Evidence
Ipamorelin and growth hormone research
The endocrine endpoints measured for ipamorelin: GH release in humans and animals, the selectivity finding, and why a GH rise need not raise IGF-1.
By the Ipamorelin Research editorial team · Last reviewed · Scientific review: pending
Short answer
Ipamorelin produces a single, self-limiting pulse of growth hormone. In 40 healthy men this peaked about 40 minutes after infusion and fell back to negligible concentrations at every dose tested. What has not been measured in humans is anything downstream of that pulse: no IGF-1, no body composition, no clinical outcome. In animals, the relationship between the growth hormone rise and an IGF-1 rise proved conditional rather than automatic.
The human measurement
The 1999 dose-escalation study remains the only indexed human measurement of what ipamorelin does to growth hormone [Gobburu 1999]. Eight healthy men received each of five infusion rates: 4.21, 14.02, 42.13, 84.27 and 140.45 nmol/kg over 15 minutes.
| Parameter | Value |
|---|---|
| Terminal half-life | About 2 hours |
| Clearance | 0.078 L/h/kg |
| Volume of distribution at steady state | 0.22 L/kg |
| Time to peak growth hormone | 0.67 hours |
| Concentration for half-maximal GH stimulation | 214 nmol/L |
| Maximal GH production rate | 694 mIU/L/h |
| Shape of the response | A single episode of release at every dose, declining exponentially to negligible concentrations |
Two features of that result are worth drawing out. The pharmacokinetics were dose-proportional, but between-subject variability was larger for the growth hormone response than for the drug concentrations — people differed more in how they responded than in how they cleared it. And the response was self-limiting at every dose: raising the dose 33-fold did not convert a pulse into a sustained elevation.
Growth hormone in animal models
In primary rat pituitary cells, ipamorelin released growth hormone with an EC50 of 1.3 ± 0.4 nmol/l and efficacy of 85 ± 5% relative to GHRP-6; in anaesthetised rats the ED50 was 80 ± 42 nmol/kg, and in conscious swine 2.3 ± 0.03 nmol/kg [Raun 1998]. Twenty-one days of dosing in young female rats increased somatotroph secretion granule volume density without changing somatotroph ultrastructure or the proportion of GH-staining cell types [Jiménez-Reina 2002]. In seabream pituitary cells, growth hormone secretion rose without a parallel change in growth hormone gene transcription, even after 48 hours[Chan 2004] — the cells release stored hormone rather than making more.
The IGF-1 question
The three animal results that bear on it directly point in different directions:
- No IGF-1 change. Adult female rats given ipamorelin for 15 days showed dose-dependent increases in tibial growth rate — 42 µm/day on vehicle rising to 52 µm/day — while total IGF-1, IGF binding proteins and bone turnover markers were unchanged [Johansen 1999]. The growth happened without a measurable IGF-1 signal.
- IGF-1 blocked by hepatic resistance. In streptozotocin-diabetic mice, ipamorelin produced growth hormone of 150 ± 35 µg/L against 62 ± 11 µg/L in non-diabetic animals, yet hepatic IGF-1 mRNA, hepatic IGF-1 peptide and serum IGF-1 rose only in the non-diabetic mice [Johansen 2003].
- IGF-1 did rise. In rats given methylprednisolone and repeated intravenous ipamorelin over 10 days, IGF-1 rose in parallel with reduced weight loss [Malmlöf 1999].
The pattern across these is that repeated dosing over days can raise IGF-1 where the liver is able to respond, and that a single provocative pulse generally does not. Neither pattern has been tested in humans.
Selectivity: what was and was not measured
In conscious swine, none of the tested secretagogues changed FSH, LH, prolactin or TSH. GHRP-6 and GHRP-2 raised ACTH and cortisol; ipamorelin did not raise them significantly beyond the levels seen after GHRH, at doses more than 200-fold above its growth hormone ED50 [Raun 1998]. This is the origin of the selectivity description. It was measured in pigs, acutely, in one study, by the developing group, and has never been measured in humans.
