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1320 DR. MALLICK, DR. BERLYNE: REFERENCES Berlyne, G. M. (1968) Lancet, ii, 368. Dent, C., Harper, C. M., Philpot, G. R. (1961) Q. Jl Med. 30, 1. Franklin, S. S., Gordon, A., Kleeman, C. R., Maxwell, M. H. (1967) J. Am. med. Ass. 202, 141. Friis, T., Hahnemann, S., Wecke, E. (1968) Acta med. scand. 183, 497. Giordano, C. (1963) J. Lab. clin. Med. 62, 23. Giovannetti, S., Maggiore, Q. (1964) Lancet, i, 1000. Liu, S. H., Chu, H. I. (1943) Medicine, Baltimore, 22, 103. Mallick, N. P., Berlyne, G. M. (1968) Unpublished. Shaw, A. B., Bazzard, F. J., Booth, E. M., Nilwarangkur, S., Berlyne, G. M. (1965) Q. Jl Med. 34, 237. Stanbury, S. W. (1957) Br. med. Bull. 13, 57. &mdash; (1962) in Renal Disease (edited by D. A. K. Black); 1st ed. Oxford. (1967) ibid. 2nd ed. - Lumb, G. A. (1966) Q. Jl Med. 35, 1. LEPROUS ENDOCRINOPATHY F. I. R. MARTIN M.D. Melb., F.R.A.C.P. SENIOR ASSOCIATE, DEPARTMENT OF MEDICINE, UNIVERSITY OF MELBOURNE IAN MADDOCKS M.D. Melb., F.R.A.C.P. LECTURER IN MEDICINE, PAPUAN MEDICAL COLLEGE, PORT MORESBY J. B. BROWN Ph.D. N.Z. READER, DEPARTMENT OF OBSTETRICS, UNIVERSITY OF MELBOURNE BRYAN HUDSON M.D., Ph.D. Melb., F.R.C.P., F.R.A.C.P. PROFESSOR OF MEDICINE, MONASH UNIVERSITY, MELBOURNE Summary Urinary total gonadotrophins, urinary &oelig;strogens, and plasma-testosterone have been studied in patients with leprosy with and without gyn&aelig;comastia and testicular atrophy. Patients with gyn&aelig;comastia and testicular atrophy had significantly raised levels of gonadotrophins and lowered plasma- testosterone. It is suggested that leprous orchitis repre- sents a form of acquired Klinefelter’s syndrome. Introduction GYN&AElig;COMASTIA and testicular atrophy occur in 10-20% of patients with leprosy (Grabstald and Swan 1952, Job 1961). The testicular lesions appear to follow direct invasion by acid-fast bacilli, and in the chronic stage closely resemble the histological features of Klinefelter’s syndrome (Grabstald and Swan 1952, Hall 1959, Job 1961). We have investigated the endocrine changes associated with the development of gynxcomastia and testicular atrophy in patients with known chronic leprosy. Materials and Methods The patients studied were New Guinea males, resident at the Gemo Island Leprosy Hospital, Port Moresby. All were personally examined by one of us (I. M.), and features of gynaecomastia and testicular size were noted. Gynascomastia was graded according to Hall (1959). No patient was receiving any hormonal treatment at the time of the investigation, and none had evidence of progressive liver disease. Two 24-hour urine samples were collected at intervals of approximately 3 months from each patient. The pH was adjusted to 2-0 and the urine deep-frozen and subsequently air-freighted direct to Melbourne and re-frozen immediately on arrival (transit-time 12 hours). Blood-samples were collected; the plasma was separated immediately and frozen and air-freighted packed in dry ice in a vacuum flask. The normal subjects studied were New Guinean medical students or hospital personnel at the Port Moresby General Hospital with no clinical evidence of endocrine or liver disease. The two nrine-samntM from each natient were extracted and assayed for total gonadotrophins by the method of Johnsen (1958) modified by Martin (1964), the normal male range being 5-50 mouse units per day, and for oestrogens by the method of Brown et al. (1957), the normal male range being 5-22 fig. per day. A bacterial count was performed on each specimen. The plasma-testosterone was measured by the method of Hudson et al. (1963), the normal male range being 0-39-0-98 flg. per 100 ml. Results The details of patients studied, with the average value of the two separate assays for oestrogens and gonado- trophins, are listed in table i. Plasma-testosterone was not TABLE I-CLINICAL DETAILS AND VALUES OF URINARY TOTAL GONADOTROPHINS, URINARY CESTROGENS, AND PLASMA-TESTO- STERONE FOR NORMAL MEN AND LEPROUS NEW GUINEA MALES TABLE II-MEAN VALUES OF HORMONES STUDIED IN NORMAL AND LEPROUS NEW GUINEA MALES measured in all subjects. There was no evidence of significant bacterial contamination in any of the urine- samples. The findings are summarised in table n, which shows that the levels of urinary gonadotrophins rose progressively from normal subjects to leprous patients without gyn&aelig;comastia to hypogonadal levels in patients with gynxcomastia. The differences between each group were significant at the 5% level, and that between normals and leprosy patients with gynaecomastia at p= <0.01. There was an associated slight fall in urinary oestrogen excretion, but the normal male pattern of metabolites with cestriol predominating was preserved in nearly all patients. There was a significant fall (P=<0-01) in plasma- testosterone in the presence of gyn&aelig;comastia and testicular atrophy, but in those patients without gyn&aelig;comastia it was within the normal male range. Comment The hormonal changes in leprous endocrinopathy appear to have not been studied in detail previously. Grabstald and Swan (1952) reported elevated gonado-

