Clinical Review
Is obstructive sleep apnea associated with cortisol levels? A systematic review of the research evidence

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Summary

The pathophysiology of obstructive sleep apnea (OSA) has been associated with dysregulation of the hypothalamic pituitary adrenal (HPA) axis; however a relationship between OSA and altered cortisol levels has not been conclusively established. We conducted a systematic review using the PRISMA Guidelines based on comprehensive database searches for 1) studies of OSA patients compared to controls in whom cortisol was measured and 2) studies of OSA patients treated with continuous positive airway pressure (CPAP) in whom cortisol was measured pre and post treatment. Five electronic databases were searched along with the reference lists of retrieved studies. The primary outcomes were 1) differences in cortisol between OSA and control subjects and 2) differences in cortisol pre-post CPAP treatment. Sampling methodology, sample timing and exclusion criteria were evaluated. Fifteen studies met the inclusion criteria. Heterogeneity of studies precluded statistical pooling. One study identified differences in cortisol between OSA patients and controls. Two studies showed statistically significant differences in cortisol levels pre-post CPAP. The majority of studies were limited by assessment of cortisol at a single time point. The available studies do not provide clear evidence that OSA is associated with alterations in cortisol levels or that treatment with CPAP changes cortisol levels. Methodological concerns such as infrequent sampling, failure to match comparison groups on demographic factors known to impact cortisol levels (age, body mass index; BMI), and inconsistent control of variables known to influence HPA function may have limited the results.

Introduction

Obstructive sleep apnea (OSA) is a prevalent sleep disorder characterized by repeated episodes of complete or partial obstruction of the upper airway, leading to disrupted breathing throughout the night (nocturnal hypoxia). Intermittent upper airway obstruction and consequent hypoxia lead to autonomic arousal during sleep of sufficient intensity to prompt transient wakening leading to a clearing of the airway and reversal of asphyxia.1 The clinical importance of OSA is highlighted by the finding of a causal link, independent of obesity, between OSA and the development of hypertension and cardiovascular disease (CVD).2, 3

Reports suggest that nocturnal awakenings in OSA are associated with alterations in hypothalamic-pituitary-adrenal (HPA) activity, specifically, increased pulsatile cortisol release.4 Cortisol is the primary human glucocorticoid product of the HPA axis and major functions include metabolic (gluconeogenesis) and blood pressure regulation and immune suppression. Excess cortisol secretion is associated with numerous adverse consequences throughout the body. Cortisol’s fluctuation throughout the night is intricately related to sleep, and dysregulation of cortisol has been proposed as a mechanism through which sleep disorders manifest some of their physiologic effects.*5, 6 Since nocturnal awakenings are associated with HPA axis activation and associated sympathetic activation, it is expected that concentrations of cortisol would be higher in patients with OSA. However, the empirical data do not seem to support this hypothesis; many studies have failed to find differences in cortisol between OSA subjects and normal controls. Further, several studies have reported that continuous positive airway pressure (CPAP), the gold standard treatment for OSA, does not reduce cortisol levels in patients with OSA. Finally, the removal of CPAP in OSA patients has not been shown to result in immediate increases in cortisol levels.7, 8

Methodological concerns, such as infrequent sampling and inconsistent timing of sample collection, may have contributed to null findings for some studies.1 Recent studies using more extensive circadian sampling have reported differences in cortisol levels between OSA patients and normal controls.*9, *10 Additional inconsistencies across studies, such as age and body composition of comparison groups, and control for variables known to be related to HPA activity (i.e., smoking), may also contribute to mixed findings.

The aim of the present review was to evaluate whether HPA function differs in patients with OSA versus controls using measures of cortisol. The two hypotheses of the study were that 1) cortisol levels would be elevated in individuals with OSA versus healthy controls and that elevations would be particularly evident at night and 2) treatment of OSA with CPAP would result in reductions in cortisol levels.

