Neuroprotective effects of female gonadal steroids in reproductively senescent female rats

Background and Purpose-Young adult female rats sustain smaller infarcts aft er experimental stroke than age-matched males. This sex difference in ische mic brain injury in young animals disappears after surgical ovariectomy and can be restored by estrogen replacement. We sought to determine whether is chemic brain injury continues to be smaller in middle-aged, reproductively senescent female rats compared with age-matched males and to test the effec t of ovarian steroids on brain injury after experimental stroke in females. Methods-Four groups of 16-month old Wistar rats (males [n=9], untreated fem ales [n=9], and females pretreated with 17 beta-estradiol [25-mu g pellets administered subcutaneously for 7 days; n=9] or progesterone [10-mg pellets administered subcutaneously for 7 days; n=9] were subjected to 2 hours of middle cerebral artery occlusion with the intraluminal filament technique, followed by 22 hours of reperfusion. Physiological variables and laser-Dopp ler cerebral cortical perfusion were monitored throughout ischemia and earl y reperfusion. In a separate cohort of males (n=3), untreated females (n=3) , females pretreated with 17 beta-estradiol (n=3), and females pretreated w ith progesterone (n=3), end-ischemic regional cerebral blood flow was measu red by [C-14]iodoantipyrine autoradiography. Results-As predicted, infarct size was not different between middle-aged ma le and female rats. Cortical infarcts were 21+/-5% and 31+/-6% of ipsilater al cerebral cortex, and striatal infarcts were 44+/-7% and 43+/-5% of ipsil ateral striatum in males and females, respectively. Both estrogen and proge sterone reduced cortical infarct in reproductively senescent females (5+/-2 % and 16+/-4% in estrogen- and progesterone-treated groups. respectively, c ompared with 31+/-6% in untreated group), Striatal infarct was smaller in t he estrogen- but not in the progesterone-treated group. Relative change in laser-Doppler cerebral cortical perfusion from preischemic baseline and abs olute end-ischemic regional cerebral blood flow were not affected by hormon al treatments. Conclusions-We conclude that the protection against ischemic brain injury f ound in young adult female rats disappears after reproductive senescence in middle-aged females and that ovarian hormones alleviate stroke injury in r eproductively senescent female rats by a blood flow-independent mechanism. These findings support a role for hormone replacement therapy in stroke inj ury prevention in postmenopausal women.