Impact of cortisol circadian rhythm on psychological well-being in treated Cushing syndrome: a cross-sectional study

CONTEXT: Patients with Cushing syndrome (CS) often experience impaired quality of life (QoL) and mood despite biochemical control. The relationship between late-night salivary cortisol (LNSC) and psychological outcomes remains poorly characterized. OBJECTIVE: Assess QoL and mood outcomes in biochemically controlled CS patients based on circadian rhythm restoration. DESIGN: Cross-sectional. SETTING: Tertiary-care center. PARTICIPANTS: Ninety treated, biochemically controlled patients with CS (84 Cushing disease (CD); 6 adrenal CS), stratified into three groups: normal LNSC (Group A), abnormal LNSC (Group B), on long-term GC replacement (Group C). MAIN OUTCOME MEASURES: Hospital Anxiety and Depression Scale (HADS), CushingQoL questionnaire, Nottingham Health Profile (NHP). RESULTS: Group A had lower HADS-Anxiety (4 vs 7, A vs B; p=0.006) and (HADS-Depression 2.5 vs 6 vs 9, A vs B; p=0.006, A vs C; p<0.001). QoL was better in group A vs C in psychosocial (67.5 vs 39.5; p<0.001) and physical (63.9 vs 44.3; p=0.005) domains. Group A had better Emotional Reaction (0 vs 24; p=0.002), A vs B; Energy Level (0 vs 63; p=0.001) and Sleep (13 vs 56; p<0.001), A vs C. In multivariable analyses excluding group C, LNSC normalization was consistently associated with better outcomes in all HADS domains, CushingQoL psychosocial, NHP Emotional Reaction, Social Isolation, Physical Abilities and Home Relationships. Group B had the highest diabetes rate. Among patients with surgically remitted CD, 18.6% had abnormal LNSC, characterizing a previously unrecognized clinical phenotype. CONCLUSIONS: In biochemically controlled CS, LNSC normalization correlates with QoL, mood, and metabolic outcomes, and could represent a therapeutic target.