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Marcus Quinkler, Sarah Johanssen, Claudia Großmann, Volker Bähr, Markus Müller, Wolfgang Oelkers, Sven Diederich, Progesterone Metabolism in the Human Kidney and Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 2 by Progesterone and Its Metabolites, The Journal of Clinical Endocrinology & Metabolism, Volume 84, Issue 11, 1 November 1999, Pages 4165–4171, https://doi.org/10.1210/jcem.84.11.6163
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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 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2. We studied the metabolism of progesterone in the human kidney in vitro and found reduction to 20α-dihydro (DH)-progesterone as the main metabolite. Ring-A reduction to 5α-DH-progesterone, 20α-DH-5α-DH-progesterone, and 3β,5α-tetrahydro (TH)-progesterone was also documented. We further showed for the first time that 17-hydroxylation of progesterone (17α-OH-progesterone, 17α-OH, 20α-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 11β-HSD type 2. The most potent inhibitor was progesterone itself (IC50 = 4.8 × 10−8 mol/L), followed by 5α-DH-progesterone (IC50 = 2.4 × 10−7 mol/L), 20α-DH-progesterone, 3β,5α-TH-progesterone, 17α-OH-progesterone, and 20α-DH-5α-DH-progesterone (IC50 between 7.7 × 10−7 mol/L and 1.3 × 10−6 mol/L). The least potent inhibitor was 17α-OH,20α-DH-progesterone. In addition to progesterone metabolism by the kidney, the inhibition of 11β-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 11β-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.
