title: Sex differences in the pituitary transforming growth factor-β1 system: studies in a model of resistant prolactinomas.
abstract: Dopamine and estradiol interact in the regulation of lactotroph cell proliferation and prolactin secretion. Ablation of the dopamine D2 receptor gene (Drd2(-/-)) in mice leads to a sexually dimorphic phenotype of hyperprolactinemia and pituitary hyperplasia, which is stronger in females. TGF-β1 is a known inhibitor of lactotroph proliferation. TGF-β1 is regulated by dopamine and estradiol, and it is usually down-regulated in prolactinoma experimental models. To understand the role of TGF-β1 in the gender-specific development of prolactinomas in Drd2(-/-) mice, we compared the expression of different components of the pituitary TGF-β1 system, including active cytokine content, latent TGF-β-binding protein isoforms, and possible local TGF-β1 activators, in males and females in this model. Furthermore, we evaluated the effects of dopamine and estradiol administration to elucidate their role in TGF-β1 system regulation. The expression of active TGF-β1, latent TGF-β-binding protein isoforms, and several putative TGF-β1 activators evaluated was higher in male than in female mouse pituitary glands. However, Drd2(-/-) female mice were more sensitive to the decrease in active TGF-β1 content, as reflected by the down-regulation of TGF-β1 target genes. Estrogen and dopamine caused differential regulation of several components of the TGF-β1 system. In particular, we found sex- and genotype- dependent regulation of active TGF-β1 content and a similar expression pattern for 2 of the putative TGF-β1 activators, thrombospondin-1 and kallikrein-1, suggesting that these proteins could mediate TGF-β1 activation elicited by dopamine and estradiol. Our results indicate that (1) the loss of dopaminergic tone affects the pituitary TGF-β1 system more strongly in females than in males, (2) males express higher levels of pituitary TGF-β1 system components including active cytokine, and (3) estradiol negatively controls most of the components of the system. Because TGF-β1 inhibits lactotroph proliferation, we propose that the higher levels of the TGF-β1 system in males could protect or delay the development of prolactinomas in Drd2(-/-) male mice.
authors.affiliation: Instituto de Biología y Medicina Experimental-Consejo Nacional de Investigaciones Científicas y Técnicas, Vuelta de Obligado 2490, Buenos Aires 1428, Argentina. gdiaz@ibyme.conicet.gov.ar.
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Recouvreux
authors.forename: Lara
authors.initials: L
authors.lastname: Lapyckyj
authors.forename: M Andrea
authors.initials: MA
authors.lastname: Camilletti
authors.forename: M Clara
authors.initials: MC
authors.lastname: Guida
authors.forename: Ana
authors.initials: A
authors.lastname: Ornstein
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rifkin
authors.forename: Damasia
authors.initials: D
authors.lastname: Becu-Villalobos
authors.forename: Graciela
authors.initials: G
authors.lastname: Díaz-Torga
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D005838:Genotype; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010902:Pituitary Gland / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000378:metabolism; D015175:Prolactinoma / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D020840:Tissue Kallikreins / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016023:Integrins; D017448:Receptors, Dopamine D2; D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; C585483:Thbs1 protein, mouse; D020840:Tissue Kallikreins