What does a baseline cortisol level of 2 μg/dL that increases to 15 μg/dL after Adrenocorticotropic hormone (ACTH) stimulation indicate in a patient taking Dexamethasone, a synthetic glucocorticoid (glucocorticoid), and how should their treatment be managed?

Understanding ACTH Stimulation Test Results in Patients on Dexamethasone

You are absolutely correct that dexamethasone suppresses baseline cortisol, and in this scenario—where baseline cortisol is 2 μg/dL rising to 15 μg/dL after ACTH stimulation—the patient demonstrates adrenal insufficiency despite the seemingly adequate rise, because the peak cortisol remains below the diagnostic threshold of 18 μg/dL. 1

Why This Represents Adrenal Insufficiency

The critical diagnostic threshold for ACTH stimulation testing is a peak cortisol <18 μg/dL (500 nmol/L), which defines adrenal insufficiency regardless of the baseline value. 1 Your example of baseline 2 μg/dL rising to 15 μg/dL demonstrates:

• An absolute increment of 13 μg/dL, which appears robust
• However, the peak value of 15 μg/dL falls short of the required 18 μg/dL threshold 1
• This indicates the adrenal glands cannot mount an adequate maximal cortisol response to ACTH stimulation, confirming adrenal insufficiency 1

The Dexamethasone Effect: Why Baseline Suppression Doesn't Change Interpretation

Dexamethasone profoundly suppresses endogenous cortisol production through negative feedback on the hypothalamic-pituitary-adrenal axis, which explains the low baseline of 2 μg/dL. 2 However, this creates a critical clinical nuance:

• Dexamethasone suppresses ACTH secretion from the pituitary, not adrenal responsiveness to exogenous ACTH 3
• When you administer synthetic ACTH during the stimulation test, you bypass the suppressed pituitary and directly stimulate the adrenal glands 4
• Therefore, the adrenal glands should still be capable of producing cortisol ≥18 μg/dL in response to maximal ACTH stimulation if they are functionally intact 1

The fact that cortisol only reaches 15 μg/dL indicates the adrenal cortex itself has impaired reserve, likely from chronic suppression by therapeutic glucocorticoids. 2

Clinical Interpretation Algorithm

Step 1: Assess the Peak Cortisol Value

• Peak cortisol <18 μg/dL = Adrenal insufficiency 1
• Peak cortisol ≥18-20 μg/dL = Normal adrenal function 1

Step 2: Consider the Clinical Context

In patients receiving therapeutic glucocorticoids (including dexamethasone), approximately one-third to one-half will have inadequate adrenal cortisol reserve even at doses as low as 5 mg prednisolone daily (equivalent to ~0.5 mg dexamethasone). 2

Step 3: Management Decision

Given the peak cortisol of 15 μg/dL in your scenario, this patient requires:

• Glucocorticoid stress coverage during physiological stress (surgery, illness, trauma) 2
• Hydrocortisone 15-20 mg daily in divided doses as physiologic replacement if dexamethasone is being discontinued 2
• Education on stress dosing, emergency injectable hydrocortisone, and medical alert identification 2

Common Pitfalls to Avoid

Pitfall 1: Focusing on the Increment Rather Than the Peak

The absolute increment (13 μg/dL in your example) can be misleading. What matters is whether the adrenal glands can achieve the minimum cortisol concentration needed for stress response, which is 18 μg/dL. 1

Pitfall 2: Assuming Dexamethasone Invalidates ACTH Testing

Dexamethasone suppresses the pituitary, not the adrenal response to exogenous ACTH. 4 The ACTH stimulation test remains valid because you're administering synthetic ACTH that bypasses the suppressed hypothalamic-pituitary axis. 4

Pitfall 3: Delaying Stress Coverage While Awaiting Recovery

When in doubt about the need for glucocorticoid supplementation during stress, always provide coverage—there are no long-term adverse consequences of short-term glucocorticoid administration, but failure to provide coverage can result in life-threatening adrenal crisis. 2

Special Considerations for Dexamethasone Users

Dexamethasone has unique pharmacological properties that complicate interpretation:

• 8 mg dexamethasone equals approximately 200 mg hydrocortisone in glucocorticoid potency 2
• Dexamethasone has no mineralocorticoid activity, making it inadequate for stress coverage in primary adrenal insufficiency 2
• The plasma elimination half-life of dexamethasone is much longer than hydrocortisone (36-72 hours vs. 90 minutes), causing prolonged HPA axis suppression 2

For patients transitioning off dexamethasone, ACTH stimulation testing should ideally be performed after a washout period, but if testing must occur during therapy, interpret the peak cortisol value using the standard <18 μg/dL threshold for adrenal insufficiency. 1

When to Suspect False-Negative Results

ACTH stimulation testing can give false-negative results (appearing normal when insufficiency exists) early in the course of secondary/tertiary adrenal insufficiency, as adrenal reserve declines slowly after pituitary stimulation is lost. 2 However, in your scenario with a peak of 15 μg/dL, this is a true positive result confirming adrenal insufficiency.

If clinical suspicion remains high despite borderline results, repeat testing at 3 months or opt for empiric replacement therapy. 2