Quantitative Assessment of the Effects of Aging on the Female Reproductive Axis

描述(由申请人提供)：受孕的可能性随着人类女性年龄的增长而减少，但其潜在的机制尚不清楚。这是一个重大的临床问题，因为许多妇女将生育推迟到第四和第五个年龄段(例如，在建立职业生涯之后)，而且现有的诊断工具不能可靠地预测卵巢储备，而卵巢储备反过来又被用来帮助确定是否应该治疗与年龄相关的生殖潜力下降的妇女。我们之前已经证明，与年轻和年长的同龄人相比，绝经前老年女性的脑下垂体生殖激素改变了分泌特征。这支持了我们的总体假设，即除了卵母细胞枯竭和/或卵母细胞/卵泡的异常相互作用外，正常衰老与下丘脑-垂体和卵巢激素之间的关系发生了明显的变化，这可能是卵巢储备减少的预测因素。我们建议通过对年轻和老年绝经前妇女的临床和数学研究的结合来进一步解决这一假说。我们将研究衰老对卵巢激素分泌模式的影响，对垂体和卵巢激素之间的剂量-反应相互作用的影响，以及对卵巢对神经内分泌功能的反馈的影响。此外，我们将使用一些现有的诊断工具来估计这些影响可以预测的程度。为此，我们将测试与年轻同龄人相比，年长的绝经前女性具有的特定假设：1.卵巢激素的分泌特征和时间关系改变；2.卵巢对神经内分泌信号的反应性降低；3.性腺激素反馈增强对神经内分泌信号的作用。此外，我们还将检验假设：4.与正常衰老相关的垂体-卵巢内分泌轴的变化不能用现有的大多数估计卵巢储备的诊断工具可靠地检测到。与现有研究不同，我们将首次使用跨学科方法来确定衰老如何影响生殖轴各组成部分之间的关系。对这些关系的识别将指导未来的介入研究对这些变化的机制进行详细的分析。最终，我们的长期目标是开发新的诊断工具和治疗方法，使临床医生能够理性地决定哪些妇女应该或不应该接受与年龄相关的生殖潜力降低的各种治疗方案。公共卫生相关性：这些研究有望阐明指导生殖系统功能的复杂内分泌机制中与年龄相关的变化。它们将使未来的研究能够将重点放在应用这一知识来开发新的诊断和治疗方法，以应对与年龄相关的生殖潜力下降。

DESCRIPTION (provided by applicant): The likelihood of conceiving diminishes with aging in the human female, but the underlying mechanisms are not understood. This presents a major clinical problem since many women delay childbearing until the 4th and 5th decades of life (e.g., after establishing a career) and existing diagnostic tools cannot reliably predict ovarian reserve which, in turn, is utilized to help determine whether a woman should be treated given her age- associated reduction in reproductive potential. We have previously shown that the pituitary reproductive hormones in older premenopausal women have altered secretory characteristics when compared to younger and older peers. This supports our overall hypothesis that in addition to oocyte depletion and/or abnormal oocyte/follicular interactions, normal aging is associated with detectable changes in the relationships between hypothalamic-pituitary and ovarian hormones, which may be predictive for reduction in ovarian reserve. We propose to further address this hypothesis with a combination of a clinical and mathematical study in younger and older premenopausal women. We will study the effect of aging on the secretion patterns of the ovarian hormones, on the dose-response interactions between pituitary and ovarian hormones and on ovarian feedback on neuroendocrine function. In addition, we will estimate the extent to which these effects can be predicted utilizing some of the existing diagnostic tools. To this end, we will test the specific hypotheses that older premenopausal women compared to their young peers have: 1. Altered secretion characteristics and temporal relationships of the ovarian hormones; 2. Reduced ovarian responsivity to neuroendocrine signaling; 3. Enhanced gonadal hormones feedback exerted on the neuroendocrine signaling. In addition, we will also test the hypothesis that: 4. Alterations in the pituitary-ovarian endocrine axis associated with normal aging cannot be detected reliably with most of the existing diagnostic tools for estimating ovarian reserve. In contrast to existing studies we will for the first time use interdisciplinary methods to define how aging affects the relationships between the components of the reproductive axis. Identification of such relationships which demonstrate the most robust changes will guide future interventional studies to perform a detailed analysis of the mechanisms of these alterations. Ultimately, our long-term goal is to develop novel diagnostic tools and therapeutic approaches to allow clinicians to make rational decisions regarding which women should or should not be subjected to the various treatment options in connection to age-associated reductions in reproductive potential. PUBLIC HEALTH RELEVANCE: The studies are expected to illuminate the age-related changes in the complex endocrine mechanisms directing the function of the reproductive system. They would allow future studies to focus on the application of this knowledge to develop novel diagnostic and therapeutic approaches to age-associated reductions in reproductive potential.