fvy THE SEX-COMPLEX A STUDY OF THE RELATIONSHIPS OF THE INTERNAL SECRETIONS TO THE FEMALE CHARACTERISTICS AND FUNCTIONS IN HEALTH AND DISEASE First Edition . . . January, 1916 Second Edition . . . June, 1920 THE SEX-COMPLEX A STUDY OF THE RELATIONSHIPS OF THE INTERNAL SECRETIONS TO THE FEMALE CHARACTERISTICS AND FUNCTIONS IN HEALTH AND DISEASE W! BLAIR BELL B.S., M.D., Lond., etc. GYNECOLOGICAL SURGEON TO THE ROYAL INFIRMARY, LIVERPOOL; LECTURER ON CLINICAL GYNECOLOGY IN THE UNIVERSITY OF LIVERPOOL. SOMETIME EXAMINER IN GYNECOLOGY AND OBSTETRICS TO THE UNIVERSITIES OF DURHAM AND BELFAST, AND TO THE CONJOINT BOARD OF THE ROYAL COLLEGES OF SURGEONS AND PHYSICIANS, ENGLAND ; HUNTERIAN PROFESSOR, AND ARRIS AND GALE LECTURER, ROYAL COLLEGE OF SURGEONS, ENGLAND SECOND EDITION LONDON BAILLIERE, TINDALL AND COX 8, HENRIETTA STREET, GOVENT GARDEN 1920 All rights reserved 594637 PRINTED IN GREAT BRITAIN QP B*f5 TO MY FELLOW-MEMBERS OF THE GYNECOLOGICAL VISITING SOCIETY OF GREAT BRITAIN Propter secretiones internas totas mulier est quod est." Arris and Gale Lectures, 1913. EXTRACT FROM THE PREFACE TO THE FIRST EDITION This small monograph is based on the subject matter of several previous communications — the Arris and Gale Lectures, delivered before the Royal College of Surgeons, England, in 1913 ; the paper with which a discussion was opened at the Royal Society of Medicine in the same year, and other contributions bearing on this subject, including, by the kind permission of the Editors and Messrs. Macmillan & Co., a small portion of the articles on * The Disorders of Function ' written for the New System of Gynecology, In the Arris and Gale Lectures probably the first definite attempt was made to demonstrate that the reproductive functions are directed and controlled by all the organs of internal secretion acting in conjunction, rather than by the gonads alone, as formerly thought. Earlier investigators had adduced evidence, it is true, of a connexion between the genital organs and some of the distant hormonopoietic glands ; but the observations made do not appear to have led to the conclusion that the association is not incidental, but, rather, that it indicates the existence of a definite genital system, in which probably all the internal secretions play a part. This correlation of the internal secretions in regard to the sex-functions — the ' sex complex ', as we may call it — appears already to be accepted by all physio- logists and clinicians, except, perhaps, those few who still deny the interrelationship of the internal secretions. There are, of course, still differences of opinion con- cerning the details ; and it is for this reason, as well as because of the intense importance of the subject to viii PREFACE physiology and to practical gynaecology1, that the investigations and communications referred to — welded together, amplified and largely rewritten — are submitted for consideration in book form, in the hope that further interest may be stimulated, fresh facts noted and recorded, and existing opinions corrected or confirmed. 1 In this work the author is chiefly concerned with the female characteristics and functions; nevertheless, the internal secretions are as closely connected with the genital functions of the opposite sex, in relation to which they must, therefore, occasionally be discussed for the sake of contrast or comparison. January, 1916. PREFACE TO THE SECOND EDITION The first edition of this work, which has now been out of print for a long time, was published less than four years ago. Before that date the war had stopped all general research- work ; consequently the alterations that will be found in the present edition are of the nature of extensive additions, amplifications and re- visions, rather than of presentations of new aspects of the subject. The title has been considered by some to be inappropriate because the term ' Sexual Complex ' has previously been used in another and more limited sense. 6 The Genital System ', which has been suggested, would not have exactly expressed my meaning. One reviewer has stated that the term ' Sex Endocrine Com- plex' would have been better, and that in regard to sex 'one cannot leave out the psychosexual system'. But have I not endeavoured to show that the ' psycho- sexual system' as related to sex is a subdivision of my subject ? Whatever terms have hitherto existed, surely ' Sex-Complex ' (I concede the hyphen) is all- inclusive. The different sections might perhaps have been clumsily qualified as * Sex-Determination-Complex ', 1 Sex-Psychosis-Complex ', and the rest, if the work were intended for unintelligent readers. Such, however, is not the case; and I prefer to leave a little to the imagination and good word-sense of those who are interested in the subject. I shall deal with criticisms of facts in the appropriate places. I am greatly indebted to many reviewers and readers not only for their generous appreciation, but also for x PREFACE calling my attention to publications that otherwise might have escaped my notice. I may, however, be allowed to say that certain typically German compila- tions such as those of Novak, Seitz, and Hofstatter had not reached this country when my material was collected ; and, further, that concerning a subject whose foundations rest on the basal processes of life — individual metabolism and reproduction — the literature must necessarily be too extensive for detailed consideration except in its most immediate bearings. This is not the kind of book that can usefully be taken through numerous editions, so with the issue of this edition it will finish its career. If the work has succeeded in denning and focussing attention on the subject, and in provoking emulative criticism, the purpose of it will have been fully served. Once more I have to thank my friend Dr. Hubert Armstrong for his careful correction and criticism of the proof-sheets, and for making the index. W. B. B. 38, Rodney Street, Liverpool. June, 1920. CONTENTS Extract prom Preface to First Edition Preface to Second Edition . . . « Introduction PAGE vii ix 1 PART I MORPHOLOGICAL, PHYSIOLOGICAL AND PSYCHOLOGICAL CONSIDERATIONS Sex-Characteristics Primary Sex-Characteristics Secondary Sex-Characteristics The Ovaries Secretory Structures of the Ovary Effects of Oophorectomy on the Genital Functions and on the Structure of the rest of the Genitalia . Effects of Oophorectomy on the General Metabolism Effects of Oophorectomy on the Thyroid Effects of Oophorectomy on the Thymus Effects of Oophorectomy on the Pineal Effects of Oophorectomy on the Suprarenals Effects of Oophorectomy on the Pituitary Ovarian Transplantation Physiological Effects of Ovarian Extracts The Thyroid Effects of Thyroidectomy on the General Metabolism Effects of Thyroidectomy on the Ovaries and Uterus Effects of Thyroidectomy on the Suprarenals Effects of Thyroidectomy on the Pituitary . Physiological Effects of Extracts of the Thyroid . 6 6 14 21 22 29 32 38 40 41 41 42 46 48 50 50 53 54 55 57 xii CONTENTS PAQK The Parathyroids . . . 59 Effects of removal of the Parathyroids 60 Physiological Effects of Extracts of the Parathyroids . . 62 The Pineal 63 Physiological Effects of Extracts of the Pineal ... 64 The Pituitary 65 Effects of removal of the Pituitary (partial or complete) . 66 Effects of removal of a portion of the Pars Anterior on the Ovaries and Uterus ........ 68 Effects of removal of a portion of the Pars Anterior on the other Hormonopoietic Organs 69 Effects of removal of the Pars Posterior on the Ovaries and Uterus . 70 Effects of removal of the Pars Posterior on the other Hormonopoietic Organs 70 Effects of separation and compression of the Infundibular Stalk on the Ovaries and Uterus 70 Effects of separation and compression of the Infundibular Stalk on the other Hormonopoietic Organs ... 70 Effects produced by artificial Tumours in the neighbourhood of the Pituitary .71 Physiological Effects of Extracts of the Pituitary ... 71 The Suprarenals 74 Effects of removal of the Suprarenals 75 Effects of removal of one Suprarenal on the Metabolism . 76 Effects of removal of the Suprarenals on the Pituitary . 78 Effects of removal of the Suprarenals on the Thyroid . . 79 Effects of removal of the Suprarenals on the Ovaries and Uterus 79 Physiological Effects of Suprarenal Extracts . . .80 The Pancreas . 81 Physiological Effects of Pancreatic Extracts . . . .82 The Thymus 83 Effects of Thymectomy and destruction of the Thymus on the Gonads and on the Calcium Metabolism ... 84 Effects of Thymectomy on the Hormonopoietic Organs . 85 Physiological Effects of Extracts of the Thymus ... 85 The Mammary Glands 86 The Hormones that influence the Mamma? .... 87 Physiological Effects of Mammary Extracts ... .98 CONTENTS xiii PA(JK Other Genital Organs 100 Uterus 100 Physiological Effects of Extracts of the Uterus . . . . 101 Placenta , 102 Physiological Effects of Placental Extracts . . . 103 Testicle and Prostate 104 The Correlation of the Internal Secretions in Regard to their Genital Functions 106 Psychological Characteristics 110 PART II PATHOLOGICAL CONSIDERATIONS Derangements in the Development of the Genital Organs, and of the genital functions 130 Derangements in the Structural Development of the Genital Organs . . . . . . . . .130 Derangements in the Functional Development of the Genital Organs 153 Derangements of the fully-established Female Charac- teristics and Functions 165 Derangements of the Sex-Characteristics .... 165 Derangements of the fully-established Genital Functions . 170 Disturbances of the Ovarian Secretion .... 170 Disturbances of the Thyroid Secretion .... 185 Disturbances of the Parathyroid Secretion .... 192 Disturbances of the Pineal Secretion 194 Disturbances of the Pituitary Secretion .... 194 Disturbances of the Suprarenal Secretion .... 198 Disturbances of the Internal Secretion of the Pancreas . 199 Disorders of the Thymus 200 The Mammae and the Genital Functions .... 201 The Placenta and Maternal Disorders 203 Sexual and Reproductive Psychoses and Neuroses . . 206 General Index 229 Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7 a. Figure 8. Figure 9. Figure 10. Figure 11. Figure 12. Figure 13. Figure 14. Figure 15. Figure 16. Figure 17. Figure 18. Figure 19. Figure 20. Figure 21. Figure 22. Figure 23. Figure 24. Figure 25. Figure 26. ILLUSTRATIONS PART I FACING PAGE Section of the human ovary, showing ripening of the Graafian follicle 22 Section of the human ovary, showing a ripe Graafian follicle 23 Section of the human ovary, showing origin of lutein cells .... ... 24 Section of the ovary of Ornithorhynchus ... 25 Section of the ovary of Ornithorhynchus ... 26 Section of the ovary of a marsupial .... 27 Corpus luteum in the ovary of the cow. Corpus luteum in the ovary of the human subject . 28 Section of the corpus luteum of the cow ... 29 Section of the corpus luteum of the human subject . 30 Section of the adult human ovary . . . .31 Section of the ovary of the adult rabbit ... 33 Section of the ovary of the young rabbit ... 34 Section of the ovary of the normal cat ... 35 Section of the uterus of the normal cat . . . 36 Section of the uterus of the cat after oophorectomy . 37 Section of the thyroid of the normal rabbit . . 38 Section of the thyroid of the rabbit after oophorectomy 39 Section of the normal pars anterior of the pituitary in the human subject ,43 Section of the pituitary of the cat after oophorectomy . 45 Section of the uterus of the normal adult rabbit . 46 Section of the uterus of the rabbit after ovarian grafting . . . . . . . .47 Section of a graft of the rabbit's ovary ... 48 Section of a graft of the rabbit's ovary ... 49 Section of the ovary of the cat after thyroidectomy . 53 Section of the uterus of the cat after thyroidectomy . 54 Section of the suprarenal of the cat after thyroidectomy 55 xvi ILLUSTRATIONS FACING PAGE Figure 27. Section of the pars anterior of the pituitary of the cat after thyroidectomy 56 Figure 28. Section of the pars nervosa of the pituitary of the cat after thyroidectomy 57 Figure 29 a. Bitch before operation. b. Same bitch 51 days after separation of the infun- dibular stalk .... ... 67 Figure 30 a. Section of the uterus of the dog before partial removal of the pars anterior of the pituitary. b. Section of the uterus of the dog after partial removal of the pars anterior of the pituitary . 68 Figure 31 a. Section of the ovary of the dog before partial removal of the pars anterior of the pituitary. B. Section of the ovary of the dog after partial removal of the pars anterior of the pituitary . 69 Figure 32 a. Sections of the uterus of the dog before and after removal of the pars posterior of the pituitary. b. Sections of the ovary of the dog before and after removal of the pars posterior of the pituitary . 70 Figure 33 a. Section of uterus of bitch before operation. b. Section of uterus of bitch 128 days after separation of the infundibular stalk 71 Figure 34 a. Section of ovary of bitch before operation. b. Section of ovary of bitch 128 days after separation of infundibular stalk ..... 72 Figure 35. Skiagram of bitch's head, showing artificial tumour in position . . * . . . . . .73 Figure 36 a. Skiagram of the forelegs of the normal rabbit. b. Skiagram of the foreiegs of the rabbit after the removal of one suprarenal ..... 78 Figure 37. Section of the pars nervosa of the pituitary of the rabbit after the removal of the suprarenals . . 79 PART II Figure 38. Photograph of an adult showing general infantilism (ateleiosis) Figure 39. Skiagram of the sella turcica from a case of ateleiosis Figure 40. Skiagram of the human sella turcica in a case of under-development of the pituitary Figure 41. Section of an under-developed ovary Figure 42. Photograph of a glandular partial hermaphrodite Figure 43. Section of an ovitestis Figure 44. Section of the testicular portion of an ovitestis . Figure 45. Photograph of a male partial tubular hermaphrodite 131 132 133 134 140 142 143 149 ILLUSTRATIONS xvii FACING PAGE Figure 46. Section of testis from a male partial tubular hermaphrodite ....... 150 Figure 47. Section of an undescended testis .... 151 Figure 48. Section of a normal testis 152 Figure 49. Photograph of a girl, showing precocity . . 154 Figure 50. Skiagram of the epiphyses in a case of precocity . 155 Figure 51. Section of the ovary of a cretin .... 156 Figure 52. Section of the uterus of a cretin .... 157 Figure 53. Section of the parathyroid of a cretin . . . 158 Figure 54. Section of a tumour of suprarenal cortex . . . 166 Figure 55. Section of suprarenal cortex showing hyperplasia . 167 Figure 56. Section of the suprarenal of a young woman who had developed masculine characteristics . . 168 Figure 57. Section of the pars anterior of the pituitary of a young woman who had developed masculine characteristics 169 Figure 47. Section of the uterus of a young woman who had developed masculine characteristics . . . 170 Figure 48. Section of the ovary of a young woman who had developed masculine characteristics . . .171 Figure 49. Section of a homogenous ovarian graft in the human uterus 181 Figure 50. Section of tjie ovary from a case of osteomalacia . 184 INTRODUCTION In the following pages our subject will be Woman, and I shall endeavour to make clear, so far as our knowledge allows, the difficult problem of the female sex-complex in all its ramifications. To do this I shall be obliged to draw upon the facts of general biology, both in argument and experiment ; but we must always remember that details which are true of one species are not necessarily so of another. We must, therefore, endeavour to go forward along the highways of the general principles, holding only to those particulars which help us to keep the path. Our disquisition resolves itself into two sub- Subjects ,. . . discussed. divisions : (1) A consideration of the factors which lead to the production and maintenance of the normal characteristics and functions of Woman ; that is to say, of the individual with feminine attri- butes, primary and secondary, both of the mind and body. (2) A discussion of the morphological and physio- logical derangements of the sex-complex. At the very outset of the first enquiry we bring Prejudice has ourselves to the threshold of lively controversy — enquiry. controversy concerning the differences between Man and Woman which has rarely been conducted on unbiassed and scientific lines. So much of this has come within my personal experience, that I feel it best at once clearly to emphasize the impossibility of taking sentiment into account in a discussion of femininity and its causes, and in my statements concerning the psychical attributes which cannot be ignored in a consideration of this subject. 1 2 THE SEX-COMPLEX importance Moreover, no pretence is made of overlooking the facts of the subject. that certain sociai and legal questions depend closely on the scientific aspects of sex, and that they are now pressing for consideration, elucidation and determination. With national and international struggles going on around us, and with the claims of posterity meeting us at every turn, no one can fail to recognize that the problems of sex and reproduction are urgent and that it is the duty of those working at this subject not only to determine, if possible, the causes of sex and of sex- characteristics, but also to specify the relations and functions of the two sexes under changing circumstances and environments. This is the twentieth century ; and, however much we may regret it, we must confess that science admits of no sentimentality or romance. When the veil overhanging the mystery of sex is completely torn aside, no doubt many cherished illusions will be taken from us. Yet somehow we survive unspoilt the ravages of science, and quite impersonally we are able to discuss the cold, hard facts related to our daily life in no uncertain manner ; for, whatever our knowledge of life, death and sex may be, our mental detachment is such that these things apply to all others rather than to ourselves and to those dear to us. Because no longer we believe that the heart is really the seat of the affections — because we do not order analgesics for ' heart-ache ' — are we any less affectionate or immune to jealousy ? So, too, we may believe that, however much we unmask the physical attributes of sex and demonstrate the material qualities of the differences in sex-psydhology, and however much we dissect the complexity of sex, we shall not disturb the sex-instincts of a single normal individual. Reason why It is, indeed, strange that such an apologia should be £^s necessary in the present day, but, as already stated, I believe it to be so. And in this conviction I am supported by the following statement, written more than thirty years ago (1889) in that fascinating little work The Evolution of Sex, by Professor Geddes and INTRODUCTION 3 . Professor Thomson, and repeated in all subsequent Reason why ,. . ( apologia is editions ! — necessary. " A third reason why the problem of the origin of male " and female has been so much shirked, why naturalists " have beaten so much about the bush in seeking to " solve it, is that in ordinary life, for various reasons, " mainly false, it is customary to mark off the repro- " ductive and sexual functions as facts altogether per se. " Modesty defeats itself in pruriency and good taste " runs to the extreme of putting a premium upon " ignorance. Now this reflects itself in biology. Re- " production and sex have been fenced off as facts by " themselves ; they have been disassociated from the " general physiology of the individual and the species. " Hence the origin of sex has been involved in special " mystery and difficulty, because it has not been " recognized that the variation which first gave rise to " the difference between male and female, must have " been a variation only accenting in degree what might " be traced universally." Apparently, and unfortunately, a quarter of a century has hardly been a period long enough to effect the change in our outlook that is surely coming. In discussing the normal factors responsible for the Correlated production and maintenance of sex-characteristics in the the organs female, and the functions appertaining to them, I shall ge^ion*1 cover a wide field and one which has only recently been opened to our view. Hitherto attempts to describe the special correlated functions of the hormonopoietic organs, or, to be more exact, of the internal secretions, appear to have been avoided by those who have worked most at the subject. Correlations have been admitted, points in support of them have been adduced, and the matter has then been dropped. In many ways this is much to be deplored, for to some extent it is accountable for the present disordered state of our knowledge. It is disappointing, for instance, to read through a work such as that of Biedl on Internal Secretion, and nowhere to find an attempt to link up — if only from an analysis of THE SEX-COMPLEX Correlated functions of the organs of internal secretion. Factors producing femininity. the isolated results of work already done — the mysterious connexions that undoubtedly exist between the organs of internal secretion in regard to the specialized functions. In Marshall's excellent book on The Physiology of Repro- duction two short pages only are set aside for the con- sideration of the relation of the ductless glands generally to the reproductive functions. No doubt this diffidence has been due partly to the incomplete state of our knowledge ; but I think it has arisen more especially from the isolated way in which we usually consider most of the structures of the body : we trace the products of metabolism from organ to organ without taking into consideration the fact of what may best be described as organic harmony between various structures themselves, in spite of the suggestive lead given us by Starling in his description of the action of secretin. It must not be inferred from these remarks that I am in any way prepared to give a complete explanation of the interactions of the hormonopoietic organs in re- gard to the genital functions and characteristics. It is necessary, however, to call attention to the fact that the genital functions in the female must be considered from a very wide standpoint in view of our accumulated knowledge concerning them. I shall deal most fully with those parts of the subject wherein I have myself worked, and shall bring forward experimental results and pathological findings to clear up many of the points at issue. The essential fact, then, to be borne in mind in regard to this subject is that femininity itself is dependent on all the internal secretions. It used to be thought that a woman was a woman because of her ovaries alone ; but, as we shall see later, there are many individuals with ovaries who are not women in the strict sense of the word, and many with testes who are really feminine in every other respect. This indicates a line of thought which is really the object and fundamental basis of this study — namely, that we can no longer consider that the gonads act alone in their influence on the female INTRODUCTION 5 characteristics and genital functions, except in regard to Factors the production of ova. We must, in fact, look upon the feminity. ovaries as part of a system, to which most, if not all, the other ductless glands belong, and in which these other organs in their relation to the reproductive functions figure with as great importance as the ovaries themselves. It must be remembered, too, that when we speak of the genital functions of the ductless, or hormonopoietic, glands, we refer not only to their influence on the in- tegrity of the uterus — anatomical and physiological — but also on the general metabolism, which is influenced to subserve the necessities of the special functions, and on the psychology of the individual. In the second part of our subject we shall confine our attention to those pathological conditions which are probably directly dependent on derangements of the normal morphological and physiological processes con- cerned in the sex-complex and considered in the first part of this work. PART I MORPHOLOGICAL PHYSIOLOGICAL AND PSYCHOLOGICAL CONSIDERATIONS At the commencement it is essential that we consider how far the internal secretions are concerned in pro- ducing and maintaining the feminine characteristics, and in ensuring the full development of the genital organs. Afterwards I shall support with experimental evidence the view that the internal secretions of the ovary alone are not the sole factors in the preservation of the integrity of the genital functions, once these have been fully established. SEX-CHARACTERISTICS Origin of primary cha- racteristics. Determina- tion of sex. PRIMARY SEX-CHARACTERISTICS It has always been considered that the primary sex- characteristics in the human subject are those peculiar to the genital organs, and especially to the gonads. I shall show later, however, that the primary sex-charac- teristics cannot be limited in this way. If we wish to seek for the origin of the primary characteristics, we are, of course, called upon to examine carefully the primary causes in the determination of sex. This question has been the subject of far more theorizing than of scientific investigation. I propose, therefore, but briefly to review some of the evidence at our disposal concerning the causation of sex. It is stated by Geddes and Thomson1 and by others that sexual dimorphism is found in protozoa — that 1 Geddes, P., and J. A. Thomson, The Evolution of Sex, 1901, Revised ed. PRIMARY CHARACTERISTICS 7 some cells exhibit a feminine tendency (anabolism), Defcermina- and others a masculine (katabolism). The conclusion of Geddes and Thomson is that u male and female are the results and expressions of relatively predominant katabolism and anabolism respectively". This conclusion may be, and probably is, perfectly true, but it does not explain how the differentiations came about. It is a statement of effect, not of cause. In the human subject the sexes are definitely differentiated : the species is dioecious. In certain of the lower animals, such as various species of worms, the sexual condition is monoecious ; that is to say, each creature has the genital organs of both sexes, and may be capable of fertilizing others of the same species and of being fertilized. The term commonly employed for this condition is ' Hermaphroditism •*• In bees there are three variations — perfect females, imperfect females and males. Further, in certain of the insects, such as the silk-worm moth, the development of an adult from the unfertilized ovum has been observed to occur occasionally. This is known as * Parthenogenesis \ It may be laid down, then, that generally speaking the higher the species stands in the scale of evolution, the greater is the differentiation between the primary characteristics of the two sexes. The various theories propounded concerning the Theories origin of sex emanate from three different points of view : theXter? (1) That sex is predetermined in the ovum and ^ineation spermatozoon. (2) That sex is determined at fertilization. (3) That sex is regulated subsequently to fertiliza- tion ; that is to say, sex-differentiation occurs during embryonic life. (1) With regard to the hypothesis that sex is pre- Predetermi- determined in the ovum and spermatozoon, it is obvious 1 In the sense just indicated it would be more correct to term the oondition * Structural Hermaphroditism', since in some worms and other invertebrates there may even be self-fertilization — a condition which should be known as • Structural and Functional Hermaphroditism \ 8 THE SEX-COMPLEX Predetermi- that very little direct information can be obtained con- nation o sex. cerning foe human species. Most of the evidence has, therefore, been derived from a study of the lower animals. The general hypothesis stated under this heading may be subdivided into the following alternatives : — (a) That sex is predetermined in the ovum (and possibly the spermatozoon) from the earliest development of the ger- minal cells, and that no alteration is possible ; (b) That, while the sex may be said to be predetermined in this way only for normal circumstances, altered conditions of nutrition and environment may affect the gametes, and thus influence the ultimate sex of the zygote. Dimorphi&m As to the unalterable primary determination of sex in the gametes which is propounded in the first subdivision, there is evidence that in some insects and in certain snails the spermatozoa are dimorphic. For instance, Henking1 found that some of the spermatozoa in the bug Pyrrhocoris possess an additional chromosome. This has been supposed to be an example of bisexuality in regard to the spermatozoa. According to Marshall2 it is certain that the ova, also, have one more chromo- some than the spermatozoa containing the lesser number. It is believed that the conjunction of ova with sperms having the greater number of chromosomes leads to the production of females, and the fusion of ova with the sperms having the lesser number to the development of males. Other investigators have shown that differences in the number of the chromosomes in the gametes are found in many species of insects, and that even in the fowl there are dimorphic spermatozoa. Beard3 and other observers believe that the sex- potentiality exists in the unfertilized ovum, and that when there are two kinds of spermatozoon in the same subject one variety is functionless. In this connexion it may be pointed out that it is, of course, quite an old 1 Henking, H., Zeitsch. f. Wiss. Zool, 1890, vol. xlix, p. 503. 2 Marshall, F. H. A., The Physiology of Reproduction, 1910, p. 623, 3 Beard, J., Zool. Jahrb. 1902, vol. xvi, p. 703, PRIMARY CHARACTERISTICS 9 view that in the female the ova in the right ovary produce Dimorphism one sex and those in the left ovary the opposite. This of sex-ceUs- wild assumption, however, is directly controverted by the simple facts that in birds, and to a great extent in the mammalian Ornithorhynchus as I have myself found, the right ovary atrophies and the left alone remains functional, and that women and animals from whom one ovary has been removed have subsequently borne offspring of both sexes. An extensive investigation recently completed has shown that either ovary, as judged by the presence of corpora lutea, may furnish ova that develop into male and female offspring \ It has been suggested by Bateson2 and others that Mendeiian J J. • A- - •" l\l « 1 laWS m r6la" pnmary sex-determination in the gametes is purely tion to sex- hereditary and conforms with Mendeiian laws. Even if £e0t£rmina" this were so in actual fact, it would be falsified by repro- ductive results ; for to obtain proof of this contention in regard to mammals it would be necessary to ensure the fertilization of every ovum, and that is impossible. With regard to the proposition contained in the second Bisexuaiism subdivision, Heape3 and many other writers hold that although the dominant sex may be predetermined in the gamete, yet there is in each a latent anlage of the opposite sex which may become active and predominant before fertilization under certain conditions of nutrition, parental vigour and general environment. Arising from this view, which I believe is correct, so far as it goes in the life-history of the individual, there have been a number of interesting studies concerning the ratio of the sexes, both in man and animals, under different conditions. From a statistical point of view the Effect of en- results are not satisfactory. On the one hand, it has been and nutrition. stated4 that in the aristocracy — presumably well-fed 1 Murray, J. G., Bull. Johns Hoph Hosp., 1918, vol. xxix, p. 275. 2 Bateson, W., Report to Evolution Committee of Roy. Soc, rep. i, 1902, Lond. 3 Heape, W., Proc. Camb. Phil. Soc, 1907, vol. xiv, p. 121. 4 Punnett, R. C, Proc. Camb. Phil. Soc, 1904, vol. xii, p. 262. 10 THE SEX-COMPLEX Effect of en- vironment and nutrition, Sex-determ- ination at fertilization. Sex-determ- ination sub- sequently to fertilization. and usually vigorous — sons are more numerous than daughters ; on the other, it has been believed x that, after the stress and indifferent nutrition which may result from a long war, male infants have been born in greater numbers than females. It is, however, almost impossible to obtain reliable statistics regarding the influence of nutrition, environ- ment and other indirect causes on the sex of the off- spring, because the factors concerned are often mixed or conflicting, and because infantile mortality plays such a large part in the final or apparent result — that is to say, in regard to the sex-ratio among adults. Be this as it may, the general opinion is held that under favourable conditions female births preponderate, and in unfavourable circumstances male. (2) The view that sex is determined at fertilization is also founded on biological evidence, for it is known that male bees and the males of certain other insects are developed parthenogenetically from unfertilized ova, while the females are produced from those which have been fertilized. Schenk2 and others have asserted that sex-determina- tion depends on the state of the nutrition of the ovum at the time of fertilization. This view was elaborated by Schenk, who claimed that by supplying the mother with a nitrogenous diet before conception he could increase the chance of the offspring being a male. Time, how- ever, has shattered these pretensions concerning the practical application of this theory, whether or not there be any substratum of truth in it. (3) We now come to the last view ; namely, that sex is determined subsequently to fertilization. It has been demonstrated by Yung3 that in tad- poles sex is not determined until late in that stage of the development of the frog ; and evidence has been obtained that nutrition affects the final outcome. 1 Geddes, P., and J. A. Thomson, Sex, 1914. 2 Schenk, L., The Determination of Sex, Eng. Trans., 1898. 3 Yung, E., Compt. Rend, de VAcad. dea Sci., 1881, vol. xciii, p. 562. DETERMINATION OF SEX 11 Similarly it has been shown by Cuenot * that the Sex-determ- differentiation of the gonads of maggots does not occur goquontiy to until the end of larval life. This observer found, fertilization. however, that the ultimate determination of sex in these creatures was not influenced by nutrition. For further biological details concerning the determ- ination of sex the writings of Morgan2, Marshall3, Geddes and Thomson4 and Doncaster5, to which I am largely indebted, may be consulted. In spite of all the information at our disposal, we Uncertainty must confess that the primary cause of sex-determination knowledge. is not definitely known, and at the same time express the opinion that since it is purely a physical question observations on animals will no doubt some day lead to a complete understanding of this matter. It is quite possible that there is more than one deciding factor. Meanwhile, it appears that no one view alone covers all the requirements, but that the truth is probably wider, and that many of the theories are correct so far as they go ; and that there is some truth in most of the views for which there is biological evidence, but not the whole truth in any one. At present in regard to the human species we only Every fertn- know, from pathological and clinical observations, that in the human there must be a latent but predominating tendency mb^uaiS every fertilized ovum towards masculinity or femininity, and that every fertilized ovum is potentially bisexual. It is obvious to all that in every person there is pre- dominating masculinity or femininity, which decides the sex-denomination ; but, at the same time, it is equally obvious that latent traits of the opposite sex are always 1 Cuenot, L., Bull. Sci. de France et Belg., 1899, vol. xxxii, p. 462. 2 Morgan, T. H., Experimental Zoology, Lond., 1907, p. 363. 3 Marshall, F. H. A., The Physiology of Reproduction, Lond., 1910, p. 623. * Geddes, P., and J. A. Thomson, The Evolution of Sex, 1901, Revised ed. 5 Doncaster, L., The Determination of Sex, 1914. 12 THE SEX-COMPLEX Every fertii- present : some men are described as being effeminate, ine?heVhiSian wnile many a woman has the smallest possible balance subject is 0f femininity in her favour. If further evidence of this bisexuality, which exists in everyone, were required, it is to be found in the embryological remains of the latent sex, which are always apparent in the genital ducts. These remains are invariable, and we must admit that it is in respect to the genitalia that there is the greatest difference between men and women — in some cases the only difference, according to our present standards. Unfortunately, however, the other charac- teristics showing less divergence have not been in- vestigated and compared with accuracy — we have, in fact, been satisfied with observing gross differences only. So much for the actual predisposition in the fertil- ized ovum towards maleness or femaleness : beyond conceiving theoretically that this is dependent on intracellular metabolism, which may possibly be subject to external interference, we know nothing definitely. Development When, however, we come to a consideration of the point of sex- further development of the ovum towards that point divergence. at wnich we can recognize sex-divergence — a term which I think best indicates the tendency of originally bisexual cells towards a predominating sex-characterization — then our knowledge becomes more definite. The organs of It appears probable that the potentiality to produce secretion and femininity, which exists in the earliest stages of segment- s?x- ation of the ovum, is directed towards the future divergence. development and correlations of the hormonopoietic organs that are subsequently to control the sexual evolution of the individual. This statement has been wrongly interpreted by certain critics to mean that the organs of internal secretion determine sex. It is, however, the original sex-potentiality that directs the activities of the organs in question, which them- selves form primary characteristics and influence the secondary. DETERMINATION OF SEX 13 It may, therefore, at once be stated emphatically Ovaries alone that the ovaries are not alone responsible either for^efor011" the primary or the secondary female characteristics, secondary O ll e\ Ve\ Pf"PT* We have very pertinent evidence on this point, to beistics. considered later, in the human monstrosities known as 'Hermaphrodites'. In certain of the invertebrates hermaphroditism to the fullest extent — that is with the power of fertilizing and of being fertilized — is well known, but generally speaking the higher we go in a consideration of the evolution of reproduction the greater do we find the differentiation of sex-character- istics and functions. It is probable, then — and I shall adduce much evidence on the point later — that many if not all the organs of internal secretion influence the primary genital characteristics ; and that all the hormonopoietic organs, as well as the gonads, have normally a primary tendency to produce either masculine characteristics and functions, or feminine. It has been stated that there is no evidence that the Differences in organs of internal secretion, other than the gonads, differ internal histologically in the two sexes1, although Kolmer2 claims secretion in . ° the two sexes. to have noted differences between the male and female suprarenals in rabbits, and Erdheim and Stumme3 have demonstrated the effect of pregnancy on the pituitary. But we need not be surprised at these differences of opinion, when we remember that although the special sex-elements — ova and spermatozoa — must necessarily be differentiated, the interstitial cells of the gonads, as we shall see in dealing with hermaphroditism, do not show any special tendency to produce either male or female secondary characteristics, as has been universally presumed hitherto. But since all persons are bi- sexual in varying degrees, one would expect to find in 1 Mcllroy, Louise, Discussion. Proc. Roy. Soct Med., (Obstet. and Oyncecol. Sect.) 1913, vol. vii, p. 76. 2 Kolmer, W.iPfluger's Archiv.f. Physiol, 1912, vol. cxliv, p. 361. 3 Erdheim, J., and E. Stumme, Beitr, z> Pathol. Anat. und z. Allg, Pathol., 1909, vol. xlv, p. 1. 14 THE SEX-COMPLEX Differences in the hormonopoietic organs — other than the generative i?nternSaif portions of the gonads— functional, even if there were secretion in no obvious structural, differences. This is an important S* point that has, strangely enough, been entirely over- looked, in spite of all the evidence from the pathology of the organs of internal secretion, to which I shall call attention later. SECONDARY SEX-CHARACTERISTICS Nature of secondary character- istics. Importance of secondary character- istics. At birth we distinguish the sex of the child by the character of the external genitalia, which in normal circumstances correspond with the internal genitalia. These genital features are generally held to constitute the primary characteristics. At the same time, as already indicated, were we able to recognize the differ- ences, we could claim primary sex-characterization, male or female, in regard to probably all the ductless glands. The secondary characteristics, however, constitute the sexe-ensemble seen not only with respect to the general conformation of the body and the details connected therewith, but also in connexion with the specialized functions peculiar to the sex, both physical and psychical. No doubt the secondary characteristics appeared after the differentiation of sex was evolved, to assist sexual selection and adapt the different species to their environment and conditions of reproduction. The secondary sex-differentiations vary considerably in different classes of animal life. In some, such as the rodents among the mammalian orders, the differences in the secondary characteristics of the two sexes are slight. In others, such as the birds, they are often most pro- nounced. The secondary sex-characteristics are to be noted not only in the various forms of external adornment, in the SECONDARY CHARACTERISTICS 15' reproductive differentiations and combative require- importance ments, but also in the metabolic factors of the physio- characte^7 logical economy. istics. Everyone is familiar with the ornamental feathers of the male Bird of Paradise, with the claspers of the male frog, with the antlers of the stag and with many other morphological sex-differentiations too numerous to enumerate. But behind these morphological variations lie physiological differences in the two sexes which are undoubtedly responsible for the more obvious morpho- logical features. It is known, for instance, that in some caterpillars the blood differs in colour in the two sexes, being green in the females and yellow or colourless in the males1. This, of course, indicates that the chemical composition of the blood is different in the two sexes. And differences — if less obvious than the example just mentioned — may be traced in the higher animals. Bucura2, referring to the researches of many observers, Far-reaching points out that the human male uses more oxygen than JJjJjJJfaji the human female, and that in men the blood has a character- higher specific gravity, more red corpuscles and a higher percentage of haemoglobin than in women. And these are only gross distinctions. The finer, and probably more important, have not been fully worked out, but I shall refer later to some of the differences which are dependent on the internal secretions, and are of the highest importance. Some day, perhaps, we shall be able to base our knowledge of these physiological and morphological dissimilarities on the variations to be found — both quantitative and qualitative — in the primary sex-characteristics of the hormonopoietic organs. In the human subject the secondary characteristics of the two sexes, when well-differentiated, appear to be strongly contrasted, as is shown in the following columns : — 1 Geddes, P., and J. A. Thomson, Sex, 1914. 2 Bucura, C. J., Qeschlechtsundterschiede beim Menschen, Wien und Leipzig, 1913, p. 12. 16 THE SEX-COMPLEX Far-reaching Man Woman ^etTndary Hair on face and trunk. Hair on head, but absent on character- face and trunk {apart from pubes and axillae). Larynx large. Voice deep. Larynx small. Voice high. Muscles powerful. Muscles relatively weak. Relatively long thorax and Relatively short thorax and short abodminal cavity. large abdominal cavity. Bones heavy and large. Bones light and small. Pelvis deep and funnel- Pelvis shallow and wide. shaped. Skin coarse. Skin fine. Stability of calcium meta- Instability of calcium meta- bolism, bolism. Psychical domination and Psychical dependence and certainty. hesitancy. These are merely examples of dissimilarities obvious to all. Many other differences — physiological, morpho- logical and psychological — might be emphasized, were it necessary to do so. The whole subject has been fully discussed in recent years by Kammerer1, Bucuras, Hofstatter3, Havelock Ellis4, and others, whose works should be consulted for further information concerning physical and psychical sex- variations. It should, how- ever, never be forgotten that Man is dimorphic, and that the prominence or otherwise of the secondary character- istics depends on the degree of masculinity or femininity present in any given individual. stages of It must be noted in passing that there are two stages ofelfc°ondarny in the development of the secondary characteristics character- jn ]yjan — a fact that requires special emphasis. The 1 Kammerer, P., AbderhalderC s Fortschr, der naturw. Forschung 1912, vol. v, p. 1. 2 Bucura, C, J., Geschlechtsundterschiede beim Menschen, Wienund Leipzig, 1913, p. 12. 3 Hofstatter, R.., Centralb. fur die Grenzgebiete der Med. u. Chir., 1913, voL xvi, p. 37. (This monograph is preceded by a list of 2324 references. ) 4 Ellis, Havelock H., Man and Woman, 1914, 5th ed. SECONDARY CHARACTERISTICS 17 first stage extends from birth until puberty. During stages of this period the development of sex-characteristics is of secondary slow : in the girl the mind is often not pronouncedly character- feminine, although girls are supposed to, and sometimes do, show a marked liking for dolls and sewing, in con- tradistinction to the preference of boys for balls and fighting. So, too, in girlhood the special characteristics of mammary development and plumpness are usually absent, and the genital functions are dormant. At puberty, however, there is a remarkable change, which is not only physical but also psychical. Normally, at this epoch a girl becomes shy, reserved, and essentially feminine in her pleasures and in her relations with men. We must now briefly consider the influence the influence of ductless glands exercise upon the pubescent develop- gj^nfaon ment of the female genital organs and their functions, pubescent ° ... development and upon the secondary characteristics in the normal of reproduct- woman. This part of the subject is one which, in its lve organs* pathological aspect, constantly confronts us in our clinical work. Although the genitalia may be normal morphologic- ally at birth (fcetal development), yet, as indicated already, they only become functionally active at puberty (complete development) if the whole hormonopoietic system is in perfect harmony, and is acting efficiently and normally in regard to its sexual functions. Thus, thyroid or pituitary insufficiency may cause the genital organs to remain infantile ; and we shall see later that disease of these structures may cause retrogression in the genitalia even after they have functionated normally. Further, it is believed that the gonads and uterus remain not fully developed until the thymus atrophies at the time of puberty1. At this period of life, owing to the withdrawal of the thymus secretion, as some think, the genital organs begin to develop ; other investigators, however, believe that it is the development of the 1 Compare p. 83 for discussion concerning the question of the status of the thymus in regard to internal secretion. The statements in this place are illustrations only. 2 18 THE SEX-COMPLEX influence of gonads which causes retrogression in the thymus1. It giTndfon is possible that both views are correct; for experi- pubescent mentally it has been found that removal of the ovaries development J of reproduct- leads to hypertrophy of the thymus, even after atrophy ive organs. ^ ^^ organ kas occurre(j in the normal course of events2, and that removal of the thymus in male guinea- pigs is followed by a rapid development of the genital glands3. It may be well to interpose a few words here by way of explanation and illustration of the inner meaning of the correlations that exist between the organs of internal secretion. One organ, such as the thymus, is not nor- mally antagonistic to another, such as the ovary, for any but specific reasons. Moreover, they probably counteract one another not only directly but also in- directly through the general metabolism. Pubescent To make the principle of this indirect effect clearer, of secondary kt us £° a little more fully into the illustration just given, character- j$ js believed, whether correctly or not is immaterial istics and the J metabolism, at the moment, that the thymus produces calcium retention in the tissues, and thus assists in building up the bony skeleton — in fact, animals from which the thymus had been removed were found by Basch4 and others to suffer with softening of the bones5. On the other hand, I have shown experimentally that the ovaries are katabolic in regard to the calcium salts6; and this is also indicated in certain pathological con- ditions to be mentioned later. Now the calcium meta- bolism, around which for the moment I am building up my argument, is differently employed, if I may so use the term, at three different periods of life. Until puberty calcium is chiefly utilized for building up the skeleton ; 1 Biedl, A., Inner e Sekretion, 1913, 2nd ed. 2 Calzolari, A., Archiv. Ital. deBiol, 1898, vol. xxx, p. 71. 8 Paton, Noel, J (mm. Physiol., 1904, vol. xxxii, p. 59. * Basch, K., Wien. Klin. Woch., 1903, vol. xvi, p. 893. 5 Compare p. 84. 6 Bell, W. Blair, 4ms and Gale. Lectures, Lancet, 1913, vol. i, p, 809. SECONDARY CHARACTERISTICS 19 after this epoch for reproduction ; and lastly, and Pubescent pathologically if the termination of life be pathological, J^^ for producing changes which are associated with senility character- ,7 . „ ,. i.i- istics and the — namely, the retention of lime salts in the tissues, metabolism. especially in the arteries. There is no need to allude to the many other important parts played by the calcium salts in the human economy at all periods of life. It must not, however, be thought that the thymus and ovaries alone influence the calcium metabolism, for, as in the metabolism of other elements, all the hormonopoietic organs are concerned, either anabolically or katabolically. And the same differences in regard to metabolic conditions are found in many — perhaps all — directions at the three essential periods of life which I have just described. As a natural consequence, we find that the Functions of functions of the organs of internal secretion differ not secretions only at different periods of life, but normally in different 4lge^J *?_ circumstances, such as those concerned with the inter- cumstances. mittent reproductive functions of women ; and not infrequently there is a coincidental alteration in structure, such as is seen in the pituitary and thyroid during pregnancy. Further work on these normal periodic variations is urgently needed. The reproductive functions in Woman are dependent on her specialized structures, both primary and secondary ; and I have just endeavoured in a broad way to show how structure and function are closely corre- lated in producing the tout ensemble. To sum up. In early life — that is to say, before Summary in puberty — the metabolism of girls is probably not very secondary0 different from that of boys: the chemical processes of both character- are for the most part engaged in promoting the growth of the body. At puberty, however, a remarkable change occurs, and it is at this period of life that the male becomes most widely differentiated from the female. As we have seen, this further development is due to the activity of the reproductive functions. In Woman the change is shown by the psychical and physical alterations which accompany the onset of menstruation. 20 THE SEX-COMPLEX Summary in As a rule, growth ceases at puberty, for with menstruation secondary there is a large excretion of calcium and the other sub- character- stances which previously were required for the formation of skeletal and other tissues, but which are now no longer wanted until pregnancy and lactation occur, when a fresh body is built up and nourished by the maternal metabolism ; consequently girls who menstruate early are often short, and vice versa. Character- The characteristic functions, then, of the female are ofwoman.0118 those associated with the genital activities— menstru- ation, gestation and parturition, and lactation. The menopause comes at the end of reproductive life, and marks the period at which the metabolism can no longer support the strain of reproduction. Functions Now, this cycle of functions is directly under the internal6 y control of the hormonopoietic organs. And it appears that secretions, although before puberty and after the menopause there is little difference between the metabolism of the male and female, yet during the reproductive period there is a considerable contrast, and this is reflected in the activi- ties and structure of the hormonopoietic organs1. The fact that the internal secretions influence the production of the fully-developed genital organs with normal functions is thus indicated generally, but we must now pass on to consider the relative part played by each member of the internal secretory system in the preservation of the integrity of these organs and their functions. 1 As I have been discussing sex-differentiation in normal circum- stances, no mention has been made of the remarkable selection different diseases, especially of the hormonopoietic organs, exercise in regard to sex, or of the different remote effects toxins may produce in men and women. These sex-selective aotions of pathological processes are most noticeably operative during the reproductive period. THE OVARIES The ovaries have two functions — the provision of ova, and the production of the specific internal secretion or secretions. The production of ova — a necessary process in reproduction — requires no further mention here, except in so far as the ripening of the follicles which contain the ova may be under the control of certain secretory elements of the ovaries. The questions, then, with which we are immediately concerned relate to the connexion of the internal secretions of the female gonads with cyclical phenomena in the ovaries and uterus in the non-pregnant subject and with the implantation of the ovum in the pregnant. With regard to 'heat' or menstruation1, there is no doubt that this function depends primarily on the normal development and subsequent integrity of the uterus, and with this the internal secretions of the ovaries are largely concerned. The relation of these internal secretions to the normal progress of gestation is, as we shall see, somewhat obscure ; for, although it is well known that the corpus luteum in the ovary of the pregnant female is consider- ably larger than in the non-pregnant, it is not certain that this hyperplasia has any more importance than that of an epiphenomenon. The internal secretions of the ovaries have never Ovarian been isolated ; indeed, it is still a matter of dispute as 1 Much confusion has been caused by certain authors attempting to look upon * heat ' in animals, such as the dog and rabbit, as a function different from menstruation. The details connected with the uterine changes are different certainly, but the functions are phylo- genetically the same. 22 THE SEX-COMPLEX Ovarian to how and where it is or they are produced. The only secretions. evidence that there is an internal secretion rests upon the results of extirpation, destruction and implantation ex- periments, and to a lesser degree on histological and clinical observations. The atrophy of the uterus which follows oophorectomy is believed to indicate the loss of some secretion which normally activates this organ. Some think that there is more than one secretion ; and various investigators have considered that, while different hormones are produced by the lutein cells of the corpus luteum, by the interstitial cells of the stroma of the ovary and by the membrana granulosa cells, these secretions all differ in regard to the degree of importance and the period of action to be assigned to each, and that the total effect differs in different animals. And herein lies one of the great difficulties in the study of our subject : different orders of mammals have organs of internal secretion which are structurally and functionally dif- ferent, although perhaps in degree only. Individuals in the same species may vary, both in animals and in Man ; consequently some of the contradictory state- ments made by different experimenters may be explained on the ground of these variations. It may be, for instance, that the secretion of the corpus luteum in women is much less important for the normal implanta- tion of the ovum than it is in rabbits1. It will make the subject clearer if I consider shortly the supposed activities of the different secretory elements in the ovary, arid reserve the discussion of the total effects produced by the removal of the secretions until later. SECRETORY STRUCTURES OF THE OVARY The follicular The follicular epithelium. — The cells which enclose epithelium, y^ ovura> an(j are known as the follicular epithelium, or membrana granulosa, are supposed by some to produce 1 See Effects of Oophorectomy, p. 29, Facing page 22. Fig. 1. The ripening of the Graafian follicle, x 300. The follicle is near the surface of the ovary. The'ovum is situated in the centre and surrounded by the cells of the membrana granulosa. The formation of liquor folliculi is seen proceeding among the cells of the membrana granulosa in various places. Eventually these collections of fluid merge together, leaving the ovum attached by a small mass of membrana cells (discus proligerus) to one part of the wall of the follicle. 