Immunolocalization of Pit-1 in gonadotroph nuclei is indicative of the transdifferentiation of gonadotroph to lactotroph cells in prolactinomas induced by estrogen.

Abstract

The pituitary protein transcription factor (Pit-1) regulates the differentiation and proliferation of somatotrophs, lactotrophs, and thyrotrophs and the c-Myc oncoprotein plays a critical role in somatotroph and lactotroph differentiation. Both were involved in the genesis of pituitary tumors. The combined analysis of Pit-1 and c-Myc expression and the morphometric and biochemical parameters of the lactotroph population after treatment with estrogen for 7, 20, and 60 days provided new information on molecular mechanisms implicated in the formation of prolactinomas. Estrogen treatment for 7 days caused a significant proliferation of lactotrophs (70%) and this increase reached an additional 55% at 60 days. The proliferation of lactotrophs was concurrent with higher serum and pituitary prolactin levels. An augmentation of Pit-1 and c-Myc expression in both cytoplasmic and nuclear extracts after estrogen can be associated with lactotroph proliferation. Moreover, the multistep correlation analysis revealed that the expression of nuclear Pit-1 was the strongest predictor of prolactinoma development. Also the Pit-1 immunolocalization in nuclei of gonadotrophs suggests the activation of genes involved in transdifferentiation of gonadotroph to lactotroph. Therefore, the understanding of the Pit-1 function may help in the design of strategies to control the secretion and proliferation of pituitary tumors of the somatomammotrope lineage.