Molecular Regulation of Parturition: A Myometrial Perspective

Abstract

The molecular mechanisms that maintain quiescence of the myometrium throughout most of pregnancy and promote its transformation to a highly coordinated contractile unit culminating in labor are complex and intertwined. During pregnancy, progesterone (P 4 ) produced by the placenta and/or ovary serves a dominant role in maintaining myometrial quiescence by blocking proinflammatory response pathways and expression of so-called "contractile" genes. In the majority of placental mammals, increased uterine contractility near term is heralded by an increase in circulating estradiol-17b (E 2 ) and/or increased estrogen receptor a (ERa) activity and a sharp decline in circulating P 4 levels. However, in women, circulating levels of P 4 and progesterone receptors (PR) in myometrium remain elevated throughout pregnancy and into labor. This has led to the concept that increased uterine contractility leading to term and preterm labor is mediated, in part, by a decline in PR function. The biochemical mechanisms for this decrease in PR function are also multifaceted and interwoven. In this paper, we focus on the molecular mechanisms that mediate myometrial quiescence and contractility and their regulation by the two central hormones of pregnancy, P 4 and estradiol-17b. The integrative roles of microRNAs also are considered.

Progestin withdrawal at parturition in the mare

“…Mammalian pregnancy is maintained by the physiological effects of progestins (Conley & Reynolds 2014) and parturition is believed to occur principally, or in large part, as a result of withdrawal of that support (Thorburn & Challis 1979, Smith 2007, Zakar & Hertelendy 2007, Renthal et al 2015. In many species, the physiological withdrawal before parturition is due to a decline in available progesterone (Nathanielsz 1998, Norwitz 1999, Jenkin & Young 2004, Mitchell & Taggart 2009, the pregnane that is generally considered the most potent endogenous progestin and that decrease is apparent in systemic blood.…”

Seipin deficiency leads to defective parturition in mice†

“…One deficiency of this study was the lack of measurement of myometrial contractility, which can be achieved using an organ bath system, in the Bscl2 Uterine myometrium has to be maintained in a quiescent state during pregnancy and transformed into a highly coordinated contractile state for parturition. P4 and E2 both play important roles in regulating these myometrium activates [1]. Since serum P4 and E2 levels were not altered in the near-term D18.5 Bscl2 −/− females, it indicated functional ovary and placenta in the Bscl2 −/− females and P4 and E2 unlikely contributed to the parturition problems in the Bscl2 −/− females.…”

“…Research from past decades has provided critical insights into parturition, but the molecular mechanisms involved in the initiation of parturition remain largely unknown. It is known that the myometrium plays an essential role in regulating uterine quiescence and contraction, and progesterone and estrogen play important roles in regulating myometrium activities [1]. Similar as other muscle cell contractions, myometrial contractions are also mediated by elevated intracellular calcium concentration ([Ca 2+ ] i ), which is regulated by both Ca 2+ release from intracellular stores in the sarcoplasmic reticulum (SR) and Ca 2+ entry from the extracellular space [2][3][4].…”

“…The timing of parturition is critical for the health of the mother and the newborn. Preterm births count for ∼11.5% of all live births in US and are the main cause of perinatal mortality and morbidity worldwide [1]. Based on a WHO 2011 report (WHO recommendations for induction of labor), up to 25% of all deliveries at term in developed countries involve induction of labor, although it is unclear about the incidence of induced labor due to difficulties in parturition.…”

Progesterone Receptor Signaling in Uterine Myometrial Physiology and Preterm Birth

“…At term, in a species dependent manner, either withdrawal of P4 by a decrease in hormone levels or alteration of PGR signaling relieves the suppression on inflammation and contraction, which allows the myometrium to adopt a contractile phenotype for laboring. Multiple mechanisms, including P4 metabolism, regulation of PGR gene expression, PGR post-translation modifications and PGR coregulators, that mediate or regulate uterine P4/PGR signaling have been identified and reviewed extensively (Bhurke et al, 2016; Grimm et al, 2016; Patel et al, 2015; Renthal et al, 2015; Rubel et al, 2016; Szwarc et al, 2014). Here we focus on discussing uterine P4/PGR signaling modifiers and effectors in myometrial physiology and diseases.…”