Ipamorelin was discovered in the late 1990s while chemists were trying to build a growth-hormone-releasing peptide that skipped the unwanted side effects of earlier compounds like GHRP-6. It works by locking onto the same receptor as ghrelin (your body's own "hunger and growth" hormone) in the pituitary gland at the base of the brain. It was tested in a real dose-finding trial in healthy volunteers and in one small hospital trial for bowel recovery after surgery, but it was never approved as a medicine for any condition. Most of what's known about its supposed muscle, bone, and gut benefits comes from animal studies, not people, and today it circulates mainly as an unregulated peptide, often sold alongside CJC-1295, and it is banned in competitive sports.
How strong is the evidence?
Ipamorelin has more real human data behind it than most research peptides, but that data is narrow. One well-designed human trial in healthy male volunteers confirmed it reliably raises growth hormone in a dose-dependent way and mapped out how fast the body clears it. A second, real placebo-controlled hospital trial tested it for bowel recovery after surgery - it was safe and well tolerated, but it did not beat placebo on the main measure researchers cared about. Everything else - muscle protection, bone strength, fat metabolism, gut pain, insulin release - comes from rat, mouse, or pig studies, or from lab dishes, not from people. Of the 40 papers on file, a large share are anti-doping detection studies (how to spot ipamorelin in urine) or broad review articles that mention it in a list alongside other peptides, rather than original research on benefits. Treat the hormone-releasing effect as solid and everything else as promising animal data at best.
Uses
What people use it for
Research tool for triggering growth hormone release
Some human dataIn the human studies that exist, ipamorelin was given by IV to healthy volunteers specifically to measure how much growth hormone it released and how quickly the body cleared it - a research and safety exercise, not a treatment.
Studied for bowel recovery after surgery
Some human dataA hospital trial gave ipamorelin by IV to patients recovering from bowel surgery, hoping it would speed up the return of normal gut function. It was safe, but it didn't produce a statistically clear benefit over placebo.
Off-label muscle, recovery, and anti-aging use
AnecdotalOutside of research, people buy ipamorelin (often combined with CJC-1295) hoping for more muscle, better recovery, and slower aging. None of this real-world use has been tested in people - it's inferred from animal studies and bodybuilding-community habits, not clinical trials.
Protecting muscle and bone during steroid treatment (animal research only)
Animal / labIn rats being given catabolic steroid drugs, ipamorelin partly offset the muscle and bone loss those drugs normally cause. This hasn't been tested in people on steroid medication.
Potential benefits
What it may help with
Reliably triggers a growth hormone pulse in people
Some human dataIn a dose-escalation study in healthy men, IV ipamorelin caused growth hormone to rise and then fall back to normal within a couple of hours, and higher doses produced bigger releases in a predictable, dose-dependent way. This is the best-established effect ipamorelin has - shown directly in humans, not just animals.
Studies:10496658Appears more selective than older GH-releasing peptides
Animal / labThe original discovery study found that, unlike older compounds like GHRP-6 and GHRP-2, ipamorelin didn't raise stress hormones (cortisol and ACTH) or other pituitary hormones even at very high doses in pigs and rats - only growth hormone went up. This selectivity is the main reason it's marketed as "cleaner," though it was shown in animals, not confirmed with matching human hormone panels.
Studies:9849822May speed up sluggish gut movement after surgery (animal evidence stronger than human)
Animal / labIn rat models of post-surgery bowel paralysis, repeated dosing of ipamorelin sped up gut transit, increased food intake, and helped restore normal stomach emptying. But the one controlled human trial in surgical patients found ipamorelin was not statistically better than placebo at getting patients back to eating solid food, even though it was safe.
May protect bone and muscle from steroid-drug damage (animal only)
Animal / labIn rats given catabolic steroid drugs (the kind used for inflammation, which normally weaken bone and muscle), adding ipamorelin partly reversed the damage - muscle strength and new bone formation both improved compared to steroids alone. Separate rat studies also found ipamorelin increased bone mineral content over 12 weeks of dosing and sped up bone growth in growing rats. None of this has been tested in people taking steroid medications.
May reduce gut pain sensitivity (animal only)
Animal / labIn rats, ipamorelin reduced sensitivity to both gut and skin pain in models designed to mimic conditions like IBS, without any active inflammation present. This is an early, animal-only signal, not something shown in people with pain conditions.
Studies:32801950Stimulates insulin release from pancreas tissue (lab/animal only)
Animal / labIn isolated pancreas tissue from both normal and diabetic rats, ipamorelin triggered insulin release. This is a lab finding about how the drug might affect blood sugar handling - it hasn't been tested as a treatment for diabetes in any animal or person.
Studies:15665799
What to watch for
Side effects & risks
- Mild
May increase appetite and body fat, not reduce it
In mice, ipamorelin increased food intake, raised the satiety hormone leptin, and increased body fat - independent of its growth hormone effect. This directly cuts against the common marketing idea that GH secretagogues are fat-loss tools; in this animal data, the opposite happened.
- Mild
Injection site irritation
As with any injected peptide, redness, soreness, or irritation at the injection site is a commonly expected issue, though the papers on file don't report detailed rates specifically for ipamorelin.
- Moderate
Hormone shifts and metabolic changes reported for this drug class
A recent clinical review covering growth-hormone-axis peptides like ipamorelin flags reported issues including fluid retention, joint or muscle aches, changes in blood sugar control, and shifts in other hormones such as prolactin and cortisol in people self-administering these peptides outside of medical care.
- Serious
Contaminated or mislabeled black-market product
Analyses of seized and online "research chemical" products have found modified or mislabeled versions of ipamorelin and related peptides. Because it's not sold as a regulated medicine, there's no guarantee a purchased vial contains what the label says, at the dose the label says.
Dosing
Dosing — what studies used
There is no approved medical dose for ipamorelin - it never completed the approval process as a medicine. What's documented comes from one human dose-finding safety study and one small hospital trial, plus a handful of animal studies. These were designed to test safety and measure hormone or tissue effects, not to define a treatment plan, so read every number below as "what researchers used to study it in a lab or hospital setting," not a recommended dose for personal use.
Human dose-finding and pharmacokinetic study in healthy male volunteers
Human trialFive ascending doses, from about 4.2 to 140 nanomoles per kilogram of body weight
Single infusion per dose level · 15-minute infusion, with blood monitored for several hours after · Intravenous infusion
A safety and pharmacokinetics study, not a treatment protocol. Growth hormone rose in a dose-dependent way and returned to baseline within a few hours at every dose tested.
Hospital trial for bowel recovery after surgery
Human trial0.03 milligrams per kilogram of body weight
Twice daily · Up to 7 days, or until hospital discharge · Intravenous infusion
Well tolerated, with side-effect rates similar to or lower than placebo, but did not produce a statistically significant improvement in the main outcome measured (time to first tolerated meal).
Rat study of bone growth in growing females
Animal study18, 90, or 450 micrograms per day
Three times daily · 15 days · Subcutaneous injection
Higher doses produced a bigger, dose-dependent increase in the rate of bone growth.
Rat study of bone mineral content
Animal study0.5 milligrams per kilogram of body weight per day
Continuous (via implanted pump) · 12 weeks · Subcutaneous injection
Increased bone mineral content to a degree comparable with growth hormone itself, though bone density per unit volume didn't change.
Rat study counteracting steroid-drug muscle and bone loss
Animal study100 micrograms per kilogram
Three times daily · 3 months · Subcutaneous injection
Given alongside a steroid drug (methylprednisolone); improved muscle strength and quadrupled the bone formation rate compared with the steroid alone.
Rat study of post-surgery gut motility
Animal study0.01 to 1 milligram per kilogram
Single dose, or four times daily for repeated dosing · Up to 2 days · Intravenous injection
Repeated dosing (not a single dose) was needed to meaningfully improve food intake and bowel output after surgery in this rat model.
Ipamorelin can also be absorbed through the nose (roughly 20% of an IV-equivalent dose reaches the blood this way), but that route has only been studied for absorption, not as a treatment protocol. No community or bodybuilding-forum dosing pattern is backed by a real study, so none is listed here - anyone using an unregulated product is dosing without any tested reference point.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
Ipamorelin is a very short chain of amino acids (a peptide) built to fit into a docking site called the ghrelin receptor, found mainly on hormone-releasing cells in the pituitary gland (a small gland at the base of the brain that controls many of the body's hormones) and in the gut. Ghrelin is the body's own "I'm hungry, release growth hormone" signal; ipamorelin mimics it closely enough to trigger the same response. When it locks onto the receptor, it tells the pituitary to release a burst of growth hormone into the blood. Unlike some older compounds designed to do the same thing, it seems to leave other hormones - like the stress hormone cortisol - largely alone, at least in animal studies. The effect doesn't last long: growth hormone peaks within about 40 minutes and fades back to baseline within a couple of hours, and the drug itself is cleared from the blood in about 2 hours.
