Lucia Dettenborn

The cortisol awakening response (CAR): facts and future directions.

In humans, the secretion of cortisol from the adrenal glands follows a diurnal cycle with a profound increase after awakening. This increase after awakening, a phenomenon termed the cortisol awakening response (CAR), appears to be a distinct feature of the hypothalamus-pituitary-adrenal (HPA) axis, superimposing the circadian rhythmicity of cortisol secretion. Several studies point towards an important role of the hippocampus and, additionally, other brain structures (e. g. amygdala, prefrontal cortex, suprachiasmatic nucleus) in the regulation of the CAR. There is increasing knowledge that the CAR is influenced by a variety of factors such as gender, health status, and health behavior or stress perception. However, the exact function of the profound cortisol increase after awakening is still not clarified. We hypothesize that the anticipation of the upcoming day is of major relevance for the magnitude of the CAR. The present paper reviews the current knowledge on the neural regulation of the CAR and factors influencing this phenomenon and considerations are addressed concerning the exact function of the CAR.

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

Hair has long been used in toxicology, forensic science, doping control and other fields as a biological specimen for the detection of environmental agents, drugs, or toxins. Most recent evidence suggests that also hormones are incorporated and trapped inside the growing hair. This has led to the hypothesis that cortisol measurement of distinct hair segments could provide a retrospective calendar of cortisol production for the individual. In this first proof-of-concept study in humans, we analyzed cortisol in hair donated by mothers with a neonate child (n-Mothers; N=103), mothers with toddlers 3-9 months of age (t-Mothers; N=19), and control women (N=20). We cut hair strands from each women into at least three 3-cm segments, which, based on an average hair growth rate of 1cm per month, would represent hair grown over the past three, six, and nine months, respectively. Since in the third trimester of pregnancy there is a well-documented increased production of cortisol, we expected to see elevated levels of cortisol in the most proximal hair segment of women who had just given birth to a child (n-Mothers) compared with the control women. Likewise, we expected to see elevated levels in the second, third, or fourth segment of mothers of 3-month olds, 6-months olds, and 9-months olds, respectively. These hair segments, cut at 4-12 cm from the scalp, would represent hair grown throughout the third trimester of pregnancy. Results showed that there was a strong monotonic decline in cortisol concentration from the segment closest to the scalp to the most distal hair segment (p<0.0001). Cortisol levels decreased by 30-40% from one segment to the next for the most recent four hair segments. Segments from hair older than one year had similarly, low levels of cortisol. Comparisons of cortisol levels in hair between n-Mothers and control women yielded the expected results: cortisol levels in the first 3-cm hair segment (i.e., closest to the scalp) of n-Mothers were two-fold higher than in controls (p<0.0001), probably reflecting increased cortisol levels throughout the third trimester of pregnancy. No differences in cortisol content were apparent for the second or third 3-cm segments in n-Mothers (p>0.2). When hair from mothers with 6-9 months old toddlers was analyzed, the hair segment representing the third trimester period contained the same amount of cortisol as the hair grown more recently in mothers with 3-4 months old toddlers only. Age of the women, hair curvature, hair color, and frequency of hair washes per week were unrelated to cortisol levels. We conclude that cortisol measured in human hair can be a valid reflection of increased cortisol production for a period of up to six months. Due to a rapid decline of cortisol levels in human adult hair, a retrospective calendar of cortisol exposure may be limited to the past six months.

