**1.1 The new concepts about GH**

At that time, relatively few researchers tried to investigate whether the hormone might could have other actions in the body far beyond those described [10]. Perhaps this situation changed when a previous study was analyzed in which it had been discovered that Insulin and Epidermal Growth Factor (EGF) could be internalized in living cells [11], contrary to the classical concept that protein hormones only carry out their biological actions after interacting with specific membrane receptors, that is, without entering cells, unlike what happens with steroid or thyroid hormones whose receptors are located in the cytoplasm or cell nucleus. That finding led to the Waters group, in Queensland, to investigate whether the same could happen with GH [12–14]. They demonstrated that this hormone, after interacting with its membrane receptor (GHR), is also internalized along with its GHR through the endosomal pathway. This mechanism allows the translocation of GH and GHR to the nucleus of the cell where they induce the transcription of many different genes. This was a key discovery, as it allegedly implied that GH could perform many diverse, tissue-specific functions, far beyond its classical known effects. Therefore, the detection of GHR in the nucleus of a cell indicates that there has been a previous interaction GH-GHR at the cell membrane. Another important finding that reinforced the idea that GH exerted many different effects in the organism was the demonstration by our group that internalized GH also undergoes specific tissue proteolytic processing, influenced by sex and age (in mice), which gives rise to different molecular forms, whose actions are unknown still [15]. **Figure 1** schematizes these concepts.

According to these concepts, it is logical to understand that GH is a hormone whose actions can affect practically the entire organism, instead of being a mere metabolic hormone and the hormone for growth. Throughout this chapter, we will

#### **Figure 1.**

*Interaction GH-GHR and translocation to the nucleus of the cell. (1) Once GH interacts with its membrane receptor GHR, it is activated (red color) and induces a cascade of phosphorylation (2) that represents GH signaling pathways. (3) GH and GHR are internalized through the endosomal pathway. In endosomes, parts of GH and GHR are proteolytically degraded, but another part translocates to the nucleus (4), where they induce gene transcription (5). In endosomes, GH gives rise (6) to different tissue-specific molecular forms (7), whose actions are still unknown.*

analyze the role of the genes that make up the GH family, as well as how this hormone is now considered a prohormone given its pleiotropic actions.
