Human hypothalamus–pituitary–adrenal axis responses to acute psychosocial stress in laboratory settings

Neuroscience and Biobehavioral Reviews 35 (2010) 91–96

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Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

Review

Human hypothalamus–pituitary–adrenal axis responses to acute psychosocial stress in laboratory settings Paul Foley, Clemens Kirschbaum * Department of Psychology, Technische Universita¨t Dresden, 01062 Dresden, Germany

A R T I C L E I N F O

A B S T R A C T

Keywords: Acute psychosocial stress Trier Social Stress Test Hypothalamus–pituitary–adrenal axis Sympathetic nervous system Immune response to stress

Cumulative acute psychosocial stress is thought to promote the development of a range of disorders which suggests that biomarkers for the physiological response may become valuable tools for biomedical research and development. The search for these biomarkers has been aided by the development of a standardised protocol for inducing psychosocial stress that combines social-evaluative threat and uncontrollability, i.e., the Trier Social Stress Test (TSST). Among other biological markers of acute stress, this test induces significant changes of the hypothalamus–pituitary–adrenal axis (HPAA), which is thought to play a pivotal role in the generation of stress-associated pathologies. The HPAA responses show differences between patients and healthy subjects as well as between pathologies. Moreover, gender, age, personality traits, social environment, and genotype can also shape the individual’s acute stress response triggered by the TSST. Characterization of the roles and interactions of these factors in generating a dysregulation of the neuroendocrine responses to acute psychosocial stress await longitudinal studies. ß 2010 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3.

4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Trier Social Stress Test (TSST) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cortisol responses to acute psychosocial stress—sources of variation. . 3.1. Demographic and biological factors . . . . . . . . . . . . . . . . . . . . . . . 3.2. Intervention effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Genetic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. The cortisol stress response and disease . . . . . . . . . . . . . . . . . . . Habituation—changing the cortisol response pattern with experience . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Biomarkers of psychosocial stress include components and substrates of the physiological systems that transduce stress. Psychosocial stress and the allostatic load compensating the stressful stimuli have been implicated in psychopathologies such as depression (Parker et al., 2003), the metabolic syndrome (Chrousos, 2000), and systemic hypertension (Esler et al., 2008). As the most important putative biomarkers of psychosocial stress, response parameters of the hypothalamus–pituitary–adrenal axis

* Corresponding author. E-mail address: [email protected] (C. Kirschbaum). 0149-7634/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2010.01.010

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(HPAA) and the sympathetic nervous system (SNS) are of focal importance to link the individual stress response to health and disease (Chrousos, 2009; McEwen, 1998; Fig. 1). In search of reliable biomarkers of psychosocial stress and individual factors modulating the stress response magnitude or kinetic, numerous laboratory tasks have been devised for studies under controlled conditions. Among those protocols, the cold pressure test, the Stroop test, public speaking, and other tasks have been employed with varying and sometimes disappointing results. With the introduction of the ‘‘Trier Social Stress Test’’ (TSST, Kirschbaum et al., 1993), a laboratory protocol has become available for a reliable stimulation of biomarkers of psychosocial stress (Dickerson and Kemeny, 2004). The TSST has been widely used to demonstrate both individual differences in the response to

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foreign language component into the TSST (Simoens et al., 2007; Smeets et al., 2007) and other groups have varied the public speaking task in the adult TSST (Gold et al., 2004) or TSST-C (Gunnar et al., 2009a,b), which also resulted in fewer responder rates. In some TSST-C studies additional inducements have been offered for performance (Jones et al., 2008). Recently, Childs et al. (2006) compared responses to the TSST between subjects who were exposed individually or in groups and found that heart rate increases where greater in grouped participants while anxiety and cortisol responses were similar to those of subjects who were exposed individually. The group version of the TSST offers the unique opportunity to investigate acute stress responses in complex social settings and will likely become a useful research tool for social neuroscientists.

Fig. 1. The neuroendocrine response to psychosocial stress is primarily transduced through the HPAA and sympathetic adrenal medulla axis. Both of these axes originate in the hypothalamus and are modulated by limbic inputs. The medial hypothalamus releases the peptide corticotrophin-releasing hormone (CRF) which stimulates the pituitary to release ACTH into the systemic circulation. The adrenal cortex responds to the ACTH signal by releasing cortisol. The sympathetic nervous system originates in the posterior hypothalamus and innervates the adrenal medulla—among other targets. Sympathetic activation stimulates the adrenal medulla to release adrenaline. Both adrenaline and cortisol target a number of tissues such leukocytes that respond by releasing cytokines. The limbic system is also a target of the cortisol signal, which thus forms a feedback loop to the hypothalamus.

psychosocial stress and the dysregulation of that response in several diseases (Hellhammer et al., 2009). Due to limited space, we will focus on studies that have employed the TSST for stimulation of HPAA and discuss the role of various mediators of the acute stress response to psychosocial stress in the present review.

