Long-term cyclic ectopic adrenocorticotropic hormone syndrome with extreme fluctuations and adrenal insufficiency

A 77-year-old woman presented with worsening glycemic control and hypokalemia and was found to have adrenocorticotropic hormone (ACTH)-dependent hypercortisolism with loss of diurnal cortisol variation and failure of suppression on low- and high-dose dexamethasone suppression tests. Computed tomography (CT) demonstrated bilateral adrenal enlargement, whereas pituitary magnetic resonance imaging and chest CT failed to identify a source of ACTH secretion, leading to a diagnosis of occult ectopic ACTH syndrome. During 15 years of follow-up, she exhibited cyclic fluctuations in ACTH and cortisol concentrations, including episodes of severe hypercortisolism with ACTH levels exceeding 2000 pg/mL (>440 pmol/L) (reference range, 7.2-63.6 pg/mL [1.6-14.0 pmol/L]) and cortisol concentrations of 30-60 μg/dL (828-1656 nmol/L) (reference range, 6.2-19.4 μg/dL [171-535 nmol/L]), alternating with spontaneous remission. Serial imaging revealed dynamic adrenal morphological changes, with enlargement during hypercortisolemic phases and regression during remission. During treatment with ketoconazole, mitotane, and osilodrostat, the patient experienced recurrent significant hypocortisolic episodes, some of which were likely treatment-associated and required hydrocortisone replacement therapy. This case highlights an exceptionally prolonged course of cyclic ectopic ACTH syndrome characterized by extreme hormonal oscillation, reversible adrenal hyperplasia, and recurrent hypocortisolism, emphasizing the importance of long-term biochemical surveillance and individualized therapeutic adjustment.