24 THE SEX-COMPLEX The influence the factors concerned in the implantation of the fertilized of the cells of the corpus OVUm. luteum on with regard to the influence of the corpus luteum on cyclical ° . _ changes in the ovarian and uterine cycles — that is, on ovulation SeruVsaryandand on menstruation— it has been suggested by Beard1, Pr6nant2 and others, and experimentally established by Loeb3, that the corpus luteum of one period during its maturity prevents ovulation, and that removal of the corpus luteum, or corpora lutea, accelerates subsequent ovulation. In other words, ovulation is incompatible with the function of the corpus luteum. Pearl and Surface4 obtained confirmatory evidence of this by another method of investigation. They found that injections of an extract of corpus luteum prevent or retard ovulation in the fowl. Loeb's5 experiments of the same character on guinea-pigs were, however, not conclusive. Since the cyclical changes in the uterus are almost certainly dependent normally on cyclical ovarian activity, it follows that a cause that suppresses ovulation also, prevents menstruation or * heat '. In other words, the formation of a corpus luteum has a definite time relation- ship to the uterine cycle. And it appears that this is so in the lower animals, although accessory factors such as copulation may be required to effect the rupture of the ripe follicles; but in the human subject I, like Lawson Tait6 and others, have often observed the absence of any ripe follicle or corpus luteum in relation to menstruation. There is no doubt, therefore, that the whole question of the connexion between the uterine cycle and the ovarian cycle requires further investigation, in spite of the excellent work of Loeb and others to which reference has been made. 1 Beard, J., Anat. Anzeiger, 1897, vol. xiv, p. 97. 2 Prenant, A., Rev. Gen. des Sci, 1898, p. 646. 3 Loeb, L., Deuts. Med. Woch., 1911, vol. xxxvii, p. 17 ; Biol. Bull, 1914, vol. xxvii, p. 30. 4 Pearl, R., and F. M. Surface, Journ. Biol. GTiem., 1914, vol. xix, p. 263. 5 Loeb, L., Trans. Amer. Gynecol. Soc., 1917, vol. xlii, p. 172. • Tait, L., Med. Times, Lond., 1884, vol. i, p. 619. Facing page 24. Fig. 3. The origin of the lutein cells. X 350. The lutein cells are formed from the theca interna. At the right upper aspect the cells of the membrana granulosa are seen becoming detached from the layer of lutein cells. Facing page 25. Fig. 4. Section of the ovary of Ornithorhynchus, showing a corpus luteum. X 60. THE OVARIES 25 In regard to the influence of the corpus luteum on The influence the implantation and subsequent growth of the ovum the corpus evidence is conflicting. There is, however, no doubt i^pi^tation6 that in most, if not in all, mammals higher in the scale of the ovum. of evolution that the marsupials, the life of the corpus luteum is prolonged in pregnancy, whether it be that the corpus luteum undergoes hyperplasia to assist implantation, or because of implantation. I have studied the question from a morphological Corpus standpoint, for this method of investigation seemed morph1-' likerv to offer some solution of many of the difficulties °J°gfcai J J studies. in regard to the corpus luteum. The Ornithorhynchus, in which the young is born in an egg, and consequently is never attached to the mother, has a somewhat remarkable corpus luteum. I have not seen a very recent one, but in those in the specimens examined there is an enormous deposit of fibrous tissue around what appear to be lutein cells (fig. 4). Ultimately the whole becomes a ball of fibrous tissue (fig. 5). This arrangement does not seem at all favour- able to the absorption of secretion from the lutein cells. In marsupials the attachment of the ovum is most primitive, and one would expect to find a correspondingly unimportant corpus luteum. But this expectation is not borne out by facts, although Fraenkel and Cohn1 must have jumped to the conclusion mentioned, for they state that the corpus luteum in the marsupial is, like that seen in the monotreme (Ornithorhynchus), rudimentary. O'Donoghue2, however, has carefully described the corpora lutea in several varieties of mar- supials, and has shown that they are highly-developed structures. That this is so will be obvious from an inspection of figure 6, in which a fully-developed corpus luteum in the ovary of a marsupial (Perameles obesula) is seen to occupy a considerable portion of the organ, and to be composed of large cells of an epithelial type. If the importance of the corpus luteum increased with 1 Fraenkel, L., and F. Cohn, Anat. Am., 1902, vol. xx, p. 294. * O'Donoghue, C. H., Archiv. f. Mikr.Anat., 1914, vol.lxxxiv, p. 1. 26 THE SEX-COMPLEX The develop- the degree of fixity of the ovum in the uterus, one would c^pus°f * 6 expect to find that the higher the animal in the scale of luteum not evolution the more important has become the corpus the degree of luteum — that in Woman this structure is more active ovum.° e than in the rabbit and other lower mammals. Evolution, however, does not necessarily entail the advancement of every structure; some atrophy, and all are dependent for their development upon the necessities of the particular species. In the human subject, in carnivora and in rodents there is an actual embedding of the ovum ; but in ungulates the placental attachment is one of apposition, and there is no invasion of the maternal tissues as in rodents, carnivora, the primates and Man. Moreover, the corpus luteum of an ungulate has a very active appearance, both macroscopical (fig. 7) and microscopical (fig. 8). Probably, however, the uterine mucosa requires as much preparation for placental apposition as for trophoblastic digestion. Such facts are bewildering ; so the conclusion we must draw provisionally is, that, if the corpus luteum be an organ of internal secretion which assists the implantation of the ovum, the importance of it varies in different species, and probably it has more than one function1. I have dwelt on the difficulties of investigating the morphophysiology of the corpus luteum, for we encounter the same difficulties and obtain the same variability in our results throughout this subject of the Sex- Complex in our search after definite information. The inter- jne interstitial cells of the ovary, also, have attracted stitial cells of . . the ovary. much attention, and they, too, are believed to possess a special internal secretion. Limon2 first called attention to la glande interstitielle de Vovaire, as he termed it. Fraenkel3, also, has investigated this subject carefully. He compared the ovaries of forty-five different species of mammals, and found an enormous difference in the pre- ponderance of interstitial cells in the various organs. 1 See also p. 31. * , 2 Limon, M., Archiv. d. Anat. Micros., 1902-3, vol. v, p. 155 3 Fraenkel, L., Archiv. /. Gynak., 1905, vol. Ixxv, p, 443. Facing page 26. Fig. 5. Section of the ovary of Ornithorhynchus, showing a corpus nbrosum. X 60. Facing page 27. Fig. 6. Section of the ovary of a marsupial (Perameles obesula), showing a fully - developed corpus luteum. (From a section kindly lent by G.H. O'Donoghue. ) X 60. THE OVARIES 27 In the human ovary he could find no trace of an ' inter- The inter- stitial gland'. $£%£" All histologists are familiar with the structure of the human ovary (fig. 10), and the obvious scarcity of secretory cells, apart from those connected with the follicles. But if we examine the ovary of an adult rabbit and of certain other rodents, we see a most remarkable structure : nearly the whole of the organ is composed of a mass of cells which are epithelioid in character ; and equally striking is the appearance of the corpora lutea, the cells of which can only be distinguished, if at all, from the cells of the stroma by their larger size ; while the Graafian follicles are crowded round the periphery of the ovary as though pushed outwards (fig. 11). What does this extraordinary appearance in rodents indicate ? From very close observation of the corpora lutea in all the stages of development I have come to the conclusion that either they do not all undergo involution in this order as in the higher mammals, but that many of them ultimately form the so-called inter- stitial stroma-cells, or that the lutein cells are developed from interstitial stroma-cells which have already become specialized. If, however, we examine the ovary of a rabbit a few weeks old we find that it is composed entirely of pri- mordial ova and a few follicles, scattered evenly through- out the organ, and that these are separated by bundles of connective tissue. There is an almost entire absence of definite interstitial cells (fig. 12). The absence of these cells in the very young rabbit also indicates the likeli- hood of their origin from the same source as — if not actually from — those of the corpora lutea in the adult, although it is probable that in the human ovary and in the ovaries of animals which contain very few inter- stitial cells these cells arise entirely from specialized stroma-cells. In approaching the question of the function, or functions, of the interstitial cells of the ovary we are arrested by the uncertainty of our knowledge concerning 28 THE SEX-COMPLEX The inter- the origin of these cells. Are they always derived from the^ovary!3 * corpus lutea or from the stroma-cells of the ovary; or is there one mode of origin in some species of animals and another in others ? I incline to the view that the interstitial cells, as they are known to us, have this dual origin. Whether, on the other hand, we are entitled to call the cells interstitial when they arise from the corpora lutea is another question, for such a standpoint seems to me to complicate a clear understanding of their function. In the following remarks it will be apparent how confused the subject becomes if we admit derivatives of the corpora lutea into the discussion, as necessarily we must in the present state of our knowledge and of our terminology. Ancel and Bouin1, and, with certain restrictions, Loeb2 advance the hypothesis that the interstitial cells inhibit ovulation in animals, such as the rabbit, that do not ovulate spontaneously, in which species these cells are plentiful (fig. 11); and it is in these very animals that the evidence points to the origin of the interstitial cells from the corpora lutea. It may be said, therefore, that the interstitial cells in the animals just mentioned play the same part — already described (p. 24) — as that fulfilled by the cells of the corpora lutea in those animals in which ovulation occurs spontaneously, and in which, therefore, periodic corpora lutea are formed. If we examine the ovary of a carnivore, such as the cat (fig. 13), we see the interstitial cells may truly be described as such, and in no way can they be considered derivatives of the corpora lutea. I have found experimentally that in the rabbit the so-called interstitial cells when grafted are capable of keeping the uterus active (see p. 47). Again, it is commonly supposed that the interstitial cells of the testes and ovaries are responsible for the 1 Ancel, P., et P. Bonin, Gompt. Bend. Soc. de Biol, 1909, vol. lxvi, p. 497. 2 Loeb, L., Trans. Amer. Gynecol. Soc, 1917, vol. xlii, p. 172. Facing page 28. :. •0 Fig. 7. A. — Ovary of the cow, showing a corpus luteum associated with the oestrum. B. — Ovary of the human subject, showing a corpus luteum associated with menstruation. Facing page 29. Fig. 8. Section of the ovary of the cow, showing on the right side the cells of the corpus luteum in which new vessels are being formed. X 60. EFFECTS OF OOPHORECTOMY 29 secondary sex-characteristics. I do not know on what The inter- ' ial cell ovary. grounds such a supposition has arisen, for it is contrary l^Qla> to all available evidence. In those animals in which the interstitial cells are prominent many of the secondary characteristics of sex are noticeably indecisive. Further, I shall show in the second part of this book that in the human subject the possession of a profusion of interstitial cells in the gonads may be associated with secondary characteristics of sex opposite to that represented in the genital glands. My own experiments concerning the functions of the Experiments ovary as a whole have been carried out on dogs, cats and ^^^ifl^ rabbits. As already stated, the ovaries of the carnivora functions of resemble in structure the human ovary more closely than is the case with the ovaries of rodents. The methods of investigation have consisted in noting the effects of oophorectomy on the pregnant and non-pregnant uterus, on the other ductless glands and on the general meta- bolism, and of the influence of grafts in various circum- stances. EFFECTS OF OOPHORECTOMY ON THE GENITAL FUNCTIONS AND ON THE STRUCTURE OF THE REST OF THE GENITALIA1 Effect of oophorectomy on the non-pregnant Atrophy of uterus. — Some years ago, in conjunction with Hick, the muscle- m coats oi tne I pointed out that the first effect of oophorectomy on uterus foUow- the uterus was the production of atrophy in the muscle- tomy?P coats2. Figure 14 shows the normal uterus of the cat with its two muscle-coats, and figure 15 that of the same cat 238 days after oophorectomy. We concluded that the normal muscle-contractions were abolished 1 Most of the experimental investigations, not otherwise indicated, concerning the functions and interrelations of the hormonopoietic organs detailed in Part I of this work were first described in the Arris and Oale Lectures in 1913, to which reference will not be made in this connexion, 2 Bell, W. Blair, and P, Hick, Brit. Med. Journ., 1909, vol. i, p, 655. 30 THE SEX-COMPLEX Atrophy of the muscle- coats of the uterus. Abortion following oophorec- tomy in pregnancy. Author's experimental results. and that atrophy supervened, especially of the circular muscle-coat. This has been confirmed by Marshall and others. Effect of oophorectomy on the pregnant uterus. — Prenant1, and later Born and Fraenkel2, were probably the first to call attention to the importance of the lutein cells ; and the ' last named showed that removal of the ovaries early in gestation leads to abor- tion in pregnant rabbits. Hick and I, also, invariably produced abortion by the removal of both ovaries in these animals3, as the following experiments show : — (a) Control experiment — Black doe. Opened in the anticipation that she was a few days pregnant. Pregnancy could not be detected, but the ovaries and uterus were examined and handled, and the abdomen closed. There was no further connexion with the buck. Twenty-three days later a single young one was born alive. This case was, there- fore, regarded in the light of a control experiment. (b) Grey doe. Oophorectomy was performed on the seventh day of pregnancy. The uterus was enlarged and small nodules were visible. No abortion was seen to occur. On the thirty-third day after operation the abdomen was opened, and the uterine cornua were found to be very small. Abortion had undoubtedly occurred, and been followed by atrophy of the uterus. (c) Black doe. Oophorectomy was performed on the fourteenth day of pregnancy. Abortion took place on the following day. The animal was killed twenty days later when the uterus was found to be atrophied. (d) White and grey doe. Oophorectomy was per- formed on the twentieth day of pregnancy. Abortion occurred on the following day. Other similar experiments were performed on rabbits, with the invariable result that abortion occurred in every case in which oophorectomy was performed. 1 Prenant, A., Rev. Gen. de Set., 1898, p. 646. 2 Fraenkel, L., Archiv. f. Gynak., 1902, vol. lxviii, p. 438. 1 Bell, W. Blair, and P. Hick, Brit. Med. Journ., 1909, vol. i, p. 655. Facing page 30. Fig. 9. Section of the human ovary, showing the lutein layer of cells. X 60. Facing page 31. W®®%Mk Hm ,-W- i^g Fig. 10. Section of the human ovary, showing a Graafian follicle, a corpus fibrosum and the stroma. ! X 60. EFFECTS OF OOPHORECTOMY 31 Great care was always taken neither to expose the Author's uterus, nor to handle it, and the operation was always reSs?6n complete in a few minutes. There has been much discussion in connexion with this question since oophorectomy was first performed experimentally during pregnancy by Fraenkel1 at the suggestion of Born. Fraenkel claimed that the secretion of the corpus luteum was necessary for the implantation of the ovum. There are, however, still those who assert that the necessary operative manipulations cause the abortion which usually occurs. I am inclined to think Oophorec- that it is not the operative manipulation in view of our ne^Ladiy10 control experiments. At the same time, I do not think cfusf. . • -it it* abortion in that a comparison can be made between rabbits and Woman. the human subject in this respect, for there are authentic cases on record in which the ovaries or corpora lutea have been removed from women early in pregnancy — in one case, in the second week (Essen-Moller)2, and in another of my own rn the seventh week — without the interruption of gestation. There could be no doubt in cases observed in women that the whole of both ovaries had been removed if parturition were followed by the artificial menopause. It would be accurate, therefore, to say that while, on the one hand, the internal secretion of the corpus luteum is favourable to the implantation of the ovum and continuation of pregnancy, yet, on the other, this secretion is not absolutely essential in that respect — at any rate, in the human subject. The work of Loeb3, indeed, indicates that in the lower animals the secretion of the corpus luteum is specifically concerned in sensitizing the uterine mucosa in which by mechanical stimulation a deciduoma— resembling the decidua of pregnancy — can be produced. 1 Fraenkel, L., Archiv. f. Oyndh., 1902, vol. lxviii, p. 438. 2 Essen-Moller, E., Centralbl. f. Gynak., 1904, vol. xxviii, p. 869. 3 Loeb, L., Joum. Amer. Med. Assoc, 1908, vol 1, p. 1897 ; Biol* Bull, 1914, vol. xxvii, p. 30. 32 THE SEX-COMPLEX EFFECTS OF OOPHORECTOMY ON THE GENERAL METABOLISM I performed the following experiments to test the effect of this operation on the general metabolism. It may with some justice be urged that metabolism experi- ments can only be of relative value unless the total intake and total output are estimated. But even in such estimates it is impossible to gauge in the excretions the results of tissue-destruction. The ovaries were removed from six cats which were kept subsequently to operation for periods ranging from 99 to 245 days. The urine was collected and fully examined at frequent intervals, both before and after operation. Author's In table I are brought together a number of records rSiite!1611*8,1 wnicn represent the averages of the 24-hours' specimens of urine collected and examined before and after opera- tion. The tables were worked out in this way, as it seemed the best for indicating the total results. All metabolism experiments require most careful handling, and the complete records here given show clearly why contradictory results have been obtained by various observers dealing with insufficient material. As I have already stated, there are both normal and abnormal individual variations in animals, just as there are in women under apparently similar circumstances. All my animals were kept together and fed on the same food. The urines were collected in special metabolism cages — not all on the same days, of course, owing to the number of these cages being limited. With regard to the details to be found in this table, it will be noticed that the daily total quantities of urine collected are not stated. I have records of these, but they have been omitted because it is rarely pos- sible in an ordinary way to make sure of collecting all the urine, and because animals, unlike women, do not pass a uniform quantity daily. I have, therefore, Facing page 33. \_ ^ ■*«a Fig. 11. Section of the ovary of the adult rabbit, showing the Graafian follicles pushed to the surface by the interstitial cells among which is lying a large corpus luteum — in the lower quadrant on the right side of the field. X 60. EFFECTS OF OOPHORECTOMY 33 thought it better to give the specific gravities and deal Author's in percentage quantities rather than total amounts. All resPuTtsmei these estimations were carried out in the Biochemical Laboratory in the University of Liverpool by a chemical assistant trained in this kind of work. Since there was inevitably a slight irregularity in the individual results, and as I had a sufficient number of animals, an average estimation of all six cases was worked out (table II) ; and from this the conclusions were drawn. It will be noticed that there is not a great difference in the averages of the specific gravities before and after operation. After oophorectomy the calcium excretion Diminution is reduced by one-half, and the chlorides are slightly Cretion after diminished. The phosphorus excretion is seen to be 0°Phorec- much increased, as are the total nitrogen and urea percentages. The ammonia is found to be slightly increased : it will be observed, however, that there is no change of any importance in the ammonia-coefficient. Knowing that there are considerable variations in the nitrogen metabolism in the normal animal we cannot regard the differences recorded in this respect as being abnormal. The increased phosphorus excretion might be considered somewhat curious in view of the definite decrease in the excretion of calcium by one half, but it is believed that there is no definite and certain relationship between the calcium and phosphorus excretions. McCrudden1, relying on what appear to be two carefully planned experiments, in which the composition of the food taken in was known and compared with the subsequent excretion in the faeces and urine, states that he found an increased calcium excretion after oophor- ectomy. At first sight the experiments appear flawless ; but an examination of the tables given soon reveals figures which require considerable explanation. In the first place, it seems incredible that each animal ate to the fraction of a gramme the same amount of food in the 1 McCrudden, F. H., Journ. Biol. Chem., 1910, vol. vii, p. 185. 3 34 THE SEX-COMPLEX Diminution same number of days before and after operation. cret^nTtef" Further, of the two bitches, weighing 13 lb. and 16 lb. oophorec- respectively, the former excreted a total of 0-529 gramme of CaO in 20 days before operation, and 0*532 gramme in the same period after operation — a very slight increase ; while the latter excreted 6*745 grammes of CaO in 20 days before operation, and only 1*869 grammes in the same time after operation. Surely these are extra- ordinary figures on which to base the conclusions at which this investigator arrived ; for the last animal excreted before operation about three and a half times as much CaO as she did afterwards, and the first an infinitesimal amount more after operation than before. This is confirmatory of my figures, and diametrically opposed to McCrudden's own statements. Louise Mcllroy1, working with a somewhat similar method on one animal only, also states that the output of calcium is increased after oophorectomy. Her work was carried out to confirm that of McCrudden ; and she gives no figures to enable us to check her conclusions. Curatulo and Tarulli2, also Neumann and Vas3, found a reduction in the excretion of calcium and phos- phorus after administering ovarian substance. Luthje4 could find no change in the metabolism after adminis- tration. Heymann, quoted by Biedl6, found reduction in the phosphorus content of the bones of rats after oophorectomy. Growth of In young animals there is almost always an increase oophorec- above the normal in the growth of the long bones after tomy. oophorectomy, due to delay in the ossification of the epiphysial cartilages. It may be of interest to call attention to a few other 1 Mcllroy, Louise, Proc. Boy. Soc. Med., 1912, vol. v, p. 369. 2 Curatulo, G. E., and L. Tarulli, Centralbl f. Gyncik., 1895, vol. xiv, p. 555. 3 Neumann, S., and B. Vas, Monatsch. /. Oeb. u. Gynak., 1902, vol. xv, p. 433. 4 Luthje, H., Archiv. f. Exper. Pathol, u. Pharmakol, 1902, vol. xlviii, p. 184 ; 1903, vol. 1, p. 268. 6 Biedl, A., Innere Sekretion, 1913, 2nd ed. Facing page] 34. Fig. 12. Section of the .ovary of the young rabbit, showing primordial ova and young Graafian follicles scattered throughout the organ, and separated bv bundles of connective-tissue cells. by X 250. Facing page 35. './ Fig. 13. Section of the ovary of the cat, showing ova near the surface, a Graafian follicle, and interstitial cells separated into groups. X85. OOPHORECTOMY AND THE METABOLISM 35 facts which afford evidence contributory to the view Other evi- that the ovaries are concerned in promoting calcium ceTmngvVew excretion. During pregnancy and for at least the first that ovaries few months of lactation the function of the ovaries is in calcium in abeyance in regard to menstruation, and at these times first the fcetus and then the mammary glands utilize all the available calcium ; indeed, the mother's calcareous tissues are sometimes drawn upon to her detriment. Menstruation in the human female, according to my views, is a function under the control of the ovarian and other internal secretions whereby the subject excretes, more or less regularly, the superabundance of chemical products that she delivers to her child when she is pregnant or is secreting milk. In both of these circum- stances menstruation is normally absent. I have found that menstrual discharge may contain a quantity of calcium as much as thirty times greater than that found in the systemic blood.1 With regard to the mammary secretion, although it is so intimately connected with the genital functions, it is in reality of subsidiary importance ; that is to say, the secretion of milk is produced by a special arrangement of the general metabolism in response to various hormones connected with the necessities of the occasion. In women there is sometimes no response. Lactation is one of the side-issues, and the metabolic processes connected with the production of milk are comparable with those which provide for the building up of the fcetus in the uterus. The mammary secretion will, however, be discussed at some length later. Again osteomalacia, to which, also, attention will again be directed, has often been cured by the removal of the ovaries ; and this result indicates the production of a condition of calcium retention in the tissues. My experi- ments are, therefore, supported by clinical observations. 1 Bell, W. Blair, Proc. Roy. Soc. Med. (Obstet. and Gynaecol. Sect.), 1911, vol iv, p. 234 ; Journ. Pathol, and Bacteriol., 1914, vol, xviii, p. 462. 36 THE SEX-COMPLEX Other evi- dence con- cerning view that ovaries are concerned in calcium excretion. Adiposity after oophor- ectomy. The ovaries and the processes of oxidation. In this connexion the experiments of Pearl1 are extremely interesting, although they require confirma- tion. This investigator has found that when moderate doses of calcium salts are added to the food of fowls the cocks are unaffected, whereas the hens show a greatly increased rate of growth in comparison with the controls. Further, the egg-laying capacity of the hens so treated was, in a given time, found to be five times greater than that of the controls. When extract of corpus luteum was given at the same time the effect of the calcium on growth was prevented. The adiposity which is seen in castrated animals probably resembles that which occurs in over fifty per cent, of all women at the menopause. It has been stated that this adiposity is due, in these circumstances, not only to ovarian insufficiency but also to a coinci- dental reduction in the activities of the pituitary and thyroid. Loewy and Richter2 found that in an estimation of the total metabolism, as expressed by the consumption of oxygen and excretion of C02, oophorectomy causes a diminution in the proportion of 14 to 20 per cent, per kilogramme in the processes of oxidation Murlin and Bailey3 and other investigators have obtained confirmatory experimental results. Biedl4, quoting and commenting on these findings, states that strong evidence of their accuracy is to be obtained by the administration of ovarian extract, which, he asserts, will raise the lowered metabolism in castrated animals to as much as 30 to 50 per cent, above the standard obtaining before operation — an effect which cannot be produced in the case of the normal subject. It is well known, of course, that from a casual 1 Pearl, R. , Science (Lancaster Pa.), NewSer., 1916, vol. xliv,p. 687. 2 Loewy, A., and P. F. Richter, Ceniralbl. f. Physiol., 1902, vol. xvi, p. 449. 3 Murlin, J. R., and H. Bailey, Surg. Qyn. and Obstet., 1917, vol. xxv, p, 332. 4 Biedl, A., Innere Sekretion, 1913, 2nd ed, Facing page 36. I / /?"*" j :/<'* ; .'•.'•"•.:.<■'•'•:•••'•'• • • A-v—I-v V'A ,v;-::. ...j j.^v: V-V' / ;^------ •••:••• /(-;0 AS*/.;.-;-, V--' v- - - 1 ° ' T. .,' ,* ■ V .- v "v. "Vio''' •.•;••■•.?•.•■:•'•■•-.•. ; ! *£•% v;;;:';iV<.-.'-.'-'---xr; •:•- &*$&$ *&& Fig. 14. Section of the cat's uterus, showing the normal muscle- coats. X 60. Facing page 37. Fig. 15. Section of the cat's uterus, illustrated in figure 14, 238 days after oophorectomy, showing atrophy of the muscle coats. X 60. OOPHORECTOMY AND THE METABOLISM 37 inspection of adult animals which have undergone General oophorectomy we can detect no outward alteration ofphorec- except perhaps some degree of adiposity, yet apparently tomv- there is a constant depression of the total metabolism, with alterations in regard to the calcium retention and phosphorus excretion as shown by the urinary analyses. On the other hand, we know from clinical experience that easily recognizable changes may occur in women in whom an artificial menopause has been induced by oophorectomy. At the same time, it has been a matter of very lively speculation why one woman should suffer with all manner of symptoms when her ovaries are removed, and another escape with very little or no dis- comfort. This is another reason why experimentation on animals has to be very carefully considered. The metabolism of women is much more easily disturbed than that of the lower animals ; and psychoses and neuroses, which are not observed after oophorectomy in animals, are often the source of the greatest distress in women. Recently Hoskins and Wheelon1 have shown experi- Oophorec- mentally that in animals oophorectomy is followed in a sympathetic ! few weeks by increased excitability in the sympathetic system. nervous system. They accept the view that this is due to some disturbance in the calcium metabolism2. In addition to certain constant and positive results, which are always reliable in regard to the metabolism, experimentation provides us with other most useful information ; and this information is just that which we cannot obtain in our clinical work, although Pathology may indicate the causal factors in many obscure phenomena. I refer to the effects produced on the other hormonopoietic organs by removal of the ovaries. No doubt the differences in the effects produced by 1 Hoskins, R. G., and H. Wheelon, Amer. Journ. Physiol., 1914, vol. xxv, p. 119. 2 Bell, W. Blair, The Principles of Gynaecology, 1st ed.. 1910 : Liver p. Med, Chirur. Journ., 1912, vol. xxxii, p, 398. 38 THE SEX-COMPLEX Variations oophorectomy in women are largely dependent on the of o6phoroc-S individual variations which we know exist with respect tomy in the to the adjustments of the internal secretions, and which human subject. are often evident in the outward characteristics of adiposity and thinness, lethargy and brightness, and in many other physical and psychical attributes. It is clear, therefore, that if one woman be better adjusted than another against the removal of the ovarian secretion she will show lesser signs of the menopause. Animals do not vary to the same extent ; they all seem to have remarkable powers of readjustment. But, with the higher psychical evolution of Woman it is not surprising that removal of the ovaries often causes in her a severe alteration of temperament. It has been supposed that the changes which occur in other members of the internal secretory system after removal of one of their number are in some cases com- pensatory, and, consequently, that disturbances in the metabolism may thus be made good or prevented. EFFECTS OF OOPHORECTOMY ON THE THYROID Changes in If we were to select any other order of mammal after osphor-'than the rodent we should come to the conclusion that ectomy most j^g alteration in the functional activity of the thyroid rodents. after oophorectomy was of little or no importance in so far as histological evidence was concerned. For instance, in the cat I have been unable to detect any material difference after oophorectomy in the thyroid itself or in the parathyroids. But when the thyroid of a normal female rabbit is compared with the thyroid of another animal of the same species after removal of the ovaries a very different picture may be seen. The thyroid of the normal non-cestrous and non- pregnant female rabbit is not a very active organ so far as the production of colloid is concerned (fig. 16). But after the removal of the ovaries the vesicles are greatly distended with colloid (fig. 17). Further, one notices that the colloid is basophil in character, and Facing page 38. Fig. 16. Section of the thyroid of the normal rabbit, showing but little colloid in the vesicles and much interstitial tissue. X 60. Facing page 39. Fig. 17. .Section of the thyroid of the rabbit after oophorectomy showing distension of the vesicles with basophil colloid. (Direct colour photomicrograph). OOPHORECTOMY AND THE THYROID 39 therefore stains blue with hematoxylin instead of pink changes in with eosin ; whereas the normal thyroid colloid is, of ^tor oophor- course, acidophil and stains with eosin. octomymost Before attempting any explanation of the changes in rodents. the thyroid after oophorectomy, we must not forget that this organ in the pregnant rabbit shows a relatively great increase in the amount of colloid, but it is then eosinophil in character. This is not the place to discuss the significance of the normal colloid collections in the vesicles, as opposed to the absence of colloid seen in conditions associated with excessive function. There can, however, be little doubt that the normal thyroid of the non-pregnant adult rabbit is not a very active structure, because removal causes little or no disturb- ance, an observation I have myself made on many occasions. On the other hand, in pregnancy, when, as is well known, increased thyroid activity occurs, we find that the colloid content is increased to a considerable extent in these animals, as already stated. It may, then, safely be asserted that there is a con- Comparison siderable increase in the functional activity of the thyroid, colloidal so far as colloid production is concerned, in rodents after ^thyroid oophorectomy. Why the colloid should be basophil and the instead of eosinophil we can only conjecture. The ques- p tion of an artefact has been carefully considered, but this explanation must be rejected for many reasons, into which we need not enter here. We are, however, assisted in our attempt to arrive at a conclusion by observations made on the pituitary body, to some of which fuller refer- ence will be made later. The normal colloidal secretion of the anterior lobe and pars intermedia of the pituitary is basophil, but under conditions of increased activity it may be eosinophil. Further, as with the thyroid, in a condition of greater hypophysial activity no * colloid' is formed, but the secretion is abstracted directly from the eosinophil cells. In the state of the greatest activity of all the secretion is directly abstracted by the blood or lymph from faintly staining basophil cells — the so-called ' chromophobe ' cells. There is, in fact, 40 THE SEX-COMPLEX Comparison a cycle of events to be demonstrated in the hypophysis coUofdai according to the needs of the moment. It is probable, tnerth°n,df then' tliat the basoPnil colloid found in the rabbit's and the thyroid after oophorectomy represents a storage secre- pi ui ary. tion, wnich is formed to meet the altered conditions of metabolism, but which is not of a great degree of physiological activity in this order of mammals. Reason of As we have previously suggested1, the inactive oTtto tayroid thyroid which is found in rodents is probably related to m rodents. the Very remarkable development of the interstitial cells in the ovaries of these animals. In consequence of this a marked change is produced in the thyroid of rodents by oophorectomy, and not to the same degree in other mammals, such as the carnivora. Moreover, thyroidectomy is comparatively harmless in rodents. Some haye argued, however, that the distance of the parathyroids from the thyroid in herbivora prevents their removal at the operation, and that the effects produced in carnivora by thyroidectomy are due to the removal of the parathyroids (see p. 50). This is not necessarily so, for I have been able to keep alive a cat with myx oedema for over a year. McCarrison2 and others, however, have pointed out that the thyroids of animals of the same species kept under similar conditions vary enormously. EFFECTS OF OOPHORECTOMY ON THE THYMUS Hypertrophy Calzolari3 first stated that castration produces afte/o^phor- hypertrophy of the thymus. His experiments were ectomy. carried out on rabbits. It has, also, been noted by Marrassini4 and by Gellin5 that castration after genital activity has been established gives rise to enlargement of the thymus. No work has been done in regard to 1 Bell, W. Blair, and P. Hick, Brit. Med. J own., 1909, vol. i, p. 655. 2 McCarrison, R., Lancet, 1914, vol. i, p. 931. 3 Calzolari, A., Archiv. Ital. de Biol., 1898, vol. xxx, p. 71. 4 Marrassini, A., Archiv. Ital. de Biol., 1910, vol. liii, p. 419. 6 Gellin, O., Zeitsch. f. Exper. Pathol, u. Therap., 1910, vol. viii, p, 1, OOPHORECTOMY AND THE SUPRARENALE 41 women, but eunuchs have been found to possess thymus Hypertrophy glands which have not undergone involution. after^Tphor- In experiments on cats I found the thymus rather ectomy. larger after oophorectomy than in the normal adult animal ; and on section the gland appeared to resemble the normal organ in the active stage before puberty. It is, however, extremely difficult to base definite assertions on such foundations. The significance of these points will be discussed later when the thymus gland is considered in more detail. EFFECTS OF OOPHORECTOMY ON THE PINEAL I have myself made no observations concerning the pineal gland after oophorectomy — indeed, very little physiological work has been done in this connexion. In 1912 Biach and Hulles1 published a paper in which they gave the results of castration of male and female kittens a few weeks old. The animals were kept sub- sequently for periods of seven or eight months. These investigators arrived at the conclusion that atrophy of the pineal gland occurred in all cases. Other observers have been unable to find changes in this organ in these circumstances. Later I shall consider the effects on the genital functions of pathological changes in the pineal. EFFECTS OF OOPHORECTOMY ON THE SUPRARENALS I have examined many suprarenals after oophorec- Hyperplasia tomy in rabbits and cats, and have found that there after^ophor- appears to be a definite increase in the reticulated portion ectomy. of the cortex at the expense of the zona fasciculata. What the interpretation of this is I cannot say, unless it be that the removal of an antagonistic secretion allows hypertrophy to occur in the part concerned. 1 Biach, P., and E. Hulles, Wien. Klin. Woch., 1912, vol. xxv, p. 373. 42 THE SEX-COMPLEX EFFECTS OF OOPHORECTOMY ON THE PITUITARY The close relationship between the pituitary body and the genital system has long been recognized, and I have made a number of observations concerning the effect of the removal of the ovaries on this intracranial organ, and vice versa. interpreta- The interpretation of the first mentioned of these in the leslons observations necessitates the formulation of definite pituitary. ideas as to what the changes observed in the pituitary mean. We read of ' hyperplasia ', or of ' increased activity ' of the anterior lobe, which can convey little meaning to anyone until we have decided what are the appearances associated with increased activity and the reverse in the pituitary body. So far, tentative views only have been put forward, and no very decided state- ments have been made concerning this complex and interesting organ. The pituitary consists of three parts — the pars anterior, the pars intermedia, and the pars nervosa. To each of these various portions, or perhaps more especially to the pars anterior, and to the pars posterior — which comprises the pars intermedia and pars nervosa — have been assigned different functions, concerning which investigators are still very much in disagreement. Thus, we find that Harvey Cushing arrived at the definite conclusion, as the result of the experiments of himself and his fellow- workers1, that the anterior portion was largely concerned in the well-being of the genital organs, and in the metabolism of the carbohydrates and of the bony skeleton. As the result of some clinical observations he completely changed his opinion, and now asserts2 that it is the posterior lobe which is responsible for the integrity of the genitalia, and for the carbohydrate 1 Crowe, S. J., H. Cushing, and J. Homans, Bull. Johns Hopk. Hosp., 1910, vol. xxi, p. 127. 2 Cushing, H., The Pituitary Body and Its Disorders, 1912. Facing page 4^. mm S 1 1 f^% * i '♦1 *p. . ■ Fig 18. Section of the normal pars anterior in the human subject, showinj. basophil, eosinophil and neutrophil cells. (Direct colour photomicrograph) . 500. OOPHORECTOMY AND THE PITUITARY 43 metabolism. Bernhard Fischer1 had previously pro- pounded this view. After careful consideration and observation I have The pituitary come to the conclusion that we must look upon the organ? °ne pituitary body as one organ, and not two. In this way only can we reconcile all the facts of morphology, experimentation and clinical observation. The secretion of the active chromophobe cells of the anterior lobe, such as are seen in pregnancy, is probably not greatly different from that of the pars intermedia before it is altered in the way about to be described. The secretion of the cells of the pars intermedia, which are develop- mentally the same as those of the pars anterior, may be regarded as pro-infundibulin, and it is only after passing into the pars nervosa that this pro-infundibulin becomes modified and acquires pressor qualities2. In connexion with this passage of secretion into the pars nervosa there are many other very important and interesting facts which are not actually concerned with our subject, so I refrain from discussing them here3. Next, we must come to some definite conclusion Differential concerning the interpretation to be placed upon the reactions of remarkable differences in staining properties possessed cells in tne pars anterior^ by the cells of the anterior lobe. Although these variations in staining affinities are well known, I must recapitulate them here in order to explain my own views concerning their significance. The cells, then, of the anterior portion are chromophobe or chromophil; that is to say, they stain indifferently or well. The chromophil cells are either eosinophil (acidophil) or haematoxylinoph.il (basophil) : with eosin the cells stain pink, and with haematoxylin blue. The chromo- phobe cells stain lightly with haematoxylin (fig. 18). 1 Fischer, B., Hypophysis, Akromegalie und Fettsucht, 1910. 8 This statement was published (Lancet, 1913, vol. i, p. 814) before the recent work of P. T. Herring {Quart. Joum. Exper. Physiol, 1914, vol. viii, p. 245). 8 A full discussion of the subject will be found in The Pituitary, 1919. 44 THE SEX-COMPLEX Views con- There are two opinions held concerning this extra- sfgnmcance ordinary grouping. The one, first put forward by of staining Saint-Remy1 and Benda2, finds expression in the belief pars anterior, that these appearances represent different phases of secretory activity; whereas the alternative view, pro- pounded by Gemelli3 and others, represents the idea that each type of cell has a special secretion. My own view coincides with the first suggestion, and after careful investigation I have come to the following conclusions regarding the cycle of events : — Author's First, the eosinophil cells represent the normal tationof actively secreting cells, which ordinarily discharge their staining secretion into the blood-vessels or lymphatics. If there pars anterior, be no great demand for the secretion the cells may enlarge and become basophil ; they then gradually become darker and more swollen until finally they discharge basophil * colloid' among the neighbouring cells, which may form a vesicle-like wall around the secretion. After the discharge of ' colloid ' the basophil cells become small, shrunken and faintly staining (chromophobe cells) with large nuclei in which a network of chromatin fibres can be seen. I have elsewhere4 illustrated these phases from direct colour photographs. Second, in certain circumstances, as in pregnancy or after removal of the thyroid or suprarenals, there is immediate demand for secretion — in the first cases from the anterior lobe, and in the last from the posterior. In pregnancy, and after thyroidectomy, the small chromo- phobe cells in the anterior lobe regenerate into large chromophobe cells, and eosinophilia — a more leisurely process — does not occur to the usual extent. These chromophobe cells have been called ' pregnancy cells ' owing to their constant appearance in the pars anterior during pregnancy. After removal of the suprarenals 1 Saint-Remy, G., Compt. Rend, de VAcad. des Sci., 1892, vol. cxiv, p. 770. 2 Benda, C, Berl. Klin. Woch., 1900, vol. xxxvii, p. 1205. 3 Gemelli, A., Folia Neuro-biol., 1908, vol, ii, p. 167, * Bell, W. Blair, The Pituitary, 1919, Facing page 45. *\% 4 if* , 7 ( 1 **r v .... :>fc * ir« Fig. 19. Section of the pars anterior of the cat after oophorectomy, showing well-marked eosinophili cells only. (Direct colour photomicrograph). X 500 OOPHORECTOMY AND THE PITUITARY 45 there is an increased invasion of the pars nervosa by Author's cells from the pars intermedia. tationof It is most important, too, in experimental work not staining to lose sight of the fact that the phases of secretory pars anterior. activity vary in different orders of animals and at different ages in the same animal, and that the large basophil cells and basophil * colloid' are not seen, so far as my experience goes, either at all or with the same regularity in the various species of rodents, as in the higher mammals. Further, it must be mentioned that the pars inter- media secretes a granular ' colloid ', normally basophil in reaction, but in some circumstances, to be mentioned directly, eosinophil. The ' colloid ' which is formed both in the pars anterior and in the pars intermedia is probably a storage secretion, like the colloid seen in the thyroid. The most active method of secretion in both parts of the pituitary is intracellular. In the actively secreting pars inter- media the cells swell up and become fused, and the secretion is, I believe, for the most part taken up immediately by the blood or lymph. Nevertheless, some of the masses of secretion which may be seen in the pars intermedia, and even the actual cells, pass directly into the pars nervosa, whence absorption occurs ; and it is in the pars nervosa that, as already stated, the pressor qualities of infundibulin are acquired. To return from this necessary digression. Removal Hyperplasia of the ovaries appears to cause a certain increase in the anterior secretory activity of the anterior lobe of the pituitary follows • • . oopnorec- body on the lines indicated ; but in my experience the tomy. change is moderate and not quite constant. Thus in one experiment — cat no. 5 of the ovarian removal series recorded above — after an interval of 208 days there was no divergence from the normal to be recognized histo- logically. The effect appears to be more or less temporary, and in no way comparable with the genital lesions seen after partial extirpation of the pituitary. In most of 46 THE SEX-COMPLEX Hyperplasia my cats, however, definite changes were found as long anterior as 245 days after oophorectomy. In these circum- o5Uhorec- stances, there was a large preponderance of brightly tomy. stained eosinophil cells in the anterior lobe (fig. 19) — a condition indicating increased activity, but not the great activity seen after the thyroidectomy. In the pars intermedia the cells were fused and there were ' colloid ' vesicles, and sometimes ' colloid ' cysts. This ' colloid ' stained with eosin, in contradistinction to the normal condition of basophilia. Effects of It is interesting to note that the changes which we tomy on find in the pituitary after oophorectomy — that is, with the^ame n0t ovarian insufficiency — are not the same as those found as those in pregnancy ; consequently the relation of the pituitary produced by * : f „ J ., , , , ,.., . Al . Lr A , f pregnancy, body to the genital glands differs, m this respect at least, from the ovarian-thyroid relationship in similar circum- stances. Fichera1, however, believes that the " hyper- plasia and hypertrophy " which follow oophorectomy resemble the condition seen in the anterior lobe during pregnancy. Accordingly, this investigator thinks that the change found in the anterior lobe during pregnancy is due to ovarian insufficiency. As already stated, I have seen nothing in my experimental results to lead me to adopt this view, however plausible it may appear at first sight. OVARIAN TRANSPLANTATION Ovarian Probably Knauer2 was the first systematically to atrophy^ of6n test the effects of ovarian transplantation. I have worked uterus after ^ rabbits and dogs, and found, as Knauer had done, oophorec- ° . tomy. that if the ovaries be excised and implanted in the muscle of the uterus or abdominal wall, atrophy of the genital ducts will not occur (figs. 20 and 21). Since these experiments by Knauer many observers have confirmed his findings regarding the integrity of the uterus after 1 Fichera, G., II Policlinico, 1905, vol. xii (Chir), pp. 250, 299, 319. 2 Knauer, E., Centralbl. /. Oyndk., 1896, vol. xx, p. 524, Facing page 46. Fig. 20. Section of the uterus of the rabbit, showing the normal muscle-coats. X 60. Facing page 47. Fig. 21. Section of the rabbit's uterus, illustrated in figure 20, 80 days after transplantation of both ovaries from the normal sites to the muscles of the abdominal wall : the muscle- coats are normal. X 60. OVARIAN TRANSPLANTATION 47 oophorectomy followed by transplantation. Limon1 Ovarian noticed that the follicles in the graft tend to Regenerate g^yST1 after a time, while the interstitial cells remain unaffected, uterus after oophorec- I found, as Marshall and Jolly2 had previously observed, tomy. that the follicles first become cystic (fig. 22) and then degenerate ; that is to say, they ripen, but, if completely buried cannot expel the contents, and therefore become cystic and retrogress. I also noted a fact of considerable importance : importance namely, that in the' rabbit if only the central portion jdjjjj^ of the ovary, which contains no follicles, be implanted ovarian (fig. 23), the interstitial cells of which the graft is com- posed can alone maintain the integrity of the uterus. Halsted3 has stated that grafts of the organs of internal secretion ' grow ' better when a condition of insufficiency exists in regard to the particular secretion. There was no evidence of this in my experiments with the ovaries of rabbits ; for the grafts ' grew ' as well when one ovary was left in situ as when both were removed. It is probable, then, that ovarian transplantations in general, and transplantations of the interstitial cells in particular, are capable of keeping normal the uterus, the mammae, the distant hormonopoietic organs, and the general metabolism in the female animal. And, since the isolated interstitial cells are effective in this respect, it is probable that the follicular secretion has no function beyond nourishing the ovum and influencing the dehiscence of the follicle — at any rate in the rabbit. In my experience ovarian transplantation in women, Ovarian which must be autoplastic, is not so certainly successful SK™11 the as it is in the lower animals. This may be due to the subject. fact that normally in the human subject the interstitial tissue is absent or poorly developed; indeed, it is in 1 Limon, M., Journ. Physiol, et Pharmacop. Oen., 1905, vol. vi, p. 864. 2 Marshall, F. H. A., and W. A. Jolly, Quart. Journt Exper. Physiol., 1908, vol. i, p. 115. 3 Halsted, W. EL, Journ. Exper. Med., 1909, vol. xi, p. 175. 48 THE SEX-COMPLEX Ovarian rabbits, in which the interstitial cells are very well human11 * developed, that the best results have been obtained. subject. Moreover, in gynaecological procedures the grafts are taken from infected, or otherwise pathological, ovaries. Nevertheless, I have implanted autoplastic grafts — which alone are viable — in a large number of cases in all of which the menopause has been averted, and in many of which menstruation has occurred more or less regularly. Effects of ovarian extracts. THE PHYSIOLOGICAL EFFECTS OF OVARIAN EXTRACTS It was found by Hick and myself1 that the physio- logical effects on the uterus of intravenous injections of whole-ovary extract are as follows : (a) No effect is produced on the inactive uterus. (b) On the cestrous uterus a well-marked increase in the force of the contractions is obtained, and this effect is augmented by repeated doses. In some cases considerable increase in the tone may also be produced. (c) The pregnant uterus is somewhat remarkably affected by ovarian extract, which causes tem- porary inhibition of the contractions. We observed no alteration in the blood-pressure. Further information has recently been put forward by Itagaki2. This investigator found that extracts made from different parts of the ovary produce different effects on the uterus and blood-pressure. He noticed that an extract made from the hilum, and believed to contain the active principle of the interstitial cells, alone produced inhibition of the uterine contractions ; and that an extract of the corpus luteum increased the tone and force of the uterine contractions, without affecting the blood-pressure, while the follicular secretion 1 Bell, W. Blair, and P. Hick, Brit. Med. J own., 1909, vol. i, p. 777. 