Is there a role for dopamine D2 receptor gene polymorphisms in determining cabergoline sensitivity in prolactin-secreting pituitary adenomas?
Marcello Filopanti, Anna Maria Barbieri, Rita Angioni, Andrea Lania, Giovanna Mantovani, Anna Spada & Paolo Beck-Peccoz
Dopamine agonist cabergoline (CB) is the first-choice treatment in prolactin-secreting adenomas (PRL-omas). It is effective in reducing PRL secretion and tumour size in about 90% of patients by binding dopamine D2 receptor (DRD2). Although no mutations in DRD2 were found, it has been reported that several polymorphisms of this locus associate with alcoholism and schizophrenia, diseases in which dopaminergic system plays an important role. To assess the possible association of DRD2 gene polymorphisms (i.e. TaqIB, HphIG/T, NcoIC/T and TaqIA) with the sensitivity to CB, a multicentric retrospective study was carried out including 252 patients with PRL-oma and 211 healthy controls. Genotyping was carried out by restriction fragment length polymorphism analysis (RFLP) on blood DNA. Pituitary MRI and PRL assay were performed at diagnosis and during CB therapy follow-up (median 17 months, range 549). Patients were defined as resistant when they failed to normalize PRL levels and/or to reduce tumor size with a CB dosage higher than 3 mg/week. According to this definition, in our series the overall prevalence of resistant patients was 8% and 3.4%, respectively. As far as DRD2 genotypes were concerned, no differences in allele frequencies between patients and normal subjects were observed. Moreover, any polymorphism correlated with clinical presentation, biochemical data and tumor size. Conversely, we observed an higher frequency of NcoIT+ allele in subjects defined as resistant to CB in term of both normalization of PRL levels [(χ2)P=0.038] and tumor size reduction [(χ2)P=0.006]. Finally, [A1-/B1-/T-/T-] haplotype was found to be associated with a greater sensitivity to CB in term of PRL normalization. In fact, this haplotype was found in 34% of patients taking less of 3 mg/week of CB vs 11% of resistant patients [(χ2)P=0.021]. In conclusion, further studies are required to assess the mechanisms underlying the involvement of DRD2 gene polymorphisms in determining the CB sensitivity.