The pituitary TGFβ1 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 beta 1 (TGF beta 1) is a known inhibitor of lactotroph cell proliferation and prolactin secretion, and it partly mediates dopamine inhibitory action. TGF beta 1 is secreted to the extracellular matrix as an inactive latent complex, and its bioavailability is tightly regulated by different components of the TGF beta 1 system including latent binding proteins, local activators (thrombospondin-1, matrix metalloproteases, integrins, among others), and TGF beta receptors. Pituitary TGF beta 1 activity and the expression of different components of the TGF beta 1 system are regulated by dopamine and estradiol. Prolactinomas (animal models and humans) present reduced TGF beta 1 activity as well as reduced expression of several components of the TGF beta 1 system. Therefore, restoration of TGF beta 1 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 TGF beta 1 important role as a local modulator of pituitary lactotroph function and to provide recent evidence of the restoration of TGF beta 1 activity as an effective treatment in experimental prolactinomas.