Who should avoid it
- Anyone with active cancer or a history of cancer - raising growth hormone and its downstream signals is flagged as a theoretical risk in review articles because those pathways can promote cell growth
- Pregnant or breastfeeding women - no safety data exists for either
- Children or growing teenagers outside of a formal medical/research study
- People with diabetes or existing blood sugar problems, given animal data showing ipamorelin affects insulin release and growth hormone's known effect on blood sugar
- Competitive athletes - it's a substance prohibited by the World Anti-Doping Agency, and specific tests exist to detect it and its breakdown products in urine
- Anyone unwilling to accept the risks of an unregulated, unverified product, since it has never been approved as a medicine
Interactions to know
- No formal drug-interaction studies exist for ipamorelin in humans.
- Animal studies gave it alongside steroid drugs (like methylprednisolone) specifically because it can offset some of the muscle- and bone-wasting side effects of those drugs - a plausible but human-unconfirmed interaction.
- Because it can trigger insulin release and growth hormone can raise blood sugar, anyone on insulin or diabetes medication should be cautious about combining them - this hasn't been studied directly in people.
- It's frequently combined with CJC-1295 and other growth-hormone peptides in self-administered "stacks"; the combined effects of stacking have not been formally studied in humans, only touched on in one mouse experiment.
The papers that matter most
Key studies
The original discovery paper. Established that ipamorelin releases growth hormone as effectively as older compounds but, unusually, doesn't raise cortisol or ACTH even at very high doses - the basis of its "cleaner" reputation.
Ipamorelin, the first selective growth hormone secretagogue
The key human study. Confirmed dose-dependent growth hormone release, a roughly 2-hour half-life, and predictable, short-lived hormone pulses - the main real evidence that ipamorelin does what it's supposed to do in people.
Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers
The only real placebo-controlled clinical trial of ipamorelin for an actual medical condition. It was safe and well tolerated but did not significantly beat placebo at speeding bowel recovery after surgery.
Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients
Showed ipamorelin could partly reverse steroid-drug damage to muscle strength and bone formation in rats - a promising but animal-only finding relevant to people on long-term steroid treatment.
The growth hormone secretagogue ipamorelin counteracts glucocorticoid-induced decrease in bone formation of adult rats
Twelve weeks of continuous dosing raised bone mineral content in rats about as much as growth hormone itself, though true bone density per volume didn't change.
The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats
Recent clinical review summarizing real-world reported risks of GH-axis peptides like ipamorelin - hormone shifts, fluid retention, blood sugar changes, joint/muscle aches - and a caution about unverified self-administered products and unproven long-term cancer-risk concerns.
The emerging landscape of performance-enhancing peptides modulating GH-IGF1 axis: bridging the gap between clinical evidence and patient self-administration
Bottom line
Ipamorelin reliably does one thing in real human studies: it triggers a short, dose-dependent pulse of growth hormone without much apparent effect on stress hormones. But its one real placebo-controlled clinical trial - for bowel recovery after surgery - didn't beat placebo, and every other benefit people chase it for (muscle, bone, fat loss, gut healing, anti-aging) comes from rat, mouse, or pig studies, not people. It was never approved as a medicine, it's banned in competitive sports, and anything bought online is an unverified product - treat every claim beyond "raises GH briefly and safely in the studies done so far" as unproven in humans.
Research papers
Studies we have on file for Ipamorelin. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
40 papers
Ipamorelin, the first selective growth hormone secretagogue.
The development and pharmacology of a new potent growth hormone (GH) secretagogue, ipamorelin, is described. Ipamorelin is a pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH2), which displays high GH releasing potency and efficacy in vitro and in vivo. As an outcome of a major chemistry programme, ipamorelin was identified within a series of compounds lacking the central dipeptide Ala-Trp of growth hormone-releasing peptide (GHRP)-1. In vitro, ipamorelin released GH from primary rat pituitary cells with a potency and efficacy similar to GHRP-6 (ECs) = 1.3+/-0.4nmol/l and Emax = 85+/-5% vs 2.2+/-0.3nmol/l and 100%). A pharmacological profiling using GHRP and growth hormone-releasing hormone (GHRH) antagonists clearly demonstrated that ipamorelin, like GHRP-6, stimulates GH release via a GHRP-like receptor. In pentobarbital anaesthetised rats, ipamorelin released GH with a potency and efficacy comparable to GHRP-6 (ED50 = 80+/-42nmol/kg and Emax = 1545+/-250ng GH/ml vs 115+/-36nmol/kg and 1167+/-120ng GH/ml). In conscious swine, ipamorelin released GH with an ED50 = 2.3+/-0.03 nmol/kg and an Emax = 65+/-0.2 ng GH/ml plasma. Again, this was very similar to GHRP-6 (ED50 = 3.9+/-1.4 nmol/kg and Emax = 74+/-7ng GH/ml plasma). GHRP-2 displayed higher potency but lower efficacy (ED50 = 0.6 nmol/kg and Emax = 56+/-6 ng GH/ml plasma). The specificity for GH release was studied in swine. None of the GH secretagogues tested affected FSH, LH, PRL or TSH plasma levels. Administration of both GHRP-6 and GHRP-2 resulted in increased plasma levels of ACTH and cortisol. Very surprisingly, ipamorelin did not release ACTH or cortisol in levels significantly different from those observed following GHRH stimulation. This lack of effect on ACTH and cortisol plasma levels was evident even at doses more than 200-fold higher than the ED50 for GH release. In conclusion, ipamorelin is the first GHRP-receptor agonist with a selectivity for GH release similar to that displayed by GHRH. The specificity of ipamorelin makes this compound a very interesting candidate for future clinical development.
Therapeutic Peptides in Orthopaedics: Applications, Challenges, and Future Directions.
Therapeutic peptides are emerging as promising adjuncts in the management of orthopaedic injuries, grounded in their ability to modulate molecular signaling networks central to cellular medicine. By acting on key pathways such as PI3K/Akt, mTOR, MAPK, TGF-β, and AMPK, peptides exert influence over tissue regeneration, inflammation resolution, and neuromuscular recovery. Wound-healing peptides such as BPC-157, TB-500, and GHK-Cu promote angiogenesis, integrin-mediated extracellular matrix remodeling, and fibroblast activation, whereas growth hormone secretagogues like ipamorelin, CJC-1295, tesamorelin, sermorelin, and AOD-9604 activate IGF-1 signaling and satellite cell repair. Recovery-enhancing agents such as epithalon, delta sleep-inducing peptide, and pinealon target circadian and mitochondrial regulators, and neuroactive peptides like selank, semax, and dihexa enhance brain-derived neurotrophic factor and HGF/c-Met pathways critical to neuroplasticity. Although preclinical studies are promising, there is a current lack of clinical trials. This review integrates current mechanistic insights with orthopaedic relevance, emphasizing safety, efficacy, and future directions for responsible integration into musculoskeletal care.
Injectable Peptide Therapy: A Primer for Orthopaedic and Sports Medicine Physicians.
Therapeutic peptides are short-chain amino acids that regulate cellular functions and facilitate biochemical processes. In recent years, there has been significant growth in the global market for therapeutic peptides and thus its popularity among patients. Given the increase in the development of peptides and increased marketing to patients for orthopaedic injuries, it is critical for orthopaedic surgeons to understand the current evidence behind these therapeutic peptides. To evaluate the current evidence and applications of injectable peptide therapy, focusing on its potential in regenerative medicine and sports performance, to help orthopaedic providers better understand the current state of different therapeutic peptide approaches. Narrative review. A comprehensive literature search was conducted using PubMed to identify biochemical and clinical studies on the most popular types of injectable peptide therapy. Key peptides evaluated included BPC-157, TB-4, TB-500, CJC-1295 + ipamorelin, tesamorelin, and GHK-Cu. BPC-157 demonstrated potential benefits in tendon and muscle repair, but these findings are largely unvalidated in human trials. A single human case series reported improvements in pain after intra-articular knee injections of BPC-157, although significant methodological flaws and a lack of controls limit its applicability and reliability. TB-4 and its derivative TB-500 promoted angiogenesis and tissue repair in preclinical models, but human orthopaedic data are lacking, and both remain banned substances in sports. CJC-1295 combined with ipamorelin showed significantly improved maximum tetanic tension in murine models with glucocorticoid-induced muscle loss, but these findings are limited to animal studies. Tesamorelin, approved for treating HIV-associated lipodystrophy, has no supporting orthopaedic evidence. GHK-Cu showed promise in wound healing and anti-inflammatory effects, but no clinical data support its use for musculoskeletal conditions. While peptide therapy may possess significant therapeutic and regenerative potential, it is critical that orthopaedic and sports medicine providers understand the current lack of evidence to support the clinical use of these peptides. Importantly, information regarding the indications, dosing, frequency, and duration of treatment remains unknown. Despite the popularity of these peptides in mainstream media and among patients, significant research regarding the safety and efficacy of these therapeutic methods is required before definitive recommendations can be made to patients.
