The HPA axis is a grouping of responses to stress by the brain and the pituitary and adrenal glands. First, the hypothalamus (a central part of the brain) releases a compound called corticotrophin releasing factor (CRF), which was discovered in 1981. The CRF then travels to the pituitary gland, where it triggers the release of a hormone, adrenocorticotrophic hormone (ACTH). ACTH is released into the bloodstream and causes the cortex of the adrenal gland to release the stress hormones, particularly cortisol, which is a corticosteroid hormone. Cortisol increases the availability of the body's fuel supply (carbohydrate, fat, and glucose), which is needed to respond to stress. However, if cortisol levels remain elevated for too long, then muscle breaks down, there is a decreased inflammatory response, and suppression of the immune (defense) system occurs.

Because they suppress the immune system, corticosteroids in measured doses are used to treat many illnesses that are characterized by inflammation or an overactive immune system, such as asthma and inflammatory bowel disease. For the same reason, they are used to help reduce the chances that our body will immunologically reject a transplanted organ. Corticosteroids also can cause fluid retention and high blood pressure. Therefore, it is critical that the response to corticosteroids be carefully controlled (modulated). This control usually is accomplished by a feedback mechanism in which increased cortisol levels feeding back to the hypothalamus and pituitary turn off production of ACTH. In addition, extremely high levels of cortisol can cause mental changes, including depression and psychosis, which disappear when the levels return to normal.

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