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 released in discrete pulses — typically 6-12 significant pulses per day in healthy adults — rather than continuously. 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 largest GH pulse occurs approximately 60-90 minutes after sleep onset, coinciding with deep slow-wave sleep (stages 3-4), which explains the clinical significance of sleep quality for GH-dependent processes (PMID 8682754).

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 12586792).

GH secretion declines significantly with aging — the so-called somatopause. After age 30, GH pulse amplitude decreases by approximately 14% per decade, and 24-hour integrated GH secretion falls accordingly. By age 60-70, mean GH secretion may be 25-30% of young adult levels. IGF-1 levels track this decline. The clinical consequence of somatopause — increased visceral adiposity, reduced lean muscle mass, decreased bone mineral density, impaired exercise tolerance, and altered sleep architecture — collectively constitute a syndrome that overlaps substantially with frank growth hormone deficiency (GHD) in adults. This is the scientific rationale for GH secretagogue therapy in aging patients without frank GHD.