more positive result upon the blood -pressure was obtained than with a similar amount of blood taken from any other vein in the body. He concludes that no specific pressor substance is ]ioured out from the kidney by the renal vein. The present writer has frequently tested the effects of different kinds of kidney extracts ujion the blood -pressure. Sometimes there is a slight rise of pressure, sometimes there is no rise, or there may be a fall. The rise is never very marked, and only occurs with imboiled "protein" extracts. The same residt may frequently be obtained from extracts made from other organs and tissues, and it may probably be concluded that, so far as the question of internal secretion is concerned, the results are not of any great importance. Further, it may be stated as f)robable that the high blood -pressure and hyper- trophy of the heart in nephritis bear no relation to the presence of a pressor substance in kidney extracts. But arguments liascd upon experijnental work of a different character and upon clinical and therapeutical observations have Iiecn urged in favour of the view that the kidnej-s furnish an internal secretion. Brown-Sequard in 1869, had expressed the opinion that the phenomena of lU'iBmia were not entirely due to the accumulation of urinary constituents in the blood, but to the absence of the normal internal secretion, or, as he expressed it, due to ' ' Texistencc de changements chimiques 52 THE KIDNEY 53 inorbides du sang rempla^ant la secretion interne normale." This view was partly based upon clinical observations in which in spite of long-continued anuria the symptoms of uraemia were practically absent. Later, in 1892, Brown-Sequard and d'Ar- sonval stated that ' ' le rein a une secretion interne d'une grande utihte. ■ ' They removed both kidneys from rabbits and guinea- pigs, and found that death occurred much earlier than after ligature of both ureters, although, of course, in both cases there was an accumulation of urinary substances in the blood. Then they administered to some of these by subcutaneous injection diluted juice of kidney from a normal animal of the same species, while they left others untouched as controls. They found that those animals which had received the injection survived one or two days longer than the controls ; the duration of life in the injected animals was, in fact, equal to or longer than that of animals which had undergone ligature of both ureters. The phenomena of urfemia were of slower develop- ment in those animals which survived the longer, owing to treatment with kidney extract. Some observations of Lepine seemed to point to the fact that the kidney blood contains peculiar substances. Working with rab])its, this observer f oiuid that tying both ureters induced death after fall of temperature, vomiting, and diarrhcea. But if the flow through the ureter were checked by connecting it with a vessel containing normal saline at a higher pressure than that in the ureter, then the symptoms induced were quite different. Instead of a fall of temperature there was a rise , and in addition one observed increased rate of respiration and convulsions. A watery extract of kiclneji" injected into the circulation produces, according to Lepine, a rise of temperature and dyspnoea. He concludes that the kidney substance con- tains materials inducing these effects, and suggests the possi- bility of auto-intoxications of renal origin. E. Meyer, a pupil of Brown-Sequard, foiurd that while the blood of ursemic animals produces no definite effects upon normal animals, when injected into nephrectomized animals, it induces dyspnea and slowing of respiration. The same observer further found that injections of kidney extract, or normal blood, or of renal venous blood from a normal animal, have the immediate effect of checking the C'heyne-Stokes respiration which is such a striking symptom of urtemia. 54 INTERNAL SECRETION Vitzou found that in rabbits and dogs the injection siibcu- taneously and intravenously of defibrinated blood from the renal vein of a normal animal prolonged the life of a nephrec- tomized animal in a very striking maimer. Thus in one rabbit the survival was fort3'-two and a half hours longer than was the case with the control, which had, hke the first, undergone double nephrectomy. Vitzou concludes that the kidney has an important internal secretion, the absence of which plaj's an important part in the causation of uraemia. Many experiments of a similar character have been per- formed. Some of these have been in favour of the views ex- pressed by Meyer and Vitzou, some have been opposed to them. The residts obtained have been in fact very contradictory. Thus Chatin and Guinard investigated the question as to whether, liy injection of blood from the renal vein of normal dogs into nephrectomized animals, there was any lengthening of life, or a diminution of the uraemic symptoms. The results were completely negative — that is to say, the animals treated with the serum died on the whole sooner than those not treated. Chatin and Guinard do not, however, definitely deny an internal secretion on the part of the kidney, for which they think there is a certain amount of clinical evidence. It is doubtful if much importance can he attached to the results obtained by Vitzou. His work has been severely criticized by Lewandowsky, who points out that as a matter of fact animals can live from three to five days after double nephrectomy ; whereas Vitzou states that he succeeded by his treatment in causing them to live sixt^' to sixty-nine hours instead of thirty -four ! As]>ointed out by Biedl, the duration of life of nephrectomized animals is extremely variable. Accord- ing to his own experience in some cases dogs and rabbits may svn-vive as long as five or six days after extirpation of both kidneys, while in other cases they may die in thirty-six hours. Again, the incidence and course of the symptoms of urasmia in such animals is no criterion of their actual condition. It frerpiently happens that nephrectomized animals show no characteristic symptoms for two, three, or even four days, and then suddenly succumb. Others, on the other hand, on the day after the operation, suffer from vomiting and dj'spnoea, then either recover or remain in a chronic condition of urivmia for several daj's. Such experiments are of little value as THE KIDNEY 55 demonstrating an internal secretion on the part of the kidney, and still less as pointing to the treatment of nephritis in man hy means of kidney extracts. Notwithstanding this certain writers report good results in cases of chronic nephritis after treatment with kidney extracts by tlie mouth. Lindemann found that guinea-pigs, after having received injections of rabbit-kidney emulsions, furnished a serum which was very toxic to rabbits, giving rise to albuminuria and uroemia. The injection of this nephrolytic serum provokes symptoms precisely similar to those induced by true kidney poisons. Here we have the formatioii of certain specific substances formed in the blood inider the influences of the processes of absorption of the renal substance injected, and these are the substances which affect the kidney. Schiiltze could not observe the nephrotoxic effect of the seriun of rabbits into which he had injected an emulsion of guinea-pig kidney. This observer also could not confirm the hepatolytic effect of the sera of animals which had been injected with liver emulsion, although Delezenne and Deutsch affirm that animals into which one injects liver emulsions furnish a serum which possesses powerful hepatotoxic properties. Nefedieff believes firmly in a specific nephrotoxic serum in Lindemann's sense. He states further that this serum is also hemolytic. The serum is analogous to the cytotoxins in general. Under the influence of hypodermic injections of kidney emulsion from healthy animals there appear in the blood of rabbits and gninea-jtigs certain substances which exercise an injurious effect on the kidneys of the species of animal whose organs have been used in the preparation of the emulsion. Nefedieff found also that the serum of rabbits in which one of tlie ureters had been tied soon acquires powerful nephrotoxic projierties. He suggests that in this case substances pass from the kidneys into the blood just as they do when an emulsion of the kidney has been injected. Arguments of an analogous kind have also been used to explain the causation of oedema in nephritis. Kast observed that the blood of nephritics with oedema contains a lymphagogue substance of great strength, which also passes out into the dropsical fluid. Blanck noted, in investigating the serum of animals with uranium nephritis and uranium oedema, and of rabbits with chromium or aloin nephritis (which does not give 56 INTERNAL SECRETION rise to oedema), that if one injects rabbits with serum or cedema- tous fluid from a rabbit affected with uranium nephritis, one gets oedema in this case also. Timofeen,from a review of the work of previous experimenters and on the basis of his own investigations, beheves that the cause of the oedema in neph- ritis is the passing into the blood of certain lymphagogue substances, the source of which is a substance he calls " nephro- blaptin " arising in the diseased kidney. A discussion of this question would not be complete without a reference to the work which has been carried out upon the influence of the kidney on metabolism. Sir J. Rose Bradford removed portions of the kidney from animals, and subse- quently studied their metabolism. He obtained results which suggested that when the amount of available kidney sidDstance is greatljf reduced the tissues of the body, and more especially the muscles, ra])idly l)reak down and liberate urea. But he states that he has no observations to show whether this is dependent upon the cessation of the action of an internal secretion supplied normally by the kidney. Biedl performed a series of exj)erimcnts of a similar nature upon dogs. He excised wedge-sha])ed jueces of the kidney, removing about a quarter of a kidney, and sometimes removed the whole of the other kidney in addition. It was found that after such operations the c^uantity of urine secreted was notably increased, even up to two, three, four, or five times the original amount. At the same time the total nitrogen excreted was much increased. V. Haberer also reports polyuria after ex- cision of portions of the kidnej' substance. It is not possible to state whether these changes are really due to a deficiency in a normal process of internal secretion on the part of the kidney. Notwithstanding tlie conflicting nature of the evidence as to an internally secreting function of the kidney, many authors insist that renal hormone therapy is of considerable value in many cases. Many French writers recommend kidney extracts in nephritis, but it is usually advised to persist in ordinary measures of treatment and to emjih.iy the renal extracts as adjunct remedies. CHAPTER VIII THE INTERNAL SECRETION OF THE INTESTINAL MUCOUS MEMBRANE AND THE NORMAL MECHANISM OF THE SECRETION OF THE PANCREATIC JUICE It was first observed by Claude Bernard that the secretion of the pancreatic juice is dependent on the passage of food into tlie duodenum, and it has long been known that in the dog the flow of pancreatic juice, although it begins immediately after food has been taken, does not reach its maximum till either the first or the second hour, but more commonly is not reached until the third or fourth hour. It is to Ije noted that this is at a time when the greatest quantity of food from the stomach contents is passing into the duodenum. There has been nmch laljorious investigation and a continued keen controversy as to the causal relationship existing between the passage of food through the pylorus and the secretion of pancreatic juice. It will be interesting to glance at the state of knowledge on this subject in the j^ear 1S89. This can be conveniently done by recalling the exfjosition in a standard textbook of the period. M. Foster says : " Stimulation of the medulla oblongata or of the spinal cord will call forth secretion in a cpiiescent gland, or increase a secretion already going on. From this we may infer the existence of a reflex mechanism, though we cannot as yet trace out satisfactorily the exact path of either the afferent or the efferent impulses ; all we can say is that the latter do not reach the pancreas by the vagus, since stimulation of the medulla is effective after the section of both vagi. " A secretion already going on may be arrested by stimula- tion of the central end of the vagus, and the stoppage of the secretion whicli has been observed as occurring during and after vomiting is probably brought about in this way. This 57 58 INTERNAL SEC^RETION effect, which, hoM'ever, is not confined to the vagus, stimulation of other afferent nerves, such as the sciatic, producing the same effect, may ))e regarded (in tlie absence of any proof that the result is due to reflex constriction of the j^ancreatic and local vessels unduly checking the blood-sujjply) as an inhibition of a reflex mechanism at its centre in the medulla or in some other part of tlie central nervous sj'stem, much in the same way as fear inhibits at the central nervous system the secretion of saliva following food in the mouth. But if so, then "we must regard the secretion of f)ancreatic juice as closely resembling that of saliva, inasmuch as it is called forth by a reflex act. Yet it is stated that, unlike the case of saliva, the secretion of pancreatic juice continues after all the nerves going to the gland have been divided, an operation which would do away with the possibility of reflex action. tSuch an experiment, however, cannot be regarded as decisive, since it is almost impossible to be sure of dividing all the nerves." It is interesting to note how the one single observation (secretion after severance of all nerves), which at this period had to be ojiposed to the theory of reflex stimulation, was dealt with by Michael Foster. At this date, then, and for some time later the prevailing view was that the flow occurring when the acid chyme passed into the duodenum is due to the action of a reflex arc ; but the observations of Bernard, Heidenhain and Pavlov, incorporated in the above account by Foster, were inconclusive, and the results obtained in different experiments were liy no means constant. In more recent years Pavlov and his pupils have multiplied ingenious experiments and develoj^ed a wonderful technique, have struggled hard to reconcile the conflicting statements of dift'erent ol^servers, and with infinite ingenuity have sought to establish on a firm basis the theory of nervous action. In searching for the channels of the reflex, Pavlov showed that, if certain precautions be taken, one can bring about a flow of pancreatic juice bj^ stinnflating the vagus or splanchnics. A great step in advance was made by Popielski and by Wertheitner and Le Page. These observers j)roved conclu- sively that introduction of acid into the duodenum still excites pancreatic secretion after section of both vagi and both splanchnic nerves or destruction of the spinal cord, or even after complete extirpation of the solar plexus. Thus it was THE INTESTINE 59 clear that ordinary reflex action was out of the question. Popielslii concluded, therefore, that the secretion is due to a local, a peripheral, reflex action, the centres for wJiich are situated in the scattered ganglia found throughout the pancreas. Wertheimer and Le Page, however, made a very interesting discovery — namely, that secretion of tlie pancreatic juice could also be induced by the injection of acid into the lower portions of the small intestine, the effect, however, gradually diminishing as the injection A\'as made nearer and nearer the lower end of the small intestine, so that no effect at all was produced from the lower two feet of the ileum. Secretion could be excited from a loojj of jejunum entirely isolated from the duodenum. They concluded that, in this latter case, tJie reflex centres are situated in the ganglia of the solar plexus, but tliey did not perform the obvious control experiment of injecting acid into an isolated loop of jejiuium after extirpation of these ganglia. About this time Bayliss and Starling were engaged upon investigations into the local nervous reflexes concerned witli movements of the intestine. These observers made numerous experiments to test the validity of a hypothesis such as that of Wertheimer and Le Page, but soon found that in the case of the pancreatic secretion they were dealing mth an entirel)' different order of phenomena, and that the secretion of the pancreas is normally called into play, not l;iy nervous channels at all, but by a chemical substance which is formed in the mucous membrane of the upjoer parts of the small intestine under the influence of acid, and is carried tJience by the blood- stream to the gland cells of the pancreas. The experiments of Bajdiss and Starling confirmed those of previous observers in so far as they found that, after exclusion of all nerve centres except those in the jjancreas, a secretion of joancreatic juice is obtained by the introchiction of acid into the duodenum. But, as pointed out above, the experimentum crucis of taking an isolated loop of intestine, dividing the mesenteric nerves supplying it, and then injecting acid into it, had not been performed. Bayliss and Starling found that when this was carried out a well-marked flow of pancreatic juice was brought about. Thej' next cut out the loop of jejunum, scraped off the mucous 60 INTERNAL SECRETION membrane, rubbed it up with sand and 0-4 per cent. HCl in a mortar, filtered and injected into a vein. The first effect was a considerable fall of blood-pressure, and, after a latent period of about twenty seconds, a flow of pancreatic juice at more than twice the rate produced at the beginning of the experiment by introduction of acid into the duodenum. Bayliss and Starling suggest the name " secretin " for the active substance present in the intestinal extract, and the term has been adopted by subsequent workers. Secretin is probably produced by a process of hydrolysis from a pre- cursor "prosecretin" jDresent in the intestinal cells. It is not a ferment, nor is it of tlie nature of an alkaloid or diamino-acid. The results ol^tained })j^ Bayliss and Starling were confirmed by Camus and Gley and others, and Wertheimer demonstrated the presence of secretin iji the blood flowing from a looj) of intestine into which acid has been introduced. In a later communication Bayliss and Starling announced tliat secretin can be prej^ared from the upper j^art of the in- testine of any animal belonging to the class of vertebrata by scraping off the mucous membrane, pounding it up, and boiling with dilute hydrochloric acid. The experimental evidence which is clearly put before us by Bayliss and Starling justifies the view that the normal sequeiice of events in the secretion of juice bj' the imncreas is as follows : The acid of the gastric juice upon reaching the duodemnu converts the prosecretin maiuifactured by tlie epithelial cells into secretin ; this secretin is then absorbed into the blood- stream, carried to the cells of the pancreas, and stimulates the organ to secretory activit}'. The external secretion of the jMHcreas is the result of the ivterncd secretion of the duodenal triK cous membrane . The formation of prosecretin in the duodenum does not appear to take place as a response to the stimulus of ingestion of food. Pringle has quite recently found that secretin jM'cparcd from newly-born kittens, before suckling, gives a fairly active flow of juice wlieia tested on a dog. When foetuses of dift'erent periods were examined, it was found that some showed tlie presence of an active secretin, some did not. In this most imjiortant discovery of Bayliss and Starling is THE INTESTINE 61 involved an important modification of our conception as to the empire of the nervous system. The production of secretin is, in fact, the best autlienticated example of internal secretion wliich can be quoted. The liitherto most oft-cited examples, such as those of the adrenal body and the thyroid gland, are, in the opinion of the present writer, more distinctly hypothetical. Beyond all doubt secretin is a powerful excitant of the pancreatic secretion, but its specific nature is denied by some authors. Bayliss and Starling admit that secretin acts to a small degree on the secretion of bile, and otlier authors state that it acts on the secretion of saliva and the gastric and intestinal juices. Again, while Bayliss and Starling affirm that secretin can only he olitained from the upper part of the small intestine, others assert that they have found this sub- stance, though only in small amount, in other parts of the intestinal tract, and even in Ijanphatic glands. Although Bayliss and Starling showed that the depressor substance in extracts of the intestinal mucous membrane is independent of secretin, and that a secretin solution can l)e obtamed free from the depressor substance, yet this has not hindered Popielski and others from urging that the flow of pancreatic juice after injection of intestinal extracts is due to the lowering of the blood-pressure and consecpient antemic stimulation of nerve centres. Fleig shows that secretin does not j)roduce its effects by acting on the nerve endings in the intestinal epithelium, and the last-named author, as well as Wertheimer and Le Page, state that they obtained a secretion of j^ancreatic juice l>y injecting acid into an isolated loop of jejunum whose nerve communications were intact, and even when the venous blood of this loop is diverted, and the thoracic duct is tied off. Fleig concludes that the mechanism of secretion of j^ancreatic juice after the injection of acid into the upper part of the small intestine is, under normal conditions, of a double character : (1) Secretin calls forth secretion of pancreatic juice by direct action on the cells of the pancreas. (2) Acids, independently of the formation of secretin, cause a secretion of pancreatic juice by reflex nervous action. These two secretions are said by Sawitsch to present c[uite different characters. The latter is thick, opalescent, rich in 62 INTERNAL SECRETION enzymes and proteins but poor in alkalies. The chemical secretion, on the contrary, is thin and waterj', contains little enzyme or protein, and is rich in alkali. Gley has recently given the accompanying classification of substances which excite the flow of pancreatic juice (p. 63). Gley points out that the part plaj^ed by the acid of the gastric juice as an excitant of the flow of pancreatic juice is altogether special, since it acts at the same time through the chemical mechanism in liljerating secretin, and by means of a nervous mechanism, that is to say, by reflex excitation of the secretory )ierves to the pancreas. y. Fi'irth and 8chwarz jjelieve that secretin is not a definite, single substance, but a mixture of several gland- stimulating suljstances, of which choline can be recognized as one. With regard to the mechanism ot the secretion of the intes- tinal juice, nothing definite is yet known. We know that the juice when it is formed is essential for the activation of the f)ancreatic juice l^y means of the enterokinase. The tryp- sinogen is onlj? converted into the proteoljdic ferment trypsin after the action of the enterokinase. According to Pavlov, the secretion of the succus entericus depends upon two factors : (1) The mechanical distension of the alimentary canal; (2) the presence of the pancreatic juice. Bayliss and Starling consider it probable that the secretion of succus entericus is called forth by the chemical action of the pancreatic juice upon the glands in the intestinal wall. Delezenne and Frouin report that the intravenous injection of secretin provokes an immediate and abundant secretion of succus entericus. It has been suggested that the increase in red and white cells in the blood after a meal is due to the stimulation of the Ijone- marrow by secretin. According to Lombroso the jirime factor in the secretion of the intestinal juice is the action of chemical substances which are produced during normal digestion, and act on the nerve endings of the mucous membrane of the intestine. It has been suggested that secretin may be useful as a drug with the object of increasing the pancreatic flow. But it must be noted that it is absent from some commercial preparations supposed to contain it, and even if it is present it would be destroyed quickly ))y the gastric juice and the trypsin. It THE INTESTINE 63 X CD fl S ''^ 1^ a 1 2 S !« II o .3 ■§> § "^ ^?5 f-l « ^ 43 ZS -- ■tf tS O cS (D S i- < o a; o rj > g .5 A^ £ ^ H _S O 1= M.2' Orf 1- O *~ u o o V: -t. 5 s^ H " CO 6 _ o CO ^ g£ 3 _fl tJ < > ■ _ — .._ ■^r-_-T=: ^^^v--_=;- CO =' S C (^ -u u P -i 'J"-' C ■c 4:: OC' oi' j2 ^ .a g -^ :o =tf a. fl .9 ° 1^ a JJ3 OJ -C M ^ ^ "5 ^ ci ::3 ■r ^ ^ s :c -1I &H !K ^ Cfi .9 6 o *^ (1 ._[, rt a 5 / ';-. > = ^ (b tM ,/: CO 2- 5 m 2^ r,''X' O -^ +J o C +- s £0 1 o CO "o f^S tfi ^ c -0 H 02 CO 'o ■- W 3 5 r— . __, OJ ffl ^ '~ d CO 1 o P3 CO s. _ CD >-; ^ ^' '^ -3 CO 13 \ X 5; 3 '0 2 "^ ^ y Hildebrandt that during jjregnancy an impulse is exerted by the ovum on the mammary glands, which stimulates them to growth. Lane-( 'laypon and Starling re- ported tluit extracts of fretus stimidatc the growth of maunnary gland. But virgin animals sometimes jDroduce milk. Hence it is clear that the source of tlie stimidus which normally calls forth the development of the mammary gland must be sf)ught elsewhere than in the developing foetus. Frank \'. Unger and O'Donogluie have definitely urged tliat this source is to be found in the corpus luteum. The last-named author, working upon Dasyurus, has found that the eiilarge- ment of the mamnui begins quite apart from fertilization, and is continued when there is no fertilized ovum present to produce an internal secretion. Ho gives tables and curves to show that as soon as the corpus luteum has begun to be formed, the growth of the mammary gland commences, and this growth is notably increased after the corpus luteum is fuUj' formed. As we have seen above (ji. S(i) O'Donoghue observed that, if follicular rupture is not followed bj' formation of cor- pora lutea, there is no growth of the mammary glands. The conclusion can scarcely be avoided that the hormone causing the growth of the mammary glai\d is produced in and secreted l)y the corjJora lutea. Reference has already been made to the " interstitial cells " or the "interstitial gland" (" pul)erty gland" of Steinach). The tissue is so often referred to in the literature, that it is astonishing how little can be definitely stated about it. It is not known certainly whether the tissue is epithelial or whether it is of connective tissue origin. It is not even known whether it is constantly present. In fact, out of more than one hundred species so far examined, 50 per cent, are said to possess none. THE PvEPROBUCTIVE ORGANS 89 It has been supposed that the cells undergo periodic changes of such a character that at certain times they may be more, at others less, abundant or conspicuous. For example, they are stated to reach their greatest development during preg- nancy and lactation. The cells have a typically glandular appearance. They have an abundant blood supply and contain granules. These are of various kinds, as indicated by their staining reactions. There is an abundant chondrioma and enclosures of a lipoid character, siderophil protoplasm, and distinctly polychromatic, large, round nuclei. The chondrioma is made up of chon- drioconta and mitochondria. It undergoes important modi- fications in the course of the evolution of the cell. The granulations, at first few, increase in number in the later stages ; the fatty products are the result of a chemical change in the mitochondrial substance. The lipoid enclosures prob- ably represent the products of secretion (Athias). When the theory of internal secretion on the part of the ovary had once become generally accepted, and when the organ was found to contain, in addition to the follicles, certain other cells of a glandular appearance, it was natural that these last should be charged with the function of internal secretion. But so far no hypothesis in regard to them has been put forward which has much direct evidence in its favour. Perhaps the best accredited of such hypotheses is that the interstitial cells j^reside over the nutrition of the reproductive organs (e.g., the uterus) and are responsible for the appearance of the secondary sexual characters. In birds there seems to be some doiibt whether the " inter- stitial " cells can be regarded as secretory elements. They appear to contain ha^mopoeetic centres. Bell urges that "femininity" is dependent, not only on influences arising from the ovary, iDut on all the various internal secretions. The relations of the thyroid gland and the adrenal to the female reproductive system are treated in other chapters (pp. 241, 400). The pineal is alleged to have an influence on sexual precocity (p. 390). It is believed that the pituitary and the thymus influence the metabolic functions, determining the onset of puberty. The question is rendered complicated by the influence of the various internally secreting organs upon each other (p. 395). 90 INTERNAL SECRETION D. Ovarian Medication. Brown-Sequard in a first communication to the Societe cle Biologie, in June, 1889, expressed the opinion that the ovaries of animals might furnish a juice which would have a beneficial effect upon women similar to that obtained in the case of men by the employment of testicular extracts. In 1890 he reports that a Parisian midwife had injected herself with a licpiid made from the ovaries of guinea-pigs, and had benefited thereby. He further calls attention to a report of Villeneuve, who made injections of ovarian extract into three individuals — two women and one man. Oiie of the women, who had undergone double ovariotomy, was very consideralaly Ijcnefited. Finally, he gives an account of the work of an American lady doctor, Mme. Augusta Brown, who " avec un grand courage " had observed good results by injection of extracts made from the ovaries of rabbits. The injections were mostly subcutaneous, but the application was sometimes made on to the skin after blistering, and in one case the juice was applied directly to the uterus (in the case of prolapse). t Brown-Sequard does not seem to regard these reports as of much value, for he concludes that it is the testicular juice which ought always to be given " comme agent dynamo- genique " in women as well as in men. He states that the ovarian extracts are less powerful than the testicular, and their action is not specific. Mainzer obtained good results in tlie treatment of heats, sweating, headache, etc., after double ovariotomj', and also in the vasomotor troubles of the menopause. Bestion de Camboulas gives many interesting references showing how completely persuaded were many physicians of the period that the ovary is a gland with an internal secre- tion. The evidence at their disposal was, however, ver}? meagre. They seem to have been led to their belief chiefiy by Brown- Sequard's famous dictum that all glands, whether or not they possess a duct, pour into the blood useful principles, whose absence makes itself felt after their extirpation or their destruc- tion by disease.' Bestion de Camboulas gives an account of the various ^ Bestion tie Cainl;)ovilas says nau'ely : '' Tlie ovary, being a gland, ouglit not to eHcape this la\^-." THE REPRODUCTIVE ORGANS 91 modes of preparing ovarian extracts. He employed (1) fresh gland, (2) dried gland, (3) ovarian juice or flnid extract. This last was watery or alcoholic, or a glycerin extract. He recom- mended the employment for medical purposes of the ovaries of the sow. This author performed a series of experiments upon animals in order to investigate the toxicity of the ovarian extracts, and found that the glycerin or watery preparation is much more toxic for the male than for the female. After large doses males died with pj'rexia, hsematuria, and other disturbances. With non-toxic doses the males lost Aveight, the females gained weight. The resistance of pregnant females Avas much less than that of non-pregnant. Clinically, his results were as follows : Troubles of the menopause, natural or after castration, are considerably relieved by ovarian extract without other medication. There is constant amelioration in cases of amenorrhoea and chlorosis, and there is a real improvement in the mental troubles which accompany genital lesions, or which occur after cas- tration. Imj)rovement in the general condition is marked in all cases. The extract should never be given to preg- nant women. Andrews speaks very cautioiisly as to the benefit accruing from the administration of ovarian extracts, while Cohn finds that the results are nearly always disappointing. Batty Shaw says that the special value of ovarian substance is shown in cases in which the ovaries are ill-developed, or have become atropliied as at the menopause, or have been removed by operation. There are numerous other papers on the subject of ovarian medication. Much of tlie work has been very uncritical. No due regard has ever yet been taken even in experiments on animals as to the condition of the ovary from which the extract is made, and it seems clear tJiat the corpus luteum will in tlie future have to be considered separately lioth experi- mentally and clinically. 1 ' Bouin and Aneel now believe that the corpus hiteum secretes a hormone which excites the mammary gland to growth, but that the hormone which excites to secretion is derived from a gland which they claim to have discovered in the muscular layer of the uterus, and to which they have given the name " myometrial gland." Recent work has thrown considerable doubt upon the existence of any such " gland " in the uterine wall. 92 INTERNAL SECRETION E. Osteomalacia Perhaps this is the most suitable jjlace in which to refer to the disease known as osteomalacia. The theory which connects this condition with hyperfunction of the ovaries has found most adherents. The argument in favour of this view is largely based upon the fact that the condition is benefited botli by removal of the ovaries and by artificially induced labour. CHAPTER XI THE INTERNAL SECRETION OF THE ADRENAL BODIES (The Cortex of the Adrenal and the Chroniaphil Tissues) A. Introductory When we consider the extraordinarily voluminous literature devoted to the adrenal bodies, and the immense amount of time and patience which has been expended Ijy physiologists, pathologists, and comparative anatomists, in the attempt to elucidate their function, it is regrettable to have to admit that we are still unable to give a satisfactory answer to the question, " What is the function of these bodies ? " We have, perhaps, a fairly reasonable suggestion to offer as to the service in the economy rendered by the ohromaphil tissues (including what in mammals is called the " medulla " of the adrenal), but of the physiology of the " cortex " we still know very little. There are two important discoveries which stand out among all others as epoch-making. The first is the observation by Addison in 1849 that certain cases of disease characterized by pigmentation of the skin, languor, and other symptoms, are associated with destructive lesions — usually tubercular — of the adrenal bodies. The second is the discovery in 1894 by Oliver and Schafer of the blood-pressure-raising activity of extracts of the medullary portion of the gland. We are, how- ever, by no means clear, as will be seen in the sequel, what is the precise relationship between the facts revealed in these two discoveries. A third very important step in our progress ought to be referred to in this place. This is the isolation in crystalline form of the active principle of the medulla of the gland (i.e., of the chromaphil tissues) by Takamine and Aldrich independently in the year 1901. The first definite account of the adrenals with illustrations 93 94 THE DUCTLESS GLANDS is given by Eustachius in 1563. For a long time the discovery was unnoticed, or the existence of the new organ was denied ! It is indeed remarkable, as pointed out by BiedL that Vesalius in 1642, Fallopiusin 1606, andFabricius in 1738 make no refer- ence to the bodies discovered by Eustachius. However, they began to be referred to even before tlie end of the sixteenth century in the medical books as the " glan dulse " or the " cap- sulse renales Eustachii." The story of Montesquieu's participation in the history of our subject is so interesting that, although it has now been told several times, it will well bear repeating. In the year 1716 the Academy of Sciences of Bordeaux offered as the subject of a prize essay, " What is the Use of the Suprarenal Glands ? " The essays submitted were placed in the hands of Montesquieu, the famous axithor of the Es-prit des Lois, who acted as judge. His report is of especial interest, not only because of the personal fame of the author, but because it gives an admirable critical account of the older views upon the adrenal bodies. The style is satirical, but it is probable that it was not intended to be so satirical as it appears to us at this date, when every theory mentioned in 1716 appears to us positively absiu'd. Montesquieu briefly discusses the older views that the glands, serve to hold up the stomach and strengthen the nervous plexus which touches them, or that "black bile " is preserved within their cavity (Bartholin), or that they serve to collect the humidities which leak out of the great vessels in the neighbourhood. He then criticizes the essays which were presented to the Bordeaux Academy. "We have found one author who declares that there are two kinds of bile : one grosser, which is separated out in the liver ; the other more subtle, secreted in the kidneys by the assistance of the ferment which flows from the suprarenal ca])sules by ducts of which we are ignorant, and of which," comments Montesquieu, " we are menaced with perpetual ignorance." "Another describes to us two small canals which carry the liquids from the cavity of the capsule into the vein belonging to it ; this humour, which man^r experiments lead us to con- sider alkaline, serves to give fluidity to the blood returning from the kidneys after it has been deprived of serosity in the formation of the urine. THE ADRENAL BODIES 95 " Another essayist, who gives a difference between conglobate and conglomerate glands, has placed the suprarenal glands among the conglobate. In his opinion they are nothing but a continuity of bloodvessels within which, just as in filters, the blood becomes more subtle. ... In these glands, as in all the conglobate glands, no excretory duct exists, becaiise there is no question of the secretion of liquids, but only of making them more subtle." In conclusion, Montesquieu announces that the Academy will not award its prize this year, since the object of the offer has not been achieved. He ventures his own opinion that " le hasard fera peut-etre c|uelque jour ce que tons ses soins n'ont pu faire," and he is polite enough to state ! " Mais ces efforts impuissants sont plutot une preuve de I'obscurite de la matiere que de la sterilite de ceux qui I'ont traitee." i In attempting to assign a function to the adrenal bodies, it is essential to bear in mind their dual nature. As we shall see later, the adrenal body of the higher animals has been derived from two separate and distinct kinds of tissue in lower vertebrates ; and although there is a more or less gradually increasing tendency for the two tissues to become united as we ascend the scale, yet it is only in mammals that the terms "adrenal cortex" and adrenal medulla" are strictly appro- priate. It is essential that, before dealing with the physiology of the adrenals, we should give some account of their comparative anatomy and development. B. Comparative Anatomy of the Adrenal Bodies 1. Introductory It is only in the Amniota that we find a definite organ whose parenchyma is divided into two distinct portions, whose cellular constituents are quite different in character from each other. In the Anamnia we have the organ represented by a number of small bodies. The Amphibians in some respects occupy an intermediate position. In Pisces and Cyclostomata we find two distinct categories of bodies each consisting of a special 1 The above account is largely taken from Bjedl. 96 THE DUCTLESS GLANDS form of cell, which categories are homologous with the two constituents of the adrenals of higher vertebrates. In Amphioxus nothing corresponding to the adrenals has so far been discovered, and in the Invertebrata the matter may perhaps be considered somewhat doubtful. 2. Invertebrata Leydig discusses the possibility of the existence in some Invertebrata of the equivalents of the adrenal bodies. Some years ago the present writer had considered the possi- bility of the existence of the rcjiresentatives of cortex and medulla of the adrenal Ijodies in the Invertebrata, )jut had not succeeded in finding any organs or tissues which seemed at all likely to corresjiond to them. But just ]3reviously to that time physiological research had rendered it possible to test any unknown organ or tissue to sec if it should be homologous with adrenal medulla. An extract made from the medulla of the adrenal or from any (chromaphil) tissue of the same nature possesses powerful pressor properties. Accordingly an extract from certain tissues (including the cells which Leydig thought might correspond to the adrenal bodies of vertebrates) of Pahidina vivifara was prepared and injected into the venous system of a cat. The result was negative, possibly because the material necessarily contained so much nervous tissue which would tend to lower the blood- pressure. C'leghorn finds that glycerin and saline extracts of sympathetic ganglia produce a fall of blood-pressure, in spite of the presence in these ganglia of chromaphil cells like those in the medulla of the adrenal l^ody.^ It appears, also, that it is impossible to obtain any rise of blood-pressure by injecting extracts of carotid glands into an animal, because there is so much admixture with various tissues whose extracts have a de]:)ressor cfTcct. Poll and Summer describe certain cells in the abdominal ganglia of Hirudo medicmalis which stain a yello\\'ish-l)rown with Midler's fluid. They consider it probaljle that these are homologous with the clii'omaphil cells discovered by Stilling. ^ ('Irglioni clid not ascertain tliat thi.s result might be obtained from any ner\-ou.s lis.siK', wlielliei' brain, spinal cord, or peripheral nerve; in fact, he states tliat this is not Itie case. THE ADRENAL BODIES 97 Such cells were later described in a large number of leeches — Gnathobdellidse and Rhynchobdellidfe — and still later Poll gives a description and some very convincing drawings of these chromaphil cells in Nephthys scolopenchoides. As regards the yellow cells of Pontobdella described by Leydig, these appear to be of a different nature. As pointed out by Poll, we are sadly in need of another micro-chemical test for adrenin- containing tissues. If the ferric-chloride reaction could be used for histological purposes, it would clear up many doubtful points. Eoaf and Nierenstein have expressed their belief that there is a substance in the hypobranchial gland of Ptirpura lapillus which is allied chemically and physiologically to adrenin. But the identity of the substance with adrenin has been denied. Eoaf has recently returned to the subject and finds that in Purpura lapillus there are associated (1) a pressor substance in the strip of tissue adjacent to the so-called rectal gland ; (2) a purple-forming material in the same area ; (3) a collec- tion of bichromate-reacting granules also in the same situa- tion. The inference is that these, if not identical, are at least functionally associated. It is curious that, so far as I can ascertain. Poll and Roaf make no reference to each other's work. It is clear that the structures they respectively describe are quite different from one another. The tissue described by Roaf is not apparently connected with the nervous system, while the chromaphil cells of vertebrates are always intimately related to the sympathetic. The cells described by Poll are, on the other hand, within the central nervous system, and, at any rate, bear a very great resemblance to the cells which are familiar to us in the vertebrate sympathetic. Further investigations on the chromaphil tissue of annelids have been carried out by Biedl and by Gaskell. Both these authors claim that they have succeeded in bringing about inhibition of the virgin uterus of the cat by means of an extract of the ganglia of Hirudo medicmalis. The cells described by Gaskell are nerve-cells which give a chromaphil reaction and which he thinks are the common ancestors of both the chroma- phil and the sympathetic systems of vertebrates. This is not in accordance with the views . of Giacomini. 98 THE DUCTLESS GLANDS 3. Anamnia In the Clyclostomata, the lowest vertebrates in which adrenal elements are certainly known to exist, our knowledge is con- fined to the Petromyzonta and Bdellostoma. In Petromyzon [CTiacomini] there are two distinct series of bodies. One of these is represented by small, irregular, lobu- lated structures in the wall of the posterior cardinal veins and the renal arteries, and of arteries dorsal to the kidney. They project into the lumen of the vessels, and consist of cyhndrical or polyhedral cells, containing granules which stain black with osmic acid. These are the cortical or inter-renal bodies. The other series, or the chromaphil series, extends from the region of the second gill cleft to the tail of the animal. The bodies of this series are thin strips of tissue running along the large arteries and their branches. These bear the same relations to the veins as the cortical bodies. This distribution of the chrome staining tissue in P . fluviatilis has recently been confirmed l)y J. F. Gaskell. Extracts of the regions in which this tissue lies, viz., the walls of the aorta and cardinal veins and the sinus region of the heart, cause a rise of blood-pressure in the cat.i In Bdellostoma the chromaphil cells have been observed, but not the inter-renal or cortical. The relationshi]is of the two adrenal representatives in Elasmobranchs were first suggested by Balfour in 1878. He called the representative of the cortex the " inter-renal," while what we now knoM^ as the " chromaphil corpuscles " (repre- senting the medulla of the adrenals of higher vcrtebrata) he called " suprarenal bodies." That the paired " suprarenal bodies " of Balfour really correspond to the medulla of the mammalian organ was first definitely shown by the present writer by the physiological test. This was fully confirmed by the chemical test [Moore and Vincent] ; and that the " inter- renal " of Balfour is really homologous with the cortex of the mammalian body was rendered clear from the negative physio- 1 The present writer, working in conjimction witli Mr. W. E. Collinge, made an attempt some years ago to find the adrenals in Cyolostomata, but we considered that there was no satisfactory evidence to show that the bodies described by Rathke, Miiller, and others had anything to do with the adrenals. THE ADRENAL BODIES 99 logical and chemical tests, and from careful histological comparisons. The paired " suprarenal bodies " (chromaphil) are situated on branches of the aorta, segmentaUy arranged, and extend on each side of the vertebral column from the front part of the sinus of Monro to the posterior end of the kidney. The anterior pair are elongated, and correspond usually to three or four segments. These bodies are in close relation to the ganglia of the sympathetic chain, and contain large numbers of chroma- phil cells, though they appear not to be made up entirely of them. (Figs. 14, 15 and 22.) The inter-renal body [Figs. 14 and 15 (i.r.)] is an " ochre- yellow " rod-shaped structure, paired in the rays, unpaired in the dogfishes and sharks, lying usually in the region of the posterior part of the kidney, but sometimes extending as far forward as the anterior extremity. It bears a striking resem- blance in its colour, general appearance, and relations to the kidney, to the ach'enals of the Anura, and in the first two of these features to those of the Reptilia. The body consists of cells which have the same general appearance and the same micro-chemical reaction as the " corpuscles of Stannius " (the cortical adrenals of Teleostean fishes), and the cortex of the adrenals of higher vertebrates. (See Fig. 21.) The effect of injection into the venous system of a mammal extract made from the " paired bodies " of Elasmobranchs is shown in Fig. 16. It will be seen that there is a very marked rise of the arterial blood-pressure. In Fig. 17 is seen the effect of the injection of an extract made from the inter -renal. There is a certain effect upon the blood-pressure which can be readily explained as the result of more or less admixture with " medul- lary glands " in making the extract. In Teleosts the cortical adrenal bodies are usually paired, round or oval, pale pink bodies, placed on the spinal or ventral surface of the kidney. They are near the posterior extremity of the renal mass, and are either free on its surface or more or less embedded in its substance (Figs. 18-20). The constituent cells are of the same character, and have the same arrangement as those of the inter-renal of Elasmobranchs (Figs. 23, 24) It is now fully ascertained that these structures (the " corpuscles of Stannius ") in Teleosts represent the inter-renal of Elasmo- branchs. It had been erroneously considered by some authors 100 THE DUCTLESS GLANDS Fig. 14. — Dissection of ScylKum canicula (yoimg female specimen), giving a ventral view of " paired suprarenals " (chromaphil bodies) and the inter-renal (cortical body). The parovarium has been dissected away. Tliis drawing may be taken as a typical representation of the position of these bodies in Ela.smobranohs. The connections with the sympatlietic are indicated to some extent in the anterior part of the figure. The chromaphil "suprarenals" were displayed by Semper's chromic-acid method, THE ADRENAL BODIES 101 Fig. 15. — Ventral view of kidneys, etc., of Raja bat if. This drawing- represents a not nnusual condition in the rays, in which tliere is bridge-like communication be- tween the inter-renals of the two sides. The sympathetic is shown to some extent to about the middle of "the left kidnev. Lettering common to Figs. 15, 18, 19 — a. a., axillary artery ; a.i.r., an- terior broken-off portions of the inter-renal body ; ao., aorta ; ax.h., anterior pair of suprarenal bodies ; h.k., head kidney ; i.a., intercostal arteries ; i.r., inter- renal body ; k., kidney ; l.k., lobe of kidney substance ; w., oeso- phagus cut across ; s.r., suprarenal bodies ; sy., main chain of the sympathetic ; sy. g., sympathetic ganglion ; sy. pL, sympathetic plexus. that the modified pronephros of Teleosts represents the adrenal body in these fishes.^ ' Since this view has now been completely abandoned, there is no need to 102 THE DUCTLESS GLANDS Dog,7-^K. Jan.zy^Q^CMcl^ Morphia, atropine. Carotid carve. Signal. Injected Ice. of extract qf paired segmental suprarenals (Scyll. can,.) 1 in 35. " Time tracing (seconds.) S\WiW5\MmMAI\lM\mi\I\ i\i\i\)\i\ Fig. 10. — Effect of injection of 1 c.c. of extract of " paired segmental supra- renals " (1 in 25) taken from ScylJiimi caninda. It will be seen that the rise of blood-pressm-e is very striking. A very important discovery has recently been made by Giacomini, who finds that the corpuscles of Stanniiis are not revive the controversy. It was Rathke ^'ho first put forward this theory, which was later revived by Weldon. The view was proved to be untenable by the present writer in 1895. THE ADRENAL BODIES 103 the only representatives of cortical adrenal substance in teleostean fishes. He has worked out the subject especially in many fishes of the eel tribe, and finds isolated bodies on the cranial border of the " head kidney," on the anterior and Carotid cunt. rv\ Wtfi^A f<^ \mrv;['Vmu/Vmwr/V^ Bog, 7-2 K. Jun.zi my. CHcl^ . ' ■ : Morphia (3min. of sol. igr. inemin.) Atropine(3mm.of izsol.) ,^iqnal. Injected Ice. of ecc tract ofinterrenal (Scylliurth canieutn), 1in35. Fio. 17. — Effect of injections of 1 c.c. of extract of " inter-renal " (1 in 25) taken from ScyUiuni canicula. It will be seen that there is a certain small rise of the arterial blood-pressure. This is not at all comparable with that produced by an extract of the " paired bodies " (see Fig. 16), and is to be explained by the fact that in extracting the inter -renal from the body, it is almost impossible to avoid rennoval also of some of the " paired bodies." posterior cardinal veins, which he considers are to be regarded as of the same general nature as the corpuscles of Stannius, though they present certain slight differences (Figs. 20 and 24). 