# Sex and gender influences on inflammation and pain in sickle cell disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $496,503

## Abstract

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...

## Key facts

- **NIH application ID:** 10991182
- **Project number:** 1R01HL175726-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Andrea Roe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $496,503
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10991182

## Citation

> US National Institutes of Health, RePORTER application 10991182, Sex and gender influences on inflammation and pain in sickle cell disease (1R01HL175726-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10991182. Licensed CC0.

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