Pituitary Disorders Medical Treatment of Cushing’s Disease with Pasireotide André Lacroix 1 and Rosario Pivonello 2 1. Professor, Department of Medicine, Centre hospitalier de l’Université de Montréal (CHUM), Montréal, Québec, Canada; 2. Assistant Professor, Department of Molecular and Clinical Endocrinology and Oncology, ‘Federico II’ University of Naples, Naples, Italy Abstract Cushing’s disease is the most common form of endogenous Cushing’s syndrome and results from excess adrenocorticotropic hormone (ACTH) production by a corticotroph pituitary adenoma. Transsphenoidal surgical removal of the corticotroph adenoma is the treatment of choice for patients with Cushing’s disease. However, despite advances in surgery, complete tumour removal is sometimes impossible and eventual disease recurrence occurs later even in patients who achieved an initial remission. Medical therapy is one of the second-line options, which can provide a primary or adjunctive role if the patient cannot safely undergo pituitary surgery, if surgery fails, or if the tumour recurs. However, until recently, few effective therapeutic options existed. Somatostatin receptors in the corticotroph tumours have been identified as potential therapeutic targets for Cushing’s disease. Pasireotide is a novel somatostatin analogue which has high affinity for these receptors. In a recent Phase III clinical trial, pasireotide treatment was demonstrated to significantly reduce elevated cortisol levels in patients with Cushing’s disease achieving normalisation of urinary free cortisol (UFC) levels in subset of patients and close to 50 % mean reduction in UFC levels were seen in the patients. Initial data also suggest that pasireotide could be highly effective as part of combined therapy for Cushing’s disease. Keywords Cushing’s disease, pasireotide, somatostatin receptors, ACTH, corticotroph tumour Disclosure: André Lacroix is an investigator in clinical trials on pasireotide in Cushing's disease and is a member of advisory boards for Novartis on the therapy of pituitary tumours. Rosario Pivonello has received research funding grants from Novartis and has been an occasional consultant for Novartis. Acknowledgements: Editorial assistance was provided by Janet Manson at Touch Medical Media and was funded by Novartis. Received: 24 October 2012 Accepted: 8 November 2012 Citation: European Endocrinology, 2012;8(2):99–104 Correspondence: André Lacroix, Centre hospitalier de l’Université de Montréal, (CHUM), 3840 Rue Saint-Urbain, Montréal, Québec, H2W 1T8, Canada. E: andre.lacroix@umontreal.ca Support: The publication of this article was funded by Novartis. The views and opinions expressed are those of the authors and not necessarily those of Novartis. Cushing’s disease is caused by a pituitary adenoma that secretes elevated levels of adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce excess cortisol. 1 The tumours are most frequently microadenomas (≤1 cm in diameter) while corticotroph macroadenomas are responsible for approximately 10 % of cases. Cushing’s disease is the most common form of endogenous Cushing’s syndrome accounting for about 70 % of patients with this condition and has an estimated annual incidence of 0.1–2.0 new cases per 100,000 worldwide. 2–4 Chronic stimulation by ACTH produces diffuse bilateral hyperplasia of the adrenal cortex which can sometimes become nodular and enlarged. The primary clinical symptoms of Cushing’s disease are due to hypercortisolism. Symptoms and signs develop gradually and include weight gain (particularly on the trunk and face), fatigue, proximal muscle weakness, oedema, diabetes, hypertension, sleep disturbances, cognitive impairment, depression, osteoporosis, infections, skin atrophy, ecchymosis, hirsutism and menstrual irregularities in women and decreased libido and erectile dysfunction in men. If Cushing’s disease is left untreated or uncontrolled, this can result in severe complications including ischaemic and thromboembolic cardiovascular events. 5 Individuals with such progression have a mortality rate four to five times higher than an age- and sex-matched population. 4,6,7 © TOUCH MEDICAL MEDIA 2012 Surgical Therapy of Cushing’s Disease The treatment goals in Cushing’s disease include elective removal of corticotroph tumour while preserving pituitary function, reversal of clinical features, normalisation of biochemical changes and long-term control without recurrence. Surgical removal of the tumour is the first-line treatment; however, the risk of initial surgical failure in microadenoma is 10–35 % and recurrence of Cushing’s disease may reach 20 % in the subsequent ten years. In the case of macroadenoma, surgery is unsuccessful in achieving remission in >45 % of cases, remission rates are lower (12–45 %) and recurrence occurs sooner than in microadenoma (mean 16 versus 49 months). 8 The reported rates of remission vary as a result of differing criteria of cortisol values and endpoints used to determine remission, and differences in the timeframe of patient monitoring (see Table 1). Patil et al. found that although surgical remission was achieved in 85.6 % of 215 patients with Cushing’s disease who underwent first line transsphenoidal surgery for resection of a pituitary microadenoma, disease recurrence was found in a quarter of these (25.5 %) at five-year follow up. 9 Another study reported a remission rate of 56 % of 63 patients at 9.6 years post-transsphenoidal surgery. 10 Treatment options for patients with persistent or recurrent disease include repeat transsphenoidal surgery, pituitary radiotherapy, medical therapy and bilateral adrenalectomy. Repeat pituitary surgery is associated with an 99