Using real world evidence to address gaps in the use of estrogen and progesterone therapy in adolescents and premenopausal women with chronic kidney disease - Project Summary Chronic kidney disease (CKD) affects 35.5 million Americans and contributes to morbidity, reduced quality of life, and heightened cardiovascular mortality, disproportionately impacting women more than men. CKD disrupts ovarian hormone levels, often leading to menstrual irregularities and low estrogen, both of which can negatively impact bone health and increase already elevated risks for reduced bone mineral density and fractures. Estrogen and progesterone (E/P) therapy is effective in improving bone mineral density and reducing fracture risk in hypoestrogenic women without CKD, but its efficacy in CKD has not been studied. Additionally, E/P therapy is associated with an increased risk of venous thromboembolism (VTE) and thrombotic stroke in the general population. This risk may be more pronounced in the CKD population, particularly among those with higher baseline thrombotic risk, such as patients with systemic lupus erythematosus with nephritis or nephrotic syndrome. However, there are subpopulations of patients with CKD who may not have increased thrombotic risk beyond the general population and thus may benefit from E/P therapy for regulation of their underlying menstrual irregularities and for bone protection. This project addresses these critical evidence gaps by leveraging two large and complementary real-world data sources, the TriNetX Research Network and Merative MarketScan, to evaluate the risks and benefits of E/P therapy in adolescent and premenopausal women with moderate to severe CKD (stage 3-5D). TriNetX organizations, integrates electronic health records for >100 million patients from 80 major healthcare and the Merative MarketScan database includes longitudinal patient-level claims data for>273 million individuals throughout all US states and territories. Specifically, the study will use a stratified sequential analysis with propensity score matching to assess the impact of E/P therapy on improving bone health by reducing fracture risk (Aim 1) while evaluating its potential to increase the risk of thrombotic events (Aim 2). These two aims will provide robust evidence on the risk and benefit of E/P therapy in CKD care. As the first and largest study of its kind, it will inform clinical guidelines for safer, more effective E/P therapy use, ultimately improving reproductive and skeletal health outcomes in this high-risk population. The grant will also provide the applicant with advanced training in pharmacoepidemiologic research methods and mentorship to support her career development and transition to an independent physician-scientist focused on the impact of chronic disease on ovarian health in adolescents and young adults.