Transcript of LEPROUS ENDOCRINOPATHY

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DR. MALLICK, DR. BERLYNE: REFERENCES

Berlyne, G. M. (1968) Lancet, ii, 368.Dent, C., Harper, C. M., Philpot, G. R. (1961) Q. Jl Med. 30, 1.Franklin, S. S., Gordon, A., Kleeman, C. R., Maxwell, M. H. (1967) J.

Am. med. Ass. 202, 141.Friis, T., Hahnemann, S., Wecke, E. (1968) Acta med. scand. 183, 497.Giordano, C. (1963) J. Lab. clin. Med. 62, 23.Giovannetti, S., Maggiore, Q. (1964) Lancet, i, 1000.Liu, S. H., Chu, H. I. (1943) Medicine, Baltimore, 22, 103.Mallick, N. P., Berlyne, G. M. (1968) Unpublished.Shaw, A. B., Bazzard, F. J., Booth, E. M., Nilwarangkur, S., Berlyne, G. M.

(1965) Q. Jl Med. 34, 237.Stanbury, S. W. (1957) Br. med. Bull. 13, 57.

&mdash; (1962) in Renal Disease (edited by D. A. K. Black); 1st ed. Oxford.- (1967) ibid. 2nd ed.- Lumb, G. A. (1966) Q. Jl Med. 35, 1.

LEPROUS ENDOCRINOPATHY

F. I. R. MARTINM.D. Melb., F.R.A.C.P.

SENIOR ASSOCIATE,DEPARTMENT OF MEDICINE, UNIVERSITY OF MELBOURNE

IAN MADDOCKSM.D. Melb., F.R.A.C.P.

LECTURER IN MEDICINE, PAPUAN MEDICAL COLLEGE, PORT MORESBY

J. B. BROWNPh.D. N.Z.

READER, DEPARTMENT OF OBSTETRICS, UNIVERSITY OF MELBOURNE

BRYAN HUDSON

M.D., Ph.D. Melb., F.R.C.P., F.R.A.C.P.PROFESSOR OF MEDICINE, MONASH UNIVERSITY, MELBOURNE

Summary Urinary total gonadotrophins, urinary&oelig;strogens, and plasma-testosterone have

been studied in patients with leprosy with and withoutgyn&aelig;comastia and testicular atrophy. Patients with

gyn&aelig;comastia and testicular atrophy had significantlyraised levels of gonadotrophins and lowered plasma-testosterone. It is suggested that leprous orchitis repre-sents a form of acquired Klinefelter’s syndrome.

Introduction

GYN&AElig;COMASTIA and testicular atrophy occur in 10-20%of patients with leprosy (Grabstald and Swan 1952, Job1961). The testicular lesions appear to follow directinvasion by acid-fast bacilli, and in the chronic stageclosely resemble the histological features of Klinefelter’ssyndrome (Grabstald and Swan 1952, Hall 1959, Job1961).We have investigated the endocrine changes associated

with the development of gynxcomastia and testicular

atrophy in patients with known chronic leprosy.Materials and Methods

The patients studied were New Guinea males, resident at theGemo Island Leprosy Hospital, Port Moresby. All were

personally examined by one of us (I. M.), and features ofgynaecomastia and testicular size were noted. Gynascomastiawas graded according to Hall (1959). No patient was receivingany hormonal treatment at the time of the investigation, andnone had evidence of progressive liver disease. Two 24-hoururine samples were collected at intervals of approximately3 months from each patient. The pH was adjusted to 2-0 andthe urine deep-frozen and subsequently air-freighted direct toMelbourne and re-frozen immediately on arrival (transit-time12 hours). Blood-samples were collected; the plasma wasseparated immediately and frozen and air-freighted packed indry ice in a vacuum flask. The normal subjects studied wereNew Guinean medical students or hospital personnel at thePort Moresby General Hospital with no clinical evidence ofendocrine or liver disease.The two nrine-samntM from each natient were extracted and

