E.F.C. van Rossum

High Long-Term Cortisol Levels, Measured in Scalp Hair, Are Associated With a History of Cardiovascular Disease

BACKGROUND Stress is associated with an increased incidence of cardiovascular disease. The impact of chronic stress on cardiovascular risk has been studied by measuring cortisol in serum and saliva, which are measurements of only 1 time point. These studies yielded inconclusive results. The measurement of cortisol in scalp hair is a novel method that provides the opportunity to measure long-term cortisol exposure. Our aim was to study whether long-term cortisol levels, measured in scalp hair, are associated with cardiovascular diseases. METHODS A group of 283 community-dwelling elderly participants were randomly selected from a large population-based cohort study (median age, 75 y; range, 65-85 y). Cortisol was measured in 3-cm hair segments, corresponding roughly with a period of 3 months. Self-reported data concerning coronary heart disease, stroke, peripheral arterial disease, diabetes mellitus, and other chronic noncardiovascular diseases were collected. RESULTS Hair cortisol levels were significantly lower in women than in men (21.0 vs 26.3 pg/mg hair; P < .001). High hair cortisol levels were associated with an increased cardiovascular risk (odds ratio, 2.7; P = .01) and an increased risk of type 2 diabetes mellitus (odds ratio, 3.2; P = .04). There were no associations between hair cortisol levels and noncardiovascular diseases. CONCLUSIONS Elevated long-term cortisol levels are associated with a history of cardiovascular disease. The increased cardiovascular risk we found is equivalent to the effect of traditional cardiovascular risk factors, suggesting that long-term elevated cortisol may be an important cardiovascular risk factor.

A polymorphic CA repeat in the IGF-I gene is associated with gender-specific differences in body height, but has no effect on the secular trend in body height.

objective  A polymorphism near the promoter region of the IGF‐I gene has been associated with serum IGF‐I levels, age‐related decline of serum IGF‐I levels, body height, birth weight and intima media thickness in hypertensive subjects.

Glucocorticoid sensitivity in mood disorders.

In this review, we provide an overview of recent literature on glucocorticoid (GC) sensitivity in mood disorders. Assessing GC sensitivity is often performed by measuring the cortisol awakening rise (CAR), by challenging the hypothalamic-pituitary–adrenal (HPA) axis using a dexamethasone suppression test (DST) or a dexamethasone/cortisol-releasing hormone test (DEX/CRH); more recently by measuring cortisol as a retrospective calendar in scalp hair. The main findings in mood disorders are higher mean cortisol levels in hair samples and a higher CAR, showing a hyperactivity of the HPA axis. This is in line with the mild resistance for GCs previously observed in challenge tests during mood episodes. GC sensitivity is partly determined by polymorphisms in the genes encoding receptors and other proteins involved in the regulation of the HPA axis. We shortly discuss the glucocorticoid receptor, as well as the mineralocorticoid receptor, the cortisol-releasing hormone receptor-1, and the glucocorticoid receptor co-chaperone FKBP5. Data clearly indicate genetic changes, along with epigenetic changes which influence the set-point and regulation of the HPA axis. Early trauma, as well as influences in utero, appears to be important. Future research is necessary to further clarify the biological background and consequences of an individual’s cortisol exposure in relation to mood.

A Novel Tool in the Diagnosis and Follow-Up of (Cyclic) Cushing's Syndrome: Measurement of Long-Term Cortisol in Scalp Hair

BACKGROUND Measurement of cortisol in 24-h urine collections and midnight saliva are standard screening tests for Cushings syndrome (CS). These tests reflect cortisol levels during a maximum of 24 h and do not provide historical information. Therefore, they can yield normal results in case of cyclic CS, which is a rare disorder that is characterized by alternating episodes of endogenous cortisol excess and normal cortisol secretion. The measurement of cortisol in scalp hair is a novel tool that might be helpful to establish the diagnosis of (cyclic) CS. Our aim was to study whether hair cortisol timelines correspond with clinical course in patients with CS and whether we could create retrospective timelines of cortisol exposure that correspond with symptomatic periods in patients suspected of cyclic CS. METHODS Scalp hair was collected in 14 patients with confirmed CS and six patients suspected of cyclic CS. Cortisol was extracted from the hair samples with methanol, and an ELISA was used to measure cortisol levels in hair extracts. A group of 96 nonobese individuals were used as a control group. RESULTS Hair cortisol levels were significantly elevated in CS patients (P<0.0001). Sensitivity and specificity of hair cortisol measurements for CS were 86 and 98%, respectively. Hair cortisol timelines of patients with CS and cyclic CS corresponded with clinical course. CONCLUSION Hair samples can provide a historical timeline that corresponds with clinical course in patients with (cyclic) CS. This new diagnostic tool can contribute significantly to early recognition of patients suffering from cyclic CS.