Safety and Efficacy of Approved and Unapproved Peptide Therapies for Musculoskeletal Injuries and Athletic Performance.
Peptides are short chains of amino acids with a unique pharmacological niche between small-molecule drugs and large proteins. Their use in sports medicine is rapidly expanding, driven by patient demand for accelerated injury recovery and performance enhancement. While numerous peptide drugs have undergone a rigorous approval process that evaluates both safety and efficacy, a parallel "gray market" of unapproved compounds has emerged, operating largely outside of regulatory oversight. Our objective is to present the pharmacological mechanisms, safety profiles, and regulatory status of prominent approved and unapproved peptides marketed direct to patients, including AOD-9604 (anti-obesity drug 9604), BPC-157 (body protection compound 157), CJC-1295, FS-344 (follistatin-344), GHK-Cu (glycyl-L-histidyl-L-lysine copper), ipamorelin, MOTS-C (mitochondrial ORF of the 12S rRNA type-c), sermorelin, SS-31 (elamipretide), tesamorelin (Egrifta), Tβ4 (thymosin beta-4), and TB-500 (thymosin beta-4 fragment). Many unapproved peptides demonstrate favorable tissue repair and metabolic outcomes in animal models, but rigorous human safety data are scarce, and there is potential for serious harm to patients. This narrative review focuses on the utilization of peptides in sports medicine, and alternative treatments that may be considered. We provide a framework to navigate patient discussions about peptides to better facilitate evidence-based practices for musculoskeletal healing and athletic performance. We also discuss the placebo effect as a mediator of peptide efficacy, and how social media amplifies this effect.
Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males.
Male hypogonadism is an increasingly prevalent clinical condition that affects patients' quality of life and overall health. Obesity and metabolic syndrome can both cause and result from hypogonadism. Although testosterone remains the gold standard for hypogonadism management, its benefits are not always conserved across different populations, especially with regards to changes in body composition. Partially in response to this, growth hormone secretagogues (GHS) have emerged as a potential novel adjunctive therapy for some of the symptoms of hypogonadism, although current data on their clinical efficacy largely remain lacking. The present review examines the existing literature on the use of GHS and explores their potential complementary role in the management of hypogonadal and eugonadal males with metabolic syndrome or subclinical hypogonadism (SH). The GHS that will be discussed include sermorelin, growth hormone-releasing peptides (GHRP)-2, GHRP-6, ibutamoren, and ipamorelin. All are potent GH and IGF-1 stimulators that can significantly improve body composition while ameliorating specific hypogonadal symptoms including fat gain and muscular atrophy. However, a paucity of data examining the clinical effects of these compounds currently limits our understanding of GHS' role in the treatment of men with hypogonadism, but does open opportunities for future investigation.
Pharmacokinetic evaluation of ipamorelin and other peptidyl growth hormone secretagogues with emphasis on nasal absorption.
1. The pharmacokinetics of three new peptidyl growth hormone secretagogues, ipamorelin (NNC 26-0161), NNC 26-0194 and NNC 26-0235, were compared with two well-known hexapeptides, GHRP-2 and GHRP-6, in the male rat following different routes of administration. 2. Following i.v. bolus injection, plasma concentrations of the peptides declined biexponentially. Ipamorelin differed markedly from the other peptides investigated, demonstrating a systemic plasma clearance 5-fold lower than that of GHRP-6. Ipamorelin was mainly excreted in the urine, whereas GHRP-6 was predominantly excreted in the bile. NNC 26-0194 and NNC 26-0235 also showed high biliary excretions. Ipamorelin and the two NNC peptides were moderately resistant towards metabolism as 60-80% of the administered dose could be recovered from bile and urine as intact peptide. 3. After intranasal application, the bioavailability of ipamorelin was estimated at approximately 20%. Higher bioavailabilities of approximately 50% were determined for NNC 26-0235, NNC 26-0194 and GHRP-2, whereas the nasal absorption of GHRP-6 was somewhat lower. Thus, the peptides could be easily transported across the nasal epithelium suggesting that the nasal route seems promising for systemic delivery of this family of peptidyl growth hormone secretagogues.
Therapeutic peptides in gerontology: mechanisms and applications for healthy aging.
Peptide therapeutics represent an emerging frontier in gerontological medicine, targeting fundamental hallmarks of aging including metabolic dysfunction, telomere attrition, tissue repair impairment, and hormonal decline. To comprehensively review the mechanisms, clinical applications, evidence base, and safety profiles of therapeutic peptides with demonstrated or potential applications in healthy aging and age-related conditions. A comprehensive narrative review was conducted through systematic searches of PubMed, Scopus, and regulatory databases (FDA, WADA) from inception through January 2026. Search terms included "peptide therapeutics," "aging," "gerontology," "healthspan," combined with specific peptide names (tirzepatide, epitalon, GHK-Cu, BPC-157, TB-500, Semax, CJC-1295, ipamorelin, bremelanotide). Peer-reviewed articles, clinical trials, regulatory documents, and preclinical studies were evaluated. A total of 20 primary sources were selected based on relevance, methodological quality, and contribution to understanding peptide mechanisms and clinical outcomes in aging populations. Nine peptides were identified spanning diverse aging interventions: metabolic restoration (tirzepatide), telomere biology (epitalon), dermal regeneration (GHK-Cu), tissue repair (BPC-157, TB-500), neuroprotection (Semax), growth hormone modulation (CJC-1295, ipamorelin), and sexual function (bremelanotide). FDA-approved agents demonstrated robust safety profiles from large-scale trials. Non-approved peptides showed promising preclinical and limited clinical evidence but lack long-term safety data and systematic validation. Significant knowledge gaps include optimal dosing regimens, combination therapy effects, and biomarkers for monitoring efficacy. Therapeutic peptides offer mechanistically diverse approaches to multiple aging hallmarks. While FDA-approved agents demonstrate clinical potential, investigational peptides require rigorous validation through well-designed clinical trials to establish safety and efficacy for healthspan extension.
A new series of highly potent growth hormone-releasing peptides derived from ipamorelin.
A new series of GH secretagogues derived from ipamorelin is described. In an attempt to obtain oral bioavailability, by reducing the size and the number of potential hydrogen-bonding sites of the compounds, a strategy using the peptidomimetic fragment 3-(aminomethyl)benzoic acid and sequential backbone N-methylations was applied. Several compounds from this series release GH with high in vitro potency and efficacy in a rat pituitary cell assay and high in vivo potency and efficacy in anesthetized rats. The tetrapeptide NNC 26-0235 (3-(aminomethyl)benzoyl-D-2Nal-N-Me-D-Phe-Lys-NH2) shows, following iv administration, comparable in vivo potency to ipamorelin, GHRP-2, and GHRP-6 with an ED50 in swine at 2 nmol/kg. NNC 26-0235 demonstrated a 10% oral bioavailability in dogs, and NNC 26-0235 and ipamorelin were able to increase basal GH level by more than 10-fold after oral administration of a dose of 1.8 and 2.7 mg/kg, respectively. The tripeptide NNC 26-0323 (3-(aminomethyl)benzoic acid-N-Me-D-2Nal-N-Me-D-Phe-ol) which showed moderate in vitro potency but lacked in vivo potency demonstrated a 20% oral bioavailability in rats.
Therapeutic Peptides in Aesthetic, Metabolic and Endocrine Conditions: Effects, Safety, Clinical Applications, and Future Perspectives.
Therapeutic peptides are short chains of amino acids used to treat metabolic and endocrine conditions such as obesity and type 2 diabetes. While several peptide drugs have undergone rigorous approval processes that evaluate both safety and efficacy, novel, unapproved compounds have emerged and are rapidly expanding into preventive medicine and performance enhancement. Our objective is to present the effects, clinical applications, safety profiles, and regulatory status of prominent peptides used to treat several conditions. We reviewed 106 articles, prioritizing systematic reviews, meta-analyses, and randomized controlled trials in the PubMed, ScienceDirect, and SciELO databases. Our results suggest that therapeutic peptides are a promising tool for treating type 2 diabetes and obesity, for skin rejuvenation, and as hormone analogs for specific diseases and conditions. Although these are strategic and innovative options that can improve health, performance, and longevity, further studies are needed before most new peptides can be used safely in humans.
Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats.
