Neuroendocrine Regulation of the Estrous Cycle

描述（由申请人提供）：压力对卵巢周期和生育力的负面影响是生育调节和妇女生殖健康的一个重要问题。该提案的总体目标是更好地了解压力如何破坏周期并降低生育率。对应激的一种常见神经内分泌反应是促性腺激素分泌的抑制（最显著的是脉冲式LH分泌），同时激活下丘脑-垂体-肾上腺轴和增强糖皮质激素分泌。最近的研究结果表明，在没有压力的情况下，循环皮质醇的急性压力样增加会抑制绵羊的脉冲式促黄体生成激素（LH）分泌。此外，周期的卵泡期和排卵前LH激增在这个物种中被循环皮质醇中的应激样增量破坏。这些发现导致了一种假设，即皮质醇的应激样增加通过作用于下丘脑和脑垂体抑制促性腺激素释放激素（GnRH）和LH的脉冲式分泌来破坏卵泡期，而促性腺激素释放激素（GnRH）和LH的脉冲式分泌是刺激排卵前雌二醇分泌增加所必需的，反过来，GnRH和LH激增。有人提出，皮质醇的这些行动有助于卵巢周期中断在压力。拟议的研究利用绵羊作为动物模型和四个特定目的来验证这一假设。首先，将确定皮质醇的应激样增加是否抑制下丘脑GnRH分泌和/或脑垂体对GnRH的反应性。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能力的影响。第三，将研究皮质醇介导卵巢周期中断的可能性，以响应某些类型的压力。第四，将鉴定介导皮质醇抑制作用的相关受体。总的来说，这四个特定目标的研究形成了一个全面和有凝聚力的综合方法，以解决皮质醇在介导压力诱导的卵巢周期和生育抑制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.