Evan Russell

Hair cortisol as a biological marker of chronic stress: current status, future directions and unanswered questions.

The detrimental effects of stress on human health are being increasingly recognized. There is a critical need for the establishment of a biomarker that accurately measures its intensity and course over time. Such a biomarker would allow monitoring of stress, increase understanding of its pathophysiology and may help identify appropriate and successful management strategies. Whereas saliva and urine cortisol capture real-time levels, hair cortisol analysis presents a complementary means of monitoring stress, capturing systemic cortisol exposure over longer periods of time. This novel approach for cortisol quantification is being increasingly used to identify the effects of stress in a variety of pathological situations, from chronic pain to acute myocardial infarctions. Because of its ability to provide a long-term, month-by-month measure of systemic cortisol exposure, hair cortisol analysis is becoming a useful tool, capable of answering clinical questions that could previously not be answered by other tests. In this paper we review the development, current status, limitations and outstanding questions regarding the use of hair cortisol as a biomarker of chronic stress.

Toward standardization of hair cortisol measurement: results of the first international interlaboratory round robin.

Background: The importance of hair cortisol as a long-term retrospective measure of systemic cortisol exposure is being increasingly recognized, and over recent years, the field of hair cortisol analysis has seen rapid expansion with laboratories around the globe, integrating hair cortisol analysis into their study designs. These laboratories use different methods of analysis, and presently, no attempt has been made to compare them. To move toward clinical utilization of this novel method, international benchmark reference values must be established. For that end, 4 leading laboratories in hair cortisol testing set up a protocol for comparison of the methods used by them. Methods: Four immunoassay methods and 2 liquid chromatograph–mass spectrometry (LC–MS/MS) methods were compared by analyzing the same hair samples representing the low, intermediate, and high ranges of hair cortisol concentrations (HCC). Results: HCC determined by the 4 immunoassay methods were highly and positively intercorrelated (r2 between 0.92 and 0.97; all P < 0.0001) in all comparisons of individual laboratories. Additionally, each laboratorys immunoassay HCC had significant positive correlations (r2 between 0.88 and 0.97; all P < 0.0001) with each of the 2 LC–MS/MS methods, which produced practically identical results. Conclusions: This study indicates that laboratories using immunoassays can use a correction factor that will convert results into standard LC–MS/MS equivalents.

Neonatal Pain-Related Stress and NFKBIA Genotype Are Associated with Altered Cortisol Levels in Preterm Boys at School Age

Neonatal pain-related stress is associated with elevated salivary cortisol levels to age 18 months in children born very preterm, compared to full-term, suggesting early programming effects. Importantly, interactions between immune/inflammatory and neuroendocrine systems may underlie programming effects. We examined whether cortisol changes persist to school age, and if common genetic variants in the promoter region of the NFKBIA gene involved in regulation of immune and inflammatory responses, modify the association between early experience and later life stress as indexed by hair cortisol levels, which provide an integrated index of endogenous HPA axis activity. Cortisol was assayed in hair samples from 128 children (83 born preterm ≤32 weeks gestation and 45 born full-term) without major sensory, motor or cognitive impairments at age 7 years. We found that hair cortisol levels were lower in preterm compared to term-born children. Downregulation of the HPA axis in preterm children without major impairment, seen years after neonatal stress terminated, suggests persistent alteration of stress system programming. Importantly, the etiology was gender-specific such that in preterm boys but not girls, specifically those with the minor allele for NFKBIA rs2233409, lower hair cortisol was associated with greater neonatal pain (number of skin-breaking procedures from birth to term), independent of medical confounders. Moreover, the minor allele (CT or TT) of NFKBIA rs2233409 was associated with higher secretion of inflammatory cytokines, supporting the hypothesis that neonatal pain-related stress may act as a proinflammatory stimulus that induces long-term immune cell activation. These findings are the first evidence that a long-term association between early pain-related stress and cortisol may be mediated by a genetic variants that regulate the activity of NF-κB, suggesting possible involvement of stress/inflammatory mechanisms in HPA programming in boys born very preterm.

Associations of hair cortisol concentration with self-reported measures of stress and mental health-related factors in a pooled database of diverse community samples.

