Ipamorelin

Ipamorelin is a synthetic pentapeptide growth hormone secretagogue (GHS) that stimulates pituitary growth hormone (GH) release through agonism of the ghrelin/GHS-R1a receptor. Developed by Novo Nordisk in the late 1990s, it was the first GHS demonstrated to selectively release GH without concomitant stimulation of ACTH, cortisol, or prolactin at physiological doses. This selectivity profile distinguishes it from earlier GHS peptides such as GHRP-6 and hexarelin.

Ipamorelin has been investigated in human clinical trials, most notably a Phase II study for postoperative ileus following abdominal surgery. While it demonstrated a favorable safety profile in that context, it did not meet its primary efficacy endpoint and development for that indication was not advanced. It remains of significant research interest as a tool compound for studying GH axis physiology and as a potential therapeutic in age-related GH decline.

Ipamorelin binds to the growth hormone secretagogue receptor type 1a (GHS-R1a), the same receptor targeted by endogenous ghrelin. Receptor activation triggers a Gq/11-coupled signaling cascade that increases intracellular calcium via phospholipase C and IP3, leading to GH vesicle exocytosis from somatotroph cells in the anterior pituitary. The peptide acts synergistically with endogenous GHRH, amplifying GH pulse amplitude without altering pulse frequency.

The selectivity of ipamorelin stems from its minimal cross-reactivity with other pituitary signaling pathways. Unlike GHRP-2 and GHRP-6, it does not significantly activate the hypothalamic-pituitary-adrenal axis at GH-releasing doses, resulting in negligible cortisol elevation. It also lacks the appetite-stimulating effects seen with less selective ghrelin mimetics, though it does activate GHS-R1a in the GI tract, which underlies its investigated prokinetic properties in postoperative ileus.