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

Am J Obstet Gynecol. 2005 Apr;192(4):1304-13; discussion 1313-5. doi: 10.1016/j.ajog.2005.01.040.

Abstract

Objective: The purpose of this study was to determine the role of 5beta-dihydroprogesterone (5beta-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 5beta-reductase and for PXR. Acute in vitro treatment with 5beta-DHP causes rapid uterine relaxation that is not mediated by PXR. Chronic in vivo administration of 5beta-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 5beta-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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Base Sequence
  • Blotting, Western
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Models, Animal
  • Molecular Sequence Data
  • Myometrium / drug effects
  • Myometrium / metabolism
  • Organ Culture Techniques
  • Pregnancy
  • Pregnancy, Animal
  • Pregnane X Receptor
  • Probability
  • Progesterone / metabolism*
  • Progesterone / pharmacology*
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cytoplasmic and Nuclear / drug effects*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Steroid / drug effects*
  • Receptors, Steroid / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Species Specificity
  • Up-Regulation
  • Uterine Contraction / drug effects*
  • Uterine Contraction / physiology

Substances

  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Progesterone