2 Itagaki, M., Quart. Journ. Exper. Physiol, 1917, vol xi, pp. 1 and 27. Facing page 48. Fig. 22. Section of the graft of the rabbit's ovary, which had been implanted in the muscles of the abdominal wall 93 days previously, showing cystic degeneration in a Graafian f ollicle. X 36. Facing page 49- Fig. 23. Section of a graft of the rabbit's ovary, which had been implanted in the muscles of the abdominal wall 24 days previously, showing (in serial sections) interstitial cells only. There was no atrophy of the uterus. X 250. OVARIAN EXTRACTS 49 increased the tone and the force of the rhythmic move- Effects of ments of the uterus and of all other involuntary muscle tract* suspended in the liquor itself, or in an extract made from the follicles. Gonalons1, however, states that he has been unable to obtain any pressor action, and that both the luteal and ovarian (without luteal) extracts are depressor in their physiological effect when intravenously injected. He also found that the liquor folliculi is inactive. It is obvious, therefore, that further investigations are required to settle the points in dispute. The effects of ovarian extracts on the secretion of milk will be mentioned later (p. 91). 1 Gonalons, G. P., Estudio fisiologico clinico y terapeutico de las funciones del ovario, 1914. THE THYROID The accessible position of the thyroid gland has enabled clinicians to pay some attention to the obvious connexion of this organ with the genital functions. At puberty a temporary enlargement — especially during menstruation — may often be observed in women ; and in all mammals we invariably find the thyroid considerably increased in size during pregnancy. This temporary enlargement indicates, of course, a change in the secretory activity of this organ to meet the metabolic requirements in these circumstances. We shall, perhaps, be in a better position to appreciate the changes that occur in the rest of the genital system if we first consider the effects on the general metabolism of removal of this organ. Effects of thyroidec- tomy vary in different animals. EFFECTS OF THYROIDECTOMY ON THE GENERAL METABOLISM Different mammals vary very much in their power of withstanding the disastrous results which may follow complete removal. Grave effects never supervene on the removal of the thyroid in rabbits ; and this ex- emption has been explained, as we have already seen, on the ground that the parathyroids are relatively large, and lie well away from the thyroid itself, and conse- quently cannot be removed without a careful search — in other words, they escape removal during the operation of thyroidectomy. Swale Vincent and Jolly1 have shown that after thyroidectomy the parathyroids actually secrete colloid, and, in fact, after this operation 1 Vinoent, S., and W. A. Jolly, Journ. Physiol, 1904-5, vol. xxxii, p. 65. THYROIDECTOMY AND THE METABOLISM 51 perform the functions of the thyroid just as they resemble Effects of it in structure. But I do not believe that this question Jomyvary in of the remaining parathyroids is the whole truth, different A , animals. Herbivora have less need of the thyroid than other mammals, such as the carnivora. It may be because the diet is different, but I feel sure it is also due in some measure to the variations in the structure and func- tion (or degrees of function) seen in the other hormono- poietic organs. I have already alluded to the differences in structure between the ovaries of rodents and those of the higher mammals. If, however, we take cats and remove their thyroids, many die in a few days, usually with con- vulsions. In these cases it is probable that the immediate result is due to the removal of the whole thyroid apparatus (thyroparathyroid). Some cats, nevertheless, may survive the operation for a long period of time ; and in all these cases one can demonstrate the removal of the whole thyroid together with the internal parathyroids, one of which is embedded in each lobe of the thyroid. In these animals, therefore, the true effects of thyroid in- sufficiency may be obtained. Further, it has been stated by Stanley Kent1 and confirmed by Hick and myself2, Castration that castration minimizes the effect of thyroidectomy. e^ecToTthy- The number of cats in my experiments in which the iridectomy. metabolism after thyroidectomy was investigated fully was small, for, as already stated, many died too soon for the metabolism, as represented by the urinary excretion, to be estimated. The record of one non- pregnant cat (table III, cat no. 1) which was destroyed two and a half months after operation, has been selected as typical. Other experiments were complicated by the cats having had kittens shortly before operation, and in consequence the figures obtained from them did not appear to be suitable for averaging with those from the uncomplicated cases. 1 Kent, S., Journ. Physiol. (Proc. Physiol. Soc), 1894, vol. xv, p. 18. 2 Bell, W. Blair, and P. Hick, Brit. Med. Journ., 1909, vol. i, p. 517. 52 THE SEX-COMPLEX Effects of It will be seen that in this animal acetone was present tomy on the three times in 20 estimations after operation. metabolism. f^ calcium excreted after operation was the same in quantity as before operation. There was a drop in the phosphorus excretion, in spite of the increase in the specific gravity after operation ; and the total nitrogen and urea are increased out of proportion to this rise in the specific gravity. It will be noticed, also, that the ammonia-coefficient was slightly increased. I am well aware that the records of one animal cannot carry much weight ; but this was the only uncomplicated and reliable result out of five non- pregnant animals on which I operated in this series. Effects of Before considering the effect of thyroidectomy on tomy during *ne res^ of the organs of internal secretion I shall first pregnancy, recount a rather important series of experiments in which thyroidectomy was performed on three pregnant cats which survived the operation for some time. They were carried out in order to observe the influence of the thyroid on the metabolism during pregnancy, especially with reference to the possible production of the symptoms of eclampsia with marked alterations in the ammonia- coefficient. Further, I had in my mind the possibility that the secretion of the total thyroid might reach the mother's circulation and mitigate the effects of the thyroidectomy performed on her. The records of each case (table IV, cats nos. 1, 2, 3) are drawn up to show the metabolism before operation, and in two cases after operation and before parturition. In one case the kittens were born alive at full term two days after the operation and before the estimations of the urinary metabolism had been resumed. It may be pointed out here that no estimations were carried out for a few days after any operation in order to avoid the effects produced by the anaesthetic. It will be noticed that acetone, albumin and sugar were found a good many times after operation in cat no. 1, and more frequently after parturition than before, without any great disturbance of the ammonia-coefficient. Facing page 53. +.-9&V+W Fig. 24. Section of the ovary of the cat after thyroidectomy, showing eosinophilia of the Graafian follicles and interstitial cells. (Direct colour photomicrograph). X 150 THYROIDECTOMY AND THE METABOLISM 53 Cat no. 3 gave birth ten days prematurely to stillborn Effects of kitten • > 1917, vol. xi, p. 77. 72 THE SEX-COMPLEX extracts. I have discussed the subject at considerable length elsewhere1. There are, however, a few important details to which allusion is necessary. Effects of Intravenously and intramuscularly injected extracts infundibuiin. of the pars posterior exhibit remarkable pressor pro- perties in regard to all unstriped muscles ; as a result of this the blood-pressure is immediately raised and main- tained at a high level for a considerable time ; similarly the normal uterine and intestinal contractions and tone are greatly increased. How these properties have been utilized by the introduction of infundibuiin into surgical and obstetrical practice2, and how universal has become its use in shock, intestinal paresis and uterine atrophy is within the knowledge of all. Ott and Scott3 first showed that the same extract is a galactogogue. It is not definitely known how this result is produced. It would be interesting if it were a fact, of which we have no proof, that the pituitary hormone normally promotes the secretion of milk. It is, however, most probable that after the birth of the child the stream of metabolic products directed to its maintenance and growth in the womb are diverted to the mammary secretion, which is to supply the post- natal necessities of the young infant. Effects of The late results that have been obtained by continued feeding with injections and ingestions have been very conflicting. the pituitary. Rosalind Wulzen4 found that the growth of young fowls was retarded by the addition of fresh unmodified anterior lobe of ox pituitary. Goetsch5, on the other hand, has found that the administration of dried and powdered pars anterior 1 Bell, W. Blair, The Pituitary, 1919. 2 Bell, W. Blair, Brit. Med. Journ., 1909, vol. i, p. 777; idem, vol. ii, p. 1509. 3 Ott, I., and J. C. Scott, Proc. Soc. Exper. Biol, and Med., 1910- 1911, vol. viii, p. 48. 4 Wulzen, R., Amer. Journ. Physiol, 1914, vol. xxxiv, p. 127. 5 Goetsch, E., Bull. Johns Hopk. Hosp., 1916, vol. lxxvii, p. 29. Facing page 72. Section of ovary of bitch before operation. (Photomicrograph). X 120 Section of ovary of bitch 128 days after separation of infundibular stalk. (Photomicrograph). X 120 Fig. 34. Facing page 73, Fig. 35. Radiograph, taken during life, showing the artificial tumours in bitch 22. {Direct photograph by Thurstan Holland.) x}. EXTRACTS OF THE PITUITARY 73 causes an increase in the rate of growth associated with early sexual development in the young animal. It is generally admitted that continued injections of, and feeding with, extracts of the pars posterior produce toxic effects with glycosuria and emaciation. THE SUPRARENALS Anatomy The suprarenal bodies are composed of two distinct r fnais BUpra" parts, the cortex and the medulla. The cortex is derived from the epithelium in the region of the inter- mediate cell-mass from which the germinal epithelium of the gonads arises. The medulla is formed from sympathetic nervous elements. Whether the union of the two parts is fortuitous and their functions are independent, or whether the conjunction indicates functional interdependence is unknown. It is quite certain, however, that the cortex, which has its origin in proximity to the gonads, is functionally related there- with. In the second part of this work evidence will be adduced to show that the cortex of the suprarenal gland is closely concerned in the production of the secondary male characteristics. Hypertrophy In this connexion it is interesting to recall the m8p?egnancy! observations of Stilling1 that the suprarenals of the male rabbit hypertrophy in the breeding season; and also the well-known fact that during pregnancy in women when the suprarenals hypertrophy, as will be mentioned directly, hair may appear on the face.2 In pregnancy certain changes occur normally in the suprarenals. So far as my own observations go these appear to be confined to the cortex: the cells of the zona fasciculata appear swollen and cloudy. Some observers (Guieysse3 and Gottschau4) have found that in pregnancy the zona fasciculata increases in thickness 1 Stilling, H., Archiv.f. Mikr. Ami, 1898, vol. lii, p, 176. 2 Compare p. 166. ■ Guieysse, M. A., Compt. Rend. Soc. Biol, 1899, vol. 1, p. 898. 4 Gottschau, M., Archiv. /. Anat. u. Physiol., Anat. AM., 1883, p. 412. REMOVAL OF THE SUPRARENALS 75 at the expense of the zona reticularis and medulla. My Hypertrophy own observations are in accord with this. The zona i'n^ognancy. reticularis does not increase at the expense of the zona fasciculata in pregnancy, as it does after oophorectomy. Conflicting views as to the effects of castration have been put forward by Schenk1, Cecca2 and others. A source of error in the estimation of the thickness of the various zones is liable to arise unless care be taken to cut mesial sections, or, better still, serial sections. EFFECTS OF THE REMOVAL OF THE SUPRARENALS In most mammals complete removal of the supra- Effects of renals causes death in from a few hours to a few days. JJSSwi^. The animal does not eat ; it sits very quietly and gradu- ally becomes weaker ; tremors occur, and death super- venes. This sequence of events follows so rapidly that as a rule no estimation can be made of the metabolism, and any changes observable in other hormonopoietic glands must be of an acute character, and therefore of less value from a practical point of view than those which are obtained by the production of chronic in- sufficiency— a condition difficult to bring about experi- mentally in the suprarenals. Acute effects may, however, be useful as indicating the trend of physiological events. Many rats, owing to the fact that a large percentage of them have accessory interrenals consisting of cortical substance, are said to be able to survive extirpation of the main organs. It is, therefore, believed that the cortical part alone is necessary to life ; and this belief is supported by other evidence which has recently been discussed by Vincent3. My investigations were carried out with rabbits and Author's cats. Those animals from which both suprarenals were experiments. removed, either at one or at two sittings, died within 1 Schenk, F., Archiv. f. Exper. Pathol u. Pharmacol., 1910-11, vol. lxiv, p. 362. 2 Cecca, R., Presse Medicate, 1904, vol. xii, p. 341. 3 Vincent, S.f Endocrinology, 1917, voL i, p. 140. 76 THE SEX-COMPLEX Author's experiments. 48 hours of the complete extirpation. I tried, therefore, the effect of the removal of one suprarenal in the hope of being able to produce insufficiency, since it is known the other suprarenal hypertrophies in these circumstances, and shows a condition somewhat comparable with the hyperplasia of pregnancy. Two cats gave negative results in regard to the metabolism, but with two rabbits certain results were obtained. One of the animals was destroyed at the end of 30 days, as it was obviously dying. It was much emaciated, its weight having dropped from 2000 grammes to 1400 grammes. The post-mortem notes run as follows : " No cause of death found. The site of the previous operation unrecognisable except for the absence of the gland ". The other rabbit died at the end of 127 days. It, also, was greatly emaciated, the weight having decreased from 1710 grammes to 1020 grammes. At first the animal gained weight after the operation, and then steadily lost ground. No cause for death was found, other than the absence of one suprarenal. These results are apparently of some value, for according to most recent writers, unilateral extirpation in rabbits produces no symptoms. Effects of removal of one supra- renal. EFFECTS OF REMOVAL OF ONE SUPRARENAL ON THE METABOLISM With regard to the metabolism I obtained very interesting records from these cases of chronic insuffici- ency. In both cases a considerable increase in the urinary excretion of calcium was observed (table VI) : in one the average quantity excreted after operation was seven times as much as that excreted before operation ; in the other case it was more than sixteen times as much. The average for the two cases was, of course, between these figures (table VII). The excretion of phosphorus, also, was much greater ; and the urea excretion was increased out of proportion to the differences between the specific gravities before and after operation. REMOVAL OF THE SUPRARENALS 77 I I i 5 . .s - I 1 f eS-e 11 11 •% NT •*9puQ 8-53 6-88 1604 11-84 981 69-8 327 2-32 87-78 91-26 80-69 85-84 '% £HH 0070 0-036 0-227 0-045 •% «3JI1 2-25 309 112 2-93 •% k moi 116 1-58 064 1-59 •% 908J 0-206 0-623 0-200 0-531 •% 10 0170 0-192 892-0 291-0 •% *0 0-0030 0-0210 2. 00017 0-0280 •UBOipui © © ibbii No. 0 4 times •iB8ng © © o © •upimqiv © © © © •ouo^aoy © © © © •ptOB 0I^80BI(I © © © o •Xjja«.i3 oypadg 1023 1026 1018 1030 •paunnuxg suauipacis jo lequinx "# CO ^e many other protein substances, a fall in the extracts. general blood-pressure, but this is not specific. Extracts of the medulla, or of the whole organ which contains the medulla, have definite pressor effects on the peripheral arterioles with subsequent elevation of the general blood-pressure. Contractions of the uterus, also, are usually produced, but in certain states of physiological rest and in certain animals inhibition of the normal uterine contractions may follow intravenous injections. This effect of inhibition is also generally seen in regard to intestinal movements. Effects of Feeding experiments have led to contradictory con- feeding with elusions. Vincent1 has failed to obtain anv positive suprarenal extracts. immediate result. D'Amato2 has shown that even large doses taken by the mouth fail to raise the blood-pressure except in the presence of suprarenal insufficiency, such as is seen in Addison's disease. Other observers have confirmed d'Amato's observations. Continued feeding has been carried out on young rats with an adequate number of controls by the Hoskins3. These investigators have come to the con- clusion that suprarenal feeding has a stimulating in- fluence on the development of the testes. But, as in more than half of the controls similar hypertrophy was noted, their inference seems hardly justified. 1 Vincent, S., Trans. Amer. Gynecol. Soc, 1917, vol. xlii, p. 157. 2 D'Amato, L., Bert. Klin. Woch., 1906, vol. xliii, p. 1100. 3 Hoskins, R. G. and A. D., Archiv. Inter. Med., 1916, vol. xvii, p. 584. THE PANCREAS It is probable that the cryptorrhoeic cells of the pancreas have no direct relation to the genital functions, although no doubt the influence of the pancreas on the general metabolism and possibly on the other hormono- poietic organs of the individual may exert an indirect control. It has been shown by Lafon1 that when the pancreas The secretion is removed from a pregnant bitch, no glycosuria is panCreas may observed until the uterus is emptied, when the same j>® tc^ veyed train of symptoms as that seen in the non-pregnant mother. animal — glycosuria, emaciation and death — rapidly supervenes. Lafon therefore came to a conclusion regarding the probable passage of the foetal pancreatic hormones into the maternal circulation in these cir- cumstances similar to the one I have formulated con- cerning the results of thyroidectomy in pregnant cats (p. 53). This matter, which is of extreme interest and importance, has been confirmed in regard to the pan- creas by Carlson2 and others. Crowe, Cushing and Homans3 have studied the Effect on effect on the pancreas of partial removal of the anterior 5*]^^? lobe of the pituitary, but the results obtained have not movai of pars been very conclusive of any definite changes. In my pituitary. experiments I was unable to find any alterations from the normal in the pancreas : in all cases it appeared to be active. Sweet and Allen4 lay particular stress on the secretory activity of the pancreas after complete or partial removal of the pituitary. 1 Lafon, G., Compt. Bend. Soc. Biol, 1913, vol. lxxv, p. 266. 2 Carlson, A J., Trans. Amer. Gynecol. Soc, 1917, vol. xlii, p. 131. 3 Crowe, S. J., H. Cushing, and J. Homans, Bull. Johns Hopk. tiosp., 1910, vol. xxi, p. 127. 4 Sweet, J. E., and A. R. Allen, Ann. Surg., 1913, vol, lvii, p. 485. G 82 THE SEX-COMPLEX Effects of suprarenin and infund- ibulin on pancreatic secretion. Pemberton and Sweet1, after a careful study of the relation of the internal secretions to pancreatic activity, have come to the following conclusions : " (1) The "inhibition of pancreatic activity by adrenalin and " pituitary extract (infundibulin) is independent of the ;t systemic blood-pressure, as shown by its persistence " when the blood-pressure is much below normal and " by other evidence. (2) The inhibition by extracts " of pituitary and suprarenal bodies also occurs when " the pancreas is stimulated by its normal excitant, " hydrochloric acid, in the duodenum." It is possible, therefore, that alterations in the carbo- hydrate metabolism are not always directly attributable to primary pituitary, suprarenal or pancreatic disease, since the activities of these organs in this direction are closely related, but that the suprarenals and pituitary may indirectly affect the functions of the pancreas and vice versa. Effects of pancreatic extracts. THE PHYSIOLOGICAL EFFECTS OF PANCREATIC EXTRACTS The effects of injections of and feeding with pan- creatic extracts have been observed chiefly in relation to the arrest of the diabetic symptoms that follow the removal of the pancreas. The temporary beneficial effect which may be seen has, however, been attri- buted to the general depressing effects of proteins, among which is a reduction in the sugar-content of the blood, rather than to any specific supplementative action2. Starling and Evans3 found that pancreatic extracts have no effect on the reduced respiratory quotient of the diabetic heart. In regard to the normal heart these observers state that pancreatic extracts have an action which resembles that of suprarenin. 1 Pemberton, R., and J. E. Sweet, Archiv. Inter. Med., 1910, vol. v, p. 466. 2 McGuigan, H., and E. L. Ross, Journ. Biol. Chem., 1915, vol. xxii, p. 417. 3 Starling, E. H., and C. L. Evans, Journ. Physiol., 1914, vol. xlix, p. 67. THE THYMUS It is widely believed that the thymus is an organ The position of internal secretion and is intimately connected with aa an organ the development of the body and of the reproductive °*J£y™al functions. It is probable that once genital activity is established the thymus rapidly undergoes atrophy, and plays no part in the metabolism of reproduction. Hoskins1, whose attitude towards unproven state- ments and to generalizations in regard to the functions of the organs of internal secretion is always sturdily antagonistic, denies that there is any evidence for or against the view that the thymus is a hormonopoietic gland. He doubts whether it is more than a lymphoid organ, and states that there is a steady decrease in the "percentage of lymphocytes in the blood, from 61 per cent, at one year to 23 per cent, at puberty (14*8 years)". Pappenheimer2, in a critical review of the literature and of his own experiments, expresses a similar view. Personally, I am inclined to think that while, strictly speaking, the thymus is not an organ of internal secretion in the sense that the thyroid and other glands are, it has, like the mammae, a definite relationship, more or less indirect, to the production of somatic and genital maturity. It is not necessary at this point to press the acceptance of the view that the individual somatic and genital metabolism are inter- dependent. 1 Hoskins, E. R., Endocrinology, 1918, vol. ii, p. 241. 2 Pappenheimer, A. M., Trans. Amer. Gynecol Soc, 1917, vol. xlii, p. 113. 84 THE SEX-COMPLEX EFFECTS OF THYMECTOMY AND DESTRUCTION OF THE THYMUS ON THE GONADS AND ON THE CALCIUM METABOLISM Effects of Paton1 found that if the operation be performed onthe gonacls before puberty there is a rapid development of the male SSSSfil genital glands. It appears, therefore, that the thymus either inhibits the development of the gonads (Biedl2), or that their development causes atrophy of the thymus. We have, on the other hand, already seen that the thymus undergoes hyperplasia after removal of the ovaries (p. 40). Hewer3 states that irradiation of the thymus with X-rays causes slight degeneration of the gonads in the rat, and delay in the onset of sexual maturity in the young male animal, but that no such effect is produced in regard to the female rat. The experiments of this investigator are, however, not satisfactory in the matter of controls. It is supposed by some that the thymus is intimately connected with the calcium metabolism ; but, although several investigators (Basch4, Cozzolino5, Tarulli and Lomonaco6) have found that rickets follows thymec- tomy in young animals, an effect not Confirmed by Paton, or by Renton and Robertson7, it can hardly be, as Biedl suggests, that the effect of its secretion is to cause calcium retention in the bones, for the skeletal structures become much more heavily laden with calcium phosphate after puberty when the gland atrophies. The matter is one of considerable difficulty. But if 1 Paton, N., Journ. Physiol., 1904, vol. xxxii, p. 59. 2 Biedl, A., Innere Sekretion, 1913, 2nd ed. 8 Hewer, E., Journ. Physiol., 1916, vol. 1, p. 488. 4 Basch, K., Wieri. Klin. Woch., 1903, vol. xvi, p. 893. 5 Cozzolino, 0., La Pediatria, 1903, vol. i, pp. 144, 620. 6 Tarulli, L., and D. Lomonaco, BoU. B. Accad. Med. di Boma, 1897-8, vol. xxiii, p. 311. 7 Renton, J. M., and M. E. Robertson, Journ. Pathol, and Bacterial, 1916, vol. xxi, p. 1. EFFECTS OF THYMECTOMY 85 thymectomy were to lead to increased calcium excretion Effects of and bone softening, the growth of the genital gland oSego^ds which promotes the excretion of calcium would not tend and calcium metabolism. to improve matters, unless — and this is possible — the development of the genital gland causes an increased secretion from the suprarenals, which may promote calcium retention. EFFECTS OF THYMECTOMY ON THE HORMONOPOIETIC ORGANS No reliable work appears to have been done on these Thymectomy lines. It is urgently needed, in order to clear up many m0dnopoietic of the difficulties concerning the relation of the thymus organs- to the general metabolism. THE PHYSIOLOGICAL EFFECTS OF EXTRACTS OF THE THYMUS So far as I am aware, experiments have chiefly been Effects of conducted in regard to the effects of feeding with thf thymus. thymus substance. These experiments are not worth detailed considera- tion as the findings are entirely conflicting. Some observers state that development in larvae and young animals is delayed, others that the results are negative. Ott and Scott1, however, state that injections of thymus extract excite the secretion of milk. 1 Ott, I., and J. C. Scott, Therap. Gaz., 1912, vol. xxxvi, p. 761. THE MAMMARY GLANDS Mammary glands not organs of internal secretion. Mammary glands are accessory reproductive organs. In spite of many assertions to the contrary, based on pure conjecture, I do not think there is any evidence that the mammary glands are organs of internal secre- tion in the accepted sense of the term. As already suggested, it is probable that every cell in the body should be considered to be an organ of internal secretion, but apart from such a generalization we cannot place the mammary glands in the same category as the ' regulators of metabolism - previously mentioned. The mammary glands have a definite function to perform : they abstract from the maternal economy nourishment for the infant after birth, and in this way carry on the function performed by the placenta before parturition. There is not, of course, an exact analogy between the two, but the general principle is the same in both cases, after due allowance has been made for the altered circumstances and environment after birth, which induce pulmonary respiration, digestion and other developments making for independence in the child. It is obvious, therefore, that maternal lactation is of more importance to the child than to the mother. Hence, we may look upon mammary secretion as a side- issue — even if it be an important one — so far as the maternal economy is concerned. Well-developed breasts form one of the secondary characteristics of the female sex ; but only so as evidence of her ability and readiness to perform the functions of reproduction. In the human subject if the mother cannot nurse, both she and the child may suffer ; but, on the other hand, the absence of mammary secretion subsequently to HORMONES AND THE MAMMJE 87 parturition does not necessarily affect either. I shall consider this matter more fully later. The chief questions that we are called upon to Questions to consider here in regard to the mammary glands are : in regard to first, what the hormones are that affect the develop- fche mammae. ment, growth and function of the mammae ; second, what effect the function of lactation has on the maternal metabolism ; and, last, what, if there be any, are the physiological effects of an extract of mammary gland. THE HORMONES THAT INFLUENCE THE MAMM.E Much speculation has existed as to the causal Causal factors in the development and functional activity of the regard to mammae. These glands have, of course, a very definite ^Tiopment function to perform in the adult female subsequently and activity. to parturition ; but given sufficient stimulus — generally mechanical — the mammae of males or virgin females may also be induced to secrete ' milk '. It is certain that the secretion from the breasts of males and virgin women is not of the same composition as that secreted by the normal woman after parturition ; but the fact that such abnormal secretion can occur, although it consists of colostrum only, is of considerable importance, as we shall see directly. It is necessary, moreover, to call attention to a point — too well-known to require dis- cussion— that has an important bearing on the ultimate understanding of the mammary function: namely, the secretion obtained from the mammae before par- turition is not milk ; that is to say, although during pregnancy the breasts enlarge and the contained glands become active, true milk is not in normal circumstances secreted until some short time after the birth of the child. In this connexion it is interesting also to re- member that milk is usually secreted after the prema- ture birth of a live child, just as it is after full-term parturition. It is, therefore, an obvious deduction that, pro- vided lactation has never existed previously, so 88 THE SEX-COMPLEX Causal long as the child remains in utero milk will not be factors in ^eove\ec\ relation to secreiea. mammary This, of course, confirms the view, already stated, activity and _ development, that the stream of nutrient materials, which has reached the foetus in utero by way of the blood-stream, is now directed as quickly as possible to the mother's breasts, in order that the child may continue to subsist on the most suitable food — that which is elaborated for the purpose from the maternal tissues. Author's It seems, then, that the actual secretion of milk Redirection, is not due to any special hormone — although hormones no doubt are indirectly concerned — or to the removal of some inhibitory substance of fcetal origin, as suggested by Hildebrandt1, Lane-Claypon and Starling2, and others, but rather to a definite redirection of certain elements in the maternal economy from the placenta to the mammae — a phenomenon almost comparable, indeed, with vicarious menstruation. Views of the This idea was somewhat vaguely expressed by the ancients, whose simple observations were not obscured by the mass of conflicting experimental ' information ' at our command. Hippocrates3 wrote : " If in a woman with child, much milk flow from the breasts, it indicates that the fcetus is weak ; but if the breasts be firm, it indicates that the fcetus is in a more healthy state ". Celsus4 states that " The nourishment, which they (mammae) draw to themselves passes from the womb (after parturition) to the breasts ". It is highly probable that those hormones which favour the nutrition of the fcetus in utero, subsequently stimulate the secretion of milk. But before we come 1 Hildebrandt, P., Hofmeister's Beitr. z. Chem. Physiol, u. Pathol., 1904, vol. v, p. 1463. 2 Lane-Claypon, Janet E., and E. H. Starling, Proc. Roy. Soc, Ser. B, 1906, vol. lxxvii, p. 505. 3 Hippocrates, Sydenham Soc. Transl. by Francis Adams, 1849, vol. ii, Aphorisms, § v, no. 5, p. 747. 4 Celsus, A. C, quoted by R. Temesvary, Journ. Obstet. and Gyncecol. Brit, Emp., 1903, vol. iii, p, 611. HORMONES AND THE MAMMAE 89 to this point we must consider what influences lead to the original development of the breasts, and give rise to their increased activity during pregnancy. As just stated, the breasts form a secondary feminine The characteristic, and in consequence should normally controlling be well developed subsequently to puberty in every °j^ 8teex- woman. That they are not always so agrees with what istics regulate is found in regard to the other sex-characteristics, for, if 0f IhePmeD there be variety in regard to the degree of total femininity mammae. present in different women, it follows that the individual characteristics must vary. In this connexion we may say, without fear of contradiction, that the woman who can and does suckle her children is strongly feminine, and that the future of the race is safe so far as she is concerned. The hormones, then, that lead to the development of the sexual functions and characteristics are responsible for the development of the mammae ; and I have en- deavoured to show that all the hormonopoietic organs, and not the gonads alone, are so concerned. Attention must be called to the fact that the casual observer may be misled into the inference that adiposity, which may occur in the region of the breasts as elsewhere, is indicative of true (glandular) mammary development ; but, as a matter of fact, large breasts due to adiposity may be associated with atrophy of the glandular tissue. The ovaries and the mammae. — In the develop- Relation of ment of maturity in the female ovarian activity plays a mammaryS large part. As is well known, removal of the ovaries development. before puberty leads in all animals (and would almost certainly, therefore, do so in woman) to infantilism of the mammary glands1. I have myself observed this on many occasions in young rabbits. Nevertheless, the castrated animal, as will be remembered, grows to a larger size and is fatter than normal. In regard to the further development which may 1 Marshall, F. H. A., The Physiology of Reproduction, 1910, p. 314. 90 THE SEX-COMPLEX Relation of take place in the mammae a distinction must be made mammary* t0 between that which occurs during gestation and im- deveiopment. mediately preceding lactation, and that actually con- cerned in the secretion of milk. It is certain that once the mammary glands have become fully developed the ovary exerts little direct influence over their further activity ; indeed, some assert1 that during the reproductive period the ovarian secretion inhibits mammary activity. I believe, however, that it is not so much a question of * inhibition ' as that the ovary causes the excretion of lime salts, a process in which the mammary glands are also concerned. Atten- tion has already been drawn to the fact that normally the two processes — ovary-induced and mammary excretions — may not be compatible, since they are con- cerned with more or less identical processes ; and this fact is well demonstrated by the absence of menstruation during the first months of lactation in normal circum- stances, although subsequently, when a metabolic re- adjustment has taken place, menstruation may be, and normally is, re-established during the later months of lactation — often to the detriment of the mother (p. 202). Effect of Further, it has been shown quite definitely by veter- onmiik^t0mymary surgeons2 that in cows in which lactation has secretion in been present for many years oophorectomy increases the quantity and richness of the milk. It is obvious, of course, that the effect of oophorectomy in this respect can only be observed in those animals which have borne young. The relation It has been suggested b}' Bouin and Ancel3, mteumC°toPUS O'Donoghue4 and others that the corpus luteum mammary furnishes an internal secretion which stimulates mam- activity. ii. rr,i . i i mary growth during pregnancy. The evidence, however, on this point appears to be against such an inference, for the corpus luteum is most prominent early in preg- 1 Battuaud, J., Rev. de Mai. de la Nutrit., 1909, vol. vii, p. 260. 2 Hobday, F. T. G., Castration and Ovariotomy, 1914, 2nd ed. 3 Bouin, P., and P. Ancel, Compt. Rend. Soc. Biol., 1912, vol. lxxii, p. 129. 4 O'Donoghue, C. H., Quart. Journ. Micr. Soc, 1911, vol, lvii, p. 187. HORMONES AND THE MAMMAE 91 nancy before the mammae undergo much change ; and oophorectomy during pregnancy does not interfere with subsequent lactation1. Again, Ott and Scott2 state that extract of corpus luteum increases the flow of milk ; but, on the other hand, Frank and Unger3 have shown that no stimulation of the mammae can be obtained by the injection of the extract, even when homogenous, in non-lactating animals. Further, in women at a menstrual period the breasts Mammary may show signs of activity, and this has been held to during^men- prove that the internal secretion of the corpus luteum is struation. responsible for the change. The investigations of Bouin and Ancel4, and also those of O'Donoghue5, apparently support this view, but it seems to me doubtful whether it represents the whole cause and effect. I shall discuss mastidynia later, but it may be mentioned here that mens- trual swelling and tenderness in the breasts is probably due to an attempt on the part of regulators of metabolism to excrete lime salts by way of the mammary glands at this period ; or, alternatively, that a high calcium content in the blood, such as is found before menstrua- tion, leads to activity in the mammse. This is entirely confirmed by the fact that with the onset of menstrua- tion the pain and swelling in the breasts immediately disappear, for this would not happen if the corpus luteum were the cause of the disturbance. Further, the ripening of the corpus luteum does not necessarily coincide with menstruation. This last objection, how- ever, is open to the argument that all women do not suffer with tenderness in the breasts during menstrua- tion ; nevertheless, a majority probably do. It may be said, then, that the ovary influences the 1 Marshall, F. H. A., and W. A. Jolly, Proc. Boy. Soc.t Ser. B, 1905, vol. cxcviii, p. 99. 2 Ott, I., and J. C. Scott, Proc. Soc. Exper. Biol and Med., 1910-11, vol. viii, p. 48. 3 Frank, R. T., and A. Unger, Archiv. Inter. Med., 1911, vol. vii, p. 812. * Bouin, P., and P. Ancel, Compt. Rend. Soc. Biol, 1912, vol. lxxii p. 129. 6 O'Donoghue, C. H., Quart. Journ. Micr. Soc.y 1911, vol. lvii, p. 187. 92 THE SEX-COMPLEX development of the breasts as an important sex-char- acteristic, but that subsequently the functions of the ovarian secretion are not specially or directly related to mammary activity. Effect of Xhe pituitary and the mammae. — Crowe, Cushing experimental r " lesions of the and Homans1 have shown that the infantilism produced theUmamm8e. DV the removal of a portion of the anterior lobe of the pituitary includes an arrest in the development of the mammae. In my own experiments on the pituitary the mammas were found to be infantile in those cases in which the genitalia showed retrogressive changes after operation — that is to say, after removal of large portions of the anterior lobe, and after the stalk had been clamped or separated. Whether this mammary infantilism is secondary to the ovarian hypoplasia which follows partial hypo- physectomy, or is direct, we have no certain means of knowing. It is obvious, of course, that the ovarian hypoplasia, produced by pituitary lesions, might lead to infantilism of the mammae, but it is quite impossible with our present knowledge to say whether the pituitary lesion itself directly affects the development of the mammary glands. This point may some day be de- cided by investigations on the state of these glands in animals in which the pituitary has been subjected to lesions during early pregnancy. It is well known that there is increased activity in the anterior lobe during pregnancy, and that the secretion so produced, like that of the posterior lobe (infundibulin), influences the retention of lime salts which are required for the foetus and also for the secretion of milk. There is, moreover, another fact of importance in this connexion. In 1910 Ott and Scott2 observed that the extract of the posterior lobe of the pituitary has a 1 Crowe, S. J., H. Cushing, and J. Homans, Bull. Johns Hopk. Hosp. 1910, vol. xxi, p. 127. 2 Ott, I., and J. C. Scott, Proc. Soc. Exper. Biol, 1910-11, vol. viii, p. 48. HORMONES AND THE MAMMAE 93 powerful augmentative influence on mammary secretion Effect of in the lactating animal. This has been confirmed by ^ m^mary Schafer and Mackenzie1 and others. There has, however, excretion been much discussion whether the extract produces this lactation. effect by its well-known action on all involuntary muscle —an expressor effect, in fact — or whether there is a selective action on the mammary epithelium ; possibly both factors are brought into play. I have recently carried out experiments, in which Effect of injections of anterior lobe extract and infundibulin have ^tradiTon been made into adult virgin and into non-pregnant the inactive parous guinea-pigs, in order to test the effect of these extracts on the mammary glands in circumstances which would avoid the possibility and consequent confusion of an expressor action. In these experiments portions of the mammae were first removed as controls, and subsequently the animals received many injections of the extracts mentioned. In no case was any histological difference found in the mammary gland before and after the injections.2 The thyroid and the mammae. — Very little Thyroid- experimental work has been recorded in this connexion, not°hiLrfere In ray own experiments it was noted that in one cat from with ™ilk- . . secretion which the thyroid had been removed during pregnancy during suckling occurred after the birth of the kittens. This lactatlon showed that, like the removal of ovaries, thyroidectomy does not interfere with the milk-secretion provided the breasts be active — that is, under the influence of preg- nancy— at the time. In animals from which the thyroid is removed at other times inactivity persists, as we would expect. According to Ott and Scott3, iodothyrin inhibits Effects of mammary secretion. On the other hand Hertoghe4 ^eoct^°n^f 1 Schafer, E. A., and K. Mackenzie, Proc. Roy. Soc.t Ser, B, 1911, vol. lxxxiv, p. 16. 2 Bell, W. Blair, The Pituitary, 1919. 3 Ott, I., and J. C. Scott, Therap. Gaz., 1912, vol. xxxvi, p. 761. 4 Hertoghe, E., quoted by H. R. Harrower, Practical Hormone Therapy, 1914, p. 186. 94 THE SEX-COMPLEX states that the administration of thyroid extract to lactating animals increases the flow. Effects of The suprarenals and the mammae. — So far as I suprarenin. know no observations have been recorded on this point except those made by Ott and Scott1. These observers found that suprarenin inhibits the secretion of milk. Effects of The thymus and the mammae. — Ott and Scott1 the thymus. s^ate that injections of thymus extract excite the secretion of milk. It will be obvious from the foregoing remarks how little is known of the influence of the ordinary internal secretions on mammary secretion. It appears that the most feasible method of reaching a conclusion, apart from direct experimentation which would be extremely complicated, is the application to the question of the metabolism of milk-secretion of the principles of the maternal- fcetal metabolism, and its relation to the in- ternal secretions. The question The foetal hormone. — Since the work of Lane- hormone Claypon and Starling2 attention has been riveted on affecting the the hormonic theory of mammary activity and milk- mammse. . J ... secretion ; and at the present time it is unnecessary to discuss the nervous theory, or the way in which it has been refuted by transplantations of mammary gland tissue3, and by observations made on paraplegic patients who have become pregnant and have nursed their children subsequently4. It is now accepted that the whole cycle of breast activity is biochemical. Lane-Claypon and Starling performed a number of experiments which proved, they thought, that the growth of the* mammary glands during pregnancy is due to 1 Ott, I., and J. C. Scott, Therap. Gaz., 1912, vol. xxxvi, p. 761. 2 Lane-Claypon, Janet E., and E. H. Starling, Proc. Boy. Soc, Ser. B, 1906, vol. lxxvii, p. 505. 3 Ribbert, A., Archiv. f. Enlwick.-Mechanik., 1898, vol. vii, p. 4. * Routh, A., Trans. Obstet. Soc, 1897, vol. xxxix, p. 191. HORMONES AND THE MAM1VLE 95 " the action of a specific chemical stimulus produced in The question the fertilized ovum "*. hormone Further, they stated that " lactation is due to the affecting the J mammae. removal of this substance, which must therefore be regarded as exerting an inhibitory influence on the gland cells, hindering their secretory activity and furthering their growth ". These authors, however, do not believe that the foetus is the only factor concerned in activating or inhibiting the mammary development — a reservation that has often been overlooked by subsequent writers who have alluded to this work. Lane-Claypon and Starling found, then, that the Foetal hor- , , n • • • i -i i mone is not mammary glands of virgin animals were stimulated to specific. growth by foetal extract, and those of muciparous animals to secretory activity. These observations have been supported by other evidence ; but Foa's2 investi- gations seem to show that the hormone is not specific to the species. Before Lane-Claypon and Starling's researches Halban3 had put forward the view that the stimulus to mammary development during pregnancy originates in the placenta. On the other hand, the views put forward by Lane- Claypon and Starling have been criticized.4 Never- theless, it is evident that the claim of these observers concerning the foetal hormone is accurate so far as it goes ; but, as they themselves admit, this explana- tion does not contain the whole truth of the matter, for it seems that many organic extracts have the same effect as foetal extract. Hill, quoted by Marshall5, and O'Donoghue4 state 1 Lane-Claypon, Janet E., and E. H. Starling, Proc. Roy. Soc., Ser. B, 1906, vol. lxxvii, p. 505. 2 Foa, C, Archiv. di Wis., 1908, vol. v, p. 520. 3 Halban, J., Archiv. f. Gynak., 1905, vol. lxxv, p. 353. * O'Donoghue, C. H., Quart. Journ. Micr. Sci., 1911, vol. lvii, p, 187. 8 Marshall, F. H. A., The Physiology of Reproduction, 1910, p. 57(3. 96 THE SEX-COMPLEX Foetal hor- that in certain marsupials the amount of mammary specific! n° development at each period of ovulation is such that it is difficult to distinguish the condition of the mammae in these circumstances from that associated with pregnancy ; and consequently these authors believe that the stimulus to the mammae comes from the internal secretion of the corpus luteum. Further, as Heape1 has described, virgin bitches have often been known to suckle puppies successfully; and, as I have myself observed, bitches subsequently to oestrus and without fertilization may have 'milk' in the mammae at the time when parturition would have occurred had they been fertilized. Males, too, are supposed2 to have performed the function of lactation. All these facts go to show that however stimulating the fcetal hormone may be in regard to the mammary activity, which subsequently leads to the secretion of milk, it is neither specific nor essential, for various hormones, mechanical stimuli, and other exciting causes such as pelvic tumours, not infrequently arouse mam- mary activity, even in the absence of pregnancy and parturition. Sensitization It may be stated, therefore, that although the breasts mammse. have a special function connected with conception, which is probably the most powerful stimulus to the prepara- tion of the breast — the sensitization of the mammae, as we may call it — the subsequent flow of milk is merely a diversion of excretion through the sensitized glands. There are, moreover, many sensitizing agents, and many secretory stimulants. INFLUENCE OF LACTATION ON THE MATERNAL META- BOLISM AND FUNCTIONS Lactation is of benefit to the normal woman, as I shall explain directly. If, however, a woman is unable 1 Heape, W., Journ. Physiol. {Proc. Physiol Soc.), 1906, vol. xxxiv, p. 1. 2 Novak, J., Erkranh. des Weiblichen Oenitales Supplemente, 1912, Vol. i, p. 539. LACTATION AND THE UTERUS 97 to nurse, the stream of nutrient material utilized by the Effect of child during gestation is either consumed by the mother {^mother! or excreted through channels other than the mammae; and this may necessitate a considerable readjustment in her metabolism, and be associated with various disturbances. If a woman be delicate and have felt the strain of preg- nancy, during which her tissues may have been depleted of lime salts, mammary inactivity may be a natural method of allowing the mother to recuperate. With regard to the benefits which may accrue to the mother if she be able to suckle her child, it is commonly stated that in these circumstances involution of the uterus occurs more quickly and completely than if she be unable to do so. Temesvary1 made observations on this point, and Effect of found a considerable difference in the rate of involution the uterus. in those who suckled and in those who did not. Observa- tions with similar results had been made previously by Mueller2, Hansen3, and others. Pfister4, also, studied the relation between lactation and uterine contractions, and found that this was very definite : contractions of the uterus occurred within three or four minutes of the baby being put to the breast, and returned every five minutes during suckling — a phenomenon which was noted up to the eighth day after delivery. It is probable that this effect is the result of a nervous reflex. In Routh's5 case of paraplegia, however, in which the patient conceived and was able to suckle, the involution of the uterus was normal. The ' sucking reflex ', as we may call it, is probably a reverse of the reflex associated with erection of the nipple which has been noted to occur on coitus1. In spite, however, of the probability of a nervous 1 Temesvary, R., Journ. Obstet. and GyncecoL Brit. Emp., 1903 vol. iii, p. 511. 2 Mueller, P., Schmidt's Jahr., 1888, vol. ccvii, p. 250. 3 Hansen, T. B., Zeitschr. f. Oeb. u. Gynak., 1886, vol. xiii, p. 16. 4 Pfister, M., Beitr. z. Oeb. u. Gynalc, 1901, vol. v, p. 421. * Routh, A., Trans. Obstet. Soc., 1897, vol. xxxix, p. 191. 7 98 THE SEX-COMPLEX Effect of reflex in the production of immediate uterine contrac- the uterus!11 tions, there is no doubt that the high calcium content in the blood during lactation, which I have found to exist, has a beneficial influence both on lactation and on involution. Superlactation which is sometimes seen in the poorer classes is dealt with in Part II. PHYSIOLOGICAL EFFECTS OF MAMMARY EXTRACTS Effects of Many observations have been made recently con- extracts.ry cerning the action of extracts of the mammary gland, • in the belief that this structure is itself an organ of internal secretion. I have already discussed this question, but it will be worth while briefly to examine the physiological evidence on which the therapeutical use of this extract is based. A short review of the work done on these lines up to the year 1913 is to be found in a contribution by Cavagnis1. This author arrived at the following experimental conclusions : — At the beginning of preg- nancy the injection of mammary extract augments to a remarkable degree the tonicity of the muscle-fibres of the uterus. This action is less marked on the non- pregnant uterus, and on the uterus towards the end of gestation. Further, it has been stated2 that injections of mam- mary extract produce abortion in pregnant animals. The action of mammary extract is, generally speak- ing, hypertonic in regard to all involuntary muscle, and it is said that the mammary extract from a pregnant female has the same action as that from the non- pregnant. If this be so, it is a point of some importance ; but of greater importance is the question whether an extract of the lactating breast gives a more marked 1 Cavagnis, G., Ann. di Obstet. e Gynecol., 1913, vol. ii, p. 563. 2 Schiffmann, J., and A. Vystavel, Wien. Klin. Woch., 1913, vol. xxvi, p. 261. EFFECTS OF MAMMARY EXTRACT 99 action than the extract of virgin mammae in regard to Effects of the properties mentioned. If so, the pressor effect ^tracts!*7 obtained might be explained by the fact that such breasts must be extremely rich in calcium salts, which themselves have a well-marked pressor action on unstriped muscle-fibres. OTHER GENITAL ORGANS In this section I shall consider certain structures, or organs, that play important roles in regard to the reproductive functions. We shall see that, with the exception of the testicles, it is hardly likely that they are organs of internal secretion in the strict sense ; but because various writers, even to-day, regard them as hormonopoietic organs it is necessary briefly to consider their status in this respect. And, in the first place, I would again emphasize the fact that, while every cell in the body has internal secretory functions in regard to itself, these do not justify us in placing individual cells in the same category as the thyroid and the rest of the indubitable regulators of metabolism in general. UTERUS The uterus Some years ago I expressed the opinion, on certain secretion™*1 theoretical grounds, that the uterus might be an organ forming an internal secretion, and this secretion I called 1 uterin ' 1 ; and Bond2 described experiments which showed, he thought, that the uterine secretion influences the growth of the corpus luteum. At a later date, Fellner3 conducted experiments the results of which led him, also, to assume that the uterus elaborates an internal secretion. Moreover, Ancel and Bouin4 believe that in rabbits 1 Bell, W. Blair, Liverp. Med. Chir. Journ., 1906, vol. xxvi, p. 234- 2 Bond, C. J., Brit. Med. Journ., 1906, vol. ii, p. 121. 3 Fellner, 0. O., Centralbl.f. Physiol., 1909, vol. xxiii, p. 347. 4 Ancel, P., and P. Bouin, quoted by L. Franke), Archiv. f. Gyndk., 1913, vol. xcix, p. 225. EFFECTS OF EXTRACTS OF THE UTERUS 101 and guinea-pigs certain epithelioid cells (? decidual cells), The uterus u- t r i J • \i u- u J aud internal which are formed during pregnancy, and which consti- secretion. tute what these writers term the ' myometrial gland ', give rise to an internal secretion which is specially con- cerned with the secretion of milk. PHYSIOLOGICAL EFFECTS OF EXTRACTS OF THE UTERUS In 1909 Hick and I recorded1 experiments in regard Effects of to the effects produced by injections of uterine secretion thVuterus. which was obtained by ligation of the uterine horns in rabbits. We observed distinct pressor effects, especially in regard to uterine contractions. Fellner2 subsequently noticed a vasoconstrictor effect following intravenous injections of an extract of the uterus. Mackenzie3 has found that extracts of the uterus involuting after par- turition cause an increase in the flow of milk from the incised nipples of lactating animals. In spite of my original suggestions, and in spite of the statements presented above, I am now of the opinion that there is insufficient evidence to prove that the endometrium itself forms an internal secretion. Because the endometrium is able to cause the uterus not disappearance of fibrinogen and fibrin ferment from i^^i of menstrual blood, and so prevent coagulation4, and secretion. because the external secretion and extracts, as already mentioned, have physiological pressor properties, it by ho means follows that there is also an internal secretion. Even the presence of tryptic ferments5' 6, is no evidence of a cryptorrhceic function. There may, possibly, be 1 Bell, W. Blair, and P. Hick, Brit. Med. Journ., 1909, vol. i,p. 777. 2 Fellner, O. O., Centralbl.f. Physiol, 1909, vol. xriii, p. 347. 3 Maokenzie, K., Quart. Journ. Exper. Physiol., 1911, vol. iv, p. 305. 4 Bell, W. Blair, Proc. Roy. Soc. Med., 1911, vol. iv, p. 234 ; Journ. Pathol, and BacterioL, 1914, vol. xviii, p. 461. 6 Halban, F., and O. Frankl., Qynak. Rundschau, 1910, vol. iv, p. 471. 6 Frankl, O. and B. Aschner, Qynak. Rundschau, 1911, vol. v, p. 647. 