Ipamorelin — identity, handling and published literature

Ipamorelin is a synthetic pentapeptide of the growth hormone secretagogue class, supplied as a lyophilised solid for laboratory use.

Presentation and physical properties

Ipamorelin has the residue sequence Aib-His-D-2-Nal-D-Phe-Lys-NH₂, where Aib is α-aminoisobutyric acid and D-2-Nal is D-3-(2-naphthyl)alanine. Two of the five residues are non-proteinogenic and three are in the D-configuration, so the sequence cannot be written in one-letter code. The C-terminus is a primary carboxamide rather than a free acid. It was described in the medicinal chemistry literature under the development code NNC 26-0161 [1].

Reconstitution arithmetic

Reconstitution is a dilution calculation and nothing more. The concentration of the resulting solution is the mass of peptide in the vial divided by the volume of diluent added:

concentration (mg/mL) = vial mass (mg) ÷ diluent volume (mL)

The table below works this through for a 10 mg vial at three diluent volumes. The final column restates the same concentration as mass per 0.01 mL, that being a common graduation interval on small-volume syringes. It is a unit conversion only.

Two arithmetical cautions apply. First, the nominal vial mass refers to peptide, whereas the gross contents of the vial include counterion and residual water; where net peptide content has been determined for a batch, the calculation should use that figure rather than the nominal one. Second, adding a volume of diluent to a solid does not produce exactly that final volume, because the dissolved solid occupies space; at the masses and volumes above the discrepancy is small, but it is a systematic error rather than a random one.

This section calculates concentration. It states nothing about what quantity of any solution should be withdrawn or for what purpose.

Storage and stability

As a lyophilised solid held cold, dry and protected from light, ipamorelin is the more stable of its two states, and this is the form in which it is normally stored for extended periods. Once reconstituted, the peptide is in the state in which hydrolytic degradation routes become available, and stability is correspondingly shorter; solutions are held refrigerated and treated as short-lived.

Repeated freeze-thaw cycling is a recognised stress on peptide solutions, acting through concentration of solutes and pH shifts at the ice interface rather than through the low temperature itself. Dividing a reconstituted stock into single-use aliquots at the point of reconstitution avoids cycling the whole quantity.

The degradation routes available to this molecule follow from its residues, and several of the most common peptide degradation pathways are simply absent:

• No cysteine, so there is no thiol oxidation and no disulfide scrambling.
• No methionine and no tryptophan, so the two classic oxidation hotspots of peptide chemistry do not apply. Histidine is the oxidation-susceptible residue that is present; the imidazole ring is a known site of metal-catalysed oxidation, which is a reason to avoid adventitious transition metal ions in buffers and to keep chelating conditions in mind.
• No asparagine and no glutamine, so side-chain deamidation — the most common degradation route in peptides generally — has no substrate. The only amide function is the C-terminal carboxamide.
• The C-terminal primary amide is therefore the principal hydrolytic liability. Its loss converts the molecule to the corresponding free acid, a distinct species one mass unit heavier. That the amide is labile in a biological setting is supported by metabolism work in which amidase activity was among the routes reported for this peptide class [18].
• The lysine ε-amine is a strong nucleophile and is the reactive handle most likely to react with electrophilic contaminants, or with reducing sugars if any are present in a formulation.
• The N-terminal Aib residue carries a quaternary α-carbon. The steric hindrance this creates is the design rationale for the molecule’s resistance to aminopeptidase cleavage, and it also constrains the N-terminal conformational freedom. Cyclisation of an N-terminal dipeptide to a diketopiperazine is a general route for peptides and should not be assumed absent without testing.
• The two D-residues resist proteolysis by virtue of their configuration. Epimerisation at those centres is a theoretical route that would produce a diastereomer of identical mass.

Several of these routes produce species that differ from the parent by little or no mass, so mass spectrometry alone will not detect all of them.

Analytical identity

Reversed-phase HPLC on a C18 stationary phase, using a water/acetonitrile gradient with an acidic ion-pairing modifier such as trifluoroacetic acid, is the standard separation for a peptide of this size and hydrophobicity. Detection at 214–220 nm responds to the amide backbone and is the general-purpose channel; a second channel near 280 nm responds chiefly to the naphthyl side chain of the 2-Nal residue, and the ratio between the two is itself a weak identity check, since an impurity lacking the naphthyl group will present a different ratio to the parent.

Electrospray mass spectrometry gives the expected values below. The molecular formula is C₃₈H₄₉N₉O₅.

