title: Pulsatile iv infusion of recombinant human LH in leuprolide-suppressed men unmasks impoverished Leydig-cell secretory responsiveness to midphysiological LH drive in the aging male.
abstract: The present investigation tests the clinical hypothesis that Leydig-cell responsiveness to pulsatile and midphysiological LH drive is impaired in older 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 testis, 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 infusing eight consecutive 6-min squarewave pulses of saline or 50 IU rhLH iv every 2 h. Analyses were carried out 48 or 72 h apart in a prospective, randomly assigned, double-blind, within-subject cross-over design. Serum concentrations of T (RIA) and LH (immunoradiometric assay) were measured in blood sampled every 10 min concurrently. Leuprolide injection suppressed pre-LH-infusion (0800 h baseline) serum T concentrations (pooled mean +/- SEM) markedly 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 an asymptotic maximum of 166 +/- 42 ng/dl in young men (P = 0.0008 vs. saline) 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 of both the initial rate and maximum of the time-dependent incremental rise in LH-driven serum T concentrations in older men. In contrast, infused serum LH concentrations, distribution volumes, and calculated LH half-lives were comparable in the two age cohorts. We conclude that older men manifest both a delayed initial and reduced maximal serum T concentration rise compared with young men exposed to identical controlled midphysiological pulsatile LH drive.
authors.affiliation: Geriatrics and Extended Care Service Line, McGuire Veterans Affairs Medical Center, Richmond, Virginia 23249, USA.
authors.forename: T
authors.initials: T
authors.lastname: Mulligan
authors.forename: A
authors.initials: A
authors.lastname: Iranmanesh
authors.forename: J D
authors.initials: JD
authors.lastname: Veldhuis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D016729:Leuprolide / Q000494:pharmacology*; D007985:Leydig Cells / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology; D012044:Regression Analysis; D013739:Testosterone / Q000097:blood
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011994:Recombinant Proteins; D013739:Testosterone; D007986:Luteinizing Hormone; D016729:Leuprolide