Reproductive Suppression by Cortisol at Pituitary Gland

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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?