Chronic fatigue syndrome is a clinical disorder of unknown and probably heterogeneous etiology. The syndrome is currently defined as continuous or relapsing, debilitating fatigue, which, together with at least 4 of 8 other signs and symptoms, has persisted for at least six months in the absence of any other fatigue associated medical condition (Fukuda et al., 1994 and Holmes et al., 1988). Although many cases of chronic fatigue syndrome develop following an acute infectious illness, some cases seem to occur independent of infection and onset may be associated with other types of physical or emotional stress (Demitrack, 1994). It is postulated that the chronic fatigue syndrome is perpetuated by a persisting, pathological response to the onset stress which includes symptoms of fatigue and low-grade inflammation (Demitrack, 1994 and Strober, 1994). It is unclear whether the syndrome arises from a central nervous system dysfunction or a more peripheral abnormality at the neuromuscular junction, in muscle, or in immunologic activity. Although several investigators have failed to detect abnormalities in peripheral neuromuscular function in patients with chronic fatigue syndrome (Edwards et al., 1993, Gibson et al., 1993, Kent-Braun et al., 1993, Lloyd et al., 1991, Riley et al., 1990 and Rutherford and White, 1991), a recent study found an increase in central motor fatigue (Samii et al., 1996). The pervasive symptoms of impaired concentration and memory in patients with chronic fatigue syndrome also point to central nervous system involvement in the etiology of the fatigue symptoms.
Both the clinical symptomatology of chronic fatigue syndrome and previous neuroendocrine studies have suggested impaired activation of the hypothalamic–pituitary–adrenal axis in patients with the syndrome (Demitrack, 1994). Adrenal steroid deficiency and adrenal steroid withdrawal is associated with several symptoms characteristic of chronic fatigue syndrome including fatigue, arthralgias, myalgias, adenopathy, exacerbation of allergic responses, feverishness, and changes in mood, cognition, and sleep (Henneman et al., 1955). Because glucocorticoids play a major role in restraint of inflammatory processes (Munck et al., 1984), reduced activation of HPA axis could contribute to symptoms and signs of chronic mild inflammation in patients with chronic fatigue syndrome and reported subtle abnormalities in laboratory measures of cell mediated and humoral immunity (Kent et al., 1992, Mawle et al., 1997 and Strober, 1994). In addition, there have been reports of varying degrees of symptom improvement during treatment with hydrocortisone (Cleare et al., 1999 and McKenzie et al., 1998) and fludrocortisone, a mineralocorticoid (Bou-Holaigah et al., 1995).
Many neuroendocrine studies of chronic fatigue syndrome, but not all (Bearn et al., 1995, Wood et al., 1998 and Young et al., 1998), have noted reduced HPA axis activity in chronic fatigue syndrome. Positive findings include reductions in urinary free cortisol (Demitrack et al., 1991 and Scott and Dinan, 1998), reduced plasma (Demitrack et al., 1991 and Poteliakhoff, 1981) and salivary (Strickland et al., 1998) cortisol levels, reduced adrenal cortisol and dehydroepiandrosterone (DHEA) responses to moderate and high dose adrenocorticotropin (ACTH) stimulation (DeBecker et al., 1998, Demitrack et al., 1991 and Scott et al., 1998a), and reduced cortisol and ACTH responses to administration of corticotropin-releasing hormone (CRH) (Demitrack et al., 1991, Scott et al., 1999 and Scott et al., 1998b), ipsapirone (Dinan et al., 1997), and naloxone (Scott et al., 1998c). These endocrine findings are most compatible with a mild central adrenal insufficiency, due to either a deficiency of corticotropin releasing hormone or some other central stimulus to the pituitary adrenal axis.
In order to further define the determinants of impaired activation of the hypothalamic–pituitary–adrenal axis in patients with chronic fatigue syndrome, we compared ACTH and cortisol responses to an intravenous infusion of vasopressin between patients with chronic fatigue syndrome and controls. Pituitary ACTH secretion in response to vasopressin is markedly potentiated by concomitant corticotropin-releasing hormone stimulation of the pituitary (DeBold et al., 1984). Prior dose-response and circadian studies of vasopressin infusion in healthy controls have shown significantly reduced ACTH and cortisol responses to vasopressin infusion in the evening when the nadir of hypothalamic CRH secretion occurs (Salata et al., 1988), suggesting that this test is sensitive to fluctuations of CRH secretion within the physiological range. Thus the degree of ACTH response to vasopressin infusion can provide an indirect measure of ambient hypothalamic corticotropin-releasing hormone secretion, particularly if performed in the morning, when hypothalamic CRH secretion is relatively high.
