Context: Whether testosterone (Te) depletion in aging men reflects deficits in the testis, hypothalamus and/or pituitary gland is unknown.

Objective: To quantify the impact of age on gonadal Te secretion driven by amplitude-varying pulses of recombinant human LH (rhLH) in the absence of confounding by endogenous hypothalamo-pituitary signals.

Design: Double-blind, placebo-controlled.

Setting: Academic medical center.

Subjects: Fifteen healthy community-dwelling men ages 22-78 yr.

Intervention: Saline or 4 separate rhLH doses were each infused twice iv in randomized order as 1 pulse every 2 h over 20 h to stimulate Te secretion, after LH secretion was suppressed by a GnRH-receptor antagonist, ganirelix.

Main Outcome: LH and Te concentrations were determined in blood samples collected every 5 min. Maximal and minimal (as well as mean) Te responses were regressed linearly on age to reflect LH peak and nadir (and average) effects, respectively.

Results: The ganirelix/rhLH paradigm yielded serum LH concentrations of 4.6 ± 0.22 [normal range 1-9] IU/L. By regression analysis, age was associated with declines in rhLH pulse-stimulated peak and nadir (and mean) concentrations of total Te (P = 0.0068), bioavailable Te (P = 0.0096) and free Te (P = 0.013), as well as lower Te/LH concentration ratios (P < 0.005). Deconvolution analysis suggested that the half-life of infused LH rises by 12% per decade (P = 0.044, R² = 0.28).

Conclusion: Infusion of amplitude-varying pulses of rhLH during gonadal-axis suppression in healthy men unmasks prominent age-related deficits in stimulated total (39%), bioavailable (66%) and free (63%) Te concentrations, and a smaller age-associated increase in LH half-life. These data suggest that age-associated factors reduce the efficacy of LH pulses.