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Use of Salivary Diurnal Cortisol as an Outcome Measure in Randomised Controlled Trials: a Systematic Review

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      BackgroundDysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with diverse adverse health outcomes, making it an important therapeutic target. Measurement of the diurnal rhythm of cortisol secretion provides a window into this system. At present, no guidelines exist for the optimal use of this biomarker within randomised controlled trials (RCTs).PurposeThe aim of this study is to describe the ways in which salivary diurnal cortisol has been measured within RCTs of health or behavioural interventions in adults.MethodsSix electronic databases (up to May 21, 2015) were systematically searched for RCTs which used salivary diurnal cortisol as an outcome measure to evaluate health or behavioural interventions in adults. A narrative synthesis was undertaken of the findings in relation to salivary cortisol methodology and outcomes.ResultsFrom 78 studies that fulfilled the inclusion criteria, 30 included healthy participants (38.5 %), 27 included patients with physical disease (34.6 %) and 21 included patients with psychiatric disease (26.9 %). Psychological therapies were most commonly evaluated (n = 33, 42.3 %). There was substantial heterogeneity across studies in relation to saliva collection protocols and reported cortisol parameters. Only 39 studies (50 %) calculated a rhythm parameter such as the diurnal slope or the cortisol awakening response (CAR). Patterns of change in cortisol parameters were inconsistent both within and across studies and there was low agreement with clinical findings.ConclusionsSalivary diurnal cortisol is measured inconsistently across RCTs, which is limiting the interpretation of findings within and across studies. This indicates a need for more validation work, along with consensus guidelines.Electronic supplementary materialThe online version of this article (doi:10.1007/s12160-015-9753-9) contains supplementary material, which is available to authorized users.

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      In response to stress, the brain activates several neuropeptide-secreting systems. This eventually leads to the release of adrenal corticosteroid hormones, which subsequently feed back on the brain and bind to two types of nuclear receptor that act as transcriptional regulators. By targeting many genes, corticosteroids function in a binary fashion, and serve as a master switch in the control of neuronal and network responses that underlie behavioural adaptation. In genetically predisposed individuals, an imbalance in this binary control mechanism can introduce a bias towards stress-related brain disease after adverse experiences. New candidate susceptibility genes that serve as markers for the prediction of vulnerable phenotypes are now being identified.
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        Prolonged calorie restriction increases life span in rodents. Whether prolonged calorie restriction affects biomarkers of longevity or markers of oxidative stress, or reduces metabolic rate beyond that expected from reduced metabolic mass, has not been investigated in humans. To examine the effects of 6 months of calorie restriction, with or without exercise, in overweight, nonobese (body mass index, 25 to <30) men and women. Randomized controlled trial of healthy, sedentary men and women (N = 48) conducted between March 2002 and August 2004 at a research center in Baton Rouge, La. Participants were randomized to 1 of 4 groups for 6 months: control (weight maintenance diet); calorie restriction (25% calorie restriction of baseline energy requirements); calorie restriction with exercise (12.5% calorie restriction plus 12.5% increase in energy expenditure by structured exercise); very low-calorie diet (890 kcal/d until 15% weight reduction, followed by a weight maintenance diet). Body composition; dehydroepiandrosterone sulfate (DHEAS), glucose, and insulin levels; protein carbonyls; DNA damage; 24-hour energy expenditure; and core body temperature. Mean (SEM) weight change at 6 months in the 4 groups was as follows: controls, -1.0% (1.1%); calorie restriction, -10.4% (0.9%); calorie restriction with exercise, -10.0% (0.8%); and very low-calorie diet, -13.9% (0.7%). At 6 months, fasting insulin levels were significantly reduced from baseline in the intervention groups (all P<.01), whereas DHEAS and glucose levels were unchanged. Core body temperature was reduced in the calorie restriction and calorie restriction with exercise groups (both P<.05). After adjustment for changes in body composition, sedentary 24-hour energy expenditure was unchanged in controls, but decreased in the calorie restriction (-135 kcal/d [42 kcal/d]), calorie restriction with exercise (-117 kcal/d [52 kcal/d]), and very low-calorie diet (-125 kcal/d [35 kcal/d]) groups (all P<.008). These "metabolic adaptations" (~ 6% more than expected based on loss of metabolic mass) were statistically different from controls (P<.05). Protein carbonyl concentrations were not changed from baseline to month 6 in any group, whereas DNA damage was also reduced from baseline in all intervention groups (P <.005). Our findings suggest that 2 biomarkers of longevity (fasting insulin level and body temperature) are decreased by prolonged calorie restriction in humans and support the theory that metabolic rate is reduced beyond the level expected from reduced metabolic body mass. Studies of longer duration are required to determine if calorie restriction attenuates the aging process in humans. Identifier: NCT00099151.
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          The neurobiology of stress: from serendipity to clinical relevance.

           B McEwen (2000)
          The hormones and other physiological agents that mediate the effects of stress on the body have protective and adaptive effects in the short run and yet can accelerate pathophysiology when they are over-produced or mismanaged. Here we consider the protective and damaging effects of these mediators as they relate to the immune system and brain. 'Stress' is a principle focus, but this term is rather imprecise. Therefore, the article begins by noting two new terms, allostasis and allostatic load that are intended to supplement and clarify the meanings of 'stress' and 'homeostasis'. For the immune system, acute stress enhances immune function whereas chronic stress suppresses it. These effects can be beneficial for some types of immune responses and deleterious for others. A key mechanism involves the stress-hormone dependent translocation of immune cells in the blood to tissues and organs where an immune defense is needed. For the brain, acute stress enhances the memory of events that are potentially threatening to the organism. Chronic stress, on the other hand, causes adaptive plasticity in the brain, in which local neurotransmitters as well as systemic hormones interact to produce structural as well as functional changes, involving the suppression of ongoing neurogenesis in the dentate gyrus and remodelling of dendrites in the Ammon's horn. Under extreme conditions only does permanent damage ensue. Adrenal steroids tell only part of the story as far as how the brain adapts, or shows damage, and local tissue modulators - cytokines for the immune response and excitatory amino acid neurotransmitters for the hippocampus. Moreover, comparison of the effects of experimenter-applied stressors and psychosocial stressors show that what animals do to each other is often more potent than what experimenters do to them. And yet, even then, the brain is resilient and capable of adaptive plasticity. Stress-induced structural changes in brain regions such as the hippocampus have clinical ramifications for disorders such as depression, post-traumatic stress disorder and individual differences in the aging process.

            Author and article information

            [ ]Palliative Care Department, Cambridge University Hospitals NHS Foundation Trust, Elsworth House, Box 63, Hill’s Road, Cambridge, CB2 0QQ UK
            [ ]Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Box 197, Cambridge, CB2 0XZ UK
            [ ]St. Nicholas Hospice Care, Hardwick Lane, Bury St. Edmunds, Suffolk IP33 2QY UK
            [ ]Department of Psychology, University of Westminster, 101 New Cavendish Street, London, W1W 6XH UK
            0044 (0)1223 274404 ,
            Ann Behav Med
            Ann Behav Med
            Annals of Behavioral Medicine
            Springer US (New York )
            23 March 2016
            23 March 2016
            : 50
            : 210-236
            © The Author(s) 2016

            Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

            Funded by: FundRef, National Institute for Health Research (GB);
            Award ID: DRF-2012-05-702
            Award Recipient :
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            © The Society of Behavioral Medicine 2016


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