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HPA-Axis Dysfunction in Chronic Fatigue Syndrome: Clinical Implications

TO THE EDITOR:  There is evidence for a hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in a proportion of the patients with chronic fatigue syndrome (CFS). Mild hypocortisolism, blunted adrenocorticotropin response to stressors, and enhanced negative-feedback sensitivity to glucocorticoids are the main findings.¹ In this letter, we emphasize the clinical implications of neuro-endocrine research in CFS.

Patients with CFS frequently adopt a somatic theory with regard to their illness, which can have negative impact on their prognosis.² The stress model allows for bridging the dualism between "body" and "mind" in CFS by integrating physical and psychological stress as predisposing, precipitating, and perpetuating factors.² In this model, the disturbances of the HPA axis can be considered as a final common pathway and as a physiological link to immunological disturbances.³

Furthermore, the search for biological markers is required for diagnostic management and for therapeutic monitoring in CFS. We need to assess the validity of challenge tests such as the test involving the administration of low-dose dexamethasone (to examine the glucocortocoid-feedback function).⁴ In the absence of any biological marker, cognitive-behavioral therapy and graded exercise are the only evidence-based treatment options in CFS.² Future studies could examine the effect of these interventions on HPA-axis disturbances, as well the effect of these disturbances on the prognosis of CFS.

Finally, the HPA axis consists of a potential target for drug therapy in CFS. One HPA axis-related strategy that has already been investigated in three trials is replacement therapy with hydrocortisone, but this therapy cannot be recommended for clinical use because of the limited benefit, the loss of efficacy upon discontinuation, and adrenal suppression when higher doses are administered.¹ Another possibility could be to activate the HPA axis in CFS inversely to the treatment strategy used in major depressive disorder (which is characterized by HPA-axis hyperfunction).⁵ With regard to this, several compounds have been suggested, such as CRF-receptor₂ antagonists and ligands that target CRF-binding protein.^6,7

REFERENCES

1. Van Den Eede F, Moorkens G, Van Houdenhove B, et al: Hypothalamic-pituitary-adrenal-axis function in chronic fatigue syndrome. Neuropsychobiology 2007; 55:112–120[CrossRef][Medline]
2. Prins JB, van der Meer JW, Bleijenberg G: Chronic fatigue syndrome. Lancet 2006; 367:346–355[CrossRef][Medline]
3. Gold PW, Chrousos GP: Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs. low CRH/NE states. Mol Psychiatry 2002; 7:254–275[CrossRef][Medline]
4. Gaab J, Hustern D, Peisen R, et al: Low-dose dexamethasone suppression test in chronic fatigue syndrome and health. Psychosom Med 2002; 64:311–318[Abstract/Free Full Text]
5. Holsboer F: The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J Psychiatr Res 1999; 33:181–214[CrossRef][Medline]
6. Grammatopoulos DK, Chrousos GP: Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists. Trend Endocrinol Metab 2002; 13:436–444[CrossRef][Medline]
7. Van Den Eede F, Van Broeckhoven C, Claes SJ: Corticotropin-releasing factor-binding protein, stress, and major depression. Ageing Res Rev 2005; 4:213–239[CrossRef][Medline]

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