ReviewHair cortisol, stress exposure, and mental health in humans: A systematic review
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.
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