Pituitary activins as inhibitors of lactotroph function and lactotroph hyperplasia development

PEÑA, M.; FARAONI, E Y; ABELEDO MACHADO, A I; PEREZ, P; MARCIAL LÓPEZ, C A; RULLI, S B; GUTIERREZ, SILVINA; DIAZ-TORGA, GRACIELA

Congreso; International Congress of Neuroendocrinology; 2022

IntroductionDifferent authors have demonstrated that prepuberal ovariectomy (OVX) prevents pituitary hyperplasia in mouse models of prolactinoma. This asserts the participation of ovarian factors in tumor development. However, a hormone replacement (E2 or E2+P4) does not restore tumor growth, suggesting that other ovarian factors are also involved. 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 counteracting the hyperplasia development.Methods/ResultsIn the present work, we analysed the expression of activin receptors and the biological function of activins in lactotrophs after an OVX. We used female mice overexpressing the β subunit of the human chorionic gonadotrophin (hCGβ+) as a model of lactotroph hyperplasia. Our first results showed that the mRNA expression (RTqPCR) of activins and activin-receptors (ActRIIA, ActRIIB and Acvr1B) are decreased in the hyperplastic pituitaries from hCGβ+ females. The protein expression of ActRIB and pp38 decreased specifically in the lactotroph population (double IF) concomitant with an increase in Pit1 expression (RTqPCR), indicating a downregulation of activin biological activity. A prepuberal OVX prevented all these alterations in the pituitary activin system. Pituitary mRNA expression of activin-subunits and activin-receptors Acvr1B, ActRIIA and ActRIIB were strongly increased by OVX in hCGβ+ females, reaching values even higher than those observed in WT pituitaries. Protein expression of ActRIB and pp38 was strongly increased by OVX specifically in the lactotroph population in hCGβ+ females, and finally, Pit-1 expression was found reduced after OVX recovering values similar to those observed in controls.ConclusionsWe conclude that the decrease in pituitary activin expression and biological activity found in hCGβ+ female pituitaries is involved in the lactotroph hyperplasia development. When an OVX is performed, gonadal inhibins are lost and the inhibitory action of pituitary activins on the lactotroph population is recovered, helping to prevent hyperplasia development.Our results highlight the impact of the inhibitory control exerted by activins on lactotroph function positioning activins as a good therapeutic target for the treatment of resistant prolactinomas.