What are the next investigations for a patient with normal serum cortisol who is suspected of iatrogenic Cushing's syndrome?

Investigating Suspected Iatrogenic Cushing's Syndrome with Normal Serum Cortisol

Direct Answer

If you suspect iatrogenic Cushing's syndrome but serum cortisol is normal, you need to first conduct a comprehensive medication history to identify ALL sources of exogenous glucocorticoid exposure—including oral steroids, inhaled corticosteroids (especially fluticasone), topical preparations, and injections—because these suppress endogenous cortisol production while causing Cushingoid features. 1

Understanding the Clinical Scenario

The key issue here is that iatrogenic Cushing's syndrome presents with clinical features of hypercortisolism (moon facies, striae, weight gain, hypertension) but paradoxically shows LOW or normal serum cortisol levels because exogenous steroids suppress the hypothalamic-pituitary-adrenal (HPA) axis. 2

• Morning cortisol measurements in patients actively taking corticosteroids are not diagnostic because the assay measures both endogenous cortisol and therapeutic steroids, with cross-reactivity varying by assay 2
• Patients on corticosteroids will have low morning cortisol as a result of iatrogenic secondary adrenal insufficiency, with ACTH also suppressed—this is expected and not diagnostic 2

Step-by-Step Diagnostic Approach

1. Comprehensive Medication History (First Priority)

Document ALL potential sources of exogenous glucocorticoid exposure: 1, 2

• Oral corticosteroids: prednisone, prednisolone, dexamethasone, hydrocortisone (any dose, any duration) 2
• Inhaled corticosteroids: fluticasone, budesonide, beclomethasone (can cause systemic absorption and Cushingoid features) 2, 3
• Topical preparations: hydrocortisone creams, clobetasol, betamethasone (especially if used on large surface areas or under occlusion) 3
• Intra-articular or epidural injections: triamcinolone, methylprednisolone 1
• Over-the-counter supplements: some may contain undeclared corticosteroids 1

2. If Exogenous Steroid Use is Confirmed

Laboratory confirmation of adrenal insufficiency should NOT be attempted in patients given corticosteroids until treatment is ready to be discontinued. 2

• The Endocrine Society indicates that failure to exclude exogenous glucocorticoid use is associated with unnecessary testing and resulting consequences without any benefit to the patient 1
• Wait until the patient has been weaned off corticosteroids before performing definitive HPA axis testing 2
• Testing for HPA axis recovery should occur after 3 months of being off maintenance therapy 2

3. If No Obvious Exogenous Source is Identified

Once iatrogenic disease is definitively excluded, proceed with standard Cushing's syndrome screening tests: 1

The Endocrine Society recommends initial testing with one or more of the following (obtain 2-3 measurements of each test due to variability): 1, 4, 5, 6

• 24-hour urinary free cortisol (UFC): More than one measurement required; values >100 μg/24h typically diagnostic 1, 3, 5
• Late-night salivary cortisol (LNSC): More than one measurement required; abnormal threshold >3.6 nmol/L with sensitivity >90% 1, 3, 7
• 1-mg overnight dexamethasone suppression test (DST): Cortisol ≥1.8 μg/dL (≥50 nmol/L) at 0800h after 1 mg dexamethasone given at 2300-2400h is abnormal 1, 3, 5

4. Critical Considerations for Test Selection

Late-night salivary cortisol is particularly useful in this scenario because: 3, 7

• It captures loss of normal circadian rhythm, a hallmark of Cushing's syndrome 3, 5
• Collection is simple and can be done at home 5, 7
• Sensitivity of 92-100% and specificity of 93-100% 3, 7
• Less affected by protein-binding issues that confound serum cortisol 8

24-hour urinary free cortisol considerations: 3, 5, 8

• Must ensure complete collection with appropriate total volume and creatinine excretion 3, 5
• At least 2-3 collections recommended due to 50% random variability 3
• Renal impairment or polyuria can invalidate results 3

Dexamethasone suppression test caveats: 3, 5, 8

• CYP3A4 inducers (anticonvulsants, rifampin) accelerate dexamethasone metabolism causing false-positives 3, 8
• CYP3A4 inhibitors increase dexamethasone levels causing false-negatives 3
• Measuring dexamethasone levels concomitantly with cortisol reduces false-positive results 3

Common Pitfalls to Avoid

• Never pursue extensive Cushing's workup without first definitively excluding ALL exogenous glucocorticoid sources 1
• Do not rely on a single screening test—obtain 2-3 measurements of your chosen modality due to test-to-test variability and possibility of cyclic Cushing's 3, 5, 6
• Beware of pseudo-Cushing's states (severe obesity, alcoholism, depression, PCOS) that can cause mild hypercortisolism mimicking true Cushing's syndrome 3, 8
• Oral contraceptives and estrogen therapy increase cortisol-binding globulin, falsely elevating total cortisol—always inquire about these before pursuing workup 3, 8
• Night-shift workers should not undergo late-night salivary cortisol testing due to disrupted circadian rhythm 3

When Initial Testing is Abnormal

If one or more screening tests are abnormal, measure 9 AM ACTH to distinguish: 4, 6

• Suppressed ACTH: Suggests adrenal cause of hypercortisolism 4, 6
• Normal or elevated ACTH: Suggests ACTH-dependent hypercortisolism (pituitary or ectopic) 4, 6

Refer to endocrinology for further evaluation as subsequent testing requires considerable expertise both in the clinic and laboratory 1