102 THE SEX-COMPLEX Uterus not such a secretion, but I think the matter is unproven, fnternai1 ° Evolutionary and morphological evidence is very much secretion. against the likelihood that an organ of so late origin, and one which when present is of so unequal functional value, is also an organ of internal secretion. I prefer now to consider that 'uterin' is the ex- ternal secretion of the uterus, and that its richness in calcium salts may account for some of its pressor properties. PLACENTA The placenta Many writers look upon the placenta as an organ secretion0*1 °^ m*ernal secretion, for the most part in consequence of certain recorded injection experiments, the results of which, however, have been shown to be erroneous. Halban1 was the first to propagate the idea that the placenta is responsible for mammary activity. In the interpretation of the results of experimental research in regard to the placenta we find much error and many assumptions that are not justified, for they take no account of basal premisses in regard to the definition of the term * internal secretion '. I mean by this last criticism that we must at once either limit our definition of ' internal secretory gland', to the well- recognized hormonopoietic organs — the gonads, the pituitary, the thyroid and parathyroids, the suprarenals, the pancreas and probably the pineal — which regulate the general and the reproductive metabolism, or we must include every cell in the body with its assimilative and excretive functions which concern its own metabolism. We must also take into account phylogeny in regard to the structures under consideration. Internal secretion, in my opinion, as distinct from the conception of the cryptorrhceic function of every cell in the body, is the function of structures of ancient phylogenetic lineage which have become specialized for the vital purposes of the general metabolism (and characterization) and 1 Halban, J., Archiv.f. Gynak., 1905, vol. lxxv, p. 353. EFFECTS OF PLACENTAL EXTRACTS 103 reproduction. Their function is co-ordinative and con- The placenta tinuous, not intermittent ; and such organs are part of secretion™ the soma of the individual. This digression is in part repetition, but I have given my own views prominence in this place because the placenta of all structures in the animal economy should never have been chosen for a seat among the elect. In the first place, the placenta has a very short phylogenetic history : it is a structure of late mammalian origin. In the second, the placenta is a foetal structure and is not maternal, excepting in so far as the ovum is maternal and in conjunction with the male contribution forms the foetus. Third, the placenta is merely a temporary occupant of the uterus. Let us now shortly consider the evidence that has been adduced to prove that the placenta gives rise to an internal secretion of value to the maternal economy. This evidence is chiefly related to investigations con- cerning the effects of extracts of the placenta. THE PHYSIOLOGICAL EFFECTS OF PLACENTAL EXTRACTS In 1907 Dixon and Taylor1 announced that placental Effects of extracts have a powerful pressor effect, especially in extracts1. regard to the involuting uterus. This, indeed, it was said, is t^ie reason why animals devour their placentae after parturition ! Rosenheim2, however, shortly after- wards showed very definitely that the pressor effect which had been obtained was due to the pressor sub- stances derived from the amino-bodies found in putre- fying meat3- 4, which are formed in the placenta when it is not properly preserved. 1 Dixon, W. E., and F. E. Taylor, Brit. Med. Journ., 1907, vol. ii, p. 1156. 2 Rosenheim, 0., Journ. Physiol., 1909, vol. xxxviii, p. 337. 3 Abelous, J. E., H. Ribaut, A. Soulie, and G. S. P. Toujan, Compt. Rend. Soc. Biol, 1906, vol. lx, pp. 463 and 530; J. E. Abelous and H. Ribaut, Compt. Rend. Soc. Biol, 1908, vol. lxiv, p. 907. 4 Barger, G.,and G. S. Walpole, Journ. Physiol, 1909, vol. xxxviii, p. 343. 104 THE SEX-COMPLEX Effects of Morley1 in a plea for the recognition of the placenta extracts*1 as an organ °f internal secretion lays emphasis on the necessity of standard and efficient methods for the preparation of extracts. The effects of the extracts prepared by him in five different ways are given. No physiological results were obtained, except in the cases of two of the preparations which caused slight contrac- tions of the isolated uterus; but in both the extracts were found to contain the products of decomposition. Seitz2 believes that the placenta plays the part of an organ of internal secretion through the medium of the chorionic epithelium, but he does not substantiate his views with any reliable evidence. We have already seen that the action of fcetal (including placental) extracts on the mammary glands is not specific; consequently this matter requires no further consideration here. TESTICLE AND PROSTATE This work is devoted especially to the female aspect of the sex-complex, so it will be enough to mention here that the testicle, like the ovary, has an internal secretion, and that it is probable that the cells of Leydig — better called the * interstitial cells ' — are chiefly responsible for this function. Further details concerning the physiology of the testicle may be obtained from such works as those of Biedl and Vincent. The prostate has been considered by some to possess an internal secretion. Serrallach and Pares3 were the first to make this declaration as the result of prostatec- tomies on dogs, which caused, they thought, retro- gressive changes in the testicles. This result, however, 1 Morley, W. H., Trans. Amer. Gynecol Soc, 1917, vol. xlii, p. 228. 2 Seitz, L., Verhand. Deutsch. Oesellsch. f. Gyndk., 1913, vol. xv, p. 213. 3 Serrallach, M., and N. Pares, Compt. Rend. Soc. Biol., 1907, vol. lxiii, p. 790. TESTICLE AND PROSTATE 105 has been questioned by Biedl1 and by Haberern2, and is now generally discredited. Arbuthnot Lane3 has asserted that the prostate is not only an organ of internal secretion, but that its con- tribution to the seminal discharge is absorbed from the vagina with beneficial results to the woman. Lane's views concerning the prostatic secretion were adversely criticized in a leading article4 which discusses the matter fully from morphological and physiological standpoints. As the subject would be a digression in this place further information must be obtained, if required, from the article mentioned. 1 Biedl, A., Innere Sekretion, 1913, 2nd Ed. 2 Haberern, J. P., Internal. Gongr. d'Urol., 1908. 3 Lane, Arbuthnot, Lancet, 1918, vol. ii, p. 622. 4 Leading Article, Lancet, 1918, vol. ii, p. 674. THE CORRELATION OF THE INTERNAL SECRE- TIONS IN REGARD TO THEIR GENITAL FUNCTIONS I have endeavoured to trace, for the most part from my own observations, the disjointed facts concerning the influences exerted by the different members of the hormonopoietic gland system upon one another, on the genital organs and on the metabolism generally, in so far as the reproductive system may be concerned ; and in so doing I have in some cases been able clearly to show the nature of the associations between the different organs. It is, however, absolutely impossible at the present time to correlate fully all their functions ; but in view of what was said at the commencement as to the necessity for a lead in this intricate matter, I cannot refrain from enunciating what I believe to be the general principles. I shall not further analyse the details. It appears, from the evidence at our disposal, that in spite of great variations in the structure of the hormono- poietic glands in different mammals, the total func- tional result is the same so far as the genital processes are concerned. The variations in function that depend on the differences of structure are probably related to differences in the food and habits of life ; and in adapting our knowledge to the requirements of human physiology we must take into account both the essential functions to which we have already referred — the individual metabolism of the mother, and the metabolism of her reproductive functions — for they are completely inter- dependent in normal circumstances. The functions We have seen as the result of our studies that the of the ovaries, ovaries, on the one hand, have as their share of these Total functional result of internal secretions. CORRELATION OF INTERNAL SECRETIONS 107 dual functions the onus of ensuring the reproduction The functions of the species by furnishing the ova, and by keeping of the ovarles- active the rest of the genital structures and functions. And, further, the secretions of the ovary are probably concerned in keeping the other members of the hormono- poietic system in touch with the necessities of the repro- ductive situation ; that is to say, the influence of the ovarian secretions on the metabolism may produce effects in regard to the activities of other organs of internal secretion. This last function, if so it can be termed, is of the deepest importance, and is one which explains much that would otherwise be obscure. Strictly speaking, then, the ovary is concerned in the temporary function of reproducing the species, and, by its hormones or internal secretions, of bending the metabolism of the body to this purpose. Any influence the ovary may have over the general metabolism is, therefore, related to and dependent on its primary re- productive functions. I do not believe that this organ influences the metabolism except in so far as this special function is concerned. Of course, removal of the ovaries may produce a temporary general disturbance, but this does not invalidate the view just mentioned. On the other hand, the rest of the hormonopoietic The genital system is related to the genital functions in various ways. theCextra ° First, some of the members — the thyroid, pituitary, genital organs i i • /i i -, i o£ internal and suprarenals — influence the development and subse- secretion. quently preserve the integrity and activity of the genitalia, as I have already demonstrated ; while others — the pineal and possibly the thymus — appear to prevent sexual precocity. Second, all the hormonopoietic organs, acting in harmony, control the metabolism in response to the necessities of the genital functions ; but, in addition, they adapt the whole organism to the possibility of the situation, and regulate the secondary characteristics, both physical and psychical, to suit the needs of the individual. Once, however, the repro- ductive organs are removed or undergo atrophy, the genital functions of the rest of the internal secretory 108 THE SEX-COMPLEX The genital system cease, and the rearrangement of the metabolism the extra-0 that follows produces the symptoms of the menopause, genitaiorgans as we shall see later. Contrariwise, insufficiency of the of internal ... . secretion. thyroid, pituitary or suprarenals may cause the cessation of the genital functions with atrophy of the uterus. As to the more particular parts played in the meta- bolism by each member of the ductless gland system, these have already been specified. In spite, therefore, of the reluctance to correlate our knowledge shown by most investigators the matter is not one of very great complexity if the views expressed be correct in a general way, although there remains much detail to be filled in. interdepend- As soon as possible we must come to a conclusion as idual and to what are the facts ; so much of the work that has been metabolism0 done *s contradictory. There is in consequence so much more need for further efforts. And I would again insist that in order completely to solve the problems surrounding the genital functions, we must focus at one and the same time the two essential processes of life — the individual metabolism and the reproductive meta- bolism. They are absolutely interdependent ; indeed, the individual metabolism is the reproductive meta- bolism. It is the neglect of this point of view that has brought about much of the confusion that still exists. Weismann and Ray Lankester describe the relation between the reproductive cells and those of the soma in still more striking terms. The latter1 says : " Among " the multicellular animals, certain cells are separated " from the rest of the constituent units of the body, as " egg ceHs ar*d sperm-cells ; these conjugate and con- " tinue to live, whilst the remaining cells, the mere " carriers as it were of the immortal reproductive cells, " die and disintegrate. The bodies of the higher animals " which die may from this point of view be regarded " as something temporary and non-essential destined " merely to carry for a time, to nurse and to nourish 1 Lankester, Ray, quoted by P. Geddes and J. A. Thomson, The Evolution of Sex, Revised edition, 1901, CORRELATION OF INTERNAL SECRETIONS 109 " the more important and deathless fission products of interdepend- " the unicellular egg ". tiZ°Int"' Whatever views we may hold as to details I question reproductive whether this philosophical statement is open to con- tradiction. The function of reproduction in all its preparations and performances commences in the early stages of segmentation, and may be said to continue in Man until the care of the offspring is completed ; but in many lower forms of life, male and female, the act of reproduction is also the cause of death. PSYCHOLOGICAL CHARACTERISTICS Although I have indicated incidentally the fact that the psychical functions are related to the physical, it will be necessary briefly to consider whether we have any grounds for believing in what may be called the 4 psychology of sex ' ; and, if so, what the special attributes may be. I shall endeavour to present the case as it appears to me and, I believe, totnost unbiassed scientists. The basis In attempting this task I must insist, for the benefit psychology. °f certam critics, that I am concerned neither with the effects of time and environment on mental processes, nor with the sociological and economic problems sur- rounding the subject. If I can show that the differ- ences in metabolism which result from differences in the activities of the internal secretions — that is, biochemical stimuli — influence the psychology of the individual my task will have been accomplished. Completely to explain sex-psychology we should in the first place be obliged to study the nature of psychical processes. This difficult task I shall not attempt ; it is one that belongs to the domain of the pure psychologist, and it is one which has for its primary basis either purely material or partly 'spiritual' conditions. By saying "partly spiritual" — for want of a better term — as op- posed to "purely material", I leave undecided the general aspects of the stormy disputation concerning the connexion of ' spirit ' with matter ; yet any views I shall put forward will not be affected — they are equally applicable whatever may be the opinions held concerning this question. I cannot, however, hope to accommodate those who assert that the mental functions are entirely * spiritual '. PSYCHOLOGICAL CHARACTERISTICS 111 Without indulging in profitless discussion, I shall Psychical take it for granted that all engaged in biological pur- dependent^ suits, to whom my statements are addressed, hold the physioiogioal _ _ , . . . . processes. view that the psychical functions are partly or solely dependent on physiological processes ; and it is on this belief that my own views are based. I shall, moreover, not enter into any discussion of what I have described as " partly spiritual " factors, whether they exist in reality or not ; I shall merely deal with the material factors which, it is certain, influence mental processes. The mental characteristics of the normal woman come Mental char- under the dominating influence of her special functions. fn fae chiid. Before puberty, when the metabolism of girls does not differ appreciably from that of boys1, the maiden is often self-reliant and somewhat of a ' tom-boy '. Some, it is true, like to nurse dolls, but many, especially when brought up among boys, prefer more masculine methods of enjoyment. At puberty a vast psychical change Mental char- occurs in normal girls : they become shy and reserved, ^puberty. and adopt a modest demeanour in the presence of men. At this time they realize the influence of their fascina- tions on the opposite sex. Marriage may bring out the best or the worst that is in a woman : if she be happy and contented her mind becomes turned in the direction of motherhood with joyous anticipation ; if discontented and unhappy she often seeks distraction outside the home. Gestation, too, normally produces in a woman Mental char- mental equanimity, and a special faculty for patience during*108 and endurance for the sake of her child. Parturition, gestation. with its attendant fears and pains, develops in the mother a very tender feeling of possession after a fight well won. Nurses have told me that women delivered by Caesarean section usually have not the same feelings of passionate guardianship that fill the hearts of women who have endured ungrudgingly the pangs of labour ; and it is possible that the so-called ' twilight sleep ' induced during parturition will likewise produce a similar 1 Bucura, C. J., Oeschlechtsunterschiede beim Menschen, Wien u. Leipzig, 1913. 112 THE SEX-COMPLEX Mental char- deficiency in the maternal emotions. Lactation, also, during 1CS incites or increases the mother-love — as poets for lactation. countless ages have told us — partly by demonstrat- ing, as it does, the dependence of the infant, and partly by inspiring the mother with the joy of self- sacrifice. After the menopause the mental attitude may revert to a more neutral type. Mental char- I shall only deal with the mentality of Woman of woman during the reproductive period — that is to say, between during the puberty and the menopause — since it is then that her reproductive x * . . ■ ' ■ « period. characteristic psychology is most evident, for the reasons given above. Dimorphism It has already been stated that every person is sex-char- dimorphic ; in other words, all normal men and women actenstics. contain the elements of both sexes. The total quantitat- ive proportion varies in different individuals and in different characteristics ; but the dominant character- istics usually indicate the declared sex of each, while the recessive' characteristics remain more or less latent. This being 'so in regard to structural disposition, logically we may expect the functional activities to correspond therewith; as, indeed, they do. It is to be regretted, however, that at present we know so little of the finer anatomical differences of the regulators of sex meta- bolism, for, were we able to point to definite and constant distinctions at all ages between the structure of the organs of internal secretion other than the gonads in the two sexes, it would be easier to convince those who are now sceptical of the differences of function dependent thereon. I believe, by reason of much physiological and pathological evidence, that there are such differences, and that if these cannot always be expressed qualitat- ively, they certainly can quantitatively. And, after all, quantity is capable of producing effects and results as surely and with as great variations as quality. Further- more, it must be obvious to all that normally different metabolic effects are due to different demonstrations of function ; and that different demonstrations of function PSYCHOLOGICAL CHARACTERISTICS 113 must be dependent on qualitative or quantitative structural conditions. Since the differentiation of sex is a process of evolu- Differentia- tion destined to meet the complexities of reproduction evolutionary1 which arise in the life-histories of the higher animals, Pr°cess- we must look upon all the functions of the body, the mental no less than the physical, as harnessed to this purpose, which has reached the highest development in Man. In the lower animals sexual selection and maternal instincts are dependent, no doubt, on sensory stimuli, probably without the interference of the intellectual faculties of altruism and choice, which form additional factors in the equipment of the human female. From a biological standpoint, according to the state- ments of Ray Lankester and others, to which reference has already been made, the individual exists merely to harbour the reproductive cells. Less crudely we may say the raison d'etre of all existence is the furtherance of the universal scheme of evolution. Retrogressions there may be, it is certain, but the total trend is towards the evo- lution of higher forms of life, and therefore of higher and more intricate functions. It is only to be expected, then, that all the functions of every individual subserve, how- ever obscurely, this one eternal purpose. Indeed, it might be urged that in serving the individual the so-called ordinary functions are indirectly assuring the welfare of the reproductive functions. It is not for us, therefore, who make a study of the processes of reproduction, to allow the possibility of any divergence of the mental functions from the path indicated. Still less is it for others with no knowledge of biology to take the mind from the body and enshrine it as a thing entirely apart — a parasitic function living on, but independent of the body. It would, of course, be absurd to deduce from these individua- remarks, as some may be inclined to do, the belief that tion: a?d , , . , . 1.1 i -, evolution. the mind is centred on the actual reproductive functions alone, or is entirely dependent thereon. Beneath the wide issue of evolution lie many incorporated but 8 114 THE SEX-COMPLEX Individua- tion and evolution. Mental processes a factor in evolution. individual parts : each is as independent as is the modern worker of the organizing capitalist who employs those under him. At the same time, just as the worker — often acting unconsciously, no doubt — is essential to the furtherance of his employer's schemes, while living himself an independent life — which, be it noted, probably often accounts for his value to his master — so, too, are the functions of the mind and body, perfected by apparently individual life, necessary for the advancement of the whole scheme of evolution through the channels of reproduction. I say " apparently ", for although individuation is accentuated in the secondary reproductive functions of Man, yet it so obtains for the benefit of evolution rather than of the individual. It is, of course, certain that in the lower forms of life too great a degree of individuation may lead to a decrease in fertility1, but at present there is little evidence of this in regard to the human race2. If, however, this were to be true from a general standpoint without regard to sex, it would be of importance to our argument, for undoubtedly the largest strain in connexion with the processes of reproduction falls upon the woman. Individuation to the extent seen normally in a man may, therefore, not be strictly com- patible with the reproductive functions of a woman. The ultimate object of all mental processes is the same — evolutionary progress, of which reproduction is an essential, if indirect, factor. Mental aspirations are the aspirations of the controlling factors of evolution, even though they appear to be the selfish ambitions of the individual. Nature adroitly furthers her scheme of evolution by teaching Man, before whom, but unknown to him, she places inducements to improve himself ; 1 Spencer, Herbert, The Principles of Biology, 1867, vol. ii, p. 470. 2 It appears to me that, however positive may be the evidence concerning the relation of individuation to infertility in the lower forms of life, all discussions of this subject in the case of Man are inconclusive because they fail to take into account the difference between physiological infertility and voluntary suppression of pro- creation. PSYCHOLOGICAL CHARACTERISTICS 115 and thus there are wheels within wheels, although the Mental effect of the hand of Time alone is visible : Repro- Factor in & duction ; Reproduction with individuation ; Individua- evolution. tion with reproduction ; Individuation . . . Evolution. The higher mental processes, then, in the human subject are turned into account in the physiology of reproduction in a manner apparently not exercised in the lower orders of creation. As I have indicated, sexual selection in animals is Sexual apparently dependent entirely on internal stimuli — due internal to metabolic factors to be discussed directly — and on stunul1- stimuli of external origin, emanating from the senses of sight, smell, hearing and touch. With regard to the instincts associated with maternity in the lower animals, these, also, appear to be directly referable to internal stimuli evolved by the processes of natural selection in the competition for survival. To illustrate how purely metabolic are the maternal Maternal instincts, and even the functions associated with and The8 maternity in animals, I may mention the case of a bitch metabolism. which lived for nearly seventeen years. When young she had several litters of puppies. Later in life, some weeks after the cessation of each oestrum 'milk' appeared in the mammae, and at the correct period she made a nest for the expected young, although she had never been allowed access to a dog during the period of heat. More- over, Marshall1 and others state that the migratory instinct of birds is due to activity in the gonads, after a period of quiescence. The human female, to whom the intellect is a source The intellect of personal pleasure and pride, utilizes — often quite ductive*0 unconsciously — the high state of perfection to which functions. her mental processes have been evolved not only to assist her in sexual selection2, but also in the care and 1 Marshall, F. H. A., The Physiology of Reproduction, 1910. 2 Modern ■ Eugenics ' have been introduced by Man in an attempt to assist the unerring laws of Nature which are concerned with sexual selection. This study may have been thrust into the mind of Man by Nature, in order to counteract the disturbances of the law of the survival of the fittest, which are produced by the humanity of mankind. 116 THE SEX-COMPLEX The intellect upbringing of her offspring. And while the environment ductive™" anc* condition of women have undergone very little, functions. ancl certainly no radical changes in regard to their special reproductive functions, those of men have altered considerably. It is, of course, true that the higher mental faculties of women must keep pace with the mental development of mankind as a whole, in order that the evolution of the mind may not be impeded ; but, properly speaking, that is the sole biological object of mental advancement in women in normal circum- stances. Men, on the other hand, must develop their intelligence not only to assist them in sexual selection, but also in order that they may be able to sustain their mates and offspring in an environment compatible with advanced civilization. This means that, whereas a strong arm, a good bow and arrow, and courage were the sole requirements of the primitive man rising above the beasts, in advanced conditions of civilization the mental faculties must be capable of all the intricate processes which go to make it possible to live under modern conditions. The earning of a livelihood by scientific enterprise, for instance, requires a vastly different intellect from that necessary for the manu- facture of a bow and arrows and the hunting of wild beasts. The selection of a mate and the provision of a suitable environment for her and her offspring may be termed the secondary reproductive functions of the human male. Theindi- In considering the psychical characteristics of the of Nature?01 m°dern woman we must bear all these facts in mind. We must, too, remember that the individual is merely a tool of Nature — a unit in a vast scheme. The man is not superior to the woman in any possible sense of the word : his functions lie in one direction, and the woman's in another ; and each is the reproductive complement of the other. If a man's primary reproductive functions may be described as fugitive owing to the claims of the secondary, a woman's may be said to be stationary, or enduring. PSYCHOLOGICAL CHARACTERISTICS 117 As far as a man is concerned the sexual act — his con- Sex-differ- tribution to reproduction — is an incident, but a woman's ™g^ and contribution is of long duration, including conception, secondary . . . reproductive gestation, parturition and lactation ; and thus we are functions. forcibly reminded of Byron's well-known lines contrasting the love of Man and Woman. But while the primary reproductive process is short where a man is concerned, his secondary processes are, in our days, long and arduous. The course of education and the striving after the success necessary before he can ensure the proper environment for a family require physical strength and mental acquisitiveness, if he is to achieve his purpose, and fulfil his destiny as a factor in the progress of Nature. On the other hand, a woman's primary reproductive functions are, as we have seen, enduring, and her secondary — individual education, and the care of the child and home — are merely a direct preparation for and sequel of the primary. Geddes and Thomson1 ingeniously describe the male metabolism as katabolic and the female as anabolic. It may also be suggested that the mental processes in the two sexes functionate on similar lines. Be that as it may, it must surely be recognized by all that the male mind and masculine form are suited to the business of life which so nearly concerns his share in reproduction ; while the female mind is specially adapted to her more protracted part in the perpetuation of the species. I cannot conclude this discussion of the more abstract Rejection of aspect of the subject without acknowledging that the ^^g rejection of maternal functions by modern women may Possibly a DTOCGSS of be Nature's plan for securing the disappearance of Man evolution. to ensure further evolution. It is strange that modern advocates of reproductive subjection have not advanced this, the only scientific reason for their point of view. Let us now discuss more exactly the psychology of Regulation women, and the factors by which the mental processes of mental. J r processes m are regulated. women. 1 Geddes, P., and J. A. Thomson, The Evolution of Sex, Revised ed., 1901. 118 THE SEX-COMPLEX Eegulation of mental processes in women. Influence of metabolism on mental functions. It has already been indicated that the central biological motive of a normal woman's existence is the propagation of the species ; and since in her this process may occupy the best period of her life almost exclusively, it is obvious that her metabolic processes must be particularly adjustable to the reproductive economy. And, as the mental attitude is considerably dependent on the general metabolism, it follows that the mental processes of every normal woman are largely subservient to the varying physiological conditions of her body. It seems almost superfluous now to point out how the mind is affected by the physical condition of the subject ; how different the mental outlook is at puberty and at the menopause ; how different usually in the normal, reproductive woman and in the barren spinster. I know quite well these truisms are often denied by women, and I do not intend to digress : it is no business of ours that social conditions force women out of their natural sphere, and it is not in the province of scientists to suggest remedies. The very fact that women are continually asking for remedies and seeking them is a tacit admission of abnormal circumstances. The mental condition of a woman is dependent on her metabolism ; and the metabolism itself is under the influence of the internal secretions. As I have said before, probably every cell in the body is^ an organ of internal secretion and is intimately connected with the life of all the other cells of the soma. But those aggrega- tions of secretory cells known as the hormonopoietic glands afford us definite information as to the processes of metabolism with which they are connected, con- sequently we can trace their relations to mental processes. It is well known that women with hypothyroidism and hypopituitarism are lethargic ; and we have ample proof that hyperthyroidism produces mental energy and excitability. So, too, we are certain that the removal of normal functionating ovaries usually produces mental depression ; while women with very active ovaries, which can be discerned from the menstrual flow, PSYCHOLOGICAL CHARACTERISTICS 119 sexual inclination and so on, are energetic and lively, influence of Now, these mental effects are due to changes in the Omental*1 metabolism which result from the conditions affecting the functions. hormonopoietic glands mentioned ; and our knowledge is such that we can often say exactly what metabolic disturbance is responsible for the abnormal mental attitude concerned ; and sometimes, too, we can directly remedy it. For example, excessive ovarian and thyroid secretions lead to an unusual excretion of lime salts ; and it appears obvious from the investiga- tions of Sidney Ringer and Dudley Buxton1 and from my own work2 that the compounds of calcium are largely responsible for vasomotor stability and the control of nervous and muscular irritability. These views have recently received further confirmation from the experimental work of Hoskins and Wheelon3. All this is extremely interesting and important : it The Corre- indicates that the mental processes can be regulated Function. therapeutically, and it shows clearly how the mind is dependent for its normal functions on the condition of the body. We have, at the present time, no need for the crude evidences of insanity, of brain lesions, or even of such diseases as cretinism to prove our contention ; we know that merely the excessive excretion of a mineral salt will lessen the mental equanimity of the subject. This is only one example of the correlation of function between the mind, the soma and the reproductive system, any disturbance of which is, therefore, shown in triplicate.4 How then does all this specially concern the psycho- logy of women as opposed to that of men ? We have seen that in men the reproductive calls on the metabolism are, unless excessive sexual indulgence 1 Ringer, Sidney, and D. W. Buxton, Journ. Physiol, 1885, vol. vi, p. 154 ; 1887, vol. viii, pp. 15 and 288. 2 Bell, W. Blair, The Principles of Gynecology, 1910 (3rd Edit., 1919) ; Liverp. Med. Chirur. Journ., 1912, vol. xxxii, p. 398. 3 Hoskins, R. G., and H. Wheelon, Amer. Journ. Physiol, 1914, vol. xxv, p. 119. 4 Bell, W. Blair, Brit. Med. Journ., 1920, vol. i, p. 787. 120 THE SEX-COMPLEX Claims of reproduction on the metabolism different in the two sexes, Sex-differ- ences in organs of internal secretion. be practised, not great. Their metabolism during the reproductive period, after growth has been established, is mainly concerned with their individual needs : the 1 nerves ' must be steady, the mind stable and the physical strength great. These attributes are so as- signed that men may be able to succeed — a term which implies a contribution towards the progress of evolution, as well as the assurance of a suitable environ- ment for the family. All the hormonopoietic organs are adjusted with this object in view : the preservation of a steady and uniform metabolism, in which no sudden alterations normally occur. Obviously the more mascu- line a man is the more this state of affairs will obtain. There is, therefore, little reason for pathological lesions of hyperplasia and hypoplasia to supervene in his organs of internal secretion. And this is exactly what we find ; for, unless the changes at puberty overstep the normal limit, it is exceedingly rare in men for hyperplastic or hypoplastic lesions to occur in the organs of internal secretion. On the other hand, in women during the reproductive period there are sudden and rapid alterations due to the demands of gestation and lactation. To a certain extent a woman by the catamenia is kept ' in practice ', as we may say, and protected from too sudden and great demands on her metabolic adaptability ; and the periodic fluctuations in her economy are provided for by the capabilities of her hormonopoietic organs — the ' regulators of metabolism ', as Paton1 has aptly called them. Now, although we know that the corresponding organs of internal secretion in the two sexes differ with regard to their weights relative to the total body- weight, at the present time we know of no absolutely definite qualitative differences, except those produced by preg- nancy, which can be set down as providing a means of sex-distinction. Possibly this disability will be removed by the work which is being done upon the subject. Not infrequently it has been disputed that differences exist, 1 Paton, Noel, The Regulators of Metabolism, 1913. PSYCHOLOGICAL CHARACTERISTICS 121 either in the organs of internal secretion or in the general Sex-differ- metabolism. It appears to me, however, that to dispute organs^ quantitative differences is to risk a reputation for logical internal 71 . . secretion. inference ; while to deny the possibility of qualitative differences is merely an indication of ignorance of actual facts, for differences have already been demonstrated in regard to the structural appearances associated with pregnancy — an essentially feminine function. It is, of course, reasonable to suppose that the qualitative and quantitative differences will vary in degree according to the proportions of dominant or recessive femininity. The instability of metabolism, actual or latent, which instability of , . , . , • i * . . .i metabolism is seen m women, is obviously the causal factor m the in women. frequency with which they suffer from disorders of the hormonopoietic organs most concerned — the thyroid and the ovaries. We may look upon the pituitary, suprarenal cortex and pineal body in women as more or less recessive in function, except during pregnancy when large quanti- ties of calcium salts are required for the foetus. This special masculine function of calcium retention is demanded at that time in the interests of the foetus rather than in those of the mother herself. We have, then, in the organs of internal secretion structures in which quantitative and qualitative changes influence metabolism towards masculinity or femininity as the case may be. In this connexion it is interesting and instructive to note that changes similar to those mentioned as occurring in the pituitary and suprarenals in pregnancy, which produce calcium retention for the benefit of the foetus without producing masculinity in the mother, may in the non-pregnant woman produce masculinity in her ; and, included in secondary char- acteristics of masculinity so produced is a metamorphosis towards masculinity in the mental processes, as we shall see later. There can, therefore, be no doubt that there is a sex- psychology, which is related to the dominant physical characteristics and functions of the individual ; and it only remains for us to consider the traits of mind which, 122 THE SEX-COMPLEX on the evidence of the facts recorded, constitute the essential attributes of feminine mentality. Relative Many philosophers, and among the most recent psychology?* "that precocious thinker Otto Weininger1, have placed the character of woman in a false light. They have taken it for granted that the natural and proper absorp- tion of the female in her reproductive career is a vastly inferior obligation to the more diverse and intellectual secondary reproductive functions, as I have called them, of the male. It is probably this attitude towards the feminine role in nature that has led to attempts at the so-called 1 emancipation ' of women. But surely we must look "upon the patient and absorbing work of the female as a far greater self-sacrifice, and consequently more altruistic — especially when carried out in the present day amid all the distractions of modern life, and amid the in- tellectual temptations offered at the expense of the normal physical processes — than was the more purely animal acquiescence in the functions of reproduction which existed in a more primitive era. ideal attitude The ideal attitude of mind of the modern woman Woman. • towards reproduction is that in which the intellect is carefully cultivated and trained both in the higher knowledge and in the most essential feminine pursuits ; the former has for its object the progress of evolution in general and the advancement of the offspring towards the same end ; while the latter makes for an increase in the capability of the individual mother to attend carefully to the environment of her child. A normal woman, therefore, would not exploit her intellect for her individual gain : it is for the benefit of her descendants. Competitive It is reasonable to believe from the evidence at our work in- jurious to disposal that the application of feminine talents to the women. competitive work in which men are engaged, which is strictly speaking an evolutionary form of the hunter's craft, is adventitious and injurious to the psychical and 1 Weininger, Otto, Sex and Cliaracter, Eng. Trans., 1906, PSYCHOLOGICAL CHARACTERISTICS 123 physical functions connected with the biological life of Competitive women'-2, 3. So long as there are two sexes it is unlikely J^iouTto that women will, without detriment to their own sex- women- psychology and physical attractions, which are so essential to sexual selection, develop the masterful mind of the male that may attain to the lofty height of genius — a level to which it is doubtful whether the intellect of any woman has ever yet ascended. Weininger4, indeed, goes so far as to say that " a female genius is a con- tradiction in terms ". The mental differences in the male and female, as determined by Heymans5, Helen Thompson6 and others, in regard to acquisitiveness, application — immediate and remote, personal and im- personal— analysis and reasoned anticipation, all bear out the view that the secondary mental characteristics especially fit men to "advance beyond women in a vocation requiring high intelligence for success ".7 The essential, higher psychological characteristics of Dependence the normal woman have been indicated ; and to those th^mak? mentioned may be added, as a logical sequence, dependence on the male — dependence on his ability to do his special share while she does hers — as a specifically feminine characteristic, which is associated with an ardent desire to be loved. Brief reference must now be made to the less idealistic Abnormal characteristics of feminine mentality. I refer, of course, Attitudes in to those reproductive instincts which women have in women- common with the lower animals — instincts which, as 1 Cf . Pearson, Karl, ' Woman and Labour,' Fortnightly Review, May, 1894. 2 Cf. Campbell, Janet, 'Women in Industry,' Rep. War Cabinet Committee, 1919, pp. 218 et seq. 3 This sentence appears to have been misunderstood. Surely it requires little explanation. Man is strong : he hunts ; he fights ; he enters into the clash of competition with other men to win a livelihood for his wife and family. A woman is not fitted for this mode of life. 4 Weininger, Otto, Sex and Character, Eng. Trans., 1906. 5 Heymans, G., Die Psychologie des Frauen, 1910. 6 Thompson, Helen B., Mental Traits of Sex, 2nd Edit.? 1905. 7 Ellis, Havelock, Man and Woman, 5th Edit., 1914. 124 THE SEX-COMPLEX Abnormal already stated, depend for their existence on internal attitudes in biochemical stimuli. There is no doubt that these women. so-called animal instincts have become modified in educated women by the evolution of the higher mental faculties. It is difficult in a few words to trace the manner in which the human race has brought the strongest of all instincts into comparative subjugation : religion, family life, education and social exigencies have effected a result which is common to all civilized races. The economic value of reproductive indiffer- ence from a natural standpoint we are not called upon to consider ; and what the final outcome and its effect on evolution will be we can only guess. It is, however, incumbent on us to observe facts as they exist, and, when possible, to identify the causal agents and their effect on the life of the individual. Such details are too often shunned by the scientist, and become the common property of those who merely record revolting details unadorned by useful information. Therepro- I propose, therefore, to glance now at the natural instincts and aspect of the subject in order that I may briefly refer mental con- %Q the pathological later* We have seen that until puberty the sexual and reproductive instincts are more or less latent. I say "more or less" because girls vary: some are more feminine than others, and much depends on environment. In the lower classes, in which, perhaps, the people live nearer to Nature, the sexual instincts of women are more natural, or animal — as some would say : the higher mental faculties play little part in modifying the reproductive instincts. But in the upper classes, in which education and social custom exert powerful influences, we find a different state of affairs1. It is an interesting fact, which I have often observed, that if a girl in the upper classes be brought up alone or 1 Statistics for the year 1911 show that in this country out of 37,633 illegitimate births in all unmarried or widowed females between the ages of fifteen and forty-five years, 20,941 occurred in women of the social grade of hawkers, charwomen, and domestic servants. PSYCHOLOGICAL CHARACTERISTICS 125 only with other girls she shows more marked femininity influence of during childhood, so far as her mental characteristics ^hiidh'ood are concerned, than do girls who are brought up before °n repr°- puberty in company with boys. But, on the other instincts. hand, the former class of girls does not show an excessive mental change at puberty in regard to its relations with men ; while the latter suddenly seems to realize that the freedom which existed before puberty is no longer possible, and in consequence such girls usually exhibit great self-consciousness in the presence of members of the opposite sex who are strangers to them. At puberty, then, the internal secretions of the Mental ovaries, which now become active, may bring about a puberty. great alteration in the outlook of the individual ; but it is probable that this mental change is not entirely dependent on the ovarian secretion, but also on the hormones from the correlated organs of internal secretion. There is no doubt that all normal girls seek the company of men, even though the presence of a man fills them with modest confusion. The thoughts and conversation of girls after puberty are commonly centred on the opposite sex. There is, of course, in girls of refinement no actual idea of sexual matters ; but, whereas prior to puberty no man interested them, at and after that epoch many do. And in this all women resemble the lower animals, in which when growth ceases the genital hormones stimulate the sexual instinct ; but with this difference : in girls of the upper classes education, religion, family life, and the pursuits and enjoyments of modern existence in ordinary circumstances quell what might otherwise become lustful desire. So girlhood grows into woman- hood. The long train of civilized ancestresses, whose desires have been kept in subjection or have been distracted by the inventions of civilization, hands on to her the tradition of restraint. The ordinary civilized woman, whose association with Civilization the opposite sex is much' restricted — much more so in objection! the upper than in the lower classes — probably remains only partly conscious of the natural desires until she 126 THE SEX-COMPLEX Civilization and sexual subjection. Sexual instinct protective. Types of women. falls in love and marries. Yet I have met normal unmarried women, in whom the sexual feelings have never been awakened, who live in the hope that one day they may have children. It is possible, therefore, for civilization to bring women to such a state of sexual subjection that the desire for children is the one repro- ductive instinct left. In the uneducated classes, as in animals, the sexual instinct is probably the stronger instinct of the two, at any rate in the first instance. There can hardly be any doubt that the sexual instinct was originally protective ; that is to say, it was a lure to ensure the propagation of the species. In Woman, in whom the reasoning faculty has been developed, there is, from a natural point of view, less need for the lure of sexual gratification to ensure the perpetuation of the race, so long as the maternal instinct does not die out. It seems that this is the curious stage to which the evolution of Woman has come or is coming. We see all types. The most natural, or — as many would say — the lowest, who enjoy sexual intercourse, and who are, perhaps, somewhat promiscuous in their desires ; yet their maternal instincts are strong. On the other hand, there are many women with strong maternal instincts who are cold in their sexual relations ; and others in whom sexual and maternal desire can only be aroused by the one man of their choice. The first type represents the natural woman un- touched by civilization, whose instincts are under no restraint. The second represents the type of woman of whom we have already spoken — her whose maternal instincts are sufficient without the lure of sexual gratifi- cation. The third type is the ideal woman in the present stage of our evolution ; she alone fulfils all the require- ments and fits in with all the restrictions of advanced civilization. The woman who delights ill sexual pleasures, but has no maternal instincts, is not strictly speaking normal, although she may be as much a product of civilization PSYCHOLOGICAL CHARACTERISTICS 127 as is the female who abhors the idea of both sexual Types of intercourse and maternity. Let us look a little more closely at these types and endeavour to find out, if we can, why such differences exist. It is important to do so in order that we may understand the pathological conditions to be discussed later. The whole character of the individual in regard to her Reproductive sexual and reproductive instincts is dependent on two dependent on factors— the psychological, which we have already j^0^*0* discussed, and the biochemical. Both these factors are chemical correlated, and are largely dependent on the original distribution of the sex-characteristics. The larger the proportion of femininity in a woman, and the less the proportion of masculinity, the greater will be her inherent sexual and maternal capacity. If a woman have a comparatively large proportion of masculinity in her composition, it will be reflected in every cell of her body : the characterization of the organs of internal secretion will be modified, and the activity of her ovaries reduced. It is, of course, well known that a woman may have her sexual capacity unimpaired after the removal of her ovaries, but, as a rule, this state of affairs only exists for a short time. In these circumstances she is, in regard to her other organs of internal secretion, largely feminine. So it comes about that the normal woman who finds pleasure in sexual intercourse, and who desires children, is truly feminine in all her characteristics : she men- struates freely, her breasts are well formed and her mind is feminine in its outlook and aspirations ; in other words, the functions of the normal woman, whether psychological or physical, are perfectly coordinated and correlated. The woman who desires children but has no sexual inclinations is a product of civilization. As a rule, the desire in her for children is idealistic, and not infrequently she menstruates feebly and does not have a large family. Her physical and psychological functions are not perfectly adjusted. 