263 Review www.expert-reviews.com ISSN 1744-6651 © 2009 Expert Reviews Ltd 10.1586/EEM.09.10 Cushing’s disease (CD) is an endocrine dis- ease due to chronic excess of cortisol secretion caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma [1,2] . The first description of patients with this disease was in a monograph by Harvey Cushing in 1932. The clinical manifestations of CD are variable and differ widely in severity. Clinical signs and symptoms of CD are widely described, as well as its morbo–mortality rate [1–5] . Cortisol excess may induce vascular dam- age both directly and indirectly, favoring the occurrence of premature atherosclerosis in these patients. Therefore, the high cardiovascular risk of these patients is related to the cortisol-depend- ent complications of the disease, including cen- tral obesity, hypertension, impairment of glucose tolerance or diabetes mellitus, abnormalities in lipid pattern and coagulation processes [6–9] . The treatment of CD is very complex and represents a challange for the clinicians [10] . Indeed, transphenoidal surgical excision of ACTH-secreting pituitary adenoma remains the treatment of choice for CD but unfortunately the rate of cure at long-term follow-up is subopti- mal and recurrences are high, even in the hands of skilled neurosurgeons [2,11–15] . Other treat- ments options, such as bilateral adrenalectomy and pituitary radiotherapy, are currently in use but no treatment has proven to be fully satis- factory during the lengthy progression of this chronic and devastating disease. Long time-to- effect of radiotherapy (at least 12–24 months), Nelson’s syndrome and hypopituitarism are of particular concern as affected patients need lifelong hormone-replacement therapy (which is often suboptimal) and have notably increased mortality [16–18] . Therefore, there is still a strong need for a medical treatment option in the management of this disease. An additional medical therapy may be useful in patients undergoing surgery (especially in the presence of diabetes, hyper- tension and marked coagulation abnormalities), as well as for those patients who have persistent or recurrent disease after unsuccessful surgery Giorgio Arnaldi, Marina Cardinaletti, Laura Trementino, Giacomo Tirabassi and Marco Boscaro † † Author for correspondence Clinica di Endocrinologia, Azienda Ospedaliero- Universitaria, Ospedali Riuniti di Ancona, 60100 Ancona, Italy Tel.: +39 071 887 061 Fax: +39 071 887300 m.boscaro@univpm.it The treatment of Cushing’s disease is very complex and represents a challenge for clinicians. Transphenoidal surgical excision of adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma remains the treatment of choice but, unfortunately, the rate of cure at long-term follow-up is suboptimal and recurrences are high, even in the hands of skilled neurosurgeons. Other treatment options, such as bilateral adrenalectomy and pituitary radiotherapy, are currently in use but no treatment has proven fully satisfactory during the lengthy progress of this chronic and devastating disease. Nelson’s syndrome and hypopituitarism are of particular concern as affected patients need lifelong hormone-replacement therapy and have notably increased mortality. Although medical treatment represents a second-line treatment option in patients with Cushing’s disease, so far pharmacological therapy has been considered a transient and palliative treatment. Many drugs have been employed: they may act at the hypothalamic–pituitary level, decreasing ACTH secretion; at the adrenal level, inhibiting cortisol synthesis (steroidogenesis inhibitors); or at the peripheral level by competing with cortisol (glucocorticoid receptor antagonists). Recently, there has been renewed interest in the medical therapy of Cushing’s disease and pituitary-directed drugs include old compounds commercially available for other diseases, such as cabergoline, and new promising compounds, such as pasireotide (SOM230) or retinoic acid. This review focuses on the tumor-directed pharmacological approaches for the management of Cushing’s disease based on the recent identification of possibile targets at a pituitary level. KEYWORDS: cabergoline • Cushing’s disease • dopaminergic receptors • medical therapy • pasireotide (SOM230) • pituitary-directed drug • retinoid acid • somatostatin receptor • thiazolidinediones Pituitary-directed medical treatment of Cushing’s disease Expert Rev. Endocrinol. Metab. 4(3), 263–272 (2009) For reprint orders, please contact reprints@expert-reviews.com