Decreased hair cortisol concentrations in generalised anxiety disorder

Previous research examining hypothalamic-pituitary-adrenal (HPA) axis activity in generalised anxiety disorder (GAD) has suggested a general hypercortisolism. These studies have mostly relied on salivary, plasma or urinary assessments, reflecting cortisol secretion over short time periods. The current study utilised the novel method of cortisol assessment in hair to obtain a retrospective index of cortisol secretion over a prolonged period of time. Hair cortisol levels were determined in 15 GAD patients and in 15 age- and gender-matched controls. In addition, participants collected six saliva samples (on awakening, +30 min, 12:00, 16:00, 20:00 h and at bedtime) on two consecutive weekdays for the assessment of the diurnal cortisol profile. Results revealed significantly lower (50-60%) cortisol levels in the first and second 3-cm hair segments of GAD patients compared to those of controls. No significant between-group differences were seen in diurnal cortisol profiles. The hair cortisol findings tentatively suggest that under naturalistic conditions GAD is associated with hypocortisolism. If corroborated by future research, this demonstrates the important qualities of cortisol measurement in hair as an ecologically valid, retrospective index of long-term cortisol secretion and as a marker for psychiatric disorders associated with hypo- or hypercortisolism.

The assessment of cortisol in human hair: Associations with sociodemographic variables and potential confounders

To inform the future use of hair cortisol measurement, we have investigated influences of potential confounding variables (natural hair colour, frequency of hair washes, age, sex, oral contraceptive (OC) use and smoking status) on hair cortisol levels. The main study sample comprised 360 participants (172 women) covering a wide range of ages (1–91 years; mean = 25.95). In addition, to more closely examine influences of natural hair colour and young age on hair cortisol levels, two additional samples comprising 69 participants with natural blond or dark brown hair (hair colour sample) as well as 28 young children and 34 adults (young age sample) were recruited. Results revealed a lack of an effect for natural hair colour, OC use, and smoking status on hair cortisol levels (all ps >0.10). No influence of frequency of hair washes was seen for proximal hair segments (p = 0.335) but for the third hair segment indicating lower cortisol content (p = 0.008). We found elevated hair cortisol levels in young children and older adults (p < 0.001). Finally, men showed higher hair cortisol levels than women (p = 0.002). The present data indicate that hair cortisol measurement provides a useful tool in stress-related psychobiological research when applied with the consideration of possible confounders including age and sex.

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

Hair cortisol concentrations (HCC) are assumed to reflect integrated cortisol secretion over extended periods of time and may provide a sensitive marker for stress-associated endocrine changes. Here, we report data from two independent studies of 155 (study I) and 58 participants (study II) in which HCC associations with different stress-related measures and body mass index (BMI) were investigated. Consistent evidence for positive associations between HCC and BMI was seen across both studies (study I: r=.33, p<.001; study II: r=.42, p=.001). On the other hand, findings failed to reveal reliable HCC associations with psychosocial variables, showing only a positive relationship with self-reported social overload in study II (r=.29, p=.03) but not with other stress-related measures.

Elevated hair cortisol concentrations in endurance athletes.

Engaging in intensive aerobic exercise, specifically endurance sports, is associated with HPA axis activation indicated by elevated cortisol levels. Whether the repeated short-term elevations in cortisol levels result in higher long-term cortisol exposure of endurance athletes has been difficult to examine since traditional methods of cortisol assessments (saliva, blood, urine) reflect only relatively short time periods. Hair segment analysis provides a new method to assess cumulative cortisol secretion over prolonged time periods in a retrospective fashion. The aim of this study was to investigate cumulative cortisol secretion over several months reflecting intensive training and competitive races by examining hair cortisol levels of endurance athletes. Hair samples were obtained from 304 amateur endurance athletes (long-distance runners, triathletes, cyclists) and 70 controls. Cortisol concentrations were determined in the first to third 3-cm hair segments most proximal to the scalp. In addition, self-report measures of training volume were obtained. Endurance athletes exhibited higher cortisol levels in all three hair segments compared to controls (p<.001). Positive correlations between the cortisol concentration in the first hair segment and each indicator of training volume were found (all p<.01). These data suggest that repeated physical stress of intensive training and competitive races among endurance athletes is associated with elevated cortisol exposure over prolonged periods of time. These findings may have important implications with regard to somatic and mental health of athletes which should be investigated in future research.