Ipamorelin is a new and potent synthetic pentapeptide which has distinct and specific growth hormone (GH)-releasing properties. With the objective of investigating the effects on longitudinal bone growth rate (LGR), body weight (BW), and GH release, ipamorelin in different doses (0, 18, 90 and 450 microg/day) was injected s.c. three times daily for 15 days to adult female rats. After intravital tetracycline labelling on days 0, 6, and 13, LGR was determined by measuring the distance between the respective fluorescent bands in the proximal tibia metaphysis. Ipamorelin dose-dependently increased LGR from 42 microm/day in the vehicle group to 44, 50, and 52 microm/day in the treatment groups (P<0.0001). There was also a pronounced and dose-dependent effect on BW gain. The treatment did not affect total IGF-I levels, IGFBPs, or serum markers of bone formation and resorption. The number of tartrate-resistant acid phosphatase-positive multinuclear cells in the metaphysis of the tibia did not change significantly with treatment. The responsiveness of the pituitary to a provocative i.v. dose of ipamorelin or GHRH showed that the plasma GH response was marginally reduced (P<0.03) after ipamorelin, but unchanged after GHRH. The pituitary GH content was unchanged by ipamorelin treatment. Whether ipamorelin or other GH secretagogues may have a place in the treatment of children with growth retardation requires demonstration in future clinical studies.
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.
This study investigated whether ghrelin mimetics, namely anamorelin and ipamorelin, can alleviate weight loss and inhibition of feeding observed during acute and delayed phases of cisplatin-induced emesis in ferrets. The potential of anamorelin to inhibit electrical field stimulation (EFS)-induced contractions of isolated ferret ileum was compared with ipamorelin. In other experiments, ferrets were administered anamorelin (1-3 mg/kg), ipamorelin (1-3 mg/kg), or vehicle intraperitoneally (i.p.) 30 s before cisplatin (5 mg/kg, i.p.) and then every 24 h, and their behaviour was recorded for up to 72 h. Food and water consumption was measured every 24 h. The effect of anamorelin (10 µg) was also assessed following intracerebroventricular administration. Anamorelin and ipamorelin inhibited EFS-induced contractions of isolated ileum by 94.4 % (half-maximal inhibitory concentration [IC50]=14.0 µM) and 54.4 % (IC50=11.7 µM), respectively. Neither of compounds administered i.p. had any effect on cisplatin-induced acute or delayed emesis, but both inhibited associated cisplatin-induced weight loss on the last day of delayed phase (48-72 h) by approximately 24 %. Anamorelin (10 µg) administered intracerebroventricularly reduced cisplatin-induced acute emesis by 60 % but did not affect delayed emesis. It also improved food and water consumption by approximately 20 %-40 % during acute phase, but not delayed phase, and reduced associated cisplatin-induced weight loss during delayed phase by ∼23 %. In conclusion, anamorelin and ipamorelin administered i.p. had beneficial effects in alleviating cisplatin-induced weight loss during delayed phase, and these effects were seen when centrally administered anamorelin. Anamorelin inhibited cisplatin-induced acute emesis following intracerebroventricular but not intraperitoneal administration, suggesting that brain penetration is important for its anti-emetic mechanism of action.
Attenuation of Visceral and Somatic Nociception by Ghrelin Mimetics.
The anti-nociceptive properties of ghrelin have been demonstrated in alleviating inflammatory and neuropathic pain. Whether a ghrelin receptor-mediated mechanism attenuates visceral and somatic pain in the absence of active inflammation remains to be explored. Here, we investigate the efficacy of peripherally restricted (ipamorelin) and a globally active (HM01) selective ghrelin receptor agonist in an experimental model of non-inflammatory visceral hypersensitivity and somatic mechanical allodynia. Visceral hypersensitivity was induced by dilute acetic acid (0.6%) infusion in the colon of rats in the absence of colonic epithelial inflammation. Ghrelin mimetics HM01 and ipamorelin were administered orally or intravenously, respectively. The ghrelin receptor antagonist H0900 was administered orally. Colonic sensitivity was assessed via a visceromotor behavioral response (VMR) quantified as the number of abdominal contractions in response to graded isobaric pressures (0-60 mmHg) of colorectal distension (CRD). Somatic mechanical allodynia was quantified by the number of ipsilateral paw withdrawals in response to a calibrated von Frey filament. Compared to vehicle controls, ghrelin mimetics HM01 and ipamorelin significantly attenuated colonic hypersensitivity and somatic allodynia. The anti-nociceptive effects of the ghrelin mimetics were blocked after administration of the ghrelin receptor antagonist H0900. We have shown that ghrelin receptor-mediated mechanisms are involved in visceral and somatic hypersensitivity in the absence of active colonic inflammation. Furthermore, visceral and somatic hypersensitivity could be attenuated by a peripherally restricted ghrelin mimetic. These results highlight a potential novel approach for treating acute visceral and somatic pain by ghrelin mimetics.
Influence of chronic treatment with the growth hormone secretagogue Ipamorelin, in young female rats: somatotroph response in vitro.
Growth hormone (GH) is secreted in the anterior pituitary gland by the somatotroph cells. Secretion is regulated by growth hormone releasing hormone (GHRH) and somatostatin. Morever, GH secretagogues (GHS) can exert a considerable effect on GH secretion. In order to determine the effects of chronic treatment with the GHS Ipamorelin on the composition of the somatotroph cell population and on somatotroph GH content, an in vitro analysis was performed of the percentage of somatotroph cells (% of total), the ratio of different GH cell types (strongly/weakly-staining) and individual GH content, in pituitary cell cultures obtained from young female rats receiving Ipamorelin over 21 days (Ipamorelin group) and the effects were compared with those of GHRH (GHRH group) or saline (saline group). The ultrastructure of somatotroph cells did not change, but the volume density of secretion granules was increased (P<0.05) by previous in vivo Ipamorelin or GHRH treatment. In 3-day basal pituitary cell monolayer cultures, the percentage of somatotroph cells showed no modifications between groups, nor was there any change in the ratio of strongly/weakly immunostaining GH cells. In the Ipamorelin group alone, in vitro treatment with Ipamorelin (10(-8) M), or GHRP 6 (10(-8) M), or GHRH (10(-8) M) for 4 hours, increased the percentage of somatotroph cells, without modifying the ratio of strongly/weakly immunostained GH cells. Basal intracellular GH content in somatotroph cells over 4 hours was lower in the Ipamorelin group and the GHRH group than in the saline group. Only in the Ipamorelin group did Ipamorelin (10(-8) M), GHRP 6 (10(-8) M) and GHRH (10(-8) M) prompt increased intracellular GH content. These data suggest that, at least in the young female rat, the GHS Ipamorelin is able to exert a dynamic control effect on the somatotroph population and on GH hormone content.
Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus.
Ghrelin and ghrelin mimetics stimulate appetite and enhance gastric motility. The present study investigates whether ipamorelin, a selective growth hormone secretagogue and agonist of the ghrelin receptor, would accelerate gastrointestinal transit and ameliorate the symptoms in a rodent model of postoperative ileus (POI). Fasted male rats were subjected to laparotomy and intestinal manipulation. At the end of surgery, a dye marker was infused in the proximal colon to evaluate postsurgical colonic transit time, which was the time to the first bowel movement. In addition, fecal pellet output, food intake, and body weight were monitored regularly for 48 h. Ipamorelin (0.01-1 mg/kg), growth hormone-releasing peptide (GHRP)-6 (20 microg/kg), or vehicle (saline) were administered via intravenous bolus infusion after a single dosing or a 2-day repetitive dosing regimen (four doses a day at 3-h intervals). Compared with the vehicle, a single dose of ipamorelin (1 mg/kg) or GHRP-6 (20 microg/kg) decreased the time to the first bowel movement but had no effect on cumulative fecal output, food intake, or body weight gain measured 48 h after the surgery. In contrast, repetitive dosing of ipamorelin (0.1 or 1 mg/kg) significantly increased the cumulative fecal pellet output, food intake, and body weight gain. The results suggest that postsurgical intravenous infusions of ipamorelin may ameliorate the symptoms in patients with POI.
Analysis of new growth promoting black market products.
Detecting agents allegedly or evidently promoting growth such as human growth hormone (GH) or growth hormone releasing peptides (GHRP) in doping controls has represented a pressing issue for sports drug testing laboratories. While GH is a recombinant protein with a molecular weight of 22 kDa, the GHRPs are short (3-6 amino acids long) peptides with GH releasing properties. The endogenously produced GH (22 kDa isoform) consists of 191 amino acids and has a monoisotopic molecular mass of 22,124 Da. Within this study, a slightly modified form of GH was discovered consisting of 192 amino acids carrying an additional alanine at the N-terminus, leading to a monoisotopic mass of 22,195 Da. This was confirmed by top-down and bottom-up experiments using liquid chromatography coupled to high resolution/high accuracy mass spectrometry. Additionally, three analogues of GHRPs were identified as Gly-GHRP-6, Gly-GHRP-2 and Gly-Ipamorelin, representing the corresponding GHRP extended by a N-terminal glycine residue. The structure of these peptides was characterised by means of high resolution (tandem) mass spectrometry, and for Gly-Ipamorelin and Gly-GHRP-2 their identity was additionally confirmed by custom synthesis. Further, established in-vitro experiments provided preliminary information considering the potential metabolism after administration.
Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers.
