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Principal Investigator: Aaron Lazorwitz
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $650,150
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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. These clinical tools will
one day allow women considering steroid hormone medications to assess their individual risk for medication
failure and adverse side effects, thus leading to better informed care and increased patient satisfaction.
Terms: <21+ years old><3-keto-desogestrel><3-ketodesogestrel><3-oxo desogestrel><3-oxodesogestrel><Accounting><Address><Adult><Adult Human><Affect><Age><Albumins><Aquadiol><Area><Biological Markers><Bleeding><Blood Serum><Caring><Client satisfaction><Clinical><Collection><Contraception><Contraceptive Agents><Contraceptive Usage><Contraceptive methods><Contraceptives><Corlutina><Corluvite><Corpus Luteum Hormone><Counseling><Cyclogest><Data><Delta4-pregnene-3,20-dione><Desogestrel><Development><Dimenformon><Diogyn><Diogyn-E><Diogynets><Drug Kinetics><Drug Precursors><Drug Prescribing><Drug Prescriptions><Drugs><Endocrine Gland Secretion><Enrollment><Enzyme Gene><Enzymes><Estinyl><Estrace><Estradiol><Estradiol-17 beta><Estradiol-17beta><Estraldine><Estrogen Metabolism><Estrogens><Ethinoral><Ethinyl Estradiol><Ethinyloestradiol><Eticylol><Etonogestrel><Failure><Family><Female><Female Health><Feminone><Fertility Control><GWA study><GWAS><Gene variant><Genes><Genetic><Genetic Diversity><Genetic Variation><Genotype><Gestagenic Agents><Gestagens><Gestiron><Gestone><Guidelines><HPO axis><Health><Health Care Providers><Health Personnel><Healthcare Providers><Healthcare worker><Hemorrhage><High Prevalence><High Risk Woman><Hormone use><Hormones><Human><Human Genome><Impairment><Implanon><Implant><Individual><Individual Differences><Inestra><Inhibition of Fertilization><Intermediary Metabolism><Intrinsic factor><Investigation><Lipo-Lutin><Literature><Luteohormone><Lutocyclin><Lutocylin M><Lutogyl><Lutromone><Lynoral><Matched Case-Control Study><Measurement><Medication><Medicine><Metabolic Processes><Metabolism><Modern Man><Moods><Oral Contraceptives><Orestralyn><Other Genetics><Outcome><Ovarian Follicle><Ovocyclin><Ovocylin><Ovulation><Ovulation Inhibition><Ovulation Suppression><PK/PD><Participant><Patient Satisfaction><Patients><Pharmaceutical Preparations><Pharmacodynamics><Pharmacogenomics><Pharmacokinetics><Phenotype><Post-Menopause><Post-menopausal Period><Postmenopausal Period><Postmenopause><Pregn-4-ene-3,20-dione><Pregnenedione><Prevalence><Pro-Drugs><Prodrugs><Progestagenic Agents><Progestasert><Progestational Agents><Progestational Compounds><Progestational Hormones><Progesterone><Progesterone Agents><Progestins><Progestogel><Progestogens><Progestol><Progeston><Progynon><Prolidon><Proluton><Questionnaires><Regulatory Protein><Research><Risk><Safety><Serum><Sex Hormone-Binding Globulin><Sex Steroid-Binding Protein><Surrogate Markers><Syngesterone><Testing><Testosterone-Estradiol Binding Globulin><Therapeutic Estradiol><Therapeutic Estrogen><Therapeutic Hormone><Therapeutic Progesterone><Therapeutic Progestin><Therapeutic Steroid Hormone><Unplanned pregnancy><Utrogestan><Variant><Variation><Woman><Women's Health><Work><adulthood><after menopause><ages><allele variant><allelic variant><at-risk females><at-risk women><base><bases><bio-markers><biobank><biologic marker><biomarker><biorepository><birth control pill><blood loss><carrier status><clinical applicability><clinical application><clinical relevance><clinically actionable><clinically relevant><cohort><contraceptive use><design><designing><developmental><drug efficacy><drug metabolism><drug/agent><enroll><ethynylestradiol><experience><female patients><females at high risk><fetal><following menopause><gene locus><genetic locus><genetic regulatory protein><genetic variant><genome scale><genome wide analysis><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genome wide studies><genome-wide><genome-wide analysis><genome-wide identification><genomewide><genomewide association scan><genomewide association studies><genomewide association study><genomic location><genomic locus><genomic variant><health care personnel><health care worker><health provider><health workforce><healthcare personnel><high risk><high risk females><hormonal contraception><hormonal contraceptive><human whole genome><hypothalamic pituitary ovarian axis><individual response><individualized response><inter-individual variability><inter-individual variation><interindividual variability><interindividual variation><life span><lifespan><medical personnel><medication prescription><men><novel><ovarian follicular pool><past menopause><patients being female><patients being women><patients who are female><personalization of treatment><personalized medicine><personalized therapy><personalized treatment><pharmacodynamic biomarker><pharmacodynamic marker><pharmacokinetics and pharmacodynamics><phenotypic data><pill><post-menopausal><postmenopausal><postmenopausal status><precision medicine><precision-based medicine><prescribed medication><prospective><recruit><regulatory gene product><reproductive><response><side effect><steroid hormone><steroid hormone metabolism><surrogate bio-markers><surrogate biomarkers><tool><treatment provider><unintended pregnancy><whole genome association analysis><whole genome association studies><whole genome association study><women at high risk><women patients>