104 THE DUCTLESS GLANDS Fig. 18. — Kidneys and cortical ad- Fig. 19. — Kidneys and cortical ad- renals (corpuscles of Stannius) of PageUus centrodonluK. The adrenals are on the spinal surface, shown by the dotted lines. Lettering same as for Fig. 1.5. renals (corpuscles of Stannius) of Ctadu.i morrhiia (ventral view). One body is on the ventral surface, the other half-way round towards the sj>inal surface. Lettering same as for Fig. 1.5. So that in teleostean fishes we have now to consider a '' cran- ial " and a "caudal" cortical body. This is of the greatest THE ADRENAL BODIES 106 Fio. 20. — Semi-diagrammatic figvire show- ing the kidneys and their relations with the cardinal veins and the cor- tical and chromaphil tissues in an adult Conger vulgaris. The parts indicated by a series of horizontal parallel lines show where one finds cortical and chromaphil tissvies inti- mately associated, a, aorta ; ia -|- sc {csd) [red] cortical and chrom- aphil substance (" suprarenal cap- sule ") contained in the right head- kidney ; I ia -f sc {ess) [res) do. in left head-kidney ; ia -f- sc (r.sfP) cortical and chromaphil substance (" suprarenal capsule ") contained in the cranial portion of the right vena cardinalis posterior ; ia -f sc (css^) do. in left side ; ip (cs), posterior cor- tical body ("corpuscle of stannius ") ; m-n, inls, lym]>hoid masses right and left ; -ms, caudal active portion of Iddney (mesonephros) ; i:cpd, vcps, post, card, veins R. and L. ; read, veas, primitive ant. card, veins, R. and L. (From Giacomini.) vcad ia»ic(cdi) mid. ,.a ...mln ip(cS) 106 THE DUCTLESS GLANDS importance as bearing upon certain experimental investigations [I'ide infra, p. 152). i To Giacomini also belongs the credit of having discovered the chromaphil or medullary structures in teleostean fishes. They consist of cells which stain brown with salts of chromium in the walls of the cardinal veins, especially on the right side and towards the cranial end of the body, along the lymphoid > /m (-a f (9 » Fig. 21. — Transverse section of tlie Inter-renal body of Trigon violaceus (fi'om Dianiare). tissue of the head kidney. The groups of cells are disposed between the lobes of the cranial cortical body. These had often been searched for by previous observers, Init in vain. In Ganoids the cortical representatives were noted by Stannius in 1840. He describes them as small whitish or yellowish bodies scattered throughout the substance of the ' Giacomini has more recently expressed the opinion that the corpuscles of Stannius are not fiomologous with the cortical bodies of petromyzon, tlie elasmobranclis, and higlier vertebrates. Their origin, structure, and func- tion put them in a sepiarate category. THE ADRENAL BODIES 107 kidney and forming alveoli, whose cells stain black with osmic acid (see Fig. 25). Quite recently Giacomini has described chromaphil elements in the walls of the cardinal veins and the venae renales revehentes. The question as to the existence of adrenal bodies in the Dipnoi has long been under discussion. In Protoptcrits Fig. 22. — Ti-ansverse section through one of the paired bodies of Torpedo (from Kohn). annectens Parker describes " around the kidney, but more particularly along its dorsal and outer sides, masses of brown cells, which in appearance remind one of the adrenal bodies of Amphibia," and he suggests the inquiry " whether they or the lymphoid cells which give rise to them have anything to do with the adrenals." In 1895 the present writer examined this point with some care, and came to the conclusion that this 108 THE DUCTLESS GLANDS tissue — a large-celled adenoid tissue — has nothing to do with the adrenal bodies, and this notwithstanding that in some regions it has a very " epithelial," a very " glandular," appear- ance. Giacomini claims to have discovered the true chromaphil bodies arranged segmentally round the intercostal arteries and ip Fig. 23. — Transverse section of a "corpuscle of Stannius " (posterior inter, renal) of Salmo fario (from Giacomini). in the wall of the cranial part of the posterior cardinal vein and the vena azygos dextra. He believes that the inter-renal body (cortical representative of the adrenal) is absent in this species of the Dipnoi, and renews Parker's suggestion that it may be replaced functionally by the adenoid tissue. It seems extraordinary that there should be no representative of the adrenal cortex in the Dipnoi. The present writer has THE ADRENAL BODIES 109 from time to time dissected specimens of Protoptcnis, and has examined series of sections of this fish and of Lepidosiren, but has never been able to detect any organ or tissue which seemed likely to correspond to adrenal cortex. If the tissue originally described by Parker is in reality adenoid tissue, we should Fig. 24. — Section of head kidney of Salmo farlo showing an islet of cortical adrenal tissue (anterior inter-renal) (from Giacomini). hesitate to ascribe to it any secretory function. The perirenal tissue is, however, very extraordinary in appearance, and deserves careful consideration. It is obvious that the subject of the adrenal bodies in the Dipnoi demands further investigation. The adrenals of Amphibians are intermedi^ite in many 110 THE DUCTLESS GLANDS respects between those of higher and lower vertebrates. In the Anura the adrenals are golden-yellow streaks on the ventral surface of the kidney, of about 15 millimetres in length in the frog to about 28 millimetres in a good-sized toad. Their width varies in a similar manner from 1 to about 3 millimetres. But their dimensions vary very considerably according to the size and development of the particular individual. In a good specimen the adrenals present a beautiful appear- ance, forming on each side a series of irregular arcs with their convexity outwards, and varying in width from place to place. Their colour is a bright golden yellow, of a somewhat fatty I. w. at. w. Fig. 25. — Section of an adrenal body (corpuscle of Stannius) of the strirgeon (Acipenser sturio). The " alveolar " arrangement is well seen, and the cell outlines are distinct. al. iv., walls of " alveoli " ; x., nuclei ; pr., granular protoplasm. aspect, and their surface is marbled with veins. In both frogs and toads, although the body reaches nearly to the anterior end of the kidney, it always ceases . at a point anterior to the posterior fifth of the organ. In the Urodela the adrenal is broken up into a series of strips and islets which extend not only the whole length of the kidnej^ but also anteriorly to that organ, as far forwards as the origin of the subclavian artery. The microscopic structure is practically the same in Anura and Urodela. The gland is seen at once to consist of two distinct kinds of structure. The greater part is made up of THE ADRENAL BODIES 111 cell columns, which are of varjdiig size and shape, and which interlace in all directions. The cells are of different shapes but mostly elongated and tapering, and they contain a large round nucleus, which stains very deeply with hsematoxyUn. This structure is the " cortical," which corresponds to the "inter-renal" of Elasmobranchs, the corpuscles of Stannius (" cranial " and " caudal " series) of Teleosts and the cortex of Mammalian adrenal (see Fig. 26 s.c). Fig. 26. — Section tlirough suprarenal body of Bufo vulgaris showing a mass of medullary substance (chromaphil tissue) surrounded by cortical substance (from CJiacomini). But in addition to the above-described structure, we get masses of a different kind of cell. These are often at the borders or ends of the cell columns, but are otherwise irregularly distributed. In the islets anterior to the kidney in the Urodela these masses of cells are more numerous, and some of the islets are made up entirely of them. This structure is analogous to the paired suprarenal bodies of the Elasmobranch fishes and 112 THE DUCTLESS GLANDS the " medulla " of the adrenals of higher vertebrates. It consists of chromaphil cells. Thus in the Amphibia we have transition stages between the single adrenal of higher verte- brates and the total separation of the two constituents in the Elasmobranch fishes (see Fig. 26 s.m., c.g.s.). 4. Amniota In reptiles the ' ' cortical ' ' and ' ' medullary ' ' constituents enter into closer rclationshij) with each other than in lower vertebrates. In some groups the chromaphil cells are arranged mostly on the dorsal aspect of the gland, and only penetrate to a small extent ; in others there is a considerable mixture of the two elements. In the Crocodilia and the C'helonia, for example, the relations of " cortex " and " medulla " are often almost identical with those of birds {q. v.). A typical representation of the microscopical appearances of the rejjtilian adrenal is given in Fig, 27. Birds show an intimate interlacement of the '" Hauptstrange" (cortical) and the " Zwischenstrange " or " Intermediar- strange " (medullary), so that the latter occupy the meshes of the former (see Fig. 28). MaiTimals, alone among animals, possess a true cortex and a true medulla, the latter as a rule completely surrounded by the former. The cortex has in all essential points the same structure as its homologues in the lower vertebrates — viz., the Haupt- strange of birds, the " cortical " columns of Rep'.iles and Amphibians, the corpuscles of Stannius of Teleosts, and the inter-renal " of Elasmobranchs. It consists of rounded groups or columns of cells with one or two vesicular nuclei, and con- taining glistening fat-like granules. These granules become blackened bj' osmic acid, and stain deeply with Sudan III. and Scharlacli Pv. They are dissolved by xylol, chloroform, etc., and so, when these reagents are used in the preparation of microscopical specimens, a vacuolated appearance of the protoplasm results. The structure of the medulla is not so easy either to discover or to describe, but we may say in general terms that it consists of cell columns which are not so distinctly marked as those of the cortex. The cell outlines are not so distinct as those of the cortex, and the granules in the protoplasm have a great THE ADRENAL BODIES 113 affinitj^ for nuclear stains such as hematoxylin, safranin, etc. These granules also reduce chloride of gold and become green in contact with ferric chloride. But their most characteristic reaction is with chromium salts. In the presence of any of these, or of chromic acid itself (in many instances, at any rate). (I- p- 'C "" ,V ' Fig. 27. — Small portion of adrenal of TJromastix Hardwlckii. Leitz panta- chrom. ; 3.0 mm. Drawn with Abbe's camera lucicla. c, cortex ; c.l., connective tissue ; g-p-, granular protoplasm of medullary cells ; i., interspaces between cell columns; m., medulla; p., protoplasm of cortical cells. the cells become stained so as to assume any tint between a bright yellow and a dark brown. This reaction was discovered by Henle in the year 1865. Stilling, who discovered the cells having the same reaction along the sympathetic and in the carotid gland of mammals, called them, the corpuscles which they formed, and the medulla of the adrenal, " chromophil." 114 THE DUCTLESS GLANDS The modification " chromaphil " will be used throughout. i 5. Accesiory Adrenals. Many important points in the comparative anatomy of the adrenals may be conveniently dealt with under this heading. 9^ / V. - iLi.TV. CO ^IcVc. me Fig. 28. — Section of the adrenal of Mekai/ri^ dallopavo. The material was fixed in Mi'iller's fluid with acetic acid and stained with ha?niatoxylin. A strand of medullary cells is seen running between the cortical columns. ai. «'., walls of " alveoli " ; {iM.c, blood corpuscles ; CO., cortex ; c.c, elongated cells ; n., nuclei ; me., medulla. The arrangement of tlie inter-renal and the " paired sup- rarenals " of Elasmobranchs at once suggests tite possibility of outstanding portions of liotli " cortical " and " medullary " constituents being found in the higher as well as in the lower ' Kolin, who repeated Stilling's observations, used the term " chromaffin, " and called the bodies "paraganglia." More recently Poll has invented still finotber term, " phaeochrome." There seems to be no need for either of these. THE ADRENAL BODIES 115 vertebrates. And the same possibility was suspected long ago from other considerations. ^m" 'H" Fig. 29. — Section through portion of the adrenal body of a dog, showing the various zones of the cortex, and the inedulla. (Dra^vn by Mrs. Thomp- son.) c, capsule ; ?».., medulla ; .:./., zona fascic\ilata ; za/., zona glomerulosa (zona arcuata) ; z.r., zona reticularis. The term ' ' accessory adrenal ' ' in mammals has been used in different senses. We must carefully distinguish between : 116 THE DUCTLESS GLANDS 1. Bodies composed entirely of cortical substance — "accessory cortical bodies. "^ 2. Bodies made up exclusively of medullary substance — " chromaphil bodies." 3. True accessory adrenals composed of both cortex and medvdla. The accessory cortical bodies represent by far the larger number of structures which have passed under the name of " accessory adrenals." They are said to show the three zones characteristic of the cortex of the adrenal of mammals, but no chromaphil cells are present — there is no "medulla." The smallest of these bodies are microscopic ; others may reach a diameter of a centimetre or more. They are found in the neighbourhood of the chief adrenal, sometimes embedded in other organs, in the retroperitoneal space, or in the genital region, as, for example, in the ligamentum latum, or in the space between testis and epididymis, where they are known as " Marc hand's adrenals." The Chromaphil Bodies. — These are found, or may be found, in any part of the body into which the sympathetic nervous system extends, and more particularly as groups of cells in connection with the abdominal sympathetic and its extensions. In connection with the abdominal sympathetic they were first noted and described by Ley dig and called " Kernnester " by Mayer. The observations of both these authors applied to the Urodela. But the recognition of the chromaphil cells and corpuscles in mammals and the characteristic reaction with chromium, by which they are now designated and homologized with the medulla of the adrenals, are due to Stilling. This author found in the abdominal sympathetic small bodies composed of cells having the same chromaphil reaction as those forming the medulla of the adrenal. He states that some are nearly a centimetre in length, while others are only just visible to the unaided eye. They are round, oval, or elongated in form, and their thickness is never more than a few millimetres. They have a tunica propria, small vessels and capillaries. Between the capillaries are cells which resemble in all respects those of ' The term " accessory inter-renal bodies " has been sometimes applied to them, but it seems best to avoid the term " inter-renal " except as applied to the Elasmobranchs. THE ADRENAL BODIES 117 the adrenal medulla. The resemblance between the chroma - phil corpuscles of the sympathetic and the medulla of the adrenal is rendered all the greater by the occurrence in the latter of occasional nerve cells. Stilling found these corpuscles in the rabbit, the cat, and the dog, and especially in young animals. He gives details of a method for displaying them. This extracapsular chromaphil material is stiU very imperfectly understood by many writers on the physiology and pathology of the adrenals. Thus RoUeston refers to Zuckerkandl's " parasomata " — the carotid body, the coccygeal, and " some cells in the pitui- tary." Now, the coccygeal body does not contain chromaphil cells, nor the pituitary, so far as I am aware. But the writer omits all reference to a very strik- ing mass of chromaphil tissue (the paraganghon aorticum of Kohn) — the abdominal chroma- phil body — which is present in the ordinary laboratory animals. ^ This important body can readily be displayed in the dog, for example, by removing the liver and ahmentary tract from the abdomen, and placing a piece of absorbent cotton soaked in a solution of potassium bichromate (3 to 5 per cent.) over the retroperitoneal tissues for six to twelve hours. On removing the whole of the remaining tissues and washing in running water for a few hours, the chromaphil bodies are plainly visible, and still more plainly if the whole preparation be placed in glycerin. The " abdominal chromaphil body " is revealed by this method as a very dark brown wavy streak of irregular diameter, placed Fig. 30. — Abdominal chroma- phil body of an adult dog. Lettering common to Figs. 30, 31, and 32. — A., aorta; Ad., adrenal ; C, abdominal chro- inaphil". body ; c, smaller chromaphil bodies. t| 1 It seems possible that the " abdominal clnomaphil body " of the dog may correspond to the " Nebenorgan " of Zuckerkandl. But the general shape and appearance of the two bodies are quite different, and Zuckerkandl's body was found only in very young subjects. ', 118 THE DUCTLESS C4LANDS in front of the aorta and extending from the region of the adrenals in front to the bifurcation of the aorta behind. Other elongated, oval, or rounded patches or specks of chromaphil tissue are also visible in different regions.^ Figs. 30, 31 and 32 will give an idea of the arrangement of the abdominal chromaphil body and other smaller chromaphil corpuscles in the dog, the cat, and the rabbit respectively. Numerous irregularly disposed smaller masses of chromajjhil tissue are found in different regions more or less closely related to the principal chromaphil body [see Figs. 30, 31, and 32 (c) ] Fig. 31. — Chromaphil bodies of adult cat. Lettering same as for Fig. 30. Fig. 32. — Abdominal chromaphil bodies of a rabbit. Lettering same as for Fig. 30. The principal body is bifurcated an- teriorly and posteriorly. In the cat (Fig. 31) the chromaphil body tends to consist of long threads of tissue. These threads are stretched along tlie sympathetic, and the relationship to the nervous system is more obvious than either in the dog or the rabliit. In the rabbit (Fig. 32) there is a distinct tendency for tlie principal chromaphil body to be paired, or it may be bifurcated anteriorly and posteriorly [Fig. 32 (C)]. The threads of ' I am indebted to tlie late Dr. Stilling and to Dr. Kolin for their kindness in giving me detailed instructions as to liow to find these bodies, and to Dr. Kohn for some specimens whicli ho generously sent me. THE ADRENAL BODIES 119 chromaphil tissue frequently run close up to, and may even be continuous with, the medullary substance of the adrenal. In some animals — viz., monkey, pig, guinea-pig, rat, gopher, and squirrel — the present writer has been unable to discover any chromaphil bodies. In regard to the microscopic structure of the chromaphil bodies, a detailed description is not necessary. It is, however, desirable to institute some comparisons between tlie liistological conn. t. bid. c. chrom. c. Fig. 33. — Transverse section through the abdominal chromaphil body of the dog. Fixed in corrosive sublimate and stained with haernatoxylin. Section 10 fj. in thickness. Leitz obj. 6. Drawing ocular. Lettering common to Figs. 33, and 34, hid. c, blood corpuscles ; bid. v., blood- vessels ; c, capsule ; chrom. c, chromaphil cells ; col.c, columnar cells of adrenal medulla ; conn, t., connective tissue ; end., endothelium of blood- vessels ; «., nuclei. appearances of the adrenal chromaphil tissue and this substance as it occurs in other places, as, for example, in the sjaupathetic ganglia and in the abdominal chromaphil bodies. These comparisons refer to the structures in the dog. A comparison of Fig. 33 with Fig. 34 will show that the general resemblance between extra-adrenal chromaphil tissue and adrenal medulla is verj' great. Both consist of columns of cells staining yellow or brown with bichromate of potash. The cell columns are, however, for the most part much thicker 120 THE DUCTLESS GLANDS in the adrenal than in the abdominal chromaphil bodies. The blood spaces are wider, and the whole aspect gives the impression that tlie adrenal medulla is more highly organized [see Pig. 34 {bid. v., col. c.)]. Many of the cells of the adrenal medulla are spherical, as in the abdominal chromaphil body, and theirJdimensions are the same — viz., about 12 /.i in diameter. The nuclei, also, are of the same order of magnitude in the two cases — viz., 5 /u or 6 /(,. But in many regions, especially where tJie cell columns are col. c. chrom. c. FiC!. 34, — Section through the ]nedulla of the adrenal of a dog, prepared as in case of previous figm'e. Same magnification. Lettering same as for Fig. 33. separated by large venous sinuses, the cells are arranged in a definitely epithelial fashion round the bloodvessels [Fig. 34 [col. c.)]. In this case the cells are columnar in shape, and may reach a length of 26 /(, and the nuclei are placed at the end of the cell remote from the bloodvessel. The protoplasm of the adrenal medulla is more distinctly granular than that of the abdominal chromaphil body, and is, moreover, more delicate in consistence, and therefore shows more shrinkage in fixation and tearing during the process of cutting sections. When the adrenal is fixed in bichromate THE ADRENAL BODIES 121 solutions, tlie section shows vacuoles as do tliose of the chrouia- phil body. These are absent in sublimate and Fleinming preparations. Thus it seems justifiable to regard the medulla of the adrenal body as composed of chromaphil cells of the same general character as those forming the chromaphil bodies. But the former have undergone specialization, and the structure of the substance has become elaborated into an organ with more definiteljr glandular form. It is clear from all that has gone before that the extra-adrenal # ^m^* I \ \>^^ ^-' #^ ^ /^ Fig. 35. — Section through a group of chromaphil cells in the inferior cervical ganglion of a dog. chromaphil tissues contain a substance which gives the same macro- and micro -chemical reactions as adrenin. It has been shown by Biedl and Wiesel that the " parasomata " (Neben- korper) discovered by Ztickerkandl in the human subject contain adrenin or some substance which has an identical effect upon the blood-pressure. The present writer has been able to prove that the abdominal chromaphil bodies of the dog contain the same or a similar substance. Fig. 36 shows the effect of injecting into the saphenous vein of a dog an extract from the chromaphil bodies of three dogs. It 122 THE DUCTLESS GLANDS will be seen that there is a very considerable and very char- acteristic rise of the blood-pressnre. The investigations of Stilling were confirmed and extended by Kohn and Kose, who laid stress on the fact that the chroma- phil cells are common and typical elements of the mammalian sympathetic system. Kohn's view is that what is ordinarily called the " cortex '" of the adrenal is in reality the only part which ought to be called adrenal at all, while the medulla is simply the " paraganglion suprarenale," a group of what he called " chromaffin "' cells, which have become included in the adrenal. This matter will be referred to again later on. Fig. 36. — Dog, 8 kilogrammcti. November 10, 1909. CHCl.,, morphine, atropine. Carotid blood-pressure. Time in seconds. At the point signalled an extract from the chromaphil bodies of three dogs was injected into the .saphenous vein. Zuckerkandl in 1901 found in the retroperitoneal space at the origin of the inferior mesenteric artery a pair of large chromaphil bodies, which he called " Nebenkorper des Sympathicus." These he found constantly in the embryo and in the new-born human sid.\ject, and, as we have seen, Biedl and Wiesel found that the bodies contained a pressor substance. True accessory adrenals, containing both cortex and medulla, like the main gland, are said to occur in the neighbourhood of the abdominal sympathetic, and in the region of the body where the cortical elements first arise. THE ADRENAL BODIES 123 6. TabvJar Statement of Chief Facts in Comparative Anatomy of the Adrenals The table ^ on page 126, modified from Poll, will render clear the chief facts in the comparative anatomy of the adrenal system. In concluding this section we would call special attention to Figs. 37 and 38, which give in a diagrammatic form a com- parison of the adrenal representatives in Elasmobranch fishes and in mammals respectively. C. Development of the Adrenals Balfour expressed the view that "in Elasmobranch fishes we thus have (1) a series of paired bodies, derived from the sympathetic ganglia, and (2) an unpaired body of meso- blastic origin. In the Amniota these bodies unite to form the compound suprarenal bodies, the two constituents of which remain, however, distinct in their development. The meso- blastic constituent appears to form the cortical part of the adult suprarenal body, and the nervous constituent the medul- lary part." This hypothesis has been fully supported, and the observations leading to it have been completely confirmed by all subsequent work upon the embryology of the adrenals. In the various classes of vertebrates there have been numerous observations, all of them clearly pointing out the totally distinct 1 In the table, the term " cortical system " has been substituted for " inter- renal systeni " employed by Poll. Each of the alternative terms has a certain and a similar disadvantage, inasmuch as it refers to an anatomical arrange- ment which is not universal tlu-oughout vertebrates, but confined to a single groujD — the term "inter-renal" being only applicable to Elasmobranchs, the term " cortical " being only appheable to mammals. But it seems on the whole preferable to use the word " cortical," because it refers to the arrange- ment in mammals which will long continue to serve as the standard of com- parison in the organology of the adrenal system. Fiu-ther, as announced previously, it is proposed to use the term " chroma- phil " instead of " chromaffin " or " phfeochrome." There is no doubt that in some respects " phsochrome " is the beet word, but " chromaphil " is only a slight modification of the original " chromophil " emploj'ed by Stilling, and was suggested to me by Sir Edward Sharpey Schafer. It is a pity that we cannot for the " cortical " cells use some name which would describe their staining reaction, or the chemical nature of their contents. But the literature of the comparative anatomy of the adrenals is already overburdened with a complicated and abtruse nomenclature, so peihaps it is best to be content with the term " cortex." 124 THE DUCTLESS GLANDS Qxrom aphil Bodi&s fpaiTS.dL Supra- r€n SympathePc G-angJia. Sympaf/idtic /Vert'e Kidney- OynipafneJ/c Ganaliou of/ietic A/srwe. vAcfeisorv Cortical Bodies ■kirfriCv Cor/ey of Adrenal Bocly (fntsr-renal Budy ) V> <^ Fig. 37. — Diagram of the adrenal representatives in elasmobrandh fishes allowing the cortical gland (inter-renal body) and the medullary glands (chromaphil bodies, " paired suprarenale ") in relation to the S5'mpathetic and the kidneys. THE ADRENAL BODIES 125 Groups 0^ Chromaphil Ce^ in Syinpa+hetic Ganalia Sympa+hefic Ga Medulla of Aol ren gl kidney Superior Cervical Ganc^lta nferior Cervical Garn^lia fcllale Gant^lta mpofhe+ic Nerve A^essoryCprtical Bodies Cortex o'i Adrenol Body edulla oiAdretiol Abdominal Chromaphil Rody r?f-Accessor Y Corfical Body ■Testicle Fig. 38. — Diagvam of the adrenal constituents and outstanding " cortical " and "medullary" (chromaphil) bodies in the mammal, showing the adrenal bodies, the chromaphil cells of the sympathetic, the abdominal chromaphil body ("accessory medullary") and accessory cortical adrenals in relation to the sympathetic and the kidneys. 126 THE DUCTLESS GLANDS H m < H 2 &H C5 3 ft H ■ tc C5 +^ H w t 0; " — ' M o PQ ■■3 i TO ^ i 55 CO .2 o 1— 1 H P3 1 Q ■3 £ 1 "3 ■3 P5 O O O O e ^ 3 "5 o ;i CO oi =3 i-i cS f~t -P ^31 i 1 1 ^ 3 ■fe rS -S oi tg h 3 w ^ 3 ft ^1 C^ CC 03 ftO 3 a CO g CO 13 c 05 « p-l ^ a r;1 8 CO E-i =6 Ph > h-l CD ^ cfl X tj Cm ti © P ft 9 © d N 03 15 >-- 3 .3 a J3 B 1 a s <1 "o THE ADRENAL BODIES 127 origin and nature of the cortex and the medulla. It will only be possible to refer to some of the more important papers. Mitsnkuri worked out the development of the adrenal body in the rabbit and in the cat. He concluded that the cortical substance arises froni tlie mesoblast, while the medul- lary substance is derived from the peripheral part of the sjan- pathetic nervous system, and is at first placed outside of the cortical substance, becoming transported into the middle of the adrenal body in the course of development. That the cortex is derived from the mesoderm and the medulla from the same blastema as the sympathetic ganglia is now almost universally conceded. The cortical substance is developed from the coelomic epithelium in a region known as the " adrenal zone." The extent of this zone varies in different'vertebrates. In mammals the origin of the cortex appears to be from tlie coslomic ei^ithe- limii on either side of the root of the mesentery or a little caudal- wards from the cranial end of the primitive kidney, appearing first as a series of buds which subsequently grow together. In regard to the development of the medulla of the adrenal body, it has been ascertained that certain cells derived (along with the sympathetic generally) from the neural ectoderm, do not develop into nerve cells, but into chromaphil cells. In the anamnia below the amphibia, these do not enter into any rela- tions with the cortical elements, but remain as chromaphil bodies or corpuscles. In Amphibia and in the Araniota some of these chromaphil cells grow into the cortical gland and form its medulla. Ultimately these acc[uire the chromaphil sub- stance. It is stated that in man this is not actually found in them until some little time after birth, but it occurs in the embryo of the ox and the sheep long before birth. ^ D. Addison's Disease and the Pathology of the Adrenal Bodies 1. Introductory and Historical The medical practitioner directs his inquiries towards experi- mental physiology and pathology in order to ascertain how far ' Brvuii in 1912 described the development of the chromaphil tissues in Rana esculenta. The chief point of importance in this paper is the observation that the chromaphil substance is not derived frorn the sympathetic, but only 128 THE DUCTLESS GLANDS modern research will enable him to understand the clinical phenomena of Addison's disease, and to treat his patients in a scientific spirit. On the other hand, the physiologist is eager to acquire whatever information can be derived from the realms of clinical pathology and pathological anatomy, as to the func- tions of the adrenal bodies. The fuller and more accurate is our knowledge of diseased conditions of the organs, the sounder will be our ]orogress in both these conditions. Pathology has taught us something of the adrenals, and physiology has contributed certain facts of primary importance. It must, however, be admitted that it is not possible at the present time to combine the knoAvledge derived from these two sources in such a way as to give an intelligent explanation of the functions of the adrenal bodies, and at the same tinie to offer a satisfactory explanation of the symptoms of Addison's disease. Addison's disease is characterized by the cardinal symptoms of extreme muscular weakness, nausea and vomiting, and an exaggeration of the normal pigmentation of the skin. Addison attempted to elucidate the nature of a malady which he had stjded " idiopathic ansemia," from an inability to associate it with any exact pathological condition. He was thus led to the discovery of the diseased state of the adrenal bodies, and the association between this diseased state and the train of symptoms which bears his name. The observations were confirmed but not much extended by Wilks, Trousseau, and Greenhow. It was Trousseau who first used the term "Addison's disease." It must be admitted that comparatively little has been added to our knowledge of the clinical aspect of the disease since it was first described. Addison considered that any lesion of the adrenal bodies which would interfere sufficiently with their function would give rise to the disease. Wilks and Greenhow were, however, of a different opinion — viz., that the true morbus Addisonii has essential peculiarities of its own, that no other disease or degeneration of the adrenal bodies is capable of producing the same associated train of symptoms. The modern view is entirely in accordance with that first expressed by Addison, that the symptoms are due to an interruption of , or a deficiency in, the functional activity of the adrenal bodies. secondarily conies into contact with tlii.s Hystcm. The cliromaphil cells appear first in close relation with the walls of certain bloodvessels. THE ADRENAL BODIES 129 2. Si/mjytonhs 1. Pigmentation. — The pigmentation is very varialsle Ijotli as to its period of onset and as to its intensity. Usually it first occurs at a later 2)eriod of the disease than the general symptoms, such as the muscular prostration. It sonietime.s occurs only shortly before death, and in some cases it never occurs at all. Occasionally, however, the pigmentation has been stated to precede the general symptoms. As for the degree or intensity of pigmentation, it may vary from the dark hue of the negro to a faint smibin-n brown. It is very interesting to note that the pigmentation is an exaggera- tion of the normal, and occurs most markedly in those parts which are normally pigmented, such as the dorsal surface of the forearm, the axillary folds, the areola around the nipples, the genitals, and the groins. The pigmented regions have no sharp margins. Friction or jiressure induces especially the increased pigmentation : thus we find dark patches or streaks brought about by corset, belt, garters, braces, or collar-stud. Pigmentation is usualty first noticed on the face, neck, and backs of the Jiands and fingers, especially over the joints. The lips may sometimes become pigmented and the tongue occa- sionally presents stains near the free border. There are also to be seen in some cases small, well-defined specks, like small moles, but occasionally of inky blackness. Pigmentation of the peritoneum and pia mater has been recorded. The hair may become darker, but the skin of the hairy scalp and other regions covered by hair does not appreciably change in colour. The linea alba may become a dark line. Rolleston says that the palms of the hands and the soles of the feet are very rarely pigmented, but he has twice seen pigmentation of the palms with intensification along the various lines. Microscopically the pigment is found in the cells of the stratum Malpighii, and the dermis shows a few pigmented cells — "carrier cells" — which, it is thought, convey the pigment from the bloodvessels of the dermis to the stratum Malpighii. The pigment is iron-free. In some few cases a combination of Addison's disease with hjemochromatosis has been reported. Pigmentation occurs in about 75 per cent, of all cases. 2. Asthenia. — Many authors regard the asthenia or muscu- lar weakness as the most constant and the most significant of 9 130 THE DUCTLESS GLANDS all the symptoms of Addison's disease. The patient suffers from an almost complete indisposition for any exertion. He is very easily tired, and is never able to get properly rested. There is no corresponding emaciation or neuritis. Asthenia is almost always the earliest sign of the disease. Long before one notices any change in the skin the patient complains of extreme lassitude. He can perhaps make a short series of movements with some energy, but he is almost immediately f atigixed . Langlois lays great stress on this feature, and recommends the use of Mosso's ergograjih as an instrument of diagnosis. He states that wliat characterizes the patient with Addison's disease is not so much the loss of ability to perform a single muscular feat, as a more or less complete disappearance of resistance to fatigue. If one submits under the same conditions a patient with Addison's disease, and another patient in a comparable condition (Ijoth, for example, tubercular to the same extent), to the crgographic test, we find that the fatigue curve is cpiite different in the two cases. We find that the simple tubercular patient can carry out a sustained labour (lift a weight of 1 kilogramme every two seconds) for a certain time ; but the patient with Addison's disease, who at first will lift the same weight to the same height, soon l)ecomes exhausted ; his curve shows a rapid fall. 3. Otlier Symptoms . — The majority of authors report that in Addisc)n's disease the blood-i:)ressure is remarkal)ly low. The heart is feeble in action ; there is a small, soft, almost imperceiit- ible pulse. From the evidence before us we are not justified in stating that a low blood-pressure is constant. The temperature is usually subnormal. In regard to the condition of the Ijlood, some authors state tliat anajmia is not characteristic, though the patients present an ana?mic ajipearancc. Others affirm that the blood always shows changes, in the directions of diminution in numlier of the red corpuscles and lowered hajmoglolun content. The number of leucocytes is in most cases normal. It has been stated also that the eosinophilous cells and the large mono- nuclear cells are increased in luimber. Status lymphaticus is not rare, and hj^perplasia of the thymus has been observed. It is stated that there is no very marked emaciation in the majority of cases. Vomiting is very common, and there is frequently hiccup THE ADRENAL BODIES 131 and sometimes diarrhoea. But there may be constipation from loss of muscular tone. Sometimes there is an alternation of constipation and diar- rhoea, which latter frequently occurs without obvious cause. Towards the end there may be pain with retraction of the abdomen, and small pulse, the condition strongly suggesting peritonitis. Various symptoms referable to the nervous system have been described. Some of these, such as twitchings and con- vulsions, point to irritation of the nervous system, but the most characteristic, such as a diminished or absent knee-jerk, are indications of depressed activity of the nervous system . Head- aches and faintness are not uncommon. Insomnia, loss of memory, noises in the ears, vertigo, pains in the trunk and limbs, and mental symptoms with hypochondria are also mentioned. The '' white line '" of Sergent has been recommended as a test for adrenal insufficiency. The method employed is to outline a square about the umbilicus ^\■ith a blunt object by quite superficial stroking withoxit using pressure or scratching. The jiatient should be kept still, and after half a minute, a pale line or band begins to appear which gradually becomes more distinct and white. It attains its maximum clearness in about one minute, persists for two or three minutes, and gradu- ally disappears. The theoretical explanation given by Ser- gent is not satisfactory. The normal response to light stroking appears to be a brief vaso-dilation followed by a vaso-constric- tion. The failure of this normal reaction is stated to be a sign of adrenal deficiency. 3. Etiology and Onset The disease is rare. It is douljtful whether one sex is affected more than the other ; it occurs about the thirtieth year on the average. The adrenal bodies may become infected in tuber- cular patients from the mesenteric glands or from disease of the vertebrae. But the adrenal bodies themselves seem to be susceptible to primary tuberculosis, and are often the only seat of tubercular infection in the body. Strains and injuries to the back or blows on the abdomen have sometimes been alleged to be the cause of the mischief. In these cases the trauma might render the gland more liable 132 THE DUCTLESS GLANDS to infection. Traumatic haemorrhage into the substance of the gland has been stated to be the starting-point of the lesion in some cases. The onset is nearly always insidious and gradual. Gastric trouble is perhaps one of the commonest causes of the patient's seeking advice. Very rarely the disease seems to come on suddenly after a shock or some cause of worry. It may be congenital. 4. Metabolism in Addison's Disease Owing to the rarity of Addison's disease, little is known as to the general (total) metabolism. Nor have we any a priori grounds for assuming that this would be either increased or diminished. According to a brief account given recently by Richter, the protein metabolism is not appreciably aifected. Senator and Pickardt observed eitlrer nitrogenous equilibrium or, with abundant food, nitrogenous gain. On administration of adrenal substance to the jiatient there was no increase of protein destruction. There is an increase in the jihosphoric acid elimination. Richter suggests that this has to do with increased destruction of bone substance, though Senator found the calcium elimina- tion not raised. Nothing certain is known of any change in carbohydrate metabolism. We might expect, since adrcnin pharmaco- dynamically induces glycosuria, that in Addison's disease, where there is jiresumably a deficiency of this substance, we should find a lowering of the sugar content of the blood. In experiments upon animals after extirpation of the adrenal bodies, this is actually found to be the case, but the clinical evidence in the case of the hinnan subject is meagre and con- flicting, although Bernstein and Falta believe that hypo- glycEcmia is a sign of some diagnostic value. There seems to be actually a diminution of the urinary pigments. .5. Morbid Anatomy In Addison's original paper eleven cases are recorded. In five of these there was caseous tubercle in both adrenal glands, and in one case tubercle was only present in one gland. One THE ADRENAL BODIES 133 case seems to have been an example of cirrhosis and atrophj^ In three cases there A\'ere secondarj' carcinomatous growths in the adrenals, bilateral in one case, unilateral in tJie other two. In one additional case there was a secondary nodule of carcinoma blocking the right suprarenal vein, and associated with hsemorrhage into the corresponding gland, but there were no growths in either. Bittorf states that in all cases there is disease of both adrenals. This may be (1) simple atrophy, or (2) inflammatory atrophy (chronic interstitial inflammation) with shriifliage and destruc- tion of the parenchyma, resembhng cirrhosis. According to this author, there is no special part of the gland which is of prime importance to life. He considers that the adrenal bodies are single organs, clearly essential to life, interference with which causes a definite train of symptoms. From the tone of this writer it would appear that he does not clearly recognize the essential and fundamental difference Ijetween the cortex and the medulla, nor does he appear to appreciate fully the significance of the fact that even if cortex and medulla do really constitute one physiological structure, there are out- standing masses of both constituents in different regions of the body, concerning which it would be out of the question to make a similar hypothesis. There may j-et be discovered some reason for looking at the adrenal gland (cortex and medulla taken together) as a functional ^\■hole, but Bittorf appears to have come to this conclusion simply because the experimental evidence as to the respective importance to life of cortex and medulla is conflicting, and because pathologists have never yet been able to determine any difference in those cases where chiefly cortex or chiefly medulla have been involved. Winkler gives an account of twenty-four cases of adrenal tumours. There were thirteen primary growths (ten epithe- liomata and three sarcomata), and eleven secondary cases. In only two cases was there any bronzing of the skin. From a careful study of these cases the author is quite unable to decide whether Addison's disease is due to an affection of the cortex or of the chromaphil tissue and the sympathetic, or is to be attributed to a lesion of both together. In cases of Addison's disease a fibro-caseous condition of tubercular origin is by far the commonest condition found. In addition, simple atrophy, chronic inflammation, syphilis, 134 THE DUCTLESS GLANDS malignant disease, and extravasation of blood have been recorded. The solar plexns and semilunar ganglia as well as the ganglia and nerves in the adrenals are often the seats of alterations. They may be atrophied from the pressure of tumours, affected by tuberculosis by extension or as j)art of a widespread invasion, or they may be involved in inflammatory processes (Dock). Hyperplasia of lymphoid tissues has been described. Wiesel has described in six cases of Addison's disease severe degenerative changes and destruction of the chromaphil cells not only in the adrenal medulla, but also in the sympathetic. He reports, further, that in a case of tuberculosis of both adrenal bodies, where there had been no sjanptoms of Addison's disease, not only was there no destruction, but there was a hyperplasia of the chromaphil tissues. Wiesel then, regards Addison's disease as due to a primary lesion of the chromaphil tissues. It is clear that such cases were easily overlooked by the earlier pathologists, and may account for some of the reports of Addison's disease without lesion of the adrenals. 6. Pathogeny. The theories as to the pathogeny of Addison's disease may be divided into two groups : (1) Nervous, (2) chemical or glandular. If we except Addison's original view (which he somewhat modified later on) and the theory that the adrenals are of no importance in the economy, most of the early theories were nervous. The view of Wilks and Greenhow was that the lesion is special and primary in the adrenals, while the sj'mp- toms of the disease are due to the secondary effects on the adjacent sympathetic, the solar plexus, and the semilunar ganglia. But in many cases of tjqaical Addison's disease no changes in nervous structures could be found, and on the other hand there are numerous examples of irritation of sympathetic gangha where no sjauptoms of Addison's disease have occurred. It may be, however, that the vomiting is of a nervous nature, and due to some effect upon the autonomic nervous system. The chemical or glandular theory is the one now generally accepted. It is usually subdivided into two : (1) The auto- intoxication theory ; and (2) the theory of internal secretion. THE ADRENAL BODIES 135 According to the latter view, the pathology of Addison's disease is to be explained on the basis of adrenal inadequacy — i.e., an interference with the normal internal secretion of the gland. According to the former, the symptoms of Addison's disease are due to the accumulation of poisonous products {e.g., of muscular activity), to remove which it is the duty of the adrenal body. It seems clear that the gland does not effect this removal after the manner of an excretory organ, but there is nothing to prevent our supporting the hypothesis that the secretion of the gland has for its function, or one of its functions, the neutrahzation of some of the poisonous products of meta- bolism. If we admit that one of the functions of the secretion of the gland is to maintain the tone of muscular structures generally, then we have at once an explanation of the extra- ordinary muscular prostration in Addison's disease. But the effects of adrenin, the secretion of the chromaphil medulla, are practicaUy confined to the muscular structures under the control of the sympathetic nervous system. It may be that the muscular weakness is to be explained on the hypothesis that the adrenals in some way neutralize the poisonous products of muscular activity. But how are we to explain the piginentation, the bronzing of the skin, which is, after all, the most striking of all the symptoms of Addison's disease ? Is this symptom related to the colour reactions given by the c]'iroma]:)]nl cells of the medulla, and extracts made from them, or is it related to a destruction of red blood-corpuscles which is stated to occur in the central portion of the cortex, or is it due to deficiency in some other function of cortex or medulla ? It seems difficult or impossible to induce pigmentation by experiments upon animals (see, however, pp. 141 and 142). The pigment is disposed for the most part in places which are exposed to thermal, chemical, and luminous stimuli. From a teleological standpoint the pigmentation might be regarded as a protective arrangement against luminous stimuli. Accord- ing to Bab (in discussing melano-sarcoma of the ovary), pigment raises the power of resistance of tissues and organs, and is therefore found in the locus minoris resistentice. In this view the pigment is a general means of protection against injury. Eiselt comments that this can scarcely hold as a general theory, 136 THE DUCTLESS GLANDS for pigment becomes developed in large ammmt in ganglion cells only during the process of degeneration.^ Wieting and Hamdi, discussing melanin-pigmentation, regard the formation of pigment as a i^rotective arrangement — e.g., it is laid down in the skin to protect the underlying structures. Solger looks upon the skin pigment as a protective against iiltra-violet light. The pigments of the body (respiratory, biliary, urinary, melanins, lipochrojnes, etc.) may be divided into — (1) iron- containing pigments ; and (2) fat-containing pigments. The second group includes the degeneration pigments, the lipo- chromes, and the melanins. The pigment in Addison's disease appears to belong to the melanins. There are various theories as to the mode of formation of the pigment. It has been suggested that it arises as a result of over-activity of the cells of tlie stratum Malpighii, due to increased nervous stimulation, the result of mechanical irrita- tion of the nerves round the adrenals. Eiselt believes that in consequence of the failure of the antitoxic adrenal function (of the coi'tex) the accumulated jiroducts act autolyticallj' upon tlie protein. Then, by the action of tyrosinase upon the aromatic molecular complexes thus formed, there arises an accumulation of melanin. A modification of this theory, but involving the liypothesis that the medulla is concerned in the pigmentation, based upon the work of v. Fiirth and Halle has been jiut forward lij' Adami. The melanin appears to be formed by tlie action of oxidases upon tyrosin and other aromatic products of protein decom- position. It seems possible that adrenin is manufactvu'ed in a similar kind of way, so that when the adrenal bodies are diseased the tyrosin and allied bodies accumulate in tlie tissues, and the greater darkening of the superficial parts most exposed to light and air gains its explanation from the more active oxidation of those aromatic ))odies in these regions. Pathologists have never until quite recently given due consideration to the essential difference between the cortex and medulla of the adrenals. We have seen that these repre- sent two separate and distinct kinds of tissue, which only come into relation with each (jther in the higher vertebrates, and ' Tliere seems no reason why tliis pigmentation in degenerating nerve cells should not be an example of a protective effort (albeit ineffective) on the part of the cell. THE ADRENAL BODIES 13? consist of " cortex "' and " medulla " only in mannnals. It is possible that pathology may j^et throw some light on the question of the function of the cortex and the cpiestion as to a possible physiological relationship betfl'een the t'wo constituents of the gland. We must remember that there are undoubted cases of Addison's disease in which both adrenal bodies are found to be healthy, and that there are other cases in which clinically no signs of the disease are present, but which at the autopsy show destruction of both glands. These facts may possibly find their explanation in the distribution of cortical and chromaphil substance outside the adrenal Ijodies. On the other hand, it seems not out of the question that we may have to resuscitate a long-buried hj'pothesis that the disease may sometimes be due to affection of the sympathetic nerves or ganglia. To bear in mind such a possibility is not so unjusti- fiable when we consider to how small an extent we are able to explain any of the symptoms of Addison's disease by anj^thing we have learnt about the functions of the adrenal bodies. In the meantime pathologists would do well to investigate, in all cases of probable adrenal disease, not only the adrenals themselves, but the rest of the cortical and chromaphil tissues in the bodj-. 7. Course and Event of the Disease — Diagnosis, Prognosis, and Treatment The course of the disease is usually progressive, but the mode of progress is paroxysmal [Greenhow]. All the symptoms are progressive, but not steadily so. The course of the disease on the whole is slow and chronic ; but it is subject to alternate exacerbations and remissions. During the remissions strength is to some extent recovered, but after each exacerbation the patient finds himself upon a lower level than during the previous remission. In cases where destruction of the glands is produced by haemorrhages or thromboses death may occur very rapidly with acute nervous and intestinal symptoms. In these pig- mentation is absent. In young subjects the disease may run a latent course — that is, the constitutional symptoms first appear suddenly in a fully developed form producing death in a few days. 138 THE DUCTLESS C4LANDS The diagnosis must depend largety on the extraordinary' lack of resistance to fatigue, ujjon the other constitutional symptoms, and upon the bronzing of the skin. Where this last is absent the diagnosis must be difficult and uncertain. The jirognosis is grave, but the patient may live a con- siderable time, and care should be exercised in foretelling to what extent life may be prolonged. At least one case is reported where the symptoms of Addison's disease have completely disappeared (Treckin). The treatment will be dealt with under the therapeutic applications of adrenal substance (p. 204). 8. Otlier Conditions involving Adrenal Insufficiency Defective development of the adrenals is not infrequently associated with imperfect growth of the brain, particularly in cases of anencephaly and hemicephaly. Total deficiency of the adrenal medulla has been reported. Wiesel records a series of cases of what he calls " hypoplasia of the chromaffin system." Lavenson, Sergent, and Cooke have described cases of acute adrenal insufficiency, which may occur with symptoms reserabhng an acute poisoning. These are apt to occur in diphtheria, scarlet fever, typhoid fever, erysipelas, and chloroform poisoning. Sergent connects certain conditions which may supervene in typhoid fever with the syndrome of adrenal insufficiency. French writers frequently refer to a condition due to adrenal insufficiency, in which muscular weakness or lack of tone and a low blood-pressure, along with digestive and nervous troubles are striking symptoms. They have even attributed the symptoms of " shell-shock " to adrenal insufficiency. 9. Excessive Adrenal Function The fact that excessive production and pouring into the circulation of the thyroid secretion appears to lead to a very definite train of sj^nptoms, has naturally suggested the question whether an analogous condition of excessive pro- duction of the adrenal secretion may be a factor of consideration in the production of disease. The most striking effect of the adrenal secretion is a rise of blood-]3ressure. As ])ointed out by Adami, hyperpiesis, or THE ADRENAL BODIES 139 pronounced and continued rise of blood-pressure, is not an uncommon condition. Roger and Gouget report hypertrophy of tlie adrenals in a case of experimental arterio-sclerosis induced bj' lead intoxication, while several authors have noted a relation between arterio-sclerosis and hypertrophy of the adrenal medulla. Three theories have been put forward to accoiuit for the hyperplasia of the adrenal bodies in arterio-sclerosis : (1) The hyperplasia is not the cause of the hypertension at all, but an " antitoxic hyperplasia '" due to the effects of the accumulated products of metabolism which possibly also produce the hj'pertension ; (2) the hyperplasia is the cause of the hyper- tension, but is secondary to a renal lesion ; (3) the hyperplasia is the cause of the liypertension, and is primarj^ and independent of the kidney mischief. It is yet too early to state which of these is the correct view. The French ^^Titers insist that the adrenal hyperplasia is almost constantly associated with chronic interstitial nephritis. According to Pearce, it may equally be associated witJi chronic parenchymatous nephritis. On the other hand, Mott states that in his experience in advanced arterio-sclerosis the adrenal medulla is more often atrophied than liypertrophied. Several writers have assumed a functional increase of the chromaphil tissue in certain forms of diabetes mellitus, but the matter cannot l)e regarded as definitely settled. The same applies to the association of interstitial nephritis and hyper- function of the chromaphil tissue. 