Stroke in the female: Role of biological sex and estrogen

Women are protected from stroke relative to men until the years of menopause. Because stroke is the leading cause of serious, long-term disability in the United States, modeling sex-specific mechanisms and outcomes in animals is vital to research. Important research questions are focused on the effects of hormone replacement therapy, age, reproductive status, and identification of sex-specific risk factors. Available research relevant to stroke in the female has almost exclusively utilized rodent models. Gender-linked stroke outcomes are more detectable in experimental studies than in clinical trials and observational studies. Various estrogens have been extensively studied as neuroprotective agents in women, animals, and a variety of in vitro models of neural injury and degeneration. Most data in animal and cell models are based on 17beta-estradiol and suggest that this steroid is neuroprotective in injury from ischemia/reperfusion. However, current evidence for the clinical benefits of hormone replacement therapy is unclear. Future research in this area will need to expand into stroke models utilizing higher order, gyrencephalic animals such as nonhuman primates if we are to improve extrapolation to the human scenario and to direct and enhance the design of ongoing and future clinical studies and trials.