I90 Postgrad Med J: first published as 10.1136/pgmj.36.413.190 on 1 March 1960. Downloaded from

FEMINIZING TUMOURS OF THE TESTIS P. PATON PHILIP, M.CHIR., F.R.C.S.* Senior Surgical Registrar, St. Bartholomew's Hospital, London, E.C. I

Certain tumours of the testis in man cause Teilum32l 33 4 has made an extensive study of symptoms of a feminizing nature and arouse testicular and ovarian tumours and from the mor- interest and comment out of all proportion to the phological viewpoint has attempted to compare and' frequency of their occurrence. Although these relate these tumours one with another. He has tumours are rare, the literature is extensive, as suggested that the ' androblastoma' of the testis most of the cases tend to be reported, and their is identical with that of the , and also that the hormonal effects have been the subject of much testicular tumour which resembles the granulosa- conjecture and speculation. celled tumour of the ovary is identical with that Despite all that has been written, this particular tumour. There is no doubt that a time will come aspect of hormone abnormality still remains when more is known about the origin and nature ,obscure and complicated. of tumours of the ovary and testis, and' it may well Some authors have introduced new nomen- be that our knowledge will then justify these con-Protected by copyright. clature and have attempted to classify the tumours ceptions. However, until we obtain further and from the standpoint of morbid histological studies; more detailed biochemical studies, such com- but mere histology alone is no basis for classifica- parisons between tumours of the male and female tion of these rare and interesting . Until gonads and attempts at their classification based they are more fully investigated any attempt at solely on morphological studies tend only to add classification is premature, and no real progress more confusion to present nomenclature. can be made in their elucidation. The tumours of the to be described are Such investigations must not only be from an grouped together for no other reason than that histological point of view, but must also include they are capable of producing symptoms of pre-operative and post-operative hormonal assays feminization. and biosynthetic studies incorporating tumour tissue. Interstitial Cell or Tumours

Mostofi et al.,24 in a recent and authoritative These are by far the most interesting and re- http://pmj.bmj.com/ article, describe a group of tumours characterized markable tumours in the group. They form about by a wide variety of histological appearances i per cent. of all testicular tumours in humans,9 arising from the primitive gonadal mesenchyme. and have also been reported in various species of They call these neoplasms ' specialized gonadal animals. Their great interest lies in the fact that stromal tumours'. In a small proportion of their two distinct varieties exist in humans, the pre- cases gynaecomastia, as evidence of feminization, pubertal and post-pubertal cases. In the pre- was reported. This article does much to simplify pubertal cases reported (average age five years) matters and dispenses with some misleading the symptoms are almost always those of sexual on September 25, 2021 by guest. nomenclature which has been used in the past. precocity, with prominent external genitalia, deep These authors have vast experience and almost ' male' voice and sometimes enlargement of the unlimited material to call upon from the American opposite testis. In very few cases have adequate Armed Forces Institute of Pathology. A further hormonal assays been performed, but nevertheless article by them on the subject of interstitial cell the symptoms are clearly those of excessive andro- tumours of the testis is eagerly awaited and will gen production. Cook et al.,6 in a five-year-old undoubtedly make a further contribution towards child with a , identified the the elucidation and further study of these fas- hormone as 3-hydroxy-I7-ketosteroid, which fits cinating tumours. the pattern of androsterone. In the majority of cases reported complete retrogression of symp- *At present on exchange scheme at Veterans' Hospital, toms followed orchidectomy. Denver, Colorado, U.S.A. In adults the hormonal symptoms produced are March I960 PHILIP: Feminizing Tumours of the Testis Postgrad Med J: first published as 10.1136/pgmj.36.413.190 on 1 March 1960. Downloaded from entirely different, despite the fact that histologically the tumours appear to be identical. Most post-pubertal cases occur at about 30 years of age, and in less than half of the cases reported there are no symptoms of endocrine dis- turbance. The patient may present with enlarge- ment of the testicle or the tumour may be found at routine examination. It may be an incidental finding at operation for undescended or hernial repairs, or occasionally may be discovered at autopsy. In the remainder of the cases, more than half, symptoms of a feminizing nature are present, such as gynaecomastia, impotence and decreased libido. Such hormonal assays that have been