Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a commonly recognized feature of many pathological conditions. Abnormal adrenal responses to experimental manipulation have been well documented in patients suffering from chronic fatigue syndrome, anorexia nervosa and major depression. Yet no defect of any single organ, gland or brain region has been identified as a cause of these abnormalities. The disruption of the HPA axis that occurs in these conditions can be understood if an interfering factor is present in these patients. Evidence indicates that this interfering factor is adrenocorticotropin hormone (ACTH) autoantibodies. Chronic high levels of ACTH autoantibodies will significantly disrupt the HPA axis and force the body to compensate for an impaired cortisol response. The resulting effect of chronic ACTH autoantibody interference is the manifestation of adrenocortical insufficient symptoms and psychological disturbances. Some symptoms of chronic fatigue syndrome, anorexia nervosa and major depression, such as anxiety, are the adverse effects of mechanisms compensating for less effective ACTH due to autoantibodies. Furthermore, these patients engage in extraordinary behaviors, such as self-injury, to increase their cortisol levels. When this compensation is inadequate, symptoms of adrenocortical insufficiency appear. Corticosteroid supplements have been demonstrated to be an effective treatment for chronic fatigue syndrome, anorexia nervosa and major depression. It allows the patients to have the corticosteroids they require for daily functioning and daily stressors. This therapy will relieve the patients of their symptoms of adrenocortical insufficiency and permit their cortisol-stimulating mechanisms to operate at levels that will not cause pathological problems.