What is Growth hormone secretagogue?
Also called: GHS, GH secretagogue, GHRP, Growth hormone-releasing peptide
Any compound that triggers growth hormone release; in research usage, mainly the synthetic ghrelin-receptor agonists such as GHRP-6, ipamorelin and MK-0677, as distinct from GHRH analogues.
By the APL Research Team · Updated
A growth hormone secretagogue is, literally, anything that makes the pituitary secrete growth hormone. In practice the abbreviation GHS has a narrower meaning: the synthetic peptides and small molecules, developed from the 1980s onward, that act at what is now called the ghrelin receptor. They were found by reverse pharmacology, screened for GH release before either their receptor or its natural ligand was known [1]. GHRH and its analogues also release GH but work through a different receptor, and most papers keep the two groups apart.
From compound to receptor to hormone
| Year | Milestone |
|---|---|
| 1984 | GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) characterised: GH release in vitro and in vivo without LH, FSH, TSH or prolactin release [2] |
| 1995 | MK-0677, a non-peptide, released GH from rat pituitary cells with an EC50 of 1.3 nM and was mechanistically indistinguishable from GHRP-6 but distinguishable from GHRH [3] |
| 1996 | The shared target cloned from pituitary and hypothalamus of swine and humans [4] |
| 1998 | Ipamorelin described as the first GHS with GH selectivity similar to GHRH [5] |
| 1999 | Ghrelin purified from rat stomach as the receptor's endogenous ligand [6] |
Knockout of the receptor later confirmed that these compounds are ghrelin mimetics [1].
Two routes to GH release
| Ghrelin-receptor secretagogues | GHRH-receptor agonists | |
|---|---|---|
| Examples | GHRP-6, GHRP-2, ipamorelin, MK-0677 | GHRH(1-44), sermorelin, CJC-1295 (No DAC), tesamorelin |
| Receptor | GHS-R1a, class A | GHRHR, class B |
| Typical size | Penta- and hexapeptides with D-amino acids, or small molecules | 29–44-residue peptides |
| Endogenous counterpart | Ghrelin, from stomach | GHRH, from hypothalamus |
The routes interact. Smith's review describes GHS acting through four mechanisms: raising GHRH release, amplifying GHRH signalling in somatotrophs, reducing somatostatin release and opposing somatostatin receptor signalling [1]. Somatostatin still brakes the system: SRIF-14 and SRIF-28 both inhibited the GH response to GHRP-6 [2]. This complementarity is why a GHRH analogue and a GHS are often studied together, as in the CJC-1295 and ipamorelin blend; the peptide blends guide covers two-component preparations.
Selectivity differs within the class
GH specificity is not uniform. In conscious swine, GHRP-6 and GHRP-2 raised ACTH and cortisol as well as GH, whereas ipamorelin's ACTH and cortisol responses did not differ significantly from those after GHRH, even at more than 200 times its ED50 for GH release [5]. GHRP-2 was the most potent of the three peptides in that study yet produced the lowest maximal GH response [5], a reminder that potency and efficacy are separate measurements.
Points of confusion
- A secretagogue is defined by effect, not receptor. Check which receptor a paper means before comparing compounds labelled "GHS".
- GHRP-6 travelled across species. It was active in rats, monkeys, lambs and calves [2], but species-matched controls remain good practice.
- Short sequences, unusual residues. D-amino acids and non-coded residues such as Aib and D-2-naphthylalanine are standard in this class [2, 5]; the peptide sequences guide explains the notation.
References
- 1.Smith RG. Development of growth hormone secretagogues. Endocr Rev. 2005. PubMed 15814848
- 2.Bowers CY, Momany FA, Reynolds GA, et al. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology. 1984. PubMed 6714155
- 3.Patchett AA, Nargund RP, Tata JR, et al. Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue. Proc Natl Acad Sci U S A. 1995. PubMed 7624358
- 4.Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996. PubMed 8688086
- 5.Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998. PubMed 9849822
- 6.Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999. PubMed 10604470