title: Sex differences in the development of prolactinoma in mice overexpressing hCGβ: role of TGFβ1.
abstract: 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,Smad4andSmad7in 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 anin vivotreatment 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.
authors.affiliation: Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors.forename: Erika Y
authors.initials: EY
authors.lastname: Faraoni
authors.affiliation: Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors.forename: María Andrea
authors.initials: MA
authors.lastname: Camilletti
authors.affiliation: Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Abeledo-Machado
authors.affiliation: Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Ratner
authors.affiliation: Instituto de Investigaciones FarmacológicasConsejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors.forename: Fernanda
authors.initials: F
authors.lastname: De Fino
authors.affiliation: Department of Surgery & CancerInstitute of Reproductive and Developmental Biology, Imperial College London, London, UK.
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
authors.affiliation: Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors.forename: Susana B
authors.initials: SB
authors.lastname: Rulli
authors.affiliation: Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina gdiaz@ibyme.conicet.gov.ar.
authors.forename: Graciela
authors.initials: G
authors.lastname: Díaz-Torga
mesh_terms: D000818:Animals; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000235:genetics / Q000378:metabolism*; D005260:Female; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000378:metabolism* / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015175:Prolactinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012727:Sex Characteristics; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D018997:Chorionic Gonadotropin, beta Subunit, Human; D053779:Latent TGF-beta Binding Proteins; C509033:Ltbp1 protein, mouse; D051901:Smad4 Protein; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1
keywords: TGFβ1; hCGβ; pituitary; prolactinoma