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/cu31924003101569 
 
The nervous and chemical regulators of m 
 
 3 1924 003 101 569 
 
LECTURES ON THE NERVQUS AND CHEMICAL 
 REGULATORS OF METABOLISM 
 
MACMILLAN AND CO., Limited 
 
 LONDON • BOMBAY • CALCUTTA 
 MELBOURNE 
 
 THE MACMILLAN COMPANY 
 
 NEW YORK • BOSTON • CHICAGO 
 
 DALLAS • SAN FRANCISCO 
 
 THE MACMILLAN CO. OF CANADA, Ltd. 
 
 TORONTO 
 
THE 
 NERVOUS AND CHEMICAL 
 
 REGULATORS OF METABOLISM 
 
 LECTURES 
 
 BY 
 
 U. JNOEL PATON, M.D., B.Sc. 
 
 PROFESSOR OF PHYSIOLOGY IN THE UNIVERSITY OF GLASGOW 
 
 MACMILLAN AND CO., LIMITED 
 
 ST. MARTIN'S STREET, LONDON 
 
 1913 
 
10 
 
 J. FRANCIS MASON, Esq., M.P. 
 
 IN RECOGNITION OF GENEROUS 
 HELP GIVEN TO RESEARCH 
 
 Ex tenebris lux 
 
PREFACE 
 
 The progress of every science and of every branch 
 of a science is like that of a ship beating to wind- 
 ward, now to one side now to the other of the 
 straight line towards the port ahead, and, every now 
 and then, it is well that the position, as regards the 
 true course, should be determined. 
 
 In the study of the regulation of metabolism 
 we have for some considerable time been sailing 
 steadily on the tack of chemical regulation, and it 
 behoves us to consider what point we have reached, 
 and how we lie as regards the true line of advance. 
 This is the object of these lectures. 
 
 The advantage, or disadvantage, of such lectures 
 is that the teacher is not only called upon to put 
 forward evidence, but also to assist his student in 
 forming an opinion, by some expression of the views 
 to which he has himself been led. Further, he is, 
 I think, required to consider, not merely the obvious 
 and definite conclusions which can be directly drawn 
 from the observations recorded, but also the prob- 
 able further significance of such observation. In 
 this way alone can any forecast of progress be made ; 
 and such forecasts are in no way dangerous if their 
 
viii PREFACE 
 
 purely tentative character is kept in mind. They, 
 at least, stimulate thought and discussion on future 
 lines of work. 
 
 I desire to acknowledge my indebtedness to 
 Biedl's^ Innere Sekretion. Students who wish to 
 prosecute further the study of the endocrinous struc- 
 tures will find it invaluable. 
 
 Biedl gives so complete a bibliography that I have 
 not considered it necessary to burden the present 
 work with more than a comparatively short list of 
 the more important books and papers, as far as 
 possible in English, and with references to certain 
 papers which I have used in support of some of the 
 theories I have ventured to advance. Such a list, 
 indicating as it does where various illustrations may 
 be found, and the excellent figures in the modern 
 text-books of Histology, obviate the necessity of 
 illustrations in this book. The lectures, when de- 
 livered, were illustrated by lantern slides and by 
 experimental demonstrations. Instead of preserving 
 the division into lectures, a sub-division according 
 to subjects has been adopted, and this is so clearly 
 indicated by the use of head-lines and of heavy type 
 in the text that an Index has been considered 
 superfluous. 
 
 I desire to thank Dr. E. P. Cathcart for his kind- 
 ness in reading and correcting proofs. 
 
 'An English translation of the first edition has been published. 
 A much extended second edition is now appearing in German. 
 
CONTENTS 
 
 Introductory 
 
 PACE 
 1 
 
 The Regulators of Metabolism 
 I. Hereditary Inertia 5 
 
 II. The Nervous System 8 
 
 III The Endocrinous Glands 34 
 (i) Those developed from the Nervous System 
 
 1. Chromaffin Tissue - 37 
 
 2. Hypophysis 64 
 
 (ii) Those developed from the Epithelium of the 
 Buccal Cavity 
 
 1. Thyroid 70 
 
 2. Pituitary 87 
 
 (iii) Those developed from the Intestine 
 
 1. Pancreas 96 
 
 2. Mucosa of Small Intestine 102 
 
 (iv) Those developed from the Epithelium of the 
 Branchial Arches 
 
 1. Thymus - 105 
 
 2, Parathyroids - 123 
 
X CONTENTS 
 
 The Endocrinous Glands — continued page 
 
 (v) Those developed from the Mesothelium of the 
 Genital Ridge 
 
 1. Gonads- 138 
 
 2. Inter-renals 171 
 
 IV. The Interrelations OF THE Endocrinous Glands 180 
 
 V. The Relationships of the Endocrinous Glands 
 
 AND the Nervous System 195 
 
 VI. The Evolution of the Endocrinous Glands 207 
 
 Bibliography - 212 
 
INTRODUCTORY 
 
 It is now universally recoo^nised that the chemical 
 changes in protoplasm which constitute its meta- 
 bolism are the basis of all the phenomena of life, 
 alike of the manifest activities of movement and of 
 the less visible but no less real activities of develop- 
 ment, growth and repair. In fact, we no longer look 
 upon protoplasm as a substance ; we now recognise 
 that it is protoplasm only in virtue of its constant 
 cycle of chemical changes. As Michael Foster has 
 put it : " We may speak of protoplasm as a complex 
 substance, but we must strive to realise that what 
 we mean by that is a complex whirl, an intricate 
 dance, of which, what we call chemical composition, 
 histological structure and gross configuration are, so 
 to speak, the figures." As is here so clearly indi- 
 cated, we now regard not only functional activity 
 but also structure as a result of the chemical changes 
 in protoplasm. 
 
 For the life of the organism co-ordination of the 
 metabolism of all the different tissues and organs is 
 necessary, and each advance in physiology empha- 
 sises the marvellous perfection of this co-ordination, 
 
2 REGULATORS OF METABOLISM 
 
 and demonstrates still more clearly of what vital 
 moment it is in the life of every being. It was 
 perceived by our forefathers only in dim outline, 
 and to them the nervous system seemed the sole 
 connecting link — 
 
 " For if the sinewy threads my brain lets fall 
 Through every part 
 Can tie these parts, and make me one of all," 
 
 expresses this conception in words written by John 
 Donne early in the seventeenth century. 
 
 But as our knowledge has increased it has been 
 found that other factors play their part. 
 
 It is the purpose of these lectures to consider 
 the various factors which bring about this co- 
 ordination and regulation, and which thus determine 
 the orderly development of the body in early life, 
 and the harmonious adjustment of the various 
 activities after full development is reached. 
 
 Three factors are chiefly concerned : 
 
 1. Hereditary Inertia or Inherited Developmental 
 
 Tendencies. 
 
 2. The Nervous System. 
 
 3. The Chemical products of various organs, the 
 
 so-called Internal Secretions. 
 
 The first factor is dominant in embryonic life. 
 The two latter become more prominent as develop- 
 ment advances, and in the fully formed higher 
 vertebrates they probably entirely displace the first. 
 It is with them that we have chiefly to deal. 
 
INTRODUCTORY 3 
 
 As already indicated, the influence of the nervous 
 system has for long been recognised. 
 
 But it is curious that only in quite recent times 
 has attention been directed to the chemical regula- 
 tion. Johannes Miiller, it is true, suggested that 
 glands did not only pour a secretion into their 
 ducts, but that they also gave off products into the 
 blood which might act upon the body. Berthold 
 in 1849 transplanted the testes in young cockerels 
 which he had castrated, and demonstrated the 
 development of the sexual characters. He concluded 
 that the testis yields a substance which acts on the 
 growth of the body. 
 
 But it was only when Brown- S^quard, on experi* 
 mental basis much less satisfactory than that of 
 Berthold, reintroduced the idea that various organs 
 yield products which react upon other organs in the 
 body, that physiologists seem to have wakened to 
 the possibility that such chemical regulation may be 
 of importance in the control of metabolism. 
 
 Since that time the subject has received very 
 great attention from an ever increasing number of 
 workers, and there seems to be a growing tendency 
 to regard chemical regulation as something quite 
 apart from nervous regulation, to look upon it as 
 something more fundamental, which existed before 
 a nervous system was evolved, and which goes 
 on acting alongside of and independently of that 
 system. 
 
 But it is possible that these products of the 
 
4 REGULATORS OF METABOLISM 
 
 activity of organs, these internal secretions, exercise 
 their influence not directly on the tissues, but through 
 the nervous system ; that, instead of the chemical 
 regulation being an older and more fundamental 
 mechanism than the nervous, it is really a newer 
 one largely developed to facilitate and to regulate 
 the action of nervous adjustment. 
 
 The enormous mass of information which has 
 now been collected concerning the internal secre- 
 tions, their action, mode of production and inter- 
 relations has put us in a position to take a general 
 view of the situation, and to give at least a partial 
 answer to the question of how they are related to 
 the action of the nervous system. 
 
 In these lectures the part played by what I venture 
 to call hereditary inertia will be very briefly con- 
 sidered ; the influence of the nervous system, more 
 especially as regards its influence on growth and 
 metabolism, will be dealt with ; the physiology of the 
 structures yielding internal secretions, and the mode 
 of action of these secretions will be described ; and 
 finally the inter-relationship of these structures and 
 their possible reciprocal action with the nervous 
 system will be discussed. 
 
THE REGULATORS OF METABOLISM. 
 SECTION I. 
 
 HEREDITARY INERTIA. 
 
 Newton's first law of motion, that every particle of 
 matter in the universe continues in a state of rest or 
 of uniform motion in a straight line unless so far as 
 it is acted upon by external force is as applicable 
 to living as to non-living material, and it applies to 
 the course of development and differentiation of the 
 ovum. 
 
 Generation after generation, a similar piece of pro- 
 toplasm, undergoing the same active molecular move- 
 ments, is placed under the same external conditions, 
 acted upon in the same way from without, and hence 
 it must undergo the same course of development and 
 differentiation which its progenitors have undergone, 
 with, of course, the possibility of alteration in this 
 course as a result of changes in the external con- 
 ditions. This, I think, we may call Hereditary 
 Inertia — defining Inertia in terms of Newton's 
 first law. 
 
6 REGULATORS OF METABOLISM 
 
 Oliver Wendell Holmes has said that e very- 
 normal man placed under the same conditions will 
 do the same thing. And in any ovum the process of 
 growth, of division and of differentiation should be the 
 same as in all others. The external conditions may 
 vary within wide limits without necessarily materially- 
 acting upon the protoplasmic metabolism, and the 
 inertia of heredity, that is, the law of movement in a 
 straight line, may carry the process onward to com- 
 plete differentiation and to the consummation of the 
 fully developed organism. 
 
 In the earlier stages of development, the influence 
 of these inherited developmental tendencies is fully 
 recognised. So marked is it that when, at a suffi- 
 ciently early stage, one blastomere is separated from 
 the rest it may undergo the same processes of 
 development and growth as the mass from which it 
 is separated. 
 
 In many of the lower vertebrates this power of 
 self-differentiation persists till an advanced stage of 
 growth, as is shown by the researches of Ross- 
 Harrison, Hooker and others upon young tadpoles. 
 All the tissues, and even so complex an organ as the 
 heart, may evolve after the nervous system has been 
 completely removed at a time when the neural canal 
 has just closed, and when presumably no emigration 
 of nerve cells has taken place into the tissues. Not 
 only does structural differentiation occur, but func- 
 tional activity develops. The normal rhythmic beat 
 of the heart appears, and, although the voluntary 
 
HEREDITARY INERTIA 7 
 
 muscles do not exhibit spontaneous movements, 
 they are capable of contracting in response to 
 stimulation. 
 
 One of the difficulties in determining the part 
 played by the nervous system in controlling the 
 metabolism of growth and development is the 
 impossibility of ascertaining when this hereditary 
 inertia becomes insufficient to carry forward un- 
 aided the developmental processes. 
 
SECTION 11. 
 
 THE NERVOUS SYSTEM. 
 
 Development. Very early in the course of de- 
 velopment in vertebrates a nervous system makes 
 its appearance. Long before any of the organs are 
 differentiated the neural groove appears down the 
 back of the blastoderm, and soon closes in to form 
 the neural canal. 
 
 From this tube of epiblastic cells an emigration 
 of neuroblasts begins to take place almost at once 
 into the differentiating organs, so that, before their 
 component tissues become recognisable, each of the 
 visceral organs is permeated by nerve structures. 
 
 Many of these neuroblasts are arrested in their 
 outward course in various ganglia. 
 
 In each metamere a massing of these cells occurs 
 to form the ganglion of the posterior root of the 
 spinal nerves — the spinal ganglion. From these 
 cells processes grow inwards to the cord and out- 
 wards to form dendritic terminations in the skin and 
 other structures. 
 
 Other cells, passing out chiefly by way of the 
 posterior roots, but also to a less extent by the 
 
THE NERVOUS SYSTEM 9 
 
 anterior roots, are arrested in front of each metamere 
 to form the sympathetic or lateral ganglia of the 
 sympathetic chain. They send out processes both 
 towards the viscera and also into the somatopleure 
 to supply the unstriped muscles, blood-vessels and 
 glands. 
 
 Some cells wandering further afield come to rest 
 in more remote situations, in collateral ganglia, 
 such as the ciliary ^ ganglion behind the eye and the 
 superior and inferior mesenteric ganglia in the abdo- 
 men. Others migrate right down into the tissues, 
 there to form the terminal ganglia — plexiform net- 
 works of cells and fibres, such as Auerbach's and 
 Meissner's plexuses in the intestine, and the ganglia 
 of the heart. The whole series of emigrated cells 
 maintains a connection with the central nervous 
 system, and constitutes the great sympathetic or 
 autonomic system of nerves, a system which, cours- 
 ing along the blood-vessels, reaches into every part 
 of the body. 
 
 This system may be divided into two parts. The 
 first is derived from the spinal roots of the thoracico- 
 abdominal region of the cord, and may for brevity 
 be called the "true" sympathetic system. The 
 second is developed in connection with the nerves 
 leaving the central nervous system at its cranial and 
 sacral parts — at its two extremities — and may be 
 called the " para " sympathetic. The term autonomic 
 
 1 Morphologically it is true that the ciliary ganglion may be of the 
 nature of a lateral rather than a collateral ganglion. 
 
lo REGULATORS OF METABOLISM 
 
 system, given to the latter by German writers, 
 appears to me misleading. 
 
 From the cells towards the ventral side of the 
 cord processes grow outwards. Some are linked up 
 to the developing muscle-plates to form the ordinary 
 nerves of the muscles, but others probably become 
 related to the emigrated cells of the sympathetic 
 system. 
 
 Influence on Metabolism. In earlier embryonic 
 life the chemical changes, which are the basis of 
 all growth and structural change, are, as already 
 indicated, controlled by hereditary inertia and by the 
 direct influence of changes in the surroundings. But, 
 as the nervous system develops, the changes in 
 environment act more and more through it, so that 
 vital processes are dominated by nerve influences, 
 and become less and less dependent on the factors 
 which previously governed them. At last, in the 
 fully formed animal, all the manifest activities of body, 
 muscular and glandular, somatic and visceral, alike, 
 are controlled and regulated by the highly developed 
 nervous system, the integrative action of which has 
 been so brilliantly elucidated by the work of 
 Sherrington. 
 
 To deal with this general co-ordinating action of 
 the nervous system would be to take up practically 
 the whole range of physiology, and we must con- 
 fine our attention to the question — What part does 
 the nervous system play in the control of these 
 
THE NERVOUS SYSTEM ii 
 
 metabolic processes which are the basis of growth 
 and development and repair ? 
 
 The problem is no easy one. The initial directive 
 influence of hereditary inertia — the "self-differentia- 
 ting " of the tissues — must be admitted. If the 
 nervous system, as it gradually evolves, comes to 
 play a part in the process of development, a stage 
 must be reached at which both factors are in 
 operation, and at this stage it must prove difficult to 
 distinguish their effects. This, I think, accounts for 
 the very contradictory conclusions arrived at by 
 various investigators of this problem in embryonic 
 amphibia, on which most of the experimental work 
 has been done. It appears to me that the question 
 should first be studied in the adult, where the full 
 influence of the nervous system may be supposed to 
 have developed, and that, if evidence is forthcoming 
 of a direct influence of the nervous system upon 
 metabolism, the investigation may then be carried 
 backwards, not to answer the question. Does the 
 nervous system have this influence ? but to ascertain 
 at. what time this influence becomes dominant, at 
 what time it replaces the " self-differentiating" action 
 of hereditary inertia. The difficulty, however, arises 
 that, in the adult, growth and development of most 
 of the tissues is completed, and hence the influence of 
 the nervous system upon these processes cannot be 
 directly observed. But the fact that in amphibia 
 regeneration of amputated limbs occurs has been 
 utilised. 
 
12 REGULATORS OF METABOLISM 
 
 A. EVIDENCE FROM REGENERATION. 
 
 In the interpretation of the results of such obser- 
 vations many difficulties arise — 
 
 1. Destruction of the cord, even when it involves 
 
 the spinal ganglia, leaves intact the autonomic 
 system. 
 
 2. The persistence of hereditary inertia is prob- 
 
 ably different in different animals, and in 
 some may actually extend on into adult life. 
 Certain it is that in some amphibia regenera- 
 tion goes on more readily than in others. In 
 the adult frog the power of regeneration is 
 poorly developed, but in one American newt, 
 used by Goldfarb in his experiments, it 
 appears to be very specially marked. 
 Wolff, in 1 895 and 1 896, recorded experiments upon 
 the development of tadpoles and upon regeneration 
 of limbs of adult newts. After removal of the part 
 of the spinal cord connected with the limb amputated, 
 regeneration occurred ; but, when the spinal ganglia 
 were also removed, regeneration was interfered with. 
 Barfurth, 1901, got regeneration of the point of 
 the tail of the axolotl when separated from the 
 nervous system. Rubin, 1903, cut all the nerves of 
 the fore limb of axolotl and amputated the fingers 
 or the whole hand, and found that regeneration 
 starts, but that later it is retarded and is incomplete. 
 Wolff's results were severely criticised by Gold- 
 stein, who, however, concerned himself generally 
 with the influence of the nervous system in, larval 
 
THE NERVOUS SYSTEM 13 
 
 forms. He concludes: "in the stage of 'organ- 
 forming development' (Roux) the developmental 
 progress of regeneration in general advances in 
 full independence of the nervous system. In the 
 stage of 'functional development' for both pro- 
 cesses a clearly expressed influence of the central 
 nervous system is present." 
 
 Walter repeated Wolff's regeneration experi- 
 ment on the adult newt, and he concludes that the 
 posterior root fibres have a direct influence on 
 the progress of regeneration. On the other hand, 
 Goldfarb, 1907, after rejecting various amphibia 
 because the results obtained were not satisfactory, 
 selected a newt, Diemyctylus viridescens, which is 
 characterised by a very marked power of regenera- 
 tion, and he states that regeneration went on nor- 
 mally after destruction of the cord and of the spinal 
 ganglia. These results were severely criticised by 
 Walter in a subsequent paper. 
 
 Of these conflicting experiments, the most careful 
 and convincing are undoubtedly those of Walter. 
 In these the histological examination was most full 
 and complete. 
 
 The result of a study of the work done is to leave 
 the impression that the nervous system, and more 
 especially the spinal ganglia, have a direct influence 
 on the process of regeneration. Even if the results 
 of Goldfarb are accepted, they by no means exclude 
 the influence of nervous tissue in the great sympa- 
 thetic system which was left intact. 
 
14 REGULATORS OF METABOLISM 
 
 With the large series of experimental investiga- 
 tions upon the effects of removal of the central 
 nervous system in larval amphibia, we need not 
 concern ourselves further than we have already done. 
 As already pointed out, the undoubted persistence 
 of the influence of hereditary inertia and the possible 
 blending of this with the influence of the nervous 
 system at this stage makes the interpretation of results 
 most difficult, and of little value in the solution of 
 the question, To what extent does the nervous 
 system dominate the metabolism ? 
 
 One interesting set of observations by Diirken 
 may be referred to. He shows that in young tadpoles 
 there is a marked co-relation between the " Anlage" 
 of the limbs and the central nervous system, and 
 that removal of one of the limb-buds may be followed 
 by failure in the development in certain definite 
 parts of the nervous system — in peripheral nerves, 
 spinal ganglia, motor cells of the spinal cord and 
 even in the hind and fore brain. In some cases he 
 finds that destruction of one limb-bud is followed 
 by malformations of others, and that these are also 
 associated with changes in the central nervous 
 system. These results indicate a close co-relation- 
 ship between the nervous system and the develop- 
 ing tissues, and support the view that the former 
 undoubtedly acts upon the latter and is reacted 
 upon by it. 
 
 It is unnecessary to discuss the large series of 
 observations which have been carried out upon 
 
THE NERVOUS SYSTEM 15 
 
 regeneration in invertebrate animals. But the recent 
 experiments of Morguli upon ophiurid starfish may- 
 be referred to as showing the influence of nerves 
 even in such simple forms of life. He found that 
 regeneration of the rays did not occur when the nerve 
 was removed from the amputation wound, but that 
 if the nerve was left, even although it had been 
 separated from the central ring, regeneration 
 occurred. This regeneration was less marked 
 when the connection of the ganglionated ray nerve 
 with the central ring had been divided. 
 
 Herbst's well-known experiment on the regenera- 
 tion of the eye of Palinurus vulgaris' also shows the 
 important influence of nerve in regeneration in 
 invertebrates. When the eye was simply removed 
 it regenerated completely ; but when the stem with 
 the eye ganglion was also removed, the regeneration 
 resulted in the formation of an antennule instead of 
 an eye. 
 
 The conclusion seems justified that at some stage of 
 development, which varies in different animals, the 
 nervous system comes to have a direct and important 
 action upon the processes of growth and development. 
 
 B. GENERAL EVIDENCE. 
 
 A. Influence of Central Nervous System. In many 
 animals, apart from regeneration, there is direct 
 evidence of the influence of the central nervous 
 system, not only upon the rapid metabolism of 
 muscle, which is the basis of its contraction, but 
 
1 6 REGULATORS OF METABOLISM 
 
 also upon the slow nutritional chemical changes 
 which maintain its growth and repair. Section of 
 the anterior roots of spinal nerves leads to paralysis 
 of the muscles supplied and to progressive atrophy. 
 It is true that the nutritional chemical changes can 
 be maintained by appropriate electrical stimulation 
 applied directly to the muscle, but this in no sense 
 disproves the action of nerve when it is intact. It is 
 a substitute for that action. 
 
 As regards other tissues there is a good deal of 
 evidence which requires examination. 
 
 In 1823 Herbert Mayo described inflammation 
 and ulceration in the eye following upon section of 
 the fifth cranial nerve. These results were confirmed 
 by Magendie in 1824, and by Bernard in 1868, 
 They have been ascribed to the influence of external 
 irritants which are not removed on account of the 
 loss of sensation. But that this is not the whole 
 explanation was proved by Sinitzen in 187 1. He 
 then showed that the ulcerative changes in the eye 
 produced by section of the fifth nerve may be pre- 
 vented by removal, a short time before, of the 
 superior cervical ganglion which leads to hypersemia 
 of the eye. His results were confirmed in 1894 by 
 Spallitta. 
 
 Baldi (quoted by Luciani) in 1889 cut the posterior 
 and anterior roots of the nerves to the fore and hind 
 legs of dogs. In both limbs he got a transient 
 hyperaemia of the skin disappearing in a few days, 
 erosion of the claws, loss of hair and excoriations on 
 
THE NERVOUS SYSTEM 17 
 
 the skin. The limb had to be kept bandaged to 
 prevent extensive ulceration. When the hair was 
 shaved on the back of the foot it took twice as long 
 to grow as in the normal limb, and was less 
 developed. When croton oil was applied, the 
 vesicles formed twenty-four hours later than in the 
 normal limb, and the new epidermis appeared 
 fourteen days later. That these results were not 
 due to paralysis of motion and sensation he proved 
 by cutting the spinal cord, when no trophic changes 
 appeared. 
 
 Clara Jacobson, working under Carlson, cut the 
 posterior and anterior nerve roots in the lumbar 
 region of pigeons on both sides, and found that 
 wounds in the paralysed area healed as well as those 
 on the normal side. Carlson and Werelius cut the 
 dorsal cutaneous rami in three contiguous spinal 
 nerves in three dogs, and the posterior roots in 
 three other cases, and found that healing of wounds 
 and growth of hair were not interfered with. Obvi- 
 ously more work upon this question is required. 
 
 As regards glands, Bidder states that section of 
 the nerves to the salivary glands brings about a 
 decrease in their size to one-half 
 
 Ndaton, from clinical experience, concluded that 
 section of the nervi spermatid caused atrophy of the 
 testis. Obolensky showed by experiments upon 
 animals that after section of these nerves the testis 
 became distinctly smaller in two or three weeks, and 
 that after four weeks it had almost disappeared. 
 
1 8 REGULATORS OF METABOLISM 
 
 Section of the vas deferens did not produce this 
 effect. 
 
 The evidence of pathology also points to the 
 direct influence of the nervous system, not only 
 upon the muscles but also upon the connective 
 tissues, bone and epidermis. 
 
 In infantile paralysis, acute anterior polioinyelitis, 
 where the cells of the anterior horn of grey matter 
 are affected, not only does atrophy of the muscles of 
 the limb occur, but the bones and connective tissues 
 stop growing, and the limb remains small. A, 
 curious point is that the growth of the bones in 
 length is much less interfered with than their growth 
 in thickness. This decreased growth is sometimes 
 ascribed to the absence of the stimulus of muscular 
 contraction. Such muscular contraction can act upon 
 the growth of bone only by modifying its blood supply, 
 and this it must do through the nervous reflex arc. 
 Such trophic disturbances of bone are not only seen in 
 children, but they may occur in hemiplegia in adults. 
 Purves Stewart states that the bones may become 
 very brittle, so that fractures are readily caused. 
 The interest of these changes in the bones through 
 the influence of the nervous system will be made 
 more manifest when the effects of some of the 
 internal secretions are being considered. 
 
 Evidence is also afforded by the somewhat rare 
 cases of progressive facial hemiatrophy in which all 
 the tissues of one side of the face undergo advancing 
 decrease in bulk. 
 
THE NERVOUS SYSTEM 19 
 
 But the best , examples of the trophic influence of 
 the nervous system is afforded in diseases which 
 involve the posterior roots of the spinal nerves. In 
 tabes dorsalis a whole series of trophic disturbances 
 occur. The skin may show peculiar symmetrical 
 perforating ulcers or loss of hair over definite areas. 
 The joints may undergo enormous thickening and 
 distortion in the so-called arthropathies. Similar 
 changes are seen in syringo-myelia, a disease in 
 which cavities exist in the spinal cord, with increase 
 of neuroglia'and disappearance of nervous elements; 
 In both diseases the bones may become brittle and 
 be easily fractured. 
 
 Herpes zoster, a vascular disturbance of the skin 
 along the area of certain nerves, has been definitely 
 associated with inflammatory conditions of the nerve 
 ganglia — the Gasserian ganglion of the fifth when 
 it occurs in the face, and the spinal ganglia when it 
 occurs on the side of the thorax. 
 
 The importance of the posterior root fibres and 
 their ganglia upon nutrition is strongly indicated by 
 these facts, and they strengthen the conclusions 
 arrived at by Wolff and Walter from their experi- 
 mental work upon amphibia (p. 1 2 ). This conclusion is 
 further supported by a study of certain monstrosities. 
 Children are occasionally born without a brain or a 
 spinal cord, and yet with perfect development of the 
 trunk and limbs. In such cases the posterior nerV6 
 roots have been found to exist with their ganglia 
 upon them, and the sympathetic nervous system has 
 
20 REGULATORS OF METABOLISM 
 
 been fully developed. Such monsters seem to be 
 much in the condition of the newts with the spinal 
 cord destroyed, but with the spinal ganglia intact, 
 which have been already described. 
 
 There is also some direct physiological evidence 
 as to the importance of these ganglia. Strieker and 
 Morat found that stimulation of the posterior roots 
 induces dilatation of the blood-vessels. These 
 observations were confirmed and extended by 
 Bayliss. Ninian Bruce, working under Hans Meyer, 
 found that croton oil applied to the conjunctiva or 
 skin causes vaso-dilatation, even when the posterior 
 roots of the spinal nerves are cut above the ganglion, 
 but, if they are cut below the ganglion and time 
 for degeneration allowed, no reaction occurs. The 
 application of a local anaesthetic, such as cocaine, 
 also abolishes the reaction. This seems to indicate 
 the existence of a controlling mechanism in these 
 ganglia, although Bruce tries to explain the results 
 on the hypothesis of a forking of fibres beyond the 
 ganglion, thus bringing the results into accord with 
 the post-ganglionic axon-reflex view of Langley. 
 
 These facts seem to throw important light upon 
 the way in which, even in cases of total absence of 
 the spinal cord, either developmental or experi- 
 mentally produced, the nutrition of the tissues may 
 be maintained if the posterior nerve roots are intact. 
 It seems unnecessary to assume with Bayliss the 
 passage of the impulses in both directions along the 
 same nerve fibres. Dogiel has shown the existence 
 
THE NERVOUS SYSTEM 21 
 
 of different types of cell in the posterior root ganglia, 
 and possibly different types of fibres, outgoing as well 
 as ingoing, may exist. 
 
 B. Influence of the Autonomic System. As regards 
 the influence of the Autonomic System, apart from 
 the central nervous system, evidence of independent 
 action upon the tissues is conclusive only as regards 
 the peripheral or terminal plexuses. 
 
 I. In the alimentary canal the plexus of Auerbach 
 has been shown by Bayliss and Starling to preside 
 over the peristaltic movements of the intestine, 
 while the more recent work of Magnus indicates 
 that even the swaying movements, formerly regarded 
 as purely muscular in origin, are really dependent 
 upon the plexus. 
 
 The onset of rhythmic contractions in the heart, 
 before nerve structures can be detected in the organ, 
 has led many observers to conclude that both the 
 onset and spread of the contraction is purely a func- 
 tion of muscle. But the most recent work upon the 
 existence of nervous elements in the auricular walls 
 and in close association with the sino-auricular node, 
 and the indications we possess of the function of 
 that structure in dominating the cardiac rhythm, 
 indicate that these terminal ganglionic structures 
 probably have a direct action. 
 
 The existence of peripheral plexuses in the walls 
 of blood-vessels has been clearly demonstrated by 
 the investigations of Dogiel, and their presence 
 
22 REGULATORS OF METABOLISM 
 
 explains many of the phenomena of local control 
 after section of nerves. 
 
 In the bladder, the demonstration by Goltz and 
 Ewald that, after removal of the lumbo-sacral part 
 of the cord in the dog, the function of the organ, 
 although abolished for a time, is partially restored, so 
 that urine can be retained and evacuated under local 
 stimulation ; and the observation of von Zeissl that 
 section of all the nerves to the bladder does not pre- 
 vent urine accumulating in the viscus and being 
 periodically expelled, point to the existence of some 
 local nerve mechanism. Lewandowsky and Schultz, 
 it is true, could confirm this result of Zeissl only in 
 bitches, but they admit the existence of sphincter tone. 
 The functions of the bkdder involve not merely mus- 
 cular contraction but co-ordinated contraction and 
 inhibition, comparable with the process of peri- 
 stalsis in the intestine, which must require the action 
 of some form of nervous mechanism. Griffiths and 
 Stewart both found that, after isolating the hypo-, 
 gastric plexus from its central connections, bladder 
 reflexes could be obtained. Metzner susfgrests that 
 these may be of the same nature as those described 
 by Langley and Anderson in the inferior mesenteric 
 ganglion as axon reflexes (p. 24). All these investi- 
 gations seem to indicate a peripheral nervous control 
 from the plexus hypogastricus, if not also from the 
 inferior mesenteric ganglion. 
 
 In giving such prominence to these terminal 
 ganglia, I am influenced not only by physiological 
 
THE NERVOUS SYSTEM 23 
 
 evidences, but also bjr W. Abel's work upon the 
 development of the autonomic system, carried out in 
 this laboratory, and by the work of Dogiel. I do not 
 think that any one who has not seen preparations 
 showing the emigration of neuroblasts to form the 
 autonomic system can realise the extent to which it 
 goes on. 
 
 The importance of these peripheral plexuses is still 
 further emphasised by recent work upon the nervous 
 mechanism of autonomous organs of invertebrates. 
 Alexandrowicz, working under Biedermann in Jena, 
 and using the methylene blue method, finds that in the 
 heart of such molluscs as the snail and octopus, in 
 the heart, intestine and sex organs of a tunicate 
 (Ciona intestinalis) and in the heart and blood-vessels 
 of various decapod Crustacea, nerve fibres and nerve 
 cells forming a true plexus are present, and that in the 
 gut of the snail the cells are differentiated into two 
 types — one small, which he supposes to be sensory 
 or receiving; one large, which he suggests as motor. 
 
 2. On the mode of action on metabolism of the 
 collateral ganglia, such as the ciliary, submaxillary 
 and sublingual, otic, the superior and inferior 
 mesenteric, and the hypogastric ganglia, our know- 
 ledge is very imperfect. 
 
 Francois Frank finds that section of the third 
 nerve produces a less marked dilatation of the pupil 
 than does section of the post-ganglionic fibres from 
 the ciliary ganglion, while Jegorow finds that excision 
 of the ganglion produces a greater effect on the pupil 
 
24 REGULATORS OF METABOLISM 
 
 than does section of the third nerve. This would 
 indicate a tonic influence of the ganglion upon 
 the dilator pupillae. P. Schultz failed to confirm 
 this. 
 
 Upon the splanchnic nerves and the plexus Solaris 
 various experiments have been performed by Vogt 
 and by Popielski. It appears that section of the 
 splanchnics causes no marked changes in the 
 intestine or kidneys. Removal of the plexus Solaris, 
 according to the investigations of Popielski, causes 
 in dogs marked symptoms in the alimentary canal, 
 such as diarrhoea, haemorrhages, masses of des- 
 quamated epithelium in the stools, etc. Such results 
 seem to indicate an influence of the ganglion on the 
 intestine independent of the central nervous system. 
 
 Less conclusive are the well-known results of 
 section of the chorda tympani nerve upon the sub- 
 maxillary and sublingual glands, producing as it 
 does an increased or " paralytic " secretion. This 
 has been ascribed to a stimulation of the submaxillary 
 and sublingual ganglia, and would seem to indicate 
 an action of these structures upon the glands. 
 
 The conclusion of Claude Bernard, based upon his 
 experiments on the submaxillary ganglion, that these 
 collateral ganglia are the seat of peripheral reflex 
 action has been discredited by the investigations of 
 Langley and Anderson. One of the best marked of 
 these apparent peripheral reflexes is that described 
 by Sokownin in the bladder. He showed that when 
 the connections of the inferior mesenteric gfanoflion 
 
THE NERVOUS SYSTEM 25 
 
 with the central nervous system were severed, stimu- 
 lation of the central end of one cut hypogastric nerve 
 caused a contraction of the bladder. Langley and 
 Anderson confirmed this observation, and showed 
 that it did not occur if the ganglion is painted with 
 nicotine. But they found that, if after section of the 
 preganglionic fibres time is given for their degenera- 
 tion to take place, the reflex can no longer be 
 elicited. From this they conclude that it is not a 
 true reflex but is dependent upon a stimulus passing 
 up the axons of efferent preganglionic fibres which 
 have not been interrupted in the ganglion, but which 
 have given off a collateral to form synapses there. 
 The conclusion as expressed by them is fairly 
 guarded — " On the whole we think that the balance 
 of evidence is distinctly in favour of the view we put 
 forward, viz. that the reflexes obtained by stimulat- 
 ing the central end of the hypogastric are due to 
 nervous impulses which pass up motor fibres and 
 spread to the branches they give off to the ganglia 
 of the opposite side, and so down the opposite hypo- 
 gastric nerve." 
 
 3. The evidence we possess for or against the influ- 
 ence of the lateral ganglia of the sympathetic chain 
 is even less satisfactory than that which we have just 
 dealt with as regards the collateral ganglia. 
 
 Section of the cervical sympathetic which carries 
 impulses from the spinal cord to the cell stations in 
 the superior cervical ganglion, does not modify the 
 action of adrenalin on the pupil of the cat, but 
 
26 REGULATORS OF METABOLISM 
 
 removal of the ganglion with the subsequent degen- 
 eration of the post-ganglionic fibres leaves the pupil 
 peculiarly sensitive to the action of adrenalin, so 
 that for some time after dilatation is readily pro- 
 duced. This seems to indicate that the cells of the 
 ganglion exercise a constant action upon the muscle 
 fibres of the iris. 
 
 As will be afterwards shown (p. 48), the explanation 
 has been offered that the point upon which adrenalin 
 acts is rendered more sensitive by degeneration of 
 the nerve fibres. But the complete disappearance 
 of peripheral plexuses, after degeneration of the 
 nerve fibres passing to them, has not been proved, 
 and investigations carried on by Pollock in this 
 laboratory seem to show that it does not occur. 
 
 Langley, as a result of his extensive and masterly 
 investigations on the autonomic system, concludes 
 (Schafer's Text Book, vol. ii. p. 677, 1900): "On 
 the whole, the evidence at present leads us to con- 
 clude that autonomic ganglia, after separation from 
 the central nervous system, do not exercise any 
 considerable tonic action on unstriated muscle, but 
 that it is possible they have a slight action. 
 
 "Apart from tonic action, it is not improbable 
 that peripheral nerve cells, severed from the central 
 nervous system, may at times stimulate the tissues 
 to which they send fibres. The nerve cells and 
 fibres remain responsive to chemical and mechanical 
 stimuli, and it is not unlikely that substances cir- 
 culating in the blood and the movements of the body 
 
THE NERVOUS SYSTEM 27 
 
 now and then serve as stimuli to the local nervous 
 mechanism, and so set in action the peripheral 
 apparatus. 
 
