FEMALE REPRODUCTIVE AGING: THE ROLE OF ESTROGEN

生殖功能的停止是女性一生中最剧烈和最迅速的内分泌变化之一，并具有深远和广泛的影响。有一段时间，人们认为是由于卵巢卵泡衰竭导致雌二醇浓度下降导致了更年期。现在，很明显，许多因素相互作用导致生殖功能下降和生殖周期停止。此外，我们开始认识到生殖状态影响着传统生殖轴之外的多种功能。越来越多和越来越多的女性将在绝经后的生活中度过更大的一部分时间。因此，加深我们对调节向非环性过渡的因素的理解，以及相反地，向非环性过渡对多个系统功能的影响是至关重要的。该计划分为五个研究项目，由一个核心支持。这些项目是整合和协调的，以测试以下假设：(1)雌激素反应的改变控制着衰老过程中卵巢卵泡的健康和功能；(2)卵巢金属蛋白酶及其抑制剂表达模式的年龄相关和雌二醇依赖性改变导致卵泡发育和排卵异常；(3)衰老和/或雌二醇的累积暴露调节了促生长和乳营养功能的变化。(4) GnRH神经元谷氨酸能和肾上腺素能调节的改变导致其诱导LH激增的能力发生变化；(5)雌二醇在大脑中起关键的保护作用；因此，雌二醇浓度的下降导致脑损伤和神经变性的易感性增加。管理/动物矿石支持所有项目，提供组织规划，将每个项目的结果整合为更全面的概述，维护所有动物记录并协调其光学内分泌治疗和使用。我们提出这个项目提案是因为我们在生殖老龄化的相互依存方面有共同的兴趣。一个贯穿所有项目的共同威胁是我们对雌二醇在衰老中的作用的兴趣。最后，这种支持机制将使我们能够以最优的方式使用衰老动物，使我们能够比较数据并节省衰老动物的成本。

The cessation of reproductive function is one of the most dramatic and fairly rapid endocrine changes in the life of a female and carries profound and broad repercussions. At one time, it was thought that decreasing estradiol concentration, resulting from exhaustion of ovarian follicles, caused the menopause. Now, it is clear that many factors interact to bring about declining reproductive function and the cessation of reproductive cycles. Furthermore, we are beginning to appreciate the most- reproductive state affects multiple functions that extend beyond the traditional reproductive axis. An increasing number and an increasing proportion of women will liver a larger fraction of their lives in the postmenopausal state. Therefore, it is critical that we deepened our understanding of the factors that regulate the transition to acyclicity and, conversely, the impact of transition to acyclicity on the function of multiple systems. The program is organized into five research projects that are supported by one Core. The projects are integrated and coordinated to test the following hypotheses (1) changing estrogen responsiveness governs the health and function of ovarian follicles during aging, (2) age-related and estradiol-dependent alterations in the pattern of expression in the ovarian metalloproteinases and their inhibitors result in abnormalities in follicular development and ovulation, (3) aging and/or the cumulative exposure to estradiol regulate changes in somatotroph and lactotroph function, (4) alterations in glutamatergic and adrenergic regulation of GnRH neurons cause changes in their ability to induce LH surges; and (5) estradiol plays a critical protective role in the brain; therefore, declining estradiol concentrations lead to an increased vulnerability to brain injury and neurodegeneration. An Administrative/Animal ore supports all of the projects, providing organizational planning, integrating results from each project into a more comprehensive overview, and maintaining all animal records and coordinating their optical endocrine treatments and use. We submit this program project proposal because we share interests in interdependent aspects of reproductive aging. A common threat that weaves through all of the projects is our interests in the role of estradiol in aging. Finally, this mechanism of support will permit us to use aging animals in the most optimal manner, allowing us to compare data and economize on the costs of aging animals.