Sermorelin and ipamorelin both cause the pituitary to release growth hormone, but they do it through two different receptors. Sermorelin is GHRH(1-29)NH2, the first 29 residues of human growth hormone-releasing hormone, and it activates the GHRH receptor, a Gs-coupled receptor that raises cyclic AMP. Ipamorelin is a synthetic pentapeptide that activates the ghrelin receptor (GHS-R1a), a Gq-coupled receptor that signals through phospholipase C and calcium.
The rest of this comparison sets out each molecule's identity, the two receptor pathways, what the original studies measured, their regulatory histories, and how the two differ at the bench.
Two routes to one output
Growth hormone release from the somatotroph cells of the anterior pituitary is controlled by more than one input. The hypothalamus sends GHRH, which stimulates release, and somatostatin, which inhibits it. A second stimulatory input was found through synthetic chemistry before its natural ligand was known.
In 1984 Cyril Bowers and colleagues described a synthetic hexapeptide, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (later called GHRP-6), that released growth hormone from the pituitary without releasing LH, FSH, TSH or prolactin. In 1996 a Merck group cloned the receptor these growth hormone secretagogues act on, and in 1999 Kojima and colleagues identified its natural ligand in rat stomach: ghrelin, a 28-residue peptide whose serine 3 carries an n-octanoyl group that is essential for activity.
So there are two stimulatory pathways, each with its own receptor, and these two compounds sit on opposite sides of that divide.
Sermorelin at a glance
Sermorelin comes directly from the discovery of GHRH. In 1982 Guillemin's group reported a 44-residue growth hormone-releasing factor isolated from a human pancreatic tumor, and Spiess, Rivier, Thorner and Vale sequenced a growth hormone-releasing factor from a second pancreatic islet tumor. Spiess and colleagues showed that a synthetic fragment, hpGRF(1-29)-NH2, was as active in vitro as the longer forms. That shortest fully active fragment became sermorelin.
| Property | Sermorelin |
|---|---|
| Class | GHRH analog (GHRH receptor agonist) |
| Sequence | YADAIFTNSYRKVLGQLSARKLLQDIMSR-NH2 |
| Length | 29 residues, C-terminal amide |
| Relationship to GHRH | Residues 1–29 of human GHRH (UniProt P01286) |
| Molecular formula | C149H246N44O42S |
| Molecular weight | 3,357.9 g/mol |
| CAS number | 86168-78-7 |
| PubChem CID | 16132413 |
| Other names | GRF(1-29)NH2, hGHRH(1-29)NH2, Geref (former US brand) |
Every residue in sermorelin is a standard L-amino acid, so it is exactly the native sequence, cut short and amidated.
Ipamorelin at a glance
Ipamorelin came out of a Novo Nordisk chemistry program in the 1990s, described by Raun and colleagues in 1998. The team started from the GHRP series and removed the central Ala-Trp dipeptide of GHRP-1, which produced a family of shorter compounds. Ipamorelin was the one they took forward.
| Property | Ipamorelin |
|---|---|
| Class | Ghrelin receptor (GHS-R1a) agonist, GHRP family |
| Sequence | Aib-His-D-2-Nal-D-Phe-Lys-NH2 |
| Length | 5 residues, C-terminal amide |
| Non-standard residues | Aib (α-aminoisobutyric acid), D-2-naphthylalanine, D-phenylalanine |
| Molecular formula | C38H49N9O5 |
| Molecular weight | 711.9 g/mol |
| CAS number | 170851-70-4 |
| PubChem CID | 9831659 |
| Other names | NNC 26-0161 |
Three of ipamorelin's five residues are not found in ordinary proteins. Aib has two methyl groups on its alpha carbon, and the two D-residues are mirror images of their natural forms. Unnatural residues of this kind are a standard way to make short peptides harder for proteases to recognize, and to hold a peptide in a shape its receptor prefers.
