What it is
Ipamorelin is a synthetic five-amino-acid peptide (Aib-His-D-2-Nal-D-Phe-Lys-NH2) developed at Novo Nordisk and described by Raun et al. (1998) as the first selective growth hormone secretagogue. It belongs to the growth hormone-releasing peptide (GHRP) family that acts on the ghrelin receptor. After early pharmacokinetic work in healthy volunteers, Helsinn took it into phase 2 trials in postoperative ileus, the slowed bowel function that follows abdominal surgery.
Mechanism of action
Ipamorelin is an agonist of the growth hormone secretagogue receptor (GHS-R1a), the receptor for the stomach hormone ghrelin. On pituitary somatotroph cells, activating this receptor triggers growth hormone (GH) release; it is a different receptor from the one targeted by GHRH analogs such as CJC-1295. Its defining feature in the original pharmacology work was selectivity. Raun et al. (1998) reported that in swine, the older peptides GHRP-6 and GHRP-2 raised ACTH and cortisol, while ipamorelin did not raise either hormone beyond levels seen with GHRH, even at doses more than 200 times its GH ED50. In healthy men, Gobburu et al. (1999) found that an infusion produced a single episode of GH release that peaked at about 40 minutes and then declined. Ghrelin receptors are also present in the gut, and rat work by Greenwood-Van Meerveld et al. (2012) attributed faster gastric emptying to a ghrelin receptor-mediated effect on stomach muscle contraction involving cholinergic nerves.
What it’s most studied for
Ipamorelin has been studied along two lines. The first is GH release: the 1998 discovery paper characterized its GH-releasing potency and hormonal selectivity, including in swine, and a 1999 study in healthy men modeled its pharmacokinetics and the GH response. Rat studies from the same period examined whether repeated dosing affects bone growth and bone mineral content. The second line is gastrointestinal motility. Because ghrelin stimulates gut movement, Helsinn developed ipamorelin as an intravenous treatment candidate for postoperative ileus, supported by rat models of surgery-induced gut slowing and two phase 2 trials in adults after bowel resection. Interest outside research settings focuses on body composition and recovery, but no published controlled trial of those outcomes was identified for this summary.
Notable findings
Each finding carries the species or population it was observed in and the dose that study used. Doses are reported as research context, exactly as published. They are not guidance.
Phase 2 trial after bowel resection surgery
Beck et al. (2014) enrolled 117 adults after small or large bowel resection, 114 of whom formed the safety and modified intent-to-treat populations. The primary endpoint, time to tolerating a standardized solid meal, had a median of 25.3 hours with ipamorelin and 32.6 hours with placebo, a difference that was not statistically significant (p=0.15). Treatment-emergent adverse events occurred in 87.5% of the ipamorelin group and 94.8% of the placebo group. The authors noted the study was small and enrolled patients with a broad range of underlying conditions.
- Dose studied
- 0.03 mg/kg by intravenous infusion, twice daily from postoperative day 1 to day 7 or hospital discharge (adults after bowel resection)
[3] Beck DE et al. · 2014 · DOI 10.1007/s00384-014-2030-8 ↗
Pharmacokinetics and GH response in healthy men
Gobburu et al. (1999) gave ipamorelin to healthy men at five dose levels and measured ipamorelin and GH concentrations. Pharmacokinetics were dose-proportional, with a terminal half-life of 2 hours, clearance of 0.078 L/h/kg and a steady-state volume of distribution of 0.22 L/kg. GH was released in a single episode that peaked at 0.67 hours and declined to negligible levels at all doses, and the half-maximal stimulating concentration was 214 nmol/L. The study measured hormone levels only, not clinical outcomes.
- Dose studied
- 15-minute intravenous infusions at 4.21, 14.02, 42.13, 84.27 and 140.45 nmol/kg, eight healthy men per dose level
[2] Gobburu JV et al. · 1999 · PMID 10496658 ↗
Selective GH release in swine
Raun et al. (1998) compared ipamorelin with GHRP-6, GHRP-2 and GHRH. In conscious swine, its ED50 for GH release was 2.3 nmol/kg, close to the 3.9 nmol/kg reported for GHRP-6, with peak GH around 65 ng/ml. GHRP-6 and GHRP-2 raised ACTH and cortisol, while ACTH and cortisol after ipamorelin were not significantly different from levels after GHRH, even at doses more than 200 times the GH ED50. The paper's title describes ipamorelin as the first selective GH secretagogue.
