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.

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Lipopolysaccharides (LPS) activate both the immune and the stress response system. The effects of these bacterial endotoxins involve the release of interleukin 1 (IL1) and other cytokines, which in turn stimulate the hypothalamic-pituitary-adrenal (HP A) axis. We studied the binding properties of the corticosteroid receptor system, which mediates feedback inhibition of the HPA axis, in two brain areas and in the pituitary gland in rats treated with LPS and recombinant murine IL1β. The binding properties of the corticosteroid receptors were determined by Scatchard plot analyses of in vitro cytosolic binding of the tritiated mineralocorticoid receptor (MR) radioligand aldosterone and the tritiated glucocorticoid receptor (GR) ligand RU28362. Tissues were collected 48 h after administration of LPS, including a 24-hour period for depletion of endogenous corticosterone. LPS teatment increased the K_d of [³H]aldosterone of the hippocampal MR 4.3-fold and the apparent maximum binding capacity (B_max) of [³H]aldosterone by 65% during a time interval when the concentration of corticosterone, the endogenous ligand of both hippocampal MR and GR, was elevated in the intact rat. Thereafter, MR binding properties were not different from vehicle-injected controls, at 96 h, when in intact animals the enhanced HPA activity subsided. GRs, determined by binding of [³H]RU28362, were not affected by LPS. IL1 evoked a 2.7-fold increase in the K_d of the hippocampal MR and a 57% increase in B_max 3 h after injection into the lateral cerebral ventricle. An autoradiographic procedure revealed that the same treatment with IL1 reduced the retention of the tritiated endogenous MR ligand corticosterone by 40-60% in all pyramidal cell layers and in the dentate gyrus of the hippocampus, when a tracer dose of the steroid was administered that gives rise to a concentration around the K_d of the MR. This reduced in vivo retention of corticosterone is predicted in view of the reduced affinity of hippocampal MRs. The data are consistent with the hypothesis that an impaired feedback of the HPA axis via deficient hippocampal MRs contributes to stimulate corticosterone secretion from the adrenals during infection.