Multifactorial Regulation of Myometrial Contractility During Pregnancy and Parturition

The steroid hormones progesterone (P(4)) and estradiol-17β (E(2)), produced by the placenta in humans and the ovaries in rodents, serve crucial roles in the maintenance of pregnancy, and the initiation of parturition. Because of their critical importance for species survival, the mechanisms whereby P(4) and its nuclear receptor (PR) maintain myometrial quiescence during pregnancy, and for the decline in P(4)/PR and increase in E(2)/estrogen receptor (ER) function leading to parturition, are multifaceted, cooperative, and redundant. These actions of P(4)/PR include: (1) PR interaction with proinflammatory transcription factors, nuclear factor κB (NF-κB), and activating protein 1 (AP-1) bound to promoters of proinflammatory and contractile/contraction-associated protein (CAP) genes and recruitment of corepressors to inhibit NF-κB and AP-1 activation of gene expression; (2) upregulation of inhibitors of proinflammatory transcription factor activation (IκBα, MKP-1); (3) induction of transcriptional repressors of CAP genes (e.g., ZEB1). In rodents and most other mammals, circulating maternal P(4) levels remain elevated throughout most of pregnancy and decline precipitously near term. By contrast, in humans, circulating P(4) levels and myometrial PR levels remain elevated throughout pregnancy and into labor. However, even in rodents, wherein P(4) levels decline near term, P(4) levels remain higher than the K(d) for PR binding. Thus, parturition is initiated in all species by a series of molecular events that antagonize the P(4)/PR maintenance of uterine quiescence. These events include: direct interaction of inflammatory transcription factors (e.g., NF-κB, AP-1) with PR; increased expression of P(4) metabolizing enzymes; increased expression of truncated/inhibitory PR isoforms; altered expression of PR coactivators and corepressors. This article will review various mechanisms whereby P(4) acting through PR isoforms maintains myometrial quiescence during pregnancy as well as those that underlie the decline in PR function leading to labor. The roles of P(4)- and E(2)-regulated miRNAs in the regulation and integration of these mechanisms will also be considered.