Metyrapone-associated improvements in health-related quality of life in Cushing's syndrome

OBJECTIVE: This analysis describes the evolution of health-related quality of life (HRQoL) over 36 weeks of metyrapone treatment in the PROMPT study, identifying patterns of early, delayed improvement, or persistence using item-level resolution. DESIGN AND METHODS: Longitudinal analysis of patient-reported outcomes from PROMPT (NCT02297945), a prospective, open-label, multicountry study of metyrapone in 49 evaluable adults with confirmed endogenous CS. HRQoL was assessed with the CushingQoL (0-100; higher = better QoL) and Tübingen CD-25 (0-100; higher = worse QoL) at weeks 4, 12, 24, and 36. Item-level analyses characterized the pattern and timing of improvement. Within-patient changes were assessed using the Wilcoxon signed-rank test. RESULTS: Both questionnaires demonstrated significant overall improvement by week 36: CushingQoL increased by 10.4 points (P < .001; 44.7% with ≥10-point improvement), and Tübingen CD-25 decreased by -7.8 points (P = .01). Early responses (by week 12) involved eating behaviour and depression symptoms. Delayed improvements (consolidating at weeks 24-36) were observed in sexual activity, environment, and social domains. Bodily restrictions (-4.3 points, P = .203) and cognition (-6.8 points, P = .143) did not show improvement over the study period. Item-level analysis identified a cluster of symptoms, predominantly psychological health anxiety and physical appearance concerns, where burden remained elevated throughout the 36 weeks despite cortisol normalization. CONCLUSIONS: Metyrapone treatment is associated with meaningful, progressive HRQoL improvements across multiple symptom domains over 36 weeks, with a pattern consistent with rapid cortisol-mediated relief (eating, mood), delayed recovery in social and sexual domains, and persistent residual burden in symptom clusters likely driven by incomplete phenotypic reversal within the study timeframe.