sentence: The first , “ window of opportunity , ” hypothesis is based on the mechanistic findings that long-term estrogen depletion ( LTED ) can cause decreased levels of estrogen receptor ( ER ) - alpha , in the CA1 region of the hippocampus , a highly responsive region to estrogen therapy , resulting in cognitive enhancement and neuroprotection.126 Therefore , the initiation of estrogen after LTED , when ER-alpha receptors are already downregulated , does not result in the neuroprotective benefits of estrogen .