Premature birth is the main cause of death in neonates. Some preterm deliveries are deliberately induced because the chances of survival of the baby outside the uterus are better than inside. Such is the case with severe complications of pregnancy—eg, intrauterine growth restriction and infection. However, in many instances, preterm labour arises spontaneously. The diagnosis of labour is difficult to make, and many episodes of threatened preterm labour resolve without treatment. Prediction and early diagnosis would give obstetricians a better chance of success with tocolytics and would avoid unnecessary treatment, of women whose pregnancy is not at risk. Future treatment will depend on an improved understanding of the endocrine and biochemical factors responsible for parturition. A role for the human fetus in determining the timing of its own delivery is supported by the observation that anencephaly, a congenital malformation that results in fetal pituitary-adrenal insufficiency, is associated with an unusually wide scatter in the timing of parturition. In many species, progesterone withdrawal from the maternal circulation triggers labour; in primates, however, parturition occurs without changes in circulating steroid concentrations. The trigger for the onset of labour in women remains elusive. The uterus is a remarkable smooth-muscle organ, since it allows considerable distension for long periods without expelling its contents. For most of the pregnancy, the uterus is in a relaxed state, gradually growing to accommodate the fetus. However, at parturition it contracts regularly and forcibly to expel the fetus. Successful labour depends not only on uterine contractions, but also on synchronised connective tissue changes that allow dilation of the uterine cervix. The myometrium is a phasic smooth muscle with spontaneous activity, which can generate action potentials. The myogenic activity is modulated by a wide range of receptors and ion channels. The basis of uterine contractions, as in other smooth muscles, is the interaction between actin and myosin. During contractions, myosin is phosphorylated by a calciumdependent enzyme and actin and myosin form cross-bridges that generate force. The muscle relaxes when intracellular calcium concentrations decrease and myosin is rapidly dephosphorylated. Uterine contractility is stimulated or inhibited by various receptors in myometrial cells. In general, receptors that provoke calcium entry or calcium release from intracellular stores stimulate contractility. However, receptors coupled to the production of cyclic nucleotides—eg, cyclic adenosine monophosphate (cAMP)—relax the uterus. Oxytocin (OT) and prostaglandin FP receptors are stimulatory. On the other hand, 2-adrenoceptors and prostaglandin EP2 receptors coupled to cAMP formation are inhibitory, probably by inhibiting calcium channels and by activating potassium channels, resulting in membrane hyperpolarisation. The use of 2-adrenoceptor agonists—eg, ritodrine—for the management of preterm labour is widespread. However, 2-agonists lack uterine selectivity and can cause serious metabolic and cardiovascular side-effects. There is no evidence that their use reduces the frequency of preterm births, but they can delay delivery for several hours to allow the transport of the mother to a centre with good neonatal facilities. Better, more-selective tocolytic agents are needed. The ideal tocolytic should be effective at between 23 and 30 weeks’ gestation, when neonatal risk is high. Furthermore, it should be effective for a specified time interval and be given orally. A better understanding of uterine receptors and their signal transduction pathways (figure) will help in the development of drugs with uterine selectivity. For instance, the clinical effectiveness of oxytocin receptor antagonists is similar to that of conventional 2-agonist therapy, but they have fewer maternal or fetal side-effects. Other potential therapeutic targets are prostanoid receptors coupled to cAMP production and potassium channel openers. Ultimately, however, simply relaxing the uterus is too naive, and is not going to be good enough. That tocolytics improve perinatal mortality or morbidity has never been shown. We need to move a step backwards in the process and concentrate our research efforts on identifying and treating the causes of preterm labour. That might mean correcting the endocrine imbalance that leads to increased uterine activity, or the treatment of intrauterine infections or other complications. To improve neonatal outcome, we need to unravel the mechanism of parturition so that we are able to prevent, rather than treat, preterm labour. Uterine receptors and their signal transduction pathways
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Feb 26, 2003
Kohji Hirata + 1
Open Access