Medical treatment of Cushing's disease.
BACKGROUND
Cushing's disease (CD) is associated with serious morbidity and, when suboptimally treated, an increased mortality. Although surgery is the first-line treatment modality for CD, hypercortisolism persists or recurs in an important subset of patients. Considering the deleterious effects of uncontrolled CD, there is a clear need for effective medical therapy.


OBJECTIVE
In this review, we discuss molecular targets for medical therapy, efficacy, and side effects of the currently used drugs to treat hypercortisolism and focus on recent developments resulting from translational and clinical studies.


METHODS
Selection of publications related to the study objective was performed via a PubMed search using relevant keywords and search terms.


RESULTS
Medical therapy for CD can be classified into pituitary-directed, adrenal-blocking, and glucocorticoid receptor-antagonizing drugs. Recent studies demonstrate that somatostatin receptor subtype 5 (sst(5)) and dopamine receptor subtype 2 (D(2)) are frequently (co-)expressed by corticotroph adenomas. Pituitary-directed therapy with pasireotide and cabergoline, targeting sst(5) and D(2), respectively, is successful in approximately 25-30% of patients. Adrenal-blocking drugs can be effective by inhibiting steroidogenic enzyme activity. Finally, the glucocorticoid receptor antagonist mifepristone induces clinical and metabolic improvement in the majority of patients. Each drug can have important side effects that may impair long-term treatment. Generally, patients with moderate to severe hypercortisolism need combination therapy to normalize cortisol production.


CONCLUSIONS
Medical therapy for CD can be targeted at different levels and should be tailored in each individual patient. Future studies should examine the optimal dose and combination of medical treatment modalities for CD.
Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands. r.feelders@erasmusmc.nl
Richard A
RA
Feelders
Leo J
LJ
Hofland
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D018491:Dopamine Agonists / Q000627:therapeutic use*; D006801:Humans; D008939:Mitotane / Q000627:therapeutic use; D015282:Octreotide / Q000627:therapeutic use; D047748:Pituitary ACTH Hypersecretion / Q000188:drug therapy*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000627:therapeutic use
D018931:Antineoplastic Agents, Hormonal; D018491:Dopamine Agonists; D011965:Receptors, Glucocorticoid; D013004:Somatostatin; D008939:Mitotane; C517782:pasireotide; D015282:Octreotide