Downstream endocrine and metabolic endpoints
Twelve weeks of ipamorelin in rats increased bone mineral content through increased bone size rather than increased volumetric density [Svensson 2000]. In prednisolone-treated rats, ipamorelin reduced hepatic urea-N synthesis capacity by 20% and neutralised nitrogen balance, where growth hormone itself achieved 33% and a 2.5-fold improvement [Aagaard 2009] — the authors noted the secretagogue was the less efficient of the two at the doses given. And in mice, secretagogue treatment increased body fat, leptin and food intake while growth hormone decreased fat mass, which the authors attributed to GH-independent mechanisms[Lall 2001].
There is also evidence that part of this class's growth hormone effect may be indirect: gastrointestinal resection attenuated the growth hormone response to GHRP-6 by 60 to 70% while leaving the GHRH response intact[Ahnfelt-Rønne 2001]. That experiment used GHRP-6 and NN703, not ipamorelin.
Every record tagged to growth hormone secretion
11 indexed records measure a growth-hormone-secretion endpoint. The full database, with filters, is on the research studies page.
| Study | Model and route | What was measured | Limitations | Grade |
|---|---|---|---|---|
| Dominikowski 2026 Front Endocrinol (Lausanne) Growth hormone secretion · Safety reporting | ReviewNo organism dosed Narrative review Among several | The 2026 review covered unregulated peptides marketed as research compounds that modulate the GH-IGF-1 axis, including ipamorelin among the growth hormone secretagogues. | Narrative review spanning a whole compound class. | Evidence grade R |
| Shimatsu 2004 Nihon Rinsho Growth hormone secretion | ReviewNo organism dosed Narrative review in Japanese Among several | A 2004 Japanese-language review of clinical perspectives on ghrelin-related drugs. No abstract is indexed. | Review; no abstract indexed; not in English. Retained for completeness of the search, not used as evidence. | Evidence grade R |
| Chan 2004 Comp Biochem Physiol C Toxicol Pharmacol Growth hormone secretion · Receptor pharmacology | In vitroAdded to culture or bath Primary culture of black seabream pituitary cells Among several | The study measured GH release from seabream pituitary cells exposed to GHRP-2, ipamorelin, human ghrelin and two non-peptide secretagogues. All tested secretagogues except human ghrelin produced dose-dependent GH release with EC50 values in the nanomolar range, while GH mRNA levels did not change correspondingly even after 48 h. | Fish cells in culture. | Evidence grade D |
| Johansen 2003 Exp Diabesity Res Growth hormone secretion · Metabolism | AnimalIntravenous Streptozotocin-diabetic and non-diabetic female mice, single intravenous injection Ipamorelin itself | The study used ipamorelin as a provocation agent in streptozotocin-diabetic and non-diabetic mice. Ten minutes after injection, GH was 150 ± 35 µg/L in diabetic against 62 ± 11 µg/L in non-diabetic mice (P < .05). Serum IGF-I was lower in diabetic animals and rose after stimulation only in non-diabetic animals; hepatic IGF-I mRNA and peptide rose only in non-diabetic animals. | Ipamorelin is the probe, not the subject. The study is useful mainly as evidence that a GH rise does not always produce an IGF-1 rise. | Evidence grade C |
| Jiménez-Reina 2002 Histol Histopathol Growth hormone secretion | AnimalSubcutaneous Young female rats dosed for 21 days, then pituitary cell cultures Ipamorelin itself | The study examined pituitary cells from young female rats given ipamorelin, GHRH or saline for 21 days. Somatotroph ultrastructure did not change but secretion granule volume density increased after ipamorelin or GHRH (P < 0.05). The percentage of somatotrophs and the ratio of strongly to weakly staining GH cells did not differ between groups at baseline in culture. | Young female rats; histological and culture endpoints with no functional in vivo outcome. | Evidence grade C |
