Long-term glucocorticoid exposure and incident cardiovascular diseases - the Lifelines cohort.

CONTEXT: Long-term glucocorticoid levels in scalp hair (HairGCs), including cortisol and the inactive form cortisone, represent the cumulative systemic exposure to glucocorticoids over months. HairGCs have repeatedly shown associations with cardiometabolic and immune parameters, but longitudinal data are lacking. DESIGN: We investigated 6341 hair samples of participants from the Lifelines cohort study for cortisol and cortisone levels, and associated these to incident cardiovascular diseases (CVD) during 5-7 years of follow-up. We computed the odds ratio (OR) of HairGC levels for incident CVD via logistic regression, adjusting for classical cardiovascular risk factors, and performed a sensitivity analysis in subcohorts of participants <60 years and >= 60 years. Also, we associated HairGC levels to immune parameters (total leukocytes and subtypes). RESULTS: Hair cortisone levels (available in n = 4701) were independently associated with incident CVD (p < 0.001), particularly in younger individuals (multivariate-adjusted OR 4.21, 95% confidence interval (CI) 1.91-9.07 per point increase in 10-log cortisone concentration (pg/mg), p < 0.001). All immune parameters except eosinophils were associated with hair cortisone (all multivariate-adjusted p < 0.05). CONCLUSIONS: In this large, prospective cohort study, we found that long-term cortisone levels, measured in scalp hair, represent a relevant and significant predictor for future cardiovascular diseases in younger individuals. These results highlight glucocorticoid action as possible treatment target for CVD prevention, where hair glucocorticoid measurements could help identify individuals that may benefit from such treatments.

Anthropometrics and Metabolic Syndrome in Relation to Glucocorticoid Receptor Polymorphisms in Corticosteroid Users.

INTRODUCTION: Corticosteroids are widely prescribed and their use has been linked to adverse cardiometabolic outcomes. A pivotal role in the action of corticosteroids is reserved for the glucocorticoid receptor (GR). Here, we assessed the relationship of glucocorticoid sensitivity-altering GR polymorphisms with anthropometrics and metabolic syndrome (MetS) in corticosteroid users. METHODS: In this population-based cohort study (Lifelines), we genotyped 10,621 adult participants for GR hypersensitive (1/2 copies BclI and/or N363S) and GR resistant (1/2 copies ER22/23EK and/or 9ß) variants. We assessed the relationship between functional GR polymorphisms with BMI, waist circumference (WC), and MetS in users of corticosteroids. RESULTS: Overall corticosteroid use was associated with a significantly higher BMI and WC in GR wild-type (WT) users (BMI, +0.63 kg/m2 [0.09-1.16], p = 0.022; WC, +2.03 cm [0.61-3.44], p = 0.005) and GR hypersensitive (BMI, +0.66 kg/m2 [95% CI, 0.31-1.01]; WC, +2.06 cm [1.13-2.98], both p < 0.001) but not in GR resistant users. Significantly higher WC in GR resistant carriers was observed only for inhaled corticosteroid users. With respect to MetS, again only GR WT users (odds ratio [OR] 1.44 [1.07-1.94], p = 0.017) and GR hypersensitives (OR 1.23 [95% CI, 1.00-1.50], p = 0.046) were more likely to have MetS; even more pronounced in only inhaled corticosteroid users (GR WT users, OR 1.64 [1.06-2.55], p = 0.027; GR hypersensitive users, OR 1.43 [1.08-1.91], p = 0.013). CONCLUSIONS: Polymorphisms associated with increased GR sensitivity and WT GR are related to increased BMI, WC, and an increased MetS presence in corticosteroid users, especially of the inhaled types, when compared to nonusers. The adverse effects of corticosteroid use are less pronounced in users harboring GR resistant polymorphisms.

Higher cortisol levels may proceed a manic episode and are related to disease severity in patients with bipolar disorder.

