The Role of Saliva Cortisol Measurement in Health and Disease

In recent decades, the technique of using ambulatory saliva sampling for measuring cortisol levels has become increasingly popular in field research and clinical studies aimed at investigating bodily responses to psychosocial stress and other psychological and clinical conditions. This interest is paralleled with frustrations on opposing and ambiguous results. To get a deeper understanding of the seemingly contradictory results, the Scandinavian cortisol and stress network (Scancort) was formed, based on 20 researchers from the disciplines of public health, psychology, biology and medicine. This book is based on a critical review of the existing empirical literature on salivary cortisol, aiming to evaluate the usefulness of salivary cortisol as a biomarker in various settings. In particular, this book focuses on how the many different ways of evaluating the levels and dynamics of salivary cortisol (i.e., with regard to time points of assessment and different algorithms used to integrate data from multiple time points) affect the interpretation of cortisol measurements in various contexts. One main question is to find out if it is possible that different results of studies involving cortisol assessments are functions of differences in the theoretic assumptions made and the methods used.

This chapter evaluates the association between salivary cortisol and socioeconomic variables (level of education, occupational status, income and related composite measures), ethnicity, age and sex. There were many non-significant findings for all variables, indicating that the associations with cortisol levels are relatively small. Regarding the significant results, there were some consistent trends. It is implied that high SES, regardless of how it is measured, is associated with a higher cortisol deviation throughout the day, and a higher capacity to react with increase in cortisol following a laboratory stress test. Regarding ethnicity, results consistently hint at a higher deviation throughout the day amongst Caucasians in comparison to Hispanics and Afro-Americans. Analyses on sex were not fully consistent, possibly due to influences of the menstrual cycle on cortisol levels. In addition, it has been reported that men and women respond differently to different stressors used in laboratory stress tests. For age, the significant findings found may hint at a small but general increase in cortisol levels throughout the day with increasing age.

This chapter systematically reviews how different measures of salivary cortisol are related to different measures of psychosocial work stress. Divergent findings were scrutinized with respect to study quality and the methods used. Measures of work stress included concepts reflecting those included in the demand-control-support model or the effort-reward-imbalance model. General bibliographic databases (PsychINFO and PubMed) were searched up to September 30, 2009. Two reviewers extracted data on study characteristics and study quality. In total 27 articles fulfilled the inclusion criteria. Cortisol measures were grouped into single time points at different times during the day, deviations at different time periods during the day, reactivity and recovery after a standardized laboratory test, area under the curve from deviations and reactivity measures. A large proportion of the analyses of the associations between cortisol and psychosocial work stressors showed nonsignificant findings. However, of the significant findings, most results showed that a high work stress was associated with high cortisol levels. Significant relationships were evenly distributed across different measures of psychosocial work stress. As regards salivary sampling or statistical analysis, no strategy seemed superior but some strategies have only been used in the past few years. Typically, older studies were of lower quality. Low quality studies tended to have a higher proportion of significant findings which is a reason for concern. The relatively few significant findings may be because many psychosocial work stressors were of mild or moderate intensity and the study groups were rather small and fairly homogeneous, thus variability was too small to reveal any effects. The results indicate a normal, healthy response to work stress in most workers, according to CATS and the Allostatic Load Models.

The aim of this chapter was to analyze associations between measures of cortisol in saliva with measures of perceived stress, using the Perceived Stress Scale (PSS), and of psychological resources in terms of mastery, locus of control, self-esteem and sense of coherence. Only studies on healthy individuals were included and cortisol measures were grouped into single time point measures, deviation measures, Area Under the Curve (AUC), laboratory test responses, and dexamethasone suppression. For both Perceived Stress Scale (PSS) and for psychological resources, most results of associations with saliva cortisol were nonsignificant particularly for single measures and for cortisol awakening response. For PSS the largest proportion of significant findings (38%) was seen for morning AUC, however with conflicting results. For psychological resource constructs, mastery and sense of coherence were related to lower cortisol level at baseline in standardized rest and high mastery was related to steeper diurnal slope in two studies. For self-esteem, no associations showed significant results. Differences in findings may to a large extent be dependent on theoretical assumptions made and methods used.

This chapter focuses on salivary cortisol in relation to biological markers. Specifically, associations with conventional cardiovascular risk factors and metabolic abnormalities (body mass index, waist circumference, waist/hip ratio, lipid status, glucose, blood pressure, heart rate and heart rate variability), markers related to inflammation (C-reactive protein, cytokines and tumor necrosis factor-alpha) and other stress hormones (adrenaline and noradrenaline) were studied. The focus was on healthy adult populations; studies on patient populations and pregnant women were excluded. Studies on genome variations and pharmacological interventions were also excluded. After meeting all exclusion criteria, 42 papers remained. In total, 273 associations between salivary cortisol and any of the markers mentioned were studied, comprising 241 associations on metabolic abnormalities, 30 on inflammation, and 2 on stress hormones. Of the salivary cortisol measures reported for evaluations of all markers tested were 136 (49%) single time points, 100 (37%) deviations, 36 (13%) AUC, and 1 (1%) dexamethasone test. Of these, 72 (26%) were statistically significant, and 201 (74%) indicated non-significant findings.Several of the markers tested showed low or no association with any of the measurements of salivary cortisol. The number of studies exploring the association between cortisol in saliva and markers for inflammation is low, which limits the possibility of interpretation. The number of studies on adrenaline and noradrenaline is also low. To sum up, the proportion of non-significant findings was considerable. This may be due to a large number of studies with relatively small study populations. This is true for metabolic abnormalities, markers related to inflammation as well as other stress hormones. Further studies on inflammatory markers and approaches designed to study variability in other systems in relation to cortisol variability are required.