To examine the pharmacokinetics (PK) and pharmacodynamics (PD) of ipamorelin, a growth hormone (GH) releasing peptide, in healthy volunteers. A trial was conducted with a dose escalation design comprising 5 different infusion rates (4.21, 14.02, 42.13, 84.27 and 140.45 nmol/kg over 15 minutes) with eight healthy male subjects at each dose level. Concentrations of ipamorelin and growth hormone were measured. The PK parameters showed dose-proportionality, with a short terminal half-life of 2 hours, a clearance of 0.078 L/h/kg and a volume of distribution at steady-state of 0.22 L/kg. The time course of GH stimulation by ipamorelin showed a single episode of GH release with a peak at 0.67 hours and an exponential decline to negligible GH concentration at all doses. The ipamorelin-GH concentration relationship was characterized using an indirect response model and population fitting. The model employed a zero-order GH release rate over a finite duration of time to describe the episodic release of GH. Ipamorelin induces the release of GH at all dose levels with the concentration (SC50) required for half-maximal GH stimulation of 214 nmol/L and a maximal GH production rate of 694 mIU/L/h. The inter-individual variability of the PD parameters was larger than that of the PK parameters. The proposed PK/PD model provides a useful characterization of ipamorelin disposition and GH responses across a range of doses.
The growth hormone secretagogue ipamorelin counteracts glucocorticoid-induced decrease in bone formation of adult rats.
The ability of the growth hormone secretagogue (GHS) Ipamorelin to counteract the catabolic effects of glucocorticoid (GC) on skeletal muscles and bone was investigated in vivo in an adult rat model. Groups of 8-month-old female rats were injected subcutaneously for 3 months with GC (methylprednisolone) 9 mg/kg/day or GHS (Ipamorelin) 100 microg/kg three times daily, or both GC and GHS in combination. The maximum tetanic tension of the calf muscles was determined in vivo in a materials testing machine. The maximum tetanic tension was increased significantly, and the periosteal bone formation rate increased four-fold in animals injected with GC and GHS in combination, compared with the group injected with GC alone. In conclusion, the decrease in muscle strength and bone formation found in GC-injected rats was counteracted by simultaneous administration of the growth hormone secretagogue.
Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients.
Postoperative ileus is a significant clinical challenge lacking effective management strategies. Ghrelin-receptor stimulation has promotility effects in the upper and lower gastrointestinal tract. This proof-of-concept, phase 2, randomized study evaluated the safety and efficacy of the ghrelin-receptor agonist ipamorelin in the treatment of postoperative ileus following abdominal surgery (ClinicalTrials.gov NCT00672074). The design was a multicenter, double-blind, placebo-controlled, clinical trial. The settings include hospital inpatients. The patients were adults undergoing small and large bowel resection by open or laparoscopic surgery. The intervention was intravenous infusions of 0.03-mg/kg ipamorelin vs placebo twice daily, on postoperative day 1 to 7 or hospital discharge. Safety was assessed by monitoring adverse events and laboratory tests. The key efficacy endpoint was time from first dose of study drug to tolerance of a standardized solid meal. One hundred seventeen patients were enrolled, of whom 114 patients composed the safety and modified intent-to-treat populations. Demographic and disease characteristics were balanced between groups. Overall incidence of any treatment-emergent adverse events was 87.5 % in the ipamorelin group and 94.8 % in placebo group. Median time to first tolerated meal was 25.3 and 32.6 h in the ipamorelin and placebo groups, respectively (p = 0.15). This proof of concept study was small and enrolled patients with a broad range of underlying conditions. Ipamorelin 0.03-mg/kg twice daily for up to 7 days was well tolerated. There were no significant differences between ipamorelin and placebo in the key and secondary efficacy analyses.
Growth hormone and growth hormone secretagogue effects on nitrogen balance and urea synthesis in steroid treated rats.
Growth hormone (GH) reduces the catabolic side effects of steroid treatment via effects on the amino-nitrogen metabolism. Ipamorelin is a synthetic peptide with GH releasing properties. We wished to study the metabolic effects of Ipamorelin and GH on selected hepatic measures of alpha-amino-nitrogen conversion during steroid-induced catabolism. Five groups of rats were included: (1) free-fed controls (2) pair-fed controls (3) prednisolone (delcortol, 4 mg x kg(-1) x day(-1)) (4) prednisolone and GH (1 mg x kg(-1) x day(-1)) (5) prednisolone and Ipamorelin (0.5 mg x kg(-1) x day(-1)). After seven days the hepatic capacity of urea-N synthesis (CUNS) was determined in parallel with measurements of liver mRNA levels of urea cycle enzymes, whole-body N-balance, and N-contents of various organs. Compared to pair-fed controls, prednisolone increased CUNS (p<0.01) as well as the expression of urea cycle genes (p<0.01), and decreased N-balance (p<0.01) as well as organ N-contents (p<0.05). Compared to prednisolone treated animals, co-administration of GH reduced CUNS by 33% (p<0.01), normalized urea cycle gene expression, improved N-balance 2.5-fold, and normalized or improved organ N-contents. In prednisolone treated rats Ipamorelin reduced CUNS by 20% (p<0.05), decreased the expression of urea cycle enzymes, neutralised N-balance, and normalized or improved organ N-contents. Accelerated nitrogen wasting in the liver and other organs caused by prednisolone treatment was counteracted by treatment with either GH or its secretagogue Ipamorelin, though at the doses given less efficiently by the latter. This functional study of animals confirms that the GH secretagogue exerts GH related metabolic effects and may be useful in the treatment of steroid-induced catabolism.
Mechanism of ipamorelin-evoked insulin release from the pancreas of normal and diabetic rats.
To examine the effect of ipamorelin (IPA), a novel pentapeptide with a strong growth hormone releasing potency, on insulin secretion from pancreatic tissue fragments of normal and diabetic rats. Diabetes mellitus was induced by streptozotocin (60 mg kg(-1)). Four weeks after the induction of diabetes, pancreatic tissue fragments of normal and diabetic rats were removed and incubated with different concentrations (10(-12) - 10(-6) M) of IPA. Insulin release from the pancreas was measured by radioimmunoassay. Ipamorelin evoked significant (p<0.04) increases in insulin secretion from the pancreas of normal and diabetic rats. Either diltiazem or yohimbine or propranolol or a combination of atropine, propranolol and yohimbine inhibited IPA-evoked insulin secretion significantly (p<0.03) from the pancreas of normal and diabetic rats. Atropine caused a significant (p<0.007) reduction in the IPA-induced insulin secretion in diabetic but not in normal rats. IPA stimulates insulin release through the calcium channel and the adrenergic receptor pathways. This is the first study to examine the effect of ipamorelin on insulin secretion in the pancreas.
Efficacy of ipamorelin, a ghrelin mimetic, on gastric dysmotility in a rodent model of postoperative ileus.
Delayed gastric emptying is a common disorder with few effective therapeutic options. The goal of this study was to investigate whether ipamorelin, a synthetic peptidomimetic that acts on the ghrelin receptor, accelerates gastric emptying in a rodent model of gastroparesis induced by abdominal surgery and intestinal manipulation. Fasted adult male rats were subjected to laparotomy and intestinal manipulation. Following the surgery rats received ipamorelin (0.014-0.14 µmol/kg) or vehicle control via intravenous administration. Gastric emptying was measured by the percent of total recovered radioactivity remaining in the stomach 15 minutes after intragastric gavage of 1.5 mL of (99m)Tc (technicium-99m) sulfur colloid in 0.5% methylcellulose. In a separate group of rats subjected to laparotomy and intestinal manipulation, the gastric fundus was isolated and tissue segments were suspended in an organ bath to assess the effect of ipamorelin (1 µM) on gastric smooth muscle contractility induced by acetylcholine and electrical field stimulation. Abdominal surgery caused a delay in gastric emptying with 78% ± 5% of the meal remaining in the stomach in vehicle controls. Ipamorelin (0.014 µmol/kg intravenous) resulted in a significant acceleration (P < 0.05 vs vehicle-treated rat) of gastric emptying with 52% ± 11% of the meal remaining in the stomach compared to nonsurgical control animals with 44% ± 6%. Following abdominal surgery and intestinal manipulation, isolated preparations of gastric smooth muscle exhibited a marked inhibition of acetylcholine and electrical field stimulation-induced contractile responses, which were reversed by ipamorelin and ghrelin. These results suggest that ipamorelin accelerates gastric emptying in a rodent model of postoperative ileus through the stimulation of gastric contractility by activating a ghrelin receptor-mediated mechanism involving cholinergic excitatory neurons.
The influence of ghrelin agonist ipamorelin acetate on the hypothalamic-pituitary-testicular axis in a cichlid fish, Oreochromis mossambicus.
