Role of the prostaglandins in labour and prostaglandin receptor inhibitors in the prevention of preterm labour

Perinatal Research Centre, Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada.
Frontiers in Bioscience (Impact Factor: 3.52). 02/2007; 12(4):1329-43. DOI: 10.2741/2151
Source: PubMed


Parturition is composed of five separate but integrated physiological events: fetal membrane rupture, cervical dilatation, myometrial contractility, placental separation, and uterine involution. Prostaglandins (PGs) have central roles in each of these events, but the most studied is myometrial contraction. Elevated uterine PGs or the enhanced sensitivity of the myometrium to PGs leads to contractions and labour. The primary regulator of PG synthesis is the mRNA expression of PG H Synthase (PGHS-2 or COX-2). Given the central role of PGs in labour, this enzyme becomes an obvious therapeutic target for the prevention of preterm labour, the major cause of perinatal mortality and morbidity. Unfortunately, even though the non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit PGHS, are usually successful in suppressing preterm labour or prolonging pregnancy in animal and human studies, the NSAIDS have had adverse effects on fetal physiology and development. Therefore, other means to suppress PG synthesis or action to arrest preterm labour need to be investigated. The PGF2alpha receptor, FP, may prove to be a reasonable target for tocolysis. FP mRNA increases in the mouse uterus at preterm birth, whereas PGF2alpha concentrations do not increase, suggesting elevated uterine sensitivity to contractile agonists is one mechanism for preterm labour initiation. New data shows that administration of a specific FP antagonist, Theratechnologies (THG) 113.31, delays preterm birth in mice and sheep with no observable maternal or fetal side effects. Hence antagonizing PG action offers new hope for delaying preterm birth.

Download full-text


Available from: David M Olson, Sep 22, 2015
  • Source
    • "There is strong evidence that PGs play a central role in initiation and progression of human labor. Generally it is believed that the main sources for PGs found in the amniotic fluid are the fetal membranes and decidua (Gibb, 1998; Olson and Ammann, 2007). The maternal plasma level of PGF metabolites increases with the onset of labor at term as well as preterm (Sellers et al., 1981). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Human labor is a complex series of cellular and molecular events that occur at the materno-fetal and uterine levels. Many hypotheses have been proposed for the initiation of human labor, one hypothesis suggests that maturation of the fetus releases a signal in the amniotic fluid that will be transmitted to myometrium via the fetal membranes and initiate uterine contractions. There is strong evidence that prostaglandins (PGs) play a central role in initiation and progression of human labor. Objectives: In this study we intended to investigate the expression of prostaglandin F synthase and the prostaglandin transporter in the human fetal membranes and to explore the relationship between cytokines and PGs in the mechanism of human labor. Methods: We used fetal membranes obtained before labor at term and after spontaneous labor at term or preterm to identify the changes in prostaglandin F synthase (AKR1B1) and human prostaglandin transporter (SLCO2A1) proteins in relation to parturition. Using fetal membranes explants we tested the effect of cytokines (interleukin-1 and tumor necrosis factor alpha) on PG production and the concomitant changes in cyclooxygenase-2 (PTGS2), AKR1B1 and SLCO2A1 expression. Results: Expression of PTGS2 and AKR1B1 was upregulated in the fetal membranes in association with term labor while SLCO2A1 was downregulated with advancing gestation and during term labor. Before labor, IL-1 increased the expression of PTGS2, however during labor TNF upregulated PTGS2 and AKR1B1 proteins. Conclusions: The prostaglandin F synthase AKR1B1 is upregulated while prostaglandin transporter is downregulated during term labor. The amnion is more responsive than choriodecidua to stimulation with pro-inflammatory cytokines. The mechanisms of term and preterm labor are different.
    Frontiers in Physiology 07/2014; 5:272. DOI:10.3389/fphys.2014.00272 · 3.53 Impact Factor
  • Source
    • "During pregnancy, PG synthesis is negatively regulated by the presence of prostaglandin dehydrogenase. 15-Hydroxy- prostaglandin dehydrogenase is the primary enzyme metabolising PGs, and during pregnancy it is found at high levels in the chorion, decidua, placenta, myometrium and cervix (Sangha et al. 1994, Ramirez et al. 1995, Giannoulias et al. 2002), with levels decreasing with the onset of term and preterm labour (Olson & Ammann 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Preterm birth occurs in 10-12% of pregnancies and is the primary cause of neonatal mortality and morbidity. Tocolytic therapies have long been the focus for the prevention of preterm labour yet they do not significantly improve neonatal outcome. A direct causal link exists between infection-induced inflammation and preterm labour. Tocolytics may therefore cause more harm by keeping the fetus in a hostile environment. Since inflammation and infection are independent risk factors for poor neonatal outcome, recent research focus has shifted towards exploring the potential for anti-inflammatory strategies. NF-κB is a transcription factor that controls the expression of many labour associated genes including COX-2, prostaglandins and the oxytocin receptor as well as key inflammatory genes. Targeting the inhibition of NF-κB is therefore an attractive therapeutic approach for both the prevention of preterm labour and for reducing neonatal exposure to inflammation. Whilst prostaglandins are considered to be pro-labour and pro-inflammatory, the cyclopentenone prostaglandin 15-deoxy-Δ12,14PGJ2 (15dPGJ2) exhibits anti-inflammatory properties via the inhibition of NF-κB in human amniocytes, myocytes and peripheral blood mononuclear cells in vitro. 15dPGJ2 also delays inflammation induced preterm labour in the mouse and significantly increases pup survival. This review examines the current understanding of inflammation in the context of labour and discusses how anti-inflammatory prostaglandins may hold promise for the prevention of preterm labour and improved neonatal outcome.
    Reproduction (Cambridge, England) 06/2014; 148(2). DOI:10.1530/REP-13-0587 · 3.17 Impact Factor
  • Source
    • "Because of the putative role of CCR5 in alloreactivity, Maraviroc is also in phase II clinical trial for acute graft-versus-host disease (GVHD). Moreover, the ECL2 mimic of the FP receptor, PDC31 (derived from the THG113 peptide), which was shown to inhibit preterm labor in different animal models, is now being evaluated in a clinical phase II trial for primary dysmenorrhea (37, 62). Other examples of allosteric and biased drugs are currently under pre-clinical investigation or in clinical trials (Table 2). "
    [Show abstract] [Hide abstract]
    ABSTRACT: G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that participate in many aspects of the endocrine function and are important targets for drug development. They transduce signals mainly, but not exclusively, via hetero-trimeric G proteins, leading to a diversity of intracellular signaling cascades. Ligands binding at the hormone orthosteric sites of receptors have been classified as agonists, antagonists, and/or inverse agonists based on their ability to mainly modulate G protein signaling. Accumulating evidence also indicates that such ligands, alone or in combination with other ones such as those acting outside the orthosteric hormone binding sites (e.g., allosteric modulators), have the ability to selectively engage subsets of signaling responses as compared to the natural endogenous ligands. Such modes of functioning have been variously referred to as "functional selectivity" or "ligand-biased signaling." In this review, we provide an overview of the current knowledge regarding GPCR-biased signaling and their functional regulation with a focus on the evolving concept that receptor domains can also be targeted to allosterically bias signaling, and discuss the usefulness of such modes of regulation for the design of more efficient therapeutics.
    Frontiers in Endocrinology 05/2014; 5:68. DOI:10.3389/fendo.2014.00068
Show more