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Elevated Plasma Cortisol Concentrations: A Link between Low Birth Weight and the Insulin Resistance Syndrome?
... One of the first publications examined data from the Hertfordshire cohort, reporting an inverse relationship between birth weight and fasting morning Cortisol concentrations in men aged 60-71 years. Fasting plasma Cortisol fell from 408nmol/l in those who weighed 5.51b (2.49kg) or less to 309nmol/l among those who weighed more than 9.51b (4.31kg) (110). Not all studies have been confirmatory. ...
... The primary aim of the study was to explore the hypothesis that HPAA responses to psychological stress may be programmed antenatally in humans. An inverse relationship between birthweight and fasting 0900h Cortisol concentrations has been found in a number of studies (110,111), but more detailed examination of basal glucocorticoid secretion in one of these cohorts found no such relationship (115). One possible explanation for this dichotomy is that the combination of fasting, venepuncture and the unfamiliar clinic setting in which the samples were taken for the initial studies constitutes a significant stressor and thus that the 0900h Cortisol concentrations partly reflect stress responsiveness. ...
... As outlined in the results, there was no relationship between 0900h Cortisol concentration and birthweight in the 678 men who form the new East Hertfordshire cohort and thus the results of the present study cannot be used to explain the nature of the HPAA abnormality in hypercortisolaemic low birthweight individuals.A detailed comparison of the two cohorts has yet to be undertaken and the candidate was not at liberty to analyse data from the new cohort, other than that directly relating to the HPAA study. The original report of an inverse association between birthweight and 0900hCortisol concentration was based on 370 men bom in the same area of Hertfordshire between 1920 and 1930(110). These men were the same age as those in the new cohort when they were studied (mean 64 years, range 59 -70 years). ...
p>The first study compared three tests of central HPAA function in a group of low birthweight men aged 60-69 years from Hertfordshire, UK. There were no differences in the free cortisol response to awakening or ACTH and cortisol responses during a 100μg corticotrophin-releasing hormone (CRH) test, but low birthweight men had significantly smaller pituitary-adrenal responses during a dexamethasone-suppressed CRH test. While these findings do not explain the HPAA abnormalities associated with low birthweight in previous studies, they provide further evidence of dysregulation of the HPAA in men who were small at birth.
In further analysis of the data, blood pressure, glucose tolerance and plasma lipid concentrations were not related to these measures of central HPAA activity, despite significant positive correlations with morning cortisol concentrations. These data suggest that other mechanisms, for example altered glucocorticoid metabolism, are responsible for elevating circulating cortisol concentrations in men with cardiovascular risk factors.
The second study explored cortisol and blood pressure responses to a series of psychological stress tests in a group of young men and women from Adelaide, Australia. Cortisol responses were not related to size at birth in either sex, but in women there was a significant inverse relationship between birthweight and blood pressure reactivity. This study provides the first human evidence that haemodynamic responses to psychological stress may be programmed antenatally, suggesting a potential mechanism linking reduced fetal growth with raised blood pressure and cardiovascular disease in later life.
In summary, this research does not support the idea that the HPAA is upregulated centrally in low birthweight individuals, but adds to the evidence that the activity of the axis may be influenced by factors affecting fetal growth. The work presented in this thesis has added complexity to the role of the HPAA in the fetal origins of adult disease, and confirms that this is likely to remain an exciting area of research in years to come.</p
... Unfortunately, long-term GC therapy is associated with metabolic side effects, including hyperglycemia, hypertension, and hepatic steatosis (14,15). Clinical studies show that GC is elevated in insulin-resistant and glucose-intolerant patients (16,17). The endogenous overproduction of GCs characterized by Cushing's syndrome is associated with glucose intolerance and the appearance of insulin resistance and altered lipid metabolism (18). ...
Chronic glucocorticoid therapy has serious side effects, including diabetes and fatty liver. However, the molecular mechanisms responsible for steroid-induced diabetes remain largely enigmatic. Here, we show that hepatic Krüppel-like factor 9 (Klf9) gene expression is induced by dexamethasone and fasting. The overexpression of Klf9 in primary hepatocytes strongly stimulated Pgc1a gene expression through direct binding to its promoter, thereby activating the gluconeogenic program. However, Klf9 mutation abolished the stimulatory effect of dexamethasone on cellular glucose output. Adenovirus-mediated overexpression of KLF9 in the mouse liver markedly increased blood glucose levels and impaired glucose tolerance. Conversely, both global Klf9-mutant mice and liver-specific Klf9-deleted mice displayed fasting hypoglycemia. Moreover, the knockdown of Klf9 in the liver in diabetic mouse models, including ob/ob and db/db mice, markedly lowered fasting blood glucose levels. Notably, hepatic Klf9 deficiency in mice alleviated hyperglycemia induced by chronic dexamethasone treatment. These results suggest a critical role for KLF9 in the regulation of hepatic glucose metabolism and identify hepatic induction of KLF9 as a mechanism underlying glucocorticoid therapy-induced diabetes.
... The principal agents by which a twin may be influenced by a co-twin are most likely to be steroid hormones (including both gonadal steroids and glucocorticoids) which are extremely lipid soluble and readily diffuse within biological tissues where they have potent influences on growth and development . There is increasing evidence that the secretion of steroid hormones can be programmed during development and that they may be mediators of the effects of restricted fetal growth (Phillips et al., 1998; Reynolds et al., 2001). If steroid programming is an important mediator of the longterm effects of fetal growth restriction, this has important significance for the interpretation of twin studies. ...
Although there is substantial evidence from studies of singletons that small size at birth is linked with long-term adverse health effects, until recently little was known as to whether these associations extend to twins. A review of published studies suggests that at present there is little consistent evidence that birthsize in twins is associated with increased morbidity or morality. While, these findings may reflect methodological limitations, it is also argued that they arise as a consequence of the substantially different biology of fetal growth in twins.
... The potential risk of protease inhibitor-based combination antiretroviral therapy in pregnancy Although controversial and often complicated by multiple confounders, data from numerous studies suggest an association between PI-based cART and preterm, low birth weight, and small for gestational age births . Preterm birth and low birth weight are significant factors contributing to infant morbidity and mortality, and have been associated with severe short-term and long-term adverse health and social outcomes including increased risk of developmental delay in children [30][31][32][33][34][35], and higher risk for developing chronic ailments such as diabetes , heart disease, and asthma later in life [36][37][38][39]. Declining progesterone levels as a potential mechanism for the impact of protease inhibitors on birth outcomes ...
Background:
In Canada, the majority of HIV-positive pregnant women receive combination antiretroviral therapy that includes a ritonavir-boosted protease inhibitor to prevent mother-to-child HIV transmission. However, protease inhibitor-based combination antiretroviral therapy has been associated with increased rates of preterm, low birth weight, and small for gestational age births. Our previous experimental findings demonstrate that protease inhibitor use during pregnancy is associated with decreased progesterone levels that correlate with fetal growth, and that progesterone supplementation can improve protease inhibitor-induced fetal growth restriction. We hypothesize that HIV-positive pregnant women who receive protease inhibitor-based combination therapy may also benefit from progesterone supplementation during pregnancy.
