Steven Thornton

The role of oxytocin in parturition

Oxytocin and the oxytocin receptor have two important roles in labour. Evidence in all mammalian species suggests that neurohypophysical oxytocin plays a role in the expulsive phase and, although there are less supporting data, a role for oxytocin in the initiation of labour is likely. The initiation of labour may be mediated in women and rhesus monkeys by paracrine rather than endocrine mechanisms. Although initial characterisation of the oxytocin knockout mouse suggested that oxytocin is not important in this species, subsequent investigations have demonstrated that oxytocin is important for the precise timing of the onset of labour. Studies in knockout mice also confirm important interrelationships between oxytocin and prostaglandins. Oxytocin stimulates prostaglandin release in many species, mainly in the decidua/uterine epithelium. The effects of oxytocin are mediated by tissue‐specific oxytocin receptor expression, which leads directly to contraction in the myometrium and prostaglandin formation in the decidua. There is a dramatic increase in oxytocin receptor expression in these tissues in late pregnancy and pharmacological inhibition delays delivery, which suggests that, in contrast to oxytocin, the oxytocin receptor is essential for normal labour.

Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial

Summary Background Progesterone administration has been shown to reduce the risk of preterm birth and neonatal morbidity in women at high risk, but there is uncertainty about longer term effects on the child. Methods We did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22–24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ≤34 weeks and 0 days of gestation, or a cervical length ≤25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth [any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears]). The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes. We defined three primary outcomes: fetal death or birth before 34 weeks and 0 days gestation (obstetric), a composite of death, brain injury, or bronchopulmonary dysplasia (neonatal), and a standardised cognitive score at 2 years of age (childhood), imputing values for deaths. Randomisation was done through a web portal, with participants, investigators, and others involved in giving the intervention, assessing outcomes, or analysing data masked to treatment allocation until the end of the study. Analysis was by intention to treat. This trial is registered at ISRCTN.com, number ISRCTN14568373. Findings Between Feb 2, 2009, and April 12, 2013, we randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons [OR] 0·86, 95% CI 0·61–1·22) or neonatal outcome (OR 0·62, 0·38–1·03), nor on the childhood outcome (cognitive score, progesterone group vs placebo group, 97·3 [SD 17·9] vs 97·7 [17·5]; difference in means −0·48, 95% CI −2·77 to 1·81). Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p=0·27). Interpretation Vaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age. Funding Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales.

Labor-associated gene expression in the human uterine fundus, lower segment, and cervix

Background Preterm labor, failure to progress, and postpartum hemorrhage are the common causes of maternal and neonatal mortality or morbidity. All result from defects in the complex mechanisms controlling labor, which coordinate changes in the uterine fundus, lower segment, and cervix. We aimed to assess labor-associated gene expression profiles in these functionally distinct areas of the human uterus by using microarrays. Methods and Findings Samples of uterine fundus, lower segment, and cervix were obtained from patients at term (mean ± SD = 39.1 ± 0.5 wk) prior to the onset of labor ( n = 6), or in active phase of labor with spontaneous onset ( n = 7). Expression of 12,626 genes was evaluated using microarrays (Human Genome U95A; Affymetrix) and compared between labor and non-labor samples. Genes with the largest labor-associated change and the lowest variability in expression are likely to be fundamental for parturition, so gene expression was ranked accordingly. From 500 genes with the highest rank we identified genes with similar expression profiles using two independent clustering techniques. Sets of genes with a probability of chance grouping by both techniques less than 0.01 represented 71.2%, 81.8%, and 79.8% of the 500 genes in the fundus, lower segment, and cervix, respectively. We identified 14, 14, and 12 those sets of genes in the fundus, lower segment, and cervix, respectively. This enabled networks of co-regulated and co-expressed genes to be discovered. Many genes within the same cluster shared similar functions or had functions pertinent to the process of labor. Conclusions Our results provide support for many of the established processes of parturition and also describe novel-to-labor genes not previously associated with this process. The elucidation of these mechanisms likely to be fundamental for controlling labor is an important prerequisite to the development of effective treatments for major obstetric problems—including prematurity, with its long-term consequences to the health of mother and offspring.

Multiple mechanisms involved in oxytocin-induced modulation of myometrial contractility

AbstractOxytocin is a small peptide hormone with multiple sites of action in human body. It regulates a large number of reproduction-related processes in all species. Particularly important is its ability to stimulate uterine contractility. This is achieved by multiple mechanisms involving sarcoplasmic reticulum Ca2+ release and sensitization of the contractile apparatus to Ca2+. In this paper, we review the data published by us and other groups on oxytocin-induced modulation of uterine contractility. We conclude that sensitization of contractile apparatus to Ca2+ is the most relevant physiological effect of oxytocin on human myometrium.

Characterization of the molecular and electrophysiological properties of the T‐type calcium channel in human myometrium

