Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease.
Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease.
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DOI：
10.1016/j.bcp.2013.09.024
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发表时间：
2013-12-15
影响因子：
5.8
通讯作者：
Khalil, Raouf A.
中科院分区：
文献类型：
--
作者：
Khalil, Raouf A.
关键词：
心血管疾病（CVD）在绝经前女性中比同龄男性或绝经后女性更少见，这表明雌激素对血管有益。雌激素激活内皮细胞和血管平滑肌（VSM）中的雌激素受体ERα、ERβ和GPR30，触发下游信号通路，导致血管舒张、降低VSM收缩和生长、减少血管重构等基因组和非基因组血管效应。然而，随机临床试验（RCT），如妇女健康倡议（WHI）和心脏和雌激素/黄体酮替代研究（HERS），显示绝经期激素治疗（MHT）对血管几乎没有好处，甚至出现不良事件，可能是由于MHT使用、ER谱和RCT设计相关的因素。一些MHT的形式、剂量、组合或给药途径可能对血管没有足够的作用。与年龄相关的内质网数量、分布、完整性和内质网后信号的变化可能改变血管对MHT的反应。受试者的年龄、既往存在的心血管疾病和激素环境也可能降低MHT的作用。进一步评估天然和合成雌激素、植物雌激素和选择性雌激素受体调节剂（SERMs），设计合适的MHT组合、剂量、途径和“时机”，可以提高传统MHT的有效性，并为围绝经期提供替代疗法。使用特异性内质网激动剂靶向内质网，局部MHT递送和激活特异性内质网后信号通路可以对抗内质网中与年龄相关的变化。检查激素环境和与激素失衡相关的条件，如多囊卵巢综合征，可以揭示激素-受体异常相互作用的原因。在新的随机对照试验（如Kronos早期雌激素预防研究（KEEPS））中考虑这些因素可以增强雌激素在绝经后心血管疾病中的血管益处。
Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women’s Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject’s age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD.
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