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.