What is the recommended approach to screen for exogenous Cushing syndrome in a patient with a history of glucocorticoid (corticosteroid) medication use?

Screening for Exogenous Cushing Syndrome

The first and most critical step in screening for exogenous Cushing syndrome is obtaining a detailed medication history to identify any glucocorticoid exposure, including prescription medications, over-the-counter supplements, topical preparations, and herbal products that may contain hidden steroids. 1, 2, 3

Initial Clinical Assessment

Key Historical Elements to Obtain

• Document all glucocorticoid sources systematically:

  • Oral corticosteroids (prednisone, dexamethasone, hydrocortisone) for any indication 2, 3
  • Inhaled corticosteroids (budesonide, fluticasone), particularly when combined with itraconazole or other azoles, which can cause exogenous Cushing syndrome 4
  • Topical steroids for skin conditions like psoriasis, where true exposure may be underestimated 5
  • Intra-articular or epidural steroid injections 3
  • Over-the-counter "herbal" supplements for joint pain or other conditions that may contain hidden glucocorticoids 6

• Assess timing and duration of exposure:

  • Recent initiation of glucocorticoid therapy within the past 6-12 months correlating with symptom onset 6
  • Chronic use patterns that may not be immediately disclosed by patients 5

Clinical Features Suggesting Exogenous Cushing Syndrome

• Cardinal manifestations include:
  • Rapid weight gain with central obesity, facial plethora, and dorsocervical fat pad 2, 7
  • Wide purple striae (>1 cm), easy bruising, and thin fragile skin 2, 7
  • Proximal muscle weakness affecting ability to rise from a chair or climb stairs 7
  • New-onset or worsening hypertension and hyperglycemia/diabetes 6, 7
  • Mood disorders, cognitive deficits, and psychiatric symptoms 2, 7

Biochemical Confirmation

Initial Laboratory Testing

When exogenous Cushing syndrome is suspected based on clinical features and potential glucocorticoid exposure, measure morning (8-9 AM) plasma cortisol and ACTH levels simultaneously: 4, 2

• Low morning cortisol (<1-5 μg/dL) with suppressed ACTH (<5 pg/mL) confirms exogenous glucocorticoid exposure and adrenal suppression 6
• This pattern distinguishes exogenous from endogenous Cushing syndrome, where cortisol would be elevated 2, 3

Synthetic Glucocorticoid Screening

If the source of glucocorticoid exposure is unclear or denied by the patient, perform synthetic glucocorticoid screening using liquid chromatography-tandem mass spectrometry (LC-MS/MS): 6, 5

• Screen plasma or urine for:

  • Dexamethasone (reference value <100 ng/dL in plasma) 6
  • Prednisolone and other synthetic steroids 5
  • This testing is essential for factitious Cushing syndrome where patients hide their glucocorticoid use 5

• Timing considerations:

  • Obtain samples while patient is still taking the suspected product 5
  • Repeat testing 5-7 days after stopping the glucocorticoid to document clearance and recovery 6

Common Pitfalls and How to Avoid Them

Hidden Glucocorticoid Sources

• Always inquire specifically about:
  • Unregulated herbal supplements marketed for joint pain, which may contain undisclosed dexamethasone or other potent steroids 6
  • Combination therapy with inhaled corticosteroids and azole antifungals (itraconazole), which inhibit steroid metabolism and cause iatrogenic Cushing syndrome 4
  • Topical steroid use that may be more extensive than initially reported 5

Distinguishing from Endogenous Cushing Syndrome

• Key differentiating features:
  • Exogenous: Low cortisol, suppressed ACTH, positive synthetic steroid screen 6, 5
  • Endogenous: Elevated cortisol, normal-to-elevated ACTH (if ACTH-dependent), negative synthetic steroid screen 2, 3
  • Do not proceed with expensive imaging or invasive testing (pituitary MRI, inferior petrosal sinus sampling) until exogenous glucocorticoid use is definitively excluded 4, 5

Factitious Cushing Syndrome

• Maintain high clinical suspicion when:
  • Patient denies glucocorticoid use despite biochemical evidence of suppressed cortisol and ACTH 5
  • Clinical features are severe but no clear medication history is obtained 5
  • Perform comprehensive synthetic steroid screening before pursuing invasive diagnostic procedures 5
  • Recognize that factitious Cushing syndrome related to hydrocortisone can be particularly difficult to prove, as it may be indistinguishable from endogenous cortisol on standard assays 5

Management After Confirmation

Once exogenous Cushing syndrome is confirmed:

• Discontinue the offending glucocorticoid immediately if medically safe 6

• Monitor for adrenal insufficiency during withdrawal:

  • Repeat morning cortisol and ACTH 1-4 weeks after stopping glucocorticoid 6
  • Recovery of adrenal function typically occurs within 12 months in 80% of patients 1
  • Provide stress-dose steroid coverage if needed during the recovery period 1

• Address associated comorbidities:

  • Aggressively treat hypertension, hyperglycemia, and other metabolic complications 4
  • Screen for and treat infections, thromboembolic disease, and cardiovascular complications 7