Reproductive Suppression by Cortisol at Pituitary Gland

描述(由申请人提供)：糖皮质激素被认为在应激期间对生殖功能的抑制起到中介作用。皮质醇快速(&lt；30min)和慢性(&gt；48h)抑制绵羊搏动性的促黄体生成素分泌。此外，去卵巢母羊体内促黄体生成素的抑制是通过降低脑下垂体对GnRH的反应性而发生的，而不是通过减少GnRH的释放，并且是由II型糖皮质激素受体(GR)介导的。基于这些发现，我建议检验以下统一的假设：皮质醇应激水平的升高直接通过不同的快速和慢性抑制机制抑制垂体对GnRH的反应。慢性效应是由细胞内II型GR通过减少的GnRH受体介导的，而快速效应是由膜结合的II型GR介导的，并且不依赖于这种抑制作用。为了解决这一假说，提出了三个目标：1)皮质醇是否直接作用于垂体以降低对GnRH的反应性？2)皮质醇的快速抑制效应是由膜结合的II型GR介导的，而慢性抑制效应是由细胞内的II型GR介导的？3)皮质醇的慢性效应是否与GnRH受体mRNA和蛋白水平的降低有关，以及这种快速效应是否独立于这些影响？

DESCRIPTION (provided by applicant): Glucocorticoids are considered to play a mediatory role in the suppression of reproductive function during stress. Cortisol rapidly (<30min) and chronically (>48 h) inhibits pulsatile LH secretion in ewes. Further, the inhibition in LH in ovariectomized ewes occurs via reduced pituitary responsiveness to GnRH, not via reduced GnRH release and is mediated by the type II glucocorticoid receptor (GR). Based on these findings, I propose to test the following unifying hypothesis: Elevations in stress levels of cortisol suppress pituitary responsiveness to GnRH directly at the pituitary via distinct rapid and chronic inhibitory mechanisms. The chronic effect is mediated by an intracellular type II GR via reduced GnRH receptors whereas the rapid effect is mediated by a membrane-bound type II GR and occurs independent of this inhibition. To address this hypothesis, three aims are proposed: 1) Does cortisol act directly upon the pituitary to reduce responsiveness to GnRH? 2) Is the rapid inhibitory effect of cortisol mediated by a membrane-bound type II GR and the chronic inhibitory effect mediated by an intracellular type II GR? 3) Is the chronic effect of cortisol associated with reduced levels of GnRH receptor mRNA and protein and the rapid effect independent of these effects?