| Ahnfelt-Rønne 2001 Endocrine Receptor pharmacology · Growth hormone secretion | AnimalIntravenous Rats, whole-body autoradiography and gastrointestinal resection Analogue | The study found that NN703 and GHRP-6 accumulated in the glandular stomach of rats, and that resection of the gastrointestinal tract attenuated the GH response to GHRP-6 by 60–70% while leaving the GHRH response uninhibited. | The compounds studied are NN703 and GHRP-6, not ipamorelin; ipamorelin appears in the derivation history only. | Evidence grade C |
| Johansen 1999 Growth Horm IGF Res Bone · Growth hormone secretion | AnimalSubcutaneous Adult female rats, 15 days of subcutaneous dosing three times daily Ipamorelin itself | The study measured longitudinal growth rate in the proximal tibial metaphysis after 0, 18, 90 and 450 µg/day of ipamorelin for 15 days. Growth rate rose dose-dependently from 42 µm/day in the vehicle group to 44, 50 and 52 µm/day (P < 0.0001), with a dose-dependent increase in body-weight gain. Total IGF-I, IGF binding proteins and serum markers of bone formation and resorption were not changed by treatment. | Rats; 15 days. The dissociation between bone growth and unchanged IGF-I limits inference about the GH–IGF-1 axis. No human equivalent exists. | Evidence grade C |
| Hansen 1999 Eur J Endocrinol Receptor pharmacology · Growth hormone secretion | AnimalOral Rat pituitary cells; BHK cells expressing human GHS-R 1A; swine; beagle dogs; rats Analogue | The study characterised NN703, an orally active secretagogue derived from ipamorelin. NN703 inhibited 35S-MK677 binding to the human GHS-R 1A, and in swine produced a 50% rise in cortisol over basal at all doses tested without dose-dependency. Oral bioavailability in dogs was 30% and a 14-day oral course increased body-weight gain in rats. | The subject is NN703. Findings here must not be read across to ipamorelin, whose reported cortisol profile differs. | Evidence grade C |
| Gobburu 1999 Pharm Res Pharmacokinetics · Growth hormone secretion | HumanIntravenous Healthy male volunteers, 15-minute intravenous infusions Ipamorelin itselfn = 8 per dose level across 5 dose levels | The study measured pharmacokinetics and GH response after 15-minute infusions of 4.21, 14.02, 42.13, 84.27 and 140.45 nmol/kg. Pharmacokinetics were dose-proportional, with a terminal half-life of 2 hours, clearance of 0.078 L/h/kg and steady-state volume of distribution of 0.22 L/kg. GH release was a single episode peaking at 0.67 hours and declining exponentially to negligible concentrations at every dose. The concentration producing half-maximal GH stimulation was 214 nmol/L. | Healthy young men only; single infusions; the measured endpoint is hormone concentration, not any clinical outcome. PubMed indexes this record with the publication types "Clinical Trial" and "Randomized Controlled Trial", but the published abstract describes a dose-escalation design and does not describe randomisation or a placebo control, so it is graded here as a human study without a control group. | Evidence grade B |
| Malmlöf 1999 Growth Horm IGF Res Growth hormone secretion · Body composition | AnimalIntravenous Rats given methylprednisolone, with venous catheters, 10 days of intravenous dosing four times daily Ipamorelin itself | The study measured whether methylprednisolone blunted the GH response to ipamorelin in rats. The acute plasma GH response to ipamorelin or GHRH was unchanged by glucocorticoid. Over 10 days, glucocorticoid-treated rats lost 13.6 ± 2.9 g against 4.0 ± 3.5 g in saline controls, while rats given glucocorticoid plus ipamorelin lost 2.3 ± 2.0 g (high dose) and 1.6 ± 2.0 g (low dose); IGF-I rose in parallel. | Rats recovering from surgery and receiving a glucocorticoid; not a healthy-animal model. | Evidence grade C |