performed on adults with interstitial cell tumours and symp- toms of feminization seem to vary considerably. In a case reported by Hermann et al.,'5 with pro- nounced gynaecomastia, decreased libido and a typical histological picture, the oestrogen excretion was found to be only slightly above normal before operation, whereas the excretion of androsterone and aetiocholanolone (excretion metabolites of testosterone) were appreciably decreased. A similar case of Decourt it al.7 exhibited marked Protected by copyright. feminizing symptoms with only a very moderate degree of biochemical change found on hormonal assay. They suggest that the findings indicate an increased susceptibility of peripheral receptors, abnormal hormonal elimination (which is qualita- tive rather than quantitative) and an imbalance of secretion of hypophyseal stimulators as a result of the autonomous secretion of the interstitial cell tumour. In the case of a young adult of 22 years, reported by the author elsewhere,27 typical symptoms of feminization were apparent. Gynaecomastia had

first appeared two years before admission to http://pmj.bmj.com/ hospital, and one year before admission he was treated by his private doctor with testosterone in- jections, which caused the swelling of the breasts to subside temporarily. When seen at hospital he FIG. i -Interstitial cell tumour. Right testis, removed had well-marked gynaecomastia affecting both at operation and bisected to show the typical breasts, hyper-pigmentation of the areolae and spherical, encapsulated appearance of the tumour loss of hair from the chest and pubic region, and in the body of the testis. From a male aged 22, he complained of loss of libido. The left testicle with feminizing symptoms and high oestrogen on September 25, 2021 by guest. was found to be smaller than average, a small output. tumour was palpable in the body of the right testicle and a small vaginal hydrocele was found to had increased in size, the patient had grown more be present. The Aschheim-Zondek test was nega- hair on his chest and the gynaecomastia had dis- tive and the excretion of i7-ketosteroids was appeared. His libido had returned to normal. A within normal limits, being 12.7 mg. in 24 hours. hormone survey showed the following results: Orchidectomy was performed and on slicing open Oestrone 7.6, oestradiol 2.9, oestriol I4.9 tg.; the testis a spherical, encapsulated tumour was total 25.4 ,ug. in 24 hours. This value is high, as seen, measuring 2 to 3 cm. in diameter (see Fig. i). the upper limit of normal is considered to be about Section confirmed a typical interstitial cell tumour I7.8 ALg. for an entire man.5 A further hormone with no evidence of malignancy (see Fig. 2). survey was performed about one year after orchid- At follow-up two months later the left testicle ectomy and the results were identical with the GI 192 POSTGRADUATE MEDICAL JOURNAL March I960 Postgrad Med J: first published as 10.1136/pgmj.36.413.190 on 1 March 1960. Downloaded from 7tvza¢>rr

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FIG. 2.-Interstitial cell tumour. A section of the FIG. 3.- tumour. From a dog aged I4 tumour shown in Fig. i. The interstitial cells are years with 5 years' history of testicular swelling. arranged in a pattern strongly suggestive of liver This is a typical appearance of such a tumour, and cords. There is no evidence of malignancy. *A shows the compact alveolar masses of cells, divided very typical appearance of an interstitial cell by thick fibrous trabeculae. H. and E. X 40. tumour. X 75. previous ones. The oestrogens still remain oestrogen by the anterior pituitary, which causes markedly raised, although the patient is entirely the formation of the testicular tumour, the gynae- http://pmj.bmj.com/ symptom-free, and the remaining testicle appears comastia, impotence and loss of libido. McCullagh clinically normal. It is difficult to explain why and Rossmiller22 reported gynaecomastia in males the oestrogen excretion still remains high and no who received large doses of testosterone. Test- Similar case has been found in the literature. In osterone seems to have had quite the opposite other reported cases the response to orchidectomy effect in the case just described! Twombly et al.35 has been a reduction in oestrogen excretion to found that anterior pituitary extract caused inter-

