Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Curr Alzheimer Res. 2012 Jan;9(1):18-34. doi: 10.2174/156720512799015109.
In both men and women, age-related loss of sex steroid hormones has been linked to an increased risk for Alzheimer's disease (AD). The primary female hormone estrogen, and the primary male hormone testosterone have numerous protective effects in the brain relevant to the prevention of AD such as the promotion of neuron viability, reduction of β- amyloid accumulation and alleviation of tau hyperphosphorylation. Therefore it has been hypothesized that the precipitous loss of these hormones either through menopause or normal aging, can increase susceptibility to AD pathogenesis. This review will discuss the basic science research and epidemiological evidence largely supporting this hypothesis, as well as the estrogen-based hormone therapy clinical findings that have recently shed doubt on this theory. The complications associated with estrogen-based hormone therapy such as the inclusion of a progestogen, hormone responsiveness with age, and natural vs. synthetic hormones will be discussed. Further, we will outline the cancer risks facing both estrogen and testosterone-based hormone therapy. Most importantly, this review will discuss the present and future strategies to translate the neuroprotective properties of sex steroid hormones into safe and efficacious treatments for AD. One of the most promising translational tools thus far may be the development of selective estrogen and androgen receptor modulators. However, additional research is needed to optimize these and other translational tools towards the successful use of hormone therapies in both men and women to delay, prevent, and or treat AD.
在男性和女性中，与年龄相关的性激素丧失与阿尔茨海默病（AD）风险增加有关。主要的女性激素雌激素和主要的男性激素睾酮在大脑中具有许多与预防 AD 相关的保护作用，如促进神经元存活、减少β-淀粉样蛋白积累和缓解 tau 过度磷酸化。因此，有人假设这些激素的急剧丧失，无论是通过更年期还是正常衰老，都会增加 AD 发病机制的易感性。这篇综述将讨论基本的科学研究和流行病学证据，这些证据在很大程度上支持了这一假设，以及最近对这一理论产生怀疑的基于雌激素的激素治疗临床发现。将讨论与基于雌激素的激素治疗相关的并发症，如孕激素的包含、激素随年龄的反应性以及天然与合成激素。此外，我们将概述面临基于雌激素和睾酮的激素治疗的癌症风险。最重要的是，本综述将讨论将性激素的神经保护特性转化为安全有效的 AD 治疗方法的当前和未来策略。迄今为止，最有前途的转化工具之一可能是选择性雌激素和雄激素受体调节剂的开发。然而，需要进一步的研究来优化这些和其他转化工具，以成功地在男性和女性中使用激素治疗来延迟、预防和/或治疗 AD。
