Insomnia and body clock, conceptual image

A cortisol pump under the skin that can mimic changes in how this hormone is naturally secreted could offer benefits over traditional steroid treatment in patients with adrenal insufficiency, a small trial suggests.

The first clinical trial of Crono P pulsatile subcutaneous pump showed no significant impact on the primary outcome of emotional processing using a facial expression recognition task.

However, there were subjective improvements in fatigue and mood compared with traditional steroid treatment.

In addition, functional magnetic resonance imaging (MRI) revealed alterations in how the brains of participants processed emotional information when using the pump.

The U.K. findings, in the Journal of Internal Medicine, suggest that taking timing—or chronobiology—into account could be important when devising treatments.

Specifically, they suggest there is potential for improving endocrine replacement therapy simply by changing the pattern through which drugs are presented to body tissues.

“The new therapy clearly shows that the timing of cortisol delivery—in line with the body’s own rhythmic pattern of cortisol secretion—is important for normal cognition and behavior,” said senior author Stafford Lightman, PhD, from Bristol Medical School.

“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.”

Senior researcher Georgina Russell, PhD, also from the Bristol University Medical School, stressed there could be debilitating psychological side effects for people who take steroids.

“This trial has shown that even at physiological levels, brain functioning is disrupted and that we need to explore not only the dose but the pattern of steroids delivery when considering any type of steroid treatment,” she added.

Cortisol regulates a wide range of physiological functions and low levels can cause fatigue, muscle weakness, low blood pressure and depression.

Patients with adrenal insufficiency, such as Addison’s disease, require long-term glucocorticoid replacement, typically with oral hydrocortisone that is given in divided dosages to mimic circadian variation.

However, this misses the anticipatory awakening rise and does not mimic the oscillating pattern in which pulses of hormone are released multiple times a day.

The PULSES trial aimed to assess the impact of ultradian hormone replacement on emotional processing, fatigue, working memory and metabolic status and was the culmination of 10 years’ work on the subcutaneous device.

The 6-week, randomized, double-blind, crossover feasibility study included 20 individuals, aged 18 to 64 years, with adrenal insufficiency.

Participants received the usual dose of hydrocortisone replacement therapy administered either via the pump or the standard oral treatment three times per day.

Although there was no difference in the primary outcome, several other parameters improved with the pump.

Pulsatile hydrocortisone altered both neural dynamics and behavioural responses relating to emotional processing, visual stimulation and resting conditions.

It reduced fatigue by approximately 10%, with improvements in both physical and mental fatigue.

The pump did not impact sleep quality, with participants having significant sleep disturbances irrespective of treatment.

However, there was improved behavior after waking and in ease of awakening on pulsatile therapy. Participant energy levels increased by approximately 30% first thing in the morning with the pump.

MRI revealed differential neural processing to emotional cues and visual stimulation with the cortisol pump, with the key glucocorticoid-sensitive regions of the left amygdala and insula affected, which are involved in emotional ambiguity.

There were four serious adverse events, including three intercurrent illnesses requiring hospitalization, one of which occurred in a pump user. A planned procedure also occurred in a pump user.

There was a small number of expected adverse events, with infusion site bruising or itching in five instances, three of which were in pump users.

Among cases of intercurrent illness, seven participants required extra steroid use, three involving pump users, while six required no extra steroids of whom four were pump users.

Dr Russell noted that patients on cortisol replacement therapy often have side effects which can make it difficult for them to lead normal lives.

She added: “We hope this new therapy will offer greater hope for the thousands of people living with hormone insufficiency conditions.”

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