Sertoli cell hyperfunction with low FSH in a pubertal boy with bilateral macroorchidism

ROMINA GRINSPON; PAULA SCAGLIA; STELLA CAMPO; DÉBORA BRASLAVSKY; IGNACIO BERGADÁ; HORACIO DOMENÉ; MIRTA GRYNGARTEN; RODOLFO REY

Houston

Congreso; 94th. Annual Meeting of the Endocrine Society; 2012

Endocrine Society

Background: Bilateral macroorchidism has been described with no testicular hyperfunction in Fragile X syndrome, testicular adrenal rest tumors or other infiltrative disorders, and with testicular hyperfunction, due to increased gonadotropin signaling activity, in gonadotropin-secreting adenomas, McCune-Albright syndrome, aromatase deficiency and severe hypothyroidism. Testis size is mainly dependent on Sertoli cell number before puberty and on germ and Sertoli cell number after pubertal onset. FSH is the most conspicuous regulator of Sertoli cell proliferation, by activating FSH-R coupled to Gsα protein.Clinical case: A 10-yr-old boy presented with a remarkable discordance between enlarged testes (20 ml) and penis and pubic hair corresponding only to incipient Tanner stage 3. He had bilateral mild gynecomastia. No signs of Fragile X or McCune-Albright syndrome, infiltrative disorders, CAH, aromatase deficiency or hypothyroidism were present. Inhibin B was abnormally high at 464 pg/ml (Tanner 3 range: 126-257), and basal FSH was low at 0.76 IU/L (1.43-7.44) with no response to GnRH (0.97 IU/L). Discordantly, T was 263 ng/dl (12-368) and basal LH 2.23 IU/L (0.67-4.65) with a normal response to GnRH (15.8 IU/L). E2 was 14 pg/mL (10-35). During 2-yr follow-up, testicular size increased to >25 ml and penis and pubic hair progressed to Tanner stage 5. Gynecomastia regressed. Inhibin B persisted high at 628 pg/ml (118-340) with FSH low at 0.82 (1.14-6.99) and normal T and LH. With suspicion of FSH-R constitutive activation, FSHR gene coding and flanking intronic regions (exons 1 to 10) were sequenced: 3 SNPs in heterozygosis in noncoding regions and 2 SNPs in homozygosis in coding regions were identified, but no allegedly activating mutation was found.Conclusion: Macroorchidism, with normal pituitary-gonadal axis function, may be a normal variant. Alternatively, macroorchidism may be a sign of gonadal hyperfunction. Increased testicular activity may involve both tubular and interstitial compartments or be dissociated. A dissociated primary testicular hyperfunction restricted to Sertoli cells is likely the underlying cause of macroorchidism in this patient. An activating mutation of the FSH-R could not be evidenced.