Abstract A pooled database from diverse community samples was used to examine the associations of hair cortisol concentration (HCC) with self-reported stress and stress-linked mental health measures, including depression, anxiety, alcohol and drug use, disability and experiences with aggression. As part of innovative research using a mobile laboratory to study community mental health, data were pooled from five sub-studies: a random sample of the general population (n = 70), people who had received treatment for a mental health and/or substance use problem (n = 78), family members of people treated for mental health and/or substance use problems (n = 49), community volunteers who sometimes felt sad or blue or thought they drank too much (n = 83) and young adults in intimate partner relationships (n = 44). All participants completed a computerized questionnaire including standard measures of perceived stress, chronic stress, depression, anxiety, hazardous drinking, tobacco use, prescription drug use, illicit drug use, disability and intimate partner aggression. HCC was significantly associated with use of antidepressants, hazardous drinking, smoking and disability after adjusting for sub-study and potential confounders (sex, body-mass index, use of glucocorticoids and hair dyed). In addition, preliminary analyses suggest a significant curvilinear relationship between HCC and perceived stress; specifically, HCC increased with higher perceived stress but decreased at the highest level of stress. Overall, HCC was associated with mental health-related variables mainly reflecting substance use or experiencing a disability. The relationship between HCC and self-reported stress is unclear and needs further research.

Cortisol and Testosterone in Hair as Biological Markers of Systolic Heart Failure

BACKGROUND Congestive heart failure (CHF) is associated with increased stress and alterations in metabolism, favoring catabolism over anabolism. Hormonal profiles of patients with heart failure have been assessed using serum and saliva as matrices, which are only point measurements and do not provide long-term information. Scalp hair is a novel matrix that allows for measurement of hormones over a period of several months. PATIENTS AND METHODS We aimed to evaluate whether levels of cortisol and testosterone and their ratio (C/T) in hair correlate with severity of heart failure. We conducted a prospective study in ambulatory male patients with a left ventricular ejection fraction (LVEF)≤40%. Hormone levels were measured using immunoassays in the proximal 2 cm of hair (representing approximately two months of systemic hormone exposure). Primary endpoints included the correlation of hair cortisol, testosterone, and C/T levels with the New York Heart Association (NYHA) class, LVEF, exercise capacity and NT-proBNP. RESULTS The 44 CHF patients had a median hair level (range) of cortisol of 207 (117.7-1277.3)ng/g. Hair cortisol levels correlated positively with NYHA class (r=0.48, p=0.001) and negatively with treadmill stress test performance, (r=-0.37, p<0.05). The hair testosterone was 5.17 (2.39-24.64)ng/g and the C/T ratio was 39.89 (12.98-173.73). No associations were found between hair testosterone and C/T ratio and heart failure severity; however, the C/T ratio was higher in patients who required a CHF-related hospitalization than in patients who did not require this in the year following the inclusion in the study. CONCLUSIONS Hair cortisol levels correlate with heart failure severity as assessed by the NYHA class and exercise capacity, while hair testosterone and C/T levels do not correlate with heart failure severity.

Hair cortisol concentrations in higher- and lower-stress mother–daughter dyads: A pilot study of associations and moderators

Hair cortisol concentrations (HCC) are receiving increased attention as a novel biomarker of psychophysiological responses to chronic stress, with potential relevance for psychopathology risk research. We examined the validity of HCC as a marker of psychosocial stress in mother (M(age)  = 37.87 years)-daughter (M(age)  = 7.62 years) dyads characterized by higher (n = 30) or lower (n = 30) maternal chronic stress. Additionally, we examined whether early care moderated similarity of HCC levels within dyads. Higher-stress mothers had significantly lower HCC compared to lower-stress mothers, consistent with other research showing that chronic stress leads to blunted HPA axis activity over time. Further, HCC in daughters were significantly and positively associated with previously assessed salivary cortisol stress reactivity. Finally, mother-daughter HCC associations were significantly moderated by negative parenting styles, such that associations became stronger as quality of parenting decreased. Findings overall indicate that HCC may be a useful marker of cortisol responses to chronic stress.

