Rare causes of exogenous Cushing’s Syndrome: a challenge for endocrinologists

PURPOSE: Exogenous Cushing's syndrome (CS) is most commonly caused by therapeutic glucocorticoids (GC), but rare and atypical sources can mimic endogenous GC. This narrative review provides a concise overview of these uncommon causes and their diagnostic implications. METHODS: A PubMed search was performed using the keywords "Cushing syndrome," "factitious Cushing syndrome," "herbal medicine", "supplements" and "endocrine disruption" on March 9th, 2026. Additional articles were identified through manual screening of reference lists. No restrictions were applied regarding language or study design, and the most relevant publications were selected. RESULTS: Three main categories of rare exogenous CS were identified. First, herbal or traditional remedies adulterated with undeclared GC. Second, compounds with GC-like activity, which activate the glucocorticoid receptor and suppress the hypothalamic-pituitary-adrenal axis. Third, factitious CS due to covert GC self-administration, often associated with psychiatric or caregiver-fabricated conditions. Diagnosis can be challenging; advanced analytical methods, including liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography-high resolution mass spectrometry (LC-HRMS), are essential to detect synthetic or undeclared GC and differentiate these cases from endogenous hypercortisolism. CONCLUSION: Rare exogenous causes of CS represent important diagnostic challenges. Careful evaluation of patient history, combined with the use of LC-MS/MS or LC-HRMS, is crucial to identify these conditions, prevent misdiagnosis, and avoid unnecessary diagnostic or surgical interventions.