Project Summary/Abstract This application is responsive to PA-17-091: Fertility Status as a Marker for Overall Health Across their reproductive years, many women experience substantial weight gain, declines in bone density and muscle mass, and worsening cardiometabolic health, each predicting later life morbidity and mortality. Most women have one or more pregnancies during this lifestage, and a large subset of women (up to 1/3), including many who have successfully conceived and carried a previous pregnancy, experience subfertility or infertility. Infertility, defined as the inability to conceive after 12 months of unprotected intercourse, is thus one of the most common conditions among reproductive age adults. A growing body of evidence suggests that fertility- related characteristics predict future health risks including excess weight gain, osteoporosis, cardiovascular disease (CVD), and type 2 diabetes mellitus. The overall goal of our proposed project is to test our hypothesis that women with evidence of impaired fertility will have more adverse body composition, bone health, and cardiometabolic outcomes in perimenopause. We propose a prospective longitudinal cohort study design as the optimal approach to address the proposed aims. We will leverage data from Project Viva, a highly engaged existing cohort of over 1000 socio-demographically diverse women from whom we have already collected detailed information on weight, diet, and other health behaviors beginning at enrollment in 1999-2002, and updated continually since. Exposures are assessed with validated self-reported, clinical, or research measures and will include several time-updated markers of fertility: cycles to conception; gravidity and parity; infertility diagnoses and treatments; diagnosis of polycystic ovary syndrome (PCOS) as well as measurement of testosterone, a defining characteristic of PCOS; and levels of anti-Müllerian hormone (AMH), an objective marker of ovarian reserve. Outcomes include markers of body composition (fat, lean, and bone mass), cardiovascular health, and metabolic health and will be assessed using gold-standard measures at an in-person research visit. Since study inception, we have also rigorously collected data on a wide set of behaviors, health measures, environmental factors, and social and family experiences. Results from the proposed series of investigations will inform clinical care for women from the reproductive years through perimenopause, guidelines regarding screening and long-term follow-up, and future research priorities. This proposal provides an exceptional opportunity to leverage outstanding existing data and resources and include over 20 years of high quality prospective assessments within a 5-year project period.

Project Narrative Identifying fertility as a risk factor for adverse levels of body composition, cardiovascular health, and metabolic health will facilitate early identification of women at especially high risk for these important contributors to death and disability. Accomplishment of our aims will thus inform clinical care for women from the reproductive years through perimenopause and guidelines regarding screening and long-term follow-up. Furthermore, our results will help target future research priorities to test potential mechanisms and field interventions.