Methods/design:
In order to test this hypothesis, we have designed an open-label, multi-centre, randomized controlled (parallel group) pilot trial. The initial goal of this trial is to test feasibility and acceptability of our intervention. Forty HIV-positive pregnant women who are either on, or intending to start or switch to a boosted protease inhibitor-based combination antiretroviral regimen will be enrolled from six sites across Ontario, Canada. Twenty-five women will be randomized to self-administer natural progesterone (Prometrium, 200 mg) vaginally every night starting between gestational week 16 and 24 until week 36, and 15 women will be randomized to no intervention. While the participants and treating physicians will not be blinded, the laboratory personnel performing the biochemical and morphological evaluations will be blinded to ensure unbiased evaluation. The primary outcome of the pilot study is the feasibility of enrolment as measured by the recruitment rate and patient-reported reasons to decline participation. Secondary outcomes in participants include safety, acceptability, and adherence to progesterone supplementation.
Discussion:
Given the safety of intravaginal progesterone and its current use in the general obstetrical population to prevent recurrent preterm delivery, this pilot study will provide data to determine the feasibility of a larger randomized controlled trial to assess the impact of this intervention on improving neonatal health in the context of HIV-positive pregnancies.
Trial registration:
ClinicalTrials.gov, NCT02400021.
... A human epidemiological study, also showed significant correlation between elevated levels of cortisol and higher blood pressure, plasma glucose levels and insulin resistance. The investigators found that independence of age and body mass index of adults, plasma cortisol levels decline dramatically with increasing birth weight, suggesting that the probable mechanism explaining the correlation of low birth weight and the metabolic syndrome in adult life, is the HPA axis programming [67]. ...
Objectives: This paper reviews the importance of maternal nutrition and weight gain with birthweigh and neonatal/childhood growth, and highlights the r isk of chronic diseases in later life.
Methods: The data was sourced based on the result of original and review articles relating to the life exposures, pregnancy weight gain, birth weight, childhood growth and the risk of chronic diseases in adult life.
Findings: Experimental studies have suggested that both maternal undernutrition and overnutrition are involved in later disease risk. Maternal macronutrient deficiency leads to LBW and subsequently insulin resistance and adiposity in later life. It seems that micronutrient deficiencies contribute to long-term negative effects such as metabolic syndrome and related disorders. As well as fetal life, early infancy, the adiposity rebound period and puberty also account as critical periods for the development of obesity in adulthood.
Conclusion: It is now widely accepted that the risks of adult chronic diseases may have their developmental origins in fetal life. Maternal under-nutrition or over-nutrition affect the infant’s health . Both macro- and micro-nutrients are critical for appropriate pregnancy outcomes. Understanding their precise patho-physiological mechanism are critical to apply new strategies to prevent the adverse effects of maternal dietary restriction and environmental factors in early stages of life.
... Стресс в пренатальный период стимулирует у беременной гипоталамо-гипофизарно-надпочечниковую систему, соответственно, и избыточный выброс глюкокортикоидов, что способствует повышению артериального давления и нарушению толерантности к глюкозе [22]. В эксперименте J. Lesage с коллегами было показано, что у мышей стресс матери способствует снижению массы всего плода, массы надпочечников и поджелудочной железы, что сопровождается уменьшением концентрации кортикостерона, глюкозы в плазме внутриутробно, но после рождения у этих особей чаще наблюдалась гипергликемия и нарушение толерантности к глюкозе [23]. Сразу после рождения регистрируется компенсаторное увеличение гликемии, нарушение толерантности к глюкозе, снижение базального уровня лептина, резко повышается аппетит. ...
Research investigating the early programming includes studies addressing the role of intrauterine nutrient availability, which is determined by maternal nutrition. This review will explore the epidemiological evidence for programming of metabolic disease and it will also discuss evidence for the proposed molecular mechanisms and the potential for intervention.
Maternal type 2 diabetes mellitus (T2DM) has been shown to result in foetal programming of the hypothalamic–pituitary–adrenal (HPA) axis, leading to adverse foetal outcomes. T2DM is preceded by prediabetes and shares similar pathophysiological complications. However, no studies have investigated the effects of maternal prediabetes on foetal HPA axis function and postnatal offspring development. Hence, this study investigated the effects of pregestational prediabetes on maternal HPA axis function and postnatal offspring development. Pre-diabetic (PD) and non-pre-diabetic (NPD) female Sprague Dawley rats were mated with non-prediabetic males. After gestation, male pups born from the PD and NPD groups were collected. Markers of HPA axis function, adrenocorticotropin hormone (ACTH) and corticosterone, were measured in all dams and pups. Glucose tolerance, insulin and gene expressions of mineralocorticoid (MR) and glucocorticoid (GR) receptors were further measured in all pups at birth and their developmental milestones. The results demonstrated increased basal concentrations of ACTH and corticosterone in the dams from the PD group by comparison to NPD. Furthermore, the results show an increase basal ACTH and corticosterone concentrations, disturbed MR and GR gene expression, glucose intolerance and insulin resistance assessed via the Homeostasis Model Assessment (HOMA) indices in the pups born from the PD group compared to NPD group at all developmental milestones. These observations reveal that pregestational prediabetes is associated with maternal dysregulation of the HPA axis, impacting offspring HPA axis development along with impaired glucose handling.
Background
Based on Barker’s hypothesis, some studies investigated the associations between birth weight and several disorders. Apart from issues with statistical power and well-known shortcomings of the observational study design, there are no studies accounting for changes in weight-related body size over the life course regarding rheumatoid arthritis, psoriasis, psoriatic arthritis and multiple sclerosis.
Methods
Using genetic information of up to 806 834 participants, this study investigated the associations between time-varying weight-related body size from birth to adulthood and the mentioned autoimmune diseases. Performing Mendelian randomisation (MR), the radial inverse-variance weighted approach was used iteratively in primary analyses. Robustness of the results was confirmed in several sensitivity analyses. Potential time-dependent mediation mechanisms were identified through network-clustering and assessed using multivariable MR.
Results
Genetically predicted birth weight (fetal effect) was positively associated with rheumatoid arthritis (OR 1.44; 95% CI 1.17 to 1.77; P adj =0.005) but not with psoriasis, psoriatic arthritis or multiple sclerosis. This association was found to be mediated by body mass index (BMI) in adulthood (OR 1.45; 95% CI 1.14 to 1.84; P adj =0.019) rather than childhood. The direct effect of birth weight attenuated (OR 1.19; 95% CI 0.88 to 1.62); P adj =1) after adjustment for time-varying BMI.
Conclusion
Increased birth weight appears to be a risk factor for later manifestation of rheumatoid arthritis due to both fetal genetic components and high BMI persisting into adulthood. Approaches to prevent and minimise the risk of rheumatoid arthritis could include preventing obesity in adults with high birth weight.
Stress, in both intrinsic psychosocial and extrinsic physical environmental forms, can impact the development of, and outcomes in, cardiovascular disease (CVD) through allostatic load. Cortisol is a core hormonal mediator of allostatic load produced in response to various stresses. Alterations in morning serum cortisol and daily diurnal cortisol have been associated with adiposity, dyslipidemia, incident diabetes, and CVDs such as hypertension. The review examines the role of cortisol as a key mechanistic link between stress physiology and cardiometabolic disease. Importantly, we discuss the role of targeting cortisol through pharmacological, behavioral, and environmental interventions to advance health equity in cardiometabolic disease.
