The GH-IGF axis in growth: An overview

The growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis is the principal endocrine system regulating postnatal growth, skeletal development, metabolism, and tissue homeostasis. Although growth hormone has long been recognized as the primary hormonal regulator of somatic growth, recent advances have demonstrated that the growth hormone receptor (GHR) is the critical molecular determinant in signal transduction and diverse biological effects of GH. This review summarizes current knowledge of GHR structure and activation, emphasizing the conformational mechanisms that initiate intracellular signaling through the JAK2-STAT5, MAPK/ERK, and PI3K-AKT-mTOR pathways. We further discuss how these signaling cascades coordinate growth, cellular differentiation, protein synthesis, and metabolic regulation. Attention is given to growth hormone receptor deficiency, Laron syndrome, which has emerged as one of the most informative human models for understanding the physiological consequences of impaired GH signaling. Studies of the Ecuadorian cohort have demonstrated that lifelong GHR deficiency not only results in severe short stature and characteristic body proportionality but also promotes enhanced insulin sensitivity, preserves glucose homeostasis despite increased adiposity, and induces a remarkably low incidence of malignancy. These findings have substantially expanded current understanding of the GH-IGF axis beyond linear growth, revealing its central role in metabolic homeostasis, aging, and cancer biology. Collectively, the evidence supports the concept that modulation of GHR signaling influences multiple interconnected physiological systems and provides valuable insights into potential therapeutic strategies targeting growth, metabolic disorders, and cancer.