 "So far we have considered nerve cells which 
 normally exercise a tonic influence on the tissues 
 with which they are in connection. Of the others 
 there is little that need be said here. There is some 
 evidence that the submaxillary ganglion passes into 
 a state of slight tonic activity after section of the 
 chorda tympani, for, so far as the experiments have 
 gone, dyspnoea increases and chloroform decreases 
 the paralytic secretion." 
 
 The subsequent work of Bayliss and Starling and 
 of Magnus on the peripheral plexuses of the gut, and 
 the evidence which has been adduced above, all 
 strengthen the view that at least many of the 
 autonomic ganglia do exercise an influence on the 
 metabolism of the tissues they supply. 
 
 The elaborate and painstaking work, both anato- 
 mical and physiological, of Langley and Anderson, 
 taken along with this more recent work, and with the 
 results of the later investigation on the development 
 of the autonomic system, seems to indicate that 
 there is no essential difference between the various 
 ganglia — lateral, collateral and terminal. The point 
 of arrest of the emigrratinsr neuron cells seems to 
 vary in different species and even in different 
 animals of the same species. Autonomic action 
 appears to be most marked where the terminal 
 plexuses are best developed, as in the wall of 
 
28 REGULATORS OF METABOLISM 
 
 the gut, but in all probability the same kind of 
 action is exercised by the more proximal ganglia. 
 It may well be that the axon reflexes of Langley 
 normally play an important part in these actions. 
 
 One undoubted purpose of these ganglia is to 
 act as distribution stations for the nervous impulses 
 coming from the central nervous system. With the 
 extensive growth of the alimentary canal, of the 
 
 Fig. I. — To show how, by development of a sympathetic system, the control of a 
 central neuron is extended. The terminal ganglia are omitted. 
 
 heart and of the blood-vessels, it becomes of advan- 
 tage that a small portion of the central nervous 
 system should be able to control a large extent 
 of these visceral structures. This is probably partly 
 effected by one set of preganglionic neurons play- 
 ing upon many sets of post-ganglionic neurons in 
 each ganglion or series of ganglia as figured by 
 Langley (Fig. i). 
 
 A curious and interesting difference between the 
 innervation of the somatic muscles and those of 
 the viscera is emphasised by Sherrington. In the 
 former, the same outgoing neuron serves for 
 
THE NERVOUS SYSTEM 29 
 
 augmentation and inhibition, whereas in the latter, 
 separate neurons, one set causing augmentation, 
 another set causing inhibition, pass to the peripheral 
 structures. If the peripheral structure upon which 
 these neurons play is the terminal nerve plexus, 
 then we have to regard this plexus as the homologue 
 of the motor neuron of the cord, possibly of the 
 spinal reflex arc. Sherrington's work most clearly 
 shows that it is neurons in the cord which act as 
 augmentors or inhibitors on the neurons to the 
 skeletal muscles, and hence they may be regarded 
 as the homologues of the autonomic nerve fibres. 
 But, since precision and not diffusion of action is 
 required, they need not be complicated by the 
 development of distribution stations similar to those 
 in the sympathetic ganglia, and such ganglia are 
 absent. 
 
 This conception of the relations of the two 
 mechanisms may be diagrammatically represented as 
 follows (Fig. 2). 
 
 I have purposely refrained from the use of the 
 term " Trophic Nerve," because it appears to me that 
 all nerves which modify the metabolism and so the 
 activity of a structure are necessarily trophic, and 
 that no nerves which do not thus modify metabolism 
 can have a trophic or any other influence. The 
 discussion by von Tschermack in the Folio Neuro- 
 biologica, Bd. 3, p. 676, 19 10, on the existence of 
 such nerves seems to me beside the mark. The 
 evidence he adduces is simply for the influence of 
 
30 REGULATORS OF METABOLISM 
 
 nerves upon metabolism, not for the existence of 
 special trophic nerves. 
 
 Modes of Action of the Nervous System. Accepting 
 the evidence that the nervous system does modify 
 
 M 
 
 M^ 
 
 Fig. 2.— To show the homologies between the various parts of the innervation (I.) of 
 visceral and (IL) of skeletal muscle. A i and 2. two afferent neurons, stimulation of 
 each leading to a definite augmentor and inhibitory result in the muscles supplied 
 M and Mi. B. The intercalated neurons resolving the stimulus into augmentor 
 (uniform line) and inhibitory (dotted line) effects. C. The distributive ganglia' of ' 
 the sympathetic system not represented in the innervation of the skeletal muscles. 
 D. The efferent nerves to skeletal muscles and the terminal ganglia in visceral 
 muscle with which they correspond. 
 
 and control the metabolism upon which (development 
 and growth depend, the ways in which this control 
 is exercised may now be considered. 
 
 The influence of efferent nerves upon growth 
 
THE NERVOUS SYSTEM 31 
 
 and development may be either direct upon the 
 living cells of the tissues, or indirect by their action 
 through the blood-vessels. Although evidence may 
 be wanting of an increase of metabolism as the 
 result of an increased blood supply, there is un- 
 doubted proof — e.g. that afforded by the develop- 
 ment of adipose tissue — that the cells can take up 
 an increased amount of nourishment when that 
 is supplied, and that, if the supply of nourishment 
 is cut off by constriction of vessels, decreased 
 growth and even death may ensue. And, further, 
 the action of ergot in bringing about a contraction 
 of the peripheral vessels and, as a result, death and 
 necrosis of the comb and legs of fowls indicates the 
 great importance of the nervous control of blood- 
 vessels upon nutrition. 
 
 Ingoing nerves may react reflexly upon tissues in 
 the same directions. 
 
 The suggestive work of Gaskell on the mode of 
 action of inhibitory nerves cannot be ignored in any 
 consideration of the influence of the nervous system 
 on metabolism. . Accepting the negative variation 
 of the current of injury in the heart as indicative of 
 increased catabolism in the contracting part, he 
 investigated the effect of stimulation of the vagus 
 and found that, during the inhibition, the current 
 of injury was increased. From this he argued 
 that the anabolic processes are increased, arid he 
 classified nerves into catabolic and anabolic; 
 
 The important influence of the nervous system 
 
32 REGULATORS OF METABOLISM 
 
 upon development, growth and nutrition is thus 
 established. But the period of development at 
 which it becomes prominent and replaces the 
 primary adjustments, generally described as "self- 
 differentiation," probably varies in different animals 
 and in different tissues of the same animal. 
 
 In thus recognising the part played by nerve, it 
 must, of course, be borne in mind that tissue growth 
 may go on independently of nerve influence. This 
 is clearly shown by the persistence and growth of 
 grafts of various organs in the animal body, when, 
 so far as we know, only the ingrowing blood-vessels 
 carry nerves with them. It is also shown by the 
 recent interesting experiments of Ross Harrison, 
 Carrel and others on the growth of tissues in a 
 suitable nutrient medium in vitro. But the question 
 of co-ordination with other structures is not here 
 involved, and such observations in no way invalidate 
 the conclusion as to the important part played by 
 the nervous system as a regulator of metabolism. 
 
 Summary. A consideration of the evidence as 
 regards the influence of hereditary inertia and of 
 the nervous system upon development, growth and 
 repair has led us to the conclusion that, while in 
 early embryonic life the former is prepotent and is 
 itself sufficient to explain the self-differentiation 
 of the various tissues and organs, at some stage in 
 development the nervous system comes to play a 
 part in the regulation and co-ordination of the 
 metabolism upon which these processes depend. 
 
THE NERVOUS SYSTEM 33 
 
 The part played by the central nervous system has 
 been seen to be fully established, while the evidence 
 as to the action of the autonomic system, although 
 less conclusive, leaves little doubt that it too exer- 
 cises an influence. 
 
SECTION III. 
 
 THE ENDOCRINOUS GLANDS AND THEIR 
 INTERNAL SECRETIONS. 
 
 In addition to the action upon metabolism of 
 hereditary inertia and of the nervous system, which 
 have been considered in the previous sections, the 
 influence of chemical changes also play an important 
 part. 
 
 The course of development and of growth may be 
 materially modified not only by artificially modify- 
 ing the chemical constitution of the fluids surround- 
 ing the organism, but also by changes qualitative or 
 quantitative in the metabolic processes of some 
 part or parts of the body. The most striking 
 example of chemical regulation is, perhaps, the 
 effect of the increased production of carbon 
 dioxide by muscle during contraction, leading 
 as it does to increased activity of the nervous 
 structures constituting the respiratory centre, and 
 thus causing the marked augmentation of the 
 respiratory movements which follow upon muscular 
 effort. 
 
 But not only may such a general product of meta- 
 
THE ENDOCRINOUS GLANDS 35 
 
 holism act upon some particular structure or group 
 of structures, but definite and specific chemical pro- 
 ducts may he elahorated in certain organs and 
 have for their special purpose the modification of the 
 chemical changes in some other organ or organs. 
 In acting in this way they may so control the course 
 of development and growth during early life, and of 
 metabolism during later life, as to bring about a 
 co-ordination between the activities of different 
 organs, and thus to merit the name of Chemical 
 Regulators. But it is needless to introduce new 
 terms. These products have already been called 
 the Internal Secretions, and the organs producing 
 them have been named the Ductless Glands — a 
 misleading title — or, better, the Endocrinous Glands, 
 a. term indicating that they produce an internal 
 secretion. 
 
 Every living tissue probably yields products which 
 may act upon other tissues, but the name endocrin-^ 
 ous glands may conveniently be reserved for those 
 structures which yield a product having some definite 
 and specific action, not necessarily of the nature of 
 excitation. Hence the name of Hormone cannot be 
 used to indicate all the internal secretions as some 
 writers use it at present. 
 
 These structures may be classified according to 
 their seat of origin into the following groups : 
 
 I. From the Nervous System,. 
 Chromaffin Tissue. 
 Hypophysis cerebri. 
 
36 REGULATORS OF METABOLISM 
 
 2. From the Buccal Cavity. 
 
 Thyroid. 
 Pituitary. 
 
 3. From the Intestine. 
 
 Pancreas. 
 
 Mucosa of Small Intestine. 
 
 4. From, the Branchial Arches. 
 
 Parathyroids. 
 Thymus. 
 
 5. From, the Mesothelium, of the Genital Ridge. 
 
 Gonads. 
 Inter-renal Bodies. 
 
 The origin, structure and physiology of these must 
 now be considered. 
 
 As development advances, in some cases tissues 
 derived from different sources become closely asso- 
 ciated with one another. Thus the chromaffin 
 tissue, formed from the nervous system, in mammals 
 becomes surrounded by the inter-renal tissue de- 
 veloped from the mesothelium of the genital ridge, 
 and they together form a structure generally known 
 as the supra-renal gland. Similarly the hypophysis 
 cerebri becomes associated with the pituitary to 
 form one structure, and the para-thyroids become 
 very closely associated with and even embedded 
 in the thyroid. Even the thymus is possibly a 
 double structure composed o( the epithelium of 
 the branchial clefts with masses of lymphocytes 
 infiltrating it. 
 
 It has been customary in considering the physi- 
 
THE CHROMAFFIN TISSUE 37 
 
 ology of these various structures to deal with them 
 according to their anatomical distribution in organs. 
 This seems to me to have led to difficulties and 
 complications, and I shall classify them according to 
 their source. 
 
 /. DEVELOPED FROM THE NERVOUS 
 SYSTEM. 
 
 I. THE CHROMAFFIN TISSUE. 
 
 Development. The chromaffin tissue is derived, 
 with the cells of the sympathetic ganglia, from neuro- 
 blasts of the central nervous system which emigrate 
 from the neural tube. Early in embryonic life it 
 extends all along the front of the vertebral column, 
 but in later life it becomes reduced in amount, and 
 in some animals it is more specially associated with 
 the inter-renal tissue, which in mammals forms a 
 cortex around it, thus constituting a supra-renal 
 body. 
 
 In fishes the chromaffin tissue remains distinct 
 from the inter-renal tissue. 
 
 In birds the medulla is not enclosed in the cortex. 
 It is, in fact, only in mammals that the inclusion is 
 complete. 
 
 Even in mammals, subsidiary masses of chromaffin 
 tissue occur outside of the supra-renals, and these 
 are specially well marked in foetal life, and persist 
 to a greater extent in some species, e.g. the rat, than 
 in others. 
 
38 REGULATORS OF METABOLISM 
 
 They are constant at the forking of the carotids, 
 where they form the carotid glands, and at the 
 branching of the aorta. 
 
 Structure. The chromaffin cells have this marked 
 peculiarity that, when fully developed, they have a 
 special affinity for chrome salts and so stain of a 
 distinct brownish colour. Hence their name. These 
 cells in the medulla of the supra-renal bodies are 
 collected in masses and columns lying closely upon 
 large sinusoid capillaries. They are destitute of the 
 fat and of the brown pigment which is present in 
 the cells of the cortex. 
 
 ' Physiology. In investigating the physiology of 
 this tissue, the great difficulty is that its main mass 
 in the medulla of the supra-renal bodies, in all higher 
 vertebrates, lies in such close connection with the 
 cortex, a totally distinct tissue. Hence it is practi- 
 cally impossible to separate and to remove the one 
 without interfering with the other. It is true that 
 in elasmobranch fishes they are separate and distinct, 
 a fact which Biedl has taken advantage of in remov- 
 ing the inter-renal tissue (p. 173). 
 
 Complete removal of the supra-renals is rapidly 
 fatal. Biedl found that excision of the inter-renal 
 bodies alone is fatal in skates and dog-fish, but 
 whether complete removal of all the chromaffin 
 tissue is compatible with the continuance of life it is 
 at present impossible to say. 
 
THE CHROMAFFm TISSUE 39 
 
 In considering the inter-renals it will be found 
 that, while grafting the supra-renals into animals 
 from which they have been removed prevents the 
 onset of death, it has been found impossible by this 
 method to determine the part played by each tissue 
 in maintaining life. 
 
 The credit of first investigating by a satisfactory 
 method the function of the chromaffin tissue is due 
 to Oliver and Schafer, who in 1894 demonstrated 
 that the intra-venous injection of extracts of the 
 supra-renals has a marked effect upon the circulation. 
 Similar results were independently obtained by 
 Cybulski and Szymonowicz, but were published 
 somewhat later. 
 
 They found that such extracts, even after boiling, 
 cause a marked rise in the blood pressure due 
 chiefly to constriction of the arterioles, an increased 
 action of the heart and cardiac inhibition if the 
 vagi are intact. 
 
 One of the most important steps in the progress 
 of the study of the action of these extracts was the 
 isolation of the active substance by Takamine in 
 1 901. This Adrenalin, as it may best be named, is 
 orthodioxyphenyl-ethanol-methylamine: 
 
 H H H H 
 
 HO—/ > C— C N— C— H 
 
 HO-i J I I I 
 
 ^^ OHH H 
 
 It is thus fairly closely related to one of the decom- 
 position products of the proteins — tyrosin or para- 
 
40 REGULATORS OF METABOLISM 
 
 oxyphenyl-amino-proplonic acid — and its relationship 
 to the protein molecule, of which it must be a deriva- 
 tive, is thus indicated : 
 
 OH 
 /\ H H O 
 
 \/— C— C— C— O— H 
 
 I I 
 H NH2 
 
 That it is a physiological secretion, and not a mere 
 post-mortem product, is clearly demonstrated by 
 many observations in which its well-marked physio- 
 logical actions are used to investigate its presence 
 and amount. Thus Dreyer and Tscheboksaroff 
 have both shown that stimulation of the splanchnic 
 nerves going to the supra-renals increases the amount 
 of adrenalin in the blood leaving the gland, as indi- 
 cated by the increased physiological action of the 
 blood of the vein. 
 
 Not only has adrenalin been isolated from the 
 supra-renals, but it and various allied products have 
 been prepared synthetically. 
 
 The fact that a pure chemical substance is obtain- 
 able has thus made it possible to study with great 
 precision the mode of action of this product of the 
 chromaffin tissue, to make commercial preparations 
 of standard strength and to use the substance 
 therapeutically. 
 
 It readily becomes oxidised to an oxy -adrenalin, 
 which gives a red colour to the fluids in which it is 
 dissolved. Various oxidising agents, e.£: iodine or 
 
THE CHROMAFFIN TISSUE 41 
 
 chlorine water, hasten the change, as was pointed 
 out by Vulpian in his observations on the supra- 
 renals in 1856. He also found that ferric chloride 
 gives a green reaction. 
 
 Many chemical tests for adrenalin, chiefly depend- 
 ing upon these reactions, have been devised, but 
 none have proved so reliable or so delicate as the 
 physiological tests depending upon its action on 
 certain tissues. 
 
 A colorimetric method described by Folin, Can- 
 non and Denis promises to be sufificiently accurate 
 and delicate for the determination of adrenalin in 
 dilute solution. It depends upon the fact that with 
 phosphotungstic acid adrenalin gives a blue colour 
 even in dilutions of i in 3,000,000, while the older 
 chemical methods are sensitive only to i in 300,000. 
 As a standard for comparison a solution of uric acid 
 of known strength, i mg. of uric acid in 100 c.c, is 
 used, to which is added the same amount of the 
 phosphotungstic and phosphoric acid mixtures with 
 a definite quantity of sodium carbonate, and the 
 colour compared in a colorimeter. This method, 
 checked by the physiological blood pressure method 
 of Elliott, gave strikingly concordant results. 
 
 Mode of Action. As already indicated, the first 
 discovered and one of the most prominent actions of 
 adrenalin is upon the vascular system. Oliver and 
 Schafer showed that there is a marked rise of 
 arterial pressure due to constriction of the arterioles 
 and a slowing of the heart, unless the vagi are 
 
42 REGULATORS OF METABOLISM 
 
 thrown out of action. That the action is a direct one 
 on the blood-vessel walls they demonstrated by per- 
 fusing the vessels and so producing the constriction. 
 Later investigations have shown that the arterioles 
 of different regions are affected to very different 
 degrees. Those of the splanchnic region are most 
 markedly acted upon, so markedly indeed that when 
 adrenalin is injected into the general circulation, the 
 blood may be forced from the viscera into the 
 limbs which may actually increase in size from the 
 increased amount of blood in them. Of the visceral 
 vessels, the renal arterioles are constricted first and 
 by the smallest dose of adrenalin. 
 
 The intra- cranial vessels are very slightly in- 
 fluenced by adrenalin. The pulmonary vessels are 
 also little acted upon, although Desbouis and Lang- 
 lois state that large doses constrict and small doses 
 dilate. Hence the intra-venous injection of adrenalin 
 leads to increased pressure in the intra-cranial vessels 
 and to congestion and oedema of the lungs. 
 
 The coronary arteries are actually dilated instead 
 of contracted. 
 
 The dose necessary to produce a marked rise of 
 blood pressure depends upon whether the vagus is 
 or is not intact. In the former case, much larger 
 doses are required to raise the pressure, since the 
 cardiac inhibition compensates for the vascular con- 
 striction. With the vagi out of action, as little as 
 .005 mg. per kilo of body weight, when intra- venously 
 injected, will give a distinct rise of blood pressure 
 
THE CHROMAFFIN TISSUE 43 
 
 in the dog or cat. A dose of .1 mg. per kilo is 
 generally sufficient to give a maximum effect. Below 
 this the extent and duration of the rise is fairly 
 proportionate to the dose. Its duration is always 
 transient, unless a continued perfusion of dilute 
 adrenalin into a vein is maintained. 
 
 The action is probably only produced on intra- 
 venous injection. Administration by the mouth 
 produces no effect, and subcutaneous injection pro- 
 duces practically none in the dog, cat and rabbit. 
 It is said to raise the pressure in man. 
 
 Hoskins and M'Clure find that very small doses 
 of adrenalin give a fall instead of a rise in blood 
 pressure. 
 
 This fall in the blood pressure has been recently 
 studied by Cannon and Lyman, and they conclude 
 that it depends largely on the condition of the 
 muscle at the time, and cite the difference in the 
 action of adrenalin on the virgin and on the pregnant 
 uterus in support of this. 
 
 The question of whether the action is upon the 
 terminal nerve structures or upon the muscle fibres 
 has been investigated by pharmacological methods. 
 Dixon showed that, after the administration of apo- 
 codeine to the extent of producing its curare effect, 
 adrenalin failed to constrict the vessels while 
 barium was still effective. He concluded that while 
 barium must act upon the muscle fibre beyond 
 the plexus, adrenalin acts directly upon the nerve 
 terminations. 
 
44 REGULATORS OF METABOLISM 
 
 In ergotoxin Dale found a substance which, 
 while stimulating in small doses, in large doses has 
 a selective paralysing action upon the motor endings 
 of the true sympathetic, but which leaves the inhibi- 
 tory endings uninfluenced. He and Elliott found 
 that after ergotoxin stimulation of the splanchnic 
 nerves causes a vaso-dilatation, and that adrenalin 
 acts in the same way. Hence adrenalin stimulates 
 both motor and inhibitory terminations, and its vaso- 
 constrictor action is due to the preponderating action 
 of these constrictor endings in the sympathetic 
 nerves. In the coronary arteries, where these con- 
 strictor fibres appear to be absent, adrenalin, as 
 already stated, causes dilatation. 
 
 Gunn and Chavasse find that adrenalin constricts 
 the peripheral veins of the sheep after removal from 
 the body and that it causes a rhythmic contraction 
 of the superior vena cava near the heart. 
 
 The action of adrenalin on the heart is at first 
 sight rather puzzling. With the vagi intact a distinct 
 slowing is produced ; but, with the vagi cut out by 
 atropin, acceleration and augmentation occur. 
 
 The inhibition is probably reflex through the 
 vagus from the raised arterial pressure. 
 
 The augmentation and acceleration which occur 
 when the vagal action is eliminated must be due to 
 some peripheral action, since it occurs in the excised 
 and perfused heart. One of two mechanisms may 
 be involved, the termination of the true sympa- 
 thetic — the augmentor nerve — or the muscle itself. 
 
THE CHROMAFFIN TISSUE 45 
 
 Dixon has shown that very large doses of apo- 
 codeine paralyse the terminations of the augmentor 
 mechanism, and that after such doses adrenalin fails 
 to augment the heart. 
 
 The conclusion seems clear that the terminations 
 of the augmentor nerves are the structures acted 
 upon. On account of this, in mammals, in spite of 
 the high pressure, the ventricular contraction is 
 distinctly increased, since in these the augmentor 
 nerves act upon the ventricles as well as upon the 
 auricles. In birds this is not the case. I find that 
 the action of the augmentor nerves is entirely con- 
 fined to the auricles, an observation which is fully 
 supported by the beautiful anatomical investigation 
 of Thebault on the vagus and sympathetic in the 
 bird which have only recently come under my notice. 
 
 Watson and I showed that in the bird adrenalin 
 causes a marked decrease in ventricular contraction, 
 the increased arterial pressure not being compensated 
 for by the stimulation of an augmentor mechanism 
 in the ventricles. 
 
 The law established as to the action of adrenalin 
 on the terminations of the true sympathetic system 
 in the vascular system was shown by Elliott to 
 apply to all parts of the viscera. Adrenalin produces 
 the same effect as stimulation of tbe true sympathetic : ^ 
 when the former causes contraction, the latter also 
 
 ' The term " true sympathetic " is used throughout as equivalent to 
 " abdomino-thoracic sympathetic," while para-sympathetic is used to 
 express " cranio-sacral sympathetic," or what German writers call the 
 autonomic system, a most misleading title. 
 
46 REGULATORS OF METABOLISM 
 
 does so ; when it causes dilatation, adrenalin dilates. 
 Hence differences are found in different animals. 
 Elliott has shown, for instance, that the bladder of 
 the ferret, which contracts upon stimulation of the 
 hypogastric nerves, also contracts under adrenalin, 
 while the bladder of the cat, which is relaxed 
 by the action of the hypogastrics, is relaxed by 
 adrenalin. 
 
 In the alimentary canal, where sympathetic stimu- 
 lation inhibits peristaltic movement, but causes 
 contraction of the pyloric and ileo-caecal sphincters, 
 adrenalin acts in the same way. Some observations 
 of Hoskins and M'Clure show that it produces this 
 inhibitory action on the bowel in doses smaller than 
 those required to raise the blood pressure. 
 
 On the reproductive organs, internal and external, 
 the same law applies. An interesting observation 
 made by Cushney and confirmed by others is that, 
 while adrenalin causes contraction of the uterus in 
 the pregnant and recently pregnant cat, it generally 
 causes relaxation in the virgin animal. Stewart's 
 observations on the uterus seem to show that large 
 doses may decrease, while smaller doses may increase 
 contraction. 
 
 On the eye, stimulation of the cervical sympathetic 
 causes dilatation of the pupil, retraction of the 
 nictitating membrane, contraction of the muscle of 
 Miiller — protrusio bulbi — and opening of the eyelids 
 from the contraction of the nonstriped muscle fibres 
 of the lid, and the same effects are produced by 
 
THE CHROMAFFm TISSUE 47 
 
 adrenalin. The dilatation of the pupil is most 
 readily produced in the excised eye of the frog. 
 Instillation of adrenalin into the eye of mammals — 
 e.g. dog, cat and man — does not cause dilatation of 
 the pupil. But Meltzer and Auer found that it did 
 produce the effect after extirpation of the superior 
 cervical ganglion. 
 
 This has been explained on the supposition that 
 the sympathetic carries both motor and inhibitory 
 fibres to the dilator pupili, that the latter are thrown 
 out of action by excision of the superior cervical 
 ganglion, and that hence adrenalin makes its 
 action manifest by causing dilatation. The exist- 
 ence of such inhibitory fibres has not been directly 
 proved. 
 
 Loewi found that in the diabetes which follows 
 extirpation of the pancreas in dogs, and in some 
 cases of diabetes in man, adrenalin produces a dilata- 
 tion of the pupil, and he explains this on the 
 supposition that the pancreas stimulates the inhibi- 
 tory sympathetic nerves (p. 10 1), and that, only when 
 its effect is removed, can the action of adrenalin pn 
 the motor terminations be made manifest. The 
 interest of this observation will be further considered 
 in dealing with the changes in metabolism produced 
 by adrenalin. 
 
 It has been found that the response to the action 
 of adrenalin is in many tissues increased after the 
 sympathetic nerve fibres have undergone degenera- 
 tion. This is well seen in the increased action of 
 
48 REGULATORS OF METABOLISM 
 
 adrenalin in bringing about dilatation of the pupil 
 and constriction of the vessels of the ear after the 
 superior cervical ganglion, from the cells of which 
 the post-ganglionic fibres pass, has been excised. 
 Fletcher finds the same condition in the retractor 
 penis after section of all its nerves. A complete 
 denervation of the tissue has been assumed, and 
 Fletcher attempted to demonstrate this by staining 
 with methylene blue. But this method is by no 
 means certain in its results, and the author himself 
 admits that these observations are not satisfactory. 
 The persistence of the peripheral plexuses in the 
 tissues has to be considered. In the iris such 
 ganglionated plexuses have been described and 
 figured by Schock, and Pollock, working in 
 this laboratory, finds that, after complete removal 
 of the ciliary and the superior cervical ganglia 
 of the rabbit leading to complete degeneration of 
 the nerves to the iris, a plexus may still be demon- 
 strated by the methylene blue method. It seems to 
 me that the influence of these " neurons of the third 
 order " have to be considered before it can be safely 
 concluded that an organ is denervated by section of 
 the fibres passing to it. 
 
 Metabolism. Blum in 1901 discovered that the 
 subcutaneous administration of adrenalin produced 
 glycosuria. 
 
 In 1902 I made the same observation, and in- 
 dependently and in conjunction with Drummond 
 investigated the condition. I found that the glyco- 
 
THE CHROMAFFIN TISSUE 49 
 
 suria is associated with a hyper-glycsemia, and that, 
 while it is most marked in rabbits on a carbohydrate 
 diet, it may also be produced in fasting animals even 
 after the carbohydrate store has been depleted by 
 phlorhizin. I also found that it is accompanied by an 
 increased excretion of nitrogen, i.e. an increased cata- 
 bolism of protein, and it thus seemed fair to conclude 
 that not only is the sugar set free from the stored 
 carbohydrates of the body, but that it is also formed 
 from the protein molecule. In fact, one element in 
 the production of the condition is an increased 
 mobilisation of sugar in the body. While glycogen 
 is certainly converted to glucose, its further storage 
 in the liver is not necessarily interfered with. 
 Drummond and I found that, after repeated admini- 
 stration of adrenalin, glycogen was still present in 
 considerable quantities. Pollok describes an actual 
 accumulation of glycogen. He states that in fasting 
 rabbits, and those rendered glycogen free by 
 strychnine, the administration of adrenalin causes an 
 increase of glycogen in the liver, but no increase 
 in the muscles, only traces being found. This may 
 indicate that the production of sugar from proteins 
 has been so great as to leave some available for 
 storage. 
 
 The condition can be produced by small doses of 
 adrenalin. I generally used .1 mg. (i c.c. i in 1000) 
 in rabbits, but as little as .01 mg. is said to be 
 efficient. The glycosuria is more readily produced 
 by subcutaneous or by intra-peritoneal than by intra- 
 
so REGULATORS OF METABOLISM 
 
 venous injection, possibly because the last method of 
 administration is apt to check the secretion of urine, 
 Straub and Ritzmann, however, have shown that the 
 continuous inflow of very dilute adrenalin into the 
 blood is sufficient to establish and to maintain a 
 glycosuria. The sugar appears in the urine in less 
 than an hour and lasts for two or three hours. A 
 second dose causes its reappearance. But, after 
 prolonged daily administration, a condition of slight 
 tolerance may be established, 
 
 As to how the adrenalin acts, various theories 
 have been advanced. Herter and Wakeman state 
 that direct application to the pancreas produces a 
 powerful effect, and describe the action of other toxic 
 agents when applied directly to the pancreas as 
 causing glycosuria. They thought that it paralyses 
 the pancreas, possibly by constricting its vessels, and 
 that it thus prevents that organ from exercising its 
 checking influence upon the mobilisation of sugar. 
 
 I found that removal of the pancreas in birds does 
 not cause glycosuria, but that upon administration of 
 adrenalin to geese and ducks without the pancreas, 
 glycosuria is produced. At that time I did not know 
 of the work of Kausch, who states that, although 
 glycosuria is not readily produced in ducks and 
 geese by removal of the pancreas, hyperrglycsemia 
 does occur. These observations have been con- 
 firmed by Fleming in this laboratory. Still, the fact 
 that in my experiments adrenalin increased the 
 glycosuria in the pancreas-less goose is opposed to 
 
THE CHROMAFFIN TISSUE 51 
 
 the view that its only action is upon the pancreas. 
 This conclusion is supported by the observations of 
 Doyen, Morel and Kareff that, in the pancreas-less 
 dog, adrenalin increases the glycaemia, an observation 
 which I have confirmed in diabetes in the human 
 subject. A direct action on the pancreas may then 
 be excluded as the cause of the production of 
 glycaemia. 
 
 It would rather seem as if both adrenalin and the 
 internal secretion of the pancreas, which, as will 
 afterwards be shown, checks the mobilisation of 
 sugar, acted at some common point. The surprising 
 generality of the law of the mode of action of adren- 
 alin suggests that this point may be the termination 
 of the true sympathetic in the liver. The work of 
 Doyen and Gautier supports this view. They found 
 that in vitro adrenalin had no action upon the conver- 
 sion of glycogen to glucose in the liver, and that in the 
 living animal, while the injection of adrenalin alone 
 was followed by an increased conversion of gly- 
 cogen, the previous injection of atropin prevented 
 or decreased this action. This observation should 
 certainly be repeated. 
 
 The liver is the great storehouse of sugar as 
 glycogen, and we know that adrenalin produces most 
 marked glycosuria when the store of glycogen is 
 large. Even after the glycogen has been used up, 
 adrenalin still causes a mobilisation of sugar from 
 the proteins, a process which probably also goes on 
 in the liver. 
 
52 REGULATORS OF METABOLISM 
 
 That adrenalin produces this mobilisation of sugar 
 in the liver by acting through the terminations of the 
 true sympathetic system is indicated, not merely by 
 the results of Doyen and Gautier already quoted, 
 but by other evidence. In the first place, a rich 
 plexus of sympathetic origin, derived by migration 
 from the terminal plexus in the gut wall, runs all 
 through the liver. Stimulation of the fibres of the 
 hepatic plexus going to this produces a glycogeno- 
 lysis, as was indicated first by the brothers Cavazzani, 
 and more recently by M'Leod and Pearce. Again, 
 Miculicich finds that the injection of 2 to 4 mg. of 
 ergotin hinders the onset of glycosuria after the sub- 
 sequent subcutaneous injection of i to 2 mg. of 
 adrenalin, and that the injection of ergotoxin after 
 adrenalin reduces the glycosuria. These results may 
 be due to the well-known effect of ergotoxin in 
 antagonising the action of adrenalin upon sympathetic 
 nerve terminations. 
 
 Is the mobilisation of sugar normally caused 
 simply by the action of adrenalin upon these nerve 
 endings ? 
 
 The observation of Starkenstein that glycsemia and 
 glycosuria may be produced by stimulation of the 
 central end of the vagus after the supra-renals have 
 been removed, shows that direct stimulation throusfh 
 the nervous reflex arc can produce the effect, and 
 that the presence of adrenalin is not essential. 
 
 It has been suggested that stimulation of the 
 splanchnics causes glycaemia, not by acting directly 
 
THE CHROMAFFIN TISSUE 53 
 
 upon the Hver^ but by stimulating the supra-renals 
 to increase their output of adrenalin (see p. 55), and 
 that the adrenalin then acts upon the liver. The 
 question of how far this direct stimulation does 
 increase the output of adrenalin will be presently 
 considered. 
 
 But admitting for the time that it does so, an 
 observation of M'Leod and Pearce seems to show 
 that it is not the sole factor. They found that 
 stimulation of the splanchnic nerve did not generally 
 cause glycogenolysis if the hepatic plexus was cut, 
 although it also failed to produce the effects if the 
 supra- renal glands were excised. They, therefore, 
 argued that, while apparently adrenalin in the blood 
 is necessary for the action of the nerves, it is not the 
 direct excitant to the liver. This, of course, does 
 not mean that it cannot, when in sufficient amounts, 
 directly stimulate the nerve endings, but simply that, 
 under normal conditions, its presence is necessary 
 to allow nervous stimulation to act. Its influence 
 might be likened to that of an activator or sensitiser. 
 
 These considerations naturally lead to the discus- 
 sion of the question of what is the relationship of the 
 puncture diabetes of Bernard to adrenalin glycosuria. 
 
 A. Meyer showed that puncture diabetes is not 
 produced in rabbits after removal of the supra-renals. 
 Kahn concluded that the puncture brings about a 
 central stimulation propagated down the splanchnics 
 to the supra-renals to increase their output of adren- 
 alin, and this conclusion is supported by the more 
 
54 REGULATORS OF METABOLISM 
 
 recent work of Elliott upon the discharge of adrenalin 
 from the chromaffin tissue under the influence of 
 nervous stimulation. 
 
 But, while Wattermann and Smit believed that 
 they could demonstrate an increase in the adrenalin 
 in the blood after diabetic puncture, Kahn has failed 
 to confirm their results, although he does not consider 
 that this disproves the outpouring of adrenalin. The 
 evidence at present seems to point to the conclusion 
 that, while puncture of the floor of the fourth 
 ventricle almost certainly increases the output of 
 adrenalin, this increase is not generally so marked 
 as alone to account for the onset of glycosuria, and 
 that probably the stimulation of those fibres of 
 the splanchnic nerves which go to the liver plays 
 a part in bringing about the increased glyco- 
 genolysis. 
 
 Whether adrenalin, in producing glycosuria, causes 
 any other change in the metabolism of sugar in the 
 body is not definitely known. But the increase in 
 the respiratory quotient observed by Fleming in 
 this laboratory, in ducks, seems to indicate that 
 sugar is used by the tissues, and that in this 
 respect adrenalin glycosuria differs from pancreatic 
 diabetes. This is confirmed by the results of 
 Falta in man. But Wilenko has published a short 
 note of experiments tending to show that under the 
 influence of adrenalin the heart muscle is less able 
 to metabolise sugar. Pancreatic diabetes seems to 
 be something more than a mere adrenalin glycaemia 
 
THE CHROMAFFIN TISSUE 55 
 
 due to an unopposed action after withdrawal of the 
 influence of the pancreas (p. 100). 
 
 Adrenalin thus seems to produce all its various 
 effects by stimulating or by sensitising to nervous 
 impulses the terminations of the true sympathetic 
 nervous system. 
 
 Influence of Nerves on the Chromaffin System. Is 
 the formation of adrenalin in chromaffin tissue con- 
 trolled by the nervous system ? The medulla of the 
 supra-renals is richly supplied by fibres from the 
 splanchnic sympathetics. Biedl described an increase 
 in the adrenalin content of the blood on stimulating 
 the splanchnics, but pointed out that a vaso-dilator 
 effect is produced upon the supra-renals. Hence 
 only an increased washing out of adrenalin may 
 be indicated. Dreyer had previously described a 
 similar increase in the adrenalin content of the 
 blood on stimulating these nerves, and had concluded 
 that they are secretory in their mode of action. 
 Tscheboksaroff got similar results. 
 
 Cannon and De la Paz showed that fright in the 
 cat caused the appearance of an increased amount of 
 adrenalin in the blood of the supra-renal vein. 
 
