Research suggests that chronic fatigue syndrome (CFS) is associated with abnormalities in the hypothalamic–pituitary–adrenal (HPA) axis. CFS is typically defined as persistent or relapsing, debilitating fatigue lasting at least six months, accompanied by symptoms such as abrupt onset of illness, low-grade fevers, joint and muscle pain, tender lymph nodes, post-exertional fatigue, neuropsychological complaints, and sleep disturbances.
A review article published in Annals of Medicine (1994; Volume 26:1–3) examined HPA axis function in patients with CFS. The authors reported that only one of 16 patients with CFS demonstrated normal suppression on the dexamethasone suppression test, a finding suggestive of altered cortisol regulation. In patients with fibromyalgia, fewer than 5% showed normal suppression. Individuals with CFS were also found to have lower plasma cortisol levels compared with healthy controls.
The symptom pattern of CFS closely resembles that seen in glucocorticoid deficiency, a condition characterized by profound fatigue. Other features of glucocorticoid insufficiency include symptom onset following a stressor, feverishness, joint and muscle pain, lymph node tenderness, post-exertional worsening, heightened allergic responses, and disturbances of mood and sleep—features that overlap substantially with CFS.
One proposed trigger for CFS is viral infection, such as Epstein–Barr virus (EBV), cytomegalovirus (CMV), or herpes simplex virus. This hypothesis aligns with research linking cortisol levels and immune function. An article published in Medical Hypotheses (1991; Volume 34:198–208) noted that plasma cortisol levels decline during various infections, including influenza. The authors referenced earlier work from Perla and Marmorston, who concluded in Natural Resistance and Clinical Medicine (1941) that the adrenal glands play a critical role in maintaining the body’s natural resistance to toxins and infections. They observed that adrenal insufficiency reduced resistance to infection, while administration of adrenal cortical hormones restored resistance in animal models.
Additional evidence was discussed in a study published in the Journal of Clinical Endocrinology and Metabolism (1991; Volume 73:1224–1234), which reported that researchers at the National Institutes of Health identified hormonal abnormalities in patients with CFS. Reduced cortisol levels were observed in a group of 30 patients with CFS. Importantly, the authors cautioned against treating these patients with cortisol directly, noting that such treatment could further suppress adrenal function.