BACKGROUND: Regulation of the hypothalamic-pituitary-adrenal (HPA) axis is implicated in the pathogenesis of bipolar disorder (BD). However, the relationship between HPA-activity and disease severity is not fully elucidated. In this pilot study we aimed to explore the temporal relationship between HPA-activity and the risk of a manic episode in BD patients type I, by assessing long-term hair cortisol concentrations (HCC). Second, we explored the relation between HCC and the number of previous episodes. METHODS: Hair samples were collected from 45 BD I patients in euthymic or manic state and compared to 17 controls. From each participant, two hair samples of 3 cm length were used to measure long-term cortisol, reflecting retrospect time frames of 1-3 months and 4-6 months respectively prior to sampling. RESULTS: HCC in the BD group was slightly higher than in the control group in both hair segments (p = 0.049 and 0.03; after adjustment for age, sex, BMI and hair washing frequency p = 0.222 and 0.139). A significant peak in hair cortisol was observed prior to a manic episode (p = 0.036). Furthermore, we found a positive correlation between the number of mood episodes HCC (p = 0.03). CONCLUSIONS: Our results indicate that long-term cortisol levels are slightly higher in BD, and in particular elevated in the months prior to a manic relapse. In addition HCC are positively associated with the number of previous mood episodes in the course of BD type I.

Systemic and Local Corticosteroid Use Is Associated with Reduced Executive Cognition, and Mood and Anxiety Disorders.

BACKGROUND: Use of local corticosteroids, especially the inhaled types, has increasingly been associated with systemic uptake and consequent adverse effects. In this study, we assessed the associations between the use of different corticosteroid types with cognitive and neuropsychiatric adverse effects related to high glucocorticoid exposure. METHODS: In 83,592 adults (mean age 44 years, 59% women) of the general population (Lifelines Cohort Study), we analyzed the relationship between corticosteroid use with executive cognitive functioning (Ruff Figural Fluency Test), and presence of mood and anxiety disorders (Mini-International Neuropsychiatric Interview survey). We performed additional exploration for effects of physical quality of life (QoL; RAND-36), and inflammation (high-sensitive C-reactive protein [CRP]). RESULTS: Cognitive scores were lower among corticosteroid users, in particular of systemic and inhaled types, when compared to nonusers. Users of inhaled types showed lower cognitive scores irrespective of physical QoL, psychiatric disorders, and high-sensitive CRP. Overall corticosteroid use was also associated with higher likelihood for mood and anxiety disorders. Users of inhaled corticosteroids were more likely to have mood disorders (OR 1.40 [95% CI 1.19-1.65], p < 0.001) and anxiety disorders (OR 1.19 [95% CI 1.06-1.33], p = 0.002). These findings were independent of physical QoL. A higher likelihood for mood disorders was also found for systemic users whereas nasal and dermal corticosteroid users were more likely to have anxiety disorders. CONCLUSIONS: Commonly used local corticosteroids, in particular inhaled types, and systemic corticosteroids are associated with reduced executive cognitive functioning and a higher likelihood of mood and anxiety disorders in the general adult population.

Long-Term Cortisol Exposure and Associations With Height and Comorbidities in Turner Syndrome.

CONTEXT: Turner syndrome (TS) usually manifests in traits as short stature and premature ovarian failure. Many patients also have an increased risk of cardiometabolic disorders and psychological distress, which are features that overlap with those of a prolonged state of hypercortisolism. OBJECTIVE: To investigate whether TS is associated with increased long-term cortisol concentrations as measured in scalp hair and whether these are linked to cardiometabolic and psychological parameters. DESIGN: Prospective observational case-control study. SETTING: Academic outpatient TS expertise center. PARTICIPANTS: Fifty-five patients with TS (53% 45,X karyotype), and 110 age-matched female community control subjects from the general population-based Lifelines cohort study. MAIN OUTCOME MEASURES: Hair cortisol concentrations (HCC), anthropometrics, biochemical parameters, and psychological questionnaires for perceived stress (Perceived Stress Scale-14), fatigue (Checklist Individual Strength-20), and health-related quality of life (RAND-36). RESULTS: Compared with control subjects, patients with TS had higher HCC [geometric mean, 3.51 pg/mg (95% CI, 2.64 to 4.65) vs 2.39 pg/mg (2.13 to 2.68); P = 0.003] and a worse cardiometabolic profile in terms of fasting glucose, and triglycerides. HCC was only associated with total cholesterol levels (standardized ß = 0.294; P = 0.047) and was not associated with the psychological outcomes. A higher HCC was inversely associated with height only in patients with TS (standardized ß = -0.307; P = 0.023). CONCLUSION: Patients with TS are chronically exposed to higher cortisol levels, which is associated with short stature and increased total cholesterol levels, and potentially contributes to the known elevated cardiovascular disease risk.

