Salivary cortisol as a biomarker in stress research
Introduction
Today, salivary cortisol is routinely used as a biomarker of psychological stress and related mental or physical diseases. Most studies consider salivary cortisol levels a reliable measure of hypothalamus–pituitary–adrenal axis (HPAA) adaptation to stress. However, the stress response of the HPAA is rather complex and modulated by numerous factors. Cortisol levels in saliva are partly dissociated from levels of paraventricular corticotrophin releasing factor (CRF), arginine vasopressin (AVP), adrenocorticotropic hormone (ACTH), and cortisol in blood or urine. Under several circumstances a partial but significant dissociation between salivary cortisol levels and other HPAA related endocrine signals can be observed. This paper describes such dissociations and putative mechanisms. We aim to illustrate the physiological significance of salivary cortisol as a biomarker of HPAA responsivity by addressing several sources of variance contributing to such dissociations.
Section snippets
Dissociations with CRF/AVP
The process between the initiation of an HPAA response in the central nervous system and salivary cortisol variations as an outcome measure is modulated by numerous psychological and biological events. Psychological events initiate an HPAA response by predominantly activating CRF/AVP neurons in the paraventricular nucleus (PVN) of the hypothalamus (see Chrousos and Kino, 2007 for a review). The degree of activation will vary, depending on the psychological components of the situation, such as
Dissociations with ACTH
In a recent review, Bornstein et al. (2008) summarized dissociations of ACTH and glucocorticoids in critical illness, inflammation, and mental disorders. They name numerous factors, such as neuropeptides, neurotransmitters, opioids, growth factors, cytokines, adipokines, and bacterial ligands, which modulate adrenal glucocorticoid release independently of pituitary ACTH. Thus, it should be noted that the salivary cortisol response to stress can be confounded by a broad array of intervening
Dissociations with blood cortisol levels
There is a high correlation between salivary cortisol levels and unbound free cortisol levels in plasma and serum, which remains high during the circadian cycle and under different dynamic tests, such as dexamethasone suppression and ACTH stimulation (Vining et al., 1983b, Umeda et al., 1981, Wedekind et al., 2000, Levine et al., 2007). Since free cortisol represents the biologically active hormone fraction, salivary cortisol measures have early been considered to be a better measure of
Dissociations with free cortisol levels in blood
Although most studies report a high correlation between free cortisol levels in blood and saliva, some studies call for caution. Levine et al. (2007) summarize such studies, reporting dissociation between both measures during the circadian circle, under challenge conditions, and with respect to the magnitude of free cortisol levels. Referring to data which suggest that about 14% of salivary cortisol is bound to CBG in saliva, they assume that this may be one important reason behind such
Dissociations with urinary cortisol levels
Free cortisol is metabolized in the liver and about 70% of these biologically inactive metabolites are excreted in urine, about 20% (via bile) in stool, and about 8% in the skin. In urine, only about 1% of free blood cortisol is excreted (Hatz, 1998). In the early stress literature, cortisol conjugates and metabolites (17-hydroxycorticosteroids and 17-ketosteroids) were commonly used as HPAA measures, before new assays were available allowing precise assessment of cortisol in blood and saliva.
Dissociations with effects on target tissues
The measurement and interpretation of (salivary) cortisol levels in stress research is often based on the implicit assumption that, firstly, a given cortisol level reflects a certain effect across different GC target tissues within one subject and that, secondly, a given level of cortisol elicits comparable target tissue effects in different subjects. Both aspects of this assumption are not necessarily correct. It is well documented that within the normal population, a considerable variability
Conclusions
Salivary cortisol is a useful biomarker in stress research, as long as the researcher is aware of possible sources of variance, which may affect this measure. Whether these modulating factors are considered as confounders or as important part of the information certainly depends on the research question. As described here, a missing or poor covariance of perceived stress and salivary cortisol is not surprising, given the complex interplay of neurobiological events that link perceived stress to
Conflict of interest
None declared.
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