Introducing a novel method to assess cumulative steroid concentrations: Increased hair cortisol concentrations over 6 months in medicated patients with depression

Depression has been linked to increased cortisol concentrations using point measures taken from urine, blood, or saliva samples. However, with regard to hypercortisolism-induced consequences, long-term cumulative cortisol burden is of relevance. Our objective was to use hair analysis as a new method to assess cortisol exposure over 6 months in depressed patients and healthy controls. We examined 23 depressed patients (8 men and 15 women, mean age: 41.6 years ( ± standard deviation (SD), 13.1 years); mean duration of current depressive episode 9 months ( ± SD, 13 months)) and 64 healthy controls, matched for age and gender. Cortisol concentrations in two 3-cm hair segments from near to the scalp were analyzed, representing cortisol secretion during the 6 months prior to sampling. Compared with healthy individuals, depressed patients had higher hair cortisol concentrations in the first (mean ± SD: 26.7 ± 20.8 vs. 18.7 ± 11.5 pg/mg, p < 0.05) and second hair segment (mean ± SD: 21.9 ± 23.7 vs. 13.4 ± 9.6 pg/mg, p < 0.05). In conclusion, hair cortisol analysis confirmed enhanced cortisol secretion in depressed patients over a prolonged time period. Because of the retrospective and cumulative nature of cortisol in hair, the assessment of hair cortisol concentration may help in addressing unanswered questions regarding hypothalamic–pituitary–adrenal axis overactivity and associated health consequences in psychiatric disorders.

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

The assessment of cortisol levels in human hair has recently been suggested to provide a retrospective index of cumulative cortisol exposure over periods of up to 6 months. The current study examined the utility of hair cortisol analysis to retrospectively detect hypercortisolism during active drinking phases in alcoholics in acute withdrawal (n=23), the normalisation of cortisol output in abstinent alcoholics (n=25) and cortisol levels in age- and gender-matched controls (n=20). Scalp-near 3-cm hair segments were sampled and analysed for cortisol content. Results showed three to fourfold higher cortisol levels in hair samples of alcoholics in acute withdrawal than in those of abstinent alcoholics (p<.001) or controls (p<.001), with no differences between the latter two groups. The current hair cortisol findings closely mirror results of previous research using well-established measures of systemic cortisol secretion and thus provide further validation of this novel method.

Elevated hair cortisol levels in chronically stressed dementia caregivers

Hair cortisol concentrations (HCC) are assumed to reflect integrated long-term cortisol levels and have been proposed as a promising endocrine marker of chronic psychological stress. The current study examined HCC in relation to caregiving burden, a well-established naturalistic model of chronic stress in humans. HCC and relevant psychosocial data were examined in 20 caregivers of relatives with dementia and 20 non-caregiver controls matched for age and sex. Results revealed elevated HCC in dementia caregivers compared to non-caregiver controls (F(1,38)=4.4, p=.04, ηp2=.10). Further, within caregivers, a trend for a positive association of HCC with self-reported caregiving burden (r=.43, p=.058) and a positive association with depressiveness (r=.48, p=.045) were observed. No other associations between HCC and subjective measures were seen. These findings concur with the notion that HCC sensitively capture endocrine aberrations in stress-exposed groups.

Children with high-functioning autism show a normal cortisol awakening response (CAR)

Individuals with high-functioning autism spectrum disorders (HFA) show difficulties in the ability to react to change. A recent study suggested that variations in the functioning of the hypothalamus-pituitary-adrenal axis, especially in one of its markers--the cortisol awakening response (CAR)--may be related to those difficulties in adolescents with Aspergers syndrome. The current study investigated the CAR in a younger sample with diagnoses from the whole autism spectrum: A group of children with HFA (N=15) was compared to a group of typically developing children (N=25). Findings suggest that the frequency of a CAR as well as the increase in cortisol levels from awakening to 30 min later were similar between groups, indicating that variations in the CAR in HFA may not be present early in life but only develop later in adolescence or may only occur in some diagnoses from the autism spectrum.