Hanke H, Hanke S, Bruck B, Brehme U, Gugel N, Finking G, Mück A O, Schmahl F W, Hombach V, Haasis R
Department of Internal Medicine, University of Ulm, Germany.
Atherosclerosis. 1996 Mar;121(1):129-38. doi: 10.1016/0021-9150(95)05710-2.
The aim of the present study was to determine the effect of progesterone on the action of estrogen in the development of atherosclerosis. A total of 48 female New Zealand white (NZW) rabbits were ovariectomized. The animals were separated into 6 groups of 8 animals each and received subsequently a 0.5% cholesterol diet for 12 weeks. During this cholesterol feeding period, either estradiol (1 mg/kg body weight (BW)/week), progesterone (25 mg/kg BW/week), or combined estradiol/progesterone (in above dosages) was administered intramuscularly in each group (n = 8 each) of ovariectomized rabbits. One additional group of 8 animals received a combined estrogen/ progesterone regimen, but with progesterone at one third of the above mentioned dosage. In another 8 rabbits, progesterone was reduced to one ninth of the maximum dosage above, whereas estrogen was kept the same, at 1 mg/kg BW/week. Eight ovariectomized animals served as the control group and received no hormone treatment. After 12 weeks, the animals were sacrificed and the proximal aortic arch was removed for further histological examination. An inhibitory effect of estrogen of intimal thickening was found, in comparison to the control group (intimal area: 0.7 +/- 0.5 mm2 vs. 3.7 +/- 2.5 mm2, P < 0.01), whereas progesterone alone did not show a significant effect on intimal plaque size (intimal area: 4.0 +/- 2.3 mm2). In combination with progesterone (high dose), estrogen was not able to reduce intimal atherosclerosis (intimal area: 3.4 +/- 2.4 mm2). However, the beneficial effect of estrogen was not affected by progesterone, when this was reduced respectively to one third (intimal area: 0.8 +/- 0.7 mm2), or to one ninth of the highest dosage (intimal area: 0.6 +/- 0.4 mm2). Interestingly, these differences in atherosclerotic plaque development were observed without significant changes in plasma cholesterol concentrations by the administered hormones. In conclusion, progesterone was dose-dependently able to completely inhibit the beneficial effect of estrogen in experimental atherosclerosis, suggesting that progesterone exerts a direct inhibitory effect on the athero-protective action of estrogen. In the context of recently published data, the present work confirms the importance of the 'non-lipid-mediated', anti-atherosclerotic effect of estrogen, probably due to an interaction with six hormone receptors in vascular smooth muscle cells (VSMC).
本研究的目的是确定孕酮对雌激素在动脉粥样硬化发展过程中作用的影响。总共48只雌性新西兰白兔接受了卵巢切除术。将这些动物分成6组，每组8只，并随后给予0.5%的胆固醇饮食，持续12周。在这个胆固醇喂养期内，每组（每组n = 8只）卵巢切除的兔子分别肌肉注射雌二醇（1毫克/千克体重（BW）/周）、孕酮（25毫克/千克BW/周）或联合使用雌二醇/孕酮（上述剂量）。另外一组8只动物接受联合雌激素/孕酮方案，但孕酮剂量为上述剂量的三分之一。在另外8只兔子中，孕酮降至上述最大剂量的九分之一，而雌激素保持不变，为1毫克/千克BW/周。8只卵巢切除的动物作为对照组，不接受激素治疗。12周后，处死动物并取出主动脉弓近端进行进一步的组织学检查。与对照组相比，发现雌激素对内膜增厚有抑制作用（内膜面积：0.7±0.5平方毫米对3.7±2.5平方毫米，P < 0.01），而单独使用孕酮对内膜斑块大小没有显著影响（内膜面积：4.0±2.3平方毫米）。与孕酮（高剂量）联合使用时，雌激素无法减轻内膜动脉粥样硬化（内膜面积：3.4±2.4平方毫米）。然而，当孕酮分别降至三分之一（内膜面积：0.8±0.7平方毫米）或最高剂量的九分之一（内膜面积：0.6±0.4平方毫米）时，雌激素的有益作用不受影响。有趣的是，在给予激素后，血浆胆固醇浓度没有显著变化的情况下，观察到了动脉粥样硬化斑块发展的这些差异。总之，孕酮能够剂量依赖性地完全抑制雌激素在实验性动脉粥样硬化中的有益作用，这表明孕酮对雌激素的抗动脉粥样硬化作用具有直接抑制作用。结合最近发表的数据，本研究证实了雌激素“非脂质介导”的抗动脉粥样硬化作用的重要性，这可能是由于与血管平滑肌细胞（VSMC）中的六种激素受体相互作用所致。
