Postmenopausal women experience a higher risk for neurodegenerative diseases, including cognitive impairment and ischemic stroke. Many preclinical studies have indicated that estrogen replacement therapy (ERT) may provide protective effects against these neurological diseases. However, the results of Women’s Health Initiative (WHI) studies have led to the proposal of “critical period hypothesis,” which states that there is a precise window of opportunity for administering beneficial hormone therapy following menopause. However, the underlying molecular mechanisms require further characterization. Here, we explored the effects of ERT on cognition decline and global cerebral ischemia (GCI)-induced hippocampal neuronal damage in mice that had experienced both short-term (ovariectomized (OVX) 1 week) and long-term (OVX 10 weeks) estrogen deprivation. We also further explored the concentration of 17β-estradiol (E2) in the circulation and hippocampus and the expression of aromatase and estrogen receptors (ERα, ERα-Ser118, and ERβ). We found that the neuroprotective effectiveness of ERT against hippocampus damage exhibited in OVX1w mice was totally absent in OVX10w mice. Interestingly, the concentration of hippocampal E2 was irreversibly reduced in OVX10w mice, which was related to the decrease of aromatase expression in the hippocampus. In addition, long-term estrogen deprivation (LTED) led to a decrease in estrogen receptor proteins in the hippocampus. Thus, we concluded that the loss of ERT neuroprotection against hippocampus injury in LTED mice was related to the reduction in hippocampus E2 production and estrogen receptor degradation. These results provide several intervention targets to restore the effectiveness of ERT neuroprotection in elderly post-menopausal women.

绝经后妇女患神经退行性疾病的风险更高，包括认知障碍和缺血性中风。许多临床前研究表明，雌激素替代疗法 (ERT) 可能对这些神经系统疾病提供保护作用。然而，妇女健康倡议 (WHI) 研究的结果导致了“关键期假说”的提出，该假说指出，绝经后有一个精确的机会窗口来进行有益的激素治疗。然而，潜在的分子机制需要进一步表征。在这里，我们探讨了 ERT 对经历短期（卵巢切除 (OVX) 1 周）和长期（OVX 10 周）雌激素的小鼠的认知能力下降和全脑缺血 (GCI) 诱导的海马神经元损伤的影响剥夺。我们还进一步探讨了循环和海马中 17β-雌二醇 (E2) 的浓度以及芳香酶和雌激素受体 (ERα、ERα-Ser118 和 ERβ) 的表达。我们发现 ERT 对 OVX1w 小鼠海马损伤的神经保护作用在 OVX10w 小鼠中完全不存在。有趣的是，OVX10w 小鼠的海马 E2 浓度不可逆地降低，这与海马中芳香酶表达的降低有关。此外，长期雌激素剥夺（LTED）导致海马中雌激素受体蛋白减少。因此，我们得出结论，在 LTED 小鼠中，ERT 对海马损伤的神经保护作用的丧失与海马 E2 产生和雌激素受体降解的减少有关。