Placental corticotrophin-releasing hormone and its receptors in human pregnancy and labour: still a scientific enigma.
ABSTRACT It is now accepted that, in humans, placental corticotrophin-releasing hormone (CRH) is involved in the mechanisms controlling the onset of labour; however, the precise biological role in foeto-maternal tissues remain enigmatic. Maternal plasma levels of CRH rise exponentially as pregnancy progresses towards term and peak during labour; however, evidence to link this with an active role in the onset and progression of labour, is still inconclusive. Certainly, one of the tissues targeted by CRH is the myometrial smooth muscle, which expresses a plethora of specific CRH receptors. This finding implicates CRH in the mechanisms preparing the myometrial microenvironment for the onset of labour and possibly in the regulation of active contractility during labour. Other gestational tissues also targeted by CRH include the placenta, foetal membranes and foetal adrenals, where CRH might regulate distinct physiological functions, ranging from control of vascular tone to adrenal steroidogenesis and prostaglandin synthesis and activity. Given the unique, among mammals, pattern of human placental CRH secretion and CRH receptor expression and signalling during pregnancy and labour, there are only limited biological tools available to delineate the actions of CRH in foeto-maternal tissues, primarily based on in vitro characterisation of the signalling and molecular events driven by CRH. This review will set in context the current concepts about the role of CRH and its receptors during pregnancy and labour, focusing on the unresolved questions and paradoxes that currently exist.
- SourceAvailable from: Danijela Markovic[Show abstract] [Hide abstract]
ABSTRACT: Context:The onset of labor appears to involve activation of myometrial inflammatory pathways and transcription factors such as NF-κB control expression of the contraction-associated proteins required to induce a pro-contractile phenotype. These responses might involve corticotropin releasing hormone (CRH), which integrates immune and neuroendocrine systems.Objectives:In human myometrium we investigated cyclooxygenase 2 (PGHS2) expression and regulation by CRH and the pro-inflammatory cytokine IL-1β before and after labor.Design:Myometrial tissues obtained from pregnant women at term before (n=12) or during labor (n=10) and pathological cases of choriamnionitis-associated term labor (n=5) were used to isolate primary myocytes and investigate in vitro, CRH effects on basal and interleukin-1β (IL-1β) regulated p65 activation and PGHS2 expression.Results:In non-laboring myometrial cells CRH was unable to induce NF-κB nuclear translocation, however it altered temporal dynamics of IL-1β-driven NF-κB nuclear entry by initially delaying entry whilst subsequently prolonging retention. These CRH-R1-driven effects were associated with a modest inhibitory action in the early phase (within 2h) of IL-1β stimulated PGHS2 mRNA expression whereas prolonged stimulation for 6-18h augmented IL-1β effects. The early phase effect required intact PKA activity and was diminished after the onset of labor. The presence of chorioamnionitis led to exaggerated PGHS2 mRNA responses to IL-1β but diminished effects of CRH.Conclusions:CRH in involved in the inflammatory regulation of PGHS2 expression before and during labor; these actions might be important in priming and preparing the myometrium for labor and cellular adaptive responses to inflammatory mediators.The Journal of clinical endocrinology and metabolism 05/2013; · 6.50 Impact Factor
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ABSTRACT: BACKGROUND: Placental production of corticotrophin releasing hormone (CRH) rises exponentially as pregnancy progresses, and has been linked with the onset of normal and preterm labour. CRH is produced in syncytiotrophoblast cells and production is increased by glucocorticoids and cAMP. It remains unclear whether cAMP acts by inducing differentiation of cytotrophoblasts and/or through induction of syncytialisation. As CRH can stimulate cAMP pathways we have tested whether a feed-forward system may exist in placental cells during syncytialisation.Reproductive Biology and Endocrinology 04/2013; 11(1):30. · 2.14 Impact Factor
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ABSTRACT: Objective:To investigate interleukin (IL)-6 and CRH secretion during the active phase of human labor and to define their potential involvement in myometrial contractility.Study design:Twenty-two primigravidae women were studied for 90 min during the active phase of term labor by every 3 min serial plasma sampling for measurement of IL-6 and CRH concentrations. Uterine contractions, measured by cardiotocograph, were evaluated in Montevideo units. Basic, quantitative, pulsatility and time cross-correlation statistical analyses were performed.Results:By linear regression analysis, a positive correlation was observed between IL-6 and CRH total AUC0s (r=0.76184, p=0.006). Mean number of pulses was 2.00±0.70 and 3.33±1.29 for IL-6 and CRH, respectively. There was a significant positive correlation between IL-6 and CRH over time, peaking at the 12 min interval, with IL-6 leading CRH. Also, there was a significant positive correlation between myometrial contractility expressed in Montevideo units and IL-6 concentrations over time, starting at +51 min and ending at +57 min with myometrial contractility leading IL-6. No significant correlation was found between myometrial contractility and CRH concentrations over time.Conclusion:IL-6 and CRH are both secreted in a pulsatile fashion during the active phase of human labor. The time-integrated concentrations of the two hormones are positively correlated, with IL-6 leading CRH secretion. It appears, thus, that proinflammatory mediators may be direct and/or indirect promoters of placental CRH release. Furthermore, the secretion of IL-6, which is a myokine, seems to be associated positively with uterine contractility. Further studies are needed to elucidate the combined effect of inflammation, placental CRH release and/or the receptors of the latter in parturition.The Journal of clinical endocrinology and metabolism 08/2013; · 6.50 Impact Factor