Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas

Abstract

Objective: 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. Results: The mean mRNA levels for D2DR, SSTR1, SSTR2, and SSTR5 were 92.3G47.3, 2.2G1.4, 1.1G0.7, and 1.6G0.6 copy/copy b-glucuronidase (b-Gus) respectively. The SSTR1 agonist, BIM-23926, did not suppress PRL in prolactinomas. In a DA-resistant prolactinoma, it did not inhibit [ 3 H]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 EC 50 (0.5G0.1 vs 2.5G1.5 pmol/l). In DA-resistant prolactinomas, BIM-23206 and SOM230 were ineffective. Cabergoline and BIM-23A760 produced a partial inhibition of PRL secretion (19G6 and 21G3% respectively). Conclusion: 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.European Journal of Endocrinology 158 595-603

Efficacy of the combined cabergoline and octreotide treatment in a case of a dopamine-agonist resistant macroprolactinoma

“…This result is in agreement with the synergistic cooperation found between these two receptors which form heterodimers with enhanced functional activity in transfected cell lines [27]. However, this cooperation appears of little utility in the control of PRL secretion in vitro, as the chimeric somato-dopamine molecule BIM23A760 which binds sstr5, sstr2 and D2R receptors, was found to suppress PRL secretion to a similar extent than D2R agonists alone in rat pituitary cells and sensitive or resistant human prolactinomas [28,29]. Taking these results based on acute pharmacological effects into consideration, it could be argued that in our patient a partial synergistic cooperation between sstr5 and D2R receptors could have been induced by the long-term co-treatment with cabergoline and octreotide; this hypothesis, however, needs to be further investigated in larger clinical studies.…”

Resistance to dopamine agonists in prolactinoma is correlated with reduction of dopamine D2 receptor long isoform mRNA levels

“…It is difficult to define standard dose thresholds to assign the status of dopamine agonist resistance. However, a dose of 1.5, 2.0, or 3.5 mg/week of cabergoline was proposed to define resistance to treatment in macroprolactinoma (19,20,21). We have classified prolactinoma patients into good and poor responders according to the threshold dose of 1.0 mg/week of cabergoline, which was the same as the median dose able to normalise PRL levels in two previous retrospective studies (19,20).…”

Somatostatin Receptor sst2 Decreases Cell Viability and Hormonal Hypersecretion and Reverses Octreotide Resistance of Human Pituitary Adenomas

“…Prolactinoma tumors do not usually respond to octreotide (12). Induced sst2 expression allowed octreotide to be fully effective in this type of tumors.…”

“…However, treatment is ineffective in 10% to 15% of treated patients, even with the most potent dopamine analogue, cabergoline (9,10). Somatostatin receptors sst5, sst1, and sst2 are expressed in these tumors (11,12).…”