Loss of Estrogen Efficacy Against Hippocampus Damage in Long-Term OVX Mice Is Related to the Reduction of Hippocampus Local Estrogen Production and Estrogen Receptor Degradation.

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.