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Cervix Stromal Cells and the Progesterone Receptor A Isoform Mediate Effects of Progesterone for Prepartum Remodeling

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Abstract

The prepartum transition from a soft to ripening cervix is an inflammatory process that occurs well before birth when systemic progesterone is near peak concentration. This 2-part study first determined that stromal fibroblasts but not macrophages in the cervix have progesterone receptors (PRs). Neither the number of PR cells in cervix sections nor the relative abundance or ratio of nuclear PR isoforms (PR-A/PR-B) were diminished in mice between day 15 of pregnancy and term. Second in mice lacking PR-B (Pgrtm20mc), the number of cells that expressed the PR-A isoform were maintained during this period of prepartum cervix remodeling. Thus, progesterone effects to sustain pregnancy, as well as soften and ripen the cervix, are mediated by a stable stromal cell population that expresses PR-A and, through interactions with resident macrophages, are likely to mediate inflammatory ripening processes in preparation for birth.

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References

  1. Word RA, Li XH, Hnat M, Carrick K. Dynamics of cervical remodeling during pregnancy and parturition: mechanisms and current concepts. Semin Reprod Med. 2007;25(1):69–79.

    CAS  PubMed  Google Scholar 

  2. Yellon SM. Contributions to the dynamics of cervix remodeling prior to term and preterm birth. Biol Reprod. 2017;96(1):13–23.

    PubMed  Google Scholar 

  3. Kjaergaard H, Olsen J, Ottesen B, Nyberg P, Dykes AK. Obstetric risk indicators for labour dystocia in nulliparous women: a multi-centre cohort study. BMC Pregnancy Childbirth. 2008;8:45.

    PubMed  PubMed Central  Google Scholar 

  4. Blencowe H, Cousens S, Chou D, et al. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health. 2013;10(suppl 1):S2.

    PubMed  PubMed Central  Google Scholar 

  5. Merlino AA, Welsh TN, Tan H, et al. Nuclear progesterone receptors in the human pregnancy myometrium: evidence that parturition involves functional progesterone withdrawal mediated by increased expression of progesterone receptor-A. J Clin Endocrinol Metab. 2007;92(5):1927–1933.

    CAS  PubMed  Google Scholar 

  6. Lockwood CJ, Stocco C, Murk W, Kayisli UA, Funai EF, Schatz F. Human labor is associated with reduced decidual cell expression of progesterone, but not glucocorticoid, receptors. J Clin Endocrinol Metab. 2010;95(5):2271–2275.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Swaggart KA, Pavlicev M, Muglia LJ. Genomics of preterm birth. Cold Spring Harb Perspect Med. 2015;5(2):a023127.

    PubMed  PubMed Central  Google Scholar 

  8. Pieber D, Allport VC, Hills F, Johnson M, Bennett PR. Interactions between progesterone receptor isoforms in myometrial cells in human labour. Mol Hum Reprod. 2001;7(9):875–879.

    CAS  PubMed  Google Scholar 

  9. Hapangama D, Neilson JP. Mifepristone for induction of labour. Cochrane Database Syst Rev. 2009;(3):CD002865.

    Google Scholar 

  10. Denison FC, Riley SC, Elliott CL, Kelly RW, Calder AA, Critchley HO. The effect of mifepristone administration on leukocyte populations, matrix metalloproteinases and inflammatory mediators in the first trimester cervix. Mol Hum Reprod. 2000;6(6):541–548.

    CAS  PubMed  Google Scholar 

  11. Clark K, Ji H, Feltovich H, Janowski J, Carroll C, Chien EK. Mifepristone-induced cervical ripening: structural, biomechanical, and molecular events. Am J Obstet Gynecol. 2006;194(5):1391–1398.

    CAS  PubMed  Google Scholar 

  12. Kirby MA, Heuerman AC, Custer M, et al. Progesterone receptor-mediated actions regulate remodeling of the cervix in preparation for preterm parturition. Reprod Sci. 2016;23(11):1473–1483.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Yellon SM, Dobyns AE, Beck HL, Kurtzman JT, Garfield RE, Kirby MA. Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth. PLoS One. 2013;8(12):e81340.

    PubMed  PubMed Central  Google Scholar 

  14. Yellon SM, Burns AE, See JL, Lechuga TJ, Kirby MA. Progesterone withdrawal promotes remodeling processes in the nonpregnant mouse cervix. Biol Reprod. 2009;81(1):1–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Lucovnik M, Kuon RJ, Chambliss LR, et al. Progestin treatment for the prevention of preterm birth. Acta Obstet Gynecol Scand. 2011;90(10):1057–1069.

    PubMed  PubMed Central  Google Scholar 

  16. Yellon SM, Oldford EJ, Heuerman AC. Progesterone effects on cervix ripening and preterm birth in a murine model for progesterone withdrawal. Reprod Sci. 2018;25:183A. 

    Google Scholar 

  17. Zakar T, Hertelendy F. Progesterone withdrawal: key to parturition. Am J Obstet Gynecol. 2007;196(4):289–296.

    CAS  PubMed  Google Scholar 

  18. Ackerman WET, Summerfield TL, Mesiano S, Schatz F, Lockwood CJ, Kniss DA. Agonist-dependent downregulation of progesterone receptors in human cervical stromal fibroblasts. Reprod Sci. 2016;23(1):112–123.

