Glucocorticoid excess and the developmental origins of disease: two decades of testing the hypothesis--2012 Curt Richter Award Winner.
TL;DR: It is demonstrated that high maternal cortisol in pregnancy and/or inhibition of HSD2 are associated with programmed outcomes in childhood including higher blood pressure, behavioural disorders as well as altered brain structure, and this may be altered in obesity.
About: This article is published in Psychoneuroendocrinology.The article was published on 2013-01-01. It has received 426 citations till now. The article focuses on the topics: Glucocorticoid & Hypothalamic–pituitary–adrenal axis.
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TL;DR: The aim of this review is to recapitulate the clinical understanding of CSCR, with an emphasis on the most recent findings on epidemiology, risk factors, clinical and imaging diagnosis, and treatments options, and the novel mineralocorticoid pathway hypothesis.
690 citations
University Hospital Southampton NHS Foundation Trust1, University of Edinburgh2, University of Western Australia3, University of London4, University of Malawi5, Erasmus University Medical Center6, University of Helsinki7, National University of Singapore8, University Health System9, Agency for Science, Technology and Research10
TL;DR: There is an urgent need for studies on causality, underlying mechanisms, and effective interventions to reverse the epidemic of obesity in women of childbearing age and to mitigate consequences for offspring.
615 citations
TL;DR: Dysfunction of the HPA axis as a result of fetal programming has been associated with impaired brain growth, altered behaviour and increased susceptibility to chronic disease (such as metabolic and cardiovascular disease).
Abstract: Fetal development is a critical period for shaping the lifelong health of an individual. However, the fetus is susceptible to internal and external stimuli that can lead to adverse long-term health consequences. Glucocorticoids are an important developmental switch, driving changes in gene regulation that are necessary for normal growth and maturation. The fetal hypothalamic-pituitary-adrenal (HPA) axis is particularly susceptible to long-term programming by glucocorticoids; these effects can persist throughout the life of an organism. Dysfunction of the HPA axis as a result of fetal programming has been associated with impaired brain growth, altered behaviour and increased susceptibility to chronic disease (such as metabolic and cardiovascular disease). Moreover, the effects of glucocorticoid-mediated programming are evident in subsequent generations, and transmission of these changes can occur through both maternal and paternal lineages.
442 citations
TL;DR: Elucidating the role of epigenetic mechanisms in intergenerational effects through prospective, multi‐generational studies may ultimately yield a cogent understanding of how individual, cultural and societal experiences permeate the authors' biology.
239 citations
TL;DR: Emerging data from human studies linking dysregulation of the maternal HPA axis to outcomes in both the mother and her offspring support longer term consequences for the offspring including re-setting of the HPAaxis and susceptibility to neurodevelopmental problems and cardiometabolic disease.
Abstract: Overexposure of the developing fetus to glucocorticoids is hypothesised to be one of the key mechanisms linking early life development with later life disease. The maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes dramatic changes during pregnancy and postpartum. Although cortisol levels rise threefold by the third trimester, the fetus is partially protected from high cortisol by activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2). Maternal HPA axis activity and activity of HSD11B2 may be modified by maternal stress and disease allowing greater transfer of glucocorticoids from mother to fetus. Here we review emerging data from human studies linking dysregulation of the maternal HPA axis to outcomes in both the mother and her offspring. For the offspring, greater glucocorticoid exposure is associated with lower birth weight and shorter gestation at delivery. In addition, evidence supports longer term consequences for the offspring including re-setting of the HPA axis and susceptibility to neurodevelopmental problems and cardiometabolic disease. For the mother, the changes in the HPA axis, particularly in the postpartum period, may increase vulnerability to mood disturbances. Further understanding of the changes in the HPA axis during pregnancy and the impact of these changes may ultimately allow early identification of those most at risk of future disease.
233 citations
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TL;DR: The fetal origins hypothesis states that fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary heart disease.
Abstract: The fetal origins hypothesis states that fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary heart disease. Animal studies have shown that undernutrition before birth programmes persisting changes in a range of metabolic, physiological, and structural parameters. Studies in humans have shown that men and women whose birth weights were at the lower end of the normal range, who were thin or short at birth, or who were small in relation to placental size have increased rates of coronary heart disease. We are beginning to understand something of the mechanisms underlying these associations. The programming of blood pressure, insulin responses to glucose, cholesterol metabolism, blood coagulation, and hormonal settings are all areas of active research.
