Loss of Progesterone Receptor-Mediated Actions Induce Preterm Cellular and Structural Remodeling of the Cervix and Premature Birth

Abstract

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.

Immunobiology of Cervix Ripening

“…A comprehensive review of immune cells at the internal fetal-maternal interface in humans and rodents recognized inflammation as a central component of the mechanism of labor (42). Though less information is available for the external fetal maternal interface that involves the cervix, evidence clearly indicates increase in presence of macrophages in the cervix before the day of birth in rodents (83)(84)(85)87). However, further study in mice during the transition from a soft to ripening cervix now indicates inflammation occurs earlier, between day 15-17 of pregnancy, with respect to reduced densities of cell nuclei and cross-linked collagen and greater abundance of resident macrophages with proinflammatory phenotypes (Figure 2).…”

“…For the proposed mechanism that regulates ripening (Figure 3B), a cross talk between cells in the stroma is proposed to regulate local responsiveness to progesterone and inflammation by resident immune cells. In mice and rats, fibroblasts in the cervix stroma are the predominant cell with classic genomic PR (83,87,118). Sparse distribution of PR cells in the luminal epithelium notwithstanding, there is little evidence to suggest resident macrophages or other cells have PR.…”

Density of Stromal Cells and Macrophages Associated With Collagen Remodeling in the Human Cervix in Preterm and Term Birth

“…35 , and images were analyzed as described previously. 24 Other sections were processed by immunohistochemistry with antigen retrieval (2-minute proteinase K; Dako North America, Carpinteria, California) to visualize CD68-stained Mjs (1:50 for 90 minutes; Dako and ABC kit; Vector Lab, Burlingame, California) and counterstained with methyl green to visualize CN. Sections lacking primary antibody incubation served as the negative control for each group of tissue stained.…”

The interaction between vaginal microbiota, cervical length, and vaginal progesterone treatment for preterm birth risk

“…This ultimately reduces myometrial contractility thereby inhibiting premature onset of labor [40]. Progesterone also exerts a quiescent effect on the cervix by limiting prostaglandin-induced collagenous remodeling of the cervical fibroblast [44–46]. Progesterone supplementation is therefore prescribed primarily for its systemic anti-inflammatory actions to maintain myometrial and cervical quiescence in high-risk pregnancies.…”