10. Adrenal Tumours Tumours of the adrenal body are perhajjs most usually of interest as bearing upon hyperf unction of the organ. But since it is conceivable that in some cases the growths may determine a reduction in activitj^ it is better to treat of them in a separate section. A. Tumours of the Adrenal Medulla {Chromaphil Tissue). — A few cases of medullary glioma have been described. Adenomata of the chromaphil tissue, or " paragangliomata " are also mentioned. The symptoms noted were arterio- sclerosis, and cardiac hypertro^jhy as well as disturbances of nutrition, and other signs of a more general character. 140 THE DUCTLESS GLANDS Malignant medullary hj'pernepliromata also occur, and, although the chief interest of these cases depends on the distribution of the secondary growths, yet it will be advisable to give a short account of their most striking features. The syndrome associated with these growths was first described by Hutchison. Most of the cases occur in children two or three years old, and in mauj^ the earliest characteristic sign is a hajmorrhagic streak upon one or both upper eyelids. This is followed by exophthalmos and optic neuritis. The disease is always fatal, usually within six months. The primary tumour is believed to arise from the chromaphil tissue of the medulla of the gland, and consists of round or oval cells with large nuclei and a granular protoplasm. It is doubtful whether it is a sarcoma or a carcinoma. B. Tumours of the Adrenal Cortex. — These may be divided into two groups. In the first are included the sarcomata, carcinomata, endotheliomata, and cysts. These for the most part only give rise to general results such as may be expected from benign or malignant tumours. In the second group are included the adenomata and hypernephromata. The clinical importance of these will be discussed later in connection with the relations of the adrenal cortex to the genital functions (p. 241). E. Extirpation Experiments in Mammals The earliest extirpations of the adrenals were performed by Brown-Secprard in 1856. He employed for extirpation of both glands forty-four rabbits, nine guinea-j^igs, two rats, and several dogs and cats. All these animals died in nine to thirty-seven hours after the operation. For the unilateral operation this experimenter used sixteen rabbits, five guinea-pigs, two cats, and two dogs. All these died in twenty-three to tlurtj'-four hours. Later he reported that two dogs survived removal of one gland for eight days. As a rule young animals survived the operation longer than adults. Brown-Secpiard came to the conclusion that the death after adrenal extirpation was not due to adventitious lesions connected with the operation, but to a cessation of the function of the glands. He notetl marked muscular weakness, but not voTniting or pigmentation, and he supposed that the absence of these two last sym2:)toms is due to the rapidity with which a fatal result supervenes. THE ADRENAL BODIES 141 These views of Brown-iSequard were vigorously conil^ated by man}" workers. Gratiolet performed several series of operations upon guinea-pigs, and came to the conclusion that extirpation of the right ach'enal was just as serious as removal of both. This was soon disproved b}^ Brown-Secpiard, who succeeded in keeping three guinea-pigs out of seven alive for three weeks after right-sided extirpation. Philipeaux succeeded in keeping white mice and also a certain number of rabliits alive after bilateral extirpation. He con- cluded that removal of the adrenals does not necessarily lead to death, and that where death ensues this is clue to the operative proceedings or some circumstance connected mth them, such as peritonitis, and that some animals can survive complete extir- pation without shomng any symptoms — that, in fact, the adrenals are no more essential to life than is the spleen. This view he firmly maintained, although three of his operated animals died in nme, twenty-three, and thirty-four days. In order to test the matter further, Brown-Sequard per- formed a further series of experiments upon rabbits, and felt justified in affirming that the adrenals are more essential to life than are the kidneys, and thought that the survival of occasional animals is due to a vicarious assmnption of the adrenal function by the thymus or the thyroid. Harley employed among other animals the white rat, and found that this animal may indefinitely sm'vive entire removal of the adrenals. From this Harley, as well as Philipeaux and Gratiolet, ascribed the fatal results in other animals to injury to adjacent nerves and bloodvessels. The observations of Nothnagel deserve special mention. This observer, from clinical observations, thought that a chronic inflammation of the adrenals would be more likely to induce symptoms resembling those of Addison's disease than removal of the glands. Accordingly he resorted to the method of crushing the bodies. He operated upon 153 rabbits, and found that if the operation were performed upon the two sides with an interval of three or four weeks between, then the animals survived and showed no serious symptoms. Among the 153 bilaterally operated rabbits, Nothnagel observed in three cases pigment spots on the mucous membrane of the mouth. These were noticeable one, three, and five months after the second operation. The author did, not, however, 142 THE DUCTLESH GLANDS attach any particular importance to them. He tlionght, indeed, that the disease of the acbenal glands had no immediate relation to pigmentation. The statement that removal of both adrenal Ijodies does not necessarily lead to death was denied by Tizzoni. This author came to the conclusion that in rabbits the destruction of one or both of the adrenals results in deatli if sufficient time be allowed to elapse. He obtained similar results with dogs. The opinion that unilateral extirj)ation could lead to death was strenuousljr ojjposed by Stilling, who found that young rabbits from which one adrenal had been removed could develop quite normally, and live more than a year without showing any untoward symptoms. In thirty cases investigated Tizzoni foiuid pigmentary changes in thirteen. These came on at the earliest two months after the operation, and occurred exclusively in the mucous membrane of the nose and mouth. They Avere of the same character as those found in Addison's disease. Stilling was miable to confirm these results. Tizzoni con- sidered that death, which might occur after removal of one capsule, was due to lesions of the nervous system. Abelous and Langlois employed various means for experi- mental lesions upon the adrenals, such as ligature, cru.shing, and cauterization, Ijut most frequently the last metliod was used. They report that after complete destruction of one gland some animals suffered a loss of weight and a small pro- portion died. After complete destruction of both adrenals nio^t of the animals soon died. The duration of life could be increased by performing the operation at two sittings with an interval of several days between them. After destruction of a fifth part of each gland, with an interval of one or two days between tlie two operations, the animals coidd be kept alive, Ijut there was considerable emaciation. If an interval of eight to fifteen days were allo%\'ed to elapse between the two opera- tions, then the animals lived without symptoms. If the half of each organ were cauterized aA\'ay, the animals rapidly A\-asted and died, but not so quickly as after total destruction. The animals employed in the experiments Mere guinea-j)igs. Alezais and Arnaud, in a series of papers entitled "Recherches Experimentales et Critiques sur la Toxicite de la Sub.stance des Capsules Surrenales," conclude that the suprarenal capsule, though still functioning in the adult, is not indispensable for THE ADRENAL BODIES 143 life. Its unknown functions may be disturbed without any other results than a hyperpigmentation of skin and mucous membranes. But a lesion of the glands frequently induces death bj^ affection of the nervous system. The pigmentation was confined to the mouth and nostrils, and the authors do not appear to be convinced that it was not accidental and indepen- dent of the lesion of the adrenals. Hultgren and Andersson in 1899 published the results of a carefully conducted series of extirpation experiments upon rabbits, cats, and dogs. The effect varied very considerably in different animals. In cats the unilateral operation (extirpation of one adrenal) never induced death, but, especially in old cats, there was some temporary disturbance of the general bodily health. Bilateral extirpation in these animals, whether carried out at one, two, or three sittings, led to death, without exception, in a few days. The average duration of survival after extirpation of both adrenals at one operation was 68 hours (nine cases) ; at two operations, 134 hours (eleven cases) ; at three opera- tions, 88 hours (five cases), but m the last instance there were three cases of infection. Extirpation of one and amputation of the other gland ^ in one sitting was generally very badly borne. Of the nine oats operated on in this fashion, only two survived any considerable time ; one died in six hoiu's, probably from the effects of the anesthetic, and three in thirty to seventy-two hours. In these last the adrenal left behind had undergone necrosis. The three remaining animals died from various diseases within three weeks after the operation. It apj^ears from these experi- ments that the removal of a large part of the adrenal tissue renders the animal more susceptible to infection. Extirpation and amputation carried out at two sittings is less dangerous ; out of thirteen animals so treated, two died from the actual oiaeration, and three from necrosis of the adrenal left behind. The remaming eight all Uved more than seven days, and of them two died of intercurrent diseases. If the removal of the glands be carried out at several operations, the length of time which elapses between the operations makes no difference to the result. ^ In these " amputation " experiments a small portion only of one gland was ,left behind. 144 THE DUCTLESS GLANDS Hiiltgren and Andersson came to the conclusion that the resistance of castrated animals to adrenal extirpation is gener- ally greater than tliat of normal animals. While, for example, normal animals survived comjilete cxtirijation at one oiseration for 61 Jiours, the corresponding time for castrated animals was 121 hoTirs. In this relation the aiithors call attention to the striking morpliological resemblance between the cells of the adrenal cortex and the interstitial cells of tlie testis and ovary. In ral:)bits total extirpation of both glands at one operation is always fatal, and death occurs on the fourth or fifth daJ^ If the operation is carried out at two sittings, the duration of life is considerably increased ; and three ral)bits in which there was an interval ( >f nine to fourteen days between the t"\\'o ojierations lived 121 to 125 days, and were then killed while still in per- fect health. After cxtirjiation of one and amputation of the other gland most of tlie rabljits lived a long time — as long as 320 days. The authors, innuediately after stating this result, say : " Dieses Ueberlel)en der totalen Entfernung der Nebennieren l)eim Kaninchen is durchaus nicht durcli die Anwesenheit wenigstens makroskopisch nachweisbarer accessorischer Nebennieren bedingt." Now, these cases were not cases of total removal of the adrenals, for some tissue of the amputated gland was always left Ijehind. But perhaps this is meant to refer to the three cases of the previous paragrapli, where the operation was performed in two sittings with an interval of nine to fourteen days between them. But apparently these were not cases of complete removal, for the gland was transplanted into the musculature. Unilateral extirpation in rabbits produces no ill effects, and the same applies to dogs. Hultgren and Andersson only per- formed one total cxtirjjation ujion a dog, which lived six days. The symptoms after removal of tlie adrenals were very characteristic. After the operation the animal recovers in a few hours, and in the first few days shows no ill effects from the operation, excejit some loss of appetite. During the last tM'enty-four liours before death, or earlier, the animal becomes stupid and quiet, and shows (especially is this the case with cats) weakness and uncertainty of movement in the hinder extremities. Dming this period, too, the temperature begins to fall, and the apathy and weakness increase. Then the hind- THE ADRENAL BODIES 145 limbs become stiff, the animals tire on the slightest exertion, and show extreme prostration. Finally, with increasing asthenia, there is dyspnoea, heart-weakness, and death. In rabbits convulsions are common, but do not occur in cats and dogs. The authors lay considerable stress upon the loss of weight which occurs even after the unilateral operation. i This symptom is less marked if the operation be carried out upon castrated animals. Fall of temperature, too, is regarded by them as a significant symptom. They could detect no change in the haemoglobin of the blood, nor in the number of red and white corpuscles. They could detect no change in the electrical excitability of the nerves, and deny that removal of the fidrenals gives rise to symptoms resembling those of poisoning by curare. Tliere was no true paralysis, but only weakness and prostration. The operated animals were verj^ sensitive to bodily movements. Adrenal extirpation has no effect on the protein metabolism. This apphes, at any rate, to rabbits and cats. The Scandinavian authors consider it very probable that the adrenals have a varying functional significance in different classes of animals.'^ Strehl and Weiss operated upon 114 animals, and found that total extirpation always causes death in from four hours to five days. If the operation was performed at two sittings, the second gland was always found to be enlarged. Among the symptoms noted by these writers after extirpation are muscular weakness, a low temperature, and a low blood-j)ressure. iStrehl and Weiss give the following tabular statement of their results : Species of Animal. Duration of Survival in Hour.'i. Nuniljci- of Auimnls. 7 i 3 1 15 o 20 20 4 ! 10 1 1 25 Dogs Dogs Cats Cats Rabbits (juinea-pigs Rats Mice Hedgehog AVeasel Fiogs 22-75 75-138 1.5-28 28-47 8-14 4-9 1.5-19 8-13 14 21 22-45 1 This result was also obtained by Elliott and Tuckett, and has been fre- quently observed by the present writer. " This is probably true of all the " ductless glands." 10 146 THE DUCTLESS GLANDS Biedl jserformed a series of exiieriments iqjon dogs, cats, and rabbits. These were carried out by a new method. In a preliminary operation by a lumbar incision the glands were " dislocated," the vascular connections were not severed, and the glands were stitched into tlieir new position between the skin of the Ijack and the dorsal musculature, so that they remained in a living condition and easily accessible extraperi- toneally. After three or four days the glands were exposed by a skin incision, the vessels tied, and thus could extirpation be performed in the easiest possible manner. It was fouiul that extirpation of one gland produced no serious effects, but that after extirpation of both adrenals the animals died, almost without exception, in two to four days. Two ralibits which survived sixteen and twenty-eight days respectively Mere found to possess accessory adrenals on the vena cava l^eneath the renal veins. As we have seen, Boinet succeeded in keeping rats alive for a considerable time after double epinephrectomy ; and Harley many years ago found that the rat is able to withstand removal of both adrenal bodies. According to Wiesel, this is due to the fact that the rat nornuxlly possesses between the testis and epididymis accessory adrenals which are found to undergo com- pensatory hypertrophy after extirpation of the chief organs. These accessory bodies consist entirely of cortex (see p. 147). In guinea-pigs a compensatory hypertrophy of accessory cortical bodies can be shown to occur, but this is never sufficient to keep the animal alive after complete removal of the main glands . The case of the rat and the results of extirpation experiments upon this animal seem to point strongly towards the cortex being the part of the adrenal body wiiich is essential to life. We shall, however, have to return to this subject again. We see, then, that later M-ork luxs confirmed in a general way the statements of Brown-Sequard as to the necessity for life of the adrenals. We cannot, however, altogether disregard the very consideraljle number of exceptions which have been recorded l^y various oltservers. Moore and Purinton report the survival of a goat for twenty-two days after comiDlete removal of Ijoth adrenal glands, and they state that no accessory bodies could lie detected. According to Mayer, tlie diabetic puncture is ineffectual in THE ADRENAL BODIES 147 animals from which the adrenals have been removed. Further, in such animals the glycosuria resulting from extirpation of the pancreas is much reduced. Frouin states that the pancreatic diabetes is also much reduced in severity in animals from which one adrenal and two-thirds of the other have Ijeen previously removed. This matter "\Aill be referred to again in connection with the subject of adrenal gtycosuria. Levin reports that the blood of animals deprived of adrenals, ^^'hen injected into another animal, raises its blood-pressure, but the tracing he gives indicates that the rise is not consider- able. He hints that the substance which has this action may be something of a different nature from adrenin.^ F. The Question as to Accessory Adrenal Bodies in Relation to Extirpation Experiments upon Mammals It will be seen, from a perusal of the section on the compara- tive anatomy of the adrenal glands, that not only may acces- sory adrenals consisting of iDoth portions of the organ be present, but there may also be some glandules consisting of cortex only. The presence of chromaphil bodies and cells in different regions must also be borne in mind (Figs. 30-33). How far does the existence of these various bodies explain the discrepancies between the results obtained by different observers after adrenal extirpation ? We know that some of the larger masses of chromaphil tissue (siTch as the parasomata of Zuckerkandl and the abdominal chromaphil bodies in various animals) contain adrenin, and this may have the same physiological purpose as that manufactured by the adrenal medulla, whatever that may be. Schafer recently exhibited a white rat operated upon by Harley some time between 1856 and 1858. This rat had the spleen and adrenals extirpated when it was only a month old and quite small. It increased in size after the operation quite ^ According to Gautrelet and Thomas, after extirpation of the adrenals in dogs the heart contraction becomes weak, and the rhythm quicker, while the blood-pressure sinks after five hoirrs to 6 centimetres Hg and later to 1 centimetre. The same authors report that in decapsulated dogs excitation of the splanchnic no longer induces glycosuria, as it does in normal animals. They further report that dogs and rabbits, after adrenal extirpation, become poikilothermic in that their body temperature, within certain limits, follows that of the external air, and that there is reduction of the excitability of the sympathetic. (See p. 235.) 148 THE DUCTLE88 GLANDS as fast as its fellows which had not been touched. The animal M'as killed when five months old, and no discoloration of the skin or hair could be detected. The lumbar and other lymphatic glands were found enlarged, i Commenting upon this, Sir Edward Schafer says : " The rat happens to be the one common animal which is able to withstand comjjlete removal of both suprarenal capsules. The reason for this was not at the time apparent, although it is now kno"^vn, for the rat is exceptic)nal in jjossessing in various parts of the back of the alxlomcn and pelvis numerous small glandular structures which are composed of cells having the same characteristic features and functions as the cells of the suprarenal medulla." But all observers have not been successful in keeping rats alive after d(juble adrenal extirpation. Tlius, H. and A. C'ristiani found that in then experiments, unless a little of the medidlary substance ^\'ere left behind, the rats always died. From these experiments we slioidd be justified in concluding that it is the chromaphil tissue (including the medulla of the adrenal boclj') which is essential to life. But, as Ave have already seen, Wiesel arrived at a diiJerent conclusion — viz., that it is the survival of accessory cortical substance which saves the animal's life. We thus see that the experimental evidence as to the effects of extirpation of the adrenals in the rat is somewhat conflicting, and the explanations offered by different observers as to the occasional or frequent absence of ill eft'ects after extirpation are also conflicting. Moreover, it does not a23j)car to be the case that the rat is more richly endowed with extracapsular chroniaphil cells than are other common animals. The present writer has been so far totally unable to demonstrate any such tissue by the method of Stilling and Kohn, and is further informed by Dr. Kohn that there is, at any rate, no essential difference between the rat and other animals as regards its chroniaphil tissues. Vassale, who has jjerformed a series of experiments «ith full knowledge of the anatomy of the chromaphil cells and their distribution in different animals, points out that the " jjaraganglion abdonnuale aorticum " is the most important mass of chrf)maphil tissue outside the adrenal body, and that 1 Tliis description is taken from tlie catalogue of the niuseiuii of Uni\'ersity College Hospital, whence the specimen was borrowed by Sir Kd%\-ard Schafer for the purpose oi his lectiire, THE ADRENAL BODIES 149 it is alwaj's present, though in varying degree in the animals ordinarily used for exi^eriment (dog, cat, and rabbit). The removal of one adrenal and tlie abdominal chromaphil l)ody causes death in young cats with the same symptoms as those obtained after bilateral extirpation of medulla only. Vassale thinks that survival of animals, wlien it occurs after extirpation experiments, can be satisfactorily explained by the extra amount of extra-adrenal chromaphil substance which haiipens to be present in these individuals. A further discussion of the question as to the relative importance to life of the cortical substance and the chromaphil material can only be carried on after the account of extirjiation experiments upon lower vertebrate animals. According to Biedl, the cortical accessory adrenals occur very rarely in dogs and cats, in rabbits in about 15 to 20 per cent, of animals examined, in rats in almost 50 per cent, of cases, in guinea-pigs not more than 4 per cent, of cases. G. Extirpation of the Adrenals in the Lower Vertebrata Perhaps the best-known and most-of ten- quoted series of extirpation experiments upon any animal is that carried out upon the frog by Abelous and Langlois in 1S92. This was, of course, at a period before the discovery of the physiological effects of adrenal extracts upon the blood-pressure. The authors employed frogs because these animals, they say, do not suffer from the shock of operations as do mammals, and, in general, tolerate operative proceedings very well. Abelous and Langlois were the first to study the pliysiology of the adrenals in the frog. Destruction Ijy means of the actual cautery was the method of extirpation employed. A platinum wire brought to a red heat was applied to the bodies on the anterior surface of the kidneys. The authors foiuid that male frogs are more suitable for the operation than female, and summer frogs better than winter frogs. There was never any post-operative shock. Total destruction of both capsules always led to death. Immediately after the operation the animals were normal. It was only after a certain period that one observed ill-effects which finally caused death. The duration of survival was variable. It varied according to the season ; winter frogs 150 THE DUCTLESS GLANDS might live twelve or thirteen days, but summer frogs never longer than forty-eight hours. On the other hand, if the winter frogs were kept at a mean temi^erature of 22° (A, their period of survival was much diminished, and from t\^'elve to thirteen days it was reduced to three. The sympttoms which followed destruction of Ijotli cai^sules consisted essentially in a progressive jjaralysis beginning in the hind-limljs, then becoming general and inducing death. On the day of the operation tlie animal remained well. It was as a rule at the end of the twenty-fourth to the thirtieth hour that symptoms came on. First one noticed a distinct inco-ordination in the movements of the hind-limbs wlien the frog jumped. Also the animals quickly became fatigued, and asthenia became more pronounced. This paresis aiSected first the flexors and adductors, and finalty the extensors ; tlie frog was finally no longer able to respond even to the strongest stimulations excej^t l)y way of the feeblest movements. Then the fore-limbs became affected, and the animal was completely inert. The respu'ation became slower and slower, and with contracted pupils the animal died. If the animal were stimulated from time to time so as to provoke movements, it was found that the paralysis came on much more quickly, and the duration of survival was considerably shortened. From these facts the autliors con- cluded that the length of survival was in inverse ratio to the chemical changes going on in the body. The more active tliese changes — as, e.g., in summer frogs — the more quickly did death supervene. Destruction of one capsule never induced death. Tlie animals after sucli an ojieration showed no untoward symptoms, and their attitude and reactions were perfectly normal. Com- plete destruction of one capside and destruction of tlie greater part of the otiier generally led to death, but tlie survival ■was always longer than after comiDlete destruction of both. If the fragment left behind were of any considerable size, the survival was as long as in the animals in which only one gland had been destroyed. The insertion under the sldn, in the dorsal lymph sac, of some fragments of kidney with the adrenals attached taken from a normal frog, prolonged the survival. Animals so treated might live twice as long as animals not so treated. The authors record that summer frogs \^'ere by this means THE ADRENAL BODIES 151 enabled to live five or six days. Post niorteiu it was found tliat the grafted capsules liad disappeared — i.e., the graft did not succeed. Injection of a saline extract of liealtliy glands only prolonged the survival bj' about twenty-four ho^u's. Now we come to some observations by Abelous and Langlois upon wliich they tliemselves laid coaisiderable stress, and wliich luive played a prominent ptirt in all subsequent discussions on the functions of the adrenal bodies. They found that intra- venous or sulicutaneous injection of the blood of a frog dj'ing after extirpation, into a frog recentl^y ojJcrated ujion induced rapid joaralysis and death. The same injection into a n(jrmal frog only produces slight temporary symptoms. Tlie autlu>rs were convinced that death after extirpation of both capsules is in reality due to the suppression of essential organs, and not simply tlie result of the shock of the operation. TJiey further proved that the effects were not due to injury to tlie kidney. Their theory was that deatli resulted from the accunuUation in. tlie blood of one or several toxic substances of unknown natiire, and that the suprarenal capsules are capable of the elaboration of a material which neutralizes the toxic effects of such substances. Tlie toxic symptoms were stated to be those of curare-poisoning — paralysis, that is to say, of the connections between nerve and muscle. These observations were in the main confirmed by C4ourfein, who, liowever, could not satisfy himself that there was any difterence between winter and summer frogs as regards the results of extirpation, and who denied also that tlie l)lood of operated frogs, when injected into others, gives rise to S3'mii- toms like those of curare-poisoning. The same author also carried out a series of observations on pigeons and tritons. The j^igeons only survived four to twenty -four hours if total extirpation had been performed ; if only one-eighth to one-tenth of the organ remained behind, the animals lived fifteen days. Unilateral extirpation in tritons jJroduced no symptoms. If only a speck of one adrenal remained behind, this was sufficient to keep the animal alive for from eighteen days to nine weeks. Pettit was apparently the first to operate upon fishes. He performed a series of experiments upon the eel, having chosen this animal because its adrenals are placed on the ventral surface of the kidneys, a condition which is rare in Teleosts. He did 152 THE DUCTLESS GLANDS not, however, perform any total extirpations, since he was only interested in noticing a compensatory hypertroijliy of one gland after removal of the otlicr. TJiis, he says, indicates a secreting function for tlie adrenal of the eel. Pettit looks upon this organ in the eel as tlie fundamental tyjje of the suprarenal capside, but he was apjjarently miaware that it consisted onlj' of cortical substance. Since the corpuscles of Stannius contained no chromaiahil tissue, tlie Teleostean fishes appieared to offer an admirable opportunity of testing liow far the cortical adrenal glands were essential to the life of the animal. Accordingly a series of exjieriments were performed by the present writer in 1898 upon eels. The results showed that an eel will siu'vive the operation for a long time. The conclusion drawn was that the cortex of the adrenal is not essential to the life of the animal, but the discovery by Giacomini of the cranial cortical adrenal in Teleosts renders such a conclusion unwarrantable (seep. JO'i). Biedl's experiments upon Elasmobranch fishes will ])e referred to in tlie following section. H. The Question as to the Relative Importance to Life of Cortex and Medulla We have seen that the extirpation experiments upon mammals have not definitely determined the cpiestion as to which constituent of the adrenal is essential to life, or whether, indeed, it is to the suppression of the compound organ in its entirety that we must attribute death after extirpation. Some autliftrs believe that there is no sjiecial part of the organ M'hich is of supreme importance in the i)atliology of Addison's disease, and consider that the adrenal bodies are single organs clearly essential to life, interference A^itli which causes definite ill- results. Some, on the other hand, have concluded from experiments upon mammals that the medulla is the vitally essential constituent, although Wiesel came to the conclusion that the cortex is the jjart essential to life. Biedl states that in mannnals he has succeeded in removing tlie cortex, leaving the medulla behind intact, and that the operation was followed by the death of the animals. So he concludes that it is the cortex which is essential to life. Biedl says that he has succeeded in determining for the THE ADRENAL BODIES 153 inter-renal of Elasmcibranclis that after its extirpation the animals can live two or three weeks, and then die witli sj'mp- tonis of general prostration, just as do niamniaLs after extir- pation of both dual adrenals. Agahi, he conclndes tliat the cortex is the essential part. These experiments ujjon Elasmobranclis must be very ditlicnlt, but so far thej^ certainly seem to point to the cortex as the vitally essential tissue. The validity of these experiments is, of course, leased upon the assumption tliat tliere is in Elasmoljranchs nothing corresponding to the cranial cortical body discovered by CTiacomini in Teleosts. Some recent experiments carried out in nij' laboratory by Sir. T. D. Wheeler lend considerable sup]3ort to the view that it is the cortex and not the nietluUa whicli is essential to life. Instead of attempting to remove the cortex and leave the medulla, Wlieeler's object was to cauterize out the latter and leave the former. Tliis was scarcely ever precisely achieved, but a systematic histological study of tlie glands after death showed that entire destruction of the medulla of both glands gives negative results. The only fatal cases (at any rate among the animals which could reasonably be supposed to have died of adrenal insufficiency) were those in which very considerable damage had been done to the cortex as well as to the medulla. In some cases the abdominal chromaphil body was removed as well as the adrenal medulla. Of course in such experiments groups of sympathetic chromaphil cells, as well as scattered cortical " accessory " Ijodies, must have Ijeen left behind. But this fact does not seriously affect the logic of the argument that it is the cortex wliicli is essential to life. For, since removal of Ijoth adrenal bodies is fatal, and removal of the medulla is not, it follows that the cortex is the essential part of the gland so far as tlie maintenance of life is concerned. We have seen in a previous section that tlie cortex is tlie more important from a morphological standpoint. It seems, then, that the symptoms observed in animals after adrenal extirpation, complete or partial, are Ijy no means characteristic. The anatomical line which separates full physiological sufficiency from fatal insufficiency is very narrow. It has not been possible to produce experimentally any well characterized symptoms associated with partial adrenal insufficiency. 154 THE DUCTLESS GLANDS I. Changes found Post Mortem after Extirpation of the Adrenals Reference has already Ijeen made to pigmentary changes after double extirpation (;ee pp. 141, 142). Tizzoni reported severe lesions in the central and peripheral nervous system. He describes also extensive destruction of nerve fibres and ganglion cells, with marked congestion, alterations in the vessel walls, and haemorrhages and leucocytal infiltration in all parts of the nervous system. But his work in this respect should be cautiously considered, for it must be remembered that he records death after removal of one or both adrenals, and this is opposed to the experience of every subsequent investigator. Poll found in some cases among his rats after unilateral removal and transplantation, numerous reddish-black spots on the skin, but never on the mucous membranes. Hypersemia and hasmorrliages of the lungs have been observed after both the bilateral and the unilateral operation. Changes in other organs have only been noted by a few observers. Donetti states that he found changes in the nerve cells of the central nervous system of guinea-pigs and rabbits, especially in the medulla oblongata. The nuclei of the cells became vesicular, eccentric, and granular, and might disappear. He also noted changes in the nerve-cell body. Acute ulcer of the stomach has also been recorded. Moore and Purinton record cardiac thrombosis follomng complete removal of the adrenals. The presence, of ante- mortem clots in the lieart lias been observed on numerous occasions after adrenal extirpations in the laboratory' of tlie present \viiter. If the veins of botli adrenal bodies be tied, the animal will survive for a much longer period tlian after double extirpation. But the operation is always fatal. The delay in fatal issue is due to a collateral circulation through the Iddney. J. Compensatory Hypertrophy of the Adrenals Numerous authors have described a compensator}' hyper- trophy of one adrenal after the removal of the other. Thus, THE ADRENAL BODIES 155 Stilling found in rabbits, after extirpation of one adrenal, a considerable increase in weight of the one which was left behind. Pettit describes a similar hypertrophy in the cortical adrenal (" corpuscle of Stannius ") in the eel, after the removal of the glandule of the opposite side. But all observers could not record sucli hjrpertropliy. It is probable that there is a difference in this respect between different species. Harley among the older workers, and Poll among the more receiit, could not observe any such hypertrophy in rats. There can be no doubt whatever that such a com- pensatory hypertrophy may be regularly and easily observed in the dog. The compensatory hj^pertrophy . of accessory adrenals in the rat, which is described by Wiesel, has already been discussed. This may be related to the absence of hypertrophy on the part of the chief organ. A similar hypertrophy of the accessory adrenals Avhich are found along the walls of the vena cava of the guinea-pig has Ijeen descri):)ed bj' Velich. According to some observers, the chromaphil cells, whether of the adrenal medulla or of the extra-medullary corpuscles, seem to be incapable of hyperplasia. If tliis really be the case, it is interesting to compare the fact mth another to be referred to again later — viz., that in grafting experiments it is only the cortex which " takes " ; the medulla disappears. It is possible that this lack of power of growtli and of resistance to absorption is related to the higli degree of specialization of the chromaphil tissues (Vassale). That the functional capacity of one adrenal left after the removalof its fellow is not increased is the conclusion drawir after some experiments by Battelli and Oriistein. These authors removed one adrenal from dogs and rabbits, and let them live for from two to seventeen days. After this period the adrenin contents of the remaining gland were estimated by Battelli's colorimetric metliod in order to obtain a measure of the degree of vicarious function. No increase in the adi'enin of the remainmg gland, but rather a decrease, was found. These experiments, of course, have no bearing on the cortex of the organ, but only on the chromaphil medulla. Elliott and Tuckett could not readily produce compensatory hypertrophy. They found that the English guinea-pig cannot survive the removal in one operation of a single gland. By 156 THE DUCTLESiS GLANDS piecemeal extii'pation a gland was successfully removed ; the medulla of tlie gland left behind grew, and the cortex apparently not. But in a rabbit both cortex and medulla grew. This does not accord with the observations of Poll and Vassale. From some experiments carried out in mj^ laboratory, I am inclined to Ijelieve that in dogs, after a large part of the ad- renals have been extirpated, there is a notable compensatory hypertrophy of tjie abdominal chromaphil body. K. Transplantation of the Adrenals Although considerable attention has been devoted to the subject of transi^lantation of tlie thyroid, comjJaratively little has been done in tliis direction with the adrenal Ijodies. C'analis appears to be the earliest worker who attemjjted adrenal transplantation. He grafted small portions of the adrenal into the kidney, but they became necrotic and \^'ere absorbed. Only once, fifteen days after the operation, did he find in tlie kidney scar the capsule of the adrenal and some of the cells of the external layer of the cortex. Boinet transplanted adrenals intraperitoneally into rats. He observed atrophj? and absorption, which, however, was sometimes delayed. He noted red spots on the transplanted organs, which he called " hemorrhagies capsulaires." Gourfein reports that six days after the transplantation of frog's adrenal into tlie lymph sac of another frog the organ became decolorized, and attached by connective tissue to the muscles. After twenty days the decolorization and adhesions were more marked, and after forty days the gland was absorljed. When the adrenals of a guinea-pig were transplanted into tlie lymph sa.c of a frog there were adhesions, leucocj^tal infiltration of tlie gland, and inflammation of the surrounding tissue. In all these experiments the effect was no more than that of the administration of a certain amount of adrenal substance in the form of the gland itself. The effects, if any, ^^-ere purely chemical. Poll was the first to make a systematic macroscopic and microscoijic investigation of the transjilanted gland. Tliis author employed rats for his experiments. He removed the left adrenal body from behind, and in one series of experiments transplanted it into the dorsal muscles, in another series THE ADRENAL BODIES 157 beneath the .sldn of the back. In addition to some changes in the elements of the capsule, Poll records that the cells of the zona glomcnilosa and the outer part of the zona fasciculata became changed into large potyhedral, at times pigmented, structures, which degenerated with the formation of fat droplets and pigment granules. The cells of tlie inner part of the zona fasciculata, the zona reticularis, and the medulla degenerate within the first week, forming a necrotic focus in the centre of the adrenal. This is alisorbed in the course of the second ^^'eek, and in connection with the process of absorption giant cells arise from the altered cells of the outer part of the gland. These finally disappear. Into the centre of the adrenal, at the place where the suprarenal vein leaves the gland, a band of connective tissue grows and develops, and remauis per- manently. In the course of the third week heaps of cells occur in the capsule, which resemble cortical cells, but possess only small compact cell bodies. These heaps fuse together, and grow into large inasses having the form of a segment of a sphere. In these masses the small cells show signs of an arrangement like that of the zona fasciculata. In the interior, progressing outwards, begins a transformation of these cells into clear, finely reticular elements in all respects like cortical cells. Intramuscular implantation gives about twice as manj^ successful results as subcutaneous. Favourable results were obtained only with young, small, and middle-aged animals. It seems, then, that in all cases where the adrenals are transjjlanted the medulla disappears. This fact is, jierhaps, not A^ithout significance as bearing ujjon the morphological relationshiiD existing l^etween the two constituents of the gland. The results of transjDlantation experiments are also of con- siderable importance in view of any future attempts to replace the adrenal function either in the human subject in Addison's disease or experimentally upon animals after extirpation of the organ. 1 ^ Numerous experiments u])on transplantation of different organs anrl tissues liave sho«Ti that as a general rrde the transplanted portions degenerate in a few months, even if they have made connection with smToimding tissues, and have imdergone some temporary growth. Among the exceptions are portions of skin, thyroids, adrenals, and the notable case of Ribbert, who succeeded in grafting the rudinient of the mammary gland of a. young guinea- pig upon the outside of the ear, The gland not only developed but ultimately secreted. 158 THE DUCTLESS GLANDS L. The Pharmacodynamics of Extracts of Adrenal Medulla (Chromaphil Tissues) and of Adrenin 1. The. General Physiological Effects of Chroma-phil Tissue Extracts and of Adrenin It has already been noted in connection with the account of extirpation experiments that a few observers have obtained beneficial results after removal of the gland from adminis- tration of adrenal su])stance either in the form of the gland itself (grafts) or as watery or saline extracts. In the present section we have to deal with the effects produced by the administration of the active principle to the normal animal. In the first instance we shall confine ourselves to the general effects (toxic) produced upon the animal as a whole, reserving the special eft'eots upon different systems — e.g., the haamodynamics — for a stdjsequent section. The earliest important investigations upon the effects of injecting adrenal extracts into animals are those of Foa and PeUacani. In their earlier exjjeriments these observers em- ployed aqueous solutions of fresh animal substances, includ- ing the adrenal body. They succeeded in causing death in a dog by injecting subcutaneously the adrenals of a calf in the form of neutral extract. Similar but more rapidly fatal effects were obtained in experimenting upon guinea-pigs and rabbits, but when injected intravenously they obtained like results from extracts of liver and kidney. So they concluded that the effect was not a specific one. In their later work, the Italian observers eliminating the injurious effects of fibrin ferment in their extracts, found that the toxic action was specific for the adrenals. They further determined that the toxicity is not due to the acids present, for if one separates these out the extracts remain active. Further, the toxic effects are not clue to a ptomaine which the authors found in the glands, for this is physio- logically inactive. They conclude that the active principle of the adrenals paralyses the spinal cord and the medulla oblongata, destroys completely all motion and sensation, and kills by paralysis of the respiratory centre. These authors prepared their extracts hy boiling, evaporating to di'yness, THE ADRENAL BODIES 159 extracting in the cold with alcohol, and redissolving in water. " After filtering and evaporating the aqueous solution, one obtains a residue coloured black, of a peculiar odour, of very acid reaction, and which, in a dose of 1 gramme, kills a healthy clog."' Thus it will be seen that the doses employed corre- sponded to very large cpiantities of the fresh gland substance. These experiments were adversely criticized by Alexander, who suggested, with considerable justice, that chemical changes might have taken place in the active principle during the complicated manipulations employed by the Italian observers. This or some such opinion has been shared by . numerous observers. Oliver and Schafcr injected subcutaneously comx:)aratively large doses of ac[ueous adrenal extracts into the dog, the guinea-pig, and the cat without obtaining any very obvious effects. But in the rabbit a large dose of adrenal extract ad- ministered subcutaneously invariably produced death. Among the symptoms noted was a very low temperature. In frogs the symptoms were those of paralysis due to the action of the poison upon the central nervous system. The animals re- covered from large doses in a comparatively short time. Gluzinsky, injecting intravenously, obtained paralysis of the posterior part of the body, and convulsions in the anterior part, with acceleration of the respiration and dilatation of the pupil. The animal succumbed amid progressive dyspnoea and general paralysis. Dubois attempts to account for the variations in the eft'ects obtained by classifying them under three heads : (1) Those depending upon the animal experimented upon , (2) those due to the animals from whose glands the extracts were made ; and (3) variations conditioned by the mode of obtaining the extracts. He found that fatigue previous to injection rendered the animal much more susceptible to the toxic action, that extracts obtained from the glands of wild animals were more powerful than those obtained from animals which had been kept in captivity, and that the medullary region was much richer in the active poison than the cortex. The present writer in 1897-98 performed a series of experi- ments upon rabbits, guinea-pigs, rats, mice, frogs, toads, as well as upon dogs and cats. The fresh-chopped glands were boiled with normal saline solution, and tlie extract filtered, 160 THE DUCTLE8S GLANDS or the fresh glands were pounded with water or normal salt solution and sand in a mortar, and the filtrate injected without boiling. Dried material was also sometimes employed for the preparation of the extracts. Sometimes cortex and medulla were carefully separated, and separately used for extracting and injecting, either by the fresh or the dry method. In addition to the above, glycerin and alcoholic extracts were employed. In most of the experiments the injection was made subcu- taneously beneath the skin of the back with a hypodermic needle. In some cases the extract was injected into the pleura or the peritoneum, and in a few cases into a vein. Niunerous control experiments were performed. Tlie adrenals employed in the making of tlie extracts were obtained mostly from the sheep, but some were taken from the ox, and occasionally those of smaller animals were used — e.g., clog, cat, rabbit, guinea-pig, etc. The conclusions reached as a resiilt of this series of experi- ments were as follows : In rabbits, guinea-pigs, rats, mice, frogs, and toads, after sufficiently large doses of adrenal extract injected subcutaneously, we get slowed muscular movements, paresis, and finally paralysis of tlie limbs (hind-limbs always becoming aft'ected first), bleeding from the mouth and nostrils, hfcmaturia (not observed in ra))bits), breathing rapid and shallow at first, finally becoming deep and infrequent, and occasionally convulsions resembling those of asphyxia pre- ceding death, before \\diich the temperature often falls very low. The paratysis is central. The effects are due to the medulla of the adrenals, the cortex containing no toxic sub- stance. Tlie effects are specific for the adrenal, and not common to other glandular exti'acts. The toxic material is easily eliminated in some waj^ or other. This accounts for the large dose required to produce a fatal result, and accounts also for the ease with -H'hich recovery takes place. Idiosyncrasy plays a large part in the conditions. A partial innnmiity can be set up l>y giving doses not sufficient to kill. This immunity passes off after a few weeks. In dogs the first eft'ect of a subcutaneous injection of an adrenal extract is excitement. There is increased muscular activity, '\\luch ])asses into a stage of agitation ^\•ith tremors, until ])aresis and finally ])aralysis come on. Thirst is also a THE ADRENAL BODIES 161 striking symptom in clogs. There is abundant mictmition, but no hsematuria. In cats by far the most noticeable result of the injection was an enormously increased rapiditj' of the respiratory movements in the early stage. Thirst and loss of ajipetite were recorded, but the paratysis was not so definite as in other animals. In the cat doses sufficient to kill do not raise the blood-pressure within half an hoiu' of injection beneath the skin. The remote effects noted by Foa and Pellacani, as well as by Oliver and Schiifer, were not noticed in this series of experi- ments. If the dose were sufficiently large to produce any effects at all, thei'e were some changes in reaction and disposi- tion within a few minutes. After it had been show n by experimental evidence (Vincent) that the ' ' paired suprarenal bodies " ( ' ' medullary " " or " chroma- phil bodies ") and the inter-renal gland of Elasmobranch fishes correspond respectively to the medulla and the cortex of the adrenal body of the higher vertebrata, and that the " cor- puscles of Stannius " of Teleostei consist solely of " cortical " substance, it appeared to be a matter of some interest to test the effects of the two kinds of tissue in Elasmobranchs and of the cortical bodies of Teleosts when extracts of them are injected subcutaneously into small animals. Naturally, only very small quantities of material could be obtained for this purpose, but the effects upon mice were quite definite. The " corpuscles of Stannius '" obtained from six specimens of the codfish {Gadus viorrhua) were found to weigh in a moist state 0-4 gramme. These were extracted by boiling with a normal sahne solution. The filtered extract was then injected beneath the skin of the back of a mouse. No effects whatever super- vened. Next, the " paired suprarenals '" of Balfour (" chroma- phil bodies "') from seven specimens of Scyllium caniciila were found to weigh, when moist, 0'3 gramme. These were simi- larly extracted, and the filtrate administered to the same mouse (which had remained in perfect health) a few days later. The animal was immediately and powerfully affected. The breathing became very rapid, the limbs became weak, the temperature lowered, and death with convulsions ensued in less than five minutes. Extracts of the elasmobranch inter- renal gland produced no effects when injected in the same 11 162 THE DUCTLESS GLANDS manner. A further exiieriment with material obtained from Raja clavaia gave harmonious results. These experiments gave further positive evidence of the homology of the "paired bodies" of Elasmobranchs with the medulla of the mammalian adrenal, and, in conjunction with the morphological and histological evidence as to the homology of the "inter-renal" and the "corpuscles of Stan- nius " with the cortex of the mammalian adrenal (Vincent, Balfour, Diamare), show that the toxic effects of subcutan- eous administration of ach'enal extracts are obtained only with chromaphil substance, whether forming the medulla of the adrenal or the paired chromaphil bodies of Elasmobranch fishes. An important observation was made by Blum in 1901. After subcutaneous or intravenous injection of adrenal extracts, glycosuria occurs, even when the animals injected are being fed upon a diet free from carbohydrates, or after several clays' inanitioji, when it is to l^e supposed that all tlie glycogen must have disappeared from the liver. ^ The author considers that the function of the adrenal is to free the organism from the poisonous products of metabolism. More recently the purified active principle of the chromaphil tissues (under various names, perhaps most commonly "adrena- lin ") has been employed for subcutaneous and other modes of injection instead of the crude extracts. The results have not been very different from those obtained when extracts of adrenal medulla were used. The immunity first observed by the present writer, working with adrenal extracts, has been recently recorded by Ssawel- jew, who employed pure adrenin. Waterman has succeeded by injecting rabbits witli larger and larger doses of r-supra- renin in Ijringing the animals into a condition in which they cannot l)e rendered glycosuria b}' means of ^suprarenin. Since Blum's original communication numerous papers upon adrenal glycosuria have appeared, and the majority of workers have used, not extracts of the adrenal or of chroma- pliil substance, but the pure active substance (adrenin). Lazarus states that after prolonged administration of adrenin there is marked liypertrophy of the islets of Langerhans, of the pancreas, as well as of the adrenal bodies. Herter and ' More recent observers conclude that the glycosuria lasts until theglycogeu stoiv of the liver becomes exhausted. THE ADRENAL BODIES 163 Richards, and also Paton, confirmed Blum's observation that, as with phloridzin and pancreatic diabetes, glycosuria occurs even when stored carbohydrates have been previously eUmin- ated. Later observers have not held this view. As pointed out by Schafer, there seem to be connecting links between the glycosuria set up by pancreatic removal and that due to the action of adrenalin. Herter and Wakeman found that quite small amounts (1 c.c. of a 1 in 1,000 solution) of adrenalin applied to the pancreas provokes marked glycosuria. According to Mayer and Frouin, as already noted {vide supra, p. 146), neither the puncture diabetes nor pancreatic diabetes occur after extirpation of the adrenals. Zuelzer has gone so far as to assign definitely an adrenal origin to the pancreatic diabetes of Mehring and Minkowski. He found that extirpation of the pancreas carried out at the same time as ligature of the adrenal veins provokes little or no glycosuria. Injection of certain doses of adrenalin remains without effect if one injects at the same time a dose of pancreatic extract. In dogs, if the pancreas and the adrenals are simultaneously extirpated, there is no glycosuria. Zuelzer also made some experiments with an artificial circulation through the liver. He concludes that the adrenal secretion is normally neutrahzed by the pancreas, and that pancreatic diabetes is really a " negative pancreatic diabetes," while it may be regarded as a "positive adrenal diabetes," the real stimulus to the genesis of glycosuria being the adrenal secretion. Similar views are held by other writers. Others again con- nect the adrenin glycosuria with the functions of the thyroid and the action of the sympathetic nervous system (Eppinger, Falta, and Rudinger). Loewi reports that in diabetes arising after extirpation of the pancreas adrenalin pjroduces dilatation of the pupil if applied to the conjunctiva, whereas it has no influence on the normal eye. This observation was confirmed by Biedl, and it is stated that this reaction may be used as a diagnostic sign of pancreatic diabetes. In 1898 Biedl discovered a new form of experimental diabetes. This was induced by tying the thoracic duct or by leading it to the exterior and allowing the lymph to flow away. The author considers that the lymph which constantly flows into the circulation from the lymphatic duct contains a 164 THE DUCTLE8S GLANDS substance which influences directly or indirectly the supply of sugar in the organism. Biedl and Offer find that iii this form of diabetes also the pupil reacts to adrenahn drojjped on the conjunctiva. They further find that admixture with lymph or simultaneous injection of lymph from another animal prevents both the adrenin diabetes and the mydriatic reaction. In this relation Schtifer recalls the observation of Lepine that in pancreatic diabetes the injection of lymph from a normal animal produces marked temporary diminution of sugar in the urine. He suggests that the Ijanph normally contains a chemical (glycolytic ?) substance, derived from the islets of the pancreas, which substance is essential to the due maintenance of normal carbohydrate metabolism. This whole question has recently been complicated by Pfliiger's announcement of a " duodenal diabetes " [vide supra, p. 40). It seems possible that the final solution of the problem may be arrived at by an accurate knowledge of the interaction between the adrenals and the pancreas through the mediation of the sympathetic nervous system. Meltzer found that subcutaneous injections of adrenalin, which normally are without effect on the pupil, produce marked dilation after removal of the superior cervical ganglion. Underbill and Closson could not find any change in the nitrogen of the urine in adrenin glycosuria, such as was recorded by Paton. It is stated that heat polypnoea hinders the onset of adrenin glycosuria, while warmth alone does not. This result appears to depend on the destruction of the adrenin by the increased chemical processes of the body, due to the polypnoea. Drummond reports that after administration of adrenalin there occur congestion of organs and histological changes, indicating that the substance acts as a protoplasmic poisons Oliver and Schiifer suggested that the material obtained from the adrenal meduUa, which produces death, is of a different nature from that which has such a powerful effect upon the blood-pressure. The paralysis is due to the action of the poison upon the central nervous system. The present writer came to the conclusion that the adrenal body contains an active principle which acts both centrally and peripherally. The central action is produced most probably upon the motor centres of the brain, while the peripheral action is shown l^y THE ADRENAL BODIES 165 the effect upon blood -pressure when the extract is injected intravenously. The question natiu'ally arises whether both these effects are due to one substance or whether there are two active materials present in adrenal extracts. It seems to be generally admitted at the present time that the toxic effects, like those on the blood-pressin-e, are due to the action of adrenin. If this be the case, it would seem that this substance has a central as well as a peripheral action. Elliott discusses the effects of subcutaneous injections of adrenin, and classifies the possible causes of the symptoms under three heads : (1) The strain thrown upon the circulatory system by the great rise of blood-pressure ; (2) a poisoning of tissues by c^uantities of adrenin exceeding that sufficient for physiological stimulation ; (3) the poisonous action of possible decomposition products of adrenin within the body. The author considers that the chief cause is No. 2 — i.e., that the excess of adrenin itself is toxic. He points out that a poisonous action of adrenin on bioplasm is suggested by its chemical con- stitution, which displays the — NH.CHo grouping that resists chemical alteration in the body with great stubbornness. Ssaweljew, as we have seen, confirmed the observation of the present writer that some immunity can be established by administering doses of adrenin not sufficient to cause death. But he reports further that he could obtain an immune serum which was capable of conferring passive immunity upon a second animal. Stradiotti, employing the " paragang- lina Vassale," produced in dogs a serum which could precipi- tate the " paraganglina " and neutralize its power of vaso- constriction. Elliott and Durham point out that these results are not in accordance with expectation, for as yet no instance has been discovered of the production of an antibody to a substance of such chemical character as that of adrenin. In their experiments no trace of an anti-adrenin could be found. 