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.
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.
Organisations
Publications
Russell GM
(2014)
Subcutaneous pulsatile glucocorticoid replacement therapy.
in Clinical endocrinology
Russell GM
(2015)
The importance of biological oscillators for hypothalamic-pituitary-adrenal activity and tissue glucocorticoid response: coordinating stress and neurobehavioural adaptation.
in Journal of neuroendocrinology
Russell GM
(2014)
Can side effects of steroid treatments be minimized by the temporal aspects of delivery method?
in Expert opinion on drug safety
Russell G
(2024)
Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial.
in Journal of internal medicine
Russell G
(2019)
The human stress response.
in Nature reviews. Endocrinology
Oster H
(2017)
The Functional and Clinical Significance of the 24-Hour Rhythm of Circulating Glucocorticoids.
in Endocrine reviews
Lightman SL
(2016)
A Time for Metabolism and Hormones
Lightman S
(2016)
A Time for Metabolism and Hormones
Kalafatakis K
(2021)
Glucocorticoid ultradian rhythmicity differentially regulates mood and resting state networks in the human brain: A randomised controlled clinical trial.
in Psychoneuroendocrinology
Kalafatakis K
(2019)
Utilization of the allen gene expression atlas to gain further insight into glucocorticoid physiology in the adult mouse brain.
in Neuroscience letters
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 |
URL | https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-001104-37 |
Company Name | Dynamic Therapeutics Ltd |
Description | |
Year Established | 2023 |
Impact | The device has already had a marked impact on the endocrinology and chronobiology research communities as it allows 24 hour monitoring of hormones, metabolites and drugs in subjects in their own home/work environments. This will immediately improve patient involvement ( patient support groups from UK, Europe and the US are already in direct communication with us), and will improve both diagnostic procedures and therapeutic strategies . initially in endocrine disease-but in future in hypertension and Diabetes mellitus. |
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 | Personalised Endocrinology: 24 hour assessment of dynamic hormone profiles during normal working days - Imperial College London Student Endocrinology Society - Endocrinology in the 21st Century (online meeting) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | This was an event organised by students at Imperial College London who requested a talk and discussion from people they were interested to hear from. |
Year(s) Of Engagement Activity | 2021 |
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 Pituitary Foundation Conference, Bristol - Does the pattern of hydrocortisone replacement therapy really matter? |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Described most recent advances in the treatment of pituitary disease. |
Year(s) Of Engagement Activity | 2019 |
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 |