The cervix is composed of epithelial and stromal tissues, and progesterone (P4) receptors are expressed in epithelial cells, fibroblasts, and smooth muscle cells. Through the regulation of cellular functions primarily centered around the action of P4, the softening of cervical tissues progresses from early pregnancy. In the late stages of pregnancy, changes in the expression of P4 receptor isoforms and local P4 metabolism lead to a functional decline in P4 action, transitioning into the ripening phase. Characteristics of cervical ripening include the breakdown of collagen fibers due to proteases and inflammatory cytokines, although the role of inflammatory immune cells remains unclear.

The shortening of cervical length detected through transvaginal ultrasound, which is used as a risk indicator for preterm birth, reflects the premature advancement of softening. Vaginal progesterone supplementation in asymptomatic pregnant women with shortened cervical length has been shown to reduce the risk of preterm birth, as indicated by a meta-analysis of highly reliable randomized controlled trials. Vaginally administered P4 may distribute within tissues at non-physiological concentrations due to the first uterine pass effect, potentially delaying the progression of softening. Studies using human uterine cervical fibroblast cultures (UCFs) suggest that administration of P4 before ascending infections occur is crucial for P4 to exhibit its anti-inflammatory effects. Additionally, UCFs derived from patients with refractant intrinsic cervical insufficiency show impaired P4 responsiveness due to the downregulation of P4 receptors, suggesting the existence of subtypes where P4 supplementation for preterm birth prevention may not be effective.

Although many studies have been conducted, there are still many questions regarding the paradigm for ripening and the decline in P4 action, and further elucidation through novel research approaches is eagerly awaited.

In land vertebrates, spermatozoa are produced in the testis, then they become functionally mature in the epididymis for their full competence. The entities and the detailed mechanisms of sperm maturation in the epididymis had left to be clarified compared with spermatogenesis in the testis, but the development of genome editing technology strongly promoted to investigate the mechanism of epididymal sperm maturation at the molecular level. A recently unveiled regulatory system for sperm maturation with gene-modified animals is lumicrine, a secreted signalling system. In lumicrine signalling, secreted proteins produced in the seminiferous tubule of the testis go through the male reproductive tract to the epididymis and act on the epididymal luminal epithelium to promote its differentiation. The differentiated epididymal luminal epithelium expresses various genes to make immature spermatozoa mature in the lumen. The molecular entities of testis-derived lumicrine factors are secreted proteins NELL2 and NELL2-interacting cofactor for lumicrine signalling (NICOL). Mice lacking Nell2 or Nicol possess deficient epididymal differentiation caused by impaired testis-epididymis lumicrine signalling. These mutant animals are male infertile because their spermatozoa ejaculated into the female reproductive tract are unable to ascend into the oviduct. These findings demonstrate how lumicrine regulates epididymal function for successful sperm maturation and male fertility.