Extensive Phenotyping for Potential Weight-Inducing Factors in an Outpatient Population with Obesity.

BACKGROUND: Obesity has been associated with miscellaneous weight-inducing determinants. A comprehensive assessment of known obesity-related factors other than diet and physical activity within one cohort is currently lacking. OBJECTIVES: To assess the prevalence of potential contributors to obesity and self-reported triggers for marked weight gain in an adult population with obesity and between obesity classes. METHODS: In this observational cohort study, we assessed 408 persons with obesity (aged 41.3 ± 14.2 years, BMI 40.5 ± 6.2) visiting our obesity clinic. They were evaluated for use of weight-inducing drugs, hormonal abnormalities, menarcheal age, (high) birth weight, sleep deprivation, and obstructive sleep apnea syndrome (OSAS). We additionally assessed self-reported triggers for marked weight gain and performed genetic testing in patients suspected of genetic obesity. RESULTS: Nearly half of the patients were using a potentially weight-inducing drug, which was also the most reported trigger for marked weight gain. For the assessed hormonal conditions, a relatively high prevalence was found for hypothyroidism (14.1%), polycystic ovary syndrome (12.0%), and male hypogonadism (41.7%). A relatively low average menarcheal age (12.6 ± 1.8 years) was reported, whereas there was a high prevalence of a high birth weight (19.5%). Sleep deprivation and OSAS were reported in, respectively, 14.5 and 13.7% of the examined patients. Obesity class appeared to have no influence on the majority of the assessed factors. Of the genetically analyzed patients, a definitive genetic diagnosis was made in 3 patients (1.9%). CONCLUSIONS: A thorough evaluation of patients with obesity yields a relatively high prevalence of various potentially weight-inducing factors. Diagnostic screening of patients with obesity could therefore benefit these patients by potentially reducing the social stigma and improving the outcomes of obesity treatment programs by tackling, where possible, the weight-inducing factors in advance.

Hair Glucocorticoids as a Biomarker for Endogenous Cushing's Syndrome: Validation in Two Independent Cohorts.

BACKGROUND/AIMS: The current diagnostic workup of Cushing's syndrome (CS) requires various tests which only capture short-term cortisol exposure, whereas patients with endogenous CS generally have elevated cortisol levels over longer periods of time. Scalp hair assessment has emerged as a convenient test in capturing glucocorticoid concentrations over long periods of time. The aim of this multicenter, multinational, prospective, case-control study was to evaluate the diagnostic efficacy of scalp hair glucocorticoids in screening of endogenous CS. METHODS: We assessed the diagnostic performances of hair cortisol (HairF), hair cortisone (HairE), and the sum of both (sumHairF+E), as measured by a state-of-the-art LC-MS/MS technique, in untreated patients with confirmed endogenous CS (n = 89) as well as in community controls (n = 295) from the population-based Lifelines cohort study. RESULTS: Both glucocorticoids were significantly elevated in CS patients when compared to controls. A high diagnostic efficacy was found for HairF (area under the curve 0.87 [95% CI: 0.83-0.92]), HairE (0.93 [0.89-0.96]), and sumHairF+E (0.92 [0.88-0.96]) (all p < 0.001). The participants were accurately classified at the optimal cutoff threshold in 86% of the cases (81% sensitivity, 88% specificity, and 94% negative predictive value [NPV]) by HairF, in 90% of the cases (87% sensitivity, 90% specificity, and 96% NPV) by HairE, and in 87% of the cases (86% sensitivity, 88% specificity, and 95% NPV) by the sumHairF+E. HairE was shown to be the most accurate in differentiating CS patients from controls. CONCLUSION: Scalp hair glucocorticoids, especially hair cortisone, can be seen as a promising biomarker in screening for CS. Its convenience in collection and workup additionally makes it feasible for first-line screening.

