Gender differences in acute CNS trauma and stroke: Neuroprotective effectsof estrogen and progesterone

Increasing evidence has demonstrated striking sex differences in the pathop hysiology of and outcome after acute neurological injury. Lesser susceptibi lity to postischemic and posttraumatic brain injury in females has been obs erved in experimental models. Additional evidence suggests this sex differe nce extends to humans as well. The greater neuroprotection afforded to fema les is likely due to the effects of circulating estrogens and progestins. I n fact, exogenous administration of both hormones has been shown to improve outcome after cerebral ischemia and traumatic brain injury in experimental models. The neuroprotection provided by periinjury administration of these hormones extends to males as well. The mechanisms by which estrogen and pr ogesterone provide such neuroprotection are likely multifactorial, and prob ably depend on the type and severity of injury as well as the type and conc entration of hormone present. Both genomic and nongenomic mechanisms may be involved. Estrogen's putative effects include preservation of autoregulato ry function, an antioxidant effect, reduction of A beta production and neur otoxicity, reduced excitotoxicity, increased expression of the antiapoptoti c factor bcl-2, and activation of mitogen activated protein kinase pathways . It is hypothesized that several of these neuroprotective mechanisms can b e linked back to estrogen's ability to act as a potent chemical (i.e., elec tron-donating) antioxidant. Progesterone, on the other hand, has a membrane stabilizing effect that also serves to reduce the damage caused by lipid p eroxidation. In addition, it may also provide neuroprotection by suppressin g neuronal hyperexcitability. The following review will discuss experimenta l and clinical evidence for sex differences in outcome after acute brain tr auma and stroke, review the evidence implicating estrogens and progestins a s mediators of this neuroprotection following acute neurological injury, an d finally, address the specific mechanisms by which these hormones may prot ect the brain following acute neurological injury.