Neuroendocrine Regulation of the Estrous Cycle

描述(申请人提供)：压力对卵巢周期和生育的负面影响是生育调节和妇女生殖健康方面的一个重大问题。这项建议的总体目标是更好地了解压力如何扰乱周期并降低生育率。一种常见的神经内分泌反应是抑制促性腺激素的分泌(最显著的是脉冲性的促黄体生成素的分泌)，同时激活下丘脑-垂体-肾上腺轴和增加糖皮质激素的分泌。最近的发现表明，在没有应激的情况下，血液中皮质醇的急性应激性增加抑制了绵羊脉动性黄体生成素(LH)的分泌。此外，该物种的卵泡期和排卵前黄体生成素高峰被循环皮质醇的应激性增加所破坏。这些发现导致假设，皮质醇的应激性增加扰乱了卵泡期，作用于下丘脑和脑垂体，抑制促性腺激素释放激素(GnRH)和促黄体生成素的脉动性分泌，这是刺激排卵前雌二醇分泌增加所必需的，反过来，促性腺激素释放激素和促黄体生成素激增。在应激过程中，皮质醇的这些作用被认为是导致卵巢周期中断的原因之一。这项拟议的研究以绵羊为动物模型，以四个具体目标来检验这一假说。首先，将确定皮质醇的应激性增加是否抑制下丘脑GnRH的分泌和/或脑下垂体对GnRH的反应。其次，将评估皮质醇破坏卵泡期的神经内分泌过程以及这种破坏对生育力的影响。第三，皮质醇在某些类型的应激反应中调节卵巢周期紊乱的可能性将被调查。第四，将确定介导皮质醇抑制作用的相关受体(S)。总而言之，针对这四个特定目标的研究形成了一个全面而有凝聚力的综合方法，以解决皮质醇在调节应激诱导的卵巢周期抑制和生育中的作用模式和生理意义。

DESCRIPTION (provided by applicant): 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.