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

Abstract

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 <or=3 ml, Group I) showed sharp increases in serum FSH compared to men with some prior evidence of partial puberty (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.

Figures

Fig. 1.

Mean (± SE) response to the first 7 days of pulsatile GnRH therapy in 25 GnRH-deficient men. The left panels display the responses to GnRH treatment in 15 IHH men with no pubertal development (Group I) and the right panels display the responses of 10 IHH men with partial puberty (Group II). Graphs depict LH and FSH response to a single i.v. dose of GnRH (25 ng/kg) during a 2-hour window on each of the 7 days. Inhibin B (IB) and testosterone (T) levels were measured each day prior to the i.v. GnRH bolus. The shaded region is the reference range for healthy adult males [16].

Fig. 2.

Gonadotropin response to GnRH stratified by genotype and degree of pubertal development. The individual graphs represent the LH and FSH (2-hour) to a single i.v. GnRH bolus on days 1 and 7 of the 8 subjects harboring a mutation in KAL1, GNRHR, FGFR1, and DAX1. The shaded region is the reference range for healthy adult males [16].