How many days after stopping oral prednisolone (corticosteroid) should a patient with suspected exogenous Cushing's syndrome wait before an early morning serum cortisol test can be conducted to screen for the condition?

Timing of Morning Cortisol Testing After Stopping Prednisolone

Wait at least 24-48 hours after stopping prednisolone before sending an early morning serum cortisol to screen for endogenous Cushing syndrome, though longer intervals may be needed for complete clearance of exogenous steroid effects.

Understanding the Interference Issue

The critical problem is that morning cortisol measurements in patients on corticosteroids are not diagnostic because therapeutic steroids interfere with cortisol assays to varying degrees 1. The measurement of exogenous steroids in the cortisol assay varies depending on the specific steroid and assay used 1.

Specific Timing Recommendations by Steroid Type

For Hydrocortisone

• Hydrocortisone needs to be held for 24 hours before endogenous cortisol function can be assessed 1

For Other Synthetic Steroids (Including Prednisolone)

• Other steroids require longer washout periods than hydrocortisone before endogenous function can be accurately assessed 1
• The guidelines specifically state "other steroids for longer" without providing an exact timeframe, but this implies at minimum 48-72 hours or more 1

Practical Clinical Approach

Immediate Steps

• First, confirm complete cessation of all exogenous glucocorticoid use (oral, injections, inhalers, topical preparations) before proceeding with any diagnostic testing 1
• Consider that topical hydrocortisone preparations can contaminate saliva samples and interfere with testing 1

Optimal Testing Strategy After Steroid Discontinuation

For screening endogenous Cushing syndrome after stopping prednisolone:

1. Wait a minimum of 3-7 days after stopping prednisolone to allow for adequate clearance, given that prednisolone has a longer duration of HPA axis suppression than hydrocortisone 1

2. Consider using alternative screening tests that may be less affected by recent steroid use:

   • Late-night salivary cortisol (performed at least 2-3 times) 1
   • 24-hour urinary free cortisol (at least 2-3 collections) 1
   • 1-mg overnight dexamethasone suppression test 1, 2

3. If morning cortisol is used, ensure the patient has been off prednisolone for at least one week to minimize interference 1

Important Caveats and Pitfalls

Assay-Specific Considerations

• Immunoassays may show cross-reactivity between cortisol, cortisone, and synthetic corticosteroids, potentially causing false-positive results 3
• Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is more specific and only measures cortisol, avoiding cross-reactivity issues 3

HPA Axis Recovery Considerations

• Patients on chronic corticosteroid therapy may have suppressed HPA axis function that persists for weeks to months after discontinuation 1
• In patients with suspected adrenal insufficiency from prior steroid use, the HPA axis should be tested for recovery after 3 months of maintenance therapy or complete discontinuation 1
• Consider consulting endocrinology for recovery and weaning protocols in patients with symptoms of adrenal insufficiency after stopping corticosteroids 1

Clinical Context Matters

• If the patient was on high-dose or prolonged corticosteroid therapy, laboratory confirmation of endogenous Cushing syndrome should not be attempted until treatment has been discontinued for an adequate period 1
• For patients who recently stopped steroids for immune-related adverse events or other conditions, wait at least 3 months before attempting to assess endogenous cortisol production 1

Recommended Algorithm

For a patient recently stopped from oral prednisolone with suspected exogenous Cushing:

1. Wait minimum 7 days after last prednisolone dose (longer is better, ideally 2-4 weeks for complete clearance)
2. Perform 2-3 first-line screening tests rather than relying on a single morning cortisol:
   • Late-night salivary cortisol (×2-3) 1, 2
   • 24-hour urinary free cortisol (×2-3) 1, 2
   • 1-mg overnight dexamethasone suppression test 1, 2
3. If morning cortisol is measured, do so only after at least 7-14 days off prednisolone and interpret with caution 1
4. Consider endocrinology consultation for complex cases or if results are equivocal 1