TY - JOUR
T1 - Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency
T2 - The PULSES trial
AU - Russell, Georgina
AU - Kalafatakis, Konstantinos
AU - Durant, Claire
AU - Marchant, Nicola
AU - Thakrar, Jamini
AU - Thirard, Russell
AU - King, Jade
AU - Bowles, Jane
AU - Upton, Thomas
AU - Thai, Ngoc Jade
AU - Brooks, Jonathan C.W.
AU - Wilson, Aileen
AU - Phillips, Kirsty
AU - Ferguson, Stuart
AU - Grabski, Meryem
AU - Rogers, Chris A.
AU - Lampros, Theodoros
AU - Wilson, Sue
AU - Harmer, Catherine
AU - Munafo, Marcus
AU - Lightman, Stafford L.
N1 - Funding Information: 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.
PY - 2024/1
Y1 - 2024/1
N2 - 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.
AB - 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.
KW - fMRI
KW - glucocorticoid replacement therapy
KW - primary adrenal insufficiency
KW - ultradian
UR - http://www.scopus.com/inward/record.url?scp=85174231658&partnerID=8YFLogxK
U2 - 10.1111/joim.13721
DO - 10.1111/joim.13721
M3 - Article
C2 - 37857352
AN - SCOPUS:85174231658
SN - 0954-6820
VL - 295
SP - 51
EP - 67
JO - Journal of Internal Medicine
JF - Journal of Internal Medicine
IS - 1
ER -