128 THE SEX-COMPLEX Reproductive The woman who takes pleasure in sexual gratifica- dependent on tion but has no maternal instincts is also the result of the and°bio°S1Cal conditions in which we live. She is an individual who chemical takes no pleasure in anything that interferes with her own enjoyment of life ; she is, in fact, a by-product of civilization, and she utilizes her intellect to the detriment of the reproductive functions. Such a woman has the maternal instincts, but she brings her mind to bear upon their suppression, and she is greatly assisted therein by her environment and habits. Last, the type of woman who shuns both sexual relations and maternity is on the fringe of femininity : her femininity is almost neutralized by her masculinity. These women are usually flat breasted and plain. Even though they menstruate, their metabolism is often for the most part masculine in character : indications of this are seen in the bones which are heavy, in the skin which is coarse, and in the aggressive character of the mind. The sexual and reproductive instincts depend, just as does the accompanying psychology, on the meta- bolism of the body, which is under the influence of the internal secretions. If a woman have well-developed genitalia and secondary characteristics, she usually is normal in her instincts. A feebly menstruating woman with flat breasts and coarse skin cannot be expected to have strong reproductive instincts, since she is largely masculine in type ; indeed, her metabolism and mind are ill adapted to the female role in reproduction. The metabolism required for reproduction in woman is, as we have seen, elastic ; and no doubt in those in whom such conditions obtain the internal secretions which control them produce also the attitude of mind required for reproductive purposes. Tendency of The tendency of evolution appears to be towards the towards complete separation of the sexes. This stage has by no separation of means ^een reached in the human race, in which the Lxic sexes. sexes are to a greater or lesser extent mingled in each individual. If this fact be kept clearly in mind, many paradoxes will disappear* and much that would otherwise PSYCHOLOGICAL CHARACTERISTICS 129 be obscure in comparisons between men and women Tendency of becomes obvious. We are, in fact, in a transition towards11 "* stage, and must seize on the evident differentiations reparation of ° . the sexes. as of the highest importance. It may be said, then, in conclusion, that the normal psychology of every woman is dependent on the state of her internal secretions, and that unless driven by force of circumstances — economic and social — she will have no inherent wish to leave her normal sphere of action. Unfortunately, the pressing necessities of highly civilized life have led men to look upon the function of reproduction as of vastly inferior importance to their own individual metabolism : they have utilized for themselves what was intended for the benefit of the species ; and women have not been slow to adapt themselves to the altered conditions. Whether the change in them is associated with an increasing hyper- plasia of the female suprarenal cortex we do not know. But just as we are beginning to think that our knowledge of their special functions is becoming well denned they invite us to follow their further evolution, which apparently they think will not involve them in the pains and joys of motherhood. van Helmont said : — " Propter solum uterum mulier est quod ed." why is a Later Chereau changed this to :— rSann?n0t " Propter ovarium solum mulier est quod est." Virchow in modern times reiterated this statement, and, according to Biedl, added : — " All the peculiarities of her body and mind . . . " everything, in fact, which in the true woman we admire "and revere as womanly, is dependent on the ovary." But in the light of our present knowledge I have ventured to think that the following aphorism most accurately represents the cause and effect : — Propter secretiones internas totas mulier est quod est.1 1 Arris and Gale Lectures, Lancet, 1913, vol. i, p. 944. PART II PATHOLOGICAL CONSIDERATIONS In considering the relation of pathological conditions of the internal secretions to the genital organs and their functions I shall follow as far as possible the arrange- ment adopted in describing the physiological processes ; that is to say, derangements in the normal development of the genital organs and their functions will first be discussed, and subsequently the derangements associated with the maintenance of these functions will be described. DERANGEMENTS IN THE DEVELOPMENT OF THE GENITAL ORGANS, AND OF THE GENITAL FUNCTIONS DERANGEMENTS IN THE STRUCTURAL DEVELOPMENT OF THE GENITAL ORGANS Primary Primary maldevelopment of the genital organs may mentsVof°the result in the following conditions : genitalia. ^ inc0mplete development of the genital ducts and gonads, which may otherwise be perfectly formed. (b) Incomplete and imperfect development of the genital ducts, with complete or incomplete develop- ment of the gonads. (c) Imperfect development of the genital ducts with complete development of the gonads. (d) Irregular development of the genital ducts, with or without irregular development of the gonads. Facing page 131. Fig. 38. Photograph of a girl, aet. 19 years, showing general infantilism due to under-development of the pituitary. The patient measured 4 ft. 3 ins. in height, and weighed 4 stones 3 lbs. STRUCTURAL ANOMALIES OF GENITALIA 131 In the primary development of the female genitalia stages in we must recognize three stages : the foetal which takes development place during intrauterine life ; the infantile which extends o£ genitalia. from birth to puberty, and the complete which occurs at puberty. It is, therefore, possible for the development to be imperfect only, or imperfect and irregular in the first stage ; while later it is only possible for the further development to be incomplete. In the first stage, then, the following anomalies may be produced : a rudimentary uterus and ovaries, all of which are otherwise normally formed ; or normal ovaries with a rudimentary uterus ; or, again, rudi- mentary or normal ovaries with imperfect development of the genital ducts, such as bicornute uterus, septate vagina and so on ; and, lastly, irregular development of the genital gland and genital ducts, constituting hermaphroditism. In the early period of postnatal development (in- fantile stage) there is normally a gradual development and enlargement of the genital organs ; the ovary, too, becomes functional. In this stage, however, we may see insufficient development, leading to the condition known as infantilism of the genitalia ; and at the age when development should be complete — that is, at puberty — this abnormal state of affairs may persist, or the genitalia may not undergo the further development, chiefly functional, normal to this time of life. Incomplete development of the Genital Ducts and Ovaries, which otherwise may be perfectly formed The pathological conditions under this heading are Ateleiosis. sometimes associated with what has been called ateleiosis, the cause of which is probably some general disorder of the hormonopoietic system. In one case under my care (fig. 38) I found that the patient had a very shallow 132 THE SEX-COMPLEX Ateleiosis. Thyroid in- sufficiency. sella turcica, indicating a condition of under-develop- ment of the pituitary (fig. 39). Further, Byrom Bramwell1 has recently shown that infantilism of the pancreas may be a cause of general (including sexual) infantilism. I have lately seen such a case, in which pancreatic insufficiency was established beyond doubt by chemical examination of the faeces. At the present time, although we have no very definite knowledge on this subject, it may be said that it is hardly possible that genital under-development with ateleiosis can be due to primary ovarian insufficiency alone, in view of our experimental and clinical evidence on this subject — indeed, in such circumstances girls are generally tall. Ateleiosis seems to be a condition of general infantilism, in which the genital organs may suffer together with the rest of the structures of the body. Again, the foetal and infantile development of the genitalia is apparently uninfluenced by thyroid insuf- ficiency, for I have found that in the cretin the genital organs may be perfectly developed although function- less ; that is to say, there is no interference with the primary development in fcetal life, nor is the growth of the organs checked until puberty — then, however, the genitalia, although well-developed, remain functionless. I shall describe the condition of cretinism more fully presently (p. 157). Incomplete and imperfect development of the Genital Ducts, with complete or incomplete development of the Ovaries Incomplete The anomalies included in this subdivision are seen and imperfect not infrequently in clinical practice. Some of them, in development . , • . of the ducts, which there is imperfect development of the genital 1 Bramwell, Byrom, Edin. Med. Journ., 1915, New Ser., vol. xiv, p. 323. Facing page 132. Fig. 39. Skiagram of the sella turcica from the case of ateleiosis illustrated in figure 38. (Direct photograph by C. Thur start Holland.) Facing page 133. Fig. 40. Skiagram of the human sella turcica in a case of under-develop- ment of the pituitary associated with an infantile uterus. (Direct photograph by C. Thur start Holland.) STRUCTURAL ANOMALIES OF GENITALIA 133 ducts — such as absence of the vagina, bicornute or incomplete rudimentary uterus — arise during fcetal life. It is not development known whether in these circumstances the internal secre- of the ducts- tions alone are responsible for the malformation, or whether local conditions help to bring about or are responsible for the abnormality present. It is probable that local conditions frequently contribute to the result1. Whether the local conditions are not themselves de- pendent on an asynchronous development of the frame, the result of some irregularity of sex-determin- ation, is an interesting question and one which it is not possible to settle satisfactorily on the evidence before us. When the postnatal development of the uterus is Causes of incomplete I have found that the pituitary frequently postnatal and sometimes the thyroid are at fault. development. In one case, in which a girl of eighteen, otherwise well-developed, was found to have an infantile type of uterus, the sella turcica was shown by a skiagram to be about one-half of the normal size (fig. 40). Evidence confirmatory of this diagnosis was found in the sugar tolerance of the patient, which amounted to over 350 grammes of dextrose. Similarly, with insufficiency of thyroid secretion occurring during the infantile stage there may be incomplete development of the uterus, with retarded activity of the ovaries. Moreover, it may be stated that under-development inactivity of the uterus continued after puberty leads before long following to permanent inactivity in ovaries previously normal : Jj£tol this I have found to be so on several occasions development on which I have had the opportunity of examining histologically ovaries from these cases. Ovarian in- activity is shown by the absence or scarcity of Graafian follicles, or by the presence of atretic follicles instead of corpora lutea (fig. 41). 1 Bell, W. Blair, Proc. Roy. Soc. Med. (Obstet. and Gyncecol Sect.), 1909, vol, ii, p. 311. 134 THE SEX-COMPLEX Imperfect development of the Genital Ducts with complete development of the Ovaries In these circumstances the genital ducts, although imperfectly developed from a morphological standpoint, may be functional. imperfection What has been said already of the causes of imper- ductsTas1 fections in the development of the ducts probably atavisms. ^oes not apply to the malformations included in this category : these imperfections are believed to be re- versions to a lower type1. This interesting view cannot be discussed here, as it has no special bearing on our subject so far as we know at present. Irregular development of the Genital Ducts with or without irregular development of the Gonads (Hermaphroditism) Herm- This subdivision comprises an extraordinarily in- aphroditism. Cresting series of anomalies which arise during foetal life. They are grouped under the general term ' Herm- aphroditism ', and I propose to consider them at some length for they throw considerable light on the sex- functions of the internal secretions. Hermaphroditism has been a subject of interest from the earliest times, but it is only within the last few years that the essential features of this condition have been scientifically investigated and considered. And in the study of hermaphroditism, in all its varieties, lies our hope of discovering the factors concerned in the determination of sex in the human subject subsequently to fertilization. inversion As already described (p. 6 et seq.), Man is originally frfm herm- bisexual, and in the adult there is always evidence — aphroditism. structural if not functional — of the recessive sex. In some cases the latent secondary characteristics become pronounced in one or more particulars, without 1 Jones, F, W., Lancet, 1915, vol. i, p. 1113. Facing page 134. Fig. 41. Section of an under-developed ovary from an inguinal hernia sac to which it was attached together with a unilateral uterine body, showing the remains of atretic follicles. X 60. HERMAPHRODITISM 135 any real disturbance of the features of the predominant inversion sex-characterization. Such conditions are known as fromherm- 1 Inversions ', and they are common in the minor degrees, aphroditism. in which such phenomena as hair on the face, a coarse skin and other masculine characteristics are seen in women. Moreover, definite states of psychical and physical inversion are not very rare. Hermaphroditism may with justice be held to be akin to inversion ; but in partial hermaphroditism the genitalia as well as the secondary characteristics are affected, and this distinction makes a very wide boundary-line between inversion and hermaphroditism from many points of view. It must be remembered that hermaphroditism in man Hermaphro- is probably an atavistic phenomenon, and one which is atavism.8 an never complete. Berry Hart1 has suggested dropping the word ' hermaphroditism ' and substituting the term ' atypical sexe-ensemble ' for all varieties of this con- dition. This, however, is not desirable for two reasons : first, since hermaphroditism exists normally in certain invertebrates, and is, therefore, probably only a rever- sion when seen in man, the term should be preserved ; and, second, so-called 'true hermaphroditism', better termed ' glandular partial hermaphroditism ', does occur in the human subject, although Berry Hart denies that it has ever been demonstrated. I shall myself describe an example of this anomaly presently. The following is a classification of hermaphroditism Classification drawn up to illustrate the forms in which the condition aphroditism occurs normally and abnormally. A consideration of this scheme will also demonstrate the biological significance of the phenomenon. With regard to ' total hermaphroditism \ which is only seen in the invertebrates, I shall have little to say, for the subject is a most complicated and extensive one, and still awaits a complete description at the hands of a biologist. 1 Hart, Berry, Edin. Med. Journ., 1914, New Ser., vol. xiii, p. 295. 136 THE SEX-COMPLEX eg ^^►S ^'S 53 r-55 '^S? J4 3^ a J a a ■^ © © Sac a a C C G .2 .2 .2 '43 '.£ *-3 © © © fl fl S3 p a a " 1 12 © © ill ja © K e3 P C3 r e3 e8 I a a PhPhH ■"d "S © J|2 ill 111 3 S m J?? ill QrSi © O e3 e3 a a a o © © goo -f3 © © 5'S © © GO 3§ OH - ft > J2 « JC ^© © c3 c3 •P d a 00 P. » © © © > * § 2 § © © © <2 ©^J £ " "75 > © « ^ „-, w OB'S H © kS © s ° © © © M oow PARTIAL HERMAPHRODITISM 137 It may, however, be of interest to point out that Classification while ' structural hermaphroditism ' is a very common aph^odrtism. condition, structural and functional with the power of self-fertilization is very rare ; and probably for the following reason. In structural hermaphrodites the male and female gonads rarely become functional at the same time. The creature plays the part at one time of a male and at another time that of a female. It is, of course, certain that total hermaphroditism could not exist in man. The so-called ' true herma- phroditism ' in man is represented by the variety better known as ' glandular partial hermaphroditism ', which I shall now consider. Glandular partial hermaphroditism. — All the Glandular recorded cases of glandular partial hermaphroditism aphroditism! which may be accepted as authentic — and I can discover only two or three other cases of this interesting and rare phenomenon in addition to one reported by myself1, and to be described directly — have been found to possess mixed gonads, so-called ' ovitestes ', with or without irregularities in the sex-characteriza- tion of the genital ducts, external genitalia and secondary characteristics. In 1873 Klebs2, in his classical paper on the subject, So-called claimed that ' true hermaphroditism ', as he called it, aphroditism.' might occur in the following varieties in Man. (1) Bilateral hermaphroditism, in which an ovary and Kieb's ciassi- testis are present on both sides. . true°herm- (2) Unilateral hermaphroditism, in which there is an aPhr<>ditism-' ovary or testis on one side, and an ovary and testis on the other. (3) Lateral hermaphroditism, in which an ovary is present on one side and a testis on the other. 1 Bell, W. Blair, Proc. Roy. Soc. Med. (Obstet. and Gyncecol. Sect.), 1915, vol. viii, p. 77. 2 Klebs, E., Han&buch d. Pathol. Anal., 1873, vol. i, p. 725, 138 THE SEX-COMPLEX Rarity of glandular herm- aphroditism, Evidence of cases reported. This classification has been adopted by many subse- quent writers, and it is supported by Blacker and Lawrence1, who in 1896 reported the first case of ovi- testis, or combined ovary and testis. These writers investigated the literature up to that date, and came to the conclusion that of the enormous number of supposed cases of what was called ' true hermaphroditism ' there was only one — their own — recorded of the unilateral variety, after the classification of Klebs ; and that there was possibly one — Heppner's2, recorded in 1870 — of the bilateral variety, and two — recorded by Schmorl3 and Obolonsky4 in 1888 — of the lateral. The evidence in regard to these, except possibly to Blacker's and Lawrence's, cannot, however, be con- sidered satisfactory, and it has been demolished by Meixner5 and others. Tuffier and Lapointe6, also, in their paper published in 1911 apparently accept only the case of Blacker and Lawrence of those published prior to 1897 ; but they add to this case those of von Salen7, Garre8, Landau and Pick9, and Schickele10, all recorded subsequently to Blacker's and Lawrence's paper. Pick11, in an important paper published in 1914, discusses exhaustively the question of this so-called 4 true hermaphroditism ', and comes to the same general conclusions as Tuffier and Lapointe — namely, that all the cases of this variety reported and accepted should 1 Blacker, G. F., and T. W. P. Lawrence, Obstet. Trans., 1896 vol. xxxviii, p. 265. 2 Heppner, C. L., Reichetfs Archiv., 1870, p. 679. 3 Schmorl, G., Virchow's Archiv., 1888, vol. cxiii, p. 229. 4 Obolonsky (No initial in original), Ze.it. f. Heilkunde, 1888, vol. ix, p. 211. 6 Meixner, K., Zeit.f. Heilkunde, 1905, vol. xxvi, p. 318. 6 Tuffier, T., and A. Lapointe, Rev. Gynecol., 1911, vol. xvi, p. 209. 7 Salen, E. von, Verh. d. Deutsch. Path. Ges., 1899, vol. ii, p. 241. 8 Garre (No initial in original), Deutsch. Med. Woch., 1903, vol. xxxix, p. 77. 9 Landau, L., and L. Pick, Verh. d. Berl. Med. Gesellsch., 1914, vol. xliv, p. 186. 10 Schickele, G., Hegar's Beit. z. Gel. u. Gyn&k., 1907, vol. ii, p. 263. 11 Pick, L., Archiv. f. Milr. Anat., Bonn, 1914, vol. Ixxxiv, p. 119. PARTIAL HERMAPHRODITISM 139 be called ' glandular partial hermaphrodites '. This Evidence author records five cases of ovitestes occurring in pigs, reputed. all of which he had himself examined. He states that the condition is only known in that species among all the orders of the lower mammals. Other authors, however, have published accounts of this phenomenon in moles and in other mammals. Pick also states that there had been four genuine cases recorded in man up to the date of his paper. Of those already mentioned apparently he admits only the case of von Salen1, but he adds those of Simon2, Uffreduzzi3, and Gudernatsch4. I have examined the reports of these cases, and believe that only that of Simon, in addition to von Salen's, could possibly be accepted, and that this case is somewhat doubtful. I shall not discuss in detail the points for and against these and the other reported cases. Enough has been said to indicate the rarity of glandular partial herm- aphroditism ; but attention must be called to the fact, to which I shall again refer later, that in most of the cases an ovitestis has been present. In Simon's case the ovarian and testicular portions were separate. Foster5 has recently recorded a similar case, which, however, cannot be accepted, as no histological details are given.6 It is interesting from a critical point of view to note that all the cases of ovitestis have had mostly feminine secondary characteristics, while Simon's and Foster's cases have been masculine. As we shall see, 1 Salen, E. von, Verh. d. Deutsch. Path. Ges., 1899, vol. ii, p. 241. 2 Simon, W., Virchow's Archiv., 1903, vol. clxxii, p. 1. 3 Uffreduzzi, 0., Archiv. de Antrop. Crim., Torino, 1910, vol. xxxi, p. 602. 4 Gudernatsch, J. P., Amer. Journ. Anat., 1911, vol. xi, p. 267. 6 Foster, G. S., New York Med. Journ., 1914, vol. c, p. 560. 6 Owing to the kindness of Dr. Foster I have, since this work first went to press, had an opportunity of examining sections from this case. In my opinion there is no real evidence that the so-called ' ovarian ■ portion contains the essential elements of the ovary, The most that can be said is that the arrangement of the connective tissue, of which it is entirely composed, is somewhat similar to that seen in the ovary. 140 THE SEX-COMPLEX Evidence this is enough to throw doubt on these two cases. reported. Lastly, it may be mentioned that in some of the sup- posed cases, such as that of Landau and Pick, large tumours have been said to be ovitestes. These growths can hardly be accepted as ovitestes, for they must present many difficulties in the way of such a diagnosis. Author's I shall now describe my own case, which is probably glandular tne most complete example of glandular partial herma- partiai phroditism on record, and may, therefore, be taken as a aphroditism. prototype of this class of case. S.B., set. 17 years, was first seen on 8th November 1912. Past History. — Menstruation had commenced during the f ourteenth year. The cycle had been ^8 days. There had been no menstrual pain. The patient was said to have suffered with inflammation of the bowels when she was 7 years of age. Present History. — The patient has had amenorrhcea for 18 months, and there have been no menstrual molimina. The general health is good. There has been no trouble with the bowels or bladder. The voice has been getting deeper. On examination nothing abnormal was felt in the abdomen, or per rectum. The thyroid was found to be slightly enlarged. A diagnosis of hyperplasia of the suprarenal cortex was made, and the patient was treated with ovarian and thyroid extracts for some time. On August 25th 1914 the patient, who had not been seen for eight months, again presented herself. It was then at once noticed that she had become more masculine in appearance : she had a slight moustache and a masculine distribution of hair on the trunk and legs (fig. 42). There was still complete amenorrhcea. The patient under anaesthesia was examined a few days later. The clitoris was found to be much enlarged, measuring two inches in length, and there was a well- marked prepuce. Per vaginam the left genital gland could be felt somewhat enlarged. No tumour was discovered in the suprarenal region. Subsequently the patient was admitted to hospital. Facing page 140. Fig. 42. Photograph of a glandular partial — so-called ' true ' — hermaphrodite, showing the masculine contour of the limbs and trunk, and distribution of hair. PARTIAL HERMAPHRODITISM 141 She was then 19 years of age, and amenorrhcea had Author's persisted for over three years. case of it •> KlanduJar On September 3rd 1914 the abdomen was opened partial in the middle subumbilical line. The left genital gland hGfm" . . was found to be of the same size as that of a plum. ap ro tlsm' It had a very smooth surface, and resembled a testis ; the superficial blood-vessels were injected, especially in the neighbourhood of the hilum. No adhesions were present. A wedge-shaped piece was removed length- wise from the convexity of the organ for histological examination. When cut into for the removal of this piece of tissue, the organ presented a yellow, fatty appearance. The raw surfaces were brought together with a cat-gut suture. The genital gland on the right side appeared to be a normal, but somewhat small, ovary. A piece was removed for section in a manner similar to that adopted in the Case of the left genital gland. Finally, a small graft from an ovary removed irom a patient operated upon a few minutes before was implanted in the uterus. The suprarenal regions were palpated with the hand in the peritoneal cavity, but beyond a slight rough feeling in the neighbourhood of the left, which might have been due to the tail of the pancreas, nothing abnormal was discovered. For obvious reasons these and the other organs of internal secretion could not be closely studied. It is possible, however, that changes existed in some, if not in all, of them. Report from the Pathological Laboratory (Prof. E. E. Glynn) on the pieces excised. — " Right ovary. Section " shows an ovary, the stroma of which consists of very " dense connective tissue, but ovulation has taken place, " there being present a large corpus luteum and the " scars of the corpora lutea, and also an almost mature " Graafian follicle. " Left ovary. Section shows what is undoubtedly " a columnar -celled carcinoma with well-marked acini." Acting on this report, I re-opened the abdomen on September 22nd 1914 and removed both ovaries, the tubes, and the fundus of the uterus. When I came to examine the sections myself I came to the conclusion that the left genital gland was an ovitestis, and not the seat of a malignant growth as reported.1 1 This opinion was afterwards confirmed by the report of the Pathological Reference Committee of the Liverpool Medical Institution 142 THE SEX-COMPLEX Author's case of glandular partial herm- aphroditism. After-history. — The patient made a good recovery from the operation, but subsequently suffered with slight menopausal symptoms. When she was examined eight months after operation I found that all the hair had disappeared from the legs and the upper lip. The voice was slightly higher in tone, and the figure and skin were greatly altered towards the feminine type. The breasts, however, showed very little development, but this was not to be expected in the absence of ovaries. The specimen1 consists of the fundus uteri, the Falloppian tubes, and the gonads — the genital glands being in the position normal to the female and attached to the uterus by ' ovarian ' ligaments. Scars can be seen running lengthwise along the convexity of each gland, indicating the sites from which the pieces were excised for examination. The fimbriated extremity of the left Falloppian tube has become attached to the scar in the corresponding gonad. There is evidence also of a ' parovarium ' on this side. A portion of the ovarian graft, which on histological examination was found to be necrotic, can be seen in the anterior wall of the fundus uteri. An X-ray examination of the patient by Mr. Thurstan Holland showed no ossification in the thyroid cartilage; but this would not be expected even in the male at such an early age. A laryngeal examination was made by Mr. Guthrie who reported as follows : — " I examined the larynx of your patient S.B. again " to-day. The larynx appears to me to present definitely " male characteristics ; the cavity is very roomy, and " the vocal cords are both broader and larger than those " of the ordinary female larynx. Using a graduated " laryngeal mirror I attempted to measure their length, (F. T. Paul, J. M. Beattie, E. E. Glynn, R. J. M. Buchanan, and W. Blair Bell), and by other independent authorities (S. G. Shattock, A. Keith, R. Muir). It may be mentioned that an anonymous reviewer {Edin. Med. Journ. New. Ser., 1916, vol. xvii, p. 56) of the first edition of this work dismissed the case in the following words : " His case is merely this — a female with some slight inversion in hair and larynx and the very rare condition of an inclusion of Miillerian epithelium in one sex gland ". As this critic has not seen sections of the gland in question, we may disregard a statement of this kind made ex cathedra. 1 Now in the Museum of the Royal College of Surgeons, London. Facing page 142. H ■*"'■ *£ ^•«i& *J$£C! &.^* < IM m Fig. 43. Section of ovitestis from the case illustrated in figure 42, showing central testicular portion — (the part that is enclosed in a ring is shown more highly magnified in figure 44) — and outer capsule of ovarian tissue containing a Graafian follicle in the lower part of the field. X 40. Facing page 143. Fig. 44. Section of ovitestis stained with haematoxylin and eosm, showing seminal tubules and large eosinophil interstitial cells. x 300. PARTIAL HERMAPHRODITISM 143 " and, although it is difficult to do this with much Author's "accuracy owing to the distance between the mirror gf^nduiar " and the objects reflected in it, I was able to satisfy partial " myself that they measured not less than 24 mm. he'm- " which is scarcely below the average in the male. ap ro * lsm* " The breadth appeared to be nearly 1| times what is "usual in the female. The epiglottis and arytenoids " are large for a female, but I think less strikingly so " than the true cords and the laryngeal cavity." The histological findings in this case are probably Histological typical of glandular partial hermaphroditism, in which authoS case there is an ovitestis on one side only ; and therefore of glandular . partial merit a short discussion. herm- The right genital gland is a normal ovary, although aPhroditism- small and not in a particularly active state. There are to be seen in section a mature Graafian follicle and small hyaline bands in the ovarian stroma — the remains of corpora albicantia. The histological appearances of the left organ present quite a different picture. A low- power view shows that the central portion, which forms nearly the whole of the organ, is made up of what, in the first instance, was supposed by the pathologist to be a malignant neoplasm. A thin capsule of normal ovarian tissue — Graafian follicles, primordial ova, and stroma covered in places by capsular epithelium — surrounds this central portion (fig. 43). The nature of the internal part of the organ is, of course, the interesting feature of the case. It contains tubules lined for the most part with several layers of columnar cells, although in places the tubules are seen to be lined with one layer of epithelium and to be widely distended with secretion ; there are, also, irregular masses of columnar cells, and a large number of interstitial cells which are eosinophil and resemble exactly the interstitial cells of the testicle (fig. 44). Among the epithelial cells lining some of the tubules are to be seen, here and there, large cells with big nuclei : these may possibly represent spermatogonia. There is, too, betwaen the tubules, a large quantity of fat which stains well with sudan III. 144 THE SEX-COMPLEX Histological The masses and columns of cells, which do not form author's case tubules, resemble what may be seen in the early stage of glandular m the development of the normal testis : they have none herm- of the appearances of malignant cells, for their nuclei are ap ro i ism. regUjar ancj qUiescent, and the cells themselves are nearly all of one size and appear stable in their mode of growth. With regard to the interstitial cells it might be thought that they were ovarian and not testicular. As a rule, however, the interstitial cells of the ovary are much smaller, and never have I seen them so well marked, either in normal or pathological circumstances, as here shown. Further, if these interstitial cells were really ovarian one would expect to find them in the ovarian portion of the ovitestis — from which they are entirely absent — rather than in the testicular portion. This is the general picture presented by an ovi- testis ; but in the histological diagnosis of the condition there must always be difficulty. In the first place, there are masses of columnar cells which have no definite tubular arrangement. It was probably this irregularity of distribution which gave rise to the opinion, to which allusion has already been made, that in the case described the growth was malignant. In some parts, of course, there is a definitely tubular arrangement of the darkly staining columnar cells ; and in other places tubules may be found lined with a single layer of epithelium, and containing secretion. There is, however, never any definite spermatogenesis to be seen. Clinial It is particularly interesting to note in regard to the history of case recor(jed above, that the patient commenced life author s case * of glandular and passed puberty as a normal girl, menstruating hern> regularly for eighteen months ; that menstruation had aphroditism. i\ien ceased and masculine characteristics had developed, and that in spite of this she suffered with slight meno- pausal symptoms after operation, and has now reverted entirely to the feminine or to a neutral type. This, surely, is dual sex-characterization,if ever there were such a thing : an interesting question which we shall discuss more fully after considering the other varieties of PARTIAL HERMAPHRODITISM 145 hermaphroditism. Yet it is eertain that the changes Clinical following removal of the genitalia were not dependent au8thoJ'8°case solely on that removal. Such an operation, as experi- ofa^andular ments show, affects the other hormonopoietic glands, herm- Were it not so, our whole thesis of the sex-complex aPhrodltlsm- would be groundless. With regard to the occurrence of the gonadal elements of the two sexes in one individual, one would naturally infer, from a developmental point of view, that the different elements would be combined in one organ. A brief consideration of the development of the ovary and testis will make this point clear. In the earliest stages of development — that is, until Development between the fifth and sixth week— the histological ap- of the gonads. pearances of the gonads give us no indication as to the future sex-differentiation about to take place. In this undifferentiated stage the gonad is divided into two por- tions— the capsular epithelium, and the central epithelial nucleus composed of 4 indifferent ■ cells. Subsequently, however, if a testis is to be evolved, very soon after this date the cells of the epithelial nucleus immediately underlying the capsular epithelium become condensed and form the tunica albuginea, while the rest of these indifferent cells, among which the genital cells lie, become arranged in the form of cell masses or cords. These cords, around which and in which the spermatogonia, as the genital cells are now called, are collected, become the seminal tubules and eventually join the genital (pro- nephritic) tubules outside the gonad. The interstitial cells of the testis are formed from connective tissue cells (mesoderm), which grow in from the direction of the hilum and fill the interstices between the seminal tubules. We shall see directly that the interstitial cells do not originate from primary or secondary genital cells. If, on the other hand, an ovary is in process of forma- tion the indifferent cells (epithelial nucleus) of the genital cell mass remain undifferentiated longer than in the case of testicular development, and they never become arranged in cell masses or cords. Instead, the epithelial 10 146 THE SEX-COMPLEX Development nucleus becomes broken up by branching septa of s* ingrowing connective tissue, which divide the ovary into a mesh-work of compartments. The tunica albuginea is formed by the meeting of these septa beneath the capsular epithelium. The indifferent cells enclosed in the con- nective tissue mesh-work are believed to form secondary oogonia ; but ultimately most of these degenerate, and the spaces they previously occupied in the mesh-work of connective tissue become filled by ingrowths from the septa. The interstitial cells of the ovary, like those of the membrana granulosa surrounding the surviving ova, are derived from the connective tissue stroma. In these circumstances, of course, the genital tubules outside the gonad atrophy, and their remains may be recognized, extending from the hilum of the ovary through the mesovarium into the mesosalpinx, as the epoophoron. It is not difficult to understand, then, that, if there be any hesitancy in the primary determination of sex, seminal tubules may commence to develop in the epithelial nucleus, even though they do not become functional in the ordinary sense of the word, and that the testicular interstitial cells may develop around them. But if, in these circumstances, masculine genital cells are absent and female are present the interstitial cells around the tubules cannot arise from genital cells, nor can there be spermatogenesis. Unilateral One great difficulty, so it appears to me, and one aphroditism. which requires further elucidation, is why an ovitestis may be found on one side in these conditions, and not on the other. In this connexion it is interesting to recall the fact that in ' true hermaphroditism ' (ovitestis) in birds, unilateral distribution of the sex- characteristics in regard to the plumage has been observed by Poll1, Bond2 and others. It must be remembered, also, that in hens the right ovary and ducts atrophy. Nevertheless, the plan of development described above almost negatives the possibility of the 1 Poll, H., Sitzb. d. Ges. Naturf. Freunde, Berlin, 1909, p. 331. 2 Bond, C. J., Journ. Qenet., 1914, vol. iii, p. 205. PARTIAL HERMAPHRODITISM 147 development of a separate ovary and testis on the same Unilateral side ; for it is extremely difficult to understand how aphroditism. one part of the same genital cell mass could separate itself from the other and develop into a testis, while the remaining portion developed into an ovary. It would seem, therefore, almost inevitable that, The ovitestia when there is dual characterization in the gonads, the m°g\tndUiar 6 only possible combination must be a testicular central partial portion surrounded by an ovarian, and that the pre- aphroditism. dominating genital cells must be female rather than male. If this be found not to hold good in any well- investigated case, we shall have to revise our views concerning the normal development of the gonads and their sex-differentiation. It is important to observe, in passing, that in some of those cases in which a testis or a testicular rudiment has been found on the same side but separated from the ovarian, as in Uffreduzzi's case, no interstitial cells have been present. This alone is enough to throw very grave doubt upon the true nature of the supposed male elements in the gonad concerned. In Simon's and Foster's cases the supposed ovarian portion of the double gonad was not certainly ovarian. These are, so far as I know, the only cases which at all controvert the statements made, and this want of conformity renders them doubtful. I would, therefore, lay down the following as essential Essential conditions which must be established before any case can gSnduTar be considered one of glandular partial hermaphroditism : Partial 1. The hermaphroditic gonad must be an ovitestis, aphroditism. composed of ovarian tissue with definite Graafian follicles or primordial ova surrounding a central portion containing seminal tubules and testicular interstitial cells. 2. The subject must show in the primary or secondary characteristics, other than the sex-glands, evid- ences of hermaphroditism. If these conditions be considered critical very few cases, probably only three, including my own, would pass the test. 148 THE SEX-COMPLEX So-caiied Tubular Partial Hermaphroditism. — Tubular herm- ° partial hermaphroditism is the modern name for the aphroditism \ variety of hermaphroditism which has been known, since Klebs' classification, as 'pseudohermaphroditism'. The subdivisions, according to the anomalies met with, adopted by this author, hold good for tubular herma- phroditism. These subdivisions and the contained abnormalities are set forth in the table given above. It is, too, the custom in the present day to follow Klebs in regard to the criteria of sex ; that is to say, a male tubular partial hermaphrodite is indicated by the testicular character of the gonads, and a female by the ovarian structures present. We shall see presently that this arbitrary ruling is open to very serious objec- tions in many cases. No useful purpose would be served by a discussion here of the details of the, different varieties shown in the table (p. 136), for the relation of all these monstrosities to the principles of sex-determination and sex-character- ization is the same, and what is said of one variety applies to the others, respectively for the different sexes. General The ' atypical sexe-ensemble ', as Berry Hart1 terms of cOTLditions &> °f tne genital ducts and external genitalia is tubular18 in contrasted with the gonads ; and it is interesting to partial observe that in these circumstances the secondary aphroditism. characteristics — the distribution of hair on the body, contour of the limbs and trunk, breasts, psychical attributes, and the rest — are, almost invariably, of the sex-character opposite to that of the gonads. This is a well-known fact and one which explains why these subjects are so frequently brought up as, and pass for, members of the sex different from that indicated by the gonads ; but it is a fact which has not been sufficiently emphasized, as we shall see presently. Tubular Another most interesting point is that the gonads, herm- m a very large proportion of all cases of tubular partial aphrodites hermaphroditism, are testicular in structure : the male gonads. i Hart, Berry, Edin. Med. Journ., 1914, New Ser., vol. xiii, p. 295. Facing page 149. Fig. 45. Photograph of a male partial tubular hermaphro- dite, showing the complete development of feminine secondary characteristics. PARTIAL HERMAPHRODITISM 149 subjects are what are known as male tubular partial hermaphrodites. By way of illustrating the statements made concern- Andrews' ing the peculiar conflict of sex-characterization seen in tubular most of these cases, I will first briefly mention a case, Partlal under the care of Dr. Russell Andrews, that I had an aphroditism. opportunity of seeing. I am indebted to this surgeon for permission to make use of the following particulars : — The patient (fig. 45), supposed to be a young woman, was twenty-three years of age. ' She ' was very good- looking, and had typically feminine secondary character- istics. The external genitalia were of the normal feminine character, and there was a short vagina (urogenital sinus) ; the urethra opened in the position normal in women. Laparotomy was performed, and the internal geni- talia were then found to consist of two testicles attached by the lower poles to thick bands (? gubernacula). This patient was a woman in all particulars except in the character of the gonads, according to the nature of which it has been the custom to determine the sex. But in modern terms the individual was a male tubular partial hermaphrodite of the ' external ' variety. Many instances, moreover, of female partial tubular Tubular hermaphroditism have been described ; Neugebauer1, {^errS indeed, has collected 88 cases, and fresh examples, such aphrodites r with ovaries. as that described by Quinby2, are continually being recorded. Less difficult is the diagnosis of those cases in which the external genitalia conform to the sex-type exhibited by the gonad : an ensemble which constitutes the ' internal ' variety of tubular partial hermaphroditism. The ' complete ' variety, in which the gonad differs in type from the rest of the internal and from the external genitalia, is probably the most obscure of all from a diagnostic point of view. In all these varieties the 1 Neugebauer, F. L. von, Hermaphroditismus, Leipzig, 1918. 2 Quinby, W. C, Bull. Johns Hopk Hosp., 1916, vol. xxvii, p. 50. 150 THE SEX-COMPLEX Etiology of tubular partial herm- aphroditism. Relation of suprarenal neoplasms to tubular partial herm- aphroditism. Etiology of of the ' free- martin.' secondary characteristics differ in sex -type from that of the gonads, as already stated. In the etiology of partial hermaphroditism lies hidden much of the mystery surrounding the causes of sex-de- termination ; and attention may be recalled to the fact that even though there be some sex-dominance inherent in the early segmentation cells, there are probably other controlling factors, which come into action later and influence the sex-differentiation of the gonads. We have, indeed, some direct evidence as to the causative factors in partial hermaphroditism. Glynn1, who analyzed the cases recorded in Neugebauer's comprehensive work on hermaphroditism2, states that out of the 88 cases of female tubular partial hermaphro- ditism 15 per cent, had obvious suprarenal neoplasms ; while, on the other hand, only 0*7 per cent, of the male tubular partial hermaphrodites had growths in the suprarenal cortex. Moreover, as will be mentioned directly, suprarenal tumours and disturbances in other organs of internal secretion may influence the secondary sex-characteristics in women previously normal in this respect. Lillie3 states that the 'free-martin' in cattle is a female whose characteristics have been altered by the hormones of the male twin. This investigator found that in such cases there is a definite anastomosis between the arterial and venous vessels in the chorionic mem- branes which had become united. On the other hand, he asserts that, if there be no anastomosis between the chorionic vessels, the twin (when not a male) to the male calf is not a ■ free-martin ' but a fertile female. This is a very interesting and important series of observations, and, if confirmed, they form most important substantial evidence in regard to the views already expressed. 1 Glynn, E. E., Quart. Journ. Med., 1912, vol. v, p. 157. 2 Neugebauer, F. L. von, Hermaphrodilismus, Leipzig, 1908. 3 Lillie, P. R., Journ. Exper. Zool, 1917, vol. xxiii, p. 371 Facing page 150. Fig. 46. Section of the testis from the male partial hermaphrodite illustrated in figure 45, showing a large number of interstitial cells and a scarcity of seminal tubules. X 250. Facing page 151. Fig. 47. Section of an undescended testis, showing seminal tubules and a few interstitial cells. X 250. PARTIAL HERMAPHRODITISM 151 I shall not, therefore, dwell on this aspect of the Paramount etiology of partial hermaphroditism, beyond saying that SteJ^S1100 o£ all the evidence we have concerning the production and secretions mamtenance of the sex-characteristics subsequently to tenance of fcetal life points to the paramount influence of all of^^^ the internal secretions. And, as this is so, it is not illogical to suppose that the same factors are responsible during fcetal life for the production of the normal primary characteristics : we have, in fact, as already stated, strong and direct evidence on this point. Before concluding these remarks on partial herm- Specification aphroditism, I wish to call attention to the method £artiaim adopted in the specification of the sex in the human herm\. . aphroditism. subject. As is well known, the character of the gonad is considered indicative of the sex of the person. I believe this often to be as unjustifiable on scientific grounds as it is unfair from a social point of view, for the following reasons. In view of many pathological observations on the subject it appears probable that in female tubular partial hermaphrodites, with male characteristics in association with ovaries, certain of the other organs of internal secretion, such as the suprarenals and pituitary, are of a male type ; and that in male tubular partial hermaphrodites — the commonest variety — with testes in association with feminine secondary characteristics, the other organs of internal secretion are of a female type. Again, it is extremely interesting to note how erroneous has been the view, generally held, that the interstitial cells of the gonads are chiefly responsible for the secondary sex-characteristics. For many years I have contended that the gonads play but a subservient part ; and this is emphatically demonstrated in the sub- ject under discussion by the fact that in the testes of tubular partial hermaphrodites with feminine secondary characteristics, as in the case recorded above, the inter- stitial cells are always developed to a remarkable extent (fig. 46) — to a degree which is rarely seen even in the undescended testis (fig. 47) and never in the normal testis 152 THE SEX-COMPLEX Specification (fig. 48). These cells cannot, therefore, be accountable partial"1 ^ or tne secondary characteristics. Spermatogenesis, how- herm- ever, is not often present in the testes of partial tubular aphroditism. . , . , • ' « « -, i hermaphrodites, but it has occasionally been recorded. The gonads, therefore, especially in the absence of active genital cells may be described as more or less indifferent organs in the matter of sex-characterization. It is probable that the other organs of internal secretion must be admitted into the circle of primary character- istics, and that they usually act in conjunction with the functional gonad but often quite independently of it. It is, also, an almost incontestable fact that the mental attitude and instincts of a partial hermaphrodite accord with the predominating secondary characteristics. This was very obviously so in Russell Andrews' case, already described, in Turner's and Lapointe's case, and in many other recorded cases. It is not possible to ascribe these psychological attributes to education alone. importance Since, therefore, we can demonstrate the fact that touTmsembU the psychical and physical characters of sex are not in deciding necessarily dependent on the gonads, each case of herm- partial hermaphroditism should be considered as a ap ro i ism. wj10je . y^ -g to s&y^ foe sex should be determined by the obvious predominance of characteristics, especially the secondary, and not by non-functional gonads alone. A few partial hermaphrodites have secondary character- istics of the same sex as the gonad ; but that common type of case in which the gonads alone, and then only on histological examination, proclaim the state of hermaphroditism should be considered on a separate basis, and the sex-denomination should be adapted to the peculiar circumstances, and to our modern knowledge of the complexity of sex. It would be justifiable, too, to undertake surgical procedures in these special cases in order to establish more completely the dominant sex of the individual, and the one which is most in accordance with the social happiness of the person concerned. A legal ruling on this matter of sex-denomination is urgently required. Facing page 152. !»>■«♦•.• ^-. '■•'• W J "* - * v»* IIP *• . -*»«> v* * 0:v^ •- * <^jf v* • & * -ti * *» Fig. 48. Section of the normal testis, showing widely distended tubules, in which spermatogenesis is taking place, and a few interstitial cells. X 250. PRECOCIOUS PUBERTY 153 DERANGEMENTS IN THE FUNCTIONAL DEVELOPMENT OF THE GENITAL ORGANS The term ' functional development ' of the genital Derange- organs and secondary female characteristics refers to function de- the changes which normally occur at puberty. The^^tof advent of functional activity in the genital organs and of the associated secondary sex -characteristics, which become evident at this time, change the girl into a woman. Since the appearance of puberty is dependent on the general metabolism, which is influenced by the internal secretions, we can easily understand how disorders of the hormonopoietic system may affect the phenomena associated with this period of life. Precocious Puberty. — The usual age of puberty in Appearance this country is about the end of the fourteenth year, but puberty. the appearance of it between the tenth and sixteenth years cannot strictly be considered abnormal. Heredity, health, feeding and environment all play an important part in the result. When, however, a child under nine years of age shows definite signs of puberty — such as hair on the pubes, development of the breasts, and menstruation — we may look upon the condition as abnormal. Now, a close investigation of the recorded cases Etiology of has shown1 that the production of precocious puberty puberty. in girls is not due to all those causes which may produce precocity in boys. This is a point of some importance, but future observations possibly may modify the follow- ing statements which are based upon our present somewhat limited knowledge of the subject. On the one hand, there is no doubt that in boys Sexual sexual precocity may be produced by neoplasms and in boys. hyperplasia in the suprarenal cortex, in the testes and 1 Bell, W. Blair, Proc. Roy. Soc. Med, (Obstet. and Gynaecol. Sect.), 1913, vol. vii, p. 47. 154 THE SEX-COMPLEX Sexual precocity in boys. Sexual precocity in girls. in the pineal1, 2'3,4, and possibly also in the pituitary4. It is believed that in these circumstances there is an increase in the normal secretion of the organ concerned, except in the case of the pineal in which there is a decrease. On the other hand, my investigations concerning the details of the recorded cases of sexual precocity in girls showed that true feminine sexual precocity appears to be produced by tumours and hyperplasia in the ovaries almost invariably ; for changes in the suprarenal cortex, the pineal, and the pituitary, resembling those which in boys produce precocity, in girls tend to produce mascu- linity4. Now, masculinity cannot be considered female sexual precocity, although there is little doubt that in some of the recorded cases5,6 masculinity with, per- haps, adult manifestations, such as hair on the pubes, has been described as feminine precocity. The essential phenomena, however, associated with feminine sexual precocity are the early development of the adult feminine secondary characteristics, and the functional activity of those organs which are peculiar to the female sex. It can quite easily be understood that the mere appearance of hair on the pubes and other signs of puberty may, as explained above, have no relation to feminine precocity, but, rather, to the change to adult (or precocious) masculinity, which may be produced in a true female or in a female partial hermaphrodite. If this be so, we have almost always to consider pre- cocious puberty in girls in relation to ovarian neoplasms 1 Williams, Roger, Brit. Oynmcol. Journ., 1902, vol. xviii, p. 85. 2 Bulloch, W., and J. H. Sequeira, Trans. Path. Soc, 1905, vol. Ivi, p. 189. 3 Glynn, E. E., Quart. Journ. Med., 1912, vol. v, p. 156. 4 Bell, W. Blair, Proc. Roy. Soc. Med. (Obstet. andGyncecol. Sect.), 1913, vol. vii, p. 47. 6 Orth, Arbeiten aus den Path. Institut za Qottingen, Berlin, 1893. (Quoted by W. Bulloch and J. H. Sequeira, Trans. Path. Soc., 1905 vol. Ivi, p. 189.) 6 Pitman, H. A., Lancet, 1865, vol. i, p. 175. Facing page 154. Fig. 49. Photograph of a girl, aet. 8 years, showing precocious development of the secondary characteristics. Facing page 155. Fig. 50. Skiagram of the wrist and part of the hand of the girl illustrated in figure 49, showing development equal to that seen in a girl of thirteen years of age. The pisiform and sesamoid bones are fully formed. (Direct photograjih by C. Thurstan Holland.) X I PRECOCIOUS PUBERTY 155 and hyperplasia. There is a number of such cases on Ovarian record. One of the most interesting is that of a girl JJ2JJ5 & under the care of Clement Lucas1. This patient, who sexual Was seven years of age, had a large ovarian tumour m giris. which was associated with early menstruation and the usual signs of puberty. After the removal of the tumour menstruation and the other adolescent manifestations disappeared. A similar case has been recorded by Harris2. I have seen a girl, seven years of age, belonging to the upper middle class, who had menstruated regularly, but very slightly, with definite molimina for two years. There was slight development of the breasts, but no axillary or pubic hair. No tumour could be felt in the abdomen, but a pelvic examination was not allowed. Roger Williams3 states that in eleven cases, which he had collected, of sexual precocity in female children associated with ovarian neoplasms, histological examina- tions of the tumours showed that eight were sarcomata, two cystomata, and one a fibroma. The same writer points out that in girls sexual precocity is not associated with excessive muscular or skeletal development as is the case in boys. This, of course, is what we would expect, for muscularity is not a feminine characteristic. Gaudier4 has recorded a case in which a tumour of the ovary, resembling a suprarenal cortical neoplasm, gave rise to sexual precocity. If the neoplasm were really a suprarenal growth, about which there is con- siderable doubt, the feminine precocity may have been due to hyperplasia of the ovary caused by the tumour. Gautier (?), quoted by Williams3, found that of twenty-three sarcomatous ovarian tumours in young children only four were associated with the signs of sexual precocity ; consequently it must not for a moment be assumed that all ovarian tumours in young girls 1 Lucas, R. C, Trans. Clin. Soc., Land., 1888, vol. xxi, p. 224. 2 Harris, R. H., Surg. Gynecol, and Obstet., 1917, vol. xxiv, p. 604, 3 Williams, Roger, Brit. Gyncecol. Journ., 1902, vol. xviii, p. 85. 4 Gaudier, H., Echo Med. du Nord, 1908, No. 30, p. 357. 156 THE SEX-COMPLEX Ovarian tumours a cause of sexual precocity in girls. Atypical sexual precocity in girls. cause precocious development. Indeed, as I have pointed out elsewhere1, and have emphasized here, the whole hormonopoietic system is concerned in the develop- ment of the genital organs and their functions, and the determination of sex -characteristics ; so unless there are associated changes in the other organs of internal secretion as well as in the ovaries, sexual precocity will probably not occur. And in this connexion it may be suggested that insufficiency of the suprarenal internal secretion, which normally is antagonistic to the ovarian, may lead to hyperplasia in the genital glands, and so to precocious puberty. Apart, however, from those cases of precocious puberty which are produced by definite lesions in the ovaries, and which include almost all the examples of this condition, and apart from those cases which are not really instances of feminine precocity, but rather of precocious masculinity in the female with absence of menstruation and ill-development of breasts — quite apart from these abnormalities are certain anomalous cases of incomplete feminine precocity of doubtful origin. I have seen a case of this kind which was under the care of the late Dr. Percy Marsh, to whose courtesy in inviting me to examine the patient I was indebted, in which all the external secondary feminine characteristics were well developed in a child, eight years of age, whose mentality was much below that of a child of her own age, while her physical development resembled that of an adult (figs. 49 and 50). Menstruation, however, had never appeared. In this case no enlargement of the ovaries could be made out, and the uterus was found to be infantile on examina- tion with the child under anaesthesia. The pituitary fossa on skiagraph examination was found to be of normal size, and the thyroid was well developed. The diagnosis of the lesion responsible for the precocious development in this case is extremely difficult in the 1 Bell, W. Blair, Proc. Roy. Soc. Med. (Obslet. and Gynaecol. Sect.), 1913, vol. vii, p. 47 ; Arris and Gale Lectures, Lancet, 1913, vol. i, pp. 809, 937. Facing page 156. Fig. 51. Section of the ovary of a cretin, aet. 33 years, showing a dense stroma and patches of hyaline material which may be the remains of corpora lutea or atretic follicles. X 60. Facing page 157. Fig. 52. Section of the uterus of a cretin, set. 33 years, showing the under-developed and inactive condition of the endometrium. PRECOCIOUS PUBERTY 157 absence of further evidence. It may be suggested that Atypical there is hyperplasia of the pineal. This condition would precocity best account for the development of the adult secondary m girl8, characteristics with inactivity of the internal genitalia in the female. The absence of menstruation practically excludes ovarian hyperplasia. Precocious puberty, however, in quite young girls Treatment of 4. 