Study highlights potential role of restoring cortisol circadian rhythm in Cushing syndrome recovery
Presenter: Angeliki Theodorou, MD, Memorial Sloan Kettering Cancer Center, New York, NY
Impact of cortisol circadian rhythm on psychological well-being and functional outcomes in treated endogenous Cushing syndrome: a cross-sectional study. Presented June 14, 2026.
Among patients with endogenous Cushing syndrome who achieved surgical remission or biochemical control, those with normal cortisol circadian rhythm had less anxiety and depression and better disease-specific quality of life than those with abnormal cortisol circadian rhythm and those on glucocorticoid replacement therapy, according to this cross-sectional study presented at ENDO 2026.
The findings suggest that restoring cortisol circadian rhythm, assessed by measuring late-night salivary cortisol, may be a clinically meaningful component of psychological recovery in treated Cushing syndrome, according to the investigators. Study results highlight the potential value of normalizing late-night salivary cortisol levels in addition to normalizing urinary free cortisol levels.
Cross-sectional study highlights recovery marker limitations
Cushing syndrome is associated with psychological and functional disturbances that often persist despite biochemical control. Although normalization of 24-hour urinary free cortisol is the standard biochemical marker of disease control in Cushing syndrome, many patients continue to experience persistent neuropsychiatric symptoms, cognitive dysfunction, sleep disturbances, fatigue, and impaired quality of life. This highlights the limitations of urinary free cortisol as the sole indicator of recovery, according to the investigators.
This cross-sectional study enrolled 90 patients with endogenous Cushing syndrome who achieved surgical remission or biochemical control for at least 6 months. Investigators stratified participants into three groups:
- Those with normal late-night salivary cortisol values (n = 52)
- Those with abnormal late-night salivary cortisol values (n = 19)
- Those on long-term glucocorticoid replacement due to persistent adrenal insufficiency (n = 19).
Participants completed the Hospital Depression and Anxiety Scale (HADS), the CushingQoL questionnaire, and the Nottingham Health Profile (NHP).
Better outcomes when late-night salivary cortisol was normal
Participants with normal late-night salivary cortisol levels consistently scored better across the board, with statistically significant differences from the other two groups in a variety of measures:
|
Measure |
Patients with normal late-night salivary cortisol values |
Patients with high late-night salivary cortisol values |
Patients on glucocorticoid replacement |
|
Median HADS anxiety scoresa |
4 |
7 |
8 |
|
Median HADS depression scoresa |
2.5 |
6 |
9 |
|
Mean CushingQoL psychosocial domain scoresb |
67.5 |
52.5 |
39.5 |
|
Median NHP emotional reaction scoresb |
0 |
24 |
34 |
|
Median NHP physical abilities scoresa |
0 |
22 |
15.5 |
|
Median NHP energy level scoresa |
0 |
37 |
63 |
|
Median NHP sleep scoresa |
13 |
|
56 |
|
aLower is better bHigher is better |
|||
In multivariable analyses excluding patients receiving glucocorticoid replacement therapy, normal late-night salivary cortisol concentrations remained independently associated with lower anxiety and depression scores and better disease-specific quality of life, emotional well-being, social functioning, and physical abilities.
While the prevalence of diabetes or prediabetes at diagnosis did not differ between subgroups, patients with high late-night salivary cortisol levels had higher rates of diabetes or prediabetes (68.4%) compared with those with normal levels (34.6%, P = .011) and those on glucocorticoid replacement (15.8%, P = .001). This suggests that ongoing circadian dysregulation may contribute to persistent metabolic risk, the investigators reported.
Among the 43 patients with surgically remitted Cushing syndrome, the late-night salivary cortisol level failed to normalize in 8 (18.6%), even though they had no clinical or biochemical evidence of early recurrence. These participants exhibited worse psychological outcomes than those with normal late-night salivary cortisol levels, suggesting they had a previously unrecognized clinical phenotype, according to the investigators.
Disclosures
No disclosures.
References
Theodorou A, Tan EC, Reiner AS, et al. Co-secretion of cortisol and aldosterone in individuals with resistant hypertension: results from the MOMENTUM trial. Presented June 14, 2026.
Theodorou A, Tan EC, Reiner AS, et al. Impact of cortisol circadian rhythm on psychological well-being in treated Cushing syndrome: a cross-sectional study. J Clin Endocrinol Metab 2026; June15:dgag232. doi:10.1210/clinem/dgag232. https://doi.org/10.1210/clinem/dgag232