Hypothalamic–pituitary–adrenal axis dysfunction in chronic fatigue syndrome

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The weight of current evidence supports the presence of the following factors related to hypothalamic–pituitary–adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS): mild hypocortisolism; attenuated diurnal variation of cortisol; enhanced negative feedback to the HPA axis; and blunted HPA axis responsiveness. Furthermore, HPA axis changes seem clinically relevant, as they are associated with worse symptoms and/or disability and with poorer outcomes to standard treatments for CFS. Regarding etiology, women with CFS are more likely to have reduced cortisol levels. Studies published in the past 8 years provide further support for a multifactorial model in which several factors interact to moderate HPA axis changes. In particular, low activity levels, depression and early-life stress appear to reduce cortisol levels, whereas the use of psychotropic medication can increase cortisol. Addressing these factors—for example, with cognitive behavioral therapy—can increase cortisol levels and is probably the first-line approach for correcting HPA axis dysfunction at present, as steroid replacement is not recommended. Given what is now a fairly consistent pattern of findings for the type of HPA axis changes found in CFS, we recommend that future work focuses on improving our understanding of the cause and relevance of these observed changes.

Key Points

  • The bulk of evidence points to modest reductions in cortisol levels in some cohorts of patients with chronic fatigue syndrome (CFS), and these changes are more apparent in women than in men

  • Underlying the reduction in cortisol levels is a hypothalamic–pituitary–adrenal (HPA) axis with attenuated diurnal variation, enhanced negative feedback and blunted response to challenges

  • Low cortisol levels have clinical relevance as they might contribute to symptoms—along with other factors—and are associated with a worsened outcome of currently recommended treatments for CFS

  • A multidimensional etiological model remains most probable, with low cortisol levels occurring at a later stage of the illness, moderated by factors such as activity levels, depression, early-life stress and psychotropic medication

  • Cortisol levels can be increased by treatment with cognitive behavioral therapy, potentially because of reversal of some moderating factors

  • Further improvements in research designs remain necessary to fully understand HPA axis dysfunction in CFS

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Figure 1: Schematic representation of the hypothalamic–pituitary–adrenal (HPA) axis.

Change history

  • 26 June 2012

    In the version of this article initially published online in Table 3 the findings in relation to the study by Van den Eede et al. should have read "Patients without early-life stress had lower mean cortisol post DEX and lower AUC total post DEX plus CRH than both controls and patients with early-life stress". The error has been corrected for the HTML and PDF versions of the article.


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The authors' work was supported by the NIHR Biomedical Research Centre at South London and Maudsley NHS Trust & Institute of Psychiatry (King's College London).

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Both authors contributed equally to all aspects of this manuscript.

Correspondence to Anthony J. Cleare.

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