Two-week pulsatile gonadotropin releasing hormone infusion unmasks dual (hypothalamic and Leydig cell) defects in the healthy aging male gonadotropic axis

Objective: To examine the possibility that lower serum bioavailable testosterone concentrations, without increased LH release, in healthy older men, reflects hypothalamic GnRH deficiency. Design: We used a randomized, double-blind, placebo-controlled design. Methods: We treated each of five young (ages 20-34 years) and five older (ages 60-78 years) men with 2 weeks of randomized infusions of saline or pulsatile GnRH (100 ng/kg i.v. every 90 min). Results: At baseline (saline infusion), older men had more LH pulses (young compared with old, 10 ± 0.6 compared with 15 ± 1, P=0.0026) per 24h, reduced fractional LH pulse amplitude (219 ± 17% compared with 167 ± 40%, P=0.0376), and more disorderly hormone release as judged by approximate entropy (ApEn) (LH, P ≤ 0.0001; testosterone, P ≤ 0.0047). In response to pulsatile i.v. GnRH infusions, serum 24-h LH concentrations (measured by immunoradiometric assay (IRMA)), increased equivalently in young and older men (to 7.3 ± 1.2 and 7.2 ± 1.8 IU/I respectively). GnRH treatment also normalized LH pulse frequency and amplitude, ApEn, and plasma biologically active LH (pooled) concentrations. In contrast, 24-h testosterone concentrations failed to increase equivalently in older men (young compared with old, 869 ± 88 compared with 517 ± 38 ng/dl, P=0.0061), reflecting lower testosterone peak maxima (995 ± 108 compared with 583 ± 48 ng/dl, P=0.0083) and interpeak nadirs (750 ± 87 compared with 427 ± 26 ng/dl, P=0.0073). Conclusions: We have demonstrated that, in older men, successful reconstitution of 24-h pituitary (bioactive) LH output and pulsatile (IRMA) LH release patterns could be achieved by a fixed exogenous GnRH pulse signal, thereby implicating altered endogenous hypothalamic GnRH release in the relative hypogonadotropism of aging. The failure of testosterone concentrations to increase concomitantly points to a simultaneous Leydig cell defect. We conclude that aging in men is marked by a dual defect in the central nervous system-pituitary-Leydig cell axis.