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Renal Inactivation, Mineralocorticoid Generation, and 11ß-Hydroxysteroid Dehydrogenase Inhibition Ameliorate the Antimineralocorticoid Effect of Progesterone in Vivo

Department of Endocrinology, Klinikum Benjamin Franklin, Freie Universität, 12200 Berlin, Germany

Address all correspondence and requests for reprints to: Dr. Marcus Quinkler, Division of Medical Sciences, Queen Elizabeth Hospital, University of Birmingham, Edgbaston, Birmingham, United Kingdom B15 2TH. E-mail: m.o.quinkler{at}bham.ac.uk.

Progesterone (P) is a strong mineralocorticoid receptor (MR) antagonist in vitro. The high P concentrations seen in normal pregnancy only moderately increase renin and aldosterone concentrations. In previous in vitro studies we hypothesized that this may be explained by intrarenal conversion of P to less potent metabolites. To investigate the in vivo anti-MR potency of P, we performed an infusion study in patients with adrenal insufficiency (n = 8). They omitted 9-fluorocortisol for 4 d and hydrocortisone for 0.5 d before a continuous iv infusion of aldosterone for 8.5 h, with an additional iv P infusion commenced at 4 h. During aldosterone infusions the initially elevated urinary sodium to potassium ratio decreased significantly. Despite the 1000-fold excess of P over aldosterone, the urinary sodium to potassium ratio and urinary sodium excretion increased only slightly after 3 h of P infusion. We detected inhibition of renal 11ß-hydroxysteroid dehydrogenase type 2 by P, thus giving cortisol/prednisolone access to the MR. Urinary and plasma concentrations of 17-hydroxyprogesterone, a major metabolite of renal P metabolism, and those of serum androstenedione and deoxycorticosterone, a mineralocorticoid itself, increased significantly during P infusion. This supports the hypothesis of an effective protection of the MR from P by efficient extraadrenal downstream conversion of P.

This work was supported by Grant DI 741/1-3 (to S.D.) and Postdoctoral Research Fellowship Grant QU 142/1-1 (to M.Q.) from the Deutsche Forschungsgemeinschaft.

Abbreviations: DHEA, Dehydroepiandrosterone; 4-dione, androstenedione; DOC, deoxycorticosterone; MR, mineralocorticoid receptor; 17-hydroxy-P, 17-hydroxyprogesterone; P, progesterone.

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