11 T 4- A A 4-U 4- 4- 4- ' precocious is not usually complicated, and the treatment in a puberty in majority of cases is well defined : when there is an girls* ovarian tumour it should be removed. These neoplasms are usually solid and often malignant; and when the tumour is not benign the prognosis, so far as life is concerned, is extremely grave. If no lesion be found, or on bimanual examination the ovaries appear large (hyperplasia), the treatment will consist in the adminis- tration of some extract, such as that of the suprarenals, which is antagonistic to the ovarian secretion. When puberty is slightly precocious — that is, occurs between the ninth and tenth years of age — ovarian hyperplasia or tumours are not often found. Such cases may be due to inherited tendencies, or to early develop- ment of the ovarian function with associated changes in the other hormonopoietic organs. This in some obscure manner may be caused by the climate, feeding, and surroundings of the child ; or by masturbation, which will be considered later. Absence of the Onset of Puberty. — In certain Absence of pathological conditions puberty may never supervene. In puberty. such circumstances the patients are the victims of some severe general disorder, usually connected with the cryptorrhceic system. Thus, with cretinism the patient remains in a condition of sexual inactivity, and the secondary sexual characteristics and functions are in abeyance. In the case of a female cretin, who died at the un- Absence of usually late age of thirty-three years, I had an oppor- cretins^ m tunity of examining the genital organs, and the distant hormonopoietic glands. The ovaries were large and 158 THE SEX-COMPLEX Ovaries in the cretin. Ductless glands in the cretin. Cortical suprarenal tumours before puberty. Sexual ateleiosis. smooth, and the uterus was well formed. On histological examination the ovaries were found to be devoid of Graafian follicles, but bands of hyaline substance, which represented the remains of atretic follicles, or possibly of corpora lutea, were seen (fig. 51). The stroma of the ovary, which was very dense, was not composed of fibrous tissue for it was stained yellow by van Gieson's method. The endometrium contained but few glands, and these were embedded in a very dense stroma (fig. 52). The thyroid was entirely absent, but the parathyroids were present and showed a tendency to form colloid (fig. 53). The pituitary was enlarged and altered in structure. The pars anterior was very rich in chromo- phobe and basophil cells, but there were very few eosino- phil cells. This lobe was divided up by broad bands and masses of a structureless substance that might be secretion. There was a thick fibrous tissue capsule surrounding the whole pituitary body. The pars inter- media contained some ' colloid ' and appeared normal. The pars nervosa also appeared almost normal. It was, however, more teased out in appearance than is usual. This patient had taken thyroid extract for some years. It is possible that if she had been treated from an early age the genital functions might have been aroused, for there was no doubt that development of the repro- ductive organs had advanced far beyond the fcetal stage, and had, indeed, reached that seen at puberty. Again, cortical neoplasms in the suprarenals which, as we have seen, lead to sexual precocity and muscular development in boys, cause atrophy of the genitalia in women, and when present before puberty would prob- ably, if the child survived, prevent that period of development occurring. In the type of infantilism described by Hastings Gilford1 under the name of ' sexual ateleiosis ', and in that defined by Byrom Bramwell2 as ' pancreatic 1 Gilford, Hastings, ' Infantilism ', Hunterian Lect., Lancet, 1914, vol. i, p. 587. 2 Bramwell, Byrom, Edin. Med. Journ., 1915, New Ser., vol. xiv, p. 323. Facing page 158. Fig. 53. Section of the parathyroid of a cretin, showing attempts at colloid formation. X 250. INCOMPLETE PUBERTY 159 infantilism ', the patient may remain under-developed Sexual in every respect, and the absence of sexual development a e e10818, is merely part of the general infantilism, as we have already seen. It is probable, then, that certain hormones arising from the hormonopoietic system, which normally stimulate growth and development, are suppressed or are insufficient. At the present time our knowledge is not definite enough to enable us to lay down specific lines of treat- ment in cases in which the patient remains infantile, except, perhaps, in those cases in which there is pan- creatic infantilism. Yet even now a careful examina- tion of any individual case may enable us to improve the condition of the patient, if we can trace it to the imperfect action of one of the organs of internal secretion. Incomplete Puberty. — By ' incomplete puberty ' is incomplete meant that the girl arrives at puberty with all her adult u erty* secondary characteristics fully developed, but that her genital functions are permanently in abeyance. This may occur as the result of : (1) Incomplete or incomplete and imperfect develop- Conditions ment of the whole or part of the genital ducts, with puberty"^ normal ovaries. (2) Incomplete development of the ovaries and genital ducts, with or without imperfect formation of the whole or part of the ducts. (3) Constitutional disturbances. With regard to the first condition, which is very common, we usually find that the parts forming the genital ducts — Falloppian tubes, uterus and vagina — are perfectly formed but that the uterus is infantile, and that in consequence menstruation does not appear. We are not concerned, however, with the malformations as such, but only in so far as they affect the genital functions. It is, of course, not always easy, without histological examination, to be certain that the ovaries of any given 160 THE SEX-COMPLEX Conditions woman are active, since, as I have shown elsewhere1, pubertyQplete tneY are not necessarily concerned in the production of the secondary characteristics. If, however, the woman have strong sexual feelings and potency we may presume the presence of active sexual glands. Causes of The causes of underdevelopment of the uterus are development now gradually being recognized. In the presence of of uterus. normal ovaries we must seek for anomalies of the pituitary or the thyroid ; in the latter especially there may be insufficiency not amounting to congenital cretinism. Occasionally both organs are at fault. On several occasions I have seen under-development of the pituitary in cases of infantile or rudimentary uteri. Causes of In the second class of case with incomplete puberty development tne ovaries are under-developed or inactive, and the of ovaries. uterus is usually rudimentary or infantile, and may be imperfectly developed. Such a condition is not very common, and of course nothing can be done to remedy the state of affairs. If the experiments of Paulesco2 and of Crowe, Cushing and Homans3 be correct, con- genital under-development of the pituitary might be responsible for the pelvic anomalies. As already stated, my own experiments largely confirm the results obtained by the investigators mentioned. In many cases, moreover, the condition of affairs just described must undoubtedly be due to local lesions, such as tuberculous or gonococcal infections, with pelvic peritonitis, and possibly in some cases to pelvic infection from appendicitis Delayed Delayed Puberty. — An undue delay in the appearance Puberty. Qj pUberty is a matter of considerable importance in 1 Bell, W. Blair, Proc. Roy. Soc. Med. (Obstet. and Gyncecol. Sect.), 1913, vol. vii, p. 47 ; Arris and Gale Lectures, Lancet, 1913, vol. i, pp. 809, 937. 2 Paulesco, N. C, Journ. Physiol. Path. Generate, 1907, vol. ix, p. 441 ; Uhypophyse du cerveau, 1908. 3 Crowe, S. J., H. Cushing, and J. Homans, Bull. Johns Hopk. Hosp., 1910. vol, xxi, p. 127. DELAYED PUBERTY 161 many cases ; but first of all it will be necessary to define what we mean by ' delayed puberty '. Strictly speaking ' delayed puberty ' should refer to Definition the temporary non-appearance of all the phenomena of puberty. puberty in a girl who is past the period of life at which they appear normally (complete delay). But that is not what is always implied by the term : it is often employed to denote the temporary absence of menstruation in a girl who is otherwise fairly well developed, both in regard to the uterus and the secondary characteristics (incomplete delay) ; hence there is considerable con- fusion as to the pathological conditions which may be responsible for the delay. It will, therefore, make the discussion of the subject clearer if we consider the subject under the two headings indicated. Completely delayed Puberty. — By ' completely delayed Completely puberty ' is implied that not only menstruation is puberty. delayed, but also the development of the adult secondary characteristics. This condition may be distinguished from general persistent infantilism by the fact that there is merely delay in and not suppression of further development. To understand best this retardation in reaching puberty we have only to look at the girls who come under our notice every day, and observe how differently they develop under different conditions. The influences at work may be divided into two classes — psychical and physical. With regard to psychical conditions, there is no Psychical doubt that the mental character of the individual is de?ayed° altered at puberty by the physical changes which occur in P^berfcy- the body at that time : the secretions from the hormono- poietic glands play the chief part in effecting this result. On the other hand, it is certain that the mind itself can hasten or unconsciously delay the onset of sexual activity1. In this connexion it must be clearly under- stood that the mind can certainly influence function, and vice versa, however impossible it may be for the 1 Engelmaim, G. J., Amer. Journ. Obstet., 1900, vol. xlii, p. 753. 11 162 THE SEX-COMPLEX Psychical causes of delayed puberty. Physical causes of delayed puberty. mind to alter structure. So in the first case we find that, with the onset of the physical phenomena associated with puberty, modesty and shyness develop in a girl hitherto untroubled with self-consciousness. Even then she may have but a vague instinctive knowledge of sexual matters. In the second case, in which the mind influences the onset of the physical phenomena of puberty, investigation has shown1 that the effect of enlightenment concerning sexual matters, with perhaps the stimulation of the sexual appetite by various means, hastens the onset of puberty. Conversely, seclusion and innocence tend to delay it. Further, hard mental work, such as studying for examinations at school, may lead to a delay in the de- velopment of the girl. Such cases are seen by most gynaecologists, but we know of no statistics giving the age incidence in a large number of girls who have studied closely between the ages of twelve and twenty years, although Catherine Chisholm2 denies that study affects either menstruation or the general health of these girls. Further investigations properly carried out would have considerable interest at the present time, especially as her results not only lack support, but are diametrically opposed to the observations of others3. With regard to many of the physical causes of delayed puberty there is much conflicting evidence. It is, however, well established that general ill-health, bad feeding, unhygienic surroundings and hard work in factories tend to delay the development of the girl and the onset of puberty. The disorders met with may be produced by the causal factors enumerated above in different ways : the food may be deficient in calcium salts, which are required for building up the skeleton before any can be 1 Ellis, Havelock, Studies in the Psychology of Sex, 1913. 2 Chisholm, Catherine, Joum. Obstet. and Gynaecol. Brit. Emp., 1913, vol. xxiii, p. 288. 3 Cardew, G. A., Discussion, Brit. Med, Assoc, Brit. Med, Journ., 1900, vol. ii, p. 792. DELAYED PUBERTY 163 spared for the reproductive functions ; there may be Physical constipation and chlorosis ; or, again, hard muscular delayed1 exercise or a sedentary life may each prevent the develop- pubeity. ment of the sexual functions — the former by using up the reserve metabolic forces, and the latter by failing to stimulate metabolic energy. With regard to muscular exercise, evidence has been produced to show that in gymnasts puberty may be delayed or incomplete ; but, on the other hand, Angenette Parry1, in an enquiry among members of this class of woman, found that they were nearly all normal with respect to their genital functions. The truth probably lies halfway between these extreme statements, as was pointed out in the discussion following the paper just referred to : moderate exercise is beneficial, and excessive harmful. In races in which the women always perform muscular work, agricultural and domestic, heredity appears to play an important part ; and by a process of selection women are produced whose functions remain undis- turbed. The same argument may apply to healthy gymnasts, many of whom have a long line of gymnastic ancestresses. But if we were to take a girl of ten years of age from the upper classes and put her to work con- tinuously in a factory or even in fresh air in the fields, or bring her up as a professional gymnast, it is probable that the onset of puberty in her case would be delayed, if not prevented. In the lower classes the effect of hard work, a sedentary life, or bad feeding on the onset of puberty is in part mitigated by heredity, by the close association with the opposite sex, and by the free discussion of sexual matters common among girls in this station of life ; but, in spite of all, the fact remains that girls of the upper classes who are well tended commence menstru- ating at an earlier age than their poorer sisters2. Incompletely delayed Puberty. — By this term I wish incompletely to imply a temporary state of incomplete puberty. In puberty. 1 Pcarry, Angenette, Amer, Journ. ObsteL, 1912, vol. lxvi, p. 341. 2 Engelmann, G, J., Amer. Journ. ObsteL, 1900, vol. xlii, p. 753. 164 THE SEX-COMPLEX incompletely these circumstances the absence of menstruation is the puberty. only abnormal phenomenon. Incompletely delayed puberty may be caused by all the conditions just described as responsible for completely delayed puberty, and also by minor degrees of insuffi- ciency in the internal secretions, which may not be sufficient to delay the appearance of the secondary characteristics ; for instance, we usually find that, when there is deficiency of the internal secretion of the thyroid, the uterus is well developed, if a little small, but that menstruation does not occur. These cases are well known, and they readily respond to treatment with , thyroid extract. DERANGEMENTS OF THE FULLY-ESTABLISHED FEMALE CHARACTERISTICS AND FUNCTIONS DERANGEMENTS OF THE SEX-CHARACTERISTICS The secretions of the hormonopoietic organs, which Causes in have produced the normal adult female, continue sub- seCretory sequently to act in the same way — passively, no doubt — Grange-1 and it is only some extensive alteration in the structure merits of sex- of certain units of the internal secretory system which ^£1™ can bring about an alteration in the female sex-character- istics, once they have been determined and developed to maturity. So far as we know, the withdrawal of any one secretion — such as the ovarian — will not produce any definite change. There must be some gross change in those parts of the internal secretory system, especially apart from the genital glands, which normally produce masculinity — a potentiality that appears to be con- centrated in the suprarenals, the pituitary, and probably in the pineal. The term ' inversion ' is usually applied to the Inversion. derangements of the normal secondary characteristics to be described here. Apert.1 has asserted that masculine characteristics may be produced in women by simple ovarian tumours. I do not believe that this is so. As we have already seen (p. 154) such tumours may produce feminine precocity, but they never produce masculinity. It is possible that Apert overlooked an ovitestis and considered it a new growth, as was done by an expert pathologist in the case already recorded (p. 141). With an ovitestis, such as that described, masculinity may be indicated by the testicular elements in the gonad in part, but it is probable that in these circumstances other organs, such 1 Apert, M. E., Bull. Med., Paris, 1910, vol. xxiv, p. 1161. 166 THE SEX-COMPLEX Beiteration of essential sex-differ- ences in metabolism. Suprarenal cortical tumours and derange- ments of sex- character- istics. as the suprarenals and pituitary, are also more masculine than feminine in type. It will not be waste of time to reiterate for a moment the essential differences that occur in the metabolism in response to stimulation from the masculinity-producing secretions. Probably the most important and obvious changes are associated with the metabolism of the lime salts. The male skeleton is far heavier and stronger than that of the female, so in men one of the most essential metabolic conditions is a considerable calcium retention during growth ; besides, there is normally in men a stable and invariable metabolism of calcium during the reproductive period. In women there is less calcium retention during growth, and throughout her reproductive life rapid alterations in the metabolism of lime salts occur during menstruation, pregnancy and lactation. It is not surprising, therefore, to find that those parts of the hormonopoietic system which are largely concerned in the storage of calcium and the building up of the skeleton will also, when abnormally active in the female, produce or lead to the production of other masculine characteristics, such as growth of hair on the face and alterations in the formation of the larynx and breasts. We have already seen, that hyperplasia and neo- plasia of the suprarenal cortices in girls before puberty lead to the production of male characteristics. These growths have generally been found to be malignant, so no further relevant history has been obtained in regard to the cases recorded1,2. Many instances of suprarenal cortical tumours (fig. 54) and hyperplasia (fig. 55) in adult women associated with alterations in the sex-characteristics have been described3. 1 Bulloch, W„ and J. H. Sequeira, Trans. Path. Soc, 1905, vol. lvi, p. 189. 2 Glynn, E. E., Quart. Joum. Med., 1912, vol. v, p. 157, 3 Glynn, E. E., and J. T. Hewetson, Joum. Pathol, and Bacieriol., 1913, vol. xviii, p. 81. Facing page 166. Fig. 54. Section of suprarenal cortical tumour from a woman who had developed masculine secondary characteristics, showing neoplasia (hypernephroma). ( X 250.) (From a section kindly lent by E. E. Glynn.) From article by Author in New System of Gyncecology. Facing page 167. Fig. 55. Section of the suprarenal cortex from a woman who had developed masculine secondary characteristics, showing hyperplasia ( x 250). {From a section kindly lent by E. E. Glynn.) From article by Author in The Neiv System of Gynaecology. DERANGED SEX-CHARACTERISTICS 167 It is important to note that there is no case on record Suprarenal of a suprarenal lesion in a woman after the menopause tumours and associated with changes in the secondary characteristics, derange- . ments of sex- Yet we know that often after this period of life the character- characteristics may normally incline towards the mascu- lstlC8, line type, the skin becoming coarse and hair growing on the face. I have, however, seen a suprarenal tumour in a duck of considerable age, which had partially acquired the plumage of the drake. The paradoxical circumstance that in women after the climacteric suprarenal lesions cause no considerable development of the masculine characteristics, which, however, may occur normally after that period of life, may be explained by the fact that Sex, as such, has ceased to exist ; and that although the withdrawal of certain feminine functions and characteristics may lead to the latent masculinity developing to a slight extent, yet no further sex-demonstration can be aroused, even though the masculinity-producing organs be disturbed. During the reproductive period of life the changes in the sex-characters of women, which may be brought about by suprarenal lesions, are remarkable. In one case of Krafft-Ebing, quoted by Halban1, the voice which was previously soprano became " like that of a lieutenant", and the woman, formerly gentle and amenable, became rough and aggressive. Amenorrhcea is a constant phenomenon in these circumstances, and the breasts atrophy. In fact, all the essentially feminine attributes of mind and body retrogress or disappear, while the male characteristics become pronounced. I have just explained why this can occur during the reproductive period and not after the menopause. It has been mentioned that the pituitary is largely Pituitary concerned in promoting the growth of bone and the derange^ retention of calcium salts. It is interesting, therefore, ments of sex^ . character- to note that when there is hyperplasia of this organ in istics. women, such as is seen in acromegaly, the sex-character- istics are disturbed. Every woman with acromegaly 1 Halban, J., Archiv. f. Gynak., 1903, vol. lxx, p. 205. 168 THE SEX-COMPLEX Pituitary lesions and derange- ments of sex- character- istics. Pluri- glandular lesions in derange- ments of the sex-character- istics. exhibits masculine characteristics : the heavy features, the coarse skin, the deep voice at once attract our notice. Yet this alteration of sex-characterization does not appear to have been recorded as such until recently1. But the alteration may go further than the phenomena mentioned above, which are constant : amenorrhcea is nearly always seen ; and this is not primarily due to hypoplasia of genitalia but to the general change towards masculinity, in association with which menstruation would be anomalous. Buday and Iansci2, Cushing3 and Goetsch4 have stated that in men the onset of acromegaly is not infrequently associated with increased sexuality. This probably indicates increased masculinity. There is no doubt that in women hypoplasia of the pituitary (dystrophia adiposogenitalis) leads to decreased function in the ovaries, consequently the apparent paradox of amenorrhcea with increased secretion in the anterior lobe of the pituitary can only be explained on the ground of the production of masculinity in these circumstances. If further evidence than that mentioned of the production of masculinity in women with acromegaly were required it would be found in one case which came under my notice : in this patient the clitoris was enlarged to the size of a small penis. We must, of course, always bear in mind the fact that in diseases of the internal secretory system there may be — indeed, there usually is — what is called a pluriglandular syndrome ; that is to say, more than one organ of internal secretion is affected. So it might be suggested that in acromegaly there may also be hyperplasia in the suprarenal cortices, and that it is the latter condition which is responsible for the masculinity in this disease. 1 Bell, W. Blair, Arris and Gale Lectures, Lancet, 1913, vol. i, p. 937 ; and Proc. Roy. Soc. Med. (Obstet. and Gyncecol. Sect.), 1913, vol. vii, p. 47. 2 Buday, K., and N. Iansci, Deutsch. Archiv. /. Klin. Med., 1898, vol. lx, p. 385. 3 Cushing, H., The Pituitary Body and Its Disorders, 1912. 4 Goetsch, E., Bidl. Johns Hopk. Hosp., 1916, vol. xxvii., p. 60. Facing page 168. • '. '"' " •• ;: •."' '.'' :'!■■ \'^". .'. /. ■ '-.' h"^ : •! "Qv <* Fig. 56. Section of the suprarenal of a young woman who had developed masculine characteristics, showing encapsuled hyperplasia in the lower part of the picture. (From a section kindly lent by J. Anderson.) X 60. Facing page 169. Fig. 57. Section of the pars anterior of the pituitary of a young woman who had developed masculine characteristics, showing a chromophobe adenomatous tumour in the upper portion. (From a section kindly lent by J. Anderson.) X 60. DERANGED SEX-CHARACTERISTICS 169 According to Cushing1, hyperpituitarism (acromegaly) Piuri- is often associated with a low blood-pressure, asthenia fesions fn and pigmentation — symptoms which indicate insuffic- dera£ge- iency of the suprarenal medulla. Indeed, I have sex-character- myself seen a case of acromegaly which also presented ls 1CS' all the symptoms of Addison's disease. But it must not be forgotten that hyperplasia of the suprarenal cortex might be associated with insufficiency of the medulla (Addison's syndrome), even if we accept the view that the two portions are interdependent. An interesting case is recorded by Anderson2 in which hyperplasia in the left suprarenal (fig. 56) was found in association with an adenomatous chromophobe tumour (fig. 57) in the pars anterior of the pituitary of a woman aged 28 years, in whom certain male characteristics had developed. A complete post-mortem examination was made. The author states that the anterior lobe was in a state of increased activity, and this is certainly borne out by the appearance of the chromophobia present in the cells of the pars anterior, apart from the tumour. The uterus was atrophied (fig. 58), and so were the ovaries (fig. 59). Somewhat similar cases have been recorded by Cushing1 and others. In these circum- stances we would expect male characteristics to be produced by both lesions, with atrophy of the female genitalia, as was found in the case described. Never- theless it appears to me certain that acromegaly alone may give rise to a change in the secondary characteristics of the female towards the masculine type. So far as I am aware, no cases are on record in which pineal tumours have led to the development of masculine characteristics in adult women, although on the evidence at our disposal such an occurrence might be expected. 1 Cushing, H., The Pituitary Body and Its Disorders, 1912. 2 Anderson, J., Glasgow Med. Journ., 1915, vol. Ixxxiii, p. 178. 170 THE SEX-COMPLEX DERANGEMENTS OF THE FULLY -ESTABLISHED GENITAL FUNCTIONS Derange- In considering derangements of the fully -established established functions I shall take in order each of the chief organs functions. 0f internal secretion, and endeavour to show how they are individually related to various gynaecological and obstetrical disorders. In some cases we have to take into account certain correlations ; especially is this so when the ovary is concerned. It will make this complicated subject clearer if it be treated in this manner, instead of being subdivided into the pathological anomalies themselves, although the latter is undoubtedly the more scientific method. Some day, when many more clinical observations have been recorded, and conditions such as those we are discuss- ing here become matters of daily consideration, it will be possible intelligibly to describe the pathological phenomena related to the internal secretions as definite disorders. It will be remembered that consideration has already been given to disturbances of genital develop- ment— anatomical and physiological — and of the sex- characteristics ; consequently the further discussion of the individual relationships of the hormonopoietic organs to derangements of the fully-developed functions will be largely complementary, and in many particulars necess- arily fragmentary. Primary derangements of the cryptorrhceic organs may be considered as giving rise to insufficiency or excess of the normal secretions ; and I shall deal with them from these points of view. Disturbances of the Ovarian Secretion Absence and Absence and insufficiency of ovarian secretion. oTovarian°y — These conditions are rare as primary disorders during secretion. the reproductive period, except when produced by Facing page 170. Fig. 58. Section of the uterus of a young woman who had developed masculine characteristics, showing atrophy of the endometrium. (From a section kindly lent by J. Anderson.) X 60. Facing page 171. Fig. 59. Section of the ovary of a young woman who had developed masculine characteristics, showing a dense stroma and an atretic follicle. (From a section kindly lent by Dr. J. Anderson.) X 60. OVARIAN INSUFFICIENCY 171 operative interference. As we have already seen, when Absence and the ovaries are removed experimentally definite changes 0TovarianCy occur in the general metabolism, in the uterus and in secretion. the structure of the other organs of internal secretion ; and these changes appear to be more marked in the higher than in the lower mammals. From observations made on the human subject Oophorect- there is no doubt that a train of events similar to that samo°effects seen in animals follows complete oophorectomy. In }n womeij as women, however, there are, in addition to the phenomena already described, frequently to be noted psychical disturbances which are no doubt dependent on the general disturbance of the metabolism. It must not be forgotten, also, that marked individual variations exist in regard to the symptoms produced, just as normally there are considerable variations in the degrees of femininity in different women. Many surgeons have stated that complete oophor- Effects of j ji.-4-i x. ; o6Phor- ectomy produces no detrimental symptoms, or, at any ectomy pro- rate, no disturbances worthy of consideration. Such KjJSiof8 10 surgeons remove both ovaries without the slightest femininity. hesitation. Nevertheless, those who have asserted that oophorectomy is of small moment to the patient have failed to make good their scientific position in the matter by any reliable evidence. Of course, as already mentioned, women differ considerably in their reactions to oophorectomy. Knowing this, by the exercise of a discretion that appears obvious in view of what has been said regarding individual variability, we might be able to avoid seriously injuring the patient. If one were to gauge the degrees of femininity and ovarian activity in women before operation — and in many cases it would not be difficult — it might be possible to assert that in those cases in which these were obviously in abeyance or below the average standard little disturbance of the metabolism would result from oophorectomy ; and, consequently, it might be justifiable in such cases com- pletely to remove the ovaries with a fibromyomatous uterus or with infected tubes. But, unless such a 172 THE SEX-COMPLEX Effects of scientific distinction, which undoubtedly exists and ecfomy accounts for the individual variations to be observed proportionate after oophorectomy, be made, it does not seem right femininity, blindly and systematically to remove the genital glands as some operators do in the circumstances mentioned. I do not think the explanation I have given of individual variability with respect to the disturbances following oophorectomy has been suggested before ; but there can hardly be any doubt that the symptoms pro- duced by oophorectomy in any given case are directly proportionate to the degree of femininity. Since the natural menopause bears a close resemblance to the artificial, I shall briefly discuss together the disturbances which may be associated with either. Causes of the It is more or less generally supposed that the natural menopause. men0pause occurs in women as the result of the gradual withdrawal of the ovarian secretion ; and it is, of course, certain that the artificial menopause is produced by the absence of it. At the natural or physiological meno- pause there is undoubtedly ovarian insufficiency sooner or later ; but, as with the artificial menopause, it has always seemed to me that the symptoms produced depend for their severity upon the correlations that exist between all the internal secretions, on the uterine changes which prevent the monthly excretions, and, lastly, on individual variability in regard to repro- ductive activity and to the stability of and capacity for readjustment in the cryptorrhceic system. That the phenomena associated with the physiological menopause depend partly on ovarian insufficiency is demonstrated by the onset of similar manifestations in most women after oophorectomy ; and that they are related to the coincidental uterine atrophy is proved by the fact that women may suffer with the same symptoms after the removal of the uterus alone. Further, I have seen monthly molimina, which reminded me of some of the symptoms of the menopause, in women in whom there was congenital absence of the uterus, or malformations OVARIAN INSUFFICIENCY 173 sufficient to prevent menstruation, in the presence of functional ovaries. The chief types of general menopausal phenomena to Menopausal be observed clinically may be classified as follows : — phenomena. (1) Psychical. (2) Vasomotor. (3) General metabolic. (4) Gross changes in the cryptorrhceic organs and in the mammary glands. The psychical disturbances I shall deal with later. Vasomotor disturbances. — The regulation of the vaso- Vasomotor motor system is very definitely under the control of the internal secretions, although as yet we do not know exactly the different parts played by all the hormono- poietic organs. It has, of course, long been known that the chromaffin system, of which the suprarenal medulla is probably the most important element, exerts a controlling influence over the tone of the vessels. We have not only physio- logical evidence of this in the pressor action of the prepared extract, but also morphological, since the secretory cells of the suprarenal medulla are derived from the same anlage as the sympathetic nervous system. Again, Weed, Cushing and Jacobson1 have demon- strated that stimulation of the superior cervical sympath- etic leads to an increased output of infundibulin, followed by glycosuria. It is true that this is merely a secretory -nervous phenomenon ; but we know that the connexion does not stop there, and that the infundib- ulin has a powerful action on the blood-pressure : not, of course, through the sympathetic -nervous system, but owing to its direct, peripheral effect on the blood-vessels. With regard to the thyroid we know that the extract of this gland, when injected intravenously, lowers the blood-pressure. The modus operandi is somewhat doubtful ; many authorities believe that the action is not specific, but common to many animal extracts ; 1 Weed, L. H., H. Cushing, and C. Jacobson, BuU. Johns Hopk. Hosp., 1913, vol. xxiv, p. 40. 174 THE SEX COMPLEX others look upon the effect produced as specific for reasons which need not be discussed here. indirect Behind these direct effects of the internal secretions internal in regard to the vasomotor system are the indirect there is a large demand for calcium over and boiism. above the amount necessary for the normal maternal metabolism, and, as a result, softening of the bones may occur. This condition is known as osteomalacia. Osteomalacia. Osteomalacia is not common in England, but is more frequently encountered in other countries such as Italy, Austria and India. The disease used to be treated by removal of the ovaries, and many patients were cured. Figure 61 is of a section of an ovary, which was greatly enlarged, from a case of osteomalacia. It will be seen that the interstitial cells are very prominent, much more so than in normal ovaries during pregnancy. Hyperplasia Wallart1 was probably the first carefully to examine ceiistrftitial the ovaries in this disease by histological methods. osteomalacia. The ovaries from five cases are described. In four the interstitial cells were particularly well developed. More- over, he states that this is always so in osteomalacia, whether the patient be pregnant or not ; and he agrees with Bossi2 that osteomalacia is due to vasodilatation, which affects the vessels of the bone-marrow as well as those of other tissues. Suprarenin Some years ago Bossi2 of Genoa suggested the bulin in injection of suprarenal extract as an alternative to treatment of oophorectomy ; and apparently manv cures have been osteomalacia. r J ' rsr J J effected by this treatment. I have also suggested treatment with injections of infundibular extract, and Miss Kate Knowles, of Srinagar, Kashmir, working in conjunction with me, has found that infundibulin is most beneficial in a number of cases of this disease. It may, therefore, be argued that there is insufficiency in the suprarenals and pituitary as well as an excess of ovarian secretion ; and this, indeed, is quite possible. On the other hand, it may be suggested, as has been done by Bossi and Wallart, that the general vasodilatation caused by hyperplasia of the intestitial cells is a primary 1 Wallart, J., Zeitsch.f. Gel. u. Gynah, 1908, vol. fad, p. 581. 2 Bossi, L. M., Centralbl. /. Gyriak., 1907, vol. xxxi, p. 69. Facing page 184. Fig. 61. Section of the human ovary from a case of osteomalacia, showing hyperplasia of the interstitial cells lying in the stroma. X 250. THYROID INSUFFICIENCY 185 condition, and that suprarenin overcomes the dilatation Osteomai- by producing vasoconstriction — an effect that can equally acia* well be obtained by removing the source of the vaso- dilating secretion, that is by oophorectomy. Further, Erdheim1 has stated that with osteomalacia hyperplasia of the parathyroids is found. If this be so, it would appear that the hyperplasia of the parathyroids represents an attempt on the part of these organs to counteract the effects of an excessive ovarian secretion, and thus lead to calcium retention, if indeed the hyperplasia be greater than that seen normally in pregnancy. Be this as it may, substitution of other extracts is a great advance on removal of the ovaries in the treatment of osteomalacia ; and the success thus obtained indicates the line of attack that will probably be followed in the future in regard to all those diseases of the hormono- poietic glands in which there is an excessive secretion ; that is to say, metabolically antagonistic extracts will take the place of removal of portions of the affected organs. Disturbances of the Thyroid Secretion Absence and Insufficiency of Secretion. — Absence Absence and of thyroid secretion is, of course, extremely rare, and can oTthyroid only be seen in the congenital cretins. In these circum- secretlon- stances there is an absence of the onset of puberty, should the patient live to that period of life. A case of this character has already been described (p. 157). Although the genital organs were well developed it appears that they were unable to functionate in the absence of thyroid secretion. With thyroid insufficiency there is usually a decrease Thyroid in, or the complete cessation of, the function of menstrua- anTameno-7 tion, according to the degree of insufficiency. We rrhcea. have already seen that considerable atrophy is found 1 Erdheim, J., Sitz. der Akad. d. Wiss. Math, naturw. i£Z.,Wien, 1907, cxvi, 3 Alt, p. 311. 186 THE SEX-COMPLEX Thyroid to occur in the uteri of animals from which the thyroid and* ameno^ nas been removed, but that the ovaries do not undergo rrhcea. hypoplasia. Apparently in the human subject atrophy of the uterus is never complete with pathological insufficiency of the thyroid — not even with myxoedema, for patients who have suffered with this disease for some years have been known not only to menstruate, but also to con- ceive after treatment with thyroid extract. Myxedema Paradoxically, as it appears, menorrhagia is stated by rrhda^aen°" certain writers (Allen Starr, » Ewald2, Hertoghe3 and others) to occur as the direct result of myxoedema, and to be relieved by the administration of thyroid extract. Of all the cases of thyroid insufficiency I have myself seen, and the number is very large, I have never encountered menorrhagia which could be attributed to the thyroid lesion. I have, however, in such cases seen menorrhagia which could be traced to other causes, such as uterine polyps. Minor It is, however, chiefly the disturbances arising from thyroid minor degrees of thyroid insufficiency which come under insufficiency, foe notice of gynaecologists. Delayed puberty and menstruation have already been discussed. Secondary amenorrhoea and scanty menstruation, the latter also associated with dysmenorrhcea, are very frequently seen with thyroid insufficiency ; and the patients are usually obese, lack energy, and have deficient sexuality. As a rule, the administration of thyroid extract entirely cures all these disabilities. Mastidynia There is another menstrual disturbance of interest in insufficiency. tm?s connexion — namely, mastidynia, which sometimes occurs regularly each month before the onset of menstrua- tion. Usually the menstrual cycle is protracted beyond 30 days in these cases. If, however, a ' period ' occur earlier than usual, the patient does not suffer with the 1 Starr, Allen, Med. Record, 1893, vol xliii, p. 168. 2 Kirk, R., Lancet, 1893, vol. ii, p. 743. 3 Hertoghe, ^., Practitioner (Spec. Number on Internal Secretions), 1915, p. 26. THYROID INSUFFICIENCY 187 pain in her breasts. The administration of thyroid Mastidynia extract relieves the patient by producing a shorter ^u^iencj. menstrual cycle. It appears not unlikely, therefore, that the protraction of the menstrual cycle with the accompanying mastidynia is due to a slight degree of insufficiency in the thyroid. The thyroid secretion is associated with the integrity Thyroid of the function of conception, just as it is with that of pregnancy. menstruation. It is well known that the thyroid gland enlarges in the early stages of pregnancy ; and the enlargement is found to be due to the storage of colloid in the vesicles. This change is probably associated with the alterations in metabolism which occur in these circumstances. A marked degree of insufficiency, such as is seen in myxcedema, almost invariably leads to sterility unless it be treated. Cases, however, have been recorded in which pregnancy has occurred in minor or variable states of ' this disease ; and in such circumstances an improve- ment has usually been produced in the general condition of the patient as the result of an increase in the thyroid activity. There is another important point in regard to thyroid Thyroid insufficiency — namely, its relation to the toxaemias of theToxjemias pregnancy. of P^gnancy. Fischer1 and Lange2 many years ago propounded the theory that the enlargement of the thyroid which occurs during gestation is connected with a protective influence on the part of the thyroid secretion against the toxic elements that are elaborated in pregnancy. Such reasoning naturally led to the assumption, advocated in this country by Nicholson3, which has been taken up extensively by clinicians, that eclampsia is due to thyroid insufficiency in the later months of preg- nancy. It will be remembered that in my experiments 1 Fischer, J., Wein. Med. Presse, 1895, vol. xxxvi, p. 1922. 2 Lange, M., Zeitsch.f. Qeb. u. Gynak., 1899, vol. xl, p. 34. 3 Nicholson, H. O., Scot. Med. Surg. Journ., Edin., 1901, vol. viii, p. 503, 188 THE SEX-COMPLEX Thyroid no evidence, either metabolic or symptomatic, was theToxjBmias obtained in support of this view ; indeed, as indicated, of pregnancy, ft appeared that the animals from which the thyroid was removed in the later stages of pregnancy were considerably less affected than those which were not pregnant. An explanation of this has already been suggested (p. 54). Hyper- thyroidism. Hyper- thyroidism and the genital functions. Excess of Thyroid Secretion. — It is a common experience to meet with an excess of thyroid secretion in connexion with pelvic lesions, and we must be careful to distinguish between those cases which are the result of genital affections and those which are the cause of them. In a recent analysis of 93 cases of exophthalmic goitre it was found that 92*5 per cent, of the cases occurred in women, and that in 9 per cent, of these the origin of the disease could definitely be traced to disturbances in the genital organs1. It is certain that after the menopause the thyroid normally undergoes some retrogression, after, perhaps, a period of minor hyperthyroidism ; and it is probable that removal of the ovaries leads, eventually at all events, to the same condition in a majority of cases. But, as previously mentioned, in some cases acute exophthalmic goitre may intervene. Experimentally, we have seen that a considerable increase in the colloid formation follows oophorectomy, but it is certain that this is a condition entirely different from Graves' disease. At the same time, we know far too little about exophthalmic goitre — especially in its relation to simple goitre, and to myxcedema with which it not infrequently alternates — to speak definitely on this question. Excessive thyroid secretion may affect the genital functions in two ways : first, it may stimulate them to unusual activity ; or, second, the general metabolism may be so upset that the genital functions cease. There is no doubt that there is a condition of hyperthyroidism 1 Gurney, Helen M., Brit. Med. Journ., 1915, vol. i, p. 924. THYROID EXCESS 189 which produces excessive menstruation, and which is Hyper- totally unassociated with any of the symptoms of andThe18"1 exophthalmic goitre. This condition is most often seen gential in girls about puberty, usually just before and during menstruation. It may be that the excessive activity is due to the incomplete functional development of the ovaries ; but, whatever the cause, there is not infre- quently menorrhagia. I have, however, seen this same enlargement of the thyroid with amenorrhcea. This paradoxical phenomenon is to be explained on the supposition of ovarian insufficiency in these circum- stances, and of an inability of the thyroid in some cases, in spite of its enlargement, to meet the deficiency1. When there is menorrhagia I have found that it can always be controlled with calcium lactate. It is usually stated that with true exophthalmic goitre amenorrhcea coexists. I have not been able to satisfy myself that this is so until the metabolism has been seriously disordered, and the increased quantity of calcium which is being excreted by way of the urine and faeces — a constant phenomenon in Graves' disease — is so large that there is no excess for the ovaries to excrete in the menstrual fluid. Generally, in the early stages of the disease there is menorrhagia. Should a large body of evidence eventually disprove this view it will be a positive argument of great value that in Graves' disease the secretion is perverted even if there be also an excess of the normal. But in this matter, too, we must remain in comparative ignorance until our knowledge of the pathology of exophthalmic goitre is more definite. Helen Gurney2 found amenorrhcea in 15 per cent, of the cases analysed, but she makes no statement as to the stage of the disease in her cases. Further, she says that " in some cases it (amenorrhcea) appeared before the disease and improved when the goitre developed ". The same writer adds, " The effect of menstruation on 1 See also article by the Author on ' The Disorders of Function ' in The New System of Gynaecology, 1917. 2 Gurney, Helen M., Brit. Med. Journ., 1915, vol. i, p. 924. 190 THE SEX-COMPLEX exophthalmic goitre is not constant ; sometimes the goitre diminishes in size, and sometimes it is increased during the period ". Hyper- The relation of excessive thyroid secretion to preg- and'preg-111 nancy is very interesting, but very little has been nancy. written on this aspect of the subject. In 1911 Clifford White1 briefly reviewed the literature, and found it as contradictory as the literature usually is on subjects con- nected with the internal secretions. I think there can be no doubt that excess of thyroid secretion, except that seen in connexion with an advanced stage of Graves' disease, does not interfere with fertility. It would be strange if it did, for we know that there is an increase in thyroid activity during the early months of pregnancy, and possibly throughout ; but it is no less a fact that women with marked exophthalmic goitre rarely become pregnant, and if they do the disease is aggravated. In the case of one patient who had suffered with exophthal- mic goitre for some years and had given birth to several children, there had always been haemorrhage after delivery — an occurrence which has not infrequently been noted in these cases. One of my colleagues removed one half of the thyroid gland, with the result that there was marked amelioration in her symptoms. Shortly afterwards, however, she became pregnant again, and this caused her symptoms to become considerably worse than they had been since her operation, so I suggested that she should take large doses of calcium lactate, and should rest as much as possible. Subsequently she went comfortably to full term, and there was no post- partum haemorrhage. The patient was advised not to nurse the child, which was normal, owing to the drain on her lime salts lactation would entail. There was very considerable improvement after parturition, and the patient subsequently remained in good health. It is most important that these women should be given large doses of calcium salts if they become pregnant, 1 White, Clifford, Journ. Obstet. and Gyncecol. Brit. Emp., 1911, vol. xx, p. 126. THYROID EXCESS 191 for there is an excessive excretion of lime salts in this Hyper- disease, and consequently much danger of haemorrhage and'preg-111 post partum, and even ante partum. If no improvement nancy. follow this treatment infundibulin should be adminis- tered. It may be mentioned here that some time ago I sug- gested injections of pituitary extract in the treatment of hyperthyroidism. Suprarenal and pituitary extracts counterbalance the action of the ovaries and thyroid and lead to calcium retention ; this, as we have already seen, is a normal function of the suprarenals and pituitary. It is probable that both portions of each of these organs are concerned in the result. Infundibulin should, there- fore, be given immediately after labour to all patients with exophthalmic goitre, in order that by its direct action on the musculature of the uterus bleeding may be prevented. Whether pregnancy can cause exophthalmic goitre has recently been debated. Equally eminent clinical obstetricians have made diametrically opposed state- ments. Personally, I do not feel competent to express an opinion as to whether pregnancy can cause exophthal- mic goitre, but I have certainly seen this disease arise during pregnancy on several occasions. In one case, contrary to expectation, the condition did not improve after parturition. Marked improvement, however, was effected by treatment with pituitary extract ; and when the patient was last seen she had no evidence of the disease beyond a somewhat rapid pulse and excitable temperament. In another woman the exophthalmic goitre commenced immediately subsequently to parturi- tion and lactation, the latter being only possible for a few weeks. I saw her eleven months after her confinement, when there was amenorrhcea with superinvolution of the uterus. This patient, who was treated with pituit- ary extract, completely recovered, and menstruated regularly from a uterus measuring 2 \ inches. After the disappearance of all symptoms the pituitary extract was discontinued ; but a fortnight later the 192 THE SEX-COMPLEX Hyper- patient returned and asked that it might again be pre- and preg- scribed, as the palpitation of the heart was causing her nancy. much discomfort. She immediately responded to treat- ment, and became well again, except for a somewhat rapid pulse. Rapidity of the pulse should always be taken as a guide to the condition of the patient when one is considering the advisability of discontinuing treatment in these cases. Disturbances of the Parathyroid Secretion Disturbances As we have seen, the role of the parathyroids is foidsecretion. ProDably directly connected with the calcium meta- , bolism (p. 59), and possibly with the functions of the thyroid1. We have also some evidence of a relationship with the anterior lobe of the pituitary, but at present nothing definite is known of the connexion of these cervical organs with the rest of the hormonopoietic system. It is hardly necessary to repeat that all that concerns the calcium metabolism closely concerns the reproductive functions, as I first pointed out many years ago ; conse- quently the parathyroids may be involved in many disorders of menstruation, pregnancy and lactation, although as yet we have little direct evidence that this is so. Osteomal- Erdheim2 has stated that in osteomalacia he has parathyroids, found hyperplasia of the parathyroids. If this exceed that seen normally in pregnancy, it is probable that this change indicates an attempt on the part of these organs to prevent the excessive excretion of the lime salts which occurs in osteomalacia, for it has been shown3 that after removal of the parathyroids there is a deficiency of calcium salts in the tissues. And this action represents one phase of what we call ' antagonism ' 1 Vincent, S., and Jolly, W. A., Journ. Physiol, 1904-5, vol. xxxii, p. 65. 2 Erdheim, J.. Sitz. der Akad. d. Wiss. Math.-naturw. Kl., Wien, 1907, cxvi, 3, Alt., p. 311. 8 MacCallum, W. G., and Voetglin, C, Bidl. Johns Hopk. Hosp., 1908, vol. xix, p. 91. DERANGEMENTS OF THE PARATHYROIDS 193 between internal secretions : it is probable that although interaction such antagonism may be direct or inhibitory, more often secretions. it is related to the results produced by the opposing secretions in the general metabolism, as here shown ; that is to say, an excessive ovarian secretion, such as may occur in osteomalacia, causes too great an excretion of lime salts, and if the parathyroids undergo hyperplasia in this disease it may be in order to bring about the opposite state of affairs in regard to the calcium meta- bolism. Tetany of pregnancy is attributed to insufficiency of Tetany of parathyroid secretion ; and the experiments of Vassale and lactation and General i1 and of Adler and Thaler2 appear to bear ^ratiTroids out this view. These observers found that partial para- thyroidectomy may give rise to no symptoms unless the animal be pregnant, when tetany is prone to occur or to follow parturition. It is, therefore, more than probable that the tetany which may be seen in the human subject during the later stages of pregnancy is associated directly or indirectly with the metabolism of calcium and the control of this metabolism by the parathyroids. It is possible, also, that the parathyroids influence the metabolism of the lime salts during lactation, and that the tetany of lactation may be due to some insufficiency of the parathyroids in this respect. Vassale3 believes that insufficiency in the para- Eclampsia thyroids is to be found in eclampsia — a toxaemia which parathyroids. he thinks may be successfully treated by an extract of these organs. It seems likely that this method of treatment acts indirectly — that is, calcium retention is promoted and excessive acidosis, so constant in this disease, is prevented4. 1 Vassale, G., and F. Generali, Archiv. Ital. de Biol., 1896, vol. xxv, p. 459. 2 Adler, L., and H. Thaler, Zeitsch. f. Geb. u. Gynak., 1908, vol. lxii, p. 194. 3 Vassale, G., Archiv. Ital. de Biol, 1905, vol. xliii, p. 177. 4 For a disoussion of the role of the alkaline bases in this connexion the reader is referred to an excellent review of ' Acidosis ' by E. I. Spriggs, Quart. Journ. Med., 1908-9, vol. ii, p. 325. 