Medical management of Cushing's disease: what is the future?

Abstract

Cushing's disease (CD) is caused by a corticotroph, adrenocorticotropic-hormone (ACTH)-secreting pituitary adenoma resulting in significant morbidity and mortality. Transsphenoidal surgery is the initial treatment of choice in almost all cases. Remission rates for microadenomas are good at 65-90 % (with an experienced neurosurgeon) but remission rates are much lower for macroadenomas. However, even after postoperative remission, recurrence rates are high and can be seen up to decades after an initial diagnosis. Repeat surgery or radiation can be useful in these cases, although both have clear limitations with respect to efficacy and/or side effects. Hence, there is a clear unmet need for an effective medical treatment. Currently, most drugs act by inhibiting steroidogenesis in the adrenal glands. Most is known about the effects of ketoconazole and metyrapone. While effective, access to ketoconazole and metyrapone is limited in many countries, experience with long-term use is limited, and side effects can be significant. Recent studies have suggested a role for a pituitary-directed therapy with new multireceptor ligand somatostatin analogs (e.g., pasireotide, recently approved in Europe for treatment of CD), second-generation dopamine agonists, or a combination of both. Mifepristone (a glucocorticoid receptor antagonist) is another promising drug, recently approved by the FDA for treatment of hyperglycemia associated with Cushing's syndrome. We review available medical treatments for CD with a focus on the two most recent compounds referenced above. Our aim is to expand awareness of current research, and the possibilities afforded by available medical treatments for this mesmerizing, but often frightful disease.

Fig. 1

Current approaches to medical therapy in CD, with compounds listed aside their main level of action. Ref. [10] (adapted from Petersenn S, Endocrine Updates, 2011 with kind permission from Springer Science+Business Media B.V.)

Fig. 2

Preferential affinities of somatostatin, somatostatin analogs octreotide and lanreotide, and the new multi-receptor ligand somatostatin analog pasireotide for the five known somatostatin receptor subtypes sst1–sst5. Ref. [10] (adapted from Petersenn S, Endocrine Updates, 2011 with kind permission from Springer Science+Business Media B.V.)

Fig. 3

Absolute change of UFC from baseline to month 6 in 103 patients treated with pasireotide. Black dashed line represents ULN. Ref. [34]. Reproduced with kind permission from the Massachusetts Medical Society

Fig. 4

Change from baseline to month 12 in systolic blood pressure, diastolic blood pressure, body weight, and health-related quality of life (HRQoL) (measured using CushingQoL questionnaire, scored from 0 to 100, with higher scores indicated better QoL) among patients treated with pasireotide. Bars indicate SEM. Ref. [34] (adapted from Colao A, et al. N Engl J Med 2012). Reproduced with kind permission from the Massachusetts Medical Society

Fig. 5

Mean change from baseline to week 24/ET in glycemic parameters (AUC_glucose and plasma and fasting plasma glucose as measured by 2-h OGTT, and HbA_1c) among patients treated with mifepristone. Bars indicate SD (AUC, area under the curve; C-DM, Cushing's with diabetes mellitus or hyperglycemia; OGTT, oral glucose tolerance test; ET, early termination) [67] (adapted from Fleseriu M, et al. J Clin Endocrinol Metab 2012. Copyright 2012, The Endocrine Society)

Fig. 6

Mean change from baseline to week 24/ET in body weight and composition among patients treated with mifepristone. Bars indicate SEM [67] (mITT, modified intent to treat) (adapted from Fleseriu M, et al. J Clin Endocrinol Metab 2012. Copyright 2012, The Endocrine Society)