Differential diagnosis between endogenous Cushing´s syndrome and pseudo-Cushing

The differentiation between pathological Cushing's syndrome (CS) and pseudo-Cushing's states, also termed non-neoplastic hypercortisolism (NNH), remains one of the biggest challenges in clinical endocrinology. NNH is defined as a reversible condition of clinical and/or biochemical hypercortisolism resulting from persistent activation of the hypothalamic-pituitary-adrenal (HPA) axis by a secondary, non-tumorous etiology. Prevalent conditions such as major depressive disorder, chronic alcoholism, obesity, and eating disorders are frequent causes. Neuropsychiatric disorders drive HPA axis hyperactivity via corticotropin-releasing hormone (CRH) excess and impaired glucocorticoid feedback, while metabolic states often feature tissue-specific amplification of cortisol action via 11β-hydroxysteroid dehydrogenase type 1. Critically, emerging evidence suggests that even functional hypercortisolism may actively contribute to cardiometabolic and neuropsychiatric morbidity, underscoring the importance of accurate discrimination. Clinical evaluation, though essential, is often insufficient, as specific catabolic signs may be absent and metabolic features are common to both entities. Consequently, refined biochemical dynamic tests are pivotal. This review synthesizes evidence on key second-line tests: the combined dexamethasone-CRH test, the desmopressin (DDAVP) test, which exploits aberrant vasopressin receptor expression on corticotroph adenomas and demonstrates high specificity; the combined dexamethasone-DDAVP test, offering a robust and practical alternative; and the 4 mg intravenous dexamethasone suppression test. Radiological studies have no role in this specific differential. A systematic, stepwise diagnostic approach-prioritizing thorough clinical assessment, followed by validated dynamic testing-is imperative to avoid misdiagnosis and ensure appropriate management for both true CS and clinically significant NNH.