Self-reported and measured stress related responses associated with exposure to wind turbine noise

The current study was the first to assess stress reactions associated with wind turbine noise (WTN) exposure using self-reported and objective measures. Randomly selected participants, aged 18-79 yr (606 males; 632 females), living between 0.25 and 11.22 km from wind turbines, were exposed to outdoor calculated WTN levels up to 46 dBA (response rate 78.9%). Multiple regression modeling left the great majority (77%-89%) of the variance in perceived stress scale (PSS) scores, hair cortisol concentrations, resting blood pressure, and heart rate unaccounted for, and WTN exposure had no apparent influence on any of these endpoints. PSS scores were positively, but weakly, related to cortisol concentrations and resting heart rate (Pearson r = 0.13 and r = 0.08, respectively). Across WTN categories, modeled mean PSS scores ranged from 13.15 to 13.84 (p = 0.8614). Modeled geometric means for hair cortisol concentrations, resting mean systolic, diastolic blood pressure, and heart rate were 150.54-191.12 ng/g (p = 0.5416), 113.38-116.82 mmHg (p = 0.4990), 67.98-70.34 mmHg (p = 0.5006), and 68.24-70.71 bpm (p = 0.5223), respectively. Irrespective of WTN levels, diastolic blood pressure appeared to be slightly (2.90 mmHg 95% CI: 0.75,5.05) higher among participants highly annoyed by blinking lights on turbines (p = 0.0081). Collectively, the findings do not support an association between exposure to WTN up to 46 dBA and elevated self-reported and objectively defined measures of stress.

Hair cortisol concentration is unaffected by basic military training, but related to sociodemographic and environmental factors

Abstract The analysis of hair cortisol concentrations (HCC) is a promising new biomarker for retrospective measurement of chronic stress. The effect of basic military training (BMT) on chronic stress has not yet been reported. The aim of this study was to investigate the effect of 10-week BMT on HCC, while further exploring the role of known and novel covariates. Young healthy male recruits of the Swiss Army participated twice, 10 weeks apart, in data collection (1st examination: n = 177; 2nd examination: n = 105). On two occasions, we assessed HCC, perceived stress and different candidate variables that may affect HCC (e.g. socioeconomic status, meteorological data). Military training increased perceived stress from the first to the second examination, but did not affect HCC. In line with this, there was no correlation between HCC and perceived stress ratings. This could be interpreted as a missing influence of mainly physical stress (e.g. exercise) on HCC. In contrast, significant correlations were found between HCC and ambient temperature, humidity and education. Future studies should control for meteorological data and educational status when examining HCC.

Hair Cortisol as a Biomarker of Stress in Mindfulness Training for Smokers

OBJECTIVES Stress is a well-known predictor of smoking relapse, and cortisol is a primary biomarker of stress. The current pilot study examined changes in levels of cortisol in hair within the context of two time-intensity matched behavioral smoking cessation treatments: mindfulness training for smokers and a cognitive-behavioral comparison group. PARTICIPANTS Eighteen participants were recruited from a larger randomized controlled trial of smoking cessation. OUTCOME MEASURES Hair samples (3 cm) were obtained 1 month after quit attempt, allowing for a retrospective analysis of hair cortisol at preintervention and post-quit attempt time periods. Self-reported negative affect was also assessed before and after treatment. INTERVENTION Both groups received a 7-week intensive intervention using mindfulness or cognitive-behavioral strategies. RESULTS Cortisol significantly decreased from baseline to 1 month after quit attempt in the entire sample (d=-0.35; p=.005). In subsequent repeated-measures analysis of variance models, time by group and time by quit status interaction effects were not significant. However, post hoc paired t tests yielded significant pre-post effects among those randomly assigned to the mindfulness condition (d=-0.48; p=.018) and in those abstinent at post-test (d=-0.41; p=.004). Decreased hair cortisol correlated with reduced negative affect (r=.60; p=.011). CONCLUSIONS These preliminary findings suggest that smoking cessation intervention is associated with decreased hair cortisol levels and that reduced hair cortisol may be specifically associated with mindfulness training and smoking abstinence. RESULTS support the use of hair cortisol as a novel objective biomarker in future research.

Clinical Applications of Hair Analysis

The objective of this chapter is to present selected clinical applications of hair analysis published in the last decade, to highlight the tremendous potential of this matrix. Due to limited space we have chosen not to review some long-used clinical methods of measuring heavy metals (mostly lead, arsenic, and mercury) in the diagnosis of chronic poisoning. Rather, we have selected to focus on relatively new clinical methods which have not been reported extensively before. These include the diagnosis of fetal alcohol spectrum disorder, the neonatal abstinence syndrome, the identification of social risks for children in care of drug using adults, and the measurement of hair cortisol as a biomarker of chronic stress and Cushing’s syndrome. In all of these examples, hair analysis has allowed discoveries that can dramatically change clinical diagnosis and management of patients.