Growth hormone (GH), a polypeptide secreted from the pituitary in a pulsatile fashion, has multiple actions on growth and metabolism (Sperling 2016; Dehkhoda et al., 2018). Because of its body growth promotion activity, it is administered to children with short stature, not only those with GH deficiency conditions, but also to children with other growth disorders, even if they present normal GH status (Deodati and Cianfarani, 2017; Loche et al., 2014; Savage and Storr, 2021).

GH action begins upon hormone binding to its specific receptor, the GHR, at the cell membrane. There, the GH signaling complex engages three major pathways, namely the JAK2/STAT, the PI3K/AKT, and the MAPK/ERK1/2 pathways, which can be activated by other cytokines and growth factors as well. These signaling cascades are pro-proliferative and anti-apoptotic and thus related to cellular growth and oncogenesis (Able et al., 2017; Dehkhoda et al., 2018). Moreover, the GHR/JAK2 complex transactivates the epidermal growth factor receptor, EGFR, which is also pro-mitogenic (González et al., 2021; Li et al., 2011). Therefore, some concern has risen due to the tumorigenic potential of GH, considering it is administered for several years to under-statured children (Tidblad 2022; Strous et al., 2020).

Acromegalic patients present higher incidence of epithelial-derived cancers (Ruchała et al., 2012; Dehkhoda et al., 2018). Mice overexpressing GH develop liver tumors at advanced ages (Snibson 2002; Snibson et al., 1999; Orian et al., 1990), while they present several signs of hepatic alteration very early in life (Miquet et al., 2008, 2013; Martinez et al., 2015, 2016; Bacigalupo et al., 2019). Liver is a major target organ for GH action (Liu et al., 2016; Donato et al., 2021). Thus, the scope of the present work was to elucidate if GH treatment administered to mice throughout the GH-dependent growth period at a pharmacological dose sufficient to promote body growth induces hepatocellular alterations that may give rise to a pro-oncogenic environment. GH was administered in an intermittent fashion imitating the masculine pulsatile secretory mode, both to female and male mice since GH secretion and action are sexually dimorphic. Focus was placed on GH signaling pathways related to corporal and cellular growth, and on cell cycle controllers, since dysregulation of these processes precedes the malignant transformation of the cells. Mice were evaluated immediately after treatment and after a 4-week washout period to assess if GH-induced changes were transitory or permanent. Results indicate masculinizing GH profile does not promote significant hepatocellular damage, as it can be reverted four weeks after withdrawal, but drives system exhaustion.