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·MONOGRAPHS OF THE FEDERAL COUNCIL OF THE
BRITISHI MEDICAL ASSOCIATION IN AUSTRALIA
NURIBER 2
GYNÆCOMASTIA
PETER F. HALL, ID (Sydney), mr AC.I., M.R.C.P.
Honorary Issıslant Physician, Sydney Hospital; Assistant Lecturer
Department of Physning Vuirersity of Sydney
l'ith a Forci ord by
PF BISHOP, DS FRCP

·11 bollyset op and printed Australia by lustralasian Vedical l'ublishing Company Limited Seamer Strec: Glebe, Sew South Wales Registereit at the GPO Sylnes for transmissiur by post as bork ·CONTENTS Muce $ 6 { 7 14 20 29 L'orchor Irelace Chapter Xfittoti Chay 11 Chapter Refrain! Litera}af Chapter Clinical an Labaf1951 Vetrin (191 com Chapter The Vair 135031 Chapter The Content (tragis VII (untsmartial forexiated with 's alexicon taten haiter IN 1.115 i fost atac urt's Mosfelry (1 apie tnt stta site sth Thunft 1x mine (lanks {apret 1.18 omaa sux Lt 30 ct the 12 (hapter 11 (11 14wxts with Walnutrinos thapps 11 Imut fans of (111023521 Chapter 1 (1814-(Ma- knytbital with its of ths (M114 WOUS 5348m {}s pythy 11 11133-ts wat uit 1842 of the Lung f.13121m2 91 lite: {hapter 11 This Varastot ani Fratment of Tutti 11mars at nun 45 - 10$ 3 38 150 153 ·11 holly set up and printed in Lustralia by ustralasan Vecca Publishins Cupany Limsted, Deaner Street, Giede, New South Wales Refrstered at the GPO Sydney, fur transmission by preust as n bai** ·FOREWORD - So far as I am an are this is the only book or monograph that has ever been Witten on necomastia, and this is surpring for it is a condition wluch often *stum " the clinician There is for instante considerable disagrement between pediatricians, endocrinologists, physicians and surgeons concerning the management of puberty, gynecomastia Will it stappear spontaneously: how embarrassing is it to the adolescent boy , hou neatly can the surgeon deal with it? The association xetween pinacomastia and hilincfelter's yndrome is of considerable interest, for typerplasia of the Leydig cells is a characteristic feature is the gynecomastia due to austrogen and is the oestrogen prolucci by these cella > Perhaps it is in the adult, however, that gyna:comastia is espacially puzzling So ofter it is difficult to explain the cause and to predict the prognosis It is in this type of case that cven the experienced physician flounders and fints himself tempted to give serious consideration to such ranties as feminizing adrenocortical tumours Dr Hall has made a valuable contnbution by putting this puzzling physical sig in its true perpepective His extensie testiculas hrognay studies have emphasized the frequency with which garcomastia ás accompanied by the" Klinetelter" picture of interstitial-cell hyperplasia and tubular hyalinization I had the proud ptr deke of watchmg the book grou For some time I had regardert gynacomastia as an endanne enigma and I challenged Ds all to make a contnbution to its solution He chose the subject for a MD These and I was vell aware of the much tandard required for the Sydney ID I have been intimately concerned with the preparation of many MD Theas, including my own but I have fieter seen a project tackled so thoroughly He was not content only to read the literature He established personal contact wits 5933535 of its principal authors No doubt, as time goes on, the problem of onexomasta will be completely solved. but when it is I believe this book will be regarded as one of the major contributions to that volution Pr Biskor, D. FRCX June, 1959 ·TO PROFESSOR LORIMER DODS whose stimulating influence was felt during the preparation of this book ·CHAPTERY DEFINITION great deal of confusion cysts in the literature dealing with finecomastia ; much of ths can l'attributed to the want of a satisfactory definition of the condition. Some uiters hare -24% di finitions which refer to the eternal fom of the breast, Gynatomista mare defined as an atletion of the main brtant in when the plant tends foame the size, shape anulometimes the function of the Stelle lireast (Chrati ani! Cutler) Apart from the objection that the secretion Erich may sufit times we proiedl from the supple in cases of gynacoma tra has nese's been shown to pomeni the chemical and plugsiological pratx They of mulk, this defimion cuns the appearance of an organ (the breast) with the state of a ghind the mamman gland) Sturla,: as tarly as 1805, claimed that thyr etymology of the word estixcomautia only rarmittel its 11-e to describe the external forma and volume of the breast, and, furthermore, that the hi-tology of the breast in cahol gyn comastra differed considerably fronts that of the functional lureasts of women On the other hand, Karmer la récents promoved an eueniri definition of the word gynecomast13, in which her includes a detailed decriptun of the u-tallustological changes seen in the condition Gynekomat in an cara ment of the mummirs mans) or slunch of main due to prosferation of connes tuc tuc den in the fincral strama anu niten Ionels arranca meniducial regions Ingrihet : variable searces of multiplication clanzallon or branchina of ducts or of all three without formalma of acın alumpansen! Ix ferluctal or raone walespread in filcsatus of tymphostre plasma cells last mononitrar elle anl casonally eosinopril or currapal polymorphony kar << or with ortni tron ta frekuent). pre-cn in ducts mas be discharged spontaneously ur manuals espresse & lout ratek verir true colostrum or milk Than detinatorului de pe ulasatcomastia due to the demton of fat sa tam maniman tp, 9103 as soll x suppuraine or othrt entsallt sammatort processo granulomatous lessons and neoplasms tither fx1.5 or malignant The principal objections to this definition are that it in seri cumbersome and that it can only be used after histological study of the breat The same objections apply to the most recent defintion of gylcomasti3 namely that of Wheeler anst his colleagues Webster' has suggested a much simple definitios "(max.com-a is a term applied to enlargement of the hreast in male The Concise Oxford Dictionary defines the word breast as "the milk secreting organ in women or ihe corresponding rudiment in men This allows one to speak oi" a breast in normal men, implying the existence of a nudimentary organ and not merely denoting an area of the body as in the purefs literary use of this word Enlargement of such an organ could be judge in three mass (1) By comparison with the opposite broast where the condition is unilateral. (12) comparison with the previous dimensions of the breast, and (1) bs comparison with the breasts of normal men However, one in generally concerned with enlargement of the glandular component of the male breast, as distinct from the deposition of fat in the breast or the occurrence of neoplastic and inflammatory swellings This objection could be eliminated by speaking of true and false gynacomastia ternativels the word gytLcomastia could be reserved for enlargement of the glandular tissue Die following definition is therefore suggested Gytit comastia ts a term apphed to enlargement of the breast in males due to increase in the glandulas component of the organ .

·PREFACE Tits book was written on the basis of a thesis prepared at Guy's Hospital betucen 1952 and 1955 The patients whose chincal hsstories form the subject matter of the text belong to tuo series, 85 men were studied at Guy's Hospital and a second series of 25 patients have been examined at Sydney Hospital i am greatly indebted to the numerous phystcians and surgeons who have so generously provided clinical and laboratory data concerning their patients and, in some cases, histological preparations Special thanks are due to Dr Fuller Albright, who provided extensive data concerning tuo patients, to Dr 11' 0 Velson, whose assistance in the interpretation of some of the more difficult testicular kjopsies and whiosc generous encouragement have prosed invaluable, and to Dr Charles 1 Chasny, of Philadelphia, who very kindly provuded a series of testicular biopsies of normal boys, without which it would have been impossible to discuss the microscopic appearance of the testis in adolescent patients Dr Gordon Thomas, of Gus's Hospital, was entirely responsible for the photomicrogsapıs, and for this exacting and time-consuming labour I sish to expreso my armest thanks The Departments of Medical Illustration at Guy's Hospital and Sydney Hospital have hindly provided photographs of patients and biopsies De RA Velick has read the teit in its various stages and has provided stimulating criticism, which I gratefully acknowledge Without the encouragement and assistance of Dr PNF Bishop this book would never have been written, and for 2 guidance and inspiration I am sincesely grateful fy task has been facilitated throughout hy the total and frienctis support of the publishers PETER FH13.L Macquarie Street, Sydney, October, rose ·CHAPTER 11 HISTORY ad Gynacomastia, ulien well developed, as such an arresting phenomenon that it not only excites meclical interest but arounes the curiosity of the layman Reference is made to the condition in numerous myths and folk korcs, in which it is often regarded as a punishment sent by the goch Herodotus, uho lived during the fifth and sixth centuries BC., Gare one of the first descriptions of 63 necomastia, 3 conction which he encountered among the Scythians, who were considered an elemunate Tace. Hippocrates* mentions Hyn1.ccomasta among the same race, but he regarded the condition as a disease of equatson, resulting from ricesne linse ding is support of this rien he jointed to the absence of gracomastia among the lower classes, who nere too poor to buy horses Aristotle mentioned Aynacomastia in hr furstory of animals He descrixx the secretion of " milk" which could be expressed from the breast and clasmei to have seen several cases Bamseil He further stated that when the prresis enquire of the God of Lemnos as to the significance of gynacomastra, they learnt that it was an ominous signs, The teachings of Aristotle were widely disseminated untu the time of Galen, who zmented the world cynacomastiz, ulich ke defined 25 unnatural increase in the constituint lat of the breasts of men Galens, also wrote about enlargement of the glandular part of the male breast, a condition which he did not call 832ecomastia He attribuind a far-reaching significance to such enlargement It was an orthodox belse among the ancients that both scies had "seed", but Galen was the first to suggest that the seed was the same in the tuo seves, being expelled in men and retained in somen He regardert gynæcomastra* as being the Tesult of retention of femining seed He appears to have seen intcomastia associated 11t bopogonadism and failure of cusculatio These steus of Galen concerning sex differentiation remained in the batrsatore for centunes The first surviving chnical description of necomastia *as that of Paulus Agoneta,' the last great Byzantine physician, uho used at the end of the seath and beginning of the seventh century & D 1s at the season of puberty the breasts of female ! 250 in like sanger those of ales also swe}} to a certain extent but for the most part then subsidie vain But in some cau.heses haung Balfusrcd a beginnur they go on inurramy own to the fextration of fat bulow This description of the normal breast der clopment of boys at puburty was overlooked until recent years, when it becarne apparent that some degree of transient brcast development is part of a normal male puberty Chapter VIX) Egineta goes on to advise surgical treatment in those patients in whom the condition persists Wherefore as this deformity has the reproach of efferrimacy tus proper to operate upon it" He gives a beautiful and concise description of the operation The remarks of Paulus Agneta passed almast word for word into the writings of Arabic and Moorish authors 15 houe i orks uere read throughout Europe during the Viddle Ages * The word s necomasta ts here used as defined in this book, not as defined by Galen.

·8 GYNECOMASTIA .. 1 Sometimes enlargement due to the deposition of fat is difficult to distinguish from gynæcomastia Generalku, hou na even in the presence of fat in this way, include pain and of the areola When secret glandular enlargement is present Finally, when fat is deposited in the region of the breasts, it is usually from vhich requires treatment by restriction of food i been lost, the glandular component of the breas ccasionally this form of treatment is a necessar This definition is short and simple and avoids all controversial issues In addition it enables the term gynæcomastia to be used after a simple clinical examination At the same time it does not prevent pathologists from using the term, especially since the morbid histology in cases of gynæcomastia is essentially the same, no matter what has caused the condition to develop (see page 22) 11: be di this clinically at buys Hospital, 27 were submitted to operation, and in every instance macroscopic and microscopic evidence of glandular hypertrophy was found Peters and his colleaguess also found a very high degree of accuracy in the diagnosis of cases of gynæcomastia as revealed by specimens removed at operation It would therefore seem that clinical examination is sufficiently accurate to justify the simple definition already given Defined in this way, gynæcomastia is not a disease, but a symptom or sigri, the causes of which vary from a transient manifestation of puberty to a major disturbance of the general health The histological characteristics of gynæcomastia are discussed in a later chapter (page 22) Here it may be pointed out that the exhaustive studies of Merville and Karsner3 have done much to justify the simple definition to be used throughout this book, in so far as these authors have shown that certain histological features invariably accompany enlargement of the gland, while other features are less constant in their appearance It has never been shown, however, that a particular histological e is therefore complicated The words gynæcomastism, gynecomasty and gynæcomazia (gynæcomasia) are sometimes used instead of gynecomastia Gynæcomastısm is occasionally seen in the American literature, and is an attempt to anglicize the Greek word, but it is not euphonious Gynæcomnasty is seldom used, and is neither Greeh nor English. Gynacomazia is derived from the Greek word mazos, which is confined to the Ionic dialect, and is therefore not suited to the medical vocabulary It is not true, as some have said, that mazos refers to the male breast and mastos to the female (Liddell and Scott) Gynecomastia is clearly, therefore, the word of choice, since it is both correct and orthodox REFERENCES 1 CHEATLE GL, and CUTLER, X (1931). " Tumours of the Breast ", Arnold, London STIED4 H (1893) Best Khin Chr. 14. 179 * KARSYER HT (1946). "Gynecomastia ", Ain Path 22 235 + WEBSTER GV (1944). "Gynecomastia in the lans", wol Surgeon, 95 375 . PETERS ) II SIEBAR U K and Deus X (1955) Tamilial Gynecomastia Associated with "amily C Tudocrinol 15 182 Arch Surg. 26 1054 Oxford IT, and CritiS, AC (1954). "Gynecomastia Review and an analysis of 160 Lases ". * Inf Ved . 40 985 ·CHAPTER III RELEVANT LITERATURE Since 1930, a fumber of falfits late afeared on the subject of gtxcomast23 The contributions form the basis of primant-day know fale of the subject and are tutelare separated from the works of puruks kustorical interest retium in the last chaples Thme grafx deal with the subject as a whole, as opposed to a number of papers to be rexed 153 later chapters which treat only sprial a-gacts of f**icomasti In 1930 Knat publiked an impurtant paper on till subject of gyucomasta; he gave an earlive review of the pyet tous literature from which he gathered uniormatson concerning :(*) examples of the cosmetion Krt tre the importance of Arguing synecomastia (109 enlarg13533t of the brand due to the accumulation of lat and to the presence of tumour and also from *kat he called mastitis Blolewcentrum" In order to reclude the condition, but the fonction. Krin dehned necomasta m the following terms trenlargement of ofte at lath make lore333 ORLorin: at ant 3.14 and brought about txt ***rpilasıx of the glandulet port of the vast ako ng bspwrplasa of glasular and 21) nutral Issue com] This definition formie a useful bass for the author's anals of the catalen from the literature This was the first paper to stress the importance of stological change 19 the breast In di-cuming the tipfogy of fynzcomastia, Kriss brgan by considering such factors as estal continence (taking us back to Calen's idea of retainer seedi, trauma and local presure Ilc then digired into a di-cution of the two theories of the determination of es nehich were widely held at the time namel (the Hottnt- Steinach throny, wych, attributed mery aspect of seu (praman as neli as secondary ketual characteristics) to the action of location, and (is) Hallian's theory that sex is genetically determined Knay accepted the second theory which was harilly surprning because Hallian was his chuset Kass endeavoured to support Halli3n, thens br >> Oun veys on the utsolars of gynecomastia These aretations are interesting in $leof racent studies *hich point to disturbances in sex differentiation as a factor in the atrology of certas types of gynecomastia (page 95} Kristated that castration of male animals did not proluce breast den elupinent, and from this he concluded that the testes plased no important part is the ætsology of narcomastia In 1933 llenville published a paper on sy naamastia which summarized the Luterature up to that year The chief value of Benville's paper lies in ith splendid account of the histology of the breast in gynecomastia The author honed that increase in stroma as well as in parenchyma 133 Een in all cases of gynacomastia Ventille showed that the histological changes wen in gecomasta resernble those of styroadenoma oi the fesnale breast He fussher pointed out that there ras no virtue in describing fibroadenoma of the male breast which he hoved was merely a further extension of the usual changes found 33 naconustia and was seen in longstanding cases By his thorough and scientific approach to the histology of the breast in gynecomastia, lenville cut short the use of numerous terms and clasat fications which threatened to reduce the subject to a state of confusion ·10 GYXACONISTI.A During and after the Renaissance, gynæcomastia received the passing mention afforded to a medical curiosity. For example, in 1669 Charletont described an interesting case of gynecomastia suth secretion from the nipples: l'idi enam Januse sintonin Benzuem ex oppido Portus Hlaunch, an agentem XXX: pallidum barba rara, pingu habitu e un mamil lactis fanfio proftuebat, ut infantım ferini lactau potisset, ne solum efluebal, "pr'sferebatter Viles diu erat, et non lenía folus ssfit passus incommoda * "1 1694, used gynæcomastia was due to the expression e puerperium During the next 150 years little appears to have been written on the subject of Synecomastia For example, a book on diseases of the breast, written by Velpea, appeared in Pans in 1854, during the last half of the nineteenth century this became a standard testbook on the subject Velpeau does not mention the word gynæcomasnia and devotes only a few pages to diseases of the male breast. However, in 1848 von Rasedow mentioned gynæcomastia in descnbing the discase which bears He referred to the case of a man suffering from a severe degree of thyrotoucos who showed gynæecomastia, while women similarly affected showed atrophy of the breasts In the first volumes of Annals of Surgery. Jonathan Hutcheson published three papers reporting cases of gynecomastia One patient was a boy whose mother suffered from acromegaly In more recent times (1925) Cordalo pointed out that testicular atrophy was scen in some cases of cirrhosis of the liver, and in the following year Silvestrinit drew attention to an observation he had first made in 1904, namely, that gy comastia is sometimes seen in patients suffering from cirrhosis of the liver The triad of cirrhosis, testicular atrophy and gynæcomastia is sometimes referred to as the Silvestrini-Corda syndrome Silvestrini was of the opinion that cirrhosts produced "endocrine imbalance” which in turn caused gynecomastia " Perturbamento dell' equalibrio ormonicu che mantiene i carrattice sesuale " his name an REFERENCES HERODOTE > (1870) Eintis 105 126 Fd de H Stern, Berlin * HIPPOCRATES (100) Treatise on tur Water and I'laces' pp 100 335 larin TRISTOTLE (154) Histors of animals, Calvarini Lib III Chap XY Parts ARISTOTLE History of Inimals', (rcurge and Bell Hook UI, Chap XVI. (reuswell Oxford (ALF De Semine Lib 01 • GALES fimtiones lleder Lib Ip I GENITA1101 The Sukah of Mulus Lene ta Vol 1 Book II, Sectron XLVI. and Vol 1 Booh Section SLUT Ssdenham Society, London .LON BISEDOW KI14 Dic coloranzell chuschi pl ges Heilk 49 709 "HITCHESUS (i hot 1432) Ovna comazia and Other Thorations in the I) elopment of 50 Irch Surg load 3 327 + 701297) 8 10 CORD L (1925) '(nicomastia peria Wed 5 100,7 11 MILFSTRINI R (1920) Gyomonlasta Riforma ed 142 701 "CHARLCtos, 1 (1009) (L40 Nm pril 3 London 13 EI PEAL Tretise on the pinces of the rest Таг: Vaurti u in nas 32nd year, much milk foued forth that tutto out Hr han & twhole of his life des clopment IL + Disturbance v the hormnal bulance !!

·RitchINT LITERATURE 13 relevant hterature in the light of his own uberations, citing selesant esperimental evidence and suggesting a possible mechanism for each group of cases of gynacomastia. Honever, this segregation of different groups of patients with gyna comasta mas not carried to the fullest possible extent, and the author sometimes discusses gi narcomastia as a uhole uken it would have been more appropriate to deal with the condition from an ætrological point of vier. For esampie, Karsser studied the age incidence of gynacomastia by decades, although it sould be preferable to separate (for example) those casrs associated with Iner dease from those associated with puberty Today more is knoun about the causative disease concerned, and it is usual to consuder wynacomastia according to the associated etiological factors, REFERENCES krca, }) (1939), "Gyurcomastia ", ck 1 Ginak. 131. 503 BIENVILLE, 1 C (1933), "Gynecomastia". Arch. Surg, 26. 1034 * KARSUER, 1 T (1946), "Gynecomastia ". Am Path, 32 235 ·12 GyxÆCOMASTIA Benville also gave a careful review of the occurrence of gynecomastia during the course of a number of endocrine diseases. After a study of all the recorded examples of gynæcomastia associated with testicular lesions, he concluded that any disturbance of the "endocrine system could produce gynæcomastia Unhke Kriss, Menville sau the importance of testicular lesions in the ætiology of gynaecomastia Beyond this, however, Venville's conception of the ctiology of the condition was lost in speculation on the subject of sex differentiation He believed that sex differentiation was the result of a balance bets een male and female factors, and that important causes of gynæcomastia included bisexuality and a lack of " male sexual influence" It is of course true that sex differentiation is the result of competition betucen male and female influences, but Vienville was not in a position to understand the possible role of these influences in the etiology of Bynecomastia He failed to state clearly that gynæcomastia can affect young men m whom no other evidence of " lack of male sexual infuence" exists Moreover, Menville was not to know that synthetic cestrogens were soon to be widely used in medicine and that gynecomastia could be induced in normal men by these hormones, the breast showing histological appearances identical with those which he described so carefully as typical of gynecomastia Karsner reviewed the literature dealing with gynecomasba before 1946 19 this paper we encounter clinical endocrinology as we know it today The author found that unilateral gynecomastia was more common than bilateral, and that the left and right breasts were affected with almost equal frequency The third decade pronded most of his 280 cases, and the majonty of patients described a gradual increase in the size of the breasts during a period of several weeks and thereafter no change One case in ten gave a history of trauma, although this was sometimes as long as three years before the onset of gynæcomastia Karsnes gave an excellent account of the histology of the breast in gynecomastia , he distinguished between the stroma of collagenous tissue and the periductal connective tissue, a distinction which tie stated was not possible in the normal male breast The stroma shows great hypertrophy in gynecomastia, with fibroblasts and infimatory cells, the whole tissue being loosely arranged as the result of adema in discussing the ætiology of gynæcomastia, Kassner made it clear that the histological changes in the breast were not related to the causal factors involved In other words, the morbid anatomy is essentially the same, no matter under what circumstances the gynecomastia appears He favoured excessive secretion of @strogen as the fundamental cause of gyn.tcomastia and stated that both breasts were usually enlarged when the condition resulted from some manifest endocrine disease, although there is often some mequality in the size of the two breasts Karaner nelieved that trauma s either coincidental of merch. serves to draw attention to an existing swelling of the breast, but does syot cause gynaecomastia In ardıtion to these ciscal and histological observations Kariner macle free use of the methods of hormone assay in current use at the time Throughout the following discusson impiasi ly lasd on the ssetsoortante al xnct of torrones or their proxłucts This? ** fu riision of the sources of #TOT 491 the fact that seh asvais do not gelisarily indicate what happens to the hormonts in the truly Yet these anays are te nearest objecthe approach to the prot} This statement gives sume iadscation of the progress marle by endocrinology in the (unsistent thirteen years such separate the papers a Menule and harner with this enlightened attitude tar-ner remains cautuus in applung inimal rypsin ments to nati For example he was able to see that, although androgens cause proliferation of the 113mary glands of experimental animals, there is little evidence to show that they have the same effect in man This approach to the problem enabled Karsner to see that fynecomasti atose from a number of different canses, and these he dealt with a turn rewing the ·RELEY.XT LITER ITU'RE 13 relevant literature in the light of lus our oneratione, citing relesant experimental esidence and suggenting a funsible mechani«m for each group of cases of gynacomastia. Floueter, this segregation of different groups of patients with STIX comastia was not carried to the fullent facsible evlent, and the author sometimes di cui si gynacom massa as a whole when it would has e xxn more appropnate to deal with the condition from an .ctrological point of view, for example, Karner studied the age incidence of gynacomastia by decades, altfionch it would be preferable to separate (for example) those caves asiated with liver disease from those asociate will puberty Today more s hnout about the causative diseases concerned, and it is usual to consider $77.xcom.stir according to the ass673}<! atrological factors REFERENCES KKS 8 (1930) "Gymrcomastia : frck Gino. 135 503 SEKVILLE, I C (1933), "Gynecomastia Arck Surg. 26: 1034 * KARSVER, T 7948), "Gynecomastia", dmt, 32 235 ·CHAPTER IV CLINICAL AND LABORATORY METHODS IN GYNÆCOMASTIA CLINICAL METHODS HISTORY It goes without saying that a thorough history is the first requirement for the investigation of a patient suffering from gynæcomastia In particular, certain points deserve special emphasis. Gynacomastia --The onset and evolution of breast development, together with the presence or absence of pain and secretion, are important Puberty —The age of onset of puberty and the timing of the individual events which go to make up puberty are of special interest (1 e, age at which pubic and axillary hair appeared, shaving first became necessary, breaking of the voice, erections and emissions first occurred, etc Sexual Function ---It is necessary to obtain some measure of sexual function following the onset of puberty, eg libido, erections, emissions and fertility Past Health - Some clue to the cause of gynæcomastia can occasionally be found in the previous medical history. The following conditions are especially Televant (1) Jaundice and liver disease (2) Mumps (3) Traumatıc lesions of the breasts or testes (4) Addison's disease (5) Thyrotoxicosis (6) Prostatectomy (7) Tuberculosis (8) Syphilis (9) Leprosy (10) The use of or exposure to the following drugs (1) astrogens, (11) androgens, (111) chorionic gonadotrophin, (v) deoxycorticosterone or adrenocortical extract, (v) digitalis, (vi) decp-ray therapy, (vil) radioactive isotopes, (v11) liver poisons (11) Undescended testes (12) Malnutrition Famy History - Gynecomastia sometimes appears to run in families PHYSICAL EXAMINATION In addition tn the usual physical examination, certain points are especially important Breasts 1 ppearance -The size shape and symmetry of the breasts are recorded Vipples — The size, shape, symmetry and presence of pigmentation are noted Glandular 115site -- The presence, extent and tenderness of glandular tissue as well as evidence of extraneous lumps are important Fat - The amount and distribution of body fat in general and the presence of fat in the vicinity of the briasts in particular should be recorded Searchion --in attempt can be made to express secretion from the breast by Lentle manipulation ·CLINIC IL METHODS 15 The size of the breasts is important for purpose of subsequent comparinon. Most attempts to measure the chest wall liave proved fruitless so far as providing a record of the size of the breasts is concerned (especially in dealing with groung boys). B TIGURE 1 female breast A rough measure of the extent of gynecomastia in a given individual can be obtained by means of a photograph An oblique view of the chest is taken, and this will serve for the purpose of comparison with subsequent photographs to indicate changes in ·16 GYNECOVASTIA the severity of the condition (Figure 1) Enlargement of the breasts which is quite obvious on clinical examination but which is scarcely evident in an oblique view of the chest is described as being of Grade I severity Grade III includes patients whose breasts are comparable in size with those of adolescent girls Grade II severity refers to those breasts which are obviously enlarged in a photograph of an oblique view of the chest but which fail to reach the size of those of Grade III (Figure 1). This classification is necessarily very crude, but it gives some measure by means of which one patient can be compared with another, The examination of the breast should be conducted with the patient first lying down, then standing Palpation is best performed against the contracted pectoral muscle by asking the patient to put his hands on his hips. The breasts should be handled gently because they are frequently tender. Occasionally lymph glands can be palpated in the aulla in patients suffering from gynæcomastia The most important disease of the male breast to be distinguished from gynecomastia is carcinoma Usually this distinction is possible on clinical examination 2.-ndari...hante -f42 L... 13 somcermes encountered, suggestive of malignant concentre in relation to of cases Body Jeasurements The height and weight of patients should be measured; the height enables the rate of growth of adolescents to be estimated and by comparison with the span assists in defining eunuchoidism (page 18) The span is measured from the tip of onc middle finger to that of the other, with both arms outstretched. The upper segment of the body (US) 15 measured from vertes to pubic symphysis, and the lower segment (LS) from the symphy is to the floor When the span exceeds the height by more than two inches, and when the lower segment (LS) exceeds the upper (US) by more than one inch in patients over the age of 14 years, in the absence of arachnodactvly, the stature may be described as eunuchord This conclusion can be checked by reference to tables in which span, US and LS measurements are given for various heights, weights and 1 ages Genital Organs The genital organs are examined in the usual way Unfortunately, measuredients Secondary Sernal Characteristics Secondary sexual characterstics can be examined and conveniently si coreled as folloss (a) Jian ---(1) Head temporal recession of the hair-line and baldness (11) Face come estunate of the frequency of shaving and the distribution and texture of facial hair (m) Pubes amount and distribution (IV) fulla amount and 011- tribution (0) Budy bar amount and distribution (VI) Limb hair amount and distribution (b) l'oice Broken or unbrohen (c) Prostate rough estimate of the size of the prostate gland can be made by comparison with the size of the normal adult gland ·SPECIAL INVESTIGATIONS 17 SPECIAL INVESTIGATIONS Hormone Assays (a) 17-ketosteroid Estimation -Throughout this book estimation of 17-ketosteroid excretion refers to t adult men of 4 to 20 mg from the figures of Robins (6) Urinary Gonadotrophins-Urinary gonadotrophins were measured by the method of Klinefelter, Albright and Griswold, using immature female mice and expressing the result in mouse units In a series of roo normal men whose urinary gonadotropluns were studied at Guy's Hospital, the values fell within the normal range of >6<32 mouse units FIGURE 2 The normal adult male testis A specimen obtained by means of biopsy from a man, aged 33 years, who complained of psychogenic impotence (A) Shous normal spermatogenesis Meiotic figures are seen in spermatocytes and Sertolt cells are seen between the germinal cells (B) Shows spermatogenesis and a nest of Leydig cells (c) Urinary Estrogens --Unless otherwise stated, urinary cestrogens were measured by a chemical method performed at University College Hospital under the direction of Dr G IM Swyer The method (a modification of that described by Brown) is described in detail by Braunsberg and her colleagues 7, 8, 9, 10, 11 The range for normal males is discussed in Chapter VII Eramination of Semen The chief interest in the examination of semen in cases of gynæcomastia lies in the detection of azoospermia in Klinefelter's syndrome and prepubertal testicular failure The volume of the ejaculate and the number of sperins per milliltre are given, and the motility is graded from o to 4 (4 means that more than 80% of sperms are motile) B ·18 GYNECOMASTIA Testicular Biopsy The most satisfactory method of testicular biopsy is that described by Simmonsta and by Charny 13 The most important precaution is to avoid the epididymis, which in most cases is not difficult if its presence is kept in mind. The histology of the tubules and their contents is of particular importance in patients suffering from synæcomastia Some quantitative estimation of the amount of Leydig cell tissue 18 years method relates the number of Leydig cells to the number of tubules and is based upon counts of the number of these cells related to 100 tubules * The method is easily mastered, and counts performed on one biopsy by different observers are in close agreement. It remains, however, to establish the relationship between the number of Leydig cells and their functional capacity. DEFINITIONS The three words hypogonadism, infantilism and eunuchoidism are loosely applied in the literature of endocrinology at the present time, and different authors use these Words to denote different entities Throughout this book these words are defined in the following terins Hypogonadism may be defined as a condition of failure, partial or complete, of the endocrine or germinal functions of the gonads, or failure of both This definition implies that the failure is bilateral In the male, hypogonadism is sometimes referred to as testicular failure The word infantilism, unqualified, is not used in this book, and sexual infantilism is defined as the persistence of the prepubertal condition of the genital organs (other than the gonads) and the failure of development of secondary sexual characteristics in adults. An adult will be defined for this purpose as an individual over the age of It should be noticed that sexual infantilism defined in this way takes no account of stature The state of the gonads is excluded from the definition, because in cases of sexual infantilism this may not be that of the formal prepubertal gonad Eunuchordism may be defined as a bodily configuration in which, after the age of 14 years, the span exceeds the height by more than two inches and/or the lower segment exceeds the upper by more than one inch The terms "span "and" upper segment" have been defined above (page 16) This definition does not take into It may be argued that the word zin of the word bears little relation the term is frequently applied to genital organs will either greatly restrict the use (and hence the value) of the word or will preclude exact definition The term eunuchoidism or eunuchoid stature is a useful way of referring to the physique of individuals in whom growth of the limbs is excessive because it has continued beyond the stage at which the epiphy'ses fuse in normal individuals This can occur in hypogonadism of gonadal or of pituitary origin Sometimes such a stature is encountered in individuals with no endocrine abnormalities, cg in cases of arachnodactyly. Here the context wil indicate the nature of the condition REFERENCES 1 WILKINS, L (1950) "Endocrine Disturbances of Childhool and Idolescence Thomas Illinors CALLOX, XII. CALLOW, RK, and EMVENS, CH. (1918). "Colorimetric Determination of Substances Containing Grouping CH,CO- 1 Urine Extracts as Indication of Introxen Content", Biochem }, 32 • Roersson, I. (1949) Excretion of 17-ketosteroids in Ven of Different Age-croufr with Special Reference to trostatic Cancer". Bru! ] Cancer, 2. 13 • The count is expressed as the number of Leydig cells per tubule :בונו

·SPECIAL INVESTIGATIONS
19
Viin.si "Katatorul in Flenlth and sense **
Si Mart's Hoss J. 52: 40
etosteroids with Special
rience with Quantitative
Hormone in Unne in
ination of Estrogens in
of stronc, (Estradiol
ination of strogens in
y Partition Chromato.
of Steroid Estrogens by
Huorimetry ". Pror Soc Exper Biol Ned. 64.64
10 MARRIAN, G r (1948). "Chemical Issay of Unnary (Estrogen") Endocrinol. 5 77
!! BRAUNSBERG, H1, STERN, VI 1, and SWYER, GIA (1954), "Experiences with strogen
Determination by Fluorimetry". Nemoirs of the Society for Indocrinology, Xo 3, P 41,
Canıbridge University Press
" SIMMONS (1952). "Correlation of Testicular Biopsy Material with Semen Analysis in
Male Infertility", ER New York icad Sc. 55. 043
** CHARAY, C W. Coxstov, ! S, and Meranze, D R. (1952). "Testicular Desclopmental
Histology, A Vew York Acad Sc. 55 397
1 SARGENT, J W, and McI)OVALD, J R (1948). "A Methout for the Quantitative Estimate of
Leydig Cells in the Human Testis". Proc Staff Weel Mayo Chin, 23
249

·CHAPTER V THE MALE BREAST ANATOMY Except in obese subjects, the male breast is so poorly developed as to remain invisible to inspection of the chest wall, and the only evidence of glandular tissue consists of a few minute nodules which can be felt as irregularities by the examining fingers as the areola is moved across the chest wall When masses of fat cause the loose subcutaneous tissue of the chest wall to fill out in imitation of the female breast, no glandular tissue can be felt beyond the margin of the areola This accumulation of fat is usually seen in the presence of well-marked generalized obesity and is seldom a purely local phenomenon When the glandular component of the male breast does enlarge, it is separated from the overlying skin (except in the region of the arcola) by a layer of adipose tissue, as in the female. The mammary tissue, lowever, is not encapsulated, and some of this can be felt directly beneath the skin Even in the presence of considerable amounts of fat it is generally possible to feel the glandular component of the breast when this is enlarged EMBRYOLOGY Between the third and fourth months, the basal cells surrounding the primitive nipple form a series of down-growing sprouts, which gradually invade the underlying tissue and are canalized to form milk channels In the final stage of embryonic mammary development, the milk ducts form a series of branching channels with a definite lumen lined by two or three layers of cells The nipple gradually everts as the result of subepidermal connective tissue proliferation The lobular buds, from which clusters of alveoli form (in the female) after sexual maturity, do not develop until puberty 1, 2 After birth, epithelial activity continues for a feu wechs, and then in the male in hortui ? A crnering to Tinhric Jolandular tissue between icu born, he third 'ath the nipple, together with some secretion, is said to occur in 10% of infants. At this 1-4 WELL epithelium with desquamation of lining cells occurs The lumen of the ducts becomes closed, and the penductal connective tissue is seen to be hyalınized These changes are seen in normal infants of either sex 1. PUBERTY At the time of puberty about 70% of boys show a palpable button-like nadle, the puberty rode", beneath the nipple Jung and Shafton. refer to this structure as the "subareolar node" The terms " puberty mastitis " and " adolescent mastitis" imply something more than physiological activity, and are therefore less desirable

·TIE VALT BREAST
21
This anakening of the male breast is seen under the microscope to proluce
changes like those found after birth The tubules dilate and increasr in length, and
Tha garistal tissue becomes more vascular,
the ends of the terminal tubules
the al col which later develop
in the female
FIGURE 3
(Al Essential gyn.z.comastia (8) Prepabertal testiculas failure (C) Klinefelter's syndrome
Between the ages of t6 and 17 years, involutional changes occur which involve
collapse of the tubules, condensation of connective tissue and a diminution in size
of the epithelial cells The male breast has now run its full life span, and gradually
sclerosis of the stroma, with obliteration of the ducts and vessels, sets in.

