Research librarySecretagogues and GHRH analogues
GH Peptides and HGH: Different Receptors, Different Pharmacology
For laboratory research use only. The compounds discussed here are sold strictly for in vitro research. They are not drugs, supplements or cosmetics and are not for human or animal use. This article summarizes published literature for reference and is not medical or usage advice.
People lump GH peptides and HGH together as if they were the same thing in different packaging. They are not. HGH is a 191 residue protein and it goes straight to the growth hormone receptor out on peripheral cells. The peptides, sermorelin and CJC-1295 and ipamorelin and the rest of them, never touch that receptor at all. They work a level up, on two different receptors in the pituitary, and that difference decides where the signal starts and what measurements are worth taking. We pulled the receptor papers and laid it out below.
Key findings
- The GHRH receptor: class B GPCR, cloned from rat pituitary in 1992, cAMP as the second messenger, and the transcript sits almost nowhere except the anterior pituitary [1].
- GHS-R1a, the other pituitary target, is a class A GPCR cloned in 1996 and signals through phospholipase C [3]. Ghrelin is its endogenous ligand [4].
- Activating GHS-R1a alone produced no cAMP response, but activating it alongside the GHRH receptor roughly doubled the cAMP response versus GHRH alone [5].
- The growth hormone receptor itself is not recruited by any of these peptides. It exists as a constitutive dimer and is activated by subunit reorganisation, signalling through JAK2-STAT5 and in parallel through Src and ERK [6].
- CJC-1295 in healthy adults: half-life estimated at 5.8 to 8.1 days, plasma GH up 2 to 10 fold for 6 days or more, IGF-I up 1.5 to 3 fold for 9 to 11 days [7]. Days, plural.
- Ipamorelin, by contrast, cleared with a terminal half-life near 2 hours and produced one GH episode peaking around 0.67 hours [8].
Two receptors upstream, one receptor downstream
Somatotroph cells in the anterior pituitary carry two separate receptors that feed into GH release. Mayo cloned the first one, the GHRH receptor, from rat pituitary mRNA in 1992 and showed it binds human GHRH with high affinity and drives intracellular cAMP. The transcript sits predominantly, maybe exclusively, in the anterior pituitary [1]. Later work from the same lab tied that receptor to somatotroph proliferation as well as secretion, and showed its gene is regulated by the pituitary transcription factor Pit-1 [2].
The second receptor was cloned four years later. Howard and colleagues pulled GHS-R1a out of swine and human pituitary and hypothalamus and confirmed it as the target of the synthetic secretagogues [3]. Its natural ligand, the octanoylated 28 residue stomach peptide ghrelin, was identified in 1999 [4].
Now the part worth sitting with. These two receptors are not redundant copies. Cunha and Mayo expressed both in one cell background and tested them together: GHS-R1a activation on its own did nothing to cAMP, yet co-activation produced a cAMP response about twice that of GHRH alone, and the effect did not appear with the related secretin or VIP receptors [5]. Convergence, not addition.
Where recombinant HGH acts instead
Recombinant HGH skips all of that and binds the growth hormone receptor out on peripheral cells. Textbooks used to say the hormone cross-links two loose receptor monomers. That picture got torn up. The receptor already sits as a constitutive dimer, and the hormone rearranges the subunits, because its two binding sites are placed asymmetrically on one monomer. JAK2 and STAT5 carry the signal, with Src and ERK running alongside [6].
So the comparison is not peptide versus protein. It is a pituitary GPCR versus a peripheral cytokine receptor family member, with an entire regulatory layer, the somatotroph and its feedback, sitting in between.
| GHRH analogues | GHS-R1a agonists | Recombinant HGH | |
|---|---|---|---|
| Examples | Sermorelin, CJC-1295, tesamorelin | Ipamorelin, GHRP-2, GHRP-6, hexarelin | Somatropin |
| Receptor | GHRH receptor, class B GPCR | GHS-R1a, class A GPCR | GH receptor, cytokine receptor family |
| Main second messenger | cAMP [1] | Phospholipase C pathway [3] | JAK2-STAT5, plus Src and ERK [6] |
| Site | Anterior pituitary [1] | Pituitary and hypothalamus [3] | Peripheral target cells [6] |
| Endogenous ligand | GHRH | Ghrelin [4] | Pituitary GH |
The peptides are not one class
Calling everything a GH peptide hides the split that actually shows up in the data.
GHRH side
Sermorelin is GHRH(1-29), the short end of the parent hormone that still works at the receptor. CJC-1295 is a modified GHRH analogue engineered to hang around in plasma much longer. How much longer? Teichman’s group ran two randomised placebo-controlled trials in healthy adults: half-life 5.8 to 8.1 days, mean plasma GH up 2 to 10 fold for 6 days or more, mean IGF-I up 1.5 to 3 fold for 9 to 11 days, and signs of accumulation when exposure repeated [7]. Those are the real numbers behind the “long acting” label, and they are days, not hours. Our CJC-1295 DAC and no-DAC comparison covers the chemistry behind that difference.
Secretagogue side
Ipamorelin is the cleanest published example here. On rat pituitary cells its EC50 was 1.3 plus or minus 0.4 nmol/L with an Emax of 85 plus or minus 5 percent of the GHRP-6 maximum, and in conscious swine GHRP-6 and GHRP-2 raised ACTH and cortisol while ipamorelin did not, even far above its ED50 for GH release [9]. In healthy volunteers its terminal half-life came out near 2 hours, with clearance of 0.078 L/h/kg, and GH rose as one episode peaking around 0.67 hours [8]. Compare that with CJC-1295’s multi-day curve and you can see why the two are not interchangeable in any experimental design. More on the hexapeptides in our GHRP-2 and ipamorelin comparison.
What this means for reading the literature
Three habits save a lot of confusion here.
Start with the receptor a paper is actually interrogating. Antagonist controls are the giveaway: Raun’s group used both GHRP and GHRH antagonists to establish that ipamorelin works through the GHRP-like receptor rather than the GHRH receptor [9]. Papers without that control leave the mechanism open.
Second, watch the endpoint. Plasma GH is episodic and sampling time decides what you see, which is exactly why the ipamorelin modelling paper found wider variability in the hormone response parameters than in the pharmacokinetic ones [8]. IGF-I integrates over days and behaves quite differently, as the CJC-1295 data show [7].
Third, do not port a swine result into a human claim, or a transfected cell result into either. The cell work in reference 5 is a clean mechanism experiment in an engineered background, and the authors framed it as speculation about receptor interactions, not as pituitary physiology [5].
Material quality
All this receptor detail collapses if the compound in the vial was never properly characterised. Two methods do the work: reversed phase HPLC, which gives you a percentage for that sample on that run, and mass spectrometry, which says whether the molecular mass matches the sequence you think you have. A bare purity number with no method, no date and no batch behind it tells you next to nothing. Our certificates are published at wholesalepeptide.com/coas, every batch goes to a U.S.-based third-party laboratory, and the peptides are USA-made.References
- Mayo KE. Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone. Mol Endocrinol. 1992. PMID 1333056
- Mayo KE, Miller T, DeAlmeida V, et al. Regulation of the pituitary somatotroph cell by GHRH and its receptor. Recent Prog Horm Res. 2000. PMID 11036940
- Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996. PMID 8688086
- Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999. PMID 10604470
- Cunha SR, Mayo KE. Ghrelin and growth hormone (GH) secretagogues potentiate GHRH-induced cyclic AMP production in cells expressing transfected GHRH and GH secretagogue receptors. Endocrinology. 2002. PMID 12446584
- Brooks AJ, Wooh JW, Tunny KA, Waters MJ. Growth hormone receptor; mechanism of action. Int J Biochem Cell Biol. 2008. PMID 17888716
- Teichman SL, Neale A, Lawrence B, et al. Prolonged stimulation of growth hormone and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. J Clin Endocrinol Metab. 2006. PMID 16352683
- Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. 1999. PMID 10496658
- Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998. PMID 9849822