Associations Between Systemic and Local Corticosteroid Use With Metabolic Syndrome and Body Mass Index.

Context: Use of systemic corticosteroids (CSs) may induce adverse cardiometabolic alterations, potentially leading to obesity and metabolic syndrome (MetS). Although evidence is accumulating that local CSs have considerable systemic effects, their effects on cardiometabolic factors in the general population remain unclear. Objective: To investigate the association between overall CS use and specific CS types with MetS, body mass index (BMI), and other cardiometabolic traits. Design: Cross-sectional cohort study. Setting: General population from the northern Netherlands. Participants: A total of 140,879 adult participants in the population-based Lifelines Cohort Study. Main Outcome Measures: BMI, waist circumference, systolic and diastolic blood pressure, fasting metabolic serum parameters, and a comprehensive set of potential confounding factors. Results: In women, overall, systemic, and local CS use was associated with higher odds of having MetS. Among local female users, only nasal (odds ratio [OR], 1.20 [95% confidence interval (CI), 1.06 to 1.36]) and inhaled CSs [OR, 1.35 (95% CI, 1.24 to 1.49)] users were more likely to have MetS. In men, no association was found between overall and specific CS use and presence of MetS. Use of local-only CSs in women, specifically inhaled CSs in both sexes, was associated with higher BMI. Conclusions: Use of local CSs, particularly inhaled types, as well as systemic CSs, was associated with higher likelihood of having MetS, higher BMI, and other adverse cardiometabolic traits, especially among women. Because the inhaled agents are the main group of prescribed CSs, this might be a substantial risk to public health in case of a yet-to-be-proven causal relationship.

Systematic Evaluation of Corticosteroid Use in Obese and Non-obese Individuals: A Multi-cohort Study.

Background: Although the use of corticosteroids has been linked to high incidence of weight gain, no data are available concerning the differences in corticosteroid use between a diverse obese population and non-obese individuals. The main purpose of this study was to systematically explore the use of corticosteroids in obese subjects compared to non-obese controls. In addition, we also explored self-reported marked weight gain within obese subjects. Methods: Two hundred seventy-four obese outpatients (median [range] BMI: 40.1 kg/m2 [30.5-67.0]), and 526 non-obese controls (BMI: 24.1 kg/m2 [18.6-29.9]) from two different Dutch cohort studies were included. Corticosteroid use at the time of clinic or research site visit for up to the preceding three months was recorded in detail. Medical records and clinical data were evaluated with regard to age and body mass index in relation to corticosteroid use, single or multiple type use, and administration forms. Results: Recent corticosteroid use was nearly twice as high for obese subjects than for non-obese controls (27.0% vs. 11.9% and 14.8%, both P<.001). Largest differences were found for use of local corticosteroids, in particular inhaled forms, and simultaneous use of multiple types. Marked weight gain was self-reported during corticosteroid use in 10.5% of the obese users. Conclusion: Corticosteroid use, especially the inhaled agents, is higher in obese than in non-obese individuals. Considering the potential systemic effects of also local corticosteroids, caution is warranted on the increasing use in the general population and on its associations with weight gain.

Effect of diet-induced weight loss on lipoprotein(a) levels in obese individuals with and without type 2 diabetes.