·22 GYNECOMASTIA THE BREAST IN GYNÆCOMASTIA The breast in cases of gynæcomastia shows histological evidence of stimulation and closely resembles the mammary tissue of girls at the time of puberty. MACROSCOPIC When the breast is removed at operation in cases of gynecomastia, it resembles the female breast at puberty in its gross appearance Sometimes it has a firm, discrete, nodular character, which some observers have called fibroadenoma, on the grounds that in certain cases the tissue is encapsulated 5 This encapsulated form of the male breast is seen in those patients in whom gynæcomastia has been of long duration and calls for no special terminology, the use of the term fibroadenoma in this context is misleading and superfluous MICROSCOPIC Briefly, the picture is one of growth of mammary ducts and of periductal stroma, but lobule formation is absent Proliferation of duct epithelium occurs together with some desquamation of cells into the lumen Small projections of epithelium in the lut may occur, and in some instances the ducts are dilated and full of secretion 2, 6, 7 Around the ducts there is an increase in connective tissue, infiltrated by wandering cells Sometimes the subcutaneous sweat glands undergo hypertrophy The picture is often indistinguishable from the early development of the normal female breast at puberty 2, 5, 6 Mitoses are sometimes seen in the periductal connective tissue cells, and lymphocytic and plasma cell infiltration with a few eosinophil cells may occur in this tissue Menville5 has followed the changes in the microscopic features of gynæcomastia in long-standing cases After one year changes are seen which resemble fibroadenomatous hypertrophy in women Menville produced convincing evidence that this appearance is a further extension of hyperplasia and not a separate pathological entity guishes the stroma from the periductal connective tissue The stroma 01 Bytwomastra differs from that normal male breast only in amount The periductal tissue, however, is loosely arranged and is infiltrated with lymphocytes, plasma cells and mononuclear cells This distinction is not possible in the normal male breast L...-ha- of layers of cells lining netimes seen-either as he duct or its branched that the myocpithelial -, lie within the are stimulated mastia may be so extensive that they push their way into the lumina of the ducts All observers seem to agre -- coon in the female breast do not appear namely, neonatal gynæcomasti produce considerable quantities of " bitches milk SCILLLULL VIULUmean that alveoli are present, because gynæcomastia occurring at puberty may be SO associated with some secretion, but acını are not to be found histologically & far there have been feu reports of the microscopic appearance of the breast in neonatal eynecomastia, but in general they are said to resemble miniature lactating glans U ·ACTION OF HORJOXES ON THE BREAST 23 Although differences in microscopic features are noticed between one case and another, and even within one specimen, these differences are of minor importance. As yet there is no evidence to show that histological differences are consistently associated with different cau<31 factors. Furthermore, elaborate classifications of histological features of the breast in gynecomastia have not increased our understanding of the ætiology or pathogenesis of the condition and are best avoided, because they are tedious and confusing. In the pages which follow, reference will be made to the typical microscopic appearance of the breast in gynecomastia. This should be taken to mean that the changes already described are present-ie. (a) increase in length and branching of ducts; (b) epithelial hyperplasia (c) increase in stroma and in periductal connective tissue; and (d) invasion of the stroma by inflammatory cells. These figures serve to emphasize the fact that the appearances are not specific for any one type of gynecomastia THE ACTION OF HORMOXES ON THE BREAST Until more is known of the endocrine control of mammary function in man under nonnal conditions, our knowledge of this subject will be based upon conclusions drawn from experiments in which individual hormones are administered to animals and the response of the breast is studied. Some of these experiments are relevant to the ætrology of gynaecomastia. ESTROGENS The action of estrogens upon the breast varies from species to species. The chief difference lies in the capacity of these hormones to induce alveolar development Three types of response to cestrogens are encountered in anımals", 10, 11. (i) that in (dog) Van appears to belong to the first group, although detailed studies have not been undertaken (c) Periductal connective tissue increases, becomes more vascular, and is invaded by lymphocytes and polymorphonuclear cells (d) Lobule formation does not occur, although sometimes the ends of the ducts become dilated, forming the so-called lobule buds These changes are reflected by an increase in the overall size of the breasts. The breasts may be stumulated in this way both in man and animals by natural and synthetic oestrogens, which appear to produce the same effects both by local inunction and by oral administration. In the case of locally applied ointments one breast alone is affected, unless the ointment is very strong and is applied frequently, in which case both breasts enlarge--presumably because sufficient hormone has been absorbed into the bloodstream to affect the other breast 12 In certain species very large doses of oestrogen appear to stimulate the develop ment of alveoli It is generally believed that alveoli in the breasts of women do not ove their formation to cestrogens ·22 GyxÆCOMASTIA THE BREAST IN GYNÆCOMASTIA The breast in cases of gynecomastia shows histological evidence of stimulation and closely resembles the mammary tissue of girls at the time of puberty. MACROSCOPIC When the breast is removed at operation in cases of gyn.ecomastia, it resembles the female breast at puberty in its gross appearance. Sometimes it has a firm, discrete, nodular character, which some observers have called fibroadenoma, on the grounds that in certain cases the tissue is encapsulated 5 This encapsulated for of the male breast is seen in those patients in whom gynæcomastia has been of long duration and calls for no special terminology, the use of the term fibroadenoma in this context is misleading and superfluous MICROSCOPIC Briefly, the picture is one of growth of mammary ducts and of periductal stroma, but lobule formation is absent. Proliferation of duct epithelium occurs together with some desquamation of cells into the lumen. Small projections of epithelium into the lumen may occur, and in some instances the ducts are dilated and full of secretion 2, 6,7 1. ....A... cells pictt breas tissue cells, and lymphocytic and plasma cell infiltration with a few eosinophil cells may occur in this tissue. Menvilles has followed the changes in the microscopic features of gynæcomastia in long-standing cases After one year changes are seen which resemble fibroadenomatous hypertrophy in women Jenville produced convincing evidence that this appearance is a further extension of hyperplasia and not a separate pathological entity Karsner pointed out that too little attention is generally given to the alterations of the stroma In fact, the enlargeme to proliferation of connective tissue, as a rule, contribute very much to th guishes the stroma from the periductal connective tissue The stroma of gyneco. mastia differs from that of the normal male breast only in amount The periductal tissue, however, is loosely arranged and is infiltrated with lymphocytes, plasma cells and mononuclear cells This distinction is not possible in the normal male breast Epithelial hyperplasia leads to an increase in the number of layers of cells fining the ducts up to five or six deep Budding of the ducts is sometimes secn- either as partos branchung structures or as spherical projections from the duct or its branched prolongations (Figure 3) Karnauchow" has recently shown that the myoepithelial TL.-. -- Ire within the are stimulated mastia may be so extensive that they push their way into the full hd UI KHU UU All observers seern to agre the female breast do not appear may titches uk truly cause gynæcomastia occurring at Puberty may be associated with some secretion, but acons are not to be found histologically. So far there have been fex reports of the microscopic appearance of the breast in neonatal gynæcomastia, but in general they are said to resemble miniature lactating glands * JUILLIUI VUL) UV ILLU ·ACTION OF HORMONES ON THE BREAST 25 in the presence of (estrone. Androsterone does not cause mammary growth in mice, but 17-methyl testosterone causes alveolar development in this species and duct growth in the male guinca-pig, Enough has been said to indicate that differences in the response of thic breast to androgens, as between one specics and another and between one androgen and another, are so great that no simple general statement can be made 'The importance of this point lies in the fact that gy'n.rcomastia has sometimes been attributed to the action of androgens However, in the money, the animal whose breast tissue is thought most closely to resemble that of man, stimulation of the ducts does not occur, but instead a characteristic heaping up of duct epithelium is seen,' and this change is not found in the breast in cases of gynxcomastia , : HORNOSIS OF THF. ADEONLYPOPHYSIS Recent evpurimental data make it unnecessary to postulate the cxistence of mlarnmoger typical of physectom prolactın, ACTH and growth hormone ", , 11 Changes in the relative doses of these hormones will produce lactation With these results obtained by using known hormones, it is tempting to envisage the control of mammary gland activity as proceeding without the aid of hypothetical hormones In these cxperiments ACTH is used to restore the physiology of the hypophysectomized animal to normal, but growth hormone appears to evert some specific effect upon breast development, It is true that the punty of present-day preparations of prolactın, ACTH and growth hormone may be suspect "However, these hormones conform to certain chemical 1 The mammary growth-promoting actions of cestrogen and progesterone are abolished by hypophysectomy but restored by the concomitant administration of insulin This observation accords well with the fact that growth hormone and of cestrogens and progesterone from the ovary, and by way of prolactin, which There stimulates the development of alveoli and promotes the function of lactation is no evidence to suggest that prolactin plays an important part in the metrology of gynecomastia, and the significance of prolactin in the male is uncertain It is - L1 ILLA AL. ul grow TROLIulte mi lollidi uledst lulit on all alls lurther elucidation CHORIOVIC GONADOTROPHIN The action of chorionic gonadotrophın in men has been studied in detail by Maddock and Nelson 1 Nine men were treated by injection Of these, five complained of a decline in sexual potency which was not absolute, normal adult sexual development being present, two suffered from hypogonadotrophic hypogonadism (see page 46), one was a recent traumatic castrate, and one had Addison's disease The effects seen in the five patients who complained of some decline in potency may be summanized as follows (1) increase in the urinary excretion of oestrogen. (11) increase in 17-ketosteroid excretion, (m) changes in testicular histology ·24 GYNACOMASTIA It would secm that, in the absence of the pituitary gland, oestrogens either do not stimulate the breast or produce only a partial response In the presence of even minute remnants of anterior pituitary, however, cestrogens appear to produce their full effect 13, 14, 15, 16, 17 Malnutntion increases the threshold of estrogenic stimulation of the breast.18 The changes produced by @strogen are almost identical with those of gynæcomastia Geschinlitar tareh. *1.. men recciving suffering fron produced by monkey's by the injection of 500 rat units of cestrin daily for ten days Further support for the role of cestrogens in the xetiology of gynæcomastia has emerged from histochemical studies of the breast in this condition, Fisher and Creed" found abnormal quantities of hyaluronic acid in the stroma of enlarged male breasts. Ihnen and Perez-Tamayo'l made similar observations in the case of fibroadenoma in the female, and it has been shown that the administration of cestrogens causes an increase in the content of hyaluronic acid in the connective tissue of those stt res which are especially sensitive to østrogens, eg, the breast, the sexual skin of the monkey," and the rooster's comb 3 ANDROGENS Under certain conditions androgens are capable of stimulating the breast Astwood and Geschickter29 studied the effect of androgens upon the breast in rats and reported the following findings I Until the rat is six weeks old, breast development is identical in males and females, normal and castrate In fact, in each case the breast weight increases in proportion to the body weight 2. After the sixth week in females, increase occurs in length and diameter of the ducts Twigs develop along the course of the ducts Thereafter the breast undergoes cyclical changes The duct lumen increases and the twigs also enlarge during pro-oestrus and di-cestrus, after estrus, regression takes place Pregnancy brings about the first appearance of lobules and alveoli 3 After the sixth week in males, dense clusters of alveoli are seen along the sides and around the ends of the ducts No further increase in size and number of ducts occurs (Estrone will bring about the appearance of adult female breasts in sexually immature rats of either sex Testosterone will cause alveolar development but does not affect the length and size of the ducts-le it produces the type of breast seen in the adult male, when injected into immature rats of either sex There appears to be a considerable difference between the response shown by different species to androgens Van Wagenen and Folley, 80 using monkeys, found very little macroscopic duct development with testosterone but a characteristic heaping up of duct epithelium In man, no reports have appeared concerning the action of androgens upon the male breast, and the response seen in the monkey may not be the same as that seen in man. Klinefelter has reported the occurrence of gynecomastia in a man during androgen therapy in a personal communication Dr Klinefelter stated that the histological appearance of the breasts, which were removed at operation, was essentially the same as that seen in other forms of gynæcomastia Again, the conversion of androgens to cestrogens in the body is now an accepted metabolic reaction in man, 37, 38, 39 so that the action of androgens upon the breast may be complicated by conversion of these hormones to cestrogens Dehydroepiandrosterone causes duct growth in the mouse, but causes alveolar development ·Tic NI ALE BREAST 27 ectomized-ovariectomized animals were treated with hydrocortisone and cestrogen, or when ovariectomized animals were treated with ACTH and cestrogen. Sclye believes that his results may help to explain the occasional example of the sudden onset of lactation following exposure to acute stress Tuykorn Evidence is lacking that thyroid hormone is necessary for the growth of the CONCLUSION It is apparent that much remains to be learnt about the action of hormones on the human breast It seems likely that estrogens are responsible for duct development and for increase in stroma, while progesterone causes alveolar development, and prolactin supplies the further stimulation required for lactation As in of androgenic activity So far it has not been possible to obtain such proof, and animal experiments make it seem probable that the microscopic changes seen in REFERENCES FOLLEY, S J (1952). “ Physiology of Reproduction ", Jarshall, London, Chap XX * GESCHICKTER, C F (1945). " Diseases of the Breast Lippincott Baltimore #FABRIS, S (1927). "Tumefanone Alammaria e secrezione lattea nel Veonato". Pediatrica, 34. 457 Gynecomastia I 2.93 ny and Fibro- Brustrüsse im 1. •",Chap 16, LUller worth, London 10 SILVER, M (1953), Quantitative Analysis of Role of Estrogen in Mammary Development in Rats", Endocrinol , 10 17 11 KIRKHAM, W Rand TURNER, C W (195+), "Induction of Mammary Growth in Rats by Estrogen and Progesterone". Proc Soc exper Biol E Ded. 87 139 18 MACBRYDE, C M (1939). " Production of Breast Growth in Human Female by Local Application of Estrogenic Ointment". J AM A, 112 1045 12 GOMEZ, E T. and TURNER, C'W (1936), " Non-Effect of Estrogenic Hormones on Mammary Gland of Hypophysectomized Guinea Pg. Proc Sec. esper Biol & Med, 34. 320 * GOMEZ, E T, and TURNER, C W (1936), Hypophysectory and Replacement Therapy in Relation to the Growth and Secretory Activity of the Mammary Gland", Res Bull M10 Agric Exp Slut, No 259 ·26 GYNÆCOSASTIA (a) evidence of Leydig cell stimulation, (6) signs of seminiferous tubule damage; (iv) gynæcomastia (in two cases). Increase in cestrogen excretion began during the 24 hours following the first injection and reached levels of more than four times the amount excreted before treatinent A rapid fall was noticed within the 24 hours following the last injection. The 17-ketosteroid excretion also increased during the course of treatment, but varied considerably in relation to previous levels and in comparison with estrogen excretion The Leydig cells were smaller and darker than normal and increased in number. They showed more granules and more lipoid droplets, although the size of the latter was diminished. The tubules were small and showed necrosis of the gerin cells, cessation of spermatogenesis and peritubular fibrosis The Sertoli cells appeared to be normal Sperm counts fell during treatment and returned to normal after injections were stopped In the two cases showing gynecomastia, tenderness of the breasts was a feature, and the size of the swellings was between 3 and 5 cm in diameter The two cases of hypogonadism showed a rise in 17-ketosteroid and aestrogen excretion The castrate showed no increase in the excretion of 17-ketosteroids or estrogens, while the patient with Addison's disease showed a rise in the excretion of both 17-ketosterords and aestrogens These studies suggest that chorionic gonadotrophin affects the breasts ındırectly - motor 1.1 - na falley injections of this hormone ile histological eroids suggest of the patient source of the atients This paper provides the best evidence so far available in man that the Leydig cells represent the major source of testicular oestrogens Chorionic gonadotrophin exerts an effect upon the Leydig cells which resembles that of interstitial cell-stimulating hormone The importance of these observations will be seen in Chapter VIII, where it will be argued that gynaecomastia may result from excessive stimulation of the Leydig cells, which produce, as the result of this stimulation, excessive quantities of estrogen TY PROGESTERONE Progesterone stimulates the formation of lobules and of alveoli in females after puberty, and in this way prepares the breast for its definitive role in lactation Progesterone probably plays no part in the behaviour of the norinal male breast. and so far there is no evidence to incriminate this hormone in the production of gynæcomastia ? ADRENOCORTICAL HORMONES Studies of breast development in adrenalectomized animals have so far farled to establish an essential role for the adrenal cortex in the nortnal development of mammary tissue Variable results have been reported from experiments involving the administration of cortical hormones Some workers report growth of ducts under the influence of the monkey and in the guinea-pig, 11 hile othe lings 1, 32, 33, 31 Deoxycorticosterone exerts in in promoting duct development in spayed produces little effect 35 Results with cortisone and hydrocortisone are frankly contradictory Some workers have described inhibition of duct growth by cortisone, 95 while Selye36 reported considerable mammary gland stimulation with secretion when adrenal- 1n ·CHAPTER VI THE CAUSES OF GYNECOMASTIA It has already been stated. caused by a number of diseases. those cases of synuaccomastia re, is available to establish the true nature of the underlying condition and its relationship to the gynecomastia. 1. Gynecomastia associated with physiological states (a) Neonatal gynæcomastia. (6) Essential gynæcomastia (c) Involutional gynecomastia 2. Gynecomastia due to underlying disease. A Discases of the endocrine glands I. Diseases of the testes. (a) Prepubertal testicular failure (b) Klinefelter's syndrome (c) Leprosy (d) Mumps le Orchitis of unknown ætiology, () Tumours: Teratoma Chorionepithelioma Seminoma Interstitial cell tumour Sertoli cell tumour. (g) Radiation (h) Undescended testes (1) Castration 6) Trauma (k) Unilateral testicular lesions Varicoccele, atrophy of unknown ætiology II Diseases of the adrenal cortex (a) Tumour (6) Hyperplasia (c) Stress III Diseases of the thyroid gland (a) Hyperthyroidism (6) Hypothyroidism IV Diseases of the pituitary gland (a) Acromegaly (6) Chromophobe adenoma (c) Hypopituitarism V Disorders of sex. (a) Hermaphroditism. True False. (6) Transvestism ·28 GYNÆCOMASTIA Ula 15 LEONARD, SL (1943). "Stimulation of Nammary Glands in Hypophysectoniized Rats by Estrogent and Testosterone", Endocrinology. 12. 229 1* LYOYs, , and PEACHARZ, RI (1936). "Rcaccions of Mamintary Glands of Normal and Hypophysectomized Guinea Pigs to Female Sex Hormones". Proc Soc exper Btola lled , 33 589, 1% REECE, I P., TURNER, C W., and HILL, RT (1936), "Mammary Gland Development in Hypophysectomized Albino Rat", Proc Soc exper Biol 6 dled, 34. 204 I TRENTIN, J J. Responsive 1. LYONS, IV R. Hormone, valule alliy altiolls Diculdw-IU, INEW ** Nelson, \ O (1954), "Endocrine Factors in Mammary Gland Function ", Rec Canal Biol. 13 371 21 LYONS, WR. LI, CH, COLE, RD, and JOHNSOY, RE (1953). "Some of the Hormones Required by the Mammary Gland in Its Development and Function". J Chu Cndocrinol , 13 836 ** Aurtn, K. and JACONSOHN, D (1956), "Mammary Gland in Hypophysectomized Rats Injected with Ovarian Hormones and Insulin". Acta physiol scandinav. 37 190 * FOLLEY, S J, and MALPRESS, F II (1948). "The Hormones ", Academic Press, New York ** MILMAN, A E, DE VOOR, P, and LUKENS, F DW (1951), "Relation of Purified Pituitary Growth Hormone and Insulin in Regulation of Nitrogen Balance", am ] Physiol. 166 35-4 ** Fok, PP, GALANSINO, G, WEINSTEIN, H R, and MAGILL, A. M (1955). "Influence of Prolactın on Blood Sugar in Normal and Depancreatized Dogs": AM / Physiol. 180 313 * LUKENS, F, D W. and McCANV, S (1955). "The Hypophyseal Growth Hormone, Nature and Actions", Chap 14. McGraw-Hill, New York "RANDLE. P j , rhidem, Chap 24 * CHEN, T T. JOHNSON, R E. LYONS, WR, L1, C H. and COLE, R D (1955)." Hormonally Induced Xlammary Growth and Lactation in the Ibsence of the Thyroid ", Endocrinology. 57 153 ** ASTWOOD, E B, GESCHICKTER, C F. and RAUSCH, E O (1937). " Development of Mammary Gland of Rats Study of Normal Experimental and Pathologic Changes and Their Endocrine Relationships". Am ] Axat, 61 373 VAN WAGENEN, G, and FOLLEY, SJ (1939), “ Effect of Androgens on Mammary Gland of Terrtale Rhesus Monkey", ) Endocrinol. 367 # MADDOCK, W O, and NELSON, "O (1952). "Effects of Chorionic Gonadotrophen in Adult Men Increased Estrogen and 17-ketosteroid Excretion, Gynecomastia, Leydig Cell Stimulation and Seminiferous Tubule Damage". J Clin Endocrinol. 12 985 * VAN HEUVERSWYN, I TOLLEY, SL, and GARDNER, WU (1939) "Mammary Growth in Male Nice Receiving Androgens. Estrogens and Desoxycorticosterone Acetate", Proc Soc exper Biol & Med. 41 389 ** SPEERT, E *Y-keys". Bull John 94 NELSON 11 Compounds on L » FLUX D ters, Thymus and angectomized Mice". Endocrinol. II 238 * SELYE, H (1954), “Stress and Lactation", Rev Canad Biol, 13 377 » BAGGETT. B. ENGEL, L L., SAYARD, K. and DORFMAN, R I (1955), 'Formation of Estradiol- 17-C from Testosterone-3-C14 by Surviving Human Ovarian Slices", red Prac, 14 175 "West CD. DAMASI, BL, SARRO, SD, and PEARSON, OI (1955), "Conversion of Testosterone to Estrogens in Castrated, Adrenalectomized Human Temales ] Biol Chem, 218 409 * SLAUNWHITE, WR and SAMUELS, LT (1956). "Progesterone as a Precursor ol Testicular Androgens". Biol Chem, 220 341 10 FISER, ER, and CREED, D L (1956), Nature of Periductal Stroma in Conacomastia" Lab Invest, 5 +1 IHNEN, M. and Perez-TAMAYO, R (1953). "Breast Stroma orphological and Histochemical Study". A VA Arch Path, 56 46 ** DURAN-REYBALS, F, BUNTING, HI, and VAN WAGENEN, G (1950), “Studies on Sex Skin of Toob Macaca Mulatta', unn New York Acad Sc 52 ** BON HK, and EvANS, N (1942), “Extragenital Chorioepithelioma in Vale 15sociated with Gynaromastia ", dm) Starg 58 125 1169 ** KARNAVCHOW, P X (1954). "fy oepithelium in Gynecomastia", Am J Path 30 IVA. 267 ·CHAPTER VI THE CAUSES OF GYNÆCOMASTIA to the gynarcomastia. I Gynecomastia assented with plynological states {a} Veonatal gynecomastia (0) Essential synxcomastia (c) Involutional gynecomasti. . (incomastia due to underlying drea Discases of the endixcrine glands 1. Diseases of the testes, {u} Prepubertal testicular failure (b) Kunelelter's syndrome (c) Leprosy (d) Mumps le Orchitis of unknown etolog Tumours Teratom Chorioneputheloma Seminama Interstitial cell tumour. Sertoli cei tumour ( Radiation (hi Undescended tntes 0} Castration U) Trauma (k) Unilateral testicular lesions Varicocele, atrophy of unknown etinlogy II Discases of the adrenal cortes. (a) Tumour (5) Hyperplasia (c) Stress 111 Diseases of the thyroid gland. (0) Hyperthyroidism (8) Hypothyroidism IV. Diseases of the pituitary giand (a) Acromegaly (6) Chromophobe adenoma (c) Hypopitustarsın V Disorders of sex. (a) Hermaphroditism True. False (O) Transvestisi ·30 GYNÆCOMASTIS VI. Afiscellaneous. (a) Following prostatectomy. (6) Albright's syndrome, (c) Diabetes mellitus (d) Cushing's syndrome B Diseases of the liver I Cirrhosis II Hepatitis III. Carcinoma IV Hæmochromatosis. C Diseases of the alimentary canal Ulcerative colitis D Walnutrition and renutrition. E Diseases of the central nervous system. I Traumatic paraplegia II Friedrerch's ataxia, III Syringomyelra IV Dystrophia myotonica F Pulmonary disease I Bronchogenic carcinoma II Tuberculosis III Bronchiectasis IV Empyema G Drugs Estrogens Androgens Chorionic gonadotrophin Adrenocortical hormones Digitalis Radioactive iodine Amphetamine In the pages which follow, an attempt is made to analyse the data of recorded cases of gynæcomastia arising in association with these vanous diseases In some of the diseases in the above list (eg bronchiectasis) it will be argued that insufficient evidence has so far been presented to establish the association of gynæcomastia and the disease in question as anything more than coincidental Unless the onset and gynæcomastia are so poorly documented in this respect that the simultaneous occurrence of the two conditions must be regarded, for the present, as fortuitous On the other hand, cases of bronchogenic carcinoma have been described in which the onset was marked by gynæcomastia, and the latter has disappeared within a few days of operative removal of the affected lung In most of the diseases which cause gynæcomastia, this symptom affects only a small proportion of those who suffer the causative disease For example, a number and nm--- thoro suffering from traumatic ersal, and no correlation e, seventy or duration of of cases of bronchogenic

·The CatsES OF GYNECOVASTI
31
form of stimulation are more likely to show breast development when exposed to a
second stimulus of a different nature?. Are boys who show syn.ecomastia at puberty
more likely to develop this symptom if they later suffer traumatic paraplegia or
bronchogenic carcinoma > So far the data required to answer such questions arc
not available.
's symptom disappears when
or responds to treatment;
breast requires continuous
other occasions the cause of
I yet gynecomastia persists,
plained by reference to the
sof response are encountered.
miod of administration of the
oestrogens, and the breasts return to normal when treatment stops. When larger
doxes are used or treatment is continued for longer penods, the gynecomastia persists
in varying degrees for varying periods after the drug is withheld; in some cases a
slight degree of breast development persists indefinitely Presumably the response
is dependent upon a number of factors, including the nature and intensity of the
stimulating agent, the duration of stimulation, the age of the patient when first
exposed to stimulation, and the sensitivity of a given breast to a given stimulus

·CHAPTER VII GYNÆCOMASTIA ASSOCIATED WITH PHYSIOLOGICAL STATES NEONATAL GYNÆCOMASTIA .: Microscopic evidence of stimulation is found in the normal neonatal breast and persists for as long as six months Thereafter shrinkage of duct epithelium and desquamation of lining cells occur Neonatal gynæcomastia commonly disappears sithin two weeks, but in exceptional cases it may persist for six months or even longer A history of neonatal gynæcomastia persisting for several years is sometimes revealed by patients suffering from gynæcomastia during adult life (or by their mothers) Neonatal gynæcomastia is so common and transient that it has not been studied extensively However, it would be interesting to know whether any correlation exists between neonatal gynæcomastia and the swelling of the breasts commonly seen in males at puberty Estrogens have been found in the urine and blood of infants during the first five days of extrauterine life, 4, 5, 6, 7 and it is generally assumed that neonatal gynæcomastia is the result of direct action of mat. --- Inntnim-rarang unan the newborn breast Recent studies have shown 1: the urine during the first two or three days after neonatal gynæcomastia secretion of colostrum ular experiments have wborn male guinea-pigs d active secretion from t. 22 Taman firm thar Prolactin may also play some part in the pathogenesis of neonatal gynecomastia Lyonsø, 10, 11 developed a method of assay for this hormone which involves a local intradermal crop test in young pigeons, the response being compared with the effect of purified prolactin derived from sheep pituitary glands The urine of newborn infants was subjected to this assay each day for the first seven days of life to Of these infants three were male, two of whom showed neonatal gynæcomastia (one with active secretion), the third boy showed neither swelling nor secretion, while the gırl showed swelling only In all four infants the urine showed mammogenic activity", that of the boy with secreting breasts showing greater activity than the others Lyons does not claim that these results are strictly quantitative, but concluded that the newborn baby has in its tissues hormones capable of stimulating the mammary glands, and that secretion may result from the action of prolactin upon 41 in ... * hoc honn cuegested ! !

·GYXACOVISTIA AT PUBERTY 33 The activity of mammary tissue in the new born is part of a general state of gyntcomastia may presage the occurrence of gynacomastia later in life. The presence of costrogens, progesterone and prolactin in the urine of new born infants provides adequate explanation for the development of alıcoli and hence for lactating mammary testic The climination of these hormones from the body may account for the appearance of colostrum. GYXCOMASTIA IT PUBERTY Some degree of breast enlargement is common at puberty and may escape notice unless pain or secretory activity causes the breasts to be examined In most cases this is a transient phenomenon, but sometimes the enlargement is conspicuous and persistent. Jung and Shaſton' in 1938 undertook an extensive study of the onset and arcolt of most normal boys at puberty. The authors referred to this mass as the subarcolar nole and regarded it as part of normal puberty Jung and Shafton further showed that the subareolar node commonly appears at 13 years of age, reaches its maximal sıze after about 15 months, maintains this for a further 15 months, and finally disappears, so that by the age of 17 years it is no longer to be found in most normal boy's These statements describe the most frequently encountered of many possible variations in onset and duration jung and Shafton estimated that some enlargement of the breasts can be detected in approximately 77% of normal boys during puberty but in only 15 of men by the age of 20 years In most cases the subareolar noxle is bilateral Puberty is sometimes artificially induced by means of chorionic gonadotrophin when this hormone is used to bring about descent of the testis This artificial puberty closely resembles normal puberty except that the sequence of events is sometimes more rapid In about 33°, of boys treated with chorionic gonadotrophin between the ages of cight and 12 years," a transitory subarcolar node, which closely resembles that enhanh. T. Claften Tinormnal puberty In contrast to the small" button" of breast tissue which appears during puberty in boys, it sometimes happens that a considerable enlargement of one or both breasts occurs, and the organs may reach the size of adolescent female breasts Such 1 the other is one of degree ſhe subareolar node requires careful examination of the chest before it is detected, while essential gynecomastia is at least of Grade I severity (see page 15), being obvious on general inspection of the chest Essential syrecomastia may then be defined as obvious enlargement of the breasts which appears ·34 GYNÆCOMASTIA during an otherwise normal puberty in healthy boys. The subareolar node is excluded from this definition by the words "Obvious" and " otherwise normal", because this structure does not produce gross enlargement and because it is seen during normal puberty, CLINICAL FEATURES Age of Onset Essential gynæcomastia makes its appearance between the ages of 12 and 20 years, and it is characteristi- -file nadition that he han ... seen, puberty is still incom at the age of 14 years AI began before the patient's between 17 and 20 years of age, it was associated with a late and protracted puberty. For example, a patient who first noticed gynæcomastia at 19 years of age had shown some development of pubic and axıllary hair at the age of 14 years, but the voice was unbroken and puberty remained incomplete until the age of 19 years, when a ages are of course unreliable, and most patients find it difficult to recall when they began shaving, etc, but after patient enquiry it became apparent that essential gynæcomastia first appeared during puberty Affected Breast Essential gynæcomastia more often affects both breasts than either alone Usually both breasts reach the same size, but one may become larger than the other Again the two sides usually enlarge synchronously, but one may precede the other, both eventually reaching the same size (Table 1) Among unilateral cases the left and right breasts are affected with equal frequency Some authors describe a high percentage of unilateral cases of gynecomastia, but this is not found among patients in whom gynæcomastia appears during puberty 14.15 TABLE I Breast Detelopment in Gynecomastia Bilateral and Symmetrical Cases (23) Asymmetrical Cases (0) Number of Cases Number of Cases Grade Grade 6 II INT II and o VII and II I and o 8 + Severity Table I shows the seventy of gynæcomastia among the Guy's Hospital patients These observations indicate that essential gynæcomastia most commonly brings about the appearance of two well-developed breasts, which, however, fall short in size of the normal breasts of nulliparous young women Asymmetrical cases may result from the presence of one normal breast, less often from the unequal development of two affected breasts Three patients complained of secretion from the breasts ·EssexTIL GYXECOSI ASTIA 35 Pain The turcasts acre painful in the early stages of essential gynecomastia in 12 of 32 patients. In five the pain was intermittent, but persistent as long as the breasts remained enlarged intermittent pain was often associated with tratation from clothing (eg, braces) or changes in boily temperature, but in some cases it was spontaneous Four patients stated that the breasts brcame acutely tender when they became overheated during exertion, in a hot bath, or in an dierhotel room. The incidence of pain was not related to the age at onset of 677.rcomastia. These findings recall the work of Jung and Shafton,"? ulo found that the subarcolar node appeared for the first time most frequently at the age of 13 years and that it reached its maximal development after a further 15 months. The authors stated that the subarcolar node was detected at the age of 13 years hy careful M FIGURE + Essential gynacomastia associated with acne examination The Guy's Hospital patients most frequently noticed essential gynæcomastia at the age of 14 years, but perhaps this would have been detected earlier by cawadi of normal! age and ur . normal puberty Ione ilys Hiusculai buildi, showed considerably less body hair, and were less interested in ·36 GYNECOMASTIA such manly activities as sport, preferring more artistic recreations. These observations merely represent a general impression and cannot readily be subjected to measurement, but certainly about half of those a" also showed severe acne It is worth mentioning severe acne may occasionally be due to the use intractable acne, this is a point of some diagnostic importance Natural History At present the æetiology of essential gynæcomastia remains in doubt, and no rational endocrine treatment has been discovered It is, however, common practice treatment, whether surgical or conservative The value of surgery is therefore closely related to the natural history of the condition If it can be shown that this benign condition undergoes remission shortly after it appears in a high proportion of cases, surgery is unnecessary On the other hand, if essential gynæcomastia, once it has developed, tends to persist indefinitely, then surgery is to be advised TABLE II * The Natural History of Essential Gynæcomastia Number of Patients Duration of Follow-up (Years) Untreated (16) Submitted to Operation (18) 4 2 6 2 3 >8 5 Among 34 patients suffering from essential gynæcomastia at Guy's Hospital only two showed spontaneous remission In the remaining 32 cases the swelling reached its maximal development during a period of between six and 24 months, and thereafter rerrained constant in size Table II shows the result of follow-up studies in these 34 patients The size of the breasts was compared by means of photographs taken at first attendance and at follow-up Cases in which follow-up was artificially terminated by operation are treated separately These studies therefore indicate the minimal duration of gynæcomastia In no case was partial, unilateral or temporary regression noticed These studies indicate that essential gynecomastia is a condition in which spontaneous remission cannot be anticipated, at least during the first eight years after its appearance, and such a finding will influence the treatment of the condition (Chapter XVI) Past Health No finding of ætiological importance was made in the previous health of patients affected by essential gynæcomastia Mumps had affected nine out of 34 of the patients in the Guy's Hospital series, but none suffered from orchitis Traumatic lesions of the testis, prolonged fevers and the use of drugs known to cause gynæcomastia were not discovered Three patients had suffered from protracted neonatal gynæcomastia The first showed this condition for two years with profuse secretory activity At the age of 14 years the patient developed marked (Grade III) painless gynæcomastia, * The two patients showing spontaneous remission are pot included in this table (sce page 37) ·ESSCATIIL GYXI COVASTI 37 Tatient's brother was similarly affected, astia, with Grade III 5) nxcomastia at the age of 17 years The second omastia and painless y nacomastia (Grade I) at sixteen years of age, showing spontaneous remission at the age of 18 years. TIGERE 5 An example of spontaneous remission of essential ginxcomastia of Grade I severity (A) Iged 14 years (B) Aged 20 years The third two years, and then painless the age of 12 years, and was tient stated that his only bro that his cousin also suffered from gynæcomastia (Table III) TABLE III The Relationship betu een Neonatal, Essential and In olutonal Gynecomastia Essential Gynacomastia ramily History Neonatal Gynacomastia Casc 1Between the Years of Outcome of Gynecomastia Sature Relation 1 of Ginacomastia Outcome of Gynecomastia VII Severe and protracted 14 and 16 Disappeared Only spontaneously brother Operation rather XVIII 14 and 22 XIX 15 and 17 l'ersisted Only brother Xeonatal and Disappeared essential spontaneously Essential and Disappeared involutional spontaneously Essential Persistent (>8 years) Neonatal and Disappeared essential spontaneously Neonatal and Disappeared ini olutional spontaneously XXII 16 and 18 Severe and protracted Only brother Disappeared spontaneously Operation XX 12 and 18 Severe and protracted First cousin Whether these findings indicate a special type of gynæcomastia occurring in certain families cannot at present be stated * The relatives of these three patients are not included in the present senes

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·ESSENTIAL GYNECOYISTIA 39 Urinary Estrogens Table IV shows the results of assay's perfonnel upon seven patients suffering from essential gynecomastia. Unfortunately, present methods of estrogen assay leave much to be desired, especially when the levels to be measured are low. Voreover, the range of normal during puberty has not been established with great accuracy. However, six normal boys between the ages of 14 and in years, each of whom showed some signs of puberty, but in whom puberty was not complete, showed the following range of urinary cestrogens, measured by the same method (see page 17): cstrone, <0.5 us. per 24 hours ; cestradiol, <2.0 ug per 24 hours; (estrol, 2-11 HS. per 24 hours. TIGL RE 6 (A) the appearance of the germinal epithelium in the testus of a normal box, aged 16 years (B) The testis of a boy, aged 16 years, suffering from essential gynacomastia This testis is normal, but the tubules are highly cellular In adult males urinary oestrone may reach 1-0 ug per 24 hours It is unwise to be dogmatic about the range of normal at such low levels as these However, in Cases I and XIX the level of estrone recorded in Table IV exceeds that found among of the onset of gynæcomastia Testicular Biopsy In general, testicular biopsy is normal in essential gynecomastia Frequently the tubules appear to be crowded with germinal cells in the manner descnbed by 1' 1.- 1 L - 11 1 ·GyxÆCOXLASTI 4 Semen The results of sperm counts and of motility tests and the appearance of the on themselves are all normal in essential gynæcomastia Histology of the Breast The micrcopic appearance of the breast in essential gynæcomastia does not Yn that seein in other forms of gynæcomastia (page 22) and consists essentially *t hy«rplasia and increase in the cellularity of the stroma without alveolar Sint. These findings are based upon 18 patients submitted to operation at Hapital OTRER INVESTIGATIONS The rules of other investigations, including liver function tests, estimation of Miveritabolic rate, full blood count and X-ray examination of epiphyses, are also Hili ni Inats. AETIOLOGY fszal 2.2comastia occurs at the same age as and under similar circum- Ar to the subarcolar node and the enlargement of the female breast The erlopment of the breasts in girls at puberty appears to result from the direct action of hormones tiskin the mammary tissue These statements rarse three questions : la the xulareolar node strictly analogous to enlargement of the female breast, that is, it it real froin the same cause? If so, why is the development of the male breast ut furt while that of the female continues until the dimensions of the adult female Der an attained ? Is essential synecomastia to be regarded as an exaggeration of the normal development of a subareolar node ? The first changes in the female breast at puberty involve duct hypertrophy and in new in the cellislarity of the breast stroma, but without alveolar development Phimaple changes are thought to result from the direct action of oestrogeris upon the Bare in this presence of a normal antenar pituitary gland (page 24) Progesterone Palily clean not play an important part at this stage, since the first menstrual We are anovulatary, but it is likely that progesterone subsequently produces whir quvelogunent** These observations may be regarded as circumstantial idents in Rivour of the view that the subareolar node is due to the direct action of trunkens upon the male breast at puberty The quantitative difference between the ve uykening of the mammary tissue of the two sexes is presumably due to greater conut of strogens in the female, or to some inherent difference in the end-organs bilmades the response greater in the case of the female or to both factors The other hormones which could be consadered as possible causes of the subareolar thwir annet sf essential gynecomastia are androgens Although cases are known in picha frutment with androgens leads to gynæcomastia (page 125). this is not a urmott nequel of androgen therapy On the other hand, gynæcomastia regularly hallinto the administration of æstrogens in boys and men I:Vilnice in favour of the view that essential gynæcomastia is an exaggeration the nunt breast development of Boy's is entirely circumstantial The two 28511111 occur at the same age and under the same circumstances--that is, during Per? In spite of the lack of more positive evidence, it is difficult to escape the mely that essential gynæcomastia results from the direct action of hormones *** breast If this is the case, tuo possibilities must be considered--namely, a Bajkrativity of mammary tissue to normal concentrations of some hormone or 2730333 on the one hand, or the presence of excessive concentrations of one or more mittain on the other hand A third possibility exists-namely, that breast Athu sesults from the action of an abnormal hormone, se one which is not }rept itt tormal individuals For the third possibility there is no clinical or ·EssENTIAL GYULCOV ASTIA 41 laboratory evidence, such a hormone could produce only one demonstrable effectnamely, breast stimulation; and until some positive evidence for its existence is forthcoming, this possibility will be rejected The next problem is the nature of the hormone concerned Estrogens and serious objection to the case for androgens as the important cause of essential These two patients were seen nearer upon whom this assay was performer of the limitations of the methods u Louvol TIent................ mastra This could suggest that such individuals are subjected to greater concentrations of maternal or placental cestrogens, which produce greater development of ---- C f is to case ► the the concentration of these hormones declines This is further suggested by the observation that the only two patients with raised urinary estrogens were those examined soon after the onset of gynaecomastia, By contrast, the majority of andnud. J.--- gynæcomastia, or a history o spontaneous remission. The a special type of essential gynæcomastia, and these points may be of some prognostic and atrological significance The presence of severe acne in about half the patients affected by essential gynæcomastia, and the observation that these patients are conspicuously muscular and vinile individuals, might be taken as indirect evidence in favour of excessive androgen secretion However, such evidence is not supported by consistently high levels of 17-ketosteroid excretion, and since the Leydig cells appear to represent the source of both estrogens and androgens (page 25),18 stimulation of these cells would produce androgenic effects, and gynaecomastia may represent the only effect of the cestrogens concurrently produced which can be detected clinically A number of workers have endeavonred to char, that ennent--1 is associated with a disturbance in Nathanson,21 for example, has expl in estrogen assays make conclusior mush In they are converted into ratios when in reality in the case of 21 ·42 GYNACOMASTIA In short, it is tentatively concluded that the subareolar node is due to the action of testicular cestrogens upon the breast and is a normal phenomenon. In a small number of boys this response is exaggerated as the result of higher oestrogen levels or of greater sensitivity of the breast (or both). This abnormal response produces essential gynæcomastia. The management of essential gynæcomastia is discussed in Chapter XVI, where a strong case will be made for early surgical treatment INVOLUTIONAL GYNÆCOMASTIA When gynecomastia first appears after middle age, it usually points to some serious under! this time of life is not always so sinister, in libido and sexual potency (Figure 7) be overlooked because of the great vanatio il period of their lives Some are affected by a male climacteric, while in others the approach of old age is so stealthy as to defy exact localization. Gynæcomastia which first appears at or shortly after TIGURE 7 An example of involutional gynecomastia (a) Shows gynæcomastia of grade III severity in a man of 56 years (o) Shows testicular biopsy taken from the same patient, basement membrane, spermatogenesis and Leydıg cells are normal (c) Shows high power field of the same specimen the period of sexual decline in men who are otherwise healthy can be referred to as involutional gynæcomastia The condition is not common, and the diagnosis is justified only after careful examination and investigation have eliminated any underlying disease The diseases to be eliminated in this way are those mentioned as causes of gynacomastia in the succeeding chapters of this book Involutiona) gynæcomastia is illustrated by the following case history da nad notands from about the age of 52 years At about the same age he ood health in the past and, abnormal The results of chest x-ray examination, blood count, liver futetion tests, esmunauon of basic metabolic rate, The patient was seen this time The investiears of observation and The difficulty in diagnosing involutional gynæcomastia lies in establishing the fact that the patient is free of any senous underlying disease By contrast, it is relatively easy to eliminate senous underlying disease at puberty in the case of essential gynæcomastia The diagnosis of involutional gynæcornastia is therefore reached by exclusion and should be supported by a period of observation ·INVOLUTIONAL GyxÆCOM ASTIA 43 CLINICAL FEATURES In a series of 10 patients the age of onset of the gynecomastia was between 52 and 66 years It was associated with loss of libido and potency in every patient, but only hall of those afíected complained of other symptoms such as hot flushes, lethargy and irritability. The condition is usually bilateral and symmetrical, and may undergo remission (complete or partial) The previous history of libido, potency and fertility are not remarkable, and past health has usually been good. SPECIAL INVESTIGATIONS gonadotrophic hormones is extremely variable in normal men Elamination of semen has not revealed any consistent abnormality, and the results of testicular biopsy are normal for the patient's age (Figure 7). ETIOLOGY It is at present not possible to discuss the ætiology of involutional gynecomastia Little is known about the quantitatre and qualitative changes in endocrine activity during the time of sexual involution in men. 1 sia Years of complete sexual inactivity. The sudden return of sexual activity was associated with painful gynæcomastia, interval of between one and two years associated with loss of libido and a ret provide an example of a phenomenon to be encountered in later chapters of this book--namely, the appearance of gynæcomastia at a time when sevual activity reappears after a period of loss of erections and Ibido (page 113). This sequence of events has something in common with gynæcomastia at puberty, except that puberty represents the first episode of gonadal stimulation rather than a reawakening of sexual activity In one patient studied soon after the onset of this form of involutional gynecomastia, urinary estrogens were found to be too low to measure by the method described on page 17 MANAGEMENT The management of involutional gynæcomastia is discussed in Chapter XVI, where a conservative policy is advocated 114 REFERENCES 1 Faaris, S (1927). "Tumefazione Mammana e Secrezione laſtea nel Neonato". Pediatrica, 35 457 HOELAND, H (1927), DIschr Geburtsh Gynäk, 77 • DIETRICI, E F (1927). " Untersuchungen über das Cerhalten der menschlichen Brustdrüse 1181 Ersten Lebensjahre", Arck path Anat, 264 486 BRUHL, R (1929). " Das Vorkommen zon weiblichem Sexualhormon und Hypophysenuorderlappenkormon 1n Blute und Russ von Neugeborenen Der Zusammenhang Swischen den hormonalen Vorgangen und der Brustdrüsenschwellung", Klin IVchnschr, 8 1766 * Joseph, S (1929), “ Zur biologie der Brusldrüse beim neugeborenen", Afschr Geburtsh Gynak, 83 219 NEUMANN, Ho, and PETER, F (1931), Zerts / Kinderk. 52 24 ? WINTER, E W (1932). "Hormonanalysen im Unn und im Brustdrüsekret und Pathologie der Brustdruse in und ausserhalb der Schwangerschaft". Arch Gynak, Beitrag zur Biologie 151 201 * ABRAHAM, G (1930). "Hormone und Brustdráse", Aſed Klin, 28 164 ·42 GYNÆCOMASTIA In short, it is tentatively concluded that the subareolar node is due to the action of testicular cestrogens upon the breast and is a normal phenomenon. In a small number of boys this response is exaggerated as the result of higher aestrogen levels or of greater sensitivity of the breast (or both). This abnormal response produces essential gynæcomastia. The management of essential gynæcomastia is discussed in Chapter XVI, where a strong case will be made for early surgical treatment INVOLUTIONAL GYNÆCOMASTIA When gynæcomastia first appears after middle age, it usually points to some serious underlying cause However, gynecomastia at this time of life is not always so sinister; it may appear together with a decline in libido and sexual potency (Figure 7) The significance of this association may be overlooked because of the great variation with which men enter the involutional period of their lives. Some are affected by a male climacteric, while in others the approach of old age is so stealthy as to defy exact localization Gynæcomastia which first appears at or shortly after FIGURE 7 An example of involutional gynecomastia (a) Shows gynæcomastia of grade IIf severity in a man of 56 years (6) Shows testicular biopsy taken from the same patient, basement membrane, spermatogenesis and Leydig cells are normal (c) Shows high power field of the same specimen hthama hon1thwenn ha referred to as TOSIS IS * underoned as causes of gynecomastia in the succeeding chapters of this book Involutional gynæcomastia is illustrated by the following case history The patient noticed a gradual decline in libido and potency from about the age of 52 years This was associated with hot flushes, irritability and loss of energy At about the same age he Doticed painful bilateral gynecomastia The patient had enjoyed good health in the past and, apart from gynecomastia, physical examination revealed nothing abnormal The results of band - ), a functia teste estimation of basic metabolic rate, mal limits The patient was scen od during this time The investithe five years of observation and The difficulty in diagnosing involutional gynæcomastia lies in establishing the fact that the patient is free of any senous underlying disease By contrast, it is relatively easy to eliminate serious underlying disease at puberty in the case of essential gynæcomastia The diagnosis of involutional gynæcomastia is therefore reached by exclusion and should be supported by a penod of observation ·CHAPTER VIIT GYNÆCOSLASTIA ASSOCIATED WITH DISEASES OF THE TESTIS In 18zy Williams suggested that diseases of the testis vluch cause destruction of testicular tisue could produce gynxcomast13 This led to the idea that the testis protects the male boly from a tendency to develop certain female characteristics Since that time many Workers have concluded that the testis plays an important part in the etiology of gynacomastia The following diseases of the testis may be associated with gnecomastia (I) Certain forms of hypogonadism (2) Tumours of the testis (3) Lerrous orchits (4) lumps orchats (51 Bilateral architts (6) Radiation of the testis (7) ndescended tistes (8) Castration (o) Traumatic kesians of the testis (ro) Certain unilateral testicular lesions HYPOGOSADISJI Certain forms of rule hypogonadism are commonly associated with grecomastia, and since a number of rather confusing systems for the classification of these conditions are at present in use, it is necessary to begin with a brief account of the nomenclature to be used Hypogonadism may result frost lesions of the adenohypophy ses or from diseases of the tests In rare instances, the possibility of an inherent resistance of the tissues or nd-ogans to the action of normal quantities of hormone may be responsible for the appearance of signs and symptoms which resemble thoxe encountered in hyphon gonada res possibility is not relevant to the problem of Vittomasta The signs and symptoms of hypogonadismn vary not only according to the site of the lesion, but also with the age of the patient at the onset of the condition For example, failure of Leydig cell function before puberty leads to the gross abnormalities of eunuchautism and failure of the development of secondary sexual charactenstics On the other hand, when failure of Leydig cell function first cuss dunng adult life. the regresuon of established secondary sexual characteristics 13 remarkably slov When hypogonadism is the result of fariure of the adenohypophysis to secrete aufficunt gonadotrophic hormones, the urinary output of gonadotrophins is low, and the capacity of the test is to respond to pituitary stimulation as indicated by the response to 3}ection of chononic gonadotrophm, uhich brings about the appearance of secondan evval characteristics or muntains sexual activity in the case of adults When hypogonadism is due to testicular failure, urinary gonadotrophin levels are higher than normal, and the testis is incapable of responding to choronic gonadotrophins Classification of hypogonadism is based upon these observations, and Heller, Velson and Roth proposed a useful system of classification in 1945 which is illustrated in Table '. has been enticized on the grounds of over-simplification, but until trological factors are better understood it provides a useful skeleton for descriptive purposes This sistern, ·44 GYNACOWASTIA . Lyons, W. R (1937), " Preparation and Assay of Mammotrophic Hormone", Proc Soc. exper Brol Bed, 35 645 19 LYONS, W R (1937). " Hormonal Basts for 'Witches Milk". Proc Soc exper Brol & Med, 37. 207 11 LYONS, W. R, and Page, E (1935). "Detection of Mammotropin in Urine of Lactating Women". Proc Soc exper B.01 & led, 32. 1949. 12 JUNG, F T, and SHAFTON, À L. (1938), "Mastitis, Mazoplasia, Mastalgn and Gynecomastia in Normal Adolescent Jales Illinois I. 73. iis 13 De NIOWBRAY, R (1953). "The Treatment of Infantilism", DN thesis, Oxford MENVILLE, J G (1933). "Gynecomastia", arch Surg. 26 1054 15 KARSNER, A 1 (1996). Gynecomastia" Am Path, 22 235 vil ... 676 C, and NELSON, WO (1952). 1 Classification of Testicular ", din New York Acad Se, 5-) ----I--fon, 2. 525 on Mammary Gland of Urinary Excretion in Adolescent Mastitis 16 BISH 17 DAV 16 HEL 20 25e ad CANLORBE, P (1956), e hóp. Parts, 32 1763 ·PRETUHEKTAL TESTICULAR FAILURE 47 It will be seen that gynæcomastia occurs in cases of testicular farlate supervening belpre or during puberty but not in other forms of testicular failure. Testicular failure before or during puberty is of two types Hamely; prepubertal testicular failure and Kiinclelter's aj zdrome Prepubertal testicular fatlure is a condition in which no functioning testicular tissic can be found in the scrotum, ulule Klinefelter's Gure 8 I'repulertal testu,ular failure in a Patient aged 18 years The character- 1932 eunuchoxi proportioni and 50. comastia (grade it) are well shown The des elapment of putro Hair 35ceased aftes treatment testosterone before tur photograph Was taken syndrome is associated with characteristic histolomcal changes in the testis. Prepubertal testicular failure is also called prepubertal non-castrate eunuchordlism, and the word prepubertal x spelled prepuberal by most American authors Throughout this book the English spelling is used, and the name prepubertal testicular failure is preferred Tlus classification docs not include testicular failure due to specific tiological agents, such as mumps orchitis, traumatic lesions, leprosy, castration, etc Bany ·TAALE V 1 Classification of Wale Ilypogonadism Response 1 inc af Onnet Unary Gonado trophins Hulure of Other l'ituitary Functions Skeletal Desclopment Gyna co- Mestia (horioni Gonadostrophins Size of 1 estes Testicular Biopsy Potency Diagnosis I ow l'ostive Yes Dwarfism Absent Halí adult size Poor Panhypopituitarism Tubules infantile Leydig cells infantile Tubules Infantile Leydig cells infantile 1.ow l'ositive No Eunuchoidism Absent Before Half adult size Poor UT During Puberty Fligh N1 No Eunuchoidism Ilypogonadotrophic hypogonadism Prepubertal testicular failure Present or absent Poor Bagh Nit No Normal Present Poor Absent Absent (Wolffian remnants) One-quarter Hyalınızation of adult size tubules Clumping of Leydig cells Three-quarters Tubules and Ley dig adult size cells return to an infantile state Klinefelter's drome syn- GYNECOMASTIA LAW l'ositive Yes Normal Absent Poor dult panhypopituitarism Low Positive No Normal Alisent Poor Three-quarters Tubules and Ley dig adult size cells return to an infantile state Vler Sexual Maturity High High Nil No Normal Absent Adult hypogonadotrophic hypogonadism Adult hypergonadotrophic hypogonadism Poor Iligh ilܕ No Normal Normal Atrophy absence or disorganization of tubules or Leydig cells Normal to three-Tubules are small of quarters adult hyalinized, sloughsize og of germinal egisthelium Absent Normal Adult seminiferous tubular failure

