In 1936, Hans Selye defined the “general adaptive syndrome” as the response that the body makes to deal with stress. Under stress, the brain focuses on the event that seems to be threatening. Heart output, respiration, catabolism and the most useful flow of circulation are increased. The responses to stress are behavioral, endocrine, autonomic and immune.
The hypothalamus and brain stem are the parts of the brain involved in adapting to stress. These include the cells that produce corticotropin-releasing hormone (CRH) and the locus ceruleus (LC), which releases norepinephrine for the autonomic nervous system. The brain influences the body by way of both the hypothalamic-pituitary-adrenal (HPA) axis and the nerves of the autonomic nervous system that project into the body.
Hypothalamic stimulation produces beta-endorphins, which suppress pain sensation and produces CRH, which is a chain of 41 amino acids. CRH produced hypothalamic stimulation releases growth hormone (ACTH) by the pituitary, inhibits appetite, reproductive, growth and thyroid functions and increases heat production. ACTH stimulates glucocorticoid (including cortisol and corticosterone) production by the adrenal gland.
The autonomic nervous system includes the sympathetic projections and the parasympathetic nerves that project to the intestine and control many internal responses to stress. Activation of the sympathetic nervous system releases IL-6 to the blood, which is a chemical that stimulates the HPA axis.
The autonomic nervous system provides a rapid response by the cardiovascular, respiratory, gastrointestinal, renal, endocrine and other systems. The sympathetic and parasympathetic nervous systems balance each other in stress. The parasympathetic portion of the autonomic nervous system can reduce sympathetic activity by increasing its’ own activity or can increase sympathetic activity by reducing its own activity.
Glucocorticoids are the final products of the HPA axis and they have a feedback function on the pituitary to inhibit the production of more ACTH, pituitary gonadotrophin and thyroid-stimulating hormone. Glucocorticoids contribute to insulin resistance and poor control of diabetes mellitus in patients under stress and promote osteoporosis. Glucocorticoids alter the stability of RNA and, thereby, alter the production of certain proteins and can alter the electrical charges of nerve cells.
Inflammation, by way of chemicals called cytokines, such as IL-6, and other hormones, can stimulate the stress response. The immune system is inhibited by the HPA axis stimulation. Cortisol, produced by the adrenals under stress, inhibits all parts of the immune system. The autonomic nervous system can either stimulate or inhibit the immune system during stress.
The “general adaptive syndrome” is intended to be a temporary way of enabling the organism to survive, but there is evidence that prolonged stimulation of the HPA can be maladaptive. There are manifestations of this in the metabolic syndrome, excessive exercise, chronic depression and fibromyalgia.
The metabolic syndrome is promoted by the glucocorticoids produced by stress. The signs of the metabolic syndrome are increased fat tissue, insulin resistance, abnormal lipid levels, hypertension and elevated levels of blood cortisol.
The suppression of gonad function by chronic HPA axis stimulation has been reported in highly trained athletes, ballet dancers, people with anorexia nervosa and people with starvation. Glucocorticoids have an inhibitory action on reproductive functions at the levels of the hypothalamus, the pituitary and the gonads.
Depression and anxiety can be chronic and result in chronic stimulation of the stress system of the body. The patients may manifest the metabolic syndrome with physical, endocrine, immune and metabolic changes. The patients have an increased risk of death from many causes and chronically suppressed immune systems can result in infections and cancers. Chronic activation of the HPA with inhibition of the inflammatory and immune reactions is caused by cortisol. CRH antagonists are useful in these conditions.
Patients with hyperactivation of the HPA system may include those with melancholic depression, anorexia nervosa, obsessive-compulsive disorder, panic anxiety, chronic active alcoholism, alcohol and narcotic withdrawal, excessive exercising, poorly controlled diabetes mellitus, childhood sexual abuse and hyperthyroidism. Dysfunction of the HPA may play a role in autoimmune disease and rheumatoid arthritis.
Another group of patients have evidence for reduced response to HPA stimulation. People with fibromyalgia, chronic fatigue syndromes, nicotine withdrawal, atypical depression and postpartum depression have reduced CRH production and may be benefited by promoters of CRH production. Low central stress response, low HPA axis activity, fatigue, depression, increased sensitivity to pain and increased inflammatory responses characterize these problems.
CONCLUSION: The “general adaptive syndrome” is the way the hypothalamo-pituitary-adrenal (HPA) axis enables us to deal with stress. The benefits of this system become liabilities when people are subjected to chronic stress with over-activity of the HPA axis. Such people would benefit from treatments that would be antagonists of the HPA response. Low response of the HPA axis is seen in people with certain disease states. These people would benefit from promoters of the HPA response.
NOTE: Kick boxers who receive blows to the head have been reported to have interruption of the HPA axis with resultant temporary erectile dysfunction.
Adaptogens are supplements that help patients deal with chronic stress by reducing the HPA axis response to stress with relief of the physical effects of stress. Bacopa (Bacopa monniera,) rhodiola (Rhodiola rosea,) eleuthro (Eleuthrococcus senticosus,) schizandra (Schizandra chinensis) and l-arginine are adaptogens. (Eleuthro was previously known as Siberian ginseng.)
IL-6 is a chemical cytokine, which increases the response of the HPA axis to stress. Other agents that stimulate the HPA axis are cocaine, caffeine and nicotine, although they are not suggested as being therapeutic.
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