Holm P, Shalmi M, Korsgaard N, Guldhammer B, Skouby S O, Stender S
Novo Nordisk A/S, Denmark.
Arterioscler Thromb Vasc Biol. 1997 Oct;17(10):2264-72. doi: 10.1161/01.atv.17.10.2264.
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.
雌激素替代疗法可延缓绝经后女性心血管疾病和骨质疏松症的发展。然而，长期无对抗使用会增加子宫内膜癌以及可能的乳腺癌风险。外消旋化合物奥洛昔芬在印度广泛用作抗生育剂，它是一种具有抗骨质疏松特性的部分雌激素受体激动剂。本研究旨在探讨左旋对映体（左美洛昔芬）和右旋对映体（右美洛昔芬）对动脉粥样硬化发展的影响。在一项短期实验（6周）中，给4×10只去卵巢雌性兔子喂食富含0.25%胆固醇的饮食，并研究其对血浆胆固醇水平的影响。在一项长期实验（13周）中，使4×15只去卵巢雌性兔子和4×15只假手术雄性兔子维持在相似的血浆胆固醇水平25 mmol/L，并研究其对未受损和球囊损伤动脉壁的影响。在这两个实验中，兔子分别接受左美洛昔芬、右美洛昔芬、17β-雌二醇或安慰剂治疗。在短期实验中，与右美洛昔芬相比，左美洛昔芬与安慰剂组相比显著降低血浆胆固醇30%。在长期实验中，与右美洛昔芬相比，左美洛昔芬在雌性和雄性兔子未受损动脉壁中显著降低动脉粥样硬化50%。由于这些兔子处于胆固醇钳制状态，其抗动脉粥样硬化作用不是通过降低血浆胆固醇介导的。与雌激素一样，左美洛昔芬在主动脉内皮剥脱部位不抑制动脉粥样硬化。因此，左美洛昔芬的抗动脉粥样硬化作用与雌激素相似，但在对子宫或睾丸组织没有任何明显雌激素作用的情况下产生。
