An investigation of the relationship between estrogen, estrogen metabolites and blood cholesterol levels in ovariectomized rats

17 beta-Estradiol (E-2) has long been known for protecting against coronary heart disease by lowering cholesterol levels in premenopausal women. A recent study in our laboratory suggested that two hydroxylated metabolites of E-2 possess similar hypocholesterolemic effects in male rats. This effect has been further investigated with additional estrogen metabolites in ovariectomized rats with a view toward mimicking the true postmenopausal situation in humans. Their effects in reproductive tissues were also evaluated histologically. Fundamentally, the following issues were addressed: (1) Do oxidized metabolites of estradiol lower total cholesterol levels? (2) Can a hypocholesterolemic effect be achieved without eliciting estrogenic activities on reproductive tissues? The results of this investigation showed that a number of oxygenated metabolites of estradiol can lower cholesterol levels. Among them, 4-hydroxyestradiol (4-OHE2) produced a striking hypocholesterolemic effect and a substantial uterotropic effect. 2-Hydroxyestradiol (2-OHE2), 2-methoxyestradiol (2-meoE(2)) and 2-methoxyestrone (2-meoE(1)) produced a significant decrease in cholesterol levels at doses that did not produce significant uterotropic effects.