The long-term clinical follow-up and natural history of men with adult-onset idiopathic hypogonadotropic hypogonadism

Abstract

Context and objective: Adult-onset idiopathic hypogonadotropic hypogonadism (AHH) is a rare disorder characterized by an isolated failure of gonadotropin secretion occurring after an otherwise normal sexual maturation in men. This study aims to examine the etiology and long-term natural history of this disorder.

Design and setting: Long-term follow up, including detailed clinical, biochemical, and genetic examinations, were performed and compared with those at diagnosis.

Patients: Patients included 10 men with AHH [serum testosterone (T) <125 ng/dl].

Interventions: Overnight neuroendocrine studies, semen fluid analyses, and genetic screening were performed (KAL1, FGFR1, PROK2, PROKR2, NELF, TAC3, TACR3, and GNRH1) over a decade of longitudinal follow up.

Results: Follow-up evaluations were conducted 10.6 +/- 5.9 yr after initial studies and revealed that the clinical characteristics and seminal fluid analyses of AHH men (body mass index, 28.8 +/- 4.1 vs. 27.0 +/- 4.3 kg/m(2); testicular volume, 18 +/- 6 vs. 19 +/- 6 ml) do not change over a decade with no spontaneous reversals. Several men exhibited some variability in their endogenous GnRH-induced LH secretory patterns, including emergence of endogenous pulsatility in three individuals. However, all remained hypogonadal (T < or =130 ng/dl). A single heterozygous DNA sequence change in PROKR2 (V317L) was identified, although this rare sequence variant did not prove to be functionally abnormal in vitro. Seven days of pulsatile GnRH therapy in this subject nearly normalized his serum T, supporting that the site of the defect is hypothalamic and not pituitary.

Conclusions: 1) AHH in men appears to be a long-lasting condition. 2) Although minor changes in the abnormal pattern of endogenous GnRH-induced LH secretion occurred in some AHH patients, all remained frankly hypogonadal.

Figure 1

Baseline and follow up in 12-h overnight frequent sampling studies of 10 men with AHH to compare the endogenous LH pulse patterns. LH pulses were assessed using a modification of the Santen and Bardin algorithm (33,34).

Figure 2

Clinical phenotype of subject 6 (denoted by arrow). A, Pedigree of subject 6. B, LH secretory pattern at baseline and follow-up frequent sampling studies. C, LH and T response to 7 d of exogenous pulsatile GnRH therapy.