3,228 citations
"Glucocorticoid excess and the devel..." refers background in this paper
...Low birthweight, a marker of an adverse intra-uterine environment, is associated with increased mortality and a range of cardiometabolic diseases, neurological and mental health disorders (Barker, 1995; Seckl, 2004)....
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TL;DR: This paper shows how fetal undernutrition at different stages of gestation can be linked to these patterns of early growth in babies who are small at birth or during infancy.
2,594 citations
TL;DR: Treatment with antenatal corticosteroids (compared with placebo or no treatment) is associated with a reduction in the most serious adverse outcomes related to prematurity, including perinatal death and neonatal death.
Abstract: Background
Respiratory morbidity including respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. While researching the effects of the steroid dexamethasone on premature parturition in fetal sheep in 1969, Liggins found that there was some inflation of the lungs of lambs born at gestations at which the lungs would be expected to be airless. Liggins and Howie published the first randomised controlled trial in humans in 1972 and many others followed.
Objectives
To assess the effects of administering a course of corticosteroids to the mother prior to anticipated preterm birth on fetal and neonatal morbidity and mortality, maternal mortality and morbidity, and on the child in later life.
Search methods
We searched Cochrane Pregnancy and Childbirth's Trials Register (17 February 2016) and reference lists of retrieved studies.
Selection criteria
We considered all randomised controlled comparisons of antenatal corticosteroid administration (betamethasone, dexamethasone, or hydrocortisone) with placebo, or with no treatment, given to women with a singleton or multiple pregnancy, prior to anticipated preterm delivery (elective, or following spontaneous labour), regardless of other co-morbidity, for inclusion in this review. Most women in this review received a single course of steroids; however, nine of the included trials allowed for women to have weekly repeats.
Data collection and analysis
Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach.
Main results
This update includes 30 studies (7774 women and 8158 infants). Most studies are of low or unclear risk for most bias domains. An assessment of high risk usually meant a trial had potential for performance bias due to lack of blinding. Two trials had low risks of bias for all risk of bias domains.
Treatment with antenatal corticosteroids (compared with placebo or no treatment) is associated with a reduction in the most serious adverse outcomes related to prematurity, including: perinatal death (average risk ratio (RR) 0.72, 95% confidence interval (CI) 0.58 to 0.89; participants = 6729; studies = 15; Tau² = 0.05, I² = 34%; moderate-quality); neonatal death (RR 0.69, 95% CI 0.59 to 0.81; participants = 7188; studies = 22), RDS (average RR 0.66, 95% CI 0.56 to 0.77; participants = 7764; studies = 28; Tau² = 0.06, I² = 48%; moderate-quality); moderate/severe RDS (average RR 0.59, 95% CI 0.38 to 0.91; participants = 1686; studies = 6; Tau² = 0.14, I² = 52%); intraventricular haemorrhage (IVH) (average RR 0.55, 95% CI 0.40 to 0.76; participants = 6093; studies = 16; Tau² = 0.10, I² = 33%; moderate-quality), necrotising enterocolitis (RR 0.50, 95% CI 0.32 to 0.78; participants = 4702; studies = 10); need for mechanical ventilation (RR 0.68, 95% CI 0.56 to 0.84; participants = 1368; studies = 9); and systemic infections in the first 48 hours of life (RR 0.60, 95% CI 0.41 to 0.88; participants = 1753; studies = 8).
There was no obvious benefit for: chronic lung disease (average RR 0.86, 95% CI 0.42 to 1.79; participants = 818; studies = 6; Tau² = 0.38 I² = 65%); mean birthweight (g) (MD -18.47, 95% CI -40.83 to 3.90; participants = 6182; studies = 16; moderate-quality); death in childhood (RR 0.68, 95% CI 0.36 to 1.27; participants = 1010; studies = 4); neurodevelopment delay in childhood (RR 0.64, 95% CI 0.14 to 2.98; participants = 82; studies = 1); or death into adulthood (RR 1.00, 95% CI 0.56 to 1.81; participants = 988; studies = 1).
