Role of seminiferous tubular development in determining the FSH versus LH responsiveness to GnRH in early sexual maturation.

BACKGROUND: The onset of sexual maturation at puberty is a unique developmental period from a neuroendocrine perspective in that it is characterized by enhanced FSH secretion and FSH responsiveness to exogenous GnRH (vs. LH) from the gonadotrope, yet the mechanism of these dynamics remains unclear. This study aimed to elucidate this phenomenon using a human disease model of GnRH deficiency (idiopathic hypogonadotropic hypogonadism, IHH) in which GnRH input can be experimentally controlled. METHODS: 25 GnRH-deficient men were selected for study based upon their baseline testicular volumes (TV) and serum inhibin B (I(B)) levels to represent a spectrum of pubertal/testicular development. Subjects underwent: (i) a 12-hour overnight neuroendocrine evaluation for hormonal profiling and determination of endogenous LH secretion pattern, and (ii) a 7-day exposure to a physiologic regimen of exogenous pulsatile GnRH (25 ng/kg every 2 h). Daily measurements of serum testosterone (T) and I(B) levels were made and a 2-hour window of frequent blood sampling was monitored to measure LH and FSH following a single i.v. GnRH bolus (25 ng/kg). All subjects were screened for known loci underlying GnRH deficiency and the response to GnRH was tracked according to genotype. RESULTS: Among the entire cohort, no changes were noted in serum T or I(B) during the 7 days, thus keeping gonadal feedback relatively constant. However, serum LH and FSH levels increased significantly (p < 0.0001) in the entire cohort. When analyzed by degree of pubertal/testicular development, men with no evidence of prior spontaneous pubertal development (TV 3 ml, Group II, p < 0.0001). Group I exhibited a decreased LH response to GnRH on day 2 compared to day 1 (p < 0.01), which did not recover until day 5 (1-4 vs. 5-7 days, p < 0.0001). Group II displayed robust and equivalent LH responses to GnRH throughout the 7-day study. Genetic studies identified 8 mutations in 4 different loci (DAX1, KAL1, GNRHR, and FGFR1) in this cohort. CONCLUSIONS: GnRH-deficient men undergoing GnRH-induced sexual maturation display an inverse relationship between FSH responsiveness to GnRH and baseline testicular size and I(B) levels. This observation implies that increasing seminiferous tubule maturity represents the major constraint on FSH responsiveness to GnRH in early puberty. In contrast, LH responsiveness to GnRH correlates directly with duration of GnRH exposure. Attenuated pituitary gonadotropin responses were noted in subjects harboring DAX1 mutations, consistent with known pituitary defects.

Multifocal extra-adrenal myelolipoma arising in the greater omentum.

Myelolipomas are rare benign tumors composed of mature fat and hematopoietic elements. They are most often discovered incidentally within the adrenal glands, with extra-adrenal myelolipomas being extremely rare tumors. We report a case of multifocal omental extra-adrenal myelolipoma in a patient who had undergone bilateral adrenalectomy. To our knowledge, this is the first reported case of an intraperitoneal extra-adrenal myelolipoma.

Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice.

Idiopathic hypogonadotropic hypogonadism (IHH) with anosmia (Kallmann syndrome; KS) or with a normal sense of smell (normosmic IHH; nIHH) are heterogeneous genetic disorders associated with deficiency of gonadotropin-releasing hormone (GnRH). While loss-of-function mutations in FGF receptor 1 (FGFR1) cause human GnRH deficiency, to date no specific ligand for FGFR1 has been identified in GnRH neuron ontogeny. Using a candidate gene approach, we identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes. These patients exhibited varied degrees of GnRH deficiency, including the rare adult-onset form of hypogonadotropic hypogonadism. Four mutations affected all 4 FGF8 splice isoforms (FGF8a, FGF8b, FGF8e, and FGF8f), while 2 mutations affected FGF8e and FGF8f isoforms only. The mutant FGF8b and FGF8f ligands exhibited decreased biological activity in vitro. Furthermore, mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. In conclusion, we identified FGF8 as a gene implicated in GnRH deficiency in both humans and mice and demonstrated an exquisite sensitivity of GnRH neuron development to reductions in FGF8 signaling.

Reversal of idiopathic hypogonadotropic hypogonadism.

BACKGROUND: Idiopathic hypogonadotropic hypogonadism, which may be associated with anosmia (the Kallmann syndrome) or with a normal sense of smell, is a treatable form of male infertility caused by a congenital defect in the secretion or action of gonadotropin-releasing hormone (GnRH). Patients have absent or incomplete sexual maturation by the age of 18. Idiopathic hypogonadotropic hypogonadism was previously thought to require lifelong therapy. We describe 15 men in whom reversal of idiopathic hypogonadotropic hypogonadism was sustained after discontinuation of hormonal therapy. METHODS: We defined the sustained reversal of idiopathic hypogonadotropic hypogonadism as the presence of normal adult testosterone levels after hormonal therapy was discontinued. RESULTS: Ten sustained reversals were identified retrospectively. Five sustained reversals were identified prospectively among 50 men with idiopathic hypogonadotropic hypogonadism after a mean (+/-SD) duration of treatment interruption of 6+/-3 weeks. Of the 15 men who had a sustained reversal, 4 had anosmia. At initial evaluation, 6 men had absent puberty, 9 had partial puberty, and all had abnormal secretion of GnRH-induced luteinizing hormone. All 15 men had received previous hormonal therapy to induce virilization, fertility, or both. Among those whose hypogonadism was reversed, the mean serum level of endogenous testosterone increased from 55+/-29 ng per deciliter (1.9+/-1.0 nmol per liter) to 386+/-91 ng per deciliter (13.4+/-3.2 nmol per liter, P<0.001), the luteinizing hormone level increased from 2.7+/-2.0 to 8.5+/-4.6 IU per liter (P<0.001), the level of follicle-stimulating hormone increased from 2.5+/-1.7 to 9.5+/-12.2 IU per liter (P<0.01), and testicular volume increased from 8+/-5 to 16+/-7 ml (P<0.001). Pulsatile luteinizing hormone secretion and spermatogenesis were documented. CONCLUSIONS: Sustained reversal of normosmic idiopathic hypogonadotropic hypogonadism and the Kallmann syndrome was noted after discontinuation of treatment in about 10% of patients with either absent or partial puberty. Therefore, brief discontinuation of hormonal therapy to assess reversibility of hypogonadotropic hypogonadism is reasonable. (ClinicalTrials.gov number, NCT00392756 [ClinicalTrials.gov].).