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Testotoxicosis: Gonadotrophin - Independent Male Sexual Precocity

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Testotoxicosis: Gonadotrophin - Independent Male Sexual Precocity Postgrad Med J: first published as 10.1136/pgmj.68.797.225 on 1 March 1992. Downloaded from Postgrad Med J (1992) 68, 225 - 228 i) The Fellowship of Postgraduate Medicine, 1992 Testotoxicosis: gonadotrophin - independent male sexual precocity ArifAbdul Aziz, S.M.W. Jafri and Naeem Ul Haque Department ofMedicine, The Aga Khan University Hospital, Stadium Road, PO Box 3500, Karachi 74800, Pakistan Summary: In this era of rapidly developing investigational tools and pharmacology, the patho- physiology of precocious puberty is becoming well defined. What was previously thought to be a form of gonadotrophin releasing hormone (GNRH)-dependent central precocious puberty is now classified as GNRH-independent familial testotoxicosis. We present two such cases and review the clinical features, pathophysiology and treatment of testotoxicosis. Introduction Sexual precocity is defined as the appearance of medications during pregnancy. He was noted to physical signs of puberty before 8 years of age in have a rather large penis at 6 weeks of age when he females or 9 years of age in males. The clinical was circumcised. At the age of 6-9 months pubic disorders that induce sexual precocity can be hairs were noted. At age 2 years his height was by copyright. classified as gonadotrophin releasing hormone 99.7 cm and weight was approximately 15 kg both (GNRH) dependent or GNRH independent.' being above 97th percentile. He had a bone age of Male sexual precocity first described as a form of 6.4 years. He had stage IV genital development, central precocious puberty has recently been char- Stage IV pubic hair and testicular volume of 8 ml acterized as a familial intratesticular disorder.2'3 (Figures 1 and 2). His voice was husky and he was Sexual development, symmetrical testicular enlarge- extremely hirsute. There was no family history of ment and accelerated rate of growth are noted by precocious puberty. Reports of hormonal assays 3 -4 years ofage."3 The pulsatile pattern ofluteiniz- are shown in Table I. An overnight gonadotrophin ing hormone (LH) secretion and the immuno- profile showed low level pulsatility of LH but no http://pmj.bmj.com/ reactive and bioactive LH responses to GNRH are measurable follicle stimulating hormone (FSH). similar to these seen in prepubertal children despite Testicular biopsy showed Leydig cell hyperplasia. markedly elevated concentrations of serum testos- An injection of Lupron (LHRH agonist) increased terone. We describe two sporadic cases and will serum testosterone to 1064.8 ng/dl. Computed review clinical features, diagnosis and treatment of tomographic (CT) scan of the brain and adrenal testotoxicosis. was normal as was ultrasound of the testes and adrenals. on September 29, 2021 by guest. Protected Case report Case 2 Case I This patient presented to us at 8 years of age. He was born full term and there was no history of any The first patient, born in December 1986, the drug intake except diazepam by his mother. At 3 product of normal pregnancy delivered by Caesa- years of age he was found to have enlargement of rean section due to transverse lie, weighed the penis and appearance of pubic hair. At presen- approximately 6 lb at birth. The mother took no tation his height was 135 cm and weight was 32 kg. There were downy facial hairs. Axillary hairs were present. The penis was 7-8 cm in length and pubic hair was Tanner Stage IV. The right testis was 10 ml in volume and the left was 12 ml. Investiga- tions revealed a bone age of 14 years. X-ray skull Correspondence: S.M.W. Jafri, F.R.C.P.(Edin.). and CT scan of brain were normal. Hormonal Accepted: 22 July 1991 assay results are shown in Table I. Postgrad Med J: first published as 10.1136/pgmj.68.797.225 on 1 March 1992. Downloaded from 226 CLINICAL REPORTS Figure 2 Case 2. The patient aged 2 years. Table I Endocrine screening Case Case Normal Hormone 1 2 range by copyright. Serum testosterone (ng/dl) 598.0 631.0 4.1-9.1 Dehydroepiandrostenedione 21.4 310.5 60-254 (tg/dl) Serum follicle stimulating < 1.5 < 1.7 1-16 hormone (mIU/ml) Serum luteinizing hormone < 2.8 < 1.0 1.8-6.0 (mIU/ml) http://pmj.bmj.com/ age. Enlargement of external genitalia may be noted as early as birth.5 The testes may be appropri- ate in size or slightly small in relation to the stage of sexual maturation. Rapid virilization and prema- ture epiphyseal fusion results in short adult sta- ture.76,7 Figure 1 Case 1. The patient aged 2 years. The hypothalamic-pituitary gonadotrophin unit operates at a prepubertal level in these patients.8 on September 29, 2021 by guest. Protected The characteristic findings are low basal gonado- trophin levels, absence of sleep-associated LH pulses and lack of a pubertal-type rise in LH Discussion concentration after luteinizing hormone releasing factor (LHRF). However, affected adults show a Testotoxicosis or familial male precocious