Reproductive Suppression by Cortisol at Pituitary Gland

糖皮质激素被认为在生殖功能的抑制中起着介导作用， 应力皮质醇快速（<30 min）和慢性（>48 h）抑制绵羊LH脉冲式分泌。此夕h 卵巢切除母羊的LH抑制是通过降低垂体对GnRH的反应性，而不是通过 减少GnRH释放，并由II型糖皮质激素受体（GR）介导。根据这些发现， 我建议测试以下统一的假设：应激水平的皮质醇抑制垂体 通过不同的快速和慢性抑制机制直接在垂体对GnRH的反应。的 慢性效应是由细胞内II型GR通过减少GnRH受体介导的，而快速效应 由膜结合II型GR介导，并且独立于这种抑制而发生。为了解决这个 假设，提出了三个目标：1）皮质醇是否直接作用于垂体以降低反应性 GnRH？2)皮质醇的快速抑制作用是由膜结合II型GR介导的， 由细胞内II型GR介导的慢性抑制作用？3)皮质醇的慢性效应 GnRH受体mRNA和蛋白水平降低，且快速效应独立于这些效应？

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?