Obesity-associated T-cell and macrophage activation improve partly after a lifestyle intervention.

BACKGROUND: The relation between low-grade inflammation and metabolic dysfunction in obesity is not fully explored. OBJECTIVE: To evaluate immune parameters in the obese state and after a lifestyle intervention program. METHODS: Patients with obesity (n = 87) from an academic obesity clinic were compared with controls with regard to macrophage and T-cell activation (reflected by serum levels of soluble CD163 (sCD163) and soluble IL-2 receptor (sIL-2R), respectively), and an array of cytokines, chemokines, and growth factors. In addition, these parameters and regulatory T-cells (Treg), were studied in 27 patients who followed a 75-week lifestyle intervention (dietary advice, exercise, and psychoeducation). RESULTS: Mean sIL-2R and sCD163 levels were higher in patients than controls (sIL-2R:2884 ± 936 pg/ml vs. 2207 ± 813 pg/ml, p = 0.001; sCD163:1279 ± 580 pg/ml vs. 661 ± 271 pg/ml, p < 0.0001 respectively). Patients with metabolic syndrome (MetS) had higher sCD163 than those without (1467 ± 656 pg/ml vs. 1103 ± 438 pg/ml). Patients had higher IL-1ß, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-15, IL-17A, MCP-1/CCL2, MIP-1α/CCL3, MIP-1ß/CCL4, G-CSF, GM-CSF, FGF, IFN-γ, and TNF-α than controls, whereas VEGF-A, PDGF-BB, and eotaxin were lower. Upon intervention, sIL-2R decreased while peripheral Treg frequencies increased within the reference range (p = 0.042 and p = 0.005 respectively). The sIL-2R decrease correlated to a decrease in waist circumference (rho = 0.388, p = 0.045) and in trend to a decrease in MetS components (rho = 0.345, p = 0.078). The Treg increase was unrelated to weight loss or metabolic improvement. Mean sCD163 did not change significantly upon intervention, nor did the cytokines, chemokines, and growth factors (except IP-10/CXCL10). CONCLUSION: In obesity, T-cell homeostasis improves after a lifestyle intervention. Immunologic alterations can occur independently of metabolic improvement.

Long-term glucocorticoid concentrations as a risk factor for childhood obesity and adverse body-fat distribution.

BACKGROUND: Childhood obesity is an important risk factor for premature development of the metabolic syndrome (MetS) at adulthood. There is need for understanding of the mechanisms underlying the MetS and obesity. Patients with Cushing's disease suffer from similar metabolic complications, leading to the hypothesis that inter-individual cortisol variation may contribute to the onset of obesity. In addition, glucocorticoid receptor (GR)-gene polymorphisms resulting in differential glucocorticoid (GC) sensitivity, have been associated with an adverse metabolic profile. AIM: To study associations of GC levels in scalp hair, as a marker of long-term systemic GC concentrations, and genetically determined GC sensitivity with obesity and body-fat distribution in children. METHODS: We performed a cross-sectional study of cortisol and cortisone concentrations over a 3-month period, measured by LC-MS/MS (Liquid Chromatography Tandem Mass Spectrometry) in hair of 3019 6-year-old children participating in the Generation R study. Genotyping of GR-gene polymorphisms was performed. RESULTS: Of all children, 4.3% was obese and 13.4% overweight. Cortisol was significantly associated with risk of obesity (odd ratio (OR): 9.4 (3.3-26.9)) and overweight (OR: 1.4 (1.0-2.0)). Cortisone was associated with risk of obesity (OR: 1.9 (1.0-3.5)). Cortisol and cortisone were significantly positively associated with body mass index, fat mass (FM) index and android/gynecoid FM ratio. GR polymorphisms were not associated with adiposity parameters. CONCLUSION: Long-term cortisol concentrations are strongly associated with an increased risk of childhood obesity and adverse body-fat distribution. Future research may reveal whether these are causal relations and may be a target for therapy.

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.

Elevated hair cortisol concentrations in children with adrenal insufficiency on hydrocortisone replacement therapy.