Ghrelin, a peptide found in the brain and gut, is predicted to play a significant role in the control of various physiological systems in fish. The objective of this study was to examine the impact of ipamorelin acetate (IPA), a ghrelin agonist, on the reproductive axis of the tilapia Oreochromis mossambicus. The administration of either 5 or 30 µg of IPA for 21 days led to a significant and dose-dependent rise in food intake concomitant with a significant increase in the numbers of primary spermatocytes, secondary spermatocytes, and early spermatids compared to the control group. There was a significant rise in the number of late spermatids, as well as the areas of the lobule and lumen, in fish treated with 30 µg of IPA, compared to the control group. Moreover, there was no significant difference in the percentage of gonadotropin-releasing hormone (GnRH)-immunoreactive fibres in the hypothalamus and anterior pituitary gland across different groups. However, a significant elevation in the expression of androgen receptor protein was observed in fish treated with 30 µg of IPA. Furthermore, the concentrations of luteinizing hormone (LH) and 11-ketotestosterone (11-KT) in the serum of fish treated with either 5 or 30 µg of IPA were significantly elevated in comparison to the control group. Collectively, these findings suggest that the administration of ghrelin enhances the development of germ cells during the meiosis-I phase and that this effect might be mediated via the stimulation of 11-KT and androgen receptors at the testicular level and LH at the pituitary level in the tilapia.
Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues.
Growth hormone secretagogues (GHSs) stimulate growth hormone (GH) secretion, which is lipolytic. Here we compared the effects of twice daily s.c. treatment of GH and the GHS, ipamorelin, on body fat in GH-deficient (lit/lit) and in GH-intact (+/lit and +/+) mice. In +/lit and lit/lit mice ipamorelin induced a small (15%) increase in body weight by 2 weeks, that was not further augmented by 9 weeks. GH treatment markedly enhanced body weight in both groups. Ipamorelin also increased fat pad weights relative to body weight in both lit/lit and +/lit mice. Two weeks GHS treatment (ipamorelin or GHRP-6) also increased relative body fat, quantified by in vivo dual energy X-ray absorpiometry (DEXA) in GH-intact mice. GH decreased relative fat mass in lit/lit mice and had no effect in GH-intact mice. Treatment with GHS, but not GH, increased serum leptin and food intake in GH-intact mice. Thus, GHSs increase body fat by GH-independent mechanisms that may include increased feeding.
Determination of growth hormone releasing peptides metabolites in human urine after nasal administration of GHRP-1, GHRP-2, GHRP-6, Hexarelin, and Ipamorelin.
Growth hormone releasing peptides (GHRPs) stimulate secretion of endogenous growth hormone and are listed on the World Anti-Doping Agency (WADA) Prohibited List. To develop an effective method for GHRPs anti-doping control we have investigated metabolites of GHRP-1, GHRP-2, GHRP-6, Hexarelin, and Ipamorelin in urine after nasal administration. Each compound was administrated to one volunteer. Samples were collected for 2 days after administration, processed by solid-phase extraction on weak cation exchange cartridges and analyzed by means of nano-liquid chromatography - high resolution mass spectrometry. Six metabolites of GHRP-1 were identified. GHRP-1 in the parent form was not detected. GHRP-1 (2-4) free acid was detected in urine up to 27 h. GHRP-2, GHRP-2 free acid and GHRP-2 (1-3) free acid were detected in urine up to 47 h after administration. GHRP-6 was mostly excreted unchanged and detected in urine 23 h after administration, its metabolites were detectable for 12 h only. Hexarelin and Ipamorelin metabolized intensively and were excreted as a set of parent compounds with metabolites. Hexarelin (1-3) free acid and Ipamorelin (1-4) free acid were detected in urine samples after complete withdrawal of parent substances. GHRPs and their most prominent metabolites were included into routine ultra-pressure liquid chromatography-tandem mass spectrometry procedure. The method was fully validated, calibration curves of targeted analytes were obtained and excretion curves of GHRPs and their metabolites were plotted. Our results confirm that the detection window after GHRPs administration depends on individual metabolism, drug preparation form and the way of administration.
Novel orally active growth hormone secretagogues.
A novel class of growth hormone-releasing compounds with a molecular weight in the range from 500 to 650 has been discovered. The aim of this study was to obtain growth hormone secretagogues with oral bioavailability. By a rational approach we were able to reduce the size of the lead compound ipamorelin (4) and simultaneously to reduce hydrogen-bonding potential by incorporation of backbone isosters while retaining in vivo potency in swine. A rat pituitary assay was used for screening of all compounds and to evaluate which compounds should be tested further for in vivo potency in swine and oral bioavailability, fpo, in dogs. Most of the tested compounds had fpo in the range of 10-55%. In vivo potency in swine after iv dosing is reported, and ED50 was found to be 30 nmol/kg of body weight for the most potent compound.
Highly potent growth hormone secretagogues: hybrids of NN703 and ipamorelin.
A series of NN703 analogues with lysine mimetics combined with naphthyl- or biphenylalanine in the core has been prepared and tested in vitro in a rat pituitary cell based assay and subsequently in vivo in pigs in a single dose at 50 nmol/kg. Re-introduction of certain pharmacophores in the C-terminal of NN703, which were originally removed during optimisation for oral bioavailability, led to unexpectedly potent compounds in vitro as well as in vivo.
The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats.
Growth hormone (GH) is of importance for normal bone remodelling. A recent clinical study demonstrated that MK-677, a member of a class of GH secretagogues (GHSs), increases serum concentrations of biochemical markers of bone formation and bone resorption. The aim of the present study was to investigate whether the GHSs, ipamorelin (IPA) and GH-releasing peptide-6 (GHRP-6), increase bone mineral content (BMC) in young adult female rats. Thirteen-week-old female Sprague-Dawley rats were given IPA (0.5 mg/kg per day; n=7), GHRP-6 (0.5 mg/kg per day; n=8), GH (3.5 mg/kg per day; n=7), or vehicle administered continuously s.c. via osmotic minipumps for 12 weeks. The animals were followed in vivo by dual X-ray absorptiometry (DXA) measurements every 4th week. After the animals were killed, femurs were analysed in vitro by mid-diaphyseal peripheral quantitative computed tomography (pQCT) scans. After this, excised femurs and vertebrae L6 were analysed by the use of Archimedes' principle and by determinations of ash weights. All treatments increased body weight and total tibial and vertebral BMC measured by DXA in vivo compared with vehicle-treated controls. However, total BMC corrected for the increase in body weight (total BMC:body weight ratio) was unaffected. Tibial area bone mineral density (BMD, BMC/area) was increased, but total and vertebral area BMDs were unchanged. The pQCT measurements in vitro revealed that the increase in the cortical BMC was due to an increased cross-sectional bone area, whereas the cortical volumetric BMD was unchanged. Femur and vertebra L6 volumes were increased but no effect was seen on the volumetric BMDs as measured by Archimedes' principle. Ash weight was increased by all treatments, but the mineral concentration was unchanged. We conclude that treatment of adult female rats with the GHSs ipamorelin and GHRP-6 increases BMC as measured by DXA in vivo. The results of in vitro measurements using pQCT and Archimedes' principle, in addition to ash weight determinations, show that the increases in cortical and total BMC were due to an increased growth of the bones with increased bone dimensions, whereas the volumetric BMD was unchanged.
Metabolism of growth hormone releasing peptides.
New, potentially performance enhancing compounds have frequently been introduced to licit and illicit markets and rapidly distributed via worldwide operating Internet platforms. Developing fast analytical strategies to follow these new trends is one the most challenging issues for modern doping control analysis. Even if reference compounds for the active drugs are readily obtained, their unknown metabolism complicates effective testing strategies. Recently, a new class of small C-terminally amidated peptides comprising four to seven amino acid residues received considerable attention of sports drug testing authorities due to their ability to stimulate growth hormone release from the pituitary. The most promising candidates are the growth hormone releasing peptide (GHRP)-1, -2, -4, -5, -6, hexarelin, alexamorelin, and ipamorelin. With the exemption of GHRP-2, the entity of these peptides represents nonapproved pharmaceuticals; however, via Internet providers, all compounds are readily available. To date, only limited information on the metabolism of these substances is available and merely one metabolite for GHRP-2 is established. Therefore, a comprehensive in vivo (po and iv administration in rats) and in vitro (with human serum and recombinant amidase) study was performed in order to generate information on urinary metabolites potentially useful for routine doping controls. The urine samples from the in vivo experiments were purified by mixed-mode cation-exchange solid-phase extraction and analyzed by ultrahigh-performance liquid chromatography (UHPLC) separation followed by high-resolution/high-accuracy mass spectrometry. Combining the high resolution power of a benchtop Orbitrap mass analyzer for the first metabolite screening and the speed of a quadrupole/time-of-flight (Q-TOF) instrument for identification, urinary metabolites were screened by means of a sensitive full scan analysis and subsequently confirmed by high-accuracy product ion scan experiments. Two deuterium-labeled internal standards (triply deuterated GHRP-4 and GHRP-2 metabolite) were used to optimize the extraction and analysis procedure. Overall, 28 metabolites (at least three for each GHRP) were identified from the in vivo samples and main metabolites were confirmed by the human in vitro model. All identified metabolites were formed due to exopeptidase- (amino- or carboxy-), amidase-, or endopeptidase activity.
