Growth Hormone Secretagogues

Growth hormone (GH), also known as somatotropin, is a 191-amino-acid single-chain polypeptide synthesized by somatotroph cells in the anterior pituitary gland. GH is secreted in discrete pulses rather than continuously, and it is preferentially released during deep slow-wave sleep (PMID 15135771). This pulsatile pattern is physiologically critical: the pulsatile profile drives gene transcription responses that continuous GH exposure does not, and receptor sensitivity is maintained by allowing receptor recovery between pulses. The most reproducible GH pulse occurs shortly after sleep onset, coinciding with the first period of deep slow-wave sleep (stages 3-4), which explains the clinical significance of sleep quality for GH-dependent processes (PMID 8627466).

GH secretion is regulated by a hypothalamic push-pull system. Growth hormone-releasing hormone (GHRH), produced by arcuate nucleus neurons, stimulates GH synthesis and release from somatotrophs via GHRH receptor (a Gαs-coupled GPCR) activation. Somatostatin (also called SRIH, somatotropin release-inhibiting hormone), produced by periventricular nucleus neurons, inhibits GH secretion by hyperpolarizing somatotroph cells through Gαi/o-coupled SSTR2/5 receptors. The alternating dominance of GHRH and somatostatin generates the pulsatile pattern of GH release. A third regulatory input comes from ghrelin, an endogenous ligand for the GHS-R1a receptor (the growth hormone secretagogue receptor) produced primarily by the stomach and hypothalamus. Ghrelin acts synergistically with GHRH to amplify GH pulses and is the endogenous analog of the synthetic GHRPs (growth hormone-releasing peptides).

GH acts on peripheral tissues directly and indirectly through its induction of insulin-like growth factor 1 (IGF-1) synthesis, primarily in the liver. GH binds the GH receptor (a cytokine receptor family member) and activates JAK2-STAT5 signaling, which drives IGF-1 gene transcription. IGF-1 then mediates many of GH's anabolic and growth-promoting effects, cell proliferation, protein synthesis, glucose uptake in muscle, lipolysis in adipose tissue, bone formation. IGF-1 also exerts negative feedback on GH secretion at both the pituitary and hypothalamic levels, closing the GH-IGF-1 axis regulatory loop (PMID 41912291).

GH secretion declines significantly with aging, the so-called somatopause (PMID 10938176). GH secretion falls steeply from early adulthood to midlife, in parallel with the loss of slow-wave sleep, and then continues to decline more slowly (PMID 10938176). By late life, 24-hour GH secretion is far below young-adult levels, having declined markedly from early adulthood to midlife and more gradually thereafter (PMID 10938176). IGF-1 levels track this decline. Declining GH secretion with age contributes to reduced lean body mass, increased adipose tissue and thinning of the skin, changes that overlap with adult growth hormone deficiency (PMID 2355952). This is the scientific rationale for GH secretagogue therapy in aging patients without frank GHD.