Transactions from the Annual Meeting of the American Gynecological and Obstetrical Society
Metabolites of progesterone and the pregnane X receptor: A novel pathway regulating uterine contractility in pregnancy?

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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.

Section snippets

Tissue collection

All protocols for human tissue collection were approved by the University of Alberta Human Ethics Review Board. Uterine samples were obtained from hysterectomy specimens from women undergoing surgery for non-neoplastic and noninflammatory indications. Human liver and kidney samples were obtained through the Department of Pathology at the University of Alberta Hospital with patient permission. The human lower segment myometrium, placenta, fetal membranes, and umbilical cord tissues were obtained

Results

Our first question was whether reproductive tissues had the capacity to form 5β-reduced metabolites of P4. Using nonquantitative RT-PCR, we demonstrated the presence of mRNA for 5β-reductase in human liver and kidney, as well as several reproductive tissues, including fetal membranes, decidua, placenta, myometrium, and umbilical vessels (Figure 1A). Using a radiolabel enzyme assay, we also detected 5β-reductase activity in a variety of reproductive and nonreproductive tissues of human and mouse

Comment

These data provide information about a potentially important pathway that may influence uterine contractility. We have demonstrated the presence of the enzyme necessary to produce 5β-reduced metabolites of P4 within human and rat uterine tissues. We also have demonstrated the presence of mRNA and protein for PXR on myometrial and endometrial cells from both human and mouse uterus. Further, we have provided evidence that treatment of PXR+/+ mice with 5β-DHP increases iNOS-mediated suppression of

Acknowledgments

We acknowledge the assistance of Dr Glen Baker and Gail Rauw from the University of Alberta Neurochemical Research Unit, who performed the HPLC-MS assays for serum 5β-DHP, and to Dr Xin Fang for assistance with the Western analyses. We also are grateful to Capital Health and the Obstetrical staff of the Royal Alexandra Hospital for collection of the human myometrial samples, and to the staff of the University of Alberta Health Sciences Laboratory Animal Services for their excellent care of the

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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.

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