Role of pituitary activins as inhibitors of lactotroph function and prolactinoma development

PEÑA, M.; FARAONI, E Y; ABELEDO MACHADO, A I; PEREZ, P; MARCIAL LÓPEZ, C A; RULLI, S B; GUTIÉRREZ, S; DÍAZ-TORGA, G

Congreso; Reunión Anual SAIC - SAI - AAFE - NANOMED-AR; 2021

A prepuberal ovariectomy (OVX) prevents pituitary hyperplasia in mouse models of prolactinoma indicating the participation of ovarian factors in tumor development. However, a hormone replacement does not restore tumor growth suggesting the participation of other ovarian factors. Pituitary activins inhibit lactotroph function, and activin expression is reduced in prolactinomas. We demonstrated that the loss of gonadal inhibins after OVX improves pituitary activin expression, it could be involved in the inhibition of prolactinoma growth. In the present work, we analyzed if the OVX also recover activin receptor expression and biological function in lactotrophs. We used female mice overexpressing the β subunit of the human chorionic gonadotrophin (hCGβ+) as a model of prolactinoma.Our results show that the expression of activins, activin-receptors (ActRIIA, ActRIIB, Acvr1B by RTqPCR), and pp38 (double IHC, as a signal of activin biological activity in lactotrophs) are decreased in prolactinomas from hCGβ+ females, concomitant with an increase in Pit1 expression. But surprisingly the protein expression (IHC) of activin receptors, did not decrease in prolactinomas. We observed high expression in lactotrophs from transgenic females but mainly in the cytoplasm, contrary to the plasma membrane localization in lactotrophs from wt pituitaries. A prepuberal OVX prevented all these alterations in the pituitary activin system, even changes in receptors localization.We conclude that the decrease in pituitary activin expression and biological activity found in hCGβ+ female pituitaries is involved in prolactinoma development. The loss of gonadal inhibins after an OVX recovers activin inhibitory function on lactotrophs preventing prolactinoma growth. Alterations in receptor localization could involve specific proteins (ARIPs) which interact with activin receptors type II and down-regulate their activity by controlling mechanisms of endocytosis (study in progress).