The doubly charged ion is normally the more abundant for a peptide carrying two readily protonated basic sites, here the N-terminal amine and the lysine side chain, and it is the ion on which tandem fragmentation is usually performed. Sequence confirmation requires that fragmentation, not the intact mass: the intact mass alone cannot distinguish the parent from a sequence isomer or from a diastereomer, all of which are isobaric.

Analytical methods for ipamorelin and related secretagogues in biological matrices have been developed principally in the anti-doping literature, including liquid chromatography–mass spectrometry methods for urine [16, 20], characterisation of metabolites [18], and structure–activity work across the peptidic secretagogue class [21].

What area-percent purity does and does not measure

An area-percent figure from an HPLC trace is the area of the main peak expressed as a fraction of the total integrated area, at one detection wavelength, under one set of chromatographic conditions. It is a useful measure of chromatographic homogeneity. It is frequently misread as something broader, so it is worth stating what it excludes:

• It is not peptide content. It says nothing about how much peptide is in the vial. Counterion, residual water and residual solvent are not chromophoric at the detection wavelength and do not appear in the integration at all, yet they contribute to the mass on the balance. Peptide content requires a separate determination such as quantitative amino acid analysis or nitrogen determination.
• It is not identity. A single sharp peak of high area percent establishes that one species dominates the trace, not which species it is.
• It does not see co-eluting impurities. Deletion sequences differing by one residue, and diastereomers arising from epimerisation, may not resolve from the parent under a given gradient; an orthogonal method is needed to exclude them.
• It weights by absorbance, not by mass. An impurity with a weaker chromophore is under-represented relative to its true mass fraction, and one with a stronger chromophore is over-represented.
• It is method-dependent. The same material can return different figures on different gradients, columns or wavelengths, so a figure without its method is not comparable with another figure.

The relevance of orthogonal identity testing to this compound class is not theoretical. Analyses of grey-market and seized material have reported products whose contents did not correspond to their labelling, including modified secretagogue analogues such as glycine-extended variants [22, 23].

What the published literature investigated

The following summarises what published studies examined and reported. Each statement is a description of a study, not a statement about what the compound does.

In vitro

The compound was first described in 1998 by a group at Novo Nordisk, which reported its development and pharmacological characterisation [1]. In primary rat pituitary cell culture the study reported growth hormone release with potency and efficacy compared against GHRP-6, and reported that ipamorelin did not release ACTH or cortisol at levels significantly different from those observed following GHRH stimulation — the basis on which the authors described it as selective relative to earlier compounds in the class [1]. Medicinal chemistry series derived from the structure were reported in the same year [2], and later work examined how conformational restriction at the C-terminus related to potency across the class [21].

A 2002 study examined somatotroph responses in vitro in pituitary tissue from young female rats that had received chronic treatment [10]. Work in a non-mammalian system reported that stimulation of growth hormone secretion from seabream pituitary cells in primary culture by growth hormone secretagogues was independent of growth hormone transcription [12].

Rodent and other animal models

Pharmacokinetics in rats, including a comparison of absorption across routes, were reported in 1998 [3]. A 1999 study in rats reported dose-dependent increases in longitudinal bone growth rate and in body weight gain, and reported that circulating IGF-I was not altered [4]. A 2000 study using osmotic minipumps over twelve weeks in adult female rats reported increases in body weight and in tibial and vertebral bone mineral content relative to vehicle, and attributed the bone mineral content increase to expanded bone dimensions rather than to increased mineral density [7]. A 2001 study examined the compound in a model of glucocorticoid-induced reduction in bone formation in adult rats [9], and an earlier study reported that methylprednisolone did not inhibit growth hormone release following administration of the secretagogue in rats [5].

A finding relevant to interpreting the rest of the animal literature was reported in 2001: in growth-hormone-deficient lit/lit mice as well as growth-hormone-intact mice, stimulation of adiposity by growth hormone secretagogues was reported to occur independently of growth hormone [8]. Other animal work examined responses in streptozotocin-diabetic mice [11], insulin release from pancreatic tissue of normal and diabetic rats [13], and nitrogen balance and urea synthesis in steroid-treated rats [14].

A series of studies examined rodent models of postoperative ileus, reporting effects on colonic transit, faecal output, food intake and body weight over 48 hours [15], and on gastric dysmotility [17]. Later work from an overlapping group examined visceral and somatic nociception in rodents [24]. A 2024 study in ferrets examined two growth hormone secretagogue receptor agonists in a model of cisplatin-induced weight loss [25].

Human

Human data are limited to two published studies with pharmacological endpoints and a small analytical literature.