Side-by-side comparison
| Feature | Sermorelin | Ipamorelin |
|---|---|---|
| Parent molecule | Human GHRH (44 residues) | GHRP-1 and the GHRP series (synthetic) |
| Length | 29 residues | 5 residues |
| Molecular weight | 3,357.9 g/mol | 711.9 g/mol |
| Receptor | GHRH receptor (GHRHR) | Ghrelin receptor (GHS-R1a) |
| Receptor family | Class B (secretin-family) GPCR, 423 residues | Class A GPCR, 366 residues |
| Main G protein | Gs | Gq/11 |
| Second messenger | Cyclic AMP via adenylyl cyclase | IP3 and diacylglycerol via phospholipase C, then calcium |
| Endogenous ligand of the receptor | GHRH | Ghrelin |
| First described | 1982 (as a GHRH fragment) | 1998 |
| US regulatory history | Approved as Geref; withdrawn from sale in 2008–2009 for business reasons | Never approved; reached a Phase 2 study |
Key differences in brief
Sermorelin is a GHRH analog: it is the first 29 amino acids of the natural hormone, and it binds the GHRH receptor on the somatotroph cells of the pituitary gland. Ipamorelin is a GHRP (growth hormone-releasing peptide), a synthetic peptide that binds the growth hormone secretagogue receptor, whose natural ligand is ghrelin. Each one stimulates growth hormone release from the same cells through a different second messenger, so whether an experiment calls for sermorelin or ipamorelin depends on which receptor is under study.
Other research peptides sit on the same two branches. CJC-1295 and tesamorelin are GHRH analogs like sermorelin, while GHRP-2 and GHRP-6 are growth hormone secretagogues that act at the ghrelin receptor like ipamorelin. Downstream of both branches, UniProt describes the major growth-related role of growth hormone as stimulating the liver and other tissues to secrete IGF-1.
The receptors in more detail
The GHRH receptor
UniProt describes the human GHRH receptor (Q02643) as a 423-residue receptor for GRF coupled to G proteins that activate adenylyl cyclase, stimulating somatotroph growth, growth hormone gene transcription and growth hormone secretion. It belongs to the class B, or secretin-family, GPCRs. That matches the ligand: Spiess and colleagues noted in 1982 that GHRH is closely related to the glucagon-secretin peptide family.
Class B receptors bind their peptide ligands in two steps. A large extracellular domain captures the C-terminal part of the peptide, and the N-terminal residues then reach into the transmembrane core to switch the receptor on. That is why the very first residues of GHRH and sermorelin matter so much, and why trimming them destroys activity (see the stability section below).
The ghrelin receptor
The human ghrelin receptor, GHS-R1a (UniProt Q92847), is a 366-residue class A GPCR. UniProt notes that it couples to Gq proteins and mediates production of diacylglycerol and IP3, and that besides ghrelin it binds other growth hormone-releasing peptides, such as GHRP-6, and non-peptide secretagogues such as MK-0677. The receptor also shows activity in the absence of any ligand, a property that has made it a subject of study in its own right.
GHS-R1a is expressed in the pituitary and in the hypothalamus, where Howard and colleagues first located it in 1996, and more widely in the brain.
What the original studies measured
Ipamorelin's selectivity
The 1998 ipamorelin paper is the reason the compound is still discussed. Raun and colleagues tested it in primary rat pituitary cells, in anaesthetized rats and in conscious swine, alongside GHRP-6 and GHRP-2.
- In rat pituitary cells, ipamorelin released growth hormone with a potency and efficacy close to GHRP-6.
- Experiments with GHRP and GHRH antagonists showed that ipamorelin, like GHRP-6, works through the GHRP receptor rather than the GHRH receptor.
- In swine, none of the compounds changed FSH, LH, prolactin or TSH. GHRP-6 and GHRP-2 raised ACTH and cortisol. Ipamorelin did not raise either above the levels seen after GHRH, even at more than 200 times the level needed for half-maximal growth hormone release.
