The negative impact of stress on ovarian cyclicity and fertility is a significant problem in fertility regulation and women's reproductive health. The overall goal of this proposal is to gain a better understanding of how stress disrupts the cycle and reduces fertility. A common neuroendocrine response to stress is the suppression of gonadotropin secretion (most notably pulsatile LH secretion) coupled to activation of the hypothalamic-pituitary-adrenal axis and enhanced glucocorticoid secretion. Recent findings indicate that, in the absence of stress, an acute stress-like increase in circulating cortisol suppresses pulsatile luteinizing hormone (LH) secretion in sheep. Further, the follicular phase of the cycle and preovulatory LH surge in this species are disrupted by stress-like increments in circulating cortisol. These findings lead to the hypothesis that a stress-like increase in cortisol disrupts the follicular phase by acting at the hypothalamus and pituitary gland to suppress the pulsatile secretion of gonadotropin-releasing hormone (GnRH) and LH necessary for stimulating the preovulatory increase in estradiol secretion and, in turn, the GnRH and LH surges. It is proposed that these actions of cortisol contribute to ovarian cycle disruption during stress. The proposed research tests this hypothesis utilizing the sheep as an animal model and four Specific Aims. First, it will be determined if a stress-like increment in cortisol inhibits hypothalamic GnRH secretion and/or responsiveness of the pituitary gland to GnRH. Second, the neuroendocrine processes through which cortisol acts to disrupt the follicular phase and the impact of this disruption on fertility will be assessed. Third, the possibility that cortisol mediates ovarian cycle disruption in response to certain types of stress will be investigated. Fourth, the relevant receptor(s) that mediate the suppressive actions of cortisol will be identified. Collectively, the research in these four Specific Aims form a comprehensive and cohesive integrated approach to address the mode of action and physiological significance of cortisol in mediating stress-induced suppression of the ovarian cycle and fertility.
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