Glucocorticoid replacement duration after unilateral adrenalectomy for mild autonomous cortisol secretion and adrenal Cushing syndrome: a multicenter cohort study.
Lee Y, Park S, et al. • European journal of endocrinology • 2026
Kaplan-Meier-estimated median time to hypothalamic-pituitary-adrenal axis recovery after unilateral adrenalectomy was 8.2 months in mild autonomous cortisol secretion and 14.8 months in adrenal Cushing syndrome, with older age consistently associated with delayed recovery while biochemical markers contributed differentially by disease subtype.
Key Findings
Results
Median time to HPAA recovery (glucocorticoid discontinuation) was 8.2 months for MACS and 14.8 months for adrenal Cushing syndrome after unilateral adrenalectomy.
Kaplan-Meier-estimated median (95% CI) time to recovery was 8.2 (6.5–9.7) months in MACS
Kaplan-Meier-estimated median (95% CI) time to recovery was 14.8 (13.2–16.3) months in adrenal CS
Study included 139 adults with MACS and 280 with adrenal CS who required postoperative glucocorticoid replacement
HPAA recovery was defined as discontinuation of glucocorticoids
Design was a retrospective multicenter cohort study
Results
Older age was consistently associated with delayed HPAA recovery in both MACS and adrenal Cushing syndrome.
In MACS, older age had HR = 0.72 per 10 years, with age >61 years associated with +94 days longer recovery (τ = 540 days)
In adrenal CS, older age had HR = 0.74 per 10 years, with age >36 years associated with +198 days longer recovery (τ = 1095 days)
Older age was the only factor consistently associated with delayed recovery across both disease subtypes
Associations were evaluated using Cox proportional hazards models and restricted mean survival time (RMST) regression
Results
Higher post-overnight dexamethasone suppression test (ODST) cortisol levels were associated with delayed HPAA recovery in both MACS and adrenal CS, but at different thresholds.
In MACS, post-ODST cortisol >10.0 µg/dL was associated with +113 days to recovery
In adrenal CS, post-ODST cortisol >7.9 µg/dL was associated with +364 days to recovery
Post-ODST cortisol contributed differentially between disease subtypes, with a larger effect size observed in adrenal CS
Results
Higher preoperative ACTH levels were associated with faster HPAA recovery in both MACS and adrenal Cushing syndrome.
In MACS, higher ACTH was associated with faster recovery: HR = 1.61 per log-unit
In adrenal CS, higher ACTH was associated with faster recovery: HR = 1.27 per log-unit, with ACTH >5.1 pg/mL associated with −130 days to recovery
ACTH was a shared predictor of faster recovery across both disease subtypes
Results
In MACS, a higher dehydroepiandrosterone-sulfate (DHEA-S) ratio was associated with faster HPAA recovery.
Higher DHEA-S ratio was associated with faster recovery in MACS: HR = 1.50 per log-unit
DHEA-S ratio >0.61 was associated with −91 days to recovery in MACS
The DHEA-S ratio was identified as a MACS-specific factor and did not appear as a significant factor in adrenal CS
Results
In adrenal Cushing syndrome, higher glycated hemoglobin (HbA1c) was associated with delayed HPAA recovery.
Higher HbA1c was associated with delayed recovery in adrenal CS: HR = 0.81 per 1% increase
HbA1c was identified as a CS-specific factor not observed as significant in MACS
This represents a biochemical marker that contributed differentially by disease subtype
Results
The study distinguished HPAA recovery factors between MACS and adrenal Cushing syndrome, finding that biochemical markers contributed differentially by disease subtype.
Previous data on HPAA recovery were limited by small samples, heterogeneous criteria, and no distinction between MACS and adrenal CS
The multicenter cohort included 139 MACS and 280 adrenal CS patients, representing a larger and more clearly differentiated sample than prior studies
Older age was the only consistently shared predictor, while DHEA-S ratio (MACS) and HbA1c (adrenal CS) were subtype-specific
Cox proportional hazards models and RMST regression were used to evaluate associated factors
What This Means
This research studied how long it takes for the body's stress hormone system — the hypothalamic-pituitary-adrenal axis (HPAA) — to recover after surgical removal of one adrenal gland in patients with cortisol-producing adrenal tumors. The study looked at two groups: those with a milder form of excess cortisol production called mild autonomous cortisol secretion (MACS) and those with full adrenal Cushing syndrome. Recovery was defined as the point when patients no longer needed steroid replacement medication. On average, MACS patients recovered in about 8 months, while adrenal Cushing syndrome patients took about 15 months to recover.
The study identified several factors linked to how quickly or slowly recovery occurred. Older patients took longer to recover in both groups — for example, in adrenal Cushing syndrome, patients older than 36 years took roughly 6 additional months compared to younger patients. Higher levels of a hormone called ACTH before surgery predicted faster recovery in both groups, suggesting the pituitary gland was still somewhat active. Higher cortisol levels on a standard suppression test predicted slower recovery in both groups, but at different cutoff values. Some factors were unique to each group: a higher DHEA-S ratio predicted faster recovery only in MACS patients, while higher blood sugar (HbA1c) predicted slower recovery only in adrenal Cushing syndrome patients.
This research suggests that clinicians may be able to use patient age and specific blood test results before surgery to better predict how long a patient will need glucocorticoid replacement therapy after adrenal surgery. Because recovery timelines differ substantially between MACS and adrenal Cushing syndrome, the findings highlight the importance of treating these as distinct conditions rather than grouping them together when planning postoperative care.
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Lee Y, Park S, Park M, Lee J, Hong A, Ku E, et al.. (2026). Glucocorticoid replacement duration after unilateral adrenalectomy for mild autonomous cortisol secretion and adrenal Cushing syndrome: a multicenter cohort study.. European journal of endocrinology. https://doi.org/10.1093/ejendo/lvag172