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

Abstract

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.

Immunobiology of Cervix Ripening

“…This conclusion was also supported by electron microscopic analyses of collagen fibril diameter and length in rodents (30,56,57). In a survey of picrosirius-stained sections that focused on the stroma from ectocervix through endocervix in mice (39), findings provided the first indication that degradation of cross-linked collagen occurred much earlier than previously thought, more than 3 days before birth (Figure 2, top panel). This approach was also used to study degradation of collagen in HSV2 infectioninduced cervix ripening and preterm birth (58).…”

“…These findings suggest that sex steroids may regulate morphological characteristics of the cervix for softening and the increased presence of immune cells associated with ripening. This contention is further supported in subsequent studies of progesterone receptor (PR) antagonistinduced advance in preterm cervix remodeling, as well as in PR agonist forestalled preterm parturition (39).…”

“…In circulation at term, increased proinflammatory myeloid and lymphoid phenotypes, related cytokines, regulators of chemotaxis, and the capability to induce oxidative stressors may be key components of the parturition process at term and, if inappropriately advanced, may contribute to processes that lead to preterm birth (78)(79)(80). As apparent in mice (Figure 1 insets and 2), changes in characteristics of ripening in mice occurs 2-4 days before birth (days 15-17 postbreeding) when progesterone is near or at peak concentrations in circulation (39,47). These findings in 2 rodent species and a variety of strains, as well as in women (15), indicate that structural changes in the stroma, i.e., reduced cell nuclei density and degradation of cross-linked collagen while progesterone in circulation is elevated, occur well before the uterus develops contractile capabilities for labor at term (62).…”

“…Other sentinels that reflect the transformation in cervix morphology characterize the process of inflammation, generally defined by swelling, increased presence of immune cells, and loss of function (4). Specifically as shown in Figure 2 middle and lower panels, reduced cell nuclei density attests to fewer or larger cells/area, possibly an expansion of extracellular space or cell growth (39). In addition, increased census of macrophages/area of cervix before term reflects a local source for collagenases, metalloproteinases (MMPs), proinflammatory cytokines, nitric oxide, and prostaglandins that regulate extracellular matrix structure (59).…”

Cervical Gene Delivery of the Antimicrobial Peptide, Human β-Defensin (HBD)-3, in a Mouse Model of Ascending Infection-Related Preterm Birth

“…In particular, HBD3 is shown to promote skin re-epithelialization, granulation tissue formation and collagen I deposition. In preterm birth, premature remodeling, and shortening of the cervix involves degradation of cervical stromal collagen, particularly collagen I and III, by matrix metalloproteinases (68)(69)(70). Therefore, HBD3 gene therapy could help to inhibit this process by encouraging collagen I deposition.…”