Growth hormone signaling and clinical implications: from molecular to therapeutic perspectives

Growth hormone (GH) is a key polypeptide hormone secreted by somatotroph cells in the anterior pituitary gland, essential for postnatal growth, metabolism, and systemic homeostasis. Its secretion is regulated by hypothalamic neuropeptides, including GH-releasing hormone and somatostatin. GH exerts effects through direct interaction with the growth hormone receptor and indirect pathways mediated by the GH-IGF-I axis. GHR activation triggers signaling pathways, such as JAK-STAT, PI3K/AKT, and MAPK, promoting cellular proliferation, differentiation, and metabolic balance. The GH-IGF-I axis is critical for bone growth, lipid and carbohydrate metabolism, and organ-specific physiological functions. Dysregulation of GH results in diverse disorders. Congenital deficiencies, like isolated GH deficiency and syndromic conditions (e.g., Turner syndrome), stem from genetic mutations. Acquired deficiencies arise from trauma, tumors, infections, or autoimmune damage, while GH overproduction causes gigantism in children and acromegaly in adults, often due to pituitary adenomas. Idiopathic deficiencies, lacking identifiable causes, complicate management further. Advances in therapy have transformed outcomes for GH disorders. Recombinant human growth hormone provides effective replacement therapy for deficiencies. Somatostatin analogs, dopamine receptor agonists, and GH receptor antagonists are pivotal for managing GH excess. Surgical and radiotherapeutic interventions remain essential for pituitary adenomas. However, GH therapy requires close monitoring to prevent side effects like insulin resistance and metabolic complications. This review provides a comprehensive evaluation of the molecular mechanisms underlying GH action, its physiological roles, GH-related disorders, and therapeutic approaches to optimize patient outcomes.