Cushing's disease (CD), or pituitary-dependent
Cushing's syndrome, is a severe
endocrine disease caused by a corticotroph
pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary
radiotherapy, adrenal surgery, and/or medical
therapy. Pituitary
radiotherapy is effective in controlling
cortisol excess in a large percentage of patients, but it is associated with a considerable risk of
hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of
cortisol excess in nearly all patients, but it induces
adrenal insufficiency. Medical
therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control
cortisol secretion or action. Currently, medical
therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical
tumor resection; or as bridging
therapy before, during, and after
radiotherapy while waiting for disease control; or, in selected cases, as primary
therapy, mainly when surgery is not an option. The adrenal-directed drug
ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the
glucocorticoid receptor antagonist,
mifepristone, is highly effective in controlling clinical comorbidities, mainly
glucose intolerance, thus being a useful treatment for CD when it is associated with
diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the
pituitary tumor. Among this group of drugs, the
dopamine agonist cabergoline and the
somatostatin analog
pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently,
pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and
mifepristone has been approved for the treatment of
Cushing's syndrome when associated with impairment of
glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control
cortisol excess in a great majority of patients with CD.