What is GHRH?
Also called: Growth hormone-releasing hormone, GRF, GHRF, Somatocrinin, GHRH(1-44)-NH2
Growth hormone-releasing hormone: a 44-residue hypothalamic peptide that drives growth hormone synthesis and release through the GHRH receptor on pituitary somatotrophs.
By the APL Research Team · Updated
GHRH (growth hormone-releasing hormone) is the hypothalamic peptide that tells the anterior pituitary to make and release growth hormone. Its structure was first solved in 1982, not from hypothalamus but from a human pancreatic tumour that had caused acromegaly: a 44-residue C-terminally amidated peptide whose synthetic copy stimulated growth hormone secretion in vitro and in vivo and matched the activity of the factor in hypothalamic extracts [1]. Older papers call it GRF or GHRF.
Sequence and active core
Human GHRH(1-44)-NH2 reads, in one-letter code [1]:
YADAIFTNSY RKVLGQLSAR KLLQDIMSRQ QGESNQERGA RARL-NH2
Calculated from that sequence, the formula is C215H358N72O66S with an average mass of 5039.7 Da. Only the first 29 residues are needed: sermorelin, GHRH(1-29)-NH2 (3357.9 Da), is the shortest synthetic peptide with the hormone's full biological activity [2]. An alanine scan of the 1–29 fragment showed how unevenly that activity is spread [3]:
| Effect of alanine substitution | Positions |
|---|---|
| Near-complete loss of potency | 1, 3, 5, 6, 10, 11, 13, 14, 23 |
| 2–6-fold more potent than the standard | 8, 9, 15, 22 |
| Roughly equipotent | 16, 18, 24, 25, 26, 29 |
The same study linked potency to amphiphilic, helical character, which is why so many analogues add helix-stabilising substitutions or lactam bridges [3].
The GHRH receptor
The GHRH receptor (GHRHR) was cloned from rat pituitary in 1992. Its human counterpart, expressed in HEK293 cells, bound GHRH with high affinity, raised intracellular cAMP, and resembled the secretin and VIP receptors, placing it in class B; rat GHRHR mRNA was found predominantly in the anterior pituitary [4]. Receptor function is required for normal growth in mice: the dwarf little mouse carries a missense mutation in the GHRHR extracellular domain that disrupts signalling and reduces GH secretion [5].
A short-lived native peptide
In human plasma in vitro, a dipeptidyl peptidase removed Tyr1-Ala2 from GHRH(1-44)-NH2 with a half-life of 17 minutes measured by HPLC; the GHRH(3-44)-NH2 product retained less than 1/1000 of the parent's activity [6]. Immunoassay alone gave a misleading 63 minutes because the antibody still recognised the inactive fragment [6]. Most GHRH analogue chemistry targets this weakness:
| Analogue | Basis | Modification |
|---|---|---|
| Sermorelin | GHRH(1-29)-NH2 | None [2] |
| CJC-1295 (with DAC) | Tetrasubstituted GHRH(1-29) | C-terminal lysine bearing a maleimidopropionamide that conjugates to albumin; detected in rat plasma beyond 72 h [7] |
| CJC-1295 (No DAC) | The same tetrasubstituted 1–29 amide, also called modified GRF(1-29) | No albumin-binding group |
| Tesamorelin | GHRH(1-44)-NH2 | trans-3-Hexenoyl group on Tyr1; resisted DPP-4 and degraded more slowly in rat, dog and human plasma [8] |
Points of confusion
- GHRH analogues are not ghrelin mimetics. Both raise GH, but through different receptors; peptides such as ipamorelin act at the ghrelin receptor and are classed as growth hormone secretagogues. The CJC-1295 and ipamorelin blend pairs one of each.
- Residue numbering follows the native hormone. "1-29" and "1-44" refer to positions in the sequence above; the guide to reading peptide sequences explains the notation.
- Measure the intact peptide. As the plasma study showed, an assay that cannot distinguish GHRH(1-44) from GHRH(3-44) overstates stability [6].
References
- 1.Guillemin R, Brazeau P, Böhlen P, et al. Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science. 1982. PubMed 6812220
- 2.Prakash A, Goa KL. Sermorelin: a review of its use in the diagnosis and treatment of children with idiopathic growth hormone deficiency. BioDrugs. 1999. PubMed 18031173
- 3.Cervini LA, Donaldson CJ, Koerber SC, et al. Human growth hormone-releasing hormone hGHRH(1-29)-NH2: systematic structure-activity relationship studies. J Med Chem. 1998. PubMed 9513600
- 4.Mayo KE. Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone. Mol Endocrinol. 1992. PubMed 1333056
- 5.Godfrey P, Rahal JO, Beamer WG, et al. GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat Genet. 1993. PubMed 8395283
- 6.Frohman LA, Downs TR, Williams TC, et al. Rapid enzymatic degradation of growth hormone-releasing hormone by plasma in vitro and in vivo to a biologically inactive product cleaved at the NH2 terminus. J Clin Invest. 1986. PubMed 3093533
- 7.Jetté L, Léger R, Thibaudeau K, et al. Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog. Endocrinology. 2005. PubMed 15817669
- 8.Ferdinandi ES, Brazeau P, High K, et al. Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue. Basic Clin Pharmacol Toxicol. 2007. PubMed 17214611