Pulsatile iv infusion of recombinant human LH in leuprolide-suppressed menunmasks impoverished Leydig-cell secretory responsiveness to midphysiological LH drives in the aging male

The present investigation tests the clinical hypothesis that Leydig-cell re sponsiveness to pulsatile and midphysiological LH drive is impaired in olde r men. To this end, we implemented a novel clinical investigative paradigm consisting of preadministration of an LH-down-regulating dose (3.75 mg) of leuprolide acetate followed, 3-4 wk later, by controlled challenge of the t estis, with pulsatile iv infusions of saline vs. recombinant human (rh) LH. Based on a preliminary dose-finding experiment, we evaluated LH action in 8 young (ages, 18-25 yr) and 7 older (ages, 60-85 yr) volunteers by infusin g eight consecutive 6-min squarewave pulses of saline or 50 IU rhLH iv ever y 2 h. Analyses were carried out 48 or 72 h apart in a prospective, randoml y assigned, double-blind, within-subject cross-over design. Serum concentra tions of T (RIA) and LH (immunoradiometric assay) were measured in blood sa mpled every 10 min concurrently. Leuprolide injection suppressed pre-LH-inf usion (0800 h baseline) serum T concentrations (pooled mean +/- SEM) marked ly in both age groups (P < 10(-3)); namely, to 40 +/- 20 ng/dl (young) and 12 +/- 3.1 ng/dl (older; P < 0.05 vs. young) (to convert to nM, multiply by 0.0347). Successive iv pulses of rhLH stimulated T output, over time, to a n asymptotic maximum of 166 +/- 42 ng/dl in young men (P = 0.0008 vs: salin e) and 57 +/- 9.8 ng/dl in older subjects (P = NS vs. saline; and P < 0.05 vs. young). Further regression analyses identified significant reductions o f both the initial rate and maximum of the time-dependent incremental rise in LH-driven serum T concentrations in older men. In contrast, infused seru m LH concentrations, distribution volumes, and calculated LH half-lives wer e comparable in the two age cohorts. We conclude that older men manifest both a delayed initial and reduced maxi mal serum T concentration rise compared with young men exposed to identical controlled midphysiological pulsatile LH drive.