    CAS  PubMed  Google Scholar 

  19. Amini P, Michniuk D, Kuo K, et al. Human parturition involves progesterone receptor-A phosphorylation at serine-345 in myometrial cells. Endocrinology. 2016;157(11):4434–4445.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Mesiano S, Chan EC, Fitter JT, Kwek K, Yeo G, Smith R. Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium. J Clin Endocrinol Metab. 2002;87(6):2924–2930.

    CAS  PubMed  Google Scholar 

  21. Lopez V, Wagner CK. Progestin receptor is transiently expressed perinatally in neurons of the rat isocortex. J Comp Neurol. 2009;512(1):124–139.

    PubMed  Google Scholar 

  22. Yellon SM, Heuerman AC, Kirby MA. Utility of optical density of picrosirius red birefringence for analysis of collagen. Integr Gynecol Obstet J. 2018;1(2):1–5.

    Google Scholar 

  23. Yellon SM, Oshiro BT, Chhaya TY, et al. Remodeling of the cervix and parturition in mice lacking the progesterone receptor B isoform. Biol Reprod. 2011;85(3):498–502.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Invitrogen. Normalization in western blotting to obtain relative quantitation. Thermo Fisher Scientific. 2018. https://assets.thermofisher.com/TFS-Assets/BID/Technical-Notes/ibright-normalization-western-blotting-relative-quantitation-technical-note.pdf. Accessed October 5, 2018.

  25. Miller L, Hunt JS. Sex steroid hormones and macrophage function. Life Sci. 1996;59(1):1–14.

    CAS  PubMed  Google Scholar 

  26. Yoshida M, Sagawa N, Itoh H, et al. Prostaglandin F(2alpha), cytokines and cyclic mechanical stretch augment matrix metalloproteinase-1 secretion from cultured human uterine cervical fibroblast cells. Mol Hum Reprod. 2002;8(7):681–687.

    CAS  PubMed  Google Scholar 

  27. Keelan JA. Intrauterine inflammatory activation, functional progesterone withdrawal, and the timing of term and preterm birth. J Reprod Immunol. 2018;125:89–99.

    CAS  PubMed  Google Scholar 

  28. Miller L, Hunt JS. Regulation of TNF-alpha production in activated mouse macrophages by progesterone. J Immunol. 1998;160(10):5098–5104.

    CAS  PubMed  Google Scholar 

  29. Collins JJ, Usip S, McCarson KE, Papka RE. Sensory nerves and neuropeptides in uterine cervical ripening. Peptides. 2002;23(1):167–183.

    CAS  PubMed  Google Scholar 

  30. Longo LD, Yellon S. Biological timekeeping during pregnancy and the role of circadian rhythms in parturition. In: Kunzel W, Jensen A, eds. The Endocrine Control of the Fetus. Berlin, Germany: Springer-Verlag; 1988:173–191.

    Google Scholar 

  31. Chai SY, Smith R, Fitter JT, et al. Increased progesterone receptor A expression in labouring human myometrium is associated with decreased promoter occupancy by the histone demethylase JARID1A. Mol Hum Reprod. 2014;20(5):442–453.

    CAS  PubMed  Google Scholar 

  32. Patel B, Elguero S, Thakore S, Dahoud W, Bedaiwy M, Mesiano S. Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum Reprod Update. 2015;21(2):155–173.

    CAS  PubMed  Google Scholar 

  33. Mahendroo MS, Cala KM, Russell DW. 5 alpha-reduced androgens play a key role in murine parturition. Mol Endocrinol. 1996;10(4):380–392.

    CAS  PubMed  Google Scholar 

  34. Mahendroo MS, Porter A, Russell DW, Word RA. The parturition defect in steroid 5alpha-reductase type 1 knockout mice is due to impaired cervical ripening. Mol Endocrinol. 1999;13(6):981–992.

    CAS  PubMed  Google Scholar 

  35. Lei K, Chen L, Georgiou EX, et al. Progesterone acts via the nuclear glucocorticoid receptor to suppress IL-1beta-induced COX-2 expression in human term myometrial cells. PLoS One. 2012;7(11):e50167.

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Longo Center for Perinatal Biology, MRW A572, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA

    Anne C. Heuerman BA, Trevor T. Hollinger BA & Steven M. Yellon PhD

  2. Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX, USA

    Ramkumar Menon PhD

  3. Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Sam Mesiano PhD

  4. Division of Physiology, Department of Basic Sciences, and Departments of Basic Sciences and Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA

    Steven M. Yellon PhD

Authors
  1. Anne C. Heuerman BA
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  2. Trevor T. Hollinger BA
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  3. Ramkumar Menon PhD
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  4. Sam Mesiano PhD
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  5. Steven M. Yellon PhD
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Correspondence to Steven M. Yellon PhD.

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Heuerman, A.C., Hollinger, T.T., Menon, R. et al. Cervix Stromal Cells and the Progesterone Receptor A Isoform Mediate Effects of Progesterone for Prepartum Remodeling. Reprod. Sci. 26, 690–696 (2019). https://doi.org/10.1177/1933719118820462

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