Sex differences and the effect of hormonal therapy on ischemic brain injury

Epidemiological data emphasize the importance of sex differences in the mortality and morbidity of stroke and cardiovascular disease. The importance of hormonal influences on stroke outcome has pointed out the importance of gender, age, and presence of neural hormones. This clinical data has been substantiated by various experimental studies using clinically relevant models of cerebral ischemia and stroke. Published findings emphasize that male and female animals respond differently to periods of cerebral ischemia and that various combinations of hormonal treatments can provide protection, both histopathological and behavioral. Mechanisms underlying the hormonal effects on ischemic outcome are multifactorial. These include effects on vascular integrity and cerebral blood flow, excitotoxicity, oxidation pathways, inflammation, and apoptosis. Although many studies have shown positive results with hormonal treatments, negative findings have also been presented. Explanations for the limitations of hormonal treatment include uncertainties regarding therapeutic window, specific therapeutic dose range, as well as the specific pathophysiological processes being targeted. Additional studies are therefore required to clarify under what conditions hormonal therapy is most protective or not warranted. Experimental studies utilizing a variety of cerebral ischemia and stroke models are reviewed to indicate under what conditions sex differences and hormonal therapy are most important in terms of functional outcome.