The aim of the present chapter was to analyze whether measures of cortisol in saliva were associated with measures of sleep and to explore if divergent results were related to underlying differences in theoretic assumptions and methods. Measures of sleep quality included sleep duration, overall sleep quality, difficulty falling asleep, disturbed sleep, and sleep deprivation. Twenty-three papers were found to fulfil the inclusion criteria. Cortisol measures were grouped into single time points at different times during the day, deviations at different time periods during the day, reactivity and recovery after a standardized laboratory test, area under the curve and response to dexamethasone test. A large proportion of the studies included showed nonsignificant findings, which, in several cases, may be a result of low power. The most consistent results were a positive association between sleep duration and single measures of salivary cortisol at awakening, which was observed in 3 studies. In these studies, sleep duration was also associated with low evening cortisol levels, steep diurnal deviation of cortisol and/or high area under the curve. Together these findings suggest that longer sleep duration is related to a more dynamic cortisol secretion. Two of the 6 studies on disturbed or restless sleep showed relations to flat diurnal deviation and low laboratory stress test reactivity. This to some extent corroborates the findings on sleep duration. However, the many nonsignificant findings as well as the theoretical and methodological differences (e.g., heterogeneity in measures) complicate comparisons. Conflicting results may be at least partially due to differences in methods and underlying assumptions.

The aim of this chapter was to analyze associations between measures of cortisol in saliva and mental health and to see if divergent results were functions of the methods used. Measures of mental health outcome included Major Depressive Disorder (MDD), symptoms of depression, and symptoms of anxiety, Burnout (BO), and Vital Exhaustion (VE). Only studies on otherwise healthy individuals were included. Cortisol measures were grouped into single time point measures, measures of deviations, laboratory test responses, Area Under the Curve (AUC), and response to dexamethasone. Some consistency is seen for MDD, mainly higher mean levels. The results regarding single measures and depressive mood are less consistent, but the overall picture for depression shows poorer diurnal deviation and response to stress. Inconsistency among papers studying depression seems to be related mainly to the study population. Very few significant findings were found for anxiety, therefore cortisol does not seem to be strongly related to anxiety. Most of the statistical analysis does not show a significant relationship between BO and cortisol, and when these are present, the results are inconsistent. One explanation seems to be the measures of BO used, probably due to the different conceptual basis for BO. VE measured using the Maastricht Questionnaire seems to be related to a poorer cortisol response to stress and poorer diurnal deviation. The coexistence of BO and VE in many studies does make it difficult to conclude how the different concepts are related to cortisol. However, an interesting difference appeared between MDD and VE in response to dexamethasone administration, showing lower suppression in MDD patients and higher suppression in VE patients. A general conclusion for all mental health measures is that a large proportion of non-significant findings are due to low power and few sampling days combined with low contrasts between study groups and within study populations. Generally, deviation measures such as diurnal deviation seem to be more valid measures compared with single measures to capture possible changes in the hypothalamus-pituitaryadrenal axis, measured using salivary cortisol.

Stress is a well-known predictor of somatic disease. Although most clearly demonstrated for Coronary Heart Disease (CHD), stress has also been shown to be involved in several other somatic diseases e.g. rheumatoid arthritis, cancer and for pain syndromes. The psychoneuroendocrine mechanisms of these effects have been examined in terms of cortisol levels and cortisol dynamics. The aim of this chapter is to investigate if there are associations between salivary cortisol and somatic disease in terms of cardiovascular disease (CVD), rheumatoid arthritis, cancer and pain, and whether divergent results can be explained by differences in the theoretic assumptions made and methods used. A literature research identified eight articles on CVD, four articles on cancer (all breast cancer), three papers on rheumatoid arthritis and 15 papers on the term pain. CVD, CHD and atherosclerosis were associated with low morning cortisol levels, high evening cortisol levels and a flat diurnal curve. Among patients with metastatic breast cancer, high evening levels and low diurnal deviation characterized patients compared with healthy controls, and low diurnal deviation predicted poorer survival. No relationships with salivary cortisol were found early in the breast cancer disease process. Patients with rheumatoid arthritis, especially with high disease activity, had higher evening levels and a poorer reactivity for laboratory stress. In most studies on pain, low morning cortisol, high evening cortisol, low cortisol awakening response and low diurnal deviation were associated with more pain. Fibromyalgia and pelvic pain among men were an exception. We found few studies where the relationship between salivary cortisol and somatic disease/illness was analyzed. However, among these, a relatively large proportion showed significant findings. The results suggest that, across outcomes, low morning cortisol levels, high evening cortisol levels and a low dynamic cortisol response to stress are related to poorer somatic outcome.

The aim of this book was to evaluate the usefulness of salivary cortisol as a biomarker in various settings. Our hypothesis was that observed diversities in results can be a function of different kinds of assessments. In this chapter, we try to respond to this aim by giving a summary of the results from different cortisol measures in relation to the health-related variables and conditions investigated in this review. The overarching pattern shows a predominance of non-significant findings but also a couple of rather consistent trends emerged when comparing the results from different chapters. The most apparent is that single measures of absolute concentrations of salivary cortisol, for most health-related variables, seldom give significant findings; deviation measures, in terms of diurnal deviations and/or laboratory stress tests seem to be more strongly and consistently associated with a number of factors, such as Socioeconomic Status (SES), psychological characteristics, biological variables in terms of overweight and abdominal fat accumulation, and mental and somatic disease. Across disorders, the pattern related to ill-health/stress is generally characterized by a flatter diurnal cortisol curve, which in most cases is due to attenuated morning and/or increased evening levels, or a reduced response to a laboratory stress test. For some specific questions, single mean values seem to provide valuable information, but in all cases a careful design in terms of power and standardization is important. Thus, salivary cortisol can be a useful biomarker in many settings, if caution is taken in the choice of methods used.

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