·PRETCHERTIL TESTICILAR FAILURE
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·GYXACOSIASTIA other classifications of hypogonadism have been devised, but as these are usually complicated by the inclusion of lesions which do not cause gynæcomastia, the system of Heller, Nelson and Roth is considered adequate for present purposes " PREPUBERTAL TESTICULAR FAILURE In 1943 Heller and Nelson described a syndrome which they called functional prepubertal castration in males This is characterized by (a) the presence of Wolffian duct derivatives in the scrotum but absence of functional testes, (6) sexual infantilism, (c) some delay in osseous development, (d) high urinary gonadotrophin excretion, and (e) response to treatment with testosteronc but not with chorionic gonadotrophin This syndrome may result from a variety of causes, but the essential feature is that total failure of the testis (germinal and endocrine) appears before puberty o treatment with pituitary failure, that the tissues themselves are not inherently resistant to the action of androgens That the ætiological factors concerned operate before puberty is indicated by the presence of eunuchoidism The condition closely resembles surgical castration before puberty and is so named as to exclude this possibility. The etiological factors responsible for this syndrome are varied Some cases appear to have followed operations for inguinal hernia before puberty, and it has been suggested that during operation the blood supply to the testis has suffered In other cases a sclerosis of unknown etiology affects the walls of the tubules, which as a result fail to develop fully In yet another group failure of union between the Wolffian duct and the testis may occur, so that derivatives of the former structure may appear in the scrotum unaccompanied by the testes, which remain in the abdomen. Sometimes failure of union between the Wolffian duct and the testis results in the appearance of the epididymis alone in the scrotum 9, 10, 11, 12, 13 Finally, some cases may be due to congenital failure of the testes to develop (anorchia) Before the diagnosis of this syndrome can be established, testicular biopsy is necessary in order to demonstrate the absence of functional testicular tissue Consideration of the ætiological factors involved will show that the results of biopsy are varied In cases following surgical operations upon the inguinal canal and in those associated with sclerosis of the tubules, some testicular tissue will be found That this tissue is not functional will be indicated by the rudimentary appearance of the tubules and by the absence of normal Leydig cells These findings will be reflecte] by the presence of eunuchoidism and sexual infantılısm These clinical signs will, moreover, prove that the causal factors operated before puberty, thereby establishing the diagnosis of prepubertal testicular failure In cases resulting from failure of union between the Wolffian ducts and the testis, biopsy will reveal no testicular elements but germinal epithelium or Sertoli cells (Figure 9) Again, immature epididyal tissue or ductus deferens may be found When testicular biopsy reveals epicidymal tissue, it may be argued that biopsy has been unsatisfactory and that testicular tissue, although present in the scrotum, has not been located by the operator, who has simply cut into the epididymus That this argument is realistic is shown by the appearance of epididymal tissue without testis in the biopsy of normal gonads However, if the scrotal contents are less than 1'0 cm in diameter, and if bilateral testicular biopsy reveals some form of Wolffian duct derivatives but no testis, it is highly probable that functional testicular tissue is absent from the scrotum Similarly, the diagnosis of anorchia during life can be substantiated only by a major surgical exploration of the scrotum, inguinal canals and abdomen For the most part these

