CONICET | Buscador de Institutos y Recursos Humanos

Pituitary adenomas are benign tumors with low prevalence of malignant transformation. We hypothesize the involvement of senescence as protective anti-tumoral cell mechanism and we aimed to determine its contribution in estrogen-induced pituitary hyperplasia. Wistar male rats were treated by subcutaneous implantation of estradiol benzoate (30 mg) for 10, 20, 40 and 60 days. Empty capsules were implanted in controls. By immunodetection of Ki67 and flow cytometry DNA analysis we detected estrogen-induced pituitary hyperplasia with a biphasic response: a significant proliferation rise after 10 and 20 days followed by its decrease after 60 and 80 days of treatment (p<0.05; ANOVA-Fisher). This cytostatic phase was accompanied by increase in beta-galactosidase activity; cyclin inhibitor p21, mitochondrial fission (DRP1) and fusion (MFN1) and IL-6 protein expression; all considered cellular senescence-associated markers. Moreover, increase in phosphorylated-ATM (DNA damage response) was detected throughout the estrogenic treatment (p < 0.05). The correlation of this cytostatic phase with an intrinsic cell arrest mechanism during the development of pituitary hyperplasia les us to suggest a predisposition of pituitary gland self-regulation to activate senescence pathways. Since evidences of in vivo senescent lesions associated with tumor suppression are incipient, our findings contribute to understanding the senescence process in pituitary syndromes. The experimental protocols were approved by the local Institutional Committee for the Care and Use of Laboratory Animals of School of Medicine, National University of Cordoba. These studies are supported by CONICET, FONCyT and SECyT-UNC.