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

Thomas Mulligan, Ali Iranmanesh, Roger Kerzner, Laurence W. Demers, Johannes D. Veldhuis

Research output: Contribution to journalArticlepeer-review

115 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)257-266
Number of pages10
JournalEuropean Journal of Endocrinology
Issue number3
StatePublished - Sep 1999

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


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