Early-life environmental factors can have persistent effects on physiological functions by altering developmental procedures in various organisms. Recent experimental and epidemiological studies now further support the idea that developmental programming is also present in mammals, including humans, influencing long-term health. Although the mechanism of programming is still largely under investigation, the role of endocrine glucocorticoids in developmental programming is gaining interest. Studies found that perinatal glucocorticoids have a persistent effect on multiple functions of the body, including metabolic, behavioral, and immune functions, in adulthood. Several mechanisms have been proposed to play a role in long-term programming. In this review, recent findings on this topic are summarized and the potential biological rationale behind this phenomenon is discussed.
Animal and human data demonstrate independent relationships between fetal growth, hypothalamic-pituitary-adrenal axis function (HPA-A) and adult cardiometabolic outcomes. While the association between fetal growth and adult cardiometabolic outcomes is well-established, the role of the HPA-A in these relationships is unclear. This study aims to determine whether HPA-A function mediates or moderates this relationship. Approximately 2900 pregnant women were recruited between 1989-1991 in the Raine Study. Detailed anthropometric data was collected at birth (per cent optimal birthweight [POBW]). The Trier Social Stress Test was administered to the offspring (Generation 2; Gen2) at 18 years; HPA-A responses were determined (reactive responders [RR], anticipatory responders [AR] and non-responders [NR]). Cardiometabolic parameters (BMI, systolic BP [sBP] and LDL cholesterol) were measured at 20 years. Regression modelling demonstrated linear associations between POBW and BMI and sBP; quadratic associations were observed for LDL cholesterol. For every 10% increase in POBW, there was a 0.54 unit increase in BMI (standard error [SE] 0.15) and a 0.65 unit decrease in sBP (SE 0.34). The interaction between participant's fetal growth and HPA-A phenotype was strongest for sBP in young adulthood. Interactions for BMI and LDL-C were non-significant. Decomposition of the total effect revealed no causal evidence of mediation or moderation.
Background
In recent decades, several studies have shown changes in the intestinal microflora among patients with rheumatoid arthritis (RA). Therapeutic measures using probiotics have shown favorable effects on the recovery of these patients. However, most studies have used probiotic supplements. In this study, we aimed to investigate the effect of probiotic cheese consumption on inflammatory and anti-inflammatory factors, disease severity, and symptoms in these patients.
Methods
This study is a randomized, double-blind clinical trial, in which forty patients with mild to moderate severity of RA will be randomly allocated to receive either 30 g/day probiotic cheese ( n = 20) or only low-salt and low-fat cheese without any added probiotic ( n = 20) for 12 weeks. Assessment of anthropometric measures and biochemical indicators, including serum concentrations of high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10), will be done at the study baseline and end of the trial. In addition, disease severity and disability will be assessed by DAS-28 and the HAQ-DI questionnaire, respectively.
Discussion
Diet is the leading environmental factor affecting the gut microbiota. A prebiotic-rich diet and probiotics might be beneficial in this regard. To the best of our knowledge, the effect of probiotic supplements on inflammation in these patients has widely been assessed; however, there is only one study that examined the effect of probiotic-containing food in these patients. Further studies are needed to investigate the effect of probiotic-containing foods on inflammatory markers and symptoms in patients with RA.
Trial registration
Iranian Registry of Clinical Trials IRCT20201120049449N1 . Registered on 14 February 2021
We assessed the association between anxiety and hypertension in adults via a systematic review/meta-analysis. We searched PubMed, Ovid, and PsycINFO through 27 March 2020 with no language or publication type restrictions and systematically contacted study authors for unpublished information/data. We meta-analysed 59 studies including a total of 4,012,775 participants. Study quality was rated with the Newcastle-Ottawa Scale and random-effects analyses were performed. A significant anxiety-hypertension association was found in cross-sectional (OR = 1.37, 95% CI = 1.21-1.54) and prospective studies (OR = 1.40, 95% CI = 1.23-1.59). In sensitivity analyses, results were influenced by method of hypertension diagnosis, but not by study quality, method of anxiety diagnosis, study population, and effect size type. In subgroup analyses, study location, in particular country economic status, but not participant age, influenced the results. Longitudinal data and theoretical literature indicate that anxiety may precede hypertension. These findings have important clinical implications for the early detection and treatment of both anxiety and hypertension. Suggestions for future research are discussed.
Bone mass, a composite of bone size and mineral density, is a determinant of bone strength and is acquired during skeletal growth and development. Although up to 85% of bone mass is heritable, genetic polymorphisms explain only a small portion bone mass variation in healthy individuals. Many additional factors influence bone acquisition during infancy and childhood, including gender, calcium intake, vitamin D status, physical activity, obesity, and pubertal timing. In addition, studies have highlighted the importance of the intrauterine environment and maternal factors such as maternal smoking, physical activity, and nutrition on fetal bone acquisition and long-term bone health. Animal calciotropic hormone knockout models have provided significant insights into transplacental calcium transport mechanisms, whereas epidemiologic studies have provided insights into the life-long significance of bone acquisition during fetal development, infancy, and childhood. Finally, randomized clinical trials have demonstrated that physical activity and calcium intake impact pediatric bone acquisition.
The worldwide increase in metabolic diseases has urged the scientific community to improve our understanding about the mechanisms underlying its cause and effects. A well supported area of studies had related maternal stress with early programming to the later metabolic diseases. Mechanisms upon origins of metabolic disturbances are not yet fully understood, even though stressful factors rising glucocorticoids have been put out as pivotal trigger by programming metabolic diseases as long-term consequence. Considering energy balance and glucose homeostasis, by producing and/or sensing regulator signals, hypothalamus-pituitary-adrenal axis and endocrine pancreas are directly affected by glucocorticoids excess. We focus on the evidences reporting the role of increased glucocorticoids due to perinatal insults on the physiological systems involved in the metabolic homeostasis and in the target organs such as endocrine pancreas, white adipose tissue and blood vessels. Besides, we review some mechanisms underlining the malprogramming of type 2 diabetes, obesity and hypertension. Studies on this field are currently ongoing and even there is a good understanding regarding the effects of glucocorticoids addressing metabolic diseases, few is known about the relationship between maternal insults rising glucocorticoids to pups' metabolic disturbances, a thorough understanding about that may provide pivotal clinical clues regarding those disorders.
The long-term influence of gestational diabetes mellitus (GDM) on offspring and the effect of omega-3 polyunsaturated fatty acids (n-3 PUFA) on GDM offspring are poorly understood. We studied the long-term diabetic risk in GDM offspring and evaluated the effect of n-3 PUFA intervention. Healthy offspring rats were fed standard diet (soybean oil) after weaning. GDM offspring were divided into three groups: GDM offspring (soybean oil), n-3 PUFA adequate offspring (fish oil), and n-3 PUFA deficient offspring (safflower oil), fed up to 11 months old. The diabetic risk of GDM offspring gradually increased from no change at weaning to obvious impaired glucose and insulin tolerance at 11 months old. N-3 PUFA decreased oxidative stress and inflammation in the liver of older GDM offspring. There was a differential effect of n-3 PUFA and n-6 PUFA on hepatic telomere length in GDM offspring. Non-targeted metabolomics showed that n-3 PUFA played a modulating role in the liver, in which numerous metabolites and metabolic pathways were altered when GDM offspring grew to old age. Many metabolites were related to diabetes risk, such as α-linolenic acid, palmitic acid, ceramide, oxaloacetic acid, tocotrienol, tetrahydro-11-deoxycortisol, andniacinamide. In summary, GDM offspring exhibited obvious diabetes risk at old age, whereas n-3 PUFA decreased this risk.
