Sex differences in the development of prolactinoma in mice overexpressing hCGB: Role of TGFB1

Female transgenic mice that overexpress the human chorionic gonadotrophin B subunit (hCGB+) develop prolactinomas, whereas hCGB+ males do not. The high levels of circulating hCG induce massive luteinization in the ovary of hCGB+ females, and progesterone becomes the primary steroid hormone produced, but estradiol remains at physiological level. The involvement of high levels of progesterone in lactotroph proliferation is not clearly understood; hence, the pathogenesis of prolactinomas in hCGp+ females remains unclear. TGFp1 is an inhibitor of lactotroph function, and the reduced TGFp1 activity found in prolactinomas has been proposed to be involved in tumor development. The aim of the present work was to study the role of TGFp1 in the gender-specific development of prolactinomas in hCGB+ mice. We compared the expression of different components of the pituitary TGFB1 system in males and females in this model. We found reduced TGFB1 levels, reduced expression of TGFB1 target genes, TGFB1 receptors, Ltbpl, Smad4 and Smad7 in hCGB+ female pituitaries. However, no differences were found between the transgenic and wild-type male pituitaries. We postulate that decreased pituitary TGFB1 activity in hCGB+ females is involved in the development of prolactinomas. In fact, we demonstrated that an in vivo treatment carried out for increasing pituitary TGFB1 activity, was successful in reducing the prolactinoma development, and the hyperprolactinemia in hCGB+ females. Moreover, the stronger TGFB1 system found in males could protect them from excessive lactotroph proliferation. Sex differences in the regulation of the pituitary TGFB1 system could explain gender differences in the incidence of prolactinoma.