Progesterone binds with high affinity to the mineralocorticoid (MC) receptor, but confers only very low agonistic MC activity. Therefore, progesterone is a potent MC antagonist in vitro. Although progesterone reaches up to 100 times higher plasma levels in late pregnancy than aldosterone, the in vivo MC antagonistic effect of progesterone seems to be relatively weak. One explanation for this phenomenon could be local metabolism of progesterone in the human kidney, similar to the inactivation of cortisol to cortisone by the 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2. We studied the metabolism of progesterone in the human kidney in vitro and found reduction to 20alpha-dihydro (DH)-progesterone as the main metabolite. Ring-A reduction to 5alpha-DH-progesterone, 20alpha-DH-5alpha-DH-progesterone, and 3beta,5alpha-tetrahydro (TH)-progesterone was also documented. We further showed for the first time that 17-hydroxylation of progesterone (17alpha-OH-progesterone, 17alpha-OH, 20alpha-DH-progesterone), normally localized in the adrenals and the gonads, occurs in the human adult kidney. We found no formation of deoxycorticosterone from progesterone in the human adult kidney. Using human kidney cortex microsomes, we tested the inhibitory potency of progesterone and its metabolites on the 11beta-HSD type 2. The most potent inhibitor was progesterone itself (IC50 = 4.8 x 10(-8) mol/L), followed by 5alpha-DH-progesterone (IC50 = 2.4 x 10(-7) mol/L), 20alpha-DH-progesterone, 3beta,5alpha-TH-progesterone, 17alpha-OH-progesterone, and 20alpha-DH-5alpha-DH-progesterone (IC50 between 7.7 x 10(-7) mol/L and 1.3 x 10(-6) mol/L). The least potent inhibitor was 17alpha-OH,20alpha-DH-progesterone. In addition to progesterone metabolism by the kidney, the inhibition of 11beta-HSD type 2 by progesterone and its metabolites could be a second explanation for the weak MC-antagonist activity of progesterone in vivo. Inhibition of 11beta-HSD type 2 leads to an increase of intracellular cortisol in a way that the local equilibrium between the MC agonist cortisol and the antagonist progesterone is shifted to the agonist side.