Objective:
Maternal overweight has been associated with increasing offspring birth weight, but epidemiological data on potential biological mechanisms are limited. This study aimed to examine whether steroid hormones mediate the association between maternal prepregnancy BMI (pre-BMI) and birth weight.
Methods:
This study involving 2,039 participants was conducted from an ongoing cohort study in Wuhan, China. Mediation analysis was used to identify the extent to which steroid hormones mediated associations.
Results:
Each one-unit increase in pre-BMI was significantly associated with lower log2 -transformed cord blood levels of cortisol and corticosterone. Levels of cortisol and corticosterone were also negatively associated with birth weight. It was estimated that corticosterone mediated 3.48% of the association between pre-BMI and birth weight, and no significant mediation effect was observed in cortisol. After stratification by maternal gestational weight gain (GWG; within or in excess of the Institute of Medicine [IOM] guidelines), the associations of pre-BMI with cortisol and corticosterone levels were significant in the women with GWG > IOM but not in women with GWG ≤ IOM. When the mediation analysis in the women with GWG > IOM was limited, the mediation effects of cord blood cortisol and corticosterone were both significant (P < 0.05).
Conclusions:
Cord blood cortisol and corticosterone partially mediate the association of increased maternal pre-BMI with higher birth weight.
Maternal malnutrition is deleterious for the health of offspring throughout their life. The pathological process is thought to involve foetal programming and includes adult manifestations of the metabolic syndrome. Although the mechanism for programming is not proven, it is thought to involve epigenetic change, possibly including imprinting. Effects of maternal starvation are thought to affect multiple generations. The thrifty genotype hypothesis, more recently supplanted by the Barker hypothesis, or foetal programming, or thrifty phenotype hypothesis, might still contribute to the process. Proof or disproof of this will be possible when databases for the whole genome sequence of single tissues or even single cells can be compared within tissues of interest of populations exposed to maternal starvation and controls.
Infants born with low birth weights (<2500 g, LBW), accounting for about 15 % of newborns, have a high risk for postnatal growth failure and developing the metabolic syndromes such as type 2 diabetes, CVD and obesity later in life. Improper nutrition provision during critical stages, such as undernutrition during the fetal period or overnutrition during the neonatal period, has been an important mediator of these metabolic diseases. Considering the specific physiological status of LBW infants, nutritional intervention and optimisation during early life merit further attention. In this review, the physiological and metabolic defects of LBW infants were summarised from a nutritional perspective. Available strategies for nutritional interventions and optimisation of LBW infants, including patterns of nutrition supply, macronutrient proportion, supplementation of amino acids and their derivatives, fatty acids, nucleotides, vitamins, minerals as well as hormone and microbiota manipulators, were reviewed with an aim to provide new insights into the advancements of formulas and human-milk fortifiers.
Objectives Our research provides evidence on the intergenerational fetal programming effect by examining associations in the low birth weight (LBW, birth weight <2500 g) and intrauterine growth restriction (IUGR) status between two adjacent generations from both the maternal and paternal sides. Methods Birth certificate data of the entire Taiwanese population are used to construct three-consecutive-generational samples. The final samples consist of the third-generation children born during 1999–2006 to at least one second-generation (G2) parent born during 1978–1985. Maternal and paternal samples are distinguished based on the gender of G2. We first fit the samples with linear probability models while including extensive explanatory variables to control for myriad confounding factors. We then include G2 sibling fixed effects to account for family-specific heterogeneity. Alternative explanations of sample selection, parents’ assortative mating, and grandmothers’ postnatal investment are examined. Results We find that significant intergenerational associations in LBW and IUGR only occur matrilineally. Children born to LBW mothers are 2.28 (95% CI, 0.71–3.85; p < 0.01) percentage points, corresponding to 36%, more likely to be LBW compared to children born to non-LBW mothers who are sisters. These associations cannot be explained by the above alternative explanations. Conclusions Under G2 sibling comparisons, children born to LBW (IUGR) mothers are more likely to be LBW (IUGR), but children born to LBW (IUGR) fathers are not. The findings suggest that maternal health is pertinent and that socio-economic interventions may not yield the desired outcomes within a short period of time.
European countries, including France, have experienced a strong gain in life expectancy due to advances in science and health policy implemented in last 60 years. However, even if several devices have main role to reduce social inequalities in health care provision trying to diversify to meet different kinds of people, we still found strong disparities in terms of: use of care, medical consumption, and between social groups. This raises wider issues of social justice. Therefore, our study focuses on access to reproductive health care and reproductive health in a territory of Aquitaine (France).
Accumulating evidence suggests that both the intrauterine environment and growth during early life can influence the development of chronic noncommunicable diseases, such as type 2 diabetes mellitus and cardiovascular disease, in adulthood. Here, we review the available human data supporting increased metabolic risk among children born premature or small for gestational age; the adrenal and pubertal modifications that contribute to this risk; metabolic changes that occur during adolescence and early adulthood; and approaches to potentially modify or decrease risk of metabolic disease. The risks associated with delivery at term or preterm are compared for each period of life. Knowledge of these associations is fundamental for the paediatric community to develop preventive strategies early during postnatal life.
Aim/hypothesis
Hepatic forkhead box q1 (FOXQ1) expression levels are regulated by nutritional and pathophysiological status. In this study we investigated the role of FOXQ1 in the regulation of hepatic gluconeogenesis.
Methods
We used multiple mouse and cell models to study the role of FOXQ1 in regulating expression of gluconeogenic genes, and cellular and hepatic glucose production.
Results
Expression of hepatic FOXQ1 was regulated by fasting in normal mice and was dysregulated in diabetic mice. Overexpression of FOXQ1 in primary hepatocytes inhibited expression of gluconeogenic genes and decreased cellular glucose output. Hepatic FOXQ1 rescue in db/db and high-fat diet-induced obese mice markedly decreased blood glucose level and improved glucose intolerance. In contrast, wild-type C57 mice with hepatic FOXQ1 deficiency displayed increased blood glucose levels and impaired glucose tolerance. Interestingly, studies into molecular mechanisms indicated that FOXQ1 interacts with FOXO1, thereby blocking FOXO1 activity on hepatic gluconeogenesis, preventing it from directly binding to insulin response elements mapped in the promoter region of gluconeogenic genes.
Conclusions/interpretation
FOXQ1 is a novel factor involved in regulating hepatic gluconeogenesis, and the decreased FOXQ1 expression in liver may contribute to the development of type 2 diabetes.
Background:
Childhood obesity is an important risk factor for premature development of the metabolic syndrome (MetS) at adulthood. There is need for understanding of the mechanisms underlying the MetS and obesity. Patients with Cushing's disease suffer from similar metabolic complications, leading to the hypothesis that inter-individual cortisol variation may contribute to the onset of obesity. Additionally, glucocorticoid receptor (GR) gene polymorphisms resulting in differential glucocorticoid (GC) sensitivity, have been associated with an adverse metabolic profile.
Aim:
To study associations of GC levels in scalp hair, as a marker of long-term systemic GC concentrations, and genetically determined GC sensitivity with obesity and body-fat distribution in children.
Methods:
We performed a cross-sectional study of cortisol and cortisone concentrations over a 3-month period, measured by LC-MS/MS in hair of 3019 6-year-old children participating in the Generation R study. Genotyping of GR-gene polymorphisms was performed.
