What investigations should be ordered in a patient with suspected exogenous Cushing syndrome?

Investigations for Suspected Exogenous Cushing Syndrome

The most critical first step is to exclude all exogenous glucocorticoid exposure before ordering any biochemical tests, as this is the most common cause of Cushing syndrome and failure to do so leads to unnecessary testing without benefit to the patient. 1

Initial Clinical Assessment

Document all potential sources of exogenous glucocorticoids systematically:

• Oral corticosteroids (prescription and over-the-counter) 2
• Inhaled corticosteroids, particularly when combined with azole antifungals like itraconazole, which can cause iatrogenic Cushing syndrome 2
• Topical steroids including creams, ointments, and nasal drops 1, 2
• Herbal supplements and unregulated products that may contain hidden synthetic glucocorticoids (e.g., products marketed for joint pain) 2, 3
• Injectable steroids including intra-articular and epidural injections 1

The European Society of Hypertension emphasizes that substances like nasal drops, cocaine, amphetamines, oral contraceptives, steroids, non-steroidal anti-inflammatory drugs, erythropoietin, and cyclosporin can all raise blood pressure and mimic or cause Cushing features. 1

Biochemical Confirmation Tests

If exogenous exposure is confirmed or strongly suspected based on history, order the following tests to confirm suppression of the hypothalamic-pituitary-adrenal axis:

• Morning plasma cortisol (typically <1.0-1.8 μg/dL in exogenous Cushing) 2, 3
• Morning plasma ACTH (typically <5 pg/mL in exogenous Cushing) 2, 3

These tests should be measured simultaneously. 2 In exogenous Cushing syndrome, both cortisol and ACTH will be suppressed due to negative feedback from the exogenous glucocorticoid. 3, 4

Advanced Testing for Occult Exogenous Exposure

When clinical features strongly suggest Cushing syndrome but the patient denies glucocorticoid use, screen for synthetic glucocorticoids:

• Plasma or urine screening for synthetic glucocorticoids (dexamethasone, prednisolone, betamethasone) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) 2, 3

This is particularly important because antibody-based immunoassays can generate false results due to cross-reactivity between cortisol, cortisone, and other metabolites. 5 LC-MS/MS only measures the specific synthetic steroid and has become available for routine clinical practice. 5

In documented cases, dexamethasone levels >100 ng/dL while taking supplements confirmed exogenous exposure, with levels normalizing to <20-24 ng/dL within 5 days of stopping the product. 3

Physical Examination Findings

Look specifically for features that suggest Cushing syndrome:

• Facial plethora, moon facies 1, 4
• Wide purple striae (>1 cm), particularly on abdomen 1, 6
• Dorsocervical and supraclavicular fat pads 1, 4
• Thin, fragile skin with easy bruising 1, 5
• Proximal muscle weakness 1
• Skin hyperpigmentation (more prominent with ACTH excess, but absent in exogenous cases) 1

The European Society of Cardiology guidelines note that physical examination should actively search for features of Cushing syndrome as part of evaluating secondary hypertension. 1

Management After Confirmation

Once exogenous Cushing syndrome is confirmed:

• Stop the glucocorticoid source immediately if medically safe 1, 2
• Monitor for adrenal insufficiency during withdrawal by repeating morning cortisol and ACTH 1-4 weeks after stopping glucocorticoid 2
• Aggressively treat metabolic complications including hypertension, hyperglycemia, and other cardiovascular risk factors 1, 2
• Educate patients on stress dosing and provide medical alert identification if prolonged suppression is present 7

Common Pitfalls to Avoid

Do not order screening tests for endogenous Cushing syndrome (24-hour urinary free cortisol, late-night salivary cortisol, dexamethasone suppression test) until exogenous glucocorticoid use is completely excluded. 1 The Endocrine Society explicitly states this is a strong recommendation based on high-quality evidence that failure to exclude exogenous use leads to unnecessary testing and consequences without benefit. 1

Do not assume patients will volunteer information about all glucocorticoid sources. 3 Patients may not recognize that herbal supplements, topical creams, or inhaled medications contain steroids. 2, 3 Direct questioning about all potential sources is essential. 1

Do not rely solely on patient denial of steroid use if clinical suspicion is high. 3 Consider LC-MS/MS screening for synthetic glucocorticoids in cases where occult use is suspected. 2, 3