Mulligan T, Iranmanesh A, Veldhuis J D
Geriatrics and Extended Care Service Line, McGuire Veterans Affairs Medical Center, Richmond, Virginia 23249, USA.
J Clin Endocrinol Metab. 2001 Nov;86(11):5547-53. doi: 10.1210/jcem.86.11.8004.
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.
老年男性睾丸间质细胞对脉冲式及接近生理水平的促黄体生成素（LH）驱动的反应性受损。为此，我们实施了一种新的临床研究模式，即先给予醋酸亮丙瑞林3.75mg的LH下调剂量，3至4周后，通过对睾丸进行对照激发，静脉内脉冲输注生理盐水与重组人（rh）LH。基于一项初步的剂量探索实验，我们通过每2小时静脉内输注8个连续的6分钟方波脉冲生理盐水或50IU rhLH，评估了8名年轻志愿者（年龄18 - 25岁）和7名老年志愿者（年龄60 - 85岁）的LH作用。分析在48或72小时间隔进行，采用前瞻性、随机分配、双盲、受试者内交叉设计。每10分钟同时采集血样，测定血清睾酮（T，放射免疫分析法）和LH（免疫放射分析法）浓度。亮丙瑞林注射显著抑制了两个年龄组LH输注前（0800h基线）的血清T浓度（合并均值±标准误）（P < 10⁻³）；即，年轻组降至40±±20ng/dl，老年组降至12±3.1ng/dl （老年组与年轻组相比P < 0.05）（如需换算为nM，乘以0.0347）。随着时间推移，连续静脉内注射rhLH刺激了T的分泌，年轻男性最终达到渐近最大值166±42ng/dl（与生理盐水相比P = 0.0008），老年受试者为57±9.8ng/dl（与生理盐水相比P =无显著性差异，与年轻组相比P < 0.05）。进一步的回归分析发现，老年男性LH驱动的血清T浓度随时间增加的初始速率和最大值均显著降低。相比之下，两个年龄组输注的血清LH浓度、分布容积和计算得出的LH半衰期相当。我们得出结论，与接受相同的接近生理水平的脉冲式LH驱动的年轻男性相比，老年男性血清T浓度升高的初始反应延迟且最大值降低。
