Ten percent of patients with prolactinoma fail to respond with normalization of prolactin (PRL) and tumor shrinkage under dopamine agonist (DA) therapy. The resistance to treatment is linked to a loss of dopamine receptor 2 (D2DR). Prolactinomas express somatostatin (SST) receptor subtypes, SSTR1, 2, and 5. The aim of this study was to determine whether different SST compounds could overcome the resistance to DA in prolactinomas.
Design and methods
The efficacy of SSTR1, SSTR2, and SSTR5 ligands; the universal SST ligand, SOM230; and the chimeric SST-DA compound, BIM-23A760, was compared with cabergoline in suppressing PRL secretion from primary cultures of ten prolactinomas (six DA responders and four DA resistant). Receptor mRNAs were assessed by quantitative PCR.
The mean mRNA levels for D2DR, SSTR1, SSTR2, and SSTR5 were 92.3±47.3, 2.2±1.4, 1.1±0.7, and 1.6±0.6 copy/copy β-glucuronidase (β-Gus) respectively. The SSTR1 agonist, BIM-23926, did not suppress PRL in prolactinomas. In a DA-resistant prolactinoma, it did not inhibit [3H]thymidine incorporation. The SSTR5 compound, BIM-23206, produced a dose-dependent inhibition of PRL release similar to that of cabergoline in three DA-sensitive prolactinomas. BIM-23A760 produced a maximal PRL inhibition superimposable to that obtained with cabergoline with a lower EC50 (0.5±0.1 vs 2.5±1.5 pmol/l). In DA-resistant prolactinomas, BIM-23206 and SOM230 were ineffective. Cabergoline and BIM-23A760 produced a partial inhibition of PRL secretion (19±6 and 21±3% respectively).
Although the SSTRs are expressed in prolactinomas, the somatostatinergic ligands analyzed do not appear to be highly effective in suppressing PRL. D2DR remains the primary target for effective treatment of prolactinomas.