The clinical–molecular interface of somatostatin, dopamine and their receptors in pituitary pathophysiology

Abstract

The role of somatostatin and dopamine receptors as molecular targets for the treatment of patients with pituitary adenomas is well established. Indeed, dopamine and somatostatin receptor agonists are considered milestones for the medical therapy of these tumours. However, in recent years, the knowledge of the expression of subtypes of somatostatin and dopamine receptors in pituitary adenomas, as well as of the coexpression of both types of receptors in tumour cells, has increased considerably. Moreover, recent insights suggest a functional interface of dopamine and somatostatin receptors, when coexpressed in the same cells. This interaction has been suggested to occur via dimerisation of these G-protein-coupled receptors. In addition, there was renewed interest around the concept of cell specificity in response to ligand-induced receptor activation. New experimental drugs, including novel somatostatin analogues, binding to multiple somatostatin receptor subtypes, as well as hybrid somatostatin-dopamine compounds have been generated, and recently a completely novel class of molecules has been developed. These advances have opened new perspectives for the medical treatment of patients with pituitary tumours poorly responsive to the present clinically available drugs, and perhaps also for the treatment of other categories of neuroendocrine tumours. The aim of the present review is to summarise the novel insights in somatostatin and dopamine receptor pathophysiology, and to bring these new insights into perspective for the future strategies in the medical treatment of patients with pituitary adenomas.

The role of somatostatin and dopamine D2 receptors in endocrine tumors

“…Behavioral and clinical evidence in brain research indicated an interaction between the somatostatinergic and dopaminergic systems (Chneiweiss et al 1985, Martin-Iverson et al 1986, Izquierdo-Claros et al 1997, Marzullo et al 1999, recently confirmed by in vitro studies (Rocheville et al 2000a, Baragli et al 2007, Kidd et al 2008. It is well known that SSTR and DR are widely expressed both in normal human neuroendocrine tissues and in tumors (Reubi et al 1987, Pivonello et al 2007b, such as pituitary adenomas (Stefaneanu et al 2001, Moller et al 2003, Saveanu et al 2008, Ferone et al 2009) and adrenal tumors (Pivonello et al 2007a,b, de Bruin et al 2009a. Since SSTR and D 2 -like receptors mainly exert inhibitory functions, medical therapies targeting these receptors with selective agonists have been developed for the treatment of a number of neuroendocrine disorders.…”

“…In recent years, somatostatin (SS) and dopamine (DA) receptors have been highlighted as two critical regulators involved in the negative control of hormonal secretion in a wide group of neuroendocrine tumors (NET), including pituitary adenomas (Ben-Jonathan & Hnasko 2001, Guillemin 2005, Ferone et al 2009). Moreover, SS, DA, and their receptors represent two major systems that share a number of structural and functional characteristics (Rocheville et al 2000a, Baragli et al 2007, Srirajaskanthan et al 2009).…”

Experience with pegvisomant treatment in acromegaly in a single Brazilian tertiary reference center: efficacy, safety and predictors of response

“…The efficacy of other DA, like bromocriptine, is probably lower than that of cabergoline (4). These two drug classes (SA and DA) act on somatotropinoma through binding to its receptors (17,18).…”

DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours

“…Nevertheless, its negative effects on glucose tolerance are even more pronounced than with Octreotide (14,20). On the other hand, BIM-23A760 (Dopastatin), a chimeric molecule directed towards somatostatin (mainly sst2 and sst5) and dopamine D2 receptors (21,22,23), suppresses GH in vitro but was ineffective when applied to acromegalic patients in clinical trials (press release 15 Dec 2010, Ipsen Pharma).…”