We have previously shown that oral conjugated equine estrogen (CEE)reduces plasminogen activator inhibitor (PAI-1) levels in postmenopausal women, an effect associated with proportionate increases in degradation products of fibrin. However, oral estrogen reduces low-density lipoprotein cholesterol (LDL-C) levels that may account for PAI-1 effects, as oxidized LDL stimulates endothelial synthesis of PAI-1 in cell culture experiments. To assess the importance of LDL on PAI-1, we administered CEE .625 mg, simvastatin 10 mg, or the combination daily for 6 weeks each to 25 hypercholesterolemic (LDL=165+/-37 mg/dL; mean+/-SD) postmenopausal women in a randomized, double-blind, double-crossover study. LDL-C was reduced from respective baseline values by 11+/-11% (p<.001) on CEE, by 25+/-14%(p<.001) on simvastatin, and by 32+/-15%(p<.001) on the therapies combined. Apolipoprotein B was reduced from respective baseline values by 9+/-8%(p<.001) on CEE, by 23+/-10%(p<.001) on simvastatin, and by 27+/-13% (p<.001) on the therapies combined. Therapies including simvastatin reduced LDL-C and apolipoprotein B levels to a greater degree than CEE alone (both p<.005). PAI-1 antigen levels were reduced by 25+/-45% (p<.005) on CEE, by 16+/-51%(p<.02)on the therapies combined, but increased by 22+/-83% on simvastatin alone from respective baseline values. Thus, only therapies including CEE reduced PAI-1 antigen levels, despite a greater effect of simvastatin on reduction in LDL-C and apolipoprotein B levels. Further, there was no synergism of combined CEE and simvastatin therapy on PAI-1 levels. These data suggest that estrogen reduces PAI-1 levels independent of changes in LDL. This primary effect of CEE on fibrinolytic potential may favor its use in hypercholesterolemic postmenopausal women, even if they are already on lipid-lowering therapy.
