Variation in the Glucocorticoid Receptor Gene: Consequences for Body and Brain

Glucocorticoids are hormones, of which the production is increased in response to physical or psychological stress. In basal conditions these hormones are also present in the circulation, but in lower levels. The major glucocorticoid in man is cortisol. The effects of glucocorticoids are mainly mediated by the glucocorticoid receptor, which is present in virtually all tissues throughout the body. This thesis is focused on the gene coding for the glucocorticoid receptor

Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition

Most actions of glucocorticoids (GCs) are mediated by the glucocorticoid receptor (GR). The interindividual response to GCs varies considerably, as demonstrated by a variable suppressive response to 0.25-mg dexamethasone (DEX). Several polymorphisms in the gene coding for the GR have been described. It is unclear to what extent the observed response variability is due to GR polymorphisms or to other factors. However, at least three polymorphisms seem to be associated with altered GC sensitivity and changes in body composition and metabolic parameters. The N363S polymorphism has been associated with increased sensitivity to GCs, increased insulin response to DEX, a tendency towards lower bone mineral density, and increased body mass index (BMI). However, other reports found no associations with BMI. Another polymorphism, previously described as a BclI restriction fragment length polymorphism, recently was identified as a C --> G nucleotide change. The G allele also was associated with increased sensitivity to GCs. In middle-aged subjects

Children’s hair cortisol as a biomarker of stress at school: a follow-up study

In a previous study, we examined hair cortisol concentrations (HCCs) in children when first entering elementary school (at 4 years). In this follow-up study, we examined their HCC when they entered third grade (at 6 years), where the more playful first grades proceed into a more formal learning setting. Participants were 30 6-year-old children (14 boys). Hair samples (≥5 cm) were collected 2 months after the summer holidays. Hair analysis was conducted using two 2-cm long segments, reflecting the first 2 months of school attendance in grade 3 (the scalp-near segment), and 2 months prior to the start in grade 3. Between these two sections, we left a gap of 1 cm to avoid overlap of periods (due to differences in hair growth rate). Children showed a significant increase in cortisol levels when they entered third grade. This increase was not associated with social fearfulness or academic achievement, but did show significant associations with inhibitory control: children with less inhibitory control had higher cortisol levels after entering third grade, and larger increases in cortisol than children with higher scores on inhibitory control. This suggests that the ability to inhibit or control impulsive responsivity is important for children’s stress regulation when making the transition to a more formal school environment

Intermitterend vasten en de effecten op overgewicht en cardiometabole gezondheid: wetenschap en praktijk

• Intermittent Fasting (IF) is a broad concept and covers several fasting regimes. • Studies of 'early time restricted feeding' and 'alternate day fasting' with energy restriction show a greater effect on weight and cardiometabolic health in overweight people in the short term, compared to a continuous caloric restriction (CCR). 'Late time restricted feeding' seems to have no or unfavorable effects. • Long-term studies (up to 2 years) suggest that IF regimens are not superior to continuous caloric restriction. • The few studies available show a similar compliance and metabolic adaptation between IF and CCR. • There is insufficient knowledge about long-term safety in various groups of people, the influence of dietary quality and the practical feasibility of IF regimes. • As a result, no recommendations can yet be made on the use of IF in the treatment of overweight and related diseases

Stress and Obesity: Are There More Susceptible Individuals?

PURPOSE OF REVIEW: Stress has long been suspected to be interrelated to (abdominal) obesity. However, interindividual differences in this complex relationship exist. We suggest that the extent of glucocorticoid action partly explains these interindividual differences. We provide latest insights with respect to multiple types of stressors.RECENT FINDINGS: Increased long-term cortisol levels, as measured in scalp hair, are strongly related to abdominal obesity and to specific mental disorders. However, not all obese patients have elevated cortisol levels. Possibly, the interindividual variation in glucocorticoid sensitivity, which is partly genetically determined, may lead to higher vulnerability to mental or physical stressors. Other evidence for the important role for increased glucocorticoid action is provided by recent studies investigating associations between body composition and local and systemic corticosteroids. Stress may play a major role in the development and maintenance of obesity in individuals who have an increased glucocorticoid exposure or sensitivity. These insights may lead to more effective and individualized obesity treatment strategies

T cell deficits and overexpression of hepatocyte growth factor in anti-inflammatory circulating monocytes of middle-aged patients with bipolar disorder characterized by a high prevalence of the metabolic syndrome

