Testosterone Role In Male Sensitivity To Ischemia

Despite the fact that male sex is a well-acknowledged risk factor for human stroke, most research aimed at understanding gender differences in stroke has focused exclusively on female sex steroids. Available epidemiologic studies suggest that testosterone, the major mammalian androgen, has a neutral or favorable effect on cardiovascular disease (43). This possibility is likely related, in part, to beneficial effects on vascular endothelial function and the vasodila-tory properties of testosterone at physiologic concentrations. In the clinical setting, testosterone declines in men after stroke, presumably as a stress response (44). However, testosterone has recently emerged as another sex steroid that has the potential to alter ischemic cell death. For example, surgical castration and subsequent low testosterone decrease histologic damage after focal cerebral ischemia in the young adult male rat (45,46) and negatively affect outcome from experimental spinal cord injury (47). When administered in supraphysiologic doses, testosterone increases brain damage after cardiac arrest and cardiopulmonary resuscitation (48). These new studies suggest that gender differences in stroke outcome are not solely due to female sex and/or sex steroids and that androgens might adversely shape experimental stroke outcome. However, many questions remain to be addressed. We do not know how "andropause," the natural decline of androgen levels in aging men, affects cerebrovascular function and sensitivity to cerebral ischemia. Current observations suggest that when testosterone is replaced in aging male animals to levels similar to that of young males, the steroid protects the brain from ischemic injury (49). Thus, it seems that testosterone acts in an age-specific manner during ischemia. Testosterone can act either directly on the androgen receptor or indirectly via conversion to dihydrotestosterone by 5 -reductase. Alternatively, testosterone can exert its effects via metabolism to estrogen by the cytochrome P450 enzyme aromatase. Both aromatase and the androgen receptor pathway are important for the effects of testosterone on brain function, but it is not yet clear which mechanism is the major mediator of the deleterious effects of testosterone in cerebral ischemia.

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