Metabolites of progesterone and the pregnane X receptor: A novel pathway regulating uterine contractility in pregnancy? Bryan F. Mitchell, MD, a, * Jana M. Mitchell, BSc, a Jeeshan Chowdhury, a Michelle Tougas, MD, a Sanne M. E. Engelen, MD, a Nancy Senff, MD, a Iris Heijnen, MD, a John T. Moore, PhD, c Bryan Goodwin, MD, PhD, c Susan Wong, MSc, a Sandra T. Davidge, PhD a,b Department of Obstetrics and Gynecology, a Perinatal Research Centre, and Department of Physiology, b University of Alberta, Edmonton, Alberta, Canada, and Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC c Received for publication December 21, 2004; revised December 21, 2004; accepted January 19, 2005 KEY WORDS Parturition Uterine quiescence Uterine sensitivity Oxytocin Objective: The purpose of this study was to determine the role of 5b-dihydroprogesterone (5b-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 5b-reductase and for PXR. Acute in vitro treatment with 5b-DHP causes rapid uterine relaxation that is not mediated by PXR. Chronic in vivo administration of 5b-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 5b-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. Ó 2005 Elsevier Inc. All rights reserved. During pregnancy there is a delicate balance between the forces that stimulate uterine contractions and those that promote uterine quiescence. Throughout most of gestation, uterine smooth muscle must remain in a state of relative quiescence to facilitate nidation, growth, and development of the fetus. Though the uterus contracts in response to stretch, 1-3 it remains quiescent during gestation despite the rapidly growing mass of placenta and fetus. This suggests the presence of an active 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 Gyneco- logical and Obstetrical Society, September 9-11, 2004, Bolton Landing, NY. * Reprint requests: Bryan F. Mitchell, Perinatal Research Centre, 220 HMRC, University of Alberta, Edmonton AB Canada T6G 2S2. E-mail: brymitch@ualberta.ca 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2005.01.040 American Journal of Obstetrics and Gynecology (2005) 192, 1304–15 www.ajog.org