Section snippets

Methods

A systematic review of peer-reviewed studies of adult human subjects (age 18+) that have examined the relationship between cortisol and OSA was conducted. 1) Existing literature comparing cortisol levels in patients with OSA and controls was reviewed and 2) studies examining the impact on cortisol levels of successful treatment of OSA using CPAP were reviewed. Careful attention was paid to the group compositions and methodology and timing of sample collection used to assess cortisol, and to

Study flow

Fig. 1 shows the PRISMA flow diagram. In relation to aims 1 and 2, the literature search identified: 1) seven studies in patients with OSA versus healthy controls fulfilling the inclusion criteria,*9, 13, *14, 15, 16, 17, 18 2) eight studies in patients with OSA who were treated with CPAP.*9, *10, 13, 15, 19, 20, 21, *22 Three studies fit into both categories (e.g., data was presented comparing OSA versus healthy controls followed by treatment of the OSA group with CPAP).*9, 13, 15

OSA versus controls

The seven

Discussion

The present review summarizes data from case-controlled studies comparing cortisol levels in OSA and control subjects and studies comparing cortisol levels in OSA patients before and after CPAP treatment. Of the studies reviewed, the majority assessed cortisol at only one or two time points. None of these investigations found differences in cortisol between obstructive sleep apneics and control subjects. Similarly, of treatment studies that assessed cortisol at only one time point, all failed

Subject matching

Age is associated with alterations in cortisol profiles25, 26 and cortisol response to challenge27; yet, of the case controlled studies identified, OSA patients and controls were matched for age in only four of seven studies. Additionally, obesity has been associated with alterations in cortisol28, 29; however several studies failed to match their control and OSA groups on measures of obesity. Matching OSA patients and controls on variables with known associations to cortisol, or at a minimum,

Exclusion criteria

Investigations evidenced significant variability regarding control for variables known to be associated with the HPA axis. Smoking is associated with increases in cortisol levels and smoking cessation is associated with hypocortisolism.30, 31 Despite associations between smoking and cortisol, few studies considered smoking or recent cessation as exclusionary criteria. Additionally, depression, a variable prevalent in OSA,32 and implicated in dysregulation of the HPA axis33, 34 was considered an

Future directions

This paper reviewed existing literature on cortisol levels as they relate to OSA. There are other ways of characterizing HPA axis activation, such challenge tests*9, 15, 17 and they may well be fruitful topics for future research. For example, individuals with OSA evidence decreased cortisol suppression after low-dose dexamethasone, which is corrected after treatment with CPAP.15 Additionally, OSA patients also show hyperresponsiveness of adrenocorticotropic hormone (ACTH) in response to

Conclusions

Given the heterogeneity of subject composition across studies, inconsistent sampling times and techniques and variable exclusion criteria, it is difficult to draw definitive conclusions about the relationship between OSA and cortisol levels. If there are alterations in cortisol concentrations or rhythms associated with OSA, they are small enough that one has to be precise regarding the timing of blood draws and accounting for confounds such as obesity, age, smoking and depression.

Practice points

Acknowledgements

This work was supported, in part, by Grants HL36005, HL44915 and HL091848. We would like to thank Dr. Linda Gallo for her thoughtful comments on the initial draft of this manuscript. We also thank the anonymous reviewers for their encouraging comments and recommendations.

References∗ (35)

  • T.M. Buckley et al.

    On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders

    J Clin Endocr Metab

    (2005)
  • F. Lanfranco et al.

    Neuroendocrine alterations in obese patients with sleep apnea syndrome

    Int J Endocrin

    (2010)
  • T. Nakamura et al.

    Acute effect of nasal continuous positive airway pressure therapy on the systemic immunity of patients with obstructive sleep apnea syndrome

    Sleep

    (2001)
  • R.R. Grunstein et al.

    Acute withdrawal of nasal CPAP in obstructive sleep apnea does not cause a rise in stress hormones

    Sleep

    (1996)
  • A.N. Vgontzas et al.

    Hypothalamic-pituitary-adrenal axis activity in obese men with and without sleep apnea: effects of continuous positive airway pressure therapy

    J Clin Endocrinol Metab

    (2007)
  • D.E. Henley et al.

    Hypothalamic-pituitary-adrenal axis activation in obstructive sleep apnea: the effect of continuous positive airway pressure therapy

    J Clin Endocrinol Metab

    (2009)
  • A. Liberati et al.

    The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration

    Ann Intern Med

    (2009)

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