Genetic Epidemiology of Ovarian Aging

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DESCRIPTION (provided by applicant): The ovary is a unique organ in that the age associated with decline in function (in fact, frank failure) appears to have remained constant despite increasing longevity. Beyond this apparent biological constant in the population, wide interindividual variability exists both in the age at which menopause occurs and the rate of decline in oocyte number and reproductive capability. We propose a study of the genetic and environmental factors that influence the age-specific variability in reproductive aging. We hypothesize ovarian aging, as reflected by antral follicle count (AFC), is largely determined by common genetic polymorphisms that impact the initial oocyte endowment and or the rate of oocyte loss over time thus lowering antral follicle count for any given age. We further hypothesize AFC will be an improved marker of ovarian aging. We propose to develop a cohort of 1250, ethnically diverse, regularly cycling women, ages 25-45 who will provide blood specimens for DNA and other biomarkers, undergo a transvaginal ultrasound to obtain AFC, and complete questionnaires and anthropometric measurements. In Specific Aim 1, we will characterize AFC as a marker of ovarian age by comparing it to other available biomarkers, FSH, FSH/LH, and inhibin B, and will determine effect modification of these relations by age. In Specific Aim 2, we will examine the relationship between the frequency of genetic polymorphisms in DAZL (Deleted in Azoospermia-Like), and interacting protein and RNA genes, and antral follicle count. In Specific Aim 3, we will determine the association between race/ethnicity, body fat, and active and passive smoking and AFC independently of age, and explore the effect modification of those relationships by identified genetic polymorphisms. In Specific Aim 4, we will determine the change in AFC over time and its relation to genetic and environmental characteristics based on approximately 450 women who complete the three-year follow-up examination. This project has several unique strengths. These include: 1) the collaboration of a reproductive endocrinologist, a molecular geneticist and an epidemiologist; 2) a broad population based strategy which will more fully characterize AFC as a prospective marker of ovarian aging; 3) the use of a multi-ethnic population to document racial/ethnic differences and 4) the ability to establish a cohort that can be followed longitudinally to associate rate of change in AFC with genetic risk factors for ovarian aging.