The following points are taken into account when explaining pathophysiological stress: first, the emotional, behavioral and physiological components of a stress reaction are controlled by corticotropin-releasing hormone; second, the intensity and duration of the reaction of the hypothalamic-pituitary-adrenal axis to stress are modulated by the release of glucocorticoids from the hippocampus, which is very sensitive to hippocampal neuronal activity and glucocorticoid insufficiency, and variation in the effectiveness of the brake system for hypothalamic-pituitary-adrenal axis activity likely accounts for interindividual differences in stress responses; and third, through a combination of cytokines and glucocorticoids, the reciprocal interactions between the immune system and the CNS constitute another regulatory element, and altered function of these interactions can be the origin of a pathology . Chronic stress produces alterations in hippocampal neurons, resulting in memory problems. Similarly, chronic stress can suppress immune system defenses and produce a range of psychophysiological symptoms such as adrenal fatigue caused by reduced cortisol levels. Emotional distress has a direct influence on inflammatory processes due to the chronic upregulation of proinflammatory cytokines, which are direct causes of respiratory allergies, rheumatoid arthritis, fibromyalgia, obesity, metabolic syndrome, type 2 diabetes, cancer and cardiovascular diseases. In addition, depression, insomnia, and chronic fatigue syndrome are caused by a reduction in cortisol levels . Such diseases are the result of a continuous process of multidirectional interactions among the frontal lobe of the brain (which perceives stress), the autonomic nervous system, the endocrine system and the immune system . A better understanding of the molecular actions of cortisol in the processes of memory and learning or in sleep disorders such as insomnia would facilitate progress in the prevention and both pharmacological and psychological treatment of stress disorders for those who are predisposed to such conditions . Figure 1 shows the impact of stress on the psychoneuroimmunoendocrine axis.Fig. 1Stress and psychoneuroimmunoendocrinology axis. ANS: autonomic nervous system; HPA: hypothalamic-pituitary-adrenal; IL-6: interleukin 6; RAA: renin-angiotensin-aldosterone