Dr Georgina Russell, Consultant Endocrinologist at Bristol updates us on the PULSES trial, following the results from the clinical trial being published in the Journal of Internal Medicine. The PULSES trial is a first-of-its-kind hormone replacement therapy that more closely replicates the natural circadian and ultradian rhythms of hormones. The results from the clinical trial have shown that pulsatile cortisol pump therapy can improve symptoms in people with adrenal conditions.

History of the Research

It was back in 2014 when the ADSHG first welcomed Dr Georgina Russell and Professor Stafford Lightman to our AGM meeting. Their fantastic medical lecture informed members about the forthcoming clinical trial on the pulsatile pump, and a question and answer session followed with many eager questions from the audience! In March 2015, the ADSHG was able to let members know recruiting for volunteers was open via our magazine, and online forum, and we are very grateful to all the ADSHG members who responded and took part in the trial allowing this vital research to proceed. At our 2021 AGM, Dr Georgina Russell kindly updated our members again on progress and now in 2023 we're delighted to speak with Dr Georgina Russel about the results.

Pulsatile cortisol pump therapy is the culmination of ten years of research by the Bristol team as this timeline shows. We thank the whole PULSES trial team for their perseverance, hard work and commitment to this research for our rare condition.

Research Facts:

• Research title: Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial
• Disease: Primary Adrenal Insufficiency
• Lead researchers: Dr Georgina Russell and Professor Stafford Lightman
• Organisation: University of Bristol
• Research link: https://onlinelibrary.wiley.com/doi/10.1111/joim.13721

Welcome Dr Georgina Russell! What are the aims of this research? 

The aim of the research was to assess the effect of pulsatile cortisol pump therapy on quality of life, mood, sleep, behavioural and cognitive processing and metabolism in primary adrenal insufficiency due to Addison’s and Congenital Adrenal Hyperplasia.

Why is this research important?

This research is a breakthrough for the management of adrenal insufficiency. An issue faced is that standardised tests can’t detect or quantify the issues that people with Addison’s describe. This is the first time that it has been shown that the pattern of steroid replacement does affects a person’s brain and how an individual processes emotional information. Steroid treatment is of course bigger than just primary adrenal insufficiency, there are also the patients who have pituitary problems and those who have had long-term steroids for many years and are now steroid dependent who also require cortisol replacement therapy. 

These findings also have potential knock-on effects for looking at steroids that are used to treat other medical conditions such as rheumatoid arthritis, asthma etc as this information may help us to explore new avenues to help minimise the side effects.

And finally, the basic idea behind this research was that cortisol replacement therapy should mimic what happens normally in the body, why should this not be the case for all forms of replacement therapy be it thyroid, oestrogen, testosterone, the list is endless. We hope that this research will help open the eyes of other scientists and the drug industry to what is possible! 

How will findings benefit people with Addison’s disease and adrenal insufficiency?

It is important to investigate new forms of replacement therapy, when you think about it of course any form of hormone replacement therapy needs to mimic what happens naturally. PULSES has shown that over 6 weeks an improvement in symptoms of fatigue. Functional MRI (Magnetic resonance imaging) has also shown that pulsatile hormone replacement changes the way in which people with adrenal insufficiency brains’ process emotional information.  

This is all very exciting, pulsatile pump therapy is a good first step, the work we did in PULSES needs to be further fine-tuned and looked at over the longer term. Pump therapy will not be the right answer for every patient, it is cumbersome to have to wear a pump and not always practical. We hope that this will inspire drug companies to look more closely at all forms of hormone replacement therapy so that it matches normal patterns - the technology does exist to produce pulsatile release pills using nanotechnology. 

What are the next steps/ timelines for this research? 

Our next steps are hopefully to look at personalisation of pump therapy, as we strongly believe that one size does not fit all and to apply for funding to perform a larger longer term definitive multicentre trial with pulsatile cortisol replacement therapy.

How can we support this research? 

Spread the word about the results from the clinical trial via social media, so that patients, doctors, industry, and funding bodies know about this work and the technology that is available. Addison’s may be rare, but it is important, spread the word!

Share the Journal of Internal Medicine publication on The PULSES trial

If people feel the pump may be suitable for themselves, how can they access this treatment? 

The pulsatile cortisol pump therapy is at present still a research tool, where it has only been used in trials for up to 6 weeks. We do not have any formal long-term safety or efficacy data. However as people in the Addison's community are aware, there are some individuals who have self-funded a pump privately. This is where patients are able to be considered on a case-by-case basis. The protocol for the pulsatile cortisol pump infusion therapy is in the Journal of Internal Medicine paper which is discussed in this article, if you would like to take this research to your own endocrinologist to discuss as a treatment option.

In those individuals there has been no longer-term consequences noted, but this is anecdotal. You can read a case study kindly provided by Joe Miles, a 40-year-old male who has Addison's and uses the Crono-P pump (pulsatile cortisol pump infusion therapy) here on the Bristol University website. People on pumps also share their experiences on the ADSHG online forum if you would like to speak with others about their journey in starting pump therapy.

