Disorders in the pituitary TGFβ1 system could participate in the development of a prolactinoma in female mice overexpressing the β subunit of human chorionic gonadotropin (hCGβ +), and in the sex differences observed in these transgenic mice.

ERIKA FARAONI; MARÍA ANDREA CAMILLETTI; ABELEDO ALEJANDRA; LAURA RATNER; SUSANA RULLI; DÍAZ DE TORGA, GRACIELA

Congreso; ENDO 2016; 2016

Endocrine Society

: It has been previously reported that female mice, but not males, that overexpress the β subunit of human chorionic gonadotropin, develop prolactinomas. The marked increase observed in serum progesterone (P4) levels in those females was suggested to be involved in the tumor development. However an in vivo chronic P4 treatment does not induce a prolactinomaper se. TGFβ1 is a potent cytokine expressed in pituitary lactotrophs, cells that also express the type I (ALK5) and type II (RTβII) TGFβ1 receptors. TGFβ1 inhibits both lactotroph functions: cell proliferation and prolactin secretion. We have previously demonstrated that alterations in the pituitary TGFβ1 system are involved in the development of a prolactinoma (1-3). In this work we evaluated whether pituitary abnormalities in the TGFβ1 system could account for the development of prolactinomas in hCGβ+ female mice, and whether these alterations could be involved in the sex differences observed in this model. At 6 months old, hCGβ+ females, showed a significant increase in pituitary weight, with concomitant hyperprolactinemia compared with their wild type (wt) counterparts (4). However, males of the same age showed no differences between genotypes in these parameters. Active and total TGFβ1 levels were assayed by ELISA in pituitary homogenates of females and males at 6 months of age. TGFβ1 biological activity was measured as target genes (TMEPAI and KLF14) expression by RT-qPCR. We found a significant decrease in the active TGFβ1 levels in female hCGβ+ pituitaries (7,12±0,81 pgTGFβ1/mg prot in wt vs. 2,88±0,20 in hCGβ+), and it was reflected in a decreased biological activity assayed by expression of TGFβ1 target genes (TMEPAI: 1,01±0.127 a.u. in wt vs. 0,47± 0,042 in hCGβ+; KLF14: 1,00±0,041 a.u. in wt vs. 0,55±0,39 in hCGβ+). Moreover, the expression of the TGFβ1 receptors (RT-qPCR), were also found decreased in female hCGβ+ pituitaries (RTβII: 1,02±0,131 a.u. in wt vs. 0,62±0.069 in hCGβ+; ALK5: 1,01±0,06 a.u. in wt vs. 0,67±0.03 in hCGβ+). On the other hand, we found that male pituitaries express higher levels of active cytokine than females (12,05±1,02 pgTGFβ1/mg prot in wt males vs. 7,12±0,81 in wt females), higher levels of TGFβ1 receptors (RTβII: 1,02±0,131 a.u. in wt females vs. 1,30±0,078 in wt males; ALK5: 1,01±0,06 a.u. in wt females vs. 4,28±0,18 in wt males), and higher levels of target genes expression. Interestingly, we did not find alterations among genotypes in any of these parameters in male pituitaries. We postulate that the decreased active TGFβ1 levels, TGFβ1 biological activity and TGFβ1 receptors expression are involved in the development of prolactinomas in female hCGβ+. On the contrary, the higher expression of the components of TGFβ1 system in male pituitaries protects this sex from the development of a prolactinoma..