Frick Karyn M, Fleischer Aaron W, Schwabe Miranda R, Abdelazim Farah A, Sem Daniel S, Donaldson William A
Department of Psychological and Brain Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States of America.
Department of Psychological and Brain Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States of America.
Horm Behav. 2025 Jul;173:105773. doi: 10.1016/j.yhbeh.2025.105773. Epub 2025 Jun 6.
Although the menopausal transition causes a panoply of unpleasant and disruptive symptoms, many women are reluctant to use estrogen-based treatments due to risks of cancer, cardiovascular disease, and stroke. As we learn more about how estrogens regulate the cellular and circuit mechanisms underlying menopausal symptoms such as hot flashes and brain fog, drug development that specifically targets these mechanisms could provide the therapeutic benefits of estrogens without adverse health effects. This review discusses the rationale for targeting estrogen receptor beta (ERß) with highly selective synthetic agonists to alleviate two common menopausal symptoms: memory dysfunction and hot flashes. We begin by reviewing the history of estrogen-based menopausal hormone therapy, including conjugated equine estrogens and related products. We then describe the neurobiological mechanisms underlying estrogenic regulation of memory and hot flashes, with a particular focus on the role of ERß. Finally, we discuss past and current clinical trials of ERß agonists and highlight pre-clinical data showing that a highly potent and selective synthetic ERß agonist can enhance object recognition and spatial memory, and reduce a drug-induced hot flash, in mouse models of ovarian hormone loss and Alzheimer's disease. Collectively, this work supports the targeted development of highly selective ERß agonists to relieve memory and vasomotor symptoms of menopause.
尽管更年期过渡会引发一系列令人不适且具有干扰性的症状，但许多女性因癌症、心血管疾病和中风风险而不愿使用基于雌激素的治疗方法。随着我们对雌激素如何调节潮热和脑雾等更年期症状背后的细胞和回路机制了解得越来越多，专门针对这些机制的药物研发有望在不产生不良健康影响的情况下提供雌激素的治疗益处。本综述讨论了用高度选择性合成激动剂靶向雌激素受体β（ERβ）以缓解两种常见更年期症状——记忆功能障碍和潮热的基本原理。我们首先回顾基于雌激素的更年期激素疗法的历史，包括结合马雌激素及相关产品。接着我们描述雌激素对记忆和潮热调节作用背后的神经生物学机制，特别关注ERβ的作用。最后，我们讨论ERβ激动剂过去和当前的临床试验，并着重介绍临床前数据，这些数据表明一种高效且选择性的合成ERβ激动剂在卵巢激素丧失和阿尔茨海默病的小鼠模型中可增强物体识别和空间记忆，并减少药物诱发的潮热。总体而言，这项工作支持了高度选择性ERβ激动剂的靶向研发，以缓解更年期的记忆和血管舒缩症状。
