Endocrine Abstracts (2009) 20 P193

Effectiveness and safety of combined therapy with low dose ketoconazole and cabergoline in patients with Cushing's disease partially responsive to monotherapy with cabergoline

Rosario Pivonello, Monica De Leo, MariaCristina De Martino, Alessia Cozzolino, Renata S Auriemma, Mariano Galdiero, Gaetano Lombardi & Annamaria Colao


Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, Naples, Italy.


The first-line treatment of Cushing’s disease is surgery, although it is effective in inducing a long-term remission in around 50% of patients with Cushing’s disease (CD). Nowadays, no pituitary tumor-directed medical treatment is available with the exception of cabergoline, which has been recently demonstrated to control cortisol secretion without major side effects in around 40% of patients with Cushing’s disease. Cabergoline has been recently demonstrated to induce cardiac valve insufficiency in patients with Parkinson’s disease, usually long-term treated with high dose of the drug. A widely used adrenal-directed palliative medical treatment is represented by ketoconazole, which however can be associated with different side effects mainly including liver damage especially when used at high dose (until 1200 mg/day) for a long period of time. The aim of the current study was to evaluate the effectiveness and safety of the combined treatment with cabergoline and low-dose ketoconazole in patients with Cushing’s disease partially responsive to cabergoline mootherapy. Six patients with post-surgical persistent Cushing’s disease had been treated with cabergoline at the maximal dose of 3.5 mg/week with a significant reduction but not normalization of urinary cortisol levels (from 530.5±136.2 to 258.0±107.1 μg/day, P<0.05) associated with a partial clinical improvement after 6 months of treatment. Ketoconazole at the initial dose of 50 mg was added to cabergoline in all patients, and increased by 50 mg every month until normalization of urinary cortisol levels had been achieved. After 6 months of combined treatment with cabergoline (3.5 mg/week) and ketoconazole (50–200 mg/day), urinary cortisol levels were 107.8±19.8 μg/day (P<0.05), and were in the normal range in all patients. A significant clinical improvement was observed in parallel with the decrease and normalization of cortisol levels. No cardiac valve disease occurred or worsened during the 1-year treatment with cabergoline, except a worsening of tricuspidal regurgitation in one patient. No liver damage was observed in any patient. In conclusion, the combined treatment with cabergoline and low dose ketoconazole seems to be effective and safe in the management of patients with Cushing’s disease, and can be considered in patients who had unsuccessful surgical treatment or are not candidates for alternative definitive treatments.