Preclinical and clinical experiences with the role of dopamine receptors in the treatment of pituitary adenomas Diego Ferone, Rosario Pivonello 1 , Eugenia Resmini, Mara Boschetti, Alberto Rebora, Manuela Albertelli, Valeria Albanese, Annamaria Colao 1 , Michael D Culler 2 and Francesco Minuto Department of Endocrinological and Medical Sciences and Center of Excellence for Biomedical Research, University of Genova, Genova, Italy, 1 Department of Molecular and Clinical Endocrinology and Oncology ‘Federico II’ University, Naples, Italy and 2 Biomeasure Inc./IPSEN, Milford, Massachusetts, USA (Correspondence should be addressed to Diego Ferone; Email: ferone@unige.it) Abstract Pituitary tumors can cause symptoms of mass effect and hormonal hypersecretion that can be reversed with surgical resection or debulking of the adenoma, radiotherapy, or medical treatment. Medical treatment is the primary choice for prolactinomas because dopamine agonists are very effective in the treatment of these tumors, with rates of control (tumor size reduction and hormone suppression) as high as 80–90% for microprolactinomas and 60–75% for macroprolactinomas. The function of dopamine receptors in other histotypes of pituitary adenoma is still debated. However, new insights into receptor physiology and the introduction of new clinically available, as well as experimental, compounds have reopened a potential role of dopaminergic drugs in the medical treatment of pituitary tumors. The differences between the effectiveness and the resistance to different dopaminergic agents, the new challenging results from clinical and experimental studies, as well as the future of dopamine agonists in the therapy of pituitary tumors are discussed. European Journal of Endocrinology 156 S37–S43 Introduction The therapeutic strategy for pituitary adenomas includes surgery, radiotherapy, and medical therapy. Therefore, a combination of treatments may be required to attain the therapeutic goal. Among the medications, dopamine agonists represent the first generation of effective drugs used in the treatment of pituitary tumors. The introduction of this class of compounds was based on the evidence that in the hypothalamic–pituitary system, the neurotransmitter/neuromodulator dopamine inhibits pituitary hormone secretion, in particular prolactin (PRL)- and proopiomelanocortin-derived hormones. It is well known that dopamine agonists, such as bromocriptine, pergolide, terguride, lisuride, quinagolide and cabergoline, can inhibit PRL secretion by binding to the D 2 dopamine receptors (D 2 ) located on both normal and pituitary adenoma cells (1). Moreover, they can effectively decrease excessive PRL secretion, as well as the size of the tumor in patients with prolactinoma (2). Furthermore, dopamine agonists can also be used in the treatment of patients with other pituitary tumor histotypes although less frequently. The major requirement for its use is that the tumor cells should express D 2 receptors. Therefore, in addition to prolactinomas, targets of dopamine agonist therapy are somatotrope tumors, nonfunctioning pituitary tumors, corticotrope pituitary tumors including Nelson’s syn- drome, gonadotropinomas and thyrotropin-secreting pituitary tumors (2). Different dopaminergic agents have been introduced into clinical practice over the last decades, and the role of this group of compounds has been recently renewed due to the availability of novel clinical as well as experimental molecules, representing one of the most interesting future perspectives for the medical therapy of pituitary tumors. Dopamine receptors Dopamine receptors (DRs) belong to the family of G protein coupled receptors and they modulate the activity of adenylate cyclases through G proteins. Based on their interaction with adenylate cyclase, the five known DRs are divided into two subfamilies: the D 1 - like (D 1 and D 5 ) and the D 2 -like (D 2 ,D 3 and D 4 ) receptors. D 1 -like receptors stimulate adenylate cyclase activity through G s proteins, while D 2 -like receptors decrease intracellular cAMP accumulation through G i /G o proteins (1). The D 2 receptor exists in two This paper was presented at a symposium held at the Erasmus Medical Center, Rotterdam, The Netherlands, 2005. The symposium was jointly organized by LJ Hofland, Erasmus Medical Center, and A Colao, Federico II University of Naples, Italy. Ipsen partially supported the publication of these proceedings. European Journal of Endocrinology (2007) 156 S37–S43 ISSN 0804-4643 q 2007 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02351 Online version via www.eje-online.org