Elsevier

Psychoneuroendocrinology

Volume 38, Issue 8, August 2013, Pages 1220-1235
Psychoneuroendocrinology

Review
Hair cortisol, stress exposure, and mental health in humans: A systematic review

https://doi.org/10.1016/j.psyneuen.2012.11.015Get rights and content

Abstract

The deleterious effects of chronic stress on health and its contribution to the development of mental illness attract broad attention worldwide. An important development in the last few years has been the employment of hair cortisol analysis with its unique possibility to assess the long-term systematic levels of cortisol retrospectively. This review makes a first attempt to systematically synthesize the body of published research on hair cortisol, chronic stress, and mental health. The results of hair cortisol studies are contrasted and integrated with literature on acutely circulating cortisol as measured in bodily fluids, thereby combining cortisol baseline concentration and cortisol reactivity in an attempt to understand the cortisol dynamics in the development and/or maintenance of mental illnesses. The studies on hair cortisol and chronic stress show increased hair cortisol levels in a wide range of contexts/situations (e.g. endurance athletes, shift work, unemployment, chronic pain, stress in neonates, major life events). With respect to mental illnesses, the results differed between diagnoses. In major depression, the hair cortisol concentrations appear to be increased, whereas for bipolar disorder, cortisol concentrations were only increased in patients with a late age-of-onset. In patients with anxiety (generalized anxiety disorder, panic disorder), hair cortisol levels were reported to be decreased. The same holds true for patients with posttraumatic stress disorder, in whom – after an initial increase in cortisol release – the cortisol output decreases below baseline.

The effect sizes are calculated when descriptive statistics are provided, to enable preliminary comparisons across the different laboratories. For exposure to chronic stressors, the effect sizes on hair cortisol levels were medium to large, whereas for psychopathology, the effect sizes were small to medium. This is a first implication that the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in the development and/or maintenance of psychopathology may be more subtle than it is in healthy but chronically stressed populations. Future research possibilities regarding the application of hair cortisol research in mental health and the need for multidisciplinary approaches are discussed.

Introduction

A frequently assessed hormone in psychoneuroendocrine research is cortisol. Cortisol is a glucocorticoid hormone and is released by the adrenal cortex through stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol is crucial for proper body and brain functioning as it regulates numerous basal processes such as fat and glucose metabolism, blood pressure, inflammatory and immune responses, and thereby aids the organism to flexibly adjust to environmental challenges (Marieb and Hoehn, 2007). It is also commonly known as the stress hormone because it is released in higher doses under stressful conditions. In the reaction to basically all stressors, two classes of hormones are released; catecholamines and glucocorticoids, and the speed and magnitudes of both parts depend on the specific stressor (Pacák and Palkovits, 2001). Catecholamines such as noradrenaline or adrenaline work via the nervous system and within seconds, thereby enabling immediate physical reactions associated with the flight-or-fight response (also known as acute stress reaction). Glucocorticoids such as cortisol act via the hormonal route and support the activity of catecholamines over the course of minutes or hours. Cortisol affects and enables the coordination of brain and body functions involved in coping with a stressor (de Kloet et al., 2005). Effective coping with a stressor involves the rapid activation of a stress response when it is needed, as well as the efficient termination afterwards. The increased secretion upon the appearance of a stressor can result in temporarily increased availability of energy by increased muscle strength, increased memory function, increased immunity, and decreased sensitivity to pain (Marieb and Hoehn, 2007). This increased release is under normal circumstances terminated by cortisol itself as its production is part of a negative feedback-loop involving all parts of the HPA axis. However, the initiation as well as the termination of the stress response is susceptible to dysregulation; these processes can be delayed, excessive, flattened, or prolonged (McEwen, 2003, Oitzl et al., 2010).

A stress response consists of three phases: stress reaction, recovery, and adaptation (Oitzl et al., 2010). The bodily processes that maintain homeostasis during the different stress phases are called “allostasis” (McEwen, 2003). A state of increased activity of one “mediator” such as cortisol is an “allostatic state”. Accumulation of mediator dysregulations over time are called “allostatic load” and can result in receptor desensitization and tissue damage (McEwen, 2003). Allostatic load is for example reflected in a chronic dysregulation of the HPA axis. Functioning of the HPA axis (measured in cortisol concentrations) in psychiatric populations has frequently been subject to research, and both hypo- and hyperactivity of the HPA axis have been found in different psychiatric populations, for example in patients with depressive and anxiety disorders (Olff et al., 2006, Vreeburg et al., 2009, Vreeburg et al., 2010), or with personality disorders (Lieb et al., 2004).

