Regulation of maternal ACTH in ovine pregnancy: does progesterone play a role?

Abstract

Pregnancy is characterized by increased plasma adrenocorticotropic hormone (ACTH) and cortisol. Studies suggest that progesterone acts as an antagonist at mineralocorticoid receptors. Therefore, we tested the hypothesis that chronic progesterone, produced by treatment of nonpregnant ewes or during pregnancy, will result in increased plasma ACTH relative to the plasma cortisol concentrations. We studied three groups of ewes: ovariectomized nonpregnant, nonpregnant treated with progesterone, and pregnant ewes. In two series of studies, ewes were adrenalectomized and replaced with 0.35 mg x kg(-1) x day(-1) or 0.5 mg x kg(-1) x day(-1) cortisol. In both studies, aldosterone was infused at 3 microg x kg(-1) x day(-1). In the first study, additional infusions of cortisol over 24 h were used to increase daily replacement doses to 0.5, 1, or 1.5 mg x kg(-1) x day(-1), and intact pregnant and nonpregnant ewes were studied with infusions of cortisol at 0, 0.5, and 1 mg x kg(-1) x day(-1). In adrenalectomized ewes chronically replaced to 0.35 mg x kg(-1) x day(-1) cortisol, plasma ACTH concentrations were decreased significantly in the nonpregnant progesterone-treated ewes compared with the ovariectomized nonpregnant ewes. With 0.5 mg x kg(-1) x day(-1) cortisol, plasma ACTH levels were greater in pregnant ewes than in nonpregnant ewes with or without progesterone. Overall plasma ACTH levels at 0.35 mg x kg(-1) x day(-1) were significantly related to the plasma protein concentration, suggesting that the ACTH levels in the hypocorticoid ewes are most closely related to plasma volume. Across all steroid doses, ACTH was positively related to plasma proteins and progesterone, and negatively related to cortisol. We conclude that increased progesterone does not alter the feedback relation of cortisol to ACTH, but may modulate ACTH indirectly through plasma volume.

Fig. 1.

Plasma progesterone, cortisol, and adrenocorticotropic hormone (ACTH) concentrations in adrenal intact ewes (right) and in adrenalectomized ewes replaced with 0.35 mg·kg⁻¹·day⁻¹ cortisol and 3 μg·kg⁻¹·day⁻¹ aldosterone (left). Data are mean values ± SE in samples collected over 8 h. *Values in pregnant ewes (P, black bars) greater than in nonpregnant ewes (NP, open bars). ^aValues in adrenalectomized pregnant (aP, black bars) or adrenalectomized nonpregnant treated with progesterone (aNP4, gray bars) that were significantly different from in adrenalectomized nonpregnant (aNP, open bars), P < 0.05.

Fig. 2.

Changes in plasma cortisol concentrations and plasma ACTH concentrations during different replacement doses of cortisol in adrenal-intact or adrenalectomized ewes. Bar graphs on right depict mean plasma ACTH and cortisol concentrations between 4 and 24 h of cortisol infusion in adrenal-intact nonpregnant (NP, open bar) compared with adrenal-intact pregnant (P, black bars), and bars on left indicate mean ACTH and cortisol in adrenalectomized nonpregnant (aNP, open bars), adrenalectomized pregnant (aP, black bars), and adrenalectomized nonpregnant progesterone-treated ewes (aNP4, gray bars). ^aDifferent from aNP; ^bDifferent from aP; ^cdifferent from aNP4. Cortisol infusion doses are indicted in mg/kg for the 24 h of infusion.

Fig. 3.

Mean arterial pressure values in adrenal-intact (A and C) and adrenalectomized (B and D) ewes. Data were collected over 24 h; mean data at 24 h with no infusion of cortisol in intact ewes (right) or adrenalectomized ewes (left) with infusion of cortisol at 0.2, 0.7, and 1.0 mg·kg⁻¹·day⁻¹. Symbols are as indicated in the legend to Fig. 2.

Fig. 4.

Plasma protein (A), sodium (B), and potassium (C) concentrations in adrenalectomized ewes (left) and adrenal-intact ewes (right). Values shown are means of samples collected from 4 to 24 h during each of the infusion rates of cortisol in the adrenalectomized ewes. Symbols are as indicated in the legend to Fig. 2.

Fig. 5.

Mean plasma cortisol concentrations (left) and plasma ACTH concentrations (right) in adrenalectomized ewes replaced with 0.5 mg·kg⁻¹·day⁻¹. Data shown are mean concentrations over 24 h in adrenalectomized nonpregnant (aNP, open bars), adrenalectomized pregnant (aP, black bars), and adrenalectomized nonpregnant progesterone-treated ewes (aNP4, gray bars). ^aDifferent from aNP; ^bdifferent from aP; ^cdifferent from aNP4.