·PREFL'RERT.14 TLSTICL'LIR FAILURE,
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·50 TABLE VI Clinical Features of Patients with Prepubertal Testcular Failure Pubic Hair US LS Cane Number Ieight Weight Span (Inches) (Pounds) (Inches) Erectrons Emissions Beard Temporal Voice Aullary Dis. Hair tribution Amount Hlairline Age (when first seen) VI.VII 60 123 70 300 36 Absent Absent Female Scanty Scanty Poor No recession High 25 LVIII 73 238 741 351 371 Some Absent Female Scanty Scanty Poor No recession High 18 L 73 176 745 351 378 Some Few Female Scanty Scanty Poor Low No recession 19 LI 711 173 751 331 381 Some Absent Female Scanty Normal Voor Low 21 No recession LII GYNECOMASTIA 134 767 331 405 Some Few Temale | Scanty Normal Poor Low 18 No recession Լ.Այ 69 143 71 331 35 Some Few Female Scanty Scanty Poor No recession High 19 19 LIV 71 2tt 721 34 37 Some Absent Female Scanty Scanty Normal No recession Low 53 LVI 671 152 691 324 35 Some Absent Female Normal Scanty Poor No recession High 25 LVII 74 140 75+ 337 381 Some Few Female Scanty Normal Poor No Te cession High 20 1.1111 72 158 74 34 381 Few Absent | Female Scanty Scanty Normal No recession High 22 63 143 65 301 12} Гету Absent Temale Normal Scanty l'oor No re- Low 22 cession ·PREPUNERTAL TESTICULAR FAILURC. SZ TABLE 133 Cynalomasta > Prefelesla! T'es sulay } astust Care Number Ige at Onset (Years? Scients (Grade Duration at Follow Us {Years) Sesunty at Toys Up (Grade) Duration at Operation (Years) XLV33 14 1 1 XLVII IS 19 1 ! 1.2 20 3 3 LII 15 2 1 14 111 39 211 16 1 LV11 6 1 3 LV311 56 1 LV 27 testis before puberty, the name prepubertal testicular failure is a convenient way of referring to this heterogenous group of conditions The disease which is most likely to cause difficulty un diagnosis is hypogonadism as an isolated manifestation of pituitary failure. In this condition urinary gonadotrophins are ion, the testis shows arrest of spermatogenesis in the presence of well-formed tubules, and the condition responds to treatment with chorionic gonadotrophin TABLE V131 Duration of Gynecomastia in Pretuberiad Testaular Failure Duration of Gyn.comastia {Yeats) Patients Submitted to Operation Patients Xot Submitted to Operation (7) Z Z 6-1 12-20 The chnical and laboratory data of 12 patients who fulfilled the requirements of prepubertal testicular fatlure are shown in Tables VI, VII, VIII and IX It will be seen that in this syndrome gynæcomastia is usually mild (Grade I) and first appears between the ages of 14 and 21 years (Table VII), once it is established. gynecomastia in prepubertal testicular failure shows no tendency to spontaneous Tetussion (Table VIII) The principal symptorns of which these patients complain are connected with fazlure of development of the secondary sexual characteristics, which proves such a source of embarrassment that the gynaecomastia, which is mild, is not regarded so ·TABLE IX Laboratory Inrestigation in Preorderlal Testicular Failure Epiphyses Unnary Estrogens (u8 per 24 Hours) Cave Number 17-Keto steroids (i per 24 flour) L'rinary Gonadotrophins Mouse l mtu per 24 Hours) Semen (Number of Tests) Testicular Biopsy Bone Age Chronological ge (Estrone (Estradiol Estriot KIN? 1 2 3 21 0 Adult -48-14 96 Izoo pertnia l'as dcferents 25 XL.VIII Adult 21 . 96 96 Aroospermia (2) Vas deferens 70 Azoospermia Adult 21 17 O 3 90 630 11 0 15 1 2 4 -96 : 96 90 Poorly deteloped tubules Adult 22 100 15 O ? O 20 0 11 200 perina (3) 02 .24332 0490 > 95 Vas delerens 1210 GYNECOMASTIA JIL 60 Izoospermia (2) Immature epididymis 17 20 O 5 2.0 1111 11 7 28 > 96 Szoospermia (2) Vas deferens 22 -- LIE 37 130 > 96 ->0896 NO cjaculate Vas dcferens Adult 33 LVI Epididymis No ejaculate Idult 25 I! 8 90 -- > 96 > 96 0 ܐ ܐ - TIJI 102 1632 Azoospermia l'oorly 17 26 90 13) des eloped tubules LWIN TO 2 > 1632 No Epdidymis Adult 22 >ენ ejaculate 10 O >64 <96 Azoospermia Vas 20 25 120 >96 (3) deferens * It is probable that some of these patients had teen gtson hormones before they were scen at Guy's liospital This would no doubt have advanced their emphisal maturation -- ·I'REPUNERTAL TESTICULAR FAILURE. 53 seriously. As a result the age of onset and other features of the breast development are not clearly rememberel. However, it can be stated that the gynecomastia is painless and not associated with secretion from the nipples. These patients all shoxel Smooth clear skins and maintained that they had never suffered from acne It is inevitable that some patients who turn out to be examples of prepubertal testicular failure are regarded as suffering from undescended testes before puberty. Unless senafl noulules are felt in the scrotum, it is scarcely possible to distinguish the tuo conditions (before pułyerty), and it is not surprising that two of the present series of patients received hormone treatment is the hope of causing descent of the testes. The treatment did not cause the associated By Racomastia, since breast development preceded hormone therapy by more than two years When chorionic gonadotrophuin is the hormone used, one would not expect gynecomastia to occur in cases of prepubertal testicular failure, because this horinone is thought to cause breast development by stimulating the actsvity of the Leydig cells (rage c5) Prepubertal testicular failure is not familial, and except in the case of patients submitted to herniorrhaplıy, the past health reveak nothing of interest. The 17-ketosteroid excretson was normal and the level of unnary gonadotrophins ligh in every matic The three patients in whom urinary estrogens were estimated (Table IX) showed levels within or just beyond the normal range Histological change seen in the breast are those found in other forms of gynecomastia (see page 22) Pathogenesis Boy's subjected to surgical castration before puberts do not develop cynacomastia On the other hand, about one-half of those who suffer prepubertal testicular failure show a mild degree of breast stimulation? In those cases of prepubertal testicular failure due to anorchia or to failure of umon between testis and Wolffian duct, it may be assumed that the patient lacks any functional testicular tissue In the absence of any evidence to show that the adrenal cortex in this condstron is responssble for the secretion of excessive quantities of restrogens or androgens, it is difficult to see how breast stimulation in cases of this syndrome could result from excessive quantities of esther of these groups of hormones It seems logical to conclude that the difference from a functional point of views) betueen prepubertal testicular failure and surgical castration before puberty must lie in the activity of testicular tissue before the time of surgical castration There is good Teason to believe that the testis is active before birth, and while still situated within the abdomen, this structure directs the development of the Wolffian ducts at the expense of the fullerian ducts and influences the differentiation of the external genitalia. In this way it is possible to account for the etiology of Turner's syndrome. which is associated with female phenotypic or functional scx in individuals with male chromosomal ser 6, 4, 6,7 It is not at present possible to do more than guess at the pathogenesis of prepubertal testicular failure It the testes were absent or functionless during intrauterine life, one would expect such individuals to develop female phenotypic Sex We can only suppose that the gonads are present in the abdomen untal after the time of differentiation of the genital ducts and external genstala is accomplished, and that they subsequently undergo some destructive process Perhaps the destruc tion of the testes exposes the breasts to some femiaszing influence during the last stages of intrauterine life, which tenders the mammary tissue unduly susceptible to the influence of the small quantities of testrogens or to the androgenis secreted at puberty by the adrenal cortex Most patients with Turner's syndrome do not show breast development af puberty, but the mammary gland responds to the administration of sestrogenic hormones However, in some patients affected by Turner's syndrome slight breast development with rudimentary mpples is seen at puberty. and thus would no doubt pass for a mild degree of gynecomastia in the case of male patients. Prepubertal testicular failure is a heterogeneous condition, and until ·54 GYNÆCOMASTIA luce this syndrome the patho- No doubt future studies of e, although II cases reported uy Nelson dl Sloved midle mulear sex, The patients with prepubertal testicular failure reported by Heller and Nelson? were not excessively tall, unlike those affected by other forms of eunuchoidism. The heights of their patients were between 58} in, and 701 in. In the present series the range was 63 in to 74 in. (five of 11 patients being taller than 72 in). At present it is not possible to account for this difference Certain features of prepubertal testicular failure remain puzzling In the absence of testicular tissue it might be expected that pubic and axillary hair would be absent and 17-ketosteroid excretion low, as in prepubertal pituitary failure. However, there is good evidence in animals to show that castration soon after birth produces adrenocortical hyperfunction with increased production of androgens 104, 106 There is further evidence of a sort of reciprocity between testicular and adrenal androgens, as for example the fall in urinary excretion of the metabolites of adrenal androgens which follows the administration of 17-methyl testosterone20s; this substance is not metabolized to 17-ketosteroids. Presumably, therefore, some compensatory increase in adrenal androgen output accounts for the ultimate (but delayed) fusion of epiphyses (the delay permitting growth hormone to produce eunuchoidal changes in the skeleton), for the development of sex hair and for the normal 17-ketosteroid excretion in patients suffering from prepubertal testicular failure KLINEFELTER'S SYNDROJIE In 1942 Klinefelter, Reifenstein and Albright described the condition which is generally referred to as Klinefelter's syndrome This syndrome was said to consist of gynæcomastia, sinall testes, azoospermia, evidence of normal to moderately reduced Leydig cell function, increased excretion of pituitary gonadotrophins and (usually) a reduced excretion of 17-ketosteroids This description was based upon a series of ninc patients, each of whom had been quite normal until puberty, which began between the ages of 12 and 14 years Gynæcomastia was present in every case and first appe was of G paper and in two The testes were uniformly small and symmetrical throughout the group, the average size being 1.5X10X0.5 cm, and the patients stated that their testes had always been small Three patients had never ejaculated, and of the remaining six four are known to have shown azoospermia In eight of the patients Leydig cell the voice, the distribution adotrophins were uniformly subnormal » Testicular biopsies were always divina between two extremes in different patients Some cases showed partial hyalinization and defective spermatogenesis in certain tubules, while other cases shoued extensive hyalımızation of all the tubules and no cells within the tubular remnants Betueen the two extremes intermediate states occurred, in which hyalinization was moderate and only Sertos cells remained inside the tubules This hyaline tissue stained pink with eosin and like collagen with anuline blue In no instance was normal spermatogenesis present The authors state that, ss than normal, owing ct the interstitial cells to be 40 times as numerous as I Be Ju] Jaidi h $123 In لوبه دهها ما ·KLINETELTEK's SymDROME 55 They Albright and his colleagues believed that the occurrence of normal Ley dig cells in the presence of defective spermatogenesis and raised urinary gonadotrophins was best explained by the existence of a second testicular hormone secreted by the germinal epithelium- the so-called "X" hormone. By analogy with the female, follicle-stimulating hormone (FSI) promotes spermatogenests and at the same time stimulates the secretion of "X" hormone, instead of stimulating the maturation of the Graafian fobicle and indirectly leading to the production of restrogens hormone controls the pituitary secretion and/or release of follicle-stimulating hormone, and lack of this "X" hormone, resulting from tubular damage, would lead to raised urinary gonadotrophins The histology of the breast in one of these cases of Klinclelter's syndrome was compared by the authors with a biopsy taken from the breast of a man, aged 7o years, who suffered from gynxcomastia following astrogen therapy for carcinoma of the prostate Albright and his colleagues stale that restrogens produced greater duct hyperplasia and fess dense periductal connective tissue than were seen in cases of Klinefelter's syndrome. In one case an assay of urinary cestrogens uns performed, and the result was normal. Upon this evidence the anthors conclude that the Anacomastia of Klinefelter's sstidrome is not due to "hyperestrinum" regard testosterone as unlikely to cause gynecomastia in this syndrome because normal men do not develop this symptom The authors suggest the theory that gynecomastia in Klinefelter's syndrome is the result of androgen secretion in the absence of "X" hormone They admit that testosterone does not regularly produce gynecomastia in castrates but believe that a thurd factor is necessary ---namely. that the patient be growing when this hormonal ubalance becomes establtsted. Some of the conclusions drawn from the excellent descriptive data sn this paper merit further discussion In the first place, the important observation of Leydis cell clumping is dismissed as being the result of a relative increase in the promence of these cells following atrophy of the tubules The authors are in error when they state that " one would evxct the interstitial cells to be 10 times as numerous as in the normal testis" One would expect these cells to be 40 times as concentrated as in the normal testis--that is, the number in a given microscopic field would increase by 40 It will be necessary to return to this point later Again the comparison betu een the breast of a man of 70 years abruptly stimulated by large doses of exogenous estrogen and that of a young man suffering from gynæcomastia at or soon after puberty is certainly open to question This is especially true when the photomicrographs presented for comparison are exammed the sislarity between the two specimens is more apparent than the differences any case, the histology of the breast undergoes considerable change with age, and the sudden stimulation of a breast which has long since ceased to show signs of activity, by enormous doses (by physiological standards) of restrogen, can hardly be e\pected to produce changes identical with those seen at puberty under the mfluence of the same hormone Moreover, it has been shown that the histology of gynecomastia is not specific for any particular cause, and that in general the appearances resemble those seen after oestrogenic stimulation of the breast (page 23) One normal urinary restrogen assay performed some years after the onset of gynæcomastia, by the methods in use in 1942, would add little to the case against testrogens as the cause of gynæcomastra in Klinefelter's syndrome The conception of an "X" hormone was purely hypothetical in 1942, and its existence has never been confirmed since that time The idea that such a hormone specifically prevents gynecomasta during the grou th spurt of adolescence seems to attribute an exceptional role to this hypothetical substance Three years after the paper of Albright and his colleagues, Heller and Nelson's offered a new concept of Klinefelter's syndrome Beginnng with the view that hyalınization of the basement membrane was the fundamental abnormality in this ·56 GYNÆCOMASTIA condition, they used the device of postulating four basic or constant features of the syndrome without which it could not be diagnosed and a number of variable or inconstant features The constant features are (i) small testes, (ii) hyalınızation of the basement membrane of the seminiferous tubules, (ui) azoospermia, and (iv) high urinary gonadotrophin content. Patients who show these four abnormalities vary from eunuchoid individuals with slight breast development to those who show normal for nearly normal) male secondary sexual characteristics together with gross gynæcomastia For descriptive purposes three major types are described--namely, eunuchoid, intermediate and Pumn] {Enro voi .absent. e sexual development and well-marked gynæcomastia The intermediate type shows some evidence of eunuchoidism, some failure of secondary sexual characteristics, and moderate gynæcomastia T. d poorly MM TIGURE 10 The three types of Künefelter's syndrome according to the concept of Heller and Nelson. (A) Marked eunuchoidism without synacomastia (B) Moderate development of the secondary sexual characteristics with some gynecomastia (C) Normal sexual development and marhed gynæcomastia Heller and Nelson at this time envisaged Klinefelter's syndrome as the outcome of a process of hyalinization of the basement membranes which may affect the testis before or during puberty. If this process starts before puberty, eunuchoidism results, if it begins towards the end of puberty, the so-called normal group of Klinefelter's syndrome results Nou the normal group is composed of patients who fulfil the requirements of Albright and his colleagues in their onginal description of the syndrome, while the intermediate and eunuchord groups are examples of prepubertal testicular failure The only features of the eunuchord group which could distinguish these patients from other examples of prepubertal testicular failure are the presence of hyalınızation of the basement membrane and the state of the Leydig cells. The photomicrographs in the original paper of Heller and Nelson do not llustrate the condition of the basement membrane in the eunuchoid group. On the other hand, they do show an example of the Ley dig cells in one patient ol this ·KLIXEFELTER'S SYNDROVE 57 group. and these cells are described as being in "fair functional state". Whatever their functional state, however, these cells Have failed to secrete nomal quantities af androgenic hormones, because the patients are cunuchoid and slow inadequate development of secondary sexual characteristics. It seems clear that the changes in the Leydig cells of the cunuchoid group are not sufficiently characteristic to set them apart from other forms of prepuberta! failure of the testis While hyalinization of the basement membrane does undoubtedly occur in patients showing cunuchodesin, it remains to be shown that there is in this finding some specificity, etiological or other, which justifies linking these patients with the classical type of Klincfeiter's syncrome. Until the specificity of this hyaline change is established, it seems more satisfactory to group all cases of prepubertal failure of the testis together and to confine the use of the term Khnelelter's sixtrome to the soxalled formal group, se, the type of patient described by Albright and his co-sorhers. Here the subject of Klinefelter's syndrome remained for more than 10 years, until it was shown by Watsch, Yeloa and Segall, that some of the patients who ucre regarded as typical examples of the condition shoued female chromatin pattern in the cells of the skin and other Lissues und uals have bees ca pseudomales, and they appear » etery respect like normal boys throughout childhood .It puberty they may notice gynecomastia, which causes them to seek medical advice, is also may sher subsequent infertility The male secondary sexual characteristics shou moderate to normal del elopment In one patient described by Witsch and his colleagues, a feu seminiferous tubules shoued the full histological pattern of spermatogenesis and the chromatin sex was female, this is the nearest approach to complete sex reversal which has yet been described in man Witsch and his co-worhers have gone so far as to dras an analogy between this state of partial sex reversal and sex reversal in amphibians which can be induced by delay in fertilization of the ovulated egg, which, as a result, shows evidence of degradation Under these conditions the primordial germ cells exhibit degenerative features, multiplying slowly and entering the gonadal tolds in small numbers or not Il no germ cells succeed in entering the gonadal folds, permanent sterility results If, however, a fev gonia reach the primordial gonad, the latter develops as a testis regardless of the genetic sex of the host, since the small number of germmal cells (the main inductor of ovarian development) leads to icahening of the cartes, with the result that the redulla gains ascendency over the cortex in the case of minor defects in penetration by the gonia, the competation between cortex and medulla may not be completely resolved, thus leads to the production of or otestes The important factor appears to be the smber of germ cells which enter the developing gonad This factor rifluences the follicular and interstitial cell development, auch In turn affects the capacity of these structures to exert their inductive effect upon the genital ducts and external genitalia It is perhaps too early to press this analogy further, but such a concept more nearly fits these confusing aspects of human sex revcrsal than other theories so far presented The concept of over-ripeness of the sun suggests that acquired or environmental factors are responsible for Klmelelter's syndrome rather than hereditary factors. This idea is in accordance with the observation that the syndrome is usually neither familial not hereditary However, recest evidence suggests that this syndrome is more often herited than was formerly belseved 110 Among the patients suffering from Klinefelter's syndrome who were examined by Nelson and Boccabella 17 the ratio of chromosornal females to males sas 49 to 13. *}t will be recalled that the germ cells arise outside the deselopsag gonad, probably from the endoderm of the handgut and that they migrate by amaboxd shovement to the genital folds, hah they pxsxceed to penetrate 1stscki's conception of Kisszefelter s syndrome is based upxin a theory of de creat germ plasm in the zygote resulting from orey-Typesless of the ovum before tertilizatIOR ·58 GYNÆCOMASTIA If Klinefelter's syndrome is due to some such acquired or environmental cause, this sex difference must be explained, since there is no reason why zygotes of XX genotype should be more frequently affected than those with XY genotype. Presumably the predominance of chromosomal females results from the fact that only the extreme 1. nedel. --.11.12 L. ...:..........11 L. and no all degrees of severity When the genotype of the affected zygote is XX and no without ample of rm cells, Turner's syndrome and allied syndromes). With more successful penetration men of low fertility will develop These ideas can be presented in tabular form (after Witschi, Nelson and Segal") TABLE X U Cenotype of the Affected Zygote Surviving Germ Cells in Gonadal Fold XX XY None (or very few) Agonadal women Pseudofemales Few Pseudomales and true her. maphrodites Men of very low fertility Moderate and Amenorrhrea fertility low Men of low fertility Normal Normal women Normal men In other words, the result of defective germ cell penetration will depend upon the extent of this deficiency and the genotype of the zygote concerned. Zygotes of XX and of XY genotypes will be affected with equal frequency Some of the patients who suffer from Klinefelter's syndrome with male genetic ses are examples of some acquired but usually unrecognized lesion of the testis which destroys the basement membrane and brings about the same clinical and histological picture If this concept of Klinefelter's syndrome is correct, there are really three types of this condition (1) Chromosomal females in whom degeneration of the germ plasm has proceeded to such a stage that this ovarian organizer can no longer induce adequate cortical development in the indifferent gonad, which consequently develops as a testis (2) Chromosomal males in whom the degeneration of the germ plasm, while not sufficiently severe to produce Tumer's syndrome, is yet sufficiently advanced to cause infertility and the features of Klinefelter's syndrome auth.lam rrecs, the nature of which brane and hence the lity and the develop- So far it has not been possible to distinguish these litt groups by any clinical or laboratory evidence, and the histological features of the testis appear to be similar in all three groups 18 The patients of Group I will be recognized by the female ·TAPLE X1 (shoral Fratures of Ve Parents with hlonefriters from Pulnc Ilir Case Number Hesght Weight Span LY (inthe) (Nound (Iru hes) (inches) (inches) Prectren Sons 1119 mount Inillary Bears! 1.tr Tem. Final Flatine Voice tribution C (Years) XXXII 09 6171 Normal Vorm 1! Vale Normal vormut Yormal XXX Rece 1Broken 671 08 337 Xurmat tent Vulc Scanty Nusanal Vinmal XL Recent Shen Broken us 42 031 33 32 Narsal Normal Mate LINEFELTER'S SYA DROVE XXVII Normal Normat Normal Keces. hion 70] 1tract 20 140 641 35 351 Vormal Normal Wule XLIT Sormuł Sarnst Yormal Meces- Brohen 69 31 140 09 03 34 35 Normal Xormal als Sarnial Xormal Normal XXVII 721 Broker Recet slon IS 154 727 36 36% Yormat Ved Male Varnas Xornial Xerms! Keces. Unbroken 17 1 מיני 59 ·60 GYNECOMASTIA 1. chromosomal pattern of their cells, while those of Groups 2 and 3 will be indistinguishable Since the gynecomastia shows no features peculiar to any one of these groups € , age of onset, severity, histology, ptr and sinan tha the testis is similar in all three groups the chromosomal females it would -.c females may be endowed with breast tissue which is inherently moře sensitive to hormonal influences than the breast tissue of genetic males. TABLE XII Gynæcomastia in Klinefelter's Syndrome Case Number Age at Onset of Gynacomastia Severity of Gynæcomastia at First Attendance (Grade) Duration of Severity of Duration of Gynæcomastia (Gynæcomastia Gynæcomastia at Follow-up at Follow-up at Operation (Years) (Years) XX.X11 14 II 8 II XXXV 14 III 42 III XL 14 III XXXVIII 13 111 11 111 XLVI 14 II XXVII. 1+ II + II Certain workers108, 109 have described features by which the testes of cases showing female chromosomal sex can be distinguished from those showing male chromosomal sex In the former, tubules are smaller, less regularly spaced, and more severely hyalınized, they are also less likely to show complete spermatogenesis These differences do not however affect the overall picture, which is one of germinal cell failure and clumping of Leydig cells TABLE XIII Duranon of Gynæcomasta in Klinefelter's Syndrome Duration of Gynecomastia (Years) Patients Submitted to Operation Patients Not Submitted to Operation (2) 58 f >8 20 >20 1 7 SIX cases of Klinefelter's syndrome are shown Small testes and gynæcomastia were present ame evident during puberty, although it is e testes before puberty In spite of the fact that the testes were small, they were jarger than the scrotal contents in prepubertal testicular failure, being roughly 1.5 XI'Oxo 5 cm It can be seen that eunuchoidism ·KLINEFELTCR'S SYNDROVE 61 and decisive evidence of failure of secondary sexual development were absent in these patients (Table XI). Gynecomastia appeared at about the age of 14 years and reached Grade II or Ill severity (Table XII). Pain and secretion from the breasts were absent. The brcast development soon reached its greatest extent and remained at this level indefinitely, in no case was spontaneous remission scen (Table XIII). None of these patients showed acne; in fact, their shins were remarkably clear. No relevant findings were discovered in the previous health of these patients, and in particular no history suggestive of attacks of orchitis was discovered 1 cells (l'able XV). TABLE XIV Laboratory Inrestigations in Klinefelter's Syndrome 17-ketostermds (Mg per 24 Hours) Urinary Gonadotrophine (Mouse Units per 24 Hours) Semen (Number of Examinations) Emphyses (age at Examination) Case Number XXXII 8 98 >96 > 96 1 zoospermie (s) Normal for age (19) XXXV No ejaculate 90 40 63 > 48<98 >96 >96 E.prphy ses fused (56) XI. Normal for age 17 124 14 2 10 8 >96 >96 > 96 Azoospermia (3) (16) XXXVIII أو ز I O 12 4 > 96 Normal for age (14) Azoospermia (3) Azoospermia (3) ILVI Normal for age IO O I 24 11 2 >96 >90 >90 (15) XXVII 89 94 >96 >90 Izoospermia Xornal for age (16) are The essential features of Klinefelter's syndrome, as the term is used in this book, (1) gynæcomastia, (11) testicular atrophy, (111) defective spermatogenesis, (iv) raised urinary gonadotrophin, (v) clumping of Leydig cells These changes may be reduced to a sort of common denominator, because defective spermatogenesis of the degree encountered in Klinefelter's syndrome leads to raised urinary gonadotrophins and to testicular atrophy, since the bulk of the ut Lyub "LIJ It will be shown elsewhere that this combination of signs is seen in a number of diseases (eg male pseudohermaphroditism, diseases of the spinal cord, leprosy, thyrntaviensis et It is thorofnun tratam 1 ·62 GYNECOMASTIA A number of workers have described the occurrence of hyperplasia of the interstitial cells of the testis accompanied by defective spermatogenesis. This histological nunturis cann ne tha recult of a Anturinty of machidnavnerimental arnoncen TABLE XV Teshcular Biopsies in Cases of Klinefelter's Syndrome Leydig Cells Case Number Basernent Membrane Germinal Epithelium Distribution Appearance XXXII Prominent clumps Eosinophilic, moderately granular Hy alınization well Normal spermatomarked genesis absent Some tubules contain only Sertoli cells Increased thickness Normal spermato- Hyalinization and genesis absent fibrous thichen Some tubules coning weil marked tain only Sertoli cells XXXV A few small clumps Small, only granular pale, XL Hyalinization well marked Prominent clumps Eosinophilic, mod. erately granular Normal spermatogenesis absent Some tubules con tain only Sertoli cells XXXVIII Hyalınızation well marked Prominent clumps Losinophile, moderately granular Normal spermatogenesis absent Some tubules con tain only Sertoli cells XLVI Hyalinization well marked Prominent clumps Eosinophilic, moderately granular Xormal spermatogenesis absent Some tubules contain only Sertoli cells XXVIJ Prominent clumps Very eosinophilic and granular Increased thickness Normal spermato- Hyalınization well genesis absent marked Some tubules contain only Sertoli cells the shrinkage of the tubules lowers the pressure exerted upon the interstitial cells, thereby allowing the nests or groups of these cells to expand He adds that the hyperplasia may be so extreme as to maintain the size of the testis in the face of considerable shrnkage of the tubules Among the conditions which can give rise to these changes are the following Chronic diseases Pulmonary tuberculosis, cachexia in carcinoma, cardiac failure, chronic nephntis, syphilis, leprosy, untreated advanced diabetes mellatus, pernicious anemia Acute illnesses Pneumonia, pulmonary tuberculosis, typhoid fever, polyarthntis. Miscellaneous. Senile testicular atrophy, undescended testes ·KLINCFELTER'S SY, DROME. 63 Jemerin quotes Kauſmans' as stating that, in general, in discascs associated completely destroyed, the hyperplasia is great. 1 7 $$ FIGUREN Klinefelter's syndrome showing syutico- Tastia and small testes without eunuchoidism intensive or long-lasting to produce at least cessation of spermatogenesis Félizet and Branca23 state that in undescended testes interstitial cells are rarely seen before puberty However, in ectopic testes removed after puberty they found atrophy of the seminiferous tubules, accompanied by an increase of the interstitial cells between the tubules, to be the rule ·64 GYNECOMASTIA In support of these observations Jemerin19 has quoted certain experimental observations The testes of dogs were exposed to roentgen irradiation and biopsies taken after each of three successive exposures The testes were finally reduced to about half of normal size After each exposure atrophy of the germinal epithelium was more advanced, and hyperplasia of the interstitial cells became more evident. The authors (Kyrle22 and Simmonds24) concluded that Leydig cell hyperplasia was secondary and compensatory to the parenchymal degeneration This concept was emphasized by the observation that when recovery was permitted after atrophy of the parenchyma had not proceeded too far, regeneration of the epithelium occurred, followed by regression of the interstitial cell hyperplasia Bouin and Ancel21 ligated the vas deferens of young rabbits and found that the semınıferous tubules contained no spermatozoa and only a few germinal cells, while there was slight hypertrophy of the interstitial cells When this procedure was performed on one side and the opposite testis removed, after a period of six months the tubules came to contain only Sertoli cells and a few spermatogonia, while the interstitial gland" was enormously hypertrophied FIGURE 12 The testes in Klinefelter's syndrome (A) Clumps or masses of interstitial cells between atrophic tubules (B) Tubules lined by Sertol cells Hyalinization of the basement membrane is seen in the tubule on the left (C) 4 typical clump of interstitial cells In the regeneration of the testes of dogs exposed to radiation, the parenchyma recovered before the interstitial cell hyperplasia regressed Similarly, in experimental ligation of the vas deferens, defects of spermatogenesis preceded the changes in the Leydıg cells Again, some of these causative conditions occasionally produce cells but never r these reasons to those in the Leydig cells and that the latter were compensatory From his use of the term hyperplasia and from his concept of the pathogenetic basis of the changes in the Leydig cells, it is clear that lemerin regarded the latter as more than a relative increase in number and prominence Summanzing these observations, Jemerin states that " in any condition, local, general or experimental, in which cessation of spermatogenic activity and tubular atrophy occur, hyperplasia of the interstitial cells may secondarily ensue The secondary hyperplasia may be so marhed as to form almost the entire stroma and even to maintain the size of the testicle despite marked tubular atrophy He goes on to suggest that the hyperplasia may cause further tubular atrophy by pressure ** The primary and imtiating factor, however, 13 the parenchymal destruction ·KLINEFELTER'S SYDROVE 65 Among other writers u bo have reported the association of clumping of Leydig cells in association with destniction of germinal epithelium the following deserve mention: (1) -1.14. o.--- in canilantronhy of the tastis (2) saine cha (3) Hausemann? found the same histological changes in cases of tuberculosis, carcinomato is, syphilis and pernicious anæmia, while Lubatsch?and Cordesa confirmed these findings in tuberculo»s and carcinomatosis, 1 ม and the same changes were to be found (5) In the case of alcoholism (sometimes complicated by cirrhosis, tuberculosis and carcinomatosis) Weichschaumn", 33 made similar observations (6) In acute illnesses Cordes, Bouin and Ancef21 and Kytic" described the same changes in the testis. (7) In undescended testes Félizet and Branca, Grynfeldt, Pack, Simmonds, 24 Kocha and Kyrle* all describe absence of germinal epithelium and Leydig cell hyperplasia (8) Stroches Pichss and de Josselin de Jongo made similar obscrvations in cases of male incudohermaphroditim. Mont attempts to elplain the ætiology of Klinefelter's syndrome have tahen the view that hyalinization of the basement membrane is the essential pathological change The work of Jemerin" suggests a mechanism whereby two of the three fundamental features of the syndrome may be finked. FIyalinization interferes during fixation On the other hand, the nests of Leydig cells seen in an ordinary histological preparation of the testis should be looked upon as a section of a long strand of such it -- ha ---- lestruction of tubules <ation of a stretched s in place This will with the result that tika ·66 GyxÆCOVASTIA cells do not usually show mitoses, while occasional mitotic figures are encountered in the clumps of these cells seen in Klinefelter's syndrome 100 Such mitotic figures were found in all six testicular biopsies of the patients with Klinefelter's syndrome descnbed in this chapter. In order to explore the possibility that the condition of the Leydig cells in Klinefelter's syndrome does not result from an anatomical rearrangement in the testis as the result of destruction of tubules, some estimate of the volume occupied by these cells is required. Experiments of this nature have been undertaken at Guy's Hospital. P. of testicular biopsy thin The areas oc From the relative weights of the Leydig cell areas and total area it is possible to calculate the relative area occupied by Leydig cells, and from this relative area the proportionate volume of Leydig cells is calculated and expressed as a percentage, thus 4,XP, Proportionate volume p= where Ay is the area of one field and P, is the proportionate area of Leydig cells, i e Area of Leydig cells Total area This technique is a modification of that described by Eranko3, and was devised by Dr G Thomas of Guy's Hospital Table XVI shows the change in volume of the tubules calculated as the cube of the mean tubular diameter The expected proportionate volume of Levdig cells is calculated by assuming that this will increase in proportion to the fall in volume of the tubules. In five cases the observed proportionate volume of Leydig cells exceeds that expected on the basis of these calculations The sixth case is that of a man aged 56 years 1 ho 14 years The fact that this biops: ia may explain the fact that clump ortunately the exact dimensions of a whole testis in Klinefelter's syndrome have never been reported External measurements of the testis in the scrotum are so inaccurate as to be worthless, but even these rough dimensions suggest that the reduction of testicular volume is greater than the decrease in testicular volume calculated above This is probably at ibank testas ita at joubt r ps of Leydig cells result from relative prominence of the interstitial tissue does not provide an entirely satisfactory explanation for the appearance of these cells in the clumps characteristic of Klinefelter's syndrome and that the possibility of a true increase in the number of Leydig cells must be considered It is to be hoped that carctul measurements of testicular volumes in Klinefelter's syndrome will be undertaken in 'UN LLILU t and Branca 23 37s appeared in jarge clumps At puberty the interstiliai ltal al gonadotrophic stimulation from the adenohypophysis, and it is probable that the appearance of these cells in clumps represents a response to such stimulation If we now consider some of the conditions which lead to destruction or loss of germinal epathchum and clumping of Leydig cells, it will be seen that these changes are encountered in genetic females in whom some developmental anomaly has interfered with the development ·KLIXCFCLTCK'S SYNDROVE 67 of tubules, in unde cenderl testes where the tubules themselves have developed characteristic appearance, which is essentially indistinguishable, regardless of the cause It seems likely that the appearance of the Leydlig cells from causes as diverse as a developmental anomaly on the one hand and a progressive descase of adult life on the other, is more readily understood as the result of hormonal stimulation of these cells than as an architectural change brought about by loss of elasticity or TABLE XII Mein Duzmeters of 100 Tubules (Vin ) l'escentage Dis. tribution of the Three Groups of Tutules 'TO- Case Xumlar Mean Diameter (C mm) 10-6 Expected portionate 1ro- Volume mrtionate of Leydig Volume Cells of Leydig (Olycrved) Cells (a) (a) (c) XXXII 0 061 o os O 15 X X 0 0 0 130 14 23 15 60 22 461 14 09 XXXV o ob X O 0) 59 20 20 10 50 30 0 14 1016 ooo14 XL O 07 х 010 23 18 59 22 35.0 o 13 16 O 00 O 05 XXXVIII 0 14 X DIS 22 19 59 17 480 18 000 013 XXVII O 06 X o to o 07 0 14 < 013 015 19 23 58 22 30 0 14 000 O 05 017 XLVI 20 52 17 39 2 18 O 0 O 14 O 15 10 normal con. trols 0 14 X9 17 41 7 5 pressure follou ing the destruction of tubules This is especially so in the case of that no histological distinction can be drawn between the testes in Klinefelter's syndrome in genetic females and in genetic males It is therefore proposed that the term Klinefelter's syndrome is at the present stage of our knowledge a useful one and is most useful if reserved for a condition involving gynecomastia, defective spermatogenesis, azoospermia and raised unnary ·68 GYNECOMASTIA gonadotrophins without eunuchoidism but with normally developed male secondary females The tubules show hyalinization of the basement membrane because their development is, as it were, hall-hearted. This group can be called true Klinefelter's syndrome, and rarely the full pattern of spermatogenesis is seen in an occasional tubule, pointing to a potentially complete reversal of sex 4 In other cases, in chromosomal males, the testis is affected by some infiammatory or degenerative process the nature of which is obscure and the onset usually latent In either case, abnormal relationship is clumping of Leydig cells and gynæcomastia The same changes can occur in chromosomal males in whom the germ plasm is deficient (see page 57) A similar assault on the testis may occur in adult life and change the normal balance between testis and pituitary to an abnormal one, like that seen in Klmefelter's -1-1.h. --- Antholin J are consistently associated with gynæcomastia The diseases which have been found to produce this sequence of events are (1) Klinefelter's syndrome (2) Tumours of the testis (3) Radiation of the testis (4) Leprous orchitis (5) Jumps orchitis (6) Hyperthyroidism (7) Jale pseudohermaphroditism (8) Traumatic paraplegia (9) Friedreich's ataxia (10) Dystrophia myotonica The term Klinefelter's syndrome is reserved for those cases with hyalınızation of the basement membrane of unknown ætiology, originally described by Albright and his colleagues 14 including cases of female genotype : Nelson believes that the appearance of the testis in male pseudohermaphroditism is more in favour of the idea that the Lev dig cells produce the estrogens which stimulate and maintain the development of the breasts in this condition He has -- hartalommal andence to sunnast thus belief and considers that extrapunted (because castration causes netrerons Here we have a conditivi a gonadotrophin levels and testicula syndrome, except that hyalınızation of the basement membrane is less evident Ji the Leydig cells secrete cestrogens in this condition, it is likely that they do so in response to pituitary stimulation since astrogenic activity first appears at puberty. le at a time when the pituitary gland actively secreting gonadotrophic hormones The clumps of Leydig cells may then be under the influence of the interstitial cell. stimulating hormone (ICSH) ·TESTICULAR TUNOURS 6) II the X jbility that the Lej dig cells in Klinefelter's syndrome have been stimulated by an increase in the proluction of ICSH be considered, some explana- **er puberty testicular s that the 1+ 10 . anti nut Custration in this controll caut regression olultat de clopinient ste page 99) 101 If the testis of Klinefelter's syndrome plays some part in the production of fynacomastia, it seems logical to attribute this action to the Leydig cells, since the Sertoli cells show no evidence of overactivity and in advanced cases become almost obliterated. The cells of Leydig secrete androgens and probably also astrogens," but until more refined methods are available for estimating urinary estrogens, the hormonels) responsible for the gynacomastia of Klinefelter's syndrome will remain syndrome (sce page 13-1) It is offered as a hypothesis that gonadotrophic stimulation (by ICSH) of the Leydig cells may lead to the development of gynecomastia Sometimes this stimulation is part of the physiological processes of puberty (subareolar node and of or the production of these abnormal quantities of ICSH from the pitustary Gyntcomastia does not always follow destruction of the germinal epithelium and clumping of Leydig cells Jemerin makes no mention of gynecomastia in the numerous conditions which he describes as associated with clumping of Leydig cells tissue are important in this respect Recent studies 119 of nuclear sex in Klinefelter's syndrome have produced interesting but confusing data For example, in some cases a disparity between the chromosomal pattern in skin cells and neutrophul leucocytes has been reported Evidence has also been produced for possible translocation of the autosomal elements involved in sex determination, ie chromosomal males could possess less than their share of autosomal sex determining factors (MXY) and chromosomal females could possess more than their share of these factors (MMXS) These interesting possibilities are purely speculative at present, but are being subjected to further exploration TUMOURS Certain tumours of the testis may be associated with gynaecomastia, and although they represent an uncommon cause of this condition the association is important from a diagnostic point of view The following tumours have been reported in association with gynæcomastia (1) chorionepithelioma . (11) serninoma, (111) interstitial cell tumour, (iv) Sertoli cell tumour, (v) adreno-cortical rest tumour Sarcoma of the testis has been reported" as a cause of gynæcomastia, but this claim has not been supported by histological data Similarly, one case of a tumour ·70 GYN&COYASTIA of the epididymis associated with gynæcomastia was reported by Galliert 6 Such tumours are very rare, and the association with gynecomastia may have been fortuitous Moreover, in both cases the nature of the tumour must remain in doubt CHORIONEPITHELIOMA Chorionepithelioma is more frequently associated with gynæcomastia than other testicular tumours This association was first described by Cooke in 1915, and Gilbert 52 reviened the hiterature on the subject Gilbert's paper is based upon 123 cases of choriocarcinoma of the testes, extragenital choriocarcinoma and teratoma of the testis with choriocarcinoma in metastases Bilateral gynacomastia was present in most cases, and in many a white fluid could be expressed from the nipple On the basis of these cases, Gilbert described a syndrome of choriogenic gynæcomastia, characterized by the follou ing features (1) Chorionepithelioma is found in the primary testicular tumour or in its metastases, (2) Gynæecomastia, usually bilateral, is often the only clinical symptom present. (3) hc areolæ usually show increase size and/or hyperpigmentation (4) Milky fluid can be expressed from the nipple, and there may be microscopic evidence of secretory activity in the breast (5) Chorionic gonadotrophın is present in the urine (sometimes in very large quantities). Estrone may be present in the urine in abnormal concentrations (6) The anterior pituitary gland show's the so-called " pregnancy cells". (7) Hyperplasia of the prostate and seminal vesicles sometimes occur The term pregnancy cell refers to the hypertrophic basophil cell found in the adenohypophysis during pregnancy Jechamsin of Production of Gynaconaste The observations of Gilbert recall the action of chorionic gonadotrophin upon the normal adult testis Maddock and Nelson 53 showed that the hormone produced ? urinary østrogens es gynæcomastia by Moreover, Shimkins upon the mammary os hormone upon the breast is indirect Hvperplasia of Leydig cells in both the chorionepithelioma is reported hv Arendt ös cells in testes of normal size among his own c. of spermatogenesis in the unaffected testis The facts at present available do not pernit a final statement, but it seems likely that there are two possible explanations for the gynæcomastia seen in chorioncpithelioma of the testis--namelythat the tumour secretes chorionic gonadotrophın in such concentration as to stimulate the cells of Leydig to produce an estrogenic (or possibly an androgenic) hormone, which in turn stimulates the development of breast tissue, 53 or alternatively, that the tumour itself secretes æstrogens, which cause gynæcomastia The correlation betu een hyperplasia of Leydig cells and a high output of gonadotrophins has not been established in the cases so far reported, although in one series it is likely that such a correlation existed * Since large doses of chorionic gonadotrophin have been shown to cause damage to the germmal epithelium, it is not unlikely that atrophy of the contralateral testis in patients suffering from chononepithelioma could result from the production of this hormone by the tumour l'ntil more is known of the action of chorionic • In a personal communication (175 DERI Moore stated that the data in this seturs stere derived from seseral sources and that the normal ranges of the gonadotrophin aysay mentioned could not be stated with ans preusion ·TrsTICULAR TUMOURS 71 gonadotrophin upon other cnclocrine structures such as the adrenal cortex, and until the possibility that these tumours secrete (estrogens has been explored, the mechanism of gynecomastia in the presence of chorioncpithelioma is attnbuted to the action of chorionic gonadotrophin upon the interstitial cells, which are stimulated to secrete cuccisive concentrations of (Lstrogens Although chorionepithelioma is a rare cause of gynecomastia, Gordon-Taylor and Tulle have pointed out that in this group of tumours gynecomastia indicates a poor prognosis Less often sy nacomastia is an early sign in chorionepithelioma, and urinary assay for chorionic gonadotrophin should be undertaken in cases of gynxcomastia affecting young men between 19 and 10 years of age in whom no other cause of gym.comastia can be found IGURE 13 Seminoma of the testis in a patient who showed well developed gynecomastia The uniform cellular arpearance of this type of tumour 19 Well shown SEMINOVA It is not generally recognized that seminoma may occasionally cause gynecomastia. The nomenclature of testicular tumours is somewhat confusing, so that it is difficult to assess the incidence of this association from reports in the literature Herzenbergs? has recorded a case of seminoma with gynæcomastia, and the following patient, who showed gynæcomastia and seminoma, was seen at Guy's Hospital At the age of 32 years the antsant concultod dantne honnina At that time the testes were of the left testis Biopsy of operation the gynæcom. showed the microscopic fea destruction of germinal epu test belore operation was negatise ·72 GYNECOMASTIA Mechanism of Gynecomastia Ferguson and his colleagues 58 showed that a quantitative modification of the Aschheim-Zondek test gave the following results in 117 cases of malignant disease of the testes Adult teratoma 50- 500 units Seminoma 400- 2,000 units Embryonal carcinoma 2,000-10,000 units Chorionepithelioma 10,000-40,000 units Normal male urine <52 units Today, however, such diagnostic accuracy is not expected of the Aschheim- Zondek test Hamburger and Godtfredsens studied the hormonal changes in cases of seminoma of the testis. They concluded that an incre found in 75% of cases of seminoma, and s pituitary origin by means of three observatic - 1€ 1 trophin found in the urine of castrates. In 75% of patients with seminoma urinary gonadotrophın levels between 50 and 400 mouse units were found before surgical or radio-therapeutic treatment. These levels are similar to those found in castrates, but were not found after the removal of the affected testis, even in the presence of metastases Unnary aestrogen levels as measured by bioassay were normal, and urinary androgens were reduced to levels found in normal subjects after the removal of one testis, in the treatment of conditions other than seminoma The authors suggested that the rise in urinary androgens by the testes the cause of gynecomastia in n reported, and the findings of Hamburger and Godtfredsen relate to cases without gynæcomastia. Seminoma rarely causes gynæcomastia, but the case reported above indicates that breast stimulation may be an early symptom, so that careful and repeated examination A number of reports slogical identity of the tend+mon LLITTUUAJI INTERSTITIAL CELL TUMOURS bed the enterstaten cells of the testis, and in 1895 Sacch16 se cells without realizing that he was of Leydig cells Rowlands, Nicholson and Webster were list sesi - ibe a case of interstitial cell tumour in 11 hich the clinical picture was correlated with a detailed pathological description of - b way resemble interstitial Clinical Picture Before puberty, interstitial cell tumours cause se\ual precocity, as distinct from precocious puberty, 62-45, 49 That is to say, although the penis and secondary the testes (apart from the tumour) remain " The tumour may be so small as to escape is difficult, because adrenocortical hyper- ·TESTICULIR TUMOURS 73 genesis 67 - function may produce the same clinical picture. Under these circumstances, when a tumour is felt in one tests, the diagnosis lies between an interstitial cell tumour and an adrenal rest tumour The distinction in this case can only bc made histologically." Sometimes adrenal rest tumours are bilateral, so that both testes are enlargel. In this case the diagnosis lies betu een precocious puberty of cerebral or idiopathic origin with spermatogenesis and consequent testicular enlargement on the one hand and bilateral adrenal rest tumour on the other. This distinction can be made by testicular biopsy, which will reveal the presence or absence of spermato- In adults, interstitial cell tumours, for the most part, present as testicular id S Dy modern methods are fit beel avall.ble in the report cases Showing Bynecomastia. It is therefore not possible to draw any final conclusions about the pathogenesis of gynecomastia in those patients who show precocious puberty and all the crected effects of increased androgen secretion in addition to gynrcomastia. Unfortunately, the cases so far reported have not been accompanied by sufficient cvilence to exclude the possibility of adrenal rest tumours 67 The pathogenesis of 8 nocomastia in patients suffering from interstitial cell tumours leads once more to the disputed ongin of testicular oestrogens In spite of convincing evidence that Sertoli cell tumours in dogs produce cestrogens, 66, 87, 86 there is still much evidence in favour of the Leydig cells as a source of aestrogens. Maddox and Nelsons have reported a series of experiments which indicate that contained fully differentiated Leydig cells, and castration led to signs of destrogen withdrawal and a fall in the level of urinary cestrogens Nelson concluded that the Leydig cells constituted a more probable source of cestrogens than the Sertoli cells, These observations are not necessarily mutually exclusive. Perhaps both cells can produce cestrogens The activity of neoplastic tissue may not provide reliable evidence of the functional capacity of a normal cell or may present a distortion of reconciled in such a way as to explain the source of testicular cestrogens under physiological conditions Two examples of feminizing interstitial-cell tumours have been reported in dogs.70.91 and in one of these elaborate hormone studies were made. Bjoassay clit 1 authors believe that these hndings are in favour of cestrogen secretion by the tumour rather than conversion of androgens to cestrogens Thn hort haal por by } mas diari enia perfolirled as shown in Table Avili ·72 GYNECOMASTIA Mechanısı of Gynecomastia Ferguson and his colleaguess8 showed that a quantitative modification of the Aschheim-Zondek test gave the following results in 117 cases of malignant disease of the testes : Adult teratoma 50- Seminoma 500 units 400- 2,000 units Embryonal carcinoma 2,000-10,000 units Chorionepithelioma 10,000-40,000 units Normal male urine <52 units Today, however, such diagnostic accuracy is not expected of the Aschheim- Zondek test. of th fount pitui not. gona excreted in the urine in cases of seminoma were identical with those of the gonadotrophin found in the urine of castrates In 75% of patients with seminoma urinary gonadotrophin levels between 50 and 400 mouse units were found before surgical or radio-therapeutic treatment. These levels are similar to those found in castrates, but were not found after the removal of the affected testis, even in the presence of metastases Urinary oestrogen levels as measured by bioassay were normal, and urinary androgens were reduced to levels found in normal subjects after the removal of one testis, in the treatment of conditions other than Seminoma The authors suggested that the rise in urinary gonadotrophins resulted from a fall in the secretion of androgens by the testes. Further studies are required in order to establish the cause of gynæcomastia in seminoma The state of the Leydig cells has not been reported, and the findings of Hamburger and Godtfredsen relate to cases without gynecomastia Seminoma rarely causes gynæcomastia, but the case reported above indicates that breast stimulation may be an early symptom, so that careful and repeated examination of the testes is required in cases of gynæcomastia in adult men A number of reports of seminoma in the literature are confusing because the histological identity of the tumours reported has not been clarified INTERSTITI AL CELL TUMOURS In 1850 Leydig described the interstitial cells of the testis, and in 1895 Sacch6 described the first case of a tumour of these cells without realizing that he was presenting the clinical picture of over-activity of Ley dig cells Rowlands, Nicholson and Webster 61 were the first authors to describe a case of anterstitial cell tumour in Clinical Picture Before puberty, interstitial cell tumours cause sexual precocity, as distinct from precocious puberty 63-65, 69 That is to say, although the penis and secondary sexual characteristics are well developed, th consistent in size with the patient's age detection, in which case the diagnosis 15 ·TESTICULAK TUVOURS 75 In addition, the titre of urinary chorionic gonadotrophin nas negative at 750 1.U. per 24 hours and that of FS II, was positive at 13 and negative at 52 M U per 24 hours. The affected testis contained a tumour which proved to be of interstitial cell type, while the remainder of the totis shoxei defective spermatogenesis with few spermatids and no more than occasional spermatozoa This case is instructive in several ways. In the first place, urinary estrogen levels are only slightly raised, although gynecomastia was recent and pronounced and the state of the germinal epithelium compatible with recent exposure to (estrogens This must mean that either the secretion of oestrogens was variable or slight increase in urinary levels is compatible with marked gynecomastia (including pain and secretory activity) and defective spermatogenesis. It is therefore not surprising that high urinary estrogens have not been reported in esential gyneco- TAHLF X1111 Flormone Issays in Intersthal Cell Tutour of the Testus (Case of Blertminn et ain) l're operative Value per post-operative 1 Normal Ringe (Vale) l'rinar Steroid 1 Value fer 24 Ilours 24 Hours Iso-andronterone and dehydro- ID-androsterone 2 2mg 0 m Indrosterone 1 2mg 19 mg 1 tiocholanoline 2 g mg 5 omg 11-oxy-17-ketosteroids Ismg I 9 mg astrol 13 7 UR <82416 astrone 66 к. <7oHS Estradiol-179 3 2 CUIS mastia and in conditions associated with clumping of Leydig cells, such a slight increase can be detected only by sensitive methods It is hard to conceive that the gynecomastia in this patient could be due to any cause other than the direct action of cestrogens upon the breast Kolated reports of normal urinary cestrogens in patients suffering from gynecomastia should not, therefore, be taken to mean that such gynecomastia cannot be due to excessive secretion of estrogens In the second place, the urinary output of soandrosterone and dehydroisoandrosterone was high before operation, and an increase in the urinary output of dehydroisoandrosterone has been reported following the administration of estrogens 81 Again, the excretion of androsterone and ætiocholanolone (metabolites of testosterone) was low before operation, while that of 11-oxy-17-ketosteroids remained normal, which suggests that the secretion of testosterone was depressed in the presence of the tumour Modern concepts of the synthesis of hormones suggest a series of equilibra governed by appropriate enzyme systems The outcome of a given equilibnum is governed, among other factors, by the nature and concentration of the substate and the nature of the enzyme systems at hand In consequence, a which it hormone It is now established that the body can convert androgens to estrogens 81, 82, 83 In any case ·TABLE XVII Gynecomasha and Interstitial Cell Tumours buthor Ige (Years) Gynacomastia Estrogens Libido 17-Keto steroids/ 24 hours Ilunt and Budd" linne Bilateral Tumour Urinary Gonadotrophins Decreased Huffman" Clinical Features 12 muigm 6 Bilateral Positie Zondek test National alır? 30 Bilateral Grabstuld et al,75 32 Bilater. Decreased Mayers? 20 Bilateral Decreased Negative Fried- Precocious genital de man test velopment Gynæcomastia sent two and a hali years after operation Negative Fred Died of coronary disman test ease one year after diagnosis Prolan normal Breasts normal 15 months after operatron Libido increased after operation 4 75m after operation 1 2 3 mg after operation und GynæCOMASTIA 70 Christenson Vettleship" lisenstadt and Petr ? Bilateral transitory and +2 Bilateral Decreased 60 mg before operation 20 mg after opera- 13 5 mg (17 OHCS normal) FSH normal Tierrmann et al 20 tion Decreased Bilateral Tender and secretion preent Raised See Table XVIII Sommal 4-30 mg Breasts normal nine months after opera. tion Sperm count and libido normal Reported as mg by Eisenstadt and Petry, presumably a misprint for him ·TESTICULAR TUMOURS 75 In addition, the titre of urinary chorionic gonadotrophin was negative at 750 1 U. per 24 hours and that of FSH. was positive at 13 and negative at 52 MI.U. per 24 hours The affected testis contained a tumour which prosed to be of interstitial cell type, while the remainder of the testis showed defective spermatogenesis with few spermatids and no more than occasional spermatozoa This case is instructive in several ways. In the first place, urinary strogen levels are only slightly raised, although gynecomastia was recent and pronounced and the state of the germinal epithelium compatible with recent cxposure to cestrogens. This must mean that either the secretion of estrogens was variable or slight increase in urinary levels is compatible with marked gynæcomastia (including pain and secretory activity) and defective spermatogenesis It is therefore not surprising that high urinary estrogens have not been reported in essential gyneco- TABLE XVIII Hormone Assays in Interstitial Cell Tumour of the Testts (Case nf Herrmann et al.) l're operative Value per l'ont-operative Normal Ringe (Viale) l'rinary Steroid Value per 24 Hours 24 Hours Iso-androsterone and dehydro- 150-andronterone 2 mg 09 mg Androsterone 1 ms 19 mg Etrocholangtone 2 9 mg 5 om 11-oxy.17-ketosteroid 1 8 mg 19 mg Estriol 15 78 <8.2 48 Estrone 6 6 8 <a opg Estradiol-179 3245 <I! US mastia and in conditions associated with clumping of Leydig cells, such a slight increase can be detected only by sensitive methods It is hard to conceive that the gy necomastia in this patient could be due to any cause other than the direct action of cestrogens upon the breast Isolated reports of normal unnary estrogens in patients suffering from gynæcomastia should not, therefore, be taken to mean that such gynecomastia cannot be due to excessive secretion of restrogens in the second place, the unnary output of isoandrosterone and dehydroisoandrosterone was high before operation, and an increase in the urinary output of which suggests that the secretion of testosterone was depressed in the presence of the tumour Modern concepts of the synthesis of hormones suggest a series of equilibria governed by appropriate enzyme systems The outcome of a given equilibrum is governed, among other factors, by the nature and concentration of the substate and the nature of the enzyme systems at hand In consequence, a histological concept has given place to a histochemical one, as the result of which it is now held that the important feature of an endocrine cell, as far as its hormone production is concerned, is not its appearance but its enzyme content It is now established that the body can convert androgens to cestrogens.81, 82, 63 In any case ·76 GYNECOBLASTIA there should be no difficulty in accepting the cells of an interstitial cell tumour as the source of gestrogens in the patient descnbed This observation shous that over-activity of Leydig cells, whether neoplastic or hyperplastic, is sometimes associated with gynecomastia A patient reported by Cook and his colleaguess showed an interstitial cell tumour of the testis without gynecomastia The urine in this case was studied by chromatographic separation of steroids and was found to contain a high proportion of androsterone and aetiocholanolone but no 33-hydroxysteroids. This information suggests that the urinary steroids were derived from testosterone rather than from adrenocortical steroids, and hence established the nature of the tumour, which on histological grounds might have been confused with an adrenal rest tumour. SERTOLI CELL TUMOURS Sertolt cell tumours might be expected to solve the disputed question of the origin of testicular oestrogens Hugginsoo described a number of examples of this tumour in dogs which showed femınızıng changes including gynacomastia These cases include examples of bilateral tumours and of a tumour in an undescended testis The cells of the tumours contained fat, which distinguished them from germinal cells, and either were minutely tubular or else showed a diffuse, uniform cellularity. The histological appearance of these tumours was quite distinct from that of Leydig cell tumours The tumours were rich in estrogens Tellum97 reported a testicular tumour in a man of 53 years, who presented with gynecomastia of one year's duration, loss of libido, and impotence. The left testis was large and contained a palpable tumour; the right was atrophic After removal Ann-hun T.. why some of the former appeared to cause feminization Recently, authors have given Kay before this confusion and prefer to speak of a group of testicular and ovarian tumours as Sertoli-Leydig cell tumours It is at present impossible to simplify matters any further, and it seems unwise to conclude on the basis of these tumours that a given type of cell produces a certain hormone. LEPROSY T 2....mantranh Baptista 40 found gynæcomasti. in 8.000 of 842 cases ot leprosy Grabsidid Swan have reviened the literature upon the subject, and in one of the cases they described the patient was submitted to breast biopsy, which showed changes typical of gynecomastia (see page 22) The changes in the testis in leprosy occur in three stages, '1 a vascular phase, an interstitial cell phase, and an obliterative phase l'ascular Phase (Acute Leprous Orchitis) - In the vascular phase infiltration of the walls of blood vessels of all sizes by lymphocytes is the earliest change to be scen The wall of the vessel increases in thickness at the expense of the lumen, and lepromata are seen as nodules projecting into the lumen Lymphocytes are also seen in the perivascular and interstitial tissue All stages of spermatogenesis are seen, the basement membrane is normal, and both Sertoli and Leydig cells are histologically intact Intertral Cell Phase – The interstitial cell phase, which imperceptibly follow's the first, begins as a reactive, obliterative endarteritis Leydig cells are very ·ORCHITIS 77 prominent, appearing in masses or clumps, and fibrous strands appear in the interstitial tissuc. The vessel walls remain thick, but lack the stigmata of inflammation seen in the previous stage Tlie seminiferous tubules are small, and in most cases they contain only Sertoli cells with occasional spermatogonia, but no spermatids. The basement membrane is thicker than normal, and concentnc lamelle of fibrous tissue are laid down At the same time the interstitial tissue is seen to contain diffuse collagenous deposits with aggregations of Leydig cells, which are larger, more granular and more rovinophilic than normal Vany Leydig cells contain coarse brown granules Obliteralite Phase...The obliterative phase gradually follows, and the vasculature of the testis is further impaired. The outlines of the tubules are finally lost in the progressive fibrosis which follows. Bacilli are usually absent were more common in the lepromatous than in the tuberculoid type of leprosy In patients with testicular atrophy, 17-ketosteroid excretion was normal and the level of urinary gonadotrophins was raised. These observations recall the reciprocity which appears to exist between the Les dig cells and the adrenal cortex (page 54) Cases with adrenal amyloidosis may have shown clumping of Leydig cells with greater regularity because these cells were called upon to compensate for loss of adrenal androgens The authors drew attention to the similarity between the final stages of leprous orchitis and Klinefelter's syndrome, Small testes, gynxcomastia, raised urinary gonadotrophins, clumping of Leydig cells and only Sertoli cells within the tubules are common to both conditions Azouspernia is not mentionel in the cases of leprous orchitis, but in view of the histological appearance of the testis it seems unlikely that the semen could contain mature sperms The interest in leprous orchitis lies in the fact that the pathogenesis of the condition has been followed in detail and shown to lead to the same end result as other ܙܢܬܝ ܕ ܠܐܝܚܙܘ ܫܬ ܬܝ ܬ ܝܝܝ ܘ ܝܫܝܙ TL... . . as in the case of Klinefelter's syndrome (sec page 69) MUMPS ORCHITIS C. nc - blo+cal at: clie - K. -AL. LAS. L. 1.- 1 following bilateral murnporchitis in a soldier Histological findings of the testis in mumps orchıtıs have been reported infrequently Recaluss described the condition as a parenchymatous sclerosis, and Malascz states that the interstitial tissue is normal but the tubules contain no germinal epithelium Wesselhoeſt, 7 in a study of biopsy specimens taken during incision of the tumour in order to allow expansion of the swollen testis, describes the presence of inflammatory tissue represented by lymphocytes and polymorphonuclear cells Wesselhoeſt produced a similar histological picture by injecting the salıva of patients with mumps into the testes of cats ·78 GYNÆCOMASTIA However, in those patients who developed gynæcomastia following mumps orchitis an interval of six to 12 months elapsedi between the attack of mumps and the first appearance of gynæcomastia We are therefore concerned with the histology of the testis after the acute orcliitis has subsided. Howard et ali148 studied the ents who suffered testicular atrophy The authors described destruction Icaving only Sertoli cells Some thickening of the basement membranc occurred, and clumping of Leydig cells was prominent Urinary gonadotrophin levels were raised, while 17-ketosteroid excretion was normal So far no report is available of the histology of the testis in patients showing gynecomastia after mumps orchitis Gynæcomastia is not a common complication of mumps orchitis. Four patients with bilateral testicular atrophy following mumps orchitis have been seen at Guy's Hospital, and none of these showed gynecomastia. The resemblance of the testis affected by mumps orchitis to that of Klinefelter's syndrome is quite striking, and is tempting to suggest that the same mechanism produces gynecomastia in the two conditions although nonaf of the kernthneris lacking The fact that mumps orchitis does ? surprising, since none of the known cases of symptom BILATERAL ORCHITIS OF UNKNOWN ÆTIOLOGY patients suffering from Klinefelter's syndrome is simply one of failure of testicular development, together with the appearance of gynæcomastia at puberty Presumably the same clinical picture could follow any condition which causes destruction of the germinal epithelium In the cases of atrophy of unknown ætiology no retrospective evidence of syphilis, gonorrhæa, tuberculosis or mumps could be found Three patients who belong to this group were studied at Guy's Hospital of these, two were typical examples of Klinefelter's syndrome, differing from other examples of this syndrome only in the history of acute orchitis The third patient suffered an attack of pain in the testes with urethral discharge at the age of 14 years This attach lasted three weeks, and the testes remained small thereafter At the age of 22 years the patient noticed swelling of the right breast He had suffered an attack of mumps without orchitis at the age of eight years The patient was of normal stature and showed pubic hair of female distribution, 17-ketosteroid excretion was normal, and the level of urinary gonadotrophins was raised Testicular biopsy (Figure 14) from both testes revealed defective spermatogenesis of such severity as to lead to the appearance of Sertoli cells only within the tubules The basement membrane was normal in most tubules and showed slight hyalınızation in the remainder Ley dig cells were prominent and occurred in large chumps between the tubules No evidence of mumps, tuberculosis, gonorrhoea or syphilis could be discovered in the history or in the laboratory examinations This patient differs from those suffering from Klinefelter's syndrome in the psy and in the the illness at of destruction of the germinal epithelium, cumpilig vi ljuig uus anu by a LCX ·RADIATION OF THE TESTIS 79 It is possible that this syndrome of orchitis followed by Klinefelter's syndrome is not rare but has either escaped detection through lack of follow-up studies or has not FIGURE 14 The tests in a patient who showed all the features of Kincfelter's syndrome and who gise a history of an attack of orchutis Tubules are lined by Sertoli cells, and some thickening of the basement membrane is esident A group of well developed darkly stained interstitial cells is seen RADIATIOX OF THE TESTIS Woodham reported three cases of gynecomastia occurring in men who had undergone operations for testicular tumours and thereafter been subjected to deep X-ray therapy The records of these patients have been made available through the hindness of Dr Levitt of St Bartholomew's Hospital CASE I On February 13, 1935, at the age of 32 years, the patient underwent left orchidectomy for teratoma From February 18 to March 26 deep X-ray treatment was given to the whole pelvis, scrotum and right half of the abdomen On September 3 gynæcomastia affecting the nght breast was noticed at a follow-up examination The swelling was painful and had not been present at the previous visit in June On October 10 bilateral gynæcomastia was discovered On October 17 both breasts were removed surgically. The pathologist reported the presence of " hyperplasia of the breast tissue, with dilatation of the duct system and increase in the stroma 5 ·78 GYNÆCOMASTIA IT-- However, in those patients who developed gynæcomastia following mumps orchitis an interval of six to 12 months elapsed between the attack of mumps and the first appearance of gynecomastia We are therefore concerned with the histology of the testis after the acute orchitis has subsided Howard et aliae studied the --ccnts who suffered testicular atrophy The authors described destruction leaving only Sertoli cells. Some thickening of the basement membrane occurred, and clumping of Leydig cells was prominent Urinary gonadotrophin levels were raised, while 17-ketosteroid excretion was normai. So far no report is available of the histology of the testis in patients showing gy'narcomastia aſter mumps orchitis Gynæcomastia is not a common complication of mumps orchitis Four patients with bilateral testicular atrophy following mumps orchitis have been seen at Guy's Hospital, and none of these showed gynecomastia. The resemblance of the testis afíected by mumps orchitis to that of Klinefelter's syndrome is quite striking, and it is tempting to suggest that the same mechanism produces gynæcomastia in the two conditions, although proof of this hypothesis is lacking The fact that mumps orchitis does not often produce gynacomastia is not surprising, since none of the known cases of gynæcomastia invariably produce this symptom BILATERAL ORCHITIS OF UNKNOWN ETIOLOGY Sometimes a clinical syndrome * St.-'s syndrome results from orchitis of unknown to puberty and causes painful swelling of both testes The acute stage is followed by testicular atrophy and, after a latent interval, by gynecomastia It has often been suggested that certain cases of Klinefelter's syndrome follow some form of orchitis which may not be recognized S, 18 Usually the history given by patients suffering from Klinefelter's syndrome is simply one of failure of testicular development, together with the appearance of gynæcomastia at puberty Presumably the same clinical picture could follow any condition which causes destruction of the germinal epithelium In the cases of atrophy of unknown ætiology no retrospective evidence of syphilis, gonorrhoea, tuberculosis or mumps could be found Three patients who belong to this group were studied at Guy's Hospital of these, two were typical examples of Klinefelter's syndrome, differing from other The third patient of 14 years At the age of 22 years the patient noticed suelling of the right breast He had suntered an attack of mumps without orchitis at the age of eight years The patient was of normal stature and showed pubic hair of female distribution, 17-ketosteroid excretion was normal, and the level of urinary gonadotrophins was raised Testicular biopsy (Figure 14) from both testes revea to lead to the appearance of Sert ent membrane was normal in most the remainder Leydig cells were prominent and occurred in large clumps betueen the tubules No evidence of mumps, tuberculosis, gonorrhoea or syphulis could be discovered in the history or in the laboratory examinations This patient differs from those suffering from Klinefelter's syndrome in the fact that hyalınızation was not a prominent feature of the testicular biopsy and in the Whatever the nature of the illness at history of acute orchitis of unknown cause the age of 14 years, this patient is another example of the combination of destruction cells and gynecomastia of the germinal epithelium, clumping of as ·TESTICULAR LESIONS St UYDESCEYDED TESTES Undescended testes are rarely associated with gynæcomastia. in a series of more than 400 cases of undescendexi totes Bishop encountered none with gynacomastia Crookest reported the case of a man aged 24 years with a nght undlescended (inguinal) testis and a small left scrotal testis. The patient suffered from gynxcomastia, he had to share only twice a week, his voice remainal unbroken, and although he was potent, ejaculation had never occurred. Biophy of the left testis revealed atrophic tubules and "hypurtrophy of the interstitial cells". The 17-ketosteroid cxcrction was 33 mg per hours. In this paticnt gyntcomastia uas probably not specifically related to the presence of one undescended testis but rather to a testicular lesion vluch proluced atrophic tubules in testes ol wluch one happened to be widescended In the absence of further data it is not possible to regard this as an example of Klinefelter's syndrome, but it scems likely that the gynecomastia is to be explained by changes in the tests which resemble those found in that syndrome. CASTRITION Castration has been given as a causc ol gynacomastia," and although prepubertal testicular failure is sometimes associated with synacomastia, the occurrence of necomastia in cases of prepubertal castration is uncertain Hekmet and Regnant and Wagenccil-, *3 studied a large group of Turkish eunuchs and found no evidence of gynacomastia Vost authors agree that castratson, shether before puberty or after, does not cause gynacomastia. None of mae post-pulcrtal castrates seen at Guy's Hospital showed gynecomastia TRAUMA Although reports, *, 97, 107 have appeared m the literature of cases in which gynacomastia has followed traumatic testicular lesions, only one" of these reports is sufficiently detailed to be convincing In this case repeated opxodes of testicular injures led to atrophy of one testis and left the other smaller than normal Soon after the last of these injuries, at the age of 18 y cars, gynæcomastia appeared Presumably the germinal epithelum suffered considerable destruction in this case, and this may have been related to the occurrence of gynæcomastia Testicular trauma must be regarded as a very rare cause of gynxcomastia, and the mechanism of breast development under such circumstances remains unknown UNILATERAL TESTICULAR LESIONS VARICOCELE A number of cases are recorded in the literature of g necomastia associated with varicocele *9, **, av Sometimes gynæcomastia follous an operation for varicocele One patient seen at Guy's Hospital had a small night testis which had been operated upon for varicocele and shoned the histological picture of Klinefelter's syndrome, while the left tests was undescended and could be felt in the inguinal canal The 17-detosterold excretion was normal, and the level of urinary gonadotrophins was raned Gynecomastia appeared at 20 years of age-tuo years after the operation for varicocele The gynæcomastia in the patient was probably due to the same cause as that seen in the patient reported by Crookesi(see above), and in both patients it is suggested that the mechanism involved is similar to that which operates in Klinefelter's syndrome in these two patients we are dealing with one testus like those encountered in Klinefelter's syndrome and another undescended testis in which it seems likely that a similar histological picture would be seen P ·So GYNECOMASTIA The deep X-ray therapy in this case involva anterior and posterior pelvic fields and a loin field without protection of the scrotum. The patient was alive and well in 1955. He had been married one year before the orchidectomy and has since remained potent, but has no children The right testis was soft and atrophic CASE II On September 1, 1936, the patient, aged 37 years, was subjected to right orchidectomy for teratoma On October 13 painful left-sided gynæcomastia was noticed Deep X-ray treatment was begun On December 12 deep X-ray treatment finished. Throughout this treatment the left breast had grown larger, while the right remained normal The gynecomastia disappeared during the next four months On April 15, 1937, the patient was well, and no evidence of gynæcomastia was to be found. The technique of radiation in this case was the same as that used in the first patient, and again the scrotum was not protected CASE III In 1935, at the age of 28 years, the patient underwent right orchidectomy for an undescended testis, which was found to be the site of a seminoma On March 9, 1937, deep X-ray therapy to the para-aortic glands was begun On March 23 a mass in the right leg was noticed, and radiation was applied to the leg On April 6 radiation was again directed at the para-aortic glands On May 28 deep X-ray therapy was stopped On June 17 bilateral painful gynæcomastia was noticed On July 29 the gynæcomastia had quite disappeared In this case a "bath" of deep X-ray therapy was directed at the para-aortic glands, agroin mastia remained potent but has no children The left testis was descnbed as normal before deep X-ray treatment but is now soft and atrophic During the treatment pubic hair fell out and has remained scanty ever since COMMENT The fact that the first and third patients did not notice gynæcomastia before gynæcomastia after operation but before deep X-ray treatment Unfortunately. further endocrine studies were not possible in these patients, so that the ætrology with clumping of Leydig cells (see page og) It is interesting that no cases of gynæcomastia have been reported among the Japanese victims of atomic blasts Colonel Meneces examined a large number of the survivors and in personal communication (1954) stated that he had not seen gynecomastia although testicular atrophy has been reported 111 ·DiskASES OI TUE TESTIS 83 HRE, CE 1939), "Coxigenital pucha, with Heport of Sır i robudlo Carcy of Jaarcha". Surgery, 4, 376 ** STEFONIS, CR (1915). "Bladder Intrapentonral Rupture", Jed Press and Circ. Londott, $29° 26 KLINEFELTEX, Br, REIFENSTEN, L C. and JLBRICHT, 1 (1962), "Syndrome Characterised d's Gynecomastia, Aspermatogeness Without l-leydım, and increased Etcretion of 613. Semmiferous Tabules Asunciated of Relationship to Eunuchoidim, thetosteroids and Estregear", IC: Developmental and Ilormonal ”, C. wwwwa, T. q2. 17 in of the Sex Chromatia Test", Fernl & Steril, 8 313 ** GRLMRACKS, MM. BLANC, A, 354 INGLE, CT (1937), "Ser Chromatin l'attert in Semniferous Tubulc Dysgrnests and ather Testicular Dsmiders" ] Clin Endocrinol, 03 " JENERI, E E (1937). "Hyperplasia and Neoplasia of Interstitial Cells of the Testicle". Arch. Surg. 35 997 + KA1"F, I. (1907). " Veher Zwischenzellengescherilske des lladens". 1'cranul deutsch Asch Gesellsch, 15 237 * BOCI, P, and ANCEL, P (1910). "Inner Sekretun". p 361, Predi, Ierla ** KYRLE, ) 11910). " Ueter experimenurile Hodenairoase , l'erkandi deutsch pack Gesellsch. ** Ferizer G. and Brusc, A (1902), ) Anal Haris, 36 * 320 **SAVONUS, MI (1010).' L'eber Fibrosas Tosts", Arth fath Anal, 201. 108 * SPANGARO S, quoted by Jemesin, CE, lex cyl LANGHANS. S. quuted by Jemenn, EE, loc cu * BACSENWW, D (1895), irch palk Anal, 147 539 * LLBARSCH O (18) Arch path Anal, 145 370 ** CORDES 3? (1999). Hrck Pad dual $56 101 Mkon K (19105. Zwischenzelkn und lladenatrostáse". fich fath inai. 202 376 * BEYBLINGER } {1925), C'eber die Zwischenzellen des Hoctens . Berhand! deutsc park Gesellsch, S181) ** WISCHSELBAUM, A (1910). " Veber l'eranderungen der Hoden bei Chromischem Alkoholismus". Serhandl deutsch path Gesellsch, 14 234 * WECHSELBAL., and KYLE, I quoted h Jenierin, CE, loc cst "GRENFELDT, L, quoted in Jemenn'Elof al *SICK A (19951, Arch / Gynach, 76 291 *STHOEBE. 1 (1807) Deur path inal, Jos " de Josselin De Jong, quuted to Jement, E E loc cu 2. ERANKO, " Dixor Armed Forces Institu "BAPTISTA, 2 "GRABSTALD, 11, and Swan L L (1952) Genitourinary Lesuns ir Leprosy with Sperzas Reference to the Problem at Atrophy of the Testes í 4 JE 119 1287 "SARRIES EAR, 20d ATHAN, M (195}, Infectious I exers, 4th ed. 344, Logstone, Idinburg COOVBY (1993Bibliotheque .fed ** LPRENOVILENT (1877). Gar Hebdom de Ved Parus 14 533 " RECALLS, quuted by Coomby, loc mi ** VALASEZ, quoted by Coombs, lor att ** KESSELNDEFT C (1930), “Orchitis ir Jumpy Buston Med Surg 1.183 495 495, 120 + HOWARD), K ĽSNIFFE* RC SIX ons, and ALBRIGHT" (1950). Testicular Der science a Clinical and Pathralogic Study , 1 Clin Endocrinul, tu 325 * BIENVILLE, JC (1933). "Gynecomastia ". Arch Surg SOS 5* GALLIERT quoted by Hennie, loc ni .) CROOKE * C11945-1946) Jale Gin cuttiastra Testicular Atrophy" Froc Rı» Sot 516 » GILBEPT JB (1940) Studes ia Malgnant Testis Tatours Sysdrome of Chorogenic Gynecomastia Report of Six Cases and Ressew of 129 { [roº . 44 345 "ADDUCX, WO and VELSON HO (1952) Effects at Chorionic Gonadotropiun in Adult Ven Intressed Estrogea and 17-ketosterosd Excretion Gyreeriastsa Ley dis Cell Stimulation and Semimferous Tubule Damage! Clin Endocrinol, 12 Srryx, I B (1945) Mammary Tumours in Nice p 85 Washington 44 ARENDT, quotrd by Gilbert, } B, lo F 263 ved 39 ·82 GYNACOMASTIA UNILATERAL TESTICULAR ATROPHY Unilateral testicular atrophy of unknown aetiology is occasionally associated urance of both testes in a man, aged before the biopsy was taken The puberty. The atrophic right testis showed defective spermatogenesis and thickening of the basement membrane, while the left testis was normal clinically and hustologically. Urinary gonadotrophin excretion was low. In this patient the gynecomastia was associated with loss of libido and impotencc. TIGERE 15 The testes in a patient with unilateral testicular atrophy and gynæcomastia (A) The left testis is normal, (b) the right (atrophic) testis shows defective spermatogenests Gynæcomastia is difficult to explain in such a patient The explanations suggested in previous pages to explain the occurrence of breast stimulation in bilateral testicular lesions can scarcely apply in such a case REFERENCES * WILLIAMS, V R (1894),' A Monograph on Diseases of the Breast ", London 1 HELLER, C G. NELSON, "V Oand Rotii. A A (1943), “ Functional Prepuberal Castration in Males 1 Clin Endocrinol 3 573 3 HEL W11 S BARR, ML (1950). Jemi MA. Al J. 74 419 • WITSCHI, E (1953). "The Experimental Adrenogenital Syndrome in the Irog". J Clin Endocrinol, 13 376 JOST, A (1950). "Recherches sur la differentiation sexuelle de l'embryon de lasın", Arch anat micret morph Exper, 39 577 * WILKINS, L (1950), "The Diagnosis and Treatment of Endocride Disorders in Childhood and Adolescence "Springheld, Illinois Thomas ANDREWS, E, and OSLUND, R (1927). " Autolysis of the Testicle". J Urol, 18 121 1 COUNSELLER, V S, and WALKER, MA (1933). "Congenital Absence of Testes (Anorchra)", AMR Surg. 98 101 12 HENRY, A K (1922), " Descent of the Spermatic Cord with Imperfect Descent of the Testicle", Irish red Sc. 5 317 ·DISEASFS OF THE TESTIS 85 Trupas "v rfnisi "Coutine in intent Fartynas Vanagement of the C'ndescended 10 : Ewnvchodemus 1 on an Chinesere, Deutsche met. SzAnschr. 32: 2127 ** LaCis50GE (1877), Gaz Hebdomi de Ved Paris, 11. 333 * GOODMA, B (1937), "Gynecomastia mith Concomstant Testiculat Atrophy". Am J Surg. 33. 1211 It,nu sit 1 le frartement de la gynécomaste", Reu Ir 1 monalde l'organogenese sexuelle du lapin el remarques sur certaines malformations de l'appareil sirutal humor". Arch Inai. Sur et Jorp Exger, 40: 247 LO SERRA, A (1937), Bali ser ke Soc Hal Derm Sı, 16: 375 * KOSAYLI, (1929), quoted by Grab tald, for to ** FR1T2. I J and KIRSCKBALS (1049). "Sex Horroone Secretron by Tumours of the Adrenal Cortex uf Miec", Cancer Research, 9. 257. *** REITESSTEIN, E CILS1on), FORBES, A PALENIC#7, F. DO ULDSON, E, and CARROLL, E (1945). "CHect of Methi Testosterone on t'rinary 17-ketosterods of idrenal Origin", J. Clin Incest, 24 416 *** SPEGEL, A (1939). "Ober das Auftrelen Low Geschuulsten der Vebernierenrinde mut vermd buckender livekuong de frutasinerten Steerschweinchenmanschen, l'irchou's arch s. path Anoi. 303: 367. »»* APERT, E, and Declert, J (1918), "Gynécomastie unilateral a lux suske de fraumanism des douses". Bull a mént Soc mit d'Aop de Pur. 43 . 1071 *** XELSON, WO (1936), "Sex Differences in Human Sucies with Special Relerence to the Künefelter Syndrome, Conadat geness and Other Types of Flermaphroditism Acta Endocrinologica 23 127 19* SILBERMANN, RC (1958), Symposium on Xuclear Sex', page x16, William Biergemann, London 150 STEWART, ISS, tout, 93-327 112 Ditoy, F. and MOORE, RA (1952) Tutours of the fale Sex Organs" Armed Forces lastitute of Pathology, Ilashington, 18 1 LIEBOW, A, SHIELDS, Wand De Coursey, E (1949). " l'athology of atomic Bonub Casualties". Am Path , 25 853 1 ·. 84 GyxXCOMASTIA 56 GORDON-TAYLOR, G, and TILL, S (1938), "On Malignant Disease of the Testicle, with Special Reference to Neoplasms of Undescended Organ", Bril Urol. 10. ! 57 HERZENBERG, #1 (1927). Beiträge zur Lehre von der Gynakomastit, wat Besonderer Berücksichtigung Ebrer Bezinchung zum Chorionepithelion beim Vanne". Arch. path Anat, 263. 781 58 FERGUSON, quoted by Gordon-Taylor and Till, loc. cít ** HAMBURGER, C, and GoDfFREDSEN, E (1941), "Studies on Excretion of Androgenic Substances and Gonadotrophia in Cases of Maligaant Tumors of the Testis, Especially Serinoma", Acta palk et microbiol scandinav., 18. 485 * SACC), E (1895), Rev Sper de Francaio, 21. 149 61 RAWLANDS, R. NICHOLSON, GW. and WEBER, P (1929), Guy's Hosp Rep.79: 401 ** DIAMOND, ) ), and IUPINX, R R (1956). "Interstitral-Cell Tumot of the Testicle, Report of a Casc and Correlation with Review of the Literature ", doch Surg, 73: 247, ** LEWIS, L G (1949). " Advances in Surgery", 2. 419, Interscience Publishers, New York * Melicow, MI, ROBINSON, IN, IVERS, W*, and RAINFORD, L K (1949), "Interstitial Cell Tumours of the Testis", I Urol, 62. 672. 45 WARREN, S, and OLSHAUSEN, KW (1943), "Interstitial Cell Growths of the Testicle" am ] Path, 19 307 "JOLLY, II (1958), "Sexual Precocity", Thomas, Springfield, Ilinois *7 Bissor, P F (1954), " Recent Advances in Endocrinology". P 176. London ** NELSON, WO (1951), "Estrogen Secretion by the Testis", Fed Proc, 10. 97 4WILLIS, RA (1948). " Pathology of Tumours", Butterworth, London 70 KAITAN, I H. (1955), "An Atypical Case of Interstitial Cell Turnour of the Testicle in a Dog", Am v'el Bed Ass, 126 471 71 LAUFER, A., and SULMAN, FG (1956), "Estrogenic Les dig-Cell Tumor with Multiple Metastases in a Dog The Problem of Bisexual Hormone Iroduction by Gonadal Cells", 1 Clin Endocrinol 16 115). "HUNT, V C, and BUDD, W. (1939). "Gynecomastia Associated with Interstitial Cell Tumor of the Testicle". J Urol, 42 1242 ** HIUFFMAN, L F (1941), " Interstitial Cell Tumor of the Testicle Report of a Casc". / Urol, 45 692 ** NATION, E F. Epsovpsox, I A, and HAMMACK, R W (1944), " Interstitial Cell Tumors of the Testis, Report of Threc New Cases"Irch Surg. 48 415 GRAPSTALD, H, HAINES. J S, and MORROW, A G (1951), Interstitial Cell Tumor of the Testis" / Urol, 66 708 "DIAYERS, MM (1952). “Interstitial Cell Tumors of the Testicle, Report of Three Cases“, J Urol. 68 19 Christenson, W. and NETTLESHIP, (1952), Interstitial Cell Growth of the Testis, Evidence Urol, 67' 351 'Istitial Cell Tumor with Femuniza. 834 78 79 # BAGC Interstatial Cell Tumor of the Testos with Gynecomastia" J Clin Endocrinol, 18 83 30 Bupp, JW (1937), “Gynecomastia Associated with Interstitial Cell Tumor of the Testis", Am , Path, 13 650 nation of Estradiol. Fed Proc, 14 175 #1 IVES onsersion of Testo- ../ Biol Chem, 208 409 * SLAUNWIITE, WR, Junior, and SAMUELS, LT (1956). "Progesterone as a Precursor of Testicular Androgens " ) Biol Chern, 220 341 et FIALKERSTON, I D, HILLMAN, J, PALMER, D, and RUNDLE, I (1956). "Changes in the Excretion Pattern of Neutral 17-ketosteroids During Estrogen Administration to Male Subjects", / Endocrinol, 13 433 As Cook, C D Gross, R E, LANDING, BH, and ZYGYUNTOWICZ, A S (1952), " Interstitial Cell Tutar of the Testis Study of 5-Year-Old Boy with Pseudoprecocious Puberty", Clin Endocrinol, 12 ** HIVECINS, C, and MOULDER, P 1 (1945), "Estrogen Production by Sertoli Cell Tumors of the Testis", Cancer Res. 5 510 *7 TEILUM. G' (1949), "Estrogen-Producing Sertoli Cell Tumors (Apdroblastoma Tabulare Lipoides) of Human Testis and Ovary, Honologous Ovarian and Testicular Tumors' Clin Endocrinol , 9: 301 * TEILUM, G (1950), "Estrogen Production by Sertol Cells in Etiology of Bepiga Senile Hypertrophy of Human Prostate Testicular Lipoid Ce!! Ratia and strogen-Androgen Quotient in the Hutrian Male", dita enconnol, 4' 43 89 WOODHEAM, C. W B (1938). “Hyperplasia of Alale Breast Accompanying Valignant Disease of the Testis Treated by X-rays "Lancet, 2 307 ·DISEASES OR SE ADREXAL CORTEX 87 Special Inrestigations Hormone & ssays {a) Urinary 17-K'stosteronds... Urinary 17-hetosteroid levels are raised in most icminizing adresocortscal tumours, but it 40% of those cases in which only one estimation is recorded the level was normal. The percentage of 27-ketosteroids which belong to the 8-fraction mar les bole the normal levels of 5% to 18 reaching 500ml This increase in the A-fraction is the basis of the Ilution and of a method using the Pettenkoffer react w & stumber of similar quantitative tests which give positne results wilen the proportion of dehydroisoandrosteronc (the principal $ 17-ketosteroid) caceeds 50% of the total 17-ketorteroid output. The B-fraction is chiefly composed of steroids of adrenocortical origin, and this test helps to distinguish adrenocortical from interstitial cell tumours (see page 70, (0) Urinary Estrogens The estimation of urinary cestrogen levels is a most valuable diagnostic procedure in adrenocortical tumours. In only one case among 15 in which urinary exstrogen levels are recorded was the result within normal limits (see Table XIX). The principal drawback to urnary estrogen stales les in the technical difficulties involved Howeser, chemical methods are now being usexi more widely, although these procelures are labrrious, they are accurate, and it is to be Proped that they will facilitate the diagnosis of feminizing adrenocortical tumours (s) Urinary Gonadotrophins --Estimation of urinary gonadotropin levels has not been of value esther un diagnosis or in elucrlaing the hormonal changes found in adrenocorticaloveractivity in some cases the levels are lon, the majority are normal, while in a fex instances high levels have been found Semen Eramtsalon. Azoospermia is commonly seen Testicular Biopsy Diminution in the number of Leydig cells and defective spermatogenesis Bave been described X-ray Examination fa) Plain X-ray examination of the abdomen may reveal calcification within the tumour (5) Intravenous pyelography may show displacement of the kulgey. (c) Presztrat insumation of air may reveal the outline of the tumour This method can be combined with intravenous pyelography Diagnosis Since synecomastia is a relatsvely early symptom of feminizing adrenocortica? tumours, at follows that every case of unexplamed gynæcomastia deserves investigation to eliminate this possible cause No clinical evidence except abdominal tumour will prove helpful in this investigation, since tumours occur at all ages, and loss of libido and testicular atrophy are inconstant The 17-ketosteroid ercretion may be raised, but nommal levels do not exclude cortical tumour The logical diagnostic procedure would seem to be estimation of urinary restrogen levels, but this is soll not widely available Only one case of the 15 investigated showed normal levels, and the possibility remains that repeated assays may have revealed raised levels in this case Presacral air insufflation combined suith intravenous pz elography may help to demonstrate the presence of a tumout Any patient who shows gynæcomastia and Taised wrinary estrogen levels or raised 17-ketosteroid levels in the absence of testicular tumour should be suspected of adrenocortical disease and treated accordingly Prognosis Feminizing adrenocortical tumours are usually malignant, and in four of the 34 recorded cases the condition was inoperable when diagnosed , 18 patients were treated surgically, and more than half of these died within seven years of the onset of ·CHAPTER IX GYNÆCOMASTIA ASSOCIATED WITH DISEASES OF THE ENDOCRINE GLANDS DISEASES OF THE ADRENAL CORTEX Overactivity of the adrenal cortex may be due to the presence of a tumour or to hyperplasia of the gland. In men it is not possible to recognize a state of "supermasculinization" due to an excess of androgens, but in certain cases of adrenocortical overactivity some loss of the features of masculinity is seen together with gynæcomastia 1,2,3 This state of affairs is referred to as feminization, and the group of adrenocortical lesions causing it as examples of femmizing tumours or adrenocortical hyperplasia with feminization, as the case may be. Adrenocortical overactivity is not a common condition, and feminizing adrenocortical overactivity is of great rarity Wallach et alıd found 34 examples of Seminszing adrenocortical carcinomata (including one of their own up to 1957. while Bishop' found three cases of adrenocortical hyperplasia with feminization FEMINIZING ADRENOCORTICAL TUMOURS does not facilitate carly diagnosis of these conditions and does not demand special treatment In the case of adrenocortical tumours it is otherwise Here gynecomastra may be the first symptom which takes the patient to the doctor, and since these tumours are usually malignant, the only hope of effective treatment lies in early surgical removal The problem is made more difficult by the rarity of adrenocortica? tumours as a cause of gynecomastia In other words, it is necessary to eliminate thus Ta urgent need for ear': .. 'r of patients will be I Amon! Clinical Features enerirar molemant in every case except one, s as judged .. the latter is very variable and difficult to, , varied from 5 to 59 years, the patient ag > patients aged 14 and 15 years are the only adolescents iive Teamg Pallehs were drstnbuted almost equally between the third, fourth and fifth decades 1 اما به یاد داليا hypertension are recorded, but other features of Lusings Syllulum su in only two cases ·DISE ASCS OF THE ADRENAL CORTEX 89 removal ol the tumour revealed a considerable fall in the incretion ol these hormones and a decrease in the extent of the synecomastia.$, 10, 11, 11, 2), 23 Although the normal adrenal cortex produces small amounts of estrone, these Bre insufficient to stimulate the normal male breast. The evidence provided by the recorded cases is over helmingly in favour of the view that leminization in these tumours results from the production of excess oestrogens, and no doubt gynecomastia results fross the direct action of these hormones upon the breast. Tumours of the testis may occur in ectopic adrenal tissue (so-called adrenal rest tumours). Ectopic cortical tissue can occur in the kidney or in the layer, along the path of descent of the testis or within the testis itscil. Apart from these sites, adrenocortical tissue may be found almost anys here within the abtiomen. Adrenal rest tumours of the testis may closely resemble interstitial cell tumours under the microscope (page 12). The occurrence of gynacomastia in association with such tumours is the result of aestrogens secreted by the cells of the tumour and is of the same diagnostic importance as that seen with cortical tumours elsсu here. Ostergaard has reported such a tumour in a man of 28 years who complained of Synecomastia The right testis was small, and a tumour was le}t at the upper pole of the lett testis Hormone assays before and after operation gave the following results. Assay Relore Operation Ifter Operacion Lrinary gonadotrophms 50 mouse units normals 50 mouse amts (normal) rin antragens 100 ne units ratsu) 30 mouse units (normal) tried man reactron Segatrie Indrogens 25 IV raised) 6 21 (norm 11) HYPERPLASIA All that has been said about gynecomastia in adrenocortical tumours can be repeated m the case of hyperplasia except that hyperplasia is more difficult to demonstrate radiologically Although the number of recorded cases is insufficient to support dogmatic statements, it appears that, apart from the presence of the tumour itself, the clinical picture of hyperplasia is identical with that of tumour, and the mechanism by which the two conditions produce gynecomasta is the same It is interesting to notice that patients suffering from female pseudohermaphrodsessm (due to adrenocortical hyperplasia) show breast development when the cortisone, with which they are commonly treated, is withheld The onset of mammary gland enlargement has been seen in this condition in patients as young as six years of age when cortisone treatment is abruptly suspended for some reason. 84 STRESS In rare instances, breast development has been reported following extensive burns, and the sudden onset of lactation occasionally follows exposure to stress 67 Selye explains this interesting observation as the result of the action of hydrocortisone upon the breast Exposure to stress results in an increase in the secretion of glucocorticoids, and Selye88, 182, 6has shown that hydrocortisone given to adrenalectomized-ovanectomized animals treated with small doses of estradiol, produces considerable stimulation of the mammary gland together with secretory activity.

·88 GYN&COJIASTIA symptoms. The only patient who could be regarded as showing a benign tumour underwent surgical treatment 16 years after the onset of symptoms and was well one year later, The prognosis of these tumours is therefore grave, but the disease may run a prolonged course with metastases in the liver, lung and elsewhere. One possible way of improving this state of affairs involves thorough investigation of cases of unexplained gynæcomastia. TABLE XIX Urinary Ostrogens in idrenocortical Tumours Case Report and Reference Estrogen (Brossay) per 24 Hours Normal tor Patient's Age of Companison with Normal Simpson and Joll? 3200 JIU Raised Roholm and Terlum 5000 IU <20 3 | Hurrthal and Musulin 60 RU <IORU Ostergaard 200 MIU Raised Scottia Normal 5348 (3-estradiol equivalent) Witkinst) 5 RU IRU Luft and Sjogren" 250 IU Nusimovish to 5000 units/ litre Pickard et al., 100 IU Dohan et al., 17 Case I 4000 MU 13-44 ALU Donan et alı, 17 Case 2 16 YU 13-44 MIU Staubitz et al 3340 IU 25-130 IU Case record,' MGH 40-80 ug 1235 g estrogen 2600-6300 g Higgins et al Raised Wallach et ain' 2-29 U8 73-177 ug æstrone (equivalent) Pathogenesis The mechanism by which overactivity of the adrenal cortex produces gynæcomastra seems clear. In all but one of the recorded cases in which urinary cestrogen levels were reported there was a distinct rise in the level of østrogens escreted, Presumably, adrenocortical overactivity can produce a number of different hormones, some of which may be abnormal (1 e not produced by the normal cortex) Increased amounts of cestrone, estrol, cestradiol and pregnanediol have been found in the urine in two cases, 5, 21 while in one case the tumour itself was found to be rich in progesterone and in equilerin, which is a weak estrogenic steroid, not previously identified in man. In six cases estimations of unnary cestrogens after surgical ·DISEASES OF TILE ADREXAL CORTEX 89 removal of the tumour revealed a considerable fall in the excretion of these hormones and a decrease is the extent of the gym.xxomastia.5, 10, 17, 18, 20, 53 Although the normal adrenal cortex produces small amounts of astrone, these arc insufficient to stimulate the normal male breast. The evidence provided by the recorded cases is overwhelmingly in favour of the view that feminization in these tumours results from the production of excess erstrogens, and no doubt gynecomastia results from the direct action of these hormones upon the breast. Tumours of the testis may occist in ectopic adrenal tissve (so-called adrenal rest tumours). Ectopic cortical tissuc can occur is the kidney or in the ser, along the path of descent of the testis or within the testis itsell Apart from these sites, adrenocortical tissuse may be found almost anywhere within the abdomen Adrenal rest tumours of the testis may closely resemble interstitial cell tumours under the microscope (page 12) The occurrence of gynacomastia in association with such tumours is the result of estrogens secreted by the cells of the tumour and is of the same diagnostic importance as that seen with cortical tumours elseu here. Ostergaard has soported such a tumour in a man of 28 years who complained of Tecomastia The right testis nas small, and a tumour was felt at the upper pole of the left testis Hormone assay's before and after operation gave the following results Assay Before Operation After Og eration Unnary gonadotropluss 59 mov«e unsts (normal) 200 Mise umts rarsed) So mouse »mts (normal) 30 mouse unuts (normal) $ary astrogens Esedun reaction Negative 25 14 raised) Indrogens 6210 (normal) HYPERPLASIA All that has been said about gynecomastia in atrenocortical tumours can be repeated in the case of hyperplasia except that hyperplasia is more difficult to demonstrate radiologically Although the number of recorded cases is insufficient to support dogmatic statements, it appears that, apart from the presence of the tumour itself, the clinical picture of hyperplasia is identical with that of tumour, and the mechanism by which the two conditions produce gynæcomastia is the same It is interesting to notice that patients suffering from female pseudo hermaphroditism (due to adrenocortical hyperplasia) shou breast development when the cortisone, with which they are commonly treated, is withheld The onset of mammary gland enlargement has been seen in this conditioft in patrents as young as six years of age when cortisone treatment s ahruptly suspended for some reason.sk STRESS In rare instances, breast development has been reported following extensive bums, and the sudden onset of lactation occasionally follous exposure to stress o? Selye explains this interesting observation as the result of the action of hydrocortisone upon the breast Exposure to stress results in 353 increase in the secretion of glucocorticosds, and Selyes, 863, 69 has shown that hydrocortisone given to adrenale ectomized-ovariectomized animals treated 19th small doses of cestradiol, produces considerable stimulation of the maninary gland together vith secretory activity.

·90 Gyx COMASTIA DISEASES OF THE THYROID GLAND HYPERTHYROIDISM In 1848 Basedow2s published his famous paper on hyperthyroidison described atrophy of the female hranet - in, L-1 YM.- ULUJA Ainong the 22 reported cases of homme the majority are either incomplete to exclude the possibility of a for Haltiy, the two conditions have appeared at the same time and have undergone synchronous remissions in such a way as to suggest a more significant association Two patients to be described are exceptional in that they raise the possibility that the enlarged breasts contained active thyroid tissue Table XX contains some relevant facts about the ported cases, together with three other cases not so far reported and one case studied by the author. It will be seen that most of these cases have not been studenti detail to heln in al... 18 of and + - Welwywe described a U table Ve ffered bilateral as followed by were given of JUL Temoved at operation Dr Albright's first patient un had suffered from ہے او Lue patient was given a course of potassi... unde after whrch the thyrotoxicosy and the gynecomastia disappeared synchronously within three months This case illustrates the association of thyrotoxicosis and gynæcomastia which appeared together and disappeared after treatment of the hyperthyroidism These observations suggest that in some way the two conditions were ætsologically associated, but the available data give no hint as to the way in which such an association might be brought about 111-1-- ·TABLE XX Ilyperthyroidism and Gynecomastia 151 tsent I low-u! Tott) Ke 45 Onnet Relatie tusen *}sper Onset of thyroxins GD&<<3!1,1*!! and Il perthururdum Dugust af flyer thy sont en (rynicaehitat? 11131 3511 Chnal 331 strat ? Vente Van lycecton's 37 trin Tenmastia fo wc hypet. tromly clsree 1970t)14 Freemanta 1971 al Bilateral .37 (Breutast Sol- Ieder ty Poudesta loyilstre Clinical Slurphy" heit 2 Curesi Lynx Flestred ulter einset of hyperthstom Mastretmay end thyraud ectomy HYFEXTHYROID 153 Xerrbach simultaneous (local fetes ECSKE I houdt tamy Cure at Inith corretto 12 himultaneous (n.1 Blazerat Besley Sterling - nult.neon 7 Braletal ? Ceat Shenjatru 11 fralxic 11ellitus Sterling 17** 1t snes C3sascal 1}atitas Sterling 11138 399 tut,1983155 33. Laterni Cosc.t! 1.5Jxxl rosp?s> Clinitat Va Blusa Mertuille hauit.11.1954 }}}rfrtal 3 Thyroid ectany Cut of the (otitions 16 ·TABLE XX-Continued Hyperthyroidism and Gynecomastia–Continued Author Age at Onset Relation between of Hyper- Onset of thyroidism Gynacomastia and (Years) Hyperthyroidism Diagnosis of Hyperthyroidism Gynacomastia Testes Sexual Power Treatment Menville tai Follow-up Simultaneous Bilateral Chnical No laboratory data ? Wheeler [1 Thyroid ectomy Cure of both conditions 42 Left Normal Gynecomastia fol- Clinical lowed hyper BMR, +59º. thyroidism by two months Thiouracil Wheeler II" BMR, +2%. cholesterol, 240 mg%; cure of both conditions Bilateral I'ravers Normal ? 7 43 Simultancous Clinical BMR, +90° Gynacomastia fol Clinical and lowed hyper laboratory thyroidism by findings typical several months Bilateral Normal Reduced I'ropylthrouracil Starr 134 Cure of both conditions GYNÆCOMASTIA 45 Simultaneous Clinical Bilateral BMR. +31°o! Atrophy Yormal Start 11 28 Thyroid ectomy Remission of both and later relapse of both Right Normal Ginacomastia fol Clinical lowed hyper BMR, +5490 thyroidism by 10 months Normal Thyroid ectomy Albright Lºs Cure of both conditions 45 Simultaneous Albright 11 Right Normal Normal 29 Hyperthyroidism before gynæcomastia by nine months Clinical BMR, +38% Clinical and laboratory Potassium jodide Bilateral Remission of both conditions Small Impotence Guy's Hospital 56 Thyroidectomy Simultaneous Remission of both conditions Clinical and laboratory Bilateral Normal Impotence Propylthiouracil Remission of both conditions ·PARLE XX Continued Il yperlkytuossm and inacomastian-Continued { Iznosis of its gues- (151ราจร lathus geit svet Relation tretien ot tluper Ost et thulden (roma 22 am Hyperthyred Trettricat Tenten 133ow-ur exual l'ouer Gynatomasti Rosenthal 11 Tulatesas Xorunt Carlom izole Jimicus and Hemoratory Gyntiomatu. fol. laul hyper 1917 Tindem » months Resisyon koth conditions lcowenthalt 48 Bitsteral Hormat Carismszale ? Gynecom intia ful ex Pet thiroidism in i en month Clint al anul 1.1xristy Romson of Xxxth function Banger" Bilateral 27 Usecenter Impotence Thiouraut So change comita frev Sent from puberty Clinical and Salxoratory Contal and fal story HIYPERTHYROIDISSE Freucs 56 Belateral 1 Nemission on loth conditions Berron Wimultaneous 33ateral Normal Normal Cukul 253 Salxmaton Subtotal thyrdretom) Tapaznio and thyroid octomy Tapirolo and hod. ectomy Cure of lxsha conditions Jer on 17" 27 33:13 Sormi? Normal Gy.romastia fol. fowed PCIthyrudism by four months Ccal and {almratary Curo of both canstsong Berson 1117 24 ucuneong Bilateral Nossal Normal Chical and laboratory Tagarolo and slysolil actomy Cura of kuch cris Derson wym 55 Sinulta nexus Stight Normal Clicul 15$ It{x53 topy Vorms! Til und tapazole Cure of both condicions 03 ·TABLE XX-Continued Ilyperthyroid:51 and Gynecomastia-Continued 92 Author ge at Onset Relation between of Hyper- Onset of thyroidism Gynæcomastia and (V'ears) Hyperthyroidism Simultaneous Diagnosis of Hyper. thyroidism Gynaco. inastia Testes Sexual Power Treatment Follow-up Mentille 11% Bilateral Clinical No laboratory data ? Thyroidectomy Wheeler 153 Cure of both conditions +2 Left Normal Gynacomastia fol- Clinical lowed hyper BMR, +59 thyroidism by two months Thiouracil BMR, +2% cholesterol, 240 Whecler 11 42 me 7o. Cure of Bilateral both conditions Normal Fraser ? 43 > Simultancous Clinical BMR, +90% Gynæcomastia fol Clinical and lowed hyper. laboratory thyroidism by findings typical several months Bilateral Yormal Reduced Propylthiouracil Cure of both conditions GYNÆCOMASTIA Starr 14 45 Simultaneous Clinical BMR, +31. Bilateral Atrophy Normal Starr 11 Thyroidectomy 28 Remission of both and later relapse of both Right Yormal Ginecomastia tol Clinical lowed hyper BMR, +5400 thyroidism by 10 months Normal Thyroid ectomy Albright I's Cure of both conditions 45 Simultaneous Albnght II* Right Normal Normal 29 Clinical BMR, +38% Clinical and laboratory Potassium todide Hyperthyroidism before gynecomastia by nine months Bilateral Remission of both conditions Small impotence Guy's Hospital Thyroidectomy 56 Simultaneous Remission of both conditions Chnical and laboratory Bulateral Normal Impotence Propy! thiouracil Remission of both conditions ·HYPERTHYROIDISSE 95 0981 per 100 ml : albumun, 3.6gm per zog ml ; globuss, 3. ! gm per soom, albumun globulia salio, 5.16 The myrunate tolerance test gave the following results. fastsssg bloon pyruvic acid, 1 29 mg JXT 100 ml, 60-minute blood pyruvic acid, 2.35 mg per roonil, 90-minute blood pyruvic acid. $ $ $16 per $00m} The normal urper lauts are fasting, smg : oo and go mnutes, 139 mg per too mt This test was repeated after to dir, during which time the patient was gren injections of Vitamin 13 see lion The results then were: lasting blood pytanic acn!, some per 100 ml , 10-minute blood pyrous acid, 1.37 mg sree too ml; minute blood pytausc acid, 1:11 mg, per Job 31 Belsre antithyroid drugs were administered, the patient secened a course of intramuscular Injections of vstamin 1, the daily dose berag thaamune ia mk, nolite 4 mg. ndoxne 1 mg, and nicotinamide to mg mnch in the form of Blechen, ?cc daily I'IGURE 36 Gynæcomastia in a patient sullering from hyperthyroidism {o} The breasts Extore treatment (o) Tbe breasts after one month's treatment with props Ithjourcs fc) Testar normal for the patient's age At the end of one weck ng change was seen in the breasts 'topy Itluguracil was then adminsstered in duses of 400 mg daily Three weeks later the patient had gained 12 pounds meight and chmal evidence di hyperthyrortsm had disappeared Gynacomastia became much tess pronounced, and during this treatmeat the patient nouced that he beard stopped growing for two weeks Thereafter st began to grow, and isbido and petency returned. The basal metabolic rate was -2° A maintenance dose of propelthrourac} {200 mg daily) was prescribed After "x weeks of treatment the patient stopped taking the tablets and noticed that libido and pritency declined, while the breasts became tender lle resumed the tablets, and these changes were reversed During the next one months he took the tablets and remained well the ginecomastia did not return This patient suffered a severe and acute form of thyrotoxicosis which was complicated by gynecomastia, lous of libido and impotence. These complications appeared soon after tt successfully treated tests, and scanning oft tron of 70 uc. of 1031 18 sssue Liver functior liser as a factor in the after treatment with suamin B indicated that relative avitaminosis produced by the metabolic stimulation of hyperthyroidism was not a factor in causing breast stimulation The result of testicular biopsy was normal for the patient's age and excluded any possibility of the mechanism suggested in the patient reported by Dr Albright The only positive finding of any significance in this patient was a high urinary castrogen level. Although the levels recorded in this patient are kugher than those ·94 GYNECOMASTIA & cells which are usually present, except for an occasional pigment granule resembling lipofuchsin This is considered to be hyperplasia of the Leydig cells The patient received a course of Lugol's 1odine, followed five months later by subtotal thyroidectomy One month after operation the thyrotoxicosis had disappeared and the breasts were normal, the testes had reached normal size, and librdo and potency had returned In this patient appears to be more tha (11) small testes, (111) changes are those of distinguished by the a 'ry and by the absence of the The occurrence of destruct are further points in 10η 16 reminiscent of the case of leprous orchitis, in which the changes of Klinefelter's basement membrane but by It is not clear how hyperippearance of gynecomastia following successful treatment of the thyrotoxicosis suggests that this disease was directly or indirectly responsible for stimulation of the breasts; and in view of the resemblance which this case bears to cases of Klinefelter's syndrome, it seems likely that the gynecomastia is the result of a similar mechanism. The Guy's Hospital patient was rather different *".- 1 June, 1954, when he complained of folness in weight during the previous six months iving up smoking Three months later, in was beating rapidly, and although at the At this stage his weight was 98 pounds. The patient was ordered to bed for one month, during which time he suffered attacks of palpitation which were rapid, and at times irregular He also complained of trembling of the hands and vid. fnghtening nightmares During this period in bed he noticed that his breasts were swollen and tender On several occasions they discharged a thin whitish flud He was allowed up after one month to bed and three months later he complained of sudden, complete ympotence and loss of libido 1 auricular fibrillation with a pulse rate of of mercury (Edema was absent The a Six inches from the midirne, and an apic was not enlarged, and exophthalmos was tremor and warm moist 818 were found The genital organs and secondary sexual tests were performed (1) Thyroid function The basal metaboli was 105 mg per 100 ml A radioactie jodi plasma protein-bound activity was o 89 of limit of normal was o 4º.). (6) scanning of r gland showed a high uptake of 1131, no retros protein-bound iodine was o 5% per too m) (2) Hormone assays The 17 hetostered ercretion was 12 3. 13 0, 11 o and io g mg per The urinary gonadotrophins were >12<16, >10<24 and >12<26 mouse units per The urinary estrogens were astrone 15 ug per 24 hours, cestrado) 2p8 per 24 hours, astrol 31 5 ug per 24 hours (3) Testicular biopsy in the tubules the basement membrane was normal The germinal epithelium of most tubules shoned normal spermatogenesis In a few tubules spermatogenesis kas arrested at the stage of primary spermatocs tes, and to a few cases only Sertoli cells were seen In the interstitial tissue the Ley dig cells appeared normal, and a count of these cells was nunc per tubule (normal) (see page 10) serum protein, 6 rgm per 100 m), albumin, pom albumin/globulin ratio. 11, thymol ue, colloidal gold reaction, negative serim th later the disect Van den Bergh reaction was & per 100 ml, the thymol turbidity and thymol negative Other values were serum protein, 24 hours 24 hours ·DISEASES OF THE PITUITARY GLIND 97 above, has been discredited by Simpson," who regards this paradox as invariably resulting from carcinoma of the thyroid These observations lend no support to the suggestion that necomastia may de clop in association with hyperthyroidism as the reult of hyperplasia of thyroid flyste wathin the breast. Moreover, an neither the case of Murphy 27 nor in that of Sterlingo) was histological evidence given of the nature of the breast tissue. HyrOTTISROIDES Menville! and! Wccler"* cach referred to the currence of a comastia associated with hypothyrotdum, and Marine" has stated that "impotence, loss of libido, testicular atrophy and gynxcomastia are common in myxcedema". Xone of these authors has supported his claims asth accurate clinical and laboratory data. While impotence and loss of hbido are not infrequently encountered in hypothyroidism, Aynacomastia is not common. Among 18 men with myxcxema, proved by clinical asid laboratory data, at Guy's Hospital, gynecomastia was not encountered Untit further positse evidence to the contrary is obtained, it seems more prudent to regard the association of hypothyroidism and gynecomastia as fortuitous, DISCASES OF THE PITUITARY GLASD ACROMEGALY Roth described hypertrophy of the left breast with secretory activity in a man suflening from acromegaly The breast showed histological features typical of 83 becomastia (see page 22) In somen, acromegaly may be associated with persistent lactation, and it has been suggested that certain cossnoplul adenomata nyay produce excessive quantities of prolactin as well as grouth Hormone The association of acromegaly and gynircomastia is probably very rare It is not mentioned by Davidoff, who made an exhaustse study of ioo cases of the disease Until detaileri investigations have been reported it will not be possible to indicate the mechanism by which acromegaly causes gyntcomastia CHRONOPHOUT ADEXOW4 Three cases of gynecomastia associated with chromophobe adenoma hase byeen described Hanel" reported the case of a man with enlarged breasts showing secretory activity at the age of 25 years The patient later became the father of tuo chuldren and died at 43 years, a chromophobe adenoma was found at autopsy Mochling" reported the case of a man of 52 years who complained of impotence and gynæcomastra for two years The testes were small and pubic hair of female distribution At operation a chromophobe adenoma was found McCullagh and his colleaguess reported gynæcomasta with secretory activity in an adult male who shoxed an enlarged prtuntary fossa without change in fields of Viszon Sexual activity had alv.ays been belon normal, although this improved considerably after treatment with testosterone Urinary yg-ketosterord, gonadotrophin and cestrogen levels were all within normal limits, and a semi-quantitatne assay of prolactin was performed upon the urine this gave normal values, although ageing of the specimens may have occurred The breasts were surgically removed and showed the histological features of gynæcomastia (see page 22), while testicular biopsy (taken after deep wradiation of the pituitary and treatment with testosterone) showed normal spermatogenesis and fewer than normal Leydig cells It is not possible to explain the pathogenesis of gynæcomastia in this patient The histological appearance of the breasts suggests cestrogen stimulation, and yet no evidence of a testicular or adrenal source of excessive cestrogen secretion could be found, and the urinary oestrogen levels were within normal limits Excessive secretion of prolactin try the potutary gland is conceivable, but this hormone requires ·96 GYNACOMASTIA found in normal however, we juu tilalt in a younger WWW uslovens is uncertain The abrtint ont and the recu features of th a situation in which is tam + 1 JAULU FALLS UL Rosenthal and Lees?4 were studied from a different point of view The authors riere interested in the state of adrenocortical function in patients suffering from hyperthyroidism Although the excretion of 17-ketosteroude 75 78 17-hydroxycorticosteroids 77, 78, 79 and more is niinll...1 st ta ULIJ al normal bomu paldinte ancho. levels of 1 In one of within nor function. These uuwigs were internrated h 10 ALL ully Lat ( 111 85 y divuun for the high urinary cestrogen levels in the Guy's Hospital case, and adrenocortical estrogens may be the cause of gynæcomastia associated with hyperthyroidism This explanation will not account for the findings in Dr Albright's second patient Ectopic Thyroid Tissue Although a number of authors have stated that ectopic thyroid tissue can occur in many parts of the body, Nicholson 38 has discussed the cash and considers that "thyroid tissue can occur in foramen caecum of the tongue and the arch of thi glossal duct or lateral thereto as aberrant masses tions-usually in the middle of a line joining the the clavicle" He claims that thyroid tissue does PUL OLCUr elsewhere as a result of embryological misplacement In addition, thyroid tissue may occur in the ovary as part of a teratoma, while some authors38 describe the condition of "goitre plongeant in which the und may appear as for daun the most In one recor ор myxædema, The exis பயl illeldstases hich were said to account for the occurrence of thyroid tissue in parts of the body other than those mentioned - In the case of hyperthyroidism, however, the gynæcomastia appears at the height of the discase and disappears during treatment in the case of malnutrition gynecomastia appears during refeeding (see page 113) m 1 ·DISORDERS OF SEX 99 biopsy of these glands was not performed. On histological examination the gonads are shown to be composed of tubules devoid of germinal epithelium The tubules contain only Sertoli cells, and the basement membrane may be normal or in some tubules it shows hyaline changes Les dig cells are abundant and appear in clumps 18-55 Urinary gonadotrophin levels are considerably raised, and 17-keto steroid excretion is within the normal range for adults of either sex. Vaginal smear examination indicates æstrogenic stimulation. Castration in this condition may lead to the occurrence of hot flushes, some atrophy of the breast tissue and ancestrus vaginal smear.'s, 11 In a case described by Wikins, castration led to the disappearance of aestrogens from the urine fas measured by the Kober reaction). Male paeudohermaphroditism shows a strong familial tendency; for example, Schneider-2 described sis cases in three generations of one family. These factors indicate that the testes in this condition are producing estrogens, and it seems likely that these hormones are responsible for the breast development, especially since castration leads to some regression of the gynaecomastia The testes resemble the testes in Klinefelter's syndrome except that hyalınization of the basement membrane is less evident These observations suggest that the factors responsible for the occurrence of male pseudohermaphroditism interfere with rat.-----1 - L1 r another example of gynecomastia associated with clumping of Leydig cells, and it seems probable that the breast development is due to the same mechanism as that View TRANSVESTISY Transı estism is a condition which has recently excited a great deal of popular interest as the result of articles appearing in newspapers The term is loosely applied to a heterogeneous group of patients who suffer from an overwhelming desire to wear clothes appropriate to the opposite sex. Among men affected in this way, overt homosexual tendencies are usually absent, and in many cases this strange urge goes beyond the desire to assume feminine clothing to a desire to acquire the physical attnbutes of woman Most of those affected believe that they are in fact women in whorn some developmental aberration has robbed them of their rightful physical heritage, and they point to subtle behaviour patterns which they claim support this For example, some are said to have preferred dolls to the usual toys appropriate to their apparent sex, this preference may appear at the early age of two years Others follow the hobbies and interests of girls during their childhood and adolescent years In Hamburger's 57 first paper on this subject a patient is mentioned with testicular atrophy and gynæcomastia, but no further details are given Among the Guy's Hospital cases of Klinefelter's syndrome three patients complained of transvestite desires i unfortun Still58 ha vestisin Of the three patients seen at Guy's Hospital, tuo have received androgen therapy and psychotherapy, which, so far from decreasing their desire to become women", have confirmed the patients in the unshakeable conviction that they are in reality women Both have (in accordance with this belief) refused operative treatment for the gynæcomastia and have stated their intentions of undertaking any measures which may assist their "real sex to emerge.

