EP1265 - ECE_2329 - When the source remains hidden-diagnostic dilemmas in ACTH-dependent Cushing's syndrome

Abstract Aim To analyze the diagnostic challenges in ACTH-dependent Cushing's syndrome when no causative lesion is initially identified, with emphasis on the differentiation between pituitary and ectopic sources of ACTH excess, and on the role of medical therapy during prolonged diagnostic evaluation. Summary/Methods A 23-year-old male presented with progressive clinical features of Cushing's syndrome (CS), including rapid weight gain, central obesity, proximal muscle weakness, moon facies, erythroviolaceous striae, buffalo hump and acanthosis nigricans. He also had arterial hypertension, diabetes mellitus and dyslipidaemia. Biochemical evaluation confirmed endogenous ACTH-dependent hypercortisolism. Initial pituitary magnetic resonance imaging (MRI) showed no identifiable lesion. Given the absence of a visible pituitary adenoma, a structured diagnostic approach was undertaken to localize the source of ACTH excess. Differential diagnostic considerations included pituitary Cushing's disease (CD) and ectopic ACTH secretion (EAS). Cross-sectional thoracic imaging and extensive functional nuclear medicine studies, including 68Ga-DOTATOC PET/CT, 18F-FDG PET/CT and 18F-DOPA PET/CT, failed to identify an ectopic ACTH-producing tumor. Inferior petrosal sinus sampling (IPSS) was performed to further differentiate between pituitary and ectopic ACTH secretion. However, the procedure was non-diagnostic due to incomplete bilateral catheterization, precluding definitive exclusion of a pituitary source. Repeated hormonal assessments demonstrated marked fluctuations in ACTH and cortisol concentrations during follow-up, complicating the interpretation of dynamic testing and the overall diagnostic process. Results Medical therapy with the 11β-hydroxylase inhibitor osilodrostat was initiated to control hypercortisolism while diagnostic evaluation continued. Treatment resulted in effective biochemical control and substantial clinical improvement. Glycemic parameters normalized, blood pressure and lipid profile improved, and classical manifestations of CS regressed, including recovery of muscle strength. Following treatment initiation, a paradoxical transient decrease in ACTH levels was observed. Several pathophysiological mechanisms were considered, including cyclic ACTH secretion, partial tumor cell dysfunction, and complex feedback effects related to the accumulation of steroid precursors with residual glucocorticoid or mineralocorticoid activity. These observations underscore the non-linear and dynamic regulation of the ACTH–cortisol axis in ACTH-dependent CS under medical therapy. Subsequent repeat pituitary MRI revealed a subtle hypointense lesion measuring <4 mm, supporting a normotopic ACTH source and favoring a diagnosis of pituitary Cushing's disease despite initially negative imaging.