Progesterone Receptor-Mediated Actions Regulate Remodeling of the Cervix in Preparation for Preterm Parturition.

This study determined whether a progesterone (P) receptor (PR)-mediated mechanism regulates morphological characteristics associated with prepartum cervix remodeling at term and with preterm birth. With focus on the transition from a soft to ripe cervix, the cervix stroma of untreated controls had reduced cell nuclei density/area and less organized extracellular collagen, while the density of macrophages/area, but not neutrophils, increased just 2 days before birth (day 17 vs day 15 or 16.5 postbreeding). Preterm birth was induced within 24 hours of treatment on day 16 postbreeding with PR antagonist or ovariectomy (Ovx). Pure or mixed PR antagonists increased the density of macrophages in the cervix within 8 hours (day 16.5 postbreeding), in advance of preterm birth. However, neither PR antagonists nor P withdrawal after Ovx affected the densities of cell nuclei and neutrophils or extracellular collagen compared to the same day controls-an indication that the cervix was sufficiently remodeled for birth to occur. To block the effect of systemic P withdrawal, Ovx pregnant mice were given a PR agonist, either pure or mixed. These treatments forestalled preterm birth and prevented further morphological remodeling of the cervix. The resulting increase in macrophage density in cervix stroma following Ovx was only blocked by a pure PR agonist. These findings support the hypothesis that inflammatory processes in the prepartum cervix that include residency of macrophages, cellular hypertrophy, and extracellular collagen structure are regulated by genomic actions of PR in a final common mechanism both at term and with induced preterm birth.

Macrophage gene expression associated with remodeling of the prepartum rat cervix: microarray and pathway analyses.

As the critical gatekeeper for birth, prepartum remodeling of the cervix is associated with increased resident macrophages (Mφ), proinflammatory processes, and extracellular matrix degradation. This study tested the hypothesis that expression of genes unique to Mφs characterizes the prepartum from unremodeled nonpregnant cervix. Perfused cervix from prepartum day 21 postbreeding (D21) or nonpregnant (NP) rats, with or without Mφs, had RNA extracted and whole genome microarray analysis performed. By subtractive analyses, expression of 194 and 120 genes related to Mφs in the cervix from D21 rats were increased and decreased, respectively. In both D21 and NP groups, 158 and 57 Mφ genes were also more or less up- or down-regulated, respectively. Mφ gene expression patterns were most strongly correlated within groups and in 5 major clustering patterns. In the cervix from D21 rats, functional categories and canonical pathways of increased expression by Mφ gene related to extracellular matrix, cell proliferation, differentiation, as well as cell signaling. Pathways were characteristic of inflammation and wound healing, e.g., CD163, CD206, and CCR2. Signatures of only inflammation pathways, e.g., CSF1R, EMR1, and MMP12 were common to both D21 and NP groups. Thus, a novel and complex balance of Mφ genes and clusters differentiated the degraded extracellular matrix and cellular genomic activities in the cervix before birth from the unremodeled state. Predicted Mφ activities, pathways, and networks raise the possibility that expression patterns of specific genes characterize and promote prepartum remodeling of the cervix for parturition at term and with preterm labor.

Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth.

A decline in serum progesterone or antagonism of progesterone receptor function results in preterm labor and birth. Whether characteristics of premature remodeling of the cervix after antiprogestins or ovariectomy are similar to that at term was the focus of the present study. Groups of pregnant rats were treated with vehicle, a progesterone receptor antagonist (onapristone or mifepristone), or ovariectomized on day 17 postbreeding. As expected, controls given vehicle delivered at term while rats delivered preterm after progesterone receptor antagonist treatment or ovariectomy. Similar to the cervix before term, the preterm cervix of progesterone receptor antagonist-treated rats was characterized by reduced cell nuclei density, decreased collagen content and structure, as well as a greater presence of macrophages per unit area. Thus, loss of nuclear progesterone receptor-mediated actions promoted structural remodeling of the cervix, increased census of resident macrophages, and preterm birth much like that found in the cervix at term. In contrast to the progesterone receptor antagonist-induced advance in characteristics associated with remodeling, ovariectomy-induced loss of systemic progesterone did not affect hypertrophy, extracellular collagen, or macrophage numbers in the cervix. Thus, the structure and macrophage census in the cervix appear sufficient for premature ripening and birth to occur well before term. With progesterone receptors predominantly localized on cells other than macrophages, the findings suggest that interactions between cells may facilitate the loss of progesterone receptor-mediated actions as part of a final common mechanism that remodels the cervix in certain etiologies of preterm and with parturition at term.