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Pituitary

, Volume 20, Issue 3, pp 295–300 | Cite as

Cabergoline and prolactinomas: lack of association between DRD2 polymorphisms and response to treatment

  • CBF BuenoEmail author
  • EB Trarbach
  • MD Bronstein
  • A Glezer
Article

Abstract

Background

About 80% of prolactinomas respond to dopamine agonists (DA) with hormonal normalization and tumor shrinkage. Mechanisms of DA resistance include reduction of dopamine receptor subtype 2 (DRD2) expression, short and long isoform ratio and post-receptor mechanisms. It was suggested that polymorphisms in the gene encoding dopamine receptor subtype 2 gene (DRD2) could be associated with variable effectiveness of cabergoline (CAB).

Objective

To assess the influence of DRD2 polymorphisms in responsiveness of CAB treatment in patients with prolactinoma.

Study design and patients

Cross-sectional retrospective case–control study analyzing the frequency of five DRD2 polymorphisms in 148 patients with prolactinoma and 349 healthy subjects. The association of genetic variants and clinical characteristics with CAB responsiveness was performed in 118 patients (mean age at diagnosis 29 years; range 11–61 years) with hormonal evaluation. Patients with prolactin (PRL) normalization were considered as responders.

Results

No association in genotypes and allele proportions was found comparing patients and controls. On pharmacogenetic study, 118 patients on CAB were included and 20% were non-responders. No association was found between clinical characteristics (gender, age, PRL level and tumor size at diagnosis) and polymorphisms of DRD2 with CAB responsiveness. Otherwise, there was association between polymorphisms rs1076560 (allele A) and rs1800497 (allele T) and the presence of macroadenomas.

Conclusion

No correlation was found between DRD2 polymorphisms and CAB responsiveness in patients with prolactinoma. More data are necessary in order to assess the influence of DRD2 genotyping on DA treatment response.

