Improved Physical and Mental Health After a Combined Lifestyle Intervention with Cognitive Behavioural Therapy for Obesity.

Background: Obesity is a multifactorial, chronic, progressive disease associated with decreased health-related quality of life, comorbidities, and increased mortality risk. Lifestyle interventions, focusing on dietetics, physical exercise, and behavioral therapy, are a cornerstone of therapy. Despite this very multidisciplinary treatment approach, the definition of treatment success is often based only on a weight loss of ≥ 5%. However, the heterogeneous nature of obesity may necessitate a more comprehensive approach to assessing treatment effects. Objectives: Here, we describe changes in physiological, psychological, and behavioral health after a multidisciplinary combined lifestyle intervention (CLI). Additionally, we investigated whether these changes were related to weight loss. Methods: This prospective observational longitudinal study comprised 96 adults with obesity (73 women, 81 Caucasian) participating in a CLI at the Obesity Center CGG, Erasmus University Medical Center, Rotterdam, the Netherlands. The 1.5-year intervention comprised multidisciplinary professional guidance towards a healthy diet, increased physical activity, and included cognitive behavioral therapy. Physiological health outcomes, psychological well-being, eating behavior, and physical activity were assessed after ten weeks and 1.5 years and compared to baseline. Results: An average of 5.2% weight loss (-6.0 kg) was accompanied by a mean 9.8% decrease in fat mass (-5.9 kg; both P < 0.001) and significant improvements in metabolism, hormonal status, and immune parameters (all P < 0.05). Moreover, we observed decreased psychopathology, increased quality of life, and decreased disordered eating (all P < 0.05). Weight loss correlated with most metabolic changes (all P < 0.05) but not with most psychological/behavioral changes. Conclusions: Combined lifestyle intervention in patients with obesity was accompanied by significant improvements in body weight and body composition along with cardiometabolic, endocrine, immunological, psychological, and behavioral improvements. Interestingly, most changes in psychological and behavioral health occurred independently of weight loss. Obesity treatment success should be evaluated based on a combination of physical and patient-reported outcomes rather than weight loss alone.

Approach to the Patient: Diagnosis of Cushing Syndrome.

Cushing syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing syndrome) or autonomous cortisol overproduction, whether or not ACTH-dependent (endogenous Cushing syndrome). An early diagnosis of Cushing syndrome is warranted; however, in clinical practice, it is very challenging partly because of resemblance with other common conditions (ie, pseudo-Cushing syndrome). Initial workup should start with excluding local and systemic corticosteroid use. First-line screening tests including the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement should be performed to screen for endogenous Cushing syndrome. Scalp-hair cortisol/cortisone analysis helps in the assessment of long-term glucocorticoid exposure as well as in detection of transient periods of hypercortisolism as observed in cyclical Cushing syndrome. Interpretation of results can be difficult because of individual patient characteristics and hence requires awareness of test limitations. Once endogenous Cushing syndrome is established, measurement of plasma ACTH concentrations differentiates between ACTH-dependent (80%-85%) or ACTH-independent (15%-20%) causes. Further assessment with different imaging modalities and dynamic biochemical testing including bilateral inferior petrosal sinus sampling helps further pinpoint the cause of Cushing's syndrome. In this issue of "Approach to the patient," the diagnostic workup of Cushing syndrome is discussed with answering the questions when to screen, how to screen, and how to differentiate the different causes. In this respect, the latest developments in biochemical and imaging techniques are discussed as well.

Coping with stress before and after mild traumatic brain injury: a pilot hair cortisol study.

Background: Cortisol is a crucial hormone for adaptation to challenging and stressful situations. Hair cortisol measurement is used to determine chronic stress; the growth rate of hair allows to determine averaged cortisol levels for a longer period. Objective: Pre- and post-injury measures of hair cortisol were compared in patients with mild traumatic brain injury (mTBI), and related to their coping styles.Methods: For 46 patients with mTBI, 3 cm scalp hair samples were collected 4-6 weeks post-injury, resulting in two 1 cm segments, pre- and post-injury. Hair samples were also collected for 11 healthy controls. Hair cortisol was quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Complaints, anxiety, depression and coping style were measured two weeks post-injury and long term (six-twelve months), added with measures for post-traumatic stress and functional outcome.Results: There were no differences between patients' pre- and post-injury cortisol levels, nor between cortisol levels of patients and controls. However, pre- and post-injury cortisol levels of patients were negatively correlated with both passive and an avoidant coping style.Conclusions: Our findings suggest that mTBI has no separate impact on chronic long-term cortisol levels, possibility indicating that variability in cortisol levels reflects individuals' premorbid characteristics determining coping with stress in general.