 An elaborate investigation of the question has 
 been made by Elliott, who takes as his index the 
 amount of adrenalin in the gland. He shows that 
 the two glands contain a closely similar amount 
 under normal conditions, and that the emotional 
 disturbance called by him "fright," which in the cat 
 
S6 REGULATORS OF METABOLISM 
 
 accompanies the administration of morphine and 
 tetra-hydro-;8-naphthylamine, is followed by a marked 
 decrease in the adrenalin content of the glands. 
 Section of the splanchnic nerve prevents this dis- 
 charge. Curiously enough, Elliott did not find that 
 faradic stimulation of the splanchnic caused a marked 
 decrease in the adrenalin content of the gland, 
 although the work of Dreyer and Tscheboksaroff 
 had indicated an increased discharge of adrenalin. 
 On the other hand, stimulation of the central end of 
 an ingoing nerve, such as the sciatic, decreased the 
 adrenalin content of the glands unless the splanchnic 
 nerve had been cut, in which case the gland was not 
 acted upon. Direct injury and stimulation of the 
 brain acted in the same way. The evidence thus 
 clearly points to the existence of a reflex nervous 
 control of the discharge of adrenalin from the medulla 
 of the supra-renal, but whether this is a true secretory 
 action, which actually modifies the production of 
 adrenalin, is not indicated. 
 
 But Elliott points out that, important as the 
 reflex control probably is, it is not essential for the 
 continued action of the chromaffin tissue, since a 
 cat, with one supra-renal removed and with the 
 splanchnic on the opposite side divided, does not 
 die till the second supra-renal is removed. The 
 results of Haberer and Stoerk upon grafts afford 
 similar evidence. But this may simply mean that 
 the animal can continue to live without the action of 
 the chromaffin tissue of the supra-renals. 
 
THE CHROMAFFIN TISSUE 57 
 
 Asher excluded, by removal and ligature, all ^the 
 abdominal viscera from the circulation except the 
 supra-renals, and found that stimulation of the 
 splanchnics causes a rise of blood pressure. This 
 does not occur if the supra-renal veins are ligatured. 
 The rise of pressure does not occur for about thirty 
 seconds, and it takes place even when the spinal 
 cord is cut across high up. Evidently the stimulation 
 has caused an increased output of adrenalin. 
 
 He is unable to confirm the observation of Stahl 
 and Weiss, that a fall of the blood pressure occurs 
 on clamping the supra-renal vein, and in this he is 
 supported by Kahn and by Hoskins and M'Clure. 
 
 What is the Physiological Significance of Adrenalin 
 in the Blood ? Dixon has advanced the theory that 
 the reaction to stimulation of the true sympathetic 
 system may be due to a liberation of adrenalin in the 
 nerve terminations, and that the chromaffin tissue is 
 a special development of such terminal structures in 
 which adrenalin accumulates. The suggestion is in- 
 genious but lacks proof, and the fact that the nervous 
 response occurs so rapidly is perhaps opposed to it. 
 
 That adrenalin is present in the blood has been 
 shown by the use of various physiological methods. 
 Fraenkel estimates that the amount in normal blood 
 is about I in 500 millions. According to the results 
 of Fraenkel and of Ehrmann i in 20 millions is 
 required to produce manifest effects. In a small dog 
 the injection of about .005 mg. is generally necessary 
 
58 REGULATORS OF METABOLISM 
 
 to produce a rise of blood pressure, and this amount 
 diluted with the looo c.c. of blood in the animal 
 would give about i in 20 millions. 
 
 Janeway and Park, testing the presence of adren- 
 alin by its action on a strip of peripheral and a strip 
 of coronary artery (see p. 62), found that i in 20 
 millions of blood or i in 50 millions of Locke's solution 
 gave a positive reaction with both preparations. But 
 they entirely failed to get any result with peripheral 
 blood, although they sometimes got a constrictor 
 substance for both vessels. This, according to 
 them, cannot be adrenalin, and hence they conclude 
 that adrenalin cannot be present in the blood 
 in sufficient amount to produce its stimulating 
 effect. 
 
 Another method of ascertaining how much adren- 
 alin may be present in the blood, is to determine 
 the amount in the blood of the adrenal vein, and to 
 try to ascertain how much blood flows from the 
 gland. Hoskins and M'Clure have recently at- 
 tempted to do this, and conclude that in the dog 
 about .25 c.c, of a I in I million adrenalin may leave 
 the gland per minute. The results of O'Connor in 
 the rabbit give about . 2 c.c. This amount is wholly 
 insufficient to influence the blood pressure. Hoskins 
 and M'Clure further argue that since .4 c.c. of i in 
 500,000 adrenalin is necessary to produce an initial 
 effect on the blood pressure, while a difference of 
 .1 c.c. of the same strength will produce a difference 
 in effect, the amount of adrenalin normally present 
 
THE CHROMAFFIN TISSUE 59 
 
 in the blood is quite insufficient to influence blood 
 pressure. In a more recent paper they point out 
 that the adrenalin produced is only about one- 
 quarter of what is required to influence the blood 
 pressure, and that increasing the amount by con- 
 tinuous inflow into a vein leads first to a fall of 
 pressure, and that five times the amount required to 
 produce the primary depression is necessary to cause 
 a minimum sustained rise. They, therefore, argue 
 that the amount of adrenalin produced is only one- 
 twentieth of that required to give a pressor effect. 
 They further show that before the pressor effect 
 is produced the paralysing influence on the gut is 
 manifest. This seems to indicate that the adrenalin 
 normally in the blood can play no part in maintain- 
 ing the tone of the vessels. 
 
 Their conclusion is that the relationship between 
 adrenalin and the sympathetic system is merely a 
 means of promoting muscular efficiency in times 
 of stress. 
 
 But the results of Dreyer, and more especially of 
 Elliott, seem to show that the percentage in the 
 blood may be increased by reflex stimulation, and 
 the question arises — Is the increased outpouring in 
 order to bring about a direct stimulation of the 
 peripheral terminations of the sympathetic nerves 
 or merely so to activate them that the one which is 
 being played upon by nerve impulses may more 
 markedly respond? Is the adrenalin in the blood a 
 stimulator or a sensitiser ? 
 
6o REGULATORS OF METABOLISM 
 
 There seems some evidence that, under powerful 
 reflex stimulation, a generalised excitation of all the 
 endings of the sympathetic system may be produced. 
 In the excitation accompanying such emotional dis- 
 turbances as fear, the erection of the hairs, the dila- 
 tation of the pupils, the prominent eyeballs, the pallor 
 and the acceleration of the heart suggest a generalised 
 action, but they do not demonstrate whether this is a 
 general stimulation by adrenalin or a general activa- 
 tion to the influence of an exaggerated nervous 
 outflow. 
 
 Under ordinary conditions the amount of adrenalin 
 in the blood is so small that its action seems more 
 probably that of an activator than of a direct 
 stimulator. 
 
 In this connection some recent work of von Anrep 
 is of interest. His results tend to show that in stimu- 
 lation of the splanchnic nerves the initial rise of 
 blood pressure is due directly to the influence of 
 vaso-constrictor fibres upon blood-vessels, but that a 
 secondary constriction is due to the stimulation of 
 the supra-renals and to the increased outpouring of 
 adrenalin. Whether this simply activates the sym- 
 pathetic terminations or whether it acts directly as a 
 stimulant is not shown, although a second paper on 
 " Local Vascular Reactions " tends at first siffht to 
 support the latter view, in as much as it shows a 
 constriction of vessels in denervated limbs when the 
 nerves are not stimulated. But the amount given 
 was greater than that which is found in the bloody 
 
THE CHROMAFFIN TISSUE 6i 
 
 and no one denies that in sufficient quantities adren- 
 alin does stimulate directly. 
 
 The recent work of Hoskins and M'Clure, of 
 Stewart and of others, showing that the action of 
 adrenalin in small doses may be the reverse of that 
 in such large doses as are generally used in studying 
 its action, tells markedly against the idea that adren- 
 alin in the blood is a direct excitor of the nerve 
 endings. 
 
 The evidence seems to show that the initial effect 
 of any activity of the autonomic system is apart from 
 the influence of adrenalin, but that if the action is to 
 be sustained it is accompanied by an outpouring of 
 adrenalin which must fortify the nervous effect either 
 by making the endings more sensitive — by activating 
 — or by replacing and superseding this effect — by 
 directly stimulating. The fact that the nervous 
 effects under normal conditions remain definite and 
 limited tells against the latter hypothesis. 
 
 Physiological Methods of detecting and determining 
 the Amount of Adrenalin present. Various methods 
 have been devised, depending upon the relationship of 
 the physiological effect to the percentage of adrenalin. 
 
 The most satisfactory of these are — 
 
 I St. The Meltzer-Ehrmann Method, depending 
 upon the action of adrenalin in dilating the pupil 
 of the enucleated eye of the frog. It is stated that 
 I in 20 million is sufficient to produce the effect. 
 
 2nd. Action on the blood pressure in atropinised 
 
62 REGULATORS OF METABOLISM 
 
 rabbits. Dr. J, D. Cameron, working under my 
 directions, investigated various methods of testing 
 for adrenalin, and came to the conclusion that 
 the most satisfactory is that of determining 
 the effect upon the blood pressure of the rabbit 
 previously atropinised. She found that in this way 
 .0003 mg. per kilo of animal could be detected. 
 Taking the blood volume of the rabbit at 1/20 
 of its body weight, and supposing the dose of 
 adrenalin uniformly distributed, this would give .6 
 mg. in a million, or i part in 160 millions. She further 
 found that adrenalin preparations may be standard- 
 ised against a known dose of nitroglycerine, and that 
 this gives the most reliable results. 
 
 A modification of this method, using a pithed 
 rabbit, was employed by Elliott. 
 
 3rd. Fraenkel uses the excised uterus of the rabbit 
 in Ringer's solution with a stream of oxygen as 
 devised by Magnus for the gut. The uterus is 
 attached to a recording lever. The introduction of 
 adrenalin increases and alters the character of the 
 contractions. The presence of i in 20 or 30 millions 
 may be detected by this method. 
 
 4th. Hoskins uses a loop of rabbit's intestine in 
 oxygenated Ringer's solution, and finds that the 
 movements are inhibited by adrenalin. This may 
 occur with i in 400 million. 
 
 5th. Janeway and Park use (a) a strip of a peri- 
 pheral artery which is constricted by adrenalin, and 
 (d) a strip of coronary artery which is relaxed by 
 
THE CHROMAFFIN TISSUE 63 
 
 the substance, each in blood or Locke's solution. 
 Taking the contraction of the former and relaxation 
 of the latter as their index, they find that i part of 
 adrenalin in 20 millions of blood and i in 50 millions 
 of Locke's solution may be detected. 
 
 Toxic Action of Adrenalin. In large doses adren- 
 alin may cause rapid death with cardiac inhibition. 
 The onset of death may be delayed for some minutes 
 — the respirations being quickened and panting. In 
 these cases congestion and oedema of the lungs is 
 marked, while a desquamation of the epithelial lining 
 of the vesicles is also to be seen (Drummond). 
 
 In more chronic poisoning a necrosis of the liver 
 tissue was observed by Drummond. 
 
 Prolonged administration leads to a degenerative 
 atheromatous change in the walls of the arteries. 
 How far this is a result of the increased pressure is 
 not clearly demonstrated. But the fact that sub- 
 cutaneous administration causes atheroma, but does 
 not cause increase of arterial pressure, is opposed to 
 the idea that the action is a mechanical one, and 
 suggests that it may be secondary to changes in the 
 arterioles of the vessel wall. 
 
 Summary. In this section we have dealt with the 
 origin of chromaffin tissue from neuroblasts similar to 
 those forming the sympathetic nervous system, and 
 with the production of a specific product, adrenalin, 
 
 It has been shown that adrenalin has a definite 
 action in stimulating the terminations of the " true " 
 
64 REGULATORS OF METABOLISM 
 
 (thoracico-abdominal) sympathetic system, and that 
 not only its action upon the blood-vessels, heart and 
 other muscular structures, but also its effect upon the 
 metabolism of carbohydrates is to be explained in 
 terms of this selective action. 
 
 Whether the adrenalin in the blood under normal 
 conditions actually stimulates the terminations, or 
 whether it merely sensitises them to the influence of 
 nerve impulses, or whether it has a secondary action 
 in fortifying the effect of the acting nerve, has been 
 discussed. 
 
 II. HYPOPHYSIS CEREBRI. 
 
 Development. The hypophysis, like the chro- 
 maffin tissue, is derived from the nervous system. 
 
 It is formed by a hollow downgrowth from 
 the fore brain in the floor of the third ventricle. 
 In some animals, such as the cat, it remains hollow, 
 but in others, man, monkey, etc., the lumen is closed 
 by the approximation of the walls, and a solid stalk 
 is thus produced. The terminal portion develops a 
 somewhat bulbous swelling of a whitish colour and 
 soft consistence, and it is embraced by the true 
 pituitary (p. 87). 
 
 Structure. The hypophysis is made up of neu- 
 roglia cells and fibres. It is invaded by epithelial 
 cells from the pars intermedia, and colloid matter is 
 found in it. Herring considers this to be a product of 
 the epithelial cells, and he described its passage into 
 
THE HYPOPHYSIS 65 
 
 t^e third ventricle of the brain in the cat. This is 
 confirmed by Gushing. 
 
 Physiology. — 1. Bemoval. The removal experiments 
 of Paulesco seem to show that the hypophysis 
 is not essential to life. If the anterior lobe is 
 not interfered with, the animal goes on without 
 symptoms; 
 
 2. Action of Extracts — Hypophysin. As in the case of 
 the chromafifin tissue, evidence of function has been 
 afforded by the study of the effects of administration 
 of extracts. Oliver and Schafer first showed that 
 the intra-venous injection of these caused a marked 
 rise in the blood pressure, due chiefly to constriction 
 of the arterioles. 
 
 The active principle has not been isolated. That 
 it is not of the same nature as adrenalin is shown by 
 the facts that the extracts do not give the chemical 
 reactions of adrenalin, and that in certain respects 
 its physiological action is different. It is dialysable, 
 it is not destroyed by heating or by reducing agents, 
 and it is insoluble in alcohol and ether. It may be 
 called Hypophysin, although the name Pituitrin has 
 unfortunately also been given to it. 
 
 By perfusion experiments and by oncometric 
 observations, it may readily be demonstrated that 
 the extracts of the true hypophysis cause a con- 
 striction of the arterioles in mammals. In birds 
 (ducks), on the other hand, I found that it causes 
 a dilatation. Howell first showed that a repetition of 
 
66 REGULATORS OF METABOLISM 
 
 the dose within a half to one hour is not followed by 
 a constriction of the vessels, and Schafer and Herring 
 found that a dilatation and a fall of blood pressure 
 may occur. They argued for the presence of two 
 products of the hypophysis, and maintained that the 
 vaso-dilator one was not cholin because the fall of 
 pressure was not abolished by atropin. If their 
 conclusion is correct, it would seem that the second 
 substance, the vaso-dilator, alone acts on the arte- 
 rioles of the bird. On the renal artery even of 
 mammals hypophysin has a dilator action, and 
 on the coronary arteries it acts as a constrictor, thus 
 differing from adrenalin. 
 
 Hypophysin appears to act at a point peripheral 
 to that at which adrenalin acts, since Dale has 
 shown that it still produces its effect after a dose 
 of ergotoxin sufficient to abolish the constriction 
 produced by adrenalin. 
 
 On the heart its action is to increase the force 
 of the contractions whether the vagus is intact or 
 cut. After section of the vagus it does not cause 
 the same quickening as does adrenalin. Its action 
 on the heart appears to be upon some structures 
 peripheral to the endings of the augmentor nerves 
 which are stimulated by adrenalin (p. 44). This 
 is indicated by the fact that in birds, in which I 
 have shown that the augmentors act upon the 
 auricles only, Watson and I found that adrenalin 
 has no stimulating action on the ventricles, while 
 hypophysin acts upon these structures. This action 
 
THE HYPOPHYSIS 67 
 
 of hypophysin in augmenting the contraction of the 
 ventricle of the bird in the absence of augmentor 
 fibres and their terminations appears to me to be the 
 strongest piece of evidence in favour of the direct 
 action upon the contractile substance of muscle apart 
 from the neuro-myal junctions. 
 
 On the pupil of the enucleated eye of the frog it 
 acts like adrenalin. 
 
 On the bladder of the dog and cat it has a stimu- 
 lating action. Not only does it act upon the muscle, 
 but it also increases the excitability of the motor 
 pelvic nerves to the faradic current. 
 
 On the uterus It also acts as a powerful excitant, 
 causing very full contractions. At the same time it 
 increases the excitability of the hypogastric nerves, 
 which act as motor nerves to the organ. 
 
 Ott and Scott state that it increases the extent of 
 contraction of the intestine. 
 
 Magnus and Schafer discovered that it has a 
 marked diuretic action, and Schafer and Herring 
 found that this occurs after a second dose, which 
 causes no rise of the blood pressure. This diuresis 
 is accompanied by a dilatation of the renal vessels 
 and an increase in the volume of the kidney. 
 
 Schafer and M'Kenzie have demonstrated that 
 hypophysin increases the flow of milk, and it has been 
 assumed that this indicates that an increased secre- 
 tion is produced. But the very transitory character 
 of the increase suggests that the action is rather 
 upon the visceral muscular fibres of the ducts leading 
 
68 REGULATORS OF METABOLISM 
 
 to an increased excretion of the milk accumulated 
 in them, just as the flow of bile may be increased 
 without any augmentation of secretion by a similar 
 contraction of the muscular fibres in the bile ducts. 
 This would explain the increased flow of milk by 
 the well-known action of hypophysin on visceral 
 m'uscle. This view is supported by the observa- 
 tion of M'Kenzie that atropin does not abolish 
 the action of hypophysin, and by some unpub- 
 lished observations made in this laboratory by 
 Leonard Findlay, which show that no increase in the 
 amount of milk yielded by a goat in the course of a 
 day can be produced by the injection of hypophysin. 
 Quite recently Schafer has published a short paper 
 giving an account of some observations on a woman, 
 and Gavin has published experiments upon the 
 influence of hypophysin on milk production in cows, 
 which fully confirm Findlay s findings in the goat, 
 and prove pretty conclusively that the production of 
 milk is not increased. 
 
 Metabolism. The protein catabolism seems to be 
 increased by the administration of hypophysin, 
 according to the results of Manson and Johnson 
 and of Falta. Crowe, Gushing and Romans also 
 describe marked emaciation as a result of continued 
 administration. 
 
 The results of different writers on its influence 
 on the excretion of the inorganic constituents of the 
 urine are so conflicting that at present no conclusion 
 can be arrived at. 
 
THE HYPOPHYSIS 69 
 
 On carbohydrate metabolism its action appears to 
 be of the same kind as that of adrenalin, but much 
 less marked. Borchardt found that injection in 
 rabbits causes hyper-glycaemia and glycosuria, and 
 this observation is confirmed by Gushing and 
 Goetsch. They further find that stimulation of the 
 hypophysis, as in operations, is apt to be followed 
 by glycosuria and by a decreased assimilation of 
 sugar, so that alimentary glycosuria can be readily 
 caused. Removal leads to increased assimilation of 
 sugar and to a tendency to put on fat. 
 
 Thus, in cases of disease of the pituitary, the 
 investigation of the tolerance of carbohydrates may 
 throw light upon the question of whether the func- 
 tions of the hypophysis are increased or decreased. 
 
 Falta describes a rise in the respiratory quotient 
 after intra-muscular administration to man, indicating 
 an increased metabolism of sugar. 
 
 The Source of Hypophysin. The evidence as 
 regards the source of the active principle or prin- 
 ciples of the extracts of the posterior lobe of the 
 hypophysis is not conclusive. Herring strongly 
 maintains that they are formed in the colloid sub- 
 stances of the pars intermedia, and that they pass 
 backwards into the pars nervosa. Some observa- 
 tions of Swale Vincent seem to indicate that the 
 pars nervosa is the more active part, and that, 
 therefore, the active constituents are probably 
 formed there. 
 
70 REGULATORS OF METABOLISM 
 
 Summary. The mode of development of the 
 hypophysis from the nervous tissue at the base of 
 the brain and its close connection with the true 
 pituitary have been considered in this section. 
 Evidence has been adduced that it is not essential 
 to life, but that it either elaborates within itself or 
 takes from the pars intermedia of the pituitary 
 certain products which act upon the tissues much in 
 the same way as adrenalin, but at a point peripheral 
 to that acted upon by adrenalin. 
 
 //. DEVELOPED FROM THE EPITHELIUM OF 
 THE BUCCAL CAVITY. 
 
 I. THE THYROID. 
 
 Development. The true thyroid develops as an 
 unpaired hollow outgrowth from the fore gut ventrally 
 to the branchial arches and in the middle line. This 
 afterwards branches into two lateral divisions which 
 form the two lobes of the thyroid. A trace of the 
 original opening may persist as the ductus thyreo- 
 glossus or foramen caecum. 
 
 Position. Each lobe lies on the lateral aspect 
 of the trachea below the level of the cricoid cartilage. 
 Small accessory thyroids may exist from the lower 
 jaw downwards to the aorta. 
 
 Structure. The organ consists of a loose fibrous 
 tissue framework enclosing vesicles of different 
 sizes each lined by a cubical epithelium and 
 filled with a clear transparent mucin-like material, 
 
THE THYROID 71 
 
 the colloid substance of the thyroid. This substance 
 is strongly oxyphil and stains deeply with eosin. It 
 appears to be formed in the epithelium, in which 
 granules may be seen, and these are converted into 
 colloid. This colloid may also be demonstrated in 
 the lymph spaces between the vesicles and even in 
 the blood-vessels. 
 
 The thyroid is enormously vascular. So abundant 
 is the blood supply that the theory has been 
 advanced that its function is to regulate the blood 
 supply of the brain. 
 
 Chemistry. Kocher, from the beneficial effects 
 of the administration of iodine in goitre, concluded 
 that it must be a constituent of the gland. 
 
 Baumann in 1895 demonstrated its presence, and 
 found .3 to .9 mg. per grm. of the dry substance, 
 and 6 to 7 mg. in the whole gland of an adult man ; 
 in fact, the thyroid is ten times richer in iodine than 
 any other organ. The element is absent in the 
 newly-born child, and appears to be stored from the 
 food, while the taking of iodine may increase its 
 amount from 15 to 16 mg. The quantity present is 
 lowest in carnivora and highest in herbivora, and it 
 is generally proportionate to the amount of colloid 
 in the gland. Baumann showed that it is in organic 
 combinations. By boiling for seven hours with 10 
 per cent. H^SO^ and extracting with 90 per cent, 
 alcohol he separated a substance which he called 
 lodothyrin. Oswald showed that the iodine which 
 Baumann separated as lodothyrin really exists in a 
 
72 REGULATORS OF METABOLISM 
 
 protein combination — lodothyreo-globuHn. This is 
 not a definite substance, but contains a varying 
 amount of iodine. It is the active material of the 
 thyroid, and its activity is proportionate to the 
 amount of iodine it contains. Hence in goitre with 
 no colloid the thyroid substance has no action, 
 lodothyreo-globulin is the most important constituent 
 of the gland, forming as much as 30 to 50 per cent, 
 of the dry substance, and in colloid goitre as much 
 as 75 per cent. 
 
 A nucleo-protein free of iodine and without 
 physiological action is also present. 
 
 In 1905 Reid Hunt recorded experiments to show 
 that by feeding white mice on thyroid their resist- 
 ance to the toxic action of acetonitrile is markedly 
 raised. In one batch of mice the fatal dose in those 
 fed upon thyroid-containing food was 1.4 mg. as 
 against 0.32 mg. on ordinary food. 
 
 It has been suggested that this method might be 
 used for determining the activity of various thyroid 
 preparations, and Koch applied it to show that the 
 greatest activity is manifested by the more complex 
 combinations of iodine. 
 
 Physiology. On this subject an immense amount 
 of work has been done. The speculative hypothesis 
 of older writers may be neglected, since they 
 were not based upon experimental investigations. 
 J. F. Meckel about 1806 pointed out the interesting 
 fact that enlargement of the thyroid occurs during 
 menstruation and during pregnancy, thus showing 
 
THE THYROID 73 
 
 a close relationship between the thyroid and the 
 gonads of the female. 
 
 Another theory early put forward is that the thyroid 
 acts as a regulator of the blood supply to the brain — 
 a theory which has been recently revived in a modified 
 form by von Cyon (see p. 208). 
 
 The first real advance in our knowledge of the 
 functions of the thyroid was made through clinical 
 medicine. In 1873 Gull described the condition 
 now known as Myxoedema, and in 1877 Ord asso- 
 ciated this with changes in the thyroid gland. 
 
 In 1882 Kocher described a cachexia strumipriva 
 after removal of goitrous thyroids, and the Reverdins 
 described the same condition as myxcedeme post 
 operatoire. Von Brunn, a few years after, described 
 the decrease in growth and other characteristic 
 symptoms which occur when the gland is removed 
 in the child. Schoneman in 1892 called attention 
 to the hypertrophy of the pituitary which accom- 
 panies the condition. 
 
 The earlier experimental work upon removal of 
 the thyroid — such as that of Horsley in 1892 — at 
 first led to considerable confusion as to the function 
 of the gland, because in these earlier experiments 
 the parathyroids^ first described by Sandstrom in 
 1880, were more or less completely removed with 
 the thyroid, and symptoms of parathyroidectomy 
 appeared. 
 
 The older experimenters had described various 
 tremors and other nervous symptoms as due to 
 
74 REGULATORS OF METABOLISM 
 
 thyroid removal, and it was noted that these were 
 most marked in the dog and cat and were practically 
 absent in herbivora — the reason being that in herbi- 
 vora at least two parathyroids lie at a distance from 
 the thyroid, so that a sufficient amount of parathyroid 
 tissue is left after thyroidectomy, while in dogs and 
 cats they are largely embedded in and are thus 
 removed with the thyroid. 
 
 It was only when the importance of the parathy- 
 roids was recognised, and when care was taken to 
 leave a sufficient amount of parathyroid tissue, that 
 it became possible to study the direct effects of 
 removal of the thyroid. 
 
 I. EFFECTS OF REMOVAL. 
 
 1, General Symptoms — A. In the Young. Hofmeister 
 in 1892 was one of the first to describe the symptoms 
 of thyroid removal in young rabbits, the para- 
 thyroids being left. Jeandelize has published a very 
 elaborate account of the whole subject. 
 
 In young rabbits there is a checking of cartilaginous 
 ossification, and hence the bones are only about one- 
 third their normal length. Degenerative changes 
 also occur in the epiphyseal line. The hypophysis 
 cerebri enlarges. The ovaries degenerate and 
 some follicles ripen precociously. The develop- 
 ment of the testes is decreased. 
 
 In lambs the same symptoms occur. They be- 
 come idiotic, and there is a decreased growth of 
 hair. 
 
THE THYROID 75 
 
 In goats the bones are short and thick, but there 
 is an increase rather than a decrease in the growth 
 of hair. The animals also suffer from meteorism, the 
 temperature falls, and atheroma of the aorta may 
 occur. 
 
 In dogs there is decreased growth, and the bones 
 are slender. The skull becomes globular from 
 failure in the growth of the cartilaginous bones at 
 the base. The belly is prominent. According to 
 Biedl's observations, in pups there is no apathy. 
 He states that the thymus persists. This statement 
 is opposed to the findings of M'Lennan, and of 
 Blumreich and Jacobi. Hypertrophy of pituitary 
 occurs and the gonads decrease. 
 
 In chicks there is decreased growth, decreased 
 development of the genitals and psychic torpor. In 
 hens only a few thin-shelled small eggs are laid. 
 Feeding with thyroid is said to increase the egg 
 production (Lanz). 
 
 In the child, as the result of operative removal 
 of the thyroid, there is the same decrease in growth 
 of the bones in length but not in thickness. The 
 periosteal ossification is not modified, but the de- 
 creased growth is at the epiphyseal line. Hence 
 the child is stunted. There is shortening of the 
 base of the skull, and the cranium is prominent. 
 The gonads are undeveloped, and the secon- 
 dary sex organs infantile in type. The pituitary 
 shows enlargement. Mental deficiency is a marked 
 symptom. 
 
76 REGULATORS OF METABOLISM 
 
 B. In Adults. The results of removal of the 
 thyroid in the adult may be much less marked than 
 in the young, although in certain species they are 
 very striking. 
 
 In such animals as the dog there is wasting, 
 apathy, loss of hair, a dry skin and advancing 
 anaemia. In cats these symptoms are still more 
 marked. 
 
 Kocher states that in man symptoms appear in 70 
 per cent, of cases of complete removal, and that, 
 when they do not, it is because accessory thyroids 
 are present. He considers that in operating at least 
 one-fourth of the thyroid tissue should be left. 
 
 The symptoms of cachexia thyreopriva are gener- 
 ally very characteristic. Muscular weakness and 
 mental apathy become marked ; the skin becomes 
 thickened, white and wax-like ; the superficial veins 
 stand out ; a peculiar oedema develops under the 
 skin and mucous membranes, and the pitting which 
 occurs after pressure at once disappears. This 
 oedenia gives a look of fatness. The skin is 
 cold and dry, and the hair becomes white and 
 falls out. 
 
 The functions of the sexual organs are disturbed 
 — in women menorrhagia is frequent, and in men 
 impotence is common. If pregnancy occur, the 
 symptoms are generally aggravated. Walter showed 
 that after removal of thyroid tissue from newts, 
 regeneration of amputated limbs was markedly inter- 
 fered with. He concludes that this is due to an 
 
THE THYROID 77 
 
 action through the nervous system, but gives no 
 facts to prove it. 
 
 Disease. The clinical evidence of disease is fully 
 in accord with the experimental evidence of re- 
 moval. 
 
 i. In the Young. Setting aside endemic cretinism, 
 to be considered presently, cases occur of con- 
 genital non-development of the thyroid with the 
 symptoms just described in very extreme form. 
 Occasionally the condition supervenes after birth — 
 up to the fifth year — and an infantile myxcedema 
 of less marked character is produced. In this 
 there is an advancing atrophy of the thyroid 
 gland. 
 
 Endemic cretinism is a disease of great import, 
 ance on account of the number of individuals who 
 suffer from it in the goitrous Alpine districts. 
 
 This condition is one of congenital goitrous 
 atrophy of the thyroid, and the intensity of the 
 symptoms varies with the profoundness of the 
 change in the gland. 
 
 We cannot at present stop to consider the cause 
 of this condition or the interesting experiments 
 which have been made on animals to induce it by 
 drinking the water of these goitrous districts. 
 
 ii. In Adults. Disease in the adult affords the 
 same sort of evidence as it does in the child. The 
 observations of Gull and of Ord have, already been 
 referred to. The disease myxcedema is simply a 
 thyreoprivic cachexia. 
 
78 REGULATORS OF METABOLISM 
 
 In these cases the thyroid is small, atrophic and 
 pale, with degenerated epithelium and increased 
 connective tissue. Eighty per cent, of the cases are 
 in women. 
 
 Recently cases have been described where the 
 clinical picture is incomplete ; where only some 
 symptoms are present, and, since these improve on 
 thyroid treatment, it has been concluded that they 
 are milder forms of hypothyroidism. 
 
 Some maintain that adipositas dolorosa — or 
 Dorcum's disease, in which local accumulations of 
 fat, often tender to the touch, appear in various 
 situations — is connected with hypothyroidism. 
 Stockman, who has given much attention to the 
 condition, is not inclined to accept this theory. 
 
 The peculiar relations of the symptoms of myx- 
 cedema to those of old age raises the question of 
 whether the physiological involution of the thyroid 
 plays any part in senility. Apparently it, like all 
 other organs, undergoes an involution, but whether 
 primary or concomitant cannot be decided. 
 
 2. Metabolism. A large number of investigators 
 have dealt with this question. 
 
 i. Protein Metabolism. All the results recorded agree 
 in showing that removal of the thyroid decreases the 
 protein metabolism. In fasting it may lower it to 
 one-third of the normal. The sparing action of carbo- 
 hydrates and fats on protein catabolism is decreased, 
 since apparently they are not so readily used. 
 
THE THYROID 79 
 
 Manseld finds that deprivation of oxygen, which 
 usually increases the nitrogenous excretion in the 
 urine, does not do so in animals deprived of the 
 thyroid. 
 
 ii. Fat Metabolism. The metabolism of fat is said to 
 be decreased, but the evidence upon this point is not 
 conclusive. 
 
 iii. Carbohydrate Metabolism. Eppinger, Falta and 
 Rudinger showed that after removal of the thyroid 
 large amounts of sugar may be administered without 
 glycosuria appearing, especially if the parathyroids 
 are not interfered with. The sugar is stored to a 
 greater extent and not mobilised. 
 
 It has been shown that the chromafifin system has 
 an action in mobilising sugar, and it is thus possible 
 that removal of the thyroid decreases the action of 
 adrenalin in causing glycosuria. Eppinger, Falta 
 and Rudinger state that it does act in this way, but 
 Underbill denies the correctness of their results. 
 
 It may, however, act in another way. Evidence 
 will be adduced later to show that the pancreas 
 has an action in checking the mobilisation of sugar. 
 Removal of the organ leads to a glycaemia and 
 glycosuria, with rapid conversion of glycogen to 
 sugar and to a formation of sugar from proteins. 
 
 Lorand showed that removal of the thyroid from 
 a dog with pancreatic diabetes caused a decrease 
 or disappearance of the sugar from the urine. 
 
 Eppinger, Falta and Rudinger have further in- 
 vestigated this point, and generally confirm Lorand's 
 
8o REGULATORS OF METABOLISM 
 
 conclusions. They show that, if the thyroid has 
 been removed a week or so before the pancreas is 
 excised, the diabetes produced is characterised by 
 a lessened rate of protein catabolism, and therefore 
 a rise in the quotient Dextrose -=- Nitrogen from 2.8 
 to 3,5, and a decreased loss of body weight, as 
 compared with the condition in the dog simply 
 depancreatised. 
 
 An increase of the colloid of the thyroid has been 
 described after removal of the pancreas, while Falta 
 aiid Bertelli found increase in the islets of Langer- 
 hans after thyroid extraction. This evidence seems 
 to indicate that the thyroid opposes the action of 
 the pancreas, and that it facilitates the mobilisation 
 of sugar which is held in check by that organ. 
 
 It would thus seem that, as regards carbohydrates, 
 the thyroid and chromaffin system act as facilitators 
 for the mobilisation of sugar, whether from glycogen 
 or protein ; that probably the thyroid facilitates the 
 action of the chromaffin tissue ; and that both are 
 opposed to the pancreas which keeps the process in 
 check. It is the balance between them which regu- 
 lates the carbohydrate metabolism and keeps it in 
 the normal condition (Fig. 5, p. 185). 
 
 Eppinger, Falta and Rudinger also state that 
 the thyroid facilitates the action of adrenalin on the 
 peripheral blood-vessels, and that after its removal 
 adrenalin causes a smaller rise of blood pressure. 
 Fleming and I have not been able to confirm this in 
 experiments upon rabbits. 
 
THE THYROID 8i 
 
 2. TRANSPLANTATION. 
 
 This was first successfully carried out by Schiff in a 
 dogin 1 884. By transplanting the thyroid into the peri- 
 toneal cavity, he kept the animal alive for a long time. 
 
 Von Eiselberg proved that the grafts live. Appar- 
 ently the centre of the graft generally necroses, but 
 budding from the periphery takes place. Cristiani 
 and also Salzer find that the activity of proliferation 
 is more marked in animals without the thyroid, 
 taking place in three weeks, as against six to eight 
 weeks in those with the thyroid left. 
 
 Bucher did a successful operation of the kind on a 
 woman after thyroidectomy, and others have also suc- 
 ceeded. Payr transplanted part of the thyroid of the 
 mother in the spleen of a child of six which suffered 
 from severe infantile myxoedema, and which had 
 been treated, without benefit, for three years with 
 thyroid preparations, with markedly favourable 
 results on mind and body. 
 
 But such operations are not without danger, and 
 the discovery in 1891 by Vessale, and by Gley, that 
 the intra-venous injections of watery extracts of thy- 
 roid acted in the same way ; and the further discovery 
 by Murray of Newcastle that glycerin extracts given 
 not only subcutaneously, but by the mouth, are effec- 
 tive has led to the abandonment of transplantation. 
 
 3. ADMINISTRATION OF EXTRACTS. 
 
 That the administration by the mouth of thyroid 
 extracts keeps in check the symptoms of removal of 
 
82 REGULATORS OF METABOLISM 
 
 the thyroid and of myxcedema of the adult, and 
 brings about a marked improvement in infantile 
 forms of myxcEdema, is one of the best established 
 facts of medicine. The generally lowered meta- 
 bolism is restored to a normal level. 
 
 The explanation of these results is afforded in part 
 by the study of the influence of thyroid extracts on 
 the metabolism of lower animals. The effects are 
 not produced in normal animals at once, but only 
 after a considerable time. They are an increase in 
 the protein and in the carbohydrate metabolism. 
 
 As regards the action upon fats, and especially 
 upon the fats in the body of fat people, Magnus- 
 Levy states that the increase of the COg excretion 
 and of the Og uptake is not sufficient to account for 
 the disappearance of the fat. This is difficult to 
 explain, and the question requires reinvestigation. 
 
 The continued administration of large doses of 
 thyroid extracts produces marked symptoms of hyper- 
 thyroidism in man as well as in the lower animals — a 
 rapid wasting, thirst, increased appetite, sometimes 
 glycosuria, digestive disturbances and diarrhoea. 
 
 Kraus and Friedenthal describe in rabbits after 
 intra-venous injection a protrusion of the eyeball, 
 retraction of the nictitating membrane and a widen- 
 ing of the pupil. Hoennicke by continued adminis- 
 tration also produced exophthalmos. In rabbits the 
 acceleration of the heart is generally marked. 
 
 In man excessive doses of extracts may produce 
 the same effects — psychic excitement, sleepless- 
 
THE THYROID 83 
 
 ness, emaciation, tachycardia and digestive troubles. 
 Norhaft describes a case of a fat man of forty-three 
 who in five weeks took 1000 tablets, and who 
 developed the symptoms of Graves' disease. These 
 symptoms disappeared when the use of the tablets 
 was stopped. 
 
 Gudernatsch records the effects upon tadpoles of 
 feeding with thyroid. He finds that growth stops, 
 and that development occurs rapidly, so that the 
 limbs grow and the tail atrophies while the tadpole 
 is still very small. 
 
