Difference of in vivo and in vitro antimineralocorticoid potency of progesterone

Progesterone (P) given intramuscularly increases renal sodium excretion. We tested the in vitro capacity of P to bind to the human mineralocorticoid receptor (MR) with a reticulocyte lysate system and Ps transactivation potency in transfected CV-1 cells. Progesterone binds with higher affinity to the MR than aldosterone, but shows only low transactivation activity. This results in a very strong anti-mineralocorticoid (MC) potency of P in vitro. To test the in vivo anti-MC potency of P we infused aldosterone intravenously to hypo-MC Addison's patients, followed by increasing P infusions. During the study we measured normal aldosterone plasma concentrations and high P concentrations similar to the third trimester of pregnancy. Despite the 1000-fold higher plasma P concentrations, the in vivo anti-MC effect of P (increase of urinary sodium/potassium ratio) was rather small. We suggest that this may be due to effective MR protection mechanisms, such as conversion of P to inactive metabolites.