Until a few years ago, cortisol has solely been analyzed from blood serum, saliva, or urine. These analyses offer the possibility to explore the dynamics and the concentration of acutely (serum, saliva) or short-term (urine) circulating cortisol concentrations. Studies using these methods have provided insight into dysregulations of stress reactions and have established the connection between HPA axis activity alterations and mental illness. For example, dysregulation of the HPA axis is supposed to be an important causal factor in the development of panic disorder (de Kloet et al., 2005), which could therefore be considered a maladaptation to stressors. Furthermore, abnormal cortisol awakening responses (CAR) and/or disturbed negative feedback mechanisms as shown by the dexamethasone suppression test (DST) have been linked to different psychiatric diagnoses (Yehuda et al., 2004, Vreeburg et al., 2009, Vreeburg et al., 2010). Moreover, a normalization of the HPA axis activity is considered a prerequisite for convalescence (Holsboer, 2000).

Unfortunately, the cortisol levels obtained by the aforementioned techniques show considerable intra- and interindividual differences which are due to cortisol's circadian rhythm as well as its pulsatile secretion (Lightman et al., 2008), daily variation, and reactivity to acute transient stress, such as nervousness (Hellhammer et al., 2007). Also, the use of oral contraceptives has been reported to increase the adrenal cortisol production (Meulenberg et al., 1987). These techniques further call for invasive or frequent sampling and they are especially prone to measurement error and sloppiness as the samples are often collected by the participants themselves, without supervision (Kudielka et al., 2003). These are confounding variables that hamper the comparability of existing studies in this area. In addition, these techniques do not cover the long-term effect of stress exposure very well.

For a few years now, a new and very different method to measure cortisol exposure in humans has been developed; the extraction of cortisol from human hair, with first evidence provided in 2004 (Raul et al., 2004). Since then, several research groups have been focusing on this promising technique with some of its numerous advantages being the non-invasiveness, the standardized sampling, and, maybe most intriguing, the possibility to use hair as a retrospective biomarker of cortisol exposure. As hair grows approximately one centimeter per month (Wennig, 2000), hair analysis offers the possibility to show the average long-term activity of the HPA axis, and to compare several hair segments/months with each other, including segments before the presence of a stressful event. As hair cortisol most probably reflects the amount of free, unbound cortisol, it is also unaffected by oral contraceptives (Dettenborn et al., 2012).

For the analysis, a strand of hair is usually cut from the scalp and minced, and the cortisol in this hair is then extracted by methanol and further analyzed by either immunoassays or liquid chromatography–mass spectrometry (LC/MS) (Gow et al., 2010, Manenschijn et al., 2011a).

It is important to emphasize that, while the articles using short-term circulating cortisol levels provide valuable information about cortisol dynamics and stress reactivity, studies on hair cortisol assess a completely different phenomenon of the HPA axis, namely that of long-term (i.e. months to years) total cortisol exposure. Therefore, consensus between those kinds of measurements is neither desired nor required to add up to a more complete understanding of the role of cortisol concentrations in the stress system. If anything, integrating both methods to display both baseline activity and stress reactivity of the HPA axis seems the most promising approach to understand the neurobiological components of development and remission of (mental) illnesses.

To date, most hair cortisol research has been conducted in the light of somatic diseases and their connection to cortisol. Two diseases that show abnormal cortisol levels are Cushing's Disease (CD) and Addison's Disease (AD). In CD, a tumor of the pituitary gland produces large amounts of adrenocorticotropic hormone (ACTH) which then leads to extremely high cortisol levels, whereas in AD the adrenal glands fail to produce sufficient cortisol, which results in unusually low cortisol levels. For both conditions, our group, as well as others, has shown that the clinical course of the disease and the effect of treatment are well reflected in hair cortisol levels (Thomson et al., 2010, Gow et al., 2011, Manenschijn et al., 2011a, Manenschijn et al., 2012a). An example for the clinical applicability of hair cortisol measurements is that for one patient with CD and one patient with AD, their long hair (more than 12 cm) was used to design retrospective hair cortisol level timelines, which corresponded perfectly with the presentation of symptoms and the pharmaceutical as well as surgical treatment (Manenschijn et al., 2011a).