Injectable Peptides in Sports Medicine: A Structured Narrative Review of Evidence, Safety, and Antidoping Implications.
Injectable peptides are increasingly promoted for musculoskeletal recovery, tissue repair, and performance enhancements; however, clinical adoption has outpaced high-quality evidence and regulatory consensus. To summarize contemporary human and translational evidence (January 1, 2020-August 31, 2025) for injectable peptides relevant to orthopaedics and sports medicine, and to clarify safety, product quality, regulatory, antidoping implications, and clinical outcomes. Structured narrative review. PubMed/MEDLINE, Embase, and Web of Science were searched (January 1, 2020-August 31, 2025). Eligible studies included randomized controlled trials, prospective human studies, and translational investigations directly applicable to musculoskeletal care; noninjectable formulations and nonmusculoskeletal indications were excluded. Results were synthesized qualitatively; risk of bias for human trials was appraised using standard tools. Five functional peptide classes were identified. Glucagon-like peptide-1 receptor agonists (e.g., semaglutide) are the only class supported by reproducible randomized evidence of symptomatic improvement in knee osteoarthritis, with benefits primarily mediated by clinically meaningful weight loss and putative anti-inflammatory effects, whereas structural cartilage modification remains unproven. Collagen-derived injectable preparations show preliminary postoperative symptom/early recovery benefits in small, single-center prospective human studies. Regenerative peptides (e.g., body protection compound-157 and thymosin derivatives) and growth hormone axis secretagogues (e.g., CJC-1295, ipamorelin, and tesamorelin) remain investigational, with uncertain safety profiles, product quality concerns, and widespread antidoping restrictions. Injectable peptides for sports medicine remain largely experimental. Clinical use should be confined to approved metabolic agents for indicated conditions and to rigorously designed research protocols. Clinicians caring for athletes must counsel patients regarding uncertain efficacy, product quality, safety risks, and antidoping implications. Level V. See Instructions for Authors for a complete description of levels of evidence. Predominantly C.
Structure-activity relationship for peptídic growth hormone secretagogues.
Growth hormone releasing peptides (GHRPs) could be widely used by cheating athletes because they produce growth hormone (GH) secretion, so may generate an ergogenic effect in the body. Knowledge of the essential amino acids needed in GHRP structure for interaction with the target biological receptor GHSR1a, the absorption through different administration routes, and the maintenance of pharmacological activity of potential biotransformation products may help in the fight against their abuse in sport. Several GHRPs and truncated analogues with the common core Ala-Trp-(D-Phe)-Lys have been studied with a radio-competitive assay for the GHSR1a receptor against the radioactive natural ligand ghrelin. Relevant chemical modifications influencing the activity for positions 1, 2, 3, and 7 based on the structure aa-aa-aa-Ala-Trp-(D-Phe)-Lys have been obtained. To test in vivo the applicability of the activities observed, the receptor assay activity in samples from excretion studies performed after nasal administration of GHRP-1, GHRP-2, GHRP-6, Hexarelin, and Ipamorelin was confirmed. Overall results obtained allow to infer structure-activity information for those GHRPs and to detect GHSR1a binding (intact GHRPs plus active metabolites) in excreted urines. Copyright © 2016 John Wiley & Sons, Ltd.
A new era of doping? Use of peptide and peptide-analog drugs in recreational and professional sport and bodybuilding: a critical review.
The pursuit of pharmacological enhancement in sport has evolved from the widespread use of anabolic-androgenic steroids (AAS) to novel agents such as peptides and peptide analogues. Marketed as more selective and ostensibly safer alternatives, peptides-including growth hormone secretagogues (e.g., Ipamorelin), growth hormone-releasing hormone analogues (e.g., CJC-1295, Sermorelin), and synthetic fragments (e.g., Frag 176-191, KPV)-are promoted for muscle growth, fat metabolism, recovery, and anti-inflammatory effects. Their pharmacological profiles, including enhanced stability and receptor selectivity, have made them attractive in both medical research and bodybuilding communities. Despite their growing popularity, the clinical evidence supporting peptide use in sport is limited. Most published studies examine therapeutic applications under controlled dosing regimens, not the supraphysiological or combined protocols common in bodybuilding. Emerging data highlight potential risks: cardiovascular strain, insulin resistance, dyslipidemia, and psychiatric instability. The largely unregulated supply chain exacerbates these dangers, as products are often mislabeled or contaminated. Regulatory bodies such as the World Anti-Doping Agency (WADA) have responded by expanding detection technologies, yet analytical challenges remain due to peptides' structural similarity to endogenous hormones and short half-lives. Beyond elite sport, the extent of peptide use in the general population is unknown. Anecdotal reports and widespread promotion on social media suggest growing uptake among recreational gym-goers, including younger individuals, but prevalence studies are lacking. This represents a critical gap in current knowledge. In conclusion, peptides represent a new phase in performance enhancement but remain experimental substances with poorly defined long-term risks. Until longitudinal data clarify their safety and prevalence, peptide use in both competitive and recreational settings should be considered high-risk and ethically problematic.
The emerging landscape of performance-enhancing peptides modulating GH-IGF1 axis: bridging the gap between clinical evidence and patient self-administration.
Performance-enhancing drugs (PEDs) marketed as "research compounds" include unregulated peptides intended to modulate the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis. The agents most commonly encountered in clinical practice and online self-administration protocols include growth hormone-releasing hormone (GHRH) analogues (e.g., sermorelin, tesamorelin, CJC-1295 with Drug Affinity Complex [DAC], CJC-1295 without DAC), growth hormone secretagogues (GHS; e.g., growth hormone-releasing peptide-2 (GHRP-2), growth hormone-releasing peptide-6 (GHRP-6), hexarelin, ipamorelin), the growth hormone (GH) fragment - AOD9604 (hGH 176-191), and insulin-like growth factor-1 (IGF-1) analogues (e.g., pegylated mechano growth factor (PEG-MGF), IGF-1 Long R3 (IGF-1 LR3)). Reported adverse effects span endocrine and metabolic disturbances (including prolactin and cortisol elevations, appetite changes, and dysglycaemia), fluid retention syndromes, musculoskeletal symptoms (myalgia/arthralgia), and injection-site reactions. Given the absence of regulatory approval for physique- or performance-related indications and the uncertainty surrounding product composition, dose, and stacking practices in unregulated supply chains, clinicians increasingly require a pragmatic framework to interpret symptoms and laboratory abnormalities in patients using these compounds. This narrative review contrasts peer-reviewed pharmacokinetic/pharmacodynamic and clinical evidence with commonly encountered online self-administration protocols, stratifying peptides into evidence tiers from regulatory-grade randomized trial data to a complete absence of human studies, and highlights the resulting uncertainty around putative performance and recomposition benefits. We summarise structural characteristics, pharmacologic effects, and commonly reported dosing patterns, and we synthesise clinically relevant adverse effects with particular attention to hormonal imbalance, endocrine-metabolic risk, and biologically plausible but unproven mitogenic concerns. Finally, we propose a clinically oriented assessment algorithm to support exposure history taking, triage of symptom domains, and risk communication without legitimising off-label peptide regimens.
Seabream ghrelin: cDNA cloning, genomic organization and promoter studies.
Recent studies have indicated that ghrelin stimulates growth hormone release from the pituitary via the growth hormone secretagogue receptor (GHSR). We have previously isolated two GHSR subtypes from the pituitary of the black seabream Acanthopagrus schlegeli. In the present study, we have cloned and characterized ghrelin from the same fish species at both the cDNA and gene levels. The full-length seabream ghrelin cDNA, isolated from sea-bream stomach using a novel approach by exploiting a single conserved region in the coding region, was found to encode a prepropeptide of 107 amino acids, with the predicted mature ghrelin peptide consisting of 20 amino acids (GSSFLSPSQKPQNRGKSSRV). Embedded in this full-length cDNA is a putative fish orthologue of the recently reported mammalian obestatin peptide. The ghrelin gene in black seabream, obtained by genomic PCR, was found to encompass four exons and three introns, possessing the same structural organization as in tilapia and goldfish, but different from that in rainbow trout. In addition, a 2230-bp 5'-flanking region of the seabream ghrelin gene was obtained by genome walking. Sequence analysis revealed that, as in the case of the human ghrelin gene, there is neither a GC box nor a CAAT box present in the isolated 5'-flanking region. However, a number of putative transcription factor-binding sites different from the human counterpart were found in the 5'-flanking region of the seabream ghrelin gene, suggesting that different cis- and trans-acting elements are involved in controlling their gene expression. Functional activity of this 5'-flanking region was examined by cloning it into the pGL3-Basic vector upstream of the luciferase reporter gene and transfected into various cell lines. Positive promoter activity could only be recorded in the colon-derived Caco-2 cells, suggesting that the cloned 5'-flanking region represents the functional promoter of the seabream ghrelin gene, which exhibits tissue-specific promoter activity. Using reverse transcriptase PCR analysis, expression of ghrelin was detected only in the seabream stomach, but not in the other tissues examined, including the brain, gill, intestine, kidney, liver and spleen. This stomach-specific expression of ghrelin in seabream is subject to regulation, as administration of growth hormone or ipamorelin to the fish in vivo was demonstrated to enhance its expression. Reminiscent of the homologous upregulation found in the transcriptional control of the seabream GHSR gene, a similar homologous regulatory mechanism might also exist in controlling the expression of seabream ghrelin. The identification of both GHSR and ghrelin from a single fish species would facilitate our subsequent studies on the elucidation of the physiological functions of the ghrelin/GHSR system in teleost. The possible existence of obestatin in teleost opens up new research avenues on the somatotropic axis in fish.
