Metabolites of progesterone and the pregnane X receptor: a novel pathway regulating uterine contractility in pregnancy?
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.
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In liver and some peripheral tissues such as placenta and myometrium, AKR1D1 reduces progesterone to 5β-DHP, while SRD5A1 and SRD5A2 form 5α-DHP.
“In liver and some peripheral tissues (e.g. placenta and myometrium) AKR1D1 catalyzes reduction of progesterone to 5β-dihydroprogesterone (5β-DHP) while the 5α-reductases SRD5A1 and SRD5A2 form 5α-dihydroprogesterone (5α-DHP)”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [39]
Higher AKR1C1 and AKR1C2 levels in endometriotic tissue may contribute to increased conversion of progesterone to 20α-hydroxy-pregn-4-ene-3-one.
“Higher levels of AKR1C1 and AKR1C2 in endometriotic tissue may contribute to enhanced metabolism of the protective progesterone to 20α-hydroxy-pregn-4-ene-3-one”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [39]
Concurrent action of SRD5A1 may lead to formation of pro-proliferative 5α-pregnanes.
“and the concurrent action of SRD5A1 may lead to the formation of the pro-proliferative 5α-pregnanes [39] (N. Beranič and T. Lanišnik Rižner, unpublished data).”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [39]
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- Authors
- Mitchell, B. F., Mitchell, J. M., Chowdhury, J., Tougas, M., Engelen, S. M. E., Senff, N., Heijnen, I., Moore, J. T., Goodwin, B., Wong, S., & Davidge, S. T.
- Affiliations
- University of Alberta (CA)
- GlaxoSmithKline (United States) (US)
- Corresponding author
- Mitchell, Bryan F.
- ORCID
- Venue
- American Journal of Obstetrics and Gynecology
- Publisher
- Elsevier BV
- Published
- 2005-04
- Volume
- 192
- Issue
- 4
- Pages
- 1304-1313
- ISSN
- 0002-9378 (ISSN-L)
- OpenAlex
- W1992013033
- Cited by
- 47
- References
- 36
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 1 · 2014: 3 · 2013: 2 · 2012: 4
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Obstetrics and Gynecology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Alberta
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy-related medical research
- Health Sciences › Medicine › Epidemiology › Preterm Birth and Chorioamnionitis
- Keywords
- pregnane X receptor, progesterone metabolites, uterine contractility, 5beta-reductase, inducible nitric oxide synthase, 1400W, uterine relaxation, pregnancy, uterine tone
- MeSH terms
- Pregnane X Receptor, Analysis of Variance, Animals, Base Sequence, Enzyme-Linked Immunosorbent Assay, Female, Humans, Microscopy, Fluorescence, Molecular Sequence Data, Myometrium, Organ Culture Techniques, Pregnancy, Pregnancy, Animal, Probability, Progesterone, Receptors, Steroid, RNA, Messenger, Species Specificity, Uterine Contraction, Blotting, Western, Up-Regulation, Rats, Sprague-Dawley, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Models, Animal, Mice, Rats
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