Opposing effects of estrogen and progestins on LDL oxidation and vascular wall cytotoxicity: Implications for atherogenesis

Estrogens are widely regarded as beneficial to arterial wall health. Among the mechanisms of this benefit are antioxidant effects on LDL and the arter ial wall. Because progestins oppose the effect of estrogen in several syste ms, we asked if progestins oppose the antioxidant effect of estrogen, To st udy this question, LDL and various female sex hormones were incubated alone and combined in the absence or presence of bovine aortic endothelial cells , placental trophoblast, or macrophages, and LDL oxidation and cytotoxicity were quantitated. In the absence of cells, LDL incubated with copper in ph osphate-buffered saline enhanced the oxidation of LDL. When 17 beta-estradi ol was added to this system, an antioxidant effect was observed. Progestins inhibited this protective estrogenic effect. In endothelial cell culture, progestins also opposed the antioxidant effect of estrogen, with the strong est antiestrogenic effect seen with the synthetic progestins, levonorgestre l and medroxyprogesterone acetate (MPA). Endothelial cell cytotoxicity was proportional to the enhanced lipid peroxide formation observed with progest ins or estrogen. Similar opposing effects were seen when estrogen and proge sterone were added to primary cultures of placental trophoblast or macropha ges, Thus, three cell culture systems modeling circulating arterial blood c ontact with cell surfaces demonstrated opposing effects of estrogens and pr ogestins on LDL oxidation and cell cytotoxicity, These studies are in keepi ng with published reports that female sex steroids influence LDL oxidation in vivo and consequent arterial wall injury.