title: Renal inactivation, mineralocorticoid generation, and 11beta-hydroxysteroid dehydrogenase inhibition ameliorate the antimineralocorticoid effect of progesterone in vivo.
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.
authors.affiliation: Department of Endocrinology, Klinikum Benjamin Franklin, Freie Universität, 12200 Berlin, Germany. m.o.quinkler@bham.ac.uk
authors.forename: M
authors.initials: M
authors.lastname: Quinkler
authors.forename: B
authors.initials: B
authors.lastname: Meyer
authors.forename: W
authors.initials: W
authors.lastname: Oelkers
authors.forename: S
authors.initials: S
authors.lastname: Diederich
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases; D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000303:Adrenal Cortex Diseases / Q000188:drug therapy / Q000378:metabolism; D000328:Adult; D000450:Aldosterone / Q000097:blood / Q000494:pharmacology; D000735:Androstenedione / Q000652:urine; D003900:Desoxycorticosterone / Q000652:urine; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005438:Fludrocortisone / Q000627:therapeutic use; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008901:Mineralocorticoids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D017698:Postmenopause; D011188:Potassium / Q000652:urine; D011239:Prednisolone / Q000652:urine; D011241:Prednisone / Q000652:urine; D011374:Progesterone / Q000037:antagonists & inhibitors* / Q000097:blood / Q000494:pharmacology*; D012964:Sodium / Q000652:urine; D014563:Urodynamics / Q000187:drug effects / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D008901:Mineralocorticoids; D000735:Androstenedione; D003900:Desoxycorticosterone; D000450:Aldosterone; D011374:Progesterone; D019326:17-alpha-Hydroxyprogesterone; D012964:Sodium; D011239:Prednisolone; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D011188:Potassium; D005438:Fludrocortisone; D011241:Prednisone