Keenan Daniel M, Takahashi Paul Y, Liu Peter Y, Roebuck Pamela D, Nehra Ajay X, Iranmanesh Ali, Veldhuis Johannes D
Department of Statistics, University of Virginia, Charlottesville, Virginia 22903, USA.
Endocrinology. 2006 Jun;147(6):2817-28. doi: 10.1210/en.2005-1356. Epub 2006 Mar 2.
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.
睾酮（Te）的分泌在老年男性中会下降，尽管原因不明。可能的机制包括促性腺激素释放激素（GnRH）分泌减少、黄体生成素（LH）的前馈作用减弱和/或全身性Te的反馈改变。本研究在一组10名年轻（20 - 35岁）和8名年长（50 - 72岁）男性中对这三种假设进行了检验。实验范式包括对GnRH受体进行分级阻断，以在每个受试者中创建四个不同层次的LH和Te脉冲性。开发了一种新颖的分析形式来重建隐式剂量反应函数，该函数将1）虚拟GnRH流出与LH分泌正向关联，2）LH脉冲与Te分泌正向关联，以及3）Te浓度与LH分泌脉冲的大小和数量负向关联。通过对马和羊进行直接垂体采样进行验证。统计比较表明，年龄降低了1）虚拟GnRH流出（P < 0.01）、2）LH对Te分泌的驱动作用（P < 0.01）以及3）总Te、生物可利用Te和游离Te对GnRH驱动的LH分泌的反馈作用（P = 0.015）的效能。相反，年龄增加了虚拟GnRH前馈作用的效力（P = 0.013），并且不影响Te对LH脉冲频率的抑制作用。无法解释的方差小于10%。重采样技术显示了该模型的稳健性。因此，对一个控制位点的竞争性沉默和基于整体的分析确定了老年男性性腺轴中的三重调节缺陷。本整合模型的通用性表明其在解析其他生理网络中相互关联的适应性方面具有实用性。
