Age and Testosterone Feedback Jointly Control the Dose-Dependent Actions of Gonadotropin-Releasing Hormone in Healthy Men

Healthy older men manifest combined declines in testosterone concentrations, LH secretory burst mass (amount of LH released per pulse), and feedback-sensitive regularity of unknown cause. To test a unifying hypothesis of simultaneous reductions in GnRH outflow, gonadotrope responsiveness to GnRH, and androgenic negative feedback, we monitored LH secretion 1) after bolus iv injection of a 1000-fold range of randomly ordered individual doses of GnRH on separate mornings, 2) during unmodified (eugonadal) or testosterone-withdrawn (hypoandrogenemic) negative feedback, and 3) in 16 young (age, 18-35 yr) and 15 older (age, 60-85 yr) healthy men. LH secretory burst mass and pattern regularity were quantitated by intensive blood sampling, high specificity LH beta-subunit-directed immunoradiometric assay, deconvolution analysis, and approximate entropy. GnRH dose responsiveness was assessed by four-parameter nonlinear regression analysis. We demonstrated that older men exhibit 1) delayed attainment of GnRH-evoked maximal LH secretion; 2) enhanced potency of GnRH stimulation in both the feedback-intact and feedback-withdrawn states; 3) elevated gonadotrope sensitivity to GnRH, unmasked by experimental testosterone depletion; 4) comparable young adult-like GnRH efficacy, independent of testosterone feedback milieu; and 5) diminished regularity of GnRH-induced LH release evident only during unmodified androgenic feedback. We conclude that a 3-fold interaction among GnRH dose, testosterone concentration, and age governs GnRH action, and age determines both testosterone-modulated and testosterone-independent actions of GnRH.