Hair cortisol research is a rapidly emerging research area and has successfully been applied to studies of patients with physical and psychological symptoms such as Cushing's Disease, chronic pain, and depression. Five reviews on this topic have been published until now, providing an in-depth summary of different methodological issues such as advantages and yet to overcome challenges, as well as the applicability of hair cortisol measures in general (Gow et al., 2010, Meyer and Novak, 2012, Russell et al., 2012b, Sharpley et al., 2012, Stalder and Kirschbaum, 2012). This current review specifically focuses on the relationship between hair cortisol, stress, and mental illness. Furthermore, to enable direct comparisons among studies, effect sizes were calculated when descriptive statistics were provided. After discussing the first results, we also will look ahead into a number of intriguing research questions which have yet to be answered.

Section snippets

Methods

To achieve this, we entered the search terms “hair cortisol” and “long-term cortisol” into Web of Knowledge and into PubMed to find relevant literature. The literature search resulted in 93 articles in Web of Knowledge and 75 articles in PubMed. The articles were individually scanned to elaborate whether they fulfill the following requirements: a) research in humans, b) using scalp hair from the posterior vertex, c) providing information about the used sample and cortisol extraction method, and

Hair cortisol and chronic stress exposure

Here we describe the relationship between hair cortisol and stress. Stress can be elicited by either physiological or psychological stressors. When the stressor regularly resurfaces and/or does not disappear, the stress response cannot be terminated but continues. Individuals that undergo this prolonged stress reaction are therefore hypothesized to have higher cortisol concentrations in their body than individuals who are not exposed to chronic stress. As the increased release of cortisol for a

General discussion and future perspectives

The main aim of this review was to describe the state of the moment regarding the relationship between hair cortisol, stress, and psychopathology. Even though only few studies on this relationship have been published until now, an already established finding is the value of the additional information that hair cortisol provides. Connections between endocrine function and mental health have been explored for decades, with many inconsistent results. Measurements of the acutely circulating

Conclusion

In conclusion, the combination of endocrine, genetic and psychological paradigms is a prerequisite to an integrated approach that aims to understand etiology and mechanisms of the HPA axis dysregulation. Hair cortisol research has repeatedly been used for this aim, with promising results. In the long run, this integrated approach will eventually help to predict the response to one or another pharmacological or psychotherapeutic treatment, and thus, to design personalized tailored interventions.

Role of the funding source

The last author (EFCvR) is supported by NWO (grant number 916.96.069), and the Netherlands Brain Foundation (grant number F2011(1)-12).

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgement

None.

References (106)

  • R. Gow et al.

    An assessment of cortisol analysis in hair and its clinical applications

    Forensic Sci. Int.

    (2010)
  • K. Hammerfald et al.

    Persistent effects of cognitive-behavioral stress management on cortisol responses to acute stress in healthy subjects – a randomized controlled trial

    Psychoneuroendocrinology

    (2006)
  • J. Hellhammer et al.

    Several daily measurements are necessary to reliably assess the cortisol rise after awakening: state- and trait components

    Psychoneuroendocrinology

    (2007)
  • K. Hinkelmann et al.

    Cognitive impairment in major depression: Association with salivary cortisol

    Biol. Psychiatry

    (2009)
  • R. Hoehn-Saric et al.

    Anxiety and arousal: physiological changes and their perception

    J. Affect. Disord.

    (2000)
  • F. Holsboer

    The corticosteroid receptor hypothesis of depression

    Neuropsychopharmacology

    (2000)
  • S.S. Inslicht et al.

    Increased cortisol in women with intimate partner violence-related posttraumatic stress disorder

    Psychoneuroendocrinology

    (2006)
  • L. Johnson et al.

    Age of onset in affective disorder: its correlation with hereditary and psychosocial factors

    J. Affect. Disord.

    (2000)
  • C. Kirschbaum et al.

    Hair as a retrospective calendar of cortisol production-increased cortisol incorporation into hair in the third trimester of pregnancy

    Psychoneuroendocrinology

    (2009)
  • K. Lieb et al.

    Increased diurnal salivary cortisol in women with borderline personality disorder

    J. Psychiatr. Res.

    (2004)
  • S.L. Lightman et al.

