Prolonged exposure to growth hormone (GH) in mice is associated with hepatomegaly, due to hypertrophy and hyperplasia of hepatocytes, and old GHoverexpressing transgenic mice frequently develop liver tumors. Young adult transgenic mice present preneoplastic pathology in the liver and exhibit alterations in signaling pathways involved in cell growth and proliferation in that tissue. These changes could be a direct effect of prolonged GH action or secondary to the pathological context produced by hormone excess. Consequently, the aim of this
work was to assess if lower levels of GH administered for a limited period would also induce any of these alterations. For that purpose, mice were treated with 6 μg/g of body weight of GH per day by osmotic pumps between 3- and 8-weeks of age and livers were removed at the end of treatment. To evaluate hepatocellular
proliferation, the expression of proliferating cell nuclear antigen (PCNA) was determined in liver sections. In comparison to controls, GH-treated males exhibited an increased percentage of PCNA positive nuclei, whereas non-significant differences were observed in females. As a consequence of GH-treatment, both male and female mice exhibited higher hepatic mRNA levels of GH receptor than controls, together with an increased gene expression of negative modulators of GHsignaling (CIS and SOCS2). Signaling pathways known to be involved in cell growth and proliferation processes were also evaluated. GH-exposed animals displayed an increase in STAT3 activation in comparison to controls. Akt and ERK1/2 protein content was also higher in treated mice, only in males, although it did not result in an exacerbated activation of these mediators. When the expression of cell cycle regulators was analyzed, GH-treated males exhibited higher gene expression of cyclin D1 than control animals, with no changes in c-Myc, c-Fos and c-Jun expression. On the other hand, females exposed to GH displayed increased levels of c-Myc mRNA, but not of any of the other proto-oncogenes analyzed, in comparison to non-treated mice. Consequently, limited exposure to sustained low levels of GH is associated with morphological and molecular changes in the liver that could provide a pro-tumorigenic environment, especially in males.