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Progesterone Metabolites Produced by Cytochrome P450 3A Modulate Uterine Contractility in a Murine Model

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Abstract

Objective

We seek to characterize the effect of progesterone metabolites on spontaneous and oxytocin-induced uterine contractility.

Study Design

Spontaneous contractility was studied in mouse uterine horns after treatment with progesterone, 2α-hydroxyprogesterone, 6β-hydroxyprogesterone (6β-OHP), 16α-hydroxyprogesterone (16α-OHP), or 17-hydroxyprogesterone caproate (17-OHPC) at 10−9 to 10−6 mol/L. Uterine horns were exposed to progestins (10−6 mol/L), followed by increasing concentrations of oxytocin (1-100 nmol/L) to study oxytocin-induced contractility. Contraction parameters were compared for each progestin and matched vehicle control using repeated measures 2-way analysis of variance. In vitro metabolism of progesterone by recombinant cytochrome P450 3A (CYP3A) microsomes (3A5, 3A5, and 3A7) identified major metabolites.

Results

Oxytocin-induced contractile frequency was decreased by 16α-OHP (P = .03) and increased by 6β-OHP (P = .05). Progesterone and 17-OHPC decreased oxytocin-induced contractile force (P = .02 and P = .04, respectively) and frequency (P = .02 and P = .03, respectively). Only progesterone decreased spontaneous contractile force (P = .02). Production of 16α-OHP and 6β-OHP metabolites were confirmed in all CYP3A isoforms tested.

Conclusion

Progesterone metabolites produced by maternal or fetal CYP3A enzymes influence uterine contractility.

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Authors and Affiliations

  1. Department of Obstetrics & Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA

    Avinash S. Patil MD & Xiaomei Zheng MD

  2. Department of Obstetrics & Gynecology, Duke University Medical Center, Durham, NC, USA

    Geeta K. Swamy MD, Amy P. Murtha MD, R. Phillips Heine MD & Chad A. Grotegut MD

Authors
  1. Avinash S. Patil MD
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  2. Geeta K. Swamy MD
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  3. Amy P. Murtha MD
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  4. R. Phillips Heine MD
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  5. Xiaomei Zheng MD
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  6. Chad A. Grotegut MD
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Corresponding author

Correspondence to Avinash S. Patil MD.

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Patil, A.S., Swamy, G.K., Murtha, A.P. et al. Progesterone Metabolites Produced by Cytochrome P450 3A Modulate Uterine Contractility in a Murine Model. Reprod. Sci. 22, 1577–1586 (2015). https://doi.org/10.1177/1933719115589414

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  • DOI: https://doi.org/10.1177/1933719115589414

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