M Victoria Recouvreux

National Scientific and Technical Research Council, Buenos Aires, Buenos Aires F.D., Argentina

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Publications (3)14.15 Total impact

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    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. Transforming growth factor beta 1 (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 (LTBP) isoforms, and possible local TGF-β1 activators, in males and females in this model. Furthermore, we also evaluated the effect of dopamine or estradiol administration, to elucidate their role on TGF-β1 system regulation.The expression of active TGF-β1, LTBP isoforms and several putative TGF-β1 activators evaluated was higher in male than in female mouse pituitaries. However, Drd2(-/-) female mice were more sensitive to the decrease in active TGF-ß1 content, as reflected by the down-regulation of TGF-β1 target genes. Estrogen and dopamine caused a differential regulation of several components of TGF-β1 system. Particularly we found a sex- and genotype- dependent regulation of active TGF-β1 content and a similar expression pattern of two of the putative TGF-β1 activators, TSP1 and KLK1, 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 more strongly the pituitary TGF-β1 system in females than in males. 2- Males express higher levels of pituitary TGF-β1 system components including active cytokine. 3- Estradiol negatively controls most of the components of the system.Since 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.
    Endocrinology 09/2013; · 4.72 Impact Factor
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    ABSTRACT: Prolactinomas are the most prevalent type of secreting pituitary tumors in humans and generally respond well to a medical therapy with dopamine agonists. However, for patients exhibiting resistance to dopaminergic drugs, alternative treatments are desired. Antiangiogenic strategies might represent a potential therapy for these tumors. Thrombospondin 1 (TSP-1) is a large multifunctional glycoprotein involved in multiple biological processes including angiogenesis, apoptosis, and activation of TGF-β1. Because tumors that overexpress TSP-1 grow more slowly, have fewer metastases, and have decreased angiogenesis, TSP-1 provides a novel target for cancer treatment. ABT-510 and ABT-898 are TSP-1 synthetic analogs that mimic its antiangiogenic action. In the present study, we explored the potential effect of ABT-510 and ABT-898 on experimental prolactinomas induced by chronic diethylstilbestrol (DES) treatment in female rats. We demonstrated that a 2-wk treatment with ABT-510 and ABT-898 counteracted the increase in pituitary size and serum prolactin levels as well as the pituitary proliferation rate induced by DES. These inhibitory effects on tumor growth could be mediated by the antiangiogenic properties of the drugs. We also demonstrated that ABT-510 and ABT-898, in addition to their described antiangiogenic effects, increased active TGF-β1 level in the tumors. We postulate that the recovery of the local cytokine activation participates in the inhibition of lactotrope function. These results place these synthetic TSP-1 analogs as potential alternative or complementary treatments in dopamine agonist-resistant prolactinomas.
    Endocrinology 06/2012; 153(8):3861-71. · 4.72 Impact Factor
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    ABSTRACT: Dopamine, acting through the dopamine type 2 receptor (Drd2), is the main inhibitor of pituitary prolactin (PRL) secretion and lactotroph proliferation. TGF-β1 is involved, at least in part, in mediating these actions. It was described that TGF-β1 synthesis in rat pituitary lactotrophs is up-regulated by dopamine and down-regulated by estradiol. TGF-β1 is secreted as a large latent complex. The local regulation of cytokine activation in the pituitary has not yet been explored. In this work, we studied pituitary active and total TGF-β1 content, as well as TGF-β1 mRNA, and the in vivo role of dopamine and estradiol on pituitary TGF-β1 levels. Adult female mice (wild type), and female mice with a null mutation in the Drd2 (Drd2(-/-)), were used. The loss of dopaminergic tone induced a decrease in TGF-β1 mRNA expression, in active and total cytokine content, and in TGF-β type II receptor expression. Dopamine regulation of pituitary TGF-β1 activation process was inferred by the inhibition of active cytokine by in vivo sulpiride treatment. Interestingly, in the absence of dopaminergic tone, estradiol induced a strong increase in active TGF-β1. PRL secretion correlated with active, but not total cytokine. TGF-β1 inhibitory action on lactotroph proliferation and PRL secretion was decreased in Drd2(-/-) pituitary cells, in correlation with decreased TGF-β type II receptor. The study of the TGF-β1 activation process and its regulation is essential to understand the cytokine activity. As an intermediary of dopamine inhibition of lactotroph function, TGF-β1 and local activators may be important targets in the treatment of dopamine agonist-resistant prolactinomas.
    Endocrinology 07/2011; 152(7):2722-30. · 4.72 Impact Factor

Publication Stats

12 Citations
14.15 Total Impact Points

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Institutions

  • 2011–2013
    • National Scientific and Technical Research Council
      • IBYME - Instituto de Biología y Medicina Experimental
      Buenos Aires, Buenos Aires F.D., Argentina