Objective: Enhancement of negative feedback control of the HPA axis in patients with chronic fatigue syndrome (CFS) has been reported using the low dose dexamethasone suppression test. We have developed the use of prednisolone (5 mg) as a more physiologically appropriate alternative to dexamethasone in the investigation of mild degrees of glucocorticoid resistance or supersensitivity. The objective of the study was to use this test to look for alterations in negative feedback control of the HPA axis in CFS patients.
Methods: Fifteen patients with CFS were recruited after fulfilling strict criteria including the absence of comorbid psychiatric diagnosis. They collected urine between 0900 and 1800 h and saliva at 0900 h pre-prednisolone. At midnight, they took prednisolone (5 mg) orally and then collected urine and saliva at the same intervals the following day.
Results: Salivary cortisol was lower in CFS subjects pre-prednisolone than controls. Urinary cortisol metabolites were lower in CFS subjects pre-prednisolone, but did not reach significance. Both measures were significantly lower in CFS subjects post-dose. Mean percentage suppression of both salivary cortisol and urinary cortisol metabolites was significantly higher in CFS compared to controls.
Conclusion: There is enhanced sensitivity of the HPA axis to negative feedback in CFS as demonstrated using the prednisolone suppression test. This provides further evidence of alterations in the control of the HPA axis in patients with established CFS.
Chronic fatigue syndrome (CFS) is characterised by persistent debilitating fatigue and exhaustion, together with a number of other characteristic symptoms, unexplained by identifiable organic disease (Fukuda et al., 1994). Since many of the symptoms of CFS can also be associated with glucocorticoid deficiency states, evaluation of HPA axis activity in CFS has been undertaken in numerous studies. As a result of this, it has been hypothesised that some features of CFS are a result of moderate hypocortisolism. The majority of the well designed studies in this area have demonstrated low levels of cortisol in blood, urine or saliva (reviewed by Cleare, 2003). More recently, we have also found low levels of urinary and salivary free cortisol in a well characterised group of 15 CFS patients free from medication or comorbid psychiatric disorders (Jerjes et al., 2005 and Jerjes et al., 2006a). However, the research in this area is not entirely consistent, and some other studies have shown no differences in serum cortisol levels (Racciatti et al., 1998; Altemus et al., 2001), and we have found no difference in 24 h urinary cortisol metabolite excretion between CFS and control subjects (Jerjes et al., 2006c).
A second hypothesis is that CFS symptoms result from alterations in central neuroendocrine pathways underlying the control of the HPA axis. Specifically, it has been suggested that there is deficient suprahypothalamic drive, reflected in reduced hypothalamic output of corticotropin-releasing hormone (CRH, Demitrack et al., 1991). Being the principal modulator of the stress response, CRH not only modulates endocrine and autonomic responses but also influences nociception and behaviour (Clauw and Chrousos, 1997). Several symptoms such as lethargy, pain and fatigue have been associated with a deficiency of hypothalamic CRH secretion (Gold and Chrousos, 1999).
Third, enhancement of negative feedback control of the HPA axis has also been proposed as a cause of a hypofunctional HPA axis in CFS (DeKloet et al., 1998). Preliminary reports suggested a heightened negative feedback in CFS subjects using dexamethasone (Poland et al., 1996) or hydrocortisone infusion (Lavelle and Dinan, 1996), while Gaab et al. (2002) examined salivary cortisol levels before and after low dose dexamethasone (0.5 mg), finding greater suppression in CFS, although levels of salivary cortisol in CFS were not different from controls pre-medication. However, dexamethasone may not be physiologically appropriate, since it has much higher relative affinity for the glucocorticoid receptor over the mineralocorticoid receptor (DeKloet et al., 1998), does not bind to corticosteroid binding globulin (Pugeat et al., 1981), and has a much longer half life compared with cortisol (Cassidy et al., 2000).
We have recently reported the use of prednisolone (5 mg) for investigation of mild degrees of glucocorticoid resistance or hypersensitivity, based on cortisol assay in a convenient pre and post dose saliva sample at 0900 h or on a urine sample collected 0900–1800 h (Jerjes et al., 2006b). Suppression was found to be approximately 50% for both saliva and urine in healthy subjects, but correlation between these measures was not established. Thus, the objective of the study was to explore alterations in negative feedback control of the HPA axis in CFS patients, using the prednisolone suppression test and assessing both saliva and urine approaches. We hypothesised that there would be enhanced negative feedback sensitivity in patients with CFS in comparison to healthy subjects.
