What is the recommended screening approach for adrenal insufficiency?

Screening for Adrenal Insufficiency

Begin screening with a morning serum cortisol level (measured between 8:00-9:00 AM) as the initial test, with values >300 nmol/L (10-11 μg/dL) effectively ruling out adrenal insufficiency and eliminating the need for dynamic testing.

Initial Screening Approach

The algorithmic approach to screening depends on clinical context:

For Suspected Primary or Secondary Adrenal Insufficiency

Morning cortisol is your first-line screening tool 1. The interpretation follows a three-tier system:

• Cortisol >300 nmol/L (10-13 μg/dL): Rules out adrenal insufficiency; no further testing needed 2, 3
• Cortisol 150-300 nmol/L (5-10 μg/dL): Indeterminate zone; proceed to dynamic testing (cosyntropin stimulation test)
• Cortisol <150 nmol/L (5 μg/dL): Highly suggestive of adrenal insufficiency; dynamic testing unlikely to change diagnosis 2

Recent evidence from 2026 suggests that with newer generation immunoassays, a morning cortisol of 11.1 μg/dL has 93% specificity for ruling out AI 3. This is slightly higher than older cutoffs and reflects improved assay specificity.

For Glucocorticoid-Induced Adrenal Insufficiency

The approach differs significantly for patients tapering systemic glucocorticoids 2:

1. Only test after reaching physiologic replacement doses (prednisone 4-6 mg daily or hydrocortisone 15-25 mg daily)
2. Hold glucocorticoid dose for at least 24 hours before testing (except dexamethasone)
3. Measure morning cortisol between 8:00-9:00 AM
4. Use the same three-tier interpretation as above

Critical caveat: Biochemical adrenal insufficiency is far more common than clinically significant adrenal insufficiency in this population. The risk of actual adrenal crisis remains very low even with biochemical suppression 2.

Dynamic Testing: When and Which Test

The 250 μg cosyntropin stimulation test remains the gold standard for confirming or excluding adrenal insufficiency 1. Perform this when:

• Morning cortisol falls in the indeterminate range (150-300 nmol/L)
• Clinical suspicion remains high despite borderline-normal morning cortisol
• Differentiating primary from secondary AI is necessary (measure ACTH simultaneously)

Interpretation of cosyntropin test: A 30-minute cortisol ≥420-500 nmol/L (≥14.6-18 μg/dL) rules out adrenal insufficiency 1, 4. Note that newer immunoassays support a lower threshold of ≥14.6 μg/dL rather than the historical ≥18 μg/dL 3.

Adjunctive Screening Tools

Recent evidence supports additional markers to reduce unnecessary dynamic testing 5:

• DHEAS (age- and sex-adjusted): Can help rule out primary adrenal insufficiency in indeterminate cases
• Salivary cortisone: Emerging as a practical home-based alternative that avoids cortisol-binding globulin variability
• Baseline ACTH: Measure alongside morning cortisol for initial screening 1

High-Risk Populations Requiring Lower Threshold

Screen aggressively (even with atypical presentations) in 1:

• Acutely ill/hospitalized patients with unexplained hypotension or shock
• Pregnant women with persistent nausea, fatigue, and hypotension
• Patients on immune checkpoint inhibitors (especially ipilimumab-nivolumab combinations) 6
• Anyone with predisposing autoimmune conditions

For checkpoint inhibitor patients specifically, current practice shows significant underscreening—only thyroid function is routinely monitored while adrenal screening is neglected, leading to 35% of AI cases being diagnosed during hospitalization 6. Implement baseline and periodic ACTH/cortisol screening in all patients receiving CTLA-4-containing regimens.

Common Pitfalls to Avoid

1. Don't test too early during glucocorticoid taper: Wait until physiologic doses are reached 2
2. Don't use arbitrary cutoffs rigidly: Cortisol exists on a continuum; higher values progressively increase confidence in HPA axis recovery 2
3. Don't over-interpret biochemical suppression: In glucocorticoid-induced AI, biochemical insufficiency doesn't equal clinical risk 2
4. Don't forget timing: Morning cortisol must be drawn between 8:00-9:00 AM for valid interpretation
5. Don't ignore assay differences: Newer immunoassays (like Elecsys Cortisol II) may have different cutoffs than LC-MS/MS 4

Frequency of Repeat Testing

For patients with confirmed biochemical insufficiency on physiologic replacement:

• If cortisol <150 nmol/L: Recheck every 1-6 months depending on prior glucocorticoid dose/duration 2
• If cortisol 150-300 nmol/L: Recheck every few weeks until recovery 2
• Continue physiologic replacement between tests to allow HPA axis recovery while preventing crisis