| Raun 1998 Eur J Endocrinol Growth hormone secretion · Receptor pharmacology | AnimalIntravenous Primary rat pituitary cells; pentobarbital-anaesthetised rats; conscious swine Ipamorelin itself | This 1998 report described the discovery of ipamorelin as a pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH2) and measured GH release from primary rat pituitary cells (EC50 1.3 ± 0.4 nmol/l, Emax 85 ± 5% of GHRP-6), in anaesthetised rats (ED50 80 ± 42 nmol/kg) and in conscious swine (ED50 2.3 ± 0.03 nmol/kg). Antagonist profiling indicated GH release through a GHRP-like receptor rather than the GHRH receptor. In swine, none of the secretagogues tested altered FSH, LH, PRL or TSH; GHRP-6 and GHRP-2 raised ACTH and cortisol, whereas ipamorelin did not raise them significantly above levels seen after GHRH stimulation, at doses more than 200-fold above its GH ED50. | Animal and cell models only. The selectivity finding is a measurement of pituitary hormone levels in swine after acute dosing, not a human safety result. Conducted by the originator company. | Evidence grade C |
References
- Raun K, Hansen BS, Johansen NL et al. (1998). Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. PubMed 9849822 · doi:10.1530/eje.0.1390552[Animal, grade C]
- Gobburu JV, Agersø H, Jusko WJ et al. (1999). Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. PubMed 10496658 · doi:10.1023/a:1018955126402[Human, grade B]
- Johansen PB, Nowak J, Skjaerbaek C et al. (1999). Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats. Growth Horm IGF Res. PubMed 10373343 · doi:10.1054/ghir.1999.9998[Animal, grade C]
- Malmlöf K, Johansen PB, Haahr PM et al. (1999). Methylprednisolone does not inhibit the release of growth hormone after intravenous injection of a novel growth hormone secretagogue in rats. Growth Horm IGF Res. PubMed 10629165 · doi:10.1054/ghir.1999.0128[Animal, grade C]
- Johansen PB, Segev Y, Landau D et al. (2003). Growth hormone (GH) hypersecretion and GH receptor resistance in streptozotocin diabetic mice in response to a GH secretagogue. Exp Diabesity Res. PubMed 14630569 · doi:10.1155/EDR.2003.73[Animal, grade C]
- Jiménez-Reina L, Cañete R, de la Torre MJ et al. (2002). Influence of chronic treatment with the growth hormone secretagogue Ipamorelin, in young female rats: somatotroph response in vitro. Histol Histopathol. PubMed 12168778 · doi:10.14670/HH-17.707[Animal, grade C]
- Svensson J, Lall S, Dickson SL et al. (2000). The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats. J Endocrinol. PubMed 10828840 · doi:10.1677/joe.0.1650569[Animal, grade C]
- Aagaard NK, Grøfte T, Greisen J et al. (2009). Growth hormone and growth hormone secretagogue effects on nitrogen balance and urea synthesis in steroid treated rats. Growth Horm IGF Res. PubMed 19231263 · doi:10.1016/j.ghir.2009.01.001[Animal, grade C]
- Lall S, Tung LY, Ohlsson C et al. (2001). Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues. Biochem Biophys Res Commun. PubMed 11162489 · doi:10.1006/bbrc.2000.4065[Animal, grade C]
- Chan CB, Fung CK, Fung W et al. (2004). Stimulation of growth hormone secretion from seabream pituitary cells in primary culture by growth hormone secretagogues is independent of growth hormone transcription. Comp Biochem Physiol C Toxicol Pharmacol. PubMed 15556068 · doi:10.1016/j.cca.2004.09.008[In vitro, grade D]
- Ahnfelt-Rønne I, Nowak J, Olsen UB (2001). Do growth hormone-releasing peptides act as ghrelin secretagogues?. Endocrine. PubMed 11322495 · doi:10.1385/ENDO:14:1:133[Animal, grade C]