13 194 THE SEX-COMPLEX Disturbances of the Pineal Secretion Sexual Beyond what has already been said of the influence of precoci y. ^e pineal on sexual precocity and on the sex-character- istics (p. 153, etseq.), very little is known of the relation- ship, if there be any, of the pineal to the genital functions. Ott and Scott1 state that injections of pineal extract have a galactogogue effect ; but this was not confirmed by Schafer and Mackenzie2. It is probable that since partial involution occurs at puberty the pineal exerts but little influence in normal circumstances on the genital functions. Kidd3, in a comprehensive review of the literature concerning the pineal body, gives no case in which a lesion of this organ has been recorded in an adult woman ; indeed, practically all the known cases have occurred in male children. Disturbances of the Pituitary Secretion The unity of In any attempt to understand the influence pituitary and^sterior lesi°ns exercise over the normal genital functions we are lobes of the forced to recognize the unity of the pituitary body. By this statement I do not mean to create a paradox, for it has already been demonstrated that extracts of the two main portions of the pituitary do not produce the same physiological effects, and that removal of the two lobes separately in different individuals in the same species of mammal may lead to different results. At the same time these results in themselves are somewhat paradoxical, for the extract of the posterior lobe is active — and extremely so — while that of the anterior lobe is, so far as we know, inactive from an experimental point of view ; and, although removal of the anterior 1 Ott, I., and Scott, J. C.,Proc. Soc. Exper. Biol, and Med.s 1910-11, vol. viii, p. 48. 2 Schafer, E. A., and Mackenzie, K., Proc. Roy. Soc, Ser. B., 1911, vol. lxxxiv, p. 22. 3 Kidd, L. J., Rev. Neurol, and PsycMat., 1913, vol. xi, p. 1. DERANGEMENTS OF THE PITUITARY 195 lobe or a large portion of it may be fatal, removal of the posterior lobe produces no symptoms (p. 66 et seq.). This unexpected diversity in regard to experimental Supposed results has led to much confusion when attempts have between been made to correlate experimental data with clinical exSer}j^j^aial observations ; indeed, so conflicting apparently were observations. these two methods of investigation in the results they gave, that Cushing1 felt it necessary to discard experi- mental findings in favour of clinical evidence. But surely this is neither scientific nor helpful, especially when there is one simple and obvious way out of all these difficulties : namely, the acceptance of the view I have put forward2 concerning the unity of the whole organ. There is certainly as much evidence in favour of this opinion in connexion with the pituitary as there is concerning the same views in regard to the thyroid and parathyroids, and the medulla and cortex of the suprarenals. I shall not enter into a long dis- cussion of this question here, as I have considered it more fully elsewhere3. Pituitary Insufficiency. — The degrees of pituitary Pituitary insufficiency vary considerably. With all degrees of this J^ds toenCy condition in women there is always scanty menstruation geni*?i J J inactivity. or amenorrhcea. Since the development and normal functions of the genitalia are dependent on the full development of the pituitary body, it is only consistent that pathological lesions causing insufficiency and withdrawal of its secretion should lead to hypoplasia in the reproductive organs with the cessation of their functions. Now the only specific lesions in the pituitary of which Lesions we have any clinical knowledge occur in connexion with ^sufficiency the anterior lobe ; and insufficiency may result from : intt}Jfarv (1) destructive lesions, such as cysts; (2) hypoplasia, 1 Cushing, H., The Pituitary Body and Its Disorders, 1912. 2 Bell, W. Blair, Arris and Gale Lectures, Lancet, 1913, vol. i, pp. 809 and 937. 3 Bell, W. Blair, The Pituitary, 1919. 196 THE SEX-COMPLEX Lesions producing insufficiency in the pituitary. Distinction between thyroid and pituitary insuffici- encies. Treatment with pituitary extracts. primary or secondary to hyperplasia ; (3) pressure from tumours in the neighbourhood, or distension of the third ventricle. All these conditions may affect the posterior lobe indirectly — that is to say, by causing pressure on it. If the pressure be not too great, and merely irritative, glycosuria is produced, but it is doubtful if other symptoms can be caused by lesions of the posterior lobe : genital disturbances result from lesions in the anterior lobe. This conforms with Cushing's and my own experimental results, but not with Cushing's clinical observations. I think, however, that the confusion in the views of this observer has arisen — if I under- stand him correctly — from the fact that amenorrhcea is seen with hyperplasia as well as with hypoplasia in the anterior lobe. The explanation of this apparent paradox has already been given : hyperplasia in women causes masculinity, and, therefore, indirectly genital hypoplasia with amenorrhcea, while hypoplasia in the anterior lobe directly causes hypoplasia of the genitalia. With both of these pathological conditions sterility co- exists. Sometimes there may be difficulty in distinguishing at first sight between thyroid insufficiency and pituitary insufficiency. In both cases there is obesity ; but the site of the lesion may usually be discovered by noting the state of the skin : with thyroid insufficiency it is rough and coarse, and with pituitary insufficiency it is smooth and fine. This observation can be confirmed by the other scientific methods of investigation at our disposal. I have found that in minor degrees of pituitary in- sufficiency an extract of the anterior lobe or of the whole gland occasionally produces good results. In the case of a man, who suffered from an extreme degree of dystrophia adiposogenitalis with impotency, and of whose history I have an intimate knowledge, not only did sexual potency return, but his wife subsequently gave birth to a child. I have not come across any case PITUITARY EXCESS 197 either in the literature or in my own experience in which Treatmont a woman suffering from a major degree of pituitary ^tracts?1*"7 insufficiency has become pregnant. We have already seen that infundibular extract appears to act as well as suprarenal medullary extract in the treatment of osteomalacia ; it is possible, therefore, that there is a minor degree of insufficiency of this part of the pituitary in this disease ; but it is more likely that a good result is obtained because this extract is antagon- istic to the ovarian secretion in regard to the calcium metabolism. Excess of pituitary secretion.— As a rule, hyper- Hyperplasia plasia of the pituitary commences at puberty; but°?t^ there is no reliable evidence that hypoplasia in the acromegaly, gonads induces the condition. Nevertheless, it has been stated by Kalledey1 and others that intravenous injections of ovarian extract will cure acromegaly. It must be remembered, however, that this disease shows remarkable remissions, even with the return of men- struation for many months. In Kalledey's case the patient became pregnant, but parturition had not taken place at the time his paper was written. In connexion with acromegaly it is interesting to note that there is considerable calcium retention in the bones and tissues of the patient — a masculinity-producing phenomenon which would be incompatible with menstrua- tion and pregnancy, as already explained. For the same reason an increase in sexual excitability is never seen in women at the onset of acromegaly — a phenomenon described by Cushing2 and others as sometimes occurring in men in these circumstances. It is, of course, well known that an increase in the Hyperplasia activity of the pituitary— particularly in the pare^J^JJ anterior — is to be found normally in pregnancy. Some- pregnancy. times acromegalic symptoms, such as enlargement of the lips, tongue, lower jaw, hands and feet, have been 1 Kalledey, L., ZentraM.f. Gynak., 1913, vol. xxxvii, p. 1030, 2 Cushing, H., The Pituitary Body and Its Disorders, 1912. 198 THE SEX-COMPLEX Hyperplasia of the pars anterior in pregnancy. observed ; indeed, the swelling of the fingers and face commonly seen during gestation has been attributed to the increased activity in the pituitary. After parturi- tion these enlargements usually disappear. Marek1 has recorded a case in which there was glycosuria with the typical symptoms of acromegaly, all of which disappeared during the puerperium. It is probable, then, that the pituitary may play some part in the disorders of pregnancy, but no facts have been discovered which can be considered definitely pathognomonic. Another interesting question is whether the absence of milk-secretion after parturition may be attributed to hypoplasia or insufficiency of the pituitary, for probably in normal circumstances the hyperplasia seen in preg- nancy is maintained during lactation to influence the calcium metabolism, if not to stimulate directly the secretory cells of the mammary glands. Addison's syndrome. Disorders of pregnancy. Disturbances of the Suprarenal Secretion Suprarenal insufficiency. — This condition has re- ceived recognition in Addison's syndrome, in which there is an extensive derangement in the metabolism with general asthenia. Amenorrhcea with sterility is always found in this disease if it be at all advanced. From experimental evidence it is probable that the uterus undergoes some degree of atrophy. It has been suggested by Silvestri2 that excessive vomiting of pregnancy may be due to suprarenal in- sufficiency, and this writer claims to have treated hyperemesis successfully by the administration of suprarenin. If this be so, the therapeutical effect is probably somewhat complicated : the suprarenals, being damaged by the toxaemia of pregnancy, allow an excessive excretion of lime salts, and the loss of calcium may induce a condition of acid intoxication with associated vomiting. 1 Marek, B>.,Zentralhl. f. Qynak., 1911, vol. xxxv, p. 1612. 2 Silvestri, T., Sem. Med., 1909, vol. xxix, p. 535. DISTURBANCES OF THE PANCREAS 199 Again, it will be remembered that Bossi1 has shown Disorders of that osteomalacia may be relieved by injections of Pr°snancy- suprarenin, and that this author concluded that in this disease there is suprarenal insufficiency. Whether this be so is very doubtful, for both injections of in- fundibulin and the operation of oophorectomy will also produce good results. Suprarenin, like infundibulin, causes the retention of lime salts in the tissues, and thus prevents the depletion of calcium salts from the bones ; and in this way it may be said that suprarenin and infundibulin are indirectly antagonistic to the excessive ovarian secretion which is believed to exist in osteo- malacia. Excess of suprarenal secretion. — I have already Alterations discussed the effect of suprarenal cortical hyperplasia acteristic"" in connexion with alterations of sex-characteristics (p. 166). In well-marked cases there is always ameno- rrhcea with hypoplasia of the genital and mammary glands. Disturbances of the Internal Secretion of the Pancreas. Insufficiency of the internal secretion of the pancreas, Pancreatic the result of lesions of that organ, leads to the disease lnsufficlency- commonly known as * diabetes '. It is universally accepted that the internal secretion is formed by the epi- thelial cells which comprise the islands of Langerhans, and that this secretion has functions separate and distinct from those of the external secretion, being largely con- cerned in the control of the carbohydrate metabolism. There is, however, no doubt that other internal secretions are concerned in this metabolism, and that there is some interrelationship between the pancreas and the other hormonopoietic organs which is not fully understood. It will, therefore, easily be realized how little is known concerning the influence of minor dis- turbances of the pancreas on genital disorders. It is, 1 Bossi, L. M.. Zentralbl.f. GynaL, 1907, vol, xxxi, p. 69. 200 THE SEX-COMPLEX Pancreatic however, commonly supposed that minor degrees of ciency. jnsufficjenCy? as measured by the constancy and degree of glycosuria, do not effect the functions of menstruation and conception to any recognizable extent. Carlson1 states that diabetes tends to produce impotence and loss of sexual desire, both in men and women, and that in women diabetes of marked severity causes amenorrhcea, sterility and premature menopause with atrophy of the uterus. This, however, can hardly be considered a specific genital syndrome, but rather the result of impaired vital processes. As already mentioned, conception is incompatible with the more advanced stages of diabetic glycosuria ; and it is stated2' 3 that, when conception does take place in women with diabetes, 50 per cent, of the foetus are still-born or die shortly after delivery. But, as we have seen (p. 81), the normal pancreatic hormones of the foetus may be conveyed to the mother. The low sugar-tolerance and the glycosuria of preg- nancy, which may be unassociated with pancreatic lesions (see p. 198), must be differentiated from pancreatic diabetes ; and, needless to say, lactosuria, which is normally seen in the later stages of gestation and during lactation, is connected with the formation of milk in the mammae, and is not related to any abnormal disturbance in the carbohydrate metabolism. Disorders of the Thymus involution of Inactivity of the Thymus. — This, so far as we the thymus. j£n0Wj js natural after puberty, when the genitalia are fully developed. Nothing is definitely known concerning premature involution of the thymus ; but if it be that there is a close relationship between the onset of puberty — that is, 1 Carlson A. J., Trans. Amer. Gynecol. Soc, 1917, vol. xlii, p. 131. 2 Fellner 0. 0. (quoted by A. J. Carlson, Trans. Amer. Gynecol. Soc, 1917, vol. xlii, p. 131). 3 Fruhinsholz, A., Ann. Gynecol, 1913, vol. x, 2c,neser., p. 477. DERANGEMENTS OF THE THYMUS 201 ovarian activity — and involution of the thymus, there involution of may be some connexion between retrogression in this fche thymus' organ and premature and precocious puberty. It has been believed that the thymus has a secretion which is con- cerned in promoting calcium retention in the tissues, and so in building up the growing skeleton : early involution might, in such circumstances, be associated with stunting in regard to the growth of the girl ; and this, in fact, is commonly seen with precocious, or even early, puberty. It must, however, be remembered that it is doubtful whether the thymus has an internal secretion, even though changes in this organ are coincidental with natural phases in growth and maturity. Excessive activity of the Thymus. — Enlargement status of the thymus is found in the condition known as ' status 1ymPhatlcus' lymphaticus ', in which the thymus does not undergo the normal involution but remains large and active. Persons with this disease are usually tall, and often are somewhat undeveloped mentally. It has been supposed that in these circumstances the gonads remain infantile, but this view, although possibly true in some cases, is not uni- versally so. I have had an opportunity of examining the ovaries of a woman who had died suddenly as the result of status lymphaticus. This patient had borne children, and her genital organs were normal. This disease, therefore, needs further pathological investiga- tion before definite statements can be made concerning the associated condition of the genitalia. When more evidence has been collected in regard to the status lymphaticus we shall be in a position better to understand the relationship between the thymus and gonads. The Mammae and the Genital Functions But little remains to be said in regard to the mammae. Their influence on the genital functions is purely indirect ; 202 THE SEX-COMPLEX Relation of marnmse to genital functions. but in this sense amenorrhcea and sterility may be temporarily produced during lactation. Parke1 has recorded a case in which a patient from whom both breasts had been removed subsequently became pregnant and 'carried' to full term. During parturition there was an entire absence of labour ' pains '. In the discussion that followed this paper it was stated by other gynaecologists that they had attended patients from whom both breasts had been removed, but they had not observed any alteration from the normal course of events. Mammary inactivity. Absence of breasts and absence of secretory activity. — Removal of the breasts has been practised for eclampsia2, and the results were thought to be good. No explanation of this effect has been given, but it is possible that in these circumstances the calcium which would have been taken up by the secretory cells is retained in the maternal tissues. Amputation of both breasts, however, seems an unusually drastic method of securing this result. Absence of secretory activity after parturition has been mentioned already (p. 97). In saying " absence of secretory activity " I refer to the effect of some unknown derangement in the maternal metabolism responsible for this abnormal state of affairs. It is probable that the high calcium content which is found in the blood during normal lactation favours involution of the uterus, and that the absence of milk secretion not only interferes with normal involution, but is also associated with disturbances in the maternal metabolism. Superlacta- tion. Superlactation. — During lactation, menstruation is absent normally, at any rate for many months. When this obtains the mother is able to stand well the strain of suckling ; but if she nurse beyond the normal 1 Parke, W. E., Amer. Journ. ObsteL, 1914, vol. lxx, p. 606. 2 Cavagnis, G., Ann. di Obstet. and Gynecol., 1913, vol. ii, p. 563. FCETAL TOXINS 203 time — say, nine months — then her health is liable to Superiacta- be affected: she may suffer with headaches, lassitude, lon* and with menorrhagia and epimenorrhcea, or epi- menorrhagia1. Now, these symptoms are all produced by the with- drawal of calcium salts from the tissues for the purpose of milk -formation ; and the patient can be quickly cured if the child be weaned, and she herself take large doses of calcium lactate. The Placenta and Maternal Disorders The history of the scientific study of eclampsia may Foetal toxins be woven around the question of the effect of foetal eclampsia toxins on the mother. It goes without saying that Nature in the evolution of the mammals, in which the placenta gradually assumes an important position in regard to reproduction, has provided the mother with some means of meeting the demands on her metabolism of the growing foetus, and on her biological resistance to foreign substances in her blood. Even to-day it is impossible to enunciate the position in more definite terms than these. It may be stated here, as will have been obvious in what has gone before, that too readily has it been assumed that eclamptic convulsions resemble the spasms of tetany. There are many toxins that will cause con- vulsions unless they be neutralized; and it is certain that the convulsions of eclampsia are in some way due to poisons elaborated by the fcetal tissues. But it must not be forgotten that there are two sides to this question — the fcetal and the maternal. It is probable that the fcetal tissues, through the medium of the placenta, eliminate substances which are always taken into the maternal circulation, but with which the mother is able successfully to deal, provided her protective processes are normal. 1 * Epimenorrhcea', ■ epimenorrhagia ' : terms coined by the author to indicate too frequent, and too profuse menstruation. (See ' The Disorders of Function ', in The New System of Gynaecology, 1917.) 204 THE SEX-COMPLEX Foetal toxins In 1911 Dold1 showed that saline extracts of many eclampsia, viscera contain a toxin, lethal to animals, which is completely neutralized by normal blood-serum. To this toxin he gave the name of ' organgift \ The nature of the substance has not been satisfactorily determined. Obata2, following the investigations of Dold, has recently made an important contribution to the subject. This investigator has found that when an extract of fresh human placenta is injected into mice symptoms resembling those of eclampsia are produced, and that there is no difference between the effect produced by the extract of placenta from a normal case and the extract of the placenta from a case of eclampsia. Further, Obata observed that fresh serum from the blood, either of a normal person or of an eclamptic patient, produces similar symptoms in mice; but no increase in the toxicity was noted in regard to the serum of eclamptic patients. When, however, the extract of a placenta is mixed with the serum from a normal person — and it was found that sex and pregnancy did not effect the issue — the toxic effects of the placental extract, and also apparently of the serum, were neutralized; but, on the other hand, the serum from the blood of an eclamptic patient failed to neutralize the toxin of the placenta. It appears, therefore, that there is some substance in normal blood that neutralizes the toxins of the placenta, and it seems curious that this is present in the blood of males as well as females, until we remember that the foetus is the product of the male no less than of the female. With these facts in mind, I was confronted with the prospect of losing a patient who was suffering with severe eclamptic convulsions and in labour. I delivered her without difficulty of full-term still-born twins. I 1 Dold, H., Zeitsch. f. Immunol, u. Exper. Therap., 1911, vol. x, p. 53. 2 Obata, I., Journ. Immunol., 1919, vol. iv, p. 111. FCETAL TOXINS 205 hoped her condition would then improve. The con- Treatment of vulsions, however, continued, and only two ounces of wiod-trans-7 albumen-laden urine were obtained by catheter during fusion eighteen hours subsequent to her admission. Later, I received a message informing me that she appeared to be dying. When I saw her a few hours afterwards she was lying semi-comatose, was jaundiced and had a pulse that was hardly perceptible at the wrist. I immediately suggested to her husband, a robust-looking man, that I would like to transfuse his wife with his blood. He readily consented. So, after we had found out that he belonged to group iv, we proceeded to transfuse the patient with approximately 500 c.cm. of his blood citrated. The response was almost immediate, and within a few hours the patient saw, and spoke to her husband. In the sixteen hours subsequently to the transfusion the patient passed 50 ounces of urine, and 71 ounces in the next twenty-four hours. In this case the blood was transfused, in order that an antitoxin might be introduced into the blood-stream of the patient to neutralize the toxins from the placenta. I have no hesitation in suggesting that this may be the proper treatment for all severe cases of eclampsia. It is probable that a more immediate and lasting effect will be obtained with blood-transfusion after the patient has been completely delivered ; but if delivery has not taken place, it may be advisable to transfuse before parturition, and, if necessary, after the uterus has been emptied. Indeed, if the transfusion be effected im- mediately the eclamptic symptoms are observed, it is possible that the life of the child may also be saved.1 1 Bell, W. Blair, Brit. Med. Journ., 1920, vol. i, p. 625. SEXUAL AND REPRODUCTIVE PSYCHOSES AND NEUROSES1 Psychoses in I have emphasized repeatedly in the foregoing pages tWenital and elsewhere2, that the mind is influenced by the functions. metabolism, and therefore by the condition of the organs of internal secretion ; and I have already described what I believe to be the normal attitude of mind in Woman. These views — no doubt old enough so far as the general principle is concerned — are now being endorsed by alienists who are becoming alive to the fact that insanity may actually depend on the state of the internal secre- tions— a fact to which hitherto they have been blind. 1 It should be evident — apparently it has not been, judging by the complaints of certain critics with regard to the brevity of, and omissions from, this section — that I am not dealing with the relation- ship between the internal secretions and mental derangements generally, although I have indicated the connexion between the two, but that I am only concerned here with the dependence of certain abnormal psychical states on the reproductive functions and the metabolism. Those who wish to make a more complete study of the more general aspects of the relationship between insanity and the internal secretions, should study the work of Mott and his fellow-investigators : {Proc. Roy. Soc. Med., 1913, vol. vi, p. 75; idem, 1915, vol. viii, pp. 1, 21, 58; idem, 1917, vol. x, pp. 65, 88), and the contributions of T. A. Williams (Internal. Clin. Philadelph., 1916, voL ii, p. 173) ; H. A. Cotton, E. P. Corson- White and W. W. Stevenson (Journ. Nerv. and Ment. Die., Lancaster, 1917, vol. xlv, p. 144); C. P. McCord and H. A. Haynes (New York Med. Journ., 1917, vol. cv, p. 583) ; N. C. Borberg (Bibliotek. f. Laeger, Copenh., 1918, vol. ex, pp. 45, 126, 187, 231, 338), which will repay careful perusal. 2 Bell, W. Blair, Arris and Gale Lectures, Lancet, vol. i, pp. 809, 937; Proc. Roy. Soc. Med. (Obstet. and Gynacol. Sect.), 1913, vol, vii, p. 47. SEXUAL PSYCHOSES AND NEUROSES 207 Mott1 has expressed his belief in the important Psychoses in part played by the internal secretions in insanity ; ^genital but the arguments set forth by him do not break functions. any new ground. This writer states : " It must have struck everybody that has to do with insanity that there are two periods of life when its onset specially occurs — namely, early adolescence and the involutional period ". The recognition of these facts is not new, for. a similar statement was made many years ago by Wynn Westcott2. This observer — a well-known coroner — said that out of over 200 inquests on female suicides " the majority of these women had killed themselves about the change of life, and of the younger women the majority appeared to have been menstruating at the time of suicide ". We must now consider the nature of the stimuli con- cerned, and the abnormal effects they may produce. In normal circumstances puberty supervenes in stimuli about the fourteenth year, but, as already described, sexual8 with certain disturbances of the hormonopoietic system psychoses and * , J neuroses. puberty may be precocious. Now, in precocious puberty we have a phenomenon which gives us a clear indication of the effects of abnormal sex-development, and of the causes which later in life may produce excessive sexu- ality ; for in girls precocity is induced by ovarian hyper- plasia or neoplasia. This is important, for it proves conclusively that when excessive sexuality, amounting perhaps to sexual insanity, exists in women we must look for an excessive ovarian secretion as the primary cause of the condition ; and contrariwise we find that deficient ovarian secretion may lead to melancholia, probably indirectly. A brief description of the sexual and reproductive psychoses and neuroses dependent on derangements of the internal secretions, which may be found in women, must now be given ; I shall not attempt, i Mott, F. W., Proc. Roy. Soc. Med. (Sect PaychiaU), 1915, vol. viii, p. 1. 2 Westcott, Wynn W., Brit. Med. Journ., 1900, vol. ii, p. 792. 208 THE SEX-COMPLEX Stimuli however, to classify these alienations on a psycho- sexual8 logical basis, but, rather, from a physical point of psychoses and view. neuroses. , In describing the reproductive psychoses and neuroses we might classify our subject according to the period of reproductive life during which such disturb- ances may arise ; but such a classification would lead to much repetition. It will be better, therefore, briefly to consider the mental and nervous disturbances with regard to the actual cause to which they are due — that is to say, to excessive ovarian secretion, to deficient ovarian secretion, and to the metabolic dis- turbances associated with menstruation, gestation and lactation respectively. I shall make no attempt to describe in detail the performances and mentalizations associated with the psychical disorders under discussion ; I shall merely give an indication of the mental tendency. Meanwhile, it must not be forgotten that specific mental diseases may themselves affect the genital functions — an aspect of the subject, about which we know practically nothing, except in a general way. In the consideration of all questions concerning psychical derangements it must be remembered that a neuropathic history is an important factor both in regard to the onset of the derangement, to the gravity of the mental disturbance, and to the prognosis. Neuropathic history im- portant. Excessive ovarian during precocious puberty. Excessive Ovarian Secretion. — Psychoses and secTeUon pro- ^euroses commonly arise at puberty, even when this supervenes at the normal time ; consequently it may be assumed in those instances in which we find these dis- orders commencing at this epoch that in some way the awakening of the genital functions is accountable for them. Since we have no other way of expressing it, we must say that for the girl so affected the ovarian secretion is the exciting cause : there is excessive stimulation by the hormone of the genital glands, which leads to some derangement of the nervous system. SEXUAL PSYCHOSES AND NEUROSES 209 The neuroses occurring at puberty may be sensory, Neuroses of motor or visceral. These have been fully investigated Puberty« by physicians, and a clear account is given by Osier1, which should be studied by those interested in the subject. Here it will be sufficient to recall the chief manifestations. The sensory disturbances are represented by various forms of anaesthesia or hyperesthesia. There may also be derangement or impairment of the special senses of taste, smell, vision and hearing, giving rise to unpleasant tastes and smells, to photophobia, or to continuous noises. Derangement of the motor nerves is seen in chorea. True chorea occurs very much more frequently in girls (70 per cent.) than in boys. At the same time it is not a disease which is more than incidentally connected with puberty. The psychical element in true chorea is very marked, although often overlooked ; and, whatever the usual idea of the etiology may be, there is no doubt fear or fright is frequently a causal factor in the onset. So it comes about that the disease is common during the period of nervous tension which may be found at puberty in girls of a neuropathic temperament. False chorea, or 1 habit spasm ', is, likewise, most frequently seen in girls from ten to fourteen years of age. Twitchings of the face or limbs are the commonest movements. These habits tend to disappear as the girl grows up and her nervous system becomes less irritable. Again functional paralyses are sometimes observed at puberty. They may be paraplegic, hemiplegic, or monoplegic; indeed, any known form of organic paralysis may be simulated. Contractures and spasms occur in hysterical patients, but not so frequently at puberty as at the menopause. Visceral manifestations are seen in regard to the respiratory mechanism, which may be altered in rhythm, or there may be a 'catching' during inspiration. Occasionally, there is a spasmodic cough Alimentary 1 Osier, W., The Principles and Practice of Medicine, 1916. 14, 210 THE SEX-COMPLEX Neuroses of puberty. Sexual psychoses first evident at puberty. disturbances, such as a depraved appetite, are not un- common. Sometimes there is incessant regurgitation of food, or there may be difficulty in swallowing. Diarrhoea or extreme constipation may be seen. Cardiovascular derangements are very common: flushing of the skin, palpitation and rapid alterations of the pulse-rate are most frequently observed. When excessive ovarian secretion occurs early in life puberty may supervene precociously ; and in these cir- cumstances with the development of the adult physical phenomena a mental change occurs which often produces sexuality greatly in excess of the normal. This mental disturbance is abnormal for two reasons : first, the stimulus from the ovaries to the brain is far stronger than that normally occurring at puberty ; and, second, the mind of the child is taken by surprise, as it were, before it has been educated slowly to self- restraint and decent conduct. Such children may be sexually insane, and indulge in masturbation and any other form of gratification which presents itself to them. Apart from precocious puberty there may be an excessive ovarian secretion not only at normal puberty, but also throughout the sexual life of the individual. We know how much more coquettish some girls are than others ; we know, also, how much more lax in their morals many women are than others, and how some women cannot obtain sufficient satisfaction from one man. It may be said that excessive sexuality always commences at puberty, whether the condition amount to actual insanity or merely to excessive stimulation of the sexual instincts, which are normally kept within reasonable bounds ; indeed, we may say that the border line between sexual insanity and excessive sexual desire is merely a question of whether there be shamelessness in sexual conduct or not. Let me illus- trate this statement by two examples which have come under my own notice. In the first, a young lady at puberty developed habits SEXUAL PSYCHOSES AND NEUROSES 211 of masturbation ; shortly afterwards she began to entice Case of sexual men to gratify her desires ; she kept a diary in which ln8anlty- her thoughts and feelings were described ; and the climax came when she took to dropping notes in the road asking men to meet her — evidently in order that she might induce them to satisfy her cravings. She had no self-respect, no sense of decency or shame — the world was blotted out of her consciousness when the over- whelming stimulus of her ovarian secretion flooded her mind ; and she had no remorse, but, rather, took a pride and pleasure in the methods adopted to consummate her desire. In the other case, a married lady, a little over thirty Case of years of age, who had several beautiful children, told me sexual*™ that she was never able to resist the advances of men desire, she liked, and that she had indulged in immoral relations with three different men in one year. This patient recognized the error of her ways, and was full of remorse after each adventure ; nevertheless, the sexual stimuli were so great that until they were exhausted her sense of right and wrong was completely obliterated. It is certain that in the first case the patient, judged by any standard, was insane ; while in the second the woman was merely intemperate from a social and moral standpoint. In both cases the stimuli consisted of the internal secretions of the ovaries ; but in the former there was constant mental instability as well, while in the latter there was temporary mental aberration in the face of a stimulus temporarily stronger than those directing her will. Excessive ovarian secretion in women may lead to Excessive masturbation or to habits associated with sexual in- tion causing version. It is probable that if with the onset of puberty ^ads^ersion. marriage took place in European countries, as it does in some Eastern countries, such indulgences would not be practised by educated women. Once, however, these habits have become established, even matrimony may fail to provide a satisfactory substitute, although, fortunately perhaps, it may sometimes do so. 212 THE SEX-COMPLEX Ovarian in- sufficiency. Primary ovarian in- sufficiency. Ovarian Insufficiency. — Before attempting to assign to ovarian insufficiency the causation of mental aberra- tions, we must decide whether the ovarian lesion itself be primary or secondary. Yet some recent writers, as we shall see later, have assumed, because atrophy of the gonads has been found in association with insanity, that the mental condition is the result of the genital lesion. Moreover, it is not always an easy matter to apportion the blame to this organ of internal secretion, or to that ; for, as we have seen, lesions of one hormono- poietic gland are usually associated with changes in the other members of the cryptorrhceic system. How- ever, when secondary lesions are found, and are definitely ascribable to pre-existing primary changes in the ovaries then, of course, we can safely look upon ovarian in- sufficiency as the primary cause in a complicated sequence of events. In this way we narrow our field of inquiry, for in the human subject the only condition which can without doubt be ascribed to ovarian in- sufficiency is the menopause, natural or traumatic. Primary ovarian insufficiency, — It is extremely doubtful whether primary ovarian insufficiency is ever congenital. Apparently congenital ovarian insufficiency may be seen, but in such circumstances we have no evidence to show that the lesion is primarily genital ; it is probably an epiphenomenon. Apart from the actual menopause — artificial or natural — the evidence that atrophy of the ovaries is the primary cause of insanity is most unsatisfactory, as we shall see later when considering the effect of insanity on the genital organs. I believe it may be taken as an axiom that when ovarian insufficiency gives rise to mental disturbances there has previously been normal activity in these organs. Atrophy of previously normal ovaries does not occur as a primary lesion during the reproductive period. This cannot be too forcibly emphasized. In a large experience in gynaecology I have never seen such a thing. There are many conditions to which atrophy SEXUAL PSYCHOSES AND NEUROSES 213 may be secondary, but — unless there be mental disease Primary associated with such lesions, and, of course, apart from guffid^ncy" primary menopausal atrophy — no positive mental dis- turbances are ever seen. Negative mental anomalies, such as aversion from sexual intercourse and child- bearing, are, however, not uncommon — the stimulus from the ovaries, which normally excites reproductive instincts, is absent. At the menopause there is a more or less severe Menopausal disturbance of the metabolism dependent chiefly on the Psychoses- degree of activity that previously existed in the ovaries. Many sexually apathetic women — that is, women with not very active ovaries — pass through the menopausal period with very little disturbance ; while women who have been sexually active often have the ' change of life ' late, and suffer from violent derangements of the metabolism. These sexually active women may at this period of life be subject to increased and almost in- satiable sexual desire — probably due to the irregular output of the ovarian stimuli. The ' change of life' is anticipated by a majority of women with fear. In the first place they look upon this period as synchronous with the disappearance of their feminine attractions : youth, beauty and charm, and all that makes them desirable to men. We need not here discuss how far this may be true ; it is sufficient to know that this idea presents itself to most women as the time draws near. With an artificial or sudden natural menopause the patient, if she were previously sexually active, may suffer with melancholia : the rapid removal of the ovarian secretion, which previously moulded her tem- perament, and directed her pursuits and pleasures, involves the loss of the guiding force of her existence ; consequently depression, if ynot melancholia, may supervene. Moreover, many women are under the impression that insanity is a frequent concomitant of the meno- pause. This idea naturally tends to disturb the patient, 214 THE SEX-COMPLEX Menopausal psychoses. Changes in the nervous system in hypo- thyroidism. Menopausal neuroses. but in most cases all that is necessary is the assurance that such fears are unfounded. Nevertheless, we occasionally see a complete mental change ; the patient becomes melancholic and suspicious. As a rule, careful management and suggestion will tide over the period of uncertainty. If, however, a woman have a strong psychopathic tendency she may become insane. Melan- cholia, with ideas of persecution, is the most common form of mental derangement. I have for many years treated all cases of mental depression with thyroid extract, alone or in combination with ovarian extract, and have found it most beneficial ; ovarian extract alone is useless. This indicates, appar- ently, that when the ovarian secretions are withdrawn the thyroid also atrophies, and the loss of thyroiodin leads to mental lethargy and physical adiposity. In connexion with this question of hypothyroidism, the interesting work of Mott1 and of Brun and Mott2, must be mentioned. These investigators have found that in cases of myxcedema the nerve-cells in the nervous system show general chromatolysis of a subacute character. The changes appear to affect the nuclei of the ninth and tenth nerves, the cerebrospinal motor neurons, and the sympathetic system. Local neuroses are not uncommon. Neuralgias, functional paralyses and contractures, hyperesthesias and sleeplessness may occur, and are sometimes most difficult to alleviate. Massage and autosuggestion are probably the most useful methods of treatment in severe cases. Sedatives and alcohol should be avoided. General specific treatment of the nervous disorders of the menopause is impossible until we are aware of the exact etiological factors concerned. Bromides have been extensively prescribed, but in my opinion they are almost valueless, if not actually harmful. 1 Mott, F. W., Congres Internat. deMed., 1907, Sect, vii, fasc. i,p. 111. 2 Brun, R., and F. W. Mott, Proc. Roy. Soc, Med. (Sect. Psychiat.), 1913, vol. vi^p. 75. SEXUAL PSYCHOSES AND NEUROSES 215 Careful attention to the state of the bowels ; as Menopausal much fresh air and exercise as possible, with moderate occupation and company are essential. Tonics together with thyroid extract, or thyroid and ovarian extracts combined, with the relief of special symptoms, will assist us in the majority of cases to tide the patient over the period of stress, until such time as a natural readjust- ment of her metabolism shall have occurred. Secondary ovarian insufficiency. — There is another Secondary aspect of diminished ovarian secretion in relation to 8UfficienCy. the mentality of the individual that requires brief mention here in order to complete the picture — I refer to the ovarian insufficiency seen in association with masculinity or reduced femininity in women. It has already been stated (p. 212) that except in the presence of outspoken insanity, in association with which ovarian atrophy is a secondary lesion, no marked mental change is found as the result of the genital retrogression. But in the circumstances now mentioned the secondary ovarian atrophy is an essential part of the phenomenon — the losing of femininity and the assumption of masculinity. When any of the masculinity-producing internal The ,. -. , ii . • • j_i_ assumption secretions become abnormally active m women the o{ maScuiine ovarian secretions are antagonized or inhibited, partly ?^*cter" or completely, and the metabolism is directed towards the necessities of masculinity. In such circumstances, with the development of the physical changes towards masculinity, the mind becomes less feminine in its outlook. Cases of so-called * true hermaphroditism ' are, as we have seen, rare ; but there is little doubt that women with a larger share of masculinity than is normal are extremely common. These unnatural individuals are easily detected by the coarseness of their skins, by the size of their extremities, by the ill-development of the breasts, and by the assertiveness and aggressiveness of their conversation and schemes. No doubt many of them have hyperplasia of the suprarenal cortices or of the pituitary ; and atrophy of the ovaries, when it exists, is 216 THE SEX-COMPLEX character istics. The secondary to the primary changes in the other organs otm^uiSe °* internal secretion which are responsible for the development of masculinity. In this connexion, I have been interested to hear from Professor Wood Jones that he has observed that many female lunatics are endowed with certain mas- culine secondary characteristics. Disturbances associated with men- struation. Menstrual psychoses. Disturbances associated with Menstruation. — Apart from the direct effects, to which reference has just been made, of excessive or insufficient ovarian secretion, we must take into account the metabolic disturbances during menstruation, which may be so extensive as to affect the mind of the patient. Exactly what the anomalies are we do not always know, but it is probable that mental disturbances of an active or hysterical nature are due in part to an excessive excretion of calcium salts. And there may sometimes be a recognizable disturbance of the internal secretory system, especially in connexion with thyroid. In addition to the effects primary mental diseases may have on menstruation, which will be mentioned directly, it is well recognized that various mental derangements may occur both as the result of disturbances of menstruation and in association with the otherwise apparently normal catamenia. Before attempting to specify the various conditions observed I must again emphasize the fact that both the manifestations and the prognosis are worse in a person who has a neuropathic family history ; indeed, it is generally difficult in these circumstances to say whether menstruation or some special disorder of this function is the cause of the condition, or whether it has only precipitated the attack or aggravated the mental instability of the patient, in the same way as an attack of true epilepsy may be excited. Neverthe- less, it appears probable that certain psychoses may be initiated as well as aggravated by menstruation or some disorder of this function. SEXUAL PSYCHOSES AND NEUROSES 217 In a consideration of the subject it is advisable, as Menstrual indicated above, not to limit too closely our discussion psyc 08es* to psychoses which occur only during menstruation (the ' psychosis menstrualis ' of Krafft-Ebing), but also to include those which may be supposed to depend on some disturbance of this function, such as amenorrhcea. Many authors include in the term * menstrual psychosis ' the mental derangements seen at puberty and the meno- pause : such a classification is given by Konig1. But it appears simpler to discuss the epochal psychoses under the description of disorders of puberty and the meno- pause, and to confine the term ' menstrual psychosis ' to mental disturbance dependent on the cyclical occur- rence of menstruation or some anomaly of it. It is, nevertheless, obvious that some psychoses of puberty are exactly the same as those seen later in life, puberty having been merely the starting-point of the exciting cause — menstruation, Psvchoses occurring during menstruation are prob- Psychoses as- , , ■. • *. t f . sociated with ably very common, and may, as pointed out by apparently Konig1, occur regularly at each menstrual period, or g^SSon?en" only occasionally. Further, the seriousness of the psychosis varies from a very slight alteration in tem- perament to serious mental irresponsibility. The subject, considering its importance, is one that has been greatly neglected by gynaecologists, and it has been left to sexual psychologists to present the subject in a somewhat unattractive form. It appears strange that women should not definitely be freed from the psychical stigma of menstruation, or be forced to accept the fact that menstruation may produce mental disturbances which render them unfitted for those strenuous masculine occupations which require well-balanced mental judgments. Many women, of course, are unaffected mentally by the occurrence of menstruation ; many are affected in a minor, and some in major degree. From a social and medicolegal point of view the matter is of considerable importance. In 1 Konig, H., Berl. Klin. Woch.% 1912 vol hrix, p. 1645. 218 THE SEX-COMPLEX Psychoses as- the present day, when women are claiming so much for apparently1 themselves, it is very difficult to get at the truth of normal men- matters, for women engaged in scientific pursuits spend much of their time trying to convince the public that the psychical and physical economies of their sex differ not at all from those of men. Statistics are produced to prove this contention ; but in all these statistics the ready acceptance of the patient's statement is note- worthy, yet we know how unreliable are personal con- fessions when the mental condition is challenged. It is difficult, however, to discuss the matter in general terms, so I shall proceed to the particular. The minor degrees of psychical disturbance are seen in mental depression, vacillation or timidity. What is often ascribed to carelessness in breaking crockery or forgetfulness of orders in servants may be due to inattention brought about by menstruation; and with this inattention are associated mental irritability, dull- ness of perception and imperfect judgments, phenomena which are often accompanied by a feeling of physical exhaustion. The rarer major psychoses may be represented by temporary insanities, of which Konig * states the com- moner forms are the maniacal, the melancholic and the hallucinatory. More frequently the patient suffers either with severe mental depression or with kleptomania. Sometimes a patient may be a kleptomaniac without showing any other definite psychical disturbance. The etiology of menstrual psychoses of a cyclical nature is imperfectly understood. There is no doubt, of course, that they are due either to temporarily dis- ordered metabolism or to the circulation of what may be called 'toxins' in the blood. But these are very general terms. In view of the influence of the crypto- rrhceic organs on the psychical condition of everyone, normal and abnormal, it is not improbable that disturb- ances in the thyroid and other organs of internal secretion may play a large part in causation. Indeed, 1 Konig, H., Berl. Klin. Woch., 1912, vol. lxix, p. 1645. SEXUAL PSYCHOSES AND NEUROSES 219 in cases of great mental depression during menstrua- Psychoses as- tion I have usually found thyroid extract to be most apparently1^ beneficial. normal men- The medicolegal point of view, especially in regard to kleptomania, is of great importance — on the one hand, lest an irresponsible person be unjustly punished, and, on the other, lest advantage may be taken of the difficulty in denning the extent of the influence of menstruation. No harm would accrue from treating women accused of criminal acts committed at this time in the same way as those of tender age are treated when detected breaking the law. An interesting discussion on this subject took place at the Annual Meeting of the British Medical Association in 1900. Among other important statements was that of Wynn Westcott1, to which reference has already been made (p. 207). A careful investigation — biochemical and physical — should be made of every case in an endeavour to dis- cover evidence which will suggest lines of treatment. The relation of menstrual disorders to psychoses has Psychoses as- been discussed by a joint meeting of the Gynaeco- menstrua™ logical and Psychiatrical Sections of the Royal Society disorders. of Medicine2. Ewart, opening the discussion from the psychological point of view, favoured the existence of true amenorrhceal insanity; but the general opinion, expressed both by gynaecologists and by alienists, was that amenorrhcea is a concomitant of insanity rather than a causal factor in the disease. So, too, it may be said that while dysmenorrhcea and menorrhagia aggravate mental disturbances there is no evidence that they initiate them. It has been found that when the mental derangement is accentuated by menstrual dis- orders the patient has a definite psychopathic family history in about 82 per cent, of all cases. 1 Westcott, W. Wynn, Brit. Med. Journ., 1900, vol. ii, p. 792. 2 Ewart, C. T., and others, Proc. Roy. Soc. Med. (Obstet. and Gyncecol. Sect.), 1911, vol. v, p. 81. neuroses. 220 THE SEX-COMPLEX Menstrual There is little doubt that apparently normal menstrua- tion may give rise to neuroses ; but, as a rule, it is some dis- order of menstruation, especially dysmenorrhcea, which causes what are known as ' functional ' disturbances. When normal menstruation causes a neurosis, it is my experience that the neuropathic condition is cyclical and only exists in relation to menstruation, and that it is usually most acute just before and for the first two days of the flow. The disturbances most commonly seen are neuralgias in the face and limbs, headaches, giddiness and muscular weakness. Generally, there is some slight psychopathic condition associated with these symptoms. With dysmenorrhcea the general pains and muscular weakness may be very great. Menorrhagia may give rise to headaches and occasionally to neuralgias ; fre- quently, however, especially when the patient rests during the period, there may be none of these symptoms, but only great lassitude. This often leads to invalidism, especially in young girls who are petted and spoilt when suffering with menorrhagia at puberty. Amenorrhcea itself probably does not give rise to neuroses, although the condition causing the amenorrhcea may do so. The etiology of these functional lesions appears to be twofold. Those which occur during apparently normal menstruation, or are associated with dys- menorrhcea, are probably metabolic or < toxic ' in origin, while those which are produced by menorrhagia are due to the effect on the system of the excessive losses of blood. The treatment of cases associated with dysmenorrhcea and menorrhagia consists of the cure of the menstrual disorder. When the neurosis accompanies normal menstruation the management of it is more difficult. A careful examination of each case should be carried out — not infrequently the metabolism of calcium and nitrogen is found to be deranged — and the treatment based on scientific grounds. neuroses. SEXUAL PSYCHOSES AND NEUROSES 221 Hysterepilepsy is a pathological entity and occurs Menstrual only in association with the menstrual function. It must, however, be pointed out that practically all female epileptics suffer with more fits during men- struation than during the interval ; indeed, the fits during the menstrual week may greatly exceed in number those occurring during the other three weeks in the month1. As I shall show directly, this periodic increase in the frequency of true epileptic seizures is in all probability due to the same causes as those which lead to hysterepilepsy. This disorder is seen both in those who otherwise menstruate normally, and in those who cannot men- struate owing to the absence or . malformation of the uterus, yet have active ovaries. Probably the worst cases are those in which there is no menstruation. In some the epileptiform seizures recur with great regu- larity and severity, and, in consequence, the mind and health of the individual may be seriously impaired. When the attacks occur with menstruation they are as a rule of a minor character, and may resemble petit mal. Some years ago I observed two cases carefully, and found that in the interval the patients had a low calcium index in the blood, and that the sudden further drop, which always occurs at the onset of menstruation, reduced the blood calcium index to such a low level (0*2 in one case) that epileptiform seizures resulted. I also found that these cases could be successfully treated by the administration of calcium salts 2. Ringer,3 many years previously, had proved that calcium salts reduce muscular excitability. Since my work was published Voetglin and Mac- Callum4 have shown that the convulsive seizures 1 Litteljohn, A. R., Lancet, 1909, vol. i, p. 1382. 2 Bell, W. Blair, Proc. Roy. Soc. Med. (Obstet. and Oyncecol. Sect.), 1908, vol. i, p. 291. 3 Ringer, S., Journ. Physiol, 1884, vol. v, p. 247 ; and 1887, vol. viii, p. 20. 4 Voetglin, C, and W. G. MacCalluni, Journ. Pharmacol. andExper. Therap., 1911, vol. ii, p. 421. 222 THE SEX-COMPLEX Menstrual following thyroid-parathyroidectomy can be controlled by the intravenous infusion of calcium salts. Litteljohn1, of the Hanwell Asylum, also, has found that fits of true epileptics, which occur in female patients so much more frequently during menstruation, can be checked to an astonishing degree by the administration of calcium compounds. Since my original observations I have treated successfully with calcium salts many other cases. When, however, there is no menstruation owing to the absence or underdevelopment of the uterus, the condition is precipitated solely by cyclical ovarian activity. If the uterus be slightly undeveloped, and the patient be under 18 years of age, as in a case under my care recently, an attempt should be made to find the cause of the underdevelopment and to treat the case accordingly. Often it will be found that hypo- thyroidism is the primary cause of the underdevelopment of the uterus. When the uterus is absent or rudimentary, probably the best treatment may be to remove all but a small portion of one ovary. Lockyer2 successfully treated one patient, whose condition was serious, by the complete removal of both ovaries. Reproductive Disturbances associated with gestation, the puerperium and lactation. — During pregnancy the mental attitude rarely undergoes profound alterations, but in nearly all cases it is normally affected to some slight extent. How far this is due to fcetal hormones, and how far to changes in the metabolism it is somewhat difficult to estimate. Apparently, the normal mental change is towards quietness and resigna- tion, and if this be exceeded melancholia may supervene. Extract of the thyroid gland is most beneficial in these circumstances, hence it may be presumed that normally this organ is taxed to the fullest extent, and that some- times it may partly fail in the supply of its internal secretion. 