3. Cortisol responses to acute psychosocial stress—sources of variation The best characterized HPAA marker for the response to acute psychosocial stress is the release of cortisol. Measured in blood or saliva, cortisol levels gradually increase within a few minutes (usually less than 10 min) after stimulation onset and reach peak concentrations 10–30 min after stress cessation. Although reliably detected in groups of healthy individuals and patients alike, the cortisol response to acute psychosocial stress shows considerable variation between individuals. These variations are, in part, explained by demographic variables (e.g., gender and age), biological factors (e.g., corticosteroid binding globulin levels, genetic polymorphisms), psychological variables (e.g., personality, chronic stress), or treatments (e.g., stress inoculation, physical training) and will be discussed below. Since numerous biological parameters are systematically confounded with certain demographic variables, for example, differences between men and women in sex steroid levels throughout the life span, we will consider those variables jointly (Table 1).

2. The Trier Social Stress Test (TSST) 3.1. Demographic and biological factors The TSST is a standardised motivated performance task protocol that combines high levels of social-evaluative threat and uncontrollability (Dickerson and Kemeny, 2004). The TSST is a task consisting of a brief preparation period followed by a test period in which the subject is required to deliver a free speech concerning their suitability for employment in a mock job interview and to perform mental arithmetic in front of an audience that is trained to withhold verbal and non-verbal feedback (Kirschbaum et al., 1993). The TSST produces a two- to threefold rise in salivary cortisol levels in 70–85% of tested subjects (Kudielka et al., 2007). Exposure to the TSST also leads to rises in other HPAA marker levels such as ACTH (one- to threefold), SNS markers including salivary alpha amylase (sAA), adrenaline and noradrenaline, or heart rate responses; and markers of immune system activation, for instance the cytokines interleukin (IL)-1b, IL-6, IL-10 or tumour necrosis factor (TNF-a). The TSST has been adapted to improve its applicability to various subject groups such as children: TSST-C (Buske-Kirschbaum et al., 1997), retired subjects (Kudielka et al., 1998), and psychiatric patients (Brenner et al., 2009). The introduction of a non-stressing TSST-like control exposure (Het et al., 2009) will aid standardisation. Variations have been introduced to the TSST to either increase throughput or to increase the element of psychosocial threat or to adapt the test to subjects for whom a mock job interview is not a relevant stressor. Some of these changes in the stress protocol can lead to substantial alterations of the biological stress responses, e.g., the use of a virtual audience results in lower salivary cortisol responses (Kelly et al., 2007). Some groups have introduced a

While cortisol levels in blood and saliva show similar response kinetics in most cases, significantly different steroid patterns can be observed under clinical and normal circumstances with alterations in corticosteroid binding globulin (CBG) levels. Once released into the blood stream, 90–95% of cortisol will be readily bound to the high-affinity binding protein CBG and other carrier molecules with lower affinity for cortisol (e.g., albumin, erythrocytes). As a result, less than 10% of the secreted cortisol circulates in the body as the ‘free’ fraction of the hormone. Only the ‘free’, i.e., unbound cortisol can penetrate the cell membranes and activate the mineralo- (type 1) and glucocorticoid (type 2) receptors. It is thus thought that only the free cortisol fraction is biologically active. Since unbound cortisol easily enters cells via passive diffusion, the correlation between free cortisol levels in blood (serum or plasma) and saliva is high (usually r > .90). In contrast, the correlation between total (bound and unbound) cortisol and salivary cortisol can be as low as r = .50 if samples are obtained from individuals with variation in CBG levels. Factors known to affect CBG levels include ethinyl estradiol (EE2) containing medication (oral contraceptives) and production of sex steroids throughout the menstrual cycle. It is, thus, not surprising that the acute cortisol response to psychosocial stress is linearly correlated with the individual’s CBG level (Kumsta et al., 2007a,b). Measured in blood, the vast majority of studies report total cortisol levels, i.e., bound and free cortisol. When cortisol is assessed in saliva, however, only the free hormone fraction will be determined. Due to the buffering effect of CBG and other influences, the net response is usually greater in free cortisol than in total cortisol (Follenius

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Table 1 Variables, factors, and clinical conditions associated with increased ("), decreased (#), or unchanged ($) HPA responses to acute psychosocial stress under laboratory conditions in different age groups. See text for references.