BACKGROUND: Glucocorticoid replacement therapy in patients with adrenal insufficiency needs to be tailored to the individual patient based on body composition and clinical signs and symptoms as no objective method for assessment of treatment adequacy is available. Current treatment regimens are often not satisfactory, which is shown by the adverse metabolic profile and doubled mortality rates in treated adrenal insufficiency patients. Measurement of cortisol concentrations in hair reflect the long-term systemic cortisol exposure and may be of use in refinement of hydrocortisone treatment. OBJECTIVE: We aimed to study whether long-term cortisol (hydrocortisone) levels, as measured in scalp hair, are similar in children with adrenal insufficiency and healthy children. MATERIAL AND METHODS: We set up a case control study, measuring anthropometric characteristics and hair cortisol concentrations (HCC) in 54 hydrocortisone substituted children with adrenal insufficiency (AI patients) in the age of 4-18 years and 54 healthy children matched for gender and age. RESULTS: Mean HCC were significantly higher in AI patients compared with healthy controls (mean 13·3 vs 8·2 pg/mg, P = 0·02). AI patients also had a higher BMI (P < 0·001) and waist circumference (WC) (P = 0·02). HCC was significantly associated with BMI (P = 0·002) and WC (P = 0·002). HCC explained 13% of the difference in BMI and 29% of the difference in WC between AI patients and controls. CONCLUSION: Hydrocortisone-treated AI patients have increased HCC and adverse anthropometric characteristics compared with healthy controls. HCC measurement may be of value in identifying overtreatment and thereby improve hydrocortisone replacement therapy.

Hair cortisol measurement in mitotane-treated adrenocortical cancer patients.

The only approved drug for the treatment of adrenocortical cancer (ACC) is mitotane. Mitotane is adrenolytic and therefore, hydrocortisone replacement therapy is necessary. Since mitotane increases cortisol binding globulin (CBG) and induces CYP3A4 activity, high doses of hydrocortisone are thought to be required. Evaluation of hydrocortisone therapy in mitotane-treated patients has been difficult since there is no good marker to evaluate hydrocortisone therapy. Measurement of cortisol in scalp hair is a novel method that offers the opportunity to measure long-term cortisol levels. Our aim was to evaluate whether hair cortisol measurements could be useful in evaluating recent hydrocortisone treatment in mitotane-treated ACC patients. Hair cortisol levels were measured in 15 mitotane-treated ACC patients on hydrocortisone substitution and 96 healthy individuals. Cortisol levels were measured in 3 cm hair segments, corresponding to a period of 3 months. Hair cortisol levels were higher in ACC patients compared to healthy individuals (p<0.0001). Seven ACC patients (47%) had hair cortisol levels above the reference range. None of the patients had hair cortisol levels below normal. In contrast to hydrocortisone doses (ß=0.03, p=0.93), hair cortisol levels were associated with BMI (ß=0.53, p=0.042). There was no correlation between hair cortisol levels and hydrocortisone doses (ß=0.41, p=0.13). Almost half of the ACC patients had high hair cortisol levels, suggesting long-term over-substitution of hydrocortisone in some of the patients, whereas none of the patients was under-substituted. Hair cortisol measurements might be useful in long-term monitoring hydrocortisone treatment in mitotane-treated ACC patients.

[New insights into ways of determining cortisol exposure in patients with bipolar disorder]. / Nieuwe inzichten in de evaluatie van cortisolblootstelling bij patiënten met een bipolaire stoornis.

BACKGROUND: Previous research has shown a relationship between the stress hormone cortisol and bipolar disorder. The level of cortisol exposure is usually examined by means of measurements that provide a snapshot of cortisol exposure or by means of dynamic testing. Recently, a new technique has been introduced which can measure, retrospectively, the cortisol level in scalp hair over longer periods of time. AIM: To provide insight into various methods used in psychiatry for measuring the hypothalamus-pituitary-adrenal (HPA)-axis activity and also to highlight recent research into measurements of cortisol in scalp hair of patients with bipolar disorder. METHOD: We give a brief overview of the literature relating to HPA-axis testing in psychiatric patients. As a result of our recent studies with 100 patients suffering from bipolar disorder, we are now able to determine the levels of cortisol in scalp hair. RESULTS: Tests that measure hpa activity can be divided into three categories: point measurements, stimulation tests and inhibition tests. In our recent study of bipolar patients we found that a raised level of cortisol in scalp hair was related to a later onset of bipolar disorder (in patients over 30) or to multiple psychiatric diagnoses. Lower levels of cortisol level in scalp hair of bipolar patients were observed in bipolar patients with comorbid panic disorder. CONCLUSION: The use of hair analysis to measure mean cortisol levels over long periods seems to give added value to the hpa-axis tests currently used for measuring cortisol exposure. The technique may make it easier to differentiate between various subtypes of bipolar disorder.

