Ipamorelin

Ipamorelin came out of a Novo Nordisk chemistry programme that stripped the central Ala-Trp dipeptide out of GHRP-1. The resulting pentapeptide released growth hormone from rat pituitary cells about as potently as GHRP-6, and antagonist experiments placed its action at the GHRP (ghrelin) receptor rather than the GHRH receptor [1].

What made it interesting. The older GH-releasing peptides are not clean: GHRP-6 and GHRP-2 also push ACTH, cortisol and prolactin [3]. In pigs, ipamorelin released growth hormone without moving FSH, LH, prolactin, TSH, ACTH or cortisol, even at doses more than 200 times its ED50 for growth hormone [1]. Its developers called it the first selective growth hormone secretagogue.

What happened next. It was not developed as a growth hormone drug. The one controlled human trial used it for postoperative ileus, on the ghrelin receptor's effect on gut motility, which had worked in rats [4]. In 114 patients after bowel resection, intravenous ipamorelin 0.03 mg/kg twice daily for up to seven days was well tolerated, but the median time to tolerating a solid meal was 25.3 hours against 32.6 on placebo, which was not statistically significant [2]. In rats it also protected against glucocorticoid-induced loss of bone formation [5].

Everything else said about ipamorelin — that it raises IGF-1, adds lean mass, or does so more cleanly than other secretagogues in people — is extrapolation from the pig study. No published human trial has measured growth hormone or IGF-1 on ipamorelin at all.

Ipamorelin is a GHS-R1a agonist, the same receptor ghrelin and MK-677 use [1]. Agonists at this receptor raise growth hormone partly at the pituitary and partly by opposing somatostatin in the hypothalamus, which is why GH-releasing peptides synergise with GHRH [6].

Its distinguishing feature is what it does not do. Structure-activity work on this peptide family shows that small changes in the core residues separate growth hormone release from ACTH and prolactin release [7], and ipamorelin sits at the selective end of that range in animals [1]. Whether that selectivity holds in humans has not been tested.

Ipamorelin is a pentapeptide, Aib-His-D-2-Nal-D-Phe-Lys-NH2, normally supplied as the acetate salt [1]. The only published human route is intravenous infusion [2]; the subcutaneous route used in practice has not been studied in humans. Peptides of this kind are common in grey-market "growth" products, whose actual contents often differ from the label [8].

The only human safety data come from the ileus trial: over up to seven days of twice-daily intravenous dosing in 114 post-surgical patients, treatment-emergent adverse events occurred in 87.5% on ipamorelin and 94.8% on placebo — a population where nearly everyone has some adverse event after bowel surgery — and no safety signal was attributed to the drug [2].

There is no human data on longer use, on glucose, on IGF-1, or on what happens to the pituitary over months. By analogy with the rest of this class, chronic dosing would be expected to blunt the growth hormone response over time, as it does with hexarelin [10], but this has not been measured for ipamorelin.

No human interaction studies exist. GH-releasing peptides in general synergise with GHRH on growth hormone release [6], so combining ipamorelin with a GHRH analogue would be expected to produce a larger response than either alone, but this has not been shown for ipamorelin specifically.