Growth hormone / GHRH / GHS axis

Category: endocrine_axis

Overview

Hypothalamic GHRH stimulates pituitary GH release; somatostatin (SST) inhibits. GH acts on hepatocyte GHR → JAK2 → STAT5 → IGF-1 production (the main mediator of GH growth effects). Synthetic GHRH analogs (sermorelin, mod-grf-1-29, cjc-1295 — DAC-extended) pulse-stimulate endogenous GH. GHS-R agonists (ghrelin pathway — ghrp-2, ghrp-6, ipamorelin, hexarelin) are an orthogonal route to GH release via the stomach ghrelin receptor. Tesamorelin is a GHRH analog approved for HIV-associated lipodystrophy. mk-677 (ibutamoren) is an oral non-peptide GHS-R agonist. Direct GH replacement: somatropin (recombinant human GH) for GH deficiency. IGF-1 analogs: igf-1-lr3 (research only) + mecasermin (Increlex). ACE-031 inhibits myostatin (negative muscle-growth regulator). AOD-9604 is a GH fragment with claimed lipolytic activity (research-only). Acromegaly Rx: octreotide/lanreotide (SST analogs — see somatostatin pathway in END-6).

Organ Systems

• endocrine
• musculoskeletal

Pathway Steps

1. ghrh → pituitary-gh-release — via GHRH-R on somatotrophs → Gs → cAMP → GH secretion. Hypothalamic GHRH stimulates pituitary somatotrophs to release growth hormone, while somatostatin inhibits it; the stomach peptide ghrelin (via the GHS receptor) also potently stimulates GH and appetite. This dual GHRH/ghrelin drive made the GHS receptor a target for GH secretagogues.
2. pituitary-gh-release → hepatic-igf-1 — via GHR → JAK2 → STAT5 → IGF-1 transcription. Much of GH’s anabolic, growth-promoting action is mediated by hepatic insulin-like growth factor 1 (IGF-1), which it induces. IGF-1 feeds back to suppress GH — and the GH/IGF-1 axis is measured to diagnose acromegaly and GH deficiency, and is targeted by pegvisomant (a GH-receptor antagonist).

Known Modulators

• cjc 1295 (activator) — GHRH-R (DAC-extended GHRH analog). GHRH analog with drug affinity complex extending t½ to ~8 days; research peptide (no FDA approval); pulse-amplification of endogenous GH
• sermorelin (activator) — GHRH-R. GHRH(1-29) — minimum bioactive fragment; pediatric GH-deficiency diagnostic + adult research; short half-life
• mod grf 1 29 (activator) — GHRH-R (tetrasubstituted GRF analog). modified GRF(1-29) with 4 amino-acid substitutions for enzymatic stability; research peptide
• ghrp 2 (activator) — GHS-R1a (ghrelin receptor agonist). growth-hormone-releasing peptide; orthogonal to GHRH pathway; research peptide
• ghrp 6 (activator) — GHS-R1a. GHRP-6; food-craving side effect from on-target ghrelin-receptor activation
• ipamorelin (activator) — GHS-R1a (selective). cleaner GHS-R agonist (no significant prolactin/cortisol/glucose effects); research peptide
• hexarelin (activator) — GHS-R1a. older GHRP; cardiac receptor activity beyond GH release; research peptide
• tesamorelin (activator) — GHRH-R. FDA-approved (Egrifta) for HIV-associated lipodystrophy; SC qd
• mk 677 (activator) — GHS-R1a (oral non-peptide). ibutamoren; oral nightly; sleep architecture changes + appetite increase; research-stage for sarcopenia
• somatropin (activator) — GH receptor (recombinant hGH). GH-deficiency replacement; pediatric + adult; bypasses hypothalamic-pituitary regulation entirely
• igf 1 lr3 (activator) — IGF-1R (research peptide, extended t½). long-arg-3 IGF-1 modification reduces IGFBP binding → extended free t½; research only
• des igf 1 (activator) — IGF-1R (truncated). des(1-3) IGF-1 — reduced IGFBP affinity, similar logic to LR3; research only
• mechano growth factor (activator) — IGF-1Ec splice variant receptor. IGF-1 Ec/Eb splice variant; muscle-injury upregulated; tissue repair claims
• ace 031 (inhibitor) — myostatin / activin (soluble ActRIIB). soluble activin-receptor decoy; muscle-growth claims; suspended phase II for vascular adverse events (DMD trial)
• aod 9604 (activator) — lipolytic GH C-terminus fragment (research). GH(176-191); claimed lipolytic effects without growth-promoting activity; research-only — minimal clinical evidence

References

• PMID 10604470
• PMID 18057375