PROJECT ABSTRACT Females with sickle cell disease (SCD) in the United States face a health disparity triple threat as a result of their chronic disease, race, and sex. In addition to overall reduced survival rates in both sexes and maternal mortality rates that exceed those of Black females without SCD, females with SCD experience significantly more frequent and more severe vaso-occlusive pain episodes (VOEs) compared to their male counterparts. However, the pathophysiology of this pain disparity – whether biological, sociocultural, or both – is not understood. With this proposal, we will test our central hypothesis, that female sex hormones modulate cyclic increases in inflammation that predispose to VOEs. We will also explore whether and how gender modifies our proposed relationship between sex, inflammation, and VOEs. SCD is characterized by chronic inflammation, with acute rises in inflammatory markers during VOEs. VOEs exhibit a perimenstrual pattern, peaking during or prior to menses in many females with SCD. Our preliminary data show that inflammatory markers may exhibit a similar pattern, peaking in the follicular phase. Together, the established correlation between pain and inflammation and newer evidence of a cyclic pattern to pain and inflammation in SCD lead us to postulate that female sex hormones mediate inflammation and VOEs. Moreover, hormonal contraception may play a therapeutic role in SCD. Depot medroxyprogesterone (DMPA, Depo-Provera®) is a progestin-only contraceptive that reduced VOE frequency in small studies. Since DMPA suppresses hormonal fluctuations in the menstrual cycle, we hypothesize that DMPA may reduce cyclic fluctuation in inflammation and thereby relieve VOE pain. The pathophysiologic pathway of perimenstrual VOE is likely multifactorial. The objectives of this study are (1) to ascertain sex- and gender-related mechanisms of perimenstrual VOE and (2) to determine the therapeutic effectiveness of DMPA on VOE and inflammatory biomarkers. We propose two prospective studies of patients with SCD recruited from university-based clinical practices at the University of Pennsylvania and Johns Hopkins University. In Aim 1, “Inflammatory Biomarker Patterns in Females and Males with Sickle Cell Disease,” we will evaluate traditional and functional inflammatory biomarkers via serial blood sample collections across the menstrual cycle in 20 females with SCD, and compare to serial biomarker levels over one month in 8 male controls with SCD. In Aim 2, “Clinical and Biomarker Effects of Depot Medroxyprogesterone Acetate in Females with Sickle Cell Disease,” we will assess 52 females with SCD pre- and post-intervention with DMPA to measure effects on VOEs and the same biomarkers. With these studies, we plan (1) to demonstrate that key inflammatory biomarkers are modulated by both sex and gender and (2) to determine whether DMPA prevents VOEs and reduces inflammation, and how gender affects these outcomes. This research will f...