 Our knowledge of the action of thyroid extracts 
 on the circulation is far from satisfactory. On the 
 heart Oliver and Schafer state that there is no action, 
 but that a fall of arterial pressure occurs from dilata- 
 tion of the arterioles. 
 
 Von Cyon and Oswald state that it increases the 
 action of the heart when the vagi are cut. Von Cyon 
 long ago showed that the administration of ipdothyrin 
 or iodothyreoglobulin increases the excitability of the 
 vagus on the heart. More recently Asher and von 
 Rodt have also found in many cases that the 
 administration of thyroid preparations increase the 
 excitability of the vagus and of the depressor nerve. 
 
 They also find that thyroid extracts sensitise the 
 nerve terminations upon which adrenalin acts. Upon 
 stimulating the splanchnic nerve the usual vaso- 
 constriction and rise of blood pressure becomes 
 more marked after the administration of thyroid 
 preparations. 
 
84 REGULATORS OF METABOLISM 
 
 The study of the condition of hyper-thyroidism, 
 produced by the continued administration of the 
 thyroid preparation, leads to the consideration of 
 Graves' disease, which seems to be due to excessive 
 activity of the thyroid. In it the various symptoms 
 produced by hyper-thyroidism are manifest. 
 
 The thyroid shows parenchymatous hypertrophy, 
 with marked vascularity and proliferation of the 
 epithelium of the vesicles. In later cases increase of 
 the connective tissue is found. Curiously enough, 
 the percentage of iodine is decreased. Does this 
 mean a lessened power of fixing and storing the 
 iodothyreoglobulin ? 
 
 Hypertrophy of the thymus is common — but 
 Graves' disease is apt to occur in people of the thymo- 
 lymphatic type. Gierke holds that in these cases 
 operative interference leads to bad results. Possibly 
 there is an antagonism between thyroid and thymus. 
 
 The heart's action is exaggerated and quickened, 
 and the left ventricle becomes hypertrophied. There 
 is increased vaso-motor activity, and flushings are 
 common. The temperature is also frequently in- 
 creased. Exophthalmos from widening of the eye- 
 slits and protrusion of the eyeball from contraction 
 of the muscle of Miiller are present. 
 
 As shown by Magnus- Levy, there is a most 
 marked increase in the rate of chemical exchange 
 and in the total oxidation of the tissues. The power 
 of assimilating sugar is decreased, and it tends to 
 appear in the urine. 
 
THE THYROID 85 
 
 The work of Asher and von Rodt support the view 
 that in Graves' disease there is an increase of 
 thyroid secretion in the blood. In order to get rid 
 of any adrenalin that might be present, they treated 
 the blood with formaldehyde, which destroys 
 adrenalin, and found that the injection of the 
 serum in a series of cases caused increased vagus 
 excitability, increased action of adrenalin, and in- 
 creased irritability of the splanchnic and of the 
 depressor nerves. 
 
 The treatment which has proved most successful 
 is ligature of some of the vessels of the thyroid or 
 removal of part of the organ. Kocher states that 
 76 per cent, of the cases so treated were cured, and 
 14 per cent, were benefited. The mortality is 
 between 3 and 4.7 per cent. The utility of X-rays 
 has not been demonstrated as a means of decreasing 
 the function of the thyroid. 
 
 General Conclusions. The evidence is thus quite 
 conclusive that the thyroid exercises a marked 
 action on the development and growth of soma and 
 gonads. That its action on the soma is a direct 
 one, and not through any action on the gonads, is 
 indicated by the marked difference in the changes in 
 the characters of bone development after thyroidec- 
 tomy and after castration. In the former there is 
 a failure in the bone formation at the epiphyseal 
 junction, in the latter a too prolonged continuance 
 of growth at this point. In the former the growth of 
 
86 REGULATORS OF METABOLISM 
 
 periosteal bone is not interfered with, in the latter it 
 is decreased, and the bones are more slender. 
 
 Is its action on the gonads direct or through the 
 soma ? The action is so marked and so out of pro- 
 portion to the nutritional changes in the soma 
 that there can be little doubt that it is a direct one, 
 and that we are justified in concluding that the 
 thyroid is of importance in the growth of the gonads 
 in the pre-pubertal period of life. 
 
 Influence of Nerves upon the Thyroid. The work 
 of Asher and von Rodt seems to indicate that the 
 activity of the production of its internal secretion by 
 the thyroid is under the control of the nervous 
 system. Taking the sensitising action on the abdo- 
 minal sympathetic nerves as their index of an in- 
 crease of the secretion into the blood, they tried the 
 effect of stimulating the nerves of the thyroid, and 
 found that it increased the effect of stimulating 
 the splanchnics. From this they concluded that 
 the nerves to the thyroid had caused an increased 
 production of the active substance. 
 
 Summary. After describing the development, 
 structure and chemistry of the thyroid, its physi- 
 ology has been considered in the light of experimental 
 and of clinical evidence. The results of removal, of 
 suppression of function by disease or by arrested 
 development, and the effects of excessive action 
 brought about by administration of the active prin- 
 ciple of the gland and by Graves' disease have been 
 dealt with. The conclusion has been arrived at that 
 
THE PITUITARY 87 
 
 the thyroid supplies to the organism an internal 
 secretion which has a stimulating action on the 
 course of metabolism, thus increasing the activity of 
 development and of growth of soma and gonads. 
 Its manifest action on the activity of the central 
 nervous system has been pointed out, and its probable 
 action upon the termination of the true sympathetic 
 and the para-sympathetic has been discussed. 
 
 II. THE PITUITARY. 
 
 Development. The true pituitary — the anterior 
 part of the so-called pituitary body or hypo- 
 physis cerebri — develops like the thyroid from an 
 epithelial out-growth of the anterior part of the 
 alimentary canal. 
 
 This outgrowth is upon the dorsal aspect of the 
 canal. It is, according to some, entirely derived 
 from the ectoderm of the oral cavity, but others 
 maintain that the endoderm of the fore-gut is also 
 implicated in its formation. 
 
 Growing upwards it forms a series of branches, 
 and becomes a gland-like structure with solid 
 columns of cells and no acini. It embraces the 
 anterior part of the true hypophysis cerebri, and is 
 convex anteriorly and concave posteriorly. It has 
 a pale yellow or greyish-red colour and hard con- 
 sistence, while the true hypophysis has a white 
 colour and is soft. Accessory glandules may remain 
 along the track of the developing pituitary. 
 
88 REGULATORS OF METABOLISM 
 
 Structure. It consists of two somewhat different / 
 parts : / 
 
 1st. A pars anterior consisting of dense columns of 
 cells of two kinds — (i) The chief cells or 
 chromophobe cells with a protoplasm which 
 does not stain readily. They are large and ill 
 defined. (2) The chromophil cells, which 
 may be divided into (a) those staining readily 
 with eosin, and having a finely granular 
 protoplasm, and (d) those staining with basic 
 stains — larger cells with coarser granules. 
 It is very vascular, the capillaries being 
 sinusoid. The nervous supply is from the 
 sympathetic. 
 2nd. A pars intermedia, a layer composed of 
 several rows of cells, and separated from 
 the anterior lobe by a cleft. It is closely 
 applied to the posterior or nervous lobe — the 
 true hypophysis (p. 64). Colloid matter is 
 present between some of the cells, and these 
 are not of the two distinctly separated classes 
 found in the anterior part. This part is not 
 so vascular. 
 Physiology. By Galen the pituitary was con- 
 sidered a structure, the function of which is to 
 separate the mucus from the brain for secretion. 
 Since his time, many other theories resting on bases 
 even less substantial have been put forward. They 
 do not require consideration. 
 
 The first real advance was made through clinical 
 
 / 
 
THE PITUITARY 89 
 
 observation. Marie in 1886 described a peculiar 
 overgrowth of the bones which he called acromegaly, 
 and in 1891, in conjunction with Marinesco, he 
 showed that this is usually associated with tumours 
 of the pituitary. 
 
 Experimental work on the subject has proceeded 
 on certain definite lines. 
 
 1. Bemoval. The operative difficulties of reaching 
 the pituitary and of removing one part alone proved 
 a great obstacle in the way of older experimenters. 
 They generally attempted to reach the structure 
 through the roof of the mouth and base of the 
 skull. It was only when Paulesco in 1907 devised 
 the method of opening the cranial cavity in the 
 temporal region and raising the brain, so as to 
 expose the side of the hypophysis and pituitary, 
 that satisfactory results were obtained. 
 
 Operating in this way and on different animals, 
 Paulesco, Gushing Crowe and Homans and Biedl 
 have shown that removal of the true pituitary — 
 as distinguished from the hypophysis — is rapidly 
 fatal, death generally occurring within a few days 
 or weeks, and being preceded by muscular tremors, 
 slow pulse and respiration and an ante-mortem fall 
 of temperature. 
 
 Removal of the posterior part, the true hypo- 
 physis, as already stated, is not fatal. 
 
 Partial removal of the true pituitary in young 
 animals is not generally fatal, and is followed by 
 decreased growth and persistence of infantile char- 
 
90 REGULATORS OF METABOLISM 
 
 acters, hypertrophy of the thyroid, atrophy of the 
 gonads and an accumulation of fat chiefly in the 
 omentum and retroperitoneal tissues. 
 
 According to Paulesco, section of the stem of the 
 pituitary produces all the symptoms of removal, but 
 Gushing is unable to confirm this. 
 
 These results are confirmed by recent experi- 
 ments of Aschner, who removed the whole of the 
 pituitary body from young dogs less than three 
 months old by the oral method. Some of the animals 
 lived for more than six months. In both males 
 and females the genital organs remained small. 
 Spermatogenesis was delayed, and was sparse and 
 atypical. The uterus remained small, and in the 
 ovaries the interstitial cells almost disappeared. 
 The development of ova was delayed for six 
 months, and the ovaries remained less developed 
 than in the normal animals. A marked deposition 
 of fat appeared, and the hairy coat and bones 
 remained infantile. 
 
 Benedict and Romans have recorded a series 
 of observations on the metabolism of dogs from 
 which the pituitary was either completely or nearly 
 completely removed. These lived for a considerable 
 time. 
 
 They found that the gain of body weight was 
 retarded, that the skin was thickened and the hair 
 tended to fall out, that there was a gain of fat and 
 that the gonads did not develop. The temperature 
 fell, and the heat- regulating mechanism was inter- 
 
THE PITUITARY 91 
 
 fered with. The rate of the heart decreased, and con- 
 comitantly the rate of respirations diminished. The 
 excretion of carbon dioxide was markedly decreased. 
 
 2. Transplantation. Gushing, by transplanting the 
 anterior lobe, has succeeded in prolonging the life of 
 the animal, the graft apparently continuing to live 
 for at least a month. 
 
 3. Administration. Gushing states that by injecting 
 extracts he succeeded in keeping animals alive after 
 removal of the pituitary, and in improving the con- 
 dition of patients suffering from hypo-pituitarism. 
 
 Schafer, in the Groonian Lecture, 1909, gives 
 experiments to show that feeding and also grafting 
 pituitary increases the growth of young animals. 
 His results, however, are not very definite, and 
 they are not confirmed by the findings of Goetsch 
 and Gushing, while the observations of Aldrich give 
 no support to the view that the rate of growth is 
 modified by the addition to the food of the pituitary, 
 of the testicle or of the ovary. 
 
 4. Physiological Hypertrophy of the Pituitary. During 
 pregnancy the pituitary hypertrophies, and the 
 hypertrophy is due chiefly to an increase in the 
 chief or chromophobe cells. It has been maintained 
 that pre-existing pregnancy may actually be deter- 
 mined by the development of these cells, although 
 after each pregnancy and during lactation they 
 undergo a process of involution. This condition of 
 the pituitary may, perhaps, be associated with the 
 thickening of the subcutaneous tissue of the nose, 
 
92 REGULATORS OF METABOLISM 
 
 lips and hands which so frequently accompany 
 pregnancy. 
 
 Hypertrophy of the pituitary is also caused by 
 castration and by removal of the thyroid. This, of 
 course, indicates a reciprocal action of these structures 
 on one another. 
 
 The thyroid and pituitary have more or less a 
 common origin, and their action upon metabolism, 
 growth and development is in some respects similar. 
 They appear to be compensatory to one another. 
 
 On the gonads the pituitary has an augmenting 
 action. Both structures have an important influence 
 on growth and development. When the gonads are 
 removed, the pituitary undergoes what is probably 
 a compensatory hypertrophy. But without the 
 pituitary, complete development of the gonads ap- 
 pears impossible. 
 
 5. Disease. The consideration of these hyper- 
 trophies of the pituitary leads to the study of the 
 condition described by Marie as acromegaly. This 
 disease generally affects adults. It begins with 
 fatigue, muscular pain, apathy and sleepiness. In 
 the later stages the sexual activity is decreased, and 
 in women, menstruation generally stops. 
 
 A diffuse increase of the soft parts of the face 
 and increased growth of the bones of the face occur. 
 The superciliary ridges become more prominent, 
 the nose enlarges, the lower jaw increases, the lips 
 thicken and the tongue hypertrophies. 
 
 Later, the hands and feet increase, partly by 
 
THE PITUITARY 93 
 
 increase of the connective tissue generally and of 
 the true skin, partly by growth of the terminal 
 phalanges. Very often symptoms of intra-cranial 
 tumour are present. Glycosuria is evident in a large 
 proportion of cases, and is probably due to implica- 
 tion of the posterior lobe — the hypophysis (p. 69). 
 As regards the metabolic changes, nothing very 
 definite is known. A retention of phosphorus, cal- 
 cium and chlorine has been described, but the 
 evidence is by no means satisfactory. 
 
 The progress of the disease is usually slow. After 
 death the most constant change found is in the 
 pituitary, which shows either a hypertrophic hyper- 
 plasia or tumour formation. 
 
 Cases of treatment of the disease by operative 
 removal of the pituitary have been recorded by 
 Hochenegg, by Gushing and by Exner. In some 
 of these cases a marked improvement occurred, 
 and the deformity caused by the hypertrophy 
 of the soft parts and the bones was decreased. 
 In two of the cases menstruation reappeared, 
 and in these two hypertrophy of the thyroid was 
 observed. 
 
 The evidence thus seems to indicate that the 
 symptoms of the disease are due, in part at least, to 
 exaggerated and possibly perverted action of the 
 pituitary. Tumour formation can hardly be expected 
 to give rise to a pure stimulating action such as 
 might be produced by electrical stimulation. Gush- 
 ing's careful analysis of his series of cases seems to 
 
94 REGULATORS OF METABOLISM 
 
 prove that the disease begins by exaggerated func- 
 tional activity of the pituitary, characterised by 
 increased growth of bone and, in some cases, by 
 precocious sexual development ; but that later a 
 condition of decreased activity supervenes, with 
 decrease of sexual activity. 
 
 The true hypophysis is also involved, and hence 
 the assimilation of glucose is altered either positively 
 or negatively. 
 
 Marie's investigations on acromegaly suggested 
 that cases of giantism may be related to increased 
 action of the pituitary. A study of living examples 
 of this condition and of the skeletons of some of the 
 famous giants has tended to confirm this view. 
 Many of these giants during life have shown a 
 persistence of the infantile habit — they were often 
 mentally deficient and apathetic, the growth of hair 
 was often poor and the reproductive organs were 
 undeveloped. Post-mortem, the sella turcica, in 
 which the pituitary rests, has been found enlarged. 
 It would almost seem as if giantism was an acro- 
 megaly of youth, while true acromegaly was a 
 manifestation of the disease occurring after the 
 epiphyseal cartilage had ossified. 
 
 A condition which, in the light of the physio- 
 logical observations of Gushing on the effects of the 
 partial removal of the pituitary in young animals, 
 seems to be associated with a decreased activity of 
 the pituitary in young people, has been described 
 by Frohlich. It has been called dystrophia adiposo- 
 
THE PITUITARY 95 
 
 genitalis. It is characterised by deposits of fat often 
 on the buttocks and breast, and by the non-develop- 
 ment of the sexual organs. Cases have been 
 described with lesions of the pituitary. Von Eisel- 
 berg described one in which the removal of a 
 tumour growth was followed by amelioration of the 
 symptoms. 
 
 The evidence thus points to the pituitary acting 
 somewhat in the same way as the thyroid upon 
 development, growth and metabolism. 
 
 Evidence has been adduced in the case of the 
 thyroid that its action upon metabolism is through 
 the nervous system, probably through the terminal 
 plexuses of the true sympathetic and of the para- 
 sympathetic systems. But in the case of the pituitary 
 there is not the same evidence. 
 
 Summary. The development of the true pituitary, 
 as an epithelial upgrowth from the buccal cavity, and 
 its subsequent association with the hypophysis, its 
 division into a pars anterior and pars intermedia, 
 and the structure of each of these has been de- 
 scribed. The effects of removal, of transplantation, 
 of administration of its substance after removal, and 
 the pathological changes which occur in acromegaly, 
 have been dealt with. The two stages of this disease, 
 the first irritative, the second atrophic, and their 
 effects on metabolism, have been indicated. 
 
 The conclusion is arrived at that the pituitary, 
 like the thyroid, produces an internal secretion which 
 stimulates the metabolism and growth of tissues, and 
 
96 REGULATORS OF METABOLISM 
 
 more especially of the gonads and of the connective 
 tissues, including bone. 
 
 So far no indication is forthcoming as to whether 
 the internal secretion acts directly on the tissue 
 elements or operates through the nervous system. 
 
 ///. DEVELOPED FROM THE MID-GUT. 
 I. THE PANCREAS. 
 
 Development. The pancreas is developed as a 
 paired outgrowth from the mid-gut. Each division 
 branches and again branches to form a compound 
 racemose gland. From the epithelium lining the 
 ducts, separate groups of cells grow out to form solid 
 islands of epithelial tissue — the islets of Langerhans. 
 These are very richly supplied with blood-vessels. 
 
 It is, I think, probable that two kinds of islets 
 exist, the true islets formed as described above and 
 false islets which may be produced by changes in 
 the acinal tissue, as was first described by Dale. 
 
 That true islets exist is shown by embryological 
 research, by the observation of Rennie that in 
 teleostean fishes the islets are definitely encapsulated, 
 by the distinctive staining reaction with Bensley's 
 neutral gentian described by Kirkbride, and by the 
 recent work of Romans. 
 
 Physiology. Primarily the pancreas is to be re- 
 garded as a digestive gland, which pours its secretion 
 into the duodenum, there to play a most important 
 part in the digestion of food. 
 
THE PANCREAS 97 
 
 But just as Bernard discovered that the liver, which 
 is also primarily a digestive gland, has most import- 
 ant relations with the general metabolism, so von 
 Mering and Minkowski have demonstrated that the 
 pancreas also is intimately related with the metabolic 
 processes throughout the body. And the pancreas, 
 like the liver, is chiefly concerned with the meta- 
 bolism of carbohydrates. 
 
 In 1889 these investigators discovered that re- 
 moval of the pancreas in dogs leads to a condition of 
 true diabetes. Sugar appears in the urine and 
 increases in the blood, there is polyuria, great thirst, 
 rapid wasting, with increased appetite and increased 
 excretion of nitrogen. The animal rarely survives 
 for more than four weeks. 
 
 This discovery has been confirmed in many species 
 of animals in all groups of vertebrates by a number 
 of investigators. 
 
 The removal of the pancreas must be complete. 
 If one- third or even one-fifth is left, the symptoms do 
 not develop. 
 
 The question arises whether it is the islets or the 
 acinal tissue, or both, which are the important ele- 
 ment in this result. The evidence cannot be con- 
 sidered as conclusive, but so far as it goes it points 
 to the islets. Cases have been recorded where 
 a part of the pancreas has been ligatured off from the 
 rest, and where, .on examination, it has been found 
 to consist entirely in islet tissue. M'Callum in 1909 
 (quoted by Kirkbride) described such a case in a 
 
98 REGULATORS OF METABOLISM 
 
 dog where removal of the sound piece of pancreas 
 led to only a slight glycosuria, but where subsequent 
 removal of the degenerated part composed, as 
 afterwards found, entirely of islet tissue produced 
 a very marked glycosuria. 
 
 Minkowski showed that transplanting a piece of 
 the pancreas prevented the onset of symptoms, and 
 he thus proved that the effect of removal is through 
 an internal secretion and not through the nervous 
 system, as was maintained by Pfliiger. 
 
 Subsequent removal of the graft induced the con- 
 dition of diabetes. 
 
 So far the administration of pancreatic extracts 
 has failed to prevent the onset of symptoms or to 
 check them when developed. Hedon gives some 
 not very satisfactory evidence that the blood coming 
 from the pancreas has some influence. He states 
 that, when a cross circulation is arranged between 
 two dogs, one normal and one rendered diabetic by 
 removal of the pancreas, so that the blood of the dia- 
 betic dbg flows through the tail of the pancreas of 
 the normal animal into the portal system of the 
 former, the glycosuria is markedly decreased. When 
 the blood enters the systemic vein, the effect is not 
 produced. He further says that he finds that injec- 
 tion of the blood of the pancreatic vein into the 
 mesenteric vein of a diabetic dog decreases the 
 glycosuria. At first sight these observations would 
 seem to point to a direct action of pancreatic secre- 
 tion on the liver, but the facts that the mere estab- 
 
THE PANCREAS 99 
 
 lishment of a cross circulation may reduce glycosuria 
 and that the glycsemia is not reduced in these ex- 
 periments materially decrease their significance. 
 
 The direct action of the pancreatic secretion upon 
 the liver indicated by these results is in accord with 
 the old observation that glycosuria does not occur 
 in frogs if the liver as well as the pancreas is 
 removed. 
 
 As to how the internal secretion acts, various theories 
 have been advanced. Lupine thought that it 
 stimulated the combustion of sugar in the tissues. 
 This view seemed to be supported by the finding of 
 Cohnheim that sugar is not oxidised by muscle juice 
 alone outside the body, but that it disappears in a 
 mixture of muscle juice and pancreatic extract. This 
 finding, however, was not confirmed by the careful 
 investigations of Claus and Embden. Certain results 
 obtained by Knowlton and Starling, to be presently 
 considered, give, however, some support to the 
 theory. 
 
 The view that the pancreas controls the mobilisa- 
 tion of sugar both from the glycogen stored in liver 
 and muscle and from the protein molecule seems 
 most in accordance with the evidence we at present 
 possess. 
 
 In the first place, the rapid disappearance of 
 hepatic glycogen and the marked decrease of muscle 
 glycogen on removal of the pancreas supports this 
 view. In fasting or in protein feeding, the per- 
 sistence of sugar in the urine and the increased 
 
loo REGULATORS OF METABOLISM 
 
 excretion of nitrogen show that there is a loss of 
 control over the formation of sugar from proteins. 
 This too rapid mobilisation of sugar leads to its 
 increase in the blood and its excretion in the urine. 
 Hence it is less available as a source of energy, and 
 fats and proteins have to be utilised. As a result, 
 the various abnormalities of metabolism which follow 
 the withdrawal of carbohydrates manifest them- 
 selves. Cathcart and Taylor have shown that creatin 
 appears in the urine, and the modified metabolism of 
 fats leads to the appearance of /3-oxybutyric acid 
 and to the various symptoms of acidosis. 
 
 That the combustion of available sugar by the 
 tissues is interfered with, is indicated by the low 
 respiratory quotient on a carbohydrate diet. Nor- 
 mally on a carbohydrate diet the oxygen consumed 
 
 CO 
 is equal to the carbon dioxide excreted: -~~=i. 
 
 But on a protein or fatty diet, since the proportion 
 of oxygen in the molecule is so small, the oxygen 
 consumed exceeds the COg excreted, and the respira- 
 tory quotient falls to less than i. Hence a low 
 respiratory quotient on a carbohydrate diet indicates 
 the non-utilisation of sugar. 
 
 That there is a real failure of certain tissues 
 to use sugar is indicated by the recent experi- 
 ments of Knowlton and Starling, confirmed by 
 Maclean and Smedley. They perfused the excised 
 heart of the normal and of the depancreatised 
 dog with blood containing sugar, and they found 
 
THE PANCREAS loi 
 
 a much greater utilisation of sugar in the heart of 
 the normal than in that of the depancreatised and 
 diabetic animal. Knowlton and Starling record 
 experiments to show that the addition of pancreatic 
 extracts to the blood circulating through the heart 
 restores the power of the muscles to use sugar. 
 The results of Maclean and Smedley do not so 
 definitely confirm this observation. 
 
 It would thus seem that the pancreas exercises a 
 double influence on carbohydrate metabolism, first 
 checking its mobilisation in the liver, and, secondly, 
 determining or facilitating its utilisation in the 
 tissues. 
 
 Does the pancreas act directly upon the liver cells 
 and other carbohydrate storing structures, or does 
 it act indirectly through the nervous system ? 
 
 In favour of the latter view is the antagonism of 
 adrenalin and the pancreatic secretion — the former 
 mobilising sugar, the latter checking its mobilisa- 
 tion. Since we have seen reason to conclude 
 that the former acts by activating or stimulating 
 the endings of the true sympathetic in the liver, 
 it may be argued that the endocrinous secretion of 
 the pancreas inhibits them. 
 
 Loewi has described an increased action of adren- 
 alin on the pupil in cases of diabetes, presumably of 
 pancreatic origin, and argues from this that the 
 pancreas must have a checking influence on all the 
 true sympathetic terminations. The problem lends 
 itself to further investigation on lower animals, ex- 
 
I02 REGULATORS OF METABOLISM 
 
 tending them to the heart, blood-vessels, uterus and 
 intestine. 
 
 Summary. The pancreas is primarily a digestive 
 gland, from the epithelium of the developing ducts 
 of which specialised masses of cells, the true islets 
 of Langerhans, are formed. Secondary islets may 
 possibly be produced later from alteration in the 
 secreting acini. Removal of the pancreas has been 
 found to cause a condition of diabetes, the onset of 
 which may be checked by grafting pancreatic tissue. 
 In this condition there is a too rapid mobilisation of 
 sugar, and a failure on the part of muscular tissue to 
 use sugar. These results indicate that the pancreas 
 produces an internal secretion or secretions which 
 hold in check the mobilisation of sugar, thus oppos- 
 ing the secretions of the chromaffin tissue, of the 
 hypophysis and of the thyroid, and which facilitate 
 the utilisation of sugar by the muscles as a source of 
 energy. The former effect is probably brought 
 about by an action upon the terminations of the true 
 sympathetic system in the liver. About the essential 
 nature of the latter action, nothing is known. 
 
 II. THE MUCOUS MEMBRANE OF THE SMALL 
 INTESTINE. 
 
 The fact was discovered by Bayliss and Starling 
 that from the mucous membrane of the upper part 
 of the small intestine an extract can be made which, 
 when injected into the jugular vein, causes a copious 
 
THE INTESTINAL MUCOSA 103 
 
 flow of pancreatic juice. The active constituent of 
 this extract they called Secretin. Although the sub- 
 stance has not been isolated, it is known to resist 
 the action of heat and of acids, to be diffusible, 
 and not to give any of the protein reactions. They 
 also confirmed the observations of Wertheimer and 
 Popielski that the introduction of acid into the 
 duodenum caused a secretion of pancreatic juice, 
 even after the vagi and splanchnic nerves have been 
 cut and the spinal cord destroyed. They further 
 state that, when all the nerves to a loop of intestine 
 have been cut, the introduction of acid causes a 
 flow of pancreatic juice. From this they conclude 
 that the action of the acid is not of the nature of 
 a peripheral reflex, as suggested by Wertheimer 
 and by Popielski, but that it is due to the pro- 
 duction of secretin from a hypothetical prosecretin, 
 and that this, passing into the circulation, reaches 
 the pancreas and acts directly upon it. Not only is 
 the secretion of pancreatic juice increased, but the 
 flow of bile is also augmented. 
 
 About the facts recorded there can be no doubt. 
 But whether this chemical stimulation of the pancreas 
 is the normal mechanism in evoking secretion is 
 not so clear. At first sight everything seems simple. 
 Acid chyme enters the duodenum from the stomach. 
 Pancreatic juice is required for its further digestion. 
 The acid of the chyme changes prosecretin into 
 secretin, which at once acts upon the pancreas to 
 call forth its activity. 
 
104 REGULATORS OF METABOLISM 
 
 Were the pancreas, as is the liver, supplied by 
 blood coming from the intestine, the evolution of 
 such a mechanism would be easily understood. But 
 in order to reach the pancreas the secretin must be 
 carried through the portal circulation of the liver, 
 through the right heart, through the lungs and into 
 the systemic arterial system, and so at length reach 
 the pancreas just as it reaches every other organ of 
 the body. 
 
 It may, of course, be urged that all internal secre- 
 tions are primarily poured into the blood of the veins, 
 and have to pass through the lesser circulation to 
 reach the structures upon which they act. But in no 
 other case is the action of the internal secretion so 
 definitely from one organ to a particular and closely 
 adjacent one, in no other case is it so difficult to 
 understand how such a lengthy route should have 
 been evolved. 
 
 On the other hand, the work of Pawlow has quite 
 clearly shown that pancreatic secretion is evoked by 
 stimulation of the vagus — that in fact there is a direct 
 nervous control. And, I think, it is perhaps some- 
 what rash to allow ourselves to be carried away by the 
 brilliant experiments and fascinating explanations of 
 Bayliss and Starling. It may very possibly be that, 
 in the future, the nervous control will be shown to 
 have a greater importance than we at present believe 
 it to possess. 
 
 Edkins has described the formation of an internal 
 
THE THYMUS 
 
 105 
 
 secretion similar in character to secretin which is 
 produced from the mucosa of the stomach and 
 which seems to act in supplementing the nervous 
 mechanism of gastric secretion. 
 
 IV. DEVELOPED FROM THE BRANCHIAL 
 CLEFTS. 
 
 I. THE THYMUS. 
 Development. The thymus, as already stated, is 
 derived from epithelial outgrowths from the bran- 
 chial arches, and in Petromyzon it seems to persist 
 
 p.thyr.lV 
 :hym.rV 
 
 Fig. 3. — To show the origins of the thyroid, thymus and parathyroids. 
 From Brgebnisse der Physiologic 
 
 in this condition. The close association of such a 
 structure with the original direct channel of the 
 blood-flow to the body suggests the occurrence of 
 some modification in the blood en route for the 
 tissues. 
 
 In mammals the thymus is derived chiefly from 
 the ventral end of the third branchial cleft, but a 
 
io6 REGULATORS OF METABOLISM 
 
 small bud from the fourth cleft forms a little nodule 
 of thymus lying in the thyroid (Fig. 3). 
 
 Position. In most mammals it is situated chiefly 
 in the upper mediastinum of the thorax, lying just in 
 front of the cephalic end of the heart and the great 
 vessels. In the guinea-pig it is entirely confined 
 to the neck, and lies on each side of the trachea, 
 extending from the larynx downwards. In birds it 
 lies as a series of separate masses down each side of 
 the neck. 
 
 In mammals it consists of two chief lobes, one on 
 each side, each lobe being subdivided into a number 
 of small lobules. 
 
 Structure. Each lobule is surrounded by a fibrous 
 capsule, and the peripheral part is denser than the 
 central. 
 
 It is essentially an epithelial structure and, while 
 the organ persists, its epithelial cells may be traced 
 as a network or groundwork throughout the lobules 
 and as a series of large more or less circular bodies 
 — the corpuscles of H assail. These, in their fully 
 developed state, must be considered as degenerative 
 products of the epithelium. In the embryo they 
 appear as masses of reticulum cells. They are 
 invaded by polymorpho-nuclear leucocytes, and the 
 protoplasm of the cells shows the development of 
 granules staining deeply with basic stains. 
 
 The epithelial groundwork has its interstices 
 filled with lymphocyte-like cells. The nature of 
 these is still under dispute. Hammar maintains 
 
THE THYMUS 107 
 
 that they are true lymphocytes derived from outside 
 the epithelial thymus, Stohr contends that they 
 are formed from the epithelial cells and that they 
 are really epithelial in nature. 
 
 The evidence upon the subject is very fairly stated 
 by Hammar. He points out that the evidence in 
 favour of their epithelial or autochthonous origin 
 is : 
 
 1st. The presence of intermediate forms. He is 
 inclined to maintain that the existence of these has 
 not been proved. 
 
 2nd. The special character of the mitosis of 
 thymus cells as compared with that of lymphocytes. 
 He is sceptical of the possibility of demonstrating 
 this. 
 
 3rd. The absence of lymphocytes in the rest of 
 the body while these small cells are seen in the 
 thymus. He cites Bryce's work on the development 
 of lymphocytes in Lepidosiren which shows that 
 they are formed outside of the thymus. This 
 evidence does not seem to be of much importance 
 either way as regards the origin of the cells in the 
 thymus. 
 
 4th. The absence of lymphocyte infiltration round 
 the thymus which should be present if migration 
 were taking place. This seems of little importance. 
 
 5th. The change of the lymphocyte-like cells to 
 epithelial cells. This is simply a repetition of the 
 first argument. 
 
 6th. The chemical difference between the thymus 
 
io8 REGULATORS OF METABOLISM 
 
 and lymphatic glands. Ivar Bang gives the follow- 
 ing analysis : 
 
 
 Thymus. 
 
 Lymph Gland. 
 
 Protein 
 
 15-52 
 
 13-79 
 
 Nucleinate 
 
 3-15 
 
 0.69 
 
 Ash- 
 
 1.59 
 
 i-oS 
 
 In favour of the immigration theory he cites : 
 
 1. The morphological similarity of the small cells 
 of the thymus and the lymphocytes — a somewhat 
 difificult point to determine in dealing with cells so 
 small as these. 
 
 2. The physiological similarity as shown by the 
 presence of amoeboid movement and the similar 
 reaction to X-rays. 
 
 3. The evidence of immigration from surrounding 
 tissues. 
 
 4. The partial disappearance of these cells in 
 fasting, and their restoration by immigration after 
 feeding. That the restoration is by immigration 
 seems to me a difficult point to establish. 
 
 5. The observation of Ritchie that injecting the 
 thymus of guinea-pigs into ducks yielded a cytolytic 
 serum acting not only on the cells of the thymus but 
 also upon the lymphocytes of lymph glands. Since 
 the thymus emulsion injected contained blood, the 
 possibility of a double cytotoxine has to be con- 
 sidered. 
 
 The recent work of Hart certainly strongly 
 supports Hammar's view as to the lymphocyte 
 nature of the small cells. 
 
THE THYMUS 109 
 
 If this is the case, it brings the structure of the 
 thymus into accord with that of the tonsil, a derivative 
 of a higher branchial cleft, where epithelial outgrowths 
 become surrounded by true lymphoid tissue. 
 
 Reviewing the evidence we possess, we are, I 
 think, forced to confess that further work must be 
 done before any definite conclusion can be arrived at. 
 
 Pensa and others have described peculiar long 
 cross-striped cells like muscle fibre in many verte- 
 brates, which Hammar has called myoid cells. 
 Herman considers that these are modified epithelial 
 cells. Pensa finds that they are distinct from the 
 epithelial network. 
 
 In Amphibia especially, spaces of different kinds 
 are found in the thymus. 
 
 I. Vacuoles in the epithelial cells. 2. Lacunae 
 between the cells. 3. Enclosed vesicles with colloid 
 or mucous material. 
 
 Some of these are lined by epithelial cells like the 
 rest of the thymus groundwork, and some of the 
 lining cells have cilia upon their free margin. 
 
 In triton and rana esculenta, Pensa finds rows of 
 epithelial-like cells along blood-vessels, and in the 
 adder several rows of cells projecting into the vessels. 
 They are not endothelial, and he considers them of 
 special significance in the production of an internal 
 secretion. 
 
 Life-history of the Thjrnms. Beginning as an 
 epithelial structure, the thymus early shows the 
 appearance of the small cells, the nature of which 
 
no REGULATORS OF METABOLISM 
 
 has been already considered. Parts of the epithelial 
 groundwork increase, and form accumulations of 
 cells. These undergo degeneration, and produce the 
 Hassall's corpuscles. In most animals the organ 
 reaches its greatest size in relationship to the body- 
 weight about the time of birth, but further work is 
 wanted upon this point. After birth the rate of 
 growth generally decreases, although in the dog at 
 least, according to Klose and Vogt, this is not the 
 case for some days. Growth goes on till about the 
 onset of sexual maturity, when a true involution of 
 the organ occurs, and it decreases in bulk. Fibrous 
 tissues and fat cells extend into the lobules as the 
 true tissue atrophies, and finally it is reduced to a 
 mass of adipose tissue with some islands of thymus 
 remaining. 
 
 An estimation of the relative size of the thymus to 
 the body weight in some animals is given below : 
 
 Weight of Thymus to Weight of Body. 
 
 
 Man. 
 
 
 
 Dog. 
 
 
 Birth 
 
 
 I 
 
 to 240 
 
 Birth 
 
 I to 250 
 
 5 years 
 
 
 I 
 
 „ 690 
 
 8 to 14 days 
 
 I „ 170 
 
 lo years 
 
 
 I 
 
 ,. 960 
 
 2 to 3 months 
 
 I „ 1 200 to 
 
 IS years 
 
 
 I 
 
 „ 1140 
 
 
 1600 
 
 20 years 
 
 
 I 
 
 .. 2356 
 
 
 
 
 Rabbit, 
 
 
 
 Guinea- 
 
 pig- 
 
 7 weeks 
 
 
 I 
 
 to 423 
 
 Under 2 weeks - 
 
 I to 420 
 
 i year - 
 
 
 I 
 
 ,, 923 
 
 ^ to I month 
 
 I „ 1000 
 
 h year ■ 
 
 
 I 
 
 „ 1250 
 
 I to 2 months 
 
 I „ 1700 
 
 I year - 
 
 
 I 
 
 ,, 1517 
 
 2 to 3 months 
 
 I „ 2400 
 
 2 years 
 
 
 I 
 
 „ 1922 
 
 
 
THE THYMUS iii 
 
 In birds it is said that the thymus does not 
 undergo involution (Soli), but from my own observa- 
 tions in ducks I am inclined to think that this state- 
 ment requires reinvestigation. 
 
