Glucocorticoid dynamics in health and disease

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The secretion of the stress hormone cortisol by the adrenal gland is controlled by the activity of the hypothalamus and pituitary gland. We have shown that this is a very dynamic system with both an hourly (ultradian) and a 24 hour (circadian) rhythm. This results in oscillating levels of cortisol in the blood and in all the tissues of the body.Patients who lack the hormone cortisol are treated with pills containing cortisol two or three times a day. This results in hormone levels that lack any ultradian activity. These patients often lack energy, feel generally apathetic, have high levels of unemployment and double the mortality of normal people of the same age.In this grant application we plan to investigate the mechanisms underlying the increased mortality and morbidity in these patients, by studying the importance of oscillating levels of cortisol both in an animal model and in man. In the animal model we will investigate the biological mechanisms through which pulsatility affects neural function both at the level of cellular function and animal behaviour. In human volunteers we will use brain scanning (fMRI) and changes in pupil size to look at the brain pathways responding to changes in cortisol pattern.Ultimately, we hope to better understand the brain pathways associated with apathy, and hope that this will enable us to develop more appropriate therapy not only for Addison's disease, but also other conditions associated with apathy and abnormal adrenal activity such as depression, PTSD and chronic fatigue syndrome.