Activin-inhibitory action on lactotrophs is decreased lactotroph hyperplasia

Abstract

Among all the hormone-secreting pituitary tumours, prolactinomas are the mostfrequently found in the clinic. Since dopamine is the primary inhibitor of lactotroph function, dopamine agonists represent the first-line therapy. However, a subset of patients exhibits resistance to these drugs, and therefore, alternative treatments are desired. As activins inhibit prolactin gene expression through the inhibition of Pit-1 involving the p38MAPK pathway, in the present work, we studied the local activin system as an alternative inhibitory system for lactotroph hyperplasia treatment. We used two different mouse models of prolactinoma: transgenic mice with ove rexpression of the human chorionic gonadotropin β-subunit (hCGβ) and mice lacking dopamine receptor type 2. In both models, females, but not males, develop lactotroph hyperplasia from the fourth month of life. We found reduced expression of pituitary activin subunits andactivin receptors in hyperplastic pituitaries from both models compared with wildtype counterparts. Consequently, hyperplastic pituitaries presented a reduced activininhibitory action on prolactin secretion. Additionally, while f emale wild-type lactotrophs presented high levels of phospho-p38MAPK, it was lost in prolac tinomas, concomitant with decreased activin expression, increased Pit-1 expression and tumour development.In contrast, male pituitaries express higher mRNA levels of activin subunits βA and βB, which would suggest a stronger activin inhibitory function on l actotrophs, protecting this sex from tumour development, despite genotype. The present results highlight the importance of the activin inhibitory action on lactotroph function and place the local activin system as a new target for the treatment of dopam ine agonist-resistant prolactinomas.