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

Mitchell, Bryan F.; Mitchell, Jana M.; Chowdhury, Jeeshan; Tougas, Michelle; Engelen, Sanne M.E.; Senff, Nancy; Heijnen, Iris; Moore, John T.; Goodwin, Bryan; Wong, Susan; Davidge, Sandra T.

doi:10.1016/j.ajog.2005.01.040

« Previous Next »American Journal of Obstetrics & Gynecology
Volume 192, Issue 4 , Pages 1304-1313, April 2005

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

Bryan F. Mitchell, MD
- Department of Obstetrics and Gynecology, Perinatal Research Centre
- Reprint requests: Bryan F. Mitchell, Perinatal Research Centre, 220 HMRC, University of Alberta, Edmonton AB Canada T6G 2S2.
Jana M. Mitchell, BSc
- Department of Obstetrics and Gynecology, Perinatal Research Centre
Jeeshan Chowdhury
- Department of Obstetrics and Gynecology, Perinatal Research Centre
Michelle Tougas, MD
- Department of Obstetrics and Gynecology, Perinatal Research Centre
Sanne M.E. Engelen, MD
- Department of Obstetrics and Gynecology, Perinatal Research Centre
Nancy Senff, MD
- Department of Obstetrics and Gynecology, Perinatal Research Centre
Iris Heijnen, MD
- Department of Obstetrics and Gynecology, Perinatal Research Centre
John T. Moore, PhD
- Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC
Bryan Goodwin, MD, PhD
- Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC
Susan Wong, MSc
- Department of Obstetrics and Gynecology, Perinatal Research Centre
Sandra T. Davidge, PhD
- Department of Obstetrics and Gynecology, Perinatal Research Centre
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada

Received 21 December 2004; received in revised form 21 December 2004; accepted 19 January 2005.

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.

Key words: Parturition, Uterine quiescence, Uterine sensitivity, Oxytocin

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Supported by grants from the Heart and Stroke Foundation of Canada, the Canadian Institutes of Health Research (Institute of Human Development, Child and Youth Health), and The Alberta Heritage Foundation for Medical Research.Presented at the 23rd Annual Meeting of the American Gynecological and Obstetrical Society, September 9-11, 2004, Bolton Landing, NY.

PII: S0002-9378(05)00117-1

doi:10.1016/j.ajog.2005.01.040