2. The Special Physiological Effects of Chro-maphil Tissue Extracts and of Adrenin 1. The Effects upon the Heart and Arteries. — A new stage in the history of our subject was reached in the year 1894 by the discovery of Oliver and Schafer that extract of the medulla of the adrenal bodies produces a very remarkable 166 THE DUCTLESS GLANDS rise of the blood-pressure on injection into the circulation of a living animal. These observers employed glands mainly from the calf, but also from the sheep, the guinea-pig, the cat, the dog, and man. The physiological effects noticed were identical in all, the only difference being in the case of diseased adrenals in man (Addison's disease), in which case, if the disease were extensive, no eiiect whatever was obtained. Extracts of the glands were prepared with water, with alcohol of various strengths, with glycerin, with ether, nigroin, and various other solvents. They were made either by digesting an ascertained weight of the fresh gland or of the dried gland in these men- strua, or in addition by boiling the infusion for a few minutes. The animals experimented upon were chiefly dogs, but some experiments were also made upon cats, rabbits, and guinea- pigs, and one ujjon a monkey. The extracts were usually administered by intravenous injection, and the effects upon the arterial system determined by the mercurial kymograph, various kinds of plethysmographs, and perfusion through the arterial system of the frog, after the nervous system had been destroyed . The chief and fundamental effect noticed was contraction of the arterioles. This contraction is so great as to produce (even when concomitant vagus action has caused a great diminution in the rate and force of the heart's beats) a large rise of hlood-jyressure, and, in the case of the frog with its nervous system destroyed, almost complete cessation of the flow of circulating fluid through the arterioles. The usual effect of the injection is to produce constriction of isolated organs. The limb shrinks (Fig. 39), the kidney and si^leen contract considerably, while the heart and larger bloodvessels are enormously distended. But sometimes a limb expands, and in some experiments one limb contracts while another expands. In the later stages of experimentation the passive dilatation is more usual. Hoskins, Gunning, and Berry have recently reported that adrenin causes active vasodilation of the muscles, while it gives rise to constriction in the cutaneous vessels. Removing the skin from a limb converts the usual contraction into an expansion. The rise of blood-pressure is ver}^ largely due to constriction of the splanclmic arterioles. But sometimes the intestine expands THE ADRENAL BODIES 167 168 THE DUCTLESS GLANDS (see Pig. 42). In some cases Oliver and Schafer noticed in organs enclosed by a plethysmograph an apparent struggle between the diminution in size resulting from contraction of tlie arterioles and tlie expansion due to swelling of the larger bloodvessels, and some of their curves show a passive dilation at the beginning of the effect of an injection, followed by a prolonged diminution in size due to a more marked contraction of smaller arteries having supervened. The medium-sized arteries also participate in the dilation. The contraction of the arterioles occurs in a frog with its nervous system destroyed, as stated above. It also occurs after section of the spinal cord and after section of the nerves going to the limb. Therefore the contraction must be due to the direct action of the active principle of the adrenal medulla upon the muscular tissue of the bloodvessels. This question as to the precise tissues upon which adrenin acts will be referred to again later on. The rise of blood-pressure occurs after a certain interval of latency (twenty seconds in the dog) occupied by the passage of the extract from the vein into the arteries. The rise takes place, whether the vagi be cut or not, and whether atropin has been injected or not. But it is much greater after section of the vagi or after injection of atropin, because of the concomi- tant effect of the injection upon the cardiac inhibitory centre in the medulla (see Fig. 41). The rise is rapid, but only lasts a few minutes. During the rise the Traube-Hering curves are abolished, and in the cat and the rabbit the effect of stimula- tion of the depressor nerve is in abeyance. Sometimes a rise followed by a fall is obtained, and sometimes a pure fall. These effects will be referred to again later. But the rise of blood-pressure is due not only to constriction of arterioles, but also to increased rate and energy of the heartbeat. Another striking phenomenon noticed by Oliver and Schafer was cardiac inhibition through the vagi. Sometimes in the earlier stages of the action of the extract, the heart, instead of Ijeing augmented and accelerated, is strongly inhibited. When the vagi are cut or atropin administered, this effect is abolished, and tlie constriction of the arterioles, combined with the aug- mentation of the heart, produces an enormous rise of the blood- pressure. The cardiac inhibition is of central origin, but the augmentation is due to the direct action on the heart. Some- THE ADRENAL BODIES 169 170 THE DUCTLESS GLANDS times tlie inhibitory eSect is shown only after a few minutes. The effects obtained with the isolated frog ventricle were less striking than those in mammals. Finally, it was iJroved by these authors that extracts of the cortex of the gland are quite inactive, the active principle being confined strictly to the medulla. Their general conclusion was that the medulla of the adrenal secretes a material whose action is to increase the tone of all muscular tissue, and espec- ially that of the heart and arteries. ijf*^^ Fig. 41. — Tracing .i^howing the effect of adrenalin after previous adminLstra- tion of a dose of atropin. Dog, 1.5 kilogramines. Ether and inorphine- Lower curve is that of the carotid blood-pressure, upper one the volume of the left hind-limb. The work of Oliver and Schafer was confirmed in its main outlines bj^ Cybulski and Szymonowicz. The Polish physio- logists independently observed many of the same phenomena, and brought corroboration of many of the observations. But in some details and upon one important point they obtained different results ; they considered that the extract produces its vasoconstriction effects not peripherally, but centrally upon the medulla. This was, as has been proved by all stibsequent investigations, an erroneous conclusion. 171 il2 THE DUCTLESS GLANDS As we have already seen, the effects can be induced in an animal from which tlie central nervous sj'stem ha i been completely removed. So far as the hsemodynamic effects of adrenal extracts are concerned, the papers of OHver and Schafer gave an accurate account of all the fundamental facts, and there is little or nothing to add to their account up to the present time. It had been shown by Gourfein and by Cybulski that adrenal extract in sufficient dose paralyzes the vagus (see Figs. 39 and 43). This was confirmed by Langiey. The paralysis is brief. In the cat 5 to 10 c.c. of 1 per cent, extract of dried adrenal cause, as a rule, paralysis for from thirty seconds to one or two minutes. When a dose is given a little short of that required to make stimulation of tlie vagus ineiiective, the respiratory curves disajDpear, and there is a gradual fall of pressure. This result is probably due to weakening of the heart-beat ■ndthout much variation in rate. According to Oliver and Schafer, injection of extract in the dog after section of both vagi causes only quickening of the heart-beat. In the cat Langiey found that after section of the vagi adrenal extract sometimes causes quickening only, but that sometimes the rate is irregular, and in one case the heart stopped for three muiutes. The slowing, when it occurs, is, Langiey thinks, due to the increased work thrown upon the heart ; whether the action is entirely direct on the heart muscle or is partl}^ due to a post-ganglionic axon reflex, there is hardly sufficient evidence to show, but the slow beats caused by the extract are fewer or absent after injection of nicotine, although the rise of blood-pressure is commonly higher. As pointed out by Oliver and Schafer, the extract does not act equally on all the arteries ; its effect is perhaps greatest upon those of the splanchnic area, and its action in general runs parallel with the action of the sympathetic nerves on the bloodvessels. Thus, injection of adrenal extract causes great pallor of the uterus and but little of the Ijladder. It has a strong action on all skin arteries and on all medium-sized arteries in the body. In the abdominal viscera its effect is great on the main ])ranches of the cceliac and superior mesenteric arteries. The primary effect of adrenal extract on the vessels of the submaxillary gland is constriction. The gland becomes pale r" M fc^ 173 174 THE DUCTLESS GLANDS and remains so for thirty seconds. Then it becomes flushed, and the fl^^shing■ lasts longer than the secretion caused by the injection. The pallor is not so great as that produced by stimulating the cervical sympathetic, nor is the flushing so great as that produced by stimulating the chorda tympani. Both of these nerves have their usual action on the blood- flow, if stimulated while the secretion is going on. In the dog pallor of the bucco-facial region is produced by adrenal extract. This is the effect produced by weak stimula- tion of the cervical sympathetic (Langley). Brodie and Dixon were unable to obtain evidence of con- striction of the pulmonary vessels on injection of adrenalin, and thought this was because the pulmonary arterioles possess no vasomotor nerve-supply. (Adrenalin, they considered, acts on the nerve endings.) Plumier, using larger doses, succeeded in getting a positive result — that is to say, he recorded some constriction of the pulmonary vessels on injection of adrenalin ; but, according to Schafer, the action is far less than upon the sympathetically innervated vessels. It was stated by Spina that the injection of adrenal extract causes reddening of the brain, so that the peripheral vessels were not constricted, but Wiggers, using the isolated dog's brain and perfusion with Locke's fluid containing adrenahn, has been able to observe a diminution of the outflow of fluid, from which he concludes that the brain possesses vasomotor nerves, and that adrenalin acts on the ends of these. As for the coronary vessels, it is usually stated that adrenin does not constrict these. Schafer correlates this with the absence of vaso-constrictors from the cardiac accelerators, and concludes that, with both forms of excitation, quickening of the flow through the coronaries was brought about. It may be sup- posed, however, that heart muscle is dilated bj^ adrenin just as skeletal muscle is. EUiott suggests that in the beating heart such an action cannot be dissociated from a possible secondary dilatation by metabolites from the increased work of the heart muscle. He states that when perfusing a strip of the cat's ventricle by a single coronary artery he has seen almost instant increase of flow after addition of adrenalin to the Locke's solution used. This occmTcd Avith a stiip that did not beat, and therefore independently of muscular metabolites. Langen- dorff has recently immersed sti'ips of the vascidar wall attached THE ADRENAL BODIES 175 to a lever in adrenalin solution ; lie states that whereas strips from the arteries so tested contract when adrenalin is brought in contact with them, a strip from a coronary artery will become relaxed, and he infers from this that adrenin produces inhibi- tion and therefore vasodilation. Langendorff points out that from a teleological standpoint this is advantageous ; since the adrenin increases the force of the heart-beat, it must be favourable for this action that the calibre of the vessels in the heart-wall becomes increased. Schafer has, however, not succeeded in obtaining the result described by Langendorff, and suggests that possibly there might have been some other substance than adrenin in the solution used. According to some recent experimental investigations carried out by Bar- bour and Prince, adrenin actively dilates the coronary vessels in the dog, cat, rabbit, ox, sheep, and pig, but constricts them in man and the monkey. Moore and Purinton recorded -a fall of blood-pressure instead of a rise when very small doses of adrenal extract are adminis- tered. Other authors have from time to time made reference to a depressor constituent of the adrenal. This is not to be wondered at when we remember that, as first noted by the present writer, extracts of tissues generally lower the blood- pressure ; but the presence of a depressor constituent will not explain the result obtained by Moore and Purinton, for there is no apparent reason why the depressor effect should not be swamped by the pressor with small, just as with larger, doses. Pari finds that with freshly prepared extracts there is never a lowering of the blood-pressure, but that with very dilute solutions, which have been kept for some time, this may sometimes be observed. He suggests, therefore, that the depression described by Moore and Purinton was due to chemi- cal changes in the adrenalin in the dilute solution. Pari supports the view of Hunt, that the depressor substance is choline. The matter has recently become of considerable theoretical importance as bearing upon current theories of the function of the chromaphil tissue (see p. 216). Sometimes one obtains, after a preliminary rise, a fall of blood-pressure, even with moderately large doses of adrenin. This occurs espe- cially in my experience with certain commercial preparations when the blood-pressure is high before the adrenin is admin- istered. The fall of blood-pressure with small doses is admitted 176 THE DUCTLES8 GLANDS by many workers as a regular phenomenon. It is found that the splanchnic arteries are constricted while the peripheral are dilated with very small doses. But with such doses the dilation of the peripheral vessels begins earlier and lasts longer than the constriction of the splanchnic. The result is that the splanchnic rise is masked by the peripheral fall (Hartman). It has been mentioned above that the "paired suprarenal bodies '" of Elasmobranch fishes yield an extract which pro- duces the same physiological effects as adrenal medulla. In 1898 Langlois showed that the adrenals of the frog (which contain masses of chromaphil cells) contain an analogous sub- stance and are functionally homologous with the glands of higher vertebrates. Biedl and Wiesel proved that the ' ' Neben- organe " of Zuckerkandl contain the active substance. The jiresent writer has further shown that the " abdominal chroma- phil body " of the dog also contains tlic pressor substance, and I'tdk and Macleod that the retroj^eritoneal tissue of various animals contains substances having the same effect on intes- tinal and uterine muscle as adrenin. Mulon has raised the blood-pressure of an animal by injection into the circulation of an extract made from the carotid body of the horse (which body was shown by Stilling to contain chromaphil cells). It seems clear, therefore, that all chromaphil tissues, whether contained in the adrenal or not, yield adrenin, or a substance having similar chemical and pharmacodynamical properties. ^ How far this conclusion may be adduced, in conjunction with other oljservations, as evidence of an internal secretion on the part of all these tissues, is a matter for subsequent considera- tion (see p. 237). A pathological effect which has been noted by Josue as a result of repeated injections of adrenin into the auricular vein of the rabbit is a degenerated condition of the wall of the larger arteries, especially of the aorta (arterio-sclerosis). Atheroma, calcification, and even aneurisms are also described, and the changes have been recorded in the pulmonary and other arteries. It is said that these effects are not peculiar to adrenin, l)ut are jiroduced l\y other blood-pressure raising ' Of course, lliis conclusion ih based iijjon the provisional assumption that " chromaphil " tissues are specific in their natru-e, and are everywhere of the same essential character. It is not out of the question, hovfever, that there may be some cells which stain brown with bichromate, which are, nevertheless, of a different character. THE ADRENAL BODIES 177 substances, such as digitalin and nicotine. According to Elliott, " mechanical strain is doubtless the cause of the athero- matous lesions which develop after repeated intravenous injec- tions. These occur in the coronary arteries which are not contracted by adrenin, and must, therefore, be widely distended in the general rise of blood-pressure " (see p. 175). But Batty Shaw is of a different opinion. He states that if adrenin is injected with an amount of amyl nitrite which is just capable of neutralizing its pressor effects, arterial disease identical with that produced by adrenin alone is manifested — in other words, adrenin produces its effects not because of its pressor ten- dency, but from some other much more subtle influence. " We have no experimental grounds for Ijelieving that persist- ence of any stimulus should at length lead to degeneration instead of hypertrophy of the middle coat." Braun described the degenerative changes in the arteries in considerable detail, but Kaiserling does not attach much importance to the effects so far as the rabbit's aorta is con- cerned, because, he says, such changes sometimes occur in rabbits not treated with adrenin. Etienne and Parisot have come to the conclusion that elevation of the blood-pressure is not in itself sufficient to induce atheroma. This effect is of a toxic nature. Klotz has recently made the important observation that, by periodic suspension of rabbits for a few minutes daily by the hind-legs most advanced aortic lesions can be induced, while Biedl and Braun record typical degenerative changes in the aorta and its branches, as a result of repeated compressions of short duration. The experiments which have been per- formed up to the present time do not enable us to decide what is the precise actual cause of the arterial changes after repeated injections of adrenin. There seems no reason why both the principal causes alleged — viz., a toxic action and a mechanical strain — should not both have a share in the production of the result. 2. The Effects on other Structures, and the Mode and Seat of Action of Adrenin. — Oliver and Schafer investigated the effects of adrenal extracts on the resjnra.tion of the rabbit and the dog. Similar results were obtained in both, but the effect is most marked in the rabbit. It occurs soon after the adminis- tration of the drug, and may result in arrest of respiratory 13 178 THE DUCTLESS GLANDS movements for a short time. More commonly, however, there is produced a shallowing of the respirations, which persists for a certain period and then gradually passes off. In the dog no stoppage of respiration was ever obtained, but the respirations, although proceeding with an ordinary rhythm, were for a time slightly shallower. Other observers have also noted this effect of adrenal extracts upon the respiration. It is nearly always most marked with the first injection ; with repeated injections the effect as a rule soon becomes trivial, and always becomes so if the injections are repeated a sufficient number of times. The suljject has been recently investigated by Langlois andGarrelon. These authors seem to have obtained very considerable effects in the case of the dog ; thej' report that if adrenalin be injected into a dog, expiratory apncea sets in simultaneously with the beginning of the rise of blood-pressure. The duration of this apnoea is not constant. In most cases the respiratorjr movements begin again while the blood-pressure is still very high, and the respiration has most frequently returned to its regular type before the blood- pressure has returned to normal. If the injections are repeated in rapid succession, the influence disappears. After section of the vagi, the adrenahn injection has a much less marked action on the respiration. There is then a slowing of the movements, but no apnoea. Air rich in oxygen favours the occurrence of this apnoea, while an atmosphere with a large proportion of carbon dioxide hinders it. Oliver and Schiifer discovered that adrenal extracts proloiuj the curve of contraction of the skeletal muscles, both in the frog and in the dog, though the period of latency is not increased. They were convinced that the curve is not a fatigue curve, but that it is comparable rather to the effect of a slight dose of veratrine. This eft'ect has since been noted by many observers. Boruttau says that the phenomenon occurs in excised curarized muscle, and reminds one of the first stage of fatigue. Panella describes an anticuraric action of adrenin (" hemostasine ") and states that it (" myosthenin," on this occasion) increases the activity of fatigued striated muscles. Cannon finds that the improvement of muscular contraction which apparently results from adrenal secretion (when the blood-pressure is controlled) is too slight to account for the increased muscular power observed during excitement. The main source of power THE ADRENAL BODIES 179 under these conditions is probably to be found in an immensely augmented activity of the nervous system. Fatigued muscles maj' however be prepared by secretion of adrenin for better responses to the demands of powerful nervous discharges. Adrenin improves muscular contraction by its specific effect on the muscle in eliminating fatigue and by improving the circulation through the muscle by means of its vaso-diiator action. Notwithstanding all this, it is difficult to demonstrate that there is in reality any beneficial effect of adrenin on voluntary muscular contraction. Lewandowsky found that intravenous injection of adrenal extracts produces dilatation of the i^iipil, withdrawal of the nictitating membrane, protrusion of the eyeball, and sUght opening of the eyelids. The last two symptoms are usually less marked than the action on the pupil and the nictitating membrane. The effects produced on the smooth muscle of the eye and the orbit are, in fact, the same as are called forth by stimulation of the cervical sympathetic. There is a short latent period, and the effects usually last some minutes, the period of duration being prolonged by cooling the animal. The action is peripheral, although local application to the eye is without effect. The experiments were performed upon cats. The same observer also recorded excitation of the arrectores pili and inhibition of the bladder. Boruttau confirmed the observation as to the occurrence of dilatation of the pupil on intravenous injection of adrenal extract, and observed that in the cat subcutaneous injection produces no effect upon either the blood-pressure or the pupil. This writer further recorded that the injection causes inhibition of intestinal movements . Lewandowsky pointed out that the extract is still effective after the superior cervical ganglion has been excised, and the nerve fibres proceeding from it allowed to degenerate. He concluded from this that the extract must stimulate the muscle substance directly, and not by means of the nerve endings. Langley confirmed this observation of Lewandowsky, and agrees that the various eye effects are produced by a direct action of adrenal extract on the unstriated muscle. This author also found that the extract excites the salivary and lachrymal glands, the liver, the muscular tissue of the uterus and vagina, of the vas deferens, the vesiculce seminales, the dartos, and 180 THE DUCTLESS GLANDS the muscidar coat of the stomach. In the stomach inhibition of the muscular movements is produced . The effects on the movements of the intestine appear to differ according to the strength of the adrenin solution jtist as do the effects on the uterus and the pupil, and, as we have seen above, the effects on the blood- pressure. According to Langiey, the effects produced by adrenal extract in the cat and rabbit may be arranged roughly in the following order as regards the amount of extract required per body weight to produce an obvious effect : Pkise of blood-pressiu'e. Inhibition of the sphincter of the stomach and of the intestine (rabbit). Inhibition of the bladder. Dilation of the pupil (cat). Withdrawal of the nictitating membrane (cat) ] Slightly less readily than the Separation of the eyelids (cat) J foregoing. Contraction of the uterus, vas deferens, seminal vesicles, etc. (rabbit). Salivary and lachrymal secretion. Inhibition of the stomach. Inhibition of the gall-bladder and increased bile secretion. Dilation of pupil (rabbit). Inhibition of internal anal sphincter (rabbit). Contraction of internal anal sphincter (oat) 1 Tnnp i ■ i r i Contraction of internal generative organs (cat) j ' ■ ■ y g ■ Contraction of the muscles of the hairs. Contraction of tuirica dartos of scrotum ) ..^ . . ™ , „ ,. . , yjNo certani ertect. Secretion or sweat J Langiey divides the autonomic nervous system into sympathetic, cranial, sacral, and enteric, and points out that the effect of adrenal extract in no case corresponds to that which is produced by stimulation of a cranial autonomic or of a sacral autonomic nerve. On the other hand, the ejfects produced are almost all such as are produced by stimulation by some one or other sympathetic nerve. Notwithstanding this, he is inclined provisionally in his paper written in 1901 to favour the view that adrenin acts directly on muscle fibres and gland cells, but leaves unanswered the question as to why the action in the several cases should correspond so closely with that caused by stimulation of the sympathetic nerves. Apocodeine abolishes the effects produced by sympathetic excitation, and was found by Dixon to abolish those produced by adrenin. He therefore concluded that adrenin acts upon THE ADRENAL BODIES 181 sympathetic nerve endings. It has been shown that in Mammalia, if the vagi have first been paralyzed with atropine, adrenal extract produces an augmented systole and acceleration of the heart. Both of these effects of adrenin may be abolished by the injection of large doses of apocodeine. Thus, Dixon found that in a cat + c.c. of a 1 in 30,000 solution of adrenin increased the heart-rate from 92 to 211 per minute. After the injection of 100 niilhgrammes of apocodeine the same injection of adrenin now only increased the rate from 93 to 101 per minute. A further injection of 200 milligrammes of apocodeine was then administered, and caused the rate of the heart to diminish to 87 per minute. Adrenin now, even in large doses, produced no acceleration, and there was no augmen- tation of the systole. Dixon therefore concludes that the whole effect of adrenal extract on the heart is a stimulation of the sympathetic nerve endings. Similarly, the vasomotor nerve endings are paralyzed by apocodeine, and after the administration of this drug no vasoconstriction can be induced by means of adrenin. The addition of adrenin to any of the ordinary perfusion fluids enables the heart to maintain its activity over much longer periods of time. The time may be quadrupled by such addition (Burridge). This view, that adrenin acts on nerve endings, is supported by the observations of Macfie, who found that extracts of the adrenal and other tissues are without effect upon the embryonic heart, upon leucocytes, and upon cilia. Again, the work of Brodie and Dixon, who find that there are no vasomotor nerves for the pulmonary arterioles, and that adrenin, when ])erfused through the puhnonary vessels, produces no constriction, is decidedly in favour of the theory that the substance acts upon nerve tissue only. On the other hand, Boruttau considers that the action is direct on somatic muscle, since it occurs in curarized muscle,^ and, according to Lewandowsky, the dilation of the pupil and other eye effects are produced by a direct action of adrenal extract on the constricted muscle. This was inferred from the fact, referred to above (p. 179), that the extract is still effective ^ It does not follow, of course, that, because a curarized muscle cannot be excited through its nerve, therefore the whole of the nerve endings are paralyzed. 182 THE DUCTLESS GLANDS after the superior cervical ganglion has been excised and the nerve fibres from it have degenerated. With regard to somatic muscle, Langley is inclined to accept Lewandowsky's view, while in the matter of plain mnscle he is content (in the paper of 1901-02) with the generalization that the effect of adrenin is the same as the effect of exciting the sympathetic nerves supplying the particular tissue. In studies on the action of adrenin on the bloodvessels of the rabbit's ear Meltzer and Auer showed that section of the S3anpathetic has a marked effect on the results of intravenous injection of the drug. While on the normal side the constric- tion of the vessels reaches its maximum in a few seconds, on the side of the section it lasts a very long time, and is very pronounced. Following up the discovery of Lewandowsky (confirmed by Boruttau and Langley), that intravenous injection of adrenin induces a temporary dilation of the pupil, Meltzer and Auer found that, though subcutaneous injection and conjunctival instillation produce no effect in the normal animal or after section of the cervical sympathetic, yet such administration produces very striking dilation of the pupil after removal of the superior cervical ganghon — that is to say, ' ' the paradoxical effect ' ' is marked in the case of adrenal extract .1 These observations were confirmed and extended by Elliott, who generalized as follows : "This, then, is true for all the muscles thrown into contraction by adrenalin, that after decentrahzation — i.e., degenerative section of the preganghonic sympathetic nerves — and still more clearljf after denervation (degenerative section of the post-ganglionic sympathetic nerves), they contract in the presence of adrenalin alike with greater irritability and persistence." Elliott concluded as to the localization of the action of adrenin that the excitation must be due to some substance within the mu.scle fibres being affected by the drug, and suggested that this substance is present at the " myoneural junction," where it is originally formed. 1 Meltzer and Auer point out an important difference between mammals (rabbits and eats) and the frog. In the latter animal in a normal state, subcutaneous injection or instillation into the conjmictival aac produces in a few minutes a characteristic dilation of the pupil, which may last for hours, so that the frog has become a convenient means of testing adrenal extracts. THE ADRENAL BODIES 183 Schafer adds a further suggestion — viz., that the formation of this substance, being once started, its amount is also con- trolled by the sjanpathetic, and if this control be cut off an inordinate quantity may accumulate, thus increasing the excitability of the isolated muscle fibres. Ihe observations of Macfie (see above, p. 181) prove that the presence of nerve fibres is essential to the original appearance of such hypothetical excitable substance. These different views do not accord very well togetlier, but the fact that adrenin has functionally a very intimate relation to the sympathetic nervous system is particularly interesting when we remember the accepted origin of the chromaphi) tissues. According to recent observations by Langley, in all cells two constituents at least must be distinguished : (1) Sub- stances concerned with carrying out the chief functions of the cells, such as contraction, secretion, the formation of special metabolic products ; and (2) receptive substances, especially liable to change, and capable of setting the chief substance in action. According to this author, the active substance of the adrenals produces its effects bj- combining with the receptive substance, and not on nerve endings nor the chief substance. So that in this view the controversy as to whether adrenin acts on muscle itself or on sympathetic nerve endings is com- promised by assuming that there is some material in cells originally under control of the sympathetic, which material is specially excited by adrenin. This theory of Langley has not, however, been universally accepted. There is some evidence which tends to show that after all adrenin acts directly upon the smooth muscle. Among the other effects of adrenin which have been noted are increase of intra-ocular pressure after intravenous injection, and changes in the striictvu'e and function of the kidnej'S. Bardier and Frankel record a diminution of secretion of urine owing to constriction of renal vessels after the administration of adrenin. Subsequently and more significantly the conditions are reversed. Adrenin mydriasis has been em])loyed as a diagnostic sign of increased diffusibility of the cornea. Adrenin appears to increase the activity of ansesthetics applied locally to a nerve. It is said that adrenin gives rise to increased flow from the thoracic duct as long as the blood-pressure is high. 184 THE DUCTLESS GLANDS It has been stated recently that rlwthmic contractions of arteries occur normally in the rabbit's ear and that adrenin augments these contractions. There seems to be con.siderable difference of opinion as to the effect of adrenin on the secretion of sweat. Redfield suggests that the melanophores of the amphibia are controlled by adrenin in the circulation. Cats aj)pear to be peculiarly liable to collapse after intra- venous injection of adrenin under light chloroform anfesthesia. Full chloroform auEesthcsia appears to be absolutely protective. There is probably some unknown condition of the heart under the influence of low percentages of chloroform, which renders it incapable of accommodation to vascular strain. In the experience of the present writer, also, it has very frequently happened that dogs have been killed by a dose of adrenin (administered intravenously) which it was expected would only be sufficient to produce a moderate rise of blood- pressure. This has occurred with both adrenal extracts and the purified adrenin, and it is not clear that it is dependent on the nature or amount of the anjesthetic employed. The phenomenon seems to depend upon a peculiar idiosyncrasy in some animals, and is comparable to what was found in respect of the general effects produced in various animals by sub- cutaneous injections (see p. 159). A large amount of work has been carried out upon the antagonism between adrenin and various other drugs. In many respects there appears to he a true antagonistic action between adrenin and calcium chloride, although the latter substance does not liinder the production of adrenin arterio- sclerosis. Adrenin is also stated to act as an antidote to ])oisoning by sti-ychnine, aconitinc, and belladonna. A pharmacological antagonism is alleged between adrenin and secretin, while adrenin exercises no action which can be regarded as antagonistic to that of albumoses and of jiilocarpine u])on the jjancreatic and salivary secretions. It is stated that the chlorides of calcium, barium, magnesium, and potas- sium can neutralize the mydriatic action of adrenin. The table on pp. 187-191, taken from Biedl, gives a summarj^ of the chief actions of adrenin and a comparison between these actions and those produced by stimulation of nerves belonging to the sympathetic and autonomic systems. THE ADRENAL BODIES 185 Notwithstanding the almost universal acceptance of the view that the action of adrenin is identical and co-terminous with that of sympathetic nervous action, it is well to bear in mind that the evidence is in some directions contradictory and in others rather meagre. As will be seen from the table it is by no means easy to formulate an absolute parallelism in every instance, and the difficulty becomes still greater if we take into consideration the different effects of varying doses of adrenin. The parallel problem as to the effects of varying degrees of stimulation ujDon the sympathetic fibres does not seem to have been worked out. M. The Chemical Nature of the Active Substance of the Adrenal Medulla and other Chromaphil Tissues It is one of the greatest triumphs of physiological chemistry that within seven years of the discovery^ of the powerful effects of extracts of the adrenal medulla, the active principle was obtained in crystalline form, and that five years later its composition has been so completelj' ascertained that it has been synthesized, and the pure active synthetic product can now be obtained from the manufacturing chemists. In 1856 Vulpian described a powerfully reducing substance in the medulla of the adrenal body. This material was found to give various colour reactions on being oxidized — e.g., with ferric chloride it gave a dark green or blue colour, and with chlorine, bromine, or iodine water or caustic allsalies a rose red. Several authors attempted, but without success, to isolate the " chromogen " of the gland from a lead precipitate. They all obtained decomposition products. Krukenberg, however, established the important fact that the adrenal chromogen, in regard to certain proj)erties (iron reaction, reducing power, production of a dark coloration with oxidizing agents), corre- sfjonds with pyrocatechin. Immediately after the publication of the discoverj^ of the pressor action of adrenal extracts, Moore concluded that the active substance is identical with the chromogen described by Vulpian. Frankel, by treatment of adrenal extracts with alcohol, acetone, and ether, obtained a syrupy preparation of great physiological activity. This was the first claimant to the 18C THE DUCTLESS GLANDS title of the isolated active principle of the medulla of the adrenal body. It wsiS called" Sphygmogenin." ^ Frankel was also able to show that the chromogen furnishes a benzoyl product insoluble in water, and contains nitrogen in stable combination. This author was the first to express the opinion that the pressor substance is a nitrogenous derivative of orthodihydroxy-benzene. The statement that from it l^yro- catechin could be obtained simply by boiling with hydrochloric acid was easily refuted. V. Fiirth, on the other hand, showed that by dry distillation of the chromogen a compound is obtained which, as regards its reaction towards iron salts (emerald green coloration, which on the addition of alkali becomes carmine red) and its solubility (in ether, whether out of acid or alkaline solution), corresponds with pyrocatechin. With a view to the isolation of the extraordinarily unstable and easily oxidizable active substance, v. Fiirth extracted with alcohol at a low temperature ; then, after getting rid of inactive substances by means of neutral lead acetate, threw down a precipitate with ammoniacal lead hydroxide. By decomposing with sulphuric acid, concentrating the filtrate hi. vacuo and in a stream of carbonic acid gas, extraction of the residue with alcohol, and precipitation with ether, the chromogen was obtained in the form of a slightly pigmented preci2:>itate which was extremely active physiologically. Turning to accovmt an observation by Hofmeister that by reduction of the adrenal extract with zinc dust in acid solution one could counteract to a certain extent the instability of the chromogen, v. Fiirth made use of the following improved process : The adrenals were extracted with dilute zinc sulphate solution, the extracts freed from protein by heating, and treated with excess of ammonia, by which means the chromogen was thrown down as a zinc compound. This was washed, decom- posed in a mixture of alcohol and sulphuric acid, the acid filtrate decolorized )jy means of heating with zinc dust, neutralized with zinc oxide, filtered hot, freed from zinc salts by means of alcohol and ether, and finally concentrated. The process was also varied by using ammoniacal lead hydroxide instead of the zinc compomid. The amorphous jiyrocatechin- ' No chemical criteria of tlie purity of this substance were given. Frankel did not show that it possessed a constant percentage composition, and no attempt was made to establish even an empirical formida for it. THE ADRENAL BODIES 18? H H < Ph !>| w W B O o ■^ !S jh fl i. O X rt ft 05 O © -r( ^ a ■^ Cont Rapi Vari ~ S 03 ^ d =3 K aopc; ^ S ■ o o o o O O t ^ -p i-:i tH '— -*^ S-5 +J -rH r- PS S o QP Ph < < O B Q o O w O B O < O 1-1 w . Son to e >> o h c Q fe &H £ THE DUCTLESS GLANDS O cc --^ ■'-' > ^ > r. £^ 'I' ^ 5 1^ ^ ^ ^ -jj ^ H o _c ^o Qj g cc ct > o £ p ■^ 1!^ fl 1 <; P^ P^ cc t; 1 Pl fl '£ o ci o c £ '— ' T3 o ?^ r^ '■C Ej3 CS s a "3 cS ' o 3 '3 3 ^ d S a .o fl o '■+3 o 5 § S 1 3 ^1 -1^ ^ 'P H -^ o O ^ 6 T3 o o o 1=: « ctf ffl ;h Fh 2 ^ -fi o > f;:; c fl -C 4 ^;^ g o o o r^ rH rj fH iM O o H fl C C -2 O O Oj o .2 .2 _o g o o i i: 05 '^ o tH O o o o OJ o o CJ o * H C3 a; cti ci g§ :6 03 CO OS 52 c y, P s Ih fH (h 1^ ^ Cj fH fH fH ^ c; O +J +-< d ~t^ iiii^I p: fl Vj "S o p -rn J5 C r^ a p Cb o O o o o o o o o c/d' pc; PM O O O O 3 a^ O O O o o c^ a C c ° -5 c o o fl c % o .2 o o o _o fl o o o o 3 ■S rt o +^ +-> O """ o o o o o CJ o o 6£ o o cd g 1 O o El 03 la o CO fH s CO II c o o ^ d 5 o o o C > CO ^ ^ g 1^ ^ 2 ^ o -^ o ■*/,■ ^ +-■ 03 S -o id O u o o O, c 5 O •a 7? 's a; xternal genitals : Retractor penis Ano-genital mus e C p m 'a. ?:; o o -5 s s CO 15 s ft 3 CJ o CO s 3 S QJ 5 K* H -^ Si 3 O ;s ►2 Cr ^ THE ADRENAL BODIES 189 3 bJD 3 T, -T3 ■ -a c c3 o > H:i 6 s o o O ■« "S T) " i § ca 2 o ■3 ^J 60 ^ S c! 2 £ S 4i -c ^ c^ ;2 d o o 03 CD CD Oi :i ■a -fJ a Si CQ m CD c d CD o te -i ■w -c Qq ^ a: d H « '^ -Q CD t-i w <^> >^ x: w y_, n-i 190 THE DUCTLESS GLANDS .jQ J Q o PQ w m O !> P5 n ^ §^ O > ■5 &. CO a o J^ +3 ^ c o o o m (1 i o o & > IS ti c! •A CJ to -J S5 d o d C^i bfj o m 2 bl) C o o o s t3 bC ^, bO ? (S ce p. "^t THE ADRENAL BODIES 191 d 3 > > c CI o o ^"§ .2 .2 J fe ~ ■? « ^ >e 'I o o ^ ~ <2 c, © (5 o « .2 £; o c C 1; CM < ^ o m ^ 0, >i b£i-^ rC T3 O Ti T3 'Ti ■3 -^ -4-J CO 1 p:; p:; r ^ ^ O; o 'i. c3 ^ , o 'I' cd .S » .c.c., solid columns of cells ; hJd. v., bloodvessel. In man and different mammals, Kohn distinguishes three different arrangements of the epithelium cells which may be met with : (1) A compact cell mass ; (2) a retiform tissue; and (3) a lobular conformation. These different arrangements are not characteristic of any species or any age, but may be found side by side in the same glandule. In the cat the internal parathyroid lias a peripheral layer of cylindrical cells, and there appear to be other differences in structure between this body and the external parathyroid. Thus the cells are not so closely packed in the internal as in the external gland, and their outlines are more easily distin- guished. Further, the cell nuclei of the internal parathyroid do not stain so deeply as those of the external body. This 276 THE DUCTLESS GLANDS last differeiice, however, can only be detected in adult animals. In some species, as the rabbit, the internal parathyroid is intimately connected with a "central canal" (post-branchial body) and with tlie thja-oid itself. p. thyr ^ thyr. m Fig. 79. — Hummi. A drawing, as seen under a simple lens of a portion of the thyroid and a parathyroid which is considerably hypertrophied and otherwise modified. The specimen is pathological, but there is no record of the patient. The object of this figure is to show that the structure in question is in reality morphologically and topographically a parathyroid. p. thyr., parathyroid ; Unjr., thryoid. In close contact M'ith each of the parathyroids we may find a thymus nodule, and occasionally the central portion of this last is seen to be directly continuous with the tissue V, ••—• -vAl •■: V.-' ; , .sCi^/iOyfe Ij •. , , - ''.".vVV-!..; W.' \>;*; Fia. 80. — A portion of tlie thyroid and neighbouring parathyroid, \vith a fairly thick comiective-t issue partition ; low power. On the left we see the colloid vesicles of the thyroid ; on the right the parathyroid, which is oi[a typical parathyroid structure near the connective-tissue septum ; but which shows several undoubted colloid vesicles in the left-hand portion of the drawing. THE THYROID AND PARATHYROIDS 277 of the parathyroid. Again, parathyroids may be found either in the cortex or in the medulla of the thymus gland. When we bear in mind the development of these various organs (see below, pp. 277 and 279), such intimate anatomical connections and occasionally even apparent confusions are not astonishiiag. In some cases the parathyroids are found to contain colloid vesicles. Figs. SO and 81 illustrate this very clearly. The drawings represent what topographically is, or, to be more correct, was, parathyroid ; but many parts of the substance are studded with colloid vesicles. end. F. Development of the Thyroid The thyroid is the chief of the organs arising from, or in close topographical relation to, the gill-clefts. Other organs in the same group are the thymus, the parathyroids, the post-branchial bodies, and the branchial , ; -i*W bodies of the Anura. The origin of the thyroid is practically the same throughout vertebrates. It arises from the ventral waU of the pharynx in its an- terior region, as an unpaired outward pro- jection of epithelium. As stated above, in Amphioxus and Ammo- coetes, the opening into > the buccal alimentary tube remains patent, and the thyroid appears to be an organ of very ancient origin, which shows relationship to the hypobranchial furrow of Tunicates. In Petromyzon the organ detaches itself com- pletely from its place of origin, the opening becomes closed, and a number of closed vesicles are formed, Imed with cylindrical epithelium, and containing colloid. In all vertebrates above the Cyclostomata the unpaired rudiment of the thyroid arises as an evagination of the floor Fig. 81. — A small portion of the parathy- roid show^l in tlie last two figures. Section is from a part of the parathyroid. The drawing was made with a camera lucida ; high power. It is seen that the vesicles, although small, are typically thyroidal in character. end., endothelium ; c. ves., colloid vesicle. 