Results:
Of all children, 4.3% was obese and 13.4% overweight. Cortisol was significantly associated with risk of obesity (OR 9.4 (3.3-26.9)) and overweight (OR 1.4 (1.0-2.0)). Cortisone was associated with risk of obesity (OR 1.9 (1.0-3.5)). Cortisol and cortisone were significantly positively associated with BMI, fat mass (FM) index, and android/gynecoid FM ratio. GR polymorphisms were not associated with adiposity parameters.
Conclusion:
Long-term cortisol concentrations are strongly associated with an increased risk of childhood obesity and adverse body-fat distribution. Future research may reveal whether these are causal relations and may be a target for therapy.International Journal of Obesity accepted article preview online, 24 June 2016. doi:10.1038/ijo.2016.113.
Exposure to high levels of glucocorticoids (GCs) during early life induces long-lasting neuroinflammation. GCs induce rapid degranulation of mast cells, which release pro-inflammatory molecules promoting activation of microglia and astrocytes. The possible involvement of oligodendrocytes, however, remains poorly understood. We studied whether high GC levels during gestation activate the inflammasome in hippocampal oligodendrocytes of mouse offspring. Oligodendrocytes of control pups showed expression of inflammasome components (NLRP3, ACS and caspase-1) and their levels were increased by prenatal administration of dexamethasone (DEX), a synthetic GC. These cells also showed high levels of IL-1β and TNF-α, revealing activation of the inflammasome. Moreover, they showed increased levels of the P2X7 receptor and pannexin1, which are associated to inflammasome activation. However, levels of connexins either were not affected (Cx29) or reduced (Cx32 and Cx47). Nonetheless, the functional states of pannexin1 and connexin hemichannels were elevated and directly associated to functional P2X7 receptors. As observed in DEX-treated brain slices, hemichannel activity first increased in hippocampal mast cells and later in microglia and macroglia. DEX-induced oligodendrocyte hemichannel activity was mimicked by urocortin-II, which is a corticotropin-releasing hormone receptor (CRHR) agonist. Response to DEX and urocortin-II was inhibited by antalarmin (a CRHR blocker) or by mast cells or microglia inhibitors. The increase in hemichannel activity persisted for several weeks after birth and cross-fostering with a control mother did not reverse this condition. We propose that activation of the oligodendrocyte inflammasome might be relevant in demyelinating diseases associated with early life exposure to high GC levels. This article is protected by copyright. All rights reserved.
Fetal adaptation to undernutrition leads to permanent changes in physiology, metabolism, and structure of some organs. Smaller newborns are consequently more vulnerable to a number of diseases in later life including cardiovascular diseases (CVD), particularly if they show rapid weight gain and obesity in childhood. This chapter emphasizes the mechanisms that possibly link fetal undernutrition and risk of CVD in childhood: (1) oxygen concentration and inflammation; (2) changes in the structure and metabolism of the liver; (3) changes in blood vessels and heart; (4) change in the structure of the kidneys; (5) re-set of the hypothalamic-pituitary-adrenal, growth hormone–IGF axes; (6) changes in the structure of the pancreas and muscles; and (7) catch-up growth and obesity. Regardless of the explanations for the pathophysiological mechanisms associated with the “fetal programming hypothesis” we need to know about the specific maternal factors associated with a limited delivery of oxygen/nutrients to the fetus – their nature and timing in pregnancy – in order to prevent CVD. It is also urgent to understand how exactly the fetus changes the physiology, metabolism, and structure of some organs adapting to stimuli or injuries and how oxygen, nutrients, and hormones alter gene expression. We need new ways of integrating nutritional, environmental, behavioral, genetic, and epigenetic information.
During the last 2 decades evidence suggesting a role for prenatal diet in the development of adult disease has built up. One of the mechanisms that has been proposed to mediate this association is fetal programming of the stress response. It has been hypothesized that poor nutritional circumstances during gestation can alter the set points of the stress response resulting in lifelong over- or underactivation of the response, which subsequently causes disease. Support for the fetal programming of the stress response hypothesis has come from animal experiments as well as from human studies. Animal studies have mainly been performed in rats, guinea pigs, and sheep. In these studies, pregnant animals were fed a restricted diet after which functioning of the stress systems, the Hypothalamic–Pituitary–Adrenal (HPA)-axis and the Autonomic Nervous System (ANS), was measured in the offspring. Overall, results show that maternal food restriction induces growth retardation in the offspring as well as several alterations in the development of the HPA-axis and the ANS. Due to obvious ethical constrictions to manipulate the maternal diet research in humans has mainly focused on the effects of birth weight as an indirect measure of the fetal environment. Most birth-weight studies have shown an overactive HPA-axis and ANS in response to stress in people with low birthweight. Only two studies in humans have directly measured the effects of prenatal diet on stress responsiveness in later life. The Motherwell Study found that fasting cortisol concentrations and cortisol responses to a psychological stress protocol were elevated in men and women whose mothers consumed a diet consisting of high meat and fish intake and low green vegetables intake. The Dutch Famine Birth Cohort Study investigated the effects of prenatal exposure to the Dutch famine, which happened at the end of World War II in the Netherlands. Men and women who were exposed to the famine in utero did not show altered functioning of the HPA-axis. However, men and women exposed to the famine during early gestation did show greater blood pressure responsiveness to a psychological stress protocol. It can be concluded that prenatal diet definitely affects stress responsiveness in later life. The exact effect, how it happens, to what extent, and which factors are of importance, remains to be clarified. It seems justified though, to inform women of the importance of a balanced diet during pregnancy for the health of their babies.
Adrenal cortex produces three types of corticosteroids: mineralocorticoids, glucocorticoids, and androgens. Glucocorticoids suppress and androgens accelerate growth in length/height, while mineralocorticoids have no essential influence on growth. Excess of glucocorticoids delays bone maturation, which favors the chance of good catch-up growth after the source of excess glucocorticoids has been removed. Pituitary overproduction of ACTH (Cushing’s disease) and adrenal cortisol-producing tumors represent the endogenous states of glucocorticoid excess, but adrenal androgen overproduction may also be present in these conditions and affect the growth pattern. Systemic or local glucocorticoid treatment for medical reasons (asthma, juvenile rheumatoid arthritis, nephrotic syndrome, inflammatory bowel disease, and immunosuppression after organ transplantations) can cause Cushingoid features with obesity and poor growth in length/height. These conditions represent pure glucocorticoid excess as adrenal androgen production is usually suppressed. Most children born small for gestational age (SGA) catch up during the first few years of life, but about 10% do not catch up and will be short as adults. There is some evidence that SGA children without catch-up growth may have higher activity of the hypothalamic–pituitary–adrenal (HPA) axis than those who catch up. Hyperandrogenism accelerates bone maturation causing advancement of bone age. After the cause of adrenal hyperandrogenism has been removed, deceleration of growth in height (catch-down growth) is seen. If hyperandrogenism has lasted for a long time, some growth potential is often lost resulting in lower than expected adult height. Two main hypotheses have been developed to explain catch-up growth, the neuroendocrine and the growth plate hypothesis. Neither of these theories can fully explain the catch-up growth phenomenon in children, and the biochemical basis for catch-up growth is unclear. Although it is tempting to speculate that the somatotrophic axis would somehow be involved in the regulation of catch-up growth, there is no convincing evidence of an overt increase in growth hormone secretion or of sustained elevation of IGF levels during catch-up growth. The possible role of local alterations in the function of IGF receptors, IGF-binding proteins, or intracellular signal transduction pathways related to chondrocyte proliferation and apoptosis at the growth plate level are more difficult to study. Evidence is accumulating to support the role of intrinsic growth plate properties and enhanced chondrocyte proliferation as the basis of the intriguing phenomenon of catch-up growth.
