Ultradian Hydrocortisone Replacement Alters Neuronal Processing, Emotional Ambiguity, Affect and Fatigue in Adrenal Insufficiency: The PULSES Trial

Overview

Journal J Intern Med

Specialty General Medicine

Date 2023 Oct 19

PMID 37857352

Authors

Georgina Russell

Konstantinos Kalafatakis

Claire Durant

Nicola Marchant

Jamini Thakrar

Russell Thirard

Jade King

Jane Bowles

Thomas Upton

Ngoc Jade Thai

Jonathan C W Brooks

Aileen Wilson

Kirsty Phillips

Stuart Ferguson

Meryem Grabski

Chris A Rogers

Theodoros Lampros

Sue Wilson

Catherine Harmer

Marcus Munafo

Stafford L Lightman

Affiliations

Soon will be listed here.

Abstract

Background: Primary adrenal insufficiency (PAI) mortality and morbidity remain unacceptably high, possibly arising as glucocorticoid replacement does not replicate natural physiology. A pulsatile subcutaneous pump can closely replicate cortisol's circadian and ultradian rhythm.

Objectives: To assess the effect of pump therapy on quality of life, mood, functional neuroimaging, behavioural/cognitive responses, sleep and metabolism.

Methods: A 6-week randomised, crossover, double-blinded and placebo-controlled feasibility study of usual dose hydrocortisone in PAI administered as either pulsed subcutaneous or standard care in Bristol, United Kingdom (ISRCTN67193733). Participants were stratified by adrenal insufficiency type. All participants who received study drugs are included in the analysis. The primary outcome, the facial expression recognition task (FERT), occurred at week 6.

Results: Between December 2014 and 2017, 22 participants were recruited - 20 completed both arms, and 21 were analysed. The pump was well-tolerated. No change was seen in the FERT primary outcome; however, there were subjective improvements in fatigue and mood. Additionally, functional magnetic resonance imaging revealed differential neural processing to emotional cues and visual stimulation. Region of interest analysis identified the left amygdala and insula, key glucocorticoid-sensitive regions involved in emotional ambiguity. FERT post hoc analysis confirmed this response. There were four serious adverse events (AE): three intercurrent illnesses requiring hospitalisation (1/3, 33.3% pump) and a planned procedure (1/1, 100% pump). There was a small number of expected AEs: infusion site bruising/itching (3/5, 60% pump), intercurrent illness requiring extra (3/7, 42% pump) and no extra (4/6, 66% pump) steroid.

Conclusions: These findings support the administration of hormone therapy that mimics physiology.

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