AIMS/HYPOTHESIS: Elevated levels of lipoprotein(a) [Lp(a)] are an independent risk factor for cardiovascular disease (CVD), particularly in individuals with type 2 diabetes. Although weight loss improves conventional risk factors for CVD in type 2 diabetes, the effects on Lp(a) are unknown and may influence the long-term outcome of CVD after diet-induced weight loss. The aim of this clinical study was to determine the effect of diet-induced weight loss on Lp(a) levels in obese individuals with type 2 diabetes. METHODS: Plasma Lp(a) levels were determined by immunoturbidimetry in plasma obtained before and after 3-4 months of an energy-restricted diet in four independent study cohorts. The primary cohort consisted of 131 predominantly obese patients with type 2 diabetes (cohort 1), all participants of the Prevention Of Weight Regain in diabetes type 2 (POWER) trial. The secondary cohorts consisted of 30 obese patients with type 2 diabetes (cohort 2), 37 obese individuals without type 2 diabetes (cohort 3) and 26 obese individuals without type 2 diabetes who underwent bariatric surgery (cohort 4). RESULTS: In the primary cohort, the energy-restricted diet resulted in a weight loss of 9.9% (95% CI 8.9, 10.8) and improved conventional CVD risk factors such as LDL-cholesterol levels. Lp(a) levels increased by 14.8 nmol/l (95% CI 10.2, 20.6). In univariate analysis, the change in Lp(a) correlated with baseline Lp(a) levels (r = 0.38, p < 0.001) and change in LDL-cholesterol (r = 0.19, p = 0.033). In cohorts 2 and 3, the weight loss of 8.5% (95% CI 6.5, 10.6) and 6.5% (95% CI 5.7, 7.2) was accompanied by a median increase in Lp(a) of 13.5 nmol/l (95% CI 2.3, 30.0) and 11.9 nmol/l (95% CI 5.7, 19.0), respectively (all p < 0.05). When cohorts 1-3 were combined, the diet-induced increase in Lp(a) correlated with weight loss (r = 0.178, p = 0.012). In cohort 4, no significant change in Lp(a) was found (-7.0 nmol/l; 95% CI -18.8, 5.3) despite considerable weight loss (14.0%; 95% CI 12.2, 15.7). CONCLUSIONS/INTERPRETATION: Diet-induced weight loss was accompanied by an increase in Lp(a) levels in obese individuals with and without type 2 diabetes while conventional CVD risk factors for CVD improved. This increase in Lp(a) levels may potentially antagonise the beneficial cardiometabolic effects of diet-induced weight reduction.

Hair cortisol concentrations exhibit a positive association with salivary cortisol profiles and are increased in obese prepubertal girls.

Cortisol, a key mediator of the stress response, has been associated with obesity and metabolic syndrome manifestations as early as in childhood. Scalp hair cortisol has been proposed as a reliable index of long-term circulating cortisol. We aimed to investigate whether obese prepubertal girls have higher scalp hair cortisol than normal-weight controls and whether hair cortisol levels are correlated with salivary cortisol concentrations in these groups. In this cross-sectional study, 25 obese girls and 25 normal-weighted, age-matched girls were enrolled. Anthropometric evaluation, blood chemistry and salivary cortisol measurements were performed, and body mass index (BMI) and areas under the curve with respect to ground (AUCg) were calculated. Hair cortisol determination was performed with liquid chromatography-tandem mass spectrometry. Both hair cortisol concentrations and salivary cortisol AUCs were higher in the obese than the normal-weight girls (p < .001 and p = .002, respectively). A positive correlation between hair cortisol and BMI Z-score was found (rho = .327, p = .025), while hair cortisol correlated positively with salivary cortisol AUCg (rho = .3, p = .048). We conclude that obese prepubertal girls have higher hair and salivary cortisol concentrations than their age-matched lean counterparts. Hair cortisol assessment seems to be a sensitive method of evaluating systemic cortisol exposure, which is supported by our finding that hair cortisol is associated with salivary concentrations of the hormone. Lay Summary: Cortisol is the key hormone of the stress response. Childhood obesity has been associated with cortisol production dysregulation. Our findings suggest a positive association between obesity in prepubertal girls and elevated cortisol concentrations, measured in saliva and hair.

Scalp hair cortisol for diagnosis of Cushing's syndrome.

OBJECTIVE: Current first-line screening tests for Cushing's syndrome (CS) only measure time-point or short-term cortisol. Hair cortisol content (HCC) offers a non-invasive way to measure long-term cortisol exposure over several months of time. We aimed to evaluate HCC as a screening tool for CS. DESIGN: Case-control study in two academic referral centers for CS. METHODS: Between 2009 and 2016, we collected scalp hair from patients suspected of CS and healthy controls. HCC was measured using ELISA. HCC was available in 43 confirmed CS patients, 35 patients in whom the diagnosis CS was rejected during diagnostic work-up and follow-up (patient controls), and 174 healthy controls. Additionally, we created HCC timelines in two patients with ectopic CS. RESULTS: CS patients had higher HCC than patient controls and healthy controls (geometric mean 106.9 vs 12.7 and 8.4 pg/mg respectively, P < 0.001). At a cut-off of 31.1 pg/mg, HCC could differentiate between CS patients and healthy controls with a sensitivity of 93% and a specificity of 90%. With patient controls as a reference, specificity remained the same (91%). Within CS patients, HCC correlated significantly with urinary free cortisol (r = 0.691, P < 0.001). In two ectopic CS patients, HCC timelines indicated that cortisol was increased 3 and 6 months before CS became clinically apparent. CONCLUSIONS: Analysis of cortisol in a single scalp hair sample offers diagnostic accuracy for CS similar to currently used first-line tests, and can be used to investigate cortisol exposure in CS patients months to years back in time, enabling the estimation of disease onset.