The authors called it the first GHRP-receptor agonist with a selectivity for growth hormone similar to that of GHRH. For a researcher, that selectivity is useful because it separates ghrelin-receptor signaling in somatotrophs from the ACTH-cortisol responses other GHRPs produce.
Sermorelin as a GHRH probe
Sermorelin's value in research comes from being the native N-terminal sequence. Spiess's 1982 finding that GRF(1-29)-NH2 matches the longer peptides in vitro established that the first 29 residues carry the receptor-activating information. That made the fragment a standard GHRH receptor agonist and the parent sequence for later analogs, including CJC-1295 and its no-DAC form, and tesamorelin, which is built on the full 44-residue sequence.
Stability: the N-terminus problem
Native GHRH has a short life in plasma. Frohman and colleagues showed in 1986 that plasma rapidly converts GRH(1-44)-NH2 to GRH(3-44)-NH2 by removing the N-terminal Tyr-Ala dipeptide, and that the product has less than a thousandth of the original activity. They attributed this to a plasma dipeptidyl aminopeptidase, the enzyme now known as DPP-4. After intravenous delivery to volunteers, the intact peptide disappeared with a half-life of 6.8 minutes.
Sermorelin shares that Tyr-Ala N-terminus, so it is open to the same cleavage. Later GHRH analogs were built largely to fix this, with a D-alanine at position 2 in the case of CJC-1295, or an N-terminal acyl group in the case of tesamorelin.
Ipamorelin begins with Aib rather than the Tyr-Ala motif, so the cleavage site that inactivates GHRH does not exist in its sequence.
Regulatory status
Sermorelin. Sermorelin acetate was approved in the United States as Geref, held by EMD Serono, under two applications: one for the treatment of idiopathic growth hormone deficiency in children with growth failure, and one as a diagnostic agent for testing the pituitary's capacity to secrete growth hormone. The company stopped marketing both in 2008, and FDA withdrew the approvals effective June 18, 2009. In 2013 FDA published a determination that Geref was not withdrawn from sale for reasons of safety or effectiveness.
Ipamorelin. Ipamorelin has never been approved anywhere. It was studied in a Phase 2, placebo-controlled trial of postoperative ileus after bowel resection (ClinicalTrials.gov NCT00672074), reported by Beck and colleagues in 2014, a trial whose rationale was the ghrelin receptor's role in gastrointestinal motility.
FDA status in compounding. Ipamorelin acetate appears on FDA's page of bulk substances that may present significant safety risks (Category 2 of its interim compounding policy). The entry cites a potential risk of immunogenicity from aggregation or peptide-related impurities, and notes that ipamorelin contains unnatural amino acids, which add to the complexity of characterizing the peptide. Sermorelin does not appear on that page. Neither sermorelin nor ipamorelin has a current FDA approval as a marketed product.
Both are supplied by Anhydrolabs as research reagents only, not for human or veterinary diagnosis, treatment, or consumption. Our research-use page explains what that means for an order.
Differences at the bench
The two molecules behave quite differently as reagents, mostly because of their size and composition.
- Size and mass. Ipamorelin is about a fifth the mass of sermorelin. Molar concentrations of the two differ by roughly that factor at equal mg/mL, so calculate stocks in molar units when comparing them.
- Methionine. Sermorelin carries Met27, which can oxidize to methionine sulfoxide (a +16 Da species visible by mass spectrometry). Limiting air exposure and keeping solutions cold reduces it. Ipamorelin has no methionine or cysteine.
- Analytics. Both are checked by reversed-phase HPLC and mass spectrometry. Our note on peptide purity explains how the HPLC figure on a certificate is calculated.
- Reconstitution and storage. Both ship as lyophilized powders and are reconstituted the same general way; see how to reconstitute peptides and the storage and handling page.
For background on the chemistry both molecules share, including the C-terminal amide, see the peptide bond. For the downstream end of the same hormonal axis, see our profile of IGF-1 LR3.
Anhydrolabs supplies sermorelin and ipamorelin as lyophilized powders in vacuum-sealed vials, each also available as 10-vial kits.
