Cardiovascular effects of droloxifene, a new selective estrogen receptor modulator, in healthy postmenopausal women

Selective estrogen receptor modulators, like tamoxifen and related compound s, have mixed estrogen agonistic/ antagonistic effects. Tamoxifen may confe r significant cardiovascular benefits without the estrogen-associated risks of endometrial and breast cancer. Droloxifene, a structural analogue of ta moxifen, has estrogen agonistic effects on bone and antagonistic effects on endometrial and breast tissue. Its cardiovascular effects in women are unk nown. We enrolled 24 healthy postmenopausal women in a randomized, double-b lind, 2-period crossover trial comparing the effects of droloxifene (60 mg/ d) with conjugated estrogen (0.625 mg/d). Plasma lipids, coagulation and fi brinolytic factors, and brachial flow-mediated vasodilator responses were m easured at the beginning and end of each treatment period. Droloxifene and estrogen resulted in 16.6% and 12.0% reductions, respectively, in low densi ty lipoprotein cholesterol (P<0.001) and 13.2% and 9.5% reductions, respect ively, in lipoprotein(a) (P<0.05). In contrast, estrogen, but not droloxife ne, increased high density lipoprotein (18.5%, P<0.001). Droloxifene also r educed fibrinogen by 17.8% versus a 7.3% reduction with estrogen (P=0.004) but produced no estrogen-like changes in plasminogen, plasminogen activator inhibitor-1, or tissue plasminogen activator. Droloxifene and estrogen pro duced 36.4% and 27.3% increases, respectively, in flow-mediated vasodilatio n (percent change from baseline, P<0.05 for both). Droloxifene has estrogen agonistic properties regarding low density lipoprotein and lipoprotein(a) metabolism, certain coagulation factors, and endothelium-dependent vasodila tion but, unlike estrogen, has no effect on high density lipoprotein/trigly ceride metabolism and the fibrinolytic cascade. It remains unknown whether droloxifene can confer a true cardiovascular benefit.