Adrenal Steroid Synthesis Inhibitors

Adrenal steroid synthesis inhibitors block steps in cortisol biosynthesis and lower cortisol in Cushing syndrome. They are used before surgery, as a bridge to radiotherapy, when surgery fails, and for ectopic ACTH or adrenal carcinoma. They do not treat the underlying tumour.

Mechanism. Metyrapone and osilodrostat inhibit 11-beta hydroxylase (osilodrostat also aldosterone synthase). Ketoconazole and levoketoconazole inhibit several steroidogenic enzymes (17,20 lyase, 11-beta hydroxylase and side-chain cleavage). Etomidate inhibits 11-beta hydroxylase intravenously. Mitotane is adrenolytic.

Pharmacokinetics. Metyrapone half-life is 2 hours, given three to four times daily. Osilodrostat is given twice daily. Ketoconazole needs gastric acid for absorption and is a strong CYP3A4 inhibitor. Mitotane is fat soluble with a long half-life, takes weeks to reach effect and is monitored by plasma levels.

Differences. Metyrapone and osilodrostat are fast and potent; androgen and mineralocorticoid precursor rise causes hirsutism, hypertension, oedema and hypokalaemia. Ketoconazole causes hepatotoxicity and many interactions. Mitotane is reserved for adrenal carcinoma.

• Cushing disease awaiting surgery or radiotherapy: metyrapone or osilodrostat, titrated to a mean serum cortisol of 150 to 300 nmol/L (5 to 10 micrograms/dL) on a day curve, or a normal urinary free cortisol.
• Severe hypercortisolism needing rapid control: etomidate infusion or combined metyrapone and ketoconazole.
• Block and replace: an inhibitor at high dose with hydrocortisone replacement, in severe disease, to avoid adrenal insufficiency.
• Adrenocortical carcinoma: mitotane, with hydrocortisone replacement at raised doses because mitotane increases cortisol clearance, and fludrocortisone.
• Choice in women: prefer ketoconazole where hirsutism is a concern, and in men prefer metyrapone because ketoconazole causes hypogonadism and gynaecomastia.

Special groups. Pregnancy: metyrapone is used when treatment is essential; avoid ketoconazole and mitotane. Breastfeeding: avoid. Children: specialist use. Older adults: lower starting doses. Liver impairment: avoid ketoconazole and mitotane. Regional: availability of metyrapone and osilodrostat is limited, and ketoconazole is more accessible.

Adverse effects. Adrenal insufficiency from over-treatment, nausea, dizziness, hypokalaemia, hypertension, oedema, hirsutism and acne, QT prolongation (osilodrostat and ketoconazole), hepatotoxicity (ketoconazole), gynaecomastia, neurological effects (mitotane).

Contraindications. Ketoconazole with other QT prolonging drugs and in liver disease; adrenal insufficiency; pregnancy for ketoconazole and mitotane.

Interactions. Ketoconazole is a strong CYP3A4 inhibitor and needs gastric acid, so avoid proton pump inhibitors. Mitotane induces CYP3A4 and reduces levels of many drugs. Osilodrostat adds to QT drugs.

Monitoring. Day cortisol curve or urinary free cortisol every 1 to 2 weeks while titrating, potassium and blood pressure, ECG at baseline and after dose change, liver enzymes weekly for the first month of ketoconazole and then monthly, mitotane levels every 2 to 4 weeks, and symptoms of adrenal insufficiency.

Referral and escalation. All patients are managed by an endocrinologist. Suspected adrenal insufficiency needs same-day hydrocortisone.