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 antiosteoporotic properties. The present study was undertaken to investigate the effect of the L-enantiomer (
levormeloxifene) and the d-enantiomer (d-
ormeloxifene) on the development of
atherosclerosis. In a short-term experiment (6 weeks), 4 x 10 ovariectomized female rabbits were fed a 0.25%
cholesterol-enriched diet and the effect on plasma
cholesterol levels was studied. In a long-term experiment (13 weeks), 4 x 15 ovariectomized female and 4 x 15 shamoperated male rabbits were maintained at a similar plasma
cholesterol level of 25 mmol/L and the effect on undamaged and balloon-injured arterial wall was studied. In both experiments, the rabbits were treated with
levormeloxifene, d-
ormeloxifene,
17 beta-estradiol, or placebo, respectively. In the short-term experiment,
levormeloxifene, in contrast to d-
ormeloxifene, significantly reduced plasma
cholesterol by 30% compared with the placebo group. In the long-term experiment,
levormeloxifene, in contrast to d-
ormeloxifene, significantly reduced
atherosclerosis by 50% in the undamaged arterial wall of both female and male rabbits. Because these rabbits were
cholesterol-clamped, the antiatherogenic effect was not mediated via plasma
cholesterol lowering. Like
estrogen,
levormeloxifene did not inhibit
atherosclerosis in the endothelium-denuded site of aorta. The antiatherogenic effects of
levormeloxifene were thus similar to those of
estrogen, but produced in the absence of any noticeable
estrogenic effect on uterine or testicular tissue.