Continuous growth hormone (GH) liver impact during the growth period in non-GH-deprived mice

Growth hormone (GH) is given to GH-deficient but also to non-GH-deprived children to promote growth. Since standard treatment requires tedious daily injections, long-release formulations are sought. However, non-GH-deficient conditions require higher dosing, which could entail cancer risk. To evaluate the hepatic pro-oncogenic potential of continuous GH under non-GH-deprived conditions, mice were implanted with osmotic minipumps for 5 wk during the growth period. GH secretion and hepatic actions are sexually dimorphic, thus both sexes were studied. Body growth was assessed since birth, whereas the impact on liver, a major GH target organ, was evaluated upon treatment ending, at 8 wk of age. Used dose, 6 µg/g BW, effective when given intermittently, failed to promote growth when infused continuously. Hepatocytes presented higher PCNA-stain, indicative of proliferation, in GH-treated males. STAT5 phosphorylation, related to somatic growth and metabolic GH actions, was not affected by continuous GH levels, whereas STAT3, associated with cellular growth and proliferation, was activated in females. In males, continuous GH treatment induced a female-like hepatic expression of IGF1 and cyclin D1, as well as that of MUPs and EGFR, showing that they are regulated by GH but, moreover, by the GH continuous concentration pattern. GHR and SOCS2 mRNA levels were upregulated by continuous GH in both sexes, whereas c-myc and CIS mRNA were mainly induced in female liver. These results indicate that although continuous GH administration in the used dose is not sufficient to promote growth in non-GH-deprived conditions, it may foster hepatic molecular signatures associated with potentially prooncogenic signaling in mice.