Recent research suggests that a number of the major diseases of later life, including coronary heart disease, hypertension and non-insulin-dependent diabetes, originate through restriction of intrauterine growth and development. These diseases may be consequences of “programming”, whereby a stimulus or insult at a critical, sensitive period of early life has permanent effects on body size and proportions, and on a range of physiological processes. Evidence that coronary heart disease, hypertension and diabetes are programmed came from longitudinal studies of men and women in which size at birth was related to the occurrence of the disease in middle age. People who were small or disproportionate (thin or short) at birth had high rates of coronary heart disease, raised blood pressure and cholesterol levels, and abnormal glucose-insulin metabolism. Constraint of intrauterine growth and development seems to be widespread in the population, affecting many babies whose birthweights are within the normal range. Although the influences that impair fetal development and programme adult cardio-vascular disease remain to be defined, there are strong pointers to the importance of the maternoplacental capacity to satisfy the fetal nutrient requirement. Maternal nutrition can exert important effects on both the fetal nutrient demand and the maternoplacental supply capacity and may have hitherto unrecognised effects on both intrauterine development and health in later adult life.
Osteoporosis is a skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in the risk of fracture. These fractures typically occur at the hip, spine, and distal forearm; the annual cost attributable to them in England and Wales is £1.7 billion, with over 90% of this figure ascribed to hip fracture [1]. Figure 1 shows the history of advances in the field of osteoporosis over the previous three millennia. The recognition that fractures might be a consequence of bone fragility was initiated in the writings of Hippocrates; palaeopathological studies of bone specimens removed from burial sites dating as early at the 8th century AD confirm that osteoporotic vertebral collapse has occurred among elderly individuals throughout the ages. Our recent enhanced understanding of the disorder, however, stems from the work of orthopedic surgeons such as Sir Astley Cooper in 1825, who documented the descriptive characteristics of age-related fractures, and the observations of histopathologists in France and Germany at around the same time, who first coined the time “osteoporosis” to denote the rarification of trabecular architecture observed in the central part of vertebral bodies from patients who were elderly, when compared with those who had died at younger ages. The modern era of osteoporosis research originated in the research of Dr. Albright in the United States, who first documented osteoporotic vertebral deformity as a consequence of estrogen deficiency in postmenopausal women.
Aims/Introduction
Our previous study found that dexamethasone‐induced insulin resistance (IR) was involved in 5‐hydroxytryptamine (5‐HT) synthesis and 5‐hydroxytryptamine 2 receptor (5‐HT2R) in the periphery. The present study examined the effects of inhibitions of both peripheral 5‐HT synthesis and 5‐HT2R on dexamethasone‐induced IR.
Materials and Methods
Male rats were exposed to dexamethasone for 10 days, then treated with or without a 5‐HT2R antagonist, sarpogrelate, a 5‐HT synthetic inhibitor, carbidopa, alone or in combination for 20 days.
Results
Dexamethasone‐induced whole‐body IR, with glucose intolerance, decreased insulin sensitivity, hyperglycemia, hyperinsulinemia and dyslipidemia, could be effectively abolished by sarpogrelate or/and carbidopa, whereas IR‐related actions of dexamethasone in tissues were accompanied by increased 5‐HT synthesis in the liver and visceral adipose, and upregulated 5‐HT2R (5‐HT2AR and 5‐HT2BR) expression in these two tissues as well as in skeletal muscle. Sarpogrelate or/and carbidopa treatment significantly abolished dexamethasone‐caused tissue‐specific IR. In the liver, increased gluconeogenesis, triglycerides and very low‐density lipoprotein syntheses with steatosis, and downregulated expression of plasmalemmal glucose transporter‐2 were markedly reversed. In the visceral adipose and skeletal muscle, downregulated expression of plasmalemmal glucose transporter‐4 was significantly reversed, and increased lipolysis was also reversed in the visceral adipose. Dexamethasone‐induced activations of hepatic mammalian target of rapamycin serine²⁴⁴⁸, and S6K threonine389/412 phosphorylation were also abolished markedly by sarpogrelate or/and carbidopa. Co‐treatment with sarpogrelate and carbidopa showed a synergistic effect on suppressing dexamethasone actions.
Conclusion
Inhibitions of both peripheral 5‐HT synthesis and 5‐HT2R are expected to be a dependable target for treatment of steroid‐induced diabetes.
Fetal alcohol spectrum disorder (FASD) is the term used to describe the range of pervasive and long-lasting developmental, neurobehavioral, and physiological impairments induced by maternal alcohol (ethanol) consumption during pregnancy. Multiple factors interact to increase the risk of alcohol teratogenicity in the developing fetus, including the gestational timing, duration, and dose of alcohol exposure, amount consumed per drinking session, genetic and epigenetic factors, maternal and fetal stress, nutritional status, and alcohol metabolism capacity of the mother. Research findings from clinical and experimental animal models have characterized the range of fetal impairments produced by prenatal alcohol exposure (PAE), including defects in the developing brain, hypothalamic–pituitary–adrenal axis, heart, kidneys, lungs, auditory and visual systems, metabolic organs, and immune system. Importantly, PAE induces behavioral and cognitive deficits, which often represent the most pervasive and persistent manifestations of alcohol teratogenicity in offspring. The long-term effects of PAE may impact an individual’s mental health, resulting in increased susceptibility to depression, anxiety, substance use disorders, and social behavior deficits throughout adolescence and adulthood. Results to date also suggest that PAE can increase the risk of cardiovascular disease, respiratory disorders, infection, inflammation, obesity, and diabetes in postnatal life. Currently, there is no identified safe level of maternal alcohol consumption during pregnancy. Therefore, it is advised that alcohol consumption should be avoided entirely throughout pregnancy to ensure optimal fetal development.
Mental stress is known to contribute to the risk for hypertension and coronary atherosclerosis. Withania somnifera is well known for its anti-stress and antioxidant activity. The present study was done to assess the effect of Withania somnifera extract on acute mental stress induced changes in hemodynamics and arterial wave reflection properties in human participants. In this double-blind placebo-controlled randomized crossover study, 20 healthy participants received 500 mg twice daily of an encapsulated dried aqueous extract of roots and leaves of Withania somnifera or matching placebo for 14 days with a wash out period of 14 days. Blood pressure and central arterial wave reflections were measured noninvasively using Sphygmocor before and after a standardized mental stress test. The results demonstrated an acute effect of mental stress on blood pressure and arterial wave reflections. Withania somnifera extract produced a statistically significant decrease in aortic pressure, augmentation index, radial and aortic SBP radial and aortic DBP and significant increase in the subendocardial viability ratio (SEVR) compared to baseline and placebo. A significant decrease in hs-CRR MDA, serum cortisol levels is seen with Withania somnifera extract treatment compared to baseline and placebo. These results suggest that beneficial properties of Withania somnifera extract can mitigate the effects of stress and deserves further investigation in patients with associated diseases.
