Table 2.
Medical treatments for Cushing's syndrome (in clinical use or investigational).
| Drug | Mechanism of action | Dose (range) | Side effects | Safety monitoring |
|---|---|---|---|---|
| Ketoconazole | Inhibits steroidogenesis via inhibition of cytochrome P450 function | 200–1800 mg per os (in divided doses, b.i.d.-t.i.d.) |
Reversible liver dysfunction, severe liver toxicity, GI disorders, skin rash, loss of libido, impotence | Transaminase, testosterone, and SHBG in men |
| Metyrapone | Inhibits 11-β hydroxylase in the adrenal gland | 750–6000 mg per os (in divided doses, t.i.d.-q.i.d.) |
Hirsutism, acne, GI disorders, dizziness, hypertension, edema, hypokalemia | Androgens, mineralocorticoid, electrolytes |
| Aminoglutethimide | Prevents conversion of cholesterol to pregnenolone | 250–750 mg per os (in divided doses, b.i.d.-t.i.d.) |
Generalized, self-limiting itchy rash, nausea, dizziness, blurred vision, cholestasis, bone marrow suppression | Blood count, thyroid hormones, hepatic function, abdominal US |
| Mitotane | Inhibits steroidogenesis via inhibition of cytochrome P450; adrenolytic (high doses) | 500 mg–12 g per os (daily) | Severe nausea, vomiting, diarrhea, rash, somnolence, ataxia, vertigo, dyslipidemia | Plasma mitotane, blood count, electrolytes, liver function, cholesterol |
| Etomidate | Inhibits 11-β hydroxylase and 17–20 lyase | <0.1 mg/kg/hr i.v. | Sedative effects, anesthesia | Monitoring by anesthesiologists |
| Mifepristone (RU-486) | Glucocorticoid, androgen, and progesterone receptor antagonist | 300–1200 mg per os, daily dose | Hypoadrenalism, hypokalemia, hypertension, irregular menses, endometrial hyperplasia | Blood count, electrolytes, pelvic US |
| Cabergoline | D2 receptor agonist | 1–7 mg per os, weekly dose | Nausea, vomiting, dizziness, valvulopathy | Echocardiogram |
| Octreotide | Somatostatin receptor agonist (isoform 2) | 200–1000 mcg s.c. t.i.d., or LAR formulation 10–30 mg i.m. every 4 weeks | GI disorders, gallstones or biliary sludge, hyperglycemia, sinus bradycardia | Glycaemia, HbA1c, ECG, abdominal US |
| Pasireotide (SOM 230) |
Somatostatin receptor agonist (isoforms 1, 2, 3, 5) |
600–900 mcg s.c. b.i.d., LAR formulation under investigation | GI disorders, gallstones or biliary sludge, hyperglycemia or diabetes mellitus, sinus bradycardia | Glycaemia, HbA1c, Q-T interval, abdominal US |
| Retinoic acid | Inhibits POMC transcription and cell-cycle progression | No data in vivo in humans in Cushing's syndrome | Anaemia, mucocutaneous and ocular symptoms | Toxic effects of vitamin A, liver function, blood count |
| Rosiglitazone | PPAR-γ agonist | 4–16 mg per os, daily doses | Weight increase, edema, somnolence, hirsutism | Blood count, transaminase, ECG, echocardiogram |
| Temozolomide | Alkylating agent | 150–200 mg/m2 per os for 5 days once every 28 days, or 75 mg/m2 daily for 21 days with 7 day break | Bone marrow suppression, nausea, vomiting, dizziness diarrhea, rash | Blood count, liver and renal function, electrolytes |
| Gefitinib | Tyrosine kinase inhibitor | No data in vivo in humans in Cushing's disease | Fatigue, nausea, vomiting, stomatitis, bone pain, dyspnea, interstitial lung disease | Transaminase, pulmonary toxicity |
| Everolimus | mTOR inhibitor | 5 mg/day | Bone marrow suppression, nausea, angioedema, GI disorders, extremity pain | Liver and renal function, blood count, glycaemia, HbA1c, lipid profile |
b.i.d.: twice daily; t.i.d.: three times daily; q.i.d.: four times daily; i.v.: intravenous; i.m.: intramuscular; s.c.: subcutaneous; POMC: proopiomelanocortin; US: ultrasound; HbA1c: glycated hemoglobin; GI: gastrointestinal.