Estrogen bows to a new master: The role of gonadotropins in Alzheimer pathogenesis
Estrogen bows to a new master: The role of gonadotropins in Alzheimer pathogenesis
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DOI：
10.1196/annals.1347.020
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发表时间：
2005-01-01
期刊：
影响因子：
--
通讯作者：
Smith, MA
中科院分区：
文献类型：
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作者：
Webber, KM;Casadesus, G;Smith, MA
流行病学数据显示，妇女易患阿尔茨海默病（AD），导致许多研究人员调查的作用，性类固醇，即雌激素，在疾病的发病机制。虽然有雌激素的作用的间接支持，妇女健康倡议（WHI）记忆研究的意外结果，报告了可能的痴呆症和认知能力受损的风险增加绝经后妇女与雌激素和雌激素的组合治疗，提出了关于雌激素的保护作用的严重问题。尽管对这些令人惊讶的结果的解释差异很大，但如果没有对下丘脑-垂体-性腺（HPG）轴的其他激素对衰老大脑的影响进行全面调查，就不能正确解释WHI记忆研究。HPG轴的某些激素，即促性腺激素（促黄体激素和促卵泡激素），不仅通过复杂的反馈回路参与调节生殖功能，而且已知可以穿过血脑屏障。我们认为促性腺激素浓度的增加，而不是类固醇激素的减少（例如，绝经/男性更年期后的雌激素）产生是AD发展的潜在主要致病因素。在这篇综述中，我们研究了促性腺激素如何在调节AD的易感性和进展中发挥重要作用。在此基础上，我们认为WHI记忆研究的结果不仅是可预测的，而且可以通过治疗靶向促性腺激素而不是性类固醇来避免。
Epidemiological data showing a predisposition of women to develop Alzheimer disease (AD) led many researchers to investigate the role of sex steroids, namely estrogen, in disease pathogenesis. Although there is circumstantial support for the role of estrogen, the unexpected results of the Women's Health Initiative (WHI) Memory Study, which reported an increase in the risk for probable dementia and impaired cognitive performance in postmenopausal women treated with a combination of estrogen and progestin, have raised serious questions regarding the protective effects of estrogen. Although explanations for these surprising results vary greatly, the WHI Memory Study cannot be correctly interpreted without a complete investigation of the effects of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis on the aging brain. Certain hormones of the HPG axis, namely, the gonadotropins (luteinizing hormone and follicle-stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood-brain barrier. We propose that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of AD. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, AD. On this basis, we suggest that the results of the WHI Memory Study are not only predictable but also avoidable by therapeutically targeting the gonadotropins instead of the sex steroids.