Medication Therapy options for Cushing’s Syndrome
By Tanya Warren, PharmD
Cushing’s syndrome is an endocrine disorder caused by high blood levels of the hormone cortisol, which is produced by the adrenal gland. Adrenocorticotropic hormone (ACTH) is a hormone that controls the release of cortisol. Pituitary tumors that secrete high amounts of ACTH can cause high cortisol levels. Tumors of the adrenal gland and ectopic ACTH syndrome can also cause high cortisol levels. The medications that treat Cushing’s syndrome target these causes of hypercortisolism.
ADRENAL CORTICOSTEROID INHIBITORS
Ketoconazole inhibits enzymes involved in cortisol synthesis
Ketoconazole interferes in the first step of cortisol biosynthesis. The side effects of ketoconazole include headache, sedation, nausea, and vomiting. In men a decrease in androgen production may lead to gynecomastia, decreased libido, and impotence. Men with Cushing’s syndrome can use ketoconazole and replace testosterone if necessary. Cortisol urine tests need to be done frequently to adjust the dose of any corticosteroids inhibitor, but once the dose appears to be optimal; monitoring can be done less often- Monthly or every 6 weeks.
ADRENOLYTIC MEDICATIONS
Mitotane — Mitotane is an adrenocorticolytic drug that is mainly used to treat adrenal carcinomas. It can also be used to achieve chemical adrenalectomy with or without radiation of the pituitary in patients with Cushing’s disease or as an adjunctive medication in patients with ectopic ACTH secretion.
Pituitary Targeted Therapy
The somatostatin analogue, Pasireotide, and the dopamine agonist, Cabergoline are 2 drugs that target the pituitary and have shown potential benefit.
Cabergoline — In two studies, chronic cabergoline therapy (1 to 7 mg orally per week) was associated with clinically important improvement in 24-hour urinary free cortisol (UFC) to ≤125 percent of normal in 12 of 42 patients with Cushing’s disease [38,39]. Normalization of UFC was achieved in 30 percent of patients with up to five years of follow-up [39].
Pasireotide — The somatostatin analog pasireotide binds to somatostatin receptors and blocks the release of adrenocorticotropic hormone (ACTH) from the corticotropes via its high affinity for somatostatin receptor subtype 5 [40]. Pasireotide injection has been approved in a number of countries and is recommended for the treatment of patients with Cushing’s disease for whom surgery has been unsuccessful or who are not surgical candidates [1,41]. It is now available in Europe and in the United States and Canada.
Glucocorticoid-receptor antagonists
Mifepristone (Korlym)
mifepristone blocks cortisol action, the levels of ACTH and cortisol increase in patients with Cushing’s disease, so that hormonal measurement cannot be used to judge either therapeutic efficacy or adrenal insufficiency. Mifepristone also blocks the action of oral & IV steroids, which makes it difficult to treat adrenal insufficiency if it occurs. Dexamethasone is recommended to reverse the receptor blockade of.
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