·98 GYN&COVASTIA the synergistic activity of cestrogens before it causes stimulation of the breast, and bioassay of prolactin did not indicate excessive quantities of this hormone Treatment with testosterone produced no definite change in the state of the breasts. HYPOPITUITARIS Failure of the pituitary gland involving one or more of its trophic functions is not associated with gynecomastia. It is, moreover, highly probable that gynæcomastia does not occur in the absence of adenohypophysial function, so that, in advanced failure of the gland, gynecomastia would not be expected. A patient reported by Gibson 46 is stated to have shown gynæcomastia and hypopituitarism, but no evidence is given to support the diagnosis of hypopituitarism DISORDERS OF SEX HERMAPHRODITISM » show evidence termaphrodites, a discrepancy between the sex of the gonads and the apparent sex of the individual concerned This simple classification is still convenient, although recent advances in the genetics of sex determination threaten to supplant this scheme by a more complex system True Hermaphrolitism True hermaphroditism is rare, and our know ledge of the way in which it is brought about is still incomplete However, in some cases one half of the body is masculine and includes a testis, while the other half is feminine and the gonad is an ovary. the breast on the ferninine side of the body is well developed in contrast to its fellow on the other side Such a case was described by Brachetto-Brian and his colleagues " Although it would not be correct to refer to the breast development on the female side of the body as gynecomastia, nevertheless this occurrence is of considerable theoretical interest Whatever hormonal influence has stimulated the development of the breast on the female side of the body, the same hormones must also have reached the other breast in the same concentration and at the same time Presumably, some property of one breast must cause it to respond to hormonal influences which are without effect upon the other breast This situation defies further explanation at Pseudohermaphroditism Individuals who possess testes, but who show some of the primary and secondary sexual characteristics of woman, are referred to as male pseudohermaphrodites. A great variety of "types" of male pseudohermaphroditism have been described. but one distinctive group, referred to as the Goldberg-la xwell'8 syndrome, is of interest in connection with gynecomastia in this condition the body is essentially feminine in appearance and the breasts are normal, although in some cases small nipples and areolæ are seen Pubic and axıllary hair fails to develop, * and primary amenorrhea occurs The vagina ends blindly below a vestigial uterus, and the gonads so closely resemble normal ovaries that the condition has been overlooked when • The presence of pubic and axillary hair follicles has been demonstrated by biops but these structures do not respord to therapeutic deoses of testosterone suggesting an inherent insensatiety to androgens Perhaps the response of other tissues, including the breast, to hormones may be atypical in this condition ·DISE ISES OF THE E.DOCRINC GLANDS 1ΟΣ DIABETES MELLITUS Although the association of gynecomastia and diabetes mellitus is mentioned by Wheeler and his colleagues, there is no evidence that such an occurrence is more than a coincidence. Pelner and Waldman's described gynæcomastia as a complication of what they called "liver dysfunction diabetes, but in their tuo patients the associated liver failure was almost certainly responsible for the gynecomastia (see page 104). CUşlixG'S SYNDROJE essentially metabolic changes of Cushing's syndrome. REFERENCES 1 BISHOP, I'Mr (1951). "Recent Advances in Endocrinology". 230, Churchill, London MELIcow, MM, and CAHILL, GT (1990). "Role of Adrenal Corter in Somatoserual Disturbances in Infants and Children: Chrico-pathologic Analysis. J Clin Endocrinol. 10:24 MYHRE, J. (1982). "Temanizing Adreno-cortical Carcinoma and Carcinoma of the l'rostate", Acta Endocrinol. 10 233 *WALLACH, S BROWN, H, ENGLERT, I., and Cik-Xes, K. (1957). " Adrenocortical Carcinoma with Gynecomastia Case Report and Review of the Literature". J Clin Endocrinol, 17 915, LANDAU, RL, STIMEL, BT, HUMPHREYS, I, and CLARK, DE (1954). "Gynecomastia and Retarded Sexual Development Resulting from Long-standing Estrogen-Secreting Adrenal Tumor". J Clin Endocrinol. 14: 1097, • ALLEN, WM. HAYWARD. S J. and PINTO, A (1950), "Color Test for Dehydroisoandrosterone and Closely Related Steroids, of Use in Diagnosis and Adrenocortical Tumors". J Chen Endocrinol. 10: 54 Simpsov, S L. and JOLLCA (1938), " Temnization in a Male Adult with Carcinoma of the Adrenal Cortex, Endocrinology. 22 • ARMSTRONG, C N. and Srpson, I (194" Cortex: Case Report and Review HURYTHAL, LM, and MustLIX, X (1 Tumor of Renal Ongin and Testic 10 OSTERGAARD, E (1947). "Feminizing Tumor of the Test:s presumably Aberrant Adreno cortical Tumor" J. Clin Endocrinol. 7. 483 1 Kerr, W J. and GORDOY, G S (1952), "Adrenal Cortical Carcinoma with Excess Androgen Production in Adult Man". Postgrad Med, 11: 278 119. 595......... 13 1 14 18. 05 709 1. BIERICH, R. Boue, E, and VOIGT, K D (1955). "New Aspects of the Pathogenesis of the Adreno-genital Syndrome", dda Endocrinol. 18. 512 17 DOHAN, F C Rose, É, EMMAN, J W, RICHARDSON, E N, and ZIVTEL, H (1953), "Increased Urinary Estrogen Excretion Associated with Adrenal Tumors Report of 4 Cases". ✓ Clin Endocrinol. 13: 415 * STAUBITZ, W J, ODERKIRCHER, J, and LENT, M H. (1954), " Feminization in Adult Male with Adrenal Cortical Carcinoma ". New York State ] Med. 54 2565 ·100 GYNACOVASTIA The third patient has submitted to plastic surgery to the breasts and bitterly regrets this step. He has served a sentence for homosexual offences, and neither androgen therapy nor psychoanalytical treatment has altered his desire to become a \voman. MISCELLANEOUS PROSTATECTOMY Gynecomastia has been reported following the operation of prostatectomy, Cheatic and Cutler59 regard this association as "not infrequent ", and Mann reported the occurrence of bilateral gynæcomastia ir months after prostatectomy in a man aged 70 years Kondolean described gynæecomastia in two men aged 70 years who had undergone prostatectomy. The first suffered painless bilateral enlargement of the breasts one month after operation, and this cisappeared within a year. The second reported suclling of the right breast three months after prostatectomy: this was followed by enlargement of the left breast one month later Oppenheimer62 reported gynæcomastia three months after enucleation of an adenoma of the prostate in a man of 64 years, the operation was straightforward and free of post-operative complications. The same author described bilateral gynæcomastia following sphincterotomy of the bladder in a man of 45 years. Swelling of the testes is not mentioned, and no investigations are reported. In the absence of further clinical and laboratory data these observations are difficult to explain. At the age of 60 years or more the occurrence of involutional imon than is iples of the the bladder or whether the operation has precipitated the appearance of gynæcomastia, cannot at present be stated Kuntz 63 the effect of the following after the oth ligated and cut, destruction of the germinal epithelium and hypertrophy of the Leydig cells occurs (111) The characteristic feature of the destruction of the germinal epithelium under these conditions is the wholesale sloughing of spermatıds and spermatocytes before they undergo necrosts However, in man removal of one testis and ligation of the opposite vas is performed in the treatment of tubercui encountered as a result of this operation the small number of the involutional type by operation on the prostatě ALBRIGHT'S SYNDROME Polyostotic fibrous dysplasia (Albright's syndrome) was first described by Albnight and his colleagues 64, 65 in 1937, although they referred to cascs described in carlier papers The condition is characterized by bone cysts, skin pigmentation and, in the female, precocious puberty Before 1937 four males affected by this noither did a boy described described a boy aged arked gynæcomastia n hom gynecomastia uite normal in other Tellu males affected by Albright s synuluhe w patients reported with ·DISEASES or THE EXDOCRINE GLANDS 103 Pyar • MANN, L. T (1928). " Enlargement of Breasts after I Tostatectomy",.Im J. Surg. 4: 519 "I KONDOLE AV, quoted by Jann, LT, loc cut 1 OTTENHEIMER R (1927). "Gynekomastre nach Prostatektomie", Deutsche med Schnsche, 53: 883 " KLATZ, I (1921)." Degenerative Changes in the Seminal Epithelium and Jysociated Hyperplasia of the Interstitial Tissue in the Mummalan Testis". Indocrinolngy, s 190 "ILBRIGHT, I'. SCOXILLE, 1 1, and SULKOWITCH, H. (1939). "Syndrome Characterized by Oteius librosa Disseminata, Sreas of lugnsentation, and Gonadal Dysfunction : Turther Observations Including Report of 2 More Cases". Findocrinology, 22: 411 " ALBRIGHT, I (1947), " Poly ostotic librous Dysplasia , Defence of intity". J Clin Endocrinol, 7' 307 " MOEHLIC, I C. and SCHREIBER, I (1940). "Polototic Fibrous Dysplasia. Report of a Case with Uninteral Involvement . Roentgenol. 14. 17 * T'ALCOVER, M.1 Cope, C L, and Rons-Syit, A HT (1912)." Fibrous Dysplasia of Tone with Endocrinc Disorders and Cutaneous Thgmentation (litright's Disease)". Quarl J. Ved . FI: 121 "SELSE, B (1954). "Cffect of Cortisol upon Hammary Gland, , Acta lindocrinol, 17. 394 "* SELTE, II (1954). "Stress and Lactation", het Canad_Brol, 13. 377 " TINDAL, J S, and Vc.XAL GHT, MIL (1938), "Modern Trends in Fndocrinology". Chap 6. Butterworth, London Te Nelson, WO (195" 11 WILKINS, LW (19 Childhood and Adolescence 11 SCHNEIDER, R. currence of Testes and Ibsence of Sexual Hair in Amenorrheic Women". J Chu Endocrinol. 12. 423 ** PEL ER, L, and WALDVA, S (1950), "Gynecomastia in 'Liser Dysfunction Diabetes". New York Stale red, 50, 1377. " ROSENTHAL, T D. and LEES, I (1958)." Thyrotoxicmis with Glycosuna and Idrenocortical Hyperactivt". Lancel, 2 3.40 Hyperthyroidism and Myredem Clin Endocrinol , ! 517 * ESCAMILLA, RF (1949). " Magnostic Significance of Unnar Hurmonal Issays Report of Experence with Measurements of 17-ketosterods and Follicle Stimulating Hormone in Unne". Ann Intl Wed, 30. 249 » HILL, S R. REISS, R S, FORSHAV, l''il, and THORY, G (1950). "Effect of Adrenocorticotropin and Cortisone on Thyroid function. Thyroid- Idrenocortical Interrelationshups". J Cl. Endocrinol. 10 1375 "HerYBERG, CA. and LAMBERG, BA (1953). " Adrenal Function and Thyrotoxicosis", Acta l.wdocrinol. 18 "LEVIN, MI E, and DAUGHADAY, H (1935). "Influence of Thyroid on Adrenocortical Function". J Clin Endocrinol, 15 1499 LEVELL, M J. MITCHELL, L., PAINE, C G and JORDAN. A (1937). "The Clinical Value of Urinary Path, 10 72 H HUBBLE, D 11 BALLINGER, Tepuberal Eunuchordism in the Male ** LANDING, B H (1995). "Studies of the Anatomy and Functions of the Adrenal Cortex in ri. Collog Endocrinol. 8 52 "A cytochemical Study of the Adrenal Cortex ja focrinology, 41 243 155). "The Pathology of the tuitary and Adrenal Proc Roy Socied, 48 908 Cancer, 1183 Endocrinol 13 53). "Gynæcomastia and Hyperthyroidism". J. Clin. "Dods, L (1956). Personal communication C + notnomu. ! ? C. A.AC.. 1 1126 ·102 Gyx COMIASTIA 1 i 44 29" " (1955), New England J. Hd, 252 : 496 70 II FA (1956), "Feminizing Tumors of the 11 DI Patient with Adrenal Cortical Tumor", Acta Endocrinol. 9327 ve Study on Estrogens Excreted by Alale * Catull, G T, MELICOW, M M, and DARBY, H. P lon "es.. Nonhormonal and Hormonal Tumors". S 13 SEROR, J, SIROT, L, and DEBRIE, – (1934)." Fernization", Bull Ass fr Cancer (Pas ** DOSTAL, M (1955). "Feminizing Benign Surrenal Tumor". Vnitr kk Bro, 1, 245: cited in Current List of Medical Literature" (1995), 28 593 15 BASEDOW, V (1848). "Die Glotzengen", Casper's Il'ochensch, No 49, S 769 2* FREEMAN, I (1916), Therap Gas, 40 8 17 Murray, quoted by Freeman, ) loc cul ?! REINBACII, G, and VAN MIRULICZ, . (1900), "Uber die Erfolge der Operativen Therapie bes Basedowscher Krankheit ist besonderer auf die Daneverfolge", VI, S 199 2. BESLEY, P (1917), Clin S Cl Chicago, p 659 * STERLING, W. (1932). "Les correlations endocrines des mamelles". Rev Venrol. 39. 141 1 MENVILLE, JC (1933). "Gynecomastia". Irch Surg. 26 1051 ** WHEELER, ČE, CAWLEY, E. P. GRAY, H T, and CURTIS, AC (1954). "Gynecomastia : Review and Analysis of 100 Cases". Annals of Ixt ved , 40 985. 32 FRASER, R (1954), Personal communication **STARR, P (1935), "Gynecomastia during Hyperthyroidism Report of Cases". JANA, 10. 1988 ** ALBRIGYT, " (1954), Personal communication ** NICHOLSON, G W (1937), "Studies on Tumor Formation, Ovarian Goitre". Guy's Hosp Rep. 87. 391 * SIMPSON, TV MI (1926). "Three Cases of Thyroid Aletastases to Bones, with a Discussion as to the Existence of the So-Called 'Benign Afetastasızıng Gorter", Surg. Gynec & Obst, 42 489 ** MSEANS, H (1937). "The Thyroid and its Diseases". P 495, Lippincott, Massachusetts MARINE, D (1939). "Changes in Interstitial Cells of the Testes in Gull's Disease". Arch. Path. 28 65 40 ROTA, O (1918). " Auftreten ton J/tlchsekretion bei einen an Akrontegalte lerdenden Patienten". Khin T'chnschr. 55 305 "GREENBLATT, RB, CARMONA, N, and HAGLER, W S (1956), "Chiarı-Frommel Syndrome. Syndrome Characterized by Galactorrhea, Amenorthea, and Patuitary Dysfunction, Report of 2 Cases Obst & Gynec, 7 165 « DAVIDOFF, LAI (1926). "Studies in Acromegaly Ill The Anamnesis and Symptomatology in 100 Cases"Endocrinology. 10 461 ** HANEL, H, quoted by Alenville, loc cul " MOEHLIG, RC (1929). " Pituitary Tumors Associated with Gynecomastia", Endocrinology, 13 529 *5 MCCULLAGH, E P. ALIVISATOS, J G, and SCHAFFENBURG, CA (1956), "Mtuitary Tumor with Gynecomastia and Lactation Case Report". J Clin Endocrinol. 16. 397. + Gibson, HJC (1923), "Notes on a Case of Exaggerated Ginacotizia, Eduburgh , mosta, A O (1943), " Hermafronditismus 900 ale 'seudohermaphroditis Proved by Case Report with Speculations 8 367 Amy Obst & Gynec. 38 123 - 40 HAMBLEN, E C, CARTER, F B HORTHAN, IT, and ZANARTU, ] (1951). Male Pseudo hermaphroditism Some Endocrinological and Psychosexual Aspects". Am J Obst & Gynec, 61 $L RUBOVITS, WH, and SAPHIR, W (1938). "Intersexuality". I 4N 4, 110 1823 sa Sisk, ) , and CORNWELL, PME (1942) Pseudohermaphroditism", J Urol, 47* 721 ** WILLIAMS, D I (1952), " Diagnosis of Interser", But 1 1264 B1 WITSCHI, E, and MENGERT, WF (1942), "Endocrine Studies on Human Hermaphrodites and their Bearing on Interpretation of Homosexuality . J Clin Endocrinol, 2 279 5* YOUNG, KAL (1937), "Genital Abnormalities, Hermaphroditism and Related Adrenal Disorders". Baltimore ** MISHELL, DR (1938), "Familial latersexuality 1 Report of 3 Unuspal Cases", 4» Obst & Gynec. 33 убо Hormonal, 57 HAVBURGER, C, STURUP, GK, and DAHIL-IVERSES, E (1953), "Transvestist 39 Psychiatric, and Surgical Treatment, JALA, 152 "Stili, RJ (195+), Personal communication *CHEATLE, G. Li and CUTLER, M (1931). "Tumours of the Breast". Arnold, London 30: 668 7 $ don 1 ·DISE AŞTS OF THE ENDOCRINE GLANDS 103 1. S---...ha * VAN, L. T. (19:8). " Enlargement of Breasts after Prostatectomy". Am J. Storg. 4: 549 • KONDOLEA, quoted by Jann, LT, Lc cul « OPPENHEIMER, K (1927). Girakontasíte nach Prostatzkiume", Deutsche med Schnschr. 53 883 "KUNTZ, . (1921)." plasia of the in ** ALBRIGIT, I', Scovi by teitis lib Further Olneri: 4LBRIGHT. T (1917). 7. 307 "Moenlic, kc, and SCHREIBER, L' (1990). " Polostotic fibrous Dysplasia. Repxt of a Case with Unilateral Insolement ". Am J Roentgenol, 44 17 "FALCONER, V ... Core, C Land Rove.S31TH, A H T (1942) Fibrous Dysplasia of Bone with Endocrine Disorders and Cutaneous Ingmentation (libright's Disease)". Quart J. yed, II: 121 "SELSE, 11 (1954). " Effect of Cortil upon Jammary Glanda". Acta Endocrinol, 17. 394. *** SELTE, H (1931). "Stress and Lactation ", Rev Canad_Biol. 13: 377 ** TINDAL. J S. and McNAL GHT, M L (1955). " Modern Trends in Endocrinology", Chap 6. Butterworth, London 70 XELSON, WO (1951). Estrogen Secretion by the Testes ", Fed Proc, 1097 "1 WILKINS, L W (1950). " Thc Dagnosis and Treatment of Endocrine Disorders so Childhood' and Adolescence p. 272, Springfield " SCHNEIDER, RW. VAN OMEX, R. and HOERR. SO (1952), "Hereditary Occurrence of Clin Endocrinol. 12. 423 Dysfunction. Dahetes". 71 TEL: TROS! cosuna and Idrenocortical 7 ENG tosteroids in Patients with J Clin Endocrinol, 4 517 Significance of Urinary Hormonal Issays Report of 17-ketosteroids and follicle Sumulating Hormone in H. and THORY, G (1950)," Effect of Adrenocortico. tropin and Cortisone on Thyroid function, Thyroid- Adrenocortical Interrelationships". J Clin Endocrinol, 10 1375 7* HERBERG, C. and LASBERG, B (1955). ".ldrenal Function and Thyrotoxicosrs". Aca Endocrinol. 18 41 "LEUX, ME, and DA'GHADAY. WH (1955). Influence of Thyroid on Adrenocortical I unction J Clin Endocrinol, 151499 "LEVELL, M J VIITCHELL, IL PATVECG, and JORDA, (1957). "The Clinical Value of Urinary 17-Ketogenic Steroid Determinatsons". J Che Path, 10 72 " HUBBLE, D (1955), Codocrine Relations ", Lancel, 1 ** BALLINGER, J (1947) “Co-Existence of Hyperthyroidism and Prepuberal Eunuchordism in the Male" Chun Endocrinol. 7 566 "LANDING, B H (1955). "Studies of the Inatomy and functions of the Adrenal Cortex in Vanous Functional States, Ciba Colloq. Endocrinol , 8 52 "DEANE H 1, and GREEP, RO (1947). "A cytochemical Study of the Adrenal Cortes ja Hypo- and Hyperthyroidism". Endocrinology, 41 243 15 CURRIZ, R. and SYMINGTON, T (1955). "The Pathology of the Pituitary and Adrenal Glands in Systemic Disease in Man Proc Roy Soc Ved, 49 908 TREVES, X (1958), Gynrcomastia", Cancer, II 1183 " BERSON, J A, and SCHREIBER, S S (1953). "Gynæcomastia and Hyperthyroidism". J Chr. Endocrinol. 13 1126 "Dods, L (1956), Personal communication 1 ·CHAPTER X GYNÆCOMASTIA ASSOCIATED WITH DISEASES OF THE LIVER In 1926 Silvestrini", a described gynæcomastia as a complication of cirrhosis of the liver and attributed its occurrence to an imbalance among the endocrine glands. In 1937 Dingemanse and Laquers injected cestrogens into mice and could recover these hormones from neither urine nor fæces nor carcass, which suggested that ostrogens were destroyed in the body. In the search which followed for the site of this destruction it was discovered that intraperitoneal injections of cestradiol were resided in the liver cells and not in the reticulo-endothelial cells. These discoveries were supported by a number of experiments, in which pellets i cestrogenic ormone was in the vaginal epithelium These experiments were taken to indicate that the liver is capable of inactivating natural and synthetic estrogens The mechanism of this inactivation was studied by shaking various æstrogens with liver pulp 13 vitro Such experiments showed seen - the that bilrary excretion of oestrogens was important, but Morriones showed that inactivation by liver cells was more important than biliary excretion technique ot splenic implantation was extended to show that the liver required Finally, the thramine and riboflavine in order to inactivate ostrogens 10, 11, 12 These observations provided a possible explanation for a number of symptoms liver disease, includi breasts in women, and loss and synæcomastia in men In both sexes and may be attributable to excess of circulating æstrogens * Lloyd and Williams& undertook an extensive study of the endocrine glands of 71. patients suffering from cirrhosis Among the 55 males they found that loss of bido and loss of potency were almost universal, while 420 showed gynecomastia Loss of axıllary hair was seen in 92°, and testicular atrophy in 76%, 17-ketosteroid rin -la. LLA absence of spermatogenesis It is tempting to suggest that liver failure interferes with the capacity of the liver to inactivate aestrogens secreted by the tests and perhaps by the adrenal corter, and that the consequent increase in circulating levels of free estrogens causes stimula- In Action, estrogens of axillary depressing - 1 bal. im แ44 ·DISCASES or THE LIVER 105 effect of (estrogens upon the release of and the low 17-hetosteroid levels may possible explanation of the endocrine when Glass and his colleagues demonstrated an increase in frec oestrogens in the urine of cirrhotic patients Morrionels showed that the testicular atrophy seen in cirhosis was regularly associated with destruction of the germinal epithelium, which in some cases leaves only Sertoli cells within the tubules Jorrione further showed in mice that liver ceil damage, caused by carbon tetrachloride, enabled clogenous oestrogens to produce germinal cpithelial damage in smaller doses than in normal controls, Infective hepatitis also causes destruction of the germinal epithelium Rather17 studied testicular biopsies tahen during the active stage of this disease, the criteria of activity being those established by Moon,18 which include disintegration of liver cells, the presence of Mallory boilies and proliferation of bile ducts During this phase of the disease the gerinınal epitheliuin shows changes in spermatogonia and spermatocytes before any is seen in spermatids or spermatozoa With the ciception of radiation of the testis by deep X-rays, this is the only condition in which destruction of the germinal cells occurs in this order rather than in order of maturity of the cells, spermatozoa being most vulnerable.1? Rather concluded that, although destruction of the germinal epithelium does occur during the active stage of infective hepatitis, it is not complete and is reversible I. is fess frequent than testicular atrophy, although either may occur without the other, yas bynæcomastia Bernsteina described unilateral gynecomastia in a boy, aged 17 years, who suffered from primary liver cell carcinoma The whole illness lasted 18 months, and gynecomastia was seen during the last year Histologically the tumour proved to be a primary carcinoma without cirrhosis, and liver function tests indicated a severe impairment Klatskin and Rappaport21 dr. Jents suffering from homologous seruin jaundice each case the patient recovered, and gynæcom fading It is apparent that a severe degree of liver cell damage can lead to gynecomastia, impotence and testicular atrophy, and that these symptoms probably result from the elíects of estrogens on the breast and testes Although it has been claimed that the urine contains an excess of unconjugated estrogens, the methods used in these assays are scarcely accurate in measuring such small concentrations of estrogens, and some workers have failed to recover excess of unconjugated estrogens from the uține in cirrhosis The final proof of this hypothesis awaits the development of a more sensitive method of assaying unnary estrogens ·106 GYNACOMASTI4 TEA. So far we have considered gynæcomastia occurs a level of nutrition T} w waluyler & Recent studies 26 or autopsy material indicate that a high percentage of males dying with cirrhosis of the liver show the effects of excess estrogen In 11 out of 13 testes studied, some thickening of the basement mai of 11 showed hydropic changes in the cytoplast these changes are believed to result fram innana avridad. blue epi- These findings umu ue age of 50 years, when such changes are not normally found Hyperplasia of the haranti typophysis: and a these chance no : ** call aulenat cortex remain active ou psuus than normal because the liver cells are unable to conjugate these substances and render them inert Failure detect higher than normal concentra. trons of free cestrogens in the urine of males suffering from liver cell failure is attributor to technical limitations inherent in aracant --11 in hat. UU SU continue to act upon the une lan only conclude that the balance of production and inactivation of steroid hormones is disturbed in liver failure in such a way as to favour excessive oestrogen activity ULCERATIVE COLITIS One example of gynæcomastra associates the ... as appeared ative colitis, and finally appearance VUW 1easts were affected and the patient's condition deteriorated to such an extent that colectomy was performed biopsy at this time shouted "n---- operation of colectomy disappeared It is kn ILULILL UI cirrhosis of the liver.23, .. Juu ili tle absence of turther examples of gynæcomastia in association with ulcerative colitis it may be suggested, as a hypothesis, that gynæcomastia under these circumstances is the result of liver cell damage HANOCHROM 4TOSIS If liver cell damage is the cause of gynæcomastia in cirrhosis of the liver, it would be expected that any disease which caused sufficient liver cell failure would cause gynæcomastia This is true of acute infective hepatitis, cardiac cirrhosis and carcinoma However, hæmochromatosis does not appear to cause gynecomastia Neither Sheldon 4, 35 nor Lawrence, 38 both of whom have studied this disease extensively, has encountered gynæcomastia as a complication of hemochromatosis In order to explore this paradox further, tuo patients suffering from hemochromatosis were studied at Guy's Hospital, and autopsy material from a third was obtained CASE I and darkening o discoloration, esp Thr - ·HEMOCHROMATOSIS 107 TARLE XX1 Special Intestigations in Hanochromalisis Test Case 1 Case 11 Case III Serum protein (gm /100 ml) 8. 63 Albumin content (gm /100 ml) 4.6 34 29 Glotulin content (gm 100 ml) 35 22 39 1/G ratio I 2/1 0 75/1 1.311 Vegative Thymol turbodity Negatise (10 units) Thymol flocculation Vegative + + + + legative Negative Negative + + + + Colloid gold reaction Serum bilirubin content (mg/ 100 ml) 02 O 25 1 75 Laser biopsy Hamochromitosis Hamochromatosis Hæmochromatosis (autopsy) 244 272 Serum iron (18/100 ml) Unsaturated iron-binding capacity Xal (2 estimation) X1 (3 estimations) Xormal Normal Serum sodium, potasyum and chloride contents Glucose tolerance test ormal Xormal ormal Basal metabolic rate +2° - 30 1odine Zero 20 Serum protein-bound (ugm 100 ml) 17 Ketosteroids (mg/24 hours) 49 13 O 9 3. 82 78,130 L'rinary gonadotrophins (mouse units/24 hours) 26 <6 >6<12 <6 <6 Robinson-Kepler-Power test Normal response (part I), z tests Normal response (part 1), z tests Ungary aestrogens (ug/24 hours) Estrone Estradiol (Estriol 56 > 45 <02 40 Semen Azoospermia (3) Azoospermia (3) Thorn test 17-ketosteroids Eosinophils Normal rise Normal fall Normal rise Xormal fall Adrenaline test No response No response See Tables XXII and XXIII ·106 GYNECOMASTIA 1 Recent studies 26 of autopsy material indicate that a high percentage of males dying with cirrhosis of the liver show the effects of excess oestrogen in II out of uile eight helium ; Other the epifindings are reported in men dying under the age of 50 years, when such changes are not normally found Hyperplasia of the basophil cells of the adenohypophysis39 and a narrow nodular adrenal cortex33 are also found in cases of cirrhosis; these changes are also thought to be due to cestrogen stimulation 26 There is, therefore, considerable circumstantial evidence to indicate that liver failure may lead to cestrogenic changes in the tissues It is presumed that the small concentrations of cestrogens normally released into the circulation from the testis and the adrenal cortex remain active for longer periods than normal because the liver cells are unable to conjugate these Why do these hormones not remain unconjugated and so continue to act upon the tissues One can only conclude that the balance of production and inactivation of steroid hormones is disturbed in liver failure in such a way as to favour excessive cestrogen activity ULCERATIVE COLITIS One example of gynæcomastia associated with ulcerative colitis has appeared in the literature 22 The history and findings were typical of severe ulcerative colitis, which resisted conservative treatment and eventually required ileostomy and finally colectomy The gynecomastia was unilateral at first and made its appearance during a relapse Subsequently, both breasts were affected and the patient's condition deteriorated to such an extent that colectomy was performed Liver biopsy this time showed "parenchymal de teration and fibrosis" After the operation of colectomy the patient's general health improved, and the gynæcomastia disappeared It is known that ulcerative colitis can lead to the development of cirthosis of the liver, 23, 24, 25 and in the absence of further examples of gynæcomastia in association with ulcerative colitis it may be suggested, as a hypothesis, that syn.ecomastia under these circumstances is the result of liver cell damage HEMOCHROMATOSIS If liver cell damage is the cause of gynæcomastia in cirrhosis of the liver, it would be expected that any disease which caused sufficient liver cell failure would cause gynecomastia This is true of acute infective hepatitis, cardiac cirrhosis and carcinoma However, hæmochromatosis does not appear to cause gynæcomastia Neither Sheldon31, 35 nor Lawrence, so both of whom have studied thus disease extensively, has encountered gynecomastia as a complication of hæmochromatosis In order to explore this parados further, two patients suffering from hæmochromatosis were studied at Guy's Hospital, and autopsy material from a third was obtained. CASEI The patient, who was aged 34 years, complained of fatigue, loss of libido, impotence and darkening of the skin for three years On examination the shin showed a dark greyush discoloration, especially on the face and hands Thehrer was enlarged to the umbilicus. pudic, ·HONOCHROMATOSIS 109 was palpable three inchiex lelow the left costał marta l'ubic and axillary hart *as scanty. The testes ucre normal in size but soit, and the urine showed intermittent glycosu71a The patient died (aged 8 years) as the result of hesaternesis At automy findings typical of hrmochromatosis were discos ered the testes sboked arrest of the germinal epithelium at the stage at secondary spermatocytes, normal interstitial cells, and scanty deposits of iron in the walla of some blood resets The antenos pituitary gland showed extensie deposits of ron, especially in the basophil cells (Figure 173 TABLE XXIII 1 Day Urinars 57-ketosteroids (ilg/24 hours) Chamber Cosinophil Count (Cellsch) Itrat Second SS Third 87 130 fourth I za Tith ACTII, 25 mts muscular sepertion) (intra 74 + 110 50 14 hours after intramuscular injection of ACTN) Surth 10 8 75 From the data shown in Table XXI the following conclusions may be drawn. (1) All tree patients suffered from typical hemochromatosis (2) Low urmary gonadotrophin levels suggest that the symptoms of gonadal fallure may result from failure of adenohypophysial secretion of gonadotropkins (3) Normal Kepler and normal 27-ketosteroid excretion, together with normal serum electrolyte levels and a prompt fall 19 circulating eosinophils after injection of ACTH, indicates normal adrenocortical function Failure of circulating eosinophils to fall after the administration of adrenaline suggests that the capacity of the pituitary to produce or to release ACTH may be defective, although doubt has been cast upon the signuficance of this test (4) Testicular biopsy stained by Perls' reagent shoued very little iron, and that in such places as to make it improbable that the deposition of the metal was responsible for the testicular faslure The appearance of the germinal epithelium is compatible sath fasture of gonadotrophic function of the pituitary (şi The autopsy appearance of the adenohypophy sus provides a possible explanatron lor the failure of gonadotrophin secretion Although hæmochromatosis frequently causes testicular atrophy, impotence and loss of body hair, these changes are not associated with gynæcomastia, in contrast to other forms of liver disease which not infrequently cause gynaecomastia mr addition to these other changes The findings presented above indicate that extensive deposits of iron are found in the basophil cells of the anterior pituitary gland, but that the testis escapes all but the slightest invasion by the metal Sumilar findings were reported by Hubble 93 This would suggest that testicular fazlure results from defective pituitary function rather than from failure of the testis per se The pitustary origin of this hypogonadım is further indicated by testicular biopsy, which reveals normal Leydig cells but arrest of spermatogenesis at the stage of secondary spermatocytes, and by low values or absence of urinary gonadotrophans and by response to chorionic ·108 GYXÆCOMASTIA axslary and body hairs were scanty, while the beard required shaving only twice weekly, whereas the patsent had formerly shaved every day The skin of the face was soft, and the testes were smaller than normal and soit The following intestigations were performed in addition to those shown in Table XXY (1) Thorn test (Table XXII), Tbe response to this indicates normal adrenocortical fan tim. The failure of response to adrenaline was at that time (1952) taken as evidence in favour of pituitary failure, but this conclusion would now be conwdered unjustified. (2) Testicular bopsy. In the tubules the basement membrane was oormal In the germinal epithelium arrest of spermatogenesis was apparent at the stage of secondary spermatocytes la the interstitial tissue Leydig cells were normal a number (seves per tubule) and arrearance. Perls' stata showed the deposition of iron in small amounts so the walls of some of the smaller blood vessels, but nose in the geymisa) epithelium. (3) Testosterone caused a return of sexual activity, stimulated the growth of facial har, and produced a sense of well-being. TABLE XXII Day Ustnary 17-ketosterosds (lig 124 hours) Chambes Essisophit Count (Cells/ cm) First # 9 89 Second yo 85 100 Third ACTH. 30 tag fintravenous injection during 12-hour pernd o lat the conclusion of intra enous injectron o ACTH) Fourth 91 37 62 | 78 50 Sixth Adrenaline : rou) O 3 cm thu podermic injection) 55 14 hours after hypoderte injection of adrenaline) CASE 11 - At the age of 47 years the patient's inends drew his attention to the dark colour of his skin, which became more pronounced during the eight years before the present studies were undertaken Six years after the onset of the change in skin colmr the patient became sotent, and two years later dabeles was discovered The latter responded to insula treatment but remained difficult to stabilize On examination the skin was grey in colour, and the liver was palpable lour inches below the costul margin Axillary and pufnt hair were almost abysent, kdy hair was scasty, and the testes were smaller than normal The following investigations were performed in addition to those shown in Table XXI $*! Thorn test (Table XXIII) This test indicates normaal adrenocortical function (2) Testicplar biopsy In the tubules the basement membrane was norma? In the germassal (3) Response to chorionic gonadotrophis liter a course of sotramuscular injections of chronic gonadotrophin (1000 units twice weekly for those weeks), the patient experienced a return of kbido and erections The testes increased in size and became tender Yo change in the distnbution of hair throughout the body was noticed ing of the skin dunng weck, asthough he had ey in colour, especially margin The spices ·DISE ISES OF THE LIVER 111 SILNERSTEIN, I, ENGEL r. and MoLX IR, K (1933). "C'ber das Auftreten eines Drunststoffes in Blut und gearlen unter pathologischen Verkalinissen : l'ergleich der in Blut wnd Organen nachweisbarin Bunststoffmengen', Klin Il'chnschr, 12. 1693 * Zondex, 1 (1934). "C'ter das Schicksal des rollikeljor mons (rollikulm) Orgamssmus", Skandinar Arch / Physiol. 70: 133 T ISRAEL, S. 1 Liver: Systems • ZONDEK, B, anu Sklow, J. 11941). IHALIIS ALIOHL DI l.>llulle by hul J.VUSIUL ui ...L1-1 Cant Cor Exper Biol Jed, 46: 376 "inactivation of Stilbestrol by Liner in Vitro". . 10 11 'Diminution in Ability of Loser to Icactivate ", SCIENCE, 94462 2). "Cffect of Vitamin B Complex Deficiency on Inactivation of Oranan Estrogen in Liner". Ludacrinology. 30: 819 ** RISKIND, I s, and BISKIND, G R (1942). "Cffect of Vitamin B Complex Deficiency on Inactus atson of stana ini. So walinu 1.. 11 HELLER, C G (191 l'terus upon Estrone, Estradiol and CANTAROW, A, P (1943). "Studies on Inactivation of Estradiol Ly Liver", Endrinolngv. 33: 309 1 Morrione, I G (1944). "Cflect of L'strogena on Testis in ilepatic Insufficiency". Arch r'ath. 37. 39 1° LLOYD, C, and Williaus, R II (1948). “Endocnne Changes Associated with Laennec's Cirrhosis of the Liver" 4 Ned. 4. 315 11 RATHER, L. (1987). Hepatic Corrhosis and Testicular Itrophy". Arch Int Vel, 80: 397 IT Moon, V 11 (1932). "Atrophic Cirrhosis". Arch Path, 13 091 1. RUPP, J. CANTEROW, A, RAKOPF, A E, and P'ASCHKIS K E (1991) " Hormone Fxcretion in Laser Disease and in Gynecomastia". ] Clin Endrorinol. 11. 698 ** BERNSTEIN, MH (1948). "Gynecomastia Associated with Primary Liver Cell Carcinoma", South W] 41. Ut 11 KLATSKIN, G, and RAPPA PORT, EV (1947). "Gynecomastia due to Infectious Hepatitis of Homologous Serum Type, Am Med, 214. 121 ** KYLE, LH (1949). "Gynecomastia in Association with Chronic Ulcerative Coliti'. New * Tesex, langNovocha*, , ?, and Jobb, E (1917). * Hepatic Carthosis as a complication of Chronic Ulcerative Colitis". Ann Ini Wed, 26 542 " KICKNER, MS. IUNOR, STAUFFER, MH, BARGEY, JA, and DOCKERTY, M D (1952). Hepatic Lesions in Living Patient with Chronic t'lcerative Colitis as Demonstrated by Xeedle Biopsy", Gastroenterclogy, 22 * Ross, J. R. and SHARTS, JH (1948). "Hepatic Dysfunction and Cirrhosis in Chronic Ulcerative companying Hepatic .) Path & Bacl. 68 617 t - - 1 --- "C. 4.e Morpho. ..". J Clin 1. BAR 17 TRA 11 T. vic br D T nd Prostate of Men who Die of Cirrhosis of the Liyer , Am j Clin Path, 20 814 » CAPRIGLIONE, L, BERNARDINELLI, W and DA COSTA CRUZ, T (1934). "Curhose hépatique et gynecomastie Presse séd. 42 1419 * STUMPF, HI H, and V ILEXS, S L (1953). * Inhibitory Effects of Portal Cinthosis of Liver on Prostate Enlargement, dy Arch Int Jud. 91. 304 "GLASS, S J EDMONDSOY, 11 A, and SOLL, S N (1944). " Excretion of Estrogen Alter Injection of Estradiol and Estrone into Men with Cirrhosis of the Liver", J Clin Endocrinol, "FINESTRONE, ), and SHUVAN, CR (1952) Estrogens and Neoplasia ", Thomas, Illinois "* SHELDON, JH (1935), " Hæmochromatosis', OUP London ** SHELDON _H_(1954). Personal communication ** LAWRENCE, RD (195+). I'ersonal communication * Glass, S J. EDMONDSON, HA, and SOLL, S N (1940). “ Sex Hormone Changes Associated with Liver Disease ", Endocrinology, 27 74, "CANTAROW. 1, PASCHxIS, KE, RAKOFF, A E, HANSEN, L I. and WALKING, A (1943). Excretion of Exogenous and Endogenous Estrogen in Bile of Dogs and Humans Proc Soc Exper Biol Jed. 52 256 EST54 ·IIO GYNECOMASTIA gonadotrophin (Case II). Response to intramuscular injection of testosterone (Case I) indicates that the tissues were not unresponsive to testicular androgens Failure of the anterior pituitary to secrete gonadotrophins suggests two possible explanations for the absence of gynæcomastia In the first place absence of normal stimulation of the testis may interfere with the secretion of aestrogens; hence, even when liver failure becomes advanced, the blood contains no cestrogens to be inactivated, and hence breast stimulation does not occur In the second place oestrogens do not cause stimulation of the breasts in hypophysectomized animals (page 24) Which of the hormones of the adenohypophysis are required to permit FIGURE 17 Hamochromatosis (A) Testes (Perls' stain) Small deposits of uron can be seen in the walls of a blood vessel The germinal epithelium and Leydig cells are free of iron (B) Anterior pituitary gland (Perls' stain) Extensive deposits of iron can be seen in the basophul cells cestrogenic breast stimulation remains unknown However, absence of gonadotrophins may interfere with the capacity of unconjugated estrogens to cause gynaecomastia The urinary cestrogen levels found in Cases I and II suggest that these hormones are not entirely absent, although testicular failure was present Our present knowledge of rormal male estrogen excretion does not enable one to comment on these results There is reason to suppose that the secretion of gonadotrophins is the most vulnerable function of the adenohypophysis, being the first to suffer in diseases of this structure 43 Pituitary failure has been recorded in other cases of hæmochromatosis, 44, 45 and it seems more likely that this is responsible for the absence of breast stimulation than failure of østrogen secretion REFERENCES "Porenseren-7 Hammana nell'uomo Affelo da Currosdel Laennec", n of Estrone, Estradiol, and their ynec. 33 1000 of Subcutaneous when compared none", Am J Physiol, 77. 518 ·CHAPTER XI GYNÆCOMASTIA ASSOCIATED WITH MALNUTRITION During the second world war a considerable number of American soldiers devcloped byn.ecomastia during their stay in Japanese prison camps, where they were Tinravamle Vorsselmani described the appearance --...-..chal were noticed Jacobs studied the largest group of cases His experience concerned 9000 prisoners, of whom 2400 died within the first 18 months, death being due directly or indirectly to malnutrition After they had been two years in the camp a series of Red Cross parceis began to arrive, and for four months the diet of all the men was adequate Thereafter they returned to a state of malnutrition, and this state of affairs persisted until the time of release 22 months after the arrival of the first parcels (four years after imprisonment). At the time of arrival of the first Red Cross parcels there were no knownı cases 1.... 11 hospital Subsequently Jacobs estimated that 50% of the prisoners noticed some gynæcomastia after release and that all those who had shown gynecomastia in the camp reported a return of this symptom Return of Ibido and testicular pain were noticed at the time the gynæcomastia appeared Jacobs saw synecomastia only during refeeding Because of the vast number of stamın deficiency diseases it was natural to attempt to explain minimal and barely compatible with me Hibbså studied 34 cases of gynæcomastia among 8000 prisoners The gynaecomastia occurred after 18 months in the prison, which represented an interval of 12 months between the last appearance of a nes mamfestation of dietary deficiency and the first case of gynecomastia The gynecomastia was noticed during improvement in the diet from 1200 to 1400 Calories The men affected had all been mainourished and underfed, but were not necessarily the most severely affected Usually the condition appeared when the prisoners gained weight, and for the most part the men were affected at the same time almost like an epidemic Platt20 made similar observations Klatskin and his colleagues studied a group of 300 men who, after their release from prison camps, were admitted to hospital for the treatment of malnutrition. They had been in Japanese hands between April, 1942, and September, 1945. In August, 1945, food parcels began to arrive The authors began their studies in December, 1945 Among 300 men, 48 showed gynæcomastia, of which 17 cases occurred following return to a normal diet, and another seven were aggravated

·II2
GYNÆCOYASTIA
** CANTAROW, A, PASCHKIS, KE, and RAKOFF, A, E (1945), "Hepatic 'Inactivation of
Estrogens". Science, 101 558
40 CANTAROW, A , PASCHKIS K E , KAKOFF, A E, Hansen, L P, and WALKING, A A (1943)
"Excretion of Androgers,
tration of Androgens", P
" DRILL, WA, and PFEIFFER, C
to Inactivation of Estrone
** PELNER, L. and WALDMAN, S (1950), “Gynecomastia in 'Liver Dysfunction. Diabetes ".
New York State I Med, 50 1377
HUBBLE, D (1952), "Course of Anterior Hypopituitarism". Lancet, 1 1123
** LAMBIE, A T, BURROW, B A, and Soumers, SC (1957). Clinicopathologic Conference,
Amer J Clin Path, 27 444.
45 Case Report Massachusetts General Hospital (1953), New England / of Med. 249 855.

·JIAL, UTRITION AND REFCCDING 115 with impotence, loss of libido, testicular atrophy and loss of body hair, the other appearing during refealing with the return of sexual activity. mal experiments sophysectomized If the donor were zh viable. This isis. Various studies have also been made of hormone metabolism in malnutrition Jaiter' implanted pellets of restradiol into the spleen of spayed female rats and feel thum a dict deficient in vitamin B complex until they lost 25% of their weight. Continuous estrus effects were seen in vaginal smears, and this finding was not altered by addition of thiamine and nboflavine to the diet. Jailer concluded that inantion and not lack of vitamin B was responsible for failure of the liver to inactivate (Estradiol On the other hand, Segaloft and Segaloff' showed that utamin B deficiency leads to a decline in the capacity of rat liver to inactivate cestronc and cestradiol and also to a diminated response of rat tissues to subcutaneous injection of estradiol. These effects were prevented by the administration of thiamine and riboflavine. Dull and Pfeiffer, 10 however, showed that inanition in the presence of adequate vitamin B would cause a decline in the ability of the rat's liver to inactivate oestrone and cestradiol Unna and his colleagueshi believed that methionine was the important factor required to maintain the capacity of the liver to inactivate oestrogens They showed that rats kept alive on low protein diets cannot retain normal amounts of riboflavine in their livers Methionine counteracts this fall in the riboflavine content of the liver The liver of such rats kept on a low protein diet for three months failed to inactivate estradiol, but methionine restored this capacity even when low protein intake continued These studies suggest two possible explanations for the gynecomastia of malnutrition. Firstly, it is possible that return to normal diet brings about a return of testicular activity before the liver regains the capacity to inactivate oestrogens Secondly, the reawakening of testicular activity after a period of malnutrition may bring about changes like those seen at puberty. Implicit in both hypotheses is the idea that testicular function remains in abeyance during malnutrition, an idea which is supported by the absence of libido and of erections and by the experiments with malnourished mice mentioned above This temporary 11 ..14 funf. 1.-- f normal gland in hypophysectomized mice The first theory has not been supported by any direct evidence However, it will be recalled that in Malaya a diet of polished rice produced berberi, but if beriberi was treated with pure thiamine, without change in the diet, pellagra appeared Pellagra never appeared before beriberi " This phenomenon has been reported by a number of workers 15, 16, 17, 18 It would seem that an emergency pathway is established during deficiency of one substance which temporanly renders another unnecessary In the case of gynaecomastia it may be supposed that during malnutrition the liver can inactivate cestrogens by means of metabolic pathways which do not require some component of the vitamin B complex, but that when normal feeding is resumed, the need for vitamin B returns, and this is expressed by the appearance of gynæcomastia This concept is without any experimental support, and in view of the fact that malnutrition interferes with the capacity of the liver of ·114 GYNACOMASTIA by improvement of the diet; 31 occurred during starvation The breasts were tender in every case, and both sides were more often affected than one, although sometimes asynchronously. One breast subjected to histological examination revealed the changes typical of gynecomastia (sce page 22). It was estimated that the average diet of these men consisted of approximately 1735 Calories (protein 42 srammes, fat 7 grammes and carbohydrate 375 grammes). On this diet they All the tis, while one-third showed hepatomegaly or abnormal response to liver function tests, or both. One-third had small testes as measured by a flexible metal ruler. Body hair was nonnal in every case The 17-ketosteroid excretion and urinary ostrogen values were low, but urinary gonadotrophın values were normal Zurbıran and Gómez-Monts had the advantage of applying modern laboratory mcthods to the study of malnutrition They described the testis in malnutrition as showing decrease in the size of tubules, thickening of the basement membrane and defective spermatogenesis. The germinal epithelium was almost always involved, sometimes showing arrest of maturation, at other times showing an over-all lack of germinal cells Interstitial cells were few in number, small in size, and loaded with brownish pigment These changes in the Leydig cells were said to resemble those seen in animals during periods of sexual inactivity Similar changes in testicular histology are seen in malnourished animals,13 and Zurbiran and Gómez-Mont believe that the human testis in malnutrition resembles that found in pituitary tumours with low urinary gonadotrophins 13 Zurbıran and Gómez-Mont also found low urinary 17-ketosteroid levels in both sexes The mean figure for men was 3.5 mg and for women 2.4 mg per 24 hours This suggests that both the testicular and adrenal contributions may be diminished, since the total level was lok in b. in every male patient in whom th low in 79% and raised in 21 trophin and urinary cestrogen le this increase in cestrogen excretion was very great and was almost always followed in men by gynæcomastia, which outlasted the duration of the raised urnary oestrogen excretion Unfortunately the authors do not indicate the exact correlation between high urinary oestrogens and gynæcomastia During the period of malnutrition about 20% of malnourished men showed gynæcomastra and 21%, showed raised urinary estrogen levels On the other hand, a return to normal diet was associated with gynecomastia in almost every case, and a rise in urinary cestrogens to levels above normal was also almost universal The authors studied 201 patients suffering from malnutrition and concluded that the fundamental endocrine abnormality was deficient pituitary function Landau and his colleagues? studied the effect of starvation upon the urinary output of 17-ketosterords and androgens in three normal men and one obese woman During a four-day period of fasting the 17-ketosteroid output fell by 50%, and the androgen content of the urine showed a parallel drop Kark et alııe studied the effect of malnutrition by refeeding men with cirrhosis of the liver who were poorly nourished They selected men suffering from established The patients complained of loss of libido, testes and needed to shave only two or three was enlarged The patients were given diets iring this period of refeeding hair returned on nicker Return of libido and erections as he testes Kark et alu expressed the beliel that there were two types of gynæconiastia associated with cirrhosis of the liver, one during the height of the disease, associated + ·VILNUTRITION AND REFECDING 115 with impotence, loss of libido, testicular atrophy and loss of body hair, the other appearing during refeeling with the return of sexual activity. These clinical studies have been amplified and supported by animal experiments. Mason and Wolfe, for example, found that they could restore hypophysectomized If the donor were ough viable. This ophysis Vanous studies have also been made of hormone metabolism in malnutntion Jailer implanted pellets of oestradiol into the spleen of spayed female rats and fed them a dict deficient in vitamin B complex until they lost 25% of their weight Continuous oestrus effects were seen in vaginal smears, and this finding was not altered by addition of thiaminc and nboflavine to the diet. Jarler concluded that inanition and not lack of vitamin Buas responsible for failure of the liver to inactivate (estradiol. On the other hand, Segaloft and Segaloff showed that vitamin B deficiency leads to a decline in the capacity of rat liver to inactivate cestrone and cestradiol and also to a diminished response of rat tissues to subcutaneous injection of estradiol These effects were prevented by the administration of thiamine and riboflavine. Dnll and Pfeiffer, to however, showed that inanition in the presence of adequate vitamin B would cause a decline in the ability of the rat's tiver to inactivate oestrone and cestradiol Unna and his colleagues't believed that methionine was the important factor required to maintain the capacity of the liver to inactivate cestrogens "They showed that rats kept alive on low protein diets cannot retain normal amounts of riboflavine in their livers Methionine counteracts this fall in the riboflavine content of the liver The liver of such rats kept on a low protein diet for threc months failed to inactivate ostradiol, but methionine restored this capacity even when low protein intake continued These studies suggest two possible explanations for the gynæcomastia of malnutntion Firstly, it is possible that return to normal diet brings about a return of testicular activity before the liver regains the capacity to inactivate cestrogens Secondly, the reawakening of testicular activity after a period of malnutrition may bring about changes like those seen at puberty. Implicit in both hypotheses is the idea that testicular function remains in abeyance during malnutrition, an idea which is supported by the absence of libido and of erections and by the experiments with malnourished mice mentioned above This temporary the pituitary gland of mice subjected to starvation could not substitute for the normal gland in hypophysectomized mice !. 1 : 있 Pellagra never appeared before t--hn- 14 number of workers 15, 16, 17, 18 lished dunng deficiency of or unnecessary In the case of gynæcomastia it may be supposed that during malnutrition the liver can inactivate cestrogens by means of metabolic pathways which do not require some component of the vitamin B complex, but that when normal feeding is resumed, the need for vitamin B returns, and this is expressed by the appearance of gynæcomastia This concept is without any experimental support, and in view of the fact that malnutrition interferes with the capacity of the liver of ·116 GYNECOMASTIA rats to inactivate oestrogens during the period of deficiency it does not seem very probable. Moreover, the observations of Zurbiran and Gómez-llont make it likely that the secretion of estrogens is diminished during malnutrition. It seems more probable that the gynæcomastia of refeeding is associated with the reawakening of sexual activity which occurs at that time. The return of testicular function probably resembles the endocrine activity seen at puberty, and it is possible that the same mechanism which produces the subareolar node at that time may play a part in the occurrence of gynæcomastia during refeeding. During malnutrition the testis is smaller than normal, and spermatogenesis is depressed s On refeeding, tenderness and swelling of the testes are noticed, and the whole process resembles a second puberty. Thn matlamat at this time of mæcomastia is therefore expected to be the same as The same would apply to gynecomastia seen in 1 owever, the On the other hand, gynæcomastia sometimes appears during the period of malnutrition. This may be explained by the fact that some 20% of men show an increased urinary excretion of cestrogens during starvation. Why some men show a annot be explained. There is no the malnutrition is important tion with a number of diseases which cause wasting, eg 'pulmonary tuberculosis. Wheeler et iciated with these conditions is due to cases so far reported have indicated that no close correlation exists between wasting and gynæcomastia In these cases gynecomastia has appeared at the height of the illness and has usually undergone remission with the associated disease REFERENCES MUSSELMAN, A1 M (1945). "Nutritional Diseases ia Cabanatuan ", Far Wed, 8 325 * JACOBS, E C (1948). "Gynecomastia Following Severe Starvation". Ann Int ved. 28 792 * 111BBS, RE (1947). "Gynecomastia Associated with Vitamin Deficiency Disease". Am J al Sc, 213 176 • KLATSKIN, G, SALTER, W T, and Hus3, F D (1947), "Gytiecomastra due to Malnutrition. Clinical Studies ", Amj MSc, 213 19 * ZURBIRAN, S, and Govez-NONT, F (1953). Endocrine Disturbances in Chronic Human Malnutrition", l'itamins and Mormones, 11 97 . KAR + MAS JAIL SEG: Metabolism ", Endocrinology. 34 346 10 DRILL, V A, and PFEIFFER, C A (1946). Effect of Vitamin B Complex Deficiency, Controlled Inanition and Methionine, on Inactivation of Estrogen by the Liver", Endocrinology. 38 300 11 UNNA, K, SINGHER, HO, KENSLER, C J. TAYLOR, H C, and RHOADS, C P (1944), "Effect of Dietary Protein on Liver Riboflavin Levels and on Inactivation of Estradiol by Liver". Proc Soc Exper Biol á ved, 55 254 12 LANDAU, RL, NOWLTON, K, ANDERSON, D, BRANDT, M, and KENYOX, A T (1948), "Effect of Starvation on Unnary 17-ketosteroid Excretion". J Clin Endocrinol, 8 133 18 Masox, KC (1939), "Sex and Internal Secretions P 1148, Baltimore 1. Teich, G (1954). Personal communication I CORKILL, NL, CREDITOR, H, and STEWART, GES (1948), "Wallet Beer and Peanuts as Protective Foods in Africans". Trop Jed, si 140 1. PIERS, F (1947). "Notes on Some Cutaneous Manifestations of Deficiency Disease, South African An). 24 246. 11 SIMONS, R DGP (1919), "Nutritional Disorders of Skin among Prisoners of War in the far East", Brit J Dermat Syph, di 210 16 STAPLETON, T_(1946). "Edema in Recovered Prisoners-of-War. Lancet 250 890 1. WHEELER, CE, CAWLEY, E P, GRAY, H T, and CURTIS, A Ć (1954). Gynecomastia A Resjew and an Analysss of too Cases Ann Int Jed . 40 995 SU PLATT, S S (1917). Bull US Army Ved Deri ? 403 ·CHAPTER XII DRUGS AS A CAUSE OF GYNECOMASTIA A number of driss, including certain hormones, can cause gynecomastia In some cases (eg. cestrogens) brcast stimulation is to be expected and occurs in a predictable fashion "llowever, in the case of other drugs gynecomastia is sporadic and totally uncupected leg digitalı) The following drugs can cause syn:tcomastia (1) Estrogens (2) Androgens. (3) Choricnic gonadotroplun. (4) Adrenocortical hormones. (5) Digitalis, (6) Amphetamine (7) Radioactive 10dine. (8) Reserpine ESTROGENS When adult males tahe estrogenic substances, a number of changes result, including loss of hbido, impotence, gynacomastia, diminution in testicular size and destruction of the germinal epithelium Some of these changes (loss of libido, imprimantap actic the char ") LALU ul the walls Ol the tubules. (1) Absence of Leydig cells (iv) Interstitial fibrosis These changes were descnberl in men nast thur middle years, and some of the effects mentioned could be attnbuted to age Dunn', 3, 38 studied testicular biopsies taken from a 27-3 car-old man who received 530 mg of stilbcostrol by mou.li during a period of ALICULUI. TE datur n. . luniltIOn (libido, crections and emissions) did not return to normal for a further month In the case of a boy agtesticular biopsy showed (1) (11) sclerosis of the walls of 1 Greep and Jones described experiments which raise the possibility that these changes are due not to a direct effect upon the tests, but to suppression of the secretion of gonadotrophins by the adenohypophysis They compared the gonadotrophic effenti 1 7 Lyrh, turlied the tactilar, .... IL-- (control Pregnar showed --- !!! Vej ugn, we second Of I gm, and the third of 3.0 gm This suggests that follicle-stimulating hormone administered together with cestrogen prevents the testicular atrophy which destrogens alone produce, and hence 1

·10
FIGURE 18
Ri Thi testis before
rapy
buen
e of
contain only SCI LEI
degeneration

·ESTROGENS 119 that astrogens produce testicular atrophy by suppressing the secretion of folliclestimulating hormone. The testes of the strogen-treated group returned to normal when treatment was stopped, and testicular weight also returned to normal. 11 2.1 cpiti treat Lege hypertrophy by supposing that aestrogen suppress the secretion of follicle-stimulating hormone and stimulate the release of interstitial-cell stimulating hormone. They produced “ tumours" of Leydig cells by injections of interstitial cell-stimulating hormone 's Hospital, where other respect, were were taken before and after treatment; urinary 17-ketosteroids, restrogens and gonadotrophins were also measured before and after the administration of stilboestrol Table XXIV shows the results of the cas ays in the first patient. It can be seen that the 17-ketosteroid levels show no consistent change and that the changes in trogen excretion are not striking The first implantation of stilboestrol did not alter the level of urinary gonadotrophins, although it causedl serious changes in endocrine function After the second implantation urinary the stilboestrol had caused considerable paticnt the -fraction of urinary 17-ketontation, Testicular biopsy before treatment was normal, but after two implantations of 11 cells were very pale and showed an increase in granules, and the cytoplasm had a ragged " appearance The Leydig cell count before treatment was 17.5 per tubule and after treatment 7.0 per tubule Testicular biopsy eight wecks after the second biopy (Figure 18) showed the following changes. Some thickening of the basement membrane was scen In the gerninal epithelium, normal spermatogenesis was absent, and most tubules were lined by Sertofi cells only in the interstitial tissue, Leydig cells showed further reduction in number The cytoplasm of these cells was very pale and granular. The cells were too is in number to count in relation to the tubules. Part of this spec method of Schultz at the side of the ce described in animals treated with estrogens. The studies performed on the second patient are shown in Table XXV. Again the 17-ketosteroid levels show no consistent change Although a fall is seen, all readings are within normal limits, and the S-fraction showed no change following implantation Urinary gonadotrophins and unnary restrogens also showed no consistent changes implantation of stulbcestrol caused impotence, gynecomastia and pigmentation of the nipples. Testicular biopsy after treatment showed the defective spermatogenesis with undifferentiated germinal cells, Leydig cells were normal in distribution but pale-staining and granular with ragged cytoplasm A third patient showed considerable hyalınızation of the basement membranes and similar appearances in the Leydig cells From this specimen one part was fixed in digitonin and stained by the method of Schultz This showed blue staining

·118
GYNECOMASTIA
FIGURE 18
141 ans 1 The testis hefore
contajı only Sertoli tells
لها الارها
degeneration

·ESTROGENS 121 The third patient, at the age of 17 years, received 1 mg of stilbestrol daily for 28 days This treatment produced gyn.comastia and impotence for a period of one month. Thereafter, normal sexual function returned Three years later testicular biopsy gave normal finding and the Ley dig cell count revealed 14 cells per tubule (Tigure 19) Such does of astrogen therefore produce only reversible changes. The persistent impotence in the first patient was incomplete and possibly perpetuated by psychological factors. A slight degree of gynecomastia remained, which emphasizes the previous observation that gynecomastia can persat to some extent long after the removal of the exciting cause (see page 31) FIGLRE 20 The gym tcomastia and characteristic pigmenta. tion of the nipples following Large doses of stil restrol Minute doses of cestrogen can cause gynecomastia This was seen in men handling restrogens dunng the manufacture of tablets' In drug factones it has been shown that absorption through the shin or by inhalation can cause gyneco mastia, and that at low concentrations some men are more resistant than others Gynecomastia can precede or occur without pigmentation of the nipples and without impotence This suggests that gynæcomastia results from direct action upon the breasts in concentrations too small to affect the testes Children appear to be highly susceptible to small doses of estrogenic substances For example, a worker handling estrogens in a factory where other men had been affected by gynecomastia was not himself affected by gynecomastia His son, a f 1 en estrogen in his hair (which was not washed at work)." Indicative also of the sensitivity of the young breast to minute amounts of estrogen is the observation that ·120 GYNECOMASTIA in Leydig cells and in that part of the Sertoli cells nearest the basement membrane, indicating the deposition of cholesterol and cholesterol esters at thorn mit In contrast to these acirte ornnithe testis was studied in of acne. The first patient rece..cu all unplant of 200 mg, of stilbaestrol at the age of 16 years At 25 years the patient showed slight gynæcomastia and complained of impotence. Investigations revealed the following findings : Urinary 17-ketosteroids (mg per 24 hours) 1706; 10.0, 9.0 Urinary gonadotrophins (mouse units per 24 hours) : >12516: >12<16; >12<16. Semen. Two counts showed 53 x 106 and 109 X10 per cubic centimetre respectively and in each case motility was 2. FIGURE 19 The testis following cestrogen therapy (4) High-power uew lshoitang normal tuboles and interstitial tissue The patient had recened stulboestrol nine years before this biopsy was taken (B) High-power vich showing normal tubules and interstitial tissue in a patient who had recented stubastrol three years before this biopsy was taken Testicular biopsy gave normal findings, and the Leydıg cell count was 13 i cells per tubule (Figure 19) The second patient had received an implant of 300 mg of stilbæstro) at the age of 16 years Gynæcomastia and impotence followed, but the symptoms gradually disappeared after about six months At the age of 27 years sexual function was normal, and no evidence of gynæcomastia was found Investigations revealed the following findings Unnary 17-ketosteroids 14 4 ms 24 hours Urinary gonadotrophins >16<24 mouse units/24 hours. Semen Two counts showed 80 X 10 and 112 x 10per cubic centimetre respectively, and in each case motility was 3 Testicular biopsy gave normal findings The Leydig cell count showed 14 cells per tubule.

