A PARTIAL ESTROGEN-RECEPTOR AGONIST WITH STRONG ANTIATHEROGENIC PROPERTIES WITHOUT NOTICEABLE EFFECT ON REPRODUCTIVE TISSUE IN CHOLESTEROL-FED FEMALE AND MALE RABBITS

Estrogen replacement therapy retards the development of cardiovascular disease and osteoporosis in postmenopausal women. However, long-term unopposed use increases the risk of cancer in endometrium and possibly in breast. The racemic compound ormeloxifene, widely used in India as an antifertility agent, is a partial estrogen receptor agonist with a ntiosteoporotic properties. The present study was undertaken to invest igate the effect of the L-enantiomer (levormeloxifene) and the d-enant iomer (d-ormeloxifene) on the development of atherosclerosis. In a sho rt-term experiment (6 weeks), 4x10 ovariectomized female rabbits were fed a 0.25% cholesterol-enriched diet and the effect on plasma cholest erol levels was studied. In a long-term experiment (13 weeks), 4x15 ov ariectomized female and 4x15 sham-operated male rabbits were maintaine d at a similar plasma cholesterol level of 25 mmol/L and the effect on undamaged and balloon-injured arterial wall was studied. In both expe riments, the rabbits were treated with levormeloxifene, d-ormeloxifene , 17 beta-estradiol, or placebo, respectively. In the short-term exper iment, levormeloxifene, in contrast to d-ormeloxifene, significantly r educed plasma cholesterol by 30% compared with the placebo group. In t he long-term experiment, levormeloxifene, in contrast to d-ormeloxifen e, significantly reduced atherosclerosis by 50% in the undamaged arter ial wall of both female and male rabbits. Because these rabbits were c holesterol-clamped, the antiatherogenic effect was not mediated via pl asma cholesterol lowering. Like estrogen, levormeloxifene did not inhi bit atherosclerosis in the endothelium-denuded site of aorta. The anti atherogenic effects of levormeloxifene were thus similar to those of e strogen, but produced in the absence of any noticeable estrogenic effe ct on uterine or testicular tissue.