Keywords

Polymorphism DRD2 Prolactinoma Dopamine agonist Cabergoline 

Notes

Acknowledgements

This work was supported by institutional grant from CAPES (to C.B.F.B.); Grant 2011/19932-5 from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Federico Foundation (to A.G.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Hardy J (1973) Transphenoidal surgery of hypersecretiom pituitary tumors. In: Kohler PO, Ross GT (eds). Int Congr Ser 303. Amsterdam, pp 179–194Google Scholar
  2. 2.
    Verhelst J, Abs R, Maiter D, van den Bruel A, Vandeweghe M, Velkeniers B et al (1999) Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients. J Clin Endocrinol Metab 84(7):2518–2522CrossRefPubMedGoogle Scholar
  3. 3.
    Colao A, Di Sarno A, Landi ML, Cirillo S, Sarnacchiaro F, Facciolli G et al (1997) Long-term and low-dose treatment with cabergoline induces macroprolactinoma shrinkage. J Clin Endocrinol Metab 82(11):3574–3579CrossRefPubMedGoogle Scholar
  4. 4.
    Colao A, Di Sarno A, Landi ML, Scavuzzo F, Cappabianca P, Pivonello R et al (2000) Macroprolactinoma shrinkage during cabergoline treatment is greater in naive patients than in patients pretreated with other dopamine agonists: a prospective study in 110 patients. J Clin Endocrinol Metab 85(6):2247–2252PubMedGoogle Scholar
  5. 5.
    Filopanti M, Barbieri AM, Angioni AR, Colao A, Gasco V, Grottoli S et al (2008) Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas. Pharmacogen J 8(5):357–363CrossRefGoogle Scholar
  6. 6.
    Delgrange E, Daems T, Verhelst J, Abs R, Maiter D (2009) Characterization of resistance to the prolactin-lowering effects of cabergoline in macroprolactinomas: a study in 122 patients. Eur J Endocrinol 160(5):747–752CrossRefPubMedGoogle Scholar
  7. 7.
    Molitch ME (2005) Pharmacologic resistance in prolactinoma patients. Pituitary 8(1):43–52CrossRefPubMedGoogle Scholar
  8. 8.
    Passos VQ, Fortes MA, Giannella-Neto D, Bronstein MD (2009) Genes differentially expressed in prolactinomas responsive and resistant to dopamine agonists. Neuroendocrinology 89(2):163–170CrossRefPubMedGoogle Scholar
  9. 9.
    Pellegrini I, Rasolonjanahary R, Gunz G, Bertrand P, Delivet S, Jedynak CP et al (1989) Resistance to bromocriptine in prolactinomas. J Clin Endocrinol Metab 69(3):500–509CrossRefPubMedGoogle Scholar
  10. 10.
    Caccavelli L, Feron F, Morange I, Rouer E, Benarous R, Dewailly D et al (1994) Decreased expression of the two D2 dopamine receptor isoforms in bromocriptine-resistant prolactinomas. Neuroendocrinology 60(3):314–322CrossRefPubMedGoogle Scholar
  11. 11.
    Caccavelli L, Morange-Ramos I, Kordon C, Jaquet P, Enjalbert A (1996) Alteration of G alpha subunits mRNA levels in bromocriptine resistant prolactinomas. J Neuroendocrinol 8(10):737–746CrossRefPubMedGoogle Scholar
  12. 12.
    Peverelli E, Mantovani G, Vitali E, Elli FM, Olgiati L, Ferrero S et al (2012) Filamin-A is essential for dopamine d2 receptor expression and signaling in tumorous lactotrophs. J Clin Endocrinol Metab 97(3):967–977CrossRefPubMedGoogle Scholar
  13. 13.
    Zhang JP, Lencz T, Malhotra AK (2010) D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis. Am J Psychiatry 167(7):763–772CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hirvonen M, Laakso A, Någren K, Rinne JO, Pohjalainen T, Hietala J (2004) C957T polymorphism of the dopamine D2 receptor (DRD2) gene affects striatal DRD2 availability in vivo. Mol Psychiatry 9(12):1060–1061CrossRefPubMedGoogle Scholar
  15. 15.
    Hirvonen MM, Laakso A, Någren K, Rinne JO, Pohjalainen T, Hietala J (2009) C957T polymorphism of dopamine D2 receptor gene affects striatal DRD2 in vivo availability by changing the receptor affinity. Synapse 63(10):907–912CrossRefPubMedGoogle Scholar
  16. 16.
    Noble EP, Blum K, Ritchie T, Montgomery A, Sheridan PJ (1991) Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism. Arch Gen Psychiatry 48(7):648–654CrossRefPubMedGoogle Scholar
  17. 17.
    Thompson J, Thomas N, Singleton A, Piggott M, Lloyd S, Perry EK et al (1997) D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics 7(6):479–484CrossRefPubMedGoogle Scholar
  18. 18.
    Pohjalainen T, Rinne JO, Någren K, Lehikoinen P, Anttila K, Syvälahti EK et al (1998) The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry 3(3):256–260CrossRefPubMedGoogle Scholar
  19. 19.
    Jönsson EG, Nöthen MM, Grünhage F, Farde L, Nakashima Y, Propping P et al (1999) Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 4(3):290–296CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang Y, Bertolino A, Fazio L, Blasi G, Rampino A, Romano R et al (2007) Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci USA. 104(51):20552–20557CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J et al (2003) Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 12(3):205–216CrossRefPubMedGoogle Scholar