 Not only does this true physiological involution 
 occur, but, at any period in the early life-history of 
 the thymus, accidental temporary involution is apt to 
 be produced by any interference with the nutrition 
 of the animal. Thus in the rabbit a fast of three 
 days may reduce the thymus to one-half This 
 reduction appears to be due to the disappearance of 
 the small cells, chiefly from the peripheral part of 
 the lobules. 
 
 Physiology. — Bemoval. The life-history of the thy- 
 mus points to its being a structure of importance 
 during the period of growth and development, and, 
 in order to get the most marked results from its 
 removal, this should be done at the period of its 
 greatest relative size, and in animals in which it is 
 best developed after birth. 
 
 A difficulty which has met the experimenter is the 
 position of the thymus in the thorax in the majority 
 of mammals. This makes the operation a serious 
 one, since the danger of injury to the pleura and of 
 pneumo-thorax and of injury to the great blood- 
 vessels have to be faced. In addition to these 
 dangers is that of sepsis, the onset of which probably 
 markedly interfered with the results of some of the 
 older experimenters. 
 
 On the other hand, the position of the thymus 
 
112 REGULATORS OF METABOLISM 
 
 high up in the neck of the guinea-pig renders its 
 removal a very simple operation, and for this reason 
 I have used these animals in my investigations. 
 But the state of maturity in which the guinea-pig is 
 born, and the fact that even under two weeks the 
 weight of the thymus is only i to 420 of the body 
 weight, while in the dog of the same age it is i to 
 170, is a possible indication that even at birth in the 
 guinea-pig the organ is not playing so active a part 
 as it does in some other animals. 
 
 On account of the difficulties and dangers of 
 operation, the results of the older experimenters may 
 be neglected. 
 
 Restelli in 1848, using sheep, dogs and calves, 
 had a very high mortality. In the dogs which sur- 
 vived he noted an increased and perverted appetite. 
 
 Friedleben's work (1850) has long been con- 
 sidered a classic. For his removal experiments he 
 used dogs and kids. Only a few survived. One 
 dog lived for four months, and ate voraciously, con- 
 suming corks and other similar objects. Before it 
 died it emaciated. In the kids he observed that, if 
 any of the thymus was left, regeneration tended to 
 occur. He also records imperfect bone develop- 
 ment. 
 
 The work of Abelous and Billard on frogs, after- 
 wards refuted by Hammar, and the experiments of 
 Tarulli and Le Manaco and of Ghika, threw no 
 fresh light on the problem. 
 
 In 1904 Goodall and I undertook a seriies of 
 
THE THYMUS 113 
 
 observations on young guinea-pigs, and we then 
 concluded that removal of the thymus has no 
 influence on the rate of growth of the animal, but 
 that it is followed by a slight decrease in the number 
 of leucocytes in the blood, which lasts for about two 
 months. The increase of leucocytes, which occurs 
 in the normal guinea-pig during pregnancy, after 
 injection with tubercle, and after injection of tere- 
 bene occurs also in thymusless animals. But there 
 seemed to be a less marked leucocytic response to 
 injection of staphylococci and streptococci, and a 
 decreased resistance to these infections. 
 
 Simultaneous removal of thymus and spleen was 
 not fatal in the guinea-pig. 
 
 M'Lennan describes a method of removing the 
 thymus in the rabbit and kitten, and records the 
 results of his experiments. He came to the con- 
 clusion that the growth is more active after removal 
 of the thymus, and that the epiphyseal cartilages 
 grow more rapidly. He says that, after removal 
 of the thymus, the thyroid was only to be found 
 with difficulty, and that the organ was more cellular, 
 had larger adenoid masses, and that the glandular 
 spaces were smaller. He further states that thy- 
 roidectomy causes a disappearance of the thymus, 
 and quotes Blumenreich and Jacobi as getting 
 similar results. Unfortunately he gives no details of 
 his various experiments, and his results as regards 
 the relations of the thyroid and the thymus have not 
 been confirmed by subsequent investigations. 
 
 H 
 
114 REGULATORS OF METABOLISM 
 
 Basch published an important series of papers 
 between 1903 and 1908. He removed the thymus 
 from dogs of from three to four weeks old — rather 
 older, than the age at which, according to Klose 
 and Vogt, the thymus is largest. He found that 
 the bones became softer and tended to bend, that 
 fractures tended to heal badly and with less callus. 
 He gives the following analysis: 
 
 Earthy Salts of Dried Bone. 
 Normal animal 65 per cent. 
 
 Thymusless animal, 32.02 per cent. 
 
 „ „ - 34.24 per cent. 
 
 He also states that there was an increased ex- 
 cretion of calcium. The animals became sluggish, 
 there was a loss of intelligence, and their weight 
 was less than that of the controls. Cramps of the 
 muscles, tonic and clonic, tended to develop, and 
 there was increased electrical excitability, especially 
 in the opening cathodal response. 
 
 Klose and Vogt have also done a large series of 
 experiments upon pups. They selected the tenth 
 day after birth for operation, as at that age the 
 thymus has attained its maximum development. 
 They operated on 54 pups in ten sets, each with a 
 control, and they were able to follow the changes 
 in 25. 
 
 They do not give the individual protocols, but 
 they describe generally the changes as divided into 
 three stages. 
 
 1st. A Latent Period of about fourteen days, 
 
THE THYMUS 115 
 
 during which symptoms are practically absent, but 
 which gradually passes into — 
 
 and. An Adipose Period, which lasts for two or 
 three months. The animal develops an enormous 
 appetite, becomes fat and sluggish and is easily 
 tired. Its gait becomes more and more infantile, 
 and it becomes stupid. It gradually passes into the 
 third sta^e — 
 
 3rd. A Cachectic Period, during which, although 
 it continues to eat enormously, its weight falls and it 
 emaciates. Muscular tremors, differing from those 
 of parathyroid tetany, develop: it becomes imbe- 
 cile: the hair becomes rough and falls out, and the 
 animal finally dies. 
 
 They confirm Basch's observation of the softening 
 of the bones, which have also been confirmed by 
 several other investigators. 
 
 They found in these animals a simple hyperplasia 
 of the pancreas, and of the ovaries and testes. 
 They state that removal of the spleen after thyroidec- 
 tomy causes a rapid advance of the symptoms, and 
 they therefore consider that the spleen has a com- 
 pensatory action. In this they confirm the old 
 observation of Friedleben. 
 
 The most unsatisfactory feature of the work of 
 Klose and Vogt is the absence of proper protocols 
 of the individual experiments. They make no real 
 attempt to explain the symptoms, although they put 
 forward the hypothesis that an acidosis is produced, 
 which leads to increased solution and excretion of 
 
ii6 REGULATORS OF METABOLISM 
 
 lime salts. The question of calcium distribution 
 and excretion they did not study. 
 
 The most curious part of their results is the onset 
 of symptoms at a period when the thymus is no 
 longer actively growing, but is reduced from i to 
 1 70 to I to 1 200 of the body weight. This suggests 
 that removal of the thymus must upset the meta- 
 bolic balance, so that those organs which take on 
 the action of the thymus as it disappears fail to 
 exercise their proper effect. 
 
 The most recent study of the effects of removal 
 of the thymus is by H. Matti. 
 
 He concludes that Klose and Vogt are wrong as 
 to the early cessation of growth of the thymus in 
 pups, and maintains that involution does not begin 
 till after the fourth month. His operations were 
 therefore done between the eighteenth day and 
 the eighth week. In the first few thymus glands 
 removed, parathyroids were examined for but were 
 not detected, and in the other experiments the 
 presence of the usual four parathyroids was deter- 
 mined after death. He finds that after a varying 
 latent period, during which the animals showed a 
 less gain of weight than the controls, increased 
 slowness of movements and muscular weakness 
 were observed. The bones became softer. These 
 symptoms increased and death supervened. 
 
 The bone changes resembled those of rickets. 
 Fractures were apt to occur. The long bones were 
 shorter, thicker and more easily bent. The epiphy- 
 
THE THYMUS 117 
 
 seal cartilages were markedly thickened and irre- 
 gular. The cortical parts of, the diaphyses were 
 thicker, with a thin compact layer and much spongy 
 bone in the marrow cavity. There was in fact a 
 development of bone poor in lime. The muscular 
 fibres showed degenerative changes. 
 
 There was evidence of a hypertrophy of the 
 cortex supra-renalis and the thyroid was slightly 
 increased. 
 
 In general the follicles of the spleen appeared to 
 be hypertrophied, and simultaneous removal of 
 thymus and spleen in one case was at once fatal. 
 The pancreas was increased. Changes in the hypo- 
 physis were not marked, but in the spinal cord and 
 brain, the changes described by Klose and Vogt 
 were observed. 
 
 In a few cases these changes did not appear, and 
 the author concludes that probably functionating 
 parts of thymus iv. were present, or that a vicarious 
 action of other endocrinous structures had masked 
 the symptoms. Seiler examined the blood, and the 
 changes described by him were not very pro- 
 nounced. 
 
 Transplantation of the thymus was successfully 
 tried by Basch to prevent the onset of symptoms 
 after removal of the thymus. He found that grafts in 
 the abdominal cavity survived, but that those placed 
 under the skin were absorbed and had no effect. 
 More recent work on the subject has yielded no 
 results of importance. 
 
ii8 REGULATORS OF METABOLISM 
 
 The injection of extracts of thymus into the blood 
 stream was found by Svehla to cause a marked fall 
 of blood pressure. But since a similar fall occurs 
 with many other tissue extracts it is of little signifi- 
 cance. 
 
 Feeding with thymus in thymusless animals was 
 tried by Klose and Vogt in their dogs, but it 
 produced diarrhoea and an aggravation of the 
 symptoms. 
 
 Recently Gudernatsch has described experiments 
 of feeding tadpoles upon thyroid and upon thymus, 
 and he finds that the former arrests growth and pro- 
 duces rapid development, while the latter has the 
 opposite effect and causes the tadpoles to grow to 
 a great size without undergoing metamorphosis. 
 These observations seem worthy of repetition and 
 extension. 
 
 Relation to the Gonads. The thymus has a very 
 definite relation to the gonads. It has been for 
 long known to butchers that the thymus of bullocks 
 is larger than that of bulls. Henderson, at my sug- 
 gestion, made a careful investigation of this question. 
 He finds that the thymus of castrated cattle is nearly 
 double the size of that in uncastrated and that its 
 atrophy is delayed. 
 
 I have confirmed these results in guinea-pigs. 
 
 But the converse also holds, I found that in 
 young thymusless guinea-pigs, before the period 
 of sexual maturity, the growth, of the testes was 
 usually more rapid than in normal animals. After 
 
THE THYMUS 119 
 
 the onset of sexual maturity at 300 gr. weight no 
 difference was observed. 
 
 
 Thymusless. 
 
 Normal. 
 
 
 Average 
 
 body 
 
 weight. 
 
 Averse 
 
 weight of 
 
 testes. 
 
 Average 
 
 body 
 weight. 
 
 Average 
 
 weight of 
 
 testes. 
 
 Under 200 gm. 
 
 165 
 
 0.23 
 
 152 
 
 0.18 
 
 „ 300 gm. 
 
 256 
 
 0.88 
 
 252 
 
 0.60 
 
 Over 300 gm. - 
 
 330 
 
 1.24 
 
 322 
 
 1-33 
 
 An increase in the size of testes and ovaries is 
 also recorded by Klose and Vogt in dogs, although 
 in their table they seem to have confused the 
 weights of ovaries and testes. 
 
 At first I was inclined to regard these results as 
 indicating that the thymus and testes had a 
 reciprocal inhibitory action on one another. But 
 it seemed possible that the same changes would 
 result from removal of thymus or testes if each was 
 compensatory to the other, if each exercised an 
 influence on growth and development, and if, when 
 one was removed, the compensatory increase in the 
 activity of the other led to hypertrophy. To test 
 this, thymus and testes were removed in a series of 
 young guinea-pigs, and it was found that, while 
 removal of one or other caused no delay in the rate 
 of growth, removal of both sets of organs simul- 
 taneously caused a marked delay in the gro>yth. 
 
 In the female I have been unable to detect any 
 reciprocal relationship between thymus and ovaries. 
 
 It may, therefore, be concluded that the thymus 
 like the gonads, in the male at least, exercises an 
 
I20 REGULATORS OF METABOLISM 
 
 influence on the rate of growth. Possibly at a very- 
 early age, before the testes have attained their full 
 influence on the metabolism, this is more dominant ; 
 and it may persist longer in some animals than in 
 others. Hence possibly the more marked symptoms 
 recorded in the dog than in the guinea-pig after 
 removal of the thymus. 
 
 Mors Thymica. Sudden deaths in apparently 
 healthy children and adults occur, sometimes when 
 under an anaesthetic, without any manifest cause of 
 death being discovered upon post-mortem exam- 
 ination. In some of them an abnormally large 
 thymus is found. These cases led to the theory that 
 the enlarged thymus was the cause of death — that 
 there is a mors thymica. At first it was supposed 
 that the action of the thymus is a mechanical one, 
 and that the enlarged gland produces its effect by 
 pressing on the trachea, or on the heart, or on the 
 great nerve trunks of the neck. The last explana- 
 tion was supported by reference to the old observation 
 that a spasm of the larynx and a condition of asthma, 
 is sometimes associated with a voluminous thymus. 
 Matti considers the evidence as regards the possible 
 mechanical action of the thymus in compressing sur- 
 rounding organs, and comes to the conclusion that 
 pressure of an enlarged thymus, especially on the 
 vessels, may be a factor in causing death. 
 
 Another theory has been put forward, that the 
 condition may be caused by an abnormally large 
 production of the internal secretion of the thymus. 
 
THE THYMUS 121 
 
 But no evidence is forthcoming, and until we know 
 far more than we do at present about the action of 
 the products of the thymus, we are not warranted in 
 accepting such a pure speculation. 
 
 In fact, the evidence does not point at all clearly 
 to the thymus as being the cause of these deaths. 
 Many cases of sudden death occur without enlarge- 
 ment of the thymus having been observed. 
 
 But there is some evidence that a certain number 
 of individuals show a peculiar anomaly in develop- 
 ment, characterised by an excessive growth of the 
 lymph tissue throughout the body and of the cortex 
 of the thymus, with, at the same time, other anom- 
 alies of growth and metabolism. In these people 
 subcutaneous fat is generally excessive ; the repro- 
 ductive organs are small and remain infantile in 
 type ; the hair, and especially the pubic hair, does 
 not grow. The older physicians described this 
 condition as the lymphatic temperament, and recog- 
 nised that the vitality is low. 
 
 Wiesel tried to divide such individuals into a 
 true thymus class with hypertrophy of the thymus — 
 more especially of its reticulum — and no marked 
 change in the lymph tissue elsewhere, and a true 
 lymphatic class in a number of which the thymus is 
 not affected. 
 
 It would rather seem that such individuals show a 
 condition of imperfect development, in which the 
 various ductless glands participate. There may be 
 in fact an insufficiency of several endocrinous 
 
122 REGULATORS OF METABOLISM 
 
 structures. Whether on account of this or on 
 account of the general imperfect development, they 
 are more easily killed than others, and hence they 
 are more liable to sudden death from comparatively 
 small disturbances. The condition of their thymus 
 gland has probably nothing to do with the fatal 
 issue, and the term thymus death may be considered 
 a misnomer. 
 
 Summary. We have thus seen that the thymus 
 is formed as epithelial outgrowths from the third 
 and fourth branchial arches ; that these outgrowths 
 form a branching network, at some places concen- 
 trated into masses of cells which degenerate and 
 form the corpuscles of H assail ; that the network 
 becomes filled up with lymphocyte-like cells which 
 are either true lymphocytes migrated from without 
 or which are formed from the epithelial cells. In 
 every animal the thymus reaches its greatest weight, 
 relative to the weight of the body, either at the 
 time of birth or shortly after this, and about the 
 age of puberty it ceases to grow and begins to 
 atrophy. " Accidental " atrophy may also occur in 
 malnutrition. Removal of the thymus from young 
 dogs, in which animals it attains its greatest weight 
 in relationship to the body weight, leads to a definite 
 train of symptoms — imperfect growth and defective 
 calcification of bone, deposit of fat with subsequent 
 wasting, instability of the central nervous system — 
 with tremors or convulsions, and increase in the elec- 
 trical reactions of the nerves, followed by advancing 
 
THE PARATHYROIDS 123 
 
 decrease of functional activity of the upper neurons. 
 Death finally supervenes. The condition is accom- 
 panied by compensatory hypertrophic changes in the 
 testes. The conclusion is drawn that the thymus pro- 
 duces an internal secretion which exercises a marked 
 influence upon development and growth, but that its 
 removal may be in part compensated for by the 
 internal secretion of the testes in the male. The 
 secretion also acts upon the central nervous system, 
 increasing the stability of the reflex arcs (Fig. 6). 
 Evidence is wanting as to whether its action on meta- 
 bolism is directly upon the tissues or through the 
 peripheral nervous mechanism. The condition 
 known as mors thymica has been discussed, and 
 reasons for considering the term a misnomer have 
 been given. 
 
 II. THE PARATHYROIDS. 
 
 These structures, small yellowish bodies lying in 
 close relationship to the thyroid, were first described 
 by Sandstroem in 1888. 
 
 Origin and Development. Like the thymus, they 
 are formed from epithelial outgrowths from the 
 third and fourth branchial clefts, but from the dorso- 
 cranial aspect instead of from the ventral (Fig. 3). 
 Another small cystic outgrowth from the side of the 
 fourth cleft forms the post-branchial body. 
 
 The outgrowth from the third cleft, parathyroid 
 III. or the lower parathyroid, lies free of the thyroid 
 in all animals and in man at the aboral pole. That 
 
124 REGULATORS OF METABOLISM 
 
 rom the fourth cleft, parathyroid iv., in many- 
 animals comes to lie inside the thyroid, but in man 
 it lies on the upper dorsal surface, and it may be 
 called the upper parathyroid. 
 
 As already mentioned, Pepere describes a develop- 
 ment of parathyroid tissue inside of the thymus — 
 specially well marked in the rabbit. According to 
 Harvier and Morel it is also present in the cat. 
 Accessory parathyroids may be present at different 
 parts of the neck. 
 
 Structure. Each consists of a fibrous tissue frame- 
 work with columns of cells occupying the spaces. 
 These cells are of two kinds: (i) Chief cells, polygonal 
 in shape with a protoplasm not readily stained and 
 with nuclei staining deeply ; (2) Oxyphil cells, 
 smaller than the last and with a granular protoplasm 
 staining with eosin. In some places towards the 
 margin there may be masses of colloid surrounded 
 by oxyphil cells. It is the increase in this colloid 
 which in certain conditions gives the parathyroids 
 the appearance of thyroid tissue. 
 
 Position. In such carnivores as the dog and cat 
 parathyroid iii. lies outside the thyroid at its upper 
 end, while parathyroid iv. is embedded in the organ 
 or lies closely upon it. 
 
 In the sheep and goat, parathyroid iii, is at a 
 considerable distance from and above or in front of 
 the thyroid, while parathyroid iv. is embedded 
 in it. 
 
 In the rabbit, parathyroid in. lies below the thyroid 
 
THE PARATHYROIDSl 125 
 
 (about I cm.), while parathyroid iv. is inside it. In 
 birds the parathyroid lies behind, aborally, to the 
 thyroid. 
 
 The positions and relationship of the parathyroids 
 to the thyroid are important, because these structures 
 may be removed to a greater or less extent when the 
 thyroid is excised. Hence symptoms due to para- 
 thyroid removal were at one time ascribed to removal 
 of the thyroid. 
 
 Physiology. — Removal. Sir Astley Cooper in 1824 
 experimented with dogs, and found that removal of 
 the thyroid was fatal. He of course also removed 
 at least two, probably all, the parathyroids. Schiff 
 in 1856 got a similar result. Weiss in 1880 was the 
 first to describe the onset of muscular spasms after 
 thyroidectomy and to recognise the resemblance of 
 the symptoms to tetany. 
 
 After the introduction by Billroth of the operation 
 of thyroidectomy for goitre, J. and A. Reverdin and 
 Kocher in 1882-83 independently described symp- 
 toms of tetany in some cases after thyroid removal. 
 
 Gley in 1890 showed that generally in herbivora 
 these nervous symptoms do not occur unless the 
 parathyroids, lying some way from the thyroid, are 
 removed along with it. 
 
 Apparently ignorant of Gley's work, and failing 
 to recognise the significance of Sandstroem's obser- 
 vations, Horsley in 1891 described as one of the 
 effects of removal of the thyroid in monkeys a 
 peculiar muscular tremor. 
 
126 REGULATORS OF METABOLISM 
 
 In 1896 Vassale and General! were able to show- 
 that removal of the parathyroids in dogs induced 
 tetany, while removal of the thyroid alone produced 
 a peculiar cachexia. This has been confirmed by 
 many subsequent observers. 
 
 The symptoms produced vary with the amount of 
 parathyroid tissue which is removed. The acute 
 form may be seen in dogs and cats, when both 
 thyroid and parathyroids are excised. There is 
 generally a latent period of twenty-four to seventy- 
 two hours during which marked thirst and loss of 
 appetite may manifest themselves. This is followed 
 by fibrillar twitching of individual muscles of the 
 face, head, back and tail. After twenty-four hours 
 these become more severe and more frequent. 
 In the cat a stretching out of one leg and a 
 shaking of the foot as if to remove water is often 
 seen. The gait is stiff, with tonic cramps, and a 
 peculiar clubbed position of the foot. Clonic spasms 
 appear and become more frequent. The animal 
 rapidly wastes and dies within ten days. 
 
 In rabbits the symptoms are well marked, and are 
 sometimes produced in a modified form even by 
 removing the two external parathyroids, while in 
 some old rabbits all the parathyroids along with 
 the thyroid may be removed without symptoms 
 appearing. But in these cases, Haberfeld and 
 Schilder found that subsequent removal of the 
 thymus produced the symptoms — probably because 
 of the removal of the embedded parathyroid tissue. 
 
THE PARATHYROIDS 127 
 
 Generally speaking, removal of more than two 
 parathyroids leads to symptoms of tetany, which 
 may be acute or chronic. 
 
 Gozzi describes a series of partial and of complete 
 removals of the parathyroids in dogs. Total removal 
 produced death within five days, but when supple- 
 mentary parathyroid nodules existed, life was pro- 
 longed for from nine to twenty-three days. Total 
 thyro-parathyroidectomy he found to be less rapidly 
 fatal than complete removal of the parathyroids alone. 
 After total removal of the thyroid, leaving the 
 external parathyroids, the animals lived for months. 
 
 Sometimes after two or three parathyroids have 
 been removed, a condition of latent tetany is developed. 
 The animal is free of symptoms, and these may 
 not become manifest till pregnancy or lactation 
 supervenes. Pepere emphasises the point that the 
 symptoms are more severe in pregnancy. 
 
 Iselin states that the young of rats, on which 
 parathyroidectomy had been performed, showed 
 increased muscular excitability to the electric cur- 
 rent, and suffered very acutely from parathyroid- 
 ectomy — dying within a few hours of the opera- 
 tion. 
 
 As regards the part of the neuro-muscular 
 mechanism involved in the tetany following para- 
 thyroid removal, the evidence points to the spinal 
 cord as the part chiefly affected, since section of the 
 nerves abolishes the seizures in the muscles supplied. 
 Biedl finds that after section of the cord in the dorsal 
 
128 REGULATORS OF METABOLISM 
 
 region, the muscles of the hind limbs undergo sudden 
 contractions, with intervening relaxations, while 
 those connected with the upper part of the cord and 
 brain show a more tonic condition — probably due to 
 an influence of the labyrinths and cerebellum. 
 
 Horsley and Lanz state that, after removal of the 
 cortex cerebri, the condition continues on the contra- 
 lateral side. 
 
 Mustead finds that the tetany is not modified by 
 removal of the cortex cerebri, or by section of the 
 dorsal roots of the spinal nerves, and he concludes 
 that the primary motor neurons are the structures 
 implicated. He also finds that it does not occur 
 below the point of section of the spinal cord, and 
 considers that this indicates that some part of the 
 encephalon below the cortex cerebri is also involved. 
 
 A certain number of animals show no symptoms of 
 tetany after what appears to be complete thyro- 
 parathyroidectomy. In all probability such cases 
 are to be accounted for by the fact that outlying 
 pieces of parathyroid tissue have been frequently 
 observed even as far down as the aortic arch, while, 
 as already stated, Harvier and Morel have shown that 
 nodules may occur in the thymus of the cat, and 
 Pepere finds that a considerable amount may be 
 present in the thymus of the rabbit. These varia- 
 tions in the symptoms may also be due to the fact 
 that removal of the parathyroid reduces the stability 
 of the central nervous system, but that some other 
 disturbing factor, e.g. pregnancy, is required to upset 
 
THE PARATHYROIDS 129 
 
 it sufficiently to cause the manifestation of the 
 symptoms. 
 
 Thompson, Leighton and Schwartz show that 
 ligature, so as to produce a slow interference with 
 the blood supply, may lead to no tetanic symptoms, 
 but that a slow wasting occurs and that the animal 
 dies in a cachectic condition. 
 
 In the human subject, as already stated, tetany 
 has been produced as the result of the removal of 
 parathyroid with the thyroid in the treatment of 
 goitre, and now special precautions are taken to 
 avoid this. Even with these precautions, there is a 
 certain risk that injury to the blood supply of the 
 parathyroids may lead to temporary tetany or to a 
 tetany which may remain latent and may manifest 
 itself if pregnancy supervenes. 
 
 The evidence that the disease of children known 
 as tetany and characterised by the hyper-excitability 
 of the neuro-muscular mechanism, and by more or 
 less marked attacks of cramps of groups of muscles, 
 is due to injury or decreased functional activity of the 
 parathyroids is not definitely proved. Some cases 
 have been reported with haemorrhages into the para- 
 thyroids (Erdheim), but in others no changes were 
 detected. It must be remembered, however, that 
 functional inadequacy is not necessarily accompanied 
 by manifest structural change, and the fact that para- 
 thyroid treatment has relieved a number of cases of 
 tetany indicates the probable association of the con- 
 dition with morbid conditions of these structures. 
 
I30 REGULATORS OF METABOLISM 
 
 Metabolism. In the ordinary acute tetany, after 
 parathyroid removal, symptoms of disturbed meta- 
 bolism have little time to manifest themselves. But 
 in more chronic cases, such as may be produced by 
 gradually ligaturing off the parathyroids, it is found 
 that the animal emaciates, and that the hair becomes 
 rough and falls out. In rats Erdheim has described 
 a peculiar change in the teeth — a want of calcifica- 
 tion of the dentine and enamel which leads to 
 fracture. 
 
 The fact that calcium salts have a depressing in- 
 fluence on the excitability of the neuro-muscular 
 mechanism led to the hypothesis that possibly para- 
 thyroidectomy might produce its effect by decreasing 
 the calcium content of the neuro-muscular mech- 
 anism. 
 
 The experiments of MacCallum and Vogtlin, 
 1908-9, upon dogs seemed to show that removal of 
 the parathyroids caused a decrease in the amount of 
 calcium in the blood, and in the brain. As to the 
 excretion of calcium they say that " on the whole 
 the general impression is . . . that the excretion of 
 calcium salts is increased." They also describe a 
 very great increase in the ammonia content of the 
 blood. Musset and Goodman failed to confirm 
 MacCallum's findings, and von Reuss and Welde 
 got exactly opposite results. 
 
 Jean V. Cooke gives analyses to show that the 
 brains of dogs dying of tetany contain a slightly 
 greater proportion of calcium than do those of normal 
 
THE PARATHYROIDS 131 
 
 dogs. The excretion of magnesium in the urine she 
 finds to be increased, but not the excretion of cal- 
 cium. Her results are thus opposed to those of 
 MacCallum and Vogtlin. 
 
 Leopold and von Reuss investigated the calcium 
 content of the tissues of normal and of para- 
 thyroidectomised rats. In the adult they found no 
 marked difference, but in young animals a decrease. 
 Further, they found that the bones were richer in 
 calcium and the soft parts poorer. They suggest 
 that mere alteration in the combination of calcium 
 may explain the symptoms of tetany. This view 
 receives some support from the influence of injections 
 of citrates in producing muscular spasms, probably 
 from the combination of the calcium ions in a non- 
 ionised condition. One observation which I have 
 made upon a cat with parathyroid tetany, shows that 
 the symptoms are markedly increased by the sub- 
 cutaneous injection of sodium citrate. By removing 
 the calcium from its ionised condition, its influence in 
 controlling the activity of the nerve centres may have 
 been decreased. 
 
 It is probable that the administration of calcium 
 simply acts as a sedative. Berkeley and Beebe 
 find that magnesium and strontium act in the same 
 way. Further, the fact that bleeding, which must 
 still further deplete the body of calcium, decreases 
 the symptoms seems to be opposed to the view that a 
 diminished calcium content is a factor in determining 
 the onset of tetany. The administration of calcium 
 
132 REGULATORS OF METABOLISM 
 
 produces only a temporary amelioration of the symp- 
 toms, but its repeated administration is capable of 
 keeping them in check. 
 
 The protein metabolism, as indicated by the excretion 
 of nitrogen in the urine, after removal of the para- 
 thyroids has been studied by several investigators. 
 
 Musser and Goodman describe a rise in the ex- 
 cretion of total nitrogen — an increased protein cata- 
 bolism — and an increase in the proportion of nitrogen 
 in the form of ammonia. Morel got a similar result. 
 
 More recently J. V. Cooke has confirmed these 
 results. She further finds that the other nitrogenous 
 constituents of the urine are unaltered. In two cases 
 lactic acid was present in the urine at the time of the 
 attacks of tetany. 
 
 It is well known that the administration of am- 
 monia produces muscular tremors and convulsions. 
 But the amount required to do this is large. Massen 
 and Pawlow found that about 2 mg. per hundred 
 c.cm. of blood was necessary to cause twitching. 
 
 Albertoni failed to find any increase in the am- 
 monia content of the blood after parathyroidectomy. 
 And, while MacCallum and Vogtlin describe an in- 
 crease, Carlson and Jacobson record no change, a 
 finding which is confirmed by Greenwald. 
 
 There is thus little evidence of the occurrence of 
 an acidosis, and the appearance of lactic acid in the 
 urine is probably the result of increased muscular 
 action. 
 
 Direct evidence is thus wanting that disturbances 
 
THE PARATHYROIDS 133 
 
 in metabolism are the primary and causal element in 
 the onset of tetany, and it may well be that the 
 withdrawal of the product of the parathyroids estab- 
 lishes the condition of instability in the central 
 neurons which is the basis of the tetany, and may 
 also be the basis of the metabolic disturbances. 
 
 The only evidence against this view is the tem- 
 porary benefit derived from bleeding and transfusing 
 animals in tetany. But the indication this seems to 
 afford of the presence of some poison in the blood is 
 rather negatived by the failure to produce tetany by 
 the injection of the blood of animals suffering from 
 the condition. 
 
 There is some evidence that the parathyroids 
 have an influence on the metabolism of carbohydrates. 
 Partial removal seems to lower the tolerance for 
 sugar so that when given by the mouth or hypo- 
 dermically it tends to appear in the urine. This 
 may possibly mean that the parathyroids act like 
 the pancreas in checking the mobilisation of sugar 
 in the liver, possibly by increasing the storage as 
 glycogen. Further investigations upon this subject 
 are required. 
 
 While the vast majority of investigators have 
 found a definite group of symptoms after para- 
 thyroidectomy, certain observers have failed to get 
 these results. 
 
 Blum got negative results, but his observations 
 were probably not sufficiently carefully carried out. 
 
134 REGULATORS OF METABOLISM 
 
 Swale Vincent and Jolly record a large series of 
 experiments on various species of animals. Some of 
 their results are tabulated below : 
 
 Cats 
 
 Number of 
 observations. 
 
 IS 
 
 Death. 
 10 
 
 Grave 
 symptoms. 
 
 3 
 
 No grave 
 symptoms. 
 
 2 
 
 Dogs 
 Foxes 
 
 5 
 4 
 
 4 
 
 4 
 
 — 
 
 Monkeys 
 
 7 
 
 — 
 
 2 
 
 .s 
 
 They go back to the old theory of Blumenreich that 
 the parathyroids are merely potential parts of the 
 thyroid. They base this conclusion partly on the 
 morphological similarity of thyroid and parathyroid 
 tissue, on the fact that removal of thyroid according 
 to them leads to hypertrophy of the parathyroid 
 and a change to thyroid-like tissue, and on the 
 results of their experiments. Their experiments 
 seem to me to support the work of other in- 
 vestigators who maintain that the parathyroids 
 have an independent action. A very full statement 
 of their views is given in Swale Vincent's Ductless 
 Glands. 
 
 Transplantation of the Parathyroids. This subject is 
 very fully dealt with by Thompson, Leighton and 
 Schwartz. They point out that Eiselberg in 1892 
 transplanted the thyroid gland after thyroidectomy 
 and found that no symptoms occurred, but that, 
 when the graft was removed, tetany occurred. The 
 internal parathyroids were, of course, transplanted 
 along with the thyroid. The same result has been 
 obtained by others. 
 
THE PARATHYROIDS 135 
 
 Of those who have attempted to transplant the 
 parathyroid, many have failed to get any result. 
 Others have found that the graft very soon 
 atrophies, although the symptoms of tetany may for 
 the time be controlled. Biedl, Pfeiffer, Mayer, 
 Halsted, as well as Thompson, Leighton and 
 Schwartz, have succeeded in getting the graft to 
 grow in some cases, and have found that when it 
 was removed symptoms of tetany supervened. 
 Halsted found that the grafts only grew after 
 removal of parathyroids, and that the persistence of 
 very small fragments of .5 x. 2 5 mm. is sufficient to 
 keep a dog alive. 
 
 Kocher records a case in which thyroid alone was 
 transplanted into the medullary cavity of a bone 
 prepared in a special manner and where no 
 symptoms supervened till the bone was removed. 
 
 Thompson, Leighton and Schwartz found that 
 merely trephining the bone checked the onset of 
 tetany, but did not delay the development of 
 cachexia and death. How this acts they cannot 
 explain. The observations should certainly be 
 repeated. 
 
 Eiselberg records the case of a woman who 
 suffered from chronic tetany in whom transplanta- 
 tion was followed by amelioration of the symptoms. 
 
 Administration of Extracts of Parathyroids. MacCallum 
 and Davidson report a case of tetany, after para- 
 thyroidectomy in a dog, in which the symptoms 
 were repeatedly relieved by intra-venous injection 
 
136 REGULATORS OF METABOLISM 
 
 of an emulsion of parathyroids of as many as twenty 
 to thirty dogs. The symptoms recurred and were 
 again suppressed by the same treatment. 
 
 Other observers have got no result on feeding 
 with parathyroid. 
 
 Beebe isolated the nucleo-protein of the para- 
 thyroids and found that it is the constituent 
 which is active in suppressing symptoms of tetany. 
 Its activity is destroyed by heating. Halsted has 
 used the preparation with success in a case of post- 
 operative tetany after two operations on a large 
 colloid goitre, and Pool had a similar result. 
 
 Some experimenters have found that the adminis- 
 tration of thyroid preparations control the symp- 
 toms. Biedl argues that since the thyroid contains 
 about 350 parts of thyroid to one of parathyroid, 
 this result cannot be due to the presence of para- 
 thyroid substance in the preparation. But, since 
 Halsted has shown that so tiny a bit of parathyroid 
 tissue is sufficient to suppress symptoms, this argu- 
 ment loses some of its force. Berkeley and Beebe 
 do not confirm this observation on the beneficial 
 effects of thyroid preparations. Ott and Carlson 
 and Jacobson find the condition benefited by the 
 injection of extracts of the hypophysis. 
 
 Ott has described other actions of parathyroid 
 extracts. In cats he states that they cause increased 
 contractions in the isolated intestine and uterus, a 
 fall of arterial pressure, a marked polyuria — in some 
 cases a tenfold increase in the urine secreted in half 
 
THE PARATHYROIDS 137 
 
 an hour — and the appearance of glucose in the urine. 
 These observations require to be repeated. 
 
 Lundborg (1904) suggested that alteration in the 
 activity of the function of the parathyroids may 
 have a causal relation to various modifications of 
 the neuro- muscular mechanism. Assuming that the 
 parathyroids exercise a checking influence on the 
 activity of the mechanism, he considers that tetany, 
 the laryngismus stridulus that is so often associated 
 with it, myoclonus, paralysis agitans and myotonia 
 may be due to decreased functional activity, while 
 the various forms of myasthenia may be related to 
 an increased activity. 
 
 Influence of Nerves on the Parathyroids. The ques- 
 tion of how far the activity of the parathyroids is 
 controlled by the nervous system has not been fully 
 investigated. Asher, and subsequently Edmunds, 
 have ligatured the superior and inferior laryngeal 
 branches of the vagus of one side, and subsequently 
 removed the opposite lobe of the thyroid with the 
 parathyroids, thus leaving two parathyroids the 
 nerves to which were cut. Symptoms of tetany 
 appeared. Such results seem to indicate that the 
 parathyroids are under the control of the central 
 nervous system. 
 
