STRUCTURE, SYNTESIS AND DEGRADATION
PGE2 can be produced by all cell types of the body, with epithelia, fibroblasts, and infiltrating inflammatory cells representing the major sources of PGE2 in the course of an immune response. The process of PGE2 synthesis involves phospholipase A2 (PLA2) family members, that mobilize arachidonic acid from cellular membranes, cyclooxygenases (constitutively-active COX1 and inducible COX2) that convert arachidonic acid into prostaglandin H2 (PGH2), and prostaglandin E synthase (PGES), needed for the final formulation of PGE2. While the rate of PGE2 synthesis and the resulting inflammatory process can be affected by additional factors, such as local availability of AA, in most physiologic conditions, the rate of PGE2 synthesis is controlled by local expression and activity of COX2.The rate of PGE2 degradation in vivo in individual tissues is controlled by 15-hydroxyprostaglandin dehydrogenase (15-PGDH).(Regulation of Immune Responses by Prostaglandin E2 2012)
PGE2 RECEPTORS AND SIGNALING PATHWAYS
There are four different PGE2 receptors encoded by separate genes, designated EP1, EP2, EP3 and EP4, with an additional level of functional diversity resulting from multiple splice variants of EP3 that exists in at least 8 forms in humans. EP3 and EP4 represent high affinity receptors, while EP1 and EP2 require significantly higher concentrations of PGE2 for effective signaling. The signaling through the two Gs-coupled receptors, EP2 and EP4, is mediated by the adenylate cyclase-triggered cAMP/PKA/CREB pathway, mediating the dominant aspects of the anti-inflammatory and suppressive activity of PGE2. Despite their similar nominal functions, the signaling by EP2 and EP4 is triggered by different concentrations of PGE2 and differs in duration. EP4 signaling is rapidly desensitized following its PGE2 interaction, while EP2 is resistant to ligand-induced desensitization, implicating its ability to mediate PGE2 functions over prolonged periods of time, and at later time-points of inflammation. While EP2 is believed to signal in a largely cAMP-dependent fashion, EP4 also activates the PI3K-dependent ERK1/2 pathway. However, both EP2 and EP4 have been shown to activate the GSK3/β-catenin pathway. In contrast to EP2 and EP4, low affinity EP1 and high affinity EP3 are not coupled to Gs and lack cAMP-activating functions. Most of the splice variants of EP3 represent Gi-coupled PGE2 receptors inhibit adenylate cyclase, although at least some are Gs-coupled, and show different sensitivity to ligand-induced desensitization. Signaling via EP1 involves calcium release.(Regulation of Immune Responses by Prostaglandin E2 2012)
PGE2 EFFECTS IN UTERUS
During pregnancy and labour the uterus undergoes profound physiological and biochemical changes, which require functional differentiation of the different regions of the pregnant uterus. The upper segment (US) region of the uterus must expand to accommodate the growing fetus and then at labour contract to cause expulsion of the fetus, while the lower segment (LS) must relax to allow passage of the fetus.
The prostaglandins are one of the key factors that have long been implicated in the parturition process. Inhibitors of prostaglandin synthesis have been utilized to lengthen gestation and delay human labour onset. The onset of labour is associated with increased prostaglandin synthesis within the uterus. Prostaglandin E2 (PGE2), produced in large quantities by the fetal membranes and decidua, is believed to play a key role in the onset and maintenance of labour in humans, mediating cervical ripening and myometrial contractions. Clinically, a PGE2 analogue is widely used for the induction of labour although the individual response is variable. This may be due to the diversity in PGE2 receptor signalling pathways. By signalling through different intracellular pathways the EP receptors may inhibit or promote smooth muscle contractility. As we have already said EP1 and EP3 are coupled to calcium influx and inhibition of adenylate cyclase, whereas, EP2 and EP4 both stimulate adenylate cyclase. Consequently in the uterus, activation of EP1 and EP3 are reported to cause smooth muscle contraction, while stimulation of EP2 and EP4 are more likely to lead to relaxation. EP1 was significantly increased in the LS myometrium with term labour. EP3 (and EP3 splice variants EP3I, EP3II, EP3III and EP3IV) was down-regulated in pregnancy with a further decrease at term labour in the LS. Overall, expression of EP2 was significantly higher in the LS while EP3 was significantly higher in the US. No significant EP4 changes were observed. The differential regulation of EP receptors within the myometrium indicates that they may play a role in controlling the onset and maintenance of human labour.
