Estrogen therapy: does it help or hurt the adult and aging brain? Insights derived from animal models

Hormone therapy and estrogen therapy in postmenopausal women have been thought to ameliorate cognitive dysfunction and decrease the risk and/or progress of neurodegenerative conditions such as Alzheimer's disease and stroke. Furthermore, estrogens have been shown to exert neuroprotective actions in a variety of in vitro and in vivo models of brain injury. However, the findings of the Women's Health Initiative have made us re-evaluate these assumptions. Our laboratory has shown that physiological levels of estradiol attenuate ischemic brain injury in young and middle-aged female rats. We have begun to probe the cellular and molecular mechanisms that underlie these novel non-reproductive actions of this steroid. Our findings demonstrate that in both young and aging rats, treatment with physiological concentrations of estradiol decreases ischemic injury by almost 50%, compared with oil-treated controls. Additionally, our data suggest that estradiol acts by altering the expression of genes that suppress apoptosis and enhance survival in the penumbral region of the infarct. These observations demonstrate that estrogen therapy protects against stroke-related injury in young and aging female rats and strongly suggest that middle-aged animals remain responsive to the protective actions of estradiol. Furthermore, they suggest that estrogen therapy protects against cell death by influencing the expression of genes that suppress apoptotic cell death pathways.