Arachidonic acid metabolites are considered important paracrine regulators in human myometrial contractions [148]. PGF2a and PGE2 are potent pharmacological stimulators of uterine contractility, causing labor at any stage of gestation. Other well-known uterotonins are oxytocin, PAF and endothelins. However, the physiological role of PGF2a and PGE2 in myometrial contractions has been questioned, since they caused much weaker contractions than oxytocin and endothelins in vitro [174,175], Other eicosanoids such as 5-HETE, 12-HETE and leukotrienes have only weak or no contractile effects on human pregnant myometrium [176,177], On the other hand, changes in prostaglandin levels in blood and urine have been observed during labor [178-181]. It can be concluded that, in human parturition, there is no vaginal delivery without endogenous prostaglandin synthesis [182], For these contradictory results, it is not yet possible to define precisely whether prostaglandins act as initiating factors of parturition in normal vaginal deliveries or whether their formation serves other purposes or is a mere consequence of the traumatic processes occuring during labor (for critical discussions of this issue, see Olson et al. [151] and Kelly [183]). For example, another potential role for PGE2 is the regulation of the utero-placental blood flow. New data suggest that PGE2 is a vasodilating agent in uterine vessels, increasing uterine blood flow to sustain the contractions. In contrast, it constricts placental vasculature, leading to the closure of placental resistance vessels at parturition. These opposite effects are probably mediated by different receptor subtypes [184],

For many years the amnion has been assumed to be the main source of prostaglandins initiating the onset of labor. However, in recent years findings have been accumulated which demonstrate that the contribution of the amnion to intrauterine prostaglandin production is low [185] and that prostaglandins from the amnion and amniotic fluid are inactivated during their passage through intact fetal membranes. In the chorion laeve, high concentrations of uterotonin-degrading enzymes, including 15-hydroxy prostaglandin dehydrogenase (PGHD), have been found [186]. In transfer experiments with intact fetal membranes, very little f-^H]-PGE2 crossed the membranes without being metabolized [187]. These results show that the chorion acts in part as a barrier preventing an overflow of prostaglandins and other uterotonic agents from the amniotic fluid to the decidua or myometrium under physiological conditions. Further, it was demonstrated that no more than 2% of the total output of PGE2 from the fetal membranes originates in the amnion [185]. However, recent findings suggest that decreased chorio-decidual PGDH expression [188] or an increase of the prostaglandin synthetic capacity of the chorion after COX-2 induction [189] may result in a substantial increase in prostaglandin levels reaching the myometrium during labor.

As a consequence of these new findings, the decidua at the feto-maternal interface and perhaps the myometrium itself are now regarded as the physiologically relevant sources of prostaglandin output during labor. Whereas decidual eicosanoid biosynthesis has been extensively investigated, the contribution of the myometrium to intrauterine eicosanoid production is relatively unknown. Flow cytometric analysis of human term decidual cell suspensions has shown that 47% of decidual cells are of bone marrow origin, including a large population of macrophages (approximately 19% of total decidual cells). The non-bone marrow-derived decidual cell fraction consists mainly of stromal cells [190]. Due to its cellular composition, its high capacity for arachidonic acid metabolism [119,185] and its proximity to the uterine vasculature and the myometrium, the well-vascularized decidua is likely to represent a physiologically relevant source of eicosanoids.

The production of PGF2a, PGE2, TXA2, HETEs and EETs has been demonstrated in human term decidua [119,191-197]. The biosynthetic capacity for eicosanoid formation has been reported to be higher in bone marrow-derived cells, particularly macrophages, than in decidual stromal cells [192,195] and COX activity was also mainly found in a macrophage-rich population of human third trimester decidua [198]. Production of PGF2(X exceeded that of PGE2 [194,195], However, although decidual macrophages displayed the highest prostaglandin production rates, it was estimated that, due to their relatively low abundance, they contribute only between 24% (PGE2) and 38% (PGF2ot) of the overall prostaglandin biosynthesis by term decidua. Nevertheless, bone marrow-derived cells of human decidua are likely to play an important role in the physiology of spontaneous labor at term.

