Cortisol pulses through the body every hour or so, but standard pills flatten that rhythm—and patients with Addison’s disease who take them have double the normal death rate. This matters because current cortisol replacement therapy delivers the hormone in two or three daily doses, producing steady levels that lack the natural ultradian (hourly) pulses. Patients report persistent apathy, low energy, and high unemployment. The underlying biology of why a flat cortisol profile is so damaging remains unknown. This project will investigate the mechanisms by comparing pulsatile versus constant cortisol exposure in both rats and human volunteers, using fMRI brain scans and pupil measurements to track neural responses. If successful, this fundamental science could reveal the brain pathways that link cortisol dynamics to motivation and energy. That knowledge might eventually lead to better hormone replacement regimens—not just for Addison’s disease, but for conditions such as depression, PTSD, and chronic fatigue syndrome, where abnormal cortisol patterns and apathy overlap. The work is primarily curiosity-driven: it asks why a natural rhythm matters at the cellular and behavioural level, a question with no immediate clinical product but with clear potential to reshape how hormone therapies are designed.
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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.
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