Sex Hormones in Postmenopausal Women in the Diabetes Prevention Program

描述(申请人提供)：尽管绝经后是一种普遍的衰老体验，并由卵巢功能的永久性变化来定义，但我们仍然不了解绝经后性激素如何影响糖尿病风险。耐人寻味的观察表明，内源性性激素(ESH)可能会导致绝经后女性的葡萄糖耐受。以前的观察性研究局限于ESH的单一测量，而干预研究仅限于检查外源性激素，缺乏显著的血糖变化，缺乏对潜在混杂因素的测量，如胰岛素稳态，或仅在欧洲血统的高加索人中进行检查。糖尿病预防计划(DPP)是一项大型随机对照试验(n=3,234)，包括强化生活方式干预和二甲双胍预防糖尿病。DPP招募了空腹血糖受损或糖耐量受损的参与者，其中45%是非白人，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挑战后血糖的多项测量。大约三分之二是女性，在基线水平上，一半的女性是绝经后的。因此，DPP提供了一个令人信服的机会来研究内源性性激素(ESH)的变化对绝经后女性糖耐量异常演变的贡献。我们建议对DPP进行一项辅助研究，即绝经后妇女性激素或SHIP研究。使用从基线数据收集中存储的血浆和随机两年后，我们建议使用最新的质谱仪检测未使用外源性激素的DPP妇女(n=865)和使用外源性激素的DPP妇女(n=144)的ESH(睾酮、雌二醇、性激素结合球蛋白)和卵泡刺激素(FSH)。具体目标1是检查糖尿病预防干预措施是否与ESH的变化有关。具体目标2是检查ESH水平的变化是否与干预组的血糖变化有关。具体目标3是检查肥胖症、胰岛素敏感性和胰岛素分泌的变化是否解释了这些联系。这项提案的调查人员和顾问参与了全国妇女健康研究ESH生命阶段转变方面的专家，以及在ESH中进行初步研究的民进党PIs，这些研究构成了本研究的基础。该团队包括性激素生物学家、流行病学家和糖尿病专家。民进党及其后续研究得到NIDDK的支持。DPP资源的持续管理是通过DPP协调中心进行的，SHIP研究将补充正在进行的DPP辅助研究，检查绝经前妇女的雄激素和男性的雄激素。民进党庞大的、特征良好的、种族/民族多样化的人口和储存的血浆提供了一个独特的机会来评估重复测量ESH、肥胖症、胰岛素稳态和葡萄糖耐量之间的关系。 公共卫生相关性：绝经后妇女患糖尿病的风险很高，先前的研究表明，内源性性激素(与激素替代疗法相反)可能起到一定作用。然而，之前的研究没有检验性激素的变化是否与糖耐量的变化有关，以及这些变化是否可能由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已经通过DPP收集的重要数据。SHIP研究将提供对葡萄糖耐量异常的病理生理学的洞察，这些发现不仅对糖尿病的预防，而且对其他以性激素为中介的疾病也有意义。

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.