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Human labour, both at term and preterm, is preceded by NF-κB-mediated inflammatory activation within the uterus, leading to myometrial activation, fetal membrane remodelling and cervical ripening. The stimuli triggering inflammatory activation in normal human parturition are not fully understood. We show that the neurohypophyseal peptide, oxytocin (OT), activates NF-κB and stimulates downstream inflammatory pathways in human gestational tissues. OT stimulation (1 pM-100 nM) specifically via its receptor (OTR) in human myometrial and amnion primary cells led to MAPK and NF-κB activation within 15 min and maximal p65-subunit nuclear translocation within 30 min. Both in human myometrium and amnion, OT-induced activation of the canonical NF-κB pathway upregulated key inflammatory labour-associated genes including IL-8, CCL5, IL-6 and COX-2. IKKβ inhibition (TPCA1; 10 µM) suppressed OT-induced NF-κB-p65 phosphorylation, whereas p65-siRNA knockdown reduced basal and OT-induced COX-2 levels in myometrium and amnion. In both gestational tissues, MEK1/2 (U0126; 10 µM) or p38 inhibition (SB203580; 10 µM) suppressed OT-induced COX-2 expression, but OT-induced p65-phosphorylation was only inhibited in amnion, suggesting OT activation of NF-κB in amnion is MAPK-dependent. Our data provide new insight into the OT/OTR system in human parturition and suggest that its therapeutic modulation could be a strategy for regulating both contractile and inflammatory pathways in the clinical context of term/preterm labour., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Maternal obesity is associated with increased rates of labor induction, dysfunctional labor requiring intrapartum cesarean delivery, and postpartum hemorrhage, implying that maternal obesity has an inhibitory effect on myometrial function and its ability to respond to oxytocin. This study aimed to use an in vitro model to investigate the relationship between maternal body mass index (BMI) and the ability of myometrium to contract spontaneously and in response to oxytocin. Linear mixed effects regression modeling was applied to contractile data from 609 strips from 85 women. No correlation was found between maternal BMI and any indices of spontaneous myometrial activity. A single addition of oxytocin increased contractility, however, this was not related to maternal BMI. Similarly, oxytocin concentration-response curves were unrelated to BMI. Overall, the results from this in vitro study suggest that the observed implications of obesity on parturition in vivo cannot be explained by a direct effect on myometrial contractile mechanisms per se.

Objective: Analysis of uterine contractility in vitro is usually confined to measuring a few traditional parameters of uterine contractility, such as contraction amplitude, frequency and area under the curve. In this paper, we describe parameters that provide additional information obtained from the traces of force and its first derivative. We propose an improved contractility index which is less dependent on variability between samples., Study Design: Standard organ bath recording of myometrial contractions in the presence or absence of oxytocin on samples of human myometrium obtained from 26 patients at Caesarean section. The parameters were obtained from the plots of first derivative vs. contractile force (phase portrait plot)., Results and Conclusions: Oxytocin (1nM) significantly increased the contraction amplitude (Fmax), area under the curve, maximum rate of contraction (CVmax), decreased the maximum rate of relaxation (RVmax) and had no statistically significant effect on the duration of contraction (measured as full width at half amplitude, W50). In addition to the above effects, 10nM oxytocin increased the contraction duration (P=0.0036, n=24). The fraction of force developed at the time of CVmax showed no change at any concentration of oxytocin, while the fraction of force remaining at RVmax was decreased in a dose dependent manner. The least variable (i.e. showing lowest P values in paired Student's t-Test) parameters were the Fmax and CVmax/RVmax. When non-paired t-Test was applied, P value of the CVmax/RVmax remained low, while the variability of Fmax increased reflecting the sample-to-sample variations. The product of the Fmax and CVmax/RVmax, which we propose as uterine contractility index (CI) showed low P values in both paired and non-paired t-Tests. We conclude that the phase plot analysis provides useful additional information on contraction/relaxation properties of human myometrium and the CI is suitable for characterising the contractility of uterine samples with different connective tissue content.

In this study we investigated the spatial and temporal relationship among oxytocin (OT), oxytocin receptor (OTR), and estradiol (E2) at term, with (LAB) and without labor (NIL), in human amnion (AM), chorio-decidua (CD), fundal (FU), and lower segment (LS) myometrium. RT-PCR and RIA demonstrated a labor-associated increase in OT mRNA and peptide in CD, AM, and FU, but not LS. HPLC purification and mass spectrometry analysis confirmed that immunoreactive OT corresponded to alpha-amidated OT. Immunohistochemistry localized OT to chorionic trophoblast, decidual stroma, and glandular epithelium. RT-PCR analysis of OTR mRNA demonstrated a significant difference between FU and LS samples, which remained unchanged with labor in all tissues. Immunohistochemistry localized OTR to amniotic epithelium, decidual stroma, and myometrium. Tissue E2 concentrations, as determined by ELISA, demonstrated a significant increase with labor in all tissues. E2 was highest in CD, followed by FU, AM, and LS, respectively. E2 correlated with OT in samples of FU and CD taken from NIL women and in FU, CD, and AM taken from LAB women. We conclude that a significant increase in both OT and E2 occurs at the myometrial decidual interface with labor, and this increase is reflected in both the fundal and lower segments of the uterus. In contrast to OT and E2 the OTR is spatially regulated, with significantly greater expression in the fundal region of the uterus. Paracrine OT production stimulated by E2 may be important in activating the uterus at term.

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.