Glycine-modified growth hormone secretagogues identified in seized doping material.
A number of unknown pharmaceutical preparations seized by Danish customs authorities were submitted for liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis. Comparison with reference standards unequivocally identified the content of the powders as analogs of the growth hormone secretagogues GHRP-2 (Pralmorelin), GHRP-6, Ipamorelin, and modified growth hormone releasing factor (modified GRF 1-29), which can be used as performance-enhancing substances in sports. In all cases, the detected modification involved the addition of an extra glycine amino acid at the N-terminus, and analytical methods targeting growth hormone secretagogues should hence be updated accordingly.
Do growth hormone-releasing peptides act as ghrelin secretagogues?
NN703 is an orally active and selective growth hormone secretagogue (GHS) that was derived from growth hormone-releasing peptide-1(GHRP-1) via ipamorelin by a peptidomimetic approach and has now entered into phase II clinical trials. When the disposition in rats of NN703 and GHRP-6 was studied using whole-body autoradiography following administration of an iv dose of radiolabeled material, we found that a substantial amount of these secretagogues accumulate in the glandular part of the stomach. Because this is the site of synthesis and secretion of ghrelin, the endogenous GHS, we investigated the effect of resection of the gastrointestinal (GI) tract on growth hormone (GH) release induced by GHRP-6. This procedure significantly attenuated the GH secretion response by 60-70%. By contrast, the effect of GH-releasing hormone on GH release was not inhibited. The binding of GHRPs to the glandular part of the stomach and the blunted GH response to GHRP-6 following resection of the GI tract suggest a role for ghrelin as a mediator of part of the GH-releasing effect of GHRPs.
Doping control container for urine stabilization: a pilot study.
Urine collection containers used in the doping control collection procedure do not provide a protective environment for urine, against degradation by microorganisms and proteolytic enzymes. An in-house chemical stabilization mixture was developed to tackle urine degradation problems encountered in human sport samples, in cases of microbial contamination or proteolytic activity. The mixture consists of antimicrobial substances and protease inhibitors for the simultaneous inactivation of a wide range of proteolytic enzymes. It has already been tested in lab-scale, as part of World Anti-Doping Agency's (WADA) funded research project, in terms of efficiency against microbial and proteolytic activity. The present work, funded also by WADA, is a follow-up study on the improvement of chemical stabilization mixture composition, application mode and limitation of interferences, using pilot urine collection containers, spray-coated in their internal surface with the chemical stabilization mixture. Urine in plastic stabilized collection containers have been gone through various incubation cycles to test for stabilization efficiency and analytical matrix interferences by three WADA accredited Laboratories (Athens, Ghent, and Rome). The spray-coated chemical stabilization mixture was tested against microorganism elimination and steroid glucuronide degradation, as well as enzymatic breakdown of proteins, such as intact hCG, recombinant erythropoietin and small peptides (GHRPs, ipamorelin), induced by proteolytic enzymes. Potential analytical interferences, observed in the presence of spray-coated chemical stabilization mixture, were recorded using routine screening procedures. The results of the current study support the application of the spray-coated plastic urine container, in the doping control collection procedure. Copyright © 2016 John Wiley & Sons, Ltd.
Growth hormone (GH) hypersecretion and GH receptor resistance in streptozotocin diabetic mice in response to a GH secretagogue.
The growth hormone (GH) and insulin-like growth factor I (IGF-I) axis were studied in streptozotocin (STZ) diabetic and nondiabetic female mice following intravenous (IV) injection of the GH secretagogue (GHS) ipamorelin or saline. On day 14, blood samples were obtained before and 10 minutes after the injection. Livers were removed and frozen for determination of the mRNA expressions of the GH receptor, GH-binding protein, and IGF-I, and hepatic IGF-I peptide. Serum samples were analyzed for GH and IGF-I. Following ipamorelin injection, the GH levels were found to be 150 +/- 35 microg/L and 62 +/- 11 microg/L in the diabetic compared to the nondiabetic mice (P <.05). Serum IGF-I levels were lower in diabetic than in nondiabetic animals, and rose after stimulation only in the nondiabetic animals. Furthermore, hepatic GH resistance and IGF-I mRNA levels and IGF-I peptide were increased in nondiabetic animals in response to GH stimulation, whereas the low levels per se of all these parameters in diabetic mice were unaffected. The study shows that STZ diabetic mice demonstrate a substantial part of the clinical features of type 1 diabetes in humans, including GH hypersecretion and GH resistance. Accordingly, it is proposed that STZ diabetic mice may be a better model of the perturbations of the GH/IGF-I axis in diabetes than STZ diabetic rats.
Methylprednisolone does not inhibit the release of growth hormone after intravenous injection of a novel growth hormone secretagogue in rats.
The present study was undertaken to study the growth hormone-releasing properties and growth-promoting effect of a GH secretagogue ipamorelin (IPA) in rats given the synthetic glucocorticoid methylprednisolone (MP). In a first experiment, rats received either saline or MP (5.0 mg/kg) for 8 days. Treatment with MP significantly (P< 0.001) decreased body weight gain, but the acute response to either IPA or growth hormone releasing hormone (GHRH) in terms of plasma GH was not changed. In a second experiment, venous catheters were surgically implanted. On the next day, rats were randomly allocated to receive saline alone, MP alone (5.0 mg/kg) or MP plus IPA in doses of 0.4 or 1.6 mg/kg/day for 10 days. IPA was administered intravenously four times a day.MP treatment significantly (P< 0.05) retarded recovery from surgery in terms of body weight. Thus, saline treated animals lost 4.0 +/- 3.5 g over the entire experimental period, whereas animals receiving MP lost 13. 6 +/- 2.9 g. When IPA was given together with MP, losses in body weight were significantly (P< 0.05) reduced to 2.3 +/- 2.0 and 1.6 +/- 2.0 g in animals given the high and low dose of IPA, respectively. In parallel with this IGF-I levels increased. In conclusion, this work shows that MP does not disrupt the response of the GH-IGF-I axis to an exogenous stimulus like IPA, and repeated stimulation leads to increases in IGF-I and of body weight gain.
A stable meta-carborane enables the generation of boron-rich peptide agonists targeting the ghrelin receptor.
Boron neutron capture therapy (BNCT) is a binary cancer therapy, which combines the biochemical targeting of a boron-containing drug with the regional localization of radiation treatment. Although the concept of BNCT has been known for decades, the selective delivery of boron into tumor cells remains challenging. G protein-coupled receptors that are overexpressed on cancer cells in combination with peptidic ligands can be potentially used as shuttle system for a tumor-directed boron uptake. In this study, we present the generation of short, boron-rich peptide conjugates that target the ghrelin receptor. Expression of the ghrelin receptor on various cancer cells makes it a viable target for BNCT. We designed a novel hexapeptide super-agonist that was modified with different specifically synthesized carborane monoclusters and tested for ghrelin receptor activation. A meta-carborane building block with a mercaptoacetic acid linker was found to be optimal for peptide modification, owing to its chemical stability and a suitable activation efficacy of the conjugate. The versatility of this carborane for the development of peptidic boron delivery agents was further demonstrated by the generation of highly potent, boron-loaded conjugates using the backbone of the known ghrelin receptor ligands growth hormone releasing peptide 6 and Ipamorelin.
Peptidomimetic growth hormone secretagogue derivatives for positron emission tomography imaging of the ghrelin receptor.
The ghrelin receptor is a seven-transmembrane (7-TM) receptor known to have an increased level of expression in human carcinoma and heart failure. Recent work has focused on the synthesis of positron emission tomography (PET) probes designed to target and image this receptor for disease diagnosis and staging. However, these probes have been restricted to small-molecule quinalizonones and peptide derivatives of the endogenous ligand ghrelin. We describe the design, synthesis and biological evaluation of a series of 4-fluorobenzoylated growth hormone secretagogues (GHSs) derived from peptidic (GHRP-1, GHPR-2 and GHRP-6) and peptidomