New treatments demonstrate the importance of timing. A first-of-its-kind hormone replacement therapy that more closely replicates the body's natural circadian and supracircadian rhythms of hormones has been shown to improve symptoms in people with adrenal disease. Results from the clinical trial led by the University of Bristol were recently published in the Journal of Internal Medicine.
Low levels of a key hormone called cortisol are often the result of conditions such as Addison's disease and congenital adrenal hyperplasia. Cortisol regulates a range of important processes, from cognitive processes such as memory formation, metabolism and immune response, to blood pressure and blood sugar levels. When it's too low, it can trigger symptoms such as debilitating fatigue, nausea, muscle weakness, dangerously low blood pressure and depression. Although rare, these adrenal disorders require alternative treatment with daily hydrocortisone for life.
Although existing oral hormone replacement therapies can restore cortisol levels, they can still impair patients' quality of life. Scientists believe this is because current treatments do not mimic the body's normal physiological timing, missing the expected rise in cortisol and lacking its underlying supracircadian and circadian rhythms.
The new 'PULSES' therapy is the culmination of a decade of research by the Bristol team and aims to provide patients with an alternative to standard hydrocortisone via a pump that more closely mimics the natural rhythmic secretion pattern of cortisol. A pulsatile subcutaneous pump achieved encouraging results in its first clinical trial.
In the six-week, double-blind PULSES trial, 20 patients with adrenal insufficiency aged 18 to 64 years were evaluated and received regular doses of hydrocortisone replacement therapy, either by pump or as standard oral therapy three times daily.
Although only psychological and metabolic symptoms were assessed during the trial, the results showed that pump therapy reduced patients' fatigue by about 10%, improved their mood, and increased their energy levels by 30% after waking up in the morning, a critical time that many patients struggle with. The patients' MRI scans also revealed changes in the way the brain processes emotional information.
Dr Georgina Russell, first author of the study and honorary lecturer at the University of Bristol Medical School, explained: "Patients receiving cortisol replacement therapy often experience side effects, which make it difficult for them to live a normal life. We hope that this new treatment will bring greater hope to the thousands of patients who do not produce enough hormones."
Stafford Lightman, a neuroendocrinologist and professor of medicine at Bristol Medical School, said: "Other than dose reduction, cortisol replacement therapy has not changed for decades. It is generally accepted that the current Replacement therapies are not physiological due to the lack of pre-awakening surges, supracircadian rhythmicity, and post-dose supraphysiological peaks. The new therapy clearly shows that the timing of cortisol administration - consistent with the body's own rhythmic pattern of cortisol secretion - is important for normal cognition and behavior. Our findings support hormone therapy that mimics natural physiology and is one of the first major advances to date in the treatment of adrenal insufficiency."
PULSES trial participant Joe Miles explains: "The CronoP pump changed my life. While participating in the PULSES study, I noticed a very rapid improvement with the CronoP pump compared to the pills. I went from feeling tired all the time to suddenly having more energy. After the PULSES study, I had to take the pump off But I just couldn't bear to feel like I was back to where I was, so I decided to write to as many doctors as I could and get them to give me a private prescription. I've been using it for six years now and have introduced the pump to a number of other Addison's patients and they all say it has changed their lives, in some cases, from being seriously ill to feeling better than they did years ago."
Dr Russell said: "Around 1% of the UK population are taking steroids at any one time and these people may experience debilitating psychological side effects. This trial shows that brain function can be disrupted even at a physiological level, so when considering any type of steroid treatment we need to explore not only the dose of steroids but also the mode of administration."