Glucocorticoid dynamics in health and disease

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.

This programme grant integrates cellular, tissue, whole animal and human volunteer investigations to investigate the biological mechanisms underlying the way the body has adapted to read the rhythmic output from the hypothalamic-pituitary-adrenal (HPA) axis. The underlying hypothesis we wish to test is that the dynamic oscillatory patterns of HPA activity provides patterns of glucocorticoid secretion that are critical for optimal brain function. We shall determine how different glucocorticoid receptor containing brain areas involved in cognitive and emotional responses respond differentially to altered patterns of CORT administration using genome-wide ChIP-Seq and RNA-Seq. We shall see how these region-specific changes relate to behavioural responses in the realms of motivation, effective bias and hippocampal memory. We shall go on to clinical studies looking at motivational and autonomic circuitry using fMRI and pupillometry. Ultimately our aim is to understand the role of CORT rhythmicity in brain pathways associated with apathy - and use this knowledge not only to treat patients on glucocorticoid replacement therapy but also to stratify patients with other conditions associated with apathy and HPA abnormalities such as depression, PTDS and chronic fatigue syndrome.

Short-term (0-3 years)

Patient groups: We will organise events via our outreach programme aimed at groups representing patients with hypothalamic/pituitary/adrenal related disorders. This will include the Addison's Disease Self-Help Group, the CAH Support Group, the Cushing's Syndrome Support Group and the Pituitary Foundation (whose first Chairman was Professor Stafford Lightman). During these events we will present the latest findings of our research programme to enable direct input of patients to question and answer sessions with investigators and researchers. These events will be advertised through our own web forum as well as the host organisations public engagement centres.

Medical Research Council

Our proposal satisfies the cross-board highlight notice. We would seek to actively engage with MRC representatives including their attendance at our regular outreach activities.

Longer-term (5-8 years)

Clinicians managing either primary adrenal disorders or secondary adrenal disorders for a disease to the hypothalmus or pituitary. The proposal offers the potential for developing novel treatment paradigms for cortisol replacement. Initially this will be via our MRC funded pulsatile infusion technology but we are also in discussion with the Department of Engineering at Glasgow University to produce oral pulsatile therapy via a novel capsule preparation. We shall also actively engage with the clinicians through our workshops and at research meetings to educate them about the advantages of our new treatment technologies.

Commercial sector pharmaceuticals

In additional to our collaborative studies with the University of Glasgow, we hope to plan clinical trails derived from the finding of this programme to allow the development of novel chronologically discrete methods of drug administration to mimic the body's own natural production of glucocorticoids. This should improve efficacy and decrease side effects from glucocorticoid administration.

Long-term (more than 10 years)

Patients with clinical disorders: We would hope that our programme will provide the opportunity for markedly improved treatment of hypoadrenal patients. We would also hope that the knowledge derived from our studies will enable us to improve stratification of patients with apathy in diseases such as depression, PTSD and chronic fatigue syndrome and pave the way for a more personalised medicine approach to the treatment of patients in these very heterogeneous disorders.

Health sector managers and policy makers

We would hope that in the longer term, our research will result in an improvement in the therapy of patient groups needing glucocorticoid replacement therapy and that as a result of this we would ultimately achieve a substantial saving against cost of treatment as well as improvement in patient satisfaction. Steroids are one of the most prescribed classes of drugs in the UK and consequently reducing side effects through more effective delivery systems, should also result in significant savings.