PROJECT SUMMARY (ABSTRACT) Combined oral contraceptive pills (COCPs), containing both an estrogen and a progestin, remain the most commonly used hormonal contraceptive method in the US, and overall, one of the most commonly prescribed medications among all women. Despite its high prevalence of use, little is known about the pharmacogenomics of COCPs, which are the relationships between genetic variations and interindividual variability in drug efficacy, metabolism, and safety. Pharmacogenomic investigations have led to the development of actionable clinical guidelines for over 40 drug-gene pairs, the majority of which involve drugs far less frequently prescribed than COCPs. Given the utility of COCPs and similar steroid hormone-containing medications throughout a woman's lifespan, it is imperative that we gain a better understanding of how individual genetic variation affects the wide interindividual response to these drugs. However, a major hurdle faced in conducting pharmacogenomic research with these medications is the lack of useful phenotypic data in existing biobanks. National genetic consortia are primarily made up of men or postmenopausal women, thus necessitating the creation of new biobanks that focus on reproductive-age women and collect data on phenotypes specific to steroid hormone medications. We aim to build a novel biobank of 700 COCP users to both validate previously identified genetic relationships among contraceptive implant users and to identify novel areas of the human genome associated with steroid hormone metabolism, contraceptive mechanisms, and side effects. We will collect pharmacokinetic outcomes from COCP users to evaluate the influence of CYP3A7*1C carrier status, which has been associated with increased metabolism of other exogenous and endogenous steroid hormones. We will enroll a subset of 150 COCP users into a matched case-control study to determine how CYP3A7*1C carrier status affects ovulation inhibition using pharmacodynamic measurements of hypothalamic-pituitary-ovarian axis suppression and dominant ovarian follicle creation. All participants will also complete questionnaires to assess their side effect profiles after a single cycle of COCP use and undergo serial measurements of clinically relevant biomarkers. Participants will then be given the opportunity to complete repeat questionnaires and biomarker measurements after 3, 6, and 13 cycles of continued COCP use. This prospective collection of side effect and biomarker data will allow for analyses of clinically pertinent phenotypes, such as early COCP discontinuation and enhanced estrogenecity. We will utilize genome-wide sequencing for all participants so that we can conduct exploratory genome-wide analyses in addition to our planned targeted approaches. This study will create the first biobank of COCP users specifically designed with collecting phenotypic data most pertinent for the eventual creation of precision and personalized medicine clinical tools. T...