Vascular Surgery Research Laboratory, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
Curr Drug Metab. 2010 Oct;11(8):693-714. doi: 10.2174/138920010794233477.
Epidemiological studies have shown that cardiovascular disease (CVD) is less common in pre-menopausal women (Pre-MW) compared to men of the same age or post-menopausal women (Post-MW), suggesting cardiovascular benefits of estrogen. Estrogen receptors (ERs) have been identified in the vasculature, and experimental studies have demonstrated vasodilator effects of estrogen/ER on the endothelium, vascular smooth muscle (VSM) and extracellular matrix. Several natural and synthetic estrogenic preparations have been developed for relief of menopausal vasomotor symptoms. However, whether menopausal hormone therapy (MHT) is beneficial in postmenopausal CVD remains controversial. Despite reports of vascular benefits of MHT from observational and experimental studies, randomized clinical trials (RCTs), such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative (WHI), have suggested that, contrary to expectations, MHT may increase the risk of CVD. These discrepancies could be due to agerelated changes in sex hormone synthesis and metabolism, which would influence the effective dose of MHT and the sex hormone environment in Post-MW. Age-related changes in the vascular ER subtype, structure, expression, distribution, and post-ER signaling pathways in the endothelium and VSM, along with factors related to the design of RCTs, preexisting CVD condition, and structural changes in the blood vessels architecture have also been suggested as possible causes of MHT failure in CVD. Careful examination of these factors should help in identifying the causes of the changes in the vascular effects of estrogen with age. The sex hormone metabolic pathways, the active versus inactive estrogen metabolites, and their effects on vascular function, the mitochondria, the inflammatory process and angiogenesis should be further examined. Also, the genomic and non-genomic effects of estrogenic compounds should be viewed as integrated rather than discrete responses. The complex interactions between these factors highlight the importance of careful design of MHT RCTs, and the need of a more customized approach for each individual patient in order to enhance the vascular benefits of MHT in postmenopausal CVD.
流行病学研究表明，与同龄男性或绝经后女性相比，绝经前女性（Pre-MW）患心血管疾病（CVD）的风险较低，这表明雌激素对心血管有保护作用。雌激素受体（ERs）已在血管中被鉴定出来，实验研究表明雌激素/ER 对内皮、血管平滑肌（VSM）和细胞外基质具有血管扩张作用。已经开发了几种天然和合成的雌激素制剂来缓解绝经后血管舒缩症状。然而，绝经激素治疗（MHT）是否对绝经后 CVD 有益仍然存在争议。尽管观察性和实验研究报告了 MHT 的血管益处，但随机临床试验（RCT），如心脏和雌激素/孕激素替代研究（HERS）和妇女健康倡议（WHI），表明与预期相反，MHT 可能会增加 CVD 的风险。这些差异可能是由于性激素合成和代谢的年龄相关变化，这将影响 MHT 的有效剂量和绝经后女性的性激素环境。血管 ER 亚型、结构、表达、分布和 ER 后信号通路的年龄相关变化，以及与 RCT 设计、预先存在的 CVD 状况和血管结构变化相关的因素，也被认为是 MHT 在 CVD 中失败的可能原因。仔细检查这些因素应有助于确定雌激素对血管作用随年龄变化的原因。性激素代谢途径、活性与非活性雌激素代谢物及其对血管功能、线粒体、炎症过程和血管生成的影响，应进一步研究。此外，还应将雌激素化合物的基因组和非基因组效应视为一个整体，而不是离散的反应。这些因素之间的复杂相互作用强调了精心设计 MHT RCT 的重要性，以及为每个个体患者制定更个性化方法的必要性，以增强 MHT 在绝经后 CVD 中的血管益处。
