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

Objective: Dopamine agonists normalize prolactin (PRL) levels and reduce tumour size in responsive prolactinoma. However, several cases have shown resistance to dopamine agonists upon initial treatment. Infrequently, prolactinoma initially responds, but then becomes refractory to prolonged treatment (secondary resistance). We investigated the possible mechanisms of resistance to dopamine agonists. Subjects and methods: Twelve cases of prolactinoma were surgically resected and classified according to the responsiveness of PRL levels and tumour size to dopamine agonists: good responders (n = 5), poor responders (n = 5), or secondary resistance (n = 2). We examined the expression of dopamine D-2 receptor (D2R) isoform (short: D2S and long: D2L) mRNA and protein. We investigated DNA methylation patterns in the promoter region of the DRD2 gene. Results: The predominant D2R isoform expressed in prolactinoma was D2L. Levels of D2L mRNA were significantly lower in secondary resistance and poor responders than in good responders. Expression of D2R protein was variable among cases. Almost no CpG sites of the DRD2 gene promoter region were methylated. Conclusion: Resistance of prolactinoma to dopamine agonists is correlated with a reduction in D2L isoform mRNA levels. Silencing of the DRD2 gene by methylation in the promoter region is unlikely to play a role in dopamine agonist resistance in prolactinoma.