A first-of-its kind hormone replacement therapy that more closely replicates the natural circadian and ultradian rhythms of hormones has been shown to improve symptoms in patients with adrenal conditions.
Results from a study led by the University of Bristol have been published in the Journal of Internal Medicine.
Around 8500 people in the UK have primary adrenal insufficiency, and around 10,000 people have secondary adrenal insufficiency. Low cortisol levels typically arise as a result of conditions such as Addison's disease and congenital adrenal hyperplasia and can trigger symptoms of debilitating fatigue, nausea, muscle weakness, dangerously low blood pressure, and depression.
Dr Georgina Russell, honorary lecturer at the University of Bristol Medical School, and lead study author, highlighted that "approximately 1% of the UK population is taking steroids at any moment in time." She explained that these individuals can experience side effects — including "debilitating" psychological symptoms — which made it "difficult for them to lead normal lives."
Moreover, primary adrenal insufficiency (PAI) mortality and morbidity remained "unacceptably high," alerted the authors.
Commenting on behalf of the Addison's Disease Self Help Group (ADSHG) for Medscape News UK, Dominic Hargreaves MBE, and John Wass, professor of endocrinology at the University of Oxford, highlighted that many patients "feel very frustrated that despite feeling unwell on their current cortisol replacement regimen, they are severely limited in further treatment options." The impact of poorly treated Addison's disease should "not be underestimated," they added.
Current Treatment Approach Does Not Mimic Physiological Timing
These adrenal conditions required lifelong daily glucocorticoid replacement therapy — typically oral hydrocortisone given in divided dosages to mimic circadian variation.
"Existing oral hormone replacement treatment can restore cortisol levels, but is still associated with an impaired quality of life for patients," stressed the study authors. This, they explained, is believed to be because the current treatment approach doesn't mimic the body's normal physiological timing, missing cortisol's anticipatory rise and lacking its underlying ultradian and circadian rhythms.
Joint lead author Stafford Lightman, a neuroendocrinology expert and professor of medicine at Bristol Medical School, highlighted that "besides reduction in dosage, cortisol replacement has remained unchanged for many decades." He pointed out that it was widely recognised that current replacement therapy was "unphysiological due to its lack of preawakening surge, ultradian rhythmicity, and postdose supraphysiological peaks."
Pump Replicates More Closely Natural Rhythmic Secretion Pattern
For the study, the researchers set out to compare usual dose hydrocortisone replacement therapy administered either via a pump or the standard three times daily oral treatment, and the effect on quality of life, mood, functional neuroimaging, behavioural/cognitive responses, sleep, and metabolism.
A new pulsatilite therapy was developed and designed to deliver standard hydrocortisone replacement to patients subcutaneously via a pump. This replicates more closely cortisol's natural rhythmic secretion pattern, according to the authors.
Twenty participants aged 18 to 64 years with adrenal insufficiency conditions took part in the randomised, crossover, double-blinded and placebo-controlled feasibility study, and over 6 weeks, psychological and metabolic symptoms were assessed.
Promising Results
"The pulsatile subcutaneous pump revealed promising results in its first clinical trial," enthused the authors, who reported that subcutaneous pump administration of usual dose hydrocortisone provided "safe" circadian and ultradian cortisol replacement and was well tolerated.
The researchers found that pulsatile hydrocortisone altered "both neural dynamics and behavioural responses" related to emotional processing, visual stimulation, and resting conditions. It also improved physical and mental fatigue (a decrease in fatigue of approximately 10%), improved positive mood, and increased patient energy levels by 30% first thing in the morning — which the authors highlighted as "a key time frame when many patients struggle."
Patient MRI scans also revealed alteration in the way that the brain processed emotional information.
However, irrespective of treatment, participants had significant sleep disturbances, and treatment modality had no effect on sleep quality, although improved behaviour postawakening, and ease of awakening, was seen on pulsatile therapy, the authors found. There was also no effect on either working memory or metabolic parameters over the 6-week trial.
Timing of Cortisol Delivery "Crucial"
The study showed that the pattern of cortisol presentation, even at an assumed physiological dose, influenced neuronal processes, which supported the administration of hormone therapy that mimicked physiology, the authors said. They expressed that dosage was "not the only variable that is important," and it was vital to "recapitulate normal ultradian physiology" to truly minimise side effects.
"Even at physiological levels, brain functioning is disrupted and we need to explore not only the dose but the pattern of steroids delivery when considering any type of steroid treatment," urged Dr Russell.
Professor Lightman voiced his belief that the new therapy clearly showed that the timing of cortisol delivery — in line with the body's own rhythmic pattern of cortisol secretion — was crucial 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," he proclaimed.
Dr Russell said the new therapy could offer greater hope for the thousands of people living with hormone insufficiency conditions.
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Editor's note: This article was updated on 24 October to include comments by the Addison's Disease Self Help Group.
