PhD Thesis Proposal: Olivia Palmer

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"Sex hormones tune macrophage fate and function"

Abstract

Estradiol (E2) and progesterone (P4) are the primary sex hormones that govern reproductive function in premenopausal females. Their concentrations shift by orders of magnitude across the menstrual cycle and pregnancy, and both hormones act on the immune system. Macrophages are immune cells that reside in nearly every tissue, sense local signals, and coordinate the promotion or resolution of inflammation. In the female reproductive tract, macrophages contribute to endometrial breakdown and repair, clearance of dying cells, and immune tolerance during pregnancy. Altered macrophage activity has been observed in hormone-associated conditions such as endometriosis and polyendocrine metabolic ovarian syndrome (PMOS). Macrophages express receptors for both E2 and P4, but how human macrophages respond to these hormones across physiological concentrations remains poorly defined. This thesis characterizes how E2 and P4 shape human macrophage gene expression, metabolism, and function, and examines how these responses relate to the female reproductive tract.

Multi-omic and functional profiling in an optimized culture system demonstrated that macrophage responses to E2 and P4 depend on activation state, hormone concentration, and exposure time. In inflammatory macrophages, P4 altered cytokine secretion in a concentration-dependent manner, and luteal-phase P4 increased phagocytosis. In anti-inflammatory macrophages, pregnancy-level E2 shifted metabolism toward fatty acid oxidation, and both hormones affected efferocytosis, with the largest reduction at luteal-phase P4. Hormone exposure during monocyte-to-macrophage differentiation revealed a P4-responsive transcriptional program arising before activation, which suggests that hormonal state may shape macrophage fate as well as function. In vivo, hormonal intrauterine device use was associated with a lower proportion of CD163+ cells in cervicovaginal fluid. Single-cell analysis of cervical biopsies from individuals undergoing artificial cycles extends these questions to immune populations in tissue. Together, the findings indicate that E2 and P4 act as context-dependent regulators of human macrophages, with effects determined by activation state, hormone concentration, and developmental stage. The thesis establishes a framework for linking physiological hormone fluctuation to macrophage function and dysfunction in the female reproductive tract.

Thesis Committee

• Margie Ackerman (Chair)
• Britt Goods
• Patricia Pioli

Contact

For more information, contact Thayer Registrar at thayer.registrar@dartmouth.edu .