The levonorgestrel-releasing intrauterine device potentiates stress reactivity.

BACKGROUND: The levonorgestrel-releasing intrauterine device (LNG-IUD) is currently recommended as a first-line contraceptive with an exclusively local intrauterine influence. However, recent clinical trials have identified side effects of LNG-IUD that appear to be systemically mediated, including depressed mood and emotional lability. METHODS: We performed two experimental studies and a cross-sectional study. For each study, women were included from three groups: LNG-IUD (0.02mg/24h), oral ethinylestradiol/levonorgestrel (0.03mg/0.15mg; EE30/LNG) and natural cycling (NC). Study 1-Salivary cortisol was measured at baseline and at defined intervals following the Trier Social Stress Test (TSST). Heart rate was monitored continuously throughout the TSST. Study 2-Salivary cortisol and serum total cortisol were evaluated relative to low-dose (1µg) adrenocorticotropic hormone (ACTH) administration. Study 3-Hair cortisol was measured as a naturalistic index of long-term cortisol exposure. RESULTS: Women using LNG-IUD had an exaggerated salivary cortisol response to the TSST (24.95±13.45 nmol/L, 95% CI 17.49-32.40), compared to EE30/LNG (3.27±2.83 nmol/L, 95% CI 1.71-4.84) and NC (10.85±11.03nmol/L, 95% CI 6.30-15.40) (P<0.0001). Heart rate was significantly potentiated during the TSST in women using LNG-IUD (P=0.047). In response to ACTH challenge, women using LNG-IUD and EE30/LNG had a blunted salivary cortisol response, compared to NC (P<0.0001). Women using LNG-IUD had significantly elevated levels of hair cortisol compared to EE30/LNG or NC (P<0.0001). CONCLUSIONS: Our findings suggest that LNG-IUD contraception induces a centrally-mediated sensitization of both autonomic and hypothalamic-pituitary-adrenal (HPA) axis responsivity. LNG-IUD sensitization of HPA axis responsivity was observed acutely under standardized laboratory conditions, as well as chronically under naturalistic conditions.

Hair analysis reveals subtle HPA axis suppression associated with use of local corticosteroids: The Lifelines cohort study.

BACKGROUND AND AIMS: Scalp hair is increasingly used to measure the long-term exposure to endogenous glucocorticoids hormones. Long-term cortisone (HairE) and cortisol (HairF) have been associated with obesity, metabolic syndrome, cardiovascular disease and psychopathology. However, little is known about the influence of the use of local corticosteroids and major stressful life events on hair glucocorticoids. MATERIALS AND METHODS: We determined HairE and HairF using liquid chromatography - tandem mass spectrometry in 295 adult participants of the population-based Lifelines cohort study (75% females, median age 42). We collected anthropometry and fasting metabolic laboratory values, questionnaires on hair characteristics, recent use of corticosteroids, and recent major stressful life events. RESULTS: After adjustment for covariates, hair glucocorticoids increased with age, male sex, black or brown hair color, and frequency of sweating on the scalp, and decreased with higher hair washing frequency (P<0.05). HairE was decreased in participants who used systemic corticosteroids (5.4 vs. 8.5pg/mg hair, P=0.041), and in participants who only used local agents such as inhaled, topical and nasal corticosteroids (6.8 vs. 8.5pg/mg, P=0.005). Recent life events were positively associated with HairF after adjustment for age and sex (P=0.026), but this association lost significance after adjustment for hair related characteristics (P>0.05). CONCLUSIONS: HairE can be a useful marker to detect mild adrenal suppression due to corticosteroid use in the general population, even when only inhaled, nasal or topical corticosteroids are used, which suggests that these commonly used agents induce systemic effects.

