© 1997 American Heart Association, Inc.
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A Partial Estrogen Receptor Agonist With Strong Antiatherogenic Properties Without Noticeable Effect on Reproductive Tissue in Cholesterol-Fed Female and Male Rabbits
From the Novo Nordisk A/S, Novo Allé, 2880 Bagsvaerd (P.H., M.S., N.K., B.G.), Department of Obstetrics and Gynecology, Rigshospitalet, University of Copenhagen (S.O.S.), and the Clinical Institute, Odense University (S.S.), Denmark.
Correspondence to Pernille Holm, MD, Department of Women's Healthcare Biology, Novo Nordisk Park, 2760 Maaloev, Denmark. E-mail PHIm{at}novo.dk
Abstract 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), 4x10 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), 4x15 ovariectomized female and 4x15 sham-operated 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, 17ß-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.
Key Words: antiestrogens • atherosclerosis • estrogen • plasma cholesterol • rabbits
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