Insulin resistance is followed by several prevalent diseases. The most common condition with insulin resistance is obesity, particularly when localized to abdominal, visceral regions. A summary of recent reviews on the pathogenesis of systemic insulin resistance indicates that major factors are decreased insulin effects on muscular glycogen synthase or preceding steps in the insulin signalling cascade, on endogenous glucose production and on circulating free fatty acids (FFA) from adipose tissue lipolysis. Contributions of morphologic changes in muscle and other factors are considered more uncertain. Newly developed methodology has made it possible to determine more precisely the neuroendocrine abnormalities in abdominal obesity including increased cortisol and adrenal androgen secretions. This is probably due to a hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, amplified by inefficient feedback inhibition by central glucocorticoid receptors, associated with molecular genetic defects. Secondly, secretion of gender-specific sex steroid hormones becomes inhibited and the sympathetic nervous system activated. At this stage the HPA axis shows signs of a 'burned-out' condition, and cortisol secretion is no longer elevated. Cortisol counteracts the insulin activation of glycogen synthase in muscle, the insulin inhibition of hepatic glucose production and the insulin inhibition of lipolysis in adipose tissue, leading to the well-established systemic insulin resistance caused by excess cortisol. This is exaggerated by increased free fatty acid mobilization, particularly with a concomitant elevation of the activity of the sympathetic nervous system. Furthermore, capillarization and fiber composition in muscle are changed. These are the identical perturbations responsible for insulin resistance in recent reviews. The diminished sex steroid secretion in abdominal obesity has the same consequences. It is thus clear that insulin resistance may be induced by neuroendocrine abnormalities, such as those seen in abdominal obesity. These endocrine perturbations also direct excess fat to visceral fat depots via mechanisms that are largely known, indicating why abdominal obesity is commonly associated with insulin resistance. This possible background to the most prevalent condition of insulin resistance has been revealed by development of methodology that allows sufficiently sensitive measurements of HPA axis activity. These findings demonstrate the power of neuroendocrine regulations for somatic health. Copyright (C) 1999 John Wiley & Sons, Ltd.
Alterations in brain glucose metabolism and in peripheral glucose metabolism have frequently been observed in major depressive disorder (MDD). The insulin independent glucose transporter 1 (GLUT1) plays a key role in brain metabolism while the insulin-dependent GLUT4 is the major glucose transporter for skeletal and cardiac muscle. We therefore examined methylation of GLUT1 and GLUT4 in fifty-two depressed inpatients and compared data to eighteen healthy comparison subjects. DNA methylation of the core promoter regions of GLUT 1 and GLUT 4 was assessed by bisulfite sequencing. Further factors determined were fasting glucose, cortisol, insulin, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). We found significantly increased methylation of the GLUT1 in depressed inpatients compared to healthy comparison subjects (CG). Further findings comprise increased concentrations of fasting cortisol, glucose, insulin, and increased IL-6 and TNF-α. After six weeks of inpatient treatment, significantly lower GLUT1 methylation was observed in remitted patients compared to non-remitters. GLUT4 methylation was not different between depressed patients and CG, and did not differ between remitted and non-remitted patients. Although preliminary we conclude from our results that the acute phase of major depressive disorder is associated with increased GLUT1 methylation and mild insulin resistance. The successful treatment of depression is associated with normalization of GLUT1 methylation in remitters, indicating that this condition may be reversible. Failure of normalization of GLUT1 methylation in non-remitters may point to a possible role of impeded brain glucose metabolism in the maintenance of MDD.
Objective:
Elevated maternal psychosocial stress during pregnancy and accompanying changes in stress hormones may contribute to risk of adverse birth outcomes such as low birth weight and preterm birth. Relatedly, research on fetal programming demonstrates intriguing associations between maternal stress processes during pregnancy and outcomes in offspring that extend into adulthood. The purpose of this study was to test whether hypothalamic-pituitary-adrenal (HPA) patterns in mothers during the period between 2 pregnancies (i.e., the interpregnancy interval) and during the subsequent pregnancy predict infant birth weight, a key birth outcome.
Method:
This study sampled salivary cortisol before and during pregnancy in a diverse community sample of 142 women enrolled in the Community Child Health Network study.
Results:
Using multilevel modeling, we found that flatter diurnal cortisol slopes in mothers during the interval between one birth and a subsequent pregnancy predicted lower infant birth weight of the subsequent child. This interpregnancy cortisol pattern in mothers also correlated with significantly shorter interpregnancy intervals, such that women with flatter cortisol slopes had more closely spaced pregnancies. After adding demographic covariates of household income, cohabitation with partner, and maternal race to the model, these results were unchanged. For participants who provided both interpregnancy and pregnancy cortisol data (n = 73), we found that interpregnancy cortisol slopes predicted infant birth weight independent of pregnancy cortisol slopes.
Conclusions:
These novel findings on interpregnancy HPA axis function and subsequent pregnancy outcomes strongly support life course health approaches and underscore the importance of maternal stress physiology between pregnancies. (PsycINFO Database Record
Perinatal overweight and obesity is a major public health and clinical care issue that requires deliberate and immediate attention. Preconception and prenatal assessment and counseling should address the risks associated with obesity, recommendations for weight gain, proper nutrition and dietary intake, and physical activity. Nutrition and exercise guidance should be offered to all perinatal overweight and obese women with an emphasis on effective strategies to overcome barriers. All women should be encouraged to adopt a healthy lifestyle and achieve a healthy weight before becoming pregnant.
The field of life course epidemiology has expanded rapidly since this book was first published. The purpose of this field is to study how biological and social factors during gestation, childhood, adolescence, and earlier adult life independently, cumulatively, and interactively influence later life health and disease. Contributors to this edition capture the excitement of the developing field and assess the latest evidence regarding sources of risk to health across the life course and across generations. The chapters on life course influences on cardiovascular disease, diabetes, blood pressure, respiratory disease, and cancer have been updated and extended. New chapters on life course influences on obesity, biological ageing, and neuropsychiatric disorders have been added. Life course explanations for disease trends and for socioeconomic differentials in disease risk are given more attention in this edition, reflecting recent developments in the field. The section on policy implications has been expanded, assessing the role of interventions to improve childhood social circumstances, as well as interventions to improve early growth. Emerging new research themes and the theoretical and methodological challenges facing life course epidemiology are highlighted.
Glucocorticoids (Cortisol and corticosterone) have a host of biological effects inbrain and body, underpinning adaptive responses to stress and maintaining criticalaspects of basal metabolism (de Kloet 2004). Many neural and glial systems aremodified by glucocorticoids and their target genes include neurotransmitter systems,receptors, ion channels, cytoskeletal proteins, enzymes, second messengersystems, and metabolism. Acute rises of glucocorticoid levels are adaptive responsesto diurnal cues or stress, facilitating survival pathways and inhibiting immediatelyunhelpful processes such as digestion and inflammation. In contrast, chronicelevations of glucocorticoids (e.g., Cushing's syndrome) are detrimental to homeostasisat all phases of life from embryogenesis to senescence (de Kloet 1991, 2004).In the central nervous system (CNS), chronic glucocorticoid excess exerts profoundadverse effects, producing neuropsychiatric dysfunction (depression, psychosis),cognitive impairments, structural deterioration, and neuroendocrine abnormalities(McEwen 1999, 2003). Conversely, chronic severe deficiency of glucocorticoids(Addison's disease) is also deleterious, reducing an organism's survival in stressfulcircumstances and associating with reduced mood and hippocampal neuronal loss(Sloviter et al. 1989). Thus, it is obviously crucial that glucocorticoid levels arestrictly controlled. This is ensured by negative feedback control of the hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoids act predominantly by binding tointracellular receptors of two types; lower-affinity, widely distributed glucocorticoidreceptors (GR) and higher-affinity mineralocorticoid receptors (MR), whichhave a restricted tissue distribution (de Kloet 1991, 2004). In the hippocampus,where GR and MR are both highly expressed, both receptors bind the same glucocorticoidligands in vivo. Because the genes regulated by GR and MR in the hippocampusare largely distinct (Vreugdenhil and de Kloet 1998), nuclear accessory factors(coactivators and corepressors (Jenkins et al. 2001)) and the fine kinetics ofreceptor-DNA binding are also likely to be important. However, is the product of circulating steroid levels and this transcriptional machinery all there is to glucocorticoidbiology?
