Behind the Research: U-RHYTHM Clinical Research Fellow Dr Thomas Upton updates us on the development of U-RHYTHM, a prototype wearable device to measure hormones, including cortisol levels, in the body over the full 24 hours. The device has the potential to provide both our patient community and the doctors looking after us with important information about cortisol levels over the day and how our replacement therapy can be improved by changes in both dose and timing of treatment. If you’ve been following ADSHG research news, you’ll be aware of the device from previous editions of our magazine, when ADSHG members gave their experiences of participating in the ULTRADIAN study testing the U-RHYTHM wearable device. You can read volunteer Suzanne's experience on our blog. There has been research into how doctors can improve cortisol replacement including new pump therapies and sustained or delayed release preparations of cortisol. But it has been difficult to find a way to measure the effects of these treatments on body levels of cortisol and whether they improve on current standard treatment. Many of our community feel frustrated that despite feeling unwell on their current treatment, there is no way to tell whether their hormone levels are normal over the day. Dr Thomas Upton explains to us below how U-RHYTHM aims to provide the solution to this problem. Research Facts: Disease: Addison’s disease and other diseases affecting the adrenal gland including Cushing’s syndrome and primary aldosteronism. Research Team: Our research has been conducted as part of a Horizon 2020 EU project called ULTRADIAN. This project brings together multiple centres including experts in Addison’s disease in Bristol and the Karolinska Institute in Stockholm. Organisations: University of Bristol, Karolinska Institute, University of Bergen, Evangelismos Hospital Athens, DesignWorks Windsor. Timeline: 2016 - ongoing What are the aims of this research? We have been using the portable sampling system called U-RHYTHM to profile hormones over 24 hours in people as they go about normal activities. We have several aims. Importantly we want to describe and characterise the normal healthy variation in adrenal hormones (including cortisol) across people of different ages. Alongside this we have also sampled patients with endocrine conditions including Addison’s disease. Using all this information we want to both improve the diagnosis and management of endocrine diseases affecting the adrenal gland. Why is this research important? In health, adrenal hormones are secreted in pulses and have complex rhythms that vary across the day. However, this complexity means that measuring a hormone at just one time point tells you very little, can delay diagnosis or simply be very difficult to interpret. Using U-RHYTHM we can measure 72 times per day, including during sleep, to obtain a very detailed picture of hormone dynamics. When we think about a condition like Addison’s disease, hormones are not replaced in a pulsatile manner; rather most people take a tablet just 2-3 per day. This means that there are likely to be times of the day when hormone levels are much higher or lower than you would find in person with normal adrenal function, and normal rhythms of hormones are not replicated. "We believe that in the long-term better hormone replacement modalities are needed for Addison’s disease and U-RHYTHM provides a tool to assist with that." How will findings benefit people with Addison’s disease and adrenal insufficiency? By comparing the observed profiles in Addison’s disease with profiles of healthy normal variation we will be able to quantify for the first time the important differences in cortisol exposure during normal daily life. Rather than generic standard dosing of oral medication, we aim to be able to optimise therapy to best represent healthy physiology and the needs of the individual. In future U-RHYTHM sampling technology could be used to monitor and optimise hydrocortisone pump therapy to recreate pulsatile secretion of hydrocortisone across the day and night. What are your timelines on the project? We began recruitment in mid-2017 and the last participant was recruited in Bristol in early March 2020, just prior to the pandemic. The COVID outbreak has unfortunately caused some delays in our work, but we hope to publish the healthy volunteer results later in 2021, followed by release of the results from the Addison’s cohort and other patient groups. We are actively seeking further grant funding to continue our research. “Meet the Researcher” Thank you for speaking with us Thomas and welcome! Tell us a bit about your background and how you became involved in the research? I have a background in clinical medicine and completed my endocrinology training in New Zealand before moving to the UK to work in Professor Stafford Lightman’s laboratory in Bristol to complete my PhD. I have been working with the U-RHYTHM sampling system as part of the ULTRADIAN project, and more recently, to explore measurement of other metabolites and hormones. What are your research highlights to date? Working on the ULTRADIAN project has been great because all the data we have been generating is novel and interesting. We have been able to describe for the first time how not only cortisol but many adrenal steroids change throughout the day in the tissues of people going about normal activity. In collaboration with the University of Groningen, I have also developed a method for measurement of melatonin as well as cortisol giving as the opportunity to really understand hormones in a circadian context. I have also been very fortunate to work with one of the UK’s top chronobiologists, Professor Debra Skene, on developing methods for measurement of multiple other important metabolites. Tell us more about the Dutch documentary segment on the device. AVROTROS is a Dutch radio and television broadcaster who decided to make a series of healthcare documentaries. They had heard about U-RHYTHM through one of our collaborators in Leiden and were interested enough to come to Bristol to learn more! Suzanne was kind enough to volunteer to be part of program, and so the film crew attended and spoke with her throughout the experience. It was fun to be part of, and I hope it provided some useful information! You can watch AVROTROS' documentary online here. Read Suzanne's blog about participating in the ULTRADIAN study What are your plans for the future? A key priority is to finish the analysis of the ULTRADIAN project and get the results published in academic journals. We have many plans and ideas about how U-RHYTHM could be used to help understand and treat medical conditions and some of those projects are already underway! Do you have any advice that you would give to other researchers? "Research takes time and while delays and upsets can be frustrating, perseverance will pay off." I would recommend that any clinician spend at least some time participating in a research project – the critical skills and knowledge are really helpful for patient practice. Find out more about U-RHYTHM: Ultradian Website - bioRHYTHM Blog - Ultradian Twitter - YouTube Author: Dr Thomas Upton, Post-doctoral Clinical Research Fellow, University of Bristol. Twitter: @HotmasUpton Thank you Thomas and the whole team at U-RHYTHM! We look forward to hearing more about this fantastic research, to provide both our patient community and the doctors looking after us with important information about cortisol levels, and improvements in steroid replacement regimens. 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