A 1999 pharmacokinetic and pharmacodynamic modelling study in healthy volunteers reported a short terminal half-life of approximately two hours, characterised the growth hormone response with an indirect response model, and reported that inter-individual variability in the pharmacodynamic parameters was larger than that in the pharmacokinetic parameters [6].

The only completed randomised controlled trial with a clinical endpoint was reported in 2014: a prospective, randomised, placebo-controlled proof-of-concept study in patients undergoing bowel resection, examining the management of postoperative ileus, with 114 evaluable patients [19]. The study reported that the compound was well tolerated. It reported no significant difference between the ipamorelin and placebo groups on its efficacy outcomes [19]. Development did not proceed beyond this stage.

The remaining human literature is analytical rather than pharmacological, consisting of anti-doping method development and excretion studies characterising urinary metabolites [16, 20].

Evidence gaps and limitations

The gaps in this record are larger than the record itself, and they should be stated without qualification.

No human efficacy has been demonstrated for any indication. One randomised controlled trial with a clinical endpoint has been completed and published, and it did not separate from placebo [19]. Clinical development stopped at phase 2. A negative trial is a result, not an absence of one, and it is the single most important item in this record.

Nothing that this compound is popularly associated with has been tested in a controlled human trial. There is no published randomised trial in healthy adults examining body composition, sleep, recovery from injury, connective tissue, ageing or athletic performance. The absence here is complete: these are not questions on which the human evidence is weak or mixed, they are questions on which no controlled human evidence exists at all.

Human exposure data are short and thin. Published human administration is limited to a pharmacokinetic study in volunteers [6] and a trial lasting up to a week [19]. There is no published long-term human safety data, and no published carcinogenicity, reproductive or developmental toxicology.

The animal literature does not bridge to humans. The bone and body composition studies are short-duration, use specific strains and models, and in several cases use continuous infusion by minipump [7]. Findings in growing rats, in glucocorticoid-treated rats, in diabetic mice, in ferrets and in fish are findings about those models.

Mechanistic attribution is not settled. Because a report exists of secretagogue-driven adiposity occurring independently of growth hormone [8], effects observed in animal models cannot be assumed to follow from growth hormone release. The inference “it releases growth hormone, therefore any observed effect is a growth hormone effect” is not supported by that study.

The selectivity finding is narrower than it is often reported to be. The 1998 characterisation compared cortisol and ACTH release against GHRH stimulation under the conditions of that study [1]. It is a finding about a comparison in a defined experimental setting, not a general statement about endocrine effects across doses, durations or species.

There is no compendial specification. No monograph for ipamorelin exists in the British Pharmacopoeia, the European Pharmacopoeia or the United States Pharmacopeia, which follows from its never having been an authorised medicine. There is therefore no official specification against which a batch can be assessed, and no standard method. Any specification applied is one chosen by the testing party.

Material identity in this class has been shown to be unreliable. Published analyses of grey-market and seized products have identified secretagogue analogues differing from their stated identity [22, 23]. This is a documented finding about the market for these substances.

Regulatory and standards position

United Kingdom. Ipamorelin holds no marketing authorisation. It is not an authorised medicinal product, and any presentation of it for treating or preventing disease in humans would make it an unlicensed medicinal product within the meaning of the Human Medicines Regulations 2012. It is not a controlled drug under the Misuse of Drugs Act 1971 and is not scheduled under the Misuse of Drugs Regulations 2001. Supply is on a research-use basis only.

European Union. No marketing authorisation has been granted by the European Medicines Agency, and the compound is not an authorised medicinal product in any member state.

United States. Ipamorelin is not approved by the Food and Drug Administration for any indication. It has been considered by the FDA in the course of its evaluation of bulk drug substances for use in pharmacy compounding under section 503A of the Federal Food, Drug, and Cosmetic Act; its status in that process has changed more than once, and the current position should be checked against the FDA’s own published lists rather than taken from secondary sources.

Anti-doping. Ipamorelin is named explicitly on the World Anti-Doping Agency Prohibited List at S2.2.4, “Growth hormone releasing factors”, within the sub-list of “growth hormone secretagogues (GHS) and their mimetics”. Seven substances are named in that sub-list: anamorelin, capromorelin, ibutamoren (MK-677), ipamorelin, lenomorelin (ghrelin), macimorelin and tabimorelin. Substances in class S2 are prohibited at all times, in-competition and out-of-competition, and are non-Specified Substances. The list is expressly non-exhaustive, covering also “other substances with similar chemical structure or similar biological effect(s)”.

Laboratory handling and safety

No comprehensive toxicological dataset has been published for this compound. It should be handled as a substance of incompletely characterised hazard, and any assessment made under the Control of Substances Hazardous to Health Regulations 2002 should proceed on that precautionary basis rather than by inferring low hazard from an absence of reported effects.

