The Treatment of Cushing's Disease

Abstract

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.

The degree of urinary hypercortisolism is not correlated with the severity of cushing’s syndrome

“…It is the consequence of a pituitary or extrapituitary ACTH-secreting tumor (respectively 70-75 and 5-10 % of cases), which in turn stimulate cortisol overproduction from adrenal glands, while in few patients it may depend on an adrenal tumor or hyperplasia (10-20 % of cases) [1][2][3][4].…”

Effective Medical Therapy for Cushing Disease Can Increase the Susceptibility to Relative Hypocortisolism

“…Pituitary-targeted inhibitors (such as pasireotide) theoretically represent the most physiologic approach to treating CD by suppressing ACTH secretion from the corticotrope adenoma, thereby secondarily normalizing cortisol levels (17). However, the mechanism of medical therapy in inducing eucortisolemia can vary depending on whether therapy targets the corticotrope adenoma, adrenal gland, or peripheral glucocorticoid receptors.…”

Factors affecting the probability of recurrence of the Cushing’s disease within 3 years after effective neurosurgical treatment

“…Наши результаты соответствуют резуль-татам ряда других исследований в отноше-нии того, что факторами предикции рециди-ва являются утренние уровни АКТГ и корти-зола [14,16,19]. Однако нами дополнитель-но выявлено, что перспективным фактором рецидивирования является вечерний по-слеоперационный уровень АКТГ.…”