Progesterone and corticosteroid interaction during pregnancy in ewes

Adrenal steroids are critical hormones for the maintenance of body homeostasis. Cortisol and adrenalcorticotropic hormone (ACTH) are strictly regulated by a closed feedback loop. During pregnancy, both plasma ACTH and cortisol levels increase in sheep as well as in humans. This increased level of cortisol is important and necessary for maternal and fetal normal health. Previous results showed that the set point for regulation of ACTH and cortisol has been increased during pregnancy. This dissertation is trying to explain why this set point can be increased and how it works.; Studies in rats showed that ACTH level is controlled by a dual receptor system. At basal level of cortisol, it is controlled by mineralocorticoid receptor (MR) which has high affinity and low capacity for corticosteroid. In stimulated situations when cortisol level increases, it is controlled by glucocorticoid receptor (GR) which has low affinity and high capacity. I hypothesize that during pregnancy, with high level of progesterone, MR function decreases and GR function keeps normal. I hypothesize progesterone acts as an antagonist of cortisol at MR and/or reduces MR number in the pregnant state and it acts with cortisol at GR as a partial agonist which results in the combined effects of progesterone and cortisol. To test these hypotheses, we studied pregnant or progesterone-treated nonpregnant ewes with sham adrenalectomy or adrenalectomy. Receptor binding studies showed that there was a significant relationship between the plasma progesterone concentration and the availability of MR, and between the plasma progesterone concentration and the apparent Kd of MR for cortisol. There was a significant increase in MR availability and Kd for cortisol in hippocampal cytosol in pregnant ewes as compared to nonpregnant ewes whether they were sham-adrenalectomized or adrenalectomized. The apparent Kd was also increased in the progesterone-treated, nonpregnant adrenalectomized ewes relative to the nonpregnant adrenalectomized ewes without progesterone treatment. There were no differences in hippocampal GR binding. In addition, using Western blot and real-time RT-PCR, we measured the protein and mRNA expression in hippocampus for MR as well as GR. No significant difference had been detected.; These studies support the hypothesis that increased progesterone during pregnancy reduces MR-mediated effects of cortisol, resulting in decreased feedback effects in the hippocampus at the basal level of cortisol. In addition, GR-mediated effects of cortisol haven't been changed by progesterone so that a feedback effects at the stimulated level of cortisol during pregnancy are the same as in nonpregnant state.