Estrogen rapid effects: a window of opportunity for the aging brain?

Estrogen produces several beneficial effects in healthy neurological tissues and exhibits cardioprotective effects. Hormone therapy has been widely used to treat menopausal estrogen deficiency for more than 80 years. Despite high initial expectations of cardioprotective effects, there has been substantial distrust following important randomized clinical trials, such as the Women's Health Initiative. Subsequently, the timing of treatment in relation to the onset of menopause came under consideration and led to the proposal of the timing hypothesis, that early initial treatment is important, and benefits are lost as the timing since menopause becomes prolonged. Subsequent analyses of the Women's Health Initiative data, together with more recent data from randomized and observational trials, consistently show reductions in coronary heart disease and mortality in younger menopausal women. Regarding cognitive function, the timing hypothesis is consistent with observations from basic and animal studies. There is some clinical evidence to support the benefits of hormonal therapy in this context, though skepticism remains due to the paucity of clinical trials of substantial length in younger menopausal women. It is likely that the effects of estrogens on cognitive performance are due to rapid mechanisms, including mechanisms that influence Ca homeostasis dynamics, provide protection in a hostile environment and reduce inflammatory signals from neural tissues. In the future, inflammatory profiles accounting for early signs of pathological inflammation might help identify the 'window of opportunity' to use estrogen therapy for successful cognitive protection.