below normal levels. stitial cell hyperplasia and gynaecomastia in on September 25, 2021 by guest. Typical interstitial cell tumours can be induced animals. However, despite much speculation, no in animals by the administration of oestrogens, and really satisfactory explanation has been suggested many experiments have been performed, using dif- to account for the fact that typical interstitial cell ferent oestrogens: Bonser and Robson3 used tumours in adults can give rise to the production oestradiol diproprionate. Hooker et al.16 produced of oestrogens and feminizing symptoms. One typical interstitial cell tumours with metastases would expect these tumours to produce androgens, in mice with oestradiol benzoate injections. Shim- as they do in the pre-pubertal cases. One adult kIn et al.30 produced the same effect in mice with case reported by Venning et al.36 was, in fact, implants of stilboestrol pellets. found to be excreting as much as 1,015 mg. of It has been suggested, on the basis of these I7-ketosteroids daily, but this is an exception to experimental tumours, that interstitial cell tumours the general rule, and other authors (Cook et in man are caused by excessive stimulation of al.,6 Newns25 and Philip27) have reported ex- March I960 PHILIP: Feminizing Tumours of the Testis Postgrad Med J: first published as 10.1136/pgmj.36.413.190 on 1 March 1960. Downloaded from tumours have ever been reported in humans. However, Teilum32 reports a Sertoli cell tumour in a 53-year-old male, giving rise to gynaecomastia. Stalker and Hendry31 discuss hyperplasia and neo- plasia of the Sertoli cell and describe one case in a I 7-year-old male with no endocrine symptoms, but with undoubted Sertoli cell tumour formation. Innes"9 classified these tumours in dogs as' tubular adenomata ' and reports I 5 such cases from a study of 52 animal testicular tumours. In five of these the testis was found to be ectopic and two cases gave rise to feminizing symptoms. The first histological description of Sertoli cell tumours in the dog was given by Peyron26 some 38 years ago. Huggins and Moulder18 describe five dogs with feminizing testicular tumours of spon- taneous origin, all sexually attractive to other dogs, and all with hypertrophy of mammary papillae. One dog lactated spontaneously, two lactated after b::b. prolactin injections. Seven testicular tumours were present in the five dogs (bilateral tumours in two dogs). The tumours were-classified as Sertoli cell tumours by these authors, the evidence being based on histochemical study of the lipoids and an kOe...f} oestrogen extraction and assay. The oestrogen Protected by copyright. content of the cells was found to be considerable. In one case the oestrogen content of the lipoid- rich was equivalent to 0.07 mg./km. on bioassay, calculated as c-oestradiol benzoate, being twice the content of the at oestrus and one-third of the amount in equine testis- FIG. 4.-Sertoli cell tumour. A higher powered viewv of the section in Fig. 3, to show individual Sertoli the richest known source of oestrogen. The cells. 1I. and E. x 0oo. ' feminizing ' symptoms of such tumours are assumed to be caused by the excessive oestrogen production of the Sertoli cells. cretion to be within normal limits in post-pubertal Many authors suggest that interstitial cell cases. There is no doubt that these tumours are tumours producing symptoms of feminization in capable of producing both male and female hor- adults are, in reality, Sertoli cell tumours elabor- http://pmj.bmj.com/ mones and further research would be most ating oestrogens. However, histologically the two profitable. tumours are quite different and there is no reason It could be that in adults with interstitial cell why they should be mistaken for one another. tumours and apparently no symptoms the tumour Certain cases of male pseudohermaphroditism are may be producing androgens and any symptoms found to have 'multiple tubular adenomata' in might pass unnoticed. Similarly, symptoms may their ectopic testes, absent ovaries and well- pass unnoticed in children before puberty if ex- marked gynaecomastia. Such cases were first cessive oestrogens are being elaborated by the investigated by Pick in I905,28 and later by on September 25, 2021 by guest. tumour. Kruckmann in 1937.21 The symptoms of gynae- comastia in such cases can be relieved by bilateral Sertoli Cell Tumours orchidectomy. The Sertoli cell is generally The microphotographs shown in Figs. 3 and 4 accepted as giving rise to these tumours. Witschi are typical sections of a Sertoli cell tumour from and Mengert* found an abundance of Sertoli cells a poodle dog aged I4 years. An enlargement of in abdominal testes of human hermaphrodites, to one testicle had been present for five years before which they ascribed the production of oestrogen. orchidectomy, but unfortunately no further de- Oestrogen was being excreted in the urine and tails of symptoms are available. Tumours of the disappeared after castration. Also' tubular adeno- sustentacular cells of Sertoli are quite common in mata' were reported in cryptorchid testes by dogs, but extremely rare in humans; in fact, some Vines.38 ' Sertoli cell adenomata ' are thus seen on authors doubt whether genuine Sertoli cell occasion in abnormal, immature and undescended 194 POSTGRADUATE MEDICAL JOURNAL March I960 Postgrad Med J: first published as 10.1136/pgmj.36.413.190 on 1 March 1960. Downloaded from

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FIG. 5.-Specialized gonadal stromal tumour of testis. FIG. 6.-Section of chorionepitheliomatous metastasis The tumour structure is of ' mixed ' type containing in lymph gland x IOO. spindle and interstitial cells. The patient, a young adult, had no endocrine symptoms. in two of the reported cases and seven from the testes, although in such cases every gradation can literature. The authors suggest that these tumours be found between mere hyperplasia of the cells, arise from cells of the specialized gonadal stroma