puberty mature LH response to LHRF, whereas FSH is is a form of isosexual precocious puberty, that is elevated in adults with seminiferous tubule independent of gonadotrophin releasing hormone. damage, provding evidence that central regulatory The pattern of inheritance is autosomal dominant, pathways are intact. There is lack of excessive although sporadic cases can occur.4 Transmission testosterone response to administration of human is through affected males or carrier females to their chorionic gonadotrophin (HCG) in boys and sons. absence of testosterone increase after LHRF in Clinical features are characterized by sexual adults, despite substantial rises in plasma LH development, symmetrical testicular enlargement levels. All the above findings are consistent with a and acclerated rate of growth seen by 3-4 years of primary testicular defect.' Testicular histology Postgrad Med J: first published as 10.1136/pgmj.68.797.225 on 1 March 1992. Downloaded from CLINICAL REPORTS 227 shows hyperplasia ofLeydig cells.9 In some affected are its potential hepatotoxicity and the fact that its adults, germ cell degeneration, progressive dys- use is limited to those patients whose bone age has function of spermatogenesis and elevated levels of reached pubertal age.'0 Another approach is block- FSH have been observed.9 '0 ade of androgen action with spironolactone.4"82' The pathophysiology of premature Leydig cell The commonest problem with spironolactone is activation has still not been clearly elucidated. development ofgynaecomastia. Evidence that oes- Salient features of various hypotheses are as fol- trogens may have an important role in the male lows. Negative LH-HCG activity by bioassay pubertal growth spurt22-24 has led to the use of argues against the presence of a circulating testolactone, a competitive inhibitor ofthe enzyme gonadotrophin-like factor.3'5 In addition, indirect aromatase, which converts androgens to oestro- immunofluorescence studies have been unable to gens.25127 There is recent evidence that combination identify a serum immunoglobulin in these patients, of spironolactone and testolactone may be more comparable to thyroid stimulating hormone beneficial than either alone.4 immunoglobulin in thyrotoxic patients. Derange- In conclusion familial testotoxicosis is a disorder ment of an intratesticular regulatory mechanism of male isosexual precocity that is inherited as that inhibits Leydig cell function leading to unre- an autosomal dominant condition (although spor- strained activity of these cells has also been pro- adic cases can occur) characterized by gonado- posed.3"''3 Premature Leydig cell activation may trophin-independent testicular hypersecretion. also result from local production of a stimulatory This condition should be differentiated from gona- factor not detectable in the circulation that stimu- dotrophin-dependent true precocious puberty as lates CAMP-dependent kinase to induce testoster- treatment with LHRH analogues may aggravate one secretion. For example, immunoreactive testotoxicosis. Treatment has not yet been well HCG-like material has been identified in extracts of defined and should be individualized for each case. human testes and other tissues,3'14 and human fetal We believe our two cases either represent sporadic testes appear able to synthesize HCG.3"5 cases or may be a new gene mutation in these two Various treatment options have been proposed families; long-term follow-up may answer the issue. by copyright. for testotoxicosis. Initial reports showed that medroxyprogesterone acetate and anti-androgen cypropterone acetate may have some therapeutic Acknowledgement benefit.5"0 The mode of action of ketoconazole is inhibition ofsynthesis ofboth adrenal and gonadal We thank Sulaiman S. Gilani and Rozina A. Babul for steroids.'01"67 The disadvantages of ketoconazole secretarial help. References http://pmj.bmj.com/ 1. Kaplan, S.L. & Grumbach, M.M. Pathophysiology and 9. Gondos, B., Egli, C.A., Rosenthal, S.M. & Grumbach, M.M. treatment of sexual precocity. J Clin Endocrinol Metab 1990, Testicular changes in gonadotropin-independent familial 71: 785-789. male sexual precocity: familial testoxicosis. Arch Pathol Lab 2. Schedewie, H.K., Reiter, E.O., Beiten, I.Z. et al. Testicular Med 1985, 109: 990-995. Leydig cell hyperplasia as a cause offamilial sexual precocity. 10. Holland, F.J., Fishman, L., Bailey, J.D. & Fazekas, A. J Clin Endocrinol Metab 1981, 52: 271-278. Ketoconazole in the management of precocious puberty not 3. Egli, C.A., Rosenthal, S.M., Grumbach, M.M., Montalvo, responsive to LH RH therapy. N Engl J Med 1985, 312: J.M. & Gondos, B. Pituitary gonadotrophin independent 1023-1028. male limited autosomal dominant sexual precocity in nine 11. Aoki, A. & Fawcett, D.W. Is there a local hormone from the on September 29, 2021 by guest. Protected generations: 'Familial Testotoxicosis'. J Pediatr 1985, 106: seminiferous tubules affecting activity of Leydig cells? Biol 33-40. Reprod 1987, 19: 144. 4. Lave, L., Keningsberg, D., Percovitz, O.H.
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