July 20, 2023 | The dynamics of hormone secretion over the course of a day have largely been a mystery, and at the cost of delayed disease detection that often translates into bad odds for optimal recovery. Endocrine disorders such as Cushing’s syndrome and primary hyperaldosteronism—a relatively common cause of high blood pressure—can take months if not years to diagnose because the symptoms are subtle and common to other diseases, according to Thomas Upton, Ph.D., endocrinologist and clinical research fellow in automated sampling at the University of Bristol in the UK.
Cortisol levels in the body, like most physiological processes, are intrinsically rhythmic and single timepoint measurements from blood or saliva tests can easily miss the patterns—especially changes that occur at night that would require an overnight stay at the hospital, he says. Levels can go up or down in the space of 30 minutes.
In healthy individuals, the circadian rhythm of cortisol ensures levels are higher in the morning anticipating the active part of the day, and lower in the evening coinciding with rest and sleep, says Upton. The “ultradian” rhythm of cortisol, when levels are oscillating over a period shorter than a day, is thought to be important for healthy body function and to cope with everyday stresses such as exercise or the pressure to meet a deadline.
When altered, they can also signal a health-related problem. Picking up on those clues is the goal of a wearable monitor known as U-RHYTHM, now under development by University of Bristol spinout Dynamic Therapeutics, Upton says.
Worn around the waist like a belt, the device employs a catheter that gets painlessly inserted into subcutaneous fat to read adrenal steroid levels every 20 minutes for up to 72 hours, as reported in an article published recently in Science Translational Medicine (DOI: 10.1126/scitranslmed.adg8464). For the study, the research team analyzed samples collected from 214 healthy volunteers living in four different geographies (Norway, Sweden, Greece, and the UK) over 24 hours to create adrenal hormone profiles of healthy people in real-life conditions.
This formed a baseline for normal that allows for the development of new and better ways to diagnose endocrine diseases, says Upton. The analyses looked at individual characteristics such as a person’s sex, age, and body mass index (BMI) and for now found little evidence that they were affecting variability in hormone levels, suggesting other factors are at work.
However, the study did not include people who were either obese or severely underweight, leaving open the controversy about whether BMI changes the way the body handles cortisol. That’s a question for future studies, he says, when new layers of phenotypic data might also reveal unsuspected associations between patient demographics and hormone distribution—and if that varies by other factors such as latitude or the number of daylight hours.
Looking at cortisol variations in people living in real-world settings not only helps advance the study of hormones in disease and chronobiology in general, says Upton. It also showcases the broad potential of the new wearable monitor to recognize disturbances of stress hormone rhythms, which in addition to endocrine diseases are associated with depression, heart disease, obesity, diabetes, and critical illness.
If patients can continuously measure the dynamics of their hormone secretion in their own home, complex inpatient investigations may no longer be needed to arrive at an accurate diagnosis, which is the long-term vision for U-RHYTHM, Upton says. Personalized treatments might also be possible by timing the administration of medication based on the complicated ultradian rhythms of patients, improving therapeutic outcomes.
Microdialysis, the underlying method employed by U-RHYTHM to measure samples, has been around for many years, says Upton. What is unique is that the device collects multiple samples in sequence, creating a time series that allows high resolution profiles to be formed without any blood samples.
The most analogous product on the market would be a wearable sensor for continuous glucose monitoring, which uses an electrochemical filament to convert an electrical signal into a digital readout, Upton says. But glucose is all it measures. And efforts to measure cortisol with sweat sensors have been stalled by technical issues as well as an inability to monitor multiple analytes simultaneously.
U-RHYTHM directly measures the actual hormones in a tissue sample, meaning “we can characterize lots and lots of hormones or metabolites all at once,” says Upton.
The prototype U-RHYTHM device used in the latest published study was well tolerated but admittedly a tad bulky, which annoyed some users when doing activities that involved bending over, says Upton. It was also not waterproof—a feature participants most wished for.
Professor Stafford Lightman, Ph.D., professor of medicine at the University of Bristol, was the original inventor of U-RHYTHM that a decade ago was a hand-built prototype further developed under an EU Horizon grant in 2016, Upton says. A smaller and lighter-weight version of the device has already been created by design and engineering company Designworks Windsor (UK), which has been a partner on the project from the early days and will be responsible for building U-RHYTHM into a regulatory-grade wearable.
Like bulky mobile phones that were commonplace in the 1980s, says Upton, U-RHYTHM is likely to get increasingly smaller over time. Even as it was, study volunteers had no bad reactions to the device and were able to sleep and go about their usual daily activities (e.g., drive a car, walk the dog) as hormone samples were being continuously collected from their belly. “We asked them not to do anything too vigorous because we didn’t want anything to get damaged... [and] to keep the sampling experience low key.”
Cushing’s syndrome, where the body makes too much cortisol, is among a half dozen of the most commonly occurring conditions related to the adrenal glands. It can be hard to diagnose because other illnesses have similar symptoms, says Upton, and only many sequentially repeated blood and saliva tests could potentially capture the rhythm of changing cortisol levels.
Beyond endocrine diseases, circadian and ultradian rhythm disturbances are risk factors for the development of suboptimal outcomes of diabetes, he notes. They are also important problems among otherwise healthy people who do shift work or are under prolonged periods of stress due to personal circumstances.
As a follow up to their investigation on healthy volunteers, Upton and his colleagues conducted a yet-to-be-published study comparing baseline hormone profiles to those of people with Cushing’s syndrome and primary hyperaldosteronism (associated with morbidities such as coronary artery disease, stroke, and heart attack), as well as people whose body is unable to make cortisol due to a rare autoimmune disorder known as Addison’s disease.
For individuals with Addison’s disease, the practice for many years has been to treat it with oral doses of hydrocortisone once or several times a day to replace what would normally be secreted by the adrenal glands, says Upton. But patients still feel unwell and overall have worse outcomes, and die more often, than people without the condition—the belief being that the drugs simply aren’t being administered at a time that matches fluctuations in cortisol levels that are unique to an individual.
Many people without Addison’s disease also have under-functioning adrenal glands, he adds, most commonly because of taking glucocorticoid medications for other medical conditions. It may be possible to use U-RHYTHM in these instances to ensure cortisol is being properly rather than arbitrarily replaced.
As envisioned, the device could one day be deployed early in a diagnostic workup to help pinpoint the presence of a particular disease based on an individual’s hormone profile. As part of the current project, mathematical and machine learning tools have been developed to quantify normal variation, and these will serve as a basis for new clinical decision support tools that could distinguish a healthy from an abnormal profile at the point of care.
U-RHYTHM is for now a research device and will require further clinical trials and practical improvements to demonstrate viability and enhance the user experience, says Upton. He imagines it will be another five years before the wearable gets the blessing of the U.S Food and Drug Administration and CE/CA marking certification in the UK to be used as a clinical diagnostic tool.