through nodules of tubular hyperplasia, to actual rather than from the germ cells of the testis. Fig. 5 http://pmj.bmj.com/ Sertoli cell tumour formation. is a section of one of these specialized gonadal stromal tumours (' androblastoma') and the Specialized Gonadal Stromal Tumours tumour structure is of mixed type, containing This description was coined by Mostofi et al.24 spindle and interstitial cells. This particular to describe tumours of the testis whose histological specimen was from an adult male and no particular picture varied from fairly differentiated epithelial hormonal symptoms were apparent. forms resembling Sertoli cells or granulosa cells to a -variety consisting almost entirely of fibro- Chorionepithelioma of the Testis on September 25, 2021 by guest. blast-like cells. This nomenclature dispensed with This is a rare, highly malignant and invasive such names as ' granulosa-celled tumours' and tumour and metastases may arise from a relatively ' androblastomata '. The name Sertoli cell tumour, small primary growth. Gynaecomastia is often however, should not lose its identity and be in- associated with choriogenic tumours of the testis. cluded in this group, because it is so obviously The patient may present with a testicular swelling, well defined and has such a typical histological enlargement of the breasts, hyperplasia of the picture. The cell pattern of these tumours (23 areolae and symptoms of impotence or loss of reported) varied considerably. Five of the reported libido. The testicular growth may contain obvious cases consisted entirely of epithelial cells resemb- chorionic elements on section and after orchid- ling Sertoli cells, granulosa cells, interstitial cells ectomy the following sequence of events may and lutein cells and the rest contained, in additions occur: (i) If metastases are already present the spindle-shaped cells. Gynaecomastia was present, ' feminizing symptoms' and the gynaecomastia March I PHILIP: Feminizing Tumours of the Testis I95 960 Postgrad Med J: first published as 10.1136/pgmj.36.413.190 on 1 March 1960. Downloaded from will remain. (ii) If no metastases are present the is no doubt that ' chorionic' testicular tumours, gynaecomastia will disappear, only to return again and metastases arising therefrom, which are if, and when, metastases occur. capable of elaborating chorionic gonadotrophin, A of the testis, containing apparently also possess the ability to elaborate oestrogens, only mature elements, on section, may give rise and it is in all probability the oestrogens which are to symptoms of choriogenic gynaecomastia. In responsible for the-symptom of gynaecomastia. some such cases, of course, a small area of chorionic tissue could be missed, despite careful and serial Discussion sectioning of the whole tumour, but a number of The more one reflects upon the mechanisms of cases are on record where apparently very well- hormonal changes resulting from tumours of the differentiated and mature teratomata have given testis the more it is realized how little is known rise to chorionepitheliomatous metastases. Two about the normal physiology of testicular function. such cases are described by Brewer,4 in which There is no doubt that the testis, besides elabor- section of the tumours showed no chorionic tissue, ating androgens, also produces oestrogens. but both patients died of chorionepitheliomatous Goldzieher and Roberts1' detected the presence metastases. of oestradiol-17f in human testicular tissue. Diczfalusy8 has shown that pooled human semen The section of a cervical lymph gland in Fig. 6 contains oestradiol-I7P7, oestrone and oestriol. is from a young adult male who presented with a Various authors, Vidgoff et al.37 and Berthrong2 testicular swelling and no other symptoms. The have suggested that the Sertoli cells are respon- tumour was removed and found to be a teratoma sible for producing oestrogens and there is much containing mature elements only; despite diligent evidence to support this view. Normal oestrogen sectioning of the whole tumour, no chorionic excretion in man is as follows: Oestriol 3.5 ,ug. elements were found. Six months later the patient per 24 hours, oestrone 5.4 Fg. per 24 hours, developed gynaecomastia and impotence; an en- Protected by copyright. oestradiol-17t I.5 tg. per 24 hours.5 The testis larged cervical gland was removed for biopsy and is unique in that it is the only endocrine organ in found to contain a chorionepitheliomatous meta- the body producing two quite different hormones stasis. A series of I35 cases of choriogenic tumours of the testis, with gynaecomastia, was side by side, each with separate and often opposing reviewed by Gilbert.10 He made a detailed study effects on the body. of 46 cases resulting from a primary or metastatic It is by the harmonious balance of these hor- chorionepitheliomatous tumour of the testicle and mones that testicular tissue exerts its influence found the following characteristics: the gynaeco- and so affects the character, outlook and behaviour mastia was usually bilateral, with glandular tissue of the individual. Just how the fine balance is hyperplasia, and was often the only clinical symp- maintained is not known with any degree of tom present. There was enlargement or hyper- certainty, although the pituitary has some very pigmentation of the areolae and physiological important controlling influence. The interstitial activity of the breasts, characterized by either gross cell-stimulating hormone (ICSH) of the anterior