 Summary. The parathyroids, like the thymus, 
 have been found to develop from the epithelium of 
 the third and fourth branchial clefts. Two definite 
 parathyroids are thus found on each side, but acces- 
 sory parathyroids may also be produced and may exist 
 
138 REGULATORS OF METABOLISM 
 
 in the thymus. The close association of the para- 
 thyroids with the thyroid, and the existence of these 
 accessory parathyroids, has rendered it somewhat 
 difficult to study the effects of removal. Parathy- 
 roidectomy is followed by a definite train of symptoms, 
 of which the most prominent is a condition of 
 instability of the spinal reflex arcs with the occurrence 
 of peculiar spasmodic movements — the condition of 
 tetany — and with an advancing cachexia, which may 
 be present even when the symptoms of tetany are in 
 abeyance. It is possible to remove these symptoms 
 by grafts, while the tetany may be checked temporarily 
 by the administration of calcium or of strontium salts, 
 which depress the excitability of the spinal centres. 
 The influence of parathyroidectomy on the meta- 
 bolism has been discussed, and the conclusion is 
 arrived at that the parathyroids yield an internal 
 secretion which, probably by acting directly upon the 
 spinal centres, or possibly by in some way controlling 
 the metabolism, maintains a checking influence upon 
 the reflexes. The question of whether the metabolic 
 disturbances are primary to the nervous disturbances 
 or mere accompaniments of these is still undecided. 
 
 V. DEVELOPED FROM THE MESOTHELIUM 
 OF THE GENITAL RIDGES. 
 
 I. THE GONADS. 
 
 The gonads, or sex glands, undoubtedly exercise 
 a marked influence on the metabolism, development 
 
THE GONADS 139 
 
 and structure of the body, and most materially 
 modify its activities. It is of interest that they were 
 the first structures experimentally proved to have 
 such effects. Berthold of Gottingen in 1849 re- 
 moved the testes of cockerels and transplanted them 
 into other parts of their bodies, and found that tTie 
 sex characters persisted. He concluded that the 
 testes yield a product which acts on the other 
 organs of the body. 
 
 The gametes or reproductive cells are massed in 
 the gonads. It is unnecessary here to discuss their 
 primary origin ; but the fact that, in such simple 
 forms of animal life as Ascaris, the precursor of the 
 gametic cells can be definitely shown to be separated 
 from the progenitor of the soma cells at the first 
 mitotic division, renders it highly probable that in all 
 more complex forms there is a more or less similar 
 early separation of the two elements, and that the 
 gametes thus live as parasites upon the soma, or, 
 to put it in another way, that the soma develops 
 to support and nourish the gametes, and thus to 
 secure the continuance of the life of the species. 
 Possibly the two might be described as commensals. 
 
 In vertebrates the first manifest differentiation of 
 the gametes from the soma cells occurs on the 
 genital ridge, where certain of the cells lining the 
 ccelom become the progenitors of the gametes. 
 
 Development. The gonads develop in the genital 
 ridge of the embryo by ingrowths of mesothelial 
 cells. 
 
HO REGULATORS OF METABOLISM 
 
 In the male the testis is formed (a) By the arrange- 
 ment of these cells in tubules. In these tubules are 
 the true gametic cells — the spermatogonia, from 
 which the spermatozoa are formed — and the support- 
 ing cell of Sertoli. Recent evidence clearly shows 
 that these have the same origin as the gametic 
 cells, (d) By the intercalation of other cells between 
 the tubules as the interstitial cells of Leydig. Their 
 origin from the mesothelium has not been quite 
 definitely proved. In character they are certainly 
 epithelial. They are large cells containing lipoids. 
 Some observations by Dr. Gemmill on males, made 
 in the course of an investigation on the development 
 of the ovaries in Amphibia, seem to show the meso- 
 thelial origin of these cells. 
 
 In the female the mesothelial cells, which have 
 grown inwards, become arranged in rounded bodies, 
 the Graafian follicles, with the gametic cell, the ovum, 
 in the centre, and the supporting, nourishing or 
 ancillary cells of the zona granulosa round about 
 it. Between the follicles are interstitial cells 
 resembling those of the testes. 
 
 The origin of these interstitial cells has been much 
 debated, and even at the present day it is considered 
 by many as not yet determined. 
 
 The investigations of Louise M'llroy, carried out in 
 this laboratory, leave little doubt, I think, that they, 
 like the follicle cells, are mesothelial cells of the genital 
 ridge, and that they are modified gametic cells. 
 
 She describes the primitive germ cells as first 
 
THE GONADS 141 
 
 differentiating into "capsular cells," the germ epithe- 
 lium, which is protective in function, and "oogonia." 
 These latter form (i) oocytes, (2) capsule cells of 
 the follicles, and (3) interstitial cells or reserve cells. 
 
 The commensal relationship of soma and gametes 
 raises two questions — 
 
 1st. Do the gametes, or the gonads in which they 
 lie, modify the metabolism of the soma ? 
 
 2nd. Does the metabolism of the soma react upon 
 the gametic cells ? 
 
 I. Influence of the Gonads on Development and 
 Growth. — (A) In the Male. 
 
 1. Removal. From a very remote time the effect 
 of castration of young male animals and of boys has 
 been well known. 
 
 The most manifest result is upon what may be 
 called the secondary sex organs and characters, while 
 the whole soma also undergoes changes in meta- 
 bolism and development. 
 
 In mammals the most marked change is in the 
 prostate and seminal vesicles, which cease to develop, 
 and if developed undergo atrophy. The penis does 
 not undergo so marked an arrest of growth, and if 
 developed does not show distinct atrophy. 
 
 As regards the general body characters, the various 
 organs grow, but tend to have an infantile character. 
 In man the supra-ciliary ridges are undeveloped, and 
 the pelvis and larynx are in form like those of the 
 child. The latter condition leads in man to the high- 
 
142 REGULATORS OF METABOLISM 
 
 pitched childish voice of the eunuch. Union of 
 epiphysis and diaphysis is delayed, and the bones 
 tend to be long and slender. The hair development 
 is scanty, especially on the face. There is a tendency 
 to the development of fat often on the buttocks and 
 on the breasts. The temperament is generally phleg- 
 matic. Occasionally fat does not develop, and the 
 individual may be more active. 
 
 In lower mammals the results are much the same as 
 in man. The bones do not grow so markedly in 
 girth, the epiphyseal cartilages persist and the bones 
 are long and slender. The secondary sexual char- 
 acters do not develop. Stags, when castrated young, 
 do not develop antlers. If castrated at the time 
 when antlers should grow, these form a clump or 
 "peruke," and tend to persist instead of being shed 
 annually. If the stag is castrated when the horns 
 are on, these fall off, and next season clumpy, or 
 "peruke," antlers grow. In the prong buck, which 
 has hollow deciduous horns standing straight up, 
 castration leads to the growth of horns bending down- 
 wards and inwards near the eyes. The horn sheath 
 is not shed and becomes composite. In the sheep, 
 castration leads to absence of growth of horns and to 
 the development of the appearance of the female 
 rather than of the male. In the eland, in which both 
 sexes have horns, castration does not stop the 
 growth of the horns in the male. 
 
 Generally speaking, after castration the animal is 
 less active and tends to fatten readily. 
 
THE GONADS 143 
 
 In birds, castration of young cocks leads to non- 
 development of the male type of plumage, of the 
 wattles, and of the characteristic male type of voice. 
 
 In invertebrates the influence of the testes on the 
 soma is sometimes well marked, as is shown by 
 the effects of the destruction of the testes in the 
 spider crab by a parasite, Sacculina. The crab tends 
 to develop female characters, e.g. it grows egg- 
 bearing abdominal appendages. 
 
 In the adult male, removal of the gonads has 
 naturally not the same marked and manifest influence 
 on the morphology of the soma. But upon the 
 general metabolism the influence is distinct although 
 less marked. 
 
 2. Precocious Development of Gonads — Fubertas Frsecox. 
 The influence of the sexual organs on the soma is 
 well seen in cases of pubertas prsecox. A very 
 instructive case is recorded by Sacchi of a boy 
 who had been perfectly normal till five and a half 
 years of age, and who, between that age and nine 
 and a half, showed enormous growth of bones and 
 great muscular development. His voice became 
 deep, and he had a growth of hair on the pubis and 
 on the face. At nine and a half he had a long black 
 beard. The left testicle showed a tumour growth. 
 This was removed, and proved to be an alveolar 
 carcinoma. After this all the symptoms of sexual 
 precocity disappeared. 
 
 In these cases the epiphyses tend to join the dia- 
 physis early, and hence the long bones, and the 
 
144 REGULATORS OF METABOLISM 
 
 whole individual, tend to be shorter. The peri- 
 osteal growth of bone is very vigorous. 
 
 Cases of pubertas prsecox have been associated 
 with tumours and other growths of the cortex of 
 the supra-renal bodies, but these will be considered 
 when dealing with the functions of that structure. It 
 is sufficient to point out just now that the cells of the 
 cortex supra-renalis are developed from cells very 
 similar to those yielding the gametes and interstitial 
 cells on the genital ridge (p. 171). 
 
 Other cases have been described to which tumours 
 of the pituitary body seem to stand in causal 
 relationship to the condition. 
 
 3. Transplantation. The early observations of Ber- 
 thold of Gottingen upon the effect of transplanta- 
 tion of the testes in arresting the disappearance of 
 male characters in young cocks have been already 
 referred to. 
 
 Nussbaum, in 1904, showed that in castrated frogs 
 which, at the breeding time, showed no growth of 
 the grasping thumb- pad on the fore feet and no 
 hypertrophy of the muscles of the fore limbs, the 
 implantation of testicular tissue in the dorsal lymph 
 sac caused the development of these sex characters. 
 These results are fully confirmed by those of 
 Steinach on rats and guinea-pigs. These will be 
 considered later more in detail. 
 
 1 Administration of Extracts. Various investigators 
 have found that the injection of extracts of the 
 testes produces the effects of precocious sexual 
 
THE GONADS 145 
 
 development, that the union of epiphysis and dia- 
 physis of the long bones is hastened and the bones 
 are thus shortened. 
 
 Loewi states that feeding young capons with 
 testicular substance causes the development of the 
 secondary sexual characters. 
 
 Meisenheimer maintains that in castrated male 
 frogs the injection of ovarian extract acts in a similar 
 manner to the injection of testicular extract, causing 
 a distinct if somewhat modified growth of the thumb 
 pads. He holds that the action is not specific, 
 but that the products of both organs are the same, 
 and act to increase the metabolism and to facilitate 
 the development of the somal characters which should 
 normally appear. 
 
 Brown- S^quard, in 1889, recorded results of ad- 
 ministration of extract of testes to himself. He 
 describes an increase in physical strength and mental 
 activity. These conclusions have not been borne 
 out by the work of subsequent investigators. 
 
 5. Involution. In most animals, and very markedly 
 in the human subject, with advancing age sexual 
 activity wanes, and the gonads undergo a partial 
 atrophy. Curiously enough, this is frequently accom- 
 panied by a hypertrophy of the prostate. 
 
 The general vigour and activity of the body 
 diminishes, the skin tends to wrinkle from the de- 
 crease of subcutaneous fat, and the hair may fall out. 
 
 These changes of the soma may, of course, be 
 mere concomitants of the sexual chang.^s, but since 
 
146 REGULATORS OF METABOLISM 
 
 the changes produced by castration are somewhat 
 of the same character, the evidence appears to 
 support the view that the changes in the gonads 
 are primary and at least partly the cause of the 
 somal changes. 
 
 The evidence thus seems conclusive that in the 
 male the gonad, by producing an internal secretion, 
 exercises a direct and specific influence upon the 
 whole soma, increasing the activity of growth, 
 moulding the whole course of development, and so 
 modifying the metabolism, of nerve and muscle that 
 the whole character of the animal is altered. 
 
 Meisenheimer contends against the view that the 
 gonads have this direct and specific action on the 
 development of the soma, and recounts a series of 
 experiments upon lepidoptera, in which the sex 
 organ was removed in the caterpillar stage, and the 
 imago emerged without ovaries or testes, but with 
 the secondary sex organs developed, and with the 
 sex reflexes developed. 
 
 In the face of the mass of evidence clearly pointing 
 to a specific action of the gonads, Meisenheimer's 
 contention that thi#' action is not specific, but is 
 simply one of general stimulation, cannot be sus- 
 tained. The products of the gonads of both male 
 and female probably have a stimulating action on 
 the metabolism, but such an action seems totally 
 insufficient to explain the strikingly specific effects of 
 the products of the two different gonads. 
 
THE GONADS 147 
 
 What is the nature of the action? That it is not 
 through any nervous reflex mechanism is shown by 
 the effects of transplantation and of injection of 
 testicular extracts. It is manifestly through some 
 internal secretion. 
 
 Is this secretion yielded by the testes as a whole 
 or by some special part of the organ ? 
 
 That it is not the gametic cells which determine 
 the development of sex characters has been shown 
 by the experiments of Shattock and Seligmann on 
 sheep and birds. 
 
 They found that ligature of the vas deferens in 
 young animals leads to atrophy and disappearance 
 of the spermatogenic cells, but does not interfere 
 with the cells of Leydig or of Sertoli, and that it 
 does not interfere with the development of the sexual 
 characters. 
 
 Bouin and Ancel have brought forward evidence 
 to show that it is the interstitial cells which are 
 essential. They removed one testis in the rabbit 
 and ligatured the vas deferens of the other testis. 
 They found, first the condition described above, but 
 later, after ten to twelve months, a degeneration of 
 the cells of Sertoli and a marked hyperplasia of the 
 interstitial cells. 
 
 They found that some rabbits, after ligature of the 
 vas deferens, developed characters which accompany 
 castration, and they believed that this occurred when 
 nerves as well as the duct were ligatured, 
 
 Vincent and Coleman found that ligature of the 
 
148 REGULATORS OF METABOLISM 
 
 whole spermatic canal with the blood-vessels acts in 
 the same way as castration. 
 
 The influence of X-rays in destroying the sper- 
 matogenic cells, but leaving the cells of Sertoli and 
 the cells of Leydig intact, was demonstrated by 
 Tandler and Gross in 1898. They experimented on 
 the roebuck, and showed that such secondary sexual 
 characters as the horns persist. 
 
 The evidence thus seems satisfactory that the 
 interstitial cells of the testes produce an internal 
 secretion which profoundly influences the whole 
 development and growth of the body and the habits 
 of the animal. One may use the term suggested by 
 Heape — Gonadin — for their internal secretion, recog- 
 nising that it is different in the male and in the 
 female. 
 
 How far the development of this gonadin is 
 modified and controlled by other structures in the 
 body, such as the thyroid, thymus, inter-renals and 
 pituitary, we shall have to consider in dealing with 
 the inter-relations of the various glands. There is 
 good evidence that each acts upon and is in turn 
 acted upon by the gonads. 
 
 The evidence is thus conclusive that the inter- 
 stitial cells act upon the soma. Do they likewise 
 act upon the gametes ? Upon this further work is 
 necessary. 
 
 Hofmeister, in 1872, noted these cells in the human 
 embryo at four months' gestation, and says that they 
 constitute two-thirds of the whole testes. At eight 
 
THE GONADS 149 
 
 years of age they constitute only one-tenth of the 
 organ, but at puberty they again increase. 
 
 In some animals at certain seasons they are very 
 well developed, and have very much the character of 
 the cells of the cortex supra-renalis, containing fat 
 droplets and yellowish pigment. 
 
 A careful study of the condition of these cells 
 throughout the cestrous cycle of the male mole is 
 recorded by Tandler and Gross. They find that 
 during the breeding season the interstitial cells are 
 displaced by the enlarged tubules, but that after 
 oestrus, as the tubules become reduced, the inter- 
 stitial cells again increase, and reach their maxi- 
 mum just before the onset of the next oestrus 
 period. 
 
 The evil effects of precocious sexual activity in 
 many animals would suggest that in some way 
 the excessive development of the gametic cells 
 IS associated with a withdrawal of the influence 
 of the interstitial cells from the somai to the 
 gametes. 
 
 // would seem from such considerations that the 
 interstitial cells are the connecting link between the 
 som.a and gonads through which they are enabled 
 to react on one another, and through which their 
 several activities are co-ordinated. Their mode 
 of development with the gametes, their undoubted 
 relationship to the growth and development of 
 the soma, and the cyclic change they undergo 
 throughout the cestrous cycle, all point to this 
 
ISO REGULATORS OF METABOLISM 
 
 conclusion. Through their action, the relationship 
 of the gametes to the soma becomes symbiotic 
 rather than parasitic. 
 
 (B) In the Female. The evidence may be dealt with 
 under the same divisions which were adopted in 
 considering the male. 
 
 1. Removal. The evidence afforded by castration in 
 the female is much less abundant than in the male, 
 since the operation is rarely performed before puberty 
 in women, and is not so frequently performed in 
 female as it is in male domestic animals, either 
 mammals or birds. In fowls it is attempted in the 
 making of poulets, but it is never complete. The 
 oviduct is cut so that the eggs are simply shed into 
 the abdomen and absorbed. 
 
 My own observations on guinea-pigs, undertaken 
 to study the influence of castration on the growth 
 of the thymus, show a non-development of the 
 uterus, but no apparent change in the growth of 
 the body. 
 
 Marshall and Carmichael and Louise M'llroyalso 
 record the same change in various mammals. 
 
 Removal or disease of the ovary is apt to be 
 accompanied by somatic changes in the direction of 
 the acquisition of the characters of the opposite sex. 
 Thus, cases have been recorded where hinds have 
 developed horns, and the ovaries have been found 
 diseased. 
 
 In birds, too, atrophy of the ovaries is apt to be 
 followed by the assumption of male plumage. This 
 
THE GONADS 151 
 
 has been recorded in several species, among others 
 in the duck and pheasant. 
 
 It would thus appear that the females, in many 
 species at least, have latent male characters which 
 are suppressed by the ovaries. 
 
 In certain crabs the invasion of the young gonad 
 by parasites of the Bophyridae group destroy these 
 structures. There is then a suppression of the 
 secondary sexual characters. 
 
 The negative results of Meisenheimer in butter- 
 flies have been already referred to (p. 146). 
 
 2. Fubertas Prsecox.. There is not the same evi- 
 dence that pubertas prsecox in the female leads 
 to general changes in the soma so marked as those 
 found in the male. That it is accompanied by 
 development of the mammary gland and by growth 
 of pubic hair is well known. Lucas, quoted by 
 Guthrie, records the case of a girl of seven years of 
 age who had menstruated several times, and who 
 had well developed mammae and pubic hair. A 
 tumour of the ovary resembling a round-celled 
 sarcoma was removed. Menstruation ceased and 
 the secondary sex characters gradually disappeared. 
 
 Whether the condition has the same influence on 
 the epiphyseal union of the long bones, and hence upon 
 the height of the individual as it has in the male, has 
 not been investigated, although gynaecologists express 
 the opinion that in cases of sexual precocity the indi- 
 viduals are usually short. It is of some interest to 
 find that the observations of Westhof (Marburg) on 
 
152 REGULATORS OF METABOLISM 
 
 the age of the first occurrence of menstruation puts 
 it about six months later in tall women than in short. 
 
 
 Brunette. 
 
 Fair. 
 
 Tall 
 
 ly^s 
 
 17.7 
 
 Medium 
 
 17-3 
 
 17.4 
 
 Short 
 
 17.0 
 
 17. 1 
 
 3. Transplantation. Confirmation of the results of 
 castration are yielded by transplantation experiments, 
 among the most satisfactory of which are those of 
 Marshall and Jolly. They showed that ovaries 
 might be removed from dogs and rabbits, and that 
 if part of one were transplanted in some suitable 
 tissue, such as the kidney, all its tissues may survive 
 and that no atrophy of the uterus occurs. Not only 
 so, but ova are formed and oestrus may occur. 
 Similar results are recorded in the human female. 
 Casalis, quoted by Marten, describes a case in which 
 the ovaries and appendages were removed for 
 inflammation, and the left ovary transplanted on the 
 left border of the uterus. Two and a half months 
 after, menstruation was regular. The ovarian body 
 could be felt on examination. 
 
 The cases which have been recorded in which 
 transplantation of the ovary from one woman to 
 another, from whom the ovaries had been removed, 
 was followed by a subsequent pregnancy, are more 
 probably due to incomplete removal of the original 
 ovaries than to successful grafting of the foreign ovary. 
 
 Marshall and Jolly found that homoplastic grafts — 
 i.e. grafts into the same animal — are more successful 
 
THE GONADS 153 
 
 than heteroplastic grafts, and that grafts from nearly- 
 related animals — e.g. sisters — are more successful than 
 from less nearly related. 
 
 The observations of Steinach on rats, in which 
 ovarian tissue was transplanted into young castrated 
 males, seem to show that the ovary exercises a 
 marked influence upon the soma. He found the 
 characteristic slight bony development, the growth 
 of the finer hair of the female, the development of 
 mammae and nipples, and the appearance of two 
 peculiar female reflexes — (i) "The tail erect reflex" 
 and (2) the peculiar kicking guarding reflex to keep 
 the male off before the full development of oestrus. 
 These feminised rats were followed by males as if 
 they were female. 
 
 He states that the interstitial cells alone are suffi- 
 cient to bring about these changes, since all follicle 
 cells in the grafts may atrophy. 
 
 These experiments of Steinach suggest that in the 
 ovaries, as in the testes, the interstitial cells are the 
 structures which play the active part in yielding 
 the internal secretion, and results obtained by Louise 
 M'llroy in this laboratory support this conclusion. 
 
 Apart from Steinach's work, the evidence of the 
 part played by these ovarian interstitial cells is by 
 no means so conclusive as that regarding the cells 
 of Leydig in the testes. 
 
 Bouin and Ancel and Villemin have studied the 
 influence of X-rays upon the ovaries, and state that 
 the follicle cells are destroyed, but that the inter- 
 
154 REGULATORS OF METABOLISM 
 
 stitial cells are increased, and that this condition is 
 accompanied by an atrophy of the uterus similar to 
 that produced by complete ovariotomy. 
 
 Louise M'llroy informs me that in some of her 
 cases of ovarian grafts, with absence of any atrophy 
 of the uterus, all the follicle cells had disappeared 
 and only interstitial cells remained. This appears to 
 bear out Steinach's results. The question certainly 
 requires further investigation. 
 
 II. The Influence of the Gonads on the Course of 
 Pregnancy. With the escape of the ovum from the 
 Graafian follicle, which must precede pregnancy, the 
 follicle undergoes certain changes to form the corpus 
 luteum. 
 
 The old view that a hsemorrhage occurred into the 
 follicle, and that the clot was gradually invaded by 
 the cells of the zona granulosa or theca interna 
 which removed the shed blood, has been disproved 
 by the work of Sobotta on the corpus luteum of the 
 mouse. He shows that haemorrhages do not occur ; 
 and recent work on the human ovary seems to 
 indicate that here too the essential change is a great 
 proliferation of the cells of the granulosa to com- 
 pletely fill and distend the follicle with peculiar 
 luteal cells — large cells containing fat droplets and 
 pigment, and resembling the interstitial cells of *the 
 ovary. When pregnancy supervenes, the corpus 
 luteum undergoes very much more marked develop- 
 ment than when pregnancy does not occur. 
 
THE GONADS 155 
 
 Frankel found that in the rabbit castration early 
 in the pregnancy leads to abortion, and further that 
 the same result might be obtained by destroying the 
 corpora lutea by cauterising. He came to the con- 
 clusion that the corpora lutea exercise an influence 
 in preparing the uterine mucosa for the embedding 
 of the ovum and, pushing the analogy, he maintains 
 that the corpora lutea of menstruation also act upon 
 the uterine mucosa. 
 
 Marshall and Jolly confirm Frankel's results that 
 castration early in pregnancy in rats and dogs leads 
 to abortion. They did not attempt to destroy the 
 corpora lutea, and came to no definite conclusion as 
 to whether the luteal cells are the active part of the 
 ovary. 
 
 One of the most direct pieces of evidence in 
 favour of the influence of the corpus luteum is that 
 afforded by Leo Loeb, who found in rabbits and 
 guinea-pigs, that, after ovulation and copulation, im- 
 pregnation being prevented by afterwards ligaturing 
 the Fallopian tube, if the uterine mucosa was 
 irritated by cutting through the wall, growths of the 
 nature of deciduomata — of placental tissue — occurred 
 and persisted for ten days. 
 
 Martin has also produced these in rats in a very 
 interesting manner. Ovulation and oestrus occur in 
 these animals, immediately post-partum. Two to nine 
 days after, without impregnation, the uterus was in- 
 cised, and in some cases deciduomata developed and 
 corpora lutea were found in the ovaries. 
 
156 REGULATORS OF METABOLISM 
 
 Prenant (1898) maintained that the corpus luteum 
 acts by suppressing the ovarian activity and hinder- 
 ing ovulation during pregnancy. In support of this 
 theory is the observation that in the cow, when a 
 corpus luteum persists, oestrus does hot occur. On 
 removing the corpus luteum it does occur. Against 
 this there has been cited the fact that in the mouse the 
 corpus luteum persists into the next pregnancy. But 
 this hardly tells against Prenant's theory, for structural 
 persistence is no proof of functional activity. 
 
 The experiments of Leo Loeb in guinea-pigs give 
 some support to Prenant's theory. He allowed 
 copulation in sixty-three animals to fix the date of 
 ovulation, but afterwards ligatured the Fallopian 
 tubes and so prevented the onset of pregnancy. 
 The formation of corpora lutea was demonstrated 
 by microscopic examination, and it was found that 
 few ovulated within sixteen or eighteen days. In 
 forty-five, he attempted to remove the corpora lutea, 
 and he succeeded in twenty-three. Twenty-two of 
 these ovulated within twelve to sixteen days. 
 
 The fact that in rabbits cestrus may occur during 
 pregnancy has been urged against this view. The 
 condition is so rare as to justify the conclusion that 
 it may be due to abnormal changes in the corpora 
 lutea. 
 
 III. The Infiuence of Gonads on the Mammary Gland. 
 — 1. Development of the Mamma. One of the most 
 characteristic developments in the female is the 
 
THE GONADS 157 
 
 mammary gland. This structure appears in the 
 foetus in both sexes, but while in the male it nor- 
 mally undergoes no development, in the female, at 
 the onset of puberty, it markedly hypertrophies. 
 
 That its growth is connected with the develop- 
 ment of the ovaries is shown by the fact that, after 
 early ovariotomy, it does not occur. 
 
 Further, the enlargement which occurs during 
 oestrus, indicates an ovarian influence. 
 
 2. Milk Secretion. While the action of the ovarian 
 gonadin explains the growth of the gland, the cause 
 of the onset of its secreting activity has proved a 
 more complex problem to solve. 
 
 Starling and Lane-Claypon have experimented 
 on virgin rabbits by injecting extracts of rabbit 
 foetuses, ovaries and uterine mucous membrane, 
 and they found that in certain cases at least the 
 foetal extracts lead to an hypertrophy of the gland. 
 
 This observation has been confirmed by Biedl, 
 by Konigstein, and by others. 
 
 That the placenta yields an internal secretion 
 acting on the glands to stimulate them has never 
 been proved. Hence it must be admitted that 
 the foetus may yield something acting in this way. 
 But the cause of secretion is not explained by this. 
 For secretion becomes active after the expulsion of 
 the foetus and placenta. 
 
 It seems to me that a more probable explanation 
 is that, when the young are discharged, the supply 
 of material, which has hitherto been passing from the 
 
158 REGULATORS OF METABOLISM 
 
 mother to the young, is suddenly left in the maternal 
 blood, and that this — which is practically a fcetal 
 extract — is a stimulant to milk secretion. 
 
 Opposed to the view that an internal secretion from 
 the foetus is the essential stimulus to milk secretion, 
 is the well-known fact that some bitches some weeks 
 after oestrus without impregnation secrete milk. I 
 have seen a fox-terrier bitch suckle pups in this way. 
 
 Again, in some young children, irrespective of 
 sex, secretion of milk may occur. 
 
 That milk secretion is not determined by the 
 ovarian internal secretion seems to be indicated by 
 the observations of Marshall and Jolly, that ovari- 
 otomy late in pregnancy does not interrupt gestation 
 and does not interfere with milk secretion and 
 suckling. 
 
 It is usually stated that the possibility of a nervous 
 reflex being involved is excluded by the observa- 
 tions of Goltz and Ewald that a bitch, with complete 
 transverse section of the cord in the back, can not 
 only become pregnant and bear young but can 
 suckle them. This, however, is no proof of the 
 absence of a spinal reflex. 
 
 Several cases have been reported, both in the 
 human subject and in lower animals, where continued 
 irritation of the nipple by sucking has induced a 
 secretion of milk in virgin animals. 
 
 The only possible explanation of this seems to be 
 that a direct nervous reflex is involved, the only 
 other possible explanation being that the continued 
 
THE GONADS 159 
 
 stimulation with its accompanying vaso-dilatation 
 leads to an increased formation of some internal 
 secretion of the mammary gland which acts as a 
 direct chemical stimulant to milk secretion. 
 
 The action of a nervous reflex by no means 
 excludes the possibility of the action of a chemical 
 stimulant, and in suckling probably both these factors 
 play a part, the chemical products fortifying the 
 nervous action. Hence the great abundance of the 
 milk production in normal lactation where both 
 factors are brought into play. 
 
 IV. Influence of the Gonads on (Estrus. — (A) In the 
 Male. — The enormous hypertrophy of the testes 
 which precedes the onset of oestrus in the male of 
 many species of mammals and birds, and the failure 
 of oestrus to develop after removal of the gonads, 
 clearly indicate that the onset of the condition is 
 determined by increased activity of the testes. 
 What the causal factor of this great cyclic change 
 is we do not know, but it seems primarily to involve 
 the interstitial cells. In birds the testicular change 
 seems to precede any somal change, and before 
 the breeding plumage and the breeding instinct 
 have developed the testes have grown many fold. 
 
 With the growth of the testes the whole character 
 of the bird changes. In fact, birds and mammals 
 with well-marked oestrous cycle undergo a constant 
 transition from the state of the apathetic eunuch to 
 that of energetic manhood. 
 
i6o REGULATORS OF METABOLISM 
 
 (B) In the Pemale. The fact that oestrus occurred 
 in Marshall and Jolly's animals with transplanted 
 ovaries disposes of the neurogenic theory of its 
 onset, and indicates that it is due to a secretion from 
 the ovaries. It supports the evidence afforded by 
 Ewald and Goltz' dog from which the lumbar part of 
 the spinal cord was removed and which still mani- 
 fested " heat " and became pregnant, and it is much 
 more convincing than the observation of Goltz that 
 a bitch with the spinal cord divided in the back 
 developed cestrus and became pregnant, or the fact 
 that Sherrington's spinal bitch showed the regular 
 onset of heat, or Brachet's well-known case of a 
 woman with complete transverse lesion of the cord 
 who became pregnant. 
 
 The enormous growth of the ovaries in animals 
 with a well-marked sexual cycle, as in such birds 
 as the sparrow before the breeding season, taken 
 in conjunction with transplantation experiments 
 proves that the onset of oestrus is determined by the 
 gonads. That this influence is a very profound one 
 is perhaps best seen in birds in which, not only is a 
 special breeding plumage developed, but the extra- 
 ordinary nidifying reflex is produced and the whole 
 character and habits of the bird are changed. But 
 we have as yet no definite knowledge of whether the 
 interstitial cells play the most important part or 
 whether the process is determined by the follicle 
 cells, or whether — which is probable from their com- 
 mon origin — they undergo simultaneous increase. 
 
THE GONADS i6i 
 
 That the maturation of Graafian follicles is not 
 essential to the onset of oestrus has been shown by 
 Marshall, who destroyed the ripening follicles with 
 thermo-cautery without stopping the onset of heat. 
 
 This conclusion is further supported by the fact 
 that bats have their oestrus in autumn when they 
 copulate, but the ova in the follicles do not ripen 
 till spring when they are fertilised. 
 
 V. The Influence of the Gonads on Metabolism. The 
 structural and functional changes produced in animals 
 by variation in the activity of their gonads and by 
 removal of these structures is simply an expression 
 of the altered metabolism which is the basis of every 
 physiological reaction. 
 
 The subject has been chiefly studied in two ways. 
 By the investigation of (a) the effects of castration, 
 (d) the effects of administering extracts of the gonads 
 to castrated animals. 
 
 So far as I am aware no attempt has been made 
 to study the metabolism in the anoestrous and in the 
 cestrous condition of animals, although observations 
 are recorded upon the changes in metabolism in the 
 non-menstrual and menstrual states of women. 
 
 The most general effect of castration is the ten- 
 dency to deposition of fat — although this is not 
 universal. 
 
 Loewi and Richter found a decrease of 14 to 20 
 per cent, in the respiratory exchanges of both male 
 and female dogs after castration, and they state that 
 
1 62 REGULATORS OF METABOLISM 
 
 the administration by the mouth or subcutaneously 
 of ovarian and testicular extracts to these animals 
 raised the metabolism by 30 to 50 per cent., while 
 the administration to normal animals has not this 
 effect. 
 
 Liithje, in one experiment on a dog and one on a 
 bitch, could not confirm this. His work, as well as 
 that of others, affords no evidence that the protein 
 metabolism is modified by the gonads. 
 
 The evidence as regards the influence on the 
 excretion of calcium and phosphorus is conflicting. 
 Neumann and Vas found a decrease on castration 
 and an increase on administering ovarian extract. 
 But Liithje failed to find any changes. 
 
 More work is wanted upon the subject, but the 
 changes, if any, must be so small that day by day 
 observation probably will not reveal them, and com- 
 parisons over periods of at least a week or a month 
 will have to be made. 
 
 The influence upon the calcium and phosphorus 
 metabolism is of moment on account of the possible 
 association of the ovaries with osteomalacia and the 
 reputed benefit of castration in this condition. 
 
 VI. On the Vascular System. The relationship of 
 vascular changes to the sexual functions is very 
 marked and leads to the consideration of whether 
 there is any evidence that these changes are deter- 
 mined or controlled by the products of the glands. 
 
 That dilatation of the vessels of the genitalia is 
 
THE GONADS 163 
 
 directly produced by nervous impulses is shown 
 by the effects of electrical stimulation of the nervi 
 erigentes. 
 
 Simpson and Marshall found that while stimula- 
 tion of the nervi erigentes in the normal dog leads 
 to erection of the penis and ejaculation of semen, 
 stimulation in castrated animals causes compara- 
 tively slight congestion. 
 
 These results support the view that the gonads 
 have an influence in facilitating the action of nerves 
 upon the vaso-dilator mechanism. 
 
 So far, we have considered the influence of the 
 gonads upon the soma. The question now arises, 
 Can the condition of the soma influence the gonads ? 
 
 Two distinct problems are here involved : 
 
 1st. Can the soma so influence the gametes as to 
 determine the sex of the individual into which 
 they will develop ? 
 
 and. Can it influence the growth and maturation 
 of the gonads ? 
 
 1. Influence of the Soma on Sex Determination of the 
 Gametes. The work of older investigators such as 
 that of Born and of Yung upon tadpoles, of Treat 
 upon caterpillars, and of Nussbaum upon the rotifer, 
 hydatina, seemed to give a positive answer and to 
 show that sex might be determined by the nutrition 
 of the body of the parent. 
 
 But careful examination of this work and the re- 
 petition and extension of the investigations have not 
 
164 REGULATORS OF METABOLISM 
 
 afforded confirmation, and tend to show that sex is 
 primarily determined at the time of conjugation of 
 the male and female cells by the character and dis- 
 tribution of the chromosomes, usually of the male 
 cell. 
 
 It has been found that in many classes of insects, 
 in many millipedes, worms and vertebrates, in addi- 
 tion to the ordinary chromosomes, others exist which 
 may be called the :ir-chromosomes. In the female cell 
 they are paired, and, in the process of reduction, one 
 thus lies to each daughter cell. But in the male cells 
 they are unpaired, so that, in the process of reduc- 
 tion, the spermatids are of two kinds, one containing 
 the ^-chromosome, one without it. Impregnation of 
 an ovum by the spermatozoon which contains the 
 ^-chromosome leads to the production of a female, 
 impregnation by that which does not contain an x- 
 chromosome to a male. In this way the propor- 
 tion of males and females produced is equal. 
 
 While this may be taken as a statement of the 
 typical cases of sex determination, the problem may 
 be complicated by the development of other forms of 
 chromosome and by other modifications. But in all 
 these cases the general rule seems to apply, that the 
 predominant factor in the determination of sex is the 
 distribution of chromosomes in the gametes. 
 
 If this is so, the possibility has to be considered, 
 whether there is any evidence that the distribution 
 of chromosomes may be so modified as to produce 
 an alteration in the sex-producing potentiality of the 
 
THE GONADS 165 
 
 gamete. There is considerable evidence in favour of 
 this. 
 
 Thus, in the females of the nematode Rhabdonema 
 nigrovinosum, certain sex cells lose an ;tr-chromosome 
 and become spermatogonia. 
 
 In Pteropods two chromosomes in the cells of one 
 part of the sex gland may experience a decrease, and 
 thus the chromatin, which first possessed a male 
 character, may become female in type. 
 
 Again, after the parasitic castration of the male 
 crab described on p. 143, not only are the somal 
 characters changed, but the gametes develop into 
 ova. 
 
 Such effects upon the alteration of sex poten- 
 tiality by alterations in the chromosomes seem very 
 clearly to indicate that there is no essential and 
 fundamental difference between male and female 
 gametes, and that the one may undergo change into 
 the other. 
 
 These effects upon the chromosomes must be 
 exerted through the protoplasm of the gametic cells, 
 and there is some reason to believe that this may be 
 modified by changes produced in the soma. The 
 effect of low temperature in increasing the propor- 
 tion of males to females in frogs has been recorded 
 by Hertwig. 
 
 It must, therefore, be admitted that, while as yet 
 no positive evidence is forthcoming, there is a prob- 
 ability that the sex determination of the gametes 
 may be influenced by the state of the soma. 
 
1 66 REGULATORS OF METABOLISM 
 
 The progress of parthenogenesis in various inverte- 
 brates throws light upon the question of the influence 
 of the soma on the gametes. In many forms — e.g. 
 aphis, the tree louse, daphnidse, the water fleas, 
 and hydatina, a rotifer — oocytes develop, which 
 form only one polar body and which, without 
 impregnation, develop into another generation of 
 females reproducing in the same parthenogenetic 
 manner. But, in the course of time, eggs are pro- 
 duced in which two polar bodies are formed and 
 which must be fertilised by the spermatozoa. Male 
 forms, bearing spermatogonia, are also produced. 
 Although Weismann has maintained that this 
 variation in the character of the gametes produced 
 is a purely cyclic one, the investigations of a large 
 number of independent observers seem clearly to 
 show that it is modified by surrounding conditions, 
 such as the character of the food supply and varia- 
 tions in temperature which possibly act by modifying 
 the food supply. 
 
