Neuroprotective Effects of Female Gonadal Steroids in Reproductively Senescent Female Rats

Abstract

Background and Purpose-Young adult female rats sustain smaller infarcts after experimental stroke than age-matched males. This sex difference in ischemic brain injury in young animals disappears after surgical ovariectomy and can be restored by estrogen replacement. We sought to determine whether ischemic brain injury continues to be smaller in middle-aged, reproductively senescent female rats compared with age-matched males and to test the effect of ovarian steroids on brain injury after experimental stroke in females. Methods-Four groups of 16-month old Wistar rats (males [nϭ9], untreated females [nϭ9], and females pretreated with 17␤-estradiol [25-g pellets administered subcutaneously for 7 days; nϭ9] or progesterone [10-mg pellets administered subcutaneously for 7 days; nϭ9] 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-Doppler cerebral cortical perfusion were monitored throughout ischemia and early reperfusion. In a separate cohort of males (nϭ3), untreated females (nϭ3), females pretreated with 17␤-estradiol (nϭ3), and females pretreated with progesterone (nϭ3), end-ischemic regional cerebral blood flow was measured by [ 14 C]iodoantipyrine autoradiography. Results-As predicted, infarct size was not different between middle-aged male and female rats. Cortical infarcts were 21Ϯ5% and 31Ϯ6% of ipsilateral cerebral cortex, and striatal infarcts were 44Ϯ7% and 43Ϯ5% of ipsilateral striatum in males and females, respectively. Both estrogen and progesterone reduced cortical infarct in reproductively senescent females (5Ϯ2% and 16Ϯ4% in estrogen-and progesterone-treated groups, respectively, compared with 31Ϯ6% in untreated group). Striatal infarct was smaller in the estrogen-but not in the progesterone-treated group. Relative change in laser-Doppler cerebral cortical perfusion from preischemic baseline and absolute end-ischemic regional cerebral blood flow were not affected by hormonal treatments. Conclusions-We conclude that the protection against ischemic brain injury found in young adult female rats disappears after reproductive senescence in middle-aged females and that ovarian hormones alleviate stroke injury in reproductively senescent female rats by a blood flow-independent mechanism. These findings support a role for hormone replacement therapy in stroke injury prevention in postmenopausal women. (Stroke. 2000;31:161-168.)

Progesterone Treatment for Experimental Stroke: An Individual Animal Meta-Analysis

“…4,33,34 Other studies have either not investigated survival or the reported numbers of deaths are small, thereby preventing detailed analysis. Importantly, only death post treatment should be included, and earlier culling, e.g., because of inadequate occlusion (as determined using laser Doppler), does not amount to attrition bias.…”

“…Five studies were excluded, mostly because they did not have data on total lesion volume or vital status, e.g., one study only had data on blood volume collected. 4 Data Set Characteristics Data set characteristics are reported in Tables 1 and 2. The data sets used compared the effect of exogenously administered progesterone versus no progesterone, or vehicle, on lesion volume after acute focal cerebral ischemia, as well as data sets involved in the analysis of death and progesterone plasma concentration.…”

“…[4][5][6][7][8][9][10][11][12][13][14] Progesterone has already been shown to be safe and effective for several clinical applications, e.g., hormone replacement therapy, and a variety of preparations are available for different modes of administration. 15 Furthermore, no severe adverse effects have been reported even when progesterone was used at high dose.…”

“…Studies assessing the safety and efficacy of progesterone in preclinical models of stroke [4][5][6][7][8][9]13,[20][21][22] have previously been integrated in a systematic review and meta-analysis based on published summary ('group') data. 14 However, this systematic review suggested that key questions remained to be answered, including demonstrating efficacy as a function of sex and age, and evaluating the dose and timing of progesterone administration.…”

Interrelation between inflammation, thrombosis, and neuroprotection in cerebral ischemia

“…This advantage is abolished in ovariectomized animals, due to the loss of endogenous female sex hormones (Simpkins et al , 1997 ;Alkayed et al , 1998Alkayed et al , , 2000Hawk et al , 1998 ;Liao et al , 2001 ;Gibson et al , 2005 ;Park et al , 2006 ;Dra č a, 2009 ;Selvamani and Sohrabji , 2010 ), and the consequences of cerebral ischemia in aged animals are more severe than in young animals (Davis et al , 1995 ;Alkayed et al , 1998 ).…”