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

衰老对女性生殖轴影响的定量评估

• 批准号: 7906804
• 负责人: WILLIAM S EVANS
• 金额: $ 15.63万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906804
• 关键词: Address; Affect; Age; Aging; Androstenedione; Characteristics; Clinical; Clomiphene; Complex; Coupling; Delayed Childbearing; Diagnostic; Dose; Endocrine; Entropy; Estradiol; Feedback; Female; Frequencies; Future; Goals; Gonadal Hormones; Hour; Hypothalamic structure; Inhibin A; Knowledge; Life; Luteal Phase; Methods; Modeling; Neurosecretory Systems; Oocytes; Ovarian; Ovarian hormone; Ovary; Pattern; Phase; Physiologic pulse; Pituitary Gland; Premenopause; Progesterone; Reproductive system; Sampling; Signal Transduction; Testing; Therapeutic; Woman; age effect; age related; base; career; human female; inhibin; normal aging; novel; novel diagnostics; peer; proliferative phase Menstrual cycle; public health relevance; reproductive; reproductive axis; reproductive hormone; response; time use; tool

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.

描述（由申请人提供）：女性受孕的可能性随着年龄的增长而降低，但其潜在机制尚不清楚。这提出了一个主要的临床问题，因为许多女性将生育推迟到四岁和五岁（例如，在建立职业生涯之后），而现有的诊断工具无法可靠地预测卵巢储备功能，而卵巢储备功能反过来又可用于帮助确定女性是否应该生育。鉴于她与年龄相关的生殖潜力下降，需要接受治疗。我们之前已经表明，与年轻和年长的同龄人相比，老年绝经前女性的垂体生殖激素的分泌特征发生了改变。这支持了我们的总体假设，即除了卵母细胞消耗和/或卵母细胞/卵泡相互作用异常之外，正常衰老还与下丘脑-垂体和卵巢激素之间关系的可检测变化有关，这可能预示着卵巢储备功能的减少。我们建议结合对年轻和老年绝经前女性的临床和数学研究来进一步解决这一假设。我们将研究衰老对卵巢激素分泌模式、垂体和卵巢激素之间剂量反应相互作用以及卵巢对神经内分泌功能的反馈的影响。此外，我们将利用一些现有的诊断工具来估计这些影响的预测程度。为此，我们将检验老年绝经前女性与年轻同龄人相比的具体假设： 1. 卵巢激素的分泌特征和时间关系发生改变； 2.卵巢对神经内分泌信号的反应性降低； 3.增强性腺激素对神经内分泌信号的反馈。此外，我们还将检验以下假设： 4. 大多数现有的估计卵巢储备的诊断工具无法可靠地检测到与正常衰老相关的垂体-卵巢内分泌轴的变化。与现有研究相反，我们将首次使用跨学科方法来定义衰老如何影响生殖轴各组成部分之间的关​​系。识别出表现出最强劲变化的关系将指导未来的干预研究对这些变化的机制进行详细分析。最终，我们的长期目标是开发新的诊断工具和治疗方法，使临床医生能够做出合理的决定，决定哪些女性应该或不应该接受与年龄相关的生殖潜力下降相关的各种治疗方案。公共健康相关性：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。他们将使未来的研究重点关注这些知识的应用，以开发新的诊断和治疗方法来治疗与年龄相关的生殖潜力下降。