ReviewWhy do we respond so differently? Reviewing determinants of human salivary cortisol responses to challenge
Introduction
A very prominent feature of stimulated salivary cortisol levels is the large variation in the response magnitude between individuals as well as across different situations or tests. Such variability can be observed with respect to the net cortisol output as well as the time course of hormone secretion after stress. Overall, the identification of mechanisms that determine the regulation and especially dysregulation of free cortisol responses to stress is, particularly in humans, a very challenging task. Since stress and stress-related health impairments have become major problems in human life, investigations into the biological pathways linking stress and disease are of major importance. An extensive phenotyping including salivary cortisol responsivity is essential in order to be able to uncover mechanisms mediating stress-related disorders and to potentially develop new therapeutic strategies in the future. Such a research agenda depends on substantial knowledge of moderating and intervening variables that affect free cortisol responses to different kinds of stressors and stimuli.
Besides naturally occurring acute and chronic stressors, acute cortisol responses can be stimulated in the laboratory by very different means including psychological stress protocols (e.g., cognitive tasks or public speaking paradigms like the Trier Social Stress Test (TSST)), a wide variety of pharmacological stimulants (e.g., administration of CRH, vasopressin or synthetic ACTH, etc.), intense physical exercise or even intake of standardized meals. Generally, for a research setting, laboratory stress protocols offer the advantage of standardization across test sessions but might lack the ecological validity of field studies or ambulatory assessments.
Laboratory psychological stress tasks have different potencies in their ability to reliably evoke salivary cortisol responses (Biondi and Picardi, 1999). In a meta-analysis covering 208 laboratory stress studies, Dickerson and Kemeny (2004) investigated conditions capable of eliciting HPA axis stress responses. They concluded that motivated performance tasks reliably elicited ACTH and cortisol responses if they were uncontrollable or characterized by social-evaluative threat. Tasks containing both elements were associated with the largest hormonal changes and the longest recovery times. More than 15 years ago, a psychosocial stress task was developed, which is characterized by both uncontrollable and social-evaluative elements. As it was developed in Trier, it was eventually named the Trier Social Stress Test. The TSST is a brief and highly standardized laboratory stress task consisting of a preparation period, a free speech and mental arithmetic task in front of an audience (Kirschbaum et al., 1993a) repeatedly showing cortisol responder rates of over 70% (Kudielka et al., 2007c, Kudielka et al., 2007d).
While psychological stressors are central stimuli that require processing at higher brain levels, pharmacological challenges act at different levels of the HPA system and operate in a dose-dependent manner. For example, when assessing adrenal cortex functioning via release of cortisol from the adrenal cortex with an administration of a small dose of synthetic ACTH (e.g., 1 μg Synacthen) one would test for adrenal cortex sensitivity while administration of a larger dose (e.g., 250 μg Synacthen) would assess its maximum capacity (Daidoh et al., 1995). Many HPA axis stimulation tests trigger increases in cortisol via pharmacological stimulants acting primarily at the pituitary level, like exogenously administered CRH or vasopressin. When interpreting and comparing pharmacological provocation tests, researchers should be aware of the fact that study results are largely dependent on the applied stimulant and the chosen dosage. Generally, researchers applying pharmacological stimulants use very heterogeneous study approaches and designs and therefore yield very diverse results. For instance, in humans exogenously administered human CRH (hCRH) binds with high affinity to endogenous CRH-binding proteins which show low affinity to ovine CRH (oCRH) (Sutton et al., 1995). Consequently, this results in very differential pharmacological effects. In the pharmacological testing of HPA axis regulation, reported outcome variables are typically ACTH and total plasma cortisol levels. Salivary cortisol concentrations are less frequently measured although the amount of salivary cortisol predominantly reflects the free, biologically active fraction of cortisol. Salivary cortisol agrees very well with the amount of free cortisol in blood but does not necessarily show high correlations with total cortisol levels (Vining et al., 1983, Kirschbaum and Hellhammer, 1989, Kirschbaum and Hellhammer, 1994, Kirschbaum and Hellhammer, 2007); note: compared to blood, absolute levels of cortisol are lower in saliva due to a relative abundance of the cortisol-metabolizing enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) converting active cortisol into inactive cortisone (Smith et al., 1996, van Uum et al., 2002). Further questions regarding analytical laboratory procedures are discussed by Gierens et al. (under revision).
Beside psychological stress tasks and pharmacological stimulation, intense physical exercise can elicit significant cortisol responses. Maximal exercise reaching the level of exhaustion leads to significant hormonal increases as well as sustained physical load exceeding 70% of the maximum oxygen uptake (VO2max) (Luger et al., 1987, O’Connor and Corrigan, 1987, Kraemer et al., 1989, Wittert et al., 1991, Kirschbaum et al., 1992c). In contrast, short-term physical exercise with a lower workload appears to exert no or only minor cortisol responses (Friedmann and Kindermann, 1989, Kirschbaum et al., 1993b, Kirschbaum et al., 1994, Lovallo et al., 2006). However, significant plasma cortisol responses can be observed with a physical load between 60 and 65% VO2max if maintained for hours (Deuster et al., 1992). In contrast to cortisol responses to psychological stress (see below), there seems to be no pronounced habituation effect in exercise-induced cortisol responses (O’Connor and Corrigan, 1987).
Finally, researchers should be aware of potential meal-related salivary cortisol increases (Gibson et al., 1999, Lovallo et al., 2006). Proteins have been primarily discussed as cortisol-stimulating agents (Slag et al., 1981, Anderson et al., 1987, Gibson et al., 1999, Benedict et al., 2005). Interestingly, standardized meals affect at least plasma cortisol levels differently according to time of day with higher meal-related increases at lunchtime (Brandenberger et al., 1982) compared to attenuated or even absent responses in the evening (Quigley and Yen, 1979, Follenius et al., 1982).
Section snippets
Determinants of salivary cortisol responses to challenge
The aim of this report is to provide an overview of important determinants of salivary cortisol responses to stress in humans demonstrating the role of age and gender, endogenous and exogenous sex steroid levels (e.g., the female menstrual cycle, use of oral contraceptives and hormone replacement therapy), pregnancy, lactation and breast-feeding, smoking, coffee and alcohol consumption as well as dietary energy supply in salivary cortisol responses to acute stress. Furthermore, we briefly
Final remarks
The HPA axis is a vital part of the human stress response system. Therefore, understanding determinants of inter- and intraindividual variability in cortisol regulation as well as mechanisms underlying pathologically relevant dysregulation of cortisol activity is a key topic in psychobiological stress research. Evidence from research over the last decades clearly documents that salivary cortisol is a useful and valid biomarker in stress research (see Hellhammer et al., in press). Amongst other
Role of the funding sources
This study was supported by Emmy Noether research grant KU 1401/4-1, KU 1401/4-2, and KU 1401/4-3 of the German Research Foundation (DFG) awarded to Brigitte M. Kudielka. BMK, SW and DHH are members of the International Research Training Group IRTG funded by the DFG (GRH 1389/1). The DFG had no further role in writing the report and decision to submit the paper for publication.
Conflict of interest
This work was carried out while all authors were affiliated with the Graduate School of Psychobiology, Department of Theoretical and Clinical Psychobiology, University of Trier, Johanniterufer 15, 54290 Trier, Germany.
Acknowledgements
This work was supported by Emmy Noether research grant KU 1401/4-1, KU 1401/4-2, and KU 1401/4-3 of the German Research Foundation (DFG) awarded to Brigitte M. Kudielka as well as the International Research Training Group IRTG funded by the DFG (GRH 1389/1; BMK, DHH, and SW are members of the IRTG).
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