It has been suggested that the decidua is maintained in a state of functional quiescence throughout pregnancy and that it is activated in the course of parturition [193,197]. The biochemical mechanisms involved in decidual activation are not yet sufficiently elaborated. In contrast to many other cells, the production of eicosanoids in decidual macrophages and stromal cells may not be under the control of phospholipase A2, but rather be dependent on the availibility of extracellular arachidonic acid. Intracellular arachidonic acid is metabolized mainly to epoxygenase and lipoxygenase-derived metabolites [192]. Effective regulation of prostaglandin production in decidua will thus be under the control of COXs rather than phospholipases. Various cytokines, for example IL-ip, are well-known inducers of COX expression in decidua [194,199]. The significance of COX-2 expression in the induction and progression of labor is currently still unclear [189,199,200], First results indicate that increased synthesis of COX-2 in intrauterine tissues may be involved in elevated prostaglandin production after labor [194,197] and that COX-2 expression may be upregulated by glucocorticoids and cytokines [201], Sites of production of cytokines are bone marrow-derived cells in the decidua itself [202]. Further research is needed to clarify whether this regulation principle is of importance in normal labor or is restricted to the pathomechanisms of pre-term labor. Another aspect controlling decidual prostaglandin output is the very rapid metabolization of PGE2 and PGF2a in decidual cells [193,203], It has not yet been investigated whether activation of decidua is associated with an inhibition of these degradation reactions.

The biological role of eicosanoids generated by cytochrome P-450-dependent monooxygenases has been only incompletely characterized. It has been reported that arachidonic acid epoxides (EETs) modulate hormone secretion in some organs [21,204—206]. Thus, it is possible that EETs are also involved in decidual hormone production.

The main site of action of uterotonins, the human pregnant myometrium, is itself able to produce eicosanoids, for example PGI2, PGE2, PGF2a, 12-HETE and EET, with prostacyclin being the main arachidonic acid metabolite in this tissue [119,191,207]. The expression of several enzmynes of the arachidonic acid cascade including PLA2, COX-1, COX-2, 5-lipoxygenase and prostacyclin synthase has been demonstrated in human pregnant myometrium [208,209], However, further research is needed to clarify to what extent myometrial arachidonic acid metabolites participate in the onset and maintenance of labor and how biosynthesis of eicosanoids is controlled in myometrium.

The effects of prostaglandins on the myometrium are mediated by specific receptors which, in turn, activate a variety of intracellular signalling pathways (for a review see Challis and Lye [148]). One of the major effects of PGF2a is the increase in intracellular calcium, which is the main intracellular effector of contractions. The mechanism of stimulation of myometrial contractions by prostaglandins is different from oxytocin action. Furthermore, eicosanoids have been suggested to regulate the appearance of gap junctions (for a review see Zahradnik [150]). Pre-term labor

Pre-term labor is one of the most urgent obstetrical problems in industrialized countries, since it is a major source of perinatal morbidity and mortality. It has been estimated that intrauterine infections are a leading cause of up to 30% of pre-term deliveries [210]. According to a widely accepted hypothesis, the cytokine network in fetal membranes is activated by bacterial endotoxins and cytokines released from gestational tissues (for example, IL-ip and TNFa), which in turn stimulate the production of intrauterine prostaglandins causing uterine contractions [211]. The stimulatory effects of cytokines on prostaglandin production in fetal membranes and the decidua have been demonstrated in numerous in vitro experiments [196, 212, 213] (Fig. 8-11). New findings demonstrate that the increased prostaglandin biosynthesis is based on the induction of COX-2 enzyme activity [194,199]. A key role in this process was attributed to decidual macrophages, since they produce cytokines as well as prostaglandins [195,202],

Figure 8-11. Hypothetical model of a cytokine-prostaglandin network at the chorio-decidual interface that is involved in the pathophysiology of infection-induced pre-term labor (from Mitchell et al. [211]; reproduced with permission of W. B. Saunders Co.).

Other causes of pre-term deliveries are poorly defined. Recently, some pre-term deliveries without infections were explained by a relative deficiency of PGDH in chorionic trophoblasts, allowing prostaglandins synthesized in the fetal membranes to escape metabolism in the chorion [188].

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