In an adult who has undergone curative surgery for Cushing’s syndrome (pituitary adenoma resection, adrenalectomy, or treatment of ectopic ACTH production), what is the recommended schedule for post‑operative ACTH and cortisol monitoring?

Post-Operative ACTH and Cortisol Monitoring After Curative Surgery for Cushing's Syndrome

After curative surgery for Cushing's syndrome, begin surveillance only after HPA axis recovery, then perform annual late-night salivary cortisol testing lifelong, with more intensive monitoring (every 6 months for at least 2 years) in the early post-operative period. 1, 2

Critical Pre-Monitoring Requirement

• Do not attempt any surveillance testing while patients remain on exogenous glucocorticoids (hydrocortisone, prednisone, etc.) as these suppress ACTH and endogenous cortisol production, making interpretation impossible 2
• Testing can only begin after HPA axis recovery, which requires discontinuation of glucocorticoid replacement therapy 1, 2
• If patients require chronic glucocorticoids for other medical conditions and cannot safely discontinue, focus on clinical and imaging surveillance with annual pituitary MRI to assess for tumor regrowth 2

Recommended Surveillance Schedule

Early Post-Operative Period (First 2 Years)

For adults:

• Begin monitoring at 6 months post-surgery if HPA axis has recovered 3
• Frequency may be dictated by clinical scenario, with more frequent evaluation if clinical suspicion of recurrence exists 3

For children and adolescents:

• Perform 6-monthly clinical examination, 24-hour urinary free cortisol (UFC), electrolytes, and morning serum cortisol for at least 2 years 3
• This more intensive pediatric schedule reflects the 6-40% recurrence rate in this population 3

Long-Term Surveillance (After 2 Years)

• Annual clinical assessment is mandatory for life in all patients, as recurrence can occur decades after apparent cure 3, 1
• Late-night salivary cortisol (LNSC) annually is the most sensitive test for detecting early recurrence 1, 2
• Serial LNSC measurements are advised due to wide variability in results 1, 2

Optimal Testing Sequence for Detecting Recurrence

The biochemical tests become abnormal in a predictable sequence during recurrence:

1. Late-night salivary cortisol becomes abnormal first (most sensitive early marker) 1, 2
2. 1-mg dexamethasone suppression test becomes abnormal second 1
3. 24-hour urinary free cortisol becomes abnormal last 1, 2

This hierarchy explains why annual LNSC is the preferred screening test, as it detects recurrence earliest 1, 2

Special Considerations After Bilateral Adrenalectomy

• Monitor plasma ACTH levels and perform serial pituitary imaging starting at 6 months after surgery 3
• More frequent evaluation may be necessary if clinical suspicion of corticotroph tumor progression exists (Nelson's syndrome) 3
• Corticotroph tumor progression occurs in 25-40% of patients after 5-10 years following bilateral adrenalectomy 3

Rationale for Lifelong Monitoring

• Recurrence rates range from 5-35% in adults, with approximately half occurring within 5 years but the remainder developing over 10+ years 1
• In pediatric populations, recurrence rates vary from 6-40%, though most occur within 5 years 3, 1
• The percentage of patients who relapse increases with time, making lifelong surveillance essential 3

Critical Pitfalls to Avoid

• Never interpret LNSC, UFC, or dexamethasone suppression test results while patients are on chronic prednisone or other glucocorticoids, as results will be falsely reassuring due to HPA axis suppression 2
• Do not assume that being on glucocorticoid replacement means the patient is in remission—they may have persistent disease requiring replacement for adrenal insufficiency 2
• Avoid relying on a single LNSC measurement; serial measurements are necessary due to result variability 1, 2
• Do not discontinue surveillance after several years of remission, as late recurrences (>10 years) are well-documented 1