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Salivary Bioscience Bulletin

SBB – The Cortisol Awakening Response and Circadian Cortisol Regulation

Drop Date: June 2010

In This Drop: What Will You Discover Today?

The cortisol awakening response (CAR) is a surge in cortisol production that occurs in most healthy people shortly after waking in the morning. The CAR has attracted a great deal of attention since its recognition in 1997, and in 2009-2010 alone nearly 300 papers have included some discussion of this physiological response. Dysregulation of cortisol levels has been proposed as a major factor that may be leading to an increased incidence of a broad range of disorders of the brain and body, and much of the research on the CAR has been devoted to its possible use as a biological marker of psychological and physical health status. This research has broadened our knowledge of some aspects of the CAR, but it remains difficult to understand the basic purpose of the CAR and its significance for human health.

In this issue of The Spit Report we present recent overview publications that explore the complex physiological factors that are involved in the regulation of the CAR, as well as the relationship of the CAR to the underlying circadian rhythm of cortisol. In addition, we include a newly-published study that re-examines the relationship between the CAR and health status, which may offer a way to explain the inconsistencies that have been observed to date in the CAR literature. In keeping with the belief that complex biological systems affect multiple analytes, we provide some background reading on melatonin, which is also involved in the body’s transition from night to day. Finally, in our practical “Spit Tips” section, we present two valuable articles that offer advice on various strategies for saliva collection and data analysis that may be used to characterise cortisol production, including measurement of awakening levels, the CAR, area under the curve, and diurnal slope.

Technical Advice

Assessing Salivary Cortisol in Large-Scale, Epidemiological Research

Large-scale social science and epidemiological studies are increasingly incorporating measurement of biomarkers such as salivary cortisol. Ideally, researchers would be able to collect numerous samples, but in large studies this can result in prohibitively high costs. This paper illustrates the use of several reduced-sampling protocols that provide adequate data points while keeping costs in check. Other practical considerations such as obtaining consent, response rates, compliance with the protocol, saliva collection methods, and data analysis are also examined.

Two Formulas for Computation of the Area Under the Curve Represent Measures of Total Hormone Concentration Versus Time-Dependent Change

As discussed in the article by Adam and Kumari above, there are a number of ways to analyze salivary hormone data. One method that is often used is the measurement of the area under the curve (AUC) over a certain time period. Unfortunately, as noted here, differences in the way the AUC is computed can make it difficult to compare results between different research groups. In this article the merits of two formulas for calculating the AUC are discussed. Note also the correspondence that follows.

*Salimetrics provides this information for research use only (RUO). Information is not provided to promote off-label use of medical devices. Consult full text of article.

This Just In…

Dr. Douglas Granger appointed to Johns Hopkins University

Douglas A. Granger, PhD, founder and Chief Scientific & Strategy Advisor for Salimetrics, has been appointed to the faculty of The Johns Hopkins University School of Nursing, where he will head the Center for Interdisciplinary Salivary Bioscience Research. In his dual roles with Johns Hopkins and Salimetrics, Dr. Granger furthers the advancement of salivary research by exploring ideas that will demonstrate the ability of salivary analytes to make valuable contributions to the science of salivary research.

Dr. Granger served as president and scientific advisor of Salimetrics for the past eleven years and has directed Salimetrics through the development of assays for key biomarkers in saliva research. Dr. Granger’s current role as Chief Scientific & Strategy Advisor for Salimetrics accelerates the growth in development of salivary assays for new biomarkers of interest, as well as expands the development of salivary research applications for current biomarkers.

Salimetrics is dedicated to the advancement of salivary research through its support to the Center at Johns Hopkins University, sponsorships for salivary research in key areas of science, and training in the use of salivary biomarkers for research.

Featured Article

Acute and Chronic Effects of Exercise on Markers of Mucosal Immunity.

Bishop, N.C., Gleeson, M.  Frontiers in Bioscience 14 (2009): 4444-56.

Recent research has suggested that exercise can be related to changes in immune function.  It has been observed that extended or high-intensity exercise leads to increases in upper respiratory tract infections (URTI), which seem to correlate to reductions of immune function, as measured by levels of secretory IgA (SIgA) in saliva. Conversely, modest levels of exercise have been found to lead to reduced levels of URTI, accompanied by either slight increases or no change in SIgA levels.  Establishment of a direct link between URTI and exercise-induced immune changes has proven difficult, however.  This review summarizes and discusses current research on this topic.