278 THE DUCTLESS GLANDS of the i:>harynx between the bases of the first and second branchial arches. The structure then separates itself com- pletely from its original point of growth, and appears as a closed vesicle. In fishes the organ remains unpaired, but in Amphibia it divides into two portions whose position differs in different species. In the Sauropsida the origin of the thj^roid is very similar. The original vesicle becomes a compact organ, and in Lacerta becomes develojoed into a bilobed organ with a median isthmus. In the interior one can for a long time trace a lumen which is the remains of the aperture of the original vesicle. This is lined with cylindrical epithelium. Tlie colloid-containing vesicles do not, however, communicate with a canal. In birds the two lobes become quite separate. The origin of the thyroid in mammals has been, and still is, a matter of considerable controversy. There can be no doubt about the median rudiment, which arises in the same way as in other vertebrates — i.e., as an evagination of the floor of the pharynx between the first and second branchial arches. In the human embryo the evagination is a small pouch beginning to expand laterally in an embryo of 5 milli- metres in length ; in an embryo of 10 millimetres the lateral expansion has much increased, and there is a median duct, the opening of which upon the surface of the tongue corresponds to the foramen aecum ; the duct itself is known as the ductus thyreo-glossvs. The whole structure now consists of a bilateral epithelial vesicle connected by a slender hollow pedicle witli the surface of the tongue. The duct persists up to the eightli week, gradually elongatmg as the thyroid and the tongue separate. Tlie duct usually begins to be obliterated during the fifth week, but sometimes persists. After the fifth week the vesicular portion expands raj)idly. The development in other mammals does not call for a seiDarate descrijition. Many authors describe a lateral rudiment in addition to the median, and this is accepted as the true account by the authors of some textbooks, but this lateral rudiment appears to be that of the ])ost-branchial body (vide in/ra, p. 279). In most mammals the thyroid remains a single organ, consisting, as in man, of two lobes, with a connecting isthmus. THE THYROID AND PARATHYROIDS 279 In some, however, the right and left lobes are completely separate. The colloid does not begin to be formed in mammals till towards the end of foetal life, and sometimes even not till after birth. But before going further it will be necessary to give some accoimt of the post-branchial hcdics, which are present in all Gnathostomata except Heptanchus and Teleosts. In iSelachii the organ was first observed by v. Bemmelen, who called it the " suprapericardial body." He describes it as an evagination of the ventral wall of the pharynx behind the last gill-cleft. This becomes separate from the wall of the pharynx, and now consists of a vesicle lined with epithelium cells. It bears some resemblance to the original rudiment of the median thjToid, and soon consists of a mass of sef>arate vesicles. Whether these contain colloid is not known. In Amphibia, Reptilia, and Aves, the post-branchial body is formed as an evagination behind the last gill-cleft, some- times, however, only unilaterally. In these classes of animal the vesicles never contain colloid. Of peculiar interest are the researches of Maurer upon Echidna. In this animal, as in all vertebrates, the post- branchial body arises behind the fourth gill-cleft, and soon develops into a gland having a structure like that of the tliyroid, the important point being that colloid is contained in the vesicles. In Echidna these post-branchial bodies (colloid glands) never unite with the thyroid proper, which is a large gland, with two lobes and a connecting isthmus. In other mammals the post-branchial bodies may assume a structure identical witli that of the median thyroid. How much, if any, of the fully develoj^ed tliyroid is derived from the post-branchial bodies still remains an open question. G. Development of the Parathyroids and some other Branchial Cleft Organs The development of the thymus will be treated hereafter (p. 225), but it will be convenient in this place to deal with the development of the parathyroids and the thymus nodules found in connection with the thyroid. The particular gill-clefts with which we are at present specially concerned are the third and fourth. 280 THE DUCTLESS C4LANDS From the epithelium on the ventral aspect of the third cleft arises the main portion of the thymus. This may be called "thymus III." (see Fig. 82, p. 281). The ventral proliferation of the epithelium of the fourth cleft also gives rise to thymus tissue, but this is usually simply a small nodule in the substance of the thyroid, and is called "thymus IV." The dorsal aspects of the third and fourth clefts show thickenings of the epithelium which, however, do not develop into thymus tissue, but retain a typical " epithelial " struc- ture. These are the parathyroids named respectively " para- thyroid III." and " parath5Toid IV." In connection with the last is found a cavity lined with epithelium. This is the post-branchial Ijody. The thymus nodule sometimes fouiid in close relation to the external parathyroid ("parathyroid III.") is simply an isolated portion of the main thymus ("thymus III."). The accompanying diagrams (from Kohn) will help to make the matter clear (Figs. 82, A and B). Explanation op Fig. 82. {Diagrams A and B.) A. illustrates the development of the branchial organs of mammalB, B. shows their actual relations in the adult. The different related rudiments of the same branchiomere are represented by a similar direction of shading lines ; so also the corresponding organs. Thus the rudiments from the tlrird cleft are represented in A. by horizontal lines, as also the organs thus arising in B. The rudiments and organs from the fourth cleft are characterized by vertical lines. The post-branchial body is shown in thick outline, the thyroid by crossed lines. The different kinds of tissue arising from one and tlie same branchiomere are indicated by differences in the shading. The parathyroid tissue is shown by lines, the thymus tissue by alternate continuous and interrupted lines. The post-branchial body is represented in the developed condition as a liollo«- space with several glandular nodules (sliown in dark circles). A. shows the four internal gill sUts (I. to IV.), the epithelial origins of the parathyroids {p. thyr. III., p. tJiyr. IV.), the origin of the thj^mus (thy in. III., thym. IV. ),the rudiment of the thyroid(flro/i/s«'s agitans. But hyperfunction has also been alleged to occiir in this disease, and the majority of observers fail to find any connection between the parathyroid glandules and the disease in question. THE THYROID AND PARATHYROIDS 297 Endemic Tetany. — Endemic tetany, as it occurs in Europe, seems to be a disease of large cities, usually appearing in the spring ; it has a tendency to assume epidemic proportions, and it is very local in its distribution. In India there is an endemic tetany in rural districts. Attention has been specially called to this affection by McCarrison. The distribution of tetany in India is pecidiarly local, and appears to correspond more or less with the distribution of goitre. Sufferers from tetany appear to be able to rid them- selves of it by going to a localitj^ where it does not prevail. In India tetany is a disease of child-bearing women, and there is a marked family tendency to the disease. The children of women who s\iffer from tetany are frequently cretinous. Menstruation a^^pears to increase the frequency and the severity of the attacks of tetany, especially so when this function is in any way disordered. The seasonal prevalence of tetany — its practical limitation to the spring months — is very striking. " Chill," fright, and mental distress often provide the stimulus which produces the spasms. The patients are nearly all goitrous, and incomplete myxoedema may be present. McOarrison finds thymol very useful in treatment, and this affords proof of the now generally accepted opinion that the spasms of tetany are due to the action of toxic substances absorbed from the alimentary canal. Goitre is an important cause of tetany, because it reduces the efficiency of the thyroid gland. In various forms of tetany lesions of the parathyroids have been found, but in numy cases no such changes are discoverable. There is no definite syndrome which can be clearly associ- ated with increased function of the parathj'roids. J. Early Views as to the Functions of the Thyroid According to Handheld- Jones, Galen does not give any very distinct account of the thyroid, but seems to allude to it in his work " On the Use of the Parts of the Human Body." In speaking of the glands of the larynx, he says these " are always found more loose and spongy than others, and which, by the common consent of anatomists, have been created for the 298 THE DUCTLESS GLANDS purpose of moistening and bathing all the parts of the larynx and the passage of the throat." Morgagni also qnotes the following, which shows that Galen was informed of the absence of a duct : " Now, the neck has two glands in which a mois- ture is generated. But from the two glands which are in the neck there come forth no vessels by which the moisture may flow out, as those do from the glands of the tongue." Wharton, in 1656, gives a good account of the anatomj' of the thyroid and notes that "it is much more full of blood than any other gland, also more viscid and solid, and more resembling muscular flesh. This is the only difference, that it is not of a filjrous structure but rather of a glutinous nature." He allots four functions to tlie gland: "(1) The first and principal use of these glands appears to be to take up certain superfluous moistures from the recurrent nerve, and to bring them back again into the vascular system by their own lymph channels. (2) To cherish the cartilages to which they are fixed, which are rather of a chilly nature, by their own heat ; for they are copiously supplied with arteries, and abound with blood, from whence they may conveniently impart heat to the neighbouring parts. (3) To conduce by their exhalations to the lubrication of the larynx and so to render the voice smoother, more melodious, and sweeter. (4) To contribute much to the rounded contour and beauty of the neck ; for they fill up the empty spaces about the larynx, and make its protulicrant ])arts almost to subside and become smooth, especial] J' in the female sex, to whom on this account a larger gland has been assigned, which renders their necks more even and beautiful." The tliird function, it will be noted, is only Galen's view more definitely formulated. This theory, in one form or another, long remained in vogue. Verheyen, in 172U, says : " This gland, bej^ond doubt, serves also to moisten the neighbouring parts ; but, because it is very large, there is an apparent reason why it should have rather large excretory ducts, or one at least very con- spicuous, which yet hitherto has not Ijcen discovered." Morgagni is undecided whether or no the gland has a duct. He describes vesicular cavities in enlarged thyroids, and these he correctly supposed to be the normal vesicles ('' natural cavities ") distended b}' the accumulation of their secretion. THE THYROID AND PARATHYROIDS 299 He is inclined tu think that tliere must he a duct opening into the pharynx or the trachea. Santorini fails to find a duct, but still thinks that the thyroid gland may be forced to expel its secretion by the contraction of the overhang muscles and other causes. Haller, in his textbook, written in 1776, after discussing the anatomy of the gland and detailing the fruitless attempts to discover an efferent duct, says : " Alii CI. viri, cum penitus de inveniendo ductu desperassent, ad aliam omnino utilitatem se converterunt. Liquorem peculiarcm in ea glandula parari, qui receptus venulis sanguini reddatur, qiue lienis ct thymi fit utilitas, ipse lUiyschius autumavit." Thus, in the year 1776, we have the thyroid, the thymus, and the spleen classed together as glands without ducts, which manufacture a special fluid, which is received into the veins, and so returned to the general circulation. This, so far as it goes, and, so far, at any rate, as it refers to the thyroid, is not far clrHerent from the modern concej^tion. Although from this time on the glandular nature of the thyroid was universally conceded, and there was much specula- tion as to the precise mode of secretion and the elimination of the product from the vesicles into the circulation, yet the active function of the secretion itself was for a long period not the subject of any serious incjuiry, and, indeed, the possibilitj' of its being of any great importance in the economy was scarcely suspected. Thus, C'ruveilhier, in 1834, states that the use of the secretion of the thyroid is unknown, and about this time Sir A. Carhsle supposed that the gland forms a protection to the delicate organs of the voice, against the variations of the external air. In 1844 Simon put forward a very interesting theory in regard to the function of the thyroid, all the more interesting as it has quite recently Ijeen revived. Simon considered that the thyroid exercises a regulatory function on the blood- sujiply to the brain, exerting also its secretory function in an alternating manner with the substance of the brain. " What diversion is to the stream of blood viewed quantitatively, alternative secretion would be to the composition of the blood viewed quaUtatively ; and I should conceive that the use of the thyroid gland, in its highest development, may depend on the joint exercise of these two analogous functions. 1 should 300 THE DUCTLESS GLANDS suspect not only that the thyroid receives, under certain circumstances, a large share of the blood which would otherwise have supplied the brain, but also that the secretion of the former organ bears some essential relation (which chemistry may hereafter elucidate) to the specific nutrition of the latter ; that the gland — whether or not it appropriates its elements in the same proximate combination as the brain does — may, at all events, affect in a precisely similar degree the chemical constitution of the blood traversing it, so that the respective contents of the thyroid and cerebral veins would present exactly similar alterations from the characters of aortic blood. Finally, I should suppose that tliese actions occur only or chiefly during the quiescence of the brain, and that when this organ resumes its activity, the thyroid may probably render up again from its vesicles to the blood, in a still applicable form, those materials whicli it had previously diverted from their destination." Writing a few years later (1849-1852), Handfield-Jones still thought it necessary to criticize adversely the various ancient tlieories whicli supposed the thyroid to l>ear some functional relationshi]) to the larynx. He says that there seems no doubt that the relative position of the thyroid to the larynx is cpiite unimportant, so far as the function of the organs is concerned. This is borne out by the variations of its site, wliich occur in birds, and by the results of morbid action, since prodigious goitre does not induce disease of the larjmx, except in a me- chanical way — i.e., by injurious pressure. Referring to Simon's theory, Handheld-Jones remarks, "It is the only one yet promulgated which can be said to be even probable." He does not, however, declare himself an adherent to tlie theory, of which, in fact, he offers several criticisms. K. Extirpation Experiments upon Mammals The earliest extirpation experiments ujDon animals ajtpear to Jiave been performed by llaynard. This observer reports that the treatment of goitre in dogs can be carried out just as in man. Complete removal of the thyroid was successfully carried out in dogs of medium age and in old dogs, but in young animals death occurred within a few days. The post-mortem examination did not reveal the cause of death. THE THYROID AND PARATHYROIDS 301 Astley Cooper gave some account of the structure of the thyroid and extirpated the gland from two pups ten weeks old. The animals recovered after suffering from stupidity and malaise. The animals were killed very soon after the opera- tion. Moritz Schiff, during the years 1856, 1857 and 1858, carried out a series of thyroidectomies upon various animals. Some rabbits, some rats, some fowls, and some dogs siu'vived the operation, but several clogs, a cat, and a rat died after some days. The earlier results of Schiff were apparently read before the Royal Academy of Science in Copenhagen and then buried in a work on the formation of sugar in the liver. It is not surprising that they remained unnoticed for many years. Cretinism had long been recognized, and in 1874 Gull described the condi- tion which Ord, in 1878, called " myxoedema." In 1882 the Swiss surgeons noted the symptoms of " cachexia strumi- priva," or "operative myxoedema," after operations for goitre in the human subject. After an interval of a quarter of a century Schiff was led by the observations of Kocher and Reverdin in Switzerland to take up the problem again. In 1884 he recalled his earlier experiments of 1856-1858, and published the results of a new series of investigations. In the rat and the rabbit, thyroid- ectomy was not followed by any serious result. In the dog and cat, however, complete removal was fatal. He gives an admirable account of the nervous symptoms after removal of the thyroid in the dog, and states that these may be avoided by a previous graft of the thyroid of one dog into the abdominal cavity of another. Other symptoms noted by Schiff were general malaise, arrest of growth, and in two cases cedema. It must be noted that some of these symptoms, particularly those of a nervous nature, are at the present time attributed to loss of parathyroid tissue which must have occurred when the thyroid was extirpated in clogs and cats. Wagner and others confirmed Schiff's observations, and it has been stated that the first-named author found an increased response in the nerves to galvanic currents after removal of the thyroid (and parathyroids) in cats. Horsley was the first to operate on monkeys. He states 302 THE DUCTLESS GLANDS that a week after the operation fibrillary twitchings of the muscles were noted, and that these ceased on voluntary move- ment. The animal then became "cretinoid." There was a " niyxoedematous " condition of the subcutaneous tissues. The tremors were relieved by keeping the animal warm. According to Horsley, there were swellings of the skin of the face and abdomen, due to the infiltration of the tissues by mucin. The salivary glands became enormously hypcrtro- phied and the parotid gland produced large quantities of mucin. We are not concerned in this place with the nervous symp- toms described by Horsley, but it may be observed in passing that so far as I am aware no subsequent observer has been able to obtain these " myxccdematous " synq^toms in moiikej's or in other animals. Horsley gives no detailed protocols of his experiments. Eemoval of the thyroid from different animals \\'as carried out by a number of observers during several succeeding years. The majority of these confirmed the general views of Schifi^ as to the effects of total extirpation of the thyroid. It must be remembered that at this period the possibility of a separate functional importance of the parathyroids was not suspected, so that -nhile in dogs, cats and monkeys thyroids and parathy- roids were always removed together, in the herljivora the two external parathyroids were left behind in what was called " total thyroidectomy." For, although the external para- thyroids were discovered by Sandstrom in 1880 and by Baber in 1882, it was not until Gley rediscovered them and demon- strated their functional importance in rabbits that experi- menters gave them due consideration. This was in 1S91. Following Horsley's work came a series of papers by numer- ous authors. These all supported the view of Schiff as to the effects of tota-1 extirjiations of the thyroid. But some ^^'ere inclined to deny the supreme importance of the thyroid in the animal economy and attributed the untoward sympton\s recorded by other workers to injvu'y to nerves, reflex action, and similar causes. Munk's observations are specially inter- esting in vie^^' of the results obtained by some more recent observers (vide ivj'ra). He came to the conclusion that the chronic disturbance of nutrition in thyroidless animals is nothing more than " gefangenschaftkacliexia " which may THE THYROID AND PARATHYROIDS 303 often be observed in nnoperated animals. He states that out of four monkeys operated on in England one was sent to him as " myxoedematous." The animal had nothing more than an ill-defined facial swelling, probably due to a carious tooth, and an intermittent paresis of a fore limb. The animal was, according to Munk, otherwise in good health and lived for ten months after the operation. Munk insisted that although removal of the thyroid is a dangerous operation, it does not follow that the thyroid is absolutely essential to life. And this statement must be admitted as justifiable, even if the survivals are due to thyroid or parathy- roid tissue which is so placed that it cannot be removed. It will be necessary to return to this point. The further account of Gley's work, as well as that of Vassale and Generali and Kohn, will be found in the section on the physiology of the parathyroids. The experiments of Vincent and Jolly maj^ be briefly recalled so far as they relate to the general question of extirpation of thyroids and parathyroids, and more particularly in regard to the effects alleged to be due to elimination of the function of the thyroid. On these points the general conclusions were : " Neither thyroid nor parathyroids can be considered as organs absolutely essential for life. Rats and guinea-pigs do not seem to suffer at all as the result of extirpation. Monkeys show only transient nervous symptoms. Dogs, cats, foxes and prairie wolves frequently suffer severely and die. On the other hand, badgers do not appear to be affected by the operation. " In no animals, not even in monkeys, have we been able to induce any swellings of the subcutaneous tissue, which is the most striking feature of myxoedema in the human subject. We think, therefore, that the pathology of myxojdema must be more complex than simple thyroid insufficiency." ^ Several previous observers from Schiff onwards had noted the fact that thyroidectomy in dog.s and cats is by no means always fatal. At the same time there has been a tendency to disregard the exceptions, and, when any explanations have been offered it has been suggested that they are due to parathy- roids having been overlooked at the operation, or to the exist- ence of accessory thyroids. Munk {vide siqira) indeed is among 1 On other points discussed in these papers the present writer has changed his opinion. This apphes to the change of parathyroid into thyroid. 304 THE DUCTLESS GLANDS the few observers who have laid due stress upon the cases of survival. This observer, as we have seen, admits that removal of the thyroid is dangerous, but not that the gland is an organ essential to life. We cannot assail the logic of the position that an organ which may frequently be removed with impunity is not " essential to life " and the results obtained by Vincent and Jolly forced them to extend the observation so as to include not only the thyroid but also the parathyroids. According to Noel Paton, a "contention that the removal of the parathyroids does not produce the train of symptoms terminating fatally, must in the light of the work of other investigators be explained as due to a failure to remove all the parathyroid tissue." Now, in the case of rabbits, Paton quotes Pepere to the effect that accessory parathyroids are nearly always found in the thjanus in rabbits. So that in rabbits parathyroidectomy is only fatal in the few animals which happen not to have any parathyroid tissue in the thymus. In the monkeys employed by Vincent and Jolly no symptoms of myxoedema were observed when thyroids and parathyroids were completely removed. These results differ from those obtained by Horsley {loc. cit.), Murraj? and Edmunds, who state that it is possible to induce myxoedema by operation . This m ay be compared with the results obtained by Munk {vide supra) and Kishi. Thelastnamedonly recorded one death out of six. Our animals were subject to catarrh, and one died of some laryngeal affection, and it seems probable that as in the case of other animals, removal of the thyroid gland leaves monkeys in a condition in which they are less capable of resisting disease. There is no reason to attribute death, when it occurred, to loss of thyroid or parathyroid. The animals were in good health, were active, and but for loss of weight showed no ill effects. Carlson and Woelf el report that myxoedema does not develop in thyroidectomized rabbits, at least in seven months, nor in the monkey in several months. In some groups of animals age seems to make a great differ- ence to the results both of thyroidectomy and of ' ' complete ' ' thyro- parathyroidectomy. Sutherland Simpson found that removal of the thyroid with the contained internal parathyroids in thirteen adult sheep and sixteen lambs from seven to eight months old, led to practically no ill effects (see Fig. 88). As a THE THYROID AND PARATHYROIDS 305 Fig. S8. — Photograjih of group of thyroidectomizcd sheep taken five months after operation (after Simpson — Quart. J. Exp. Physiol.). result of a similar operation, three lambs about two months old became "typical cretins." The complete operation (thyro-parathyroidectomy) in four young lambs (five to seven weeks old) resulted early in acute and fatal tetany. Removal of the two external parathyroids Fig. 89. — Photograph of cretin lamb about one year old, and of normal lamb of eleven months (after Simpson — Quart. J. Exp. Physiol.). 20 306 THE DUCTLESS GLANDS from the three cretins when about one year old was followed by only slight symptoms. According to Simpson, age is an important factor with regard to the effects of both thyroid- ectomy and parathyroidectomy. The "typical cretins" of Simpson are described as " small and stunted, with broad faces and rickety limbs. The wool was coarse, but did not tend to fall out. ' ' In some of the young animals (cats and dogs) oijerated on by Vincent and Jolly interference with growth was very striking, but the other " cretinoid " symptoms were absent. Basinger in 1916 carried out an extensive research on thyroidectomy in rabbits. Out of 140 animals operated upon "typical cretinism" was produced in 86. The experiments were carefully controlled as to feeding, and selection of subjects and normals from the same litters. The thyroidectomy was performed at the age of 2 to 3 weeks when the body weight was about 17.5 gms. Great care was taken to remove all thyroid tissue, leaving the external parathyroids intact, but it was subsequently found that in a considerable proportion of cases minute bits of the gland had been left behind and pre- vented the onset of cretinism. In different litters the propor- tion of successful results varied from 25 to 90 per cent. About two weeks after the operation the onset of cretinism was detectable. The hair became dryer than normal, did not lie smoothly and could easily be pulled out. Retardation of growth was noticeable as early as the third week ; it was greatest from the eighth to the twelfth weeks. By the end of the tenth week the average weight of the cretins was 750 gms., while that of the controls was 1400 gms. The posture of the cretins was typical. The bones were short and the muscles of the hmbs too weak to support the body weight. The bones showed a pseudo -rickety condition (Hofmeister's " chondrodystrophia thyreopriva "). The skin became in- creasingly dry and scaly and finally eczematous. The typical "pot belly " seen in human cretins developed. No evidence of the typical myxoedema such as is seen in human cases was observed. Neither chd chronic, progressive cachexia appear in any of the cretins, although they were kept for a year. Transfusion of normal blood serum into the cretins had no apparent effect on their condition. Some im]irovement, how- ever, resulted from transfusion of serum from thyroid-feel THE THYROID AND PARATHYROIDS 307 rabbits. Administration of desiccated thyroid gland suljstance markedly relieved the symptoms but failed to bring about a complete cure. The cretins proved more susceptil^lc than normal rabbits to the toxic action of thyroid feeding. It seems clear from the experiments of Sutherland Simpson and others that in young animals removal of the thyroid (one or more parathyroids being left behind) will bring about a condition reseml)ling cretinism in the human subject. In older animals symptoms may not be observed, but thickening and dryness of the integument with a tendency to loss of hair and wasting followed by adiposity have been described. It is stated that there is loss of muscular tone, and that regeneration of tissues is slower than normal. There may be an?emia. The Ijody temperature is low ; the power of heat regulation is diminished and the animal becomes poikilothermic ; the sexual functions are interfered with. It has lieen stated tliat the limit of assimilati(,)n of carljohydrates is raised. "The nervous S3'stem is markedly affected, dulness and apathy being prominent symptoms. Many nerve-cells, especially those of the cerebral cortex, exhibit a shrunken appearance, and present a strong contrast with those of the normal animal (Sehafer). A myxoedematous condition of the skin has been described by some authors, but the present writer has never seen this {vide supra). Thyroidectomy in the amphibia interferes with the normal metamorphosis, and retards or completely stops growth and ossification of bone. The operation does not appear to hinder the development of the gonads. Several observers have reported a diminution in the alexins and opsonins in the serum after removal of the thyroid. L. The Mechanism of the Thyroid Secretion It used to be asserted that the secretion of tlie thyroid gland passes, not directly into the blood-stream, but indirectly l)y means of the lymphatics. But more recent investigations have rendered this theory very doubtful. Asher and Flack utilized the observation of C'yon that the excitability of the depressor nerve is increased by the action of thyroid substance. They believe that the thyroid furnishes an internal secretion which increases the excitabihty of the 308 THE DUCTLESS GLANDS depressor nerve, and augments the effect of adrenin npon the blood-pressure. According to these authors the secretory nerves to the gland are the laryngeal nerves. More recent investigation seems to point to the synipathetic as the origin of the secretory fibres to the thyroid. Rahe, Rogers, Fawcett, and Beebe find tliat stimulation of vessels with the accompanying nerve filaments causes a diminution in the amount of iodin contained in the gland. These authors con- clude that the thyroid is at least in jiart under nervous control, and that its physiologically active substance is discharged into the circulation in response to a nerve stimulus. The view that the sympathetic fibres are true secretory nerves to the thyroid is supported by the observations of Cannon and Cattell upon the electrical response of the gland during activity. (See p. 33.) Control by the sympatJietio suggests that adrenin nuiy stimulate the thyroid to increased activity, and this was proved to be the case by intravenous injection of adrenin, and by stimulation of the adrenals through the sympathetic nerves. By continuous stimulation (fusion with the phrenic) of the cervical sympathetic a condition resembUng exophthalmic goitre was produced. It seems possible that the thyroid (like the adrenal) has an emergency function, which would increase the rate of metabolism and augment the efficiency of the adrenin secreted simultaneously. RogofE tried to detect in the blood coming from the thyroids of three dogs a physiologically active secretion, tested by feeding tadpoles -with the dried blood. The number of experiments recorded is not sufficient to warrant us in drawing any very definite conclusion. M. The Chemistry of the Thyroid ^The most striking feature of the thyroid gland from a cll^nical standpoint is the constant presence in it, under normal conditions, of measurable amounts of iodine. The folloAving elements have been stated to be present in the thyroid : carbon, hydrogen, oxygen, nitrogen, sulphur, phosphorus, sodium, potassium, calcixnn, magnesium, silicon, arsenic, fluorine, chlorine, bromine, and iodhie. It was in 18.54 that Macadam found iodine in food plants, but it was not until 1895 that Baumann discovered the presence of this THE THYROID AND PARATHYROIDS 300 element in the thyroid. It is now generally recognized that the vertebrate thyroid invariably contains iodine. The per- centage varies from 0-01 to 1'16 for dried glands. Other mammalian tissues do not contain more than about O'OOl per cent. There are now three reliable methods for the detection and estimation of iodine : those of Bourcet, Hunter, and Kendall. The two latter with 0'5 gramme of material will detect the presence of O'OOl per cent, of iodine with accuracy. Utilizing these methods, Cameron finds that iodine is an invariable constituent of all marine Algae (O'OOl to O'Tper cent, of di'ied tissue). Land plants contain much less. All marine animals contain iodine. In vertebrates this is found practically entirely in the thyroid. Small amounts of the other halogens are also found. The relative amount of thyroid tissue seems to increase as we ascend the scale of evolution. But the iodine content does not increase in a corresponding degree. It would appear that in cattle both thyroid tissue and iodine content are greater in the female than in the male. In regard to age, the maximum iodine content in the human subject is found between 40 and 60 years. The lowest figures are obtained from subjects irnder 15. According to Seidell and Fenger there is a seasonal variation in the iodine content of sheep, pig, and ox thyroids. Thus, the percentage between June and November is usually from two to three times as great as that between December and May. Diet appears to be insufficient to explain the seasonal variations. They are probably due to metabolic changes due to temperature. But the most important factor in the causation of variations in the iodine content of the thyroid is undoubtedly diet. The administration of iodine as iodides rapidly raises the iodine content of the thyroid. From the time of Baumann numerous observations have shown that the amount of iodine in the thyroid depends on the amount of this element in the normal diet. Thus the thyroids of the herbivora have more iodine than those of the carnivora. Sheep fed largely on seaweed show a large amount of iodine in the thyroid. In an ordinary human diet the thyroid iodine is obtained from fish, molluscs, milk, eggs, wine, etc. It is probable that the iodine of the thyroid is chiefly con- 310 THE DUCTLESS GLANDS tained in the colloid substance, though there is some evidence that the cells of the vesicles also contain a certain amount. In algae most of the iodine is in soluble organic (non-protein) combination, a trace only being present as iodide. Drechsel found an iodo-amino-acid in the skeleton of a coral, which was later identified as di-iodo-tyrosin. Diljrom-tyrosin is also found in corals and sponges. It is said that ^^.-iodophenyl- alanine is present in sponges. None of these can be isolated from the thyroid. In the gland most if not all the iodine is in organic coml:)ination. Some observers state that there is a small amount of iodide present. Baumann boiled thyroid glands with sulphuric acid. The residue was extracted with alcohol and evaporated to dryness. The product was called thyroiodin or iodothyrin. It contained 10 per cent, of iodine, and amounted to about 4 per cent, of the total weight of the dried thyroid. It has been found that Baumann's product was not of a constant chemical constitution, and it has been suggested that the iodine compound present was iodotryptophane. Various other thyroid preparations have been made and have been put forward as the "active principle" of the thyroid gland, lodothyroglobulin (Oswald) is possibly a definite compound and exists as such in the thyroid gland. In 1919 Kendall announced the isolation of a definite crystalline iodine compound which he calls " thyroxin." His method of isolation is given as follows : " The fresh tliyroid glands are hydrolyzed in 5 ])ev cent, sodium hydroxide in a nickel kettle, the fats are removed by rendering the sodirnn soap insoluble, and the clear alkaline filtrate is cooled and acidified. The acid insoluble constituents containing practi- cally 100 per cent, of the thyroxin present are filtered off. This material is rcdissolved in sodium hydroxide and reprceipitated. using hydrochloric acid. The precipitate is now air-dried and is dissolved in 95 per cent, alcohol. The excess h^alrochloric acid which remains in the air-dried precipitate is neutralized with sodium hydroxide until it is almost neutral to moistened blue litmus paper. A heavy, black, tariy precipitate forms, which may be removed by filtration. The alcoholic filtrate is treated Avith barium hydroxide by adding a. liot, very con- centrated aqueous solution of the hjalroxide to tJic alcohol, and rcfluxing. T])e treatment with barium removes some THE THYROID AND PARATHYROIDS 311 heavy dark impurities. A small amount of sodium hydroxide is added to the filtrate and carbon dioxide is passed through the solution. The barium and sodium carbonate are removed by filtration, and the alcohol is distilled. The last traces of alcohol are removed by heating in an evaporating dish. The aqueous residue is now acidified with hydrocliloric acid. The precipitate is dissolved in alkaline alcohol, carljon dioxide is passed through tlie solution, the precipitated sodium carbonate is removed, and the alcohol is evaporated. The last traces of alcohol are removed by heating on a ■water bath and the solution is allowed to stand. The monosodium salt of tlij^roxin will separate at this point. The yield is not quantitative, and it must be further purified by dissolving in alkaline alcohol, passing in carbon dioxide, distilling the alcohol, and allowing the monosodium salt to crystallize a second time. This may then be precipitated from an alkahne alcoholic solution by the addition of acetic acid. Re- solution in alkaline alcohol and precipitation with acetic acid for five or six times removes the impurities and will yield thyroxin containing the theoretical percentage of iodine." Kendall states that he has obtained 33 grammes of thyroxin from 6,550 pounds of fresh thyroid. Thyroxin is said to be 4,5,6, tri-hydro, — 4,5,6, tri-iodo — 2 oxybetaindolepropionic acid. It exists in three forms: (1) the keto form with the carbonyl group adjacent to the imino, (2) A tautomeric enol form, and (3) A form with an open ring structure (cp. creatine and creatinine). It can be regarded as a derivative of tryptophane. According to Kendall the third form is tluit in which iodine occurs in the body. I H V H\ Xx >C C = C — CH„ — CH„^ C'OOH j>c c c = o 1/ N (1) Keto form 312 THE DUCTLESS GLANDS I H \^ C H G C = C — CH, — CH„ — COOH ■>. I H H >C C = C--CH2 — CH, — COOH >C C COOH I H (:i) Open-ring form >C C C — O — H C N L (2) Enol form H I H c H — C C — C — CH,, — CHNH, I I! i COOH H — c c; C — H V/ \/ C N I . I H H Tryptophane C C = C — C'H„ — CH„ — COOH C C C — OH C N I /X H O H / H {-U Amino4i^Urate form THE THYROID AND PARATHYROIDS 313 The change to the open ring form is effected easily in presence of certain products of hydroh'zed protein which contain the indole nucleus. (1) The keto form (formula 1) crystallizes in needles and is tasteless and odourless. It is found in the keto form in acid solution. It is insoluble in organic solvents unless they are acid or basic. It is sohible in alcohol in the presence of mineral acid or an alkah. It is not destroyed by heating. The melting point is 250° C. Mol. Wt. = 585, and empirical formula CiiHi„OoNI;, (cf. tryptophane CiiH,.jO,N,). It is amphoteric. It can yield a sulphate, a hydrochloride, a ureide and an acetyl derivative. It gives also mono- and di-basic salts, but these are so easily decomposed that they cannot be obtained in a pure form. (2) The enol form (formula 2) exists in alkaline solution. It may be prepared by hydrolysis in the cold of the ammonium salt, solution in pyridine and addition of water, when it separates out in needles (melting point 204° C). It is easily soluble in anhydrous or aqueous pyridine and quinoline and in formic acid. It is easily changed into the keto form. (3) The open-ring form (formula 3) is obtained by adding sulphuric acid to an alkahne watery solution of thyroxin. The precipitate which is formed is suspended in water and boiled. Thyroxin is then thrown down in long crj^stals (melting-point 225° C). It is soluble in alcohol, changing in solution to the keto form. A fourth (amino-hydrate) form (formula 4) may be obtained from an alkaline solution of thyroxin by heating and adding 10 per cent, ammonium cliloride. Fine crystals with a melting- point of 216° 0. separate out. If these are suspended in water acidified with formic acid and boiled, tlie crystals are changed into the open -ring form. If nitrous acid be added to an alcoholic solution of tliyroxin or to a suspension in water in presence of hydrochloric acid a yellowish colour is developed which, on addition of ammonia, changes to deep red. This reaction serves as a test for thryoxin. Thyroxin is more suscei^tible to reduction than to oxidation. Zinc and other metals in acid or alkaline solution split off iodine and break up the nucleus. Mild oxidizing agents have no effect, stronger ones break down the molecule. Thyroxin is unstable in sunlight ; iodine is split oft' as hypoiodous acid and 314 THE DUCTLESS GLANDS subsequently as free iodine. The iodine content is 65 per cent. It is said that a small quantitjr has already been synthesized. Thus it appears that two definite compounds containing iodine have been separated from thyroid tissue, a globulin (iodo-thyro-giobulin) which exists as such in the gland, and a derivative of tryptophane (thyroxin) obtained as a cleavage product and containing 65 per cent, of iodine. The evidence before us points to thyroxin as one of the active compounds of the internal secretion of the thyroid gland. But it is too early to affirm that it is the only active compound. N. Physiological Actions of the Thyroid Secretion Kendall claims that thyroxin produces all the effects of thj^roid both physiologically and therapeutically. Thus it is found as usefvxl in myxoedema as other thyroid preparations. Thyroxin shows a curious delay in its action. Successive daily administration may bring about death, but a single injection even of enormous size produces no effect. 1 mg. of thyroxin in an adult weighing 150 pounds will increase the metabolic rate 2 ])er cent. Kendall suggests that in the normal animal organism thyroxin is not fundamentally essential to life. This agrees with the results of extirpation experiments described above, and further is in accordance with the emergency theory of Cannon {vide supra). It is suggested that thyroxin is a. catalyst, and that its function is to increase the rate of the fundamental chemical reactions of the body. Intravenous injection of thyroid extracts or of thyroid preparations produces a temporary fall of blood-pressure. This effect is in all probability not a s]iecific one. It is probal)ly the same kind of fall as is produced by the injection of extracts of most organs and tissues in the body. The fall is due to a dilatation of peripheral vessels throughout the bodJ^ Wc have no reason to behove that this effect on blood-pressure has any liearing on the question of the internal secretion of the organ. The probable nature of the substance has been dis- cussed above (p. 25). Gudernatsch and others have observed that feeding tad' poles with thyroid substance will cause precocious differenti- ation, while growth is sujiprcsscd. The tadpoles begin to THE THYROID AND PARATHYROIDS 315 undergo metamorphosis a few days after the application of the thyroid and long before the control animals do so. The reaction was supposed to be a delicate test for the presence of physiologically active thyroid substance. The reaction however does not appear to be a specific reaction of thyroid substance since it has been found to occur after administration of iodides and iodized blood-serum. Kendall states that the action on metamorphosis (which occurs with small doses of his "thj^roxin") is not due to the organic nucleus, but is due to the iodine in the molecule, which breaks off as hypoiodous acid (HI 0). Carrel states that tissues groAvn in vitro increase several times as rapidly in the presence of thyroid substance as in its absence. The administration of thyroid substance and of iodide to animals has yielded some interesting results. In determining the effect on gross weight most of the earlier observations were made on adult animals. In regard to the effect on growth in young animals, some observers have noted an increase in the rate of growth, others a decrease, while still others have recorded that no distinct effect was produced. Cameron was the first to use a dose based rigidly on and bearing a constant ratio to the body weight of the animal at the time of adminis- tration. He has found, as the result of a series of very careful experiments, that continued small doses of desiccated thyroid gland administered to young white rats produce («) a definite and invariable decrease in rate of growth ; (6) hypertrophy of the organs concerned with increased metabolism — heart, liver, kidneys, adrenals, etc. (confirmatory of Hoskins and Herring) ; (c) disappearance of fat (confirmatorj^ of Hoskins and Herring). The decrease in rate of growth is proportional to (a) the amount of thyroid administered and {h) the iodine content of the gland given. The hypertrophy varies with the dose and length of time during wfiich it is administered, and appears also to be proportional to the iodine content of the dose. (Sodium iodide given in quantities varying from amounts ecpial in iodine content to the thyroid doses to amounts a hundred times as great produces no effect on growth rate and no hypertrophy. The effects produced are not due to protein feeding, autolj'tic products, or any similar cause, but specifically to thyroid tissue, or some constituent of it. Both thyroid and iodide 31 G THE DUCTLESS GLANDS feeding increase the colloid in the thyroid. Thyroid feeding inhibits the growth rate of the thyroid while iodide does not. Similar effects were obtained in experiments upon rabbits. Since among all the organs and tissues of the body thyroid alone produces a definite effect and since iodide does not pro- duce this effect, it is suggested that decreased rate of growth, hypertrophy of liver, heart, kidneys, and adrenals, and rela- tively decreased thj^roid may be used as tests for jjreparations alleged to be the essential thyroid secretion. According to more recent observations of Cameron, Kendall's thyroxin produces effects similar to those of thyroid when given by the mouth. But quantitatively, compared on a basis of iodine content, the effects of thyroxin are distmctly less than those of desiccated thj^roid. This is probably due to bacterial decomposition ; thyroid acts as a shield. The hypertrophy of heart and lymphatic tissue resembles that observed in cases of hyperthyroidism. Many attempts have been made to induce symptoms of exophthalmic goitre by means of the administration of thyroid substance to animals. It is doubtful whether a condition strongly resembling Graves's disease has ever been brought about by such methods. But there can be little doubt that definite toxic effects can be produced by thyroid feeding. These are loss of body weight, gastro-enteritis, and diarrhoea, rather than tachycardia, nervousness, and exophthalmos. Kendall believes that in order to get " hyperthyroidism " we must have thyroid and adrenal cortex acting together. It lias not yet been determined how far the toxic symptoms just described are due to iodine qua iodine. 0. The Effects of Thyroid Gland, and Preparations made from it, upon Metabolism Many years ago it was observed that niyxcedematoiis sub- jects, when treated with thjToid, suffered loss of weight due to reduction of fat and water. Since then various thyroid preparations have been employed to reduce obesity. When sj'stematic metabolism experiments were carried out it was usually found that thyroid causes an increase of nitrogen in, tlie urine, showing increased protein metabolism. The same or similar results were obtained with " iodothyrin '' and THE THYROID AND PARATHYROIDS 317 " thyreoglolnilin," in the case of the latter the effect varying with the amount of iodine present. According to Cramer the administration of thyroid j^rac- tically abolishes the store of glycogen in the liver. The increased katabolism of jirotein and fat is secondary to increased mobilization of the glycogen in the liver. According to Fron- tali and Hunter there is a very great elimination of creatine in sheep and dogs after removal of both thyroids and parathy- roids. Kendall's thj'roxin produces a notable effect on meta- bolism. The statement has been made that certain amines derived from proteins have an effect on metabolism of the same character as that brought about by thj^roid substance. P. Transplantation of the Thyroid Gland A large number of transplantation experiments have been performed, with very variable results. Many different methods and many kinds of animals have been used. In some cases rapid degeneration and loss of the grafted organ has occurred. In others apparently the tissue has remained alive and active for months. When the gland from one animal is grafted into another of different species (heteroplastic transplantation) the operation is always unsuccessful. When the thyroid from one animal is grafted into another of the same species (homoioplastic transplantation) the proceeding is perhaps sometimes success- ful. When a piece of thyroid is grafted on to various parts of the same animal (autoplastic transplantation) the operation is quite likely to be successful. The grafts frequently " take " and are said to remain in functional activity for long periods. When transplantation takes place into nearly related indivi- duals of the same species (syngenesioplastic transplantation, Loeb) the results obtained are intermediate in point of success between those obtained by auto- and homoioplastic trans- plantation. The transplanted gland lives for a certain time, but subsequently becomes absorbed by lymphocytal infiltration. By the vessel suture method of Carrel and Guthrie the thyroid may be removed from its proper position and replaced in the neck. It would ajjpear that by this method the auto- plastic form of transplantation is the only one which has been successful. One case of homoioplastic grafting has been recorded as successful in the human subject. 