Abstract
Data from the Women's Health Initiative and other clinical trials have shown increased stroke severity in women taking hormone replacement therapy (HRT), despite evidence from animal studies demonstrating estrogen is neuroprotective. This dichotomy has spurred a debate about the safety and necessity of HRT. In the present study, we hypothesized that female rats supplemented with estrogen would suffer worsened outcome from experimental stroke due to altered post‐ischemic glycoprotein 130 (gp130) signaling. To test this hypothesis, female rats received chronic estrogen supplementation during aging and underwent occlusion of the middle cerebral artery with tissue plasminogen activator reperfusion at 18 months. Results demonstrate that aged female rats supplemented with estrogen suffer increased infarct size and higher mortality from ischemia/reperfusion. Estrogen supplementation also changed post‐ischemic mRNA levels of neuropoietic cytokines and gp130 signaling modulators in aged rats. Despite its anti‐inflammatory activity, estrogen appears detrimental to recovery from stroke in the aged brain. These findings suggest that chronic estrogen treatment play a role in worsened stroke outcomes in women taking HRT by altering post‐ischemic gp130 signaling pathways.
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