Minireview: fetal-maternal hormonal signaling in pregnancy and labor

Abstract

Mechanisms underlying the initiation of parturition remain unclear. Throughout most of pregnancy, uterine quiescence is maintained by elevated progesterone acting through progesterone receptor (PR). Although in most mammals, parturition is associated with a marked decline in maternal progesterone, in humans, circulating progesterone and uterine PR remain elevated throughout pregnancy, suggesting a critical role for functional PR inactivation in the initiation of labor. Both term and preterm labor in humans and rodents are associated with an inflammatory response. In preterm labor, intraamniotic infection likely provides the stimulus for increased amniotic fluid interleukins and migration of inflammatory cells into the uterus and cervix. However, at term, the stimulus for this inflammatory response is unknown. Increasing evidence suggests that the developing fetus may produce physical and hormonal signals that stimulate macrophage migration to the uterus, with release of cytokines and activation of inflammatory transcription factors, such as nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1), which also is activated by myometrial stretch. We postulate that the increased inflammatory response and NF-kappaB activation promote uterine contractility via 1) direct activation of contractile genes (e.g. COX-2, oxytocin receptor, and connexin 43) and 2) impairment of the capacity of PR to mediate uterine quiescence. PR function near term may be compromised by direct interaction with NF-kappaB, altered expression of PR coregulators, increased metabolism of progesterone within the cervix and myometrium, and increased expression of inhibitory PR isoforms. Alternatively, we propose that uterine quiescence during pregnancy is regulated, in part, by PR antagonism of the inflammatory response.

Figure 1

Mechanisms for progesterone/PR regulation of uterine quiescence during pregnancy and induction of uterine contractility in preterm and term labor. During most of pregnancy, the uterus is maintained in a quiescent state by the PR, which acts in a ligand-dependent and -independent manner to block activation of the inflammatory transcription factors (e.g. NF-κB). PR acts in a ligand-dependent manner to up-regulate expression of the NF-κB inhibitor IκBα in myometrial cells. Alternatively, PR acts in a dominant ligand-independent manner (likely via direct protein-protein interaction) to block NF-κB activation, DNA binding, and transactivation of contractile genes within the uterus. Labor can be initiated preterm as a result of bacterial infection, resulting in enhanced migration of macrophages to the maternal uterus with release of cytokines/chemokines and activation of NF-κB. However, at term, enhanced macrophage activation and migration and increased uterine NF-κB activity are likely induced by signals produced by the maturing fetus. These include increased secretion of surfactant proteins and lipids by the fetal lung into amniotic fluid, augmented production of CRH by the placenta, and enhanced uterine stretch caused by the growing conceptus. Within the uterus, the activated NF-κB directly acts to increase expression of contractile genes and causes an impairment of PR function by effecting 1) down-regulation of PR coactivators, 2) increased expression of inhibitory PR isoforms, 3) increased metabolism of progesterone to inactive products, and possibly 4) direct inhibitory interaction with PR. These concerted events culminate in a further increase in NF-κB activation and expression of contractile genes, leading to labor.