assayed for total gonadotrophins by the method of Johnsen(1958) modified by Martin (1964), the normal male range being5-50 mouse units per day, and for oestrogens by the method ofBrown et al. (1957), the normal male range being 5-22 fig. perday. A bacterial count was performed on each specimen. Theplasma-testosterone was measured by the method of Hudsonet al. (1963), the normal male range being 0-39-0-98 flg. per100 ml.

Results

The details of patients studied, with the average valueof the two separate assays for oestrogens and gonado-trophins, are listed in table i. Plasma-testosterone was notTABLE I-CLINICAL DETAILS AND VALUES OF URINARY TOTAL

GONADOTROPHINS, URINARY CESTROGENS, AND PLASMA-TESTO-

STERONE FOR NORMAL MEN AND LEPROUS NEW GUINEA MALES

TABLE II-MEAN VALUES OF HORMONES STUDIED IN NORMAL AND

LEPROUS NEW GUINEA MALES

measured in all subjects. There was no evidence of

significant bacterial contamination in any of the urine-samples. The findings are summarised in table n, whichshows that the levels of urinary gonadotrophins rose

progressively from normal subjects to leprous patientswithout gyn&aelig;comastia to hypogonadal levels in patientswith gynxcomastia. The differences between each groupwere significant at the 5% level, and that between normalsand leprosy patients with gynaecomastia at p= <0.01.There was an associated slight fall in urinary oestrogenexcretion, but the normal male pattern of metabolites withcestriol predominating was preserved in nearly all patients.There was a significant fall (P=<0-01) in plasma-testosterone in the presence of gyn&aelig;comastia and testicularatrophy, but in those patients without gyn&aelig;comastia it waswithin the normal male range.

CommentThe hormonal changes in leprous endocrinopathy

appear to have not been studied in detail previously.Grabstald and Swan (1952) reported elevated gonado-

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trophins and normal 17-ketosteroids in two patients, oneof whom had gynaecomastia. The present study has shownthat, in the presence of gynxcomastia and clinical testicularatrophy, men with leprosy have elevated urinary gonado-trophins, reduced plasma-testosterone, and slightlyreduced urinary oestrogens when compared with normal.Of particular interest was the trend observed for leprouspatients without clinical evidence of gynaecomastia ortesticular atrophy to have urinary gonadotrophin levelshigher than normal men of the same age and also slightlyreduced oestrogen excretion, but normal plasma-testo-sterone.

The similarity between the histological lesions of thetestes in leprosy and Klinefelter’s syndrome was firstcommented on by Grabstald and Swan (1952). Theystressed that the tubules were involved first by the disease,and that these then were obliterated by hyaline depositionassociated with endarteritis with associated clumping ofthe Leydig cells. The final stage was one of generalisedfibrosis. Job (1961) attempted to correlate the testicularlesion in leprosy with gynaecomastia and noted that, oftwenty cases, all had tubular hyalinisation, most had grossatrophy, and the majority had prominent clumping ofLeydig cells. The reason for the predilection for tubularinvolvement in leprosy is obscure, but Tilah (1968) hassuggested that it may represent a hypersensitivity reaction.The levels of urinary gonadotrophins and oestrogens and

of plasma-testosterone that we have found in patients withleprosy and gynxcomastia and testicular atrophy are verysimilar to those reported in Klinefelter’s syndrome (Giorgiand Sommerville 1963, Hudson and Coghlan 1968) andthus tend to substantiate the observed histologicalsimilarity. Since the testis is invaded in 90% of patientswith leprosy (Grabstald and Swan 1952) the finding thatthose without clinical testicular disease or gynaecomastiahad higher gonadotrophins and lower oestrogens thannormal men suggests that they also have some functionaltesticular involvement.

It seems likely that the mechanism of gonadotrophinelevation and oestrogen decrease observed in these patientsis the same as in Klinefelter’s syndrome, but whether thetwo are directly related as a feed-back system or are dueto a lack of the proposed tubular hormone " inhibin

"

(McCullagh and Schaffenburg 1952, Johnsen 1964) isunknown. The endocrine and pathological changes inleprous orchitis may provide a model by which moreinformation both on this intriguing problem and on thepathogenesis of gynaecomastia could be obtained.The help of the Matron and staff of Gemo Hospital, the technical

assistance of Mrs. A. Mirovics, Miss M. Smith, and Miss L. Peyton,and the assistance of Organon Australia in shipping specimens areacknowledged with thanks. The work was in part supported bygrants from the National Health and Medical Research Council ofAustralia.