Metabolic syndrome in adults with autistic traits: associated psychological, behavioral, and biological factors in females and males - a PharmLines initiative.

Background: While cardiovascular diseases is highly prevalent and an important cause of mortality in autistic adults, knowledge on their increased cardiovascular risk is limited. Hence, this study aimed to investigate psychological, behavioral, and physical factors associated with metabolic syndrome (MetS) in adults with autistic traits. Methods: In total, 17,705 adults from the Lifelines Cohort were included and categorized using Autism Spectrum Quotient-10 sum-scores. The quartiles with highest (HQ-traits-group females: n = 2,635; males: n = 1803) and lowest levels of autistic traits (LQ-traits-group, n = idem) were analyzed. Using multivariable logistic regression, the associations between MetS and (self-reported and interviewed) psychological, behavioral, and physically measured factors in these stratified groups were investigated. Results: Among females, MetS was more common in the HQ-traits-group than in the LQ-traits-group (10.0% versus 7.5%, p < 0.01), while this was not the case among males (HQ-traits-group 13.8% versus LQ-traits-group 13.1%, p = 0.52). In both the female and male HQ-traits-group, the presence of MetS was associated with poorer self-reported health, less daily physical activity, and altered leukocyte counts. Conclusion: These findings underline the relevance of adequate cardiovascular prevention in adults with higher levels of autistic traits. Future research could gain more insight into the relationship between cardiovascular risk and autistic traits in females, and into tailored cardiovascular prevention.

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.

Long-term cortisol levels are not associated with nasal carriage of Staphylococcus aureus.

Staphylococcus aureus (S. aureus) colonizes the anterior nares in part of the population and the persistent carrier state is associated with increased infection risk. Knowledge concerning the determinants of S. aureus nasal carriage is limited. Previously, we found that glucocorticoid receptor polymorphisms influence carrier risk, suggesting involvement of glucocorticoids. Our aim was to study long-term cortisol levels in non-carriers, intermittent, and persistent carriers of S. aureus. We hypothesized that cortisol levels are higher in carriers, since cortisol-induced immune suppression would enhance S. aureus colonization. We determined nasal carrier state and long-term hair cortisol levels in 72 healthy subjects. Nasal swabs were collected twice with an interval of 2 weeks. Cortisol levels were determined in hair segments of 3 cm, which corresponds to a period of roughly 3 months. Of all 72 participants, 38 were non-carriers, 10 were intermittent carriers, and 24 were persistent carriers of S. aureus. Cortisol levels did not differ between these carrier groups (p=0.638). Long-term cortisol levels are not associated with S. aureus nasal carriage.

Glucocorticoid receptor haplotype is associated with a decreased risk of delirium in the elderly.

Delirium is the most common mental disorder at older age in hospitals after acute admission. The pathogenesis of delirium is largely unknown. Hyperactivity of the hypothalamic-pituitary-adrenal axis, leading to increased cortisol levels, has been suggested to play a role in the development of delirium. The effects of cortisol, the most important glucocorticoid (GC) in humans, are mainly mediated by the GC receptor (GR). Several polymorphisms in the GR gene that alter the GC sensitivity are known. The aim of this study was to study the role of these GR polymorphisms in delirium in elderly patients. Patients aged 65 years and older admitted to the medical department or scheduled for hip surgery were included. Delirium was diagnosed using the Confusion Assessment Method. Five single nucleotide polymorphisms in the GC receptor gene were genotyped and haplotypes were constructed. Delirium was associated with impaired cognitive (P < 0.001) and functional function (P < 0.001), as well as with older age (P < 0.001). Homozygous carriers of haplotype 4, characterized by the presence of the BclI and TthIIII minor alleles, had a 92% decreased risk of developing delirium (P = 0.02), independent of age, cognitive, and functional state. Homozygous carriage of the BclI-TthIIII haplotype of the GR gene is related to a reduced risk of developing delirium. This suggests that altered GC signaling may be involved in the pathogenesis and development of delirium in the elderly.

[Intermittent fasting in science and practice; what are the effects on weight and cardiometabolic health?] / Intermitterend vasten in wetenschap en praktijk.

Intermittent fasting (IF) is a broad concept and covers several fasting regimes. Studies of 'early time restricted feeding' and 'alternate day fasting' with energy restriction show a greater effect on weight and cardiometabolic health in overweight people in the short term, compared to a continuous caloric restriction (CCR). 'Late time restricted feeding' seems to have no or unfavorable effects. Long-term studies (up to 2 years) suggest that IF regimens are not superior to continuous caloric restriction. The few studies available show a similar compliance and metabolic adaptation between IF and CCR. There is insufficient knowledge about long-term safety in various groups of people, the influence of dietary quality and the practical feasibility of IF regimes. As a result, no recommendations can yet be made on the use of IF in the treatment of overweight and related diseases.

[Pharmacotherapy for obesity]. / Farmacotherapie voor obesitas.

Obesity is a complex endocrine disease, mainly caused by environmental, behavioral and biological factors. Maintaining weight loss is extremely difficult due to the neuro-endocrine dysregulations that stimulate the body to return to the previous, increased, weight. Identifying underlying weight-gaining factors is needed, including medication-related, psychological and endocrine factors, as well as monogenic obesity. The cornerstone of treatment is optimization of lifestyle and all other contributing factors. Achieving at least 5% weight loss already has important health benefits. If combined lifestyle intervention (CLI) alone is not successful, pharmacotherapy or bariatric surgery can be added for patients with increased weight-related health risks. Recently, novel pharmacotherapy became available, among which, liraglutide 3 mg and the combination therapy naltrexone/bupropion, which leads to an additional 5-6% mean weight loss compared to CLI alone. For rare forms of obesity there are specific drugs that target defects in the regulation of hunger and satiety. Promising new pharmacotherapy for obesity is under development.

Working memory performance is associated with common glucocorticoid receptor gene polymorphisms.

Cortisol has a modulatory influence on cognitive functions in humans. Both impairing and enhancing effects of cortisol administration have been shown for hippocampus-dependent declarative memory, and impairing effects have been shown for prefrontal-cortex-dependent working memory function. Given the high density of glucocorticoid (GC) receptors in the prefrontal cortex, we investigated whether common polymorphisms of the GC receptor (GR) gene (ER22/23EK, N363S, BclI, 9 beta A3669G) modulate the influence of cortisol administration on working memory. Working memory performance was investigated in 169 subjects on 10 mg hydrocortisone (cortisol) and placebo using an item recognition task. No impairing effect of hydrocortisone treatment became evident. However, a sex x genotype interaction on general working memory performance was revealed (p = 0.02). While female heterozygous carriers of the 9 beta G allele displayed faster reaction times than the other genotype groups, 9 beta G heterozygous men were relatively slower. Heritability estimates for memory are roughly 50%, indicating that common genetic polymorphisms have an important impact on cognitive performance. Our results suggest that variants of the GR gene might explain some of the variance attributable to genetic factors. Furthermore, it can be speculated that they modulate the individual vulnerability for memory impairments related to stress-related psychiatric disorders.

Spontaneous remission of unidentified Cushing's disease revealed by hair cortisol analysis.

Pituitary apoplexy is an infrequent but life-threatening complication of pituitary adenomas. When apoplexy occurs in a hormonally active adenoma, this may induce spontaneous remission of the clinical syndrome. In these cases, clinical suspicion of Cushing's disease or acromegaly may arise at presentation, but due to spontaneous remission of active hormone production, it is not possible to biochemically confirm this diagnosis in retrospect. Resolution of clinical symptoms during follow up retrospectively suggests the diagnosis. However, we describe a patient with Cushing's disease presenting with pituitary apoplexy, who was biochemically in remission at presentation. The diagnosis could be confirmed in retrospect using hair cortisol analysis, thereby enabling clinicians to adequately anticipate remission of Cushing's disease.

Hair cortisol in patients with a depressive episode treated with electroconvulsive therapy.

BACKGROUND: There is substantial evidence showing changes in hypothalamic pituitary adrenal (HPA)-axis activity in patients with major depressive disorder (MDD). Also, there seem to be differences in HPA-axis functioning between MDD subgroups. It is however unclear whether hair cortisol concentrations (HCC), which are a stable marker of long-term cortisol levels, are suitable as a biomarker for identifying subgroups in MDD. METHODS: We were able to attain valid HCC from a scalp hair sample of sixty-two patients with a major depressive episode right before electroconvulsive therapy (ECT). HCC were our main biological outcome measure. We created subgroups using depression severity as defined by the Hamilton Depression Rating Scale, the presence/absence of psychotic symptoms, the presence of melancholia as defined by the CORE and catatonia as defined by the Bush-Francis Catatonia Rating Scale. RESULTS: Our analyses of the total group showed a median HCC of 4.4 pg/mg. We found patients with catatonia (N = 10) to have substantially higher median HCC (8.3 pg/mg) than patients without catatonia (3.8 pg/mg). Although presence of melancholia and depression severity were not significantly associated with HCC, more severe psychomotor agitation was associated with higher HCC. Pre-treatment HCC was not associated with ECT outcome. STRENGTHS AND LIMITATIONS: A complicating factor in interpretation of our results was the large variability in HCC. This could be related to potential confounders such as cardiometabolic and other comorbidities, that were however addressed to the extent possible. CONCLUSIONS: HCC is a potential biomarker for MDD patients with severe agitation and/or catatonia. CLINICALTRIALS.GOV: Identifier: NCT02562846.

[Obesity cannot be solved by meal replacements]. / Obesitas los je niet op met een kuurtje.

Finding new ways to reach sustainable weight reduction, which are suitable for daily practice, is important. In this commentary we discuss the article by Astbury et al. suggesting that a total diet replacement (TDR) programme in a primary care setting is safe and effective. We raise some important questions about the limited duration of the study, lack of clarity about additionally provided behavioural coaching and/or exercise in the intervention group vs the usual care control group, as well as the potential effects of low calorie dieting on muscle mass. Although other studies using meal replacements do not show an additional benefit compared to interventions based on a balanced diet with behavioural therapy, the results after this 52-week study are promising. However, longer-term follow-up and external validation is needed. Moreover, the large variation in results between participating centres shows that it is not a matter of "one size fits all" when it comes to successful dieting.

Scalp hair cortisol and testosterone levels in patients with sarcoidosis.

BACKGROUND: Patients with sarcoidosis often experience fatigue and psychological distress, but little is known about the etiology of these conditions. While serum and saliva steroid hormones are used to monitor acute steroid levels, scalp hair analysis is a relatively new method enabling measurement of long-term steroid levels, including hair cortisol reflecting chronic stress. We investigated whether scalp hair cortisol and testosterone levels differ between sarcoidosis patients both with and without fatigue and general population controls. Additionally, we studied if these hormones could serve as objective biomarkers for psychological distress in patients with sarcoidosis. METHODS: We measured hair steroid levels using liquid chromatography-tandem mass spectrometry in glucocorticoid naïve sarcoidosis patients. Patients completed the Perceived Stress Scale, Fatigue Assessment Scale, Hospital Anxiety and Depression Scale and Short Form 36 (SF-36). Hair steroid levels from 293 participants of the population-based Lifelines cohort study served as controls. RESULTS: Thirty-two patients (14 males) were included. Hair cortisol, but not testosterone, concentrations were significantly higher in patients with sarcoidosis than in general population controls (mean 6.6 versus 2.7 pg/mg, p<0.001). No differences were found in hair cortisol and testosterone levels between fatigued and non-fatigued patients with sarcoidosis. Hair cortisol of sarcoidosis patients correlated significantly with anxiety (r = 0.47, p = 0.01), depression (r = 0.46, p = 0.01), and SF-36 mental domain (r = -0.38, p = 0.03), but not with fatigue. CONCLUSIONS: Patients with sarcoidosis have chronically higher levels of the stress hormone cortisol than the normal population, while testosterone levels in hair did not differ. Hair cortisol levels were positively related to subjective measures of psychological distress, but not to fatigue. Our study shows that hair cortisol is a promising non-invasive biomarker for psychological distress in patients with sarcoidosis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03108547. Registered 31 March 2017, retrospectively registered.