We have previously when contacted by individual endocrinologists given advice to adjust the pump settings but at this point it is not widely available. In addition, hydrocortisone is not licensed to be given subcutaneously and so must be used off licence. This is why we continue to persevere with this vital work, to gain further funding for the next stages of research, all with the aim to make this treatment more easily accessible. Please direct your endocrinologist to the Journal of Internal Medicine paper if you would like to speak more with them about pulsatile cortisol pump therapy.

 

Meet the Researcher

Thank you for speaking with us Dr Georgina Russell! Tell us a bit about your background and how you became involved in the research?

My main driving force for my research is from my patients, Endocrinology is unusual in that it is primarily an outpatient-based speciality.

"I noticed that my patients on paper were fine but when I listened to them, they would describe not feeling right, having brain fog, and symptoms they could not quite put their finger on. This intrigued me and at that time steroid replacement therapy had been static for decades."

As a junior doctor, I was then introduced to Professor Stafford Lightman, a professor of Neuroscience at the University of Bristol and the rest is history! 

Tell us a bit about your background and research?

I am currently a consultant endocrinologist in Bristol, I did my undergraduate medical degree at Cardiff as well as an intercalated BSc in Psychology. After finishing my training, I moved to the South West and became interested in Endocrinology. I was introduced to Professor Stafford Lightman and was fascinated by his behavioural work. I therefore decided to do a PhD in his laboratory examining human cortisol physiology. My main interest is in translational neuroscience, this means that I work closely with basic scientists, taking their cutting-edge findings and translating their findings into something that is clinically relevant to patients.

I am particularly passionate about the effects of glucocorticoid dynamics on cognition, emotion and sleep. I have used novel approaches such as fMRI combined with more standardised tests to investigate the effect of physiological aka “normal” glucocorticoid dynamics in healthy volunteers. Following on from this to try to understand how disruption of these pathways can lead to disease states. Using this knowledge to work on new pathways to improve the diagnostic, treatment and monitoring pathways of patients as well as examining the effects of glucocorticoid based therapeutics in patients and identifying strategies to decrease side effect burden.

What are your research highlights to date? 

We now know so much more about normal steroid hormone patterns and levels, previously this was difficult as we could only measure hormone levels using blood samples in a research unit or in a hospital. This is not real life, we know also have the technology to perform continuous hormone sampling using a portable collection device - U-RHYTHYM. This means that we can measure hormone levels whilst a person is at work, with friends and family, even during sleep. This means that we can get an even better understanding of what normal hormone physiology is and use this information to inform hormone replacement in the future or to diagnose endocrine disease. 

Research DOI: 10.1126/scitranslmed.adg8464

 

What are your plans for the future?  

To enjoy getting this research out there, I am already thinking about the future and next best steps. COVID and Brexit has turned everything on its head and funding is more challenging than ever but watch this space!

Do you have any advice that you would give to other researchers?

Clinical research is full of highs and lows, at times I have wanted to give up as I have struggled to get funding, met individuals who have not believed in me or the importance of my work, but keep persevering. I stupidly once decided I wanted to climb mount Kilimanjaro, I really struggled with it, my guide Minha was incredibly wise and said “Polepole, slowly, slowly, one step in front of the other and you will get there”. I think his advice still holds true!

	Author: Dr Georgina Russell - visit her research website X (previously known as Twitter): @GeorginaRu8558
	Research paper: '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

Professor John Wass MD MA FRCP, Chair of the Addisons's Clinical Advisory Panel and Professor of Endocrinology, Oxford University and Dominic Hargreaves MBE, ADSHG Chair of Trustees comment:

"The Addison's Disease Self Help Group (ADSHG) welcomes the encouraging findings of this study. Many of our members feel very frustrated that despite feeling unwell on their current cortisol replacement regimen, they are severely limited in further treatment options. If, as the PULSES study suggests, pulsatile cortisol pump therapy provides improved quality of life and long-term treatment – this provides both our patient community and the doctors looking after them with vital hope for improvements in cortisol replacement regimens and the future of those living with the condition."

"We are grateful to Dr Georgina Russell, Professor Stafford Lightman and all of the PULSES team who have contributed to this important study. The impact of poorly treated Addison's disease should not be underestimated, Addison’s can be fatal, so effective, accessible and economical treatments improve daily health, emotional wellbeing and reduce emergency admissions – improving the lives of those with Addison's and reducing costs to the NHS."

To learn more about hydrocortisone infusion pumps, please visit our A-Z of Addison's Resources page, for links to previous articles and research.

Want to stay updated on research progress and hear the latest ADSHG news? Join our charity to become a member to hear direct.

JOIN THE ADSHG

Connect on social media! Follow us on X / Twitter, Facebook, Instagram, LinkedIn, Threads, TikTok and YouTube.