We wished to determine whether the altered nuclear estradiol (E2) receptor concentrations in middle-aged rats can explain the diminished responsiveness to E2 observed in aging rats. Therefore, we measured receptor concentrations in various brain areas and the pituitary gland of young and middle-aged ovariectomized rats 2 and 4 days after implantation of Silastic capsules containing E2. To determine whether any observable changes had physiological consequences, we correlated age-dependent changes in E2 nuclear receptor concentrations with two E2-dependent parameters: cytosol progestin receptor levels in equivalent brain areas and pituitary gland and progesterone-facilitated reproductive behaviors. Young (3-4 months old) and middle-aged (10-12 months old) Sprague-Dawley rats were ovariectomized and received Silastic capsules containing E2 dissolved in oil 1 week later (day 0). Groups of rats were killed at 1200 h on either day 2 or day 4. Nuclear E2 and cytosol progestin receptor concentrations were assessed in a nuclear and cytoplasmic extract from the medial basal hypothalamus, preoptic area, amygdala, and pituitary gland. To test steroid-induced mating behavior, ovariectomized young and middle-aged rats were treated with E2-containing capsules for 2 or 4 days. At 0900 h progesterone (0.2 mg/kg BW) was injected sc and receptive and proceptive behaviors were observed when experienced males were introduced 4-6 h later. Two days after implantation of E2 capsules, middle-aged rats exhibited lower nuclear E2 receptor concentrations in the medial basal hypothalamus and preoptic area than young rats. By day 4, there were no significant age-related differences in any brain area or in the pituitary gland. Parallel age-related differences were observed in cytosol progestin receptor concentrations on day 2 but they were not evident by day 4. Similarly, middle-aged rats exhibited deficits in proceptive behavior, lordosis quotient, and lordosis quality score on day 2, but there were no differences compared to young rats on day 4. These data demonstrate that E2-induced nuclear E2 receptor concentrations are lower in selected areas of the brain of middleaged rats. Such changes appear to be physiologically important because they are correlated with changes in E2-induced cytosol progestin receptor concentrations and steroid-induced behaviors. Furthermore, they may partially account for age-related differences in E2-induced LH surges on day 2. Because nuclear E2 receptor concentrations exhibit no age-related differences by day 4, the observed alterations in E2-induced LH surges must be explained by changes in other events required for the expression of steroid positive feedback.
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