Estradiol 17 beta inhibition of LDL oxidation and endothelial cell cytotoxicity is opposed by progestins to different degrees

Progestins oppose the effects of estrogens in many biological systems, but it is not known if progestins oppose the antioxidant effects of estrogen an d to differing degrees. To test these questions, the effects of various sex steroids on LDL oxidation and cytotoxicity were studied in the absence or presence of endothelial cells. Freshly isolated LDL was incubated in the pr esence of Cuff in the absence or presence of cultured bovine aortic endothe lial cells in phenol rid-free medium and without or with hormones in 0.5% e thanol. The hormones included 17 beta-estradiol (E-2), progesterone (Pg), n orgestimate (NGM), levonorgestrel (LNG), and medroxyprogesterone acetate (M PA). LDL oxidation was measured as formation of conjugated dienes, lipid pe roxides, and TEARS, and cyotoxicity by tetrazolium salt reduction (MTT redu ction). Progestins diminished conjugated diene lag phase, accelerated lipid peroxide and TEARS production in the absence and presence of cells and acc elerated cytotoxicity. When E-2 and progestin were incubated with cells at a molar ratio of 1:5, lipid peroxides were reduced from baseline by E-2 alo ne 31%, E-2/Pg 29%, E-2/NGM 16%, E-2/LNG 9% (all P < 0.05 or more) and E-2/ MPA 8% (ns) (E-2 or E-2/Pg > E-2/NGM, E-2/LNG and E-2/MPA [P < 0.001]; E-2/ NGM > E-2/LNG or E-2/MPA [P < 0.05]). MTT reduction followed a similar grad ient, greatest with E-2 alone, least with E-2/MPA. Conclusions: Progestins promote LDL oxidation and, conjointly, endothelial cell cytotoxicity. Proge stins oppose the antioxidant and cytoprotective effects of estrogen when gi ven in combination. MPA and LNG have the strongest prooxidant and cytotoxic effects, which may limit the cardiovascular benefit of estrogen during com bined administration in vivo. (C) 2000 Elsevier Science Ireland Ltd. All ri ghts reserved.