Multiple laboratory studies have suggested that the central nervous system may have an important role in CFS. Physical or emotional stress, which is commonly reported as a pre-onset condition in CFS patients, activates the hypothalamic-pituitary-adrenal axis, or HPA axis, leading to increased release of cortisol and other hormones. Cortisol and corticotrophin-releasing hormone (CRH), which are also produced during the activation of the HPA axis, influence the immune system and many other body systems. They may also affect several aspects of behavior. Recent studies revealed that CFS patients often produce lower levels of cortisol than do healthy controls. Similar hormonal abnormalities have been observed by others in CFS patients and in persons with related disorders like fibromyalgia. Cortisol suppresses inflammation and cellular immune activation, and reduced levels might relax constraints on inflammatory processes and immune cell activation.

As with the immunologic data, the altered cortisol levels noted in CFS cases fall within the accepted range of normal, and only the average between cases and controls allows the distinction to be made. Therefore, cortisol levels cannot be used as a diagnostic marker for an individual with CFS. A placebo-controlled trial, in which 70 CFS patients were randomized to receive either just enough hydrocortisone each day to restore their cortisol levels to normal or placebo pills for 12 weeks, concluded that low levels of cortisol itself are not directly responsible for symptoms of CFS, and that hormonal replacement is not an effective treatment. However, additional research into other aspects of neuroendocrine correlates of CFS is necessary to fully define this important, and largely unexplored, field.