• Personal protective equipment. Nitrile gloves, safety spectacles and a laboratory coat as a minimum. Lyophilised peptide is a fine, low-density solid that is readily aerosolised and prone to static dispersal; weighing and transfer of the dry solid are the steps at which airborne exposure is credible, and are best carried out in a containment device or with local exhaust ventilation.
• Reconstitution. Carry out in a clean area with the vial and diluent at a controlled temperature, avoiding vigorous agitation, which drives interfacial denaturation and foaming in peptide solutions.
• Spills. Dry solid should not be swept or brushed, as this re-suspends it; dampen and collect. Solutions should be absorbed onto inert material and the surface decontaminated. Address the residue on the container exterior as well as the spill itself.
• Disposal. Dispose of as chemical waste through the laboratory’s arranged route, under the duty of care in section 34 of the Environmental Protection Act 1990 and the relevant hazardous waste regulations. Do not discharge to drain.
• Record-keeping. Record the batch or lot identifier, date of receipt, storage location and temperature, the date and identity of the diluent used at reconstitution, the number of freeze-thaw cycles an aliquot has undergone, and the operator. Where a certificate of analysis accompanies a batch, retain it with the method and the wavelength used, since an area-percent figure is not interpretable without them.

References

1. Raun K, Hansen BS, Johansen NL, Thøgersen H, Madsen K, Ankersen M, Andersen PH. Ipamorelin, the first selective growth hormone secretagogue. European Journal of Endocrinology 1998;139(5):552–61. Model: in vitro rat pituitary cells, with in vivo work in rats and swine. PMID 9849822
2. Ankersen M, Johansen NL, Madsen K, Hansen BS, Raun K, Nielsen KK, Thøgersen H, Hansen TK, Peschke B, Lau J, Lundt BF, Andersen PH. A new series of highly potent growth hormone-releasing peptides derived from ipamorelin. Journal of Medicinal Chemistry 1998;41(19):3699–704. Model: in vitro. PMID 9733495
3. Johansen PB, Hansen KT, Andersen JV, Johansen NL. Pharmacokinetic evaluation of ipamorelin and other peptidyl growth hormone secretagogues with emphasis on nasal absorption. Xenobiotica 1998;28(11):1083–92. Model: rodent. PMID 9879640
4. Johansen PB, Nowak J, Skjaerbaek C, Flyvbjerg A, Andreassen TT, Wilken M, Orskov H. Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats. Growth Hormone & IGF Research 1999;9(2):106–13. Model: rodent. PMID 10373343
5. Malmlöf K, Johansen PB, Haahr PM, Wilken M, Oxlund H. Methylprednisolone does not inhibit the release of growth hormone after intravenous injection of a novel growth hormone secretagogue in rats. Growth Hormone & IGF Research 1999;9(6):445–50. Model: rodent. PMID 10629165
6. Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharmaceutical Research 1999;16(9):1412–6. Model: human trial. PMID 10496658
7. Svensson J, Lall S, Dickson SL, Bengtsson BA, Rømer J, Ahnfelt-Rønne I, Ohlsson C, Jansson JO. The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats. Journal of Endocrinology 2000;165(3):569–77. Model: rodent. PMID 10828840
8. Lall S, Tung LY, Ohlsson C, Jansson JO, Dickson SL. Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues. Biochemical and Biophysical Research Communications 2001;280(1):132–8. Model: rodent. PMID 11162489
9. Andersen NB, Malmlöf K, Johansen PB, Andreassen TT, Ørtoft G, Oxlund H. The growth hormone secretagogue ipamorelin counteracts glucocorticoid-induced decrease in bone formation of adult rats. Growth Hormone & IGF Research 2001;11(5):266–72. Model: rodent. PMID 11735244
10. Jiménez-Reina L, Cañete R, de la Torre MJ, Bernal G. Influence of chronic treatment with the growth hormone secretagogue Ipamorelin, in young female rats: somatotroph response in vitro. Histology and Histopathology 2002;17(3):707–14. Model: in vitro. PMID 12168778
11. Johansen PB, Segev Y, Landau D, Phillip M, Flyvbjerg A. Growth hormone (GH) hypersecretion and GH receptor resistance in streptozotocin diabetic mice in response to a GH secretagogue. Experimental Diabesity Research 2003;4(2):73–81. Model: rodent. PMID 14630569
