Department of Statistics, University of Virginia, Charlottesville, USA.
Am J Physiol Regul Integr Comp Physiol. 2011 Feb;300(2):R349-60. doi: 10.1152/ajpregu.00477.2010. Epub 2010 Nov 17.
Luteinizing hormone (LH) administered in pharmacological amounts downregulates Leydig cell steroidogenesis. Whether reversible downregulation of physiological gonadotropin drive operates in vivo is unknown. Most of the analytical models of dose-response functions that have been constructed are biased by the assumption that no downregulation exists. The present study employs a new analytical platform to quantify potential (but not required) pulsatile cycles of LH-testosterone (T) dose-response stimulation, desensitization, and recovery (pulse-by-pulse hysteresis) in 26 healthy men sampled every 10 min for 24 h. A sensitivity-downregulation hysteresis construct predicted marked hysteresis with a median time delay to LH dose-response inflection within individual T pulses of 23 min and with median T pulse onset and recovery LH sensitivities of 1.1 and 0.10 slope unit, respectively (P < 0.001). A potency-downregulation model yielded median estimates of one-half maximally stimulatory LH concentrations (EC(50) values) of 0.66 and 7.5 IU/l for onset and recovery, respectively (P < 0.001). An efficacy-downregulation formulation of hysteresis forecasts median LH efficacies of 20 and 8.3 ng·dl(-1)·min(-1) for onset and offset of T secretory burst, respectively (P = 0.002). Segmentation of the LH-T data by age suggested greater sensitivity, higher EC(50) (increased LH potency), and markedly (2.7-fold) attenuated LH efficacy in older individuals. Each of the three hysteresis models yielded a marked (P < 0.005) reduction in estimated model residual error compared with no hysteresis. In summary, model-based analyses allowing for (but not requiring) reversible pituitary-gonadal effector-response downregulation are consistent with a hypothesis of recurrent, brief cycles of LH-dependent stimulation, desensitization, and recovery of pulsatile T secretion in vivo and an age-associated reduction of LH efficacy. Prospective studies would be required to prove this aging effect.
黄体生成素（LH）以药理学剂量给药可下调睾丸间质细胞的类固醇生成。生理促性腺激素驱动的可逆下调是否在体内发生尚不清楚。大多数构建的剂量-反应函数分析模型都存在偏见，因为它们假设不存在下调。本研究采用新的分析平台，在 26 名健康男性中进行量化潜在（但不是必需的）LH-睾丸激素（T）剂量-反应刺激、脱敏和恢复（逐脉冲滞后）的周期性（脉冲），每隔 10 分钟采集一次，持续 24 小时。敏感性下调滞后构建体预测了显著的滞后，个体 T 脉冲内 LH 剂量反应拐点的中位时间延迟为 23 分钟，并且 T 脉冲起始和恢复 LH 敏感性的中位值分别为 1.1 和 0.10 斜率单位（P <0.001）。效力下调模型产生的最大刺激 LH 浓度（EC（50）值）的中位估计值分别为 0.66 和 7.5IU/l，用于起始和恢复（P <0.001）。滞后的效力下调模型预测 T 分泌爆发起始和结束时的中位 LH 效力分别为 20 和 8.3ng·dl（-1）·min（-1）（P = 0.002）。LH-T 数据按年龄分段表明，在老年人中，敏感性更高，EC（50）更高（LH 效力增加），LH 效力明显（2.7 倍）减弱。与无滞后相比，三种滞后模型中的每一种都导致估计模型残差显著降低（P <0.005）。总之，允许（但不是必需）可重复的垂体-性腺效应器反应下调的基于模型的分析与体内 LH 依赖性刺激、脱敏和脉冲 T 分泌恢复的短暂周期性的假设以及与年龄相关的 LH 效力降低一致。需要进行前瞻性研究来证明这种衰老效应。
