Placental Corticotrophin-Releasing Hormone and its Receptors in Human Pregnancy and Labour: Still a Scientific Enigma

Endocrinology and Metabolism, Division of Clinical Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
Journal of Neuroendocrinology (Impact Factor: 3.14). 05/2008; 20(4):432-8. DOI: 10.1111/j.1365-2826.2008.01660.x
Source: PubMed


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.

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    • "However, the precise biological role of CRH in foeto-maternal tissue remains subject to debate (Norwitz et al., 1999; Grammatopoulos, 2008). Figure 4 summarises the current knowledge in a hypothetical model developed by the authors on maternal, foetal and placental factors playing a role This model was based on most relevant and available sources at the moment of construction (Norwitz et al., 1999; Mesiano, 2004; Martin, 2004; Li & Challis, 2005; Bisits et al., 2005; Mesiano & Welsh, 2007; Smith, 2007; Grammatopoulos, 2008; Anubhuti & Arora, 2008; Madan et al., 2009). Legend "
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    ABSTRACT: Background: Maternal obesity is a growing public health concern in Belgium as well as in other European countries and is now becoming the most common risk factor associated with pregnancy complications with impact on the health of the women and her offspring. At this moment, there is no specific management strategy for obese pregnant women and mothers, focusing on physical health and psychological well-being. Objectives: We aimed (1) to study the influence of socio-demographic and obstetrical correlates on pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) in different regions of Flanders, Belgium, (2) to review the literature on the onset and progression of labour in normal weight and obese pregnant women, (3) to compare levels and evolution of anxiety and depressed mood during pregnancy between obese women and normal-weight women, (4) to examine whether a prenatal lifestyle intervention programme, based on principles of motivational interviewing, in obese pregnant women reduces GWG and lowers levels of anxiety and depressed mood during pregnancy, (5) to examine associations between inter-pregnancy weight change from the first to the second pregnancy and the risk for adverse perinatal outcomes during the second pregnancy and finally (6) to study predictors of postpartum weight retention (PPWR) in obese mothers at six months after delivery in order to provide clues for the design of interventions aimed at preventing weight retention related to childbearing. Methods: We performed an epidemiological study, an intervention study during pregnancy with postpartum follow up and a literature review. Results: One in three Flemish women start pregnancy being overweight or obese and this prevalence has slowly been rising since 2009 in the Flanders. We identified women at risk for a high pre-pregnancy BMI and excessive GWG, both being important predictors for increased pregnancy and birth related complications. In a literature review, we showed that the combination of a higher incidence of post-term deliveries and increased inadequate contraction pattern during the first stage of labour in obese women suggests an influence of obesity on myometrial activity. Given the low compliance for adequate GWG in obese women in the general Flemish population and their increased psycho-social vulnerability compar-ed to the normal weight pregnant women, counselling obese pregnant women can lead to a reduced GWG and increased psychological comfort. Stabilizing inter-pregnancy maternal weight for all women is an important target for reducing adverse perinatal outcomes in the subsequent pregnancy. Psychological discomfort during pregnancy does impact on PPWR in obese mothers six months after delivery. Discussion and conclusion: Focusing on weight management in obese women before, during and after a pregnancy has advantages for both the mother and her infant. Theoretical and practice based training modules should be developed and focus on: (1) awareness of techniques for identifying the clearly identified risk groups with a high pre-pregnancy BMI and excessive GWG, (2) the increased perinatal risks, (3) an adapted perinatal management and (4) counselling techniques for an adequate weight management and psychological wellbeing in obese pregnant women. To achieve better care for the future, we must focus on tackling maternal obesity. This means that obese women should be reached before they get pregnant for the first time. Targeting primary and community based care, promotion and education are challenging, but the psychosocial context should be acknowledged.
    Full-text · Article · Jul 2014
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    • "During pregnancy CRH: • Supports the physiological adaptation to pregnancy (Grammatopoulos, 2008) • Increases the numbers of prostaglandin receptors in the myometrium "
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    ABSTRACT: The emotional and hormonal pathways of labour and birth: integrating mind, body and behaviour ABSTRACT Background: Women have described normal labour and birth in terms of their emotions. Major advances in knowledge have occurred within the sciences resulting in an understanding of emotions as prime directors of human behaviour which is orchestrated by neurohormones. Method: This paper focusses on key aspects of contemporary knowledge of childbirth physiology, neuroscience and behaviour. It integrates this understanding with women's descriptions of their emotions during labour. Findings: Neurohormones associated with labour and birth are designed to trigger a transformation in the body and behaviour and create an environment which supports both the mother and the baby. Hormones and emotions are intertwined and interconnected. Labour hormones are linked to the woman's emotions and behaviour during labour and birth as well as the physical signs of labour. An interactive model is presented which explains labour in terms of both the physical effects and the emotional affects that women have described as part of their labour experience. The hypothesis for this model is that the hormones that initiate and sustain labour also cause the instinctual emotions that women feel, and the behaviour they exhibit, during spontaneous labour and birth. Conclusions: Hormonal changes are necessary to support the physical and emotional changes during labour and birth. The neurohormones which operate during pregnancy and during labour and birth also support PRACTICE ISSUE parenting behaviour. This paper integrates the contemporary scientific understanding of the role of neurohormones and their association, with the woman's behaviour and emotions during labour. It argues for, and provides the foundations of, a new conceptual framework for understanding labour and birth, one which integrates mind, body and behaviour.
    Full-text · Article · Dec 2013
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    • "Through the various CRH receptor subtypes (CRHR1 and CRHR2) CRH plays diverse roles at different stages of pregnancy and labour. For example, CRH stimulates the foetal pituitary-adrenal axis, modulates placental vascular tone and endocrine function (especially prostaglandin generation), controls myometrial contractility ⁄ quiescence, and regulates trophoblast cell growth and invasion [10]. Nevertheless, there is little research literature available on a role for CRH in trophoblast cell differentiation. "
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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. Methods The choriocarcinoma BeWo cell line was treated with cAMP, CRH or vehicle. Cell viability was determined by MTT assay, while apoptosis was analysed by DAPI staining and by FACS. Differentiation was measured by assaying message for hCG and ERVW-1 (syncytin1) by qRT-PCR, as well as the respective protein by ELISA. Fusion of BeWo cells was assessed by co-staining cell membrane and nuclei with CellMask and Hoechst 33342. CRHR1 and CRHR2 mRNA levels were measured by qRT-PCR. Results We show that cAMP has an inductive effect on syncytialisation, as evidenced by induction of hCG secretion, by ERVW-1 mRNA expression and by formation of multinuclear cells. CRH mRNA expression was found to increase prior to the changes in the other syncytialisation markers. cAMP had an inhibitory effect on BeWo cell viability, but exogenous CRH did not. However, CRH did mimic the differentiation inducing effect of cAMP, suggesting a link between CRH and cAMP signalling in syncytialisation. We also found that treatment of BeWo cells with exogenous CRH resulted in elevated cellular CRHR1 levels. Conclusions This study suggests a positive feed-forward role exists for CRH in trophoblast cell differentiation, which may underlie the exponential rise in CRH observed as gestation advances.
    Full-text · Article · Apr 2013 · Reproductive Biology and Endocrinology
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