Estrogen and progesterone reduce lipid accumulation in human monocyte-derived macrophages - A sex-specific effect

Background-Males have an earlier onset and greater prevalence of clinical a therosclerosis than age-matched females, which is consistent with an athero protective effect of the female sex steroids, estrogen and progesterone. We therefore examined the effects of estrogen and progesterone on human foam cell formation, a key early event in atherogenesis. Methods and Results-Monocytes from healthy female and male donors were obta ined from white cell concentrates and allowed to differentiate into macroph ages over 10 days. These human monocyte-derived macrophages (MDMs) were exp osed to either control (0.1% vol/vol ethanol) or estrogen or progesterone t reatment on days 3 through 10. Lipid loading was achieved on days 8 through 10 by incubation with acetylated LDL. Lipid from the MDMs was then extract ed for analysis of cholesteryl ester (CE) content. 17 beta-Estradiol at bot h physiological (2 nmol/L) and supraphysiological (20 and 200 nmol/L) conce ntrations produced a significant reduction in macrophage CE content (88 +/- 3%, 88 +/- 2%, and 85 +/- 4%, respectively; P < 0.02 compared with control ). Physiological and supraphysiological levels of progesterone (2, 10, and 200 nmol/L) produced an even more dramatic reduction in CE content (74 +/- 9%, 56 +/- 10%, and 65 +/- 8%, respectively; P < 0.002 compared with contro l), This effect could be abrogated by coincubation with the progesterone re ceptor antagonist RU486. Neither estrogen nor progesterone produced a reduc tion in lipid loading in male-donor-derived MDMs. Detailed lipid traffickin g studies demonstrated that both estrogen and progesterone altered macropha ge uptake and/or processing of modified LDL. Conclusions-Physiological levels of estrogen and progesterone are associate d with a female-sex-specific reduction in human macrophage lipid loading, w hich is consistent with an atheroprotective effect.