-
Views
-
Cite
Cite
Peter J. Trainer, Next Generation Medical Therapy for Cushing's Syndrome—Can We Measure a Benefit?, The Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 4, 1 April 2014, Pages 1157–1160, https://doi.org/10.1210/jc.2014-1054
Close - Share Icon Share
Extract
Innovations in the medical management of Cushing's syndrome seem akin to London's red buses—none come along for ages and then three arrive together, namely, mifepristone, pasireotide, and LCI699.
The contrast between developments in the medical management of Cushing's and acromegaly over the last two decades has been stark: no new treatment options for the former, whereas the latter has been transformed not only by the introduction of octreotide, lanreotide, and pegvisomant, but also by improvements in disease monitoring with serum IGF-1. Outcomes from definitive therapy for patients with Cushing's syndrome have improved with the recognition of the importance of specialist pituitary surgeons undertaking transsphenoidal surgery, refinements in radiotherapy, and the relatively low morbidity of laparoscopic adrenalectomy in the right hands. All of these have combined to reduce the number of patients requiring long-term medical therapy, but all the same, medical therapy has an important role in controlling hypercortisolism before definitive therapy and after unsuccessful surgery, often while other options are being considered. The most consistently efficacious agents are those that inhibit adrenal cortisol synthesis, although there has been a resurgence of interest in centrally acting drugs that inhibit ACTH secretion. In addition to studies with pasireotide (discussed below), cabergoline has recently been reported to normalize urinary free cortisol (UFC) in 40% of 20 patients with Cushing's disease treated with doses of up to 7 mg/wk (1). Ketoconazole has probably been the most widely prescribed agent used to inhibit adrenal cortisol synthesis, but in July 2013 the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) simultaneously issued a safety warning about the use of ketoconazole for the treatment of fungal infection because of hepatotoxicity. Although it was acknowledged by regulatory authorities that ketoconazole is “used off-label for patients with Cushing's syndrome” and that “arrangements are being put in place to ensure this group of patients continue to have access to oral ketoconazole,” to date the reality appears to be that the main manufacturer is discontinuing production, which casts uncertainty over the continuity of supply. Metyrapone has been successfully used in some countries for 40 years, but in others it is essentially an unknown quantity. It inhibits the final step in cortisol synthesis, namely the conversion by 11β-hydroxylase of 11-deoxycortisol (11-DOC) to cortisol with nadir cortisol values occurring within 2 hours of a dose, and despite inducing a rise in ACTH, it is an effective long-term treatment (2).
