Sex differences in the pituitary TGFß1 system: The role of TGFß1 in prolactinoma development.

Prolactinomas are the most frequent functioning pituitary adenomas, and sex differences in tumor size, behavior and incidence have been described. These differences have been associated with earlier diagnosis in woman, as well as with serum estradiol levels. Experimental models of prolactinomas in rodents also show a higher incidence in females, and recent findings suggest that gender differences in the transforming growth factor beta 1 (TGFß1) system might be involved in the sex-specific development of prolactinomas in these models. The aim of this review is to summarize the literature supporting the important role of TGFß1 as a local modulator of pituitary lactotroph function and to provide recent evidence for TGFß1 involvement in the sex differences found in prolactinoma development in animal models.

The pituitary TGFß1 system as a novel target for the treatment of resistant prolactinomas.

Prolactinomas are the most frequently observed pituitary adenomas and most of them respond well to conventional treatment with dopamine agonists (DAs). However, a subset of prolactinomas fails to respond to such therapies and is considered as DA-resistant prolactinomas (DARPs). New therapeutic approaches are necessary for these tumors. Transforming growth factor ß1 (TGFß1) is a known inhibitor of lactotroph cell proliferation and prolactin secretion, and it partly mediates dopamine inhibitory action. TGFß1 is secreted to the extracellular matrix as an inactive latent complex, and its bioavailability is tightly regulated by different components of the TGFß1 system including latent binding proteins, local activators (thrombospondin-1, matrix metalloproteases, integrins, among others), and TGFß receptors. Pituitary TGFß1 activity and the expression of different components of the TGFß1 system are regulated by dopamine and estradiol. Prolactinomas (animal models and humans) present reduced TGFß1 activity as well as reduced expression of several components of the TGFß1 system. Therefore, restoration of TGFß1 inhibitory activity represents a novel therapeutic approach to bypass dopamine action in DARPs. The aim of this review is to summarize the large literature supporting TGFß1 important role as a local modulator of pituitary lactotroph function and to provide recent evidence of the restoration of TGFß1 activity as an effective treatment in experimental prolactinomas.

Sex differences in the pituitary transforming growth factor-ß1 system: studies in a model of resistant prolactinomas.

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-ß1 is a known inhibitor of lactotroph proliferation. TGF-ß1 is regulated by dopamine and estradiol, and it is usually down-regulated in prolactinoma experimental models. To understand the role of TGF-ß1 in the gender-specific development of prolactinomas in Drd2(-/-) mice, we compared the expression of different components of the pituitary TGF-ß1 system, including active cytokine content, latent TGF-ß-binding protein isoforms, and possible local TGF-ß1 activators, in males and females in this model. Furthermore, we evaluated the effects of dopamine and estradiol administration to elucidate their role in TGF-ß1 system regulation. The expression of active TGF-ß1, latent TGF-ß-binding protein isoforms, and several putative TGF-ß1 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-ß1 content, as reflected by the down-regulation of TGF-ß1 target genes. Estrogen and dopamine caused differential regulation of several components of the TGF-ß1 system. In particular, we found sex- and genotype- dependent regulation of active TGF-ß1 content and a similar expression pattern for 2 of the putative TGF-ß1 activators, thrombospondin-1 and kallikrein-1, suggesting that these proteins could mediate TGF-ß1 activation elicited by dopamine and estradiol. Our results indicate that (1) the loss of dopaminergic tone affects the pituitary TGF-ß1 system more strongly in females than in males, (2) males express higher levels of pituitary TGF-ß1 system components including active cytokine, and (3) estradiol negatively controls most of the components of the system. Because TGF-ß1 inhibits lactotroph proliferation, we propose that the higher levels of the TGF-ß1 system in males could protect or delay the development of prolactinomas in Drd2(-/-) male mice.

Thrombospondin-1 (TSP-1) analogs ABT-510 and ABT-898 inhibit prolactinoma growth and recover active pituitary transforming growth factor-ß1 (TGF-ß1).

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-ß1. 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-ß1 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.