Prenatal maternal psychopathology and stress and offspring HPA axis function at 6 years.

OBJECTIVE: Intrauterine exposures such as maternal psychopathology and stress are known to influence the physical and mental health of the offspring. One of the proposed pathways underlying these associations is dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity in the offspring. This study examined the relation of perinatal maternal symptoms of psychopathology and stress with offspring HPA axis activity at 6 years as measured by hair cortisol and cortisone concentrations. METHODS: The study was part of the population-based Generation R Study, a prospective population-based cohort from fetal life onwards. 2546 children and their mothers formed the study population. Perinatal maternal psychopathology and stress were assessed by questionnaires in the second and third trimester. Principal components for both psychopathology and stress were created to reduce the number of explanatory variables. Child hair samples for cortisol and cortisone measurements were collected at the age of 6. Linear regression analysis, adjusted for covariates, was used to examine associations between maternal psychopathology and stress and child hair cortisol and cortisone levels. RESULTS: The maternal psychopathology principal component was associated with higher child hair cortisone (adjusted B = 0.24, 95%CI 0.08;0.40, p-value < 0.01). Effect estimates of the individual dimensions ranged from 0.97 (95%CI 0.21;1.73, p-value = 0.01) for interpersonal sensitivity to 1.67 (95%CI 0.86;2.47, p-value < 0.01) for paranoid ideation. In addition, children exposed to intrauterine stress, as measured by the principal component, had higher hair cortisone levels (adjusted B = 0.54, 95%CI 0.21;0.88, p-value < 0.01). Exposure to maternal psychopathology and stress was not associated with offspring hair cortisol. Stratification by child sex resulted in associations between maternal symptoms of psychopathology during pregnancy and child hair cortisone levels in boys and associations between maternal symptoms of stress during pregnancy and child hair cortisone levels in girls. CONCLUSION: Our results suggest that maternal psychopathology and stress during pregnancy are associated with long-term HPA axis activity of the offspring. The association of maternal psychopathology and stress during pregnancy with offspring hair cortisone levels is a novel finding. Future studies should examine whether these psychophysiological differences between exposed and non-exposed children underlie offspring morbidity associated with maternal psychopathology and stress during pregnancy.

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). DESIGN/PATIENTS: The study was conducted within the Longitudinal Ageing Study Amsterdam (LASA, 1992-ongoing), a cohort study in a population-based sample of older persons in the Netherlands. Data were used from 1196 and 1046 participants in the second (1995-1996) and fourth (2001-2002) cycle, respectively. MEASUREMENTS: Total serum cortisol and free cortisol were measured in the mornings of the second cycle while salivary cortisol sampled early in the morning and late at night were measured in the fourth cycle. The GR gene polymorphisms (ER22/23EK, N363SS, 9beta and BclI) were genotyped by Taqman. Appendicular skeletal muscle mass (ASMM) was measured using DXA in the second cycle and 3 years later (third cycle). Grip strength was assessed using a handgrip dynamometer in the second, third, fourth and fifth cycle. RESULTS: A relationship was found between both morning and evening salivary cortisol, and loss of grip strength: participants in the highest quartile of cortisol concentration had a twofold higher risk of loss of grip strength than participants in the lowest quartile (P < 0.05). No relationships were found between serum cortisol (loss of) ASMM, and (loss of) grip strength. The ER22/23EK and N363S-polymorphisms modified the relationships between serum cortisol, ASMM and grip strength, respectively. Due to limited power, these relationships were not significant after stratification for the polymorphisms. CONCLUSION: High salivary cortisol is associated with a higher risk of loss of grip strength in older persons. GR genotypes modify the relationship between muscle mass and muscle strength.