318 THE DUCTLESS GLANDS Q. The Relationships between the Thyroid Gland and the Reproductive Functions In the case of women some kind of relationship between the thyroid gland and the functions of reproduction has been recognized for a very long time. Thus it has been known that the gland is relatively larger in women than in men, and the conspicuousness and relatively large size are more marked after j^uberty and during the periods of menstruation and pregnancy. We know from observations on cretins and upon thyroidless animals that the proper growth and develoi^ment of the sexual organs depends on the functional integrity of the thyroid gland. It is stated that sexual intercoiu'se both in men and in women entails increased activity of the gland and gives rise to an increase in volume. McCarrison believes that married men and women under forty years of age owe their superior physicpie to the maintenance of thyroid activity which marriage assures. The ovaries are believed to exert an hihibitory action on the thyroid gland, so that the latter becomes over active after castration. This hyperactivity is revealed liy an increase in the amount of colloid matter. This is also put forward in explanation of the large number of cases of exophthalmic goitre which occur after the menopause. Bearing in mind the important thougli ill-understood relation l)etween the adrenal cortex and the rejiroductive organs it seems probable that the relations of the thyroid to the sexual functions will only be fully understood when the functions of the adrenal are better known. R. The Functions of the Thyroid Gland The evidence before us points to tJie conclusion that tlic thyroid gland provides a substance or suljstances which aid in the growth, morjjjaological differentiation, and metabolic I^rocesses of the ))ody. One of tliese sul>stances seems to be an iodized amine — tJiyroxin. IMost of the activities attribut- able to the active principle or principles are in the direction of katabolism, tJiougli, according to some authorities, there are indications of the existence of an anal)olic' ]H'inciple. It is not known wlietlier there are two sej)arate active substances — one anabolic, the other katabolic. The secretion of the active THE THYROID AND PARATHYROIDS 319 principle or i^riiiciples is probably under the control of the sympathetic. Whether the influence of the active material is direct on the tissues themselves, or indirect through the nervous system, is still doubtful. The thyroid is not equally important in all groups of animals. Adult herljivora can live in good health without a thyroid while the carnivora under such conditions will frequently suffer severely and die. Kendall regards the action of the thyroid substance as that of a catalytic agent. The substance does not alter the character of the fundamental reactions but increases their rate. The antitoxic action of the thyroid gland depends in all proljability on its metabolic function. The slowed changes of material in the body after removal of tlie thyroid will diminish the amount of alexins and opsonins and so render the animals more liable to infection. Regarding the perplexing problem of the iodine, it seems wise to assume provisionally that this element, in certain organic combinations, is of service as a catalytic agent in aiding or accelerating the fundamental metabolic processes of the body. We may also assume that the thj^roicl has for its function the utilization of the iodine in the diet to build up the particular compound or compounds which are necessary. Kendall believes that the essential part of the active substance is the NHjCOOH group, and that the iodine modifies the action, but is not essential. But he has not yet succeeded in preparing the active nucleus without iodine. S. Extirpation Experiments upon the Parathyroid Glandules The external parathyroids were discovered by Sandstrom in 1880. But it was not until their rediscovery by Gley in 1891, and the description of the internal parathyroids by Kohn in 1895, that extirpation experiments could be carried out with due regard to anatomical considerations. Vassals and Generali removed all four parathyroids from nineteen animals — ten cats and nine dogs — leaving the thyroids intact. Of the ten cats, nine succumbed within ten days, most of them at about the fifth day after the ojJcration, after presenting a typical train of symptoms. There were fibrillary twitchings, muscular spasms, psychical depression, stiff and 320 THE DUCTLESS GLANDS tottering gait, loss of appetite, tachycardia, rapid emaciation, and lowering of body temperature. One of the cats, operated upon on January 5, 1896, was still alive in March of the same year, but was much emaciated and in a state of chronic cachexia. The nine dogs all died within eight days, mostly on the third or fourth day after the operation. They were as a rule in good health the day after the operation, but began to show symptoms on the second or third day, and then rapidly died, after manifesting a variety of morbid symptoms. These were psychical depression, muscular tremors, paresis of the muscles of mastication, trismus, rigidity of the hind-limbs, uncertain gait, general muscular feebleness, and convulsions. There were also anorexia and vomiting, palpitation and dys23ncea. The urine was scanty and sometimes contained traces of allnimin. The symptoms after renujval of the four parathyroids were, as Vassale and Generali j)ointed out, analogous to those observed after removal of thyroid and parathyroids, an operation which had been so often unwittingly performed since the time of Schiff. The Italian observers did not note very marked convulsions ; these only occurred near the fatal termination. The predominating features were, in fact, ex- pressive of diminution of the excitability of the nerve centres ; there was, in fact, a rapidly fatal paralysis. The autopsy usually revealed nothing abnormal in the lung ; spleen and kidnej's were congested. The nervous system was normal with the exception (in some cases) of a certain degree of anaemia. The authors were satisfied that the fatal issue was not due to comj^lications arising from the operation itself, or to lesions of the thyroid or the surrounding nervous structures. In most cases the woxmd was in process of healing by first inten- tion ; in the cats there was very often complete cicatrization. Vassale and Generali state that the thyroid suffered little or not at all in the operation. In some eases the thja'oid left behind possessed no colloid in its lymjjhatic spaces. They were surprised to find that death supervened in a sliorter time than after removal of both thyroids and parathyroids. In their secoiid commmiication Vassale and Generali re- corded a series of variations iipon their original experiments. Thus they extirpated the two i^arathyroids of one side, -with practically no effects. Removal of the fovu" glands in two THE THYROID AND PARATHYROIDS 321 operations (first those of one side, then those of the opposite side) showed that the first operation produced little or no result ; the second operation proved rapidly fatal. Dogs could be kept in good health with only one parathyroid remaining, but the authors suspected that chronic symptoms might arise at a later period. In a still later communication the Italian authors state that the tetany induced by th3rroidectomy is less marked in old dogs than in young ones. The tetany is particularly well-marked in dogs, if, after removal of the thyroids, they are fed abun- dantly on a meat diet. If the animals are allowed to get into a condition of hunger, the tetany becomes much less noticeable. Results similar to those of Vassale and Generali liave heen obtained by several observers. The present writer, working in conjunction witli Professor W. A. Jolly, encountered difficulties where, from previous study of the literature, they had not been led to expect them, and could by no means always induce death in animals by total parathyroidectomy. From the writmgs of most authors it would appear to be a simple matter to remove, in some cases, the parathyroids leaving the thyroid intact, and in others the thyroid leaving the parathyroids in situ. Variations of these experiments would appear to be ecj^uaUy simple. Welsh, indeed, who worked with the cat, in which parathyroidectomy presents, perhaps, least difficulty, admits some difficulties in performing complete parathyroidectomy. According to Vincent and Jolly, Welsh has understated these. The obstacles in the way of success in this operation are mainly anatomical. The para- thyroids are extremely variable in position. The external pair may, as a rule, be easily seen and removed, but the internal are, in the majority of cases, embedded deeply in the substance of the thyroid. When it is remembered how vascular thyroid tissue is, how shghtly the parathyroid differs from it in appear- ance to the naked eye, and how this difEerence, slight as it is, entirely disappears when there is any bleedmg, it will be seen that the operation of digging out the internal parathyroid is one of extreme delicacy. A further difficulty presents itself in the fact that there is a nodule of thymus also embedded in the thj'roid lobe, frequently in close proximity to the internal parathyroid, resembling it on naked-eye examination, and 21 322 THE DUCTLESS GLANDS therefore easily mistaken for it in the course of the operation. Bearing all these difficulties in mind, the present writer and Professor Jolly did not hesitate to declare that, except in very favourable cases, where the internal parathyroid chances to lie near the surface of the thyroid lobe, the operation is an impos- sible one. The injury caused to the thyroid in endeavouring to excavate an almost invisible body from its substance, com- bined with the accompanying profuse haemorrhage, may account for some of the deaths which other experimenters have attri- buted to parathyroid insufficiency. It will be ol^vious that the other operation — viz., to remove all the thyroid tissue, while leaving the parathyroids with their blood-supply uninjured — is still more difficult, and it was not attempted, though it was found possible in some cases to leave one or two external parathyroids. The animals ujion which the experiments were performed were cats, dogs, foxes, monkeys, rats, guinea-j^igs, and rabbits. Ten out of fifteen cats on which the total operation was performed, either at one or more times, died soon after, the respective periods of survival varying from three to thirty-four days. Five survived the operation. Of the animals which survived, three showed grave nervous symptoms as the result of the operation. The fourth, which was a young cat, ceased for a time to grow, while remaining otherwise perfectly normal. The fifth sliowed no symptoms. On what theory are we to account for the exceptions to the rule that death rapidl}' follows the complete operation ? These exceptions are fairly numerous, and they have also formed a conspicuous feature of previous investigations. The presence of accessory thyroid or parathyroid tissue suggests itself as a probable explanation, but it must be borne in mind that a careful jjost-morteni dissection of neck, thorax, and even abdomen, failed to disclose such bodies. The symptoms usually following the comj)lete operation in the cat arc as follows : The cat is perfectly well on the day following tlie operation ; on the second day, there is usualh' a curious " paw-shaking " and some malaise. This is followed in ra])id succession, by tremors, stiffness of gait, and convul- sions. Even in a quiescent state, the fore-legs tend to be flexed, while the hind-legs are extended, a position exaggerated during convulsions. Hallucinations are fairly common. Of symp- THE THYROID AND PARATHYROIDS 323 toms not directly referable to the nervous system, conjunc- tivitis and respiratory catarrh were observed. In the dog the following symptoms have been described : restlessness, anxiety, fibrillary twitchings, stiffness, and staggering gait, convulsions and fits of rapid breathing. This may reach 250 a minute. The rectal temperature is raised as a result of the muscular activity. Exhaustion may super- vene and in extreme cases death. Emaciation is common and increased excitability of the peripheral nervous system is now regarded as pathognomonic of parathyroid tetany. The symptoms are extremely variable, so that it is difficult to judge of the effect of any curative agents. The nervous symptoms required more careful consideration. The convulsive disturbances probably proceed from the central nervous system, since division of the motor fibres to any of the muscles will abolish them. The effect seems due to the condition of the spinal cord and does not depend upon any higher centres. As already stated the electrical excitability of the peripheral nerves is increased. It has been known for a long time that the phrenic nerve may be excited by the action currents of the heart, so that we get " cardiac respira- tion," in which the diaphragm contracts with each heart beat, a phenomenon very familiar to all who have carried out extirpation experiments on dogs. Hoskins and Wheeler have shown that there is also a marked increase in the irritability of the sympathetic nervous system. Many theories have been brought forward to explain why removal of the parathyroids should give rise to the above symptoms. The two principal views are (1) calcium deficiency, (2) some toxic agent. Sabbatani and others had shown that soluble calcium salts diminish the excitability of nervous tissues. Utilizing this f act MacCallum has suggested that the pathology of tetany may consist in a deficiency of calcium in the body. An injection of soluble calcium salts into the circulation of an animal in tetany promptly checks the symp- toms. The hyperexcitability of the nerves which is char- acteristic of tetany is due to some change in the blood. It has been shown by cross-circulation experiments, that if the leg of a normal animal is suppfied with tetanic blood, this condition of hyperexcitability soon manifests itself in the jierves of the normal leg. The most powerfiil objection to the 324 THE DUCTLESS GLANDS calcium theory is that simply bleeding the animal and then replacing the blood shed by an equal amount of calcium free isotonic solution of sodium chloride (thus still further diminish- ing the calcium content of the tissues) also brings about prompt relief. Various toxic agents have been suggested as being responsible for the phenomena of tetany. Among these are ammonia, xanthin, histamine, thymus secretion, inosinic acid, guanidine, and methyl guanicUne. The only substance in this list which need be seriously considered is guanidine. In 1912, W. F. Koch made the very important discovery that methyl-guanidine is constantly present in considerable amount in the urine of Xiarathyroidectomized dog>s. In 1913 he definitely attempted to correlate this observation with the function of the parathy- roid glands. He suggests that the parathyroid secretion is concerned with anabolic processes closely related with the building up of nucleins. This hypothesis has been developed more fully by Paton and his co-workers. They claim that guanidine injected into an animal will produce all the symptoms of tetany. They attribute this condition as found experi- mentally or clinically to an abnormal accumulation of guanidine in the body, which accumulation it is the duty of the parathy- roid to prevent. It has been supposed that the thymus produces a toxin tending to give rise to tetany, and that it is the dutj? of the parathyroid to reduce or destroy this. The parathyroids do not contain any measurable amount of iodine. Other than this there is nothing to be said on the subject of the chemistry of the glandules. Attempts have been made to isolate the " active principle," but so far no very definite results have been obtained. CHAPTER XIV THE FUNCTION OF THE THYMUS A. Comparative Anatomy and Development of the Thymus 1. Nothing is certainly known of the thymus in the Cyclo- stoifiata. ,In Elasmobranchs the thymus arises on each side as epi- - thehal outgrowths of the dorsal gill-pockets. The number of clefts which give rise to thymus elements varies in different species, but it is probable that thymus buds originally arose from all the clefts. A similar origin may be assigned to the thymus in Dipnoi, CTanoids, and Teleosts ; but in these groups modifications occur in the directions of resorption and fusion of originally separate portions. In Teleosts the separate rudiments unite into a single mass which, in contrast with the course of events in Elasmobranchs, remain in connection with the gill epithe- lium. Growth is generally in a backward direction dorsal to the branchial arches, but the position varies in different species. 2. In Urodela the thymus arises in the form of compact outgrowths from the epithelium of the dorsal gill-pockets from 1 to 5. In the Anura the organ arises exclusively from the second cleft. In adult Amphibians the thymus hes behind and above the mandibular articulation. In the frog the gland is found behind the annulus tympanicus, covered by the depressor mandibulse muscle. It is a small, longish, oval body, which may be 2 to 3 milhmetres in length. 3. The thymus of reptiles has been specially investigated by de Meuron, Van Bemmelen, and Maurer. The organ 325 326 THE DUCTLESS GLANDS p. thyr. Ill thy m. Ill p. thyr. IV thym.IV p. thyr. Ill thyr. thymlll p.b.b. THE THYMUS 327 arises, as in the lower groups of vertebrates, from tfie dorsal gill-pockets, in the lizard from II. and III., in snakes from IV. and V. 4. In birds, thymus buds have been described from third, fourth, and fifth clefts. 5. The thymus of mammals apparently differs very materi- ally in many respects from that of all lower animals, inasmuch as it is much more complex, and it is not the dorsal, but the ventral, pockets of the gill-clefts which furnish its rudiment. In most cases the third cleft is the most important, but some- times the fourth, and occasionally, also, the second, plays a part. This portion of the origin of the gland is entodermal (see Fig. 90). Recent work has conirrmed the observations of Kastschenko as to the occurrence of an ectodermal component, derived from the "ductus prsecervicalis," in the thymus of certain mammals. This conception must have a far-reaching effect upon our views as to the origin and nature of the mammalian Explanation of Fig. 90. {Diagrams A. a}ul' B.}. A. iUustiates tlie development of the branchial organs of mammals, B. shows their actual relations in the adult. The different related rudiments of the same branehiomere are represented by a similar direction of shading lines ; so also the corresponding organs. Thus the rudiments from the third cleft are represented in A. by horizontal lines, as also the organs thus arising in B. The rudiments and organs from the fourth cleft are characterized by vertical lines. The post -branchial l)ody is showTi in thick outline, the thj^roid by crossed lines. The different kinds of tissue arising from one and the same bianchiomere are indicated by differences in the shading. The parathyroid tissue is shown by lines, the thymus tissue by alternate continuous and interrupted lines. The post-branchial body is repiesented in the developed condition as a hollow space with several glandulai' nodules (sho"\in in dark circles). A. shows the foiu- internal gill slits (I. to IV.), the epithelial origins of the parathyroids (p. thyr. III., p. thyr. IV.), the origin of the thymus (thyin. III., thym. IV.), the rudiment of the thyroid (thyr.), and that of the post-branchial body (p.h.h.). B. represents a schematic tiansverse section through the fully developed thyroid (at about the level of the junction of the upper and middle third of the thyroid lobe of a cat). The lettering corresponds to that in Diagram A. The structures which arise from the third cleft become the " external " para- thryoid and thymus nodule (separated fragment of thymus III.) ; those which arise froin the fourth cleft become the "internal " parathyroid and the thymus nodule {p. thyr. IV., and thym. IV.). The post-branchial body is surrounded by thyroid tissue. (A. is after Groschirff in ruminants; B. from Kohn in the cat.) 328 THE DUCTLESS GLANDS thymus. From a phylogenetic standpoint the ectodermal and the entodermal thymus representatives must l^e regarded as two distinct organs, which, through a paralleUsm in develop- ment, have acquired a similar structure. There are three types of thymus in mammals : 1. A xJurely entodermal thymus. This is found in the human subject and in the rabbit. 2. A purely ectodermal thymus. This is found in the mole. 3. A mixed entodermal and ectodermal thymus. This condition is found in the pig and the guinea-pig. While in crocodiles and birds the thymus is situated in the neck, in mammals it is for the most part situated in the thorax. But in some mammals there is a cervical portion as well as a thoracic portion, while, again, in some species, such as the guinea-pig, the structure is entirely cervical. How far the distinction between an entodermal and an ectodermal thymus corresponds to the cervical and thoracic representatives of the gland is not known. But it is stated that the cervical thymus of the guinea-pig is entirely entodermal, being derived from the third cleft, and corresponds to the human gland, which, however, is thoracic. This acceptance of a dual origin of the mammahan thymus will necessitate a reinvestigation of the development of the organ throughout vertebrates. But it must be borne in mind that a definite statement as to whether a derivative of a giU-cleft is ectodermal or entodermal in origin is often a matter of extreme difficulty. The human tlaymus is derived from the third visceral pouch, but it is not yet decided as to whether there is an accessory rudiment from the fourth pouch. The thymus is thus in its first origin bilateral. A pocket develops from the third cleft on each side, and extends itself as a thick-walled tubular prolongation along the carotid artery. The pocket persists as the ' ' thymus vesicle ' ' in the proximal section of each rudiment. From the lower end of the tube solid epithelial buds are given off, and from these lateral buds again come off, so that this part of the gland acquires a ramified lobular appearance like an acinous gland. The acini, however, are solid. The two rudiments are brought into close contact with one another in front of the trachea, and unite to form THE THYMUS 329 a single-lobed body, which comes to he in the anterior media- stinum in close relationship with the pericardium. B. Structure of the Thymus The thymus is made up of several lobules, which vary in size, and are separated from one another by connective- tissue septa, bearing bloodvessels and Ijanphatics. Each lobule may be divided into a cortical and a medullary portion. The cortex is incompletely separated into " nodules " by connective-tissue trabeculse, the arrangement bearing a strong resemblance to that of a lymphatic gland. The cortex is very vascular, and is similar in appearance to a lymphatic gland. Its structure also agrees with that of lymph glands and tonsils in exhibiting numerous signs of mitosis, l)ut without definite germ centres. In addition to the lymph cells, there are also a number of pecuhar granular cells. The medulla, hke that of a lymphatic gland, is more open in its texture than the cortex, and its reticulum is made up of large, transparent, branched cells, which are sometimes arranged in an epithehoid manner. The medulla does not contain so many leucocytes as the cortex, but is characterized by the presence of the pecuhar concentrically striated bodies — the concentric corpuscles of HassaU (see Fig. 91). These vary very considerably in general appearance, and their precise origin and significance are still matters for discussion. The above account is largely derived from that given by Schafer. It seems possible that there are many points in connection with the thjmius upon which cm'rent views may liave to be changed. It has long been taught that the human thymus reaches its greatest development at about the second year, and then begins to degenerate. But it Avas shown in the year 1890 by Waldeyer that even in advanced age a con- siderable amount of thymus tissue persists, and probably maintains its function. Zoja had previously shown that the thymus frequently persists till the age of puberty. Recently Hammar has insisted that the organ continues to grow up to the period of puberty, and reaches its greatest development between the fourteenth and sixteenth years. From that time onwards it gradually loses in weight, but microscopical investi- gation shows that it still functions. A true atrophy of the 330 THE DUCTLESS GLANDS parenchyma, with ehmination of function, comes on at about fifty to sixty years of age. It seems, then, that we must regard tlie thymus as an organ regularly present, and probably in an active functional con- dition up to the age of puberty. The explanation offered by Hammar of the opposite conclusion reached by former anatomists is this : Wharton in the seventeenth century observed that a reduction in size of the thymus frequently occurred in exhausting or wasting diseases. This has been '>M Sim, V - H.c. Fici. e. Kolliker speaks very doubtfully about the matter, even about the results of investigation by the silver chromate matter. Osborne and Swale Vincent could detect only very few undoubtedly nerve cells in the infundibular portion. These observers also confirmed and utilized experimentally the fact that the posterior lobe has an epithehal investment. The pituitary body consists of three portions : (1) The anterior lobe ; (2) the intermediate portion ; and (3) the posterior lobe, or nervous portion. 338 THE PITUITARY 339 There are three types of mammahan pituitary body. In the first, of which the organ of the cat furnishes an example, the posterior lobe is hollow, and its cavity is in free com- munication with the third ventricle of the brain, and the epitheUum of the anterior lobe almost completely surrounds the posterior lobe. In the second type (as, for example, in the dog) the body of the posterior lobe is solid, but the neck is hollow, and communicates with the third ventricle, and the posterior lobe is almost completely surrounded with epitheUum, as in the first type. In the third type — e.g., man, monkey, ox, pig, and rabbit — the body and neck of the posterior lobe are solid, although traces of a cavity are occasionally found in the neck. In this last type the epithe- lium of the anterior lobe does not spread so far roimd the posterior lobe, but is gathered around the neck and spreads over and into the adjacent surface of the brain (Herring), (Fig. 94.) The epitheUal portion is again divided into two parts : (1) An anterior lobe proper, consisting of solid columns of cells, between which run wide bloodvessels ; and (2) an inter- mediate portion, which lies between the anterior lobe and the nervous portion, forming a close investment to the latter. (Figs. 94 and 95.) The anterior lobe presents all the appearances of a true internally secreting gland. Its structure is clearly that of a gland — an " epithelial body," in Kohn's phraseology. It is made up of a branching, compact network of epithelial threads and columns. In the spaces of the epitheUal network run wide, thin-walled bloodvessels, so that in many cases the epithelial cells are placed directly on the delicate vessel wall. This arrangement is most admirably adapted for the purposes of internal secretion. The general scheme of structure is the same as in the adrenal cortex, the islets of Langerhans, of the pancreas, the thyroid, and the thymus (in its epithelial stage). (See Fig. 95.) The general nature of the cells found in the glandular pituitary may be thus stated : 1 Chromonhile i^*"^ Acidophils 1. unromopniie | (^) Bj^gopj^iig_ o Chromophobe. (See Fig. 95.) 340 THE DUCTLESS GLANDS Besides the colloid, it is probable that there are other secretory products. In no other endocrine gland are the granular products of secretion so well seen as in the anterior lobe of the pituitary body. Secretory granules are also seen in the vessels belonging to the gland. Leyton, as a result of, the examination of a large number of human pituitaries, came to the conclusion that colloid material may be found in the bloodvessels, both in the an- terior lobe and also in the so-called pars intermedia. Colloid material was not seen in the pars nervosa. In children and in the foetus the distinction between the different varieties of cells in the anterior lobe is not marked, and colloid material is small in amount. Sta/k of pituitary Infundibular csvity Anterior portion- Fig. 94. — Diagram showing relations of principal parLs of pituitary l)ocly. The size and weight of the gland and the amount of colloid material are subject to very great variation. Cushing and Goetsch find colloid masses in the posterior lobe of the pituitary, and agree with Herring that the colloid masses in this lobe are secretory products of the epithelial covering of the pars intermedia. They find in the cerebro- spinal fluid a substance which gives the same reactions as the pars nervosa itseK. The intermediate portion consists of finely granular cells THE PITUITARY 341 arranged in layers of varying thickness closely applied to the body and neck of the posterior lobe and to the under- surface of adjacent parts of the brain. The part of it which is separated from the anterior lobe by the cleft is almost P-9' 3; ■p.n. Fig. 9.5. — Section tlirough a portion of the pituitary body of tlie dog, showing the glandular and nei'vous portions and the pai'S intermedia. (Drawn by Mrs. Thompson.) r., cleft in glandular portion (between glandular portion proper and the inter- mediate portion) ; p-g., glandular portion ; p.i., intermediate portion ; p.n., nervous portion. In the glandular portion are seen three kinds of cells. devoid of bloodvessels. Colloid material occurs between the cells of the pars intermedia. (Fig. 95.) The nervous portion is made up of neurogha cells and fibres, and is invaded by the epithelial cells of the pars inter- media. A substance resembhng the colloid of the thyroid gland occurs in the nervous portion. The gha cells are longish 342 THE DUCTLESS GLANDS or cylindrical, with one, two, or more nuclei, and a granular, at times pigmented, cell protoplasm. From the protoplasm stretches a long, thin homogeneous fibre, which is sharply contoured, like an elastic fibre. These cells are young forms of ependyma cells — the ' ' radial cells ' ' of Retzius. In addition, there are ' ' protoplasmic cells ' " which are multipolar, and send out fine glia fibres. There are also " spindle cells," " giant glia cells," " keratin cells," etc. All these build up a primitive neurogha. One of the most interesting features of the posterior lobe is the pigment, which has been known for a long time. Accord- ing to Kohn, the pigment is contained within the threads of the neuroglia, and distends them here and there. When unstained, the substance is of a greenish-yellow tinge, and consists of closely packed, irregular clumps. The amount of the pigment is found to become notably increased in age and disease. For this reason it is supposed to represent some kind of breakdown product. It has been suggested that the pigment bears some relation to the functions of the organ, and especially to the secretion of the anterior lobe. Clunet and Jounesco have also given an account of the pigment in the neurohypophysis. According to these authors, the substance does not give the iron reaction. It is insoluble in alcohol, xylol, benzol, cedar oil, chloroform, and ether. It is stained red with osmic acid, red also with Sudan and Scharlach red, while it is blackened with iron hsematoxyhn. Haberfeld finds in the human subject at all ages a " pharyn- geal pituitary " — a solid string of cells about 5 millimetres long, which runs from below upwards and backwards imme- diately behind the vomer. It contains cells like those in the pituitary itself, but here the chromophobe elements pre- dominate, and the basophiles may be absent. Histologically it resembles the pars intermedia. It is the origin of most of the pituitary tumours. This structure is probably the remains of the original pituitary duct. Haberfeld describes a cystic structure in intraviterine life, which is made up of glia cells and fibres, and possessing lumina, surrounded by ependyma cells. This body is frequently, he alleges, the starting-point of gliosarcomata. Staderini gives an account of the " emincntia saccularis " (an elevation on the base of the brain immediately behind the THE PITUITARY 343 stalk of the pituitary). He considers that the structure is not homologous with the " succus vasculosus " of fishes, as Retzius thought. A very rare abnormality which has been described in con- nection with the sphenoid bone is a persistent, pei'forating foramen in the basisphenoid — the canalis craniopharyngeus. This is regarded as the place of exit of the original duct of the anterior lobe of the pituitary body. Haberfeld finds the canal wanting in all acromegalic skulls in the Vienna Pathological Institute. He reports that it is very variable in individuals of the same species of animals. He calls attention to the fact that the pharyngeal pituitary is constant in man, while it is frequently absent in the lower animals. This is not what would be expected if the structure really represents the remains of the original duct of the pituitary. 2. The Pituitary Body of Birds and Lower Vertebrates In birds the epithelial cleft appears to be absent. The cells of the anterior lobe are for the most part small and finely granular. The posterior lobe is small and hollow, and much con- voluted. Colloid bodies are sometimes present. The cells of the pars intermedia come into close contact with the nervous portion of the posterior lobe, but are gathered together for the most part in the neighbourhood of its neck and on the thin lamina of nervous tissue forming the floor of the third ventricle. In Teleostean fishes the posterior lobe has a complex vascular striicture of a glandular nature, which was called the ' ' saccus vasculosus " by Gottsche. The Teleostean pituitary is composed of three kinds of tissue, two of which are epithelial and the third nervous, the latter being comparatively small in amount. The anterior lobe of mammals is represented by a wedge-shaped mass of large and deeply staining cells. These cells vary in situation and extent in different species. The pars intermedia consists of small, round, feebly staining cells, which surround and invade the nervous tissue. The pars intermedia in the cod is divided into two main portions, which are continuous 344 THE DUCTLESS GLANDS with, and separated from one another by, the true anterior lobe (Herring). The nervous part of the cod's pituitary is small, and appears to be composed of neuroglia and ependyma cells, without any true nerve cells. It is continuous with the brain in front by the lamina post-optica, or anterior lamina, and at the sides by lateral lamina. The nervous substance is more freely invaded by cells of the pars intermedia than is the nervous substance of the mammalian body. In Elasmobranchs [Raja batis) the pituitary is a long, club-shaped body which lies for the most part behind the small lobi inferiores. Its structure is very different from that of mammals, birds, and Teleosts. There are no cells having the deeply staining characteristic of those of the anterior lobe of other vertebrates, and there are no cells exactly like those of the pars intermedia. There is no differ- entiation into anterior and posterior lobes, and the only trace of a posterior lobe is a thin lamina of nervous tissue which bounds the infundibular cavity. The saccus vasculosus is well developed. The Elasmobranch pituitary appears to be quite different from that of other vertebrates. B. Development of the Pituitary Body The earUer observers believed that the whole of the pituitary body is derived from the brain. E-athke, however, described the invagination of mucous membrane, since called " Ilathke's pouch," and put forward the view that from this pouch is derived the epithelial portion of the pituitary (which he further stated has been derived from tlie entoderm of tlie fore-gut). Dursy described the origin of the epithelial part from the fore-gut, and of the vascular stroma from the notochord. W. Miiller showed that the anterior lobe arises from Rathke's pouch, but believed this to be entodermal. It is now usually considered that the pouch is of ectodermic origin. The posterior lobe was originally conceived as the anterior extremity of the brain, but more recent researches have shown that it is an outgrowth of the thalamencephalon. Mihalkovics has given a complete account of the early de- velopment of the pituitary body in the rabbit and the chick. According to this author, the anterior lobe is developed from THE PITUITARY 345 Rathke's pouch, and is ectodermal. The beginning of the pouch is in front of the oral plate. When this ruptures, its upper stump, containing in its upper part the head of the notochord, bends forward and narrows the mouth of the epithelial pouch, leading to the formation of a definite sac — the hypophysial sac. The wall of the sac presses upon the base of the anterior brain vesicle, giving rise at its upper ex- tremity to a fold in the wall of the brain, which becomes the primitive infundibulum. The primitive infundibular process comprises the surrounding tissue of the tuber cinereum as well as the origin of the infundibulum, and the true infundi- bulum is formed at a later stage by its own growth from a portion of the primitive infundibular process. The head of the notochord, beyond presenting a barrier to the backward growth of the sac, takes no part in the formation of the pituitary body. Mihalkovics' work has been confirmed in the main by numerous authors. Kupffer described an additional origin of part of the anterior lobe of the pituitary from the entoderm of the fore-gut, and this view has received support. Herring, however, believes that the epithehal portion of the pituitary is entirely ectodermic. The accoimt of the last-named author is briefly as follows : — Development of the pituitary body begins very early in embryonic life. In mammals the epithehal portion is derived entirely from the ectodermic wall of " Rathke's pouch." Its origin is single and mesial. The epithehum is early distinguish- able into two parts. One of these — the intermediate part — is closely adherent to the wall of the cerebral vesicle ; the cells are clear, and tend to form colloid. The other portion of the buccal epithehum gives rise to the anterior lobe proper. Its cells are granular, and form solid columns separated by blood- channels. The infundibulum is an invagination of part of the wall of the thalamencephalon, which is adherent to the anterior and upper wall of Rathke's pouch. It therefore possesses an epi- thelial covering derived from the latter. The infundibular process grows backwards, and, in the cat, retains its central cavity. It is lined by ependyma cells, which, during develop- ment, become elongated, so that ependyma fibres run obliquely in its neck. The posterior lobe of the pituitary is, from the 340 THE DUCTLESS GLANDS first, a composite structure of epithelium of the pars intermedia and of neuroglia and ependyma, and the relations between the two tissues become more and more intimate. The early stages of development of the Elasmobranch pituitary resemble those in the mammal, except that there is no invagination of the wall of the cerebral vesicle in Elasmo- branchs to form an infundibular lobe. The body is derived entirely from the buccal epithelium of Kathke's pouch. The relation of the pituitary to the brain ventricles is similar to that in higher vertebrates, but this is accounted for by the development of a paired saccus vasculosus, each of which pours its secretion into a common infundibular canal. The wall of this is lined with epithelium similar to that lining the saccus vasculosus. Its nervous structure is lost, being replaced by connective tissue and numerous thin-walled bloodvessels. There is no invasion of the wall of the canal by epithelial cells, and no hyahne bodies are formed. The pituitary body of the Elasmobranch is a gland, the secretion of which is poured directly into the bloodvessels. There is no evidence of any direct secretion by the pituitary into the brain ventricles. C. Older Views as to the Functions of the Pituitary Body The oldest theory concerning the pituitary body is trans- mitted by, and survives in, the name the organ bears. The secretion of the inucous membrane of the nose (pituita) was su])posed to be derived from the " glandula pituitaria." This was the view of Galen, held also by Vesalius. At the period of Vieussens and Sylvivis, the body A\'as supposed to have to do with the formation of the cerebro-spinal fluid. ^ Gushing calls attention to a remarkalile paper bj' Lo\\'er {Dissertatio de Oi-ig'me Catarrhi, 1672), who was the first experi- mentally to disprove the Galenic doctrine. " For whatever serum is separated into the ventricles of the brain and tissues 1 It is interesting, as pointed out by Oushing, to note that a substance from the gland may under certain conditions enter the nose, and that, according to modern conceptions, the pituitary body does add something to the cerebro-spinal fluid. THE PITUITARY 347 out of them through the Infundibulum to the Glandula pitui- taria distils not tipon the palate but is poured again into the blood and mixed with it." Majendie regarded the pituitary as a kind of lymphatic gland, which collects the cerebral lymph and passes it into the circulation. "Its pars anterior does discharge its elaborated products into the circulation, and the pars nervosa apparently contains certain inter-neurogliar spaces resembling lymph channels." For a long period, the pituitary body was looked upon as a " vestigial relic," and of no importance in the animal economy. The association of Addison's disease with adrenal lesions was the starting point of adrenal physiology, and the connection between myxoedema and thyroid mischief was the beginning of our knowledge of the functions of the thyroid. In the same way, the appearance of Marie's pubhcations (1888-1889) on acromegaly and pituitary tumours, was the chief impetus towards all the modern investigation into the structure and functions of the hypophysis cerebri. Of supreme importance in the history of our knowledge of the pituitary, as indeed of all the ductless glands, was the discovery by Ohver and Schafer (1894) of the physiological activity of adrenal extracts. This led directly to the observa- tion by the same authors of the power in raising blood-pressure of extracts made from the pituitary body, and has instigated a vast amount of work depending on the investigation of the action of various tissue extracts upon the body generally and on the different systems. D. Physiological Action of Extracts of the Pituitary Body 1. Effects on the Heart and Bloodvessels Ohver and Schafer discovered that aqueous or sahne extracts of the pituitary body produce, when injected into the blood- vessels, a rise of blood-pressure, which is comparable to that produced by extracts of the adrenals. The rise is produced by an action on the peripheral arterioles, as is that brought about by adrenal extracts. The action of pituitary extracts, however, is more prolonged than that of adrenal extracts. 348 THE DUCTLESS GLANDS There was no marked effect upon the rate of the heart-beat. (See Figs. 96, 97.) Howell made a considerable step in advance. He divided the gland into its two chief portions — the anterior and posterior lobes — and determined that, while an extract of the former is devoid of physiological activity when injected into a vein, that of the latter produces the effects upon the blood-pressure. Howell further found the rise of blood-pressure to be accom- panied by a slowing of the action of the heart, and that both the raised blood-pressure and slow cardiac rhythm might be maintained for a considerable time ; and that if a second dose be administered intravenously within a certain time — which varies from haK an hour to an hour or more — after the first dose, these effects are not repeated — in other words, a certain immunity is estabhshed, which only slowly passes off. Cyon has noticed, as did Howell, that the rise of blood-p)res- sure is accompanied by slowing of the pulse. Both these effects he attributes to stimulation of the pituitary body by the extract which has been injected. He states that stimulation of the hypophysis in the body, either electrically or mechanically, will produce similar results through the vagi, and that after extirpation of the organ the effects can no longer be produced by injections. There is slowing of the isolated mammalian heart, if extract of the "posterior lolje " be perfused through it. Schafer and Vincent, working with cats, found that pituitary extract, on administration of a second or third dose, always produces a fall, and not a rise, of pressure (see Fig. 97). The depressor substance was subsequently' shown, bj' the present writer and collaborators, to be common to extracts of all organs and tissues. Osborne and Vincent, working "\\ ith dogs, found, with Howell, a preliminary fall before the rise, l_)ut, in most cases, a rise as well as a fall on a subsequent injection. This is what I have observed in a recent series of experiments.^ The main tacts have been found to hold good as well for extracts made from the human pituitary. According to Schafer and Vincent, the cardiac slowing is ^ In one experiment, even the first administration of pituitary extract produced no lise, tnd this result seems to have been due to the previous administration of adrenin. THE PITUITARY 349 not constant, and, when present, it is not aboKshed by section of the vagi or the action of atropine. It is, therefore, of periplieral origin, and is not due to the same cause as the inliibition which often accompanies the action of adrenin, and is brought about by an action on the cardio-inhibitory mechan- ism in the bulb. This action of pituitary extracts upon tlie heart and blood- FiQ. 96. — Effect upon the arterial pressure and intestinal volume of intra- venous injection of decoction of infiuicUbular body. Cat under morphine and ovirare. The time of markins indicates five seconds. vessels is a special case of their action ui^on most of the involun- tary muscles. The rise of blood-pressure already referred to is due to constriction of many of the bloodvessels of the body, combined with augmentation of the heart-beat. i With large doses, the depressor effect may be so marked as to mask the usual subsequent rise. • Paton and Watson state that in the duck there is dilation uf vessels and not constriction. 350 THE DUCTLESS GLANDS to Howell, the responses become less and less with each repeated mjection. There is great According pronounced with each repeated, mjection. inere is variation in the effects produced not only between different species of animal, but even between different individuals of the same species. It has been doubted whether the depressor action, seen with injections subsequent to the first, is whollj' due to a different principle, though the evidence before us seems to the present Fig. 97. — Effect upon the arterial pressiire of intravenous injection of decoc- tion of infundibular body. Cat. Morphine and curare. writer to be strongly in favour of such a view. Hoskins and McPeek discuss the question, whether the pressor effect of pituitary extract is due to adrenal stimulation, and come to a negative conclusion. Experiments upon the isolated heart of tlie frog and of mammals show that the slowing of the heart-beat is due to a direct action upon the musculature of the heart. Einis finds that the first effect of pituitary extract upon the heart is a diminution of the frequency, this is followed by an increase. 2. Effects on the Vasomotor Reflexes The fiicts that adrenin diminishes the excitabihty of the THE PITUITARY 351 vagus, 1 and that fluid from tlie thyroid appears to increase the excitabihty both of the vagus and the depressor, led to an investigation of the action of these and other tissue extracts upon the vasomotor reflexes. The extract of the pituitary body, sold under different names by different firms, appears to convert a depressor reflex into a pressor, or very considerablj' to exaggerate the pressor efi:ect. The latter eiiect is, in some cases, much more marked after previous administration of adrenin. This action of pituitary extract occurs only on a first injection. Brisk kneading of the intestines evokes normally a very distinct vasomotor response, which is frequently accompanied by a slowing of the heart-beat. The effect upon the heart is very noticeable after the administration of pituitary extract, and the beat is frequently of a grouped character. 3. Effects on the Resjnration Mummery and Legge have noted a diminution of the ampli- tude of respiration, as a result of pituitary injection. Pantow states that breathing stops for some time after the injection, then begins again, then once more stops ; the primary stoppage appears to be due to peripheral vagus stimulation. 4. Effects on. involuntary Muscles other than those of the Vascular System (a) The Uterus. — It was first recorded by Dale that in- fundibular extract excites uterine contractions. The obser- vation was confirmed by several investigators. The uterus is extremely sensitive to the action of the extract, whether in the body or treated as an isolated organ. Kehrer first used the uterus in the latter way, and noted the action of pituitary extract upon it. Engeland and Kutscher affirm that they have succeeded in separating, by a method of fractional precipitation, from an extract of the whole pituitary body a basic fraction possessing the characteristic action on the uterus, but not that on the blood-pressure. According to Dale and Laidlaw, the isolated horn of the uterus of the non- X^regnant cat gives fairly good results, responding with but ^ This is not always the case ; tlie precise conditions under which this occui's require careful investigation. 352 THE DUCTLESS GLANDS little diminished contraction to a second dose, after the first has been carefully washed away. It is subject, however, to inconvenient spontaneous slow variations of its average tonus, and is apt to acquire a disconcerting rhythm. The uterine horn of the young virgin guinea-pig is greatly superior in these respects, its natural tendency, when left undisturbed in the Ringer's solution, being to acquire a condition of complete relaxation, broken only by a small rhythm. It is very sensitive to the extract, which can therefore be given in very small doses, and the tissue normally relaxes with promptitude to its original level of minimal tonus on washing out and changing the solution. This method is found to detect differences of activity which escape recognition by the blood-pressure test, and is employedbyDale and Laidlaw for standardizing pituitary extracts. (b) The Bladder. — The action of pituitary extract on the bladder was first noted by Bell and Hick. In dogs and cats, pituitrin stimulates to a considerable extent the musculature of the bladder, and increases the excitability of the pelvic nerve. (c) The Intestine. — Bell observed the power of pituitary extract to restore peristalsis to the paralytically distended bowel, a capability which, according to Dale and Laidlaw, is not represented by any definite action on the bowel of the normal animal. But Beyer and Peter, working with the surviving small intestine of rabbits, find that, after a preUminary diminution in rhythm and tone, both these are very strikingly increased. The rhythmical movements are often increased tenfold. The first phase is considered by the authors to be due to stimulation of the sympathetic fibres which inhibit the muscle. The second phase, on the other hand, is due to stimulation of Auerbach's plexus and the post-ganglionic fibres. With very powerful doses, this second effect is very slightly manifested or may be absent altogether, so that an immediate and lasting inhibition may be the only result. It is usually supposed that the most distinctive difference between the action of adrenin and that of pituitrin is that the former relaxes the vmstriped intestinal muscle, while the latter uniformly contracts these fibres. But it has been shown by ShaniofE that certain posterior lobe preparations are capable of producing relaxation of the isolated intestinal loop and of THE PITUITARY 353 inhibitingitsrliythmical contractions, resembling in this respect the extracts of the chromaphil tissues. Just as Schafer and Vincent found two separate substances acting on the blood-pressure — a pressor and a dejiressor — so Beyer and Peter distinguish two separate substances having respectively the two actions on the intestine just described, the sympathetic inhibitory substance being insoluble in alcohol, the autonomic augmentor substance soluble. These eiiects on the intestine can be repeated at frequent intervals, while the effect on the bladder rapidly becomes less in successive trials. It is doubtful how far these effects are truly specific for extracts of pituitary. (d) The Stomach. — The effects of pituitary extract on the stomach appear to resemble very closely those upon the intestine just described. There is at first some inhibition, which is followed by a powerful and persistent augmentation. The rhythmical movements are very markedly exaggerated. These actions were first noted by Houssay in the frog, and then in other animals and man. Clinical observations have been made in the same direction. (e) The Pupil. — It was discovered by Cramer that pituitary extract dilates the pupil of the enucleated frog's eye. Franc hini noted also that the serum of animals which have received intravenous injections possesses slight mydriatic properties. There is thus a close resemblance between the reactions, due to administration of pituitary (posterior lobe, infundibular) extracts and those so familiarly called forth by means of adrenin. The chief differences consist in the preliminary fall (in some animals) and jirolonged rise due to pituitary, and the fact that this drug causes slowing of the pulse after atropine or section of the vagi, in the constriction of the coronary and dilatation of the renal vessels, adrenin having an opposite effect. 5. Effects on the Secretion of Certain Glands (a) The Mammary Gland. — Ott and Scott discovered that injection of pituitary extract into goats causes a marked increase in the flow of milk, Schafer and Mackenzie found that ex- 23 354 THE DUCTLESS GLANDS tracts of pituitary body, corpus luteum, pineal body, involut- ing uterus, and lactating mammary gland all manifest a galactagogue action, but the pituitary bodj^ produces the most marked results. Gavin found that the daily yield of milk in cows is not increased by the administration of corpus luteum and pituitary extract. Schiifer also reports that injection of pituitary extract into a muscle of a lactating woman caused only a temporarj' increase in the flow of milk. It has been suggested that the hypertro]ihy of the mammary glands is brought about by some secretion produced during pregnancy, which neutralizes tJie tendency of the cells to discharge under the influence of secretion from the pituitary'' and other organs. When this inhil)itor is removed, the hormones causing the discharge of the gland come into action, and so cause the secretion. This seems likety from the experiments of Mackenzie, who states that by injecting extracts of foetus or placenta together with pituitary extract into a lactating animal, the action of the pituitary is inhibited. In regard to the corpus luteum, there is a theoretical dis- crepancy between the views of those who regard the body as one of the building-up factors, and the results of Schafer and others who find that corpus luteum extract produces an imme- diate secretion. Hammond finds, as did previous observers, that the galac- tagogue effect of pituitary extract is only temporarj'. The effect is not muscular. The daily yield is onty slightly increased, and is not dependent on increased blood-pressure. The, pitui- tary gland seems not to he the origin of the ordinary changes in the mammary gland. Histological evidence points to a direct action of the extract on the glandidar epithelimn. The milk obtained after injection has a higher percentage of fat than normal ; in the subsequent milkings, however, there is a drop in the percentage of fat, although that of the other ingredients remains normal. While the proteins, lactose, and ash are secreted in close connection with the water of the milk, the amount of fat is not so connected with the amoinit of Mater. Tlie I'atio of " nitrogen to lactose " is relatively constant throughout. Hill and Sutherland Simpson state that pituitary extract THE PITUITARY 355 increases the immediate secretion of milk, but causes after- wards a decrease below normal. (6) The Kidney. — The diuretic action of pituitary extracts was discovered by Magnus and Schafer. The increase of secretion is accompanied by dilatation of the renal arteries, so that the organ swells. The action is, therefore, different upon the renal vessels from that on the arteries in general, which are strongly contracted by it. The rise in blood-pressure produced by this general contraction is not the sole cause of the increased secretion of urine, for a second dose administered a short time after the first will again accelerate secretion, although the second dose may not cause any rise of general blood-pressure, but rather a fall. There is, therefore, a specific diuretic effect upon the renal epithelium, just as there is upon the epitheUum of the mammary gland. The tolerance pro- duced by a first injection is then less marked than in the case of the blood-pressure response, but with large doses it is well marked. It is reported that, under certain circumstances, there is a secondary diminution of the flow of urine, following upon vasoconstriction of the kidney. Hoskins and Means believe that the pituitrin diuresis is due primarily to direct stimulation of the renal cells — usu- ally aided, perhaps, by a concomitant vasodilatation in the kidneys. (c) The Sto7nach. — It was shown by Edkins that extracts made from the pyloric mucous membrane in boiling water or 0"4 per cent, hydrochloric acid contain an active substance which, on injection into the bloodvessels of an animal, leads to a secretion of gastric juice. Frouin found a similar action on the injection of gastric juice. Eirenhardt confirmed the results of Edkins, but Ems- mann obtained some definite effects upon the flow of gastric juice as a result of injection of extracts of other organs, such as the intestine. Houssay has recently reported a very decided action of pituitary extracts upon the flow of gastric juice, and has pub- lished some very convincing tracings. This appears to be a direct action on the secreting cells, as in the case of the mam- mary gland and the kidney. At any rate, the effect can be observed upon the isolated stomach. 