Glucocorticoid receptor haplotype and metabolic syndrome: the Lifelines cohort study.

OBJECTIVE: An excess of glucocorticoids (Cushing's syndrome) is associated with metabolic syndrome (MetS) features. Several single-nucleotide polymorphisms (SNPs) in the glucocorticoid receptor (GR) gene influence sensitivity to glucocorticoids and have been associated with aspects of MetS. However, results are inconsistent, perhaps due to the heterogeneity of the studied populations and limited samples. Furthermore, the possible association between functional GR SNPs and prevalence of MetS remains unexplored. DESIGN: Cross-sectional population-based cohort study. METHODS: MetS presence and carriage of functional GR SNPs (BclI, N363S, ER22/23EK, GR-9beta) were determined in 12 552 adult participants from Lifelines, a population-based cohort study in the Netherlands. GR SNPs were used to construct GR haplotypes. RESULTS: Five haplotypes accounted for 99.9% of all GR haplotypes found. No main effects of functional GR haplotypes on MetS were found, but the association of GR haplotype 4 (containing N363S) with MetS was influenced by interaction with age, sex and education status (P < 0.05). Stratified analysis revealed that haplotype 4 increased MetS presence in younger men (at or below the median age of 47; odds ratio 1.77, P = 0.005) and in people of low education status (odds ratio 1.48, P = 0.039). CONCLUSIONS: A glucocorticoid receptor haplotype that confers increased sensitivity to glucocorticoids appears to increase the risk of metabolic syndrome, but only among younger men and less educated individuals, suggesting gene-environment interactions.

Hair cortisol and cortisone are decreased by natural sunlight.

BACKGROUND AND AIMS: Hair glucocorticoids (cortisol and cortisone) are increasingly used as measures of long-term integrated exposure to glucocorticoid hormones. Glucocorticoids gradually disappear from the hair shaft, which may result from exposure to ultraviolet (UV) radiation in natural sunlight. We aimed to study the influence of sun exposure on hair glucocorticoids. MATERIAL AND METHODS: Scalp hair samples were obtained from nine volunteers (median age 33 [range 21-81], 7 females), and part of each hair sample was exposed to three experimental conditions: repeated exposure to natural sunlight for 40h (natural UV), exposure to a high amount of artificial UV radiation, and storage in the dark (control). Hair cortisol (HairF) and cortisone (HairE) were quantified by liquid chromatography-tandem mass spectrometry. RESULTS: When compared to control, HairF was decreased in 9 out of 9 hair samples after natural sunlight exposure (median decrease -3.1pg/mg or -54%, P<0.001) and artificial UV radiation (-4.7pg/mg or -75%, P=0.003). HairE decreased in 8 out of 9 samples, both after natural sunlight (-7.6pg/mg or -32%, P=0.012) and artificial UV (-10.7pg/mg or -52%, P=0.026). CONCLUSIONS: Exposure to natural sunlight decreases the glucocorticoid content of scalp hair, apparently through UV radiation, and is therefore an important confounder that should be considered in studies involving the measurement of hair glucocorticoids.

Clinical applications of cortisol measurements in hair.

Cortisol measurements in blood, saliva and urine are frequently used to examine the hypothalamus-pituitary-adrenal (HPA) axis in clinical practice and in research. However, cortisol levels are subject to variations due to acute stress, the diurnal rhythm and pulsatile secretion. Cortisol measurements in body fluids are not always a reflection of long-term cortisol exposure. The analysis of cortisol in scalp hair is a relatively novel method to measure cumulative cortisol exposure over months up to years. Over the past years, hair cortisol concentrations (HCC) have been examined in association with a large number of somatic and mental health conditions. HCC can be used to evaluate disturbances of the HPA axis, including Cushing's syndrome, and to evaluate hydrocortisone treatment. Using HCC, retrospective timelines of cortisol exposure can be created which can be of value in diagnosing cyclic hypercortisolism. HCC have also been shown to increase with psychological stressors, including major life events, as well as physical stressors, such as endurance exercise and shift work. Initial studies show that HCC may be increased in depression, but decreased in general anxiety disorder. In posttraumatic stress disorder, changes in HCC seem to be dependent on the type of traumatic experience and the time since traumatization. Increased hair cortisol is consistently linked to obesity, metabolic syndrome and cardiovascular disease. Potentially, HCC could form a future marker for cardiovascular risk stratification, as well as serve as a treatment target.