  22. 22.
    Hansen KA, Zhang Y, Colver R, Tho SP, Plouffe L, McDonough PG (2005) The dopamine receptor D2 genotype is associated with hyperprolactinemia. Fertility Sterility 84(3):711–718CrossRefPubMedGoogle Scholar
  23. 23.
    Ilhan M, Kahraman OT, Turan S, Turgut S, Karaman O, Zeybek U et al (2015) Does DRD2 polymorphism influence the clinical characteristics of prolactinoma? Ann Endocrinol 76(5):614–619CrossRefGoogle Scholar
  24. 24.
    Jönsson EG, Nöthen MM, Neidt H, Forslund K, Rylander G, Mattila-Evenden M et al (1999) Association between a promoter polymorphism in the dopamine D2 receptor gene and schizophrenia. Schizophr Res 40(1):31–36CrossRefPubMedGoogle Scholar
  25. 25.
    Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Heinze G (2006) A comparative investigation of methods for logistic regression with separated or nearly separated data. Stat Med 25(24):4216–4226CrossRefPubMedGoogle Scholar
  27. 27.
    Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc. Ser B (Methodological) 57(1):289–300Google Scholar
  28. 28.
    Moura RR, Coelho AV, Balbino VQ, Crovella S, Brandão LA (2015) Meta-analysis of Brazilian genetic admixture and comparison with other Latin America countries. Am J Hum Biol 27(5):674–680CrossRefPubMedGoogle Scholar
  29. 29.
    Pena SD, Bastos-Rodrigues L, Pimenta JR, Bydlowski SP (2009) DNA tests probe the genomic ancestry of Brazilians. Braz J Med Biol Res 42(10):870–876CrossRefPubMedGoogle Scholar
  30. 30.
    Pena SD, Di Pietro G, Fuchshuber-Moraes M, Genro JP, Hutz MH, FeS Kehdy et al (2011) The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS ONE 6(2):e17063CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Schaid DJ, Jacobsen SJ (1999) Biased tests of association: comparisons of allele frequencies when departing from Hardy-Weinberg proportions. Am J Epidemiol 149(8):706–711CrossRefPubMedGoogle Scholar
  32. 32.
    Slatkin M (2008) Linkage disequilibrium–understanding the evolutionary past and mapping the medical future. Nat Rev Genet 9(6):477–485CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Delgrange E, Trouillas J, Maiter D, Donckier J, Tourniaire J (1997) Sex-related difference in the growth of prolactinomas: a clinical and proliferation marker study. J Clin Endocrinol Metab 82(7):2102–2107PubMedGoogle Scholar
  34. 34.
    Delgrange E, Vasiljevic A, Wierinckx A, François P, Jouanneau E, Raverot G et al (2015) Expression of estrogen receptor alpha is associated with prolactin pituitary tumor prognosis and supports the sex-related difference in tumor growth. Eur J Endocrinol 172(6):791–801CrossRefPubMedGoogle Scholar
  35. 35.
    Colao A, Sarno AD, Cappabianca P, Briganti F, Pivonello R, Somma CD et al (2003) Gender differences in the prevalence, clinical features and response to cabergoline in hyperprolactinemia. Eur J Endocrinol 148(3):325–331CrossRefPubMedGoogle Scholar
  36. 36.
    Delgrange E, Duprez T, Maiter D (2006) Influence of parasellar extension of macroprolactinomas defined by magnetic resonance imaging on their responsiveness to dopamine agonist therapy. Clin Endocrinol 64(4):456–462CrossRefGoogle Scholar
  37. 37.
    Zada G, Woodmansee WW, Ramkissoon S, Amadio J, Nose V, Laws ER (2011) Atypical pituitary adenomas: incidence, clinical characteristics, and implications. J Neurosurg 114(2):336–344CrossRefPubMedGoogle Scholar
  38. 38.
    Ritchie T, Noble EP (2003) Association of seven polymorphisms of the D2 dopamine receptor gene with brain receptor-binding characteristics. Neurochem Res 28(1):73–82CrossRefPubMedGoogle Scholar
  39. 39.
    Eisenstein SA, Bogdan R, Love-Gregory L, Corral-Frías NS, Koller JM, Black KJ, et al. (2016) Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status. Synapse 70(10):418–431Google Scholar
  40. 40.
    Bertolino A, Fazio L, Caforio G, Blasi G, Rampino A, Romano R et al (2009) Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia. Brain 132(Pt 2):417–425CrossRefPubMedGoogle Scholar
  41. 41.
    Peculis R, Balcere I, Rovite V, Megnis K, Valtere A, Stukens J et al (2016) Polymorphisms in MEN1 and DRD2 genes are associated with the occurrence and characteristics of pituitary adenomas. Eur J Endocrinol 175(2):145–153CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • CBF Bueno
    • 1
    Email author
  • EB Trarbach
    • 1
  • MD Bronstein
    • 1
  • A Glezer
    • 1
  1. 1.Neuroendocrine Unit, Division of Endocrinology and Metabolism, Hospital das Clínicas & Laboratory of Cellular and Molecular Endocrinology LIM-25University of São Paulo Medical SchoolSão PauloBrazil

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