(Regulation of Immune Responses by Prostaglandin E2 2012)
Localization of EP1 showed that the receptor was highly expressed in myometrial smooth muscle cells of both US and LS samples and abundant in the vascular endothelial cells, vascular smooth muscle and glandular epithelial cells. EP2 and EP4 receptor protein expression was present in myometrial smooth muscle and glandular cells, with less intense staining being observed in vascular smooth muscle and endothelial cells. Localization of EP3 receptor protein was most abundant within vascular smooth muscle and endothelial cells, with little expression observed in myometrial smooth muscle cells. In addition to the distinct pattern of EP receptor localization within the myometrium, it was also observed that EP1, EP2, EP3 and EP4 were abundantly expressed within the decidual component.
In conclusion we can say that EP2 may play a role in relaxation of the lower uterine segment necessary to allow delivery of the fetus. EP2 perhaps plays a role in controlling the timing of labour-onset possibly by maintaining quiescence until the excitatory influences become more dominant allowing a shift to a contractile phenotype. This hypothesis is supported by the observation that EP2 was significantly reduced in preterm labour in the US as this may favour premature contractility. EP1 may play a functional role in the labour process at term. It is difficult to reconcile why expression of a contractile receptor would increase in the LS during term labour, but maybe expression of this receptor plays a role in post-partum contraction.The expression of EP3 (generic) was generally higher in the US during pregnancy and may contribute to the contractile phenotype of the US. Within both the US and LS, EP3 was down-regulated in pregnancy with a further significant decrease in LS labour samples collected at term. Staining for EP1 receptor protein was consistently strong in myometrial smooth muscle cells and in numerous other cell types found to be present in the upper and lower uterine samples. Conversely, whereas EP3 showed positive staining in vessels, decidua and glandular epithelial cells, staining was generally weak and diffused in the pregnant myometrial smooth muscle cells.However, the presence of EP3 in the decidua may suggest a paracrine role for the receptor in these tissues. (Identification and localization of prostaglandin E2 receptors in upper and lower segment human myometrium during pregnancy 2005)
INDUCTION OF LABOUR
The naturally occurring prostaglandin E2 (PGE2) is known in medicine as dinoprostone. It is sold under the trade name of Cervidil (by Forest Laboratories, Inc.), Prostin E2 (by Pfizer Inc.), Propess (by Ferring Pharmaceuticals) and Glandin (by Nabiqasim Pharmaceuticals Pakistan) as a vaginal suppository, to prepare the cervix for labour; it is used to induce labour.(Prostaglandin E2)
Induction of labor is an increasingly common practice in the United States, and accounts for at least 20% of all births. Providers generally resort to induction of labor when the risks to the mother and/or the fetus with pregnancy continuation outweigh the risks involved with the intervention. While oxytocin is an effective drug in patients with favorable Bishop scores, other pharmacological or mechanical agents are frequently utilized in the event of an unripe cervix. Local administration of prostaglandin E1 (misoprotol, PGE1) or E2 (dinoprostone, PGE2) has been used for decades to achieve cervical ripening and labor induction. A recent meta-analysis showed that women receiving PGE1 are more likely to deliver vaginally, and require less oxytocin for labor augmentation when compared to those receiving PGE2 (Labor induction with intravaginal misoprostol compared with the dinoprostone vaginal insert: a systematic review and metaanalysis 2010). Rare but catastrophic complication has been observed more frequently with the administration of misoprostol, which is also responsible for increased frequency of uterine tachysystole and meconium stained amniotic fluid (Foley catheter balloon vs locally applied prostaglandins for cervical ripening and labor induction: a systematic review and metaanalysis 2010). Cervical ripening induced by PGE1 and PGE2 is associated with an increase in inflammatory mediators in the cervix, and remodeling of the cervical extracellular matrix through a decrease in collagen cross links and cervical glycosaminoglycans.(The effects of PGE1 and PGE2 on in vitro myometrial contractility and uterine structure 2012)
Clinical trials have demonstrated that when compared to oxytocin infusion, PGs improve the chance of vaginal delivery within 24 hours and reduce cesarean section rates.
RISK FACTORS FOR WOMEN WHO HAD A PRIOR CESAREAN DELIVERY
Although some of the complications associated with the use of prostaglandins (PGs) are reversible if rapidly addressed (tachysystole), their use for labor induction in women with prior cesarean delivery (CD) has been associated with uterine rupture. In women with previous CD, myometrial contractions are associated with a decrease in total myometrial collagen and possibly connective tissue content, and that incubation with misoprostol accentuates such effect, while exposure to dinoprostone does not. The more pronounced contractile response and decrease in collagen content observed with misoprostol may explain the higher incidence of uterine rupture observed with its use in women with previous CD, who usually experience uterine rupture at the site of their old scar when treated with PGs for cervical ripening as compared to other agents (Rupture of the uterine scar during term labour: contractility or biochemistry? 2005). Similarly, the milder effects of dinoprostone on collagen content seem to suggest that it may represent a safer choice for labor induction in the setting of a previous CD. (The effects of PGE1 and PGE2 on in vitro myometrial contractility and uterine structure 2012)