Hair glucocorticoids in adults with intellectual disabilities and depressive symptoms pre- and post-bright light therapy: First explorations.

BACKGROUND: Depressive symptoms and stress are common in adults with intellectual disabilities. Our aim was to explore long-term biological stress levels, assessed by hair cortisol (HairF) and cortisone (HairE) concentrations, in adults with intellectual disabilities and depressive symptoms and to investigate the effects of bright light therapy (BLT) on hair glucocorticoids. METHOD: Scalp hair samples (n = 14) were retrospectively examined at baseline and post-BLT (10.000 and 300 lux). Liquid chromatography-tandem mass spectrometry was used to measure hair glucocorticoids. RESULTS: A significant correlation was found between baseline HairF and depression scores (r = .605, p = .028). Post-intervention HairE levels were significantly increased ([95% CI: 11.2-17.4 pg/mg], p = .003), in particular after dim light (300 lux) ([95% CI: 10.0-18.3 pg/mg], p = .020). CONCLUSIONS: This study showed that retrospectively examining biological levels of stress in adults with intellectual disabilities seems a potentially promising and objective method to gain insight in the stress level of adults with intellectual disabilities.

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.

In adults with obesity, copeptin is linked with BMI but is not associated with long-term exposure to cortisol and cortisone.

CONTEXT: Obesity and cardiometabolic diseases are associated with higher long-term glucocorticoid levels, measured as scalp hair cortisol (HairF) and cortisone (HairE). Cardiometabolic diseases have also been associated with copeptin, a stable surrogate marker for the arginine-vasopressin (AVP) system. Since AVP is, together with corticotropin-releasing hormone (CRH) an important regulator of the hypothalamic-pituitary adrenal axis (HPA axis), we hypothesize that AVP contributes to chronic hypercortisolism in obesity. OBJECTIVE: To investigate whether copeptin levels are associated with Higher HairF and HairE levels in obesity. DESIGN: A cross-sectional study in 51 adults with obesity (BMI ≥30 kg/m2). METHODS: Associations and interactions between copeptin, HairF, HairE, and cardiometabolic parameters were cross-sectionally analyzed. RESULTS: Copeptin was strongly associated with BMI and waist circumference (WC) (rho = 0.364 and 0.530, P = 0.008 and <0.001, respectively), also after correction for confounders. There were no associations between copeptin and HairF or HairE on a continuous or dichotomized scale, despite correction for confounders. CONCLUSION: In patients with obesity, AVP seems not a major contributor to the frequently observed high cortisol levels. Other factors which stimulate the HPA axis or affect cortisol synthesis or breakdown may be more important than the influence of AVP on long-term glucocorticoid levels in obesity.

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.

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 cohorts, but were significantly higher in female students (F(1,332)  = 7.93, P < .01). In separate models including cohort and gender, both PSS score (OR 0.91) and HCC (OR 0.38) were significantly associated with Year-1 performance. Only students with both high PSS scores and high HCC values were significantly at risk of lower Year-1 pass rates (OR 0.27), particularly male students. CONCLUSIONS: Raising the Year-1 performance standard increased academic performance, most notably in male students. However, it also increased levels of perceived stress, especially in female students. In particular, the combination of high levels of perceived stress and biological stress, as measured by long-term cortisol, was related to poor academic performance. The study suggests a relationship between raising performance standards and student well-being, with differential effects in male and female students.

Hair cortisol concentrations in chronic central serous chorioretinopathy.