Over the last few years, a considerable amount of studies have focused on the effect of undernutrition and overnutrition during critical periods of offspring development and their risk of developing metabolic diseases later in life. Additionally, inadequate maternal diets have been involved in the malprogramming of brain functions and some behaviours. Several mechanisms have been associated with the process of malprogramming such as epigenetics modifications, excessive oxidative stress or hypothalamic alterations. This evidence supports the idea that nutritional prevention strategies must be considered for offspring during early development stages that include the preconceptional period. Additionally, studying involved mechanisms could be particularly useful in the search of efficient therapies against malprogramming.
Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.
How far is the health of middle-aged and older women shaped by biological, social, and psychological processes that begin in pre-natal development, childhood, adolescence, or early adult life? Do health risks gradually accumulate over the life course or do experiences as a child and young adult have interactive effects on health in midlife and beyond? Are women now reaching middle age in better health than those from previous generations? This book reviews the latest scientific evidence on biological and social factors at each stage of life that have long-term effects on reproductive outcomes, breast cancer, cardiovascular disease, diabetes, musculoskeletal ageing, depression, body weight, and body dissatisfaction. There is growing evidence that the sources of risk to physical and mental health occur across the course of life, not just in adult life, and in some instances reach right back to pre-natal development, or the previous generation. Contributors in this book draw on their varied expertise in epidemiology, endocrinology, physiology, developmental psychology, sociology, and anthropology to identify the pathways that link early life experiences, reproductive events, adult lifestyle and lifetime socio-economic circumstances to later health. This book looks for connections between development and ageing, and between the childhood and adult social environment.
Mounting evidence indicates that early life adversity is associated with increased vulnerability for psychiatric impairment across the lifespan. Until recently, most human studies in this field have been epidemiological in nature and focused on linking early life stress to complex clinical outcomes. This chapter advances a developmental psychophysiological model, where the chapter emphasizes the importance of considering the widespread brain systems that exert a strong influence on emotional reactivity and its regulation. This chapter reviews some of the recent work from our research group that has attempted to trace the effects of prenatal insults (using extremely low birth weight as a proxy marker) and those occurring in the postnatal time period (child maltreatment) on the functional integrity of key components within this affective neurocircuitry. The chapter emphasizes the value of non-invasive psychophysiological measures in helping to bridge the developmental pathways between early experience and psychological outcomes. © 2012 by Jacob A. Burack, James T. Enns, and Nathan A. Fox. All rights reserved.
This chapter discusses the adverse effects of prenatal ethanol exposure on neuroendocrine and immune function, with particular emphasis on the concept of fetal programming in the hypothalamic-pituitary-adrenal (HPA) axis, a key player in the stress response. The HPA axis is highly susceptible to programming during fetal and neonatal development. Early environmental experiences, including exposure to ethanol, can reprogram to HPA axis such that HPA tone is increased throughout life. The chapter presents data showing that gestational ethanol exposure increases HPA activity in both the pregnant female and the offspring. Increased exposure to endogenous glucocorticoids over the lifespan can alter behavioral and physiological responsiveness and predispose the organism to the development of certain diseases later in life.
Osteoporosis is the commonest bone disorder in Western populations. It is characterized by low bone mass and microarchitectural deterioration of bone tissue, which lead to increased bone fragility and the potentially devastating consequences of fragility fracture. It has been estimated that at age 50 the remaining lifetime risk of fracture at the wrist, spine or hip is 39% among women and 13% among men. The chapter also explains preterm delivery and bone metabolism; an infant born before 37 weeks of completed pregnancy is by definition preterm. With modern neonatal intensive care, survival is possible after as little as 23 weeks gestation. Preterm infants are born during an extremely rapid phase of mineral accretion and have low skeletal mineral stores at birth compared to a term infant that has built up large stores of mineral during the last trimester, and receives sufficient mineral substrate after delivery for the needs of normal growth and development to be satisfied. The preterm infant differs in a number of ways that renders them susceptible to mineral deficiency and metabolic bone disease: born during a phase of rapid growth and mineral accretion, poor early nutrition/mineral intake, and many more.
Genome wide association studies have identified ~100 loci associated with body mass index (BMI). Persons with low birth weight have an increased risk of metabolic disorders. We postulate that normal mechanisms of body weight regulation are disrupted in subjects with low birth weight. The present analyses included 2215 African American women from the Black Women's Health Study, and were based on genotype data on 20 BMI-associated loci and self-reported data on birth weight, weight at age 18 and adult weight. We used general linear models to assess the association of individual single-nucleotide polymorphisms (SNPs) with BMI at age 18 and later in adulthood within strata of birth weight (above and below the median, 3200 g). Three SNPs (rs1320330 near TMEM18, rs261967 near PCSK1 and rs17817964 in FTO), and a genetic score combining these three variants, showed significant interactions with birth weight in relation to BMI. Among women with birth weight <3200 g, there was an inverse association between genetic score and BMI; beta-coefficient=-0.045 (95% confidence intervals (CI) -0.104, 0.013) for BMI at age 18, and -0.055 (95% CI -0.112, 0.002) for adult BMI. Among women with birth weight ⩾3200 g, genetic score was positively associated with BMI: beta-coefficient=0.110 (95% CI 0.051, 0.169) for BMI at age 18 (P for interaction=0.0002), and 0.112 (95% CI 0.054, 0.170) for adult BMI (P for interaction<0.0001). Because TMEM18, PCSK1 and FTO are highly expressed in the central nervous system (CNS), our results suggest that low-birth weight may disrupt mechanisms of CNS body weight regulation.Journal of Human Genetics advance online publication, 19 November 2015; doi:10.1038/jhg.2015.139.
Background:
Events during foetal or early extrauterine life may affect bodily structure and/or functions and even pave the way for adult diseases.
Aims:
To find whether extremely low birth weight (ELBW) infants differ from healthy controls regarding the excretion of steroid metabolites.
Methods:
The study compared 17 female and 10 male ELBW infants, all prepubertal, aged 8-11 years, birth weight <1,000 g, with 27 age- and sex-matched controls. All were healthy at the time of the study. Height, weight and BMI did not differ between the groups. Results were adjusted according to body surface area. 36 urinary steroid metabolites were quantified by gas chromatography-mass spectrometry.
Results:
In the ELBW girls 33/36 steroid metabolites were higher (19 significantly) than in the controls. All 36 steroid metabolites were higher in the ELBW boys (9 significantly) than in the controls. Sums of mineralocorticoid precursors, metabolites descriptive for cortisol and parameters of adrenal androgen production were significantly higher in ELBW infants (both sexes). Only the sum of the metabolites known to be illustrative for adrenal 11β-hydroxysteroid dehydrogenase activity was not different.
Conclusion:
Prepubertal ELBW children have an augmented urinary excretion of adrenal androgens, cortisol and mineralocorticoid precursors. These findings corroborate and help to explain the link between early-life adversity and subsequent adrenocortical function.
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