How do you interpret an Adrenocorticotropic Hormone (ACTH) stimulation test in a patient taking Dexamethasone (generic name: Dexamethasone)

Interpreting ACTH Stimulation Testing in Patients on Dexamethasone

Dexamethasone does not interfere with cortisol assays, making the ACTH stimulation test fully interpretable in patients taking dexamethasone—this is the key advantage that distinguishes dexamethasone from other glucocorticoids like prednisone or hydrocortisone. 1

Why Dexamethasone is Unique for Testing

Dexamethasone suppresses the HPA axis but does not cross-react with cortisol immunoassays, allowing accurate measurement of endogenous cortisol production during dynamic testing. 1 This property makes dexamethasone the preferred glucocorticoid when you need to treat suspected adrenal crisis but still want to perform diagnostic testing later—use dexamethasone 4 mg IV instead of hydrocortisone, as it will not confound subsequent cortisol measurements. 1

In contrast, other exogenous steroids (prednisolone, hydrocortisone, inhaled fluticasone) directly interfere with cortisol assays and suppress the HPA axis, making ACTH stimulation testing unreliable. 1, 2

Standard ACTH Stimulation Test Protocol

• Administer 0.25 mg (250 mcg) cosyntropin IV or IM 1, 2
• Measure baseline serum cortisol and ACTH before cosyntropin administration 1
• Measure serum cortisol at exactly 30 and 60 minutes post-administration 1
• Peak cortisol >550 nmol/L (>18-20 μg/dL) at either timepoint is normal and excludes adrenal insufficiency 1
• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 2

Critical Interpretation Considerations with Dexamethasone

Timing Relative to Dexamethasone Dose

The test remains interpretable regardless of dexamethasone timing because dexamethasone does not interfere with cortisol measurement. 1 However, basal dexamethasone levels at the time of testing inversely correlate with ACTH and cortisol responses—lower dexamethasone levels allow greater ACTH and cortisol rises after stimulation. 3

Research demonstrates that despite overnight dexamethasone suppression (1-4 mg), CRH can still elicit cortisol rises in healthy individuals, but higher basal dexamethasone levels at testing time produce smaller responses (R = -0.81, P <0.001). 3

What the Test Actually Measures

The ACTH stimulation test evaluates adrenal reserve and responsiveness, not HPA axis integrity. 4, 1 In patients on dexamethasone:

• A normal response (peak cortisol >550 nmol/L) confirms intact adrenal cortical function and adequate adrenal reserve to respond to maximal ACTH stimulation 1, 2
• An abnormal response (peak cortisol <500 nmol/L) indicates primary adrenal insufficiency or prolonged ACTH suppression with adrenal atrophy 1
• The test cannot distinguish between secondary (central) adrenal insufficiency and dexamethasone-induced HPA suppression because both present with low basal ACTH 1

False-Negative Risk in Early HPA Suppression

ACTH stimulation can give false-negative results early in hypophysitis or recent-onset secondary adrenal insufficiency, as adrenal reserve declines slowly after pituitary ACTH stimulation is lost. 4 In the presence of clinical uncertainty with ongoing dexamethasone use, opt for empiric glucocorticoid replacement and test for ongoing need at 3 months rather than relying solely on ACTH stimulation results. 4, 1

Practical Clinical Algorithm

If Testing While on Dexamethasone:

1. Proceed with standard ACTH stimulation protocol without stopping dexamethasone 1, 2
2. Measure baseline ACTH simultaneously with baseline cortisol to distinguish primary from secondary patterns 1
3. Interpret peak cortisol response using standard cutoffs (>550 nmol/L normal, <500 nmol/L abnormal) 1

Interpreting Results:

Normal peak cortisol (>550 nmol/L) with:

• High baseline ACTH → Rules out primary adrenal insufficiency 1
• Low baseline ACTH → Adrenal glands can respond, but does not exclude secondary AI or dexamethasone-induced suppression 1

Abnormal peak cortisol (<500 nmol/L) with:

• High baseline ACTH → Diagnostic of primary adrenal insufficiency 1
• Low baseline ACTH → Cannot distinguish secondary AI from dexamethasone-induced suppression; requires clinical correlation and repeat testing after dexamethasone withdrawal 1

Critical Pitfalls to Avoid

• Never assume a normal ACTH stimulation test excludes secondary adrenal insufficiency in patients on chronic dexamethasone—the test only confirms adrenal responsiveness, not HPA axis integrity 4, 1
• Do not delay treatment of suspected adrenal crisis to perform diagnostic testing—give IV hydrocortisone 100 mg immediately if clinically unstable, or use dexamethasone 4 mg IV if you want to preserve testing options 1
• Avoid testing patients on other glucocorticoids (prednisone, hydrocortisone) as these interfere with cortisol assays; approximately one-third to one-half of patients taking 5-20 mg prednisolone daily fail ACTH stimulation despite adequate adrenal reserve 1
• Stop estrogen-containing drugs 4-6 weeks before testing as elevated cortisol-binding globulin increases total cortisol levels and causes false interpretation 2

When to Repeat Testing After Dexamethasone Withdrawal

If secondary adrenal insufficiency or dexamethasone-induced suppression is suspected based on low baseline ACTH with abnormal stimulation, wait 3 months after stopping dexamethasone before repeating HPA axis testing to allow recovery. 4, 1 During this interval, provide maintenance hydrocortisone 15-25 mg daily with stress-dose education and medical alert identification. 1