Reslan Ossama M, Khalil Raouf A
Vascular Surgery Research Laboratory, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
Rev Recent Clin Trials. 2012 Feb;7(1):47-70. doi: 10.2174/157488712799363253.
Cardiovascular disease (CVD) is more common in men and postmenopausal women (Post-MW) than premenopausal women (Pre-MW). Despite recent advances in preventive measures, the incidence of CVD in women has shown a rise that matched the increase in the Post-MW population. The increased incidence of CVD in Post-MW has been related to the decline in estrogen levels, and hence suggested vascular benefits of endogenous estrogen. Experimental studies have identified estrogen receptor ERα, ERβ and a novel estrogen binding membrane protein GPR30 (GPER) in blood vessels of humans and experimental animals. The interaction of estrogen with vascular ERs mediates both genomic and non-genomic effects. Estrogen promotes endothelium-dependent relaxation by increasing nitric oxide, prostacyclin, and hyperpolarizing factor. Estrogen also inhibits the mechanisms of vascular smooth muscle (VSM) contraction including [Ca2+]i, protein kinase C and Rho-kinase. Additional effects of estrogen on the vascular cytoskeleton, extracellular matrix, lipid profile and the vascular inflammatory response have been reported. In addition to the experimental evidence in animal models and vascular cells, initial observational studies in women using menopausal hormonal therapy (MHT) have suggested that estrogen may protect against CVD. However, randomized clinical trials (RCTs) such as the Heart and Estrogen/ progestin Replacement Study (HERS) and the Women's Health Initiative (WHI), which examined the effects of conjugated equine estrogens (CEE) in older women with established CVD (HERS) or without overt CVD (WHI), failed to demonstrate protective vascular effects of estrogen treatment. Despite the initial set-back from the results of MHT RCTs, growing evidence now supports the 'timing hypothesis', which suggests that MHT could increase the risk of CVD if started late after menopause, but may produce beneficial cardiovascular effects in younger women during the perimenopausal period. The choice of an appropriate MHT dose, route of administration, and estrogen/progestin combination could maximize the vascular benefits of MHT and minimize other adverse effects, especially if given within a reasonably short time after menopause to women that seek MHT for the relief of menopausal symptoms.
心血管疾病（CVD）在男性和绝经后女性（Post-MW）中比绝经前女性（Pre-MW）更为常见。尽管预防措施最近取得了进展，但女性心血管疾病的发病率仍呈上升趋势，且与绝经后女性人口的增加相匹配。绝经后女性心血管疾病发病率的增加与雌激素水平的下降有关，因此提示内源性雌激素对血管有益。实验研究已在人类和实验动物的血管中鉴定出雌激素受体ERα、ERβ以及一种新型雌激素结合膜蛋白GPR30（GPER）。雌激素与血管雌激素受体的相互作用介导了基因组和非基因组效应。雌激素通过增加一氧化氮、前列环素和超极化因子来促进内皮依赖性舒张。雌激素还抑制血管平滑肌（VSM）收缩机制，包括细胞内钙离子浓度（[Ca2+]i）、蛋白激酶C和Rho激酶。雌激素对血管细胞骨架、细胞外基质、脂质谱和血管炎症反应的其他作用也有报道。除了动物模型和血管细胞的实验证据外，对使用绝经激素治疗（MHT）的女性进行的初步观察性研究表明，雌激素可能预防心血管疾病。然而，诸如心脏和雌激素/孕激素替代研究（HERS）以及妇女健康倡议（WHI）等随机临床试验（RCT），在患有已确诊心血管疾病的老年女性（HERS）或无明显心血管疾病的女性（WHI）中研究结合马雌激素（CEE）的作用时，未能证明雌激素治疗具有保护血管的作用。尽管绝经激素治疗随机对照试验的结果最初遭遇挫折，但越来越多的证据现在支持“时机假说”，即绝经后晚期开始使用绝经激素治疗可能会增加心血管疾病风险，但在围绝经期对年轻女性可能会产生有益的心血管作用。选择合适的绝经激素治疗剂量、给药途径以及雌激素/孕激素组合，可以使绝经激素治疗的血管益处最大化，并将其他不良反应降至最低，特别是在绝经后相当短的时间内给予因寻求缓解绝经症状而使用绝经激素治疗的女性时。
