Promegestone Prevents Lipopolysaccharide-Induced Cervical Remodeling in Pregnant Mice

In most mammals, a withdrawal of the pro-gestational hormone progesterone (P4) is necessary for labor onset. In murine cervix, P4 withdrawal is mediated by enzymes steroid 5-alpha-reductase type 1 (SRD5A1) and 20-alpha-hydroxysteroid-dehydrogenase (20α-HSD). Previously, we have shown that inflammatory stimuli induce 20α-HSD levels in uterine muscle (myometrium). Here, we hypothesized that (1) infectious inflammation alters the levels of both P4-metabolizing enzymes in mouse cervix, which consequently ceases P4-mediated inhibition of cervical remodeling, thereby inducing preterm labor (PTL); (2) a progestin, selective progesterone receptor modulator promegestone (aka R5020), non-metabolizable by 20α-HSD, can block lipopolysaccharide (LPS)-induced PTL in mice by maintaining P4 signaling and preventing cervical remodeling. Using RT-PCR and IHC/IF methods, we evaluated the effect of inflammation on the expression of both enzymes in mouse cervix and determined if R5020 can prevent cervical remodeling and PTL in mice. We found significant induction of SRD5A1 and 20α-HSD proteins (p < 0.01), as well as transcript levels of pro-inflammatory cytokines Il1b, Il6, chemokines Cxcl1, Ccl2, cervical ripening enzyme Has2, hyaluronic acid binding protein/HABP (p < 0.05), and a simultaneous decrease in major extracellular fibrillar proteins, collagen type 1 and type 3 (col1a1, col3a1), in mouse cervix during PTL. The prophylactic administration of R5020 in pregnant mice significantly inhibited cervical remodeling and prevented PTL irrespective of the route of LPS-induction, systemic or local. We concluded that R5020 is a promising novel drug application for preterm birth prevention.