Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History

Abstract

Context: After completion of puberty a subset of men experience functional hypogonadotropic hypogonadism (FHH) secondary to excessive exercise or weight loss. This phenomenon is akin to hypothalamic amenorrhea (HA) in women, yet little is known about FHH in men.

Objective: To investigate the neuroendocrine mechanisms, genetics, and natural history underlying FHH.

Design: Retrospective study in an academic medical center.

Participants: Healthy postpubertal men presenting with symptoms of hypogonadism in the setting of excessive exercise (>10 hours/week) or weight loss (>10% of body weight). Healthy age-matched men served as controls.

Interventions: Clinical assessment, biochemical and neuroendocrine profiling, body composition, semen analysis, and genetic evaluation of genes known to cause isolated GnRH deficiency.

Main outcome measures: Reproductive hormone levels, endogenous GnRH-induced LH pulse patterns, and rare genetic variants.

Results: Ten men with FHH were compared with 18 age-matched controls. Patients had significantly lower body mass index, testosterone, LH, and mean LH pulse amplitudes yet normal LH pulse frequency, serum FSH, and sperm counts. Some patients exhibited nocturnal, sleep-entrained LH pulses characteristic of early puberty, and one FHH subject showed a completely apulsatile LH secretion. After decreased exercise and weight gain, five men with men had normalized serum testosterone levels, and symptoms resolved. Rare missense variants in NSMF (n = 1) and CHD7 (n = 1) were identified in two men with FHH.

Conclusions: FHH is a rare, reversible form of male GnRH deficiency. LH pulse patterns in male FHH are similar to those observed in women with HA. This study expands the spectrum of GnRH deficiency disorders in men.

Figure 1.

Representative graphs of LH secretion patterns in three men with FHH. Subjects underwent neuroendocrine profiling (every 10 minutes × 12 hours) to chart GnRH-induced LH secretion. (A) Subject 10 was the lone patient with an apulsatile LH secretion pattern. (B) Subject 6 displayed sleep-entrained pulses (hatched bar depicts sleep period). (C) Subject 8 exhibited a normal LH secretion pattern with characteristic peaks, as observed in healthy controls (42). Shaded region represents the normal reference range (27). Inverted triangles indicate LH pulses.

Figure 2.

Spectrum of LH secretion patterns of men presenting with FHH. Subjects underwent detailed neuroendocrine profiling (every 10 minutes × 12 hours) to chart LH secretion pattern. Inverted triangles depict LH pulses. Shaded region depicts the normal reference range (27). Subject 1 underwent only 8 hours of sampling and had recovered HPG axis function at the time of the neuroendocrine evaluation (normal serum T levels).

Figure 3.

Recovery from functional hypogonadotropic hypogonadism. Subjects underwent neuroendocrine profiling (every 10 minutes × 12 hours) to chart GnRH-induced LH secretion. (A) Patient 5 exhibited nocturnal sleep-entrained LH pulses and hypogonadal serum T (225 ng/dL, 7.8 nmol/L). (B) After weight gain, repeat frequent sampling showed normal LH pulse frequency and amplitude with normal serum T (442 ng/dL, 15.3 nmol/L). Note: The study was stopped at 11 hours of sampling because of a problem with the IV. Shaded region represents the normal reference range (27). Inverted triangles indicate LH pulses. The hatched bars depict periods of sleep.