Renal inactivation, mineralocorticoid generation, and 11beta-hydroxysteroid dehydrogenase inhibition ameliorate the antimineralocorticoid effect of progesterone in vivo.

M Quinkler, B Meyer, W Oelkers, S Diederich

Journal: The Journal of clinical endocrinology and metabolism 2003;88(8):3767-72

PMID: 12915667

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Abstract

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 9alpha-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 11beta-hydroxysteroid dehydrogenase type 2 by P, thus giving cortisol/prednisolone access to the MR. Urinary and plasma concentrations of 17alpha-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.

Address: Department of Endocrinology, Klinikum Benjamin Franklin, Freie Universität, 12200 Berlin, Germany. [email protected]

DOI: 10.1210/jc.2003-030092

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MeSH Terms: 11-beta-Hydroxysteroid Dehydrogenases, 17-alpha-Hydroxyprogesterone, Adrenal Cortex Diseases, Adult, Aldosterone, Androstenedione, Desoxycorticosterone, Enzyme Inhibitors, Female, Fludrocortisone, Humans, Hydroxysteroid Dehydrogenases, Infusions, Intravenous, Kidney, Male, Middle Aged, Mineralocorticoids, Postmenopause, Potassium, Prednisolone, Prednisone, Progesterone, Sodium, Urodynamics