Activin-inhibitoryaction on lactotrophs is decreased in lactotroph hyperplasia

MARCIAL-LOPEZ, C AGUSTINA; PEÑA, MILAGROS; DIAZ -TORGA G; ABELEDO MACHADO, ALEJANDRA INÉS; CAMILLETTI, MARÍA A.; GUTIERREZ, SILVINA; FARAONI, ERIKA Y; PEREZ, PABLO; RULLI, SUSANA B

JOURNAL OF ENDOCRINOLOGY

BIOSCIENTIFICA LTD

Lugar: Bristol; Año: 2019 vol. 244 p. 415 - 429

0022-0795

Among all the hormone-secreting pituitary tumors, prolactinomas are the most frequently found in the clinic. As dopamine is the main inhibitor of lactotroph function these patients generally respond well to the therapy with dopamine agonists. However, a subset of patients exhibits resistance to these drugs, and therefore, alternative therapies 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 of lactotroph function in prolactinoma development. We used two different mice models of prolactinoma: transgenic mice with overexpression of the human chorionic gonadotropin β-subunit (hCGβ), and mice lacking dopamine receptor type 2. In both models, females, but not males, develop prolactinomas. We found that the expression of pituitary activin subunits and activin receptors is reduced in prolactinomas from both models respect to wild-type counterparts, suggesting decreased activin-inhibitory activity on lactotrophs. Besides, while female wild-type pituitaries present high levels of phospho-p38MAPK colocalization in lactotrophs, this expression is lost in prolactinomas, concomitant with decreased activin expression, increased Pit-1 expression and tumor development. On the contrary, male pituitaries express higher mRNA levels of activin subunits βA and βB, which would suggest a stronger activin inhibitory function on lactotrophs, protecting this sex from tumor development, despite genotype. The present results highlight the importance of the activin inhibitory action on lactotroph function and places the local activin system as a new targets for the treatment of dopamine agonist resistant prolactinomas.