A Partial Estrogen Receptor Agonist With Strong Antiatherogenic Properties Without Noticeable Effect on Reproductive Tissue in Cholesterol-Fed Female and Male Rabbits

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), 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.

Gender Gap in Aortic Cholesterol Accumulation in Cholesterol-Clamped Rabbits

“…25,26 The long-term cholesterol-fed rabbit exhibits a characteristic regional pattern in the development of atherosclerosis: the lipid lesions are most pronounced in the aortic arch and involve smaller areas in the more distal parts of the aorta. [17][18][19][20]27,28 The present findings showing a similar regional pattern in mononuclear-endothelial cell binding in hypercholesterolemic rabbits are supportive of a relation between an early (weeks) increase in endothelial adhesiveness and later (months) development of lipid lesions in these animals. Thus, the significantly lower mononuclear-endothelial cell binding found in the aortas of female compared with male hypercho-lesterolemic rabbits may play a role in the mediation of the endothelium-dependent sex difference in aortic cholesterol accumulation described in the atherosclerosis experiment.…”

“…[17][18][19][20] Guided by weekly plasma cholesterol determinations (CHOD-PAP, Boehringer Mannheim), we maintained all animals at a plasma cholesterol level of Ϸ25 mmol/L using the 4 different chow preparations. [17][18][19][20] After 1 week of cholesterol feeding, the rabbits were anesthetized with intravenous pentobarbital (50 mg/kg body weight) and underwent balloon catheter injury in the middle thoracic aorta as described previously. 19,20 The postoperative mortality rate was 0%.…”

“…[17][18][19][20] After 1 week of cholesterol feeding, the rabbits were anesthetized with intravenous pentobarbital (50 mg/kg body weight) and underwent balloon catheter injury in the middle thoracic aorta as described previously. 19,20 The postoperative mortality rate was 0%. After 12 weeks of cholesterol feeding, blood samples were drawn for determination of the distribution of cholesterol among lipoprotein fractions.…”

“…17,18 One week later, the rabbits were injected with 5 mL of Evans blue dye (5 mg/mL), which was allowed to circulate for 5 minutes before the rabbits were killed with an overdose of intravenous pentobarbital (50 to 100 mg/kg body weight). [17][18][19][20] The aorta was then removed from the level of the aortic valves to the level of the diaphragm.…”

Postmenopausal oestrogen replacement therapy and atherosclerosis: can current compounds provide cardiovascular protection?

“…SERMs such as tamoxifen, raloxifene (Celvista ® , Evista ® , Figure 3), droloxifene, chlomiphene, toremifene, idoxifene, or ormeloxifene have only recently been introduced for cardiovascular therapy [198,[210][211][212][213][214]. Initially designed for the treatment of hormone-sensitive cancers and with first prospective clinical trials demonstrating encouraging results [215,216], these drugs are now being evaluated as therapeutic alternatives to known hormone replacement medications [209][210][211].…”