Pulsed Glucocorticoid Replacement Therapy

Lead Research Organisation: University of Bristol
Department Name: Henry Wellcome LINE

Abstract

Cortisol (also called hydrocortisone) is a hormone produced by the adrenal glands that is essential for life. It is produced in a daily (circadian) rhythm with high levels first thing in the morning, falling to very low levels at night time. There are many medical conditions such as Addison's disease, congenital adrenal hyperplasia and pituitary disease where patients cannot produce enough of this hormone and therefore require replacement therapy. At present we give patients standard replacement therapy with tablets in an attempt to mimic a normal hormonal profile. However despite this their death rates remain twice that of the background population (similar to the increased risk from smoking) and patients often feel generally unwell with severe fatigue. It is now known that cortisol is released into the blood stream in approximately hourly pulses, and that this pattern of pulses is vital for the body's normal responses. Unfortunately this pulsatile pattern is not the pattern of replacement that we currently give patients and this could well contribute to the excess death rate and the poor quality of life of these patients. We propose to develop a tailor made treatment that allows us to deliver pulses of hydrocortisone under the skin in a way that closely mimics natural hormone release. We shall initially test this in normal healthy volunteers to ensure we provide infusion rates that are equivalent to those produced in a normal individual. Once we have established the best protocol for this, we will use this infusion pattern in patients with Addison's disease and congenital adrenal hyperplasia. We shall assess the effectiveness of the treatment by measuring their hormone levels and evaluating the improvement in their quality of life and emotional well being using psychological tests that are specifically tailored to the symptoms of our patients.

Technical Summary

Glucocorticoid hormones secreted by the adrenal cortex are critical for life, and before steroid therapy was available patients with Addison's disease, congenital adrenal hyperplasia (CAH) and pituitary deficiency did not survive. However, despite the fact we now have available oral preparations of glucocorticoids and we administer these in a twice or three times daily regimen to try and mimic the normal circadian rhythm, our patients still have double the normal age related mortality and have major morbidity - predominately a feeling of generalised fatigue and lack of energy.
Underlying the classical circadian rhythm is a dynamic ultradian pulsatile pattern of cortisol secretion. This pattern is found in all mammalian species including man and is critical for normal gene regulation and for normal cognitive and metabolic function. It is now clear optimal regulation of glucocorticoid responsive genes absolutely requires pulsatile presentation of the ligand cortisol (in man) or corticosterone (in rodents). As we currently treat patients with constant as opposed to episodic receptor activation, we are inducing a very unphysiological regulation of both trans-activated and trans-repressed genes, which is likely to contribute both to the increased morbidity and mortality of our patients. We have developed a novel portable infusion pump that will deliver individually calculated pulsed subcutaneous hydrocortisone to more accurately mimic normal circadian and ultradian release. The aim of our proposed study is to validate this system in healthy volunteers and perform proof-of-concept studies in patients with Addison's and CAH. We shall examine the impact of our novel system upon biochemical parameters and assess the impact on psychological status using objective measurements of cognitive function, mood and tiredness as well as quality of life questionnaires.

Planned Impact

Currently many patients on hydrocortisone replacement therapy feel so lethargic and lacking in energy that they cannot remain in employment and simply feel and behave chronically unwell. Furthermore, their markedly increased mortality reflects their poor metabolic, immunological and cognitive status. Over and above this, many patients are put on higher than replacement doses of glucocorticoids in the hope that this might diminish their symptoms - where as in fact it just increases their glucorticoid mediated side effects. Our proposed flexible physiological, pulsatile steroid replacement should radically improve basic management as indicated by biochemical testing (appropriate pre-awakening levels, low evening levels, adequate ACTH and 17 OHP suppression), better steroid replacement during inter-current illness (never missing a dose, better flexibility for temporarily increasing dosage), improved flexibility to match lifestyle (exercise, travel). In addition due to the ability to provide oscillatory levels of cortisol, this will lead to a more physiological effect on gene pulsing which may well be the link between Addison's and CAH and the increased rates of infectious and cardiovascular diseases and of cancer. A pulsatile replacement regimen should also improve pregnancy rates through accurate replacement rather than over replacement in both women (improvement in menses and management throughout the pregnancy) and men (optimal sperm quality and production). In our CAH patients, we would expect a very specific improvement in reproductive function, secondary to the reduction of excess androgen secretion as a result of our ability to reproduce the normal profile of early morning glucocorticoid pulses which will inhibit the exaggerated ACTH surge that occurs in the absence of normal physiological feedback. The physiological replacement will also decrease excess glucorticoid crossing the placenta and reduce long-term epigenetic consequences to the foetus. The technology we are developing will also have an impact on the treatment of inflammatory disease. We believe that our pump technological has the potential to place the NHS at the cutting edge of developing systems to treat asthmatics who have morning dips and rheumatoid arthritis patients who have morning stiffness - without the need for increasing steroid dosage and the related increase in steroid side effects. Indeed with the increasing realisation of the importance of timing of steroid dosage, there is considerable potential in using our technology for the treatment of many immune-mediated and malignant conditions.

Publications

10 25 50
 
Description Use of chronotherapy in glucocorticoid replacement treatment
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Early days!
 
Title Novel ultradian infusion device and paradigm 
Description Pulsatile infusion pump 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2014 
Provided To Others? Yes  
Impact Improved quality of life 
 
Title Infusion pump 
Description This is an automated pulsatile infusion pump especially made for subcutaneous infusion of hydrocortisone. 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Small-scale adoption
Year Development Stage Completed 2018
Development Status Actively seeking support
Clinical Trial? Yes
Impact Better understanding of the importance of chronotherapy 
 
Description Addison's Disease Self-Help Group - Energy, memory, emotion and cortisol 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Discussion of scientific advances to help treatment of this patient group.

Better informed patients.
Year(s) Of Engagement Activity 2014
 
Description Bristol Neuroscience Festival - Lecture on "The importance of rhythm for stress and the brain" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Part of the University of Bristol's outreach programme.
Year(s) Of Engagement Activity 2016
 
Description British Neuroscience Roadshow - Stress and the brain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Talk sparked questions and discussion afterwards.

The local stimulation of neuroscience in Korea.
Year(s) Of Engagement Activity 2008
 
Description Cheltenham Science Festival - Hormone Fight Club 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Considerable discussion!

Contact from several media sources!
Year(s) Of Engagement Activity 2013
 
Description Public Lecture held at The Physiological Society in London and streamed world-wide on Facebook Live - The Physiology of Stress - Science of Stress. Lecture on "Mechanisms of stress" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This is the first time that The Physiological Society has streamed a public lecture for a world-wide audience.
Year(s) Of Engagement Activity 2017
 
Description Royal Institution, London - Science of Sleep 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This remains available on the Royal Institution website for all interested parties.
Year(s) Of Engagement Activity 2016
 
Description Talk to Bristol Pituitary Support Group at Southmead Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact An active discussion on recent advances in treating patients with disrupted hormone secretion
Year(s) Of Engagement Activity 2017
 
Description The Royal Institution Friday Evening Discourse - Rhythms of the body 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk sparked questions and discussion afterwards.

Discussion with membership of the Royal Institution and their friends.
Year(s) Of Engagement Activity 2010
 
Description The importance of hormone dynamics in therapies 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Presentation followed by discussion about the importance of patterns of hormone replacement for best patient wellbeing.
Year(s) Of Engagement Activity 2017
 
Description University of Utrecht - Stress and Disorders of the Brain. Lecture on "Corticosteroid rhythms and replacement strategies" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Part of EU outreach programme
Year(s) Of Engagement Activity 2016