Metabolites of progesterone and the pregnane X receptor: A novel pathway regulating uterine contractility in pregnancy?

Objective The purpose of this study was to determine the role of 5β-dihydroprogesterone (5β-DHP), acting through the nuclear receptor pregnane X receptor (PXR), in regulating uterine contractility. Study design Uterine contractility was studied in tissues from women, rats, and mice. Messenger RNA was assessed using reverse transcriptase-polymerase chain reaction (RT-PCR), and protein was measured using enzyme assays, immunofluorescence microscopy, and Western analyses. Results Human and rat uterine tissues contain mRNA and protein for 5β-reductase and for PXR. Acute in vitro treatment with 5β-DHP causes rapid uterine relaxation that is not mediated by PXR. Chronic in vivo administration of 5β-DHP to mice with intact PXR, but not in mice with disrupted PXR, causes an increased effect of 1400W, a specific inhibitor of inducible nitric oxide synthase (iNOS). This suggests that 5β-DHP increased iNOS-modulated uterine tone, as occurs during pregnancy. Conclusion These data support the hypothesis that metabolites of progesterone may act chronically through a PXR-mediated mechanism to regulate uterine contractility.