Progesterone regulation of cervix ripening in preterm and term birth

Abstract

The cervix functions both as gatekeeper barrier to maintain pregnancy and virtually vanish for birth at term in mammals. The period of remodeling well-before term is characterized by an inflammatory process associated with reduced cell nuclei density and cross-linked collagen, as well as increased density of resident macrophages in cervix stroma. Contemporarily, progesterone (P4) is at or near peak concentrations in maternal circulation. The functional or actual loss of response to P4 is thought to drive the process that enhances uterine contractile activity for labor and parturition at term. The objective of the present study was to determine if actual or functional loss of P4 regulated cytomorphological characteristics associated with prepartum cervix ripening at term and with preterm birth. On day 16 of pregnancy. Ovaries were removed to eliminate the main source of P4 production and a silastic capsule implanted (with vehicle or P4, Ovx or Ovx+P4, respectively). Controls received a vehicle-filled capsule, while a P4 capsule was implanted into an addition group of Intact mice to ensure sustained concentrations throughout pregnancy (Intact+P4). Pups were born in controls at term (days 19-20 postbreeding), but deliveries were preterm in Ovx mice within 24h (day 17). In the Ovx+P4 group, births were delayed to term and post-term in most Intact+P4 mice with adverse pregnancy outcomes commonplace. Characteristics of cell nuclei and degradation of cross-linked collagen were advanced with preterm birth in Ovx mice compared to controls that gave birth by at term. Treatment of Ovx mice with P4 blocked preterm birth, but parturition was complicated by dystocia. In addition, P4 given to ovary-intact mice sustained peak pregnancy concentrations, but had minimal effects on cytoarchitecture of the prepartum cervix stroma except term birth was forestalled with dystocia and fetal morbidity. Density of resident macrophages in the cervix stroma in term Ovx+P4 mice was reduced along with area of macrophage stain versus postpartum controls. Thus, analyses of cervix cellular cytoarchitecture provided useful biomarkers of local inflammation to assessment the ripening process for preterm and term parturition. Collectively, findings suggest a functional loss of prepartum cervix responses to progesterone are part of a final common mechanism for parturition across mammals. SummaryLoss of response to progesterone withdrawal is associated with cervix ripening while some cytoarchitectural characteristics of remodeling are regulated to block preterm birth and dystocia at term