Endocrine Abstracts

Growth hormone (GH) secreted by the anterior pituitary gland regulates skeletal growth, metabolism and body composition. Although several of these actions are mediated by production of hepatic and local tissue IGF1, GH also acts independent of IGF1. GH is mainly produced from the pituitary as a systemic endocrine hormone, yet is also expressed in local tissues acting in an autocrine/paracrine/intracrine manner. Locally produced non-pituitary GH (npGH) signals the GHR to induce epithelial cell proliferation by suppressing p53, thereby enabling epithelial cell proliferation. Although endocrine GH levels drop markedly with aging, npGH increases with aging, blocking repair of age-associated DNA damage. Consistent with these findings, npGH is a component of the senescence-associated secretory phenotype thereby enabling a pro-proliferative epithelial milieu. As p53 is increased in vivo by blocking GHR signalling these mechanisms may explain the known cancer- protective effects of GH deficiency and GHR signaling disruption, as well as contributing to age-associated pathologies. Thus, GH is a powerful inducer of skeletal growth during childhood, and maintains body composition in the adult, after maturation and with aging, GHR actions are transformed to accumulate DNA damage. Unraveling these mechanisms supports a hypothesis whereby adverse aging-related processes are in fact accelerated by GHR signalling. This notion supports the protective function of low circulating GH during aging, and also would call for vigilance against inappropriate adult GH abuse. This premise also supports the potential for trials designed to block GH action to enable extended healthspan. These insights point to pituitary and non-pituitary adult GH as a regulator of DNA damage contributing to the cellular micro-environment in addition to functioning as a promoter of skeletal growth.