Fast Glucocorticoid Feedback Inhibition of ACTH Secretion in the Ovariectomized Rat: Effect of Chronic Estrogen and Progesterone

Abstract

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.

Testosterone Suppression of CRH-Stimulated Cortisol in Men

“…The effects of estradiol on cortisol secretion are complex. In ovariectomized animals, inhibition of HPA axis responses to stressors is seen with short-term, physiological levels of estradiol replacement (Redei et al, 1994;Young et al, 2001;Dayas et al, 2000;Komesaroff et al, 1998), while higher doses and longer treatment regimens enhance HPA axis reactivity to stressors (Burgess and Handa, 1992;Carey et al, 1995;Viau and Meaney, 1991). We observed a significant negative correlation between the increase in estradiol (but not testosterone) and the decrease in cortisol AUC from the hypogonadal to the testosterone replaced condition.…”

“…While both testosterone and estradiol modulate glucocorticoid receptor activity in brain regions mediating restraint of the HPA axis (Burgess and Handa, 1992;Carey et al, 1995;Redei et al, 1994;Peiffer et al, 1991), a more parsimonious explanation suggests that the blunted cortisol secretion during testosterone administration results in less restraint on ACTH secretion, consistent with the greatest difference in the cortisol : ACTH ratios between conditions occurring from 120 to 180 min. Similarly, a central action of testosterone or estradiol should appear as increased basal ACTH levels and would not be apparent with exogenous CRH stimulation (or would appear as blunting due to CRH receptor downregulation at the corticotroph).…”

Effects of Estrogen Antagonists and Agonists on the ACTH Response to Restraint Stress in Female Rats

“…Burgess and Handa (1992) used an estradiol implant, which produced constant levels of estradiol of 75 pg/ ml, which is a physiological dose, but delivered this dose for 21 days, which is much longer than the duration of estrogen exposure in the normal rat estrus cycle. In contrast, the study by Redei et al (1994) found a reduced HPA axis response to footshock stress in ovariectomized rats 7 days following implantation of estradiol pellets which produced blood levels in the physiological range (160 pg/ml). The results of the study by Redei et al (1994) are consistent with the results from our study, which also measured stress responses after 7 days of low dose estradiol replacement.…”

“…In contrast, the study by Redei et al (1994) found a reduced HPA axis response to footshock stress in ovariectomized rats 7 days following implantation of estradiol pellets which produced blood levels in the physiological range (160 pg/ml). The results of the study by Redei et al (1994) are consistent with the results from our study, which also measured stress responses after 7 days of low dose estradiol replacement. Blunting of the HPA axis response to stress has also been found during physiological dose estrogen replacement for longer periods in species with longer estrus cycles.…”

“…In addition, estrogen may reduce hypothalamic CRH activity by acting on brain neurotransmitter and neuropeptide systems that regulate the HPA axis (Raap et al 2000). In vivo, some reports have found that estrogen increases CRH mRNA (Patchev and Almeida 1996;Roy et al 1999), while other reports found no effect (Redei et al 1994) and others reported a decrease in hypothalamic CRH mRNA or content (Haas and George 1988;Paulmeyer-Lacroix et al 1996). Again, dose may be critical, since the report of Paulmeyer-Lacroix et al (1996) demonstrated that reductions in hypothalamic CRH after estrogen treatment were dependent on increases in basal corticosterone secretion, which is likely to vary among different estrogen dosing regimens.…”