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

T. Mulligan, A. Iranmanesh, Johannes D Veldhuis

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56 Citations (Scopus)

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 dosefinding 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-rain 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 rain 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.

Original languageEnglish (US)
Pages (from-to)5547-5553
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume86
Issue number11
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

Leuprolide
Leydig Cells
Rain
Aging of materials
Serum
Assays
Blood
Scanning electron microscopy
Immunoradiometric Assay
Experiments
Cross-Over Studies
Testis
Volunteers
Age Groups
Regression Analysis
Injections

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

@article{ae7548e5446f43b4a42cb377632fe66f,
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 dosefinding 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-rain 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 rain 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.",
author = "T. Mulligan and A. Iranmanesh and Veldhuis, {Johannes D}",
year = "2001",
doi = "10.1210/jc.86.11.5547",
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T1 - 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

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AU - Iranmanesh, A.

AU - Veldhuis, Johannes D

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N2 - 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 dosefinding 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-rain 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 rain 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.

AB - 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 dosefinding 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-rain 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 rain 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.

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