How Does Ipamorelin Work?

Molecular mechanism and receptor selectivity

Ipamorelin is a synthetic pentapeptide with the sequence Aib-His-D-2-Nal-D-Phe-Lys-NH2, developed within a chemical series that lacks the central dipeptide Ala-Trp characteristic of GHRP-1. In primary rat pituitary cells, the 1998 characterization study measured growth hormone (GH) release with potency and efficacy similar to GHRP-6. Profiling with GHRP and GHRH antagonists indicated that ipamorelin acts through a GHRP-like receptor, the same target as GHRP-6.Animal study · PMID 9849822

The feature that set ipamorelin apart in that study was selectivity. In conscious swine, ipamorelin released GH to a degree comparable to GHRP-6, and none of the secretagogues tested changed FSH, LH, PRL or TSH plasma levels. GHRP-6 and GHRP-2 both raised ACTH and cortisol. Ipamorelin did not release ACTH or cortisol at levels significantly different from those seen after GHRH, across the full range the study tested.Animal study · PMID 9849822

Growth hormone release and pituitary effects

In anaesthetized rats, the same study recorded GH release from ipamorelin comparable to GHRP-6. A separate 2002 study gave ipamorelin to young female rats for 21 days and examined the pituitary somatotroph compartment: the volume density of secretion granules was higher (p<0.05) in animals receiving ipamorelin or GHRH than in saline controls.Animal study · PMID 9849822Animal study · PMID 12168778

In pituitary cells cultured from those animals, challenge with ipamorelin, GHRP-6 or GHRH raised the percentage of immunostaining somatotroph cells and intracellular GH content within 4 hours. Basal intracellular GH content was lower in the ipamorelin group than in saline controls, which the authors linked to higher GH release.Animal study · PMID 12168778

The growth hormone response in healthy volunteers

A 1999 study in healthy volunteers modelled the relationship between plasma ipamorelin concentration and growth hormone. GH followed a single-episode pattern, peaking and then falling to negligible concentrations, and the authors described the relationship with an indirect response model.Human trial · PMID 10496658

The same study found that variability between individuals was larger for the pharmacodynamic parameters, that is the GH response, than for the pharmacokinetic ones. In other words, people with similar blood levels of the peptide differed more in how much GH followed. The study was a modelling exercise in healthy volunteers and did not test any clinical endpoint.Human trial · PMID 10496658

Gastrointestinal motility and postoperative ileus

Because ipamorelin acts on the ghrelin receptor, gut motility has been studied alongside GH release. In a rat model of postoperative ileus after laparotomy and intestinal manipulation, a single exposure shortened the time to first bowel movement compared with vehicle. With repeated exposures, cumulative fecal pellet output, food intake and body weight gain at 48 hours after surgery were higher than in vehicle controls.Animal study · PMID 19289567

That rat work led to a phase 2 randomized, controlled, proof-of-concept trial in 114 adults undergoing bowel resection. Median time to first tolerated meal was 25.3 hours with ipamorelin and 32.6 hours with placebo, a difference that was not statistically significant (p = 0.15). The overall incidence of adverse events was 87.5% with ipamorelin and 94.8% with placebo.Human RCT · PMID 25331030

Metabolic and pancreatic effects

A 2004 study measured insulin release from pancreatic tissue fragments taken from normal rats and rats with streptozotocin-induced diabetes. Insulin release was higher with ipamorelin than without it (p<0.04). Diltiazem, yohimbine and propranolol each inhibited that release (p<0.03) in both preparations, and in the diabetic rats atropine also reduced it (p<0.007). The authors concluded that the effect depends on calcium channels, alpha- and beta-adrenergic receptors and, in the diabetic state, muscarinic receptors.Animal study · PMID 15665799

In rats given prednisolone, adding ipamorelin reduced hepatic urea-N synthesis capacity by 20% (p<0.05) compared with prednisolone alone and lowered expression of urea cycle enzymes. Nitrogen balance was higher than in prednisolone-only controls, though the change was smaller than with GH itself. The authors attributed the effect to the GH axis.Animal study · PMID 19231263

The GH and IGF-I axis in diabetic mice

Ipamorelin has also been used as a probe of the GH/IGF-I axis rather than as the subject of study. In a 2003 study of female mice with streptozotocin-induced diabetes and nondiabetic controls, blood was sampled on day 14 before and 10 minutes after ipamorelin. GH levels after ipamorelin were higher in the diabetic mice than in the nondiabetic mice (P<.05). Serum IGF-I was lower in the diabetic animals and rose after stimulation only in the nondiabetic ones.Animal study · PMID 14630569

Hepatic GH receptor and IGF-I measures responded to GH stimulation in the nondiabetic mice but not in the diabetic mice, where the low baseline levels stayed unchanged. The authors concluded that diabetic mice show GH hypersecretion with GH resistance, and proposed them as a closer model of the GH/IGF-I disturbance in type 1 diabetes than diabetic rats.Animal study · PMID 14630569

Body composition and adiposity

GH secretagogues and GH differ in their effects on body fat. In GH-intact and GH-deficient mice receiving ipamorelin, the compound induced a small (15%) increase in body weight by 2 weeks that was not further augmented by 9 weeks. Ipamorelin also elevated fat pad weights relative to body weight in GH-intact and GH-deficient mice. Dual energy X-ray absorptiometry (DEXA) measurement in GH-intact mice receiving ipamorelin or GHRP-6 for 2 weeks showed higher relative body fat compared to saline controls.Animal study · PMID 11162489

The same study compared ipamorelin with GH itself. In GH-intact mice, ipamorelin was associated with higher relative fat mass, serum leptin and food intake; GH lowered relative fat mass in GH-deficient mice and had no effect in GH-intact mice. The authors concluded that GH secretagogues raise body fat through mechanisms independent of GH, a finding from mice that has not been tested in people.Animal study · PMID 11162489

What the ipamorelin evidence does not show

Most of the ipamorelin literature is pharmacology in rats, mice and swine, and much of it dates from 1998 to 2009. The ACTH and cortisol selectivity that defines the compound comes from the 1998 animal study. The rodent work on body fat points in a different direction from GH itself, which is a reminder that receptor-level effects and GH-level effects are not interchangeable.Animal study · PMID 9849822Animal study · PMID 11162489

The only randomized trial in people tested a clinical question, recovery of gut function after bowel resection, and did not find a statistically significant difference from placebo on its main measure. No randomized trial summarised here measured GH, IGF-I, body composition or cortisol as a primary endpoint in people.Human RCT · PMID 25331030

The studies at a glance

Key ipamorelin studies by model, as reported in each paper's abstract.

Frequently asked questions