Sex differences in the pituitary transforming growth factor -b1 (TGF-b1) system. Studies in a model of resistant prolactinomas

RECOUVREUX, MARIA VICTORIA; LAPYCKYJ, LARA; CAMILLETTI, MARIA ANDREA; GUIDA, MARIA CLARA; ORNSTEIN, ANA MARÍA; RIFKIN, DANIEL B.; BECU-VILLALOBOS, DAMASIA; DÍAZ-TORGA, GRACIELA

ENDOCRINOLOGY

ENDOCRINE SOC

Año: 2013

0013-7227

Dopamine and estradiol interact in the regulation of lactotroph cell proliferation and prolactin secretion. Ablation of the dopamine D2 receptor gene (Drd2 ko) in mice leads to a sexually dimorphic phenotype of hyperprolactinemia and pituitary hyperplasia which is stronger in females. Transforming growth factor beta 1 (TGF-ß1) is a known inhibitor of lactotrope proliferation. It is regulated by dopamine and estradiol, and usually down-regulated in prolactinoma experimental models. To understand the role of TGF-ß1 in the gender-specific development of prolactinomas in Drd2 ko mice, we compared the expression of different components of the pituitary TGF-ß1 system, including active cytokine content, latent TGF-ß binding protein (LTBP) isoforms, and possible local TGF-ß1 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-ß1 system regulation. Active pituitary TGF-ß1, LTBPs and several putative TGF-ß1 activators evaluated were found highly expressed in male than in female mice pituitary. However, ko female mice were more sensitive to the decrease in active TGF-ß1 content, as reflected by the down-regulation of TGF-ß1 target genes. Estrogen and dopamine caused a sex- and genotype- dependent regulation of all the components of the TGF-ß1 system evaluated suggesting a strong interaction between dopamine and estradiol in the regulation of whole cytokine system. Our results indicate that: 1- the loss of dopaminergic tone affects more strongly the pituitary TGF-ß1 system in females than in males. 2- Males express higher levels of pituitary TGF-ß1 system including active cytokine. 3- Estradiol negatively controls most of the components of the system. Since TGF-ß1 inhibits lactotroph proliferation, we propose that the higher levels of the TGF-ß1 system in males could protect or delay the development of prolactinomas in Drd2 ko male mice.