Demographic variables Age

Participants/patients

Effect on acute stress response

Comments

<6 years 7–17 years 20–40 years vs. 65+ years

No cortisol response Similar to adults Larger response in elderly men

ACTH responses not studied so far

Birth weight

Young adult men

#

Gender

Adults

Men > Women

Genetic polymorphisms

Young adults

GR 9bAG: " GR BclI GG: # (men) GR BclI GG: " (women) GR N363S: " MR180V " FKPB5 " A118G " GABRA6 5-HTTLPRL " DRD4 7R # Val66Met val/met " (men)

Pregnancy

1st trimester 2nd trimester 3rd trimester

$ " $

Young adults Young adults

# #

Young adults

Hypoglycemic: #

Biological/physiological/drug factors Alcohol consumption Cigarette smoking

Glucose levels

Only observed in free cortisol

Only observed in free cortisol

Observed only after smoking of 2 cigarettes in sequence Tested only under experimental manipulation of glucose levels

Normoglycemic: $ Hyperglycemic: $ Lactation Oral contraceptives Intervention/training Behavioural stress management training Physical contact/massage Social support

Young mothers Young women

# #

Young adults Young women

# #

Young adults

Men: #

Only observed in free cortisol

Increased responses in women supported by their partners

Women: $ or " Disorders/clinical conditions Atopic dermatitis Atopic allergy Chronic fatigue Major depression Metastatic cancer Obesity Panic disorder Sexual abuse Social phobia

Children and adults Children and adults Young adults Adolescents, young adults Women Young women Young adults Young adults Adolescent girls

and Brandenberger, 1986). Thus, it appears that measuring the acute cortisol response to psychosocial stress in saliva (or only the free fraction in blood) is clearly advantageous if individual differences are sought. The individual’s gender determines their response to the TSST to a considerable degree. A consistent finding has been that men show double the elevation of cortisol levels to psychosocial stress that women show (Kirschbaum et al., 1992) when menstrual cycle phase or use of oral contraceptives is not controlled for. Some studies report equal cortisol responses with more pronounced negative affect increases for women (Kelly et al., 2008). The variation by gender in the response to psychosocial stress is probably related to differences in the internal endocrine milieu. Exogenous administration and endogenous levels of sex steroid hormones affect HPAA response to psychosocial stress. Kirschbaum et al. (1999) showed that the salivary cortisol response of women to the TSST was modulated by the menstrual cycle. Women in the luteal phase of

# # # " # " # # $

Comorbitity important

Especially in non-resolved trauma

their cycle showed comparable responses to men while women in the follicular phase of their menstrual cycle showed lower responses that were comparable to women taking oral contraceptives. Total serum cortisol responses were similar in men and women. In contrast, men showed larger ACTH responses than women irrespective of the stage of their menstrual cycle or whether they were taking oral contraceptives (Kirschbaum et al., 1999). These group differences in salivary but not serum cortisol responses can be attributed to differences in CBG levels while the stronger ACTH response appears to reflect sex differences in pituitary output and adrenal cortex sensitivity (Veldhuis et al., 2009). Pregnancy also perturbs the cortisol stress response so that women in the second trimester of pregnancy show a blunting of the cortisol stress response whereas this response appears to be amplified in the third trimester (Nierop et al., 2006) and is normalised postpartum (Altemus et al., 2001). This result is rather surprising given that basal cortisol levels dramatically increase from

