The pituitary TGFb1 system as a novel target for the treatment of resistant prolactinomas

Abstract

Prolactinomas are the most frequently observed pituitary adenomas and most of themrespond well to conventional treatment with dopamine agonists (DAs). However, a subsetof prolactinomas fails to respond to such therapies and is considered as DA-resistantprolactinomas (DARPs). New therapeutic approaches are necessary for these tumors.Transforming growth factor b1 (TGFb1) is a known inhibitor of lactotroph cell proliferationand prolactin secretion, and it partly mediates dopamine inhibitory action. TGFb1 is secretedto the extracellular matrix as an inactive latent complex, and its bioavailability is tightlyregulated by different components of the TGFb1 system including latent binding proteins,local activators (thrombospondin-1, matrix metalloproteases, integrins, among others), andTGFb receptors. Pituitary TGFb1 activity and the expression of different components of theTGFb1 system are regulated by dopamine and estradiol. Prolactinomas (animal models andhumans) present reduced TGFb1 activity as well as reduced expression of several componentsof the TGFb1 system. Therefore, restoration of TGFb1 inhibitory activity represents a noveltherapeutic approach to bypass dopamine action in DARPs. The aim of this review is tosummarize the large literature supporting TGFb1 important role as a local modulator ofpituitary lactotroph function and to provide recent evidence of the restoration of TGFb1activity as an effective treatment in experimental prolactinomas