Higher allostatic load in work-related burnout: The Regensburg Burnout Project.

BACKGROUND: Burnout and chronic work stress have been linked to various negative health outcomes. While the mechanisms underlying this interplay are still unclear, the allostatic load (AL) model was suggested to demonstrate a possible biological pathway. However, previous studies provided divergent results regarding the association between burnout and AL, probably also due to the heterogeneity of selected samples. Therefore, the aim of the present study was to examine differences in AL between a conceptually strictly specified group of individuals suffering from burnout (BO group) and a healthy comparison group (HC group). METHODS: After a multi-stage recruitment procedure with strict inclusion criteria based on burnout symptomatology and pathogenesis, the BO group (n = 56) was compared to the HC group (n = 65) regarding an index of AL. The AL-index included 14 parameters: high-sensitivity c-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), fibrinogen, d-dimer, plasminogen activator inhibitor 1 (PAI-1), glycosylated hemoglobin (HbA1c), high-density lipoprotein (HDL) cholesterol, total cholesterol to HDL cholesterol ratio (TC/HDL), dehydroepiandrosterone-sulphate (DHEA-S), systolic blood pressure (SBP), diastolic blood pressure (DBP), waist-hip ratio (WHR), and body fat percentage. RESULTS: The BO group showed significantly higher AL-scores in comparison to the HC group. This effect remained significant after adjusting for sex, age, and smoking status. Additionally, burnout symptoms (assessed with the Maslach Burnout Inventory; MBI), MBI-subscales emotional exhaustion and depersonalization as well as chronic work stress (assessed with the effort-reward imbalance questionnaire) were significantly associated with higher AL-scores. CONCLUSIONS: Consistent with our hypothesis, we detected higher AL-scores in the BO compared to the HC group, indicating a greater cumulative physiological burden in individuals suffering from burnout. Given the high heterogeneity in individuals experiencing burnout symptoms, future studies may focus on well-specified subgroups, when examining the association between burnout and psychophysiological dysregulations.

24 h urinary free cortisol in large-scale epidemiological studies: short-term and long-term stability and sources of variability.

BACKGROUND: Function of the hypothalamus-pituitary-adrenal (HPA) axis has been associated with several somatic and psychiatric health problems. The amount of free cortisol excreted in the urine during 24h (24-h UFC) has often been used as a proxy for HPA-axis function. Reference values for 24-h UFC and their stability in the short and long term, as well as sources of variability, are largely lacking. METHODS: This study was performed in a general population cohort. Participants collected 24-h UFC on two consecutive days (T1), and repeated this collection approximately 2 years later (T2). Cortisol in urine was measured using LC-MS/MS. Height and weight were measured at the research facilities; glomerular filtration rate was estimated using creatinine clearance. Psychological distress (General Health Questionnaire), smoking, alcohol use and exercise were measured by means of questionnaires. RESULTS: 24-h UFC stability on a day-to-day basis was 0.69 (T1, N=1192) and 0.72 (T2, N=963) (both p<0.001). Long-term stability as indicated by correlation between 2-day averages of T1 and T2 was 0.60 (N=972, p<0.001). Multivariable linear regression analysis revealed that 24-h UFC was predicted by urine volume (standardized beta 0.282 (T1, N=1556) and 0.276 (T2, N=1244); both p<0.001) and glomerular filtration rate (standardized beta 0.137 (T1) and 0.179 (T2); both p<0.001), while also sex explained a small part (standardized beta for female sex -0.057 (T1) and -0.080 (T2); both p<0.05). CONCLUSION: 24-h UFC is moderately stable both in the short and the long term. The effects of urine volume and glomerular filtration rate on 24-h UFC are much stronger than those of sex.

Glucocorticoid receptor gene, low-grade inflammation, and heart failure: the Heart and Soul study.

CONTEXT: A common haplotype of the glucocorticoid receptor (GR) gene has been associated with increased susceptibility to coronary heart disease (CHD). Whether this haplotype predisposes to heart failure (HF) is unknown. OBJECTIVE: The objective of the study was to determine whether GR haplotype 3 is associated with HF and whether this association is explained by low-grade inflammation (C-reactive protein). DESIGN: In a prospective cohort study, participants were genotyped for common GR gene polymorphisms (ER22/23EK, BclI C/G, N363S, 9beta A/G). Haplotype analyses were conducted. SETTING: The study was conducted at one university medical center, two Veterans Affairs medical centers, and nine public health clinics. PATIENTS: Patients included 526 white outpatients with stable CHD. MAIN OUTCOME MEASURES: Echocardiographic evidence of ventricular dysfunction, self-reported heart failure, and subsequent hospitalization for heart failure were measured. RESULTS: After adjusting for age, sex, smoking, and body mass index, participants with two copies of haplotype 3 were more likely than those with 0 or 1 copy to report heart failure [hazard ratio (HR) 4.15, 95% confidence interval (CI) 1.5-11.3, P < 0.01], have systolic dysfunction (left ventricular ejection fraction <50%) (HR 3.0, 95% CI 0.9-9.9, P = 0.07), and be hospitalized for HF during a mean follow-up of 6 yr (HR 3.0, 95% CI 1.3-7.0, P = 0.01). These associations were attenuated after adjustment for higher C-reactive protein levels in patients with two copies of haplotype 3. CONCLUSIONS: We found that the GR gene haplotype 3 was associated with prevalent HF, systolic dysfunction, and subsequent HF hospitalization in patients with CHD. This association was partly mediated by low-grade inflammation.

Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance.

Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis has been associated with the etiology of major depression. One of the factors underlying altered glucocorticoid signaling might be variability of the glucocorticoid receptor gene (GR, NR3C1). GR polymorphisms have been associated with variability in glucocorticoid sensitivity and endocrine responses to psychosocial stress. Furthermore, a common GR SNP (rs10482605), located in the promoter region, has been associated with major depression. We performed functional characterization of this SNP in vitro using a reporter gene assay under different stimulation conditions. Furthermore, we genotyped 219 subjects previously genotyped for four common GR SNPs to further characterize GR haplotype structure. The minor C allele of the rs10482605 SNP showed reduced transcriptional activity under unstimulated conditions and under different stimulation conditions in two brain derived cell lines. Linkage analyses revealed that the rs10482605 SNP is in high linkage disequilibrium with a A/G SNP in exon 9beta (rs6198), associated with relative glucocorticoid resistance and increased GRbeta mRNA stability. We provide evidence that two functional GR SNPs in linkage disequilibrium are responsible for both regulation of GR expression and mRNA stability. This newly characterized haplotype could increase the risk for the development of stress related disorders, including major depression.

Why do we respond so differently? Reviewing determinants of human salivary cortisol responses to challenge.

Stress and stress-related health impairments are major problems in human life and elucidating the biological pathways linking stress and disease is of substantial importance. However, the identification of mechanisms underlying a dysregulation of major components of the stress response system is, particularly in humans, a very challenging task. Salivary cortisol responses to diverse acute challenge paradigms show large intra- and interindividual variability. In order to uncover mechanisms mediating stress-related disorders and to potentially develop new therapeutic strategies, an extensive phenotyping of HPA axis stress responses is essential. Such a research agenda depends on substantial knowledge of moderating and intervening variables that affect cortisol responses to different stressors and stimuli. The aim of this report is, therefore, to provide a comprehensive summary of important determinants of, in particular, human salivary cortisol responses to different kinds of laboratory stimuli including acute psychosocial stress as well as pharmacological provocation procedures. This overview demonstrates the role of age and gender, endogenous and exogenous sex steroid levels, pregnancy, lactation and breast-feeding, smoking, coffee and alcohol consumption as well as dietary energy supply in salivary cortisol responses to acute stress. Furthermore, it briefly summarizes current knowledge of the role of genetic factors and methodological issues in terms of habituation to repeated psychosocial stress exposures and time of testing as well as psychological factors, that have been shown to be associated with salivary cortisol responses like early life experiences, social factors, psychological interventions, personality as well as acute subjective-psychological stress responses and finally states of chronic stress and psychopathology.

Prenatal psychosocial stress exposure is associated with insulin resistance in young adults.

OBJECTIVE: The objective of the study was to examine the association in humans between maternal psychosocial stress exposure during pregnancy and measures of glucose-insulin metabolism in the adult offspring. STUDY DESIGN: Healthy young adults whose mothers experienced major stressful life events during their pregnancy (n = 36, prenatal stress, PS group, mean age 25 +/- 5.14 [SD] years) and a comparison group (n = 22, CG, mean age 24 +/- 3.7 [SD] years) underwent an oral glucose tolerance test. RESULTS: Glucose levels were not significantly different across the groups; however, prenatally stressed subjects showed significantly elevated 2-hour insulin (P = .01) and C-peptide levels (P = .03). These differences were independent of other major risk factors for insulin resistance, including birth phenotype (birthweight, length of gestation), a family history of diabetes, gestational diabetes, body mass index, proinflammatory state, and smoking. CONCLUSION: Higher insulin responses reflect relative insulin resistance in these prenatally stressed young adults. This study is the first to provide evidence for a link in humans between prenatal psychosocial stress exposure and alterations in glucose-insulin metabolic function.

Sex specific associations between common glucocorticoid receptor gene variants and hypothalamus-pituitary-adrenal axis responses to psychosocial stress.