Requests for reprints should be addressed to F. 1. R. M.,Endocrine Department, P.O. Royal Melbourne Hospital, Victoria,3050, Australia.

REFERENCES

Brown, J. B., Bulbrook, R. D., Greenwood, F. C. (1957) J. Endocr. 16, 49.Giorgi, F. P., Sommerville, I. F. (1963) J. clin. Endocr. Metab. 23, 197.Grabstald, H., Swan, L. L. (1952) J. Am. med. Ass. 149, 1287.Hall, P. F. (1959) Gyn&aelig;comastia. Sydney.Hudson, B., Coghlan, J. (1968) in Clinical Endocrinology II (edited by

E. Astwood); p. 563. New York.&mdash; &mdash; Dulmanis, A., Ekkel, I. (1963) Aust. J. exp. Biol. med. Sci. 41,

235.

Job, K. (1961) Int. J. Leprosy, 29, 423.Johnsen, S. G. (1958) Acta endocr., Kbh. 28, 69.- (1964) ibid. suppl. 90, p. 99.

McCullagh, E. P., Schaffenburg, C. A. (1952) Ann. N.Y. Acad. Sci. 55, 674.Martin, F. I. R. (1964) Med. J. Aust. ii, 408.Tilah, C. T. (1968) Leprosy Rev. 39, 31.

COMPARISON OF CLOMIPHENE AND

HUMAN GONADOTROPHINS IN

FAILURE OF OVULATION

A. D. TSAPOULIS*M.D. Athens

A. C. CROOKEM.D. Cantab., F.R.C.P.

From the United Birmingham Hospitals Department of ClinicalEndocrinology, Birmingham and Midland Hospital for Women,

Birmingham 11

Summary 36 women with failure of ovulation weretreated at different times with clomiphene

and with human gonadotrophins. Patients with earlymenopause and with primary amenorrhoea responded toneither form of treatment. Patients with secondaryamenorrhoea, no clinical evidence of &oelig;strogenic activity,and moderately increased gonadotrophins responded togonadotrophins but rarely to clomiphene. Patients withanovular menstruation, evidence of positive oestrogenicactivity, and low excretion of gonadotrophins respondedto gonadotrophins and, usually, to clomiphene also. Theaverage dosage of follicle-stimulating hormone (F.S.H.)required by patients with secondary amenorrhoea wasthree times greater than that required by those withanovular menstruation. The diagnosis of Stein-Leventhalsyndrome was not helpful in prognosis for treatment.

* Present address: Mazika Heliadi Maternity Hospital, Athens.

Introduction

THE value of clomiphene and of the human gonado-trophins, follicle-stimulating hormone (F.S.H.), andchorionic gonadotrophins (H.C.G.), for the treatment ofwomen with failure of ovulation during the childbearingperiod of life is now well established. It is generallyconsidered, however, that gonadotrophins are effective fora wider range of patients. We have compared the twomethods of treatment directly in the same individuals.

Patients, Materials, and MethodsPatients

36 women with failure of ovulation were treated at differenttimes with clomiphene and with gonadotrophins.

31 were given clomiphene first and 5 were given gonado-trophins first. Details are given in table 1. There were five

subgroups: premature menopause (3), primary amenorrhoeaassociated with low excretion of gonadotrophins (4), secondaryamenorrhoea of six months duration or more (15), anovularmenstruation with intervals of not more than five monthsduration (8), and Stein-Leventhal syndrome (6). 2 of the

patients with the Stein-Leventhal syndrome had secondaryamenorrhcea and 4 had anovular menstruation. Clinical data onthe uterus and ovaries, and an assessment of oestrogenic activitybased on the general examination and response to progestogensare also recorded in table I together with the urinary excretionof gonadotrophins measured by the mouse-uterine-weight assayand expressed as mg. equivalents of the first internationalreference preparation (r.R.P.) of human menopausal gonado-trophin (H.M.G.), called H.M.G. 24.TreatmentTreatment with clomiphene consisted of 50 or 100 mg. daily

by mouth for four days in succession starting on the fifth dayof the menstrual cycle in women with anovular cycles or on anyday at random in women with amenorrhoea. If the responsewas negative the treatment was repeated with 100 or 200 mg.daily for 4 days.Treatment with gonadotrophins has been described else-

where (Crooke et al. 1966 a, b, 1967). It consisted of giving