IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
artículos
Título:
Sex differences in the pituitary transforming growth factor-beta1 (TGF-beta1) system. Studies in a model of resistant prolactinomas
Autor/es:
RECOUVREUX, V.; LAPYCKYJ, L.; CAMILETTI, M.A.; GUIDA, M.C.; ORNSTEIN AM; RIFKIN, DB; BECU VILLALOBOS, DAMASIA; DIAZ-TORGA G
Revista:
ENDOCRINOLOGY
Editorial:
ENDOCRINE SOC
Referencias:
Año: 2013 vol. 154 p. 4192 - 4205
ISSN:
0013-7227
Resumen:
Dopamine and estradiol interact in the regulation of lactotroph cell proliferation and prolactin secretion. Ablation of the dopamine D2 receptor gene (Drd2-/-) in mice leads to a sexually dimorphic phenotype of hyperprolactinemia and pituitary hyperplasia, which is stronger in females. Transforming growth factor beta 1 (TGF-β1) is a known inhibitor of lactotroph proliferation. TGF-beta1 is regulated by dopamine and estradiol, and it is usually down-regulated in prolactinoma experimental models.To understand the role of TGF-beta1 in the gender-specific development of prolactinomas in Drd2-/- mice, we compared the expression of different components of the pituitary TGF-beta1 system, including active cytokine content, latent TGF-beta binding protein (LTBP) isoforms, and possible local TGF-beta1 activators, in males and females in this model. Furthermore, we also evaluated the effect of dopamine or estradiol administration, to elucidate their role on TGF-beta1 system regulation.The expression of active TGF-beta1, LTBP isoforms and several putative TGF-beta1 activators evaluated was higher in male than in female mouse pituitaries. However, Drd2-/- female mice were more sensitive to the decrease in active TGF-beta1 content, as reflected by the down-regulation of TGF-beta1 target genes. Estrogen and dopamine caused a differential regulation of several components of TGF-beta1 system. Particularly we found a sex- and genotype- dependent regulation of active TGF-beta1 content and a similar expression pattern of two of the putative TGF-beta1 activators, TSP1 and KLK1, suggesting that these proteins could mediate TGF-beta1 activation elicited by dopamine and estradiol.Our results indicate that: 1- the loss of dopaminergic tone affects more strongly the pituitary TGF-β1 system in females than in males. 2- Males express higher levels of pituitary TGF-β1 system components including active cytokine. 3- Estradiol negatively controls most of the components of the system.Since TGF-β1 inhibits lactotroph proliferation, we propose that the higher levels of the TGF-β1 system in males could protect or delay the development of prolactinomas in Drd2-/- male mice.