Timing Cortisol Therapy Could Improve Adrenal Insufficiency

Liam Davenport

April 19, 2018

Timing cortisol replacement therapy to better replicate the secretion patterns of individuals with normal hormone levels could result in better outcomes, with significant improvements in cognitive function, the results of a small UK trial in healthy volunteers suggest.

Glucocorticoids such as cortisol are key regulators of cognitive, metabolic, and immunologic homeostasis. In the basal physiological state, they are released in a 24-hour circadian rhythm with a peak soon after wakening.

These dynamic oscillations, which are seen in both the blood and peripheral tissues such as the brain, modify synaptic activity and maintain stress responsiveness.

Currently those with adrenal insufficiency, which is a life-long condition, take daily hydrocortisone replacement therapy, but it does not reproduce physiologic hormone pulses and is associated with reduced quality of life, adverse metabolic and cardiovascular risk profiles, and increases in proinflammatory cytokines, alongside reduced physical activity and motivation and increased fatigue.

In this study of 15 healthy men, timing cortisol therapy in line with normal human patterns of secretion resulted in significant improvements in working memory when the participants were under high cognitive demand.

Moreover, the research reveals that individuals given the same dose of cortisol but without taking into account normal secretion patterns had poorer sleep quality than the other participants.

The study was published online April 9 by Konstantinos Kalafatakis, MD, PhD, of the University of Bristol, UK, and colleagues in the Proceedings of the National Academy of Sciences.

"The pharmaceutical industry has invested heavily in providing new and more potent drugs," said senior author Stafford L Lightman, MD, PhD, Henry Wellcome Laboratories of Integrative Neuroscience and Endocrinology, University of Bristol, UK, in a press release by the institution.

"However, our findings suggest that, rather than needing any new drugs, it is the timing of cortisol delivery, in line with the body's own rhythmic pattern of cortisol secretion, that is important for normal cognition and behavior."

This, he says, points to the potential of chronobiology for improving therapies "by taking account of the importance of the pattern of drug presentation to the tissues of the body."

Lightman adds, "This could be important not only for improving cortisol replacement therapy but also has major implications [for] understanding the role of glucocorticoid dynamics in stress and psychiatric disease."

Pulsatile Hydrocortisone Mimicking Normal Secretion Produces Best Results

To determine whether different patterns of cortisol administration had differing effects on cognitive and behavioral processes, the researchers conducted a randomized, double-blind, placebo-controlled crossover study involving 15 healthy male volunteers aged 20 to 33 years who had no history of neuropsychiatric disease.

All men were given the cortisol biosynthesis blocking agent metyrapone and a fixed daily dose of hydrocortisone 20 mg in one of three ways:

  • continuous hydrocortisone infusion, which followed a normal circadian rhythmicity but lacked any physiological ultradian rhythm (SCC group);

  • pulsatile hydrocortisone infusion, which followed a normal circadian and ultradian rhythmicity (SCP group); and

  • current optimal oral hydrocortisone replacement therapy, with suboptimal circadian and ultradian rhythms (PO group).

During each 5-day treatment period, participants answered nine questions about self-perceived reactivity and feelings of wellbeing at multiple time points.

In addition, they underwent functional MRI and completed a battery of questionnaires examining sleep quality and working memory (N-Back Task).

While there was no overall impact on either positive or negative affect in the SCC and SCP groups, PO individuals had higher negative mood ratings versus those in the SCP group, at a mean difference of 3.15 (P = .009).

The results also showed that, compared with the SCP and PO groups, individuals in the SCC group had poorer sleep quality, with more and/or longer periods of restlessness and wakefulness.

In terms of working memory, SCP individuals retained the same performance across the two- and three-back sessions, in contrast to the other two treatment groups, where performance in three-back sessions was poorer compared with the two-back sessions.

Overall, compared with the other treatments, "oscillating pulsed hydrocortisone (SCP) dosing most closely replicates normal human patterns of cortisol secretion," the researchers say. "Study participants performed significantly better across the range of cognitive tasks they were assigned during this treatment and were observed to have improved working memory capacity under high-cognitive demands."

"Current optimal cortisol replacement therapies for patients with primary or secondary adrenal insufficiently are associated with poor psychological status," they add.

So these results suggest "that closer attention to aspects of chronotherapy will benefit these patients and may also have major implications for improved glucocorticoid dynamics in stress and psychiatric disease."

"This is an ambitious study and its findings offer a welcome insight into the quality of life impairments experienced by many adrenal patients," said Katherine White, Chair of the Addison's Disease Self-Help Group charity in Guildford, UK.

"The study's reported conclusions suggest an exciting potential for chronobiological approaches in endocrine replacement therapy to improve cognitive function and sleep quality for adrenal patients," she added.

Future studies in patients with adrenocortical insufficiency are now needed, stress the authors, not only to help reduce the morbidity of current replacement regimens, "but also to provide evidence from longer-term modification of replacement cortisol rhythmicity for improved brain function and a more personalized approach to glucocorticoid therapeutics."

Funding for the research was provided by the Medical Research Council and Wellcome Trust. The authors have reported no relevant financial relationships.

Proc Natl Acad Sci U S A. Published online April 9, 2018. Abstract

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