BACKGROUND: Alterations in glucocorticoid (GC) signaling have been associated with a number of psychiatric disorders. Genetic variation of the glucocorticoid receptor (GR) might be one of the factors underlying susceptibility to stress related disease. METHODS: We investigated 206 healthy subjects and assessed associations between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress (Trier Social Stress Test, TSST) and glucocorticoid sensitivity measured by a dexamethasone suppression test (DST). RESULTS: Male 9beta AG carriers displayed the highest adrenocorticotropic hormone (ACTH) and total cortisol TSST responses (for ACTH: main effect genotype p = .02) whereas male BclI GG carriers showed diminished responses. Remarkably, the BclI GG genotype in women (all using oral contraceptives) was associated with the highest total cortisol TSST responses, resulting in a significant sex by genotype interaction (p = .03). Following the DST, male 9beta AG carriers had elevated ACTH levels (sex by genotype interaction p = .03). CONCLUSIONS: We observed significant sex specific associations between GR gene polymorphisms and HPA axis responses to psychosocial stress as well as GC sensitivity. These findings support the relevance of GR gene polymorphisms in HPA axis regulation. Genetic variations of the GR might constitute a risk factor in development of HPA axis related disorders.

A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness.

CONTEXT: Mineralocorticoid receptors (MR) mediate the action of aldosterone on sodium resorption in kidney tubular cells, but in brain they respond to the glucocorticoid cortisol in stress regulation and cognitive processes. OBJECTIVE: The objective of the study was to investigate the role of the MR gene variant I180V in the neuroendocrine response to a psychosocial stressor and in electrolyte regulation. DESIGN: Associations between the MRI180V and outcome variables in a healthy cohort subjected to psychosocial challenge (Trier Social Stress Test) and in a mild hypertensive cohort exposed to acute salt loading (Weinberger's test) were investigated. In vitro transactivational assays were applied to compare the effects of cortisol and aldosterone on the MRI180V. RESULTS: Carriers of the MR180V allele showed higher saliva (P < 0.01), plasma cortisol (P < 0.01), and heart rate responses (P < 0.05) to the Trier Social Stress Test than noncarriers (MR180I). After 3 d of a normal salt diet and the Weinberger's test, no association was found with urinary sodium excretion, plasma aldosterone, and plasma renin activity or with changes in blood pressure, aldosterone, and renin responses. In vitro testing of the MR180V allele revealed a mild loss of function using cortisol as a ligand, compared with the MR180I allele. Significantly higher doses of cortisol were needed for half-maximal induction on the TAT-1 (P < 0.002), TAT-3 (P < 0.03), or mouse mammary tumor virus (P < 0.02) promoters, whereas maximal induction was not different. These differences were not observed using aldosterone as a ligand. CONCLUSION: The findings reveal that cortisol and heart rate responses to a psychosocial stressor are enhanced in carriers of the MR180V variant.

The heritability of hypothalamus pituitary adrenal axis responses to psychosocial stress is context dependent.

Individual differences in the response of the hypothalamus pituitary adrenal axis to stress are known to play an important role in health and disease risk. The origins, or determinants, of these individual differences are not well understood. To date, no study has examined the effects of context on the heritability of psychoendocrine stress responses. In the present study, 58 male twin pairs were exposed to a psychosocial stressor (Trier Social Stress Test) three times at weekly intervals, and their salivary and total cortisol, ACTH, and heart rate responses were assessed. Modest heritabilities were observed for all measures at the first stress exposure (all h2 < 0.33), but heritability estimates increased substantially with repetition of the stressor (T3: all h2 > 0.97). Concurrently, only the first but not the second and third Trier Social Stress Test exposure induced a significant increase in state anxiety (T1: P < 0.01, T2 and T3: n.s.), suggesting low heritabilities in a new, anxiety-evoking context and high heritabilities in a familiar, low-anxiety context. These findings challenge previous reports on a low heritability of markers of stimulated hypothalamus pituitary adrenal axis activity and are the first to document the relevance of context for psychoendocrine heritability estimates.

The cortisol awakening response - normal values and confounds.

In several recent investigations it could be demonstrated that the free cortisol response to awakening can serve as an useful index of the adrenocortical activity. When measured with strict reference to the time of awakening the assessment of this endocrine response is able to uncover subtle changes in hypothalamus-pituitary-adrenal (HPA) axis activity, which are, for instance, related to persisting pain, burnout and chronic stress. Furthermore, it has been suggested that the HPA axis might serve as an indicator of allostatic load in subjects exposed to prolonged environmental noise. In the present paper four separate studies with a total of 509 adult subjects were combined in order to provide reliable information on normal values for the free cortisol response to awakening. Corresponding with earlier findings, a mean cortisol increase of about 50% within the first 30 minutes after awakening was observed. The intraindividual stability over time was shown to be remarkably high with correlations up to r=.63 (for the area under the response curve). Furthermore, the cortisol rise after awakening is rather consistent, with responder rates of about 75%. Gender significantly influenced early morning free cortisol levels. Although women showed a virtually identical cortisol increase after awakening compared to men, a significantly delayed decrease was observed. Confirming and extending previous findings, the present study strongly suggests that neither age, nor the use of oral contraceptives, habitual smoking, time of awakening, sleep duration or using / not using an alarm clock have a considerable impact on free cortisol levels after awakening. The cortisol awakening response can be assessed under a wide variety of clinical and field settings, since it is non-invasive, inexpensive and easy-to-employ. The present data provide normal values and information on potential confounds which should facilitate investigations into the endocrine consequences of prolonged exposure to environmental noise.