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the second to the third trimester (Allolio et al., 1990). Whether the increased cortisol tone prevents a stronger response to acute stimulation in the final stage of pregnancy, needs to be investigated. Notably, the physiological correlates associated with lactation modulate the response to the TSST where postpartum lactating women showed attenuated cortisol rises and amplified prolactin responses to the TSST (Heinrichs et al., 2001). Equivocal results have been reported for the interaction between gender and developmental factors on the cortisol response to the TSST. Some studies have shown a blunted cortisol response for children at age 11 which persist until age 13 for boys when girls show a robust response (Gunnar et al., 2009b). A critical methodological issue is the induction of stress by psychosocial factors in the TSST for children. The task should be perceived by the children as a social-evaluative threat (Dickerson and Kemeny, 2004), thus if modification of the TSST for children reduces this threat no response should be expected. Using a different public speaking task robust responses to the TSST have been demonstrated where children between 8 and 14 years old show a cortisol rise to the TSST (Buske-Kirschbaum et al., 2007; Gordis et al., 2006). This was recently corroborated in a study using a modified TSST protocol (TSST-M) that allowed for direct comparisons between children and adults. Yim et al. (2009) showed that the TSST-M induced comparable cortisol responses in children aged 9–12 years and young adults (18–25 years), respectively. Other HPAA responses are shown and modulated by development so that formerly pre-term children show an amplified cortisol awakening response (Buske-Kirschbaum et al., 2007). These influences persist into adulthood where in young men salivary cortisol responses to TSST-exposure were inversely correlated with the subjects’ birth weights, when born at term (Wu¨st et al., 2005). Cortisol stress responses also vary with food intake. While low blood glucose levels prevented the stress-induced HPA activation (Kirschbaum et al., 1997), glucose intake reinstates the typical cortisol response to the TSST in fasted healthy young men. The reasons or physiological mechanisms for the permissive role of glucose on the cortisol response are still unknown. Conversly, intranasal administration of insulin attenuated the cortisol response to the TSST (Bohringer et al., 2008). Food intake, on the other hand, appears to be affected by acute stress exposure: subsequent to TSST-exposure subjects ate in proportion to their cortisol level rises (Epel et al., 2001). The individual HPA stress response is also significantly modulated by recreational drug intake. Interestingly, the rise in cortisol following psychosocial stress-induced by exposure to the TSST correlated with the cortisol rise in response to amphetamine administration in the same individuals (de Wit et al., 2007). In an earlier study, de Wit et al. (2003) showed that alcohol consumption before the TSST reduced the responder rate in salivary cortisol levels. This effect might be explained by the increased GABA-ergic tone induced by alcohol consumption which, in turn, may reduce the perception of threat. Furthermore, exposure to psychosocial stress by the TSST increased the readiness to consume alcohol. Smoking cigarettes attenuates the HPAA stress response possibly through cholinergic influence on pituitary corticotrophs (Childs and de Wit, 2009; Kirschbaum et al., 1997; Roy et al., 1994; Tsuda et al., 1996). The rise in cortisol in response to TSST-exposure correlates with increases in cigarette smoking over the subsequent half-year in light smokers (de Wit et al., 2007). The gender difference in adrenocorticotropic hormone (ACTH)- and cortisol response to the TSST is reversed in smokers (Back et al., 2008). 3.2. Intervention effects The influence of the perception of social-evaluative stress, by the subjects on the response to the TSST, is illustrated by the

influence of training and social support on HPAA responses. Cortisol responses to the TSST are reduced by training in behavioural stress management (Gaab et al., 2003) or meditation that also reduces IL-6 responses (Pace et al., 2009). Social support and physical contact reduce the HPAA response to the TSST. A combination of oxytocin and social support produced the lowest cortisol rises as well as increased calmness and decreased anxiety during psychosocial stress exposure in young men (Heinrichs et al., 2001). Women who received physical contact from their partners prior to exposure to the TSST showed attenuated cortisol and heart rate rises (Ditzen et al., 2007). 3.3. Genetic factors The heritability of the cortisol response to psychosocial stress is moderate to high (Federenko et al., 2004) and a number of genetic polymorphisms have been investigated for their contribution to stress susceptibility. Carriers of the glucocorticoid receptor (GR) gene polymorphisms BclI and N363S show reduced and enhanced salivary cortisol responses to the TSST, respectively (Kumsta et al., 2007a,b; Wu¨st et al., 2004). Men who carry the GR-gene 9bAG allele showed higher ACTH and serum cortisol rises to TSSTexposure, while men carrying the BclI GG allele showed lower ACTH and salivary cortisol responses. Female BclI GG carriers showed the highest cortisol responses to the TSST (Kumsta et al., 2007a,b). Glucocorticoid-receptor variants have been shown to modulate the susceptibility of the HPAA response to psychosocial stress. The polymorphism in the mineralocorticoid-receptor MR180V confers a greater responsiveness of the cortisol response to its carriers without altering ACTH responses (DeRijk et al., 2006). Polymorphisms in the gene encoding the chaperone protein FKPB5, that interacts with the GR, increase the cortisol response to the TSST (Ising et al., 2008). The m-opioid receptor gene polymorphism A118G confers a stronger cortisol response to administration of the m-opioid receptor antagonist naloxone with an attenuated cortisol response to the TSST with an unaltered ACTH response (Chong et al., 2006). The GABAAa6-receptor subunit gene (GABRA6) shows a polymorphism in the untranslated region. Subjects with a C to T substitution in this SNP showed greater ACTH- and diastolic blood pressure-responses to the TSST than subjects homozygous for the C-form while the cortisol responses were unchanged suggesting that both HPAA and SNS responses to psychosocial stress are modulated by GABA-ergic transmission (Uhart et al., 2004). The 5HT-transporter 5-HTTLPRL allele provides resilience to SNS responses to psychosocial stress during the TSST-C in children with a secure attachment representation (Gilissen et al., 2008). For adults, Mueller et al. observed significantly larger salivary cortisol responses in 5-HTTLPRL subjects than both, the heterozygous or the homozygous 5-HTTLPRS group (Mueller et al., in prep.). An interesting gene–environment interaction was observed with a stress protocol similar to the TSST. Subjects carrying two copies of the short form allele that had experienced a high level of stressful life events showed amplified cortisol reactions to the stressor (Alexander et al., 2009). Previous studies have failed to demonstrate differences in responses to the TSST by 5-HTTLPR genotype in adults (Wu¨st et al., 2009), which may in part be due to an interaction effect with the dopamine D4 receptor gene allele DRD4 7R that predisposes to an attenuated cortisol response to the TSST which is further attenuated when the subjects are homozygous for the long form of the 5-HTTLPR (Armbruster et al., 2009). A difference in cortisol response to a painful stressor by 5-HTTLPR genotype is apparent from birth. Newborns homozygous for the short 5-HTTLPR genotype showed a significantly higher endocrine response to heel-prick stress in comparison to newborns with heterozygous or long genotype (Mueller et al., 2010).