Treatment with antenatal corticosteroids does not increase the risk of chorioamnionitis (RR 0.83, 95% CI 0.66 to 1.06; participants = 5546; studies = 15; moderate-quality evidence) or endometritis (RR 1.20, 95% CI 0.87 to 1.63; participants = 4030; studies = 10; Tau² = 0.11, I² = 28%; moderate-quality). No increased risk in maternal death was observed. However, the data on maternal death is based on data from a single trial with two deaths; four other trials reporting maternal death had zero events (participants = 3392; studies = 5; moderate-quality).
There is no definitive evidence to suggest that antenatal corticosteroids work differently in any pre-specified subgroups (singleton versus multiple pregnancy; membrane status; presence of hypertension) or for different study protocols (type of corticosteroid; single course or weekly repeats).
GRADE outcomes were downgraded to moderate-quality. Downgrading decisions (for perinatal death, RDS, IVH, and mean birthweight) were due to limitations in study design or concerns regarding precision (chorioamnionitis, endometritis). Maternal death was downgraded for imprecision due to few events.
Authors' conclusions
Evidence from this update supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. A single course of antenatal corticosteroids could be considered routine for preterm delivery. It is important to note that most of the evidence comes from high income countries and hospital settings; therefore, the results may not be applicable to low-resource settings with high rates of infections.
There is little need for further trials of a single course of antenatal corticosteroids versus placebo in singleton pregnancies in higher income countries and hospital settings. However, data are sparse in lower income settings. There are also few data regarding risks and benefits of antenatal corticosteroids in multiple pregnancies and other high-risk obstetric groups. Further information is also required concerning the optimal dose-to-delivery interval, and the optimal corticosteroid to use.
We encourage authors of previous studies to provide further information, which may answer any remaining questions about the use of antenatal corticosteroids in such pregnancies without the need for further randomised controlled trials. Individual patient data meta-analysis from published trials is likely to answer some of the evidence gaps. Follow-up studies into childhood and adulthood, particularly in the late preterm gestation and repeat courses groups, are needed. We have not examined the possible harmful effects of antenatal corticosteroids in low-resource settings in this review. It would be particularly relevant to explore this finding in adequately powered prospective trials.
2,564 citations
TL;DR: The generation and analysis of exon-level transcriptome and associated genotyping data, representing males and females of different ethnicities, from multiple brain regions and neocortical areas of developing and adult post-mortem human brains, finds that 86 per cent of the genes analysed were expressed, and that 90 per cent were differentially regulated at the whole-transcript or exon level acrossbrain regions and/or time.
Abstract: Brain development and function depend on the precise regulation of gene expression. However, our understanding of the complexity and dynamics of the transcriptome of the human brain is incomplete. Here we report the generation and analysis of exon-level transcriptome and associated genotyping data, representing males and females of different ethnicities, from multiple brain regions and neocortical areas of developing and adult post-mortem human brains. We found that 86 per cent of the genes analysed were expressed, and that 90 per cent of these were differentially regulated at the whole-transcript or exon level across brain regions and/or time. The majority of these spatio-temporal differences were detected before birth, with subsequent increases in the similarity among regional transcriptomes. The transcriptome is organized into distinct co-expression networks, and shows sex-biased gene expression and exon usage. We also profiled trajectories of genes associated with neurobiological categories and diseases, and identified associations between single nucleotide polymorphisms and gene expression. This study provides a comprehensive data set on the human brain transcriptome and insights into the transcriptional foundations of human neurodevelopment.
1,760 citations
"Glucocorticoid excess and the devel..." refers background in this paper
...Human brain development begins early in gestation, with key genes involved in neurodevelopmental processes expressed in the early embryonic period and continuing during fetal and infant development (Kang et al., 2011)....
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TL;DR: This review defines the DMN concept with regard to its neuro-anatomy, its functional organisation through low frequency neuronal oscillations, its relation to other recently discovered low frequency resting state networks, and the cognitive functions it is thought to serve, and introduces methodological and analytical issues and challenges.
1,515 citations
"Glucocorticoid excess and the devel..." refers background in this paper
...As abnormalities in MRI correlate with a variety of neurological disorders including schizophrenia, autism, anxiety, depression and attention deficit hyperactivity disorder (Broyd et al., 2009; Philip et al., 2012), our on-going work in this field will potentially enable identification of in utero biomarkers of such conditions....
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...…with a variety of neurological disorders including schizophrenia, autism, anxiety, depression and attention deficit hyperactivity disorder (Broyd et al., 2009; Philip et al., 2012), our on-going work in this field will potentially enable identification of in utero biomarkers of such…...
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