356 THE DUCTLESS GLANDS 6. General Physiological Effects {Subcutaneous and Intravenous Injections) In 1899, Schafer and Vincent reported tliat they had made a few experiments upon the effects which can be produced by the subcutaneous injection of decoctions of the infundibular part of the pituitary body. These were performed upon mice and young rats, and, although the dose required was much greater, showed that the pituitary extracts can produce results resembling in a general way those of adrenal extracts. They cause quickened respiration, increased heart's action, and ultimately paralysis, beginning in the hind-limbs. Similar experiments have since been carried out by many observers. Diuresis, hsematuria, and albuminuria have been recorded. Etienne and Parisot further record a ]3ernianent hypertension as the result of repeated injection of pituitary extracts. It is stated that the effects of subcutaneous injection are modified by previous injection of thyroid extract, or extract made from the anterior lobe of the pituitarj? Ijody or the pharyngeal pituitary. The toxic effects of pituitary extracts are not nearly so pronounced as those of the adrenals. The symptoms observed, in addition to those mentioned above, are apathy and somno- lence, excitation followed by muscular weakness, sudden cessation of heart-beat, and loss of weight after repeated injec- tions, cardiac hypertrophy, ulceration, and ha>morrhages in the intestine, and hyper;Temia and haemorrhages in the kidney. Urechia found that a reinjection after an interval of ten days gave rise to symptoms of an anaphylactic nature. E. The Question as to which Elements of the Pituitary Body furnish the Active Substance or Substances — Functions of the Different Parts of the Pituitary Body As we have already seen, Howell discovered that it is from the posterior lobe only that active extracts can be obtained. This was confirmed liy Schafer and "Vincent. Tlie observation was contrary to what might liave been expected, since, from the distinctly glandular nature of the anterior lobe, it would appear THE PITUITARY 357 a priori that it would be more likety to furnish active physio- logical substances. But we must remember that there are epithelial elements in, and in close relation to, the nervous portion (Figs. 94 and 95), and it was a natural assumption that these, and not the nervous portion proper, would be found to yield the pressor substance. But some years ago, Professor Osborne and myself tested the matter, and found that an extract made from the central part of the uxfundibular portion — devoid of epithelial elements — is much more active than one from the peripheral epithehal part. We expressed the opinion that probably the external layer would be found to be inactive if it could be obtained quite free from admixture with the central portion. iSchafer and Herrmg found this to be the case too with the substance which acts as a diuretic. Improbable, then, as it would appear at first sight, the conclusion is inevitable that it is the nervous portion proper which contains the substance or substances having such pronounced pharmaco-dynamical properties, different from those possessed by other kinds of nervous tissue. I have never had an opportunity of repeating the experi- ments carried out in conjunction with Professor Osborne, but, since they have been amply confirmed, I am strongly inclined to adopt the view of Houssay that the substance or substances are secreted by the cells of the pars intermedia, and then collected, and concentrated, or changed into more active forms in the nefvous portion jjroper. ^ No physiological^ active substances can be extracted from the anterior lobe (except a depressor substance, which is common to all organs and tissues). This j^art of the pituitary is related to the general growth of the body, and especialty of the skeleton. (See Section F.) F. Feeding and Metabolism Experiments The first metabolism experiments were performed by Schii¥. 1 Herring has recently confirmed the results of Osborne and Vincent. " The pars nervosa is from two to five times more powerful than the pars intermedia in its action." He thinks that the substance acting upon the uterus is formed at an early stage in the pars intermedia, but the substance acting upon the blood-pressure and kichrey is a later product, resulting from the breaking down of the hyaline bodies or disintegrating pars intermedia ceUs in the pars nervosa. 358 THE DUCTLESS GLANDS He found that there was no influence ou the nitrogen in any case, but that tlie jihosphorous output was sometimes increasedj due to katabolism of bony tissue. But the increase may have partly been due to nuclein. Moraczewski found in a case of acromegaly that the nitrogen output was increased, also that of phosphorus, while Oswald found no effect on nitrogen or phosphorus. ]\Ialco]m noted that the anterior lobe, administered dry, tends to cause a retention of nitrogen ; the dried nervous portion has a similar effect. The fresh entire gland, in large doses, increases the output of nitrogen. The anterior lobe causes a retention of j)hosphorus, while the posterior lobe causes a loss followed by retention. On the whole, Malcolm's results pointed to a greater activity on the part of the nervous portion. Caselli observed no effect on growth from long-continued injections of extracts made from the whole gland, but in some cases feeding with the gland retarded growth. Sandri fed young mice and guinea-jsigs with pituitary emulsion, and states that this caused an arrest of growth. Cerletti injected pituitary emulsion intraperitoneally into J'oung animals, and found that the animals receiving the injection fell uniformly below the controls in weight, and that the bones of the animals receiving the emulsion were, as compared with the controls, somewhat shorter as regards the diaphyses, but longer as regards the epiphyses. Schafer has carried out a series of feeding experiments on white rats, the general conclusion from which is that the addi- tion of small amounts of pituitary tissue to the diet of rats has little or no effect upon growth. Franchini, working with rabl)its and guinea-pigs, rejjorts that the calcium and magnesiinn metabolism is much reduced. Elfer reports that subcutaneous injection of pituitarjr extract does not affect the protein metabolism, but induces a tem- porary retention of phosphorus, calcium, and magnesium. Quite recentlj' Rosalind Wulzen has investigated the effects of administration of anterior lobe of pituitary body to J'oung growing birds. A very distinct effect is shown in the direction of retardation of growth, which is manifested both in the body and in the length of the long bones. Involution of the thymus accompanies this retardation, and the suggestion is made that THE PITUITARY 359 the former may hear a. causal rehitiou to the latti^'r. The effects are more marked in males than in females. In very few of these investigations (the last-mentioned series forming a notable exception ) has sufficient attention been paid to the difference between the anterior and posterior lobes of the pituitary. It must be pointed out that, even when ordinary care is taken to separate the anterior from the posterior lobe, the former will include a strip, which varies in thickness in different animals, of the pars intermedia. The reflection of this part over the nervous portion is now well known, and account has been taken of its presence in the consideration of the effects of posterior lobe extracts (see Section D), but the fact which I have just pointed out, viz., that there is a reflection of the pars intermedia over the anterior lobe, is not so generaUy re- cognized (Fig. 94) . If the jjars intermedia be traced round from the nervous on to the glandular jDortion, it will be noticed that the cells forming it gradually fuse with the cells of the glandular portion in the depth of the latter structure, but are continued as a layer, retaining at any rate some of the characters of the pars intermedia, along the edge of the cleft. Although the amount of pars intermedia adhering to the anterior lobe is not very considerable, it is possible that it might make a difference to the physiological extract. Houssay is the only author, so far as I am aware, who has definitely di'awn this as a continuation of the pars intermedia ; though Herring states that the anterior lobe in the cat is separated from the cleft by cells, " which are larger than endo- thelial cells," and are continuous at the anterior and posterior ends of the cleft with the cells of the epithelial reflection. He admits too that the cells of tlie intermediate portion occasionally spread down a little over the front of the anterior lobe. The general arrangements are sho^^n in Fig. 94, and the microscopi- cal structure in Fig. 95. Pituitary feeding is stated to have very similar effects to those produced by thyroid in bringing about precocious meta- morphosis in amphibia. It is also said that the rate of fission of planarian worms is increased by a diet of pituitary substance. G. Grafting Experiments The effects due to increased functional activity of the pit- uitary body cannot be induced by glandular transplantation. 360 THE DUCTLESS GLANDS Cusliing adopts the theory of W. S. Halsted that an existing " physiological deficit " is one of the essentials for a successful organo-transplantation. In support of this, Crowe, Cushing and Homans observed that the life of animals, after a total pituitary extirpation, could be prolonged by the immediate reimjjlantation into the cerebral cortex of the excised gland, which lived for a month. In the absence of such a j>reviously established deficit, the transj)lanted gland becomes absorbed in a short time. In Schafer's experiments the only distinct effect noticed was with the po.sterior lobe, which caused a temporary increase in the flow of urine. As the implanted gland soon became absorbed, this result is probably to be looked upon simply as the effect of the administration of an equivalent amount of ^Jituitary extract. It is i^ossible, however, that the transplanted gland may have functioned for a short time. In Exner's experiments on rats, transplantations were made of glands taken from young animals, and there was a temporary increase in growth and weight. But it is possible, in this case as well, to assume that the effect was comparable to a long- continued administration of an equivalent amount of extract.^ It is pointed out by Cushing that the results of these various transplantation experiments suggest some therapeutic possi- l^ilities for this method, as the slow absorption of the secretion may be an effective means of administering the active principle. Cushing appears to have obtained some clinical evidence that, when a patient is actually suffering from a physiological deficiency, fragments of a transplanted pituitary body may survive and remain permanently active. H. Stimulation of the Pituitary Body in situ. Cyon has studied the functions of the gland by the method of direct excitation. He exposed the hypophj^sis by trephining the base of the skull beneath the sella turcica. Then he exerted light pressure Tipon the gland by means of a small pad of cotton. He observed iramediatelj' a considerable variation ^ It must, however, be noted that the effects produced, viz., increase in growth and weiglit, are in a contrary sense to those observed by the majority of recent experimenters, administering tlie gland by the mouth. But tlie effect of giving whole gland would possiljly be different from that of giving anterior lobe only. THE PITUITARY 361 ill the blood-pressure and m the number and mtensity of the heart-beats. These variations occurred to some extent as tlie result of the trcphinmg, but were much exaggerated by a very slight electrical stimulation. Cyon worked with rabbits, and noted a considerable slomngof the heart-beat, M'ith increase of amplitude. Different results have been obtained l>y the majority of subsecjuent workers ; but Llasay obtains results similar to those of C!j'Oii, though his interpretation is different. The effect of direct stimulation of the gland he attributes to an increased discharge of the internal secretion into the blood-stream, where it produces the usual result due to the action of the extract upon the heart. (Schafer reports that, in dogs, partial injury to the pituitary by means of a thermo-cautery or mechanical agents induces marked diuresis. This result is specially interesting in relation to the polyuria , which occurs in injuries and tumours affecting the base of the brain. This poljairia is more likely to occur when the pars intermedia is involved. I. Extirpation Experiments The first to perform experimental extirpation of the p)ituitar_y was Horsley, in 1S86. Subsequent observers obtained con- tradictory results ; but it was established by Paulesco, in 1006, that the organ is essential for lite, and that the onset of the acute symptoms depends on the loss of the anterior rather than on that of the posterior lobe. Paulesco's results have been con- firmed in the main by Gushing and his co-workers. These find that pu2:)pies survive total extirp)ation longer than do adults ; that life can be prolonged (see iSection G) by transplantation of the removed gland ; that, in all cases which recovered, a fragment of the anterior lobe was invariably found to have survived ; that animals \^dth a fragment of anterior lobe, temporarily insufficient to support life, could be tided over a period of threatened cachexia hypophyseopriva bj' subcuta- neous mjections, or by feeding with anterior lobe ; and that removal of the jDosterior lobe leads to no very definite symptoms. The acute symptoms observed were tremors, fibrillary twitching, archmg of the back, insensitiveness, slow pulse and 362 THE DUCTLESS GLANDS respiration, a tenuiual abrupt fall in body tomperature, and apathy passing into coma and death. Gushing and his collaborators describe in animals, which recover after partial extirpation, certain constitutional disturb- ances, some of which (e.g., carbohydrate tolerance) they now admit to be due in part to posterior lobe deficiency. Tliese constitutional disturbances are adiposity, changes in the skin, disturliances of carbohj'drate metabolism, of temj^erature, of growth, and of secretion by the kidney. Sexual inactivity and changes in most of the ductless glands are also described. In some cases, the adiposity was so extreme that the weight of the animals became doubled, the dcjDOsition of fat is widely distributed, and in some regions oedema is recorded. The skin becomes dense, dry, and less movable than usual. The hair becomes biistiy and tends to fall out in joatches — changes, as pointed out by Gushing, not unlike those found after thyroid extirpation. When much pituitary substance has been removed, a sub- normal temperature is the rule, and it may fall nearly to room temperature. The normal temperature may be restored by applying heat, but this hastens the end. In some cases, Gushing found, when the temperature was not very low, that it could be raised l)y ingestion, or subcutaneous injection, of pitui- tary extract. He states that a thermic reaction occurs, upon the injection of pars anterior preparations, only in cases of anterior lobe deficiency, and can be used as a clinical test when anterior lobe deficiency is suspected. Pulse rate and respiration i\va,y be slow, and the blood- pressure low. In young animals, partial pituitary extirpatioii results in disturbances of growth, especially in skeletal undergrowth. Gushing also reports mental dulness, irritability, and a. tendency towards epileptic fits. After extirj^ation, a temporary glj'cosuria usiuxlly ensues, followed by a short period during \vhich the assimilation limit is below normal. Subsequently, the animals acquire such a tolerance for sugar, that it is often difficult to produce alimen- tarj' glycosuria with the amounts of sugar that can be retained. According to Gushing's observations, these facts are connected with removal of, or damage to, the posterior lobe, and the inter- pretation given by this wTiter is as follows : " Normal posterior THE PITUITARY 363 lobe activity is essential to effective carbolij'ckate metaljolisni ; an intravenous injection of posterior lobe extract produces glycogenolysis, and its continued administration in excessive amounts leads to emaciation. A diminution of posterior lobe secretion occurring in certain conditions of hypo-pituitarism (whether experimentally produced or the result of disease) leads to an acquired high tolerance for sugars, with the resultant accumulation of fat." It is reported that, contrary to what might have been expected, removal of the posterior lobe increases the flow of urine rather than diminishes it. There is often a true diabetes insipidus, lasting for some time. Experiments upon puppies disclose a persistence of sexual infantilism. There are as well changes in the testes, ovaries, thyroid, thymus and adrenal cortex and medulla. Moreover, changes occur in tlie reverse direction, for example in the pituitary after castration or thyroidectomy, and Gushing reports changes in the posterior lobe after extirpation of the pancreas. So far as can be gathered from Cushing's account, this author attributes most of the disturbances above described to deficiency of the anterior lobe ; indeed the only changes, which he definitely attributes to damage to the posterior lobe, are the effects upon carbohydrate tolerance and upon the secretion by the kidney. He does not state definitely whether these clianges are due to loss of the nervous portion proper, or to that reflec- tion of the pars intermedia which passes over the nervous I^ortion. Hanselmann and Horsley have failed to confirm the results of Gushing and his colleagues. In their exjDeriments there was a very high death-rate from shock, htemorrhage, and infection ; but in the animals which survived, there were lao characteristic symptoms like those described by Gusliing. Hanselmann and Horsley further state that they observed a f)arallel death-rate in animals, in whom incomplete extirpation had been carried out. It is clear that the results of this series of experiments are quite different from those obtained by Paulesco and Gushing. Aschner has opposed the view that the pituitary body is essential to life. He operates through the roof of the mouth. In adult animals, according to Aschner, there are no serious symptoms after the complete operation, although there are slight metabolic changes. In j''oung animals, on the contrary, 3C4 THE DUCTLESS GLANDS profound effects are produced. In these cases, the symptoms described are analogous to those given by Gushing, and which are detailed above. His operative proceedings are criticized by Biedl and by Gushing. Quite recently, Aschner has emphasized the relationships between the pituitary body and the genital organs, and points out the bearing of these upon pathological conditions in the human subject. Staderini believes that extirpation experiments have given contradictory results in the hands of different observers, because operators have not always taken account of the " lobi laterales " and the " lobus premamiUaris," described by him in the cat and in the ox. Perna has given a full description, with illustrations, of a " post-glandular prolongation " in the human subject. Other " accessory pituitaries," which may be men- tioned here, are the " pharyngeal pituitary Isodies " descriljed by Haberfeld and others. Gomplete extirpation can never be said to have been per- formed, unless these accessory bodies have been removed along with the main pituitary. Moreover, accordmg to Biedl, total extirpation can only be described as such when, in addition to the removal of both lobes, the hypophyseal peduncle is severed as well. This latter operation is in itseH, according to Biedl, as fatal as complete extirpation of the pituitary body. This was found to be the case also by Paulesco, and Aschner has only recorded the survival of animals in pituitary operations when not too much of the infundibuluni was removed. Morawski, however, found that cuttmg through the peduncle has no serious effect on the monkey, while cats will not survive the procedure. This difference is explained by him by the fact that, in the monkey, cutting through the iJeduncle does not make an opening into the third ventricle, which must happen in cats and dogs. Biedl thinks that the real explanation lies in the anato- mical relationshijjs of the pars intermedia in the different animals, and is of the opinion that the openmg of a communica- tion with the third ventricle is a matter of no consequence. Summing up, so far as is possible, these somewhat contra- dictory experimental results, we may conclude with some degree of probability that : — 1. Total extirpation of the pituitary body is a fatal opera- tion, though the duration of life in the operated animal varies THE PITUITARY 365 very considerably according to its age. Adult dogs and cats will not survive more than two or three days ; young animals may live as many weeks. 2. Partial extirpation of the pituitary body (if a small part of the anterior lobe be left behind) gives rise to distm'bances in growth and metabolism already described, and these may be induced in young animals by deficiency of anterior lobe only. 3. The effects upon the genital organs may be due to de- ficiency of the pars intermedia, and the preponderance of evidence is that the polyuria and disturbance of carbohydrate metaboKsm (tolerance) are due to deficiency of this part as well. 4. It seems possible that removal of the nervous portion proper would be without any serious effects. This operation can, however, scarcely be carried out -without damage to the pars intermedia, and this damage brings with it the metabolic disturbances just referred to. It is interesting to note that, just as in the case of the adrenal bodj^, so we have in the pituitary two main portions, one of them glandular, the other nervous. In the case of both organs, the physiologically active substances are found in the nervous portion (neurohypophysis, adrenal chromaphil tissue), while the glandular portion seems to be that which is essential to life. The above summary represents the views of the majority of those who have devoted themselves to the subject of pituitary extirpation. But it is somewhat disconcerting to find careful observers who express themselves in such a sceptical vein as do Camus and Roussy. These authors believe tliat the polyuria which occiurs on extirpation of the pituitary is not due to the removal of this organ, but to a lesion of the opto -peduncular region at the base of the brain. This region lies at the level of the grey substance of the tuber cinereum in the vicinity of the infundibulum. Tliis zone seems to play some part in the mechanism of water retention in the organism. Atrophy of the genital organs and the " adiposo-genital syndrome " are likewise due less to any hypophyseal lesion than to trouble at some point in the base of the brain. The same applies to the changes in tolerance to carbohydrates and the appearance of alimentary glycosuria. These experiments, if the results are confirmed, will necessitateareconsiderationof Qur whole attitude in relation to the pituitary body. 366 THE DUCTLESS GLANDS J. The Question as to a Functional Relationship between the Pituitary and the Thyroid Bodies From the time when the ductless glands first began to be known, there has been a decided tendency to regard them as physiologically more or less related to one another. In the earliest days, there can be little doubt that the grouping together of these organs was very largely to be ascribed to our uniform ignorance of their functions. But during recent years a certain amount of information has been accumulated, which renders it probable that there are true interrelationships between certain of the glands endowed with the power of internal secretion. The whole question constitutes a very fascinating, albeit a very abstruse, chapter in the physiology of internal secretion. We are, however, in this place concerned only with a possible functional relationship between the thyroid and pituitary bodies. Many of the suggestions which have Ijeen made were of an a ■priori character. Cyon has put forward a theory of an elaborate kind about the mutual function of the thyroid and pituitary bodies, and he regards the latter as a centre from which the vascular supply of the brain is influenced through the former. Rogowitscli, in 1888, observed in rabbits, killed at periods of from two to ten weeks after thyroidectomy, a marked hyper- trojihy of the 2:)ituitary body. This result was confirmed by many observers. Quite recently Lydia M. Degener has found that the increase in weight of the pituitary, after the tliyi'oid glands have been " completely removed " ^ from rabbits, runs parallel with the time which intervenes between thyroidectomy and the death of the animal. After an interval of 179 days, the pituitary body had increased to about three times the normal size. In these hypertrophied pituitaries there is increased activity of the cells of the pars intermedia, and in the proper nervous part of the posterior lobe. In these situations, granular, ' This means, presumaVjly, that, the thyroid and internal parathyroid on both sides were removed, leaving behind both external parathyroids. THE PITUITARY 367 hyaline, or colloid bodies become very numerous ; they appear to be 23artly of a cellular nature and to find their way between the ependyma cells into the infundibular recess and ventricles of the brain. The colloid appears to arise from the epithelial cells of the pars intermedia. TJie jJrecise nature of the relationship existing between the thyroid apparatus and the pituitary body is by no means clear. iSimiDson and Hunter report that complete removal of the thyroid gland in lambs does not lead to the appearance of iodine in tlie pituitar3^ On the assumption that the iodine containing substance of the thyroid represents its active secretion, this does not support the Rogowitsch theory that, in thyroid insufficiencj', the pituitary vicariously takes on its function. In the experiments of Simpson and Hunter, there was, however, some compensatory hypertrophy of the pituitary body. It only remains to make reference to some experiments of Masay in opotherapy, with the object of ascertaining whether pituitary extract can replace the internal secretion of the thyroid ; the results were entirely negative. K. Pituitary Insufficiency and a Pituitary Antiserum or Cytotoxin Masay has attempted to produce pituitary insufficiency by the method employed by Demoor and Van Lint in order to obtain an " anti-thyroid serum." Guinea-pigs were injected intraperitoneally with an emulsion of clog's pituitary at intervals of two days. After three, four, or five injections the blood of the guinea-pig was collected and centrifugalized, and the serum (about 10 c.c.) was injected under the skin of a dog. Masay gives his results in considerable detail, and the effects upon the animal are shown in a series of illustrations. After a certain number, usually two or three, of such injections the dogs show symptoms, such as loss of flesh, muscular weakness, especially in the hind limbs, changes in the skeleton and in the structure of the pituitary, the symptoms constituting, according to Masay, a veritable cachexia hypojihyseopriva. Ossokin reports that the " hypophyseolytic serum," prepared from the blood of dogs immunized with posterior lobe of 368 THE DUCTLE.SS GLANDS pituitaiy, produces a marked fall of blood-pressure. The precise significance of this is difficult to understand. It is yet too early for us to be able to determine the value of these antiserum exiieriments. L. Chemistry of the Pituitary Body Schafer and Vincent, who described a jiressor and a depressor substance, found that the latter could he separated from the former, on account of the fact that it is soluble in alcohol, in ether, and in normal saline solution. This is of course the depressor substance common to all animal tissues. iSchafer and Herring contend that two active principles exist in pituitary extracts, one acting on the cii'culatory system, the other specifically on the Iddney. Dale does not consider tlie evidence on this point to be satisfactory. Within recent j'ears three observers have claimed to have obtained, apparently independently, the active suljstance in a pure form. Houssay, in 1911, prepared tlie active substance as follows : — " The fresh hind lobes were boiled in water ; the filtrate was then precipitated with lead acetate and snlpliurio acid, filtered, and the filtrate dried in vacuo. Tlie residue is washed with chloroform, ether, and alcohol, and finally crys- tallized in vacuo. The product is insoluble in alcohol, ether, or chloroform, but very soluble in water, and is dialj^salile. It is precipitated by picric acid, platinum chloride, etc. If burnt on platinum foil, it gives oS the smell of burnt feathers." Solutions of this product in normal saline produce the effects of pituitary extracts upon the heart and vessels. Fiihner claims as well to have isolated a pure crystalline basic substance, which has been put nj^on the market in the form of its sulphate, and is called hyj)ophy$in. Fiihner 's product is said to possess aU the activities of pituitary extracts on resjiiration, blood-pressure, and the uterus. Herzberg has tested Fiihner's substance clinically, and reports that its action Tipon the uterus is powerful and prompt. " Hyjiophysin " is stated to consist of four separate substances. In still later papers, Fiihner and Schickele declare that the substance acting upon the uterus is independent of that acting u])on the Ijlood-jiressure, and can be obtained from extracts of the a-ntcrior as well as of the posterior lobe, THE PITUITARY 369 Robertson states that he has succeeded in isolating from the anterior lobe a substance called tethelin which quickens growth in young animals and is thought to have a possible value in hastening the healing process in wounds. M. The Comparative Physiology of the Pituitary Body Professor Osborne, working in conjunction with the present writer, showed that extracts of the pituitary body of the cod produce effects upon the heart and bloodvessels similar to those of extracts of the mammalian posterior lobe. Schafer and Herring demonstrated that extracts made from the cod's pituitary jjroduce kidney dilatation and diuresis when injected, just as do extracts from the mammalian posterior lobe. The subject has been recently more thorouglJy investigated by Herring. This observer finds that the posterior lobe of the pituitary body of the fowl produces an effect on blood-pressure, Iddney volume, and urine secretion, which is very similar to that produced by extracts of the posterior lobe of the mam- maUan pituitary. It was found to be impossible to determine whether the active principles in the posterior lobe of the bird's pituitary are products of the epithelial ceUs of the pars inter- media, or are formed solely in the nervous substance. No distinct effects were produced by extracts of the avian anterior lobe. In regard to Teleostean fishes, extracts of the anterior lobe proper — chromophil portion of Sterzi and Gentes — have little physiological effect. The general effect of extracts of the posterior lobe is similar to that brought about by extracts of the mammalian aird avian posterior lobes. In Teleosts the cells of the pars intermedia jDredominate in the posterior lobe, and are inseparable from the pars nervosa, so that one cannot determine which produces the active material. According to Herring, both are probably concerned, for wherever cells of pars intermedia — chromophobe cells of Sterzi — are bound up with pars nervosa, extracts of the resulting tissue produce the effects on blood-pressure, Iddney volume, and urine secretion which have been associated with extracts of the posterior lobe of the mammalian pituitary. Extracts of the saccus vasculosus are practically inactive, and Herring supports the supposition 24 370 THE DUCTLESS GLANDS of Gcntes that tliis structure has a function similar to that of a choroid plexus. The Elasinoljranch pituitary, as wc have already seen, is quite different in structure from the pituitary bodies of mam- mals, birds, and Teleosts. There is no differentiation into anterior and posterior lobes. According to Herring, there are no cells precisely corresponding to those of either the anterior portion or the pars intermedia of the mammalian body. The jiresence of the true nervous portion seems also doubtful. Extracts of the Elasmobranch pituitary give rise to no characteristic physiological effects. N. Diseases of the Pituitary Body 1. Introductory According to Gushing, a pronounced constitutional dys- pituitarism is not incompatible with a tolerable state of health and comfort. In regard to symf)toras due to each of the two lobes, there may be an overaction or underaction of one lobe only, or an overaction of one lobe associated with insufficiency of the other. In the minds of manj' authorities the subject is rendered still more complex by a tendency to regard every disorder of the ductless glands as a polyglandidar disease. This is said to be sometimes so pronounced as to make it doubtful which of the organs is primarily at fault. It is generally believed that derangement of any one of these corre- lated glands leads to disturbances in others, but a primary disorder of any one will produce its own special sjmiptoms. A functional hyperjjlasia of the pars anterior pro)notes tissue growth, chiefly shown in the skeleton, skin, and sub- cutaneous tissues, and at the same time there is an excitatory effect on the reproductive organs, as seen in the secondarj? sexual characters. On the other hand, insufficiency of the anterior lobe inhibits skeletal growth and sexual development. Little is known about functional hjiperplasia of the posterior lobe. This part seems to be concerned with tissue metabolism. Insufficiency gives rise to slowed metabolic processes. There is a high tolerance for carbohj'ckates, \\hich are stored as fat, there is drowsiness, slow pulse and respiration, subnormal tem- perature, low blood-pressure, etc. This complex of symptoms just described strikingly resembles the phenomenon of hiberna- THE PITUITARY 371 tion, in which there is markedly slowed metabolism and in which histological changes in the pituitary body have been described. There is a tendency for pituitary diseases to lapse into a condition where glandular insufficiency is the most noticeable feature, and this is especially the case with disorders of the anterior lobe. Gushing divides symptoms of pituitary disorder into three main groups : — 1. Endosecretory symptoms on the side of hyperpituitarism. 2. Endosecretory symptoms on the side of hypopituitarism. 3. Endosecretory symptoms of a polyglandular character. As one might expect, many and very complicated systems of classification have been attempted. 2. Acromegaly (1) Introductory The disease, which is characterized by enlargement of certain bones of the body, especially of the hands and feet, was first described by Marie, of Paris, in 1886. It was observed by Marie that the disease is associated with tumours of the pituitary body. It had, however, been described previously under other names,' as " hjrperostosis of the entire skeleton " by Friedreich, as "general hjrpertrophy " or " makrosomie " by Lombroso, as " giant growth " by Fritsche and Klebs. (2) Symptoms There is usually a history of definite symptoms before the characteristic deformities occur. Headache, pains in other parts, irritable temper, moroseness, loss of memory, disturbances of vision, increased appetite, thirst, and polyuria are enumerated among the early symptoms. In women amenorrhosa is fre- quently noted, while in men there may be loss of sexual power. The head increases in size, the brows become arched and prominent, the forehead retreating. The nose is large. The zygoma and malar prominences are exaggerated. The upper jaw is not much altered, but the lower is distinctly enlarged (Fig. 98). The lower teeth may project beyond the upper. The chin is thick and the face may be oval or square. The tongue becomes enlarged and may force the mouth open and plays a part in the deformity of the alveolar processes. It is ijsually indented at the sides and the papillae are enlarged. 372 THE DUCTLESS GLANDS Fig. 98. — T;\q:)ical acromegalic profile. (From Cusliing. ) is easily induced. Flushing tiuglinj changes are frequent. In the later stages the muscles become small and weak, a change which accounts for the peculiar posi- tion of the head, the kyphosis, and other deformities. Affections of sight are common, blurring of vision, concentric nar- rowing of the visual field, bitem- poral hemianopia, otitic atropli^? are often met with. The pupils may be dilated. The sixtli and third nerves may also be affected. Painful noises in the cars are fre- quent and deafness may super- vene. Loss of memory, mental slowness, depression or delusions The thorax i.s en- larged, especially from back to front. There are various degrees of kyphosis, scoliosis and lordosis. The hands are in- creased in size, the fingers are thick and sometimes sausage- shaped. Though the bones of the hand are sometimes increased in length, most of the en- largement is in the sub- cutaneous tissue. Math increase of the points of attachment of the tendons. (See Fig. 99.) The ankles and feet are decidedly enlarged. The skin is usually dry, but perspiration ; and other vasomotor Fig. 99. — Cliaracteristic square liand with deep palmar creases. (From Gushing.) THE PITUITARY 373 are frequent. Somnolence is often marked, and may pass into stupor. The urine is normal or there may be glyco- suria (Dock). (3) Mtiology and Onset Acromegaly has been sometimes ascribed to syphilis, or some other specific infection. Heredity has also been claimed as having some part in the causation. There is, however, lao sufficient evidence that any of these l^ear any essential relation to the disease. The disease occurs, perhaps, most frequently in early adult life, between the age of puberty and the thirtieth year. It is more common in women than in men. The onset is gradual. (4) Metabolism in Acromegaly If acromegaly be, in fact, due to a hypersecretion of the pituitary bodj^, we should naturally expect that in this disease the metabolism would be modified in the same direction as in animals fed upon pituitary substance. The few experiments which have been performed upon acromegalic patients have given contrary results. Retention of phosphates in the bones and muscles and increase of urinary calcium have been alleged. (5) Morbid Anatomy The bones appear to undergo a true hypertrophy in the majority of cases, though it is stated that the superior maxiUary appears to be larger on account of a simple dilatation of the antrum. In the long bones the enlargement affects the ends as well as the shaft. The view which has the greatest number of adherents at the present time is that the characteristic lesion in acromegaly is adenoma of the pituitary. This belief was first definitely put forward by Benda. Previously the tumour had been known by various names, perhaps most freqviently as a " round- celled sarcoma." Hanau had previously suggested that the typical growth is an adenoma ; and Lowenstein has given a lucid account of the development of this adenomatous tumour. Other tumours of the pituitary do not appear to give rise to acromegaly. Thus, Pende states that tumours of the " pharyngeal pituitary " (remains of the pituitary duct) never 374 THE DUCTLESS GLANDS give rise to acromegaly. Several authors report cases of pituitary sarcoma without any signs of acromegaly. The same ajjplies to carcinoma and endothelioma. Microscopical examination shows that the tumour in acro- megaly has all the characters of the anterior lobe of the pituitar_y body. The various kinds of cells found in the latter structure are also regularly found in the tumour. Thus, it would appear that an adenoma of the anterior lobe of the pituitary is the essential lesion characteristic of acromegaly. (6) Pathogeny Various theories have been sustained as to the origin and essential cause of the symptoms of typical acromegaly. It was suggested by Freund that acromegaly is simply an anomaly of development. Some writers have imagined that the essen- tial lesions in acromegaly are in the thyroid or in the thymus. It has also been suggested that defects in the reproductive organs may be responsible for the conditions {vide infra, p. 375). The nervous sj^stem has from time to time been called in question. But of late years most of the theories advanced have assumed that the i^ituitary is in some way affected in all undoubted cases of acromegaly. Of the pituitary theories, the first was that of the original describer of the disease — Marie. His view was that acro- megaly is due to destruction of the pituitary, and therefore to complete abolition of its function. Those who still uphold this view look upon the gland as supplying a Jiormone whicli regulates tlie growth of the skeleton, which growth, in the absence of such regidation, proceeds almormally. Bleibtreu has published a record of a case of acromegalJ^ in which he states that there was total destruction of the pituitary gland. The opposite view, that the symptoms of acromegaly are due to a hypertrophic condition of the pituitary, more particu- larly of its anterior' lobe, is lield by Tamburini and Woods- Hutchinson. The most important argument in favour of this view is the frec|uency with which a true adenoma has been reported as occurring in typical cases of acromegaly. It may be supposed that, according to this theory, the anterior lobe THE PITUITARY 375 of the pituitary body furnishes an abnormal, an excessive, quantity of some hormone which stimulates bone growth, and that, in consequence, the growth of bone itself becomes excessive. The cases referred to above in which after death the sub- stance of the pituitary has been completely destroyed and replaced by a malignant growth, would seem to present a certain difficulty in the way of acceptance of the hyi3ersecretir)n theory. They would seem, in fact, to furnish important evidence that the symptoms of acromegaly have been brought about as the result of the suppression of an internal secre- tion. But, of course, it is possible to assume that the tumour at its beginning was non-malignant, and that the malignant character has become develojDed shortty before death, and that death has resulted from entire supiJression of the function of the gland, owing to destruction of the normal glandular cells by those of a malignant nature ; for it appears possible that complete destruction of the gland is incompatible with continuance of life. Since, after destructive disease of the reproductive organs, the pituitary is found to be enlarged, it has been suggested that the actual commencement of the mischief in acromegaly may ]>e in the ovary or the testis. The pathogenjr of acromegaly thus appears to be analogous to that of exophthalmic goitre, the first being due to a hy23er- function of the pituitary, the second to a hyi^erfunction of the thyroid gland. Yamada has recently reported a case in which there were clear symptoms of acromegaly with a normal pituitary, but the thyroid was enlarged, the thymus was f)ersistent, the testes atrophic, the pineal contained masses of colloid, and there was hypertrophy of adrenal medulla. The case was therefore characterized as " polyglandular." We must bear in mind the recent experiments of Camus and Roussy (see aljove, p. 3(ir->). (7) Course and Event of the Disease — Diagnosis, Prognosis, and Treatment The disease runs a slow and prolonged course, and goes on to a fatal is.sue. The diagnosis is usually a matter of no great difficult J^ 370 THE DUCTLESS GLANDS From osteitis dejormans and irora arthritis deformans it maybe distinguished because the enlargement is general, instead of affecting only the shaft, as in osteitis deformans, or the ends, as in arthritis deformans. In osteitis deformans, too, as poiirted out by Marie, the face is triangular, with the base ttjnvard, wliile in acromegaly it is ovoid, with the large end downward. In congenital progressive hypertrojjhy, or " giant growth," only one limb becomes affected, and tlie shaft of the bone is involved. But the differential diagnosis from certain diseases of the nervous system, and in particular from syringomyelia , is stated to be sometimes very difficult, or even impossible. In affections of the spinal cord enlargements of the extremi- ties are liable to occur, and especially is this true in syringo- myelia. Fischer gives several examples from Schlesinger and otliers. It is stated that syringomyelia may give rise to the typical clinical and anatomical features of acromegaly. If this is true, then it will be absolutely impossible in certain cases to make a correct diagnosis during life, and it must have frequently happened that cases of syringomyelia have been described as " acroniegaly without tumour of the pitui- tary." The suggestion has been tentatively put forward that the hypersecretion of the pituitary may, after all, pro- duce the condition of acromegaly by action upon the nervous S3rstem. The prognosis is bad, and all treatment hitlierto attempted seems to be witliout avail. Naturally, treatment with pituitary ])reparations lias been tried. This, of course, lias been done on the hypothesis tliat acromegaly is due to diminished action on the part of the gland. The results are unsatisfactory, and even definitely unfavouraljle results were sometimes obtained. No reduction can be effected in the size of the extreiuities bj' juternal administration of the gland. Magnus-Levy records a case of acromegaty treated with pituitary substance. Symp- toms arose which recalled features of Graves's disease — marked perspiration, 23olyuria, and ahmentary glycosuria. It seems, from all that has gone before, that the only rational treatment for acromegaly is a partial extirpation of the pitui- tary body. This was first definitely suggested by Victor Horsley, and has been extensively carried out by Gushing and others. ^ +h Note narrow chest large ass."""" '''"»"3r''- 378 THE DUCTLESS GLANDS (8) Other Conditions involving Pittdtary Hyper function There are reasons for thinking that many forms of gigantism are due to hyperfunction of the pituitary, and proljalsly to hyperfunction of the anterior lobe. In these cases there is rarely, if ever, a definite adenoma of tlie gland. But it is Figs. 101 & 102, — Marked adiiiosity. 124 l)i. inorease in 1-1 months. (From Cushing. ) possible that the structure miglit nianufacture certain sub- stances in excess of the normal, without overgrowth of the gland as a whole, but simply by multiplication of certain cells. 3. Conditions involving Hyposecretion of the Pituitary Frohlich was the first to point out that in cases of pituitary THE PITUITARY 379 tumour without acromegaly there may be manifested a peculiar syndroma, characterized by the accumulation of fat and dis- turbance of the genital functions — degeneratio adifoso-genitalis . Erdheim, however, is of the opinion that not only pituitary tumours, but other growths in this region of the base of the brain, may give rise to a similar train of symptoms. Cf . Camus and Roussy, p. 365. It is thought by Fischer that the effects are due to damage to, or destruction of, the posterior lobe of the pituitary body. The experiments of Gushing, however, would seem to teach that it is deficiency of function of the anterior lobe which leads to degeneratio adiposo-genitaUs. Dystrophia adiposo-genitalis {Degene- ratio adiposo-genitalis). — This condition, sometimes known as Frohlich's syn- drome, is very generally supposed to be due to pituitary insiifficiency. The patient becomes obese and the fat has a peculiar distribution. It is most abund- ant on the abdomen, buttocks and the proximal portions of the extremities. (Figs. 101 and 102.) Dwarfism is a com- mon condition, due to deficient skeletal development. The genital organs remain in the infantile state and the secondary sexual characters do not develop. The skin is in most cases thin, smooth, and soft. Infantilism. — This term was first used by Lasegne and the types generally recognized are those of Lorain, Bris- saud, and Variot and Pironneau. Lor- ain's type is an infantilism in which the proportions are like those in the adult and there is a hypoplasia of heart and arteries. (Fig. 103.) Brissaud's type was that due to thyroid deficiency and called the myxoedematous type. Variot and Pironneau propose adding another type — progeria. Gilford proposes the following classification : — Fia. 103. — Typical case of Infantilism of Lorain type witli an enlarged 2 cm. sella. Patient aged 20 years months. Height 4 ft. 4 in. (after Gush- ing.) 380 THE DUCTLESS GLANDS InJaiUilisnt. 1. Evolutionary or pbyloKenetic 2. Developmental or ontogenetic infantilism infantilism A. InfantiKrnn of celV, B. ,, „ organs Q ^ „ the individual as a hole Oass I. Symptomatic General Infantilism Infantilism as a fluctuation A. Toxic B. Correlative C. Deprivational of mixed causation (a) Endocrinous (6) Simple correlative Class II Essential Infantilism Infantilism as a mutation Ateleiosis Progeria " continuous youth " Infantilism " Senilism " Premature old age (Cusliing tliinlis these two are possibly pituitary diseases.) Mr. Hastings Gilford believes that only one form of in- fantilism has been absolutely proved to be due to a deficiency of internal secretion, and this is thyroid infantilism. This is frequently referred to as iiiyxinfantilism (Brissaud's type). This author sees no objection to the use of the term '' pituitary or Frohlich's infantilism," but thinks that ^\e are not yet justified in affirming finalty that it is the result of a deficiency of pituitarj^ hormones. Crushing inchides the Lorain type as of pituitarj' origin. THE PITUITARY 381 GiHord thinks that many forms of infantilism are due to quite other causes than deficiency of internal secretion. Thus ateleiosis (delay of development, sexual organs being most delayed) is a mutation, and as such is liable to be associated with other anomalies of development — such as those of the thyroid or pitiiitary. These are, however, secondary, and not the cause of the condition. Achcmdroplasia (chondrodystrophia foetahs). — Achondro- plasic dwarfs resemble cretins, but shortness of the limbs is more noticeable in the former. According to some authors, the condition of achondroplasia is distinguished from chondro- dystrophia, the former being due to hypofunction of the repro- ductive organs arising in ntero, the latter being the result of hypofunction of the anterior lobe of the pituitary arismg in foetal hfe. The latter is sometimes a cause of brow presenta- tion and dystocia. According to some writers, there is a diminution in size of the sella turcica, and pituitary extract should be tried. The patients are not benefited by thyroid treatment. The condition has to be diagnosed from cretinism and rickets. The disease is, in brief, a foetal disorder which causes a defective growth of certain of the bones in utero and leads to congenital dwarfing of the extremities and other deformities which persist throughout life. It is said that there is an abnormal arrangement of the cartilage cells along the line of ossification. The obscurity involving the condition is shown by the very numerous names which have been employed to describe it. In addition to the above-mentioned names, the disease is referred to as Rachitis foetalis, Pseudorachitism, Pseudorachitis fcetalis micromelicci, , Cretinoid dysplasia, Chondritis foeta.lis, Micromelia. There is no certain proof that the typical cases of Achondro- p'asia arise from any disorder of any of the glands of internal secretion. Carbohydrate Tolerance in Pituitary Disorder. — An increased tolerance for carbohydrate has been recognized for some years as a test for pituitary insufficiency. One of the recognized methods of conducting this test is as follows : Twenty-five, fifty, or a hundred grammes of glucose dissolved in 150 c.c. of 382 THE DUCTLESS GLANDS water are administered to the patient on an era-pty stomach. The blood-sugar is estimated after half an hour and then at intervals of one hour. The blood-sugar increases in amount up to a certain degree and then falls again. The curve obtained must then be compared with an average normal curve. 0-200 0-190 0-180 o-no %,0-160 r^O-150 "^o-iao 0-120 0-ito- 0-100 0-090 1' — ., ' ' T 1 2 3 4- S Hours. The chart iUustrates the effect of 25 gms. of carbohydrate on a moderately severe case of diabetes. The interrupted hnes represent a normal blood- sugar cui-ve ; the upper continuous curve was obtained when the patient was receiving a diet slightly in excess of his tolerance level for carbohydrate, the blood-sugar before the test being high in consequence. The lower curve was obtained after two days' starvation which had reduced his blood-sugar to a low level. In both the initial level was not regained till after 5 hours. (From Maclean.) Diahetefy insipidus. — The symptoms of this disease are too well known to require a description. The point of immediate interest to us is the connection between the polyuria and a disturbed function of the pituitary bod5^ A considerable number of cases have been described in which a lesion of the posterior lobe was found fost mortem. Such lesions are. THE PITUITARY 383 however, not invariably accompanied by diabetes insipidus. The experimental and pathological evidence is not conclusive. Treatment of patients by means of subcutaneous injection of pituitary extracts seems to have given some very striking results. According to Kennaway there is very frequently an immediate restoration of a normal state of the urine when pitui- tary extract is given in diabetes insipidus. This writer also urges that the fact provides strong evidence for the normal activity of the gland in regulating the secretion of urine. In pituitarjr disease conditions of primary over-activity become blended later on with symiDtoms characteristic of known stages of functional insufficiency. So that in certain conditions it may be difficult to tell which predominate (Gush- ing). It will be remembered that Tamburini in 1894 described a " two-stage " process in acromegaly ; a glandular hyper- trophy with hyperactivity characterizing the first stage, while in the second or terminal there occur degenerative changes with diminished activity and resultant cachexia. 