Cushing’s disease: adrenal steroidogenesis inhibitors

Abstract

Cushing’s disease (CD), caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, is the most common form of Cushing’s syndrome (CS), accounting for approximately 70% of cases. CD requires a prompt diagnosis, an adequate treatment selection, and long-term management to limit hypercortisolism duration and long-term complications and improve patient outcomes. Pituitary surgery is the first-line option, which is non-curative in one third of patients, therefore requiring additional treatments. Medical therapy has recently acquired an emerging role, with the availability of several drugs with different therapeutic targets, efficacy and safety profiles. The current review focuses on efficacy and safety of steroidogenesis inhibitors, and particularly the historical drugs, ketoconazole and metyrapone, and the novel drugs levoketoconazole and osilodrostat, which seem to offer a rapid, sustained, and effective disease control. Ketoconazole should be preferred in females and in patients without severe liver disease; levoketoconazole may offer an alternative to classical ketoconazole, appearing characterized by a higher potency and potential lower hepatotoxicity compared to ketoconazole. Metyrapone should be preferred in males and in patients without severe or uncontrolled hypokalemia. Both ketoconazole and metyrapone may be preferred for short-term more than for long-term treatment. Osilodrostat may represent the best choice for long-term treatment, in patients with poor compliance to the multiple daily administration schedule, and in patients without severe or uncontrolled hypokalemia. Steroidogenesis inhibitors may be used alone or in combination, and associated with pituitary directed drugs, to improve the efficacy of the single drugs, allowing a potential use of lower doses for each drug, and hypothetically reducing the rate of adverse events associated with the single drugs. Clinicians may tailor medical therapy on the specific clinical scenario, considering disease history together with patients’ characteristics and hypercortisolism’s degree, addressing the needs of each patient in order to improve the therapeutic outcome and to reduce the burden of illness, particularly in patients with persistent or recurrent CD.

Medical Therapy of Endogenous Cushing’s Syndrome with Steroidogenesis Inhibitors: Treatment Rationale, Available Drugs, and Therapeutic Effects

“…Ketoconazole oral 200-1200 mg/day 45-93% [5,6,8,54,55] hirsutism (36%), hepatotoxicity (11-19%), adrenal insufficiency (5-19%), GI problems (4-19%), skin rash (4-6%), gynecomastia (new onset or worsening) (17-25%) [5,6,8,54,55] Levoketoconazole oral 300-1200 mg/day 31-81% [9,10] nausea (29-32%), headache (23-28%), hypokalemia (11-26%), hypertension (17-24%), QT prolongation (5-11%) [9,10] Metyrapone oral 250-6000 mg/day 45-100% [3,8,11,12,14,47] hirsutism (5-71%), nausea (5-33%), dizziness (10-44%), edema (6-20%), decreased appetite (18%), -fatigue (14%), headache (10%), hypokalemia (6%), hypertension (6-48%) [3,8,11,12,14,47] Osilodrostat oral 4-60 mg/day 66-100% [4,[14][15][16]39] fatigue (29-58%), nausea (32-42%), headache (25-34%), diarrhea (25-32%), adrenal insufficiency (28-32%), QT prolongation (4-13%), hypertension (12%) [4,[14][15][16]39] Mitotane oral mean drug dose 2500-3300 g/day (according to blood concentration) 76-91% [21,27,30] gastrointestinal tract problems (47-65%), neurological complications (26-36%), asthenia (68%), nausea (53%), hypercholesterolemia (54%), increased transaminases (36%), anorexia (36%) …”

“…or infections, and the consecutive need for life-long glucocorticoid replacement therapy due to permanent adrenal insufficiency). In contrast, medical therapy is able to reduce hypercortisolism fast and effectively, is usually well tolerated, and does not necessarily cause adrenal insufficiency [3,4].…”

Unmet needs on the current medical management of Cushing’s syndrome: results from a Delphi panel of Italian endocrinologists

“…In addition, preoperative medical therapy could protect against proinflammatory and procoagulant states in the peri-operative phase [29][30][31]. On the other hand, adrenal steroidogenesis inhibitors do not directly target the pituitary tumor in the case of CD; therefore, they may not restore hypothalamic-pituitary-adrenal axis circadian rhythm [28], and their use may increase the risk of pituitary tumor enlargement [32]. Notably, a new meta-analysis highlighted the role of the somatostatin receptor ligand pasireotide, which is considered an alternative drug to steroidogenesis inhibitors, in the reduction of size in corticotroph pituitary tumor, strengthening the role of this treatment particularly in patients with tumor with an invasive behavior, progressive growth and/or extrasellar extension, with a low likelihood of surgical gross-total removal, or with large postoperative residual tissue [33].…”

Clinical Utility of Osilodrostat in Cushing’s Disease: Review of Currently Available Literature

“…Metyrapone is administered 3-4 times daily, thereby posing challenges for adherence to therapy. 6 The only currently available GR antagonist is mifepristone. Although clinically effective in ameliorating the consequence of hypercortisolism in CD, cortisol levels do not decrease on mifepristone therapy, thereby necessitating dose titration based on clinical parameters.…”

“…However, serum potassium levels should be followed closely, as the drug may cause hypokalemia. 6 Metyrapone was discovered in 1950s and is still widely used. Metyrapone is administered 3–4 times daily, thereby posing challenges for adherence to therapy.…”