1 Litteljohn, A. R., Lancet, 1909, vol. i, p. 1382. 2 Lockyer, C, Trans. Obstet. Soc, 1906, vol. xlviii, p. 75. insanity. SEXUAL PSYCHOSES AND NEUROSES 223 In those very rare cases in which the patient is Reproductive hysterical and excitable, or becomes insane, it appears inBanity* probable that the cause emanates from the foetus, and is of the nature of a toxaemia. Whitridge Williams1 records a case in which the patient, during the later months of pregnancy, suffered with delusions of persecution. A large amount of albumen was found in the urine, associated with a diminished excretion of urea. Under treatment the patient entirely recovered, only to relapse if treatment were suspended. Complete recovery followed par- turition. During the puerperium insanity is more common Puerperal and the patient then usually suffers with delusions m8amfcy* and hallucinations, especially of hearing2. The onset is marked by insomnia and headache. The patient then rapidly passes from a state of restlessness and excitability to a condition of acute mania. Sexual excitement and shamelessness, religious exaltation and blasphemy, are usually prominent ; and sometimes there is special aversion from the husband and child. It appears as though the accumulation of sexual and gestational stimuli, instead of reaching an harmonious finale, end in a discordant clash. It is probable that in most of these cases — as, indeed, in all forms of in- sanity— there is a bad neuropathic family history, and, further, that the insanity is produced by exhaustion or sepsis (toxaemia) subsequently to labour, which probably involves the organs of internal secretion. The insanity seen at a later period during lacta- tion is no doubt partly caused by the drain on the maternal resources brought about indirectly by lactation, rather than by the direct influence of the hormonopoietic organs. 1 Williams, J. Whitridge, Obstetrics, 4th ed., 1919. 2 Jones, R., Journ. Obstet. and Qyncecol. Brit. Emp., 1905, vol. iii, p. 109. 224 THE SEX-COMPLEX functions. influence of The influence of psychoses on the genital tnTge™ttai°n functions. — Psychoses may arise quite independently of the genital functions, and, nevertheless, be associated with anomalies of those functions. Thus, it is quite common to see amenorrhcea in association with insanities ■ — indeed, some alienists describe an ' amenorrhceal in- sanity'1; but most observers look upon the ameno- rrhcea as a concomitant phenomenon, and not as the cause of the mental derangement. That atrophy of the ovary is the causal factor in these cases is some- what disproved by the fact that recovery frequently takes place in regard both to the mental and menstrual disorders. Mott has laid stress on the fact that the ovaries are often found to be atrophic in cases of insanity, but, while this is undoubtedly true in some cases, it is unfortunate that this author selects for an example the case of a woman, who at the post-climacteric age of 57 years was found post mortem to have an " infantile uterus " and atrophic ovaries ! One would expect to find the ovaries atrophic and the uterus senile (not infantile) at this time of life, apart from gonorrhceal infections or hypothyroidism, which, also, were said to have existed. The sexual and reproductive history of this case, although of considerable importance, is not given. In 1917, after the first edition of this work had been published, two papers, which may be of some im- portance in regard to the condition of the sex-glands in insanity, appeared. The researches on which they were based had been conducted under the supervision of Mott. In the first, by the late Laura Forster2, which was published with an addendum by Mott, it is stated that there is a definite scarcity in the number of healthy Graafian follicles in the ovaries of women suffering with 1 Ewart, C. T., and others, Proc. Roy. Soc. Med. (Obstet. and Oynmcol. Sect.), 1911, vol. v, p. 81. 2 Forster, Laura, Proc. Roy. Soc, Med. {Sect. Psychiat.), 1917, vol. x, p. 65. Dementia prsecox and genital atrophy. SEXUAL PSYCHOSES AND NEUROSES 225 dementia praecox, imbecility, melancholia, mania and Dementia general paralysis before the menopause. The control genital * ovaries, however, taken from patients, some of whomafcrophy- died of long-standing diseases such as chronic nephritis, generally showed similar changes. Moreover, the method of investigation by counting ova in a few sections is open to serious objection. The second paper published at the same time, by Kojimaf, carries the matter no further, although the conclusion is reached that in dementia praecox in early adolescence " striking changes are seen in the sexual glands, i.e. very slight spermatogenesis in the testes, and an appearance of undergoing an early involution of ovaries ". Two cases, a male and a female, both of whom had died from bronchopneumonia, were examined. Three other cases in which chronic tuberculosis was present were rejected, presumably for reasons which will be evident directly. Kojima refers to several papers in which the authors respectively found lesions in practically all of the duct- less glands other than the gonads in dementia praecox. He mentions, also, details from a paper by Parhon and Ghiorghiani2, without giving the reference, which I have been unable to trace. It is stated that these investigators noted amenorrhcea in twenty-five out of thirty-five cases of dementia praecox. If ovarian atrophy were the cause of the condition, surely ameno- rrhcea would invariably have existed. On the evidence before us, it is impossible to arrive at any other conclusion than that genital under- development and retrogression are the result of, or an 1 Kojima, M., Proc. Roy. Soc. Med. {Sect. Psychiat.), 1917, vol. x. p. 88. 2 A reviewer of the first edition of this work in one of the journals, was disappointed that this paper was not mentioned. He therefore took up some space describing it. On being asked through the Editor for the reference, he stated he had only heard of the paper, and did not know the source. Such a breach of privilege and assumption of superior knowledge cannot be allowed to pass unnoticed. 15 226 THE SEX-COMPLEX Dementia prsecox and genital atrophy. Genital atrophy with tuber- culosis and other chronic diseases. Pituitary lesions in confusional insanity. epiphenomenon of, rather than the cause of dementia praecox. A further interesting series of communications has been published recently by Mott1. These relate to normal and morbid conditions of the testes, from birth to old age, in one hundred asylum and hospital cases. The fact that long-standing disease is associated with changes in the testes similar to those found in dementia praecox is again evident in this publication. Reference is made to the observations of Kyrle2, who has shown that in chronic diseases, especially in tuber- culosis, there is usually arrest of genital development. Tt must not be forgotten that very many cases of dementia prsecox, and of other types of insanity, die of tuberculosis. Further, Mott states that "a patient may suffer with the signs and symptoms of dementia praecox, and have normal testes". By way of explanation, he adds this footnote: "It may be mentioned that non- degenerative forms of dementia praecox are occasion- ally met with, and it is not always easy to diagnose dementia praecox in the early stages. Cases of con- fusional insanity may present a similarity in clinical symptoms to dementia praecox. As Re*gis points out, chronic confusional insanity may terminate in dementia". Williams3, indeed, relates a case of narcoleptic con- fusion in a boy, seventeen years of age, which was con- sidered to be related to some lesion in the pituitary, and in which there were symptoms of dementia praecox. The boy recovered completely after some years. Other cases of confusional insanity definitely due to pituitary lesions are described by this author. It must not be forgotten, that, as has been shown in the preceding pages, pituitary insufficiency is associated with genital hypoplasia. i Mott, F. W., Brit. Med. Journ., 1919, vol. ii, pp. 655, 698, 737. 2 Kyrle, J., Wien. Klin. Woch., 1910, vol. xxiii, p. 1583. 3 Williams, T. A., Internal. Clin. (Philadelp.), 1915, ser. 26, vol. ii, p. 178. SEXUAL PSYCHOSES AND NEUROSES 227 Religious manias may lead to ideas which fill the The influence patient with abhorrence of sexual intercourse, and in on the this way directly interfere with the genital functions. J20unc"ye There is, indeed, no doubt whatsoever that the mind influences function just as function influences the mind ; for example, it has been shown that fright leads to an immediate increase in the output of suprarenin1, and we know well from repeated clinical observations that hypothyroidism leads to mental depression. The whole question of the influence of the mind on the reproductive functions is in its details intricate and difficult, and it would be out of place in this small work to invade further the realms of psychiatry. 1 Cannon, W. B., and de la Paz, D., Amer. Journ. Physiol., 1911. vol. xxviii, p. 64 ; Journ. Amer. Med. Assoc, 1911, vol. lvi, p. 742. GENERAL INDEX Abortion following mammary extract injections, 98. » is oophorectomy, 30. Acetonuria after thyroidectomy during pregnancy, 52. Acidosis in eclampsia, 193. ,, „ pregnancy, 198. Acromegaly, 167, 169. „ administration of ovarian extract in, 197. ,, amenorrhoea with, 168, 197. „ calcium metabolism in, 197. ,, in males, 168. Addison's disease, 80, 169, 198. Adiposity at menopause, 174. ,, after oophorectomy, 36, 37. Adrenal glands, see Suprarenal glands. Alcohol, avoidance of, at menopause, 214. Amenorrhcea in acromegaly, 168, 197. ,, „ dementia precox, 225. ,, ,, diabetes, 200. ,, ,, Graves' disease, 189, 191. ,, ,, insanity, 219, 224. ,, during lactation, 90, 202. ,, neuroses with, 220. ,, with pituitary insufficiency, 195, 196. „ primary, 177, 178. ,, psychoses with, 217. ,, with suprarenal excess, 199. ,, ,, ,, neoplasms, 167. ,, „ thyroid enlargement, 189. , ,, ,, ,, insufficiency, 178, 186. ,, in tuberculosis, 178. Ammonia excretion, see Nitrogen metabolism. Anabolism, 7. Antepartum haemorrhage with thyroid excess, 191. Ateleiosis, 131, 177. ,, sexual, 158. 1 Atypical sexe-ensemble ', 135, 148. Bisexuality of the individual, 11, 13, 128, 134. ,, potential, of every fertilized ovum, 11. ,, of sex-cells, 9, 11. Blood, differences of, in the sexes, 15. Blood pressure, effects of infundibulin on, 72. ,, „ ,, ,, injection of suprarenal extracts on, 80. ,, ,, ,, ,, ovarian extract on, 48. , , , , , , , , thyroid extract on, 57, 173. Bromides, administration of, at menopause, 214. 280 GENERAL INDEX Caesarian section, psychological effect of, 111. Calcium blood content in lactation, 98. ,, deposits in suprarenals, 55. ,, in menstrual discharge, 35. ,, metabolism in acromegaly, 197. ,, ,, at different periods, 18. ,, ,, in eclampsia, 193. ,, ,, effect of administration of corpus lutem on, 36. ,, ,, ,, „ ,, „ ovarian substance on, 34. ,, ,, ,, „ menstruation on, 20. ,, ,, ,, ,, oophorectomy on, 33, 37. ,, ,, ,, ,, removal of suprarenal on, 76, 78. „ ,, w ,, thyroidectomy on, 52, 55. „ ,, - „ „ „ during pregnancy on, 53. „ ,, in general disease, 178. ,, ,, „ Graves' disease, 189, 191. ,, „ ,, hysterepilepsy, 221. < ,, ,, influence of hormonopoietic organs on, 19, 174. ,, ,, ,, „ infundibulin on, 174. „ „ „ lactation on, 19(3, 193, 202. ,, ,, ,, ,, ovarian excess on, 183. „ „ ,, „ ovaries on, 18, 61, 90, 119, 174, 191, 197, 199. ,, „ ,, ,, parathyroids on, 59, 60, 61, 185, 192, 193. ,, „ ,, „ pituitary on, 92, 167, 191, 197, 199. ,y „ „ pregnancy on, 121. ,, ,, ,, ,, suprarenals on, 191, 198, 199. ,, ,, ,, ,, suprarenin on, 174. „ „ „ ,, thymus on, 18, 84, 201. ,, ,, ,, ,, thyroid on, 119, 174, 191. ,, ,, involution of uterus and, 202. ,, „ after menopause, 175. ,, in menstrual neuroses, 220. „ „ relation of, to menopause, 20. ,, ,, ,, menstruation, 20, 35, 91. in osteomalacia, 193, 199. sex differences in, 166. and phosphorus metabolisms, relation between, 33. ,, salts, administration of, effect of, on growth, 36. ,, ,, „ in epilepsy, 222. „. ,, „ „ hysterepilepsy, 221. ,, ,, ,, ,, at menopause, 174. ,, ,, ,, », in menorrhagia, 189. ,, ,, ,, ,, ,, pregnancy with Graves' disease, 190. „ ,, ,, ,, ,, superlactation, 203. ,, ,, control of muscle excitability by, 61. ,, ,, deficiency of, in food, causing delayed puberty, 162. ,, ,, excessive excretion of, in menstruation, 216. ,, ,, influence of, on vasomotor stability, 119. ,, ,, pressor action of, 174. ,, ,, ,, ,, ,, on unstriped muscle, 99. ,, ,, prevention of tetany after parathyroidectomy by injec- tion of, 60. ,, ,, in uterine secretion, 102. Capsular epithelium, 145. Carbohydrate metabolism, hormonopoietic organs in relation to, 82. >> >» II J» it J) GENERAL INDEX 231 Carbohydrate metabolism, influence of pancreas on, 109. >> ,, ,, ,, pituitary on, 175. „ tolerance at menopause, 175. Cat, effects of oophorectomy on thyroid of, 38. „ „ „ thyroidectomy in, 51. Cervical sympathetic, effects of stimulation of, 173. • Change of life ', 213. Childhood, mental characteristics in, 111. ,, reproductive instincts in, 125. Children, desire for, a sexual instinct, 126, 127, 128. Chlorosis, delayed puberty with, 163. Chorea, 209. Chromaffin system, 173. Chromophil cells of pituitary, 43. Chromophobe cells, 39, 43, 65. Chromosomes, variation in numbers of, 8. Civilization and sexual subjection, 125. Colloid, parathyroid, 50, 59. ,, pituitary, 38, 39, 45. „ thyroid, 38, 39, 45, 187, 188. ,, „ formation of, after partial removal of anterior lobe of pituitary, 69. ,, ,, increase in, after compression of infundibular stalk, 71. ,, ,, ,", ,, ,, removal of posterior lobe of pituitary, 70. ,, ,, and pituitary, staining reactions of, 39. Complete tubular partial hermaphroditism, 149. Constipation, delayed puberty with, 163. Corpus luteum, 23, 53. ,, ,, administration of, effects of, 48, 49. „ ,, ,, ,, „ ,, on calcium metabolism, 36. ,, „ in cretinism, 158. ,, ,, influence of, on implantation of ovum, 24, 25, 26, 31. ,, ,, ,, ,, ,, lactation, 90, 91. ,, „ „ mammae, 96. ,, „ ,, „ ,, menstruation, 24. „ ,', „ „ ovulation, 24. „ „ pregnancy, 31, „ ,, internal secretion of, functions of, 23. ,, ,, lutein cells of , 22, 23. ,, ,, of marsupials, 25. ,, ,, ,, ornithorhynchus, 25. ,, ,, „ rodents, 27. ,, ,, significance of, 21. Cough, hysterical, at puberty, 209. Cretinism, 119, 132, 185. ,, absence of puberty in, 157. ,, ovaries in, 158. ,, uterus in, 158. Delayed puberty, 160. Dementia prsecox, amenorrhoea in, 225. ,, ,, genital atrophy in, 224. Development of genitalia, derangements of, 130. „ ,, ,, * functional ', derangements of, 153. ,, ,, „ incomplete, 159. „ ,, ,, pubescent, 17. ,, ,, ,, stages in primary, 131. 232 GENERAL INDEX Development of gonads, 145. Diabetes, amenorrhea in, 200. ,, impotence in, 200. ,, pancreatic, 199. Dimorphism of sex cells, 8. ,, in regard to sex characteristics, 112. ,, sexual, in protozoa, 6. Diuresis, administration of parathyroid causing, 62. Dysmenorrhcea, mental disturbances with, 219. „ neuroses with, 220. ,, in thyroid insufficiency, 186. Dysphagia, functional, at puberty, 210. Dystrophia adiposogenitalis, 66, 67, 68, 168, 177. ,, ,, treatment of, 196. ,, ,, tumours in sella turcica causing, 71. Eclampsia, acidosis in, 193. ,, blood transfusion in treatment of, 205. ,, foetal toxins in causation of, 203. ,, parathyroid insufficiency in, 193. ,, removal of mammae for, 202. ,, thyroid insufficiency in causation of, 52, 53, 187. Endometrium, extract of, physiological properties of, 101. ,, prevention of coagulation of menstrual blood by, 101. Environment, influence of, on puberty, 153. Epilepsy during menstruation, 216, 221. Epimenorrhagia in superlactation, 203. Epimenorrhcea in superlactation, 203. Epithelial nucleus, 145. Epoophoron, 146. Evolution and individuation, 114. ,, „ rejection of maternal functions, 117. ,, sex differentiation a process of, 113. ,, tendency of, towards separation of sexes, 128. ,, of Woman, results of, 126. Exercise, excessive, delayed puberty with, 163. Exophthalmic goitre, 188. (See, also, Thyroid excess.) ,, ,, after oophorectomy, 175. 1 External ' tubular partial hermaphroditism, 149. Femininity, dependent on all internal secretions, 4. „ sentiment ignored in discussion of, 1. Fertilization, determination of sex in relation to, 10. Flushings at puberty, 210. Foetal extract, effect of, on mammte, 95. ,, hormone in lactation, 94. Follicular epithelium of ovary, 22. ,, secretion of ovary, effects of, 48, 49. * Free martin ', etiology of, 150. Frog, sex determination in, 10. Galactagogue, infundibulin as, 72, 92, 93. ,, pineal as, 194. „ thymus extract as, 85, 94. , , See, also, Lactation. Genital atrophy in chronic disease, 226. ,, ,, after clamping stalk of pituitary, 67. ,, ,, ,, removal of anterior lobe of pituitary, 66. , , ducts, imperfections of, as atavisms, 134. GENERAL INDEX 233 Genital organs, development of, see Develojnnenb. ,, ,, effects of hormonopoietic organs on, 17- ,, ,, „ thymectomy on, 18. ,, h maldevelopments of, 130. tt ? j stages in primary development of, 131. Gestation, mental characteristics during, 111. Glandular partial hermaphroditism, 135, 137. Glycosuria, after continued administration of pituitary (pars post- erior), 73. ,, ,, thyroidectomy during pregnancy, 52. ,, in pancreatic insufficiency, 200. ,, ,, pituitary lesions of posterior lobe, 19C. i, ,, ,, „ (tumour irritation), 71. „ „ pregnancy, 198, 200. , , , , removal of pancreas, 81, 82. „ ,, stimulation of cervical sympathetic, 173. Gonads, effect of development of, on thymus, 84. ,, ,, on, of X-ray irradiation of thymus, 84. ,, in tubular partial hermaphroditism, 148, 151. Graafian follicles, 23. ,, ,, absence of, in ovarian inactivity, 133. ,, ,, in cretinism, 158. „ ,, effect of removal of anterior lobe of pituitary on, 68. „ „ scarcity of, in insanity, 224. „ ,, as organs of internal secretion, 54. ,, „ in ovarian grafts, 181. Granulosa cells of Graafian follicles, 54. Graves' disease, 188. (See, also, Thyroid excess.) Growth, effect of administration of anterior lobe of pituitary on, 72, 73. „ „ „ „ „ calcium salts on, 36. ,, „ „ ,, ,, pineal on, 64. ,, „ ,, „ „ thyroid on, 58. ,, ,, ,, oophorectomy on, 34. Habit spasm, 209. Headache with menstruation, 200. Heart, effects of pancreatic extracts on, 82. 1 Heat ' and * menstruation ' physiologically the same, 21. Hermaphroditism, 7, 13, 131, 134. ,, glandular partial, essential conditions in, 147. „ tubular partial, 136, 148. ,, „ „ etiology of, 150. ,, unilateral, 146. Hirsuties in pregnancy, 74. Hormones, definition of, 179. ,, influencing mammary glands, 87, 89. „ in relation to ovarian activity, 179. Hormonopoietic organs, changes in at menopause, 175. , ,, ,, correlated functions of, 3. ,, ,, defined, 102. ,, ,, differences of, in sexes, 13. ,, „ effect of compression of infundibular stalk on, 70. ,, ,, ,, ,, oophorectomy on, 37. „ ovarian grafts on, 47. ,, ,, ,, „ removal of posterior lobe of pituitary on, 70. ,, ,, ,, ,, thymectomy on, 85. ,, ,, ,, „ thyroidectomy on, 53. 234 GENERAL INDEX Hormonopoietic organs, effect of tumours in sella turcica on, 71. ,, „ functions of, different in different circum- stances, 19. ,, ,, genital functions of , 4. » ,, influence of, on calcium metabolism, 174. ,i ,, ,j ,,3, metabolism, 5, 107, 153. „ „ ,, „ „ mind, 161. ,, ,, „ ,, „ puberty, 17, 125. ,, ,, ., ,, ,, secondary sex characteristics, 89, 151. ,, ,, ,, „ ,, sex divergence, 12. ,3 >, 31 ,, ,, sexual precocity, 156. ,, ,} interrelation of, 212. 3, ,, lesions of, in general disease, 179. ,, ,, quantitative and qualitative differences of, in sexes, 112. M ,, sex differences in, 120. }j ,, in tubular partial hermaphroditism, 151. „ system, disorders of, effect of, on puberty, 153. Hyperesthesias at menopause, 214. Hyperemesis in pregnancy, suprarenin administration in, 198. Hyperthyroidism, 188. (See, also, Thyroid excess.) ,, caused by excessive doses of thyroid, 57. Hypohypophysism, thymus enlargement associated with, 69. Hypopituitarism, see Pituitary insufficiency. Hypothyroidism, 385. (See, also, Thyroid insufficiency.) ,, at menopause, 214. „ mental depression with, 227. „ thyroid administration in, 57. Hysterectomy, atrophy of ovary after, 180. Hysterepilepsy, 221. Hysteria at puberty, 209. Implantation of ovum, influence of corpus luteum on, 24, 25, 26, 31. Impotence in diabetes, 200. Incomplete puberty, 159. Individuation and evolution, 114. Infantilism, 158, 177. ,, after clamping stalk of pituitary, 67. ,, of genitalia, 17, 131. ,, pancreatic, 132, 158. , , after removal of pars anterior of pituitary, 66. Inf undibulin, administration of, in labour, 191. „ galactagogue action of, 72, 92, 93. „ influence of, on calcium metabolism, 174. ,, „ „ „ pancreas, 82. ,, physiological effects of, 72. ,, pressor qualities of, 43, 45. ,, replacing suprarenin in suprarenal insufficiency, 79. Insanity, amenorrhcea with, 219, 224. ,, confusional, pituitary lesions in, 226. , , dependent on internal secretions, 206. ,, during lactation, 223. , , at menopause, 213. „ during menstruation, 218. „ ovarian atrophy in, 224. „ ,, insufficiency in, 212, 215. ,, puerperal, 223. „ reproductive, 222. GENERAL INDEX 235 Insanity, scarcity of Graafian follicles in, 224. „ sexual, 207, 210, 211. Insomnia at menopause, 214. Instincts of maternity in lower animals, 115. Intellect and reproductive functions, 116. Intermediate cell mass, 74. Internal secretion, definition of, 102. ,, „ organs of, see Hormonopoietic organs* „ secretions, correlation of, in regard to genital functions, 106. ,, tubular partial hermaphroditism, 149. Interrenals, accessory, in rats, 75. Interstitial cells of gonads, effect of, on secondary sex character- istics, 13. ,, „ ,, ovarian grafts, 47, 182. ,, ,, ,, ,, ,, influence of, on uterus, 28. ,, ovary, 26, 40. ,, ,, ,, ,, effect of removal of anterior lobe of pit- uitary on, 68. ,, ,, ,, ,, functions of, 27. ,, ,, ,, „ influence of, on ovulation, 28. ,, ,, „ ,, ,,.>»>> secondary sex character- istics, 28. „ „ „ „ origin of, 27, 28. „ „ ,? ,, in osteomalacia, 184. ,, ,, ,, „ secretion of, 22. ,, ,, ,, ovitestis, 144. ,, „ ,, testes of tubular partial hermaphrodites, 151. Intestinal contractions, effect of infundibulin on, 72. ,, ,, ,, ,, parathyroid extract on, 62. „ „ ,, „ suprarenal extract on, 80. * Inversion ', 165. ,, sexual, 135, 211. Iodothyrin, effects of, on lactation, 93. Katabolism, 7. Kleptomania during menstruation, 218, 219. Lactation, amenorrhea during, 90, 202. „ calcium metabolism in, 190, 193, 202. ,, influence of corpus luteum on, 90, 91. foetal hormone on, 94. iodothyrin on, 93. oophorectomy on, 90, 91, 176. pineal on, 194. pituitary on, 92, 198. secretion of uterus on, 101. suprarenin on, 94. thymus extract on, 94. thyroidectomy on, 93. on calcium metabolism, 190, 193, 202. „ changes in mammas at menopause, 176. „ involution of uterus, 97. ,, maternal metabolism, 96. „ „ psychology, 112. „ ovarian function, 35. ,, uterine contractions, 97. insanity during, 223. in males, 96. metabolism of, 35. 236 GENERAL INDEX Lactation, pregnancy during, 179. ,, without pregnancy, 96, 115. „ sterility during, 202. „ tetany during, 193. Lactosuria, 200. Langerhans, islands of, internal secretion of, 199. Larynx in case of glandular partial hermaphroditism, 142. Liquor folliculi, 23, 53, 54. Lutein cells, hormones of, 22. ,, ,, importance of, 30. ,, ,, origin of, in rodents, 27. Maggots, sex determination in, 11. Mammse, activity of, during menstruation, 91. „ adenomata of, influence of oophorectomy on, 176. ,, atrophy of, after compression of stalk of pituitary, 67, 71. , , changes in, at menopause, 176. ,, development of, as secondary sex characteristic, 86, 127, 128. ,, function of, 86. ,, hormones influencing, 87, 89. ,, influence of corpus luteum on, 96. ,, ,, „ foetal extract on, 95. ,, ,, ,, lesions of pituitary on, 92. ,, ,, ,, oophorectomy on, 89. „ ,, „ ovarian grafts on, 47- ,, ,, ,, ovaries on, 89, 90, 91. ,, ,, ,, pelvic tumours on, 96. „ ,, ,, placental extracts on, 104. ,, ,, ,j suprarenal excess on, 199. ii ,, ,, on genital functions, 201. ,, removal of, effect of, on eclampsia, 202. „ t „ „ „ „ „ parturition, 202. „ stimulus of, originating in placenta, 95. ,, thyroid, relation of, to, 93. Mammary extracts, physiological effects of, 98. Masculinity in the female, 121, 127, 128, 135, 154, 165, 166, 215. (See, also, Sex characteristics, secondary.) „ ,, ,, with hyperplasia of anterior lobe of pitu- itary, 196. „ ,, ,, ,, pineal neoplasms, 169. ,, „ ,, „ pituitary neoplasms, 168, 169. ,, ,, j, ,, suprarenal neoplasms, 166, 168, 169. Mas tidy nia at menstrual periods, 91. ,, with thyroid insufficiency, 186. Masturbation, 210, 211. ,, excessive menstruation with, 182. ,, precocious puberty with, 157. Maternity, instincts of, in lower animals, 115. ,, rejection of, a possible process of evolution, 117. Melancholia at menopause, 213, 214. ,, with ovarian insufficiency, 207. ,, in pregnancy, 222. Membrana granulosa, 22. ,, „ cells of, origin of, 23. ,, ,, ,, ,, secretion of, 22, 23. Mendelian laws, in relation to sex determination, 9. Menopause, adiposity at, 36, 174. „ artificial, after oophorectomy, 37, 108. ,, ,, changes in mammae at, 176. GENERAL INDEX 237 Menopause, carbohydrate tolerance at, 175. „ causes of, 172. „ changes in hormonopoietic organs at, 175. » „ ,, mammae at, 176. ,, defective oxidation at, 175. „ derangements of metabolism at, 174, 213. „ hypothyroidism afc, 214. „ mental attitude after, 112. ,, myxcedema after, 175. ,, neuroses at, 214. » » j» treatment of , 215. „ ovarian insufficiency at, 172, 212. ,, pituitary and thyroid insufficiency after, 36 )> » extract, administration of, at, 174. ,, premature, in diabetes, 200. „ psychical changes at, 173, 175. ,, psychoses at, 213. ,, relation of, to calcium metabolism, 20. „ suicide at, 207. ,, symptoms of, in ovarian insufficiency, 177. „ vasomotor disturbances at, 173, 174. Menorrhagia, administration of calcium salts in, 189. ,, in Graves' disease, 189. „ mental disturbances with, 219. ,, in myxcedema, 186. ,, neuroses with, 220. ,, at puberty, 189. „ in superlactation, 203. Menstrual neuroses, 220. Menstruation, absence of, in delayed puberty, 161, 164. ,, ,, ,, ,, lactation, 90. ,, dependent on uterine integrity, 21. ,, disorders of, psychoses with, 219. ,, disturbances of metabolism with, 216. „ epilepsy during, 216, 221. ,, influence of corpus luteum on, 24. ,, ,, ,, ovarian excess on, 182. ,, ,, ,, ovaries on, 21, 118. ,, „ „ pancreatic insufficiency on, 200. ,, ,, ,, pituitary insufficiency on, 195. ,, ,, ,, thyroid excess on, 189. ,, ,, „ ,, insufficiency on, 185, 186. ,, insanity during, 218. ,, mammary activity during, 91. „ mastidynia during, 91. ,, neuroses during, 220. „ onset of, psychical attitude at, 19. , ,, psychoses during, 217. ,, relation of ovarian insufficiency to, 179. ,, ,, ,, sterility to, 179. ,, ,, ,, to calcium metabolism, 20, 35, 91. ,, as a secondary sex characteristic, 127, 128. ,, suicide during, 207. Mental characteristics at different ages, 111. control of reproductive instincts, 124. depression with hypothyroidism, 227. disturbances with menorrhagia, 219. ,, during pregnancy, 222. function, effect of oophorectomy on, 118. 238 GENERAL INDEX Mental function, influence of metabolism on, 118, 206. Metabolism, calcium, see Calcium metabolism. ,, carbohydrate, hormonopoietic organs in relation to, 82. „ ,, influence of pancreas on, 199. „ „ „ pituitary on, 175. ,, before puberty, 19. ,, derangements of, at menopause, 174, 213. ,, ,, ,, with menstruation, 216. ,, effects of oophorectomy on, 32, 171. ,, „ -,, ovarian grafts on, 47. „ ,, „ removal of one suprarenal on, 76. ,, ,, ,, suprarenal insufficiency on, 198. „ „ ,, thyroidectomy on, 50. „ individual and reproductive, interdependent, 108. ,, influence of disease on, 179. „ ,, ,, hormonopoietic organs on, 5, 107- „ „ ,, internal secretions on, 153. „ ,, ,, on mental functions, 118, 206. ,, », # M „ sex psychology, 110. ,, instability of, in women, 120, 121. ,, male, in female, 128. ,, maternal, influence of lactation on, 96. ,, nitrogen, see Nitrogen metabolism. „ sex differences in, 120, 166. Milk, secretion of, causal factors in, 88. ,, ,, ,, in male and virgin breasts, 87. Mind and body, interdependence of, 114. ,, ideal attitude of, in Woman, 122. , , influence of hormonopoietic organs on, 161. „ ,, ,, metabolism on, 118, 206. „ „ ,, on function, 161. „ ,, ,, ,, genital functions, 227. ,, sex differences in, 123. Motor disturbances at puberty, 209. Mumps, ovarian insufficiency after, 178. Muscle, involuntary, pressor effect of mammary extract on, 98. * Myometrial gland ', 101. Myxcedema, after menopause, 175. ,, alternating with Graves' disease, 188. „ amenorrhcea with, 178, 186. „ changes in nervous cells with, 214. ,, menorrhagia in, 186. ,, pregnancy after, 186, 187. ,, sterility in, 187. ,, uterus in, 186. Neuralgia, at menopause, 214. „ with menstruation, 220. Neuroses, at menopause, 214. „ menstrual, 220. , , after oophorectomy, 37. ,, at puberty, 209. ,, sexual, 206. Nitrogen metabolism, effect of oophorectomy on, 33. ,, ,, ,, ,, removal of one suprarenal on, 76. ,, ,, ,, ,, thyroidectomy on, 52, 53. ,, ,, in menstrual neuroses, 220. GENERAL INDEX 239 Obesity, in pituitary insufficiency, 190. ,, after removal of pars anterior of pituitary, 66. ,, in thyroid insufficiency, 186, 196. Oogonia, 146. Oophorectomy, abortion following, 30. ,, adiposity after, 36, 37. ,, artificial menopause after, 37. ,, atrophy of uterus after, effect of ovarian grafts on, 46. ,, considerations in deciding upon, 171. ,, effects of, general, 37. , , , , , , on adenomata mamma?, 176. ,, ,, ,, ,, calcium metabolism, 33, 37. ,, ,, „ „ general metabolism, 32, 171. ,, ,, ,, ,, genital functions, 29. ,, ,, ,, ,, growth of bones, 34 „ ,, it M lactation, 90, 91, 176. ,, ,, „ .,, mammas, 89. „ ,, ,, „ mentality, 118. „ ,, ,, ,, nitrogen metabolism, 33. ,, ,, it t, osteomalacia, 35, 199. ,, ,, it ii other hormonopoietic organs, 37, 107. „ ,, ,, ,, oxygen metabolism, 36. ,, ,, ,, ,, phosphorus metabolism, 33, 37. „ ,, .„ „ pineal, 41. it it it it pituitary, 42. .„ ,, ,, ,, sexual capacity, 127. „ ,, ,, „ suprarenals, 41, 75, 76. ,, ,, „ ,, sympathetic system, 37. ,, ,, ,, ,_, tetany after parathyroidectomy, 61. ,, ,, ,, „ thymus, 18,40,84. ,, „ „ thyroid, 33, 53, 175, 188. ti „ », ,, uterus, 22, 46. „ ,, „ „ i, non-pregnant, 29. n „ » tt pregnant, 30. „ „ „ thyroidectomy minimized by, 51. ,, neuroses after, 37» ,, psychoses after, 37, 171. ,, thyroid enlargement and excess after, 175. ,, treatment in hysterepilepsy by, 222. ,, ,, „ osteomalacia by, 35, 199. „ ,, ,, ovarian excess by, 183. Organgift, 204. Organotherapy, 180. Ornithorhynchus, atrophy of right ovary in, 9. „ corpus luteum of, 25. Osteomalacia, 184. ,, administration of infundibular extract in, 184, 197, 199. ,, ,, ,, suprarenal extract in, 184, 197, 199. , , calcium metabolism in, 193, 199. „ effect of oophorectomy on, 35, 199. ,, ovarian excess in, 193. , , parathyroid hyperplasia in, 185, 192, 193. „ pituitary insufficiency in, 184. „ suprarenal insufficiency in, 78, 184, 199. Ova, 5. Ovarian activity, effect of, on menstruation, 21, 118. „ „ ,, ,, ,, temperament, 119. ,, ,, hormones in relation to, 179. excess, 182. 240 GENERAL INDEX Ovarian excess, effects of, 210. ,, ,, ,, ,, on calcium metabolism, 183. ,, „ ,, ,, ,, menstruation, 182. „ „ ,, puberty, 210. „ „ in osteomalacia, 193. ,, „ psychoses due to, 208. ,, ,, sexual insanity with, 207. „ ,, ,, precocity with, 207, 208, 210. ,, ,, treatment of, 183. ,, extract, administration of, in acromegaly, 197. ,, „ „ ,, at menopause, 214, 215. ,, „ physiological effects of, 48. „ grafts, 180. „ ,, Graafian follicles in, 182. ,, ,, interstitial cells in, 47, 182. ,, ,, must be autoplastic, 47, 181. „ insufficiency, 170, 212. „ „ apart from menopause, 177. „ „ ateleiosis with, 132. „ „ dependence of menopause on, 172. „ „ effect of, on growth of ovarian grafts, 47. „ „ „ „ „ hormonopoietic organs, 174. „ „ general diseases causing, 178. „ „ insanity with, 212, 215. „ „ melancholia with, 207. „ „ pituitary disease with, 177. „ „ primary, 212. „ „ relation between, and menstruation, 179. „ „ secondary, 215. „ „ treatment of, 180. „ secretion, disturbances of, 170. „ substance, administration of, effect of, on Ca. and P. metabol- isms, 34. „ „ „ „ „ „ „ Oxygen metabolism, 36. Ovary, 4. ,, atrophy of, in insanity, 224. „ „ „ one, in birds, etc., 9. „ correlation of thyroid with, 176. „ in cretinism, 158. „ development of, 145. „ effect of compression of infundibular stalk on, 70, 71, 92. pituitary on, 191. „ insufficiency on, 168. „ neoplasms on, 169. removal of pituitary (pars anterior) on, 68, 92, „ „ „ (pars posterior) on, 70. „ „ suprarenal on, 79. suprarenals on, 191 . thymus on, 17. thyroidectomy on, 53, 186. thyroid insufficiency on, 133. underdevelopment of uterus on, 133. X-rays on, 180. on calcium metabolism, 18, 61, 90, 119, 174, 191, 197, 199. „ general metabolism, 107- „ genital functions, 6. „ mammas, 89, 90, 91, 5> » » )> T) » » 55 » )) ?5 5) » J5 5> » V J> 5) » JJ » )) JJ J) )5 » 55 )» » » » » » )J » 5) )J » GENERAL INDEX 241 Ovary, effect of, on other hormonopoietic organs, 107. „ „ „ „ puberty, 125. „ follicular epithelium of, 22. » » „ „ secretion of, 23. » » m n n » function of, 47. „ functions of, 21, 106. „ „ „ effect of pregnancy and lactation on, 35. „ hyperplasia of, precocious puberty with, 155. „ internal secretions of, evidences of, 22. „ interstitial cells of, 26, 40, 53, 144. (See, also, Interstitial cells.) „ „ „ „ active principle of, 48. „ „ „ „ secretion of, 22. „ limited responsibility of, for secondary sex characteristics, 13. „ maldevelopments of, 131. „ neoplasms of, influence of, on masculinity, 165. „ „ „ sexual precocity with, 154, 155, 157. „ secretory structures of, 22. „ in status lymphaticus, 201. „ transplantation of, 46, 180. (See, also, Ovarian grafts.) „ „ „ effect of, after oophorectomy, 46. „ „ „ must be autoplastic, 47, 181. „ underdevelopment of, with incomplete puberty, 160. Ovitestis, 137, 146, 165. „ histology of, 143. ,, interstitial cells of, 144. Ovulation, influence of corpus luteum on, 24. „ „ „ interstitial cells of ovary on, 28. Ovum, dimorphism of, 8. ,, implantation of, influence of corpus luteum on, 24, 25, 26, 31. „ predetermination of sex in, 7. Oxygen metabolism, defective at menopause, 175. „ „ effect of oophorectomy on, 36. ,, ,, „ „ administration of ovarian substance on, 36. Palpitation at puberty, 210. Pancreas, 81. ,, effect of infundibulin on, 82. ,, »»m removal of, 81. „ „ „ „ „ in pregnancy, 81. ,, „ „ ,, „ pituitary (pars anterior) on, 81. „ „ „ suprarenin on, 82. ,, influence of, on carbohydrate metabolism, 199. ',, insufficiency of, diabetes with, 199. „ ,, „ influence of, on menstruation, 200. „ relation of, to other hormonopoietic organs, 199. ,, underdevelopment of, 132. Pancreatic extracts, physiological effects of, 82. ,, hormones, foetal, in maternal circulation, 81, 200. „ infantilism, 132, 158. Paralysis, functional, at menopause, 214. „ „ „ puberty, 209. Paraplegia, involution of uterus in, 97. Parathyroid insufficiency, in eclampsia, 193. „ „ „ tetany during pregnancy, 193. „ secretion, disturbances of, 192. Parathyroidectomy, effects of, 60. ,, tetany after, 60. „ „ „ during pregnancy, 193. JO 242 GENERAL INDEX Parathyroidectomy, tetany after, effects of oophorectomy on, 61. Parathyroids, 59. ,, administration of extracts of, effects of, 62. » n „ „ » ,i „ in eclampsia, 193. ,, effect of oophorectomy on, 38. ), „ „ pregnancy on, 59, 192. „ » „ thyroidectomy on, 59. „ in herbivora, 50. „ hyperplasia of, in osteomalacia, 185, 192, 193. „ influence of, on calcium metabolism, 59, 00, 61, 185, 192, 193. „ relation between anterior lobe of pituitary and, 192. » „ „ thyroid and, 195. „ secretion of colloid by, 50. Pars anterior, see Pituitary, pars anterior. Parthenogenesis, 7, 10. Parturition, effect of removal of mammas on, 202. „ psychological effect of, 111. „ tetany after, following parathyroidectomy, 193. Pelvic infections, with incomplete puberty, 160. ,, tumours, influence of, on mammae, 96. Phosphorus metabolism, effect of administration of ovarian substance on, 34. ») „ „ „ oophorectomy on, 33, 37. ii „ „ „ removal of suprarenal on, 76. » „ „ „ thyroidectomy on, 52. „ „ relation between, and calcium metabolism, 33. Phylogeny, importance of, in hormonopoietic organs, 102. Pineal, disturbances in secretion of, 194. ,, effects of extirpation of, 63. ii „ „ injections of, 64. „ „ „ oophorectomy on, 41. „ influence of, on genital functions, 194. „ „ „ „ mammas (galactagogue), 194. ., „ „ „ masculinity, 165. „ „ „ „ sex characteristics, 194. m ,, i, „ sexual precocity, 107, 157, 194. „ function of, 121. ,, lesions of, 194. „ neoplasms of, effect of, on secondary sex characteristics, 169. ,, „ „ masculinity in girls with, 154. „ „ „ sexual precocity in boys with, 154. Pituitary, anatomy of, 42. „ chromophobe cells of, 39, 43, 65, 169. „ colloid of, 38, 39, 45. „ compensatory activity of, in suprarenal insufficiency, 79. „ in cretinism, 158. „ disease of, ovarian insufficiency with, 177. „ effects of oophorectomy on, 42. „ „ „ removal of suprarenal on, 44, 78. „ thyroidectomy on, 44, 46, 55. „ „ during pregnancy on, 56. 197. masculinity with, 215. extracts, administration of, effects of, 72, 196. „ „ in Graves' disease, 191. „ „ „ menopause, 174. „ „ „ osteomalacia, 184, 197, 199. » 5> 55 » » excess 55 5) >1 extrac » 55 » 55 » 55 GENERAL INDEX 243 Pituitary extracts, administration of, in ovarian excess, 183. „ „ „ „ „ thyroid excess, 191. „ function of, 42, 121. „ functional changes in, 65. „ hyperplasia of, effect of, on secondary sex characteristics, 167. „ influence of pregnancy on, 13, 19, 44, 46, 56, 65, 92, 121, 197. stimulation of cervical sympathetic on, 173. on calcium metabolism, 92, 167, 191, 197, 199. „ carbohydrate metabolism, 175. „ development of genitalia, 195. „ genitalia, 107. „ lactation, 92, 198. „ masculinity, 165, 166. „ ovaries, 191. „ thyroid, 191. infundibular stalk of, compression of, effects of, 67, 71. „ „ „ „ „ „ „ onmammse, 67. n » ■>•> v> » » » n ovaries, 70, 71, 92. n ii ii ii ii ii » ») uterus, 70, 71. insufficiency, 133. „ amenorrhoea with, 195, 196. „ diagnosis between, and thyroid insufficiency, 196. effects of, on genital functions, 108. „ „ „ „ organs, 17, 108, 168. „ ,, „ ovaries, 168. ,, „ „ uterus, 108, 160. „ genital hypoplasia with, 226. „ lethargy with, 118. „ in osteomalacia, 184. „ postmenopausal, 36. „ scanty menstruation with, 195. „ skin with, 196. „ sugar tolerance with, 133. „ underdevelopment of uterus with, 160. lesions of, in confusional insanity, 226. „ „ effects of, on mammae, 92. „ „ sterility with, 196. neoplasms of, effects of, on ovaries, 169. n „ „ „ „ uterus, 169. ,, masculinity with, in females, 154, 169. „ sexual precocity with, in boys, 154. pars anterior, administration of, effects of, on growth, 72, 73. hyperplasia of, amenorrhoea with, 196. ,, ,, masculinity with, 196. ,, ,, after oophorectomy, 45. lesions of, 195. relation between, and parathyroids, 192. removal of, effects of, 66, 67, 68, 69, 194. „ ,, ,, „ on ovaries, 68, 92. ,i ii n ii ii pancreas, 81. ,, ,, ,, ,, „ suprarenals, 69. n ii ii ii ii thymus, 69. ,, „ „ ,, ,, thyroid, 69. n ii n ii ii uterus, 68. 11 11 11 11 11 11 11 11 ii ii 11 par n n ii ii ii a n a ii 11 » n if ii ii i) ii n 244 GENERAL INDEX Pituitary, pars anterior, staining reactions of, after removal of supra- renal, 78. intermedia, 42. , , staining reactions of, after removal of supra- renal, 79. nervosa, 42. posterior, glycosuria after continued administration of, 73. ,, ,, with lesions of, 196. ,, injection of, effects of, 72. ,, lesions of, 196. removal of, effects of, 66, 67, 70, 195. , , staining reactions of, after removal of supra- renal, 79. , , ' pregnancy cells ' in, 44, 56, 65. „ pressor secretion of, 56. „ removal of, effects of, 66, 68, 194. ,, secretion of, disturbances of, 194. „ staining reaction of cells of, 39, 43, 65. ,, ,, „ „ colloid of, 39. „ in tubular partial hermaphroditism, 151. ,, underdevelopment of, 132. „ unity of anterior and posterior lobes of, 194. Placenta, function of, 203. ,, injection of extracts of, results of, 204. ,, as an organ of internal secretion, 102. ,, stimulus of mammse originating in, 95. „ toxins of, neutralized by normal blood, 204. Postpartum haemorrhage in Graves' disease, 190, 191. Precocious puberty, 153, 201, 210. Precocity, sexual, after administration of pineal extracts, 64. „ „ effects of pineal and thymus on, 107- >j ,, in males, after pinealectomy, 63. »> h ,, ,, with pituitary neoplasms, 154. it H See, also, Sexual precocity. Pregnancy, absence of, in acromegaly, 197. „ acidosis in, 198. cells, 44, 56, 65. ,, during lactation, 179. „ effects of mammary extracts on uterus in, 98. on ovarian function, 35. „ parathyroids, 59, 192. „ pituitary, 13, 19, 44, 46, 56, 65, 92, 121, 197. „ suprarenals, 55, 74, 76, 121, 198. „ thyroid, 19, 39, 50, 187, 191. thyroidectomy on, 52, 81, 188. pituitary during, 55. ep theloid cells of uterus during, 101. glycosuria during, 198, 200. hirsuties in, 74. hyperemesis in, administration of suprarenin for, 198. influence of corpus luteum on, 31. ,, ,, on calcium metabolism, 121. ,, ,, ,, thyroid insufficiency, 187. „ „ thyroid excess on, 190. mental changes in, 222. after myxcedema, 186, 187. tetany in, 193. thyroid activity increased in, 39, 187. GENERAL INDEX 245 Pregnancy, thyroid excess in, 191. Pressor action of calcium salts, 99, 174. ,, „ ,, infundibulin, 72. ,, ,, ,, mammary extracts, 98. ,, ,, ,, parathyroid extract, 62. ,, ,, ,, suprarenal extracts, 80, 173. ,, ,, ,, suprarenin, 54. ,, „ H pituitary secretion, 56. ,, „ „ uterin, 102. Proinfundibulin, 43. Prostate as an organ of internal secretion, 104. Prostatectomy, effect of, on testes, 104. Prosuprarenin, 55. Protozoa, sexual dimorphism in, 6. • Pseudohermaphroditism', 148. Psychical changes at menopause, 173, 175. „ „ „ puberty, 125. „ sex characteristics in tubular partial hermaphroditism, 152. Psychology of individual, influence of hormonopoietic organs on, 5. „ „ sex, 110. Psychoses, menopausal, 213. „ menstrual, 217. ,, with menstrual disorders, 219. „ after oophorectomy, 37, 171. „ sexual, 206. Puberty, absence of, in cretins, 185. ,, ,, „ onset of, 157. „ amenorrhoea with thyroid enlargement at, 189. „ cessation of growth at, 20. ,, changes at, 153, 162. ,, „ in sex characteristics at, 17. ,, completely delayed, 161. ,, delayed, 160. ,, „ absence of menstruation in, 161, 164. ,, „ physical causes of, 162. „ „ psychical causes of, 162. „ ,, thyroid insufficiency with, 186. „ development of genitalia at, 131. „ effects of ovarian excess on, 210. „ excessive menstruation about, 182. „ incomplete, 159. „ incompletely delayed, 163. „ influence of environment on, 153. n „ „ hormonopoietic organs on, 17, 125. „ „ „ ovaries at, 125. „ involution of thymus at, 200. „ menorrhagia at, 189. „ mental characteristics at, 111. „ metabolism before, 19. „ neuroses at, 209. „ precocious, 153, 201, 210. M „ influence of involution of thymus on, 201. „ psychical changes at, 125. „ psychoses arising at, 208. „ thyroid enlargement at, 50. Puerperal insanity, 223. Pyrrhocoris, dimorphism of spermatozoa in, 8. 246 GENERAL INDEX Reproductive functions, sex differences in, 116. „ „ and the intellect, 116. „ instincts, influence of environment on, 124, 125. „ „ „ „ hormonopoietic organs on, 125, 128. „ „ „ „ mental control on, 124. Rodents, effect of oophorectomy on thyroid of, 38. Secondary sex characteristics, 14. (See, also, Sex characteristics, secondary.) Sedentary life causing delayed puberty, 163. Sella turcica, effects of artificial tumours in, 71. Sensory disturbances at puberty, 209. Sentiment ignored in discussion of femininity, 1. Sex cells, bisexualism of, 9, 11. characteristics, bisexuality of, 11, 13. ,, changes in, at puberty, 17. ,, derangements of, 165. ,, influence of interstitial cells of gonads on, 13, 28. ,, ,, ,, pineal on, 194. „ pituitary on, 107, 165, 166, 167, 196, 215. ,, and reproductive instincts, 127. ,, primary, 6. ,, ,, alteration in, after pinealectomy, 63. ,, ,, influence of hormonopoietic organs on production of, 151. ,, secondary, 14, 134. ,, ,, alteration in, after pinealectomy, 63. ,, ,, in birds, 14. ,, ,, description of, 16. ,, effect of pituitary hyperplasia on, 167. „ ,, ,, ,, suprarenal excess on, 199. ,, ,, m it >> neoplasms on, 150, 154, 166, 167. ,, „ feminine, with ovitestis, 139. ,, ,, influence of hormonopoietic organs on, 89, 107, 151. ,, ,, male, influence of suprarenal cortex on, 74. ,, ,, mammary development as, 86. ,, ,, menstruation as, 127, 128. ,, ,, in precocious puberty, 154. ,, ,, ,, 'pseudohermaphrodites ', 148, 150 ,, ,, ,, rodents, 14. ,, ,, stages of development of, 16. characterization, influence of gonads on, 152. criteria of, in ■ pseudohermaphrodites ', 148, 151. determination of, 6. ,, ,, effect of environment and nutrition on, 9, 10. „ ,, at fertilization, 10. ,, „ subsequent to fertilization, 10. „ „ in frog, 10. ,, „ irregularity in, 133. „ „ in maggots, 11. differences, in hormonopoietic organs, 120. ,, „ metabolism, 120, 166. „ ,, mind, 123. differentiation, a process of evolution, 113. GENERAL INDEX 247 Sex differentiation, in reproductive functions, 116. ,, divergence, 12. „ psychology of, 110. ,, „ relative values in, 122. ' Sexe-ensemble, atypical ', 135, 138. Sexual ateleiosis, 158. ,, capacity, 127. „ infantilism, 131, 132. (See, also, Infantilism.) „ insanity, 207, 210, 211. „ instinct, influence of environment on, 124, 125. „ „ „ „ hormonopoietic organs on, 125, 128. origin of, 126, 127. „ inversion, 135, 211. „ precocity, influence of ovarian excess on, 207, 208. „ „ „ „ „ neoplasms on, 154, 155, 157. „ „ „ „ pineal on, 107, 157, 194. „ „ „ „ removal of pineal on, 63. „ „ See, also, Precocity, sextial. „ psychoses and neuroses, 206. „ selection, and internal stimuli, 115. Sexuality, excessive, 210, 211. Skin, in pituitary insufficiency, 196. „ „ thyroid insufficiency, 196. Spermatogonia, 143, 145. i Spermatozoon, dimorphism of, 8. „ predetermination of sex in, 7. Status lymphaticus, 201. Sterility, causes of, 178. „ in diabetes, 200. „ during lactation, 202. „ in lesions of pituitary, 196. „ „ myxoedema, 187. „ „ relation to menstruation, 179. Still-births in diabetes, 200. 1 Sucking reflex ', 97. Sugar tolerance in pituitary insufficiency, 133. Suicide, at menopause and during menstruation, 207. Superinvolution of uterus, 180. „ „ „ in Graves' disease, 191. „ „ „ after thyroidectomy, 54. Superlactation, 98, 202. Suprarenal, effects of removal of one, on bones, 78. „ ,, „ „ n » n metabolism, 76. „ „ „ „ » „ ,, ovaries and uterus, t 9. „ „ ,, ». » » » pituitary, 44, 78. ,, h » » » » thyroid, 79. „ excess, amenorrhoea with, 199. „ „ influence of, on mammae, 199. ,, „ masculinity with, 215. „ extract, administration of, in hyperemesis of pregnancy, 198. „ „ „ „ „ osteomalacia, 184, 197, 199. „ „ „ „ „ ovarian excess, 183. „ „ precocious puberty, 157. „ „ physiological effects of, 54, 80, 173. „ insufficiency (Addison's disease), 198. „ „ compensatory activity of pituitary in, 79. „ „ effects of, on genital functions and uterus, 108. „ „ „ „ „ metabolism, 198. „ „ osteomalacia and, 78, 184, 199. 248 GENERAL INDEX Suprarenal insufficiency, precocious puberty with, 156. „ „ symptoms of, 169. „ medulla, development of, 173. Suprarenals, anatomy of, 54, 74. „ calcareous deposits in, 55. „ cortex of, derivation of, 74. „ „ „ and male secondary sex characteristics, 74. „ „ „ necessary to life, 75. „ differences of, in the sexes, 13. „ effects of oophorectomy on, 41, 75, 76. „ „ „ partial removal of pars anterior of pituitary on, 69. „ „ „ pregnancy on, 55, 74, 76, 121, 198. „ „ „ removal of, 75, 76. „ „ „ thyroid administration on, 58. „ „ „ thyroidectomy on, 54. „ functions of, 121. „ hyperplasia of, 129, 166, 169, 199. ,, hypertrophy of, in male rabbits at breeding season, 74. „ influence of, on calcium metabolism, 191, 198, 199. „ „ „ genitalia, 107. „ „ „ masculinity, 165, 166, 168. „ „ „ ovaries, 191. „ „ „ thyroid, 191. „ „ „ vessel-tonicity, 173. „ medulla of, development of, 173. „ neoplasms of, amenorrhoea with, 167. „ „ „ masculinity with, 154, 166. „ „ „ before puberty, 158. „ „ „ and secondary sex characteristics 150, 166, 167. „ „ „ sexual precocity with, in boys, 153. „ , , „ in tubular partial hermaphrodites, 150. „ relation of medulla and cortex of, 195. „ in tubular partial hermaphroditism, 151. Suprarenin, 54. (See, also, Suprarenal extract.) „ effect of, on lactation, 94. „ ,, „ pancreas, 82. ,, increased output with fright, 227. ,, influence of, on calcium metabolism, 174. ,, physiological effects of, 82. ,, replaced by infundibulin in suprarenal insufficiency, 79. Sympathetic nervous system, effect of oophorectomy on, 37. ,, ,, ,, ,, ,, stimulation of, on pituitary, 173. Testes, 4. ,, effect of thymectomy on, 18. „ internal secretion of, 104. ,, interstitial cells of, as organ of internal secretion, 104. „ neoplasms of, sexual precocity with, 153. ,, stimulating effects of suprarenal feeding on, 80. Tetany, calcium insufficiency in relation to, 60, 61. „ following parathyroidectomy, 60. m „ ,, effect of oophorectomy on, 61. ,, in pregnancy, 193. „ „ ,, after parathyroidectomy, 193. Theca interna, 23. Thymectomy, effect of, on gonads, 84. ,, ,, ,, ,, hormonopoietic organs, 85. GENERAL INDEX 249 Thymectomy, effect of, on testes, 18. Thymus, effect of oophorectomy on, 18, 40, 84. >> j» ,, partial removal of anterior lobe of pituitary on, 69. jy >, » X-ray irradiation of, on gonads, 84. ,, enlargement of, associated with hypohypophysism, 69. ,, in eunuchs, 41. ,, excessive activity of, 201. ,, extract, as galactagogue, 85, 94. ,, ,, physiological effects of, 85. ,, influence of development of genital organs on, 18. „ ,, , , on calcium metabolism, 18, 84, 201. m ?> >j >» genital functions, 107. »> » h n '■», organs, 17. „ internal secretion of, doubtful, 201. ,, involution of, 200. ,, „ ,, influence of, on precocious puberty, 201. ,, as organ of internal secretion, 83. Thyroid, absence of, in cretinism, 158. „ „ „ secretion of, 185. „ administration of, 57, 186, 187- „ „ „ in menstrual psychoses, 219. „ „ „ „ menopause, 214, 215. „ „ „ „ mental disturbances in pregnancy, 222. „ „ y, effect of, on blood pressure, 173. „ „ „ „ „ „ growth, 58. „ „ „ „ „ „ suprarenals, 58. colloid of, 38, 39, 45, 187, 188. „ connexion of, with eclampsia, 52, 53. „ correlation of, with ovary, 176. „ disturbance of, in menstrual psychoses, 218. „ „ „ during menstruation, 216. „ effect of compression of infundibular stalk on, 70. „ „ „ oophorectomy on, 38, 53, 175, 188. „ „ „ partial removal of anterior lobe of pituitary on, 69. „ „ „ removal of posterior lobe of pituitary on, 70. „ „ „ „ „ suprarenal on, 79. „ enlargement of, at puberty, 50. „ excess, 188. „ „ administration of pituitary extract in, 191. „ „ calcium metabolism in, 189, 191. „ „ excitability with, 118. „ „ influence of, on menstruation, 189. „ „ „ „ „ pregnancy, 190. „ „ after oophorectomy, 175. „ „ postpartum haemorrhage in, 191. „ „ superinvolution in, 191. „ „ thyroidectomy in, 190. „ extract of, physiological effects of, 57. „ foetal, secretion of, conveyed to mother, 53, 81. „ inactivity of, in rodents, 40, 50. „ influence of pituitary on, 191. „ „ „ pregnancy on, 19, 39, 50, 187, 191. „ „ „ suprarenals on, 191. „ „ „ on calcium metabolism, 119, 174, 191. „ „ genitalia, 107. „ insufliciency, 185. „ „ amenorrhoea with, 178. „ „ dysmenorrhoea with, 186. „ „ and eclampsia, 52, 53, 187. 250 GENERAL INDEX Thyroid insufficiency, effects of, on genital functions, 108. „ " „ „ „ organs, 17, 108, 133, 160. „ „ with incompletely delayed puberty, 164. „ „ influence of, on menstruation, 185, 186. „ „ „ „ „ puberty, 186. „ „ pregnancy on, 187. „ „ lethargy with, 118. „ „ mastidynia with, 186. „ „ after menopause, 36. „ „ minor degrees of, 186. „ „ and pituitary insufficiency, diagnosis in, 196. „ „ relation of, to mammae, 93. „ „ and sexual infantilism, 132, 133. „ „ skin in, 196. „ „ with underdevelopment of uterus, 133, 160. „ relation of, to parathyroids, 195. „ retrogression of, after menopause, 188. „ and toxaemias of pregnancy, 187. Thyroidectomy, ammonia-coefficient after, 52, 53. „ effects of, during pregnancy, 52, 81, 188. „ „ „ minimized by castration, 51. „ „ „ on calcium metabolism, 52, 55. h » n » cate, 51. „ „ „ „ general metabolism, 50. lactation, 93. „ nitrogen metabolism, 52. „ „ „ „ ovaries, 53, 186. parathyroids, 59. phosphorus metabolism, 52. pituitary, 44, 46, 55. „ during pregnancy, 56. „ „ „ „ rabbits, 39, 50. „ „ „ „ suprarenals, 54. „ „ „ „ uterus, 54, 79, 186. „ in Qraves' disease, 190. Thyroid-parathyroidectomy, convulsions after, 51, 222. Thyroiodin, deficiency of, symptoms of, 214. Thyroparathyroid apparatus, 51, 59, 60. Transfusion of blood in eclampsia, 205. Transplantation, ovarian, 180. (See, also, Ovarian grafts.) Tryptic ferments in endometrium, 101. Tuberculosis, amenorrhcea in, 178. „ genital atrophy in, 226. Tubular partial hermaphroditism, 136, 148, 151. ' Twilight sleep ', effect of, on maternal psychology, 111. Typhoid fever, ovarian insufficiency after, 178. Uteein, 102. Uterine contractions, effect of extracts of placenta on, 103, 104. „ „ „ „ parathyroid extract on, 62. „ „ „ „ pituitary extract on, 72. „ „ „ „ suprarenal extract on, 80. „ „ „ „ thyroid injections on, 57. „ „ „ „ uterine extract on, 101. „ „ influence of lactation on, 97. Uterus, atrophy of, amenorrhcea with, 178. „ „ „ in diabetes. 200. „ „ „ after oophorectomy, 22, 30. „ „ „ „ thyroidectomy, 54, 79, 186. 55 55 55 J) 55 55 55 57 55 5> 55 55 55 55 55 55 55 55 55 55 5) » >1 >J » 55 55 )) 55 55 » 55 51 » 55 55 » 5) 11 GENERAL INDEX 251 Uterus, in cretinism, 158. „ cyclical changes in, 24. „ development of, effect of thyroid insufficiency on, 133. „ effect of compression of infundibular stalk on, 70, 71. „ „ „ infundibulin on, 72. „ „ „ injections of pineal on, 64. mammary extracts on, 98. oophorectomy on, 22, 29, 30. ovarian extract on, 48. pituitary insufficiency on, 108, 160. „ neoplasms on, 169. removal of pars anterior of pituitary on, 68. „ „ „ „ „ posterior lobe of pituitary on, 70. „ „ „ „ „ suprarenal on, 79. „ „ „ suprarenal insufficiency on, 108. „ „ „ thyroidectomy on, 54, 79, 186. „ „ „ thyroid insufficiency on, 108, 186. „ epitheloid cells of, during pregnancy, 101. „ extracts of, effect of, on lactation, 101. „ ,, ,, „ » j », uterine contractions, 101. „ influence of interstitial cell grafts on, 28. „ internal secretion of, 100. „ „ „ „ doubtful existence of, 101. „ involution of, calcium blood content in, 98. „ „ „ „ metabolism, and, 202. „ „ „ effect of extract of placenta on, 103. „ „ „ influence of lactation on, 97. „ „ „ in paraplegia, 97. „ maldevelopments of, 131. „ removal of, see Hysterectomy. „ secretion of, physiological effects of, 101. „ superinvolution of, 180. „ „ „ in Graves' disease, 191. „ „ „ after thyroidectomy, 54. „ underdevelopment of, effect of, on ovaries, 133. „ „ „ with incomplete puberty, 160. „ „ „ „ pituitary insufficiency, 160. „ „ „ „ thyroid insufficiency, 17, 133, 160. Vagina, septate, 131. Vasomotor disturbances at menopause, 173, 174. Work, competitive, injurious to women, 122. ,, hard mental, effect of, on puberty, 162. X-Rays, effect of, on ovarian function, 180. „ „ „ irradiation of thymus by, on gonads, 84. Zona fasciculata, see Suprarenals. „ pellucida, 53, 79. „ reticularis, see Suprarenals. PRINTED BY WILLIAM CLOWES AND SONS, LIMITED, BECCLES, FOR BAILLIE11E, TINDALL AND COX 8, HENRIETTA STREET, COVENT GARDEN, LONDON, W.C. 2. O JUN 2 4 1971 QP Bell, William Blair 187 The sex-complex B45 1920 Biological & Medical PLEASE DO NOT REMOVE CARDS OR SLIPS FROM THIS POCKET UNIVERSITY OF TORONTO LIBRARY