ORF35-05 - Impact of Cortisol Circadian Rhythm on Psychological Well-Being and Functional Outcomes in Treated Endogenous Cushing Syndrome: A Cross-Sectional Study

Cushing syndrome (CS) is associated with psychological and functional disturbances that often persist despite biochemical control, as defined by normalization of 24-hr urinary free cortisol (UFC). Restoration of cortisol circadian rhythm, assessed by late-night salivary cortisol (LNSC), may represent an additional endpoint of long-term recovery, yet its clinical relevance following treatment remains incompletely characterized. We conducted a cross-sectional study of 90 patients with endogenous CS who achieved surgical remission or biochemical control for ≥6 months and stratified them into three groups: A: normal LNSC (n=52), B: abnormal LNSC (n=19), and C: on long-term glucocorticoid (GC) replacement (n=19) due to persistent adrenal insufficiency. Patients completed the Hospital Depression and Anxiety Scale (HADS), CushingQoL questionnaire, and Nottingham Health Profile (NHP). Patients with normal LNSC had lower anxiety and depression scores compared to those with abnormal LNSC (HADS-Anxiety median 4 vs 7, HADS-Depression 2.5 vs 6, both p=0.006) and those on GC replacement (HADS-A median 8, HADS-D 9, both p≤0.02). Disease-specific quality of life (QoL) was better in patients with normal LNSC compared to those with abnormal LNSC (mean score 67.5 vs 52.5, p=0.014) and on GC replacement (39.5, p< 0.001) in the psychosocial but not physical domain, as assessed by CushingQoL. On NHP, normal LNSC was associated with lower (better) Emotional Reaction scores (median 0 vs 24 vs 34, p=0.002, A vs B; p=0.005, A vs C) and Physical Abilities (0 vs 22 vs 15.5, p=0.011, A vs B; p=0.014, A vs C). Patients on GC replacement had worse Energy Level (0 vs 37, p=0.001, A vs C; 37 vs 63, p=0.014, B vs C) and Sleep scores (13 vs 56, p< 0.001, A vs C). In multivariable analyses excluding GC-treated patients, LNSC normalization remained independently associated with better HADS, CushingQoL total and psychosocial, NHP Emotional Reaction, Social Isolation, and Physical Abilities, with stronger associations than treatment modality. While the prevalence of diabetes (DM) or pre-DM at diagnosis did not differ between subgroups, patients with abnormal LNSC in the study had higher rates of DM or pre-DM (68.4%) compared to those with normal LNSC (34.6%, p=0.011) and on GC replacement (15.8%, p=0.001), suggesting that ongoing circadian dysregulation may contribute to persistent metabolic risk. Among patients with surgically remitted Cushing disease (n=43), 18.6% failed to normalize LNSC despite absence of clinical or biochemical evidence of early recurrence and exhibited worse psychological outcomes than those with normal LNSC, suggesting the presence of a previously unrecognized clinical phenotype. These findings identify cortisol circadian rhythm restoration as a clinically meaningful dimension of psychological recovery in treated CS and support LNSC normalization as a therapeutic goal beyond UFC normalization.