Sex Hormones in Postmenopausal Women in the Diabetes Prevention Program

描述（由申请人提供）：尽管绝经后是一种普遍的衰老经历，并被定义为卵巢功能的永久性变化，但我们仍然不了解绝经后性激素如何影响糖尿病风险。有趣的观察表明，内源性激素（ESH）可能有助于绝经后妇女的葡萄糖耐受不良。以前的观察性研究受到ESH单一指标的限制，干预性研究受到仅检查外源性激素、缺乏显著的血糖变化、缺乏对潜在混杂因素（如胰岛素稳态）的测量或仅在欧洲血统的高加索人中进行检查的限制。糖尿病预防项目（DPP）是一项关于强化生活方式干预和二甲双胍预防糖尿病的大型随机对照试验（n= 3，234）。DPP招募了空腹血糖受损或糖耐量受损的参与者，其中45%为非白人，DPP还获得了人体测量、胰岛素分泌、胰岛素敏感性以及空腹和攻毒后血糖的多项指标。大约三分之二是女性，一半的女性在基线时已绝经。因此，DPP提供了一个令人信服的机会来检查内源性性激素（ESH）的变化对绝经后妇女葡萄糖耐受不良的演变的贡献。我们建议对DPP进行一项辅助研究，即绝经后妇女的性激素或SHIP研究。使用从基线数据收集和随机化后2年储存的血浆，我们建议使用最先进的质谱法检查未使用外源性激素的DPP女性（n=865）和使用外源性激素的DPP女性（n=144）亚组中的ESH（睾酮、雌二醇、性激素结合球蛋白）和促卵泡激素（FSH）。具体目标1是检查糖尿病预防干预是否与ESH的变化相关。具体目标2是检查干预组ESH水平的变化是否与血糖变化相关，具体目标3是检查肥胖、胰岛素敏感性和胰岛素分泌的变化是否可以解释这些相关性。这项建议的调查人员和顾问参与了全国妇女健康研究ESH生命阶段过渡专家，以及对ESH进行初步研究的DPP PI，这些研究构成了这项研究的基础。该团队包括性激素生物学家，流行病学家和糖尿病学家。DPP及其后续研究得到了NIDDK的支持。DPP资源的持续管理通过DPP协调中心进行，SHIP研究将补充正在进行的DPP辅助研究，检查绝经前女性的雄激素和男性的雄激素。DPP的大量、特征良好的、种族/民族多样化的人群和储存的血浆提供了一个独特的机会来评估ESH、肥胖、胰岛素稳态和葡萄糖耐受不良的重复测量之间的关系。 公共卫生相关性：绝经后妇女患糖尿病的风险很高，以前的研究表明内源性性激素（与激素替代疗法相反）可能起作用。然而，以前的研究没有检查性激素的变化是否与葡萄糖耐量的变化有关，以及这种变化是否可以通过肥胖和胰岛素的同时变化来解释。以前的研究没有检查糖尿病预防干预措施对性激素的影响。为了解决这些差距，拟议的船舶辅助研究将利用通过DPP收集的重要数据。SHIP研究将深入了解葡萄糖耐受不良的病理生理学，研究结果不仅对糖尿病预防有意义，而且对其他以性激素为介质的疾病也有意义。

DESCRIPTION (provided by applicant): Although postmenopause is a universal experience of aging and is defined by permanent changes in ovarian function, we still do not understand how postmenopausal sex hormones affect diabetes risk. Intriguing observations suggest that endogenous sex hormones (ESH) may contribute to glucose intolerance in postmenopausal women. Previous observational studies have been limited by single measures of ESH, and intervention studies are limited by examination of exogenous hormone only, lack of significant glucose changes, lack of measurement of potential confounders such as insulin homeostasis, or examination only in Caucasians of European ancestry. The Diabetes Prevention Program (DPP) was a large randomized controlled trial (n=3,234) of intensive lifestyle intervention and metformin for prevention of diabetes. The DPP enrolled participants with either impaired fasting glucose or impaired glucose tolerance, 45% of whom were non-white, and the DPP also obtained multiple measures of anthropometry, insulin secretion, insulin sensitivity, and fasting and postchallenge glucose. Approximately two-thirds were women, and half of the women were postmenopausal at baseline. Thus, the DPP offers a compelling opportunity to examine the contribution of changes in endogenous sex hormones (ESH) to the evolution of glucose intolerance in postmenopausal women. We propose an ancillary study to the DPP, the Sex Hormones in Postmenopausal Women or SHIP study. Using plasma stored from the baseline data collection and 2 years after randomization, we propose to examine ESH (testosterone, estradiol, sex hormone binding globulin) and follicle stimulating hormone (FSH) in a subset of DPP women without exogenous hormone use (n=865) and DPP women with exogenous hormone use (n=144) using state-of-the art mass spectrometry. Specific Aim 1 is to examine if diabetes prevention interventions are associated with changes in ESH. Specific Aim 2 is to examine if changes in ESH levels are associated with changes in glucose by intervention arm. Specific Aim 3 is to examine whether changes in adiposity, insulin sensitivity, and insulin secretion explain these associations. Investigators and consultants on this proposal are involved in the Study of Women's Health Across the Nation expert in ESH life stage transitions, as well as DPP PIs who have conducted the initial research in ESH that form the basis for this study. The team includes sex hormone biologists, epidemiologists, and diabetologists. The DPP and its follow-up study are supported by the NIDDK. Ongoing management of DPP resources occurs through the DPP Coordinating Center, and the SHIP study will be complementary to ongoing DPP ancillary studies examining androgens in premenopausal women and androgens in men. The DPP's large, well-characterized, racially/ethnically diverse population and stored plasma provide a unique opportunity to assess the relationships among repeated measures of ESH, adiposity, insulin homeostasis, and glucose intolerance. PUBLIC HEALTH RELEVANCE: Postmenopausal women are at high risk for diabetes, and previous studies suggest that endogenous sex hormones (as opposed to hormone replacement therapy) may play a role. However, previous studies have not examined whether changes in sex hormones are associated with changes in glucose tolerance, and whether such changes might be explained by concurrent changes in adiposity and insulin. Previous studies have not examined the influence of diabetes prevention interventions upon sex hormones. To address these gaps, the proposed SHIP ancillary study will leverage the significant data already collected through the DPP. The SHIP study will provide insight into the pathophysiology of glucose intolerance, and the findings will have implications not only for diabetes prevention but also for other diseases that focus on sex hormones as mediators.