Growth hormone-releasing hormone (GHRH), also known as somatoliberin, was the last of the classically postulated hypothalamic hormones to be characterized, with its structure elucidated in 1982. Its existence was first inferred from selective hypothalamic lesions causing growth failure. GHRH is a 44-amino acid peptide belonging to the secretin-glucagon family of homologous peptides. The full biological activity resides within the N-terminal 29-amino acid sequence, GHRH(1–29)-NH₂, which is sufficient to activate its receptor and stimulate growth hormone secretion.

Biosynthesis and Hypothalamic Expression

GHRH is produced predominantly by neurons located in the arcuate nucleus of the ventromedial hypothalamus. These neurons project to the median eminence, where GHRH is secreted into the hypophyseal portal circulation and transported to the anterior pituitary. The human GHRH gene, located on chromosome 20, spans approximately 10 kb and encodes a 108-amino acid precursor protein known as preproGHRH. Although GHRH expression is primarily hypothalamic in humans, more recent studies have also identified its presence in the basal ganglia and several extrahypothalamic tissues, suggesting additional physiological functions.

Mechanism of Action and Receptor Signaling

GHRH exerts its biological effects through binding to the growth hormone-releasing hormone receptor (GHRH-R), a class B G protein-coupled receptor expressed mainly on somatotroph cells of the anterior pituitary. Receptor activation stimulates the G_s signaling pathway, leading to activation of adenylate cyclase and increased intracellular cyclic AMP (cAMP) production. Elevated cAMP activates protein kinase A (PKA), which phosphorylates the transcription factor CREB, thereby promoting transcription of the growth hormone (GH) gene and the pituitary-specific transcription factor Pit-1. This signaling cascade stimulates both the synthesis and secretion of GH into the systemic circulation. Rising levels of GH and insulin-like growth factor-1 (IGF-1) subsequently exert negative feedback on the hypothalamus, while the activity of GHRH is physiologically opposed by the inhibitory hormone somatostatin.