pituitary is thought to stimulate the interstitial http://pmj.bmj.com/ or microscopic secretion. cells of the testis to produce testosterone. The High titres of choriogonadotrophic hormones follicular-stimulating hormone (FSH) is supposed and the excretion of abnormally large amounts of to stimulate the development of the germinal epi- oestrogens were found. Histological changes in thelium at puberty and enables normal spermato- the pituitary gland of adenomatosis, acidophilia genesis to continue during adult life. Oestrogen and basophilia, frequently described as ' preg- will suppress the secretion of FSH. Similarly, nancy changes', were often present. He also testosterone checks further secretion of ICSH. found, in some cases, hyperplasia of the prostate Thus reciprocity exists between the testis and the on September 25, 2021 by guest. and seminal vesicles. In half the cases studied pituitary through the so-called' feed-back' mech- positive Aschheim-Zondek tests were obtained, anism. However, Heller and Nelson,14 and McCul- yielding assays of from 3,ooo to i,ooo,ooo mouse lagh and Hruby,2' demonstrated that androgens units. The qualitative Friedman test was found to are relatively weak inhibitors of pituitary gonado- be positive in nine cases. trophic secretion, compared with oestrogens, and Hamburgerl2 reported that the oestrogen output Klinefelter et al.20 have suggested that the action in patients with chorionepithelioma of the testis of testosterone in inhibiting pituitary gonado- is usually very high. He also succeeded in demon- trophin may depend on its conversion to oestro- strating human chorionic gonadotrophin activity gens. -It is well known that testosterone can be in extracts of tumour tissue and concluded that easily converted into oestrogens by the the growth itself, and not the anterior pituitary, tissues.1' 13, 39 Nevertheless, whatever balance is was responsible for the hormone production. There maintained by the pituitary between the two types POSTGRADUATE MEDICAL JOURNAL March I I96 960 Postgrad Med J: first published as 10.1136/pgmj.36.413.190 on 1 March 1960. Downloaded from of sex hormones, it undoubtedly breaks down in the tumours ' and in chorionepithiolomata of the case of an interstitial cell tumour of the testis testis is presumably the excessive oestrogen occurring before puberty. The tumour produces elaboration by the tumour cells and would not an excess of androgens which do not seem to be seem so difficult to account for as in the case of the ' damped down ' or controlled by any ' feed-back ' interstitial cell tumours. mechanism and are responsible for the seemingly uncontrolled effects of . The Conclusion identical tumour occurring in an adult after The symptoms of feminization which accom- puberty has a completely different effect. It would pany certain testicular tumours are sometimes seem here that the controlling influence of the difficult to explain, and this is undoubtedly true pituitary is over-successful and excessive amounts with regard to interstitial cell tumours, which are of oestrogen are produced to counteract the secre- responsible for such different symptoms in the two tions of the interstitial tumour cells. The result of age groups. It is hardly surprising, however, when this excess of oestrogen production is feminization. one considers how little is known about the details Before puberty the testosterone elaborated by of normal testicular function and the mechanisms the testis may be chemically different and may not which are responsible for the changes occurring have the same effect as an inhibitor of pituitary at puberty. gonadotrophin, although hormonally capable of The tumours which have been described should producing the changes of puberty. After puberty be more fully investigated, as so far information the type of testosterone may be a more active about them is scanty and only comparatively few inhibitor of pituitary gonadotrophin and may be reports of hormonal assays are available. Pre- more easily converted into oestrogen. This would operative and post-operative hormonal assays and, explain, in part anyway, the totally different effects where possible, biosynthetic studies incorporating of an interstitial cell tumour in an adult and a tumour tissue, should be performed in each case. child. Only then can we hope to advance our knowledgeProtected by copyright. It is likely that the