Background: We previously reported T cell deficits and pro-inflammatory gene activation in circulating monocytes of two cohorts of bipolar disorder (BD) patients, a cohort of postpartum psychosis patients and in bipolar offspring. Pro-inflammatory gene activation occurred in two clusters of mutually correlating genes, cluster 1 for inflammation-related cytokines/factors, cluster 2 for motility, chemotaxis, and metabolic factors. Aim: To verify these cellular immune abnormalities in yet another cohort [the bipolar stress study (BiSS) cohort] of relative old (52 years, median) BD patients and to relate immune abnormalities to hair cortisol levels, measured in this cohort and representing long-term systemic cortisol levels, and to the presence of the metabolic syndrome (MetS), which was prevalent in 29% of the BiSS patients. Methods: Monocyte immune gene activation (quantitative polymerase chain reaction) and T cell deficits (fluorescence-activated cell sorting analysis) were determined in 97 well-controlled, largely euthymic BiSS BD patients. Monocyte genes included the cluster 1 and 2 genes, the genes for the glucocorticoid receptor (GR) a and GRß, and the gene for hepatocyte growth factor [HGF, a marker of monocyte-derived circulating angiogenic cells (CACs)]. CACs serve vessel repair. Abnormal numbers are found in patients with MetS and vascular damage. Results: As compared to healthy controls: (1) the pro-inflammatory cluster 1 genes were downregulated, and the GRa and the HGF gene were upregulated in the monocytes of the BiSS patients and (2) T cell deficits were shown (reduced numbers of lymphocytes in particular of T cells). Within the reduced T cell population, a shift had taken place in the T-helper populations: T-helper 17 and T-helper 2 increased and T regulatory cells decreased. Correlations between hair cortisol, the MetS, monocyte gene activation, and T cell deficits were not found. Conclusion: T cell defic

Gender-specific effects of raising Year-1 standards on medical students' academic performance and stress levels

Context: Medical schools are challenged to create academic environments that stimulate students to improve their study progress without compromising their well-being. Objectives: This prospective comparative cohort study investigated the effects of raising Year-1 standards on academic performance and on students' chronic psychological and biological stress levels. Methods: In a Dutch medical school, students within the last Bachelor's degree cohort (n = 410) exposed to the 40/60 (67%) credit Year-1 standard (67%-credit cohort) were compared with students within the first cohort (n = 413) exposed to a 60/60 (100%) credit standard (100%-credit cohort). Main outcome measures were Year-1 pass rate (academic performance), mean score on the Perceived Stress Scale (PSS, psychological stress) and hair cortisol concentration (HCC, biological stress). Results: Year-1 pass rates were significantly higher in the 100%-credit cohort (odds ratio [OR] 4.65). Interestingly, there was a significant interaction effect (OR 0.46), indicating that raising the standard was more effective for male than for female students. PSS scores (n = 234 [response rate [RR]: 57%] and n = 244 [RR: 59%] in the 67%- and 100%-credit cohorts, respectively) were also significantly higher in the 100%-credit cohort (F(1,474) = 15.08, P <.001). This applied specifically to female students in the 100%-credit cohort. Levels of HCC (n = 181 [RR: 44%] and n = 162 [RR: 39%] respectively) did not differ between co

How childhood trauma and recent adverse events are related to hair cortisol levels in a large adult cohort

Background: Exposure to adversity is a risk factor for many mental and somatic health problems. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is a potential mechanism linking adversity exposure and negative health outcomes. However, associations between adversity exposure and HPA-axis activity have been inconsistent. To understand the impact of adversity on the HPA-axis, we examined associations between early-life and recent adversity with hair cortisol concentration, an indicator of long-term systemic cortisol levels. Methods: We included 1166 adult participants of the Netherlands Study of Depression and Anxiety (NESDA). Hair cortisol was measured in 3 cm of proximal hair, representing cortisol exposure during the previous 3 months. Childhood maltreatment, childhood negative life events, and recent negative life events were retrospectively assessed using interview and self-report questionnaires. Linear regression analyses were performed to assess the associations between childhood maltreatment, childhood life events and recent life events with hair cortisol. Associations with cumulative adversity exposure and with subtypes of childhood maltreatment, childhood and recent negative life events were also investigated, as were interaction effects between adversity and sex, age and psychopathology. Results: Childhood maltreatment (β = 0.034, p = 0.243), childhood

Hair cortisol-a method to detect chronic cortisol levels in patients with Prader-Willi syndrome

Background: Prader-Willi syndrome (PWS) is a multisymptomatic, rare, genetic, neurodevelopmental disorder in adults mainly characterized by hyperphagia, cognitive dysfunction, behavioral problems and risk of morbid obesity. Although endocrine insufficiencies are common, hypocortisolism is rare and knowledge on long-term cortisol concentrations is lacking. The aim of this study was to evaluate long-term cortisol levels in PWS by measurements of hair cortisol. Methods: Twenty-nine adults with PWS, 15 men and 14 women, median age 29 years, median BMI 27 kg/m2 , were included. Scalp hair samples were analyzed for cortisol content using liquid-chromatography tandem-mass spectrometry. In addition, a questionnaire on auxology, medication and stress were included. For comparison, 105 age- and sex-matched participants from the population-based Lifelines Cohort study were included as controls. The mean hair cortisol between the groups were compared and associations between BMI and stress were assessed by a generalized linear regression model. Results: In the PWS group large variations in hair cortisol was seen. Mean hair cortisol was 12.8 ± 25.4 pg/mg compared to 3.8 ± 7.3 pg/mg in controls (p = 0.001). The linear regression model similarly showed higher cortisol levels in patients with PWS, which remained consistent after adjusting for BMI and stress (p = 0.023). Furthermore, hair cortisol increased with BMI (p = 0.012) and reported stress (p = 0.014). Conclusion: Long-term cortisol concentrations were higher in patients with PWS compared to controls and increased with BMI and stress, suggesting an adequate cortisol response to chronic stress. Hair cortisol demonstrate promising applications in the context of PWS treatment and disease management