Hair glucocorticoids as 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 long-term cortisol levels. 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 sum of both (sumHairF+E), as measured by state-of-the-art LC-MS/MS technique, in untreated patients with confirmed endogenous CS (n=89), and community controls (n=295) from the population-based Lifelines cohort study. Results: Both glucocorticoids were significantly elevated in CS patients when compared to controls. High diagnostic efficacy was found for HairF (area under the curve (AUC), 0.87 [95% CI, 0.83 to 0.92]), HairE (0.93 [0.89 to 0.96]) and sumHairF+E (0.92 [0.88 to 0.96]; all P<.001). Participants were accurately classified at optimal cut-off threshold in 86% of cases (81% sensitivity, 88% specificity, 94% negative predictive value (NPV)) for HairF, in 90% of cases (87% sensitivity, 90% specificity, 96% NPV) for HairE, and 87% of cases (86% sensitivity, 88% specificity, 95% NPV) for the sum. HairE was shown to be most accurate in differentiating CS patients from controls. Conclusion: Scalp hair glucocorticoids, especially hair cortisone, can be seen as a promising biomarker in screening of CS. Its convenience in collection and workup additionally makes this feasible for first-line screenin

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 &lt;60 years and &gt;= 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 &lt; 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 &lt; 0.001). All immune parameters except eosinophils were associated with hair cortisone (all multivariate-adjusted p &lt; 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.</p

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 obesi

Supernova / Acceleration Probe: A Satellite Experiment to Study the Nature of the Dark Energy

The Supernova / Acceleration Probe (SNAP) is a proposed space-based experiment designed to study the dark energy and alternative explanations of the acceleration of the Universe's expansion by performing a series of complementary systematics-controlled measurements. We describe a self-consistent reference mission design for building a Type Ia supernova Hubble diagram and for performing a wide-area weak gravitational lensing study. A 2-m wide-field telescope feeds a focal plane consisting of a 0.7 square-degree imager tiled with equal areas of optical CCDs and near infrared sensors, and a high-efficiency low-resolution integral field spectrograph. The SNAP mission will obtain high-signal-to-noise calibrated light-curves and spectra for several thousand supernovae at redshifts between z=0.1 and 1.7. A wide-field survey covering one thousand square degrees resolves ~100 galaxies per square arcminute. If we assume we live in a cosmological-constant-dominated Universe, the matter density, dark energy density, and flatness of space can all be measured with SNAP supernova and weak-lensing measurements to a systematics-limited accuracy of 1%. For a flat universe, the density-to-pressure ratio of dark energy can be similarly measured to 5% for the present value w0 and ~0.1 for the time variation w'. The large survey area, depth, spatial resolution, time-sampling, and nine-band optical to NIR photometry will support additional independent and/or complementary dark-energy measurement approaches as well as a broad range of auxiliary science programs. (Abridged)Comment: 40 pages, 18 figures, submitted to PASP, http://snap.lbl.go

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

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

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

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 9β) 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/sup> [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