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The purpose of this study was to determine whether estrogen and progesterone influence fast glucocorticoid negative feedback regulation of the ACTH and corticosterone (CORT) responses to stress. Mature rats were ovariectomized and 6 weeks later implanted with 17β-estradiol (E₂,0.5 mg), E₂ and progesterone (P, 100 mg; E₂+P group) or placebo pellets (OVX). Seven days later rats were subjected to a single or repeated intermittent footshock stress (0.2 mA, 15 s duration, 0.5 s on). The repeated stress was of the same intensity and duration, and was applied either during the time domain of the rate-sensitive fast glucocorticoid feedback when plasma CORT levels are rising (5 min after the onset of the first stress), or at the time of peak CORT response (15 min) to the initial stress. Plasma ACTH and CORT were measured from serial samples. Estrogen replacement alone or in combination with progesterone lowered the immediate (t = 5) ACTH and CORT response to a single stress in ovariectomized animals. The second stress applied 5 min after the initial stress produced net ACTH responses similar to those obtained after a single stress in the OVX and E₂+P-replaced hormone groups, while total ACTH responses were lower in the E₂-treated group. In ovariectomized animals, a facilitation of ACTH response by a prior stress is apparent in response to a footshock 15 min later, when the integrated ACTH secretion is significantly greater than the response measured after a single shock, or after a repeated shock 5 min apart. Anterior pituitary proopiomelanocortin (POMC) mRNA levels were lower in groups with E₂ or E₂+P replacement compared to OVX animals. In contrast, hypothalamic corticotropin-releasing factor (CRF) mRNA levels did not increase significantly. However, hypothalamic glucocorticoid receptor (GR) mRNA levels increased after 17β-estradiol treatment, and this increase was reversed by progesterone. These results suggest that prior stress leads to both a fast-feedback inhibition and a facilitation of the subsequent stress response. In the absence of gonadal hormones this facilitation is balanced by fast-feedback inhibition during the glucocorticoid fast-feedback time domain, and is unmasked outside of this time domain. Estrogen suppresses POMC mRNA synthesis leading to a decrease in the availability of releasable ACTH, thereby reducing the facilitation. Progesterone may counter this effect of estrogen by decreasing the efficacy of the fast rate-sensitive glucocorticoid negative feedback.