- Dose studied
- Dose-response testing in conscious swine, up to more than 200-fold the GH ED50 of 2.3 nmol/kg (route and full dose list not confirmed for this summary)
[1] Raun K et al. · 1998 · PMID 9849822 ↗
Faster gastric emptying after abdominal surgery
Greenwood-Van Meerveld et al. (2012) induced postoperative ileus in fasted male rats with laparotomy and intestinal manipulation. In vehicle-treated rats, 78% of a radiolabeled test meal remained in the stomach after 15 minutes, compared with 52% at the lowest ipamorelin dose and 44% in rats without surgery. In isolated stomach tissue, surgery suppressed nerve-driven contraction, and ipamorelin and ghrelin reversed this. One author was affiliated with Helsinn.
- Dose studied
- 0.014 to 0.14 µmol/kg intravenously (significant effect reported at 0.014 µmol/kg), single dose after surgery (male rats)
[4] Greenwood-Van Meerveld B et al. · 2012 · PMID 27186127 ↗
Bone mineral content in adult female rats
Svensson et al. (2000) treated 13-week-old female rats with ipamorelin or GHRP-6 for 12 weeks. Compared with vehicle-treated controls, treatment increased body weight and total tibial and vertebral bone mineral content measured by DXA. The gain in cortical bone mineral content came from a larger bone cross-sectional area rather than higher volumetric density.
- Dose studied
- 0.5 mg/kg per day by continuous subcutaneous osmotic minipump for 12 weeks (young adult female rats, 7 to 8 per group)
[6] Svensson J et al. · 2000 · PMID 10828840 ↗
Longitudinal bone growth in rats
Johansen et al. (1999) measured the longitudinal bone growth rate in female rats given ipamorelin or vehicle for 15 days. Growth rose with dose, from 42 µm per day in the vehicle group to 44, 50 and 52 µm per day across the three ipamorelin doses.
- Dose studied
- 0, 18, 90 or 450 µg per day, given subcutaneously three times daily for 15 days (female rats)
[5] Johansen PB et al. · 1999 · PMID 10373343 ↗
Study quality
Human data on ipamorelin are limited, but they include one randomized trial. Beck et al. (2014) was a multicenter, double-blind, placebo-controlled phase 2 trial in 114 adults after bowel resection; it did not meet its primary endpoint, and the authors called it a small proof-of-concept study. A second Helsinn-sponsored phase 2 dose-finding trial (NCT01280344) is registered as completed, but no published results were found for this summary. The other human study is a 1999 pharmacokinetic study in healthy men that measured hormone levels only. No published controlled trial of body composition, muscle, sleep or recovery outcomes was identified. The remaining evidence comes from swine and rats, much of it from Novo Nordisk or Helsinn researchers. On safety, adverse-event rates in the phase 2 trial were similar with ipamorelin (87.5%) and placebo (94.8%) in a postoperative population; the long-term effects of repeated dosing in humans have not been studied.
References
- 1Ipamorelin, the first selective growth hormone secretagogue. European Journal of Endocrinology. PMID 9849822
- 2Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharmaceutical Research. PMID 10496658
- 3Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. International Journal of Colorectal Disease. DOI 10.1007/s00384-014-2030-8
- 4Efficacy of ipamorelin, a ghrelin mimetic, on gastric dysmotility in a rodent model of postoperative ileus. Journal of Experimental Pharmacology. PMID 27186127
- 5Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats. Growth Hormone & IGF Research. PMID 10373343
- 6The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats. Journal of Endocrinology. PMID 10828840
- 7Safety and Efficacy of Ipamorelin Compared to Placebo for the Recovery of Gastrointestinal Function. ClinicalTrials.gov. NCT01280344
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