    The significance of glucocorticoid pulsatility

    Eur. J. Pharmacol.

    (2008)
  • H.R. Luo et al.

    Hair cortisol level as a biomarker for altered hypothalamic-pituitary-adrenal activity in female adolescents with posttraumatic stress disorder after the 2008 wenchuan earthquake

    Biol. Psychiatry

    (2012)
  • L. Manenschijn et al.

    Evaluation of a method to measure long term cortisol levels

    Steroids

    (2011)
  • L. Manenschijn et al.

    Long-term cortisol in bipolar disorder: associations with age of onset and psychiatric comorbidity

    Psychoneuroendocrinology

    (2012)
  • J.W. Mason

    A re-evaluation of the concept of “Non-specificity” in stress theory

    J. Psychiatr. Res.

    (1971)
  • B.S. McEwen

    Mood disorders and allostatic load

    Biol. Psychiatry

    (2003)
  • P.M.M. Meulenberg et al.

    The effect of oral-contraceptives on plasma-free and salivary cortisol and cortisone

    Clin. Chim. Acta

    (1987)
  • M.S. Oitzl et al.

    Brain development under stress: hypotheses of glucocorticoid actions revisited

    Neurosci. Biobehav. Rev.

    (2010)
  • M. Olff et al.

    Changes in cortisol and dhea plasma levels after psychotherapy for PTSD

    Psychoneuroendocrinology

    (2007)
  • M. Olff et al.

    Hpa- and hpt-axis alterations in chronic posttraumatic stress disorder

    Psychoneuroendocrinology

    (2006)
  • M. Olff et al.

    Effects of appraisal and coping on the neuroendocrine response to extreme stress

    Neurosci. Biobehav. Rev.

    (2005)
  • P. Pervanidou et al.

    Neuroendocrinology of post-traumatic stress disorder

    Prog. Brain Res.

    (2010)
  • F. Pragst et al.

    State of the art in hair analysis for detection of drug and alcohol abuse

    Clin. Chim. Acta

    (2006)
  • J.S. Raul et al.

    Detection of physiological concentrations of cortisol and cortisone in human hair

    Clin. Biochem.

    (2004)
  • E. Russell et al.

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

    Psychoneuroendocrinology

    (2012)
  • N. Skoluda et al.

    Elevated hair cortisol concentrations in endurance athletes

    Psychoneuroendocrinology

    (2012)
  • T. Stalder et al.

    Analysis of cortisol in hair – state of the art and future directions

    Brain Behav. Immun.

    (2012)
  • T. Stalder et al.

    Use of hair cortisol analysis to detect hypercortisolism during active drinking phases in alcohol-dependent individuals

    Biol. Psychol.

    (2010)
  • T. Stalder et al.

    Cortisol in hair, body mass index and stress-related measures

    Biol. Psychol.

    (2012)
  • T. Stalder et al.

    Intraindividual stability of hair cortisol concentrations

    Psychoneuroendocrinology

    (2012)
  • S. Steudte et al.

    Increased cortisol concentrations in hair of severely traumatized ugandan individuals with PTSD

    Psychoneuroendocrinology

    (2011)
  • S. Steudte et al.

    Decreased hair cortisol concentrations in generalised anxiety disorder

    Psychiatry Res.

    (2011)
  • R. Wennig

    Potential problems with the interpretation of hair analysis results

    Forensic Sci. Int.

    (2000)
  • American Psychiatric Association

    Diagnostic and statistical manual of mental disorders: Dsm-iv-tr

    (2000)
  • B. Aperia

    Hormone pattern and posttreatment attitudes in patients with major depressive disorder given electroconvulsive-therapy

    Acta Psychiatr. Scand.

    (1986)
  • P. Cervantes et al.

    Circadian secretion of cortisol in bipolar disorder

    J. Psychiatry Neurosci.

    (2001)
  • J. Cohen

    Statistical Power Analysis for the Behavioral Sciences

    (1988)
  • S. Cohen

    Cognitive processes as determinants of environmental stress

    Issues Ment. Health Nurs.

    (1985)
  • S. Cohen et al.

    A global measure of perceived stress

    J. Health Soc. Behav.

    (1983)
  • E.R. de Kloet

    About stress hormones and resilience to psychopathology

    J. Neuroendocrinol.

    (2008)
  • Cited by (524)

    View all citing articles on Scopus
    View full text