The effect of estrogen (E) on the hypothalamic-pituitary-adrenal axis was investigated in female Sprague-Dawley rats. Animals were bilaterally ovariectomized (OVX), and a Silastic capsule (0.5 cm) containing 17/3-estradiol was sc implanted. Control animals received a blank capsule. Animals were killed 21 days later. In E-treated rats, we found significantly higher corticosterone (CORT) peak levels 20 min after a 5-sec footshock (1.0 mamp) or exposure to ether vapors (P < 0.05) compared to those in OVX controls. In addition, the recovery of the ACTH and CORT responses to footshock stress was significantly prolonged (P < 0.05) in the presence of E. Furthermore, the ACTH and CORT secretory responses to ether stress could be suppressed by exogenous RU 28362 (a specific glucocorticoid receptor agonist; 40 μg/ 100 g BW for 4 days) in OVX controls (P < 0.05), but not in E-treated animals. These data suggest that E can impair glucocorticoid receptor- mediated delayed or slow negative feedback. Consequently, we examined the influence of E on mineralocorticoid and glucocorticoid receptor concentrations using in vitro binding assays. E did not alter mineralocorticoid or glucocorticoid receptor concentrations in any of the brain regions examined. The administration of RU 28362 (40 μg/100 g BW for 4 days) to OVX control or E-treated rats significantly down-regulated hippocampal glucocorticoid receptor (P < 0.02) in control rats only. In contrast, aldosterone administration (40 μg/100 g BW for 4 days) significantly down-regulated hippocampal glucocorticoid receptor (P < 0.0008) in both control and E-treated animals. Thus, E treatment results in a loss of the glucocorticoid receptor’s ability to autoregulate; this suggests that E may cause a functional impairment of the glucocorticoid receptor even though receptor binding appears normal. These findings suggest that hyperactivation of the hypothalamic- pituitary-adrenal axis after stress in E-treated rats is due in part to impaired glucocorticoid receptor-mediated slow negative feedback.
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