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3.4. The cortisol stress response and disease The HPAA response to psychosocial stress varies with pathology. Most interestingly, the majority of clinical conditions were found to be associated with blunted HPAA responses. Children who experienced early life stress show an attenuated cortisol rise to the TSST (Ellenbogen and Hodgins, 2009; Ellenbogen et al., 2006) as well as attenuated sympathetic cardiovascular responses (Gunnar et al., 2009a). Likewise, patients with unresolved trauma due to sexual abuse in childhood or adults had much lower cortisol responses to the TSST, especially when the trauma was still unresolved in early adulthood (Pierrehumbert et al., 2009). A pattern of complete cortisol nonresponsiveness was observed in a larger group of patients with panic disorder (Petrowski et al., 2009), which was unrelated to the duration of the disorder or depression as a comorbid condition. Disorders characterized by chronic inflammatory processes are also associated with blunted cortisol responses as shown in children and adults with atopic dermatitis (AD) with a concomitant normal or even exaggerated SNS response to stress (BuskeKirschbaum et al., 1997)—a pattern also seen in children with allergic asthma (Buske-Kirschbaum et al., 2003). Fatigue, a common consequence of lower-grade inflammation, can be an important modulator for the HPAA response: fatigued breast cancer survivors showed an attenuated cortisol response to the TSST in comparison to non-fatigued survivors (Bower et al., 2005) while patients with metastatic breast cancer showed a blunted cortisol stress response irrespective of a comorbid depression (Giese-Davis et al., 2006). In contrast to these clinical conditions, very few disorders have been shown to present with enhanced or exaggerated cortisol responses to psychosocial stress. Both, in adolescent and adult patients suffering from major depression, larger cortisol and/or ACTH responses were found (Heim et al., 2000; Rao et al., 2008; Chopra et al., 2009). Also enhanced cortisol stress responses were observed in obese women (Epel et al., 2000). 4. Habituation—changing the cortisol response pattern with experience Prior experience of psychosocial stress modulates subsequent HPAA responses to the TSST. Normally the salivary cortisol response to the TSST habituates over repeated exposures (Pruessner et al., 1997) while in subjects suffering from chronic exhaustion the response increases, suggesting an enhanced vulnerability to psychosocial stress (Kudielka et al., 2006). Obese women with a high waist to hip ratio showed an amplified cortisol response to psychosocial stress in the TSST while lean women with high WHR lacked habituation to the stressor (Epel et al., 2000). Aggregation of successive exposures to the TSST reveals an association between the personality factors social dominance and locus of control with the cortisol stress response (Pruessner et al., 1997). Habituation of cortisol responses to repeated TSSTexposure can be prevented with a between trial interval of four months and changing test settings (Kirschbaum et al., unpublished data). 5. Concluding remarks The biological response to acute psychosocial stress has been best characterized using changes in cortisol levels as a marker of distressing challenge. Several demographic, physiological, and biological variables have been found to moderate the magnitude of the individual cortisol stress response. These factors explain to a great extent the variability observed between individual responses to acute stress documented over the past 25 years.

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