Sex differences in the development of prolactinoma in mice overexpressing human chorionic gonadotropin (hCGβ+): Role of pituitary TGFβ1

FARAONI E, CAMILLETTI MA, ABELEDO-MACHADO A, RATNER LD, HUHTANIEMI I, RULLI SB, DÍAZ-TORGA G

Mar del Plata

Congreso; LXI Reunión de la Sociedad Argentina de Investigación Clínica, SAIC.; 2016

Sociedad Argentina de Investigación Clínica

TGFbeta1 is an inhibitor of lactotroph proliferation and prolactin secretion, and the reduced TGFbeta1 TGFbeta1 activity found in prolactinomas has been proposed to be involved in tumor development. hCGbeta+ females, but not males, develop prolactinomas. In a previous work we found that hCGbeta+ female pituitaries present decreased active TGFbeta1 levels, TGFbeta1 biological activity and TGFbeta1 receptors expression compared to their WT counterpart. This weaker TGFbeta1 system was proposed to be involved in the development of prolactinomas in this group. The aim of the present work was to complete the previous work analyzing other components of the pituitary TGFbeta1 system. As dopamine increases pituitary TGFbeta1 expression and activity, acting through the dopamine D2 receptor (Drd2) expressed in lactotrophs, we also evaluated pituitary Drd2 expression, and hypothalamic tyrosine hydroxylase (TH) expression. Levels of LTBP1, Smad4 and Smad7, measured by qRTPCR, were found increased in male pituitaries compared to females, without differences among genotypes, but were found decreased in tumoral hCGbeta+ female pituitaries compared to the WT siblings. The lower expression of TGFbeta1 system found in hCGbeta+ female pituitaries was accompanied by a lower dopaminergic tone in this group, reflected by decreased hypothalamic TH and increased pituitary Drd2 expression. The high levels of progesterone present in hCGbeta+ females could be involved in the decreased expression of hypothalamic TH found in this group. We did not find disturbances, neither in the pituitary TGFbeta1 system, nor in hypothalamic TH in hCGbeta+ males. We conclude that decreased TGFbeta1 expression and activity found in hCGbeta+ female pituitaries are undoubtedly involved in the development of prolactinoma in this group. Meanwhile, the stronger TGFbeta1 system found in male pituitaries could be protecting them from excessive lactotroph proliferation and prolactinoma development, even in the presence of high levels of hCG.