12. Chan CB, Fung CK, Fung W, Tse MC, Cheng CH. Stimulation of growth hormone secretion from seabream pituitary cells in primary culture by growth hormone secretagogues is independent of growth hormone transcription. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 2004;139(1–3):77–85. Model: in vitro. PMID 15556068
13. Adeghate E, Ponery AS. Mechanism of ipamorelin-evoked insulin release from the pancreas of normal and diabetic rats. Neuroendocrinology Letters 2004;25(6):403–6. Model: rodent. PMID 15665799
14. Aagaard NK, Grøfte T, Greisen J, Malmlöf K, Johansen PB, Grønbæk H, Orskov H, Tygstrup N, Vilstrup H. Growth hormone and growth hormone secretagogue effects on nitrogen balance and urea synthesis in steroid treated rats. Growth Hormone & IGF Research 2009;19(5):426–31. Model: rodent. PMID 19231263
15. Venkova K, Mann W, Nelson R, Greenwood-Van Meerveld B. Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus. Journal of Pharmacology and Experimental Therapeutics 2009;329(3):1110–6. Model: rodent. PMID 19289567
16. Thomas A, Höppner S, Geyer H, Schänzer W, Petrou M, Kwiatkowska D, Pokrywka A, Thevis M. Determination of growth hormone releasing peptides (GHRP) and their major metabolites in human urine for doping controls by means of liquid chromatography mass spectrometry. Analytical and Bioanalytical Chemistry 2011;401(2):507–16. Model: analytical method development in human urine. PMID 21298258
17. Greenwood-Van Meerveld B, Tyler K, Mohammadi E, Pietra C. Efficacy of ipamorelin, a ghrelin mimetic, on gastric dysmotility in a rodent model of postoperative ileus. Journal of Experimental Pharmacology 2012;4:149–55. Model: rodent. PMID 27186127
18. Thomas A, Delahaut P, Krug O, Schänzer W, Thevis M. Metabolism of growth hormone releasing peptides. Analytical Chemistry 2012;84(23):10252–9. Model: analytical, with rat administration and in vitro incubations. PMID 23101768
19. Beck DE, Sweeney WB, McCarter MD; Ipamorelin 201 Study Group. Prospective, 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 2014;29(12):1527–34. Model: human trial, randomised placebo-controlled. PMID 25331030
20. Semenistaya E, Zvereva I, Thomas A, Thevis M, Krotov G, Rodchenkov G. Determination of growth hormone releasing peptides metabolites in human urine after nasal administration of GHRP-1, GHRP-2, GHRP-6, Hexarelin, and Ipamorelin. Drug Testing and Analysis 2015;7(10):919–25. Model: human excretion study. PMID 25869809
21. Ferro P, Krotov G, Zvereva I, Rodchenkov G, Segura J. Structure-activity relationship for peptidic growth hormone secretagogues. Drug Testing and Analysis 2017;9(1):87–95. Model: review. PMID 26811125
22. Krug O, Thomas A, Malerød-Fjeld H, Dehnes Y, Laussmann T, Feldmann I, Sickmann A, Thevis M. Analysis of new growth promoting black market products. Growth Hormone & IGF Research 2018;41:1–6. Model: analytical characterisation of seized and market material. PMID 29864719
23. Gajda PM, Holm NB, Hoej LJ, Rasmussen BS, Dalsgaard PW, Reitzel LA, Linnet K. Glycine-modified growth hormone secretagogues identified in seized doping material. Drug Testing and Analysis 2019;11(2):350–4. Model: analytical characterisation of seized material. PMID 30136411
24. N Mohammadi E, Louwies T, Pietra C, Northrup SR, Greenwood-Van Meerveld B. Attenuation of visceral and somatic nociception by ghrelin mimetics. Journal of Experimental Pharmacology 2020;12:267–74. Model: rodent. PMID 32801950
25. Lu Z, Ngan MP, Liu JYH, Yang L, Tu L, Chan SW, Giuliano C, Lovati E, Pietra C, Rudd JA. The growth hormone secretagogue receptor 1a agonists, anamorelin and ipamorelin, inhibit cisplatin-induced weight loss in ferrets: Anamorelin also exhibits anti-emetic effects via a central mechanism. Physiology & Behavior 2024;284:114644. Model: ferret. PMID 39043357

Research use only

Ipamorelin is supplied strictly as a laboratory chemical for research use. It is not a medicine, it holds no marketing authorisation in the United Kingdom or elsewhere, and it is not authorised for human or veterinary use. It must not be administered to humans or to animals. Nothing on this page describes a use, a quantity, a route or a regimen, and nothing on this page should be read as a statement that this compound produces any effect in humans. The literature summarised above is reported as a record of what published studies examined and concluded, in the models they used.