An ensemble model of the male gonadal axis: Illustrative application in aging men
An ensemble model of the male gonadal axis: Illustrative application in aging men
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DOI：
10.1210/en.2005-1356
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发表时间：
2006-06-01
期刊：
影响因子：
4.8
通讯作者：
Veldhuis, Johannes D.
中科院分区：
文献类型：
--
作者：
Keenan, Daniel M.;Takahashi, Paul Y.;Veldhuis, Johannes D.
随着年龄的增长，男性的睾酮（Te）分泌会下降，尽管原因不明。可能的机制包括GnRH分泌减少，LH前馈减少，和/或全身Te反馈改变。本研究在10名年轻人（20 - 35岁）和8名老年人（50 - 72岁）的队列中测试了所有这三个假设。实验范例包括对GnRH受体的分级阻断，以在每个受试者中创建四个不同的LH和Te脉搏层。我们开发了一种新的分析形式来重建隐含的剂量-反应函数，该函数将1)虚拟GnRH流出与LH分泌呈正相关，2)LH脉冲与LH分泌呈正相关，3)LH浓度与LH分泌爆发的大小和数量呈负相关。通过对马和羊的直接垂体取样进行验证。经统计学比较，年龄降低了GnRH虚流出量（P < 0.01）、LH驱动LH分泌量（P < 0.01）、总Te、生物利用度和游离Te对GnRH驱动LH分泌量的反馈效果（P = 0.015）。相比之下，年龄增加了虚拟GnRH前馈的效力（P = 0.013），而不影响Te对LH脉冲频率的抑制。无法解释的方差小于10%。通过重采样技术显示了鲁棒性。因此，一个控制位点的竞争性沉默和基于集合的分析确定了衰老男性性腺轴的三重调节缺陷。该综合模型的通用性表明，在分析其他生理网络中相互关联的适应性方面具有实用价值。
Testosterone (Te) production declines in the aging male, albeit for unknown reasons. Plausible mechanisms include reduced secretion of GnRH, less feedforward by LH, and/or altered feedback by systemic Te. The present study tests all three postulates in a cohort of 10 young (20 - 35 yr old) and eight older ( 50 - 72 yr old) men. The experimental paradigm comprised graded blockade of the GnRH receptor to create four distinct strata of LH and Te pulsatility in each subject. A novel analytical formalism was developed to reconstruct implicit dose-response functions linking 1) virtual GnRH outflow positively to LH secretion, 2) LH pulses positively to Te secretion, and 3) Te concentrations negatively to the size and number of LH secretory bursts. Validation was by direct pituitary sampling in the horse and sheep. Statistical comparisons disclosed that age decreased the efficacy of each of 1) virtual GnRH outflow (P < 0.01), 2) LH drive of Te secretion (P < 0.01), and 3) total, bioavailable and free Te feedback on GnRH-driven LH secretion (P = 0.015). In contrast, age increased the potency of virtual GnRH feedforward (P = 0.013) and did not affect Te's inhibition of LH pulse frequency. Unexplained variance was less than 10%. Robustness was shown by resampling techniques. Accordingly, competitive silencing of one locus of control and ensemble-based analyses identified triple regulatory deficits in the aging male gonadal axis. The generality of the present integrative model suggests utility in parsing interlinked adaptations in other physiological networks.