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.

High long-term cortisol levels, measured in scalp hair, are associated with a history of cardiovascular disease.

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

A novel tool in the diagnosis and follow-up of (cyclic) Cushing's syndrome: measurement of long-term cortisol in scalp hair.

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

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

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

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.

Glucocorticoid receptor gene haplotypes are not associated with birth anthropometry, blood pressure, glucose and insulin concentrations, and body composition in subjects born small for gestational age.

OBJECTIVE: Smaller size at birth has been associated with an increased risk of metabolic and cardiovascular disorders in adult life. Fetal programming of the hypothalamic-pituitary-adrenal axis has been suggested as a possible explanation. Fetal glucocorticoid (GC) overexposure has effects that suggest a role of GCs in this programming. The effects of GCs are mediated through the GC receptor (GR or NR3C1). Several functional polymorphisms have been described, which are associated with relative GC resistance or hypersensitivity. Our aim is to compare frequencies of GR haplotypes, characterized by the R23K, N363S, Bcl1, or 9ß polymorphisms, in subjects born small for gestational age (SGA) and associate birth anthropometry data, response to GH treatment, blood pressure, glucose and insulin concentrations, and body composition with these haplotypes. DESIGN: In total, 418 SGA subjects and 697 healthy controls were enrolled in this study. Methods Anthropometry data were obtained, as well as blood samples to determine fasting glucose and insulin concentrations. Dual energy X-ray absorptiometry scans were used to measure the amount of fat and lean mass. RESULTS: No differences were found between GR haplotype frequencies in SGA children compared with healthy controls. No associations were found between GR haplotypes and birth length and birth weight, growth response during GH treatment, blood pressure, glucose and insulin concentrations, and body composition. CONCLUSION: GR haplotypes and their effect on GC sensitivity do not seem to play a significant role in GH-induced catch-up growth and the risk factors of developing metabolic and cardiovascular disorders in adult life of SGA children.