·TABLE XIV Urinary Titrogens (812 Hours) Testicular Biophy fulules Lesdlig Cells men I'TUT limo 17.Keto Grinduter terde toplins Trutnienti (VA/24Vouse Hours) Lmt4/24 Hour) Gynomastia Volume Votility Number Potency Dtrone (13 tradiol 132 1ne nit Vem Hrare frt the hum Yumik Srir Ince tru . (5 11 0 Normatorin Termit Sorinal 21 tutule *4 <10 Suunat Ilment Before tre tittent 4.5 แม่แle genesis/ ESTROGENS Implantation frx) mg stillxristrul 136 12 ( 101x106 Atment - th oth dy oth duy 32nd day 15 bent lent Itsent Gracle II Grindle III Grade IT! Grade 111 ma) cells unls l'itle tuune granular cytoplein goth day 12 16 Uncut Grade 111 - 123 ·122 TABLE XXIV Time after Treatincnt 17-Ketosteroids (Mg124 Hours) Unnary Gonadotrophins (House L'nits/24 Hlours) I anary Estrogens (ug 24 hours) Testicular Biopsy Tubules Ley dıg Cells C:strone (Istradiol (Estriot Basement Membrane Epithehum Potency Gynæcomastia Number 'ppearance 1efute treatment 13 ) 120 0216 17 17 Norm.il 12 Normal spermatogenesis 17 51 tubule Normal Normal Absent Implantation 300 mg stilbestrol 10 O 3rd dus ithi 4.4 Yth das 401h day 4th das Noth dan 4th day 1? 12- 16 10 8 136 35 Declined Absent Absent Ibsent Alisent 10sent Ausent ?? Grade II Grade III Grade III Grade III Grade III Grade III Grade III GYNÆCOMASTIA 31 29 9th day 1 21st day Implantation 300 mg stilbestro! 19 O 32 094 Normal 127th day 177th clay 7 01 124 Jrrest at spermatid stage bent Absent 1964 tubule Grade III Grade III l'alc granular cytoplasma Ragged cytoplasm Some Sertal, thickening cells only Grossly reduced Absent Ibsent Grade III Grade III ·JYDROGEXS 125 All 1 remains within normal linits. action of estrogens upon the antrogens affect the testis b annot be excluded, because are semiquantitative at bet, that the 17-ketosteroids output (including the B-fraction) remains normal is evidence against gross disturbance in adrenocortical function following cestrogen therapy Presumably, gynecomastia following the administration of cestrogens is due to direct action upon the breast. ANDROGEYS Sescral reports of gynecomastia in men receiving methyl testosterone have appeared in the literature,10,11 It Guy's Hospital 101 patients who had received androgen therapy were examined and questioned concerning changes in the breasts during or after treatment The patients fell into five groups. (1) Seven patients who recen ed testosterone under the age of 20 years for delay in the obset of puberty (2) Thirteen patients who reccived testosterone after the age of 20 years for some defect in the development of secondary sexual characteristics, eg, unbroken voice. small genitals, poorly developed beard, delay in the onset of puberty (3) Xine adult castrates receiving testosterone as substitution therapy. (4) Twenty-five adults recening androgens for eunuchoidism and infantile genitalna (5) Forty-seven patients suffering from psychogenic impotence with no evidence of abnormal endocrine function Among these patients, three had suffered from synecomastia w kile receiving androgens The preparations used included tablets of methyl testosterone, intramuscular injections of testosterone propionate and implants of testosteronc enlar four tube table The implant provided effective substitution therapy but did not cause gynæcomastia. The second patient was aged 32 years and had suffered psychogenic impotence for five years Physical elamination, test ular biopsy and estimations of urinary 17-hetosteroid excretion and urinary gonadotrophin level all gave normal findings. The patient was given weekly injections of testosterone propionate (25 mg) for 32 weeks At the end of this time he complained of painful breasts, and examination revealed a tender" button" of breast tissue behind the areolae The injections were replaced by tablets of methyl testosterone (25 mg daily), and within three days the breasts returned to normal The third patient, aged 29 years, was also an example of psychogenic impotence of six years' duration He had been given intramuscular injections of testosterone propionate weekly for 24 weeks and was then given methyl testosterone tablets (25 m (75 13 and table tion of ai after injections of testosterone propionate Gynæcomastia is not usually an immediate effect of androgens, but generally follows some months of intensive therapy.

·124 GyxECOMASTIA 'alation of estrogens from the urine of when the horses were kept in stables by Sometimes the source of estrogen is not obvious, and careful enquiry is needed in cases of unexplained gynecomastia. Children, for example, may take tablets in mistake for sweets. A boy of four years was seen with gynæcomastia which resulted omastia trol, for within two weeks of stopping this treatment TABLE XXVI Gynecomastia following Estrogen Therapy Case Number Age at Time of Treat. ment (Years) Estrogen and Total Dose g.) Number of Implants Extent of Gynaco- Duration of mastia Transitory during Gynaco Treat mastia ment (Grade) Duration and Severity of l'ermanent Gynæcomastra Case LIX 16 Stubestrol 200 1 II >9 years <grade 7 I AB MB Case LX EC с 1 1 I I I 17 16 16 17 16 16 21 17 IS Stilbestro! 200 Stilbæstrol 200 Stilbaestrol 200 Stilbocstrol 200 Seilbestrol 200 Stilboestrol 700 Stilbaestrol 600 Stilbæstrol 200 Estradiol 400 6 months 4 months 2 years 3 months 2 months 9 months 10 months 8 months JD Case LXI CE Case LXII IT JI >I2 years <grade 1 I Case LXIII DI JL WL Case LXIV 18 16 16 15 21 Stilbestrol 500 Serbestrol 700 Stilberstrol 400 Stilbestrol 300 Stilbestrol 300 Stilbæstrol 400 Stilbastrol 600 8 months 3 months 4 months 6 months II II > 6 years <grade I II GR SV 6 months 6 months 18 the d in intastredk or pronellalioji UJI UL avuustinal that seen during pregnancy Although tion of 11 wall bel : these si the possibility to cestrogens - Intense pigmentation of the nipples, hull DC UNI ugmentation is permanent, although it may fade to stopped The action of estrogens upon the testis therefore involves quantitative and qualitative changes in the Leydig cells, together with arrest of spermatogenesis at af spermatids and deposition of cholesterol in Leydig and Sertoli cells. --- A notion ·AXDROGENS 125 reniains within normal limits, These findings are compatible with the vicw that the action of estrogens upon the testis is a direct one The possibility that exogenous estrogens affect the testis by depressing cannot be excludeci, because present meth 1. UPP VIL VILL, ANDROGENS Several reports of gynecomastia in men receiving methyl testosterone have appeared in the literature.:0,11 At Guy's Hospital for patients who had received androgen therapy were examined and questioned concerning changes in the breasts during or after treatment. The patients fell into five groups. (1) Seven patients who received testosterone under the age of 20 years for delay in the obset of puberty. (2) Thirteen patients who received testosterone after the age of 20 years for some defect in the development of secondary scxual characteristics, eg, unbroken voice, small genitals, poorly developed beard, delay in the onset of puberty (3) Nine adult castrates receiving testosterone as substitution therapy. (4) Twenty-five adults receiving androgens for eunuchosdism and infantile genitalia (5) Forty-seven patients suffering from psychogenic impotence with no evidence of abnormal endocrine function. Among these patients, three had suffered from gynæcomastia while receiving androgens The preparations used included tablets of methyl testosterone, intramuscular injections of testosterone propionate and implants of testosterone Of the three patients showing gynæcomastia, one, aged 49 years, showed breast enlargement (grade I) after taking tablets of methyl testosterone over a period of four years (25 mg. daily) as substitution therapy following surgical castration for tuberculous orchitus The gynæcomastia subsided within three days of stopping the tablets, and testosterone was given by implantation (600 mg. every six months). The implant provided effective substitution therapy but did not cause gynæcomastia. The second patient was aged 32 for five years Physical examination 17-ketosteroid excretion and unnary The patient was given weekly injections of testosterone propionate (25 mg) for 32 Weeks At the end of this time he complained of painful breasts, and examination revealed a tender "button" of breast tissue behind the areola The injections were replaced by tablets of methyl testosterone (25 mg daily), and within three days the breasts returned to normal The throntent of six y propion - 1 tion of From these studies it will be seen that gynæcomastia is not a common complication of androgen therapy It can occur with methyl testosterone taken by mouth or after injections of testosterone propionate Gynæcomastia is not usually an immediate effect of androgens, but generally follows some months of intensive therapy, ·126 GYNECOMASTIA ful ---- no tama nusa tha mindromastia to subside, ng gynæcoen These developed, play some considering the rarity with which androgens produce gynæcomastia, the delay in its appearance and the large doses required, this view seems unlikely. Furthermore, the action of androgens upon the breast of the monkey produces changes which are unlike the picture of duct hyperplasia seen in cases of gynecomastia (see page 241 Recent studies have shown that the body is capable of converting certain androgens to oestrogenic substances. 39, 40, 4? This discovery suggests an explanation for the occasional occurrence of gynæcomastia after the prolonged administration of large doses of androgen, Possibly in certain individuals the capacity to convert androgers to østrogens may be enhanced during prolonged administration of androgens, with the result that sufficient estrogens are produced to cause stimulation of the breast. The three patients mentioned above were not submitted to operation on the breasts, but Dr. HF Klinefelter has reported that the breast in gynæcomastia following androgen therapy in one of his patients showed the typical microscopic appcarance seen in other forms of gynecomastia (sec page 24) may result CHORIONIC GONADOTROPHIN Chorionic gonadotrophın can produce a button " of breast tissu: behind the areola (sec page 33), and in some instances, more severe degrees of gynæcomastia Two patients at Guy's Hospital showed gynæcomastia of grade II severity following a course of chorionic gonadotrophın One was submitted to testicular biopsy, which showed (1) Some fibrous thickening of the basement membrane (11) Normal spermatogenesis and prominent Sertoli cells (iu) Clumps of prominent eosinophilic Leydig cells The appearance of this biopsy suggested Leydig cell stimulation Jaddock and Nelson13 believe this form of gynæcomastia to be the result of Leydig cell stimulation, with consequent secretion of astrogens (sec page 25) Experiments in mice make it seem unlikely that chorionic gonadotrophin acts directly upon the breast (page 701, although possible contamination of this hormone by minute quantities of oestrogen should be considered, also, the action of the hormone upon the breast in man may differ from that seen in animals Until further evidence is at hand, gynæcomastia following injections of chorionic gonadotrophin is best explained as an indirect result of Leydig stimulation which causes the secretion of oestrogens in greater concentratiors than normal ADRENOCORTICAL HORMONES 1.0.1 annis second day, and at the end os oite molila ... hat hentinner for four months the stellings became pronounced *rvals 3, but itient usual dan of the extraordinary pitpunu M..

·DIGITALIS 127 Raleigh and Philipson's have reported a case of Addison's disease complicated by painful swelling of the right breast Tlus complication appeared after two years' treatment with DOCA and salt. The breast at autopsy showed the usual changes of gynecomastia. Lawrence reported the case of a man, aged 32 years, who had been treated for diabetes mellitus by means of insulin for 20 years At this time he developed Addison's disease, vluch, was complicated by a typical crisis after one year. This given conflicting results, 22, 23, 24 but it seems likely that this hormone acts synergistically with the stimulating effect of estrogens upon duct growth (see page 26) So far, no case of gynæcomastia has been reported in untreated subjects of Addison's disease or in patients treated with cortisone Neither have DOCA and eschatin been found to cause gynæcomastia in patients subsequently shown not to be suffering from Addison's disease The reported cases of gynecomastia following treatment with eschatin and DOCA occurred under such circumstances as to suggest that these drugs themselves were directly or indirectly responsible for the stimulation of the breasts and not the disease itself It seems likely that either these drugs cause gynæcomastia by direct stimulation of the breast or that some substance forned during their metabolism is responsible for this change Why so few patients have shown such a response cannot be explained DIGITALIS Le Winnas, 26 has reported 14 cases of gynæcomastia appearing during the administration of digitalis Among the first eight, five showed complete remission when the administration of digitalis was discontinued, and recurrence when the drug was resumed In every case the gynæcomastia gradually lessened after several months, even though treatment with digitalis uas continued. The ages of the affected patients ranged from 53 to 77 years, and the cause of cardiac failure was : cor pulmonale ily) was used in as seen between 'egree of breast were examined in two cases and showed the typical appearance of gynæcomastia In four of seven patients the bromsulphalein test indicated some degree of impaired liver function, and in sıx of seven the cholesterol-ester levels were low Thorn Hash. 11 1 I 1 1101ai It wall be recalled that Morrone27 showed that gynæcomastia was seen when ·128 GYNÆCOMASTIA liver disease was severe, and was inconstant in cardiac cirrhosis. In the 14 cases described by Le Winn, cardiac failure was of recent onset and showed a good response to digitalis. The present author has encountered two examples of intense breast stimulation in post-menopausal women soon after the patients were given digoxin (0.75 mg daily). The tenderness and swelling of the breasts subsided when the drug was discontinued, and reappeared when it was resumed Digitoxin did not cause breast stimulation in these patients. Calov and Whyte28 reported a case of cedema and painful breasts as toxic effects of digitalis leaf. A woman of 49 years took tincture of digitalis and digitalis leaf for more than two years without ill effect. After a lapse of two years she again took digitalis leaf, but complained of swelling of the feet and hands, which disappeared when the drug was withdrawn. Seven years later she began taking the leaf (0-1 gramme three times a day), and after three days swelling of the legs. groins, buttocks, labia, abdominal wall, arms and breasts occurred "The breasts were swollen, tense, tender with prominent vessels and enlarged, hard, lumpy glandular tissue. The symptoms disappeared two days after the drug was discontinued. The same effects were seen within 24 hours of resuming treatment and were so distressing that the patient stopped the tablets. Digoxin did not produce such symptoms. 1) result iron une uirect delion of strogens upon the cells theinselves (see page 24) The excretion of digitalis from the body has been studied by Okita and his associates,29_who used punfied isotopically labelled digitoxin administered intravenously They shoned that between 60% and 80% of the drug is eliminated either unchanged or as chloroform-soluble metabolites They believe that elimination by the liver and alimentary tract plays only a small part in total excretion. It is possible that the chloroform-soluble metabolites are largely aglycones and their derivatives, which may well have undergone modification in the liver before being excreted in the urine The chemical similarity between the cardiac glucosides and certain steroid hormones has been considered as important in the effect of these substances upon the breast Both substances contain the cyclopentanoperhydrophenanthrene nucleus : M The distinctive feature of the aglycone molecules of the cardiac glucosides lies in the unsaturated lactone attached to C7, eg HC OH HO It is tempting to suggest that dunng the metabolism of this substance changes occur in its structure which produce some steroid hormone capable of stimulating breast tissue ·DIGITALIS 129 In rabbits, large and continued doses of powdered leaf or digoxin did not produce any histological change in the testis !! One of Lc \linn's cases came to autopsy, and the testis (Figure 21) showed the following changes. Tubules: Basement membranes are normal but spermatogenesis 33 defectise in most tubules and may contain Sertoli cells only, Interstitial tisuc: Leydig cells are very prominent and in places form clumps or large group These changes resemble those seen in other forms of gynacomastia, but whether this is due to digitalis or to the effects of cardiac failure or to some other cause cannot at present be stated TIGI RE 21 The tests from a patient who died of congestive cardiac failure The patient des eloped Sincomastia doring treatment with digitalis The basement membranes are normal, spermato genesis is defective, and Ley diz cells appear in large clumps. . The fact that a careful search has failed to reveal similar experiences with digitalis the preparation of se of amphetamine & different prepara- Le Winn has since discovered other examples of this curious association among patients treated by other physicians. One can only conclude that sporadıc examples of garcomastia in digitalis therapy have previously passed unnoticed or at least unrecorded, and that minor degrees of breast development could be detected by a more spec .... and may not incon It is worth noticing that gynæcomastia appears when the patient's general health has improved in a way which recalls gynecomastia during refeeding after malnutrition. "This observation must be taken into account when any explanation of this phenomenon is to be considered ·130 GYNÆCOSIASTIA AMPHETAMINE Tooley and Lack31 recorded cases of gynæcomastia occurring in adolescent and adult males receiving amphetamine sulphate for a variety of neurological and psychiatric disorders One girl of nine years developed uterine blecding during treatment with the same substance. The authors drew attention to a statement by Karnaky,32 who clauned that amphetamine might cause uterine bleeding in susceptible patients. 1 E E July, 1948, and further administration of a new batch of amphetamine to patients hyper plastic West2eu endometrium These observations suggested the action of some cestrogenic substance which could be traced to a particular batch of amphetamine. It was subsequently shown that these side effects were due to an oestrogenic impurity which was produced during the synthesis of amphetamine During the synthesis of amphetamine, a substance arouse interest RADIOACTIVE IODINE A series of 21 males were given camer-free radioactive iodine (1132) in doses of between 2 and 2 5 mc by Bauer and Goodwin 34 The patients were all suffering from moderately severe thyrotoxicosis, and their ages ranged from 26 to 40 years Six of these patients developed acne and gynæcomastia. The authors suggested that these complications might have resulted from overactivity of the pituitary as the result of the fall in circulating levels of thyroxine which followed [131 treatment It was proposed that the adrenal cortex was stimulated as the result of this change in pituitary function However, no other evidence of adrenal stimulation was scen and although a fall in circulating thyroxine promotes an sncrease in the output of TSH, this causes a fall in ACTH, not a rise 42 The acne could not have resulted from the action of iodide, because a carrier-free preparation was used in which the total amount of iodide would not exceed a fraction of a microgramme Trunnell and his colleagues 35 studied the distribution of 1131 at autopsy in the bodies of patients who died after treatment with this substance After the thyroid gland, the pituitary and then the tests were the tissues which absorbed the greatest radioactivity per unit weight The testes shouted defective spermatogenesis, which led to the presence of only Sertoli cells within the tubules The breasts shoued little evidence of [131 uptake Gorbmans showed that similar findings applied to rats given [131 in comparable doses The pituitary gland showed changes simular to those seen after thyroidectomy,ze increase in the size of the gland and increase in the number of chromophobe These findings were confirmed (also in rats) by Goldberg and Chaikoff 37 The occurrence of gynecomastia with acne recalls the presence of these two cells halos . [131 is associated with sudden stimulation of the li slis, * & ac UNI IU HLUTI. UV- ·GYX 1 COM ISTI DUE TO DRUGS 131 and consequences similar to thoxe encountered at puberty or during the process of refeciling after malnutrition. On the other land, the evidence from animal experiments suggests that 1131 virumnus onernte in the cama u in ne nthor canristians er hanh source of speculation. RESERPINE The drugs chlorpromazine and reserpine have recently been reported to cause breast stimulation in male and female patients in one patient gynecomastia was observed during reserpine therapy. the breasts returned to normal when the drug was stopped. Although these drugs influence the activity of the hypothalamus, no explanation can be offered for the occurrence of syna comastia under these circumstances. REFERENCES LX\CH, KY (1952). Kat's Testis following Estrogen Therapy", A» Yew York Icad Sc. 55 734 * DUNX.CN (1935).' to Years Dura • Dury. CW (1940). LYNCH, K., and Sc Rat Testis as Endocrinology, 49 GREEP, RO, and Jones, IC (1950). Recent Sdsances in Hormone Research ".s 197 • FIRMINGER, HI (1952), quoted by Lynch, loc cul PFEIFFER, C A, and HOOKER, CW (1943), " Testicular Changes Resembling Early Stages in the Des elopment of Interstitial Cell Tumors in Mice of a Strain after Long Continued Injections of i'regnant Mare Serum ', Cancer Res. 3 762 Nelson, WO (1954), Personal communication • \ ITZSINOY. V P (1911), “Gynecomastu in Stilboestrol Workers", Brit Indust ved, 235 10 IcCULLACH, I, P. and Ross MILLER, II R (1941). Methyl Testosterone Androgenic Effects and I'roduction of Gynecomastia and Oligospermia". J Clin Lindocrinol, 1 496 11 Pratt. ) R (191%). " Personal Note on Meth;] estosterone in Hypogonadism Chn Endocrinni, 2 460 11 VAN Wagenen, G. and ToiLEY, $ I (1939). Effect of Androgens on Mammary Gland of the female Rhesus Jonkey") Endocrinol. 1 367 13 MADDOCK, W O, and NELSON, WO (1952). Effects of Chorionic Gonadotropin in Adult Men Increased Estrogen and 17-ketosteroid Excretion Gynecomastia, Leydıg Cell Stimulation and Seminiferous Tubule Damage! Clin Endocrinol. 12 985 11 EDWARDS RA, SIN, MB. and SHAVER, J S (1939). Hypertrophy of the Breast Due to Injections of Idrenal Cortex Lxtract in a Man with Addisons Disease", J41A 14 RALEIGH, GW, and PHILIPSBORN, II F (1944), Addison's Disease with Partial Absence of Adrenal Cortex and Gynecomastia Arch Path, 37 213. 11 LAWRENCE, R D (1943), Gynecomastia Produced by Desoxy corticosterone Icetate (Doca)'. Byst 1.1 12 11 VAN HEUVERSI'ry, Y J, FOLLEY, S J. and GARDVER, HU (1939).' Mammary Growth in Male Mice Recensing Androgens, Estrogens and Desoxycorticosterone Acetate". Proc Soc Exper Bru o vred, *1 389 ·132 GYNACOMASTIA 1ST TANDEN ST ARDA DOI. Nr- f Steroid Hormones to Induce Maimary ology, 30 : 32 "Effects of Adrenal Cortical Compounds 17 20 orticosterone in Rhesus Monkey", Bull 31 Flux,DS (1954), "Effect of Adrenal Steroids on Growth of Jammury Glands, Uteri, Thymus and Adrenal Glands of intact, Oraniectortured and strone-Treated Ovariectomized Mice Endocrinol, 11. 238 ** SELYE, H (1954), "Effect of Cortisol upon llammary Glands, Acta Endocrinol, 17. 391 ** SELYE, H (1954). "Stress and Lactation", Rev Canad Biol. 13. 377. "JOHNSON, R. M. and MEITES, J (1955). "Effects of Cortisone, Hydrocortisone and ACTII OD Mammary Growth and Patuitary Prolactin Content of Rats". Proc Soc Expo Brol & Wed, 89 455 25 LE W'INN, E B (1950) "Gynecomastia During Digitalis Therapy". Clin Proc Jewish Hosp. 123 28 LE WINN, E B (1953), “Gynecomastia during Digitalis Therapy Report of 8 Additional Cases with Liver I'unction Studies", New England J. Wed, 2.48 316 *7 MORRIOVE, T G (1944). "Effect of Estrogens on Testis in Hepatic insuficiency". Arch. Path, 37 39 18 CALOV, WL, and WHYTE, HM (1954). Edema and Jammary Hypertrophy A Toxic Effect of Digitalis Leaf", un Australia, 1 556. ** OKITA, G T, KELSEY, F E, TALSO, P ). SMITH, L B, and Geiling, E M (1952), " Renal Excretion of Radioactive Digitorin in Human Subjects with Cardiac Failure"Fed Proc. II 380 30 LE WINN, E. B (1954), Personal communication ** TOOLEY, P H, and LACK, C (1949). "Gynecomastia During Treatment with.mphetamine", Lancet, I 650 ** KARNAKY (1941), in discussion of Powers, EG, "Ephedrine Sulphate Intranasally as Cause of Uterine Bleeding", Tex St J 11ed, 37 309 * MASOX, A S, and MORRIS, P. (1919), "Gynecomastia with Amphetamine Therapy". Lancet. 839 *4 BAUER, FK, and GOODWIN, WE (1951). "Acne and Gynecomastia Following list Therapy for Hyperthyroidisin". I. Clin Endocrinol, I. 1574 * TRUNNELL, ) B. DUFFY, BI. GOODWIN, JT, PEACOCK, 'W', KIRSHINER, L, and HILL, R (1950) * Distribution of Radioactre l'odine in fluman Tissues Necropey Study in a Patients". J Clin Endocrinol, 10 J007 16 GOREMAN, A (1950). " Functional and Structural Changes Consequent to High Dosages of Radioactive lodine". J Clin Endocrinol, 10. 1177 a7 GOLDBERG, R C, and CHAIKOFF, I L (1950). "Cytological changes that occur in Anterior Pituitary Glands of Rats Injected with various Doses of 1151 and Their Sigoificance in Estimation of Thyrord Fanction ", Endocrinology, 46 91 ** DUNN, C W (1941), "Stilbestrol. Induced Testicular Degeneration in Hyper-scxual liales", J Clin Endocrinol, I 6.43 19 BAGCETT, B, EXGEL, L L , SAVARD, K, und DORFMAN, R 1 (1955), " Formation of Estradiol 178-C1 from Testosterone-3.Ch by Surviving Human Ovarian Slices", Fed Proc, 14. 175 40 VEST, CD, DAHAST, BL, SARRO, SD, and PEARSON, O 11 (1995). "Conversion of Testosterone to Estrogens in Castrated, idrenalectomized Human Females".) Biol Chem, 218 409 11 SLAUA WHITE, WR, and SAMI ELS, L T (1956). "Progesterone as a Precursor of Testicular Apdrogens". J Biol Chem, 220 341 +1 HARRIS, G W (1955). " Neural Control of the Pituitary Gland", p 145. Arnold, London « BISHOP, PM F (1954), Personal communication ++ HALL, P F (1955). "Gynacomastia ", Thesis for MD (Sydney) 4 ROBINSON, B (1957), "Breast Changes in the Male and Female with Chlorpromazine or Reserpine Therapy", MJ dustralia, 2 239 I ·CHAPTER XIII GYNÆCOMASTIA ASSOCIATED WITH DISEASES OF THE CENTRAL NERVOUS SYSTEM Certain diseases of the central nervous system may be associated with gynecomastia, namely (1) Diseases of the spinal cord (a) Traumatic paraplegia, (b) Syringomyelia (c) Friedreich's atavia. (2) Dystrophia myotonica. Extensive lesions of the spinal cord appcar capable of interlering with testicular function, although the mechanism of this interference is uncertain. On the other hand, the disease dystrophia myotonica is associated with a number of changes which are loosely descnbed as "endocrine"; these changes include testicular atrophy, Synecomastia, baldness and obesity. DISEASES OF THE SPINAL CORD TRALII VTIC PARAPLEGIA In a ward of paraplegic patients Cooper discovered that 22% were suffering from gynecomastia of these, two shoued raised urinary gonadotrophins, low 17-ketosteroid cxcretion and azoospermia. The patients were all young men who had previous1 The same worker later studied whom four showed Synecomastia ients with gynecomastia showed low urinary cestrogen levels in the more severe cases the patients showed low serum protein values and reversed albumin/glotulin ratio, together with a low basal metalolic rate The extent of these metabolic disturbances was roughly proportional to the severity of the spinal injury, but no correlation was found between the occurrence of gynecomastia and the severity of the mctabolic disturbance Cooper and Hoen? later reported a further seven examples of gyn.ecomastia associated with paraplegia Stemmermann, both by biopsy and at autopsy, studied the testicular histology of patients suffering from paraplegia The germinal epithelium showed defects of varying severity, including Sertoli cells only in some tubules The basement occurrence of synecomastia The number of patients was too small to indicate whether or not such obstruction was a factor, because it was apparent in some cases and not in others Stemmermann referred to the work of Kuntz, who cut the cmnthetia anuant...that.....f. 111 12 TN 11 Alendi. Allah-t .. b 0 OLL lyug lens (see Page 62) Cooper and his colleagues19 subsequently studied the metabolic changes of paraplegia in greater detail They shoot that tant a period of catabolism which is cha nitrogen above the level found in 1 ·134 GYNÆCOVASTIA associated with a fall in serum protein level and a decreased albumin/globulin ratio. ndeed, such patients may" starve "to to be proportional to the severity of bolism, 17-ketosteroid excretion falls (in severe cases to less than 2 mg. in 24 hours), and both gonadotrophins and cestrogens are often absent from the urine Liver function tests showed abnormal bromsulphalein retention in three of four patients seen within eight weeks of injury: patients seen later than eight seeks after injury did not show abnormal bromsulphalein retention. This retention of bromsulphalein was not associated with blood loss, fever, transfusion reactions, etc., and was considered by the authors to indicate some impairment of liver function Of 16 patients with traumatic paraplegia, four showed gynæcomastia and one complained of having suffered this symptom All four shoued testicular atrophy. and two others showed testicular atrophy without gynæcomastia Other observers, 1 have recorded gynæcomastia in patients with traumatic paraplegia. These observations suggest that gynæcomastia in traumatic paraplegia could be the result of two changes seen after spinal injury. In the first place, a severe disturbance in nutrition may play some part in the endocrine changes described, although no correlation has been found between and the severity of the nutritional changes The apparently not related to renutrition and a return malnutrition among prisoners of war This point is not in favour of a nutritional cause, because gynecomastia usually occurs during refceding rather than during the period of starvation (see page 113) In the second place, traumatic paraplegia can produce changes in the testis which resemble those of Klinefelter's syndrome and other conditions which cause gynæcomastia It seems likely that paraplegia causes 1.-L. FRIEDREICHI'S ATAXLI AND SYRINGOMYELIA Friec a rac of cystic degeneration of the spinal cord Disturbances of metabolism similar to those described in traumatic paraplegia were seen, and the microscopic appearance of the testis was the same No doubt the same mechanism produces gynecomastia in all three conditions DYSTROPHIA MYOTONICA Since 1947 a number of re Ron 's cells, and the testis showed changes Irome-utensive hyalınization of the U dise: befo ·DYSTROPHIA MYOTONICA 135 Howard and co-workersll describe one patient suffering from dystrophia myotonica and hypogonadism. He was in an extremely poor state of nutrition and showed neither clumping of -onadotrophin levels were low. In ated by Dr. H. F. Klinefelter.14 omastia with TABLE XXVII Endocrine Studies in Dystrophia Vyolonica Author and Reference Age (Years). Examination of Testes Testicular Biopsy Leydig Tubules Celts 17-keto steroids Unnary Gonadotrophins Gynacomastia 23-61 Low Yormal in b«cnt Atrophy in 6 the 4 Jacobson et al.. (9 patients) Sniffent Xadler 40 56 Atrophy Normal frequent Atrophy Clumping Hyalın Clamping ization Hyalın. Normal ization Xormat Low tested High High I'Tevent Present Atrophy Atrophy Atrophy alı, Yadler e 45 Low Yormal Present ain16 58 > Low ormal .\xent S5 Low 31 Low Yormal Ticrler and Lilienthal Martin and l'atteet Benda and Birby Dends and Bixby Caughey and Brown's Caughey and Brown De Court et alıs't (5 patients) Clark at alı.17 trophy - Atrophy Hyalınıza. Clumping tion Atrophy Hyalınıza. Clumping tion Strophy Atrophy Degeneration Atrophy Atrophy Degeneration Atrophy ins Normal Abent High absent High Abrent High Ibsent High Absent 45 Low 29 Low Low Ibsent - 26 Absent Clark di aiu," S3 Ibsent ! Atrophy Atrophy Atrophy Atrophy Atrophy Atrophy Clumping Atrophy Clumping Atrophy Clumpiog Sclerosis Yormat Low High Yormal (ICSH) Low High Normal (ICSH Normal High I 'resent - - 63 Low Lon Klinefelter et alatt Howard af ala:11 Hutchinson and longson16 Hutchinson and Long- Absent 19 - Xormal Low Ibsent - - 21 Atrophy Lon Low Absent soni* 35 Atrophy Low Low Arxent Hutchinson and Longsont. Hutchinson and Longsoni. 45 Atrophy Low High Absent persistently raised urinary gonadotrophin levels Testicular biopsy showed the changes described in other cases, and the patient has never shown any clinical evidence of lack of androgens, testosterone in no way affected either the gynæcomastia or the dystrophia myotonica Other studies of endocrine changes in dystrophia myotonica include those of Jacobson and his colleagues, who claim that 17-ketosteroid excretion is low in males, IL ·136 GYNECONASTIA Hutchinson and Longson's studied four men with dystrophia myotonica. All showed low 17-ketosteroid excretion and low urinary cestrogen levels (estimated by a chemical method). All had small 1 * three had low FSH values These workers believe precede Leydig cell failure. One patient showed nc low vestrogen levels, and after stimulation with large doses of chorionic gonadotrophin (3000 1 4 daily by intramuscular injection for seven days) both 17-ketosteroid and cestrogen excretion showed a significant nise The testes in these patients were of normal size but soft consistency. Clarke and his colleagues 7 studied tuo patients who suffered from dystrophia myotonica. The average testicular volume as I OXI-OXI-30 cm. The basement membrane did not show hyalınızation, but Leydig cells were clumped and possibly increased in number, while urinary androgens and 17-ketosteroids were low. authors attempted to measure FSH and ICSH separately--the latter by changes in the ventral prostate of the hypophysectomized rat The unnary: Jevels of FSH were normal, but excretion of ICS# was raised It is perhaps too early to place reliance upon the assay of ICSH excretion, but suggest that high urinary gonadorather than FSH or a mixture of sort to the idea that the Leydig The 1 presented the features of Klinetelter's syndrome, but gynecomastia was absent. The chief interest in these findings lies in the occurrence of a syndrome like that of Klinefelter, which appears in adult men in association with a disease of the central nervous system It is likely that the mechanism of gynæcomastia in dystrophia myotonica ist of high urina mechanism to the age of less frequently wuth advancing age Grumbach and his colleagues 25 have reported a case of dystrophica myotonica with Klinefelter's syndrome and female chroniosomal sex, while seven cases of the same disease reported by Siebenmanna showed hypogonadism and male chromosomal sex REFERENCES 1 COOPER, I S (1919). "Metabolic Consequences of Spinal Cordectom: Proc Stall Weet Vayo Clin. 27 oza * COOPER. I S. and HOEN, T I (1949) Grnecomastia ja Paraplegic Males Report of 7 Cases J Clin Endocrinol. 9 +57 *STEMMERMANN, GN, WES, L. LERBACH 0, and FRIEDMAN, 1 11950). I Stody of the Cerminal Epithelium in Vale Paraplegies im Chon Path, 20 * KUN72, A (1921), " Degenerative changes in the Seminal Epithelium and Associated Hyper 1.se in the Vammalian Testes , Ludocrinology, 5 and SCCARIY CS (1930), 'Relattan ol I Testicular Atrophy : Pror Staff Veel Vuyo iga ·DISEASES OF THE SERIOUS SYSTEV 137 . Bors, E, quoted by Coojer, * MOEBLIG, K G quoted by Cooper!,' COOPER, 1 S. MCCARTY, CS, and RY EARSON, EJ (1950), "Gynecomastia in Paraplegic Males", Neurosurg, 7. 364 Be DC and BIYB), Ed (1947), " l'rinary Cxcretion of 17-Ketusteroids in l'anous Conditions of Oligophrenia Correlated with Some Autopsy Observations". J Clin. Endocrinol, 7: 503 1* VADLER, C S. STEIGER, H. TRONCELLETI, V, and DLRANT, J V (1930). "Dystrophia Myotonica, with Special Reference to Endocrine Function (Klinefelter s Syndrome)". J Clin Endocrinol, 10: 630 11 HOWARD, R P. SHIFFEY, R C. Sruos II and ILE RIGHT, F (1950), " Testicular Deficiency Clinical and Pathologic Study". J Clin Endocrinol. 10 121 11 KLINEPELTER, Hr, in floward it alle * ALBRIGHT, r (1954). Personal communication " JACOBSON, WESCHULTZ. A L, and YDERSOX, ) (1955), "ndocrine Studies in 8 Patients with Dystropha Vyotonica". J Clin Endocrinol , 15 Sor "CAUGHEY, J E and Brou v, J (1950). "Dýstrophta Vyotonica. Endocrine Study". Quart Wed, 19. 303 "Fetchiusov, r c. and Lossos, D (1936). "Testicular railure in Dystrophia Nyotonica", Acha Endocrinol, 22: 264 17 CLARK, 13 G, SHAPIRO, S. and MONROE, RG (1056), "Jyotonia {trophica with Testicular Atrophy L'rinary Cecretion of Interstitial-Cell-Stimulating (Luteinizing) Hormone, Androgens and 17-ketosteroids". J Clin Endocrinol, 16 1235 I SNIFFEN, R C (1952). Histology of the Normal and Abnormal Testis at Puberty". iam New York Acad Sc. 55 609 1 Cooper, I S, RYNE4R50. EH MCCART), CS, and I'OWER, VIH (1950). "Metabolic Consequences of Spinal Cord Injury . J Clin Endocrinol. 10 858 * ADIE, W 11 KBYE, ) 11 TIELER, steror + MARTIN, J . Canad 72 24 De Couri, J. LERE BOULLET, ) , HEYRY, R. and TINEL, G (1951). Sur les Alterations Testiculaires de la Vyopathie Vyotonique (Maladie de Steineri) ſa Propos de Cing Observa- Irens)". 4nx Endocrinol. 12 10:46 15 GRUMBACH, BLANC, and ENGLE (1957), "Sex Chromatin Patterns in Testicular Disorders". J Clin Endocrin, 11 703 "SIEBENVANN, RE (1958), “Symposium on Nuclear Sex", page 121, William Heinemann WAT.70 ·CHAPTER XIV GYNÆCOMASTIA ASSOCIATED WITH DISEASES OF THE LUNG Gynæcomastia has been reported in certain diseases of the lung, namely: (1) Bronchogenic carcinoma (2) Pulmonary tuberculosis., 8 (3) Bronchiectasis.? (4) Empyema ? In the case of bronchogenic carcinoma the occurrence of gynæcomastia is such as to indicate an ætiological association between the two conditions. Pulmonary tuberculosis has less claim upon a specific association with gynæcomastia, and it remains to be estabhshed that the coexistence of these two conditions is more than coincidental In spite of isolated reports of gynæcomastia in cases of bronchiectasis and empyema, it is likely that these two diseases do not cause breast stimulation, the appearance of which is either fortuitous or at most is precipitated by an acute illness in one already predisposed to gynæcomastia from some other cause. BRONCHOGENIC CARCINOMA In 1941 del Castillol and his colleagues reported three cases of bronchogenic carcinoma complicated by gynæcomastia and hypertrophic osteoarthropathy, and in 19442 they reported a fourth patient showing the same clinical syndrome A man of 63 years noticed pain and swelling of his right knee, and later other occurred, and one year Loss of libido, impotence acutely tender and the 11. 141- L-AX4 . lost 30 pounds in weight androgen levels normal T and finally developed all the signs and symptoms of bronchogenic carcinoma Baytıssreported the case of a man, aged 56 years, who presented with acute arthritis associated with subperiosteal thickening of the bones of the limbs Sıx months later he developed gynecomastia and cough A bronchogenic carcinoma was removed from the lower lobe of the night lung lithin 24 hours of operation the osteoarthropathy had become quite painless, and within 48 hours the gynecomastia Liver function tests were The patient was alive and tion to this patient, Bayliss cinoma with gynecomastia and osteoarthropathy and four with gynecomastia alone Sample and JcCluskres reported two cases of bronchogenic carcinoma, pulmonary osteoarthropathy and gynecomastia and stated they had seen "several cases " of bronchogenic carcinoma and gynæcomastia Fried has suggested an endocrine basis for hypertrophic pulmonary osteoarthropathy, which he likens to certain features of acromegaly In a man who died of bronchogenic carcinoma complicated by osteoarthropathy and gynæcomastia, Fned found an increase in the size of the pituitary gland and the thyroid, together with multiple adenomata of the adrenal glands Another patient with bronchogenic carcinoma and osteoarthropathy showed testicular atrophy without gynacomastia.

