GHRHR is a G protein-coupled receptor primarily expressed in anterior pituitary somatotroph cells that mediates growth hormone (GH) secretion 1. Upon binding its ligand GHRH, GHRHR activates adenylyl cyclase signaling to stimulate GH gene transcription and pulsatile hormone release 1. GHRHR also functions in hypothalamic nuclei where it regulates GH homeostasis through integration with ghrelin, leptin, and neuropeptide Y signaling 1. Beyond classical GH regulation, GHRHR may modulate sleep-wake cycles and energy homeostasis 1. GHRHR contains splice variants expressed in extrapituitary tissues including the prostate, where they activate multiple pathways (AC/cAMP/PKA, Ras/Raf/ERK, PI3K/Akt/mTOR, JAK2/STAT3) involved in cell survival and proliferation 2. Biallelic GHRHR mutations cause autosomal recessive isolated growth hormone deficiency (IGHD), accounting for approximately 10% of familial cases, resulting in proportionate dwarfism if untreated 3. Heterozygous carriers remain phenotypically normal 3. Common variants including exon 4 polymorphisms contribute modestly to normal height variation 4. PICK1 protein interaction with GHRHR's C-terminus regulates receptor trafficking and signal intensity 5, representing a key mechanism controlling receptor function.