Estrogens, estrogen receptors, and female cognitive aging: the impact of timing

Estrogens have been shown to be protective agents against neurodegeneration and associated cognitive decline in aging females. However, clinical data have been equivocal as to the benefits to the brain and cognition of estrogen therapy in postmenopausal women. One factor that is proposed to be critical in determining the efficacy of hormone therapy is the timing of its initiation. The critical period or window of opportunity hypothesis proposes that following long-term ovarian hormone deprivation, the brain and cognition become insensitive to exogenously administered estrogens. In contrast, if estrogens are administered during a critical period near the time of cessation of ovarian function, they will exert beneficial effects. The focus of the current review is the examination of evidence from rodent models investigating the critical period hypothesis. A growing body of experimental data indicates that beneficial effects of 17β-estradiol (estradiol) on cognition and on cholinergic function and hippocampal plasticity, both of which have been linked to the ability of estradiol to exert beneficial effects on cognition, are attenuated if estradiol is administered following a period of long-term ovarian hormone deprivation. Further, emerging data implicate loss of estrogen receptor alpha (ERα) in the brain resulting from long-term hormone deprivation as a basis for the existence of the critical period. A unifying model is proposed by which the presence or absence of estrogens during a critical period following the cessation of ovarian function permanently alters the system resulting in decreased or increased risk, respectively, of neurodegeneration and cognitive decline.