The relation between long-term cortisol levels and the metabolic syndrome in HIV-infected patients.

OBJECTIVE: Patients infected with the human immunodeficiency virus (HIV) have an increased risk of metabolic complications such as dyslipidaemia, insulin resistance and hypertension; symptoms that are also associated with an excess of the hormone cortisol. We studied the relationship between long-term cortisol levels and metabolic syndrome (MetS) in HIV-infected patients. DESIGN: Cross-sectional study performed at the outpatient clinic of infectious diseases of the Erasmus MC, University Medical Center Rotterdam, the Netherlands. METHODS: Fasting blood samples and anthropometric data were collected in 126 HIV-infected patients. An ELISA-based technique was used to determine long-term cortisol levels in scalp hair. Cortisol levels were compared to 191 healthy controls. RESULTS: A higher risk of MetS was observed in HIV patients with a low hair cortisol (odds ratio lower vs upper tertile 4·23, P = 0·04). Hair cortisol levels were not significantly different between HIV patients and healthy controls (16·4 pg/mg vs 13·5 pg/mg; P = 0·14). CONCLUSION: The risk of MetS was significantly higher in HIV-infected patients in the lowest hair cortisol group compared with patients in the highest hair cortisol group. This finding contrasts with results from studies in uninfected individuals where a high cortisol level in hair is associated with metabolic syndrome. The results of this study suggest that these metabolic complications might be related to relative cortisol hypersensitivity in HIV patients.

Advances in the assessment of cortisol exposure and sensitivity.

PURPOSE OF REVIEW: To review recent progress in the field of cortisol exposure and sensitivity, and its implications for research concerning obesity and related metabolic disturbances. RECENT FINDINGS: In the past few years, scalp hair analysis had been successfully introduced as a marker for long-term cortisol exposure. With this relatively novel method, increased long-term cortisol levels have been linked to cardiovascular disease, metabolic syndrome, and stress-related measures. At the tissue level, the effect of cortisol is modulated by genetically determined glucocorticoid sensitivity. Polymorphisms in the glucocorticoid receptor gene that influence glucocorticoid sensitivity have been associated with differences in metabolic syndrome components. SUMMARY: Hair analysis provides exciting new opportunities to study the influence of long-term cortisol exposure on a wide range of health outcomes, in both observational and interventional studies. We propose that addition of genetically determined glucocorticoid sensitivity to these studies may bring about a more thorough understanding of the long-term effects of cortisol.

Long-term cortisol levels measured in scalp hair of obese patients.

OBJECTIVE: In obese subjects a relatively high cortisol output in urine has been observed compared to nonobese individuals. However, cortisol levels in blood, saliva, and urine in association with obesity have been inconsistent across studies, possibly due to the high variability of systemic cortisol levels. Cortisol levels measured in scalp hair provide a marker for long-term cortisol exposure, and have been associated with cardiovascular disease in an elderly population and to disease course in Cushing's disease. We aimed to compare hair cortisol levels between obese patients and nonobese controls. METHODS: Hair cortisol levels of 47 obese patients (median BMI 38.8, range 31.1-65.8), 41 overweight, and 87 normal-weight subjects using an enzyme-linked immunosorbent assay (ELISA) were measured. RESULTS: Obese patients had higher hair cortisol levels than overweight and normal weight subjects (respectively 30.8 vs 8.5 and 8.4 pg/mg hair, P < 0.001). No significant difference in hair cortisol levels was found between normal weight and overweight subjects. CONCLUSIONS: Our results suggest a higher long-term cortisol exposure in obese patients, which may contribute to cardiovascular disease risk. Future research will determine whether long-term cortisol levels provide a novel treatment target in the management of cardiovascular disease risk in obesity.