Testosterone's short-term positive effect on luteinizing-hormone secretory-burst mass and its negative effect on secretory-burst frequency are attenuated in middle-aged men

Background: Testosterone (T) production declines and LH pulses become smaller and more frequent in middle-aged men. The mechanisms underlying these changes are not known. Rationale: Small frequent LH pulses in middle-aged men could reflect impaired feedback by systemic T. Hypothesis: Middle age disrupts negative feedback by T on selected facets of LH secretion. Subjects and Setting: Healthy men were studied at an academic medical center. Methods: The protocol comprised blockade of gonadal steroidogenesis and graded transdermal addback of T doses of 0, 2.5, 5, or 7.5 mg/d designed to span the castrate to physiological range of T concentrations in each of 23 healthy men ages 19-71 yr (interquartile range, 28-53 yr). We quantified 12-h basal and pulsatile LH secretion (92 time series) using a mathematically justified deconvolution method. Results: Stepwise T supplementation from the hypogonadal through the eugonadal range repressed mean (12-h) LH concentrations (P = 0.001). By regression analysis, age attenuated the capabilities of increasing T concentrations to 1) increase LH secretory-burst mass (P < 0.0001); and 2) decrease LH secretory-burst frequency (P = 0.025). Age did not alter T's feedback on basal LH secretion, interpulse regularity, the waveform of LH secretory bursts, or the slow half-life of LH. Conclusion: Middle age impairs both the positive and negative actions of systemic T on pulsatile LH secretion in healthy men, thus potentially explaining earlier inconsistencies in feedback studies based upon single-sample mean LH concentrations. Longitudinal studies will be required to elucidate the precise age dependence of inferred dual feedback failure.