·DISEASES OF THE LUXG 139 -ALAL.A... Among these eight published cases all shoxed osteoarthropathy and gynrecomastia, and their ages ranged from 41 to 63 years. The neoplasms have varied from operable peripheral growths to malignant hilar carcinomata with metastases. T- of weight c function was seen without osteoarthropathy None of Fill endocrine studies, so that the mect bronchogenic carcinoma rernains obscu urinary ostrogens, but details of the method of assay are not given, and some difficulties are encountered in the estimation and interpretation of urinary estrogen levels, so that no great reliance can be placed upon this isolated observation. Furthermore, the source of pulmonary of growth he gynæcostimulation resulting from concomitant secretion of prolactin However, the reason for this overactivity of the pituitary gland remains unexplained, and this theory must be accepted with reservation The speed with which the two complications of arthropathy and gynæcomastia disappeared after operation in the patient reported by Bayliss directs attention to the tumour itself as a possible source of hormones or of some substance capable of stimulating breast tissue A further besıldering observation has recently been reported in this connexion, PULVONARY TUBERCULOSIS Osler10 is said to have taught that gynæcomastia sometimes appears early in the course of pulmonary tuberculosis, and since that time gynæcomastia has occasionally been reported in patients suffering from active pulmonary tuberculosis Wheeler et alı? recorded two cases, while Woodhams reported a case of pulmonary tuberculosis with testicular atrophy and gynæcomastia 'However, the occurrence of gynaecomastia in pulmonary tuberculosis is so jare that it would ordinarily pass as a coincidence One patient who showed such an association was seen at Guy's Hospital Hormone Assays Estimation of 17-ketosteroid excretion gave the following results 7.1, 8 5.5 2 and 9 omg per 24 hours Urinary gonadotrophin excretion was found to be >32< 72;

·140 GYRÆCOMASTIA > 24<3c and > 64<72 mouse units per 24 hours These results are within Thotma limits for a man of 70 years Testicular Biopsy Biopsy (Figure 22) showed normal Leydig cells, and the tubular contents varied between normal spermatogenesis on the one hand and Sertoli cells only on the other hand Some tubules showed arrest of spermatogenesis at the stage of primary spermatocytes, but in most there was normal spermatogenesis, and in all the basement membrane was normal This bropsy result is regarded as normal for a man of 70 years. Liver function Tests The following findings were obtained, serum protein content, 6.8 gm per 100 ml, serum albumin content, 3.2 gm per joo mi, serum globulin content, 3.6 gm per 100 ml albumin/globulin ratio, o 88, serum alkaline phosphatase content, 8-6 KA unsts per 100 ml, thymol turbidity, 10 units, thymol flocculation, +, colloidal gold reaction, + bromsulplalein test, 100°, of the dye present after 5 minutes, 5 of the dye present after 45 minutes LIGURE 22 (A) Gynecomastia in a patient suffering from pulmonary tuberculosis (B) Testicular biopsy from the same patient showing normal spermatogenesis and Leydig cells One month later the following findings were obtained direct Van den Bergh reaction, negative, serum Lulirubin content o 05 mg per too ml, thymol turbidity, negatiie, thymol flocculation, negatise, colloidal gold reaction. + , serum protein content, 6 ogm per 100 ml, serun albumin content, 3 6 gm per too ml, serum globulin content, 3 3gm per 100 ml, albumın/globulin ratio, These miestigations exclude liver failure as the cause of the gynaecomastia The thy mo! increased the demand for vitamin B complex A basal metabolic rate determination was not possible, because the patient's sputum contained acid-fast bacıth - tnanen teott we nerformed in order to exclude the possibilty of a relative or The result of the test (Table XXVIII) was almost within Pated three days after the completion of a course of intra. ee page 95). 2cc daily, for une week (second test) The the gynacomastia was unaffected by this treatment e excluded as a cause of ginecomastia in this patient 50 .

·DISEASES OF TIE Luxo 141 ætiological factor, no other cases have been reported in which this association was mastia (sce page 42) TABLE XXIII Blond lytus ate Content (Vg 100 ml) Iirst Test Second Test Ipper Limits of Yormal Time Tasting 60 minutes 90 minutes 20 1 39 [24 132 1 It 1 T 1 39 1 39 BROXCHIECTASIS AXD EJPYEMA No good evidence has so far been reported to establish the occurrence of gynacomastia associated with bronchiectasis or empyema as anything more than a coincidence REFEREXCES DEL CASTILLO, E B, DE LA BALZE I 1, and VIEMBRIVES J R (1914). "Ginecomastia 1 carcinoma pulmonar, Ensaio de Patogenia Medicina, Buenos Aires 4 176 * DEL CASTILLO, E B, DE LA BALZE, ! . and MEMBRIVES, J R (1944). Gynecomastia and Pulmonary Carcinoma', quoted in Year Book of Medicine P 235 * BLISS, R (1945), M D Thesis, Cambridge * BAYLISS, R (1954), Personal communication *Semple, T. and MCCLUSKIE, R (1955), Generalized Hypertrophic Osteoarthropathy in sociation with Bronchial Carcinoma + Reisen Based on 24 Cases Bril 754 FRIED, D (1943' " Chronic l'ulmonarı Osteoarthropathy Dispituitarist as Probable Cause Arch int Hed. 72 565 U HEELER, Ć E. Cauley, E' GRAY, H T, and Curtis, IC (1954) Gynecomastia A Review and an Analysis of 160 Casey , Pin af Ved. 40 995 llOODHAM,C WB (1938). " Ilyperplasia of Vale Breast Accompanying Malignant Disease of the Testis Treated by X Raya , Lancet, I 307 JOINER, C L, MCARDLE, B, and THOMPSOY, R H (1950). "Bluod Pyruvate Estimations in Diagnosis and Treatment of Polyneuritis Brain, 73 431 **Osler, W. quoted by Joseph A I'ratt (1949) in " A Year with Osler", Johns llopkins Press, Baltimore 11 HUCKSTEP, R L, and BodKiv, P E (1958). " Vagotomy in Hypertrophic Pulmonary Osteoarthropathy Associated with Bronchial Carcinoma Lancet 2 342 11 LOCKWOOD, C 1 (1999). "Studies of Adrenal Cortical Tunction in 3 Cases of Carcinoma", Canad ASAJ 79 728 4 ·140 GY'SACOVASTIA > 24<32 and >64572 muuse units per 24 hours man of 70 years These results are within normal limits for a T. ) Liver Tunction Tests The following findings were obtained serum protein content, 6.8 gm per 100 ml serum albumin content, 3.2 gam per ipo ml.. serum globuhn content, 3-6 gm per too ml , albumin'globulin ratio, o 88, serum alkalıne phosphatase content, 8-6 KA units per 100 ml; thymol turdity, 10 vnts, thymol flocculation, +, colloidal gold reaction, +; bromsulphalcın test, 100% of the dye present alter 5 minutes, 5 of the dye present after 45 minutes LIGURE 22 (A) Gynrcomastia in a patient suffering from pulmonary tuberculosis (13) Testicular hropsy from the same patient showing normal spermatogenesis and Leydig ceils -.A.C.and - nhe vol 1 1 1 4 VA AL 15 One month late following findings were obtained direct van de reaction, negatne, serum bılırubin content o 65 mg per too ml . thymol turbidity, negative, thymol flocculation, negatne, colloidal gold reaction, +, serum protein content, 6 ogm per 100 ml serum albumin content, 36 gm per 100 ml, serum globulin content, 3 3 gm per 100 ml , albumin/globulin ratio, 11 These investigations exclude liver failure as the cause of the gynæcomastia The thymo! ne then nur weeks later and med during a period Gross disturbance Honcrer, in view atabolist may have increased the demand for vitamin B complex A basal metabolic rate determination was not possible because the patient s sputum contained and fast baculis to exclude the possibilty of a relatie of e test (Tabie XXVII) was almost within after the completion of a course of intradaily, for one week second test) The ta was unaffected by this treatment, 50 cause of gynTuomastia in this patient After these investigations the patient was treated with streptomycin (one gramme daily) Iftar from tole the feser subsided, the sputum showed healing of cavities lastia persisted unchanged weeks ·HEREDITY 143 The endocrine component of this syndrome resembles Klinefelter's syndrome, ic.. small testes, absence of spermatogenesis, gynecomastia and raised urinary gonadotrophin levels However, the histological appearance of the testes was different from that of Klinefelter's syndrome. In these two patients the seminiferous TL .. 12...1.......he... L.1 ---L.. excretion ed (>180 prostatic The osseous lesions in these two patients included cubitus valgus, bilateral cervical ribs and a series of deformities of the cervical vertebrip-namely, reversal of the normal lordotic cervical curve due to atlanto-occipital fusion and partial fusion of the spinous processes and posterior articulations of ihe second and third cervical vertebrae, moderate hypertrophy of the bodies of the fifth, siath and seventh cervical vertebræ and diminished intervertebral spaces. The authors suggest that the occurrence of the syndrome in brothers, the association with other congenital deformities and the occurrence of mental deficiency in other members of the family all point to the congenital origin of the testicular -.L.AL Roth' has reported a family of four brothers who suffered from hypogonadism 1 ... Reifensteins has reported an interesting Syrian family, the male members of which were affected by Klinefelter's syndrome Five brothers were all affected, and of the three sisters one was the mother of two sons, both of whom showed the syndrome, and the second had three sons, of whom two were affected. In each case the typical syndrome was present and gynæcomastia was marked Klinefelter's syndrome is not usually hereditary, and it would be interesting to examine the chromosomal sex of the affected members of this family. No reports have so far appeared to indicate that prepubertal testicular failure is hereditary, THE INHERITANCE OF SUSCEPTIBLE MAMMARY TISSUE When gynæcomastia appears as an isolated symptom, it is sometimes ignored and sometimes treated with secrecy, with the result that an hereditary or familial tendency is easily overlooked The number of patients who indicate that other members of their families showed gynæcomastia must therefore be regarded as setting a minuurn to the familial occurrence of this condition.

·CHAPTER XV GYNECOMASTIA AND HEREDITY Since gynæcomastia is a symptom or sign which appears in association with a number of diseases, familial or hereditary tendencies would be expected to bear some Telationship to the familial or hereditary occurrence of the causative conditions. It is therefore a mistake to speak of the inheritance of gynecomastia without reference to such causative conditions. It is not proposed to discuss the possible inheritance of such causative factors as cirrhosis of the liver, bronchogenic carcinoma, thyrotoxicosis etc., but to confine the discussion to tuo problems, namely (1) the inheritance of those forms of male hypogonadism which are commonly associated with gynæcomastia, (ii) the possible inheritance of breast tissue which may be hypersensitive to hormonal influences THE INHERITANCE OF HYPOGONADISM In 1893 Savitskyl reported the occurrence of gynæcomastia associated with hypogonadism in a number of families. However, this aspect of the subject has been somewhat neglected until Peters and his co-workers recently described the annan GyneacoBastie, 100.aplete deacent of right testis kod by pospadis.. Gynaeonatis only ✓ Breasts kop to bo bormi. FIGURE 23 The occurrence of gynıcomastia in a family, including affected half-brothers whose fathers were unrelated The case for maternal transmission of gynæcomastia in this famly seems strong in view of the occurrence of the condition in half-brothers with unrelated fathers and the appearance of gynæcomastia in a maternal cousin (Figure 23) Sohval and Soffer have reported a syndrome in brothers which consists of mental deficiency, multiple congenital osseous anomalies, diabetes mellitus, some evidence of lack of androgen secretion, small testes, absence of spermatogenesis, gynæcomastia and raised urinary gonadotrophin levels Other members of the family were mentally deficient ·HEREDITY 143 The endocrine component of this syndrome resembles Klinefelter's syndrome, ie, small testes, absence of spermatogenesis, gynæcomastia and raised urinary gonadotrophin levels However, the histological appearance of the testes was different from that of Klinefelter's syndrome. In these two patients the seminiferous tubules ucre of tuo types. The first cre small, regular and close together, and did of the changes in the basement membrane (see page 54). In addition, the Leydig ercrction ed >180 prostatic The osseous lesions in these two patients included cubitus valgus, bilateral cervical ribs and a series of deformities of the cervical vertebrze-namely, reversal of the normal lordotic cervical curve due to atlanto-occipital fusion and partial fusion of the spinous processes and posterior articulations of the second and third cervical vertebræ, moderate hypertrophy of the bodies of the fifth, sixth and seventh cervical vertebre and diminished intervertebral spaces The authors suggest that the occurrence of the syndrome in brothers, the Roth has reported a family of four brothers si ho suffered from hypogonadism Reifenstein has reported an interesting Syrian family the male members of which were affected by Klinefelter's syndrome. Five brothers were all affected; and of the three sisters one was the mother of tuo sons, both of whom showed the syndrome, and the second had three sons, of whom two were affected. In each case the typical syndrome was present and gynecomastia was marked Klinefelter's syndrome is not usually hereditary, and it would be interesting to examine the chromosomal sex of the affected members of this family. No reports have so far appeared to indicate that prepubertal testicular failure is hereditary THE INHERITANCE OF SUSCEPTIBLE MAMMARY TISSUE is sometimes ignored and hereditary or familial tende o indicate that other members of their families showed gynecomastia must therefore be regarded as setting a minimum to the familial occurrence of this condition.

·144 GYNECOMASTIA 1 One patient in the Guy's Hospital seres and his brother both suffered from essential gynæcomastia at the age of 16 years and involutional gynæcomastia at the age of 52 years A sister showed unilateral breast development at the age of nine years--three years before the onset of other signs of puberty. It is not at present possible to account for these observations, but the isolated development of breast tissue without breast tissue in these patients Similar findings have been men which neonatal gynæcomastia lo later shoned essential gynæcomastia and in whom the essential gynecomastia underwent spontancous remission, The inheritance of hypersensitive, breast tissue, although of fundamental physiology of the breast, is too complex to be Much more information will be required before and it is to be hoped that future studies of accompanied by detailed enquiry concerning possible hereditary disturbances of breast function in members of both sexes) of the patients' families REFERENCES 1 SAVITSKY, S L (1894), S. Leurs red and Surg 1.66 118 * PETERS, J H. LIEBER, W K, and DAVIS, N (1955), " Familial Gynecomastia Associated with Genital Abnormalties". Clin Endocrinol. 15 182 #SONVAL, A R. and Soffer. L'I (1953). "Congenital Familial Testicular Deficiency". Am J died. 14 328 • ROTH, (1947). "Familial Eunuchoidism Laurence-Moon-Biedi Syodrome" / Urol. 57 427 • REIFENSTEIN, E C (1948), in discussion on Nelson, WV O, and Heller, C G, "Recent Progress in Hormone Research. 3 197. New York ·CHAPTER XII THE MANAGEMENT AND TREATMENT OF GYNECOMASTIA Since gynecomastia is a symptom or sign, the treatment of this symptom is the treatment of the cau c. Neonatal gynecomastia is common, and almost always subsides without treatpuberty shoull be mentioned to the parents, who are to be encouraged to regard such a recurrence as a matter of no great importance and to expect spontaneous recovery + { kynecomastia At puberty the most important step in the investigation of a patient with gynæcomastia is to exclude the common subareolar node, which is part of normal puberty This condition calls for no treatment, but it is important to reassure the patient and his parents and to point out that the condition invariably disappears without treatment Essential gynæcomastia is the next condition to be considered, If puberty is disease can be be confirmned if I normal limits. Essential gynecomastia persists once it has developed and may cause serious embarrassment to the patient These are the considerations which determine the management of patients suffering from essential gynæcomastia, and the physician is faced with four alternatives--namely, no treatment, hormone therapy, radiotherapy and surgery XO TREATMENT 1+ nn. 141. Anne to become very importunate in their demands tor some form of treatment. This point is illustrated by a medical student of 24 years who suffered gynæco- 'I he father jokingly dismissed the condition, but the patient insisted upon seeking another opinion and was eventually treated surgically with complete success It was to relieve such distress that 18 of 34 patients so affected were submitted to operation at Guy's Hospital In general, econteni manmartin although such rem For at least eight ·146 GYNACOJASTIA constitute a period during which gynæcomastia is most distressing to the patient. It is possible that patients in whom the condition affects a brother, and has followed severe or protracted neonatal gynecomastia, may show a spontaneous remission In such patients a conservative policy is justified for two years. If no sign of remission has occurred during this time, surgery should be advised The best way of assessing remission is by means of a photographic record. not seem to regard the condition so seriously, and perhaps under these conditions watchful expectancy is justified Parents may be more distressed than patients, although this is not easily detected with certainty during a single interviews and in any case is probably an indication for surgical treatment. HORMONE TREATMENT The most extensive clinical and laboratory studies in these patients have not revealed any hormonal deficiency. In view of these negative findings and also the fact that androgenic hormones may not be without harm during puberty,' there can be no rational basis for the use of such preparations as testosterone in the treatment of essential gynæcomastia This view is supported by the possibility that androgens may cause gynæcomastia under certain circumstances (page 125). Moreover, the empirical use of androgens has shown them to be ineffective in - ere given testosterone for ht by injection), and in no e is known at the present It is therefore concluded that hormone therapy has no place in the treatment of essential gynæcomastia. RADIOTHERAPY Deep X-ray therapy has been used in the treatment of gynæcomastia Six -Larihan hoan norted to produce improvective, and today clinicians : patients where this can SURGERY Paulus Ægineta, in the seventh century AD, was the first to recommend the surgical treatment of gynæcomastia, and described a method for removing the breast through a semicircular incision, and in more extensive cases through two incisions He advised operation upon the grounds that the condition "bears the reproach of effeminacy Today the indication for operation is still the same, but the technique of Paulus gineta should no longer be used This operation involves total mastectomy, and leaves a large scar, which constitutes as great a source of embarrassment as the gynæcomastia itself Dartigues, in 1928, described an operation which 1.- Larnain tumor1019 gives good results and leaves a scar wach is less culispiluvus can come ""*" como procedure Puma Webster, S has described the operation which has revolutionized the skin nearly always leave Ikulipscurs was ·JEROME WEBSTER OPERATION 1447 is that hemostasis is difficult, and hæmatoma can occur, but this complication responds to simple measures. Commander George W. Webster, formerly resident ܫܬܫܫ ܫ ܢ tak. 1.- Junction of the areola and the skin or the chiest wall. inis operation dlows the entire brcast to be removed and yet leaves a scar so fine that it has been known to escape Wnn such a surgical ent is at practical waiting is rarely rewarded. FIGURE 24 The Jerome Webster operation The patient is shown before and after operation, no scar is vissble on casual inspection of the chest At puberty, gynecomastia due to prepubertal testicular failure and Klinefelter's syndrome may occur, and clinical examination of the testes will show that they are abnormal, while urinary gonadotrophins are raised by the time gynæcomastra develops Testicular biopsy and chromosomal ser determination will confirm the diagnosis. Here the treatment is that appropriate to the causative condition Prepubertal testicular failure should be treated by replacement doses of testosterone implants of six pellets, each of 100 mg, will last up to six months This treatment promotes the development of secondary sexual characteristics, but of course does not affect the stenlity, which is complete and permanent, nor the gynæcomastia, which, however, is not usually severe. Here the question of operation upon the breasts will be decided by the extent to which the patient complains of the gynæcomastia If this symptom appears to be distressing, operation can be advised Some explanation of the nature of the disease and the extent to which improvement can be expected is helpful, and some such patients have married successfully. Klinefelter's syndrome presents a different problem The patient is to be treated as male, regardless of chromosomal sex, and neither he nor his relatives informed of the genetic sex in cases where this is female. Operative removal of breast tissue is ·148 GYNÆCOMASTIA advisable, and testosterone has been administered as a means of encouraging the development of male secondary sexual characteristics However, the sexual development of these patients is often adequate and not greatly improved by androgen therapy If the secondary sexual characteristics are poorly developed and libido and erections inadequate, testosterone is to be recommended These patients are, of course, permanently sterile, and should be informed of this. Gynxcomastia is nat affected by testosterone in Klinefelter's syndrome, and the indication for surgery is the same as that in prepubertal testicular failure, During adolescence and manhood gynecomastia associated with testicular tumour may occur , and although this is rare, such an association is important, because gynæcomastia may be the first sign of a testicular tumour and in this way may ofter the possibility of early treatment. At this time of life other testicular lesions may occur, such as testicular atrophy (unilateral or bilateral), undescended testes, varicocele etc. Other causes of gynecomastia, such as leprosy, cirrhosis, bronchogenic carcinoma and thyrotoxicosis, occur during adult life, and in general be considered Adrenocortical disease is another uncommon cause of gynecomastia in adult life, and for this reason estimation of urinary 17-ketosteroids and, where possible, 17-hydroxy corticosteroids and cestrogens, should form part of the laboratory investigations of a case of gynecomastia Drugs which cause gynecomastia do not provide diagnostic problems if this possibility is kept in mind, but when gynæcomastia remains unexplained, contact with aestrogens should be considered---especial note of the patient's occupation being advisable Lanciderable care is Observation tainty Most al function are nt if they are ases) Sometimes the condition undergoes spontaneous remission, so that surgery is not as frequently indicated as in the case of essential gynæcomastia Sometimes the possibility of malignant changes supervening in cases of established synecomastia has been proposed as a reason for carly and radical removal of the breasts in all cases of gynæcomastia That this argument is without foundation is shown by the observation that among more than 700 recorded cases of gynaecomastia only two have been reported as the site of malignant disease Berns? reported a carcinoma occurring in a case of gynæcomastia which eventually led to death Edheim described a malignant duct papilloma in a case of gynæcomastia, but the diagnosis of malignancy was purely histological These observations indicate that the possibility of malignant change should not influence the routine treatment of gynecomastia, but it a hard lump develops in an established case of gynæcomastia, It should be remembered that axıllary glands not infrequently becomc enlarged during the early stages of gynecomastia, especially when the breasts are tender, but this does not of course indicate the presence of malignant disease In men receiving estrogen therapy for carcinoma of the prostate, it is important It is to bear in mind the possibility of malignant change in the enlarged breasts likely that most carcinomata reported in such patients are due to metastases from the primary growth and should not be regarded as a contraindication for estrogen therapy in carcinoma of the prostate 12 Either as the result of longer survival or biopsy is indicated ·MANAGEMENT 119 because of changes in the stimulated breasts which encourage metastatic deposits to grow, secondary carcinoma has been reported in a number of cases of prostatic carcinoma receiving cestrogens Considerable care is needed to demonstrate the nature of these tumours and enzy me studies may be required to prove that the leston in the breast is not a primary carcinoma It was pointed out in Chapter IX that gynacomastia may be associated with transvestism While the definitive treatment of this condition has yet to be established, it seems unwise at present to undertake measures designed to turn these only to express deep regret at having submitted to this procedure---perhaps the photographer has captured this regret in Figure 24 Hamburgerº, 10 also mentions a patient who expressed similar feelings after such an operation. REFERENCES McCu ogenic Effects a 496 " Pau iety, London DART Vanmectomie WEBSTER, G V (1014). "Genecomastia in the Xavy", vil Surg. 95 375 #WEBSTER, J r (1946). 'Mastectomy for Gynecomastra through Semicircular Intra-Areolar Incision". Surg. 124 557 CLARKSON, P (1949). "Webster Operation for Gynecomastia". ] Roy Army 1/. Corps. ~ 1 93161 Hrn...) 11 + -- 10 HAMBURGER, C (1955). 11 HELLER, CG, and NELS with Yormal or Fa: oidism, Gynecomas Estrogens J Clin Endocrinol, 5 1 14 MOULTON, J C (1959). Mammary Neoplasm in a Male Recen tng Estrogen Therapy for Carcinoma of the Prostate". U Atestralia, i 706 ·SUMMARY AND CONCLUSIONS Gynæcomastia may be defined as enlargement of the glandular component of the breast in males This definition is useful to the clinician and the pathologist alike, being free of contention Gynæcomastia has been known since the days of ancient Greek medicine, but it. - L...1 of the normal male breast after stimulation by cestrogens Gynæcomastia may be associated with physiological life epochs, and of these there are three-namely bi-th hinh mau honoranino s... puberty, which may be as which may be associated is distinguished from the normal puberty, by its severity and its persistence Prepubertal testicular failure is frequently complicated by the presence of gynæcomastia, although the degree of breast development is usually slight and of little consequence beside the farlure of sexual development. On the other hand, surgical castration before or after puberty seldom, if ever, causes gynæcomastia Tumours of the testis (chorionepithelioma, seminoma, interstitial cell tumour and Sertoli cell turnour) occasionally cause gynecomastia, probably due to the secretion of aestrogens by the tumour cells, except in the case of chorionepithelioma, orchitis of unknown ætiology which leads to testicular atrophy. Klinefelter's syndrome consists of small testes, azoospermia, raised levels of relationship be stimulation of would not the cells could do the same, either by producing excessive quantities of androgens or of cestrogens A histological picture resembling that of Klinefelter's syndrome is found in a number of diseases, and some of these are associated with gynecomastiacg. tiene lanenolarin Aripteanhia myotonica, maphroditism I with gynæco mastia, which then becomes a sign of great diagnostic importance For this reason urinary 17-ketosteroid and estrogen excretion should be measured in any case of unexplained gynæcomastia in an adult Liver cell failure may be associated with gynæcomastia, which is possibly due to failure of the liver cells to conjugate the cestrogens nornally produced by the testis and possibly by the adrenal cortex Cirrhosts is the most important form of liver disease to cause gynæcomastia, but advanced failure of liver cells due to any cause may produce gynæcomastia.

·SUMMARY AND CONCLUSIONS 151 Hemochromatosis is probably the one exception to the last statement, and it is likely that deposits of hæmosiderin interfere with the function of the adenohypophysis; which in turn deprives the testis of its usual gonadotrophic stimulation : in the absence of adequate gonadotrophic activity, brcast stimulation does not occur. rcan state flush of puberty. Among the drugs which can potent. Prolonged administration and it is possible that conversion of responsible for this occurrence In ciceptional cases, adrenocortical hormones, 5 0 Bronchogenic carcinoma has been known to cause gynaecomastia, but the mechanism is quite obscure Pulmonary tuberculosis is rarely associated with syntcomastia Breast tissue shows considerable variation in its susceptibility to hormonal influences The age at which exposure to such influences first occurs is probably significant, and in adrlition there is con alcrable variation from one indivulual to another in the response to a given stimulus Even in one person the two breasts may develop asymmetrically, this difference is seen in its most extreme form in lateral hermaphroditum, in which a normal female brcast develops on one side of the body in the absence of any breast development on the other sule Xo doubt there are local factors inherent in mammary tissue which determine these differences Moreover, there in considerable variation in the duration of a given response following a given stimulus Sometimes a period of breast stimulation is followed by more or less permanent gynæcomastia, which persists long after the stimulating influence has been withdraun. at other times the breast resumes its onginal state after the stimulating influcnce has been removed It is possible that some of these variations in the behaviour of breast 18sule are genetic in origin Not infrequently gynæcomastia appears in patients suffering from an underlying disease not usually regarded as a cause of this symptom Such associations are for the most part fortuitous, or the underlying disease has precipitated the synaecomastia as the result of some non-specific mechanısın which cannot at present be exmained The treaf the cause Those patients who find esse sment should be advised to submit to the Under otlier circumstances the treatment of gyn.ccomastia is conservative AUSTRALASIAN MEDICAL PUBLISNING CO LTD SEAMER ANO ARUNDEL ST. GLEDE SYDNEY ·154 INDEX D Dehydroepiandrosterone See Dehydroisoandrosterone Dehydrosoandrosterone, 24, 75 Deoxy corticosterone, 26 Diabetes, 105, 142 mellitus and gynæcomastia, IOI Digitalis and gynæcomastia, 127 excretion of, 128 Digitoxin, 128 Digoxin, 128, 129 Discharge, urethral, 78 Disorders of sex, 98 DOCA, 126, 127 Drugs and gynx.comastia, 148 Ductus deferens, 133 Ducts, genital, 53 Dystropha myotonica, 62, 65, 68, 134 body proportions in, 136 chromosomal sex in, 136 E Empyema, 141 Epididymis, 48 tumour of, 69 Epiphyses, 48, 54 Eschatin, 126, 127 Essential gynæcomastia. See Gynæcomastia, essential Eunuchord stature, 16 Eunuchoidism, 18, 47. 48, 56, 125 Eunuchs, kynæcomastia in, 81 Gonadotrophins, 25, 66 assay of, 17 pituitary, 69 urinary, 56, 61, 67, 68, 72, 87, 97, 119. 142, 143 in dystrophia myotonica, 135, 136 in hamochromatosis, 106 in hyperthyroidism, 96 in male pseudohermaphroditism, 99 in malautrition, 114, 115 Gonia See Germ cells Growth hormone, 25. 97 in bronchogenic carcinoma, 139 Gynecomasia, 8 Gynæcomastia, vetrology, 11, 12 age incidence, 12, 13 and acromegaly, 10, 97, 138 and Albright's syndrome, 100 and amphetamine, 130 and androgens, 125 and bronchogenic carcinoma, 138 and cirrhosis, 10, 104, 148 and Cushing's syndrome, 101 and diabetes mellitus, 101 and digitalis, 127, 128 and diseases of the testis. 45 and dystrophia inyotonica, 134 and hepatitis, 105 and heredity, 142 and hermaphroditism, 98 and hormone assays, 12 and hyperthyroidism, 90 and hypopituitarism, 98 and lymph gland enlargement, 16 and male pseudohermaphroditism, 98 and malnutrition, 113 and obesity. 8 and cestrogens, 31, 117 and paraplegia, 134 and prostatectomny, 100 and puberty, 14 and refeeding. 113 and testicular lesions, 12 and transvestism, 99 and trauma, 12 and tuberculosis, 139 causes of, 29 clinical history 12, 14 definition, 7, 11 degrees of, 15 diagnosis, 8 drugs as causative agents in, 14, 117, 148 essential, 33, 144, 148 breasts in, 34 family history in, 37. 38, 41 fertility in, 38 17-ketosteroids in, 38 natural history, 36 cestrogen excretion in, 38 astrogens in, 41 spontaneous remission of, 36 urinary gonadotrophins in, 38 grades of, 15 histology of, 12, 14, 22, 23 history of, 9 in chromophobe adenoma, 97 involutional, 42, 144, 148 hormone levels in, 43 F Teminization 86 Fertility, low, 58 Fibroadenoma and gynæcomast12, 11. 22 Folhcle-stimulating hormone Sec FSH Friedreich's ataxia, 134 FSH, 55, 117 G Galen, 9,17 Gern cells, 58 Germ plasm, 57. Germinal epithelium, 99, 105, 108 117, 119. 133 destruction of, 61, 66 in dystrophia myotonica, 136 in haemochromatosis, 109 in malnutrition, 114 in cestrogen therapy, 117 Glucocorticoids, to6 in hyperthyroidism, 96 Gortre plongeant. 96 Goldberg-Waxwell syndrome, 98 Gonad, development of, 57 fætal activity of, 53 penetration by germ cells, 57 Gonadotrophic hormones See Gonadotrophins ·INDEX 155 K Gynecomastia continuerl. neonatal, 20. 32., 37. 41 occurrence of, 32 operation for, 9 past health in, 14 photography in, 15 treatment of, 145 conservative. 145 hormonal, 149 radiation, 146 surgical, 146 Gynt comastism, 8 Gynecomasty, 8 Gintomazia, 8 H Hrmochromatosis, 105, Ton Hepatitis, 105 anil malnutrition, 114 jlepatomegaly, 109 Ilormone ashay, methods of, 17 Hot fushes, 43, 99 Ilermaphroditism. 59. 93 true. 99 false. Sce P'scuclohermaphroditam Herodotus, 9 Flippocrates, 9 IIyaluronic acid in breast, 24 Ily drouortisone, 261, 89 17-hyclroxycorticosterous, 99. 149 livpercellitarity. 39 !!ypertenstort, 127 Hyperthyroidism, 65 90, 116 and adrenal function, 96 and Klinefelter's syndrome, 94 experimental, 96 urinary oestrogens in 95 Hypertrophic pulmonary osteoarthropathy ilypogonadism, 8. 9. 25. 45 classification of 45 46 hypergonadotrophic, 46 hypogonadotrophic, 46 Hypopituitarism. 93 Hypospadias, 142 Hypothyroidism, 97 Kepler test in hemochromatosis, 107, 101 17-ketogenic sterouls in hyperthyroidism, 99 17-ketosterouds, 26, 97. 105, 119 assay of, 17 3-fraction, 76, 119. 125 in adrenal tumour, 87 in dystrophia myotonica, 134, 136 in homochromatosis, 108 in hyperthyroidism, 96 in liver disease, 104 in malnutrition, 114 in retrogen therapy. 120 in paraplegia. 133 klincfciter's syndrome, 46, 47, 51. 78. 134. 136, 143, 147, 148 and hyperthyroidism, 94 and orchitis. 79 and transvestism, 99 autosomal translocation in, 69 chromosomal sor in, 57. 58, 60, 67 chromosomes in, 69 clinical features, 59 sy nacomastia in, 60 lalxoratory tests un, 61 Ley dug cells in, 66 meaning of, 67 neutrophu lcucocytes in, 69 pathogenesis of, 57 secondary scrual characteristics in, 59 testicular biopsy in, 62 tretes in. 54. 56. 64 60 true, 09 types of. 56.58 L 138 ICSH, 68, 69 in dystrophia myotonica, 136 Impotence, 94, 95, 104, 117. 119 120 125 Infantilism, 18 Infertility in liver disease, 104 Insulin 25. 108 Interstitial cells of testis See Leydig cells Interstitial cell-stimulating hormone See Leprosy. 68. 76, 148 testis in, 65 Leprous orchatas, 76 and Klinefelter s syndrome 77 Leydig cells in, 77 Leydıy cells 26, 41 48, 53. 54 60, 63, 65, 68, 70, 72, 73 76, 87, 94 105, 108, 117. 120, 126, 129, 135, 143 clumping of 5+, 61, 62, 90 in dystrophia myotonica, 134 counts of. 18 hyperplasia of, 119 in male pseudohermaphroditism, 99 in strogen therapy. 119 124 in paraplegia, 137 Leydig cell tumour, 72, 74 gynacomastia in. 73 hormones in 75 76 17-betosterolds in 73 Libido, loss of, 117 in malautrition 114 Liver, amyloid disease of, 105 carcinoma of, 105 disease and gynecomastia, 104 failure, diet in, 106 function in bronchogenic carcinoma, 138 in paraplegia, 134 in pulmonary tuberculosis, 140 Lobules of breast, 22 Lower segment, 16 ICSH See Leydig cell Interstitial cell tumour tumour Iodine radioactive 130 Isoandrosterone 75 4 Jaundice, homologous serum, 105 ·156 INDEX LS, 16 Lymph glands, 10, 148 Orchitis, 71 and Klinefelter's syndrome, 76 leprous, 76 mumps, 77 Ootestis, 57 11-Ory-17-ketosteroids, 75 M P Vallory bodies, los Malnutrition, 113 and ser function, 114 Mammary gland, hypertrophy ol, 8 Mastectomy, 146 Mastitis, II, 20 Siental deficiency, 142 Methionine. 115 17.Mcthyl testosterone, 25. 125 Ik, 9 Mallesian ducts, S3 Mumps, testis in, 68 Myoepithelial cells, 22 Hyxordema, 90. 97 N Paraplegia, 30, 62, 133 1'erls' stain, 108, 10g Mtuitar fossa, 97 gland after finl. 130 in malnutrition, 114 I Tecocious puberty. 72, 73 I'regnancy cells, 70 I'regnanciliol, 32, 88 Prepubertal testicular failure. See Testicular failure Prison camps, 113 Progesterone, 25, 26 Prolactın, 25. 32, 97, 139 Prostate, carcinoma of. 55. 149 metastases to breast, 148 in citthosis, 100 Trostatectomy, 100 Pscudohermaphrolitisma, 58, 62 female, 89 male, 61, OS, 68, 69. 73 and Ry naccomastra, 98 Puberty. 9. 20. 33 mastitis, 20 Precocious 72, 73 Pubic hair in hit mochromatoses, ros Pitulate tolerance test, 95, 1.40 Nipples, pigmentation of, 121 R Remke, crystalloids of, 72 Renutrition, 134 Reserpine, 231 Riboflavine 113 S Obesity. 105 adema, 128 Estradiol, metabolism of, 104 Estrol metabolism of 104 Estrogenic impurity in amphetamine, 130 Estrogens. 32 40 41, 43 53 55. 69, 70 76, 110, 117. 12.4 126 130 action on breast, 3 25 and axillary hair, 104 and synecomastia, 27 31 and hialuronic acid 24 and pituitary gland, 24 assay of, 17, 106, 148 bulary excretion of, 104 conjugatiori of. 105 effect on pituitary gonadotrophins, Ios excretion of 20 in malnutrition 114 exogenous 125 in liver disease 105 in adrenocortical tumours 97. 83, 89 in bronchogenic carunuma 138, 139 in carcinoma of prostati 148 in chorionepithelioma, 70 in cirrhosis, 105, 106 in Ley dig cell tumour 73 In male pseudohermaphroditism 68, 99 in malnutrition, 116 nactivation of, 104 metabolism of, in liver disease, 100 occupational exposure to, 121 testicular, 73 unconjugated, 110 urinary, 39. 72, 75. 94, 95, 97 119 163 bronchogenic carcinoma, 138 in hyperthyroidisın, 96 (Estrone, metalsolism of, 104 Orchidectomy, 100, JOI Schultz method, 119 Scurvy, 114 Semen after opstrogen administration, 120 examination of. 17 Scmnoma, 71 hormone excretion in 72 Sertoli cell tumour, 76 estrogens in, yo Sertoli cells 54, 62 68 99 120, 124 130, 133 Sertoli-Leydig cell tumours. 76 Serum protein 133 Sex chromosomal See Chromosomal sex Sex determination, it differentiation, 12 function in malnutrition, 114 reau akening of, 43, 114 Sexual precocity, 72 Skin ser 123 Span, 16, 18 ·Ispex 157 Spermatogenesis, 26, 63. 129. 130 aluence of, 104, !? in chorionic gonadotrophin therapy, 126 Spleen, 108 estrogen implants in, 104 Steros metabolism and pyntcomastia, 128 Stable boys and costrogeris, 124 Stariation, 113 Stulbestrol, 117. 119, 12! Stress, 27, 89 Subarcolar noxlc, 20, 33. 34. 40, 116, 149 Syphilis, testis in, 65 Syringomyelia, 134 Thyrotoxicosis See Hyperthyroidism Thyroxine, 130 Transicoft-m, 119. 149 and funcomastia, 99 in Klinefelter's syndrome, 99 Trauma, 12, 81 TSHI, 130 Tuberculosis, 116, 139 testis in. Os Tubules, ghost, 143 testicular, atrophy of, 65 Turner's syndrome, 53 т Ulcerative colitis, 106 Upper segment, 16 U.S. 16 V Vagina and strogens, 104 Vagotomy in l»ronchogenic carcinoma, 139 Varicocele, 148 Vas deferens, 100 ligation of, 100 Vas efferens, 49 Vitamin B, 95, 140 deficiency of, I15 Von Basedow, 1o. 90 Teratoma, 79 Testicular biops), 17 in hemochromatosis, 109, 10) failure, preputxertal, 46, 47, 48, 147 attiology. 49. 53 biopsy in, 48 chromosomal sct in, 54 clinical features of, 51 height in. 54 laboratory investigations in. 52 pathogenesis, 53 Testis altcr atomic blast, 80 and adrenal corter, 5+ atrophy of, 90, 134138, 148 in cirrhosis, 105 biopsy, 117, 119, 120 diseases of, 45 in dystrophia myotonica, 134, 136 in hanochromatosis os in malnutrition. 114 in paraplegia, 133 incomplete descent of, 142 radiation of, 79), 105 and gynæcomastia, 80 sarcoma of, 69 senile atrophy of, 65 small, 142 traumatic lesions of, SI tumours of, 69 undescended, 53, 63. 81, 148 Leydig cells in, 66 unilateral lesions of, 81, 82 Testosterone, 27. 55. 108, 110, 125, 148 Thorn tęst, 107, 108, 109 Thyroid gland, accessory, 90 benign metastascs, 96 ectopic, 96 hormone, 27 W Wasting diseases and Gynecomastia, 116 Webster operation, 146 Witches' milk, 20, 22 Wolffian duct, 48, 53 X "X" hormone, 55 Zona fasciculata in hyperthyroidism, 96 reticularis in hyperthyroidism, 96 Zygote, 58 ·156 INDEX LS, IO Lymph glands, 16, 148 Orchitis, 71 and Klinefelter's syndrome, 76 leprous, 76 mumps, 77 Orotestis, 53 11-Oxy-17-ketosteroids, 75 M P Mallory bodies, 105 Malnutrition, 113 and sex tunction, 114 Mammary gland, hypertrophy of, 8 Nlastectorny, 146 Mastitis, II, 20 Vental deficiency, 142 Methionine, 115 17-Mcthyl testosterone, 25, 125 Milk, 9 Miutlerian ducts, 53 dumps, testis in, 68 My oepithelial cells, 22 Myxa'dema, 90, 97 N Paraplegia, 30, 62, 133 Perls' stain, 108, 109 Pituitary foss2, 97 gland after fiat, 130 in malnutrition, 114 Precocious puberty, 72, 73 Pregnancy cells. 70 Pregnancdiol. 32, 88 Prepubertal testicular failure See Testicular failure Puson camps, 113 Progesterone. 25. 26 Prolactin, 25. 32, 97, 139 Prostate, carcinoma of, 55. 148 metastases to breast, 148 in cirrhosis, 106 Prostatectomy, 100 Pseudohermaphroditism. 58, 62 jemalc, 89 male, 61, 65, 68, 69, 73 and gynæcomastia, 93 Puberty, 9, 20, 33 mastitis, 20 precocious 72, 73 Pubic hair in hemochromatoscs, 108 Pyruvate tolerance test, 95, 140 Nipples, pigmentation of. 121 0 R Reinke crystallords of, 72 Renutrition, 13+ Reserpine, 131 Riboflavine, 113 S Obesity, 105 dema, 128 stradiol, metabolism of, 1044 Estriol, metalxolism of, L04 Estrogenic impurity in amphetamine, 130 Estrogens, 32, 40, 41, 43 53. 55 69, 70, 76, IIO, 117, 124 126, 130 action on breast, 23, 25 and axillary hair, 104 and gynæcomastia, 27. 31 and hyaluronic acid 2.4 and pituitary gland. 24 assay of, 17. ro6, 143 biliary excretion of, 104 conjugation of, 105 effect on pituitary gonadotropluns, 105 excretion of. 26 in malnutrition, 114 exogenous, 125 10 liver disease. 105 in adrenocortical tumours 87, 88, 89 in bronchogenic carcinoma 138, 139 in carcinoma of prostate, 148 in chorionepithelioma 70 in cirrhosis, 105, 106 in Leydig cell tumour 73 in male pseudohermaphroditism, 98, 99 in malnutrition 116 inactivation of, 104 metabolism of, in liver dtease, 106 occupational exposure to, 121 testicular, 73 unconjugated 110 urinary, 39, 72, 75. 94. 95, 97, it in bronchogenic carcinoma, 138 in hyperthyroidism, 96 strone, metabolism of 104 Orchidectomy. Joo, sor Schultz metbod 119 Scurvy, 114 Semen after aestrogen administration, 120 eramination of, 17 Seminoma, 71 hormonc excretion in, 72 Sertolt cell tumour. 76 restrogens in, 76 Sertoli cells 54. 62, 68 99, 120, 124, 130, 133 Sertol-Leydig cell tumours 76 Serum protein, 133 Sex chromosomal See Chromosomal sex Sex determination, 13 differentration, I2 function in malnutrition, 114 reawakening of, 43. 114 Sexua) precocity, 72 Skin, sex, 128 Span 16 18 ·I. DEX 157 Spermatogenesis, 26, 63, 129, 130 abses of, 101, 142 in chorionic gonadotrophin therapy, 126 Spleen, 108 estrogen implants in, 104 Steroid metabolism and fy nicomastia, 128 Stable boys and estrogens, 124 Starvation, 113 Stulbastrol, 117, 119, 121 Stress, 27. 89 Subarcolar nocle, 20. 33. 34, 40, 116, 148 Syphilis, testis in, 63 Syringomyelsa, 134 Thyrototicosis See Hyperthyroidism Thyroxine, 130 Transvestism, 119. 149 and gynaxcomastia, 99 in hlinefelter's syndrome, 99 Trauma, 12, 81 TSH, 130 Tuberculosis, 116, 139 testis in, 65 Tubules, ghost. 143 testicular, atrophy of, 65 Turner's syndrome, 53 U T L'lcerative colitis, 106 Upper segment, 16 U.S. 16 V Vagina and orstrogens, 104 Vagotomy in bronchogenic carcinoma, 139 Varicocele, 149 Vas deferens, 100 ligation of, 100 Vas efferens, 49 Vitamin B. 95. 140 deficiency of, 115 Von Basedow, to go Teratora, 79 Testicular biops. 17 in hæmochromatosis, 108, 109 failure, prepubertal 46, 47, 48, 147 ætiology. 48. 53 biopsy in, 48 chromosomal ser in, 5+ clinical features of, 51 height in, 54 laboratory iniestigations in, 52 pathogenesis. 53 Testis after atomic blast, 80 and adrenal cortex, 54 atrophy of. 90, 131. 139, 149 in cirrhosis, 105 biopsy, 117, 119, 120 discases of, 45 In dystrophia myotonica, 134, 136 12 hæmochromatosis, IOS in malautrition, 114 in paraplegia, 133 incomplete descent of, 142 radiation of, 79. 105 and gnacomastia, So sarcoma of, 6) senile atrophy of, 65 small, 142 traumatic lesions of, 8) tumours of, 69 undescended, 33, 63. 81, 148 Ley dig cells in 66 unilateral lesions of, 81, 82 Testosterone, 27, 55, 108, 110, 125. 148 Thom test, 107, 108, 109 Thyroid gland accessory, 90 benign metastases, 96 ectopic, 96 hormone, 27 Wasting diseases and gynecomastia, 116 Hehster operation. 145 Watches' mulk, 20, 22 Wolffian duct, 49, 53 X "X" hormone, 55 Z Zona fasciculata in hyperthyroidism, 96 reticularis in hyperthyroidism, 96 2. cote as

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