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

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.

An 80-year-old man presented with severe hypercortisolemia (101 μg/dL [reference range, 5-23 μg/dL]) and elevated plasma ACTH, 228 pg/mL [reference range, 7.2-63.3 pg/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/d, followed by block-and-replacement with hydrocortisone (20 mg/d). After 4 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 1 year.

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 11β-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.

This case suggests that prolonged global adrenocortical dysfunction persisting over 1 year after metyrapone discontinuation. Clinicians should be aware of this potential complication and ensure appropriate glucocorticoid replacement and careful long-term monitoring.