Saliva is an ideal testing fluid for studies in the field that involve athletes and exercise.  However, the paths of entry into saliva for protein biomarkers such as SIgA, alpha-amylase, lysozyme, and lactoferrin are different from those of other analytes often measured in saliva, such as the steroid hormones.  This article discusses the implications that these differences have for measurement of immune markers in saliva.  It is suggested that inconsistency in various factors such as hydration of subjects, different methods of collecting saliva, and the presence or absence of salivary stimulation makes it difficult to compare findings among studies.  The need to standardize the method of reporting SIgA data and the merits of expressing assay results in relation to total protein, saliva flow rates, or saliva osmolality are discussed.  SIgA levels can also vary widely among individuals; studies that examine the relationship between salivary SIgA levels and incidence of disease may therefore be advised to follow changes on an individual basis rather than attempting to compare them to average values.

In the discussion of mechanisms that may explain how exercise can influence levels of immune markers, the authors review studies that point to changes in sympathetic and parasympathetic nervous signals to the salivary glands.  Nervous signals affect both the rates of saliva flow and the release of proteins such as alpha amylase, lactoferrin, and lysozyme into saliva.  In contrast to these markers that are synthesized in the salivary glands, however, SIgA is produced by plasma cells located near the salivary cells and then transported through the salivary cell membranes by the polymeric Ig receptor (pIgR).  The rate of secretion of SIgA into saliva is therefore dependent both on the rate of IgA production by the plasma cells and by the rate of transport of the IgA molecules through the membranes.

The mechanisms that underlie the acute and longer-term changes in SIgA production in humans in response to exercise are not well understood, but recent animal studies suggest that sympathetic nervous system activity may affect the rate of expression and mobilization of pIgR.  This may explain the slight increases of SIgA that occur after moderate exercise.   Less is known about the mechanisms that would account for decreases in SIgA levels following intense exercise, however.   Speculative explanations include depletion of the IgA pool available for transport following prolonged mobilization of the pIgR or reductions in the amount of pIgR available following exercise of a certain intensity or duration.  Future studies are needed to investigate the control of secretion of SIgA and other immune markers in saliva, as well as the manner in which these molecules interact in the oral cavity to provide immune protection.


Cortisol Awakening Response (CAR)’s Flexibility Leads to Larger and More Consistent Associations with Psychological Factors than CAR Magnitude
Mikolajczak, M., Quoidbach, J., Vanootighem, V., et al. (2010). PNEC, 35(5), 752-7.
Inconsistencies in the findings of numerous studies on the CAR have made it difficult to understand the relationships between the CAR and health. This article presents preliminary evidence that suggests it is the flexibility in the CAR in response to varying levels of stress rather than magnitude of the response that shows more consistent associations with psychological conditions.

The Cortisol Awakening Response (CAR): Facts and Future Directions
Fries, E., Dettenborn, L., Kirschbaum, C. (2009). Int J Psychophysiol, 72(1), 67-73.
This important review article presents a thorough examination of the literature on the CAR, including a discussion of the involvement of the hippocampus, the suprachiasmatic nucleus (SCN), and other regions of the brain in the regulation of HPA axis activity. Other factors that can influence the CAR, including gender, physical or psychiatric conditions, sleep, and stress are also considered. Noting that the exact function of the CAR is still not known, the authors propose that the magnitude of the cortisol rise may correspond to activation of memory representation at awakening and anticipated demands of the upcoming day.

Stress: The Brain-Body Connection
Hellhammer, D., Hellhammer, J., eds. Key Issues in Mental Health, v. 174.Karger, 2008.
Maladaptation to the stress that is increasingly a part of modern life can lead to the development of a range of disorders that affect both the mind and the body. In this examination of stress-related disorders, the authors present detailed discussions of the cross-talk that occurs between the brain and the body and of the interactions that take place between the endocrine, the immune, and the autonomic nervous systems. Stress-related changes that can occur in the HPA axis, which significantly affect the regulation of cortisol secretion, figure prominently in these discussions.

Additional Reading >

*Note: Salimetrics provides this information for research use only (RUO). Information is not provided to promote off-label use of medical devices. Pease consult the full-text article.