The influence of ovarian steroids on hypothalamic-pituitary-adrenal regulation in the female rat

Abstract

The present study examined the association between hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-ovarian axes. HPA activity determined by plasma levels of adrenocorticotropin (ACTH) and corticosterone (B) was assessed in intact female rats as a function of oestrous cycle stage under resting conditions and after exposure to a 20 min restraint stress. To delineate the roles of oestradiol and progesterone in HPA axis modulation, plasma concentrations of ACTH and B were determined in ovariectomised (OVX) animals treated with oestradiol and/or progesterone under resting conditions and during exposure to the stress of a novel environment. The effects of these steroid treatments on the transcription and/or binding properties of the two corticosteroid receptors, the mineralocorticoid (MR) and glucocorticoid (GR) receptors, were also examined in hippocampal tissue, (i) Fluctuations in basal and stress-induced plasma ACTH and B concentrations were found during the oestrous cycle with highest levels at late pro-oestrus. (ii) In OVX steroid-replaced animals, basal and stress-induced activity was enhanced in oestradiol and oestradiol plus progesterone-treated animals compared with OVX controls. (iii) Cytosol binding assays revealed an oestradiol-induced decrease in hippocampal MR capacity. This decrease appears to be due to an effect of the steroid on MR transcription as in situ hybridisation analysis of MR mRNA showed an oestradiol-induced decrease in MR transcript in all hippocampal subfields. (iv) Treatment of oestradiol-primed animals with progesterone reversed the oestradiol-induced decrease in hippocampal MR capacity. Data from MR mRNA hybridisation in situ experiments indicate that this reversal may be due to an antagonism of the oestradiol effect on MR transcription. (v) Progesterone treatment with or without prior oestradiol-priming induced a significant decrease in the apparent binding affinity of hippocampal MR. We show that progesterone and its 11 beta-hydroxylated derivative have a high affinity for the hippocampal MR. (vi) Neither oestradiol nor progesterone affected GR binding parameters in the hippocampus. In conclusion, we find that sex steroids modulate HPA activity and suggest that the observed effects of these steroids on hippocampal MR may underlie their concerted mechanism of action in inducing an enhanced activity at the period of late pro-oestrus.

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

“…The findings in our study contrast with several previous reports of increased HPA axis responses to stress after estradiol treatment (Burgess and Handa 1992;Carey et al 1995;Viau and Meaney 1991). A major difference between our study and these prior reports is that the dosage of estradiol was much higher in these earlier studies.…”

“…mal response to stress was seen at 48 hr. Carey et al (1995) used a single dose of approximately 8 g/rat. 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.…”

“…There is no clear consensus of the effects; and, all studies examined supra physiological doses. Several studies (Carey et al 1995;Burgess and Handa 1993;Patchev and Almeida 1996) reported a decrease in MR binding and in MR mRNA in hippocampus, while Ferrini and De Nicola (1991) observed estrogen increased MR binding. A number of reports found that estradiol reduced GR binding and mRNA expression in hippocampus and pituitary (Burgess and Handa 1993;Turner 1990), but no effect was found by others (Peiffer and Barden 1987;Carey et al 1995).…”

“…Several studies (Carey et al 1995;Burgess and Handa 1993;Patchev and Almeida 1996) reported a decrease in MR binding and in MR mRNA in hippocampus, while Ferrini and De Nicola (1991) observed estrogen increased MR binding. A number of reports found that estradiol reduced GR binding and mRNA expression in hippocampus and pituitary (Burgess and Handa 1993;Turner 1990), but no effect was found by others (Peiffer and Barden 1987;Carey et al 1995). Several studies concluded that estradiol antagonized the ability of glucocorticoids to downregulate GR (Ferrini et al 1995;Burgess and Handa 1992), while other studies observed no effect (Carey et al 1995) or that estrogen potentiated glucocorticoid induced GR downregulation in ovarietomized female rats (Patchev and Almeida 1996).…”

“…Compared with male rats, female rats also have a greater ACTH response to stress, faster onset of corticosterone secretion after stress, and a faster rate of rise of corticosterone (Le Mevel et al 1979;Jones et al 1972;Young 1996). Several studies suggest that estradiol plays a role in enhanced stress responses in female rats, based on increased HPA axis responses to stress when ovariectomized rats are treated with estradiol (Burgess and Handa 1992;Carey et al 1995;Viau and Meaney 1991). In addition, female rats have enhanced HPA axis responsivity in proestrus, when estrogen and progesterone levels are relatively high, compared to diestrus, when levels of these hormones are lower (Viau and Meaney 1991).…”