Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency:The PULSES trial

Russell, Georgina, Kalafatakis, Konstantinos, Durant, Claire, Marchant, Nicola, Thakrar, Jamini, Thirard, Russell, King, Jade, Bowles, Jane, Upton, Thomas, Thai, Ngoc Jade, Brooks, Jonathan C.W. ORCID: https://orcid.org/0000-0003-3335-6209, Wilson, Aileen, Phillips, Kirsty, Ferguson, Stuart, Grabski, Meryem, Rogers, Chris A., Lampros, Theodoros, Wilson, Sue, Harmer, Catherine, Munafo, Marcus and Lightman, Stafford L. (2024) Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency:The PULSES trial. Journal of Internal Medicine, 295 (1). pp. 51-67. ISSN 0954-6820

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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.

Item Type: Article
Additional Information: Funding Information: We would like to thank all our participants, the Addison's Disease Self-Help and Living with CAH support groups. We would also like to thank Applied Medical Technology for their support in pump development and P1 Vital Limited. This work was supported by the Medical Research Council, DPFS grant, MR/J012548/1 and the Above and Beyond Charities UHBristol, 04/2014-15. CJH was supported by the Oxford Health NIHR Biomedical Research Centre. Funding Information: Medical Research Council, DPFS grant, MR/J012548/1 and the Above and Beyond Charities UHBristol, 04/2014‐15; Oxford Health NIHR Biomedical Research Centre Funding Information: The PULSES trial was a 6‐week randomised, double‐blinded, crossover and placebo‐controlled study of usual dose hydrocortisone replacement therapy (range 20–30 mg) delivered as either pulsed subcutaneous pump treatment or standard three times daily oral at the University Hospital Bristol and Weston NHS Foundation Trust (UHBristol) in the United Kingdom. Local institutional and NHS Health Research Authority and Medicines Healthcare Regulatory approval was obtained. The study was sponsored by UHBristol (identification code: ME/2011/3709) and registered with ICRCTN (identification code: 67193733) and EudraCT (identification code: 2012‐001104‐37). The study was conducted in accordance with the principles of the Declarations of Helsinki and International Conference on Harmonisation E6 guidelines for Good Clinical Practice (GCP). A CONSORT flow diagram is provided in Fig. 1 . Funding Information: We would like to thank all our participants, the Addison's Disease Self‐Help and Living with CAH support groups. We would also like to thank Applied Medical Technology for their support in pump development and P1 Vital Limited. This work was supported by the Medical Research Council, DPFS grant, MR/J012548/1 and the Above and Beyond Charities UHBristol, 04/2014‐15. CJH was supported by the Oxford Health NIHR Biomedical Research Centre. Publisher Copyright: © 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Uncontrolled Keywords: fmri,glucocorticoid replacement therapy,primary adrenal insufficiency,ultradian,internal medicine ,/dk/atira/pure/subjectarea/asjc/2700/2724
Faculty \ School: Faculty of Social Sciences > School of Psychology
Related URLs:
Depositing User: LivePure Connector
Date Deposited: 26 Jan 2024 02:15
Last Modified: 26 Jan 2024 02:15
URI: https://ueaeprints.uea.ac.uk/id/eprint/94268
DOI: 10.1111/joim.13721

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