ReproEDIC: Risk and Progression of Reproductive Abnormalities in Type 1 Diabetes

描述(由申请人提供)：卵巢储备通常被定义为卵巢中存在的原始卵泡的数量。随着储备量随着年龄的增长而下降，女性的生育力和性腺功能都会下降，即更年期。更年期反过来会增加患慢性病的风险，特别是心血管疾病。横断面研究表明，患有1型糖尿病(T1D)的女性卵巢储备受损：糖尿病女性的绝经时间比非糖尿病女性早8年。由于几个原因，对病理生理学的了解一直受到限制。目前还没有关于T1D女性卵巢储备生化标志物的纵向研究，这些标志物如何随年龄变化，以及这些标志物是否预测更年期等临床结果。没有纵向研究表明这些标记物(和结果)如何随血糖控制、胰岛素剂量和糖尿病并发症的变化而变化。因此，我们尚不清楚如何保护糖尿病女性的卵巢储备，以及卵巢储备的下降如何反过来加剧常见的糖尿病并发症。考虑到近几十年来T1D发病年龄的年轻化，这些问题变得越来越重要。由于他们随后的糖尿病病程延长，与之前的队列相比，这些年轻人可能面临更多的生育和更年期困难，以及确定的微血管和大血管糖尿病并发症。参加糖尿病控制和并发症试验(DCCT)的妇女在基线年龄为13-39岁(n=680)，这是一项针对T1D强化血糖控制的大型随机试验。这项观察性后续研究，糖尿病干预和并发症流行病学研究(EDIC)，现已进入第17个年头，队列保留率为94%，其中一半人口为绝经后。DCCT/EDIC存储了有关月经停止、卵巢切除和子宫切除以及糖尿病并发症的血清和调查信息。拟议的ReproEDIC研究的目标是描述患有T1D的女性的卵巢储备。我们建议使用储存的血清来检测卵巢储备的标志物--抗梅勒激素(AMH)。AMH已经在非糖尿病队列中进行了纵向检查，但在T1D中没有。我们的具体目标是：1)测定卵巢储备的一系列生化标记物，并描述这些标记物、年龄和临床储备指标之间的关系；2)检查强化糖尿病治疗是否影响T1D妇女的卵巢储备；3)确定卵巢储备对T1D妇女微血管和大血管糖尿病并发症的影响。通过利用DCCT/EDIC(世界上特征最广泛的糖尿病队列之一)提供的大量资源，我们可以确定T1D及其管理是否以及如何影响卵巢储备。这个问题具有临床意义：这些妇女及其家人希望了解血糖对更年期和生育力等结局的影响，以及卵巢储备对糖尿病并发症(如肾病、神经病变、心血管结局)的影响。

DESCRIPTION (provided by applicant): Ovarian reserve is commonly defined as the number of primordial follicles present in the ovaries. As reserve declines with age, women experience decreased fertility and gonadal function, i.e. menopause. In turn, menopause increases risk of chronic conditions, particularly cardiovascular disease. Cross-sectional studies suggest that women with type 1 diabetes (T1D) have impaired ovarian reserve: diabetic women experience menopause 8 years earlier than non-diabetic women. Understanding of the pathophysiology has been limited for several reasons. There are no longitudinal studies in T1D women characterizing biochemical markers of ovarian reserve, how such markers change with age, and if such markers predict clinical outcomes such as menopause. There are no longitudinal studies of how such markers (and outcomes) vary with glycemic control, insulin dosing, and diabetic complications. Therefore, it is unknown how we can preserve ovarian reserve in women with diabetes, and how declines in ovarian reserve can in turn exacerbate common diabetic complications. These questions are increasingly important given the younger age of onset of T1D in recent decades. Due to their subsequently prolonged diabetes duration, these youth may face increased difficulties with fertility and menopause, as well as established microvascular and macrovascular diabetic complications, compared to previous cohorts. Women enrolled in the Diabetes Control and Complications Trial (DCCT), a large randomized trial of intensive glycemic control in T1D (n=680), were 13-39 years of age at baseline. The observational follow-up, the Epidemiology of Diabetes Intervention and Complications Study (EDIC), is now in its 17th year, with 94% cohort retention, and half of its population is postmenopausal. DCCT/EDIC has banked sera and survey information regarding cessation of menses, oophorectomy and hysterectomy, and diabetic complications. The goal of the proposed ReproEDIC study is to characterize ovarian reserve in women with T1D. Using stored sera, we propose to measure a marker of ovarian reserve, anti-M¿llerian hormone (AMH). AMH has been examined longitudinally in non-diabetic cohorts but not in T1D. Our Specific Aims are: 1) To measure serial biochemical markers of ovarian reserve and to characterize the relationship between these markers, age, and clinical measures of reserve in women with T1D, 2) To examine if intensive diabetes therapy affects ovarian reserve in women with T1D, and 3) To determine the influence of ovarian reserve on microvascular and macrovascular diabetic complications in women with T1D. By leveraging the significant resources available through the DCCT/EDIC, one of the most extensively characterized diabetes cohorts in the world, we can determine if and how T1D and its management influence ovarian reserve. This question is of clinical significance: these women and their families wish to know the impact of glycemia upon outcomes such as menopause and fertility, as well as the impact of ovarian reserve upon their diabetic complications, such as nephropathy, neuropathy, cardiovascular outcomes.