The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options

Obesity is one of the greatest public health challenges of the 21st century. Obesity is currently responsible for ∼0.7–2.8% of a country’s health costs worldwide. Treatment is often not effective because weight regulation is complex. Appetite and energy control are regulated in the brain. Melanocortin-4 receptor (MC4R) has a central role in this regulation. MC4R defects lead to a severe clinical phenotype with lack of satiety and early-onset severe obesity. Preclinical research has been carried out to understand the mechanism of MC4R regulation and possible effectors. The objective of this study is to systematically review the literature for emerging pharmacological obesity treatment options. A systematic literature search was performed in PubMed and Embase for articles published until June 2012. The search resulted in 664 papers matching the search terms, of which 15 papers remained after elimination, based on the specific inclusion and exclusion criteria. In these 15 papers, different MC4R agonists were studied in vivo in animal and human studies. Almost all studies are in the preclinical phase. There are currently no effective clinical treatments for MC4R-deficient obese patients, although MC4R agonists are being developed and are entering phase I and II trials.

The relationship between cortisol, muscle mass and muscle strength in older persons and the role of genetic variations in the glucocorticoid receptor.

Objective  Cortisol levels increase with age and hypercortisolism is associated with muscle weakness. This study examines the relationship between cortisol, muscle mass and muscle strength in community‐dwelling older persons and the role of genetic variations in the glucocorticoid receptor (GR).

Socioeconomic status in children is associated with hair cortisol levels as a biological measure of chronic stress

INTRODUCTION Low socioeconomic status (SES) may be associated with a high risk of lifestyle-related diseases such as cardiovascular diseases. There is a strong association between parental SES, stress and indicators of child health and adult health outcome. The exact mechanisms underlying this association have not yet been fully clarified. Low SES may be associated with chronic stress, which may lead to activation of the hypothalamic-pituitary-adrenal (HPA)-axis, resulting in a higher circulating level of the stress hormone cortisol. Therefore, chronic stress may mediate the association between low SES and elevated cortisol levels and its adverse outcomes. AIM We investigated whether SES was associated with a chronic measure of cortisol exposure in a child population. METHODS Cortisol and cortisone were measured in scalp hair in 270 children and adolescents, aged 4-18 years, enrolled through school visits. Neighborhood level SES was based on a score developed by the Netherlands Institute for Social Research using postal codes, and this includes neighborhood measures of income education and unemployment. Maternal and paternal education level were used as indicators of family SES. RESULTS Neighborhood level socioeconomic status score was significantly associated with hair cortisol (β=-0.103, p=0.007, 95%CI [-0.179, -0.028]) and hair cortisone (β=-0.091, p=0.023, 95%CI [-0.167, -0.015]), adjusted for age and sex. Additionally, hair cortisol was significantly correlated with maternal education level and hair cortisone was significantly correlated with paternal education level. CONCLUSION The results of our study suggest that the widely shown association between low family SES and adverse child health outcomes may be mediated by chronic stress, given the chronically higher levels of cortisol in children and adolescents in families with low SES. It is especially notable that the association between SES and cortisol was already found in children of young age as this can have major consequences, such as increased risk of cardio metabolic diseases in later life.

