Abstract
Estrogens are a group of pleiotropic steroid hormones that exhibit diverse mechanisms of action in multiple physiologic systems. Over the past 30 years, biomedical science has begun to appreciate that endogenous estrogens and their receptors display important roles beyond the reproductive system. Our growing appreciation of novel, nonreproductive functions for estrogens has fundamentally contributed to our knowledge of their role in human health and disease. Recent findings from the Women's Health Initiative have caused clinicians and scientists to question whether estrogens are protective factors or risk factors. In light of the dichotomy between basic science and clinical studies, this review will attempt to reconcile differences between them. We will focus on studies from our laboratory and others highlighting the beneficial properties of the most abundant endogenous estrogen, 17beta-estradiol, using in vivo and in vitro models of cerebral ischemia and neuronal injury. These studies demonstrate that 17beta-estradiol powerfully protects the brain using multiple molecular mechanisms that promote: (1) decreased cell death, (2) increased neurogenesis, (3) an enhancement of neurotrophic support, and (4) the suppression of proinflammatory pathways.