CONTROL OF CORTICOTROPIN DURING PREGNANCY

University Of Florida, Gainesville FL

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Abstract

DESCRIPTION (Adapted from applicant's abstract): In pregnancy in sheep as well as in humans, plasma ACTH and plasma cortisol concentrations are increased. Whereas basal cortisol levels are doubled in pregnant subjects, further increases in cortisol cause inhibition of ACTH in pregnant as well as nonpregnant ewes. The applicant's results suggest a dual regulation of ACTH: ACTH is increased, and feedback effects of cortisol are reduced, at cortisol levels in the range of normal nonpregnant ewes, but ACTH is suppressed, with normal or even increased feedback effects of cortisol, with levels of cortisol produced by stress. This allows a doubling of basal cortisol, but prevents greater increases which would lead to overt signs of Cushing's disease. Studies in rats have indicated that a dual receptor system for corticosteroid action allows for differential control of ACTH by basal corticosteroid via high affinity low capacity mineralocorticoid receptor (MR), and by stimulated cortisol via lower affinity, but higher capacity, glucocorticoid receptors (GR). The investigators hypothesize that the changes in pregnancy result form a decrease in cortisol action at the MR but no decrease in action at the GR. The investigators hypothesize that these changes, and therefore the elevation of cortisol, are related to the increase in plasma progesterone during pregnancy. Progesterone binds to both GR and MR, acting as a weak agonist at GR and an antagonist at MR. This proposal will test the following specific hypotheses: 1) an increase in plasma progesterone will change the relationship between cortisol and ACTH at low levels of cortisol, but not at higher cortisol levels; 2) that chronic increases in progesterone act to reduce cortisol action at MR, 3) that chronic exposure to progesterone does not alter cortisol actions via GR, but may contribute to GR-mediated effects. These hypotheses will be tested in vivo experiments to compare regulation of ACTH in pregnant and nonpregnant ewes with altered cortisol and/or progesterone concentrations, and by comparison of in vivo receptor occupancy, and receptor binding, density and mRNA levels in tissue from ewes during these steroid treatments. Ability of cortisol and progesterone, alone or in combination, to activate the receptor and allow binding to the appropriate DNA response element will also be assessed. The investigators hypothesize that progesterone will bind to MR in vivo, but will not activate these receptors, leading to increased MR availability in tissues removed from progesterone-treated ewes; we predict that MR production will be unchanged, or increased in response to the reduced activation of MR. These studies are important for understanding an important physiological adaptation in pregnancy, which appears to allow increased glucocorticoid actions without excess mineralocorticoid action or frank Cushingoid symptoms.