0. The Use of Pituitary Extracts in Medicine, Surgery, and Gynaecology Reference has already been made to the use of pituitary extracts in acromegaly. We have seen that they have not been found to be beneficial in this disease. Nor should we expect them to be of service if acromegaly be, in fact, due to a hypersecretion of the gland. But there are many other conditions in which pituitary iweparations have been recommended and employed. In conditions of sJiocli, pituitary preparations are believed to be of more value than adrenin. This is due partly to the fact that pituitary preparations (" pituitrin," " infundibulin," etc.) keep the blood-pressure raised for some considerable time, while the effect of adrenin is very fleeting. Saline infusions should, however, be used ; reliance should not be placed on the j^ituitary extract alone. Owing to its powerful action on the uterus (see p. 351), pituitary substance is now employed in many ohstetric con- ditions. The action on the uterus was first noticed by. Dale, and has since been studied by several observers. Foges and Hofstatter have obtained results similar to those of Dale and 384 THE DUCTLESS GLANDS Bell, and recommend pituitrin in ^^ost-partum haemorrhage. Other observers now recommend the use of the drug hi labour. Bell strongly recommends " infundibulin " in cases of sluggish intestinal peristalsis and paralytic distension of the intestines. It is probable, also, tliat the diuretic effect of pituitary extracts may be of clinical value. The value of subcutaneous injections of pituitary extracts in diabetes insipidus has already been noted. CHAPTER XVI THE FUNCTION OF THE PINEAL BODY Much attention has been devoted to the pineal body from the standpoint of comparative anatomy. Its relationship to the pineal eye of lower vertebrates seems to have led to the con- clusion, which may, after all, turn out to be premature, that the pineal body of mammals is a purely vestigial organ, and no longer of any functional importance. Notwithstanding the numerous investigations which have been carried out upon the comparative anatomy and development of the organ, there aj)pear to be few careful and detailed descriptions of the microscopical structure in Mammalia. Moreover, the numljcr of essays in the direction of a physiological study of the struc- ture are not very numerous. The general apjiearance of the body on microscopical examination certainly suggests the possibility of a secretory function, and, as we shall see, there is some evidence that the pineal body controls in some way or other (possibly by means of an internal secretion) the early growth of the individual. Anatomy and Development of the Pineal Body The pineal body, or pineal gland (conarium),^ is a small pinkish structure situated underneath the posterior region of the corpus callosum, and resting upon the anterior elevation of the corpora quadrigemina. A section through the diencephalon of an early human embryo shows the " roof -plate " and the "floor-plate." At the posterior end of the former is an elevation, which forms a hollow evagination of the brain-roof — the jmieal process. The distal extremity of this pineal process becomes enlarged to a ^ The epiphysis of the mammal was known to the ancient Greek anatomists, Galenus described it as the " '^ui/j.a KwuoiiSes, Kuudpiov." Descartes, in 1649, as is well known, considered it to be the seat of the soul. 385 25 386 THE DUCTLESS GLANDS sac-like structure, whicli subsequently becomes lol)ed and solid. This is the j^ineaJ body. The proximal jDart of the evagination remains hollow, and forms the pineal stalk, and the whole structure, body and stalk, is usually called the epiphysis (McMurricli). In the Reptilia and other lower groups of animals the out- growth from the roof of the diencephalon is double, a secondary outgrowth arising from tlie base or from the anterior wall of the primary one. This secondary outgrowth — the anterior evagination — becomes elongated until it reaches the eiJidermis of the head, and here it develops into the pineal eye. In mammals this anterior process is not developed. In addition to the epiphysial evagination another evagination arises from the roof-i^late of the first cerebral vesicle. This is placed farther forward in the region which subsequently becomes the median portion of the telencephalon. This structure is called the paraphysis, and is found in the lower vertel^rates and in tlie marsupials (Selenka), but up to the l^resent time has not been found in other groups of the Mam- malia. It is supposed to be comparable to a choroid jjlexus which is evaginated from the Ijraiii. surface instead of Ijeing invaginatcd, as is usually the case. There is no evidence that a paraphysis is developed in the human brain (McMurrich). Histological Structure of the Pineal Body The jDineal body is covered on its upjDer surface by the pia mater, which provides the connective-tissue skeleton of the organ, and carries the ))loodvessels into the interior. This sheath of connective tissue sends in septa, whicli break up into a fine network in the parenchyma of the gland, and divide up the whole structure into "acini," or "follicles." (Figs. 104 and 10.5.) Some writers state that there are no true septa, but irregular trabeculas. It seems that in regard to the distribution of the connective-tissue frame-work of the pineal body there is considerable diiference between diiferent species and between different animals of the same sjiecies, but of different ages. In the connective-tissue cells a yellowish or brownish pigment is frequently found. A number of cross-striated muscle fibres may l)e found in PINEAL BODY 387 connection with the connective-tissue elements. The con- nective-tissue septa and bands carry in numerous bloodvessels and nerves, of which some are doubly contoured. The cylindrical epithelium of the ependyma not only covers the part of the pineal body which is nearest to the brain ventricle, but lines certain hollow spaces found within the body of the gland itself. The majority of these hollow cavities become obliterated by the proliferation of their lining cells. There appear to be no true nerve cells in the adult mammalian body. It is stated that there are nerve fibres derived from the brain substance as well as sympa- <--•"-=- .,-, thetic fibres, which enter, along with • "^ij.';';^'::?'';';^;- •' the bloodvessels, in the interior of the f- ■' "■ ,,,,.i/.v, •' pineal body. .■:^^:3;-; ''^'vA The parenchyma of the gland is ' ' .■' ''y'-."/\' made up of follicles, which, however, / are only sharjjly marked out at the ' ;: periphery of the organ (Fig. 104). The ' ,',' cells of these follicles have sometimes / , 'i been described as resembling those of V ' - - ', adenoid tissue. !■ An exact descrijDtion of the con- '' ., ■ , / . stituent cells of the follicles cannot be \ J ' compiled from the accounts of the ■ : ■ ■ • , -' various writers upon the subject. It ^--i-V'' -.; seems clear, however, that the cells ^^ ,„. c i-"" ' ^ ,, ' ' Fig. 104. — Section of the are of two chief kinds — neuroglia and pineal gland of the sheep, secretory cells. The latter are slightly (,°^^™ '^^ *I''^- Thomp- stainable with a large oval granular nucleus. The cell body contains granules, either distributed throughout its substance, or arranged round the periphery. Galeotti described secretory processes in these cells. The "brain-sand" (" acervulus cerebri") which occurs in certain follicles, has been known from the earliest times. It has not been shown to be of any physiological importance. It is found also in the choroid plexus and in the pia mater of the lobus olfactorius. Cysts are also found in the pineal body. Cutore has recently described a structure in the pineal body of the ox which is of doubtful significance. It is a rounded body of variable size in the roof of the diencephalon. It may 388 THE DUCTLESS GLANDS exist side by side witli the diaqyhysis described by Favaro, and it is connected with a very distinct bundle of nerve fibres. This structure, which the author calls " corpus prsepineale," ap- pears to reach its maximum development in the later foetal stages and the earlier period of extra-uterine life. After this it becomes reduced, and seems to be absent in the adult. C'ostantini calls special atten- tion to the granular nature of the pineal cells, and concludes that the pineal body is an in- ternally secreting gland. Similar conclusions have been reached by Galasescu and Urechia, who called .special attention to the oxyphile cells of the gland. Fig. 105. — A small portion of the pineal gland of the cat, as seen under a high power of the microscope. (Drawn by Mrs. Thompson.) Physiological Experiments upon the Pineal Body 1. Injection of Exlmclti of the Pineal Body The first experiments in this direction were made by HoA\el] in 1898. This author reports that glycerine extracts of the body produce sometimes a slight, sometimes a marked fall of blood-pressure. This observation has, of coiu'sc, little or no bearing on the function of tlie organ. (See discussion in Chapiter III. ) Cj'on in 1903 made extracts from the pineal bodies of the ox and sheep, and tested their effects upon the heart and blood- vessels on intravenous injection. There was no effect upon the blood-pressure, probably because the dose was not large enough. The number of heart-beats ^\■as, however, increased, while the excursioji was diminished. This is an effect similar to that obtained by stimulation of tJie true accelerator nerves. Such are the effects of small doses. With larger doses the heart-beats become stronger and less frequent, and also irregular. The pulsus bigeminus and the pulsus trigeminus are frequently observed : tliere is a disturbance of the harmoni- ous co-operation of the inhibitory and the accelerator cardiac nerves. With still larger doses there may be a fall of blood- PINEAL BODY 389 pressure. Cyon concludes that these effects are due to the calcium phosphate and other salts from the concretions of the gland. Dixon and Halliburton find, as might have been expected, that extracts of the pineal body, when intravenously injected, give a fall of blood-pressure (see Chapter III.). Extracts of the choroid plexus also bring about a lowering of the blood pressure. They find also that while extracts made from the choroid plexus of the ox, sheep, and man, injected into the sub-cerebellar cisterna, or the lumbar region, cause a flow of cerebro-si^inal fluid, extracts of pineal body have no such efl:ect. Ott and Scott report, in addition to some cJianges in the blood-pressure, that pineal intravenous injection has a galacta- gogue action similar to, though less than, that of pituitar}' extract (see p. 353). Jordan and Eyster in 1911 found on pineal injection a vasodilation in the intestines, a more forcible beat of the isolated cat's heart, diuresis and glycosuria. There was also increased depth of breathing for some time after the injection. The effects are comparatively slight. iSchafer and MacKenzie (see Chapter XV.) could not confirm the observation of Ott and iScott as to the galactagogue action of joineal extracts. But MacKenzie in 1911 obtained a slight effect which he thought might be clue to contamination with j)ituitarj' material by absorption from the cerebro-sj)inal fluid. 2. Direct Stimulation of the Pineal Body Cy.on appears to be the only observer who has used this method. He employed electrical stimulation applied to the pineal body of the rabbit and states that he could observe slight changes in the form and position of the gland. There was no alteration in colour, so that the effects could not be due to vasoconstriction. They were due, he thinks, to con- traction of muscle, though, it must be observed, the existence of muscle fibres in the body is exceedingly doubtful. According to Cyon, these experiments point to a mechanical function on the part of the pineal body : it is suggested that it controls the inflow and outflow of cerebro-spinal fluid of the third ventricle. The part played by the pineal body in this regard is likened to that of the thyroid and the pituitary, and all three 390 THE DUCTLESS GLANDS are supposed to be concerned in regulating the intracranial pressure. 3. Attempts to destroy the Pineal Body by means of the Cautery Sarteschi in 1910 had obtained negative results in a series of experiments upon rabbits. Exncr and Boese destroyed, by means of the thermo-cautery, the pineal body in ninety-five rabbits. Seventy-five jier cent. of the animals died within the first twelve hours from bleeding into the ventricle. Twenty-two animals were kept under obser- vation for some time. In six the authors thought the operation was complete, and the animals lived to sexual maturity. There was no sexual precocity. The autliors concluded that in rabbits extirpation of the pineal body produces no noticeable effects. But, as we shall presently see, it is, in all probability, impossible to destroy completely the pineal body of the rabbit by this method. 4. Extir'pation of the Pineal Body Sarteschi attempted extirpation by ordinary surgical means in some of his rabbits ; but, although he thought that this was complete in one case, and that in this there was some retarda- tion of development, yet the conclusion is not satisfactory. Exner and Bocse also made an attempt to remove completely the pineal body from rabbits by surgical means other than the cautery. They could not be certain that tlie operation jJro- duced any specific results. Foa came to the conclusion that the rabbit is not a suitable animal for pineal extiriDation. He turned liis attention, therefore, to the chicken, and arrived at tlie followinsj; con- elusions : — 1. Complete extirpation in the earlier months of life gives rise to a retardation of development during the first two or three months after the operation ; afterwards development of the body becomes normal. 2. In cockerels there is an earlier development of both primary and secondary sexual characters in the operated than in the control animals. 3. In cocks examined eight to eleven months after the operation there is marked hypertrophy of the comb and of the testes. PINEAL BODY 391 4. There are no corresponding changes m pullets. These interesting results with cockerels received an important confirmation by Sarteschi, who had previously failed to extirp- ate the pineal body. Following the technique employed by Foa for chickens and first recommended bj^ Lo Monaco (that is to say, by ligaturing the longitudinal sinus), Sarteschi succeeded in extirpating the pineal body in very young rabbits and dogs. In the males which survived the operation there was a notable hypertrophy of the testes, bodily overgrowth and sexual precocity — results Cjuite comparable with those obtained l^y Foa in cockerels. More recently Foa reports that pineal extirpation has no effect on female chickens or female rats. But upon male rats there is an effect comjDarable with that produced in cockerels, viz., a rapid increase in body weight and in size of the testes. He notes also an advanced development hoth of the sjaer- matozoa and of the interstitial tissue of the testis, both in rats and cockerels. The premature increase of interstitial tissue, it is suggested, corresponds to the precocity of the secondary sexual characters — growth of comb in the cock and increase of body weight in the rat. These observations are of the greatest interest and impor- tance, and point very strongly to the view that the pineal gland exercises an inhibitory function upon sexual development before puberty. At this period an involution of the gland occurs. 5. Effects of Castration tipon the Pineal Body Although Sarteschi in 1910 had failed to find cJianges in the pineal body of animals castrated in early life, yet Biach and Hulles report that castration causes atropihy of the pineal. Castration is stated to have the contrary effect upon the pituitary body. 6. Feeding Ex-periments Pineal feeding was suggested by Kidd in 1913, and the first actual experiments in this direction so far as I am aware, were carried out by Dana and Berkeley in the same year. These authors state that feeding guinea-pigs and J^oung rabbits with pineal gland causes an increase in body weight, but the opposite effect is obtained in children. 392 THE DUCTLESS GLANDS McCord has studied the effects of pineal feeding upon chicks, dogs, and especially upon guinea-pigs. He finds that the effects usually attributed to pineal deficiency (hypo- pinealism) are obtained by supplying an increased amount of pineal substance by feeding or injecting pineal preparations. Such administration of pineal substances leads to a more rapid growth of body than normal, and determines an early sexual maturity. The excess in rate of growth was most pronounced in young animals fed with pineal tissue obtained from young animals. After maximum size was attained, pineal admin- istration appeared to be ineffective. Both males and females respond, in rate of growth, to the influence of pineal substances, but the response has been more definitely manifested in males. These observations, so far as the effects upon male guinea- pigs are concerned, have recently been confirmed by Horrax, and McC'ord and Allen find that pineal substance causes con- traction of the melanophores in tadpoles. Pathological Anatomy and Clinical Pathology Cysfs of the pineal have been known for a long time. Some of these are without characteristic effects ; others give rise to serious symptoms. Teniiotiiatd are very common. They were first fully described Ijy Weigert, and have since received a considerable amount of attention. Various other tumours of the pineal body have been described, such as glioma, sarcoma, carcinoma, and mixed growths. There is now a general agreement among clinical ])athologists that diseases of the pineal body are accompanied by a char- acteristic train of symiDtoms. It is curious that there is some degree of resemblance between these symptoms and those due to lesions of the pituitary body. Our information upon the clinical symptoms in pineal disease is largely derived from the work of Marburg. Hempel records a case of carcinoma of the pineal gland in which there was at the commencement oljesity, but later very marked atrophy of the fatty tissues. In complete destruction of the body, which occurred in six cases of malignant tumour, there was a severe disturbance of the trophic functions (Biedl). Marburg found a very striking obesity in a nine-year-old PINEAL BODY 393 girl who had the sjmiptoms of a brain tumour. At the post- mortem examination a compound tumour of the pineal body was found. It is not certain whether the obesity is due to a hyper- or to a hypo-function of the gland. Marburg is inclined to the former view, but the preponderance of evidence is, perhaps, in favour of the latter (Biedl). But there are other interesting conditions besides obesitj' found in patients with pineal tumours. These are found in young subjects. It has been found that in boys under seven years of age symptoms of brain tumour and disease of the corpora quadrigemina are associated with abnormal tallness, unwonted growth of hair, premature sexual and genital development, and early maturity. In these cases there is frequently found on post-mortem examination a teratoma of the pineal body. The symptoms just enumerated are generally supposed to be due to a hypof unction of the pineal gland. Frankl-Hochwart urges the importance of the symp- toms mentioned as diagnostic of pineal tumours. Pellizi has described the pineal syndroma as " macro- genitosomia prsecox." There is a premature development of the genitals, which, particularly in regard to the volume of the penis, gives the appearance of an adult. The degree of development of the body and of the skeleton corresponds to that of an age five, ten, or twelve years more advanced. There is a premature ossification of the bones. The intelligence almost always corresponds to the age. In these cases one observes very frequentlj' that there are symptoms of cerebral tumour and destruction of the corpora quadrigemina. The condition alwa3's becomes developed before the eighth year, and very frequently before the third, and is commoner in boys than in girls. The hereditary factor has no special influence on the causation. The pathogenesis seems to depend in most cases on a destructive lesion or growth of the pineal body. In considering the results of clinical observation, it must be remembered that less than a hundred cases of tumours of the pineal gland have been recorded. In these cases two groups of symptoms have been described — the nervous and the metabolic. In adults only the nervous symptoms occur. In children, however, we get the metabolic disturbances, pre- sumably due to an alteration in the secretory activity of the gland, and these are most marked in young males. They 394 THE DUCTLESS GLANDS consist, as we have seen, in precocious sexual and mental development. This precocity has usually been attributed to a hypopineahsm, and this view was supported by the extirpa- tion experiments. But, as we have seen, a similar precocity of development accrues from feeding with pineal substance. This fact introduces a complication which renders it imjDOSsible to reconcile the results of clinical observation and exjoerimental work upon animals. CHAPTER XVII THE INTERRELATIONS OF THE ORGANS OF INTERNAL SECRETION Although the allusions to a relationship between the organs furnishing internal secretions are so numerous, and although assumptions in regard to such relationships are very common in medical and surgical literature, yet it may be affirmed that the theories and suggestions which have been put forward are out of all proportion to the established facts and any certain knowledge of the subject. In this chapter an attempt will be made to examine critically, some of the current views in connection with this part of our subject, and, if possible, to separate out a portion at any rate of the grain from the heap of chaff. The view is now so prevalent as to be almost universal among clinical workers that derangement of any one of tlie ductless glands leads to more or less evident disturbance in other members of the series. The phrase "polyglandular syndrome '" has become a commonplace of medical literature. And investigators in the fields of experimental physiology and pathology have been so impressed by cases where the internal secretion of one organ appears to stimulate another to activity, that they have for the most part joined with the clinicians in regarding the organs of internal secretion as forming a system whose several functions are very intimately related to each other. The arguments in favour of such a relationship between the ductless glands and other organs which yield internal secretions are derived from very many different sources, experimental and clinical. Although many of these relationships are re- ferred to frequently in the literature, yet it is only within recent years that an attempt has been made to collect the evidence and state it in compact form. In the compilation of this 395 390 THE DUCTLESS GLANDS chapter I am indebted to an account of the subject written by Hoskins in IQIL It is not always easy to determine from the phraseology employed precisely what kind of a system is alleged to be constituted by the association together of the various internally secreting glands. A recent writer says that the animal body is controlled by an " interlocking directorate "' made up of the glands of internal secretion, while in modern expositions of the relations of the endocrinous organs we frequently find that the " system " is made to include not only the adrenal bodies, the thyroid glands, and the pituitary, along with the thjanus, parathyroid, and pineal, but also the reproductive organs, the pancreas, liver, spleen, duodemmi, small intestines generally, the stomach, the uterus, and the mammary gland. When we remember that certain authors refer to a " kinetic system " (which includes the brain, the thj^roid, the adrenals, the liver, the pancreas, and the muscles), and that the whole of the sympathetic nervous system is supposed to be under the con- trol of the chromaphil tissues, and that the carbohydrate metaljolism of the body is alleged to be under the conjoint control of the central nervous system, the liver, the pancreas, tJie intestine, the chromaphil tissues, the thyroids and para- thyroids, and the pituitary, it will be conceded that any attempt to express all the asserted possible relationships in diagrammatic form must result in failure. A summary of the connections postulated in the last para- graph would amount to nothing less than a statement that the various organs and tissues of the body are functionally related to each other, and when the view is put forward that the secretion of one of the ductless glands produces an effect upon the nervous system as a whole or upon an important section of it, this amounts to the allegation, that the gland in question exerts its influence upon practically the whole body. It may be possible in the future, when our knowledge of the ductless glands and indeed of physiology generally sliall be consider- ably greater than at present and if current views as to the supreme directing influence of the internal secretions be confirmed and substantiated, to formulate some satisfactory theory according to which the organs of internal secretion dominate the whole of the bodily activities, normal and jjathological. INTERRELATIONS 397 In the present chapter no attempt will be made to cover the field just indicated ; it will be necessary to confine our atten- tion to the known or reasonably suspected instances of influ- ences exerted by one internally secreting gland upon others of the series, these influences being not always necessarily direct — as, for example, when the nervous system is called into play. If there has been in many instances undue haste in formu- lating theories of the functions of individual glands, much more has this been the case in regard to theories of mterrelationships . It is not certain that the clinicians have been greater offenders than the laboratory workers, though it must be confessed that many of the descriptions of syndromata which have been supposed to accrue from correlated disturbances of the endo- crinous organs are based upon an inadequate conception of the actual physiological facts and therefore form a very unsatis- factory indication for treatment. A priori and regarding the question chiefly from the morj)ho- logical standpoint, it is doubtful if one would expect the various ductless glands to be related to each other. From a broadly comparative standpoint, it is very difficult to arrange these glands in a coherent series. There are reasons, fully explained elsewhere (p. 227 et seq), for regarding the thyroid, parathyroids and thymus (along with certain less important branchial cleft organs), as morphologically related. Some authors regard the thymus as closely related to the thyroids and parathyroids from a physiological as well as a morpho- logical standpoint. The glandular portions of the pituitary body majr possibly be included in this morphological group, but it must be pointed out that the origin of these different organs is not quite identical. The only common feature is that they arise from some jaart of the primitive alimentary canal or its vascular outgrowths, the gill clefts. The pituitary body arises from the ectoderm, while the branchial cleft organs are of entodermal origin. The cortex of the adrenal body is a representative of a kind of tissue which is widely distributed in the region of the repro- ductive organs (see p. 116), and possibly it might be expected that the corpus luteum and the interstitial ceUs (as well as the rest of the elements) of the ovary and the testis might rank in the same group. 398 THE DUCTLESS GLANDS According to modern views, the chromaiihil tissues form a series which may be regarded as sympatlietic glandular organs and which are widely distributed along the course of the vegetative fibres. The majority of writers still deal with the adrenal bodies as if they represented functional entities. But as far as is defi- nitely known, the chromaphil tissues physiologically have nothing whatever to do with the adrenal system (or adrenal cortex and " accessory cortical bodies "). The pancreas, along with its islets of Langerhans, is an out- growth from the alimentary canal, and so might be regarded as belonging to the same system as the branchial cleft organs. We have not sufficient information to guide us to a decision as to whether we ought to regard morphological and embryo- logical connections as an indication of a probable physio- logical relation. Elliott quotes Gaskell as classifying together, on morpho- logical grounds, the pituitary body, the thyroid and the adrenal cortex, ])eing all modified from the coxal glands, that is, the segmental excretory apparatus of some primitive arthrojjod type. But Gaskell's theory, so far as the dvictless glands are concerned, is open to grave criticism, and the theory as a whole is, I believe, not generally accepted by morphologists. It must be remembered that a normal gland may either excite or moderate the activity of another. If an exciting organ be suppressed, there will be insufficiency of the second, and so we get a diminution of two functions. If a moderating organ be reduced in activity, the disturbance occurring in the second gland will be overaction. And further, one gland may exercise an exciting influence upon a second and a suppressing action on a third. In these actions both the sympathetic and the autonomic systems may take part. The evidences in regard to endocrinous interrelationships are derived from pathological anatomy, from clinical observation, and from experimental investigations. A. Interrelationships involving the Thyroid Gland Action of the Thyroid upon the Adrenal Bodies Sub-thj^roidism has not been shown to have any effect upon the adrenal bodies, although attempts have been made to show INTERRELATIONS 399 that thyroidectomy depresses the function of the chromaphil tissues. The Viennese school has elaborated a very complicated theory. The thyroid and parathyroids are antagonistic to each other. While the former stimulates the sympathetic, the latter inhibits this system. The parathyroid is the ally of the pancreas in checking or inhibiting metabolism, while the adrenals and the thyroid increase it. So that when the thyroid is put hors de combat four things happen : (1) Loss of thyroid secretion, inducing slowed or diminished metabolism ; (2) Absence of stimulation of the adrenals (that is to say, the chromaphil tissues) ; (3) Relaxation of the inhibition of the pancreas ; (4) Diminished excitability of the nerves to the thyroid, that is, branches of the vagus. ^ In regard to superthyroidism, there is some evidence that the amount of adrenin in the blood is increased in this con- dition. This evidence, though not very positive or great in amount, supports the theory that the secretion of the thyroid acts as a direct stimulant to the chromaphil tissues, causing them to yield adrenin to the blood in larger quantities. There are grounds for extreme scepticism regarding all this work. Cramer has put forward the view that the thyroid and the adrenal are part of an apparatus which controls the tempera- ture of the body. He regards the adrenal as a gland in itself and not as consisting of two independent constituents. One of its functions is to act with the thyroid as a humoral mechanism regulating body temperature, and supplementing the action of the nervous system. The thyroid hormone mobilizes liver glycogen by increasing the production of adrenin and sensitizing the sympathetic nerve-endings. At the same time adrenin constricts the arterioles of the skin, thereby diminishing the loss of heat from the body. Cramer has adduced a number of experimental and pathological observations in support of this theory. Relations betiveen the Thyroid and Pituitary Bodies Clinical evidence as to pituitary hypertrophy as a result of thyroid deficiency is unsatisfactory, but the experimental ^ It is more usually adnaitted that the specific nerves to the thyroid are derived from the sympathetic (see p. 308). _ 400 THE DUCTLEiSS GLANDS evidence is convincing. As we have already seen (p. 36(5), a very striking effect is caused by removal of the thyroid upon the pituitary body, which not only undergoes general enlarge- ment, but exhibits well-marked indications of increased secretion. There is, however, no increase in the amount of iodine in the hypertrophied pituitirles in, these cases, so that a true vicari- ous functioning seems out of the question. How far the parathyroids may be concerned in this question we do not know. According to Halpenny and Thompson, some of the alterations which have been described in the pituitary occur when the parathyroids only are extirpated. But other observers have failed to find any changes in the pituitary after parathyroidectomy. When the pituitary hypertrophies as a residt of sub- thyroidism, there are no symjitoms of sui^erpituitarism. So that the pituitary as a whole does not become more active. Relalionij between the Thyroid and the Reproductive Organs Many of the changes found in various organs of the body as a result of thyroidectomy are not to be attributed directly to a loss of the thyroid secretion, but to the effects of intoxication and troubles of metabolism which supervene in these eases. In the female the thyroid is known to become enlarged at puberty, at the menstrual periods, and during pregnancy. In animals from whom the thyroids have l:>een removed at an early age, the reproductive organs are late in developing or develop in an imperfect manner, so that we have a condition of sexual infantilism. Some changes in the reproductive organs have also been recorded in cases where thj'roidcctomy was carried out in the adult. Jti exojjhthalmic goitre the sex functions are often affected (menstrual disturbances); and there is sonu^times atrophy of the genital organs. In myxocdema there may l)e complete imijotence. The theory that the thyroids have a stimulating effect on the reproductive organs has therefore some evidence to support it. Some authors claim to be able to diagnose thyroid deficiency in cases of incomplete sexual develojiment and to remedy the defect by thyroid medication. INTERRELATIONS 401 Action of the Thyroid on the Thymus For the anatomical and embryological relationship l^ctween thyroid and thymus see p. 277 et seq. The thyroid secretion affects the growth of the thymus gland, which has been found to undergo an increase in size in fcBtal animals after thyroid feeding of the pregnant mother (guinea-pigs). In exoph- thalmic goitre the thymus is often hypertrophied and has been supposed to take a part in producing the symptoms of the disease. But not only in Graves's disease does thymus hyper- trophy occur ; it may also be associated with simple congenital goitre. It is not clear whether thyroidectomy causes thymus atrophy. Action of the Thyroid on the Pancreas It is well known that the thyroid has some influence on carbohydrate metabolism, and this is often exjilained as indi- cating a relation between the thyroid and the pancreas. But Krause and Cramer find that when small amounts of fresh thyroid gland are administered for two or three days to rats or cats fed on a carbohydrate-rich diet, the liver will be found to contain only traces of glycogen. This effect is clue to an inhibition of the glycogenic function of the liver, not to an increased utilization of carbohydrates. It is not accomjDanied by glycosuria, and (in dogs) the tolerance for glucose is only slightly diminished by thyroid feeding. If the parathyroids are removed also, the assimilation limit for sugar is distinctly lowered and the injection of adrenin then produces more pronounced glycosuria than in the normal animal. This is usually quoted as one of the instances of an antagonistic action between thyroids and parathyroids. The experiments involving removal of thyroids without the para- thyroids are notoriously difficult, and much further evidence is required on the subject. Some observers have reported an increase in the islets of Langerhans after thyroidectomy. Notwithstanding the meagre character of the evidence, the majority of modern writers seem fully to accept the view that the thyroid has a direct inhibitory influence upon the pancreas, and affects carbohydrate metabolism through the internal secretion of this organ. 402 THE DUCTLESS GLANDS Summarizing the effects of the thyroid upon the other endocrinous organs, we may state that there is some evidence that it stimulates the chromaphil tissue to increased activity. There is clear evidence that subthyroidism causes hypertrophy of the pituitary and this is supposed to indicate some kind of vicarious function. It seems clear that while the thyroid has a marked influence upon general metaljolism in the young animal, it has a very sj^ecial influence upon the development and growth of the reproductive organs. The direct effects of thyroid upon thymus are doubtful. The alleged action of thyroid ujion the pancreas can only be proved or disproved when our knowledge of carbohydrate metabolism has con- siderably increased. At i)resent there seems no reason to believe that the effects of thj-roid upon such metabolism are wholly or in part due to a direct effect upon the internal secretion of the jiancreas. B. Interrelationships involving the Pituitary Body Action of the Pituitary Body upon the Thyroid Some recent writers exjiress their belief that a decided anti- thyroid influence is exerted by the substance ("tethelin" Robertson) secreted by the anterior lobe of the ^Jituitary. Superpituitarism (by feeding or injection with pituitary substance) is said to cause thyroid hj^pertrophy, Ijut this is doubtful. Aj)ituitarism or subpituitarism is alleged by Cushing to cause hypertrophy of the thyroid. Exner has confirmed this so far as surgical experience in the human subject is concerned. We have seen that extirpation of the thyroid causes hypertrophy of the pituitary. A possible vicarious activity of the two glands has already been discussed. Action of the Pituitary Body upon the Reproductive Organs It seems clear that certain cases oi infantilism are associated with lesions of the pituitary body. Although tliere has been some discussion as to whether these defects are due to super- or sub-pituitarism it seems from a consideration of the most recent investigations tliat they are the result of the latter condition. The usually accepted view is that the pituitary INTERRELATIONS 403 normally supplies a secretion which stimulates the sex glands to activity. As bearing upon the relationship between the pituitary and the sexual functions, the work of Erdheim and Stumme is of great interest. These authors describe three types of cell in the glandular part of the pituitary : 1. Eosinoiihile granular cells (chromophile 1 ; acidophile). 2. Basophile granular cells (chromophile 2 ; basophile). 3. " Hauptzellen " (chief cells ; chromophobe cells) (see p. 339). The chief cells have very badly defined and poorly staining protoplasm. In pregnancy the pituitary may become hyper- trophied to two or three times its normal size. The increase consists entirely in the glandular portion. There are no longer to be seen either chromophile or chromophobe cells, but there are peculiar large, finely granular cells (tlie " pregnancy cells " ). These are derived from the chief cells, which grow from the centre of the alveolus, and occupy a large part of the secretory structure. These slowly retreat again during the period of involution. The pituitary during pregnancy resembles an epithelial tumour. The increase in the amount of secretion is seen by the fact that one can squeeze a milky juice out of the gland. The hypertrophy persists to a certain degree, even after preg- nancy, so that the weight of the gland in a multipara may be three times as great as that of a normal gland. Erdheim and Stumme thought that the hypersecretion of the pituitary in pregnancy is manifested by an enlargement of the hands and lips which is sometimes observed. Occasionally, also, there may be more strildng symptoms, due to the effects of the pituitary tumour. Among these maj^ be mentioned hemianopia. Mayer is of opmion that the pituitary changes are due to functional changes in the ovary — in other words, that the pituitary may function vicariously for the ovary. A relation between pituitary and ovary is shown by the fact, already mentioned, that in castrated women and animals there is frequently enlargement of the pituitary. Further, after destructive diseases of the reproductive glands the pituitary reacts by hypertrophying. Mayer is even inclined to believe 404 THE DUCTLESS GLANDS that the actual commencement of the mischief in acromegaly may be situated in the reproductive organs. Action of the Pituitary Body upon the Adrenal Bodies Certain French observers have described hyperplasia of the adrenal cortex after feeding with pituitary substance. Gottlieb has shown that extracts of the posterior lobe of the pituitary and of the chromaphil tissues mutually assist the action of one another upon the bloodvessels. Thus an injection of a email dose of adrenin will increase the subsequent effect of a dose of pituitrin, and vice versa. It is also stated that an excess of adrenin is jjoured out into the blood-stream as the result of an injection of extract of the posterior lobe of the pituitary. The evidence for a direct action of pituitary upon either the chroma- phil tissue or the adrenal crotex is not, however, very con- vincing. Action of the Pituitury Body upon the Pancreas How far the facts before us point to a direct action of the pituitary upon the pancreas is doubtful. We know that sub- pituitarism leads to an increased sugar tolerance. According to Gushing, this depends upon the function of the posterior lobe. Animals from whom this lobe has been removed will not develop glycosuria when the pancreas is extirpated. But the production of glycosuria by removal of the pancreas is due to an action on the liver. Glycosuria occurs in acromegaly, and this has been sup- posed to be due to changes in the pancreas. The evidence on this point is unsatisfactory. Many authors believe that there is some kind of functional correlation between pituitary, chromaphil tissue, pancreas, liver, and thyroid, so that any interference Avith the function of any one of them may affect the carbohydrate metabolism through its inflliTenoe upon the others. To sum up the influence of the pitidtary upon the other ductless glands it may be definitely affirmed that the or^an has some influence upon the growth of the reproductive organs, but the evidence for a direct effect upon the thyroid, adrenals, and pancreas is much less convincing. INTERRELATIONS 405 C. Interrelationships involving the Adrenal Bodies (Chromaphil Tissues and Adrenal Cortex) Action, of the Adrenal Bodies upon the Gonads An important connection between the adrenals and the reprodnctive organs has long been recognized. The main facts are given in another chaiDter (see Cliap. XI). In this place we need only remind the reader of the frequent association between sex anomalies and tumours of the adrenal cortex. It is stated also that vigour of reproduction is reduced by partial adrenal extirpation. The theory is that the cortex of the adrenal body stimulates the growth of the reproductive organs, especialljr in the male. So far as I am aware, there are no observations whicli point to any direct connection between the adrenal medulla or other chromaphil tissues and the sex organs. Action of the Adrenal Bodies wpon the Thymus Hypertrophy of the thymus has been recorded in cases of Addison's disease, and the association of adrenal hypoplasia and thymus hypertrophy is said to be common in status lym- ■phaticus. There is also some experimental evidence that adrenal deficiency is frequently associated with hypertrophj^ of the pancreas. Action of the Adrena.l Bodies upon the Pituitary At present there is little evidence of any relationship of the adrenals to the pituitary. Action of the Adre?ial Bodies upon the Thyroid Hypertropliy of the tlij'roids has l)een reported in some cases after extirjjation of the adrenals, but we have not sufficient data to justify any statement as to a direct action of the former organ upon the latter. Action of the Adrenal Bodies u2)on the Pancreas This matter has already been discussed in the chapter devoted to the adrenal bodies (see Chap. XI.). Here it is only necessary to point out that the whole of the effect of the adrenal bodies ujDon carbohj^drate metabolism is 406 THE DUCTLESS GLANDS not exerted through the pancreas, but part must be directly on the liver. As we have previously seen (p. 162), adrenin has a direct effect on the glycogen storage of the liver. We have then considerable evidence that the adrenal cortex stimulates the growth of the gonads, and some little evidence that adrenal hyperplasia induces overgrowth of the thymus. The most usual theory as to the relation of the adrenal body to the pancreas is that the former inhibits the latter. According to some observers, this effect is not direct, but related to an action on the vasoconstrictor nerves. D. Interrelationships involving the Organs of Reproduction Action of the Reqjroductive. Organs on the Pituitary Body Several authors report that pregnancy causes increased activity of the pituitary gland. But it has been pointed out that this may be simply a reaction to the changed metabolic conditions obtaining during pregnancy. Castration in both sexes is followed by hypertrophy of the anterior lobe of the pituitary body. There seems to be a special overgrowth of the eosinophile elements. Recent investigations lends support to the view that it is the loss of the internally secreting elements of the testes (the interstitial cells of Leydig) which leads to hypertrophy of the pituitary body. These observations indicate that the pituitarj' body is normally held in check by the secretions of the reproductive organs. When the inhibition is removed the pituitarj' shows mcreased activity leading to overgrowth of different parts of the body, as in acromegaly and after castration (Hoskins), Action of the Reproductive Organs on the Thymus The thymus normally persists till puberty, wlien the repro- ductive organs grow. A priori, castration would tend to prolong the period of persistence of the thymus. This luis been found experimentally to be the case. The work of Calzolari, Henderson, and Goodall in this direction is referred to in Chap. XIV. The sex glands tlien tend to exert a depressant effect on the thymus. INTERRELATIONS 407 Action of the Reproductive Organs on the Adrenal Bodies During pregnancy there is a distinct enlargement of the adrenal bodies. This chiefly affects the cortex, but there is some growth of the medulla also (Elliott and Tuckett). What is the mechanism or what the significance of this overgrowth is not known. Action of the Reproductive Organs on the Thyroid A direct influence of ovary and testes upon the thyroid body is not known to exist. It appears probable, then, that deficiency of the sex organs leads to hypertrophy of the pituitary body possibly by remov- ing a normal check upon it. Activity of the sex glands seems to lead to depression of the thymus. The influence of the gonads on the adrenal and thyroid bodies is of a doubtful nature. E, Interrelationships involving the Thymus Activities of the thymus upon the gonads and upon the thj'roids have been alleged, but the experimental evidence is not conclusive. F. Other Interrelationships In regard to the influences exerted upon the other endo- crinous organs bj' the pancreas, the parathyroids and the pineal body, there is little that need be said here. There is little direct evidence that the pancreas does actually depress the thyroid, though this supposition is an important part of the theory of the Vienna school. The relation of the para- thyroids to the thyroid is sufficiently discussed in Clhapter XIII. and the relations of the pineal to the organs of repro- duction in Chapter XVI. The "Pluriglandular Syndrome" Within recent years a great deal has been written about what is called the " pluriglandular syndrome." The general conception which has been evolved is by no means definite. But in general terms it may be stated as follows. In 408 THE DUCTLESS GLANDS diseases affecting the glands of internal secretion it is very common (iDerhaps even the rule) that more than one of these glands are from time to time or simultaneouslj' involved. The nature of the clinical picture produced depends upon the preponderance of symptoms arising from disorder of one or more of the glands in question whose dj'sfunction results in recognizable changes. LerebouUet classifies pluriglandular disorders as follows : (1) A primary change in one gland with secondary disorders in one or more, e.g. Graves's disease, with ovarian insufficiency and amenorrhoea ; (2) Association of two uniglandular syn- dromes, e.g. myxoedema and acromegaly ; (3) Association of several uniglandular syndromes without predominance of any one. The last condition may be due to syphilis or tubercle and affects commonly thyroid, testis, and adrenal. Timme has recently described a condition depending upon disease of thymus, adrenal, and pituitary in combination. He says that this condition is frequeiitly met with and that its various stages are easy of recognition. The chief symptoms are extreme liability to fatigue, a low blood-pressure, head- ache, and inordinate growth of the whole body. A restoration to a normal condition, or to something which approaches this, may be brought about spontaneously by compensatory over- growth and overactivity of the pituitary. Feeding with pituitary extracts is the treatment 's^hich is found to be most beneficial. Puhertas pra'cox apparently may arise from affection of the whole ductless gland system, but primarily from the repro- ductive organs, pineal and adrenal cortex. The majority of cases are probaljly due to some affection of the gonads ; next in frequency are cases apparently due to tumours of tlie pineal and finally we have those due to growths in the adrenal cortex. It is stated that pineal types occur mostly in the male, the adrenal and gonadal in the female. Dercitm's Disease, or Adiposis dolorosa, has been included by some writers in this group. It is cliaracterized by irregular, sometimes synunetrical, deposits of fatty masses in various portions of the body, preceded by and attended with pain. It occurs mostly in middle-aged women. There may be a history of alcohol, syphilis, rheumatism, or bodily injury. The fatty masses are of variable size and distributed on the trunk and INTERRELATIONS 409 extremities. The pain is sometimes spontaneous, sometimes induced by manipulation. The new fatty tissue has a soft feel, or there may be harder tumours. Haemorrhages from mucous surfaces may be observed. The disease is chronic and progressive. The morbid anatomy consists in an increase of fatty and connective tissue and degenerative changes in nerves. The thyroid has been found hard and calcareous. Dercum's disease differs from other forms of obesity in its irregular dis- tribution, in the presence of pain, and sometimes of impaired sensibility. It differs from myxoedema in that face, hands, and feet are not affected and in the absence of mental symptoms. Thyroid treatment is said to do good in some cases (Allbutt). Arachnodactyly. Some seven or eight cases have been described under this name, notably by Morvan and Poynton. The patients are children with overgrowth of the long bones, phalanges, meta- carjjals and metatarsals. The growth of bone is out of pro- portion to that of muscles and tendons ; so that contractures are produced. It is possible that the condition may be due to some defect in the organs of internal secretion. INDEX Abdominal chroma]5hil body, 117-122 physiological effects of extracts of, 121 Accessoiy adrenals, 114-122, 147 cortical bodies, 116 Acervulus cerebri, 387 Achondroplasia, 381 Acromegaly, 371-377. See Table of Contents Adamkie\yicz reaction (of thyroid colloid), 273 Addison's disease, 127-138. Ste Table of Contents adrenal preparations in, 209-210 blood changes in, 130 ergographic test in, 130 origin of pigment in, 136 Adiposity after removal of pituitary, 362 effect of castration upon, 73—74 in pituitary timiours, 378 pineal tumours and, 392-393 Adiposis dolorosa, 408 Adrenal bodies, 14, 93-249. See Table of Contents accessory, 114-122 relation to adrenal ex- tirpation, 147-149 chemistry of, 18.5-200, 202- 203, 240 defective development of, 138 extirpation of, 140-1.53 extractives from, 202 heat-regulating mechanism of, 23.5 hyperplasia of, in arterio- sclerosis, 139 hypertrophy of, in inanition, 249 in pregnancy, 243 (Marchand's), 116 of birds, 112, 114 of fishes, 98-109 secretory function of, 216- 248 signs of secretory activity "in, 237, 247 tumours of, 139, 241 Adrenal cortex, 93, 112, 115, 127, 238-248. See Table of Contents antitoxic fvmction of, 241, 462 brain of man, influence on, 241, 248 functional relationship to medulla, 235, 247 mechanism of influence on reproductive organs, 244 relation to sexual organs, 241-245 Adrenal extracts. See also Chroma- jjhil tissues, pharmaco- dynamics of effects of, 158-165 special physiological effects of, 165-185 Addi.son's disease, 210 mode of administration, 211-212 therapeutic uses of, 204 Adrenal medulla, 112, 127 theories as to functions of, 216-238, 249 pharmaco-dynamics of. See Chromaphil tissues total deficiency of, 138 tumours of, 139-140 Adrenalin {.tee also Adrenin), 192 ; formula of, 194 Adrenalon, 194-195 Adrenal secretion, excessive pro- duction of, 138 Adrenal vein blood, effect on blood- pressure of injection of, 217 Adrenal wliite line (Sergent), 131 Adrenin : Origin and chemistry of, 185-6, 192-202. Sec also Adrenal medulla estimation of, 197, 217-18 effects of, general, 158-165, 166-185, 187-191, 229-233 intestinal relaxation test for, 236 medical and surgical applications of, 204-12 not essential to life, 223 pharmaco-dynamics of. See Cluomaphil tissues 411 412 INDEX Adrenin : secretion of, mechanism of, 2.33-4 synthesis of, 196 glycosm-ia, 218-220 Alimentaiy canal, actions of adrenin on, 187 Alveoli, 4 Amines, physiological activity of, 31 sympathomimetic action of, 197-9 Amiurus, anatomy of thyroid in, 250-7 Ammocoetes, thyi'oid in, 255 Ammonia, he]:»atic convei'sion of, 15 Amniota, adrenal bodies in, 95, 112-114 Amphibians, adrenal bodies in, 1