 Thus, in a recent paper, Grosvenor and Geoffrey 
 Smith show very clearly that the sexual cycle of 
 Moina rectirostris may be materially altered by 
 external conditions. Normally the female, which 
 results from the impregnated egg, produces in its 
 first brood only parthenogenetic females, but in each 
 succeeding generation, along with parthenogenetic 
 females, ordinary males and females. In this in- 
 vestigation the production of males was taken as 
 a measure of the production of sexual forms, and it 
 
THE GONADS 167 
 
 was found that, by isolating the animals and keeping 
 them at a high temperature, the production of such 
 sexual form was entirely suppressed. Whether this 
 is the result of modified food supply is not decided. 
 But it shows very clearly that some influence, prob- 
 ably acting through the soma, checked the normal 
 development of those forms of ova which produce 
 sexually distinct creatures. 
 
 Agar's observations on Simocephalus veiulus, 
 although not specially undertaken to elucidate the 
 influence of external factors upon the gametes, show 
 that by suitable feeding parthenogenetic reproduction 
 without the appearance of sexual forms (males) may 
 be continued through many generations. 
 
 It may be maintained that these altered external 
 conditions act directly on the gametes. But the fact 
 that such a chemical change can produce a modifica- 
 tion renders it highly probable that changes in the 
 chemical products of the metabolism of the soma can 
 act in a similar manner. 
 
 While recognising that the sex of the offspring is 
 determined by the distribution of chromosomes in 
 the conjugating gametes, it must be admitted that 
 this distribution seems to be capable of alteration 
 through the influence of external conditions, and 
 probably through alterations in the soma, and that 
 the character of the nuclear divisions preceding the 
 development of the ovum into a parthenogenetically 
 developing egg, or into an egg requiring fertilisation, 
 may be modified in a similar manner. 
 
1 68 REGULATORS OF METABOLISM 
 
 2. Influence of the Soma on the Maturation of the 
 Gonads. That the soma acts in this way is shown 
 very strikingly by the influence of feeding in deter- 
 mining the growth of the gonads in bees. From 
 the great number of potential female bees — the 
 workers — a few true functionally active females — 
 the queens — are developed by special feeding. 
 
 The view has sometimes been expressed that a 
 factor in the determination of the onset of the activity 
 of the sexual organs is the nutrition of the soma. 
 The stag, for instance, ruts when the greatest store 
 of fat has been accumulated. But, on the other 
 hand, many animals manifest their sexual activity at 
 a time when the body is poorly nourished. Thus the 
 breeding season of the frog is immediately after 
 hibernation. 
 
 A most striking example of the independence of 
 the development of the sexual organs upon the nutri- 
 tion of the body was brought under my notice three 
 years ago, when a male salmon was sent to me in 
 November with the testes so ripe that the fish had 
 been used for artificial impregnation, and yet the 
 animal had remained in the spawning tank for twelve 
 months without any food, and was reduced to a 
 condition of extreme emaciation. 
 
 In the female, the activity of the ovary may un- 
 doubtedly be stimulated by the condition of the 
 soma. This is well seen in the common experience 
 of the poultry farmers. It is also well known to the 
 sheep breeder that when the ewes have been poorly 
 
THE GONADS 169 
 
 fed at pairing time the proportion of twin lambs 
 is small. 
 
 How far this is a simple nutritional influence upon 
 the gonads is not easily decided. It may be an action 
 through some of the other regulator structures of 
 the body, such as the thyroid, inter-renals or 
 pituitary. 
 
 Summary. We have seen that gonads are formed 
 in the genital ridge by the ingrowth of the meso- 
 thelium, and that the mesothelial cells differentiate 
 into the true gametes, into ancillary cells lying with 
 the gametes in the seminal tubules of the male and 
 in the Graafian follicles of the female, and into inter- 
 stitial cells. 
 
 The effects upon development and growth, of 
 removal, of precocious development, of transplanta- 
 tion, of administration of extracts, and of ligature of 
 the ducts (in the case of the testes) have been 
 described. 
 
 The conclusion has been arrived at that male and 
 female gonads yield an internal secretion which acts 
 upon the metabolism of the body to stimulate it in 
 each sex in a specific manner, and that almost 
 certainly this internal secretion is a product of the 
 interstitial cells. A consideration of the relationship 
 of these interstitial cells to the activity of the gonads 
 has led to the conclusion that they may be regarded 
 as a middleman between soma and gametes, and 
 that it is through them that the soma and 
 orametes influence one another. No evidence has 
 
I70 REGULATORS OF METABOLISM 
 
 been found as to whether this action on develop- 
 ment and growth is directly upon the tissues or 
 through the nervous system. The action of the 
 gonads upon the onset of oestrus and upon the vas- 
 cular system has been described, and the special 
 influence of the interstitial cells has been indicated. 
 In the female the relations of the gonads, and more 
 especially of the special development of the thecal 
 or ancillary cells of the corpus luteum, have been 
 discussed. It has been shown that there is good 
 evidence that the luteal cells yield a secretion which 
 plays an important part in the embedding of the 
 ovum in the uterine mucosa and in the early nutrition 
 of the embryo. The importance of the ovarian 
 internal secretion in determining the development of 
 the mammary gland has been described. On the 
 production of milk secretion the probable influence 
 of the nervous system on the one hand, and of the 
 chemical stimulation resulting from the separation of 
 the foetus from the mother and the accumulation of 
 products hitherto passed out to the foetus, have also 
 received consideration, and evidence has been 
 adduced that both play their part in normal 
 lactation. 
 
 The discussion of the question of whether the 
 soma acts upon the gonads has led to the con- 
 clusion that, while both the determination of the 
 sex potentiality of the gametes and the ripening 
 of the gonads is a cyclic phenomenon depending 
 upon hereditary inertia, there is good evidence 
 
THE INTER- RENAL TISSUE 171 
 
 that both may be modified by the external changes 
 acting through the soma. 
 
 II. THE INTER-RENAL TISSUE. 
 
 Development. Before the definite development of 
 the gonads, an ingrowth of the mesothelial cells on 
 the genital ridge occurs and gives rise to the 
 structures which may best be called the Inter-renal 
 Bodies. 
 
 In fishes these bodies remain separate and 
 independent, but in higher vertebrates they become 
 more closely related to the main mass of chromaffin 
 tissue on each side, which forms the medulla of 
 the supra-renal body, and in mammals they com- 
 pletely enclose this forming the cortex supra-renalis. 
 The cells of this tissue are large with distinctly 
 reticulated protoplasm, and strongly resemble the 
 interstitial cells of the testes and the cells of the 
 corpora lutea of the ovaries. Like these, they contain 
 granules of a lipoid nature which stain red with 
 Scharlach Rot but tend to stain brown with osmic 
 acid. Plecnik states that in sections kept for 
 a long time in Miiller's solution and stained by 
 Weigert's chrom-haematoxylin method, these granules 
 are coloured blue, as are also the fat granules of the 
 interstitial cells of the testes. He says that these 
 granules may be detected in quite young human 
 embryos and that they increase till about the end of 
 the first year. Brown pigment granules are also 
 
172 REGULATORS OF METABOLISM 
 
 found, but these are absent in the embryo and 
 increase as age advances. 
 
 Elliott and Armour have investigated the later 
 stages of the development of this tissue in the cortex 
 supra-renalis of man. They find that it first consists 
 of columns of cells lying closely round blood-vessels 
 and free of lipoid granules. Round the surface of 
 this mass of cells smaller cells develop and in these 
 lipoids make their appearance. At the time of birth 
 the supra-renal body is nearly as large as the kidney, 
 and it consists chiefly of the cells first described. 
 After birth the cells at the surface increase and the 
 original cells degenerate. So far as I am aware, no 
 similar series of changes has been described in any 
 other animal, but the subject requires investigation. 
 
 Structure. In the adult cortex supra-renalis the 
 inter-renal cells are arranged in three zones differ- 
 entiated from one another chiefly by the distribution 
 of the fibrous tissue. The outmost, zona glomerulosa, 
 has somewhat rounded or fan-shaped spaces filled 
 by cells which are generally clear and more free of 
 pigment than the deeper cells. They often show 
 mitosis. The mid-layer, the zona fasciculata, consists 
 of cells with the most typical character of inter-renal 
 tissue arranged in long columns radiating from the 
 centre. The inmost layer, the zona reticularis, is looser 
 and the spaces more irregular. The cells are again 
 clearer and they are less closely packed together. 
 This zone tends to invade the chromaffin tissue of 
 the medulla and to be invaded by it. 
 
THE INTER-RENAL TISSUE 173 
 
 Physiology. The close association of the inter- 
 renal and chromaffin tissue in higher vertebrates led 
 to the formulation of the theory that the former in 
 some way prepares a precursor of adrenalin for the 
 latter. The complete separation of the two tissues 
 in fishes, and the absence of positive evidence of this 
 ancillary action, renders this theory untenable. 
 
 The old view — a view applied at one time to every 
 tissue the function of which was not elucidated — 
 that it acted as a de-toxicating organ, neutralising 
 hypothetical poisons, hardly requires consideration. 
 The fact that the lipoids of the cortex, like lipoids 
 elsewhere, combine with many chemical substances 
 to neutralise their activity is no proof that in the 
 living cortex they act in this way. 
 
 1. JRemoval. The close association of the inter- 
 renals with the adrenal system in all vertebrates 
 above fishes makes it very difficult to study the 
 effect of simple removal of the former, because the 
 latter is so apt to be involved. 
 
 Biedl has taken advantage of their complete separa- 
 tion in fishes to remove the inter-renals of selachians, 
 and he finds that the animal gradually becomes 
 weaker, refuses food and finally dies in fourteen to 
 eighteen days. In one skate, where a piece of 
 inter-renal of about the size of a pea had been 
 unintentionally left, muscular weakness and death 
 did not supervene, and the animal lived for more 
 than four weeks and was finally killed. In this 
 animal, and in four others which died in spite of 
 
174 REGULATORS OF METABOLISM 
 
 small pieces of the inter-renal being left, a re- 
 generative process was found in progress. 
 
 Pettit and Vincent attempted the same operation 
 in eels but did not get these results. Giacomini 
 however has shown that in eels there is not only 
 the posterior inter-renal, which Pettit and Vincent 
 removed, but also an anterior one, which they did 
 not interfere with. The activity of this is probably 
 sufficient to maintain life. 
 
 It has for long been known that complete removal 
 of the whole supra-renal of mammals, unless when 
 well -developed accessory organs exist, leads to death, 
 and Biedl's experiments appear to indicate that, 
 whatever part is played by the central or adrenal 
 part, the cortical or inter-renal part is an organ 
 essential for the maintenance of life. 
 
 2. Transplantation. The results of transplantation 
 of the supra-renals help little in arriving at a conclu- 
 sion as to the mode of action of the inter-renal 
 system. Poll experimented upon rats and found 
 that the inter-renal or cortical part alone survived. 
 But, since in about 50 per cent, of rats accessory 
 inter-renals are present, the fact that the animals lived 
 was no indication that the transplanted cortex 
 was the structure upon which the maintenance of 
 life was dependent. 
 
 Haberer and Stoerk successfully transplanted 
 both parts of the supra-renal. In these cases one 
 supra-renal was left untouched. When it was 
 afterwards removed the animal lived. But upon 
 
THE INTER-RENAL TISSUE 175 
 
 subsequent excision of the successful graft death 
 ensued. Since both inter-renal and chromaffin 
 tissue were present in the graft, no conclusion could 
 be drawn as regards the special action of either. 
 
 3. The injection of extracts of the inter-renals of fish 
 were found by Vincent to be without effect on mice, 
 while injection of the adrenals produced the marked 
 symptoms which follow thfe administration of extracts 
 of the medulla supra-renalis of other vertebrates. 
 
 These ordinary methods of experiment have done 
 little to elucidate the functions of this tissue. The 
 presence of a certain amount of the structure seems 
 to be essential for the maintenance of life, but how 
 it acts we do not know. 
 
 4. Relation to the Gonads. Its relations with the 
 gonads gives a hint as to a possible action. 
 
 The commofi source and the histological simi- 
 larity of the inter-renal cells and the interstitial cells 
 of the gonads have been already indicated. Sub- 
 sidiary masses of inter-renal tissue or inter-renal 
 " rests " are very common, and especially common 
 in the epididymis testis. Kirkbride found such 
 rests in a considerable proportion of the testes 
 examined, eight out of twenty-seven, while Wiesel 
 states that they are present in 76.5 per cent, of the 
 cases examined. 
 
 Marchand has also described them in the broad 
 ligament of the female. 
 
 The recent careful investigation by Kolmer on the 
 changes in the cortex in the guinea-pig throughout 
 
176 REGULATORS OF METABOLISM 
 
 life tends to confirm the close relationship of the 
 structure with the gonads. He describes the supra- 
 renal in young animals of both sexes as the same. 
 "Siderophilous" bodies appear in the cells, and similar 
 bodies are also found in the cells of the corpus 
 luteum, in the interstitial cells of the ovaries of preg- 
 nant and puerperal guinea-pigs, and in the interstitial 
 cells of the testes. 
 
 In the female the cells of the deeper part of the 
 zona fasciculata are loaded with lipoids. 
 
 During pregnancy a breaking down of the sidero- 
 philous cells of the zona reticularis occurs which 
 leads to the escape of pigment and to the formation 
 of spaces. The cells are afterwards regenerated 
 from the periphery where numerous mitotic figures 
 appear, thus recalling the ante-natal changes de- 
 scribed by Elliott and Armour in the foetus. 
 
 Additional work upon these lines throughout the 
 oestrous cycle is urgently required. 
 
 Glynn gives a most valuable account of the evi- 
 dence of the relations of the adrenal cortex to the 
 gonads. From the consideration of the experi- 
 mental evidence and of the large number of cases 
 which he has collected, he concludes that the enlarge- 
 ment of the cortex which occurs during breeding, 
 pregnancy, and after castration, and the small size in 
 deficient sexual development indicate a relationship 
 between the cortex and the sex characters. He finds 
 that hyperplasia in females is associated with diminu- 
 tion of female characters and with the development of 
 
THE INTER-RENAL TISSUE 177 
 
 male characters, and that premature development 
 of sex characters in the male may be associated 
 with tumours of the cortex. 
 
 In children and young women where sex abnor- 
 malities appear, there is usually unilateral malignant 
 tumour formation in the cortex supra-renalis. 
 
 In pseudo-hermaphroditism, abnormalities of the 
 supra-renals, when present, are bilateral, and are of 
 the nature of a hyperplasia or of cortical rests. 
 This probably indicates concomitant abnormality 
 of growth in two structures derived from a common 
 source. 
 
 As Glynn points out, it is possible that the cortex 
 supra-renalis may play a part in determining the 
 growth of the gonads, since it is developed in man 
 at the fourth week of intra-uterine life, while the 
 gonads are not definitely developed till the third 
 month. 
 
 These observations show the close connection of 
 cortex and gonads, but they leave unsolved the pro- 
 blem of the nature of this connection. Whether 
 these structures functionate together, or whether 
 they react on one another, or whether together they 
 act to produce the various manifestations of the 
 sexual cycle, we cannot at present say. 
 
 The consideration of the physiology of the supra- 
 renals cannot be left without a brief reference to 
 Addison s Disease, a condition described in 1855 and 
 associated with destructive lesions, usually tuber- 
 cular, of the supra-renal bodies. 
 
 M 
 
178 REGULATORS OF METABOLISM 
 
 The most marked symptoms are great muscular 
 weakness, gastro-intestinal troubles, emaciation and 
 a curious bronzing which generally begins in patches 
 on the mucous membrane and extends to the skin. 
 
 The muscular weakness and emaciation are 
 probably similar to the condition produced in lower 
 animals on removal of the supra-renals, and, if these 
 are to be associated with loss of cortex as indicated 
 by Biedl's experiments on the skate, we should be 
 inclined to refer the symptoms to loss of cortex 
 from the tubercular lesion. The post-mortem reports 
 on cases are far from satisfactory, some observers 
 describing destruction of the cortex, others of the 
 medulla, most of both. 
 
 There seems little evidence that the loss of 
 medulla has any causal relations to the symptoms, 
 for there is no evidence that adrenalin exercises any 
 tonic effect upon skeletal muscle. 
 
 Summary. The cells of the inter-renal tissue and 
 of the gonads have been found to have a common 
 origin, and the morphological resemblance between 
 the cells of the former and of the interstitial cells of 
 the latter and of the corpus luteum, has been 
 indicated. 
 
 The difficulty of investigating the functions of this 
 tissue apart from the chromaffin tissue, and the 
 way in which Biedl has taken advantage of the 
 complete separation of these tissues in elasmobranch 
 fishes to effect its removal, have been described, and 
 
THE INTER-RENAL TISSUE 179 
 
 it has been seen that Biedl's results point to the 
 inter-renal portion of the supra-renal as being the 
 part which is essential to life, although they give no 
 indication of how it acts. 
 
 The relationship of the tissue to the gonads, 
 the changes described by Kolmer throughout the 
 oestrous cycle, and the co-related changes in the 
 gonads and inter-renals in physiological conditions 
 such as pregnancy, and in various abnormalities of 
 the sexual organs, have been considered. The 
 evidence has been found insufificient to show whether 
 the changes in one tissue are causal to those in the 
 other, or whether they are not merely concomi- 
 tant. The facts recorded suggest the possibility that 
 the cells of the inter-renal tissue are part of the same 
 system as the interstitial cells of the gonads and act 
 with them. 
 
SECTION IV. 
 
 THE INTERRELATIONSHIPS OF THE 
 ENDOCRINOUS GLANDS. 
 
 In the previous sections the action of the various 
 regulators of metabolism, and the way in which each 
 exercises its effects on the development, growth and 
 metabolism of the body have been considered. 
 Evidence has been forthcoming that they interact 
 upon one another. 
 
 The more difficult problem has now to be faced. 
 Is their action so co-ordinated that each produces its 
 proper effect, neither more nor less, in normal meta- 
 bolism and growth ? Is each simply controlled by 
 the nervous system ? Or, do the various structures, 
 through their products, regulate the effects of one 
 another ? 
 
 On these problems the effect of grafts and the 
 administration of extracts seem to afford some 
 evidence. The fact that a graft keeps up the 
 balance between the various endocrinous organs, 
 and prevents any disturbance of the body, is in 
 favour of the view that the interaction is primarily 
 a chemical one so far as the production of the 
 
INTERRELATIONSHIP i8i 
 
 secretion is concerned, and not an indirect one 
 through the nervous system. Although it may act 
 upon other glands through nerve endings^ the activity 
 of the graft itself can be regulated only by the 
 influence of the products of other tissues passing to 
 it in the blood. 
 
 In investigating these questions, the interpretation 
 of the results of removal or disease of one organ 
 on another is often very difficult, because it is not 
 always the same. Thus, while in most cases of the 
 hypothyroidism of cretinism, the anterior lobe of 
 the pituitary is enlarged, cases have been described 
 where no such enlargement was present. Is the 
 evidence of compensatory hypertrophy of the pitui- 
 tary on this account to be rejected.? To my mind 
 these apparently opposing findings in cretins are 
 not an argument against the association. If the 
 compensatory hypertrophy does not occur, the 
 condition of the individual probably is worse than 
 when it does occur. When studying the action of 
 testes and thymus on growth, I found that one 
 guinea-pig in my series, after removal of the thymus, 
 hardly grew at all, although remaining quite well 
 and active. When it died at over four months old 
 it was like an animal about a fortnight old, and the 
 testes were in size and structure those of an animal 
 of the same age. They had undergone no com- 
 pensator-y hypertrophy, as they usually do, and the 
 result had apparently been the arrest of growth which 
 occurs when thymus and testes are removed together. 
 
1 82 REGULATORS OF METABOLISM 
 
 Again, in assessing the functional activity of an 
 organ, the absence of definite structural change 
 cannot be taken as proving the absence of change 
 in activity, while conversely marked structural 
 change may be unaccompanied by change of 
 function. The most profound disturbances in meta- 
 bolism may occur without producing structural 
 alteration. On the other hand, extensive structural 
 changes, especially of the connective tissue frame- 
 work of an organ, may occur without its functional 
 activity being seriously implicated, e.g. in the liver. 
 And the evidence we possess is very clear that each 
 one of these endocrinous structures is more than 
 sufficient to perform its function, and that each has 
 a wide safety limit so that, e.g. one-eighth of the 
 thyroid tissue is sufficient to prevent the onset of 
 symptoms of hypothyroidism, and less than one- 
 fifth of the pancreas prevents the development of 
 diabetes. 
 
 The possible complementary action to one another 
 of these structures creates a further difficulty in 
 investigating their functions. Thus, in some species, 
 in early life the gonads can so effectually com- 
 pensate for the loss of the thymus as altogether to 
 mask the effect of its removal, and the conclusion 
 might thus be arrived at that the thymus has no 
 effect upon growth and development. A similar 
 compensatory action is seen between other structures, 
 e.g. the thyroid and pituitary. 
 
 An alteration in the activity of any one of these 
 
INTERRELATIONSHIP 183 
 
 structures may lead to changes, not only in those 
 it has direct relationships with, but in others with 
 which these associated organs are more especially 
 connected. Thus, decrease in thyroid activity may 
 lead to decrease in the gonads, and this may lead 
 to compensatory hypertrophy of the thymus. It is, 
 of course, also possible that the thyroid and thymus 
 have a direct antagonistic action, and that decrease 
 in thyroid activity may thus lead directly to thymus 
 hypertrophy. 
 
 As yet, the knowledge we possess is all too inade- 
 quate to allow us to formulate with any precision the 
 interrelations of the various endocrinous structures 
 with one another. All we can do is, in a tentative 
 manner, to express the probable interrelations, not as 
 a contribution to permanent knowledge but rather 
 as a guide to further investigation. 
 
 I have endeavoured to reduce this to the form of 
 a series of charts or diagrams. These may well be 
 a grotesque parody of what will ultimately be found 
 to be the relationship of the activities of these 
 organs. They are probably as near the truth as 
 these quaint ancient maps of the Indies with their 
 "here be much gold" scrawled across them which 
 served as the charts of our forefathers, and if, like 
 them, they merely indicate the direction which 
 further investigation should take and suggest lines 
 of attack, they will have served their purpose. 
 
 In dealing with the functions of each of the various 
 structures, its probable relations with others has been 
 
1 84 REGULATORS OF METABOLISM 
 
 considered, but this question will now be more fully 
 dealt with. 
 
 THE GONADS. 
 
 The direct and profound action of the endocrinous 
 secretions of the gonads upon the development of the 
 soma has been considered. Every tissue of the body 
 is played upon by them. 
 
 How far is their action facilitated and how far is it 
 checked by other endocrinous organs .'' 
 
 The tli3rmus undoubtedly supplements the action of 
 the testes. We do not yet know if it acts in the 
 same way as regards the ovaries. It thus seems to 
 exercise a checking action on the growth of the male 
 gonads, and they in their turn act reciprocally upon 
 the thymus. But, as we have seen, they have a 
 common action in stimulating the growth and de- 
 velopment of the tissues, and the hypertrophy of one, 
 caused by the removal of the other, is a compensa- 
 tory hypertrophy (Figs. 4 and 7). 
 
 The action of the thyroid on the gonads is also 
 fairly direct but of another kind. Its removal checks 
 their growth. Castration, however, does not appear 
 to cause any marked change in thyroid activity, 
 although the old observations of Meckel that the 
 thyroid increases during menstruation, and some 
 quite recent work by Engelhorn abstracted in the 
 Zbt. f. Phys. 19 1 3, Bd. 26, p. 1210, suggest some 
 reciprocal action. The action seems, however, to be 
 rather from thyroid to gonad than the reverse. Both 
 
Fig. 4. — To show the prob- 
 able influence of the various 
 endocrinous structures on 
 one another. The following 
 explanations apply to this 
 and to the three succeeding Hyp.(J 
 
 figures. Pitft— • - ^ ^^E^J^"" 
 
 ■ " — = stimulation. "v^ ^>^^^""— -- ^"^1^? 
 
 = inhibition. Vv-.^i:^^^^tl:^ 
 
 The arrow indicates the Th.^^^^^^' ^ ^ ^ - 
 
 direction of action. ^"".^....^^^^ Thm. 
 
 Hyp. = Hypophysis. Pit. = Pituitary. Th. = Thyroid. 
 
 Par. = Parathyroid. Thm.=Thymus. In. =Inter-renal. 
 
 Ch. = Chromaffin System. G. =Gonads. Pan. = Pancreas. 
 
 Art. = Artery. B. =Bone. M. =Mu5cle. 
 
 
 
 t ~: 
 
 ) 
 
 HypT] 
 PitO 
 
 
 
 Th. 
 
 ParT^^v^ 
 
 1 ^c. 
 
 Fig. S' — To show the prob- 
 able mode of action of the 
 
 
 V 
 
 "''■OUver 
 
 various internal secretions on 
 the mobilisation of sugar in 
 the liver. 
 
 
 / 
 
 \ 
 
 
 
 
 M 
 
 CeH^O, 
 
 
 Fig. 6.— To show the prob- 
 able mode of action of certain 
 of the internal secretions upon 
 the spinal reflex arc. 
 
 Fig. 7. — To show the prob- 
 able mode of action of the 
 internal secretions on the 
 growth of muscle and of bone 
 and other connective tissues. 
 The possibility of this being of 
 a vaso-motor reflex mechanism 
 is indicated by lines marked ? . 
 
1 86 REGULATORS OF METABOLISM 
 
 act in stimulating growth, but the action is not 
 identical, as is proved by the different effect of 
 thyroidectomy and of castration upon the carti- 
 laginous growth of bone (Figs. 4 and 7). 
 
 The relation of the pituitary to the gonads is even 
 more direct. Destruction of the pituitary leads to 
 atrophy of the sex glands, while castration causes 
 hypertrophy of the pituitary. The pituitary has a 
 stimulating action on the gonads, but the latter have 
 an inhibitory or checking influence on the former. 
 
 Both have a similar action upon growth, and especi- 
 ally on the growth of the long bones, and the un- 
 controlled action of the pituitary leads to giantism 
 and acromegaly. Its action seems to be checked by 
 the gonads, and possibly the tendency to the increased 
 length of the long bones after castration may be a 
 result of the unchecked action of the pituitary. But, 
 as will be presently shown, other structures also con- 
 trol the action of the pituitary (Figs. 4 and 7). 
 
 That the cortex supra-renalis or inter-renals are 
 closely associated with the gonads is shown by their 
 origin, structure and the association of their mal- 
 formation with abnormalities of the genitals. But 
 how gonads and inter-renals react upon one another 
 is not yet known. I have ventured to suggest that 
 the interstitial cells of the gonads and the cells of the 
 inter-renals are identical, and that they form an inter- 
 mediary between the soma and the gametes and 
 regulate their reciprocal relationship. 
 
INTERRELATIONSHIP 1 8 7 
 
 THE THYROID. 
 
 The relations of the thyroid to the gonads has 
 been already dealt with. 
 
 Its most direct physiological relationship seems to 
 be with the organ of similar origin — the pituitary. 
 Removal of the thyroid leads to hypertrophy of the 
 pituitary, and Gushing finds that in young dogs 
 removal of the pituitary causes hypertrophy of 
 the thyroid (Fig. 4). They thus exercise a mutual 
 checking influence similar to that exercised by the 
 thymus and gonads on one another. Their relation 
 to the soma seems to be similar but not quite 
 identical. Hyperthyroidism does not cause the 
 increased growth of bone and connective tissue 
 which follows excessive action of the pituitary. On 
 the other hand, hypothyroidism causes the decreased 
 development of bone in length, in spite of the com- 
 pensatory hypertrophy of the pituitary. It would 
 almost seem as if their action was co-operative, and 
 that the pituitary is unable to manifest its full 
 adequate effect without the coincident action of the 
 thyroid. 
 
 Observations upon the effects of simultaneous 
 removal of both structures should throw further light 
 upon the relations of each to the growth and 
 development of the body. 
 
 With the thymus the relations of the thyroid are 
 less clear. Boccia states that no change could be 
 found in the thymus, after removal of the thyroid 
 
1 88 REGULATORS OF METABOLISM 
 
 or parathyroid, or both of these structures. The 
 findings as to the influence of removal of the 
 thymus on the thyroid are contradictory. Klose 
 and Vogt describe an hypertrophy, M'Lennan 
 arid others an atrophy. 
 
 The direct effects of hyperthyroidism produced 
 upon the thymus by administering thyroid prepara- 
 tions does not appear to have been directly tried ; 
 but the offspring of guinea-pigs fed with thyroid 
 were found by Hoskins to have the thymus enlarged. 
 The enormous variation in the size of the thymus 
 of guinea-pigs at the time of birth makes definite 
 conclusions upon this point difficult. 
 
 In Graves' disease, generally recognised as a con- 
 dition of hyperthyroidism, hypertrophy of the thymus 
 is very frequent. The theory has been advanced 
 that these two structures antagonise one another, 
 and that when the thyroid hypertrophies in Graves' 
 disease the thymus hypertrophies to check its 
 action. 
 
 The action of these structures on the gonads seems 
 to be in opposite direction ; the thyroid stimulating 
 their growth, the thymus checking it. 
 
 Accepting the results of Basch, and of Klose and 
 Vogt, the action of thyroid and thymus upon the 
 neuro-muscular mechanism is also an opposing one 
 (Fig. 6). Hence it would seem that, at least during 
 the period of growth, a balance has to be main- 
 tained between them in order that the action of 
 each should be kept in check, so that the normal 
 
INTERRELATIONSHIP 189 
 
 activity of the neuro-muscular mechanism should be 
 maintained. 
 
 The experiments on tadpoles, showing that thyroid 
 feeding stimulates development, while thymus feeding 
 stimulates simple growth, also suggest an antagonism 
 between the structures. 
 
 Little evidence is forthcoming as to the relations 
 of the thyroid and parathyroids, and any conclusions 
 must be based upon what is known of the different 
 modes *of action of the two structures. The para- 
 thyroids act upon the nervous system in somewhat 
 the same way as does the thymus, and in this respect 
 they are thus antagonistic to the thyroid. Further, it 
 has been maintained that, while tolerance for glucose 
 is increased by removal of the thyroid when sufficient 
 parathyroid tissue is left, it is decreased if the 
 parathyroids are removed. If this is the case, it 
 also points to an antagonism. Various changes 
 have been described in the parathyroids after 
 removal of the thyroid by Vincent and others. But 
 these, so far as they go, rather point to a compensa- 
 tory hypertrophy than to identity of action. 
 
 The evidence of the relationship of the thyroid 
 and chromafSn system to one another has been con- 
 sidered in an earlier chapter. Hypothyroidism leads 
 to hypo-adrenalinaemia, while, in the hyperthyroidism 
 of Graves' disease, an increase of adrenalin in the 
 blood has been described. The same has been 
 described after the injection of thyroid extracts. 
 Hence it appears that the thyroid secretion acts as a 
 
I90 REGULATORS OF METABOLISM 
 
 stimulant to the chromaffin tissue, increasing the out- 
 put of adrenalin. 
 
 Thyroid extract probably facilitates the mobili- 
 sation of sugar, and hence it seems to act not only 
 as a stimulator of the chromaffin system, but also as 
 a facilitator to the action of the adrenalin produced. 
 This has, in fact, been used as an argument for its 
 action upon the terminations of the true sympathetic 
 system. It remains to be seen if the interesting 
 observation of Eppinger, Falta and Rudinger that, 
 after thyroidectomy, adrenalin has a less effect in 
 causing glycosuria is true. 
 
 On the reciprocal action of the thyroid and 
 hypophysis nothing definite is known. The similarity 
 in the action of adrenalin and hypophysin suggest 
 the possibility of a co-operative action between 
 these structures. 
 
 That the thyroid acts upon the pancreas, the 
 organ which plays so important a part in inhibiting 
 the mobilisation of sugar, is indicated by the 
 frequent occurrence of glycosuria in hyperthyroidism, 
 by the modification in the character of the diabetes 
 produced by the removal of the thyroid along 
 with the pancreas, and by Lorand's observation 
 that removal of the thyroid in a dog, in which 
 pancreatic diabetes has been established, decreases 
 the output of sugar (Fig. 5). The action of the 
 thyroid on the pancreas may be a direct one, as 
 is suggested by the observation that thyroidectomy 
 is followed by hypertrophy of the islets of Langer- 
 
INTERRELATIONSHIP 191 
 
 hans. But such evidence cannot be considered as 
 satisfactory or conclusive. On the other hand, it 
 may be that the influence of both structures on the 
 mobilisation of sugar is exerted through the termina- 
 tions of the true sympathetic in the liver. 
 
 THE CHROMAFFIN SYSTEM. 
 
 The important interaction of the chromaffin 
 system with the thyroid and pancreas in controlling 
 the mobilisation of sugar in the body has been 
 already fully considered. With the other ductless 
 glands no direct relationships have been established 
 (Fig. 5). 
 
 THE PARATHYROID. 
 
 About the relationship of the parathyroids to the 
 other endocrinous structures very little is known. 
 The fact that pregnancy accentuates the symptoms 
 of hypo-pa rathyroidism suggests a relationship with 
 the gonads. But the precise nature of this is not 
 clear. 
 
 The neuro-muscular instability manifested in the 
 muscular tremors which sometimes accompany the 
 activity of the gonads possibly also indicate a relation- 
 ship between these structures and the parathyroids. 
 So far as I am aware, no observations have been made 
 on the effects of removing either of these upon the 
 condition of the other (Fig. 6). 
 
 The theory that they are merely part of the thyroid 
 has been already considered. Morphologically 
 they are of independent origin, and the mere fact 
 
192 REGULATORS OF METABOLISM 
 
 that they undergo changes, with an approach in 
 appearance to thyroid tissue, when the thyroid is 
 removed, does not prove their identity. 
 
 Rudinger has developed the theory that thyroids 
 and parathyroids are antagonistic, and believes that 
 this explains the hypertrophy of each when the 
 other is removed. He refers to the prejudicial 
 effects of administration of parathyroid extracts in 
 hypothyroidism, and to its beneficial effect in Base- 
 dow's disease. He also refers to the observation 
 that adrenalin fails to produce glycosuria after thy- 
 roidectomy, but acts markedly after parathyroid- 
 ectomy, and he believes that the one stimulates 
 the sympathetic to mobilise sugar, while the other 
 depresses it. These observations have not been 
 fully confirmed, and his hypotheses cannot be 
 accepted without reservation (Fig. 5). 
 
 As to the relationship between parathyroids and 
 the thymus, the common origin of the two structures 
 from the epithelium of the third and fourth branchial 
 clefts, and the fact that at first they are alike, and 
 that parathyroids occur in the thymus, are worthy of 
 note. F urther, the observations of Basch and of Klose 
 and Vogt on dogs, seem to show that thymusectomy 
 produces nerve symptoms not unlike those of para- 
 thyroidectomy (Fig. 6). 
 
 It seems at least possible that they may be part 
 of one system, and that the thymus may develop 
 and functionate during the early growth of the body, 
 and that the action of the parathyroids may become 
 
INTERRELATIONSHIP 193 
 
 prominent at a later date. Were this the case, we 
 should expect to find the symptoms of parathyroid- 
 ectomy less marked in very young animals. So far 
 as I know, this is not the case. 
 
 The onset of symptoms resembling tetany in pups 
 after thymus removal, at a time when the thymus 
 has ceased to functionate, suggests the necessity of 
 further investigations of the thymus of these animals 
 for the parathyroid tissue which is present in the 
 rabbit and cat. Matti failed to find it. 
 
 One observation which suggests a possibility of 
 further work is Ott's finding that injection of pituitary 
 checks the tetany of parathyroidectomy. 
 
 THE THYMUS. 
 
 Apart from its relations to the gonads and to the 
 thyroid, the most intimate relation of the thymus 
 appears to be with the parathyroids. More work 
 upon this point is wanted, but it almost looks as if 
 the parathyroids might, after sexual life is reached, 
 take over a great part of the function of the thymus 
 in its controlling influence on the neuro-muscular 
 mechanism. No examination of the parathyroids in 
 cases of early thymusectomy have, so far as I am 
 aware, been recorded. 
 
 It is manifest that our knowledge of the inter- 
 relations of the endocrinous glands to one another is 
 still very imperfect, but that this interaction is a 
 matter of great importance in the regulation of 
 
194 REGULATORS OF METABOLISM 
 
 metabolism. A large field of work is open to the 
 physiologist, and results of interest should be ob- 
 tained by the simultaneous removal of pairs of 
 organs supposed to be related to one another. 
 
SECTION V. 
 
 THE RELATIONS OF THE ENDOCRINOUS 
 STRUCTURES AND THE NERVOUS SYSTEM. 
 
 In the consideration of the functions of the endo- 
 crinous structures, it has been shown -that certain of 
 them at least are to some extent controlled by the 
 nervous system, and that some exercise their func- 
 tions by acting through the nervous mechanism. 
 
 It is now necessary to summarise the evidence as 
 regards the interaction of the two sets of structures, 
 and to attempt to arrive at some conclusion as to how 
 far they are dependent upon, or independent of, one 
 another. 
 