Glucocorticoid receptor gene polymorphisms and glucocorticoid sensitivity of subdermal blood vessels and leukocytes

A considerable variability in the sensitivity to glucocorticoids (GCs) exists between individuals and these differences have been implicated in the etiology of psychiatric diseases such as depression. Glucocorticoid receptor (GR) gene polymorphisms might account in part for variability in GC responsiveness. We assessed the association between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and markers of glucocorticoid sensitivity in two target tissues (subdermal blood vessels, peripheral leukocytes) in 206 healthy individuals. The BclI GG genotype group showed the least degree of skin blanching, reflecting a lower GC sensitivity of subdermal blood vessels (p=.01). No association between GR genotype and GC sensitivity of peripheral leukocytes was observed. In the same subjects we previously observed an association between GR genotype and GC sensitivity of the pituitary. Polymorphism of the GR gene might constitute a vulnerability or protection factor for stress related disorders and altered GC sensitivity.

Glucocorticoid and mineralocorticoid receptor polymorphisms and clinical characteristics in bipolar disorder patients.

INTRODUCTION The hypothalamus-pituitary-adrenal (HPA)-axis is often found to be dysregulated in bipolar disorder (BD) while stress and changes in day-night rhythms can trigger a new mood episode. Genetic variants of the glucocorticoid receptor (GR)- and mineralocorticoid receptor (MR)-gene influence both the reactivity of the stress-response and associate with changes in mood. In this study we tested the hypothesis that these polymorphisms associate with different clinical characteristics of BD. METHODS We studied 326 outpatients with BD and performed GR genotyping of the TthIIII, ER22/23EK, N363S, BclI, and 9β polymorphisms, as well as MR genotyping of the 2G/C and I180V variants. All patients were interviewed for clinical characteristics. RESULTS Seasonal patterns of hypomania are related to the BclI haplotype and the TthIIII+9β haplotype of the GR gene (respectively, crude p=.007 and crude p=.005). Carriers of the ER22/23EK polymorphism had an almost 8 years earlier onset of their first (hypo)manic episode than non-carriers (crude p=.004, after adjustment p=.016). No evidence for a role of the MR in modifying clinical manifestations was found. CONCLUSION Polymorphisms of the GR-gene are factors which influence some clinical manifestations of BD, with respect to seasonal pattern of (hypo)mania and age of onset.

BclI Glucocorticoid Receptor Polymorphism Is Associated With Greater Body Fatness: The Hoorn and CODAM Studies

CONTEXT The BclI polymorphism in the glucocorticoid receptor (GR) gene is associated with enhanced glucocorticoid (GC) sensitivity. OBJECTIVE Our objective was to investigate the association of the BclI polymorphism with body fatness and insulin resistance. DESIGN AND SETTING We conducted an observational cohort study, combining data from 2 cohort studies enriched with individuals with impaired glucose metabolism and/or diabetes mellitus type 2 (DM2). PATIENTS AND METHODS We examined 1228 participants (mean age 64.7 years, 45% women) from the Cohort Study on Diabetes and Atherosclerosis Maastricht (CODAM, n = 543) and the Hoorn Study (n = 685). Body mass index (BMI), waist and hip circumferences, and waist-to-hip ratio (WHR) were obtained; insulin resistance was estimated using the homeostasis model assessment for insulin resistance (HOMA2-IR). RESULTS We identified 519 noncarriers (CC), 540 heterozygous (CG) carriers, and 169 homozygous (GG) carriers of the G-allele of the BclI polymorphism. Homozygous carriers had a higher BMI (28.9 vs 27.9 kg/m(2)) and waist (99.6 vs 97.2 cm) and hip (105.5 vs 103.2 cm) circumference compared with noncarriers, also after adjustment for age, sex, cohort, glucose tolerance, and lifestyle risk factors: β = 0.94 kg/m(2) (95% confidence interval, 0.24-1.63), β = 2.84 cm (0.95;4.73) and β = 2.38 cm (0.88-3.87), respectively. Similar results were obtained when comparing homozygous carriers with heterozygous carriers: β = 1.03 kg/m(2) (0.34-1.72), β = 2.20 cm (0.31-4.08) and β = 1.99 cm (0.51-3.48), respectively. There were no differences in WHR. Ln-HOMA2-IR was higher in GG carriers compared with CG carriers; 0.29 vs 0.17 [β = 0.09 (0.01-0.17)], but this effect was attenuated after adjustment for BMI [β = 0.04 (-0.04 to 0.11)]. CONCLUSION Homozygous carriers of the BclI polymorphism of the GR gene have significantly greater total body fatness, contributing to higher HOMA2-IR, compared with heterozygous carriers and noncarriers.