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

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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.