Treatment of gonadotropin-deficient boys with recombinant human FSH: long-term observation and outcome

Abstract

Background: Boys with prepubertal onset of hypogonadotropic hypogonadism (HH) are at a risk of poor testis growth and impaired spermatogenesis. One potential cause for this is deficient proliferation of immature Sertoli cells before and during puberty due to the absence of FSH. Objective: To evaluate the effects of recombinant human FSH (r-hFSH) and human chorionicgonadotropin (hCG) on testicular function and pubertal development in boys with prepubertal onset of HH. Design: Retrospective clinical study. Setting: Two university central hospitals, pediatric referral endocrinology outpatient clinics. Patients: Fourteen boys (aged, 9.9-17.7 years) with prepubertal (testicular volume (TV) !3 ml) onset of HH (idiopathic HH, nZ2; Kallman syndrome, nZ2; idiopathic panhypopituitarism, nZ4; organic panhypopituitarism, nZ6). Intervention: Treatment with r-hFSH alone (2 mo-2.8 years) prior to induction of puberty with the combination of FSH and hCG. Main outcome measures: Progression of puberty, change in serum inhibin B, spermatogenesis. Results: r-hFSH alone increased testicular volume twofold, from 0.9G0.6 ml (meanGS.D.) to 1.8G 1.1 ml (P!0.005), and serum inhibin B threefold, from 27G14 to 80G57 pg/ml (P!0.01). Three boys with an apparent absence of postnatal hypothalamic-pituitary-testicular axis activation displayed attenuated inhibin B responses to long-term (R1 year) r-hFSH (P!0.01). Further significant increase in both TVand inhibin B occurred with induction of puberty with FSH and hCG (P!0.001). Seven boys provided semen samples: one had azoospermia, and others displayed a maximal sperm count range from 2.9 to 92 million/ml (median 8.5 million/ml). Conclusions: (i) r-hFSH induces prepubertal testis growth and increases circulating inhibin B levels, findings suggesting proliferation of immature Sertoli cells. (ii) Puberty was successfully induced with hCG and r-hFSH following r-hFSH priming. (iii) Inhibin B appears useful for monitoring spermatogenetic activity in boys treated with hCG. (iv) Despite the extremely small initial testis volume, six out of seven patients (86%) primed with r-hFSH displayed sperm in the ejaculate suggesting beneficial effect of r-hFSH priming on testicular function later in life.

Metabolic evidence for impaired 17α-hydroxylase activity in a kindred bearing the E305G mutation for isolate 17,20-lyase activity

“…One explanation for the testicles growth during puberty in the affected members IV5, IV6, and IV7 can relate to their high follicle-stimulating hormone (FSH) levels, stimulating the growth of testicular tubules (17). The gynecomastia in these patients can be due to the low levels of androgens that resolved partially during testosterone replacement treatment.…”

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…198 In the most severely affected men with CHH (testicular volume <4 ml), a sequential treatment has emerged in an attempt to maximize fertility potential. 10,209,210 The unopposed FSH treatment before maturation by hCG (or alternatively, GnRH-induced LH) stimulates proliferation of immature Sertoli and germ cells. Outcomes of patients treated with this regimen demonstrate successful induction of testicular development and fertility in men with CHH who have prepubertal testes.…”

“…Outcomes of patients treated with this regimen demonstrate successful induction of testicular development and fertility in men with CHH who have prepubertal testes. 10,210 To definitively determine the optimal approach to fertility treatment in men with CHH and severe GnRH deficiency (with or without cryptorchidism), an international, multicentre randomized trial is needed (Box 3).…”

Factors affecting spermatogenesis upon gonadotropin‐replacement therapy: a meta‐analytic study

“…From animal models, it appears that there is a pre-pubertal window when FSH can induce Sertoli cell proliferation in immature testis, closed by the subsequent production of androgens from Leydig cells (Majumdar et al, 2012). In line with this hypothesis, FSH treatment in adolescents with pre-pubertal onset HHG, used as a priming before adding hCG, has been demonstrated to be able to induce inhibin B increase, testis growth and pubertal development (Raivio et al, 1997(Raivio et al, , 2007b as well as achievement of spermatogenesis. These effects have been ascribed to a FSH-mediated proliferation and maturation of Sertoli cell, that is lost in subjects with gonadotropin deficiency.…”