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.
WordRALiXHHnatMCarrickK. Dynamics of cervical remodeling during pregnancy and parturition: mechanisms and current concepts. Semin Reprod Med. 2007;25(1):69–79.
2.
YellonSM. Contributions to the dynamics of cervix remodeling prior to term and preterm birth. Biol Reprod. 2017;96(1):13–23.
3.
KjaergaardHOlsenJOttesenBNybergPDykesAK. Obstetric risk indicators for labour dystocia in nulliparous women: a multi-centre cohort study. BMC Pregnancy Childbirth. 2008;8:45.
4.
BlencoweHCousensSChouD. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health. 2013;10(suppl 1):S2.
5.
MerlinoAAWelshTNTanH. 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.
6.
LockwoodCJStoccoCMurkWKayisliUAFunaiEFSchatzF. Human labor is associated with reduced decidual cell expression of progesterone, but not glucocorticoid, receptors. J Clin Endocrinol Metab. 2010;95(5):2271–2275.
7.
SwaggartKAPavlicevMMugliaLJ. Genomics of preterm birth. Cold Spring Harb Perspect Med. 2015;5(2):a023127.
8.
PieberDAllportVCHillsFJohnsonMBennettPR. Interactions between progesterone receptor isoforms in myometrial cells in human labour. Mol Hum Reprod. 2001;7(9):875–879.
9.
HapangamaDNeilsonJP. Mifepristone for induction of labour. Cochrane Database Syst Rev. 2009;(3):CD002865.
10.
DenisonFCRileySCElliottCLKellyRWCalderAACritchleyHO. 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.
11.
ClarkKJiHFeltovichHJanowskiJCarrollCChienEK. Mifepristone-induced cervical ripening: structural, biomechanical, and molecular events. Am J Obstet Gynecol. 2006;194(5):1391–1398.
12.
KirbyMAHeuermanACCusterM. Progesterone receptor-mediated actions regulate remodeling of the cervix in preparation for preterm parturition. Reprod Sci. 2016;23(11):1473–1483.
13.
YellonSMDobynsAEBeckHLKurtzmanJTGarfieldREKirbyMA. Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth. PLoS One. 2013;8(12):e81340.
14.
YellonSMBurnsAESeeJLLechugaTJKirbyMA. Progesterone withdrawal promotes remodeling processes in the nonpregnant mouse cervix. Biol Reprod. 2009;81(1):1–6.
15.
LucovnikMKuonRJChamblissLR. Progestin treatment for the prevention of preterm birth. Acta Obstet Gynecol Scand. 2011;90(10):1057–1069.
16.
YellonSMOldfordEJHeuermanAC. Progesterone effects on cervix ripening and preterm birth in a murine model for progesterone withdrawal. Reprod Sci. 2018;25:183A.
17.
ZakarTHertelendyF. Progesterone withdrawal: key to parturition. Am J Obstet Gynecol. 2007;196(4):289–296.
18.
AckermanWETSummerfieldTLMesianoSSchatzFLockwoodCJKnissDA. Agonist-dependent downregulation of progesterone receptors in human cervical stromal fibroblasts. Reprod Sci. 2016;23(1):112–123.
19.
AminiPMichniukDKuoK. Human parturition involves progesterone receptor-A phosphorylation at serine-345 in myometrial cells. Endocrinology. 2016;157(11):4434–4445.
20.
MesianoSChanECFitterJTKwekKYeoGSmithR. 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.
21.
LopezVWagnerCK. Progestin receptor is transiently expressed perinatally in neurons of the rat isocortex. J Comp Neurol. 2009;512(1):124–139.
22.
YellonSMHeuermanACKirbyMA. Utility of optical density of picrosirius red birefringence for analysis of collagen. Integr Gynecol Obstet J. 2018;1(2):1–5.
23.
YellonSMOshiroBTChhayaTY. Remodeling of the cervix and parturition in mice lacking the progesterone receptor B isoform. Biol Reprod. 2011;85(3):498–502.
MillerLHuntJS. Sex steroid hormones and macrophage function. Life Sci. 1996;59(1):1–14.
26.
YoshidaMSagawaNItohH. 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.
27.
KeelanJA. Intrauterine inflammatory activation, functional progesterone withdrawal, and the timing of term and preterm birth. J Reprod Immunol. 2018;125:89–99.
28.
MillerLHuntJS. Regulation of TNF-alpha production in activated mouse macrophages by progesterone. J Immunol. 1998;160(10):5098–5104.
29.
CollinsJJUsipSMcCarsonKEPapkaRE. Sensory nerves and neuropeptides in uterine cervical ripening. Peptides. 2002;23(1):167–183.
30.
LongoLDYellonS. Biological timekeeping during pregnancy and the role of circadian rhythms in parturition. In: KunzelWJensenA, eds. The Endocrine Control of the Fetus. Berlin, Germany: Springer-Verlag; 1988:173–191.
31.
ChaiSYSmithRFitterJT. 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.
32.
PatelBElgueroSThakoreSDahoudWBedaiwyMMesianoS. Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum Reprod Update. 2015;21(2):155–173.
33.
MahendrooMSCalaKMRussellDW. 5 alpha-reduced androgens play a key role in murine parturition. Mol Endocrinol. 1996;10(4):380–392.
34.
MahendrooMSPorterARussellDWWordRA. The parturition defect in steroid 5alpha-reductase type 1 knockout mice is due to impaired cervical ripening. Mol Endocrinol. 1999;13(6):981–992.
35.
LeiKChenLGeorgiouEX. 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.
