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

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Abstract

Background

Dysregulation 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).

Purpose

The 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.

Methods

Six 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.

Results

From 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.

Conclusions

Salivary 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 material

The 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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Most cited references 106

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The neurobiology of stress: from serendipity to clinical relevance.

B S 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.

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The cortisol awakening response: more than a measure of HPA axis function.

Angela Clow, Frank Hucklebridge, Tobias Stalder … (2010)

In most healthy people morning awakening is associated with a burst of cortisol secretion: the cortisol awakening response (CAR). It is argued that the CAR is subject to a range physiological regulatory influences that facilitate this rapid increase in cortisol secretion. Evidence is presented for reduced adrenal sensitivity to rising levels of ACTH in the pre-awakening period, mediated by an extra-pituitary pathway to the adrenal from the suprachiasmatic nucleus (SCN). A role for the hippocampus in this pre-awakening regulation of cortisol secretion is considered. Attainment of consciousness is associated with 'flip-flop' switching of regional brain activation, which, it is argued, initiates a combination of processes: (1) activation of the hypothalamic pituitary adrenal (HPA) axis; (2) release of pre-awakening reduced adrenal sensitivity to ACTH; (3) increased post-awakening adrenal sensitivity to ACTH in response to light, mediated by a SCN extra-pituitary pathway. An association between the CAR and the ending of sleep inertia is discussed.

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Free cortisol levels after awakening: a reliable biological marker for the assessment of adrenocortical activity.

D H Hellhammer, Blair O Wolf, F Kaspers … (1996)

In three independent studies, free cortisol levels after morning awakening were repeatedly measured in children, adults and elderly subjects (total n=152). Cortisol was assessed by sampling saliva at 10 or 15 minute intervals for 30-60 minutes, beginning at the time of awakening for two days (Study 1 and 2) or one (Study 3) day, respectively. In all three studies, free cortisol levels increased by 50-75% within the first 30 minutes after awakening in both sexes on all days. Premenopausal women consistently showed a stronger increase with a delayed peak after awakening compared to men on all days. In Study 2, there was a tendency for lower early morning free cortisol levels for women taking oral contraceptives (p=.10). Stability of the area under the curve (AUC) of the early morning free cortisol levels over the three (Study 1 and 2) or two (Study 3) days ranged between r=.39 and r=.67 (p<.001). Neither age, weight, nor smoking showed an effect on baseline or peak cortisol levels. Sleep duration, time of awakening and alcohol consumption also appeared to be unrelated to early morning free cortisol levels. From these data we conclude that in contrast to single assessments at fixed times, early morning cortisol levels can be a reliable biological marker for the individual's adrenocortical activity when measured repeatedly with strict reference to the time of awakening.

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Author and article information

Contributors

Richella Ryan: 0044 (0)1223 274404 , richella.ryan@nhs.net

Sara Booth: sb628@cam.ac.uk

Anna Spathis: anna.spathis@addenbrookes.nhs.uk

Sarah Mollart: sarahmollart@nhs.net

Angela Clow: clowa@westminster.ac.uk

Journal

Journal ID (nlm-ta): Ann Behav Med

Journal ID (iso-abbrev): Ann Behav Med

Title: Annals of Behavioral Medicine

Publisher: Springer US (New York )

ISSN (Print): 0883-6612

ISSN (Electronic): 1532-4796

Publication date (Electronic): 23 March 2016

Publication date PMC-release: 23 March 2016

Publication date (Print): 2016

Volume: 50

Pages: 210-236

Affiliations

[ ]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

Article

Publisher ID: 9753

DOI: 10.1007/s12160-015-9753-9

PMC ID: 4823366

PubMed ID: 27007274

SO-VID: 7812e349-c40d-468f-9654-7ae1443fa3ae

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), 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.

History

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000272, National Institute for Health Research (GB);

Award ID: DRF-2012-05-702

Award Recipient : Richella Ryan

Custom metadata

ScienceOpen disciplines: Neurology

Keywords: salivary cortisol,diurnal rhythm,randomized controlled trial,systematic review,intervention

Data availability:

ScienceOpen disciplines: Neurology

Keywords: salivary cortisol, diurnal rhythm, randomized controlled trial, systematic review, intervention

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

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Abstract

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Results

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Electronic supplementary material

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Neuronal Signaling

Most cited references 106

The neurobiology of stress: from serendipity to clinical relevance.

The cortisol awakening response: more than a measure of HPA axis function.

Free cortisol levels after awakening: a reliable biological marker for the assessment of adrenocortical activity.

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