Rises in intracellular calcium are essential for contraction of human myometrial smooth muscle (HMSM) and hence parturition. The T‐type calcium channel may play a role in this process. The aim was to investigate the role of the T‐type calcium channel in HMSM by characterizing mRNA expression, protein localization, electrophysiological properties and function of the channel subunits Cav3.1(α1G), Cav3.2(α1H), and Cav3.3(α1I). QRT‐PCR, immunohistochemistry, electrophysiology and invitro contractility were performed on human myometrial samples from term, preterm, labour and not in labour. QRT‐PCR analysis of Cav3.1, Cav3.2 and Cav3.3 demonstrated expression of Cav3.1 and Cav3.2 with no significant change (P > 0.05) associated with gestation or labour status. Immunohistochemistry localized Cav3.1 to myometrial and vascular smooth muscle cells whilst Cav3.2 localized to vascular endothelial cells and invading leucocytes. Voltage clamp studies demonstrated a T‐type current in 55% of cells. Nickel block of T‐type current was voltage sensitive (IC50 of 118.57 ± 68.9 μm at −30 mV). Activation and inactivation curves of ICa currents in cells expressing T‐type channels overlapped demonstrating steady state window currents at the resting membrane potential of myometrium at term. Current clamp analysis demonstrated that hyperpolarizing pulses to a membrane potential greater than −80 mV elicited rebound calcium spikes that were blocked reversibly by 100 μm nickel. Contractility studies demonstrated a reversible decrease in contraction frequency during application of 100 μm nickel (P < 0.05). We conclude that the primary T‐type subunit expressed in some MSMCs is Cav3.1. We found that application of 100 μm nickel to spontaneously contracting human myometrium reversibly slows contraction frequency.

Control of uterine Ca2+ by membrane voltage: toward understanding the excitation-contraction coupling in human myometrium.

Abstract:  Myometrial contractility is a complex and dynamic physiological process that changes substantially during pregnancy and culminates in childbirth. Uterine contractions are initiated by transient rises in cytoplasmic Ca2+ concentration ([Ca2+]i), which in turn are triggered and controlled by myometrial action potentials. The sequence of events between the action potential generation and the contraction initiation is referred to as excitation–contraction coupling. Hormones and other physiologically active substances affect myometrial contractility by modulating different steps in the excitation–contraction coupling process. It is therefore imperative that we understand that process to understand the regulation of myometrial contractility. The complex action potentials generated by human myometrium result from the activity of many ion channels, transporters, and pumps. Two types of myometrial action potential waveform have been described in the literature: a plateau type and a spike type. Parameters of the myometrial [Ca2+]i transients and contractions differ depending on the type of action potential that triggers them. Some aspects of the excitation–contraction coupling are unique to human myometrium and cannot be found in animal models; some others are common between many species. This article reviews the current state and discusses future directions of physiological research on human myometrial excitation–contraction coupling.

Development of the juliá asymmetric epoxidation reaction. Part 1. Application of the oxidation to enones other than chalcones

Asymmetric epoxidation of a variety of enones 3, 6, 8, 10, 12, 14, 16, 18, 21, 22, 26, 28–30 and 36 gives the corresponding oxiranes in good to excellent yield and optical purity. The oxidation medium consists of basic peroxide or sodium perborate or sodium percarbonate or tert-butylhydroperoxide and the preferred catalyst is polyleucine, conveniently prepared from the N-carboxyanhydride using 1,3-diaminopropane.

Labor and Inflammation Increase the Expression of Oxytocin Receptor in Human Amnion

The oxytocin/oxytocin receptor (OXT/OXTR) system plays an important role in the regulation of parturition. The amnion is a major source of prostaglandins and inflammatory cytokine synthesis, which increase both before and during labor. Amnion is a noncontractile tissue; therefore, the role played by OXT/OXTR in this tissue will be fundamentally different from the role played in myometrial contractions. In the present study, we demonstrate increased OXTR mRNA and protein concentrations in human amnion epithelial cells associated with the onset of labor. We show that incubation of primary human amnion epithelial cells with IL1B results in a rapid, transient up-regulation of OXTR mRNA expression, which peaks in prelabor samples after 6 h. Incubation of prelabor amnion epithelial cells with OXT results in a marked increase of prostaglandin E2 synthesis, and we demonstrate that OXT activates the extracellular signal-regulated protein kinase signal transduction pathway to stimulate up-regulation of cyclo-oxygenase 2 in human amnion epithelial cells. The increased ability of human amnion to produce prostaglandins in response to OXT treatment suggests a complementary role for the OXT/OXTR system in the activation of human amnion and the onset of labor.

Prostaglandins and prostanoid receptors in human pregnancy and parturition.

Preterm labor occurs in up to 10% of all births but is associated with 85% of perinatal deaths in otherwise normal babies. Elucidation of the mechanisms involved in normal labor is an important prerequisite for the development of effective therapeutic strategies to prevent and treat preterm labor. Prostaglandins are important in human parturition. They have been used extensively for induction of labor. Prevention of their formation with prostaglandin synthase inhibitors can delay delivery in preterm labor. Nevertheless, the functional activity of prostaglandins in gestational tissues is complex. There are numerous classes of prostaglandins that act on many different prostanoid receptors. Receptor subtypes, even within the same class, are coupled to various second messengers and may thus be stimulatory or inhibitory. Alternate splicing leads to additional diversity. Within this complex background, the tissue-, gestation-, and labor-associated changes in prostaglandins and their receptors are reviewed.

Oxytocin Antagonists: Clinical and Scientific Considerations

Preterm delivery is the largest cause of perinatal mortality and morbidity, yet the treatment of preterm labour has not been demonstrated to improve outcome. The reasons are numerous and complex, but they include a failure to understand the mechanism(s) of preterm labour, the multitude of different causes, the difficulty in diagnosis and the problems of outcome measurement in clinical trials. Recently, an oxytocin antagonist (atosiban) has been introduced into clinical practice in Europe. Although it may be an effective tocolytic, a beneficial effect on perinatal outcome has not been demonstrated. Atosiban has an effect at both oxytocin and vasopressin (V1a) receptors, which (assuming efficacy) raises the question as to whether oxytocin or vasopressin V1a antagonism is required for tocolysis. This review examines the rationale for tocolysis in preterm labour, the evidence for administration of atosiban and the role for oxytocin, vasopressin and their receptors in the onset of labour.