Sex differences in the development of prolactinoma in mice overexpressing hCGβ: role of TGFβ1.
Female transgenic mice that overexpress the human chorionic gonadotrophin β subunit (hCGβ+) develop prolactinomas, whereas hCGβ+ males do not. The high levels of circulating hCG induce massive luteinization in the ovary of hCGβ+ 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 hCGβ+ females remains unclear. TGFβ1 is an inhibitor of lactotroph function, and the reduced TGFβ1 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 TGFβ1 in the gender-specific development of prolactinomas in hCGβ+ mice. We compared the expression of different components of the pituitary TGFβ1 system in males and females in this model. We found reduced TGFβ1 levels, reduced expression of TGFβ1 target genes, TGFβ1 receptors, Ltbp1, Smad4 and Smad7 in hCGβ+ female pituitaries. However, no differences were found between the transgenic and wild-type male pituitaries. We postulate that decreased pituitary TGFβ1 activity in hCGβ+ females is involved in the development of prolactinomas. In fact, we demonstrated that an in vivo treatment carried out for increasing pituitary TGFβ1 activity, was successful in reducing the prolactinoma development, and the hyperprolactinemia in hCGβ+ females. Moreover, the stronger TGFβ1 system found in males could protect them from excessive lactotroph proliferation. Sex differences in the regulation of the pituitary TGFβ1 system could explain gender differences in the incidence of prolactinoma.
['Faraoni|Erika Y|EY|', 'Camilletti|María Andrea|MA|', 'Abeledo-Machado|Alejandra|A|', 'Ratner|Laura D|LD|', 'De Fino|Fernanda|F|', 'Huhtaniemi|Ilpo|I|', 'Rulli|Susana B|SB|', 'Díaz-Torga|Graciela|G|']
D000818:Animals D018997:Chorionic Gonadotropin, beta Subunit, Human D005260:Female D053779:Latent TGF-beta Binding Proteins D008297:Male D051379:Mice D008822:Mice, Transgenic D010902:Pituitary Gland D010911:Pituitary Neoplasms D015175:Prolactinoma D012727:Sex Characteristics D051901:Smad4 Protein D051906:Smad7 Protein D053773:Transforming Growth Factor beta1
prolactinoma hCGβ TGFβ1 pituitary