 While there is no reason to believe that the activity 
 of the nervous system cannot go on apart from the 
 action of internal secretions, there is no doubt that 
 these have a material effect upon many nervous 
 responses. This is strikingly exemplified by the 
 influence of hyper- and hypothyroidism on the 
 reflex responses of the central nervous system. It 
 is also shown by the activation of the vagus ter- 
 minations in the heart by iodothyrin and iodo- 
 thyreoglobulin, by the facilitation in the action of the 
 
196 REGULATORS OF METABOLISM 
 
 hypogastric nerves on the uterus by hypophysin, and 
 by the action of adrenalin upon the neuro-cellular 
 junction of the true sympathetic system. Even that 
 purest example of nervous action — the stimulation of 
 skeletal muscle by a motor nerve — is modified by the 
 presence of the products of muscular activity — by 
 chemical products which resemble in their nature the 
 more typical internal secretions, 
 
 The Influence of the Nervous System on the Endo- 
 crinous Glands. That the nervous system influences 
 the output of adrenalin and probably of iodothyreo- 
 globulin has already been indicated (pp. 55 and 86). 
 How far it may modify the production of other 
 internal secretions is not known. But, while the 
 functional activity of grafts indicates that the pro- 
 duction of the secretions is not entirely dependent 
 upon nerve impulses, it is very possible that future 
 research will show that the production of many 
 secretions is controlled by the nervous system. 
 
 The Influence of the Internal Secretions on the 
 Nervous System. Evidence has already been adduced 
 to show that some of the internal secretions act 
 through the nervous system. 
 
 As regards adrenalin this evidence is conclusive. 
 It is through the terminations of the true sympathetic 
 system that all its effects are produced. Whether 
 it directly stimulates these, or whether it simply 
 sensitises them to the influence of the sympa- 
 thetic nerves, is not at present decided, but the 
 
RELATIONS OF REGULATORS 197 
 
 evidence seems to point to the second hypothesis 
 
 (P- 57). 
 
 The very conclusive character of the evidence that 
 adrenalin acts through the terminations of the true 
 sympathetic system, renders it probable that its action 
 upon metabolism is due to its influence upon the 
 nerve terminations of the liver. Cavazzani long ago 
 showed that stimulation of the splanchnic nerve to 
 the liver increases glycogenolysis, and the more 
 recent work of M'Leod shows that stimulation of 
 the hepatic plexus leads to this only when the 
 adrenals are intact. 
 
 The fact that adrenalin produces its effect after 
 section of the splanchnic nerves indicates that its 
 action is peripheral, and the antagonistic action of 
 ergotoxin and adrenalin in the production of gly- 
 cosuria, described by Miculicich, supports the view 
 that in the liver, as elsewhere, the action is on nerve 
 endings. 
 
 Hypophysin, as shown by Dale, acts at a point peri- 
 pheral to that acted upon by adrenalin, since its 
 activity is not modified by ergotoxin. But this does 
 not prove that its action is upon the contractile sub- 
 stance of muscle fibre, for, as Langley has shown, 
 the neuro-muscular junction is a more complicated 
 structure than was at one time supposed. Further, 
 the difference of its action on the arterioles of the 
 bird and of the mammal, the difference of its action 
 on the pregnant or recently pregnant and on the 
 virgin uterus, and the peculiarity of its action on 
 
198 REGULATORS OF METABOLISM 
 
 the renal as contrasted with the other arteries of 
 the body (p. 67), all indicate that it acts upon 
 something outside the contractile substance, upon 
 something more nearly allied to the nerve endings. 
 The only evidence which seems to tell markedly 
 against this view, and which seems to indicate that 
 pituitary may act upon muscle apart from nerve, is 
 my observation of its augmentor action on the 
 ventricles of the heart of the bird from which 
 augmentor nerves are absent (p. 45). But the 
 absence of the influence of extrinsic augmentor 
 nerves does not disprove the existence of a local 
 nervous mechanism. 
 
 The close similarity of the action of hypophysin 
 to that of adrenalin upon carbohydrate metabolism 
 (p. 68) suggests that it too acts upon the neuro- 
 cellular junctions in the liver. But upon this point 
 no direct experimental work has been done. 
 
 The action of the products of the thsrroid gland 
 upon the nervous system is well established, Its 
 influence upon the brain and cord is shown by the 
 marked differences in the condition of the activity 
 of these structures in hypo- and in hyperthyroidism. 
 Nothing could be more marked than the contrast 
 between the response to stimuli in a case of Graves' 
 disease and in a case of myxoedema. That the 
 central synapses are influenced, no one can doubt. 
 
 The effect of thyroid removal upon the mobilisa- 
 tion of sugar (p. 79), and upon the action of adrena- 
 lin upon this mobilisation, indicates that both 
 
RELATIONS OF REGULATORS 199 
 
 structures act upon the same mechanism, and that 
 therefore, in all probability, the thyroid secretion 
 produces its effect upon glycogenesis by stimulating 
 the terminations of the true sympathetic in the liver. 
 
 Similar evidence is afforded by the results of 
 Asher and von Rodt upon the activation of the 
 splanchnic terminations by thyroid extracts (p. 83). 
 Loewi's observation that adrenalin in the con- 
 junctival sac produces its mydriatic effect in the 
 hyperthyroidism of Graves' disease also indicates 
 an action upon these terminations in the iris. 
 
 Further, the evidence adduced by von Cyon and 
 by Asher and von Rodt indicates that thyroid 
 secretion also acts upon the inhibitory vagal ter- 
 minations and upon the depressor reflex mechanism. 
 
 Direct evidence as regards its mode of action on 
 protein metabolism is wanting ; but the indications 
 that the influence upon the carbohydrate metabolism 
 is through the peripheral nervous mechanism of the 
 liver, renders it probable that the action upon proteins 
 is at the same site. For the close association of 
 protein catabolism with the formation of sugar is 
 now recognised, and the relationship of the liver to 
 the process is undoubted. The interesting observa- 
 tion by Mansfeld (p. 79), that the increased excretion 
 of nitrogen which usually follows deprivation of 
 oxygen does not occur after thyroidectomy, shows 
 how close the association of the thyroid is with 
 protein catabolism. It would almost seem as if 
 its influence on the liver was necessary to enable 
 
200 REGULATORS OF METABOLISM 
 
 that organ to respond to the acidosis of mal- 
 oxygenation in order to catabolise the disintegrated 
 protein for excretion. As already stated, Mansfeld 
 takes another view of the mode of production of the 
 effect, a view which hardly seems to explain the facts 
 of the case. 
 
 While the features of hyperthyroidism point so 
 clearly to the implication of the nervous system, the 
 disturbances in growth in hypothyroidism, as exem- 
 plified in cretinism and myxcedema, suggest the 
 possibility of an action apart from nerve. The 
 stunted growth with the associated bone changes 
 and the low temperature might be due to a general- 
 ised action upon the tissues. But the evidence 
 already adduced (p. i8) of the influence of the 
 nervous system upon the development and nutri- 
 tion even of such tissues as bone shows that 
 these effects may be produced through an action 
 upon nerve, possibly of the nature of a vaso-motor 
 reflex (Fig. 7). 
 
 The close correspondence of the thyroid and of the 
 true pituitary as regards their origin, and as regards 
 their mode of action on the metabolism, renders it 
 probable that they produce their effects by operating 
 through a common structure. But no observations 
 are at present forthcoming as to how the pituitary 
 acts. 
 
 The internal secretion of the pancreas has been 
 shown to check the mobilisation of sugar which is. 
 facilitated by adrenalin, and less markedly perhaps. 
 
RELATIONS OF REGULATORS 201 
 
 by products of the thyroid. The evidence that these 
 latter act upon the terminations of the true sym- 
 pathetic to produce their effect has been already 
 considered, and it seems probable that the secre- 
 tion of the pancreas acts upon the same structures 
 in the opposite direction, inhibiting their activity 
 
 (Fig. 5). 
 
 The observations of Loewi, that, in the diabetes 
 which follows excision of the pancreas, the action of 
 adrenalin on the pupil is increased, suggests the 
 probability that this inhibitory action of the pan- 
 creas extends beyond the liver to other sympathetic 
 terminations. 
 
 The action of secretin on the pancreas was assumed 
 by Bayliss and Starling to be a direct one on the 
 cells, because it occurred after the administration of 
 atropine. But the more recent work of Cushney 
 tends to show that the blocking action of atropine 
 does not apply to every stimulus acting upon the 
 nerve. On the uterus it does not interfere with 
 the effect of stimulation of the hypogastric nerve or 
 with the action of adrenalin, while it antagonises 
 pilocarpine. The work of Magnus on the gut also 
 shows that it is not safe to conclude that the action 
 of the nervous mechanism is excluded by atropine. 
 A study of the influence of nicotine on the action of 
 secretin might yield valuable results. 
 
 The parathyroids and thymus have been already 
 linked together on account of the similarity of their 
 origin and on account of certain correspondence in 
 
202 REGULATORS OF METABOLISM 
 
 their physiological actions. The results of many 
 investigators on the parathyroids, and of Basch and 
 Klose and Vogt on the thymus, show that removal is 
 followed by instability of the central nervous system 
 {pp. 125 and 1 14). Both seem to exercise a depress* 
 ing or regulating effect on the spinal synapses, an 
 action opposite to that of the thyroid. The question 
 of whether this is primary, or whether it is not the 
 result of metabolic changes, has been already dis- 
 cussed, and reasons have been given for rejecting 
 alike the theory of the decrease in the calcium of the 
 tissues and of the increase of ammonia in the blood 
 as factors in the production of the symptoms of 
 parathyroidectomy. The probability of an acid 
 intoxication being the causal factor has also been 
 considered, and the absence of evidence has been 
 indicated (p. 131). 
 
 In the present state of our knowledge, there is no 
 more reason to consider that the metabolic disturb- 
 ances, which follow removal of the parathyroids, are 
 primary and causal to the nervous symptoms, than to 
 suppose that the nervous symptoms following thy- 
 roidectomy are caused by the metabolic disturbances. 
 In both, the action of the product of the gland is 
 probably a direct one upon the metabolism of the 
 nervous system and of the body generally. 
 
 Our knowledge as to the mode of action of the 
 thymus is admittedly imperfect. No evidence is 
 forthcoming as to how it produces its reciprocal 
 effect with the testes upon growth. As already 
 
RELATIONS OF REGULATORS 203 
 
 indicated, the nervous symptoms recorded by Klose 
 and Vogt point to its having a similar effect upon 
 the reflex spinal mechanism as has the parathy- 
 roid. 
 
 In the gonads two distinct sets of actions have 
 to be considered : first, their action in producing the 
 phenomena of sexual life, and, second, their action 
 on growth and development. 
 
 As regards the former there is, of course, no 
 doubt that it is through the nervous system. This 
 is well illustrated throughout the animal kingdom. 
 In birds the activity of the gonads determine not 
 only the assumption of the breeding plumage, but 
 also the development of song and of the wonderful 
 nidifying reflexes. It activates the nervous system 
 to a whole series of fresh responses. In every other 
 group of vertebrates the same phenomena are 
 manifest. A most striking example is seen in the 
 clasping reflex of the male frog in the breeding 
 season. This is a reflex which can be elicited 
 only at this season by touching the skin over the 
 sternum, and it can be elicited even when the head 
 and the lower part of the body have been removed. 
 On the other hand, at the breeding season Mac Lean 
 has recorded that the inhibition of the heart by 
 stimulation of the vagus is not readily produced, 
 the nervous mechanism being modified by the state 
 of the reproductive organs. 
 
 The evidence is by no means conclusive as re- 
 gards the mode of action of the gonads upon growth 
 
204 REGULATORS OF METABOLISM 
 
 and development. They, with their abundant inter- 
 stitial cells, along with the closely allied inter-renal 
 structures and the early thymus are all developed 
 while as yet the nervous system is in a rudimentary 
 condition, and while the regulating influence of 
 hereditary inertia is the dominant controlling mech- 
 anism. So far, evidence is wanting to show that 
 their effect is produced through the nervous system, 
 although it is possible that they exert their influence 
 by acting through the vaso-motor mechanism by 
 which the blood supply of the tissues is controlled 
 
 (Fig- 7)- 
 
 It would almost seem as if two sets of chemical 
 
 regulators exist, one which might be called the 
 Primary Chemical Regulators, possibly acting directly 
 upon the metabolism of the tissues as modifiers of 
 hereditary inertia. These are the gonads in em- 
 bryonic life, and possibly the inter-renal system and 
 the thymus. The other set might be called the 
 Neuro-Chemical Regulators, since they act through the 
 nervous system. These would include the chro- 
 maffin system, the hypophysis, the thyroid, the 
 pancreas, and the parathyroids. Evidence points 
 to the thymus and gonads as also acting in this 
 way in post-foetal life. 
 
 The part played by each of the great regulators 
 of metabolism throughout the course of embryonic 
 and post-embryonic life might be represented dia- 
 grammatically as shown in Fig. 8. 
 
 In early embryonic life the force of hereditary 
 
RELATIONS OF REGULATORS 205 
 
 inertia is the dominating factor. Later, the chemical 
 regulation of the gonads, inter- renals and thymus 
 come into play as modifying factors. Still later, the 
 influence of the nervous system becomes more and 
 more prominent, and finally this influence of the 
 nervous system is further directed and controlled 
 by the production of internal secretions from such 
 structures as the chromaffin tissue and the other 
 neuro-chemical regulators. 
 
 Embryooll: Life , Post-embryonic Life 
 
 y^ 
 
 Fig. 8, — To show the relative parts played during embryonic and post-embryonic 
 life in the regulation of metabolism by (a) hereditary inertia ; (3) the primary 
 chemical regulators ; if) the nervous system, and (^) the neuro-cbemical regulators. 
 
 This survey of the interrelationship of the internal 
 secretions and the nervous system seems to indicate 
 a dominance of the latter by the former. The mode 
 of action of the nervous system at any time is largely 
 controlled by the activity of the various secretions, 
 although their amount is in some measure in- 
 fluenced by the action of the nervous system, either 
 as the result of external conditions or, possibly, by 
 the precedent activity of other internal secretions. 
 If this is so, the question arises how far, not only the 
 bodily development and configuration, but also the 
 mental development and character of the individual 
 
2o6 REGULATORS OF METABOLISM 
 
 are simply a matter of the condition of the endo- 
 crinous structures, and how far, in abnormal child- 
 hood, education may come to be supplemented by 
 some attempt to regulate the supply of defective 
 secretions. 
 
SECTION VI. 
 
 THE EVOLUTION OF THE ENDOCRINOUS 
 GLANDS. 
 
 It is impossible to leave the study of the endo- 
 crinous glands and their secretions without some 
 attempt to solve the problem — How did they 
 originate, and how were their functions developed ? 
 
 Comparative anatomy throws little light upon 
 these questions, for, so far, no homologues of these 
 structures have been discovered in invertebrates. 
 It is true that a study of the comparative anatomy 
 of the supra-renal glands has shown very clearly the 
 independence of the adrenal or medullary part and 
 the inter-renal or cortical part. 
 
 At one time the view was much in vogue that 
 these various structures had for their purpose the 
 de-toxication of various hypothetical products of meta- 
 bolism. This view was long held as regards the supra- 
 renals, and Luciani supports it as regards the thyroid, 
 even at the present time. The evidence in its favour 
 has never been strong, and the study of the action of 
 extracts of the various glands has completely refuted 
 it. It is still maintained by some in explanation of 
 
2o8 REGULATORS OF METABOLISM 
 
 the action of the parathyroids. But it is inconceivable 
 that such minute pieces of tissue, as Halstead has 
 shown are sufficient to obviate the onset of symp- 
 toms, can act in such a manner. 
 
 The theory supported by von Cyon that the 
 thyroid and pituitary, along with the supra-renals, 
 are an arrangement for the adjustment of the 
 vascular system, and more especially of the intra- 
 cranial circulation, is ingeniously supported by its 
 author in his book, Die GefdssdrUse. 
 
 But the facts adduced, when read alongside of 
 other evidence, do not seem to me to support 
 the view. 
 
 These two theories do not require further examin- 
 ation, and some other explanation of the origin of 
 the endocrinous glands must be sought for. 
 
 The source and the position of some of the glands 
 seem to be of significance. The thymus and para- 
 thyroids develop from the branchial arches along 
 which the arterial blood flows to the body in the 
 embryo of all vertebrates and throughout life in 
 fishes. 
 
 This suggests that such structures may have a 
 regulating action on the supply of certain materials 
 to the tissues, just as the liver, placed between the 
 gut and the tissues, regulates the supply of sugar to 
 the latter. The thyroid, too, lies in close proximity 
 to the aorta and its branches, and its action might 
 thus be of the same kind. 
 
 It is not necessary to assume that a mere retaining 
 
EVOLUTION OF REGULATORS 209 
 
 and dispensing of the materials is the only action of 
 the structures. Just as the liver may elaborate its 
 sugar from other substances than the carbohydrates, 
 so these structures may produce profound changes 
 in the materials taken from the blood. 
 
 What is the nature of the substances ? The 
 chemistry of only two — iodothyreoglobulin and 
 adrenalin — is known to us. But the constitution of 
 these two bodies affords a hint as to the probable 
 character of the other substances. The iodine 
 compound of the thyroid is accumulated in the 
 colloid from iodine in the food or from iodine ad- 
 ministered in various forms. It is a definite organic 
 compound, which has a physiological action very 
 different from that of the iodine preparations. 
 
 Adrenalin is allied to tyrosin and to the group of 
 derivatives of the protein molecule, which contain 
 the benzene nucleus. It is probably built up by a 
 process of syntheses in the chromaffin tissue. The 
 presence of a minute quantity of each of these in the 
 blood is essential for the proper action of certain of 
 the tissues, and the absence of each is followed by 
 characteristic alterations in the metabolism. 
 
 These facts suggest very strongly that, in the 
 action of these substances, we have something 
 analogous to the influence of minute traces of 
 inorganic salts, which was first demonstrated by 
 Ringer. Small as is the amount of these, their 
 presence, even in such small amounts, is absolutely 
 essential for the maintenance of the activities of the 
 
2IO REGULATORS OF METABOLISM 
 
 various tissues, and not only is the absolute amount 
 of each of importance, but the relative proportions in 
 which they occur is of equal moment. And so it is 
 with the internal secretions. A certain minimum 
 amount of each seems to be essential, and some 
 proportion between the amounts of each must be 
 maintained if the metabolism is to continue in its 
 normal course. 
 
 The importance of such minimal amounts of 
 certain of the constituents of the proteins of the food 
 has been more recently emphasised by Willcock and 
 Hopkins in their work upon feeding with zein, a, 
 protein in which tyrosin and tryptophane are absent. 
 They found that mice fed upon this along with carbo- 
 hydrates and fats lost weight and died in a short time, 
 but that, when tryptophane was added, life was 
 markedly prolonged, although weight was not gained. 
 They conclude that the tryptophane must yield 
 material for the formation of something essential to 
 the metabolism, and they compare this with the 
 elaboration of adrenalin. 
 
 The evidence we possess thus seems to indicate 
 that iodothyreoglobulin and adrenalin belong to this 
 group of substances. At present we are completely 
 in the dark as to the nature of the other internal 
 secretions, but the essential similarity in the kind of 
 results which are produced by the removal of the 
 structures yielding them strongly suggests that their 
 mode of action is of the same kind. 
 
 Thus sugar cannot be properly stored in the 
 
EVOLUTION OF REGULATORS 211 
 
 absence of the internal secretion of the pancreas, 
 while in the absence of the secretions of the chro- 
 mafifin -tissue, of the hypophysis and of the thyroid it 
 is imperfectly mobilised. For the proper growth of 
 bone and for the development of the special sexual 
 characters, small amounts of gonadin are necessary. 
 Without the parathyroids the stability of the spinal 
 synapses is no longer maintained, while, on the other 
 hand, for the normal responsiveness of these synapses 
 the secretion of the thyroid is necessary. The fact 
 that more than one of these organs may act in a 
 similar manner allows of compensation being estab- 
 lished after removal of one — as is seen in the 
 case of the thymus and gonads. 
 
 It seems to me that such a conception is more in 
 accordance with the facts which we possess than that 
 of a series of hormones or excitors directly calling 
 forth the activity of the various tissues. 
 
 02 
 
BIBLIOGRAPHY. 
 
 NERVOUS MECHANISMS. 
 
 Abel, yoKr. of Anat. and Fhys., vol. 47, p. 35. 191 2. 
 
 Abel, Proceedings of the Royal Society of Edinburgh, vol. 30, 
 
 p. 327. 1910. 
 Alexandrowicz, Ztsch.f. allg. Fhys., Bd. 14, p. 358. 1913. 
 "Regeneration" — Arch. f. Entwicklungsmech. Series of papers 
 
 from Bd. 6 onwards. 
 Bayliss, _/<7«r. of Phys., vol. 26, p. 173. 1900-1. 
 Bruce, Arch.f. exp. Path. u. Pharm., Bd. 63, p. 424. 1910. 
 Diirken, Ztsch.f. wissensch. Zaol., Bd. 99, p. 139. 191 2. 
 Goltz and Ewald, Pflug Arch. 1896. 
 Griiifiths, yo«r. of Anat. and Phys., vol. 29, p. 61. 1894. 
 Herbst, Arch.f. Entwicklungsmech, vol. 9, p. 215. 1899. 
 Jacobson, Am. Jour, of Phys., vol. 26, p. 413. 1910. 
 Langley, Schafer's Text-Book of Physiology, vol. 2, p. 6 1 6. 
 Luciani, Physiologic des Menschen, Bd. 2, p. 443. 
 Magnus, Ergebnisse d. Phys., p. 27. 1908. 
 Morguli, Pflug Arch., Bd. 143, p. 501. 1912. 
 "Bladder," Nagel's Handbuch der Phys., Bd. 2, p. 310. 
 Popielski, Arch.f. [Anat. u.] Phys., p. 338. 1903. See Nagel's 
 
 Handbuch der Phys., vol. 4, p. 415. 
 "Monstrosities" — Schwalbe, Die Morphologie der Missbildungen, 
 
 Teil iii. p. 77- Fischer. Jena. 1909. 
 
 ^'"\rtt"' fLuciani, Physiologie des Menschen, Bd. 3, p. 347. 
 
 Stewart, Am. Jour, of Phys., vol. 4, p, 186. 1896. 
 Vogt, Arch.f. [Anat. u.] Phys., p. 399. 1898. 
 
BIBLIOGRAPHY 213 
 
 ENDOCRINOUS GLANDS (GENERAL). 
 
 Biedl, Innere Sekretion. Urban & Schwarzenberg. First Edition, 
 
 1910, now translated into English. Second Edition, 1913. 
 Swale Vincent, Z)«f//«j- (?/a«(/j. Edwin Arnold. 191 2. 
 
 CHROMAFFIN TISSUE. 
 
 Anrep,_/o«r. of Phys., vol. 45, pp. 307, 318. 1912. 
 
 Asher, Zisch.f. Biol., Bd. 52, p. 274. 191 2. 
 
 Cameron, Proc. Royal Soc. Edin., p. 157. 1906. 
 
 Cannon and La Paz, Am. Jour, of Phys., vol. 28, p. 64. 1911. 
 
 Cannon and Lyman, Am. Jour, of Phys., vol. 31, p. 376. 1913. 
 
 CorAs,Die Adrenalinmydriasis (good list of references). Bergmann, 
 
 Wiesbaden. 191 1. 
 Desbouis et Langlois, C.R. Soc. Biol., T. 72, p. 6747. 1912. 
 Doyen and Gautier, C.R. Soc. Biol., p. 816. 1908. 
 Doyen, Morel and KarefF, C.R. Soc. Biol., T. 2, p. 202. 1905. 
 YixvLvamoTiA, Jour, of Phys. vol. 31, p. 81. 1904. 
 Ehrmann, Arch.f. exp. Path. u. Pharm., Bd. 53, p. 97. 1905. 
 Ehrmann, Deutsche med. Wochensch. 1909. 
 Elliott, _/o«r. of Phys., vol. 32, p. 406. 1904-5. 
 Elliott, yo«r. of Phys., vol. 44, p. 374. 1912. 
 Fleming, yiwr. of Phys., vol. 46, xliii. 1913. 
 Folin, Cannon and \i&m.%. Jour, of Biol. Chem., vol. 13, p. 472. 
 
 1913- 
 Fraenkel, Arch.f. exp. Path. u. Pharm., Bd. 60, p. 394. 1909. 
 Gunn and Chavasse, Proc. Royal Soc. B, 86, p. 193. 1913. 
 H(5skins, yb«r. of Pharm. and Exp. Therap., vol. 3, p. 93. 
 Hoskins and M'Clure, Am. Jour, of Phys., vol. 31, p. 59. 191 2. 
 Hoskins and M'Clure, Arch, of Internat. Med., vol. 10, p. 343. 
 
 1912. 
 Janeway and Turk, Jour, of Exp. Med., vol. 16, p. 541. 1912. 
 M'Leod and Pearce, Am. Jour, of Phys., vol. 29, p. 419. 1911. 
 Noel YsXaw, Jour, of Phys., vol. 29, p. 285. 1903. 
 Noel Paton, _/««/-. of Phys., vol. 32, p. 59. 1904. 
 Noel Paton,y<?Kr. of Phys., vol. 45, p. 106. 1912. 
 Noel Paton and Drummond, yi»«r. of Phys., vol. 31, p. 92. 1904. 
 Noel Paton and Watson, /wr. of Phys., vol. 44, p. 413. 1912. 
 
214 BIBLIOGRAPHY 
 
 Oliver and Schafer, Jour, of Phys., vol. 18, p. 230. 1895. 
 
 See also Schafer's Text-Book of Physiology, vol. i, p. 948. 
 Shock, Ztsch.f. vergleich. OphthaL, Bd. i, Heft 3. 19 12. 
 Starkenstein, Ztsch.f. exp. Path., Bd. 10, p. 78. 1911. 
 Stewart, y<7«r. of Exp. Med., vol. 15, p. 547. 1912. 
 Thebault, Annales des Sciences nat., 8"" sen " Zool.," t. 6. 1 898. 
 Wilenko, Zbt.f Phys., Bd. 36, p. 1059. 1913. 
 
 HYPOPHYSIS. 
 
 Gushing, The Pituitary Body and its Disorders. Lippincott & Co. 
 
 1912. 
 Gavin, Q.Jour. Exp. Phys.,'i6\.. 6, p. 13. 1913. 
 Herring, Q.Jour. Exp. Phys., vol. i, pp. 121, 161 and 263. 1908. 
 Mackenzie, Q. Jour. Exp. Phys., vol. 4, p. 305. 191 1. 
 Magnus and Schafer, ybw;-. of Phys., vol. 27, p. 9. 1901-2. 
 Noel Paton and Watson,_/o«n of Phys., vol. 44, p. 413. 1912. 
 Vaalzsco, L'hypophyse de Cerveau. Paris. 1908. 
 Schafer, Croonian Lecture. 1909. 
 Schafer, Q.Jour. Exp. Phys., vol. 6,' p. 17. 1913. 
 Schafer and M'Kenzie, Proc. of Royal Soc. B., vol. 84, p. 16. 
 
 1911. 
 
 THYROID. 
 
 Asher and Rodt, Zbt.f. Phys., Bd. 26, 223. 1912. 
 
 Edmunds, Pathology and Diseases of the Thyroid Gland. Y. J. 
 
 Pentland. 1901. 
 Eiselberg, Die Krankheiten der Schildriisen. Deutsche Chirurgie, 
 
 Lief. 38. 1 90 1. 
 Gudernatsch, Zbt.f. Phys., Bd. 26, p. 323. 1912. 
 Jeandelize, Insuffisance thyroidienne et parathyroidienne. Bailliere 
 
 & Fils, Paris. 1903. 
 Koch, yb«r. of Biol. Chem., vol. 14, p. loi. 1913. 
 Mansfeld, P^iig. Arch., Bd. 143, p. 157. 1911. 
 Murray, Goulstonian Lecture. London. 1899. 
 Reid Hunt,_/o«r. of Biol. Chem., vol. i, p. 333. 1905. 
 
 PITUITARY. 
 
 Aldrich, Am. Jour, of Phys., Bd. 30, p. 352. 1912. 
 Aschner, Arch. f. Gyn., Bd. 97, p. 200. 191 2. 
 
BIBLIOGRAPHY 215 
 
 Benedict and Homa.ns, /our. of Med. Res., vol. 25, p. 409. 1912. 
 Gushing (see Hypophysis). 
 
 PANCREAS. 
 
 Cathcart and Taylor, y(?«r. of Phys., vol. 41, p. 276. 1910. 
 Homans {gives references to previous work), Proc. Royal Sac. B., 
 
 vol. 86, p. 73. 19 13. 
 Kirkbride, _/<7«r. of Exp. Med., vol. 15, p. loi. 1912. 
 Knowlton and Starling, y^jwr. of Phys., vol. 45, p. 146. 1912. 
 Maclean and Smedley, _/(?«/-. of Phys., vol. 45, p. 470. 1913. 
 Macleod. Diabetes. Edward Arnold. 19 13. 
 Rennie, Quart. Jour, of Micros. Sc, vol. 48. 1904. 
 Ross Taylor, Biochemical Journal, p. 362. 1911. 
 
 THYMUS. 
 
 'Rasch, Jahrbuch f. Kinderheil. 1906-1908. 
 
 Goodall, y<>«r. of Phys., vol. 32, p. 191. 1905. 
 
 Hammar, Funfzig Jahre Thymusforschung. Ergeb. der Anat. u. 
 
 Entwickl., Bd. 19. 1909. 
 Hart, Virchow's Arch., Bd. 210, p. 255. 1912. 
 Henderson, yo«r. of Phys., vol. 31, p. 221. 1904. 
 Klose and Vogt, Klinik u. Biol, der Thymusdriise. 1910. 
 MacLennan, Glasgow Med. Jour., Aug. 1903. 
 Matti, Ergebnisse der inneren Med. u. Kinderheil., Bd. 10. I9i3' 
 Noel Paton,y(?«r. of Phys., vol. 32, p. 28. 1904. 
 Noel Baton and Goodall, ybar. of Phys., vol. 31, p. 49. 1904. 
 Noel Baton and Goodall, Proc Royal Soc. Edin. 1905. 
 Soli, Contributo alia Funzione del Timo. Modena. 1909. 
 
 PARATHYROIDS. 
 
 Berkeley and Beebe,/«/-. of Exp. Med., vol. 20, p. 149. 1909. 
 Carlson and Jacobson, Am. Jour, of Phys., vol. 23, p. 133. 1908-09. 
 Carlson and Jacobson, Am. Jour, of Phys., vol. 25, p. 403. 1910. 
 Carlson and Jacobson, Am. Jour, of Phys., vol. 28. 1911. 
 Cooke (J. Y.),Jour. of Exp. Med., vol. 12, p. 45. 1910. 
 Cooke (J. Y.),Jour. of Exp. Med., vol. 13, p. 439. 191 1. 
 
2i6 BIBLIOGRAPHY 
 
 Edmunds (see Thyroid). 
 
 Eppinger, Falta and Rudinger, Ztsch. f. klin. Med., vol. 66, p. i ; 
 
 vol. 67, p. 380. 
 Greenwald, Am. Jour, of Fhys., vol. 28, p. 133. 191 1. 
 Halsted, _/<7z<r. of Exp. Med., vol. 11, p. 175. 1909. 
 Halsted,yb«r. of Exp. Med., vol. 15, p. 206. 
 M 'Galium and Vogtlin, four, of Exp. Med. , vol. 1 1 , p. 1 1 8. 1 909. 
 Ochsner and Thompson, T^e Surgery and Pathology of the 
 
 Thyroid and Parathyroid Glands. Krener & Co. 19 10. 
 Swale Vincent, The Ductless Glands, p. 241. 
 
 GONADS. 
 
 Agar, Phil. Trans. R.S. London B, vol. 203. 1913. 
 
 Gemmill, Arch.f. Anat. \u. Phys.], p. 230. 1896. 
 
 Grosvenor and Geoffrey Smith, Quart. Jour, of Micros. Sc, vol. 58, 
 
 p. 511. 1913. 
 Heape, Proc. Phys. Soc. Dec. 16, 1905. 
 Hertwig, Biol. Cbt. 1912. H. i, 2 and 3. 
 M'llroy, Proc. Royal Soc. Edin., vol. 31, p. 151. 1910. 
 Marshall, Physiology of Reproduction. Longmans & Co. 19 10. 
 Meisenheimer, Exp. Stud. z. Soma- u. Geschlechts-Diff. Fischer. 
 
 Jena. 1912. 
 Shattock and Seligman, Proc. Royal Soc. Feb. 1904. 
 Simpson and Marshall, Q. Jour. Exp. Phys., vol. i, p. 257. 1908. 
 Starling and Lane Claypon, Proc. Royal Soc, p. 77. 1905. 
 Steinach, Pflilg Arch., Bd. 144, p. 71. 1912. 
 Tandler and Gross, Arch.f. Entwicklungsmech., Bd. 33, p. 297. 
 
 INTER-REN A LS. 
 
 Biedl, Innere Sekretion, 2nd. Edit, p. 376. 
 
 Elliott and Armour, Jour, of Path, and Bacter., vol. xv., p. 481. 
 
 1911. 
 Glynn, Quart. Jour, of Exp. Med., vol. 5, p. 157. 191 2. 
 Kirkbride, Publications of Cornell University Medical School, 
 
 vol. 2. 1911. 
 Koimer, Pflilg Arch., Bd. 144, p. 361. 1912. 
 
BIBLIOGRAPHY 217 
 
 INTER-RELATIONS OF ENDOCRINOUS GLANDS. 
 
 Fleischmann, Wten. med. Klinik, p. 177. 1912. 
 Hoskins, Am. Jour, of Med. Sc. March and April, 191 1. 
 
 THE RELATIONSHIP OF THE ENDOCRINOUS 
 GLANDS AND THE NERVOUS SYSTEM. 
 
 Cushney,_/(7»r. of Phys., vol. 41, p. 233. 1910. 
 
 Maclean, Biochem. Jour., vol. 3. 1908. 
 
 Magnus, Ergebnisse d. Phys. 1 908. 
 
 Willcock and Hopkins, _/i7«r. of Phys., vol. 35, p. 88. 1907. 
 
 GLASGOW : PRINTED AT THE UNJVEBSITV PRESS BV ROBERT HACLEHOSB AND CO. LTD. 
 
HUMAN PHYSIOLOGY 
 
 By Professor LUIGI LUCIANI. 
 
 Translated by Frances A. Welby. Edited by Dr. M. Camis. 
 With a Preface by J. N. Langley, F.R.S. 
 
 Illustrated. In 4 vols. 8vo. 
 
 Vol. I. — Circulation and Respiration. i8s. net. 
 Vol. II. — Internal Secretion, Digestion, Excretion, The Skin. i8s. net. 
 Vols. III. and I'M .—In the Press. 
 
 SOME PRESS OPINIONS. 
 Vol. I. 
 
 BRITISH MEDICAL JOURNAL.—" The text-book is one which 
 should be read by those studying for higher examinations, and all who 
 wish for a literary and philosophic treatment of the subject. Luciani 
 has the same lucidity and charm of style which Sir Michael Foster 
 possessed, and his text-book fills almost exactly the place which Foster's 
 text-book held in English literature." 
 
 LANCET. — " We offer a hearty welcome to the work of the veteran 
 professor of physiology in Rome, one of the early Italian pupils of 
 Ludwig and the successor of Moleschott. Few men have such an all- 
 round knowledge of physiology as Luigi Luciani, or so wide an outlook 
 on physiological problems, both in their modern and in their historical 
 aspects." 
 
 NATURE. — "The book is a remai-kable achievement, especially in 
 view of the fact that it is the work of a single author, and appears to the 
 reviewer to possess special qualities and merits, which entitle it to a high 
 place amongst the existing English text-books of physiology." 
 
 Vol. II. 
 
 EDINBURGH MEDICAL JOURNAL.— " The various problems 
 are discussed in a critical and judicial manner, and the growth of 
 knowledge in each department is set forth in a fashion which brings 
 clearly before the reader the way whereby our present-day opinions 
 have been elaborated and matured. The text is thoroughly up to date 
 in each section of tiie treatise, and presents the views of the learned 
 writer in excellent idiomatic English. The volume is a further instal- 
 ment of a work that should be in the hands of every one who is interested 
 in the science of physiology." 
 
 NATURE. — " The book will prove a valuable asset to the professed 
 physiologist and to the advanced student." 
 
 LONDON : MACMILLAN AND CO., LTD. 
 
A SYSTEM OF MEDICINE 
 
 BY MANY WRITERS 
 
 SECOND EDITION 
 
 Edited by Sir CLIFFORD ALLBUTT, K.C.B., M.D., F.R.S., 
 and H. D. ROLLESTON, M.D., F.R.C.P. 
 
 Medium 8vo. 
 
 Vol. I. Prolegomena and Infectious Diseases. 25s. net. 
 
 II. Part I. Infectious Diseases (continued). Intoxications. 25s. 
 net. 
 
 II. Part II. Tropical Diseases and Animal Parasites. 25s. net. 
 
 III. Certain General Diseases, Diseases of the Alimentary Canal 
 
 and Peritoneum. 25s. net. 
 
 IV. Part I. Diseases of the Liver, Pancreas, Ductless Glands, 
 
 and Kidneys. 25s. net. 
 
 IV. Part. II. Diseases of the Nose, Pharynx, Larynx, Trachea, 
 and Ear. 25s. net. 
 
 V. Diseases of the Respiratory System, Disorders of the Blood. 
 25s. net. 
 
 VI. Diseases of the Heart and Blood-Vessels. 25s. net. 
 
 VII. Diseases of the Muscles, The Trophoneuroses, Diseases of the 
 Nerves, Vertebral Column, and Spinal Cord. 25s. net. 
 
 VIII. Diseases of the Brain and Mental Diseases. 25s.net. 
 
 IX. Diseases of the Skin. General Index. 25s. net. 
 
 A SYSTEM OF GYNECOLOGY 
 
 BY MANY WRITERS 
 
 Edited by Sir CLIFFORD ALLBUTT, K.C.B. ; 
 W. S. PLAYFAIR, M.D. ; and T. W. EDEN, M.D. 
 
 SECOND EDITION 
 
 ~S ' Medium 8vo. 25s. net 
 
 LONDON: MACMILLAN AND CO., LTD. 
 

 
 't',si^;is^:i^^y^^^^'^S^:^^^^E.