Progesterone Metabolism and Androgen Synthesis in the Human Kidney and their Influence on Blood Pressure Regulation

The glucocorticoid cortisol binds with nearly the same affinity to the mineralocorticoid receptor (MR) as the mineralocorticoid aldosterone. Plasma cortisol levels exceed those of aldosterone by at least a hundredfold. MR-expressing cells in the renal distal tubule and collecting duct are able to prevent binding of cortisol to the MR by expressing the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme, which deactivates cortisol to cortisone. Inhibition of this enzymes, such as by the licorice component glycyrrhetenic acid, or loss of function, such as in apparent mineralocorticoid excess syndrome, result cortisol binding to the MR, causing enhanced water and sodium reabsorption with subsequent hypertension. Therefore, the substrate specificity of the MR is not receptor but enzyme-mediated.

The gestagen progesterone binds with even higher affinity to the MR, but confers only little transactivation activity, making it a mineralocorticoid antagonist. Progesterone is not a substrate for 11β-HSD2. Plasma progesterone concentrations increase and exceed those of aldosterone by far in the menstrual cycle’s luteal phase and in pregnancy. The mechanism by which aldosterone can keep its mineralocorticoid regulatory role in those states was only recently elucidated.

We have shown that the human kidney is able to convert progesterone to several inactive metabolites such as 17α-hydroxy-progesterone, 20α-dihydroprogesterone, and ring-A reduced metabolites. We propose that there is a similar enzyme-mediated protective mechanism by the MR as by 11β-HSD2.

In a further study, we investigated progesterone’s in vivo anti-mineralocorticoid effect. Eight patients with adrenal insufficiency and a hypomineralocorticoid status received an i.v. infusion of aldosterone over 8 h. During this infusion, normal plasma aldosterone concentrations were measured and the urinary Na/K ratio decreased (MR activation). An i.v. progesterone infusion was started after 4 h. The urinary Na/K ratio only slightly increased despite very high plasma progesterone concentrations (similar to those during the third trimester of pregnancy). This suggests a protective mechanism for the MR in vivo. We measured highly elevated concentrations of 17α-hydroxy-progesterone in plasma and urine, suggesting an extra-adrenal, possibly renal, progesterone metabolism.

Our studies suggest that the altered progesterone metabolism influences salt and water reabsorption during the menstrual cycle and pregnancy.