Persistent Adrenocortical Insufficiency After Long-Term Metyrapone Treatment for Cushing’s Disease

Introduction:Cushing's disease is caused by pituitary tumors that secrete excess adrenocorticotropic hormone (ACTH).Metyrapone is widely used for medical management as a bridge to transsphenoidal pituitary surgery. CaseReport: An 80-year-old man presented with severe hypercortisolemia (101 g/dL [reference range, 5-23 g/dL]) and elevated plasma ACTH, 228 pg/mL [reference range, 7.2-63.3pg/mL]).Initial high-dose dexamethasone suppression and corticotropin-releasing hormone (CRH) tests suggested ectopic ACTH syndrome; however, extensive imaging failed to identify a source.Metyrapone was initiated and escalated to 3000 mg/day, followed by block-and-replacement with hydrocortisone (20 mg/day).After four years, repeat CRH testing and dexamethasone suppression supported Cushing's disease.Combined cavernous and inferior petrosal sinus sampling localized ACTH hypersecretion to the right pituitary.Transsphenoidal surgery confirmed a corticotroph pituitary neuroendocrine tumor.Despite tumor resection and metyrapone discontinuation, cortisol levels remained undetectable for more than one year.Discussion: Liquid chromatography-tandem mass spectrometry demonstrated markedly reduced mineralocorticoids, glucocorticoids, and adrenal androgens, indicating global adrenocortical dysfunction.Adrenal androgens are typically increased during metyrapone therapy, suggesting broader effects of long-term metyrapone on adrenal steroidogenesis beyond selective 11-hydroxylase inhibition.Although postoperative glucocorticoid supplementation may have contributed to adrenal suppression, preserved ACTH responsiveness to CRH supports intact hypothalamic-pituitary signaling with impaired adrenal recovery. Conclusion:This case suggests that prolonged global adrenocortical dysfunction persisting over one year after metyrapone discontinuation.Clinicians should be aware of this potential complication and ensure appropriate glucocorticoid replacement and careful long-term monitoring.