SAT-021 - Persistent and Profound Pan-Adrenal Steroidogenic Inhibition Long after Osilodrostat Discontinuation

Background
Osilodrostat, a potent CYP11B inhibitor, is an effective treatment for hypercortisolism in Cushing’s disease (CD). Adrenal insufficiency (AI), reported in approximately 40% of treated patients, is usually reversible after dose reduction or discontinuation. We report a case of exceptionally prolonged AI with sustained pan-adrenal steroidogenic suppression following osilodrostat withdrawal.

Case Description
A 56-year-old man presented in 2012 with clinical features of Cushing’s syndrome; CD was confirmed biochemically and by inferior petrosal sinus sampling. Initial transsphenoidal surgery (TSS) resected an ACTH-positive microadenoma, resulting in transient remission. Subsequent biochemical relapse without radiological evidence of residual disease led to a second exploratory TSS, which was unsuccessful. Despite stereotactic radiotherapy, hypercortisolism persisted. Partial biochemical control was intermittently achieved between 2013 and 2022 with cabergoline and ketoconazole; cabergoline was discontinued in late 2021 due to impulse control disorder, resulting in disease exacerbation.

Osilodrostat was initiated in March 2022 and titrated to 10 mg twice daily. By August 2022, biochemical control was achieved, with normal morning cortisol, ACTH concentrations 7–8-fold above the upper limit of normal (ULN), markedly elevated 11-deoxycortisol (1159 nmol/L; reference 0–57), and suppressed aldosterone. During dose reduction to 5 mg twice daily, cortisol remained controlled while ACTH continued to rise and aldosterone remained undetectable.

In October 2023, the patient was admitted with mild hyponatremia. Morning cortisol was 35 nmol/L, ACTH approximately 20-fold ULN, aldosterone remained suppressed, and plasma direct renin was >6-fold ULN. Osilodrostat was discontinued, and glucocorticoid followed by mineralocorticoid replacement was initiated. Over 27 months of follow-up, morning cortisol has remained subnormal (typically 100–150 nmol/L), ACTH persistently elevated (~8-fold ULN), and adrenal steroidogenic intermediates (11-deoxycortisol, 17-hydroxyprogesterone, androstenedione, and DHEAS) consistently suppressed. The patient’s clinical condition has markedly improved under replacement therapy.

Discussion and Conclusion
Osilodrostat-induced AI is typically reversible. Since 2023, approximately 10 cases of persistent AI after osilodrostat withdrawal have been reported, with a median duration of ~11 months. This case uniquely demonstrates 27 months of post-discontinuation AI with global suppression of glucocorticoid, mineralocorticoid, and androgen pathways, expanding the spectrum of osilodrostat-associated adrenal impairment.

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