First-of-its kind hormone replacement treatment shows promise in patient trials
Press release issued: 20 October 2023
A first-of-its kind hormone replacement therapy that more closely replicates the natural circadian and ultradian rhythms of our hormones has shown to improve symptoms in patients with adrenal conditions. Results from the University of Bristol-led clinical trial are published today [20 October] in the Journal of Internal Medicine.
Low levels of a key hormone called ‘cortisol’ is typically a result of conditions such as Addison's and Congenital Adrenal Hyperplasia. The hormone regulates a range of vital processes, from cognitive processes such as memory formation, metabolism and immune responses, through to blood pressure and blood sugar levels. When low, it can trigger symptoms of debilitating fatigue, nausea, muscle weakness, dangerously low blood pressure and depression. Although rare, these adrenal conditions require lifelong daily hydrocortisone replacement therapy.
Although existing oral hormone replacement treatment can restore cortisol levels, it is still associated with an impaired quality of life for patients. Scientists believe this is because the current treatment does not mimic the body’s normal physiological timing, missing cortisol’s anticipatory rise and lacking its underlying ultradian and circadian rhythms.
The new 'Pulsatility' therapy, the culmination of ten years research by the Bristol team, is designed to deliver standard hydrocortisone replacement to patients via a pump which replicates more closely cortisol’s natural rhythmic secretion pattern. The pulsatile subcutaneous pump has now revealed promising results in its first clinical trial.
Twenty participants aged 18 to 64 years with adrenal insufficiency conditions were assessed during the double-blinded PULSES six-week trial and treated with usual dose hydrocortisone replacement therapy administered either via the pump or the standard three times daily oral treatment.
While only psychological and metabolic symptoms were assessed during the trial, results revealed the pump therapy decreased fatigue by approximately 10%, improved mood and increased patient energy levels by 30% first thing in the morning — a key time frame when many patients struggle. Patient MRI scans also revealed alteration in the way that the brain processes emotional information.
Dr Georgina Russell, Honorary Lecturer at the University's Bristol Medical School, and the lead author, explained: "Patients on cortisol replacement therapy often have side effects which makes it difficult for them to lead normal lives. We hope this new therapy will offer greater hope for the thousands of people living with hormone insufficiency conditions."
Stafford Lightman, a neuroendocrinology expert and Professor of Medicine at Bristol Medical School: Translational Health Sciences (THS), and the study's joint lead author, added: "Besides reduction in dosage, cortisol replacement has remained unchanged for many decades. It is widely recognised that current replacement therapy is unphysiological due to its lack of pre-awakening surge, ultradian rhythmicity, and post dose supraphysiological peaks. The new therapy clearly shows that the timing of cortisol delivery- in line with the body's own rhythmic pattern of cortisol secretion – is important for normal cognition and behaviour.
"Our findings support the administration of hormone therapy that mimics natural physiology, and is one of the first major advances in adrenal insufficiency treatment to date."
Joe Miles, a participant on the PULSES trial, explained: "The Crono P pump has been life changing. I noticed a very quick improvement compared to tablets when I was on the PULSES study. I went from feeling tired all the time to having sudden energy.
"When the PULSES study ended and I had to return the pump, I simply couldn't cope with going back to how I used to be, so I made it my mission to write to as many doctors to have it prescribed privately.
"I've now been on it for six years and have introduced a number of other people with Addison's disease to the pump, and all of them have said it's life changing. Some have gone from being seriously ill to feeling better than they have done for years."
Dr Russell said: "Approximately 1% of the UK population is taking steroids at any moment in time, these individuals can experience debilitating psychological side effects. This trial has shown that even at physiological levels, brain functioning is disrupted and that we need to explore not only the dose but the pattern of steroids delivery when considering any type of steroid treatment."
The study was funded by the Medical Research Council and Bristol & Weston Hospitals Charity (formerly Above & Beyond). The team now hope to conduct a larger trial looking at personalisation of steroid replacement therapy using hormone secretion patterns from over 200 healthy volunteers.
'Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial' by G Russell et al. in the Journal of Internal Medicine
Case study: Joe Miles
I’m Joe aged 40 with Addison's disease. The main symptom of living with Addison's is perpetual tiredness and / or exhaustion, which gets worse with stress or physical strain on the body. I'm married with three kids and one more on the way, so sometimes I'm not sure if the tiredness is Addison's or just my lifestage!
About 14 years ago I was normal, but over some weeks I gradually got more and more exhausted for no obvious reason. This got to the point where I was blacking out simply crossing the road and was skeletal thin.
It baffled my GP for weeks, and she thought it may just be stress or depression which can lead to "low energy". I knew it was physical rather than mental, so I eventually saw another GP. That night she banged on my door after midnight saying she'd just realised what it was. She told me she wanted to drive me to A&E immediately as she didn't think I had long to live, and she wanted to ensure they knew it was Addison’s and to treat it like an emergency.
Since then I've led a mostly normal life. But the Crono P pump has been life changing since I switched to it from tablets six years ago. I noticed a very quick improvement compared to tablets when I was on the PULSES study. I went from feeling tired all the time to having sudden energy.
When the PULSES study ended and I had to return the pump, I simply couldn't cope with going back to how I used to be, so I made it my mission to write to as many doctors as I could until one agreed to prescribe it privately.
Since being the first in the UK to have the pump in real life (i.e. not a trial) I've introduced a number of other people with Addison's to the pump, and all of them have said it is life changing. Some have gone from being seriously ill to feeling better than they have done for years.
About Adrenal Insufficiency
Around 8,500 people in the UK have primary adrenal insufficiency due to a problem with the functioning of the adrenal gland itself. Around 10,000 people have secondary adrenal insufficiency, a problem with the pituitary gland. This gland sends signals to the adrenal telling it when and how much cortisol to make. Without this, the adrenal gland does not know it needs to make cortisol. Finally, there is tertiary adrenal insufficiency. The amount of people with this is unknown. Tertiary adrenal insufficiency arises when a person is on long term steroids for another medical reason. In this case, as there is a lot of steroid in a person’s body, the brain does not send signals to the pituitary and therefore the adrenals go to sleep as it thinks there is enough steroid on board. Around 1% of the UK population are on steroids and therefore may have undiagnosed Adrenal Insufficiency conditions.
About the Medical Research Council
The Medical Research Council is at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Thirty-three MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms.
About Bristol & Weston Hospitals Charity
Bristol & Weston Hospitals Charity sits at the heart of one of the busiest NHS Trusts in the country: University Hospitals Bristol and Weston NHS Foundation Trust. As the official charity for all ten hospitals in the Trust, the charity does great things with multi-million pound investments back into the hospitals. Working alongside NHS staff, the charity enhances the patient experience with better environments, funds the latest technology, supports innovative treatments and helps fund internationally important medical research.
We bring moments of joy, comfort and hope. Healing is hard work, so let’s help those who need it most.
Find out more at www.bwhospitalscharity.org.uk