testis functions quite dif- of both normal and abnormal testicular function. ferently before and at the time of puberty com- An ideal report on the results of investigations pared with its function in later adult life. should include hormone assay of oestrogens and Hooker,17 in studying young bulls at the time of I 7-ketosteroids and quantitative Aschheim-Zondek puberty, when the accessory sex organs develop tests, both before and after orchidectomy, an suddenly, found that there was no correspondingly histological report on the section of the tumour, large or sudden increase in the content of androgen and biosynthetic studies incorporating tumour in the testes. Presumably, he says, it is not the tissue. It is realized that few hospitals are equipped actual level of androgen in the testes, but rather for such examinations, but feminizing tumours of the responsiveness of the accessory organs to the the testis are rare enough to warrant full investiga- androgen, which undergoes a sudden rise at tion at suitable centres. puberty. This difference in responsiveness of the Summary accessory organs may be, in fact, due to a slight Some rare testicular tumours, capable of causing http://pmj.bmj.com/ difference or modification in the type of androgen symptoms of feminization, are described. The produced at puberty. literature is reviewed and some speculations are Another possibility is that an interstitial cell made regarding the mechanisms whereby the tumour elaborates androgens (as one would expect) changes in endocrine balance are brought about. at the beginning of its growth, and in an adult A plea is made for more complete investigation of symptoms of 'increased virilism', so obvious in these tumours from a functional and biochemical young children, may pass unnoticed. As the point of view. tumour enlarges, however, and becomes more on September 25, 2021 by guest. autonomous it may lose its secreting ability. Its Acknowledgments original androgen production, however, may have I wish to convey my thanks to Mr. A. W. engendered an ' oestrogenic' response from the Badenoch, M.D., Ch.M., F.R.C.S., of St. pituitary, which may continue and be responsible Bartholomew's Hospital, and R. M. Mulligan, for the feminizing symptoms. Yet another ex- M.D., Professor of Pathology in the University of planation for the paradoxical behaviour of these Colorado Medical Centre, for help and advice, tumours in adults is that excessive androgenic and also to Dr. R. R. Rember, M.D., of the hormones produced by the tumour are converted Department of Pathology, and Mr. Jack Fason, to oestrogens, and there is ample evidence that this of the Photographic Department, Denver Veterans' conversion can and does take place. Administration Hospital, for their kind co-opera- The cause of the feminizing symptoms which tion and advice in preparing the illustrations. occur in Sertoli cell tumours, in' gonadal stromal Continued on page 200. 200 POSTGRADUATE MEDICAL JOURNAAL March I960 Postgrad Med J: first published as 10.1136/pgmj.36.413.190 on 1 March 1960. Downloaded from the normal adrenal occurs in Conn's syndrome, it tion of such patients should therefore include is confined to the fasciculata. renal arteriography as well as intravenous pye- Removal of the adenoma may be followed by a lography. Urinary pressor amines must algo be period of mild aldosterone insufficiency in which measured. In doubtful cases surgical exploration the electrolyte abnormalities are reversed, hypo- of the adrenals is indicated and should be carried tension may occur, and glomerular filtration rate out without delay. decrease. Sometimes the blood pressure falls to normal after operation but rises again a few months REFERENCES I. BARRETTr, P. K. Ml., REES, J. R., and MARRACK, D. later. In such cases the remission is probably due (i959), Brit. mzed. .7., ii, 1047. to hypoaldosteronism. 2. BROWN, M. R., CURRENS, J. H., and MARCHAND, J. F. ('944).)Y. Amer. med. Ass., 124, 545. The differentiation of Conn's syndrome from 3. CHALMERS, T. M., FITZGERALD, M. G., JANIES, A. H., other causes of hypertension with hypokalaemia and SCARBOROUGH, H. (1956), Lancet, i, I27. may be extremely difficult. Cases of renal tubular 4. CONN, J. WV., and LOUIS, L. H. (i95o),J. clin. Endocr., I0, I2. or Fanconi syndrome can now be clearly 5. CONN, J. WV. (0955), Y. Lab. clin. Med., 45, 6. acidosis 6. CONN, J. XVI., and LOUIS, L. H. (1956), Ann. intertn. Mled., distinguished by the presence of metabolic 44, I. acidosis and the absence of increased mineralocor- 7. DOLLERY, C. T., SHACKMAN, R., and SHILI,NG- FORD, J. (I959), Brit. nied. Y., ii, I367. ticoid activity. Fitzgerald et al.,8 however, re- 8. FITZGERALD, M. G., FOURMAN, P., JAMES, A. H., and ported a case of malignant hypertension with SCARBOROUGH, H. (I957), Scot. nied. .7., 2, 473. alkalosis and increased 9. FOYE, L. V., Jnr., and FEICHT'MEIR, T. V. (I955), Amer. potassium depletion, Y. Med., I9, 966. urinary aldosterone in whom removal of one io. GRUNDY, H. MI., and SIMPSON, S. A. 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