During acute stress, the hypothalamus stimulates the adrenal medulla to release adrenaline and nor-adrenaline, which serve to enable a fight or flight response. If the stressor persists after this initial reaction phase, a more prolonged stress response is initiated. This is achieved by increasing Adrenocorticotropic Hormone (ACTH) secretion from the pituitary gland, prompting the release of cortisol and DHEA from the adrenal cortex. The rate of cortisol and DHEA secretion is regulated through the HPA axis negative feedback loop. A sustained demand for cortisol, in response to continued stress without adequate recovery, stimulates ongoing ACTH release by the pituitary gland. Over time, the HPA axis will adapt by downregulating ACTH production, and thus cortisol stimulation, in order to protect the tissues. If stressors continue, semi-permanent down-regulation occurs characterised by cortisol and DHEA levels below the reference range. At this stage the body will have difficulty meeting the demands of the day.