Cushing’s Disease: Drug Therapy

Therapeutic target

Normalization of serum cortisone levels.

Therapy recommendations

  • Primary surgical therapy (for indications, see “Surgical therapy” below); in rare cases, radiation therapy of the pituitary gland (e.g., for recurrence/recurrence of Cushing’s disease, in primarily inoperable patients); after surgery, substitution therapy (replacement therapy) with a cortisone drug.
  • In NNR carcinoma treatment with: Cytostatics, adrenostatics
  • In iatrogenic Cushing’s syndrome (undesirable consequence of medical treatment ): check and if necessary adjust the existing cortisol dose.
  • In case of recurrence of central Cushing’s disease (Cushing’s disease) [after resection/surgical removal of a microadenoma of the anterior pituitary]: therapy trial with somatostatin analogue; ketoconazole.
  • See also under “Further therapy.”

For recurrence of central Cushing’s disease (Cushing’s disease) [after resection of an anterior pituitary microadenoma]

Therapeutic trial with:

  • Somatostatin analog (pasireotide) 600 ug, twice daily s.c. → targeted curbing of ACTH secretion [phase II trial!]
  • Ketoconazole (inhibits synthesis of steroids, including cortisol)Red Hand Letter on Ketoconazole HRA (ketoconazole): “Risk of hepatotoxicity Ketoconazole in oral form is a potent inhibitor of cortisol synthesis due to its property as an inhibitor of cytochrome P450 enzymes in the adrenal gland. Furthermore, ketoconazole has direct effects on corticotropic tumor cells in patients with Cushing’s syndrome. It is approved for the treatment of endogenous Cushing’s syndrome in adults and adolescents over twelve years of age. Due to the risk of hepatotoxicity (liver toxicity), the marketing authorization for oral ketoconazole as an antifungal agent was suspended in October 2013. Hepatotoxicity with oral ketoconazole treatment is usually observed at treatment initiation and during the first six months. Ketoconazole HRA for the treatment of Cushing’s syndrome is expected to be on the market in Germany from March 15, 2015. The manufacturer provides advance information on the risk of hepatotoxicity and measures to minimize the risk in a red-hand letter:
    • Oral treatment with ketoconazole must be initiated and monitored by a physician experienced in the treatment of Cushing’s disease.
    • Ketoconazole in oral form is contraindicated in patients with acute or chronic liver disease or if liver enzyme levels are more than twofold above the upper limit of normal at the start of treatment.
    • Ketoconazole should be discontinued immediately if clinical symptoms of hepatitis develop.
    • Patients must be informed of the risks of hepatotoxicity and possible symptoms (eg, anorexia, nausea/vomiting, jaundice, dark urine). If appropriate symptoms occur, treatment should be discontinued immediately, a physician should be notified, and liver function tests should be performed.
    • Before starting and during treatment, liver values must be determined regularly according to the specialist information.
    • If liver enzyme levels increase to less than three times the upper limit of normal values, closer monitoring of liver function must be performed and the daily dose reduced by at least 200 mg.
    • If liver enzyme levels increase to at least three times the upper limit of normal values, treatment should be discontinued immediately.”