PURPOSE: Central serous chorioretinopathy (CSC), a distinct form of macular degeneration, has been associated with glucocorticoid use and possibly also with an increased endogenous activity of the hypothalamic-pituitary-adrenal (HPA) axis. To estimate long-term glucocorticoid exposure, measurement of hair cortisol concentrations (HCC) has emerged. This cross-sectional study aimed to investigate HCC, as a reflection of chronic endogenous steroid exposure, in a cohort of patients with chronic CSC (cCSC). METHODS: Hair cortisol concentrations (HCC) were determined in 48 patients with cCSC and 230 population-based controls (Lifelines cohort study), not using exogenous corticosteroids. RESULTS: Increased HCC (defined as >10.49 pg/mg) were present in 2 (4%) patients with cCSC and 13 (6%) controls. Mean HCC values were not different between patients and controls, and no difference in HCC was found between patients with active cCSC disease and patients with inactive disease. No correlation between HCC and urinary free cortisol (UFC) levels in patients with cCSC was found. CONCLUSIONS: This study shows that HCC in patients with cCSC are not elevated compared to population-based controls, and no association between HCC and cCSC severity was found. This finding questions the previous suggestion that cCSC is associated with increased HPA axis activity. In line, HCC do not seem useful in monitoring cCSC disease activity.

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.

Associations Among Hair Cortisol Concentrations, Posttraumatic Stress Disorder Status, and Amygdala Reactivity to Negative Affective Stimuli in Female Police Officers.

Posttraumatic stress disorder (PTSD) is associated with altered hypothalamic-pituitary-adrenal (HPA) axis function. Measurement of hair cortisol concentrations (HCC) allows retrospective assessment of HPA axis regulation over prolonged periods of time. Currently, research investigating HCC in PTSD remains sparse. Previous cross-sectional studies have included only civilian populations, although it is known that trauma type moderates associations between PTSD status and HPA axis function. We investigated differences in HCC between trauma-exposed female police officers with current PTSD (n = 13) and without current and lifetime PTSD (n = 15). To investigate whether HCC was associated with neural correlates of PTSD, we additionally performed exploratory correlational analyses between HCC and amygdala reactivity to negative affective stimuli. We observed significantly lower HCC in participants with PTSD than in participants without PTSD, d = 0.89. Additionally, within participants with PTSD, we observed positive correlations between HCC and right amygdala reactivity to negative affective (vs. happy/neutral) faces, r = .806 (n = 11) and left amygdala reactivity to negative affective (vs. neutral) pictures, r = .663 (n = 10). Additionally, left amygdala reactivity to negative faces was positively correlated with HCC in trauma-exposed controls, r = .582 (n = 13). This indicates that lower HCC is associated with diminished amygdala differentiation between negative affective and neutral stimuli. Thus, we observed lower HCC in trauma-exposed noncivilian women with PTSD compared to those without PTSD, which likely reflects prolonged HPA axis dysregulation. Additionally, HCC was associated with hallmark neurobiological correlates of PTSD, providing additional insights into pathophysiological processes in PTSD.

Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) Concentraciones de cortisol en cabello se asocian con la condición de TEPT y la reactividad de la amígdala a estímulos emocionales negativos en oficiales de policía mujeres BAJO NIVEL DE CORTISOL EN CABELLO EN PACIENTES MUJERES CON TEPT El trastorno de estrés postraumático (TEPT) está asociado con la función alterada del eje hipotálamo-hipófisis-adrenal (HPA). La medición de las concentraciones de cortisol en cabello (HCC por sus siglas en inglés) permite evaluar en forma retrospectiva la regulación del eje HPA en periodos prolongados. Actualmente las investigaciones de HCC en TEPT son escasas. Los estudios transversales previos solo han incluido población civil, aunque se sabe que el tipo de trauma modera las asociaciones entre la condición del TEPT y la función del eje HPA. Investigamos las diferencias en el HCC entre oficiales de policía de sexo femenino expuestos a trauma con TEPT actual (n = 13) y sin TEPT actual o a lo largo de su vida (n = 15). Para investigar si la HCC se asociaba con correlatos neurales del TEPT, adicionalmente realizamos un análisis exploratorio correlacional entre la HCC y reactividad de la amígdala a estímulos emocionales negativos. Observamos niveles significativamente más bajos de HCC en las participantes con TEPT que en las sin TEPT, d = 0.89. Adicionalmente, entre las participantes con TEPT, observamos correlaciones positivas entre HCC y la reactividad de la amígdala derecha a caras con emociones negativas (vs. felicidad/neutral), r = .806 (n = 11) y la reactividad de la amígdala izquierda a fotografías con emociones negativas (vs. Neutral) r = .663 (n = 10). Adicionalmente, la reactividad de la amígdala izquierda a caras con emociones negativas estuvo correlacionada positivamente con HCC en controles expuestos a trauma, r = .582 (n = 13). Esto indica que HCC más bajos se asocian con capacidad de diferenciación disminuida de la amígdala entre estímulos emocionales negativos y neutrales. Así, observamos niveles más bajos de HCC en mujeres no civiles expuestas a trauma con TEPT comparadas con aquellas sin TEPT, lo que probablemente refleja una prolongada desregulación del eje HPA. Adicionalmente, HCC se asoció con correlatos neurobiológicos distintivos del TEPT, proveyendo información adicional de los procesos patofisiológicos en el TEPT.

A comprehensive diagnostic approach to detect underlying causes of obesity in adults.

Obesity is a worldwide growing problem. When confronted with obesity, many health care providers focus on direct treatment of the consequences of adiposity. We plead for adequate diagnostics first, followed by an individualized treatment. We provide experience-based and evidence-based practical recommendations (illustrated by clinical examples), to detect potential underlying diseases and contributing factors. Adult patients consulting a doctor for weight gain or obesity should first be clinically assessed for underlying diseases, such as monogenetic or syndromic obesity, hypothyroidism, (cyclic) Cushing syndrome, polycystic ovarian syndrome (PCOS), hypogonadism, growth hormone deficiency, and hypothalamic obesity. The most important alarm symptoms for genetic obesity are early onset obesity, dysmorphic features/congenital malformations with or without intellectual deficit, behavioral problems, hyperphagia, and/or striking family history. Importantly, also common contributing factors to weight gain should be investigated, including medication (mainly psychiatric drugs, (local) corticosteroids, insulin, and specific ß-adrenergic receptor blockers), sleeping habits and quality, crash diets and yoyo-effect, smoking cessation, and alcoholism. Other associated conditions include mental factors such as chronic stress or binge-eating disorder and depression.Identifying and optimizing the underlying diseases, contributing factors, and other associated conditions may not only result in more effective and personalized treatment but could also reduce the social stigma for patients with obesity.

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.

Genetic obesity: next-generation sequencing results of 1230 patients with obesity.

BACKGROUND: Obesity is a global and severe health problem. Due to genetic heterogeneity, the identification of genetic defects in patients with obesity can be time consuming and costly. Therefore, we developed a custom diagnostic targeted next-generation sequencing (NGS)-based analysis to simultaneously identify mutations in 52 obesity-related genes. The aim of this study was to assess the diagnostic yield of this approach in patients with suspected genetic obesity. METHODS: DNA of 1230 patients with obesity (median BMI adults 43.6 kg/m2; median body mass index-SD children +3.4 SD) was analysed in the genome diagnostics section of the Department of Genetics of the UMC Utrecht (The Netherlands) by targeted analysis of 52 obesity-related genes. RESULTS: In 48 patients pathogenic mutations confirming the clinical diagnosis were detected. The majority of these were observed in the MC4R gene (18/48). In an additional 67 patients a probable pathogenic mutation was identified, necessitating further analysis to confirm the clinical relevance. CONCLUSIONS: NGS-based gene panel analysis in patients with obesity led to a definitive diagnosis of a genetic obesity disorder in 3.9% of obese probands, and a possible diagnosis in an additional 5.4% of obese probands. The highest yield was achieved in a selected paediatric subgroup, establishing a definitive diagnosis in 12 out of 164 children with severe early onset obesity (7.3%). These findings give a realistic insight in the diagnostic yield of genetic testing for patients with obesity and could help these patients to receive (future) personalised treatment.

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.

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.

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.