Ipamorelin or GHRP-2: what is the difference

Ipamorelin and GHRP-2 belong to the same class — peptide growth-hormone secretagogues that act through the ghrelin receptor. But in the endocrinological literature they are distinguished by an important feature: selectivity. GHRP-2, along with growth hormone, raises cortisol and prolactin, whereas ipamorelin in preclinical studies had almost no such effect. The editorial team examines what lies behind this difference.

The GHRP family of peptides

The history of growth-hormone-releasing peptides (GHRPs) began in the 1970s–80s with the work of Cyril Bowers, who synthesized short peptides based on the structure of enkephalins and found that they stimulate GH release. The first widely studied representative was GHRP-6; then came the more potent GHRP-2, hexarelin and other compounds.

The receptor through which these peptides act was initially called the “GH secretagogue receptor” (GHS-R1a). Only in 1999 was its natural ligand — ghrelin — discovered. Since then GHRPs have been regarded as synthetic ghrelin mimetics.

Ipamorelin was created in the 1990s at Novo Nordisk as an attempt to obtain a peptide that stimulates GH just as effectively but without the accompanying effect on other pituitary and adrenal hormones. In 1998 Raun and colleagues presented it as “the first selective growth-hormone secretagogue”.

So both peptides are “relatives” within the same pharmacological group. The differences between them concern not the target but which other signals are triggered along with GH release.

Structure and mechanism of action

GHRP-2 (international name pralmorelin) is a hexapeptide, i.e. it consists of six amino-acid residues, some of which are D-isomers, which increases resistance to enzymes. Ipamorelin is a pentapeptide of five residues, also with non-natural amino acids in its structure.

Both peptides bind to the ghrelin receptor on pituitary somatotrophs and in the hypothalamus. Activation of the receptor triggers signaling through phospholipase C and a rise in intracellular calcium, which leads to GH release. In parallel, these peptides can enhance the release of GHRH and weaken the inhibitory action of somatostatin.

The key difference is in the incidental activation of other axes. GHRP-2, like GHRP-6, dose-dependently raises ACTH and cortisol levels, as well as prolactin. Ipamorelin in animal studies (Raun et al., 1998) did not substantially raise ACTH and cortisol even at doses far exceeding those needed for maximal GH release.

Another difference concerns appetite. As ghrelin mimetics, GHRPs can enhance hunger; for GHRP-2 and especially GHRP-6 this effect is well described, while for ipamorelin it is, according to available data, less pronounced, although there are few systematic comparisons in humans.

Medical use and studies

GHRP-2 is one of the few peptides of this group to have received medical use: in Japan pralmorelin is registered as a diagnostic agent for assessing the secretory reserve of growth hormone. A single administration followed by measurement of GH helps detect hormone deficiency. This is a diagnostic, not a therapeutic, indication.

Ipamorelin was studied in a clinical program for the treatment of postoperative intestinal obstruction (ileus), since ghrelin agonists stimulate gastrointestinal motility. A phase II study (Beck et al., 2014) did not show a convincing advantage over placebo, and the drug was not registered.

There are practically no studies in the peer-reviewed literature that would assess the effect of ipamorelin or GHRP-2 on body composition, strength or recovery in healthy people or athletes. Popular notions of their benefit for “definition” and “rejuvenation” are based on extrapolation from GH stimulation.

A review by Sigalos and Pastuszak (2018) on the safety and efficacy of GH secretagogues concludes: the evidence base for most substances of this group is limited, and long-term safety data are absent.

Risks and side effects

For GHRP-2 the side effects partly stem from its “non-selectivity”: a rise in cortisol can affect glucose metabolism, sleep and mood, and a rise in prolactin can theoretically affect libido. During a single diagnostic administration, hot flushes and transient sensations of warmth were described.

For ipamorelin there are few clinical safety data, and they concern short courses in hospital patients. The selectivity with respect to cortisol shown in animals does not mean the complete absence of side effects in humans.

Shared risks are the consequences of stimulating the GH/IGF-1 axis with long-term use: fluid retention, joint pain, numbness of the fingers, worsened insulin sensitivity. A theoretical concern is also the rise in IGF-1 as a cell growth factor in people with cancer risks.

Finally, the practical risks of illegal peptides: incorrect content, impurities, breaches of sterility and endotoxins in injectable products.

• GHRP-2:↑ cortisol and prolactin, increased appetite, flushes.
• Ipamorelin:limited data in humans; selectivity confirmed mostly preclinically.
• Both:the effects of elevated IGF-1, the risks of injection and product quality.

Status in sport

Both peptides are directly mentioned in class S2 of the WADA Prohibited List among GH secretagogues and ghrelin mimetics. The ban applies at all times — in and out of competition.

Anti-doping laboratories have developed methods for detecting GHRPs and their metabolites in urine, and positive samples for peptides of this group are recorded regularly. Claims that “peptides are not visible in tests” are not true.

For athletes the principle of strict liability applies: even if the peptide entered the body as part of an unverified product, this is considered a violation.

In most countries these peptides are not registered as medicines, and their sale with the label “for research” does not make them fit for human consumption.

Editorial conclusions

Ipamorelin and GHRP-2 act through one receptor — the ghrelin receptor — but differ in selectivity. GHRP-2 potently stimulates GH and at the same time raises cortisol and prolactin; ipamorelin in preclinical studies stimulated GH without a substantial effect on these hormones.

GHRP-2 has a narrow medical use as a diagnostic agent; ipamorelin is not registered. For healthy people and athletes there is no evidence of benefit, and both peptides are banned by WADA.

We also recommend reading “Ipamorelin vs GHRP-2: what to choose and for whom”, an overview of ghrelin and appetite regulation and a material on the storage and quality control of peptides.

References

1. Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998;139(5):552–561.
2. Bowers CY. Growth hormone-releasing peptide (GHRP). Cell Mol Life Sci. 1998;54(12):1316–1329.
3. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–660.
4. Sigalos JT, Pastuszak AW. The safety and efficacy of growth hormone secretagogues. Sex Med Rev. 2018;6(1):45–53.
5. Beck DE, Sweeney WB, McCarter MD, et al. Prospective, randomized, controlled, proof-of-concept study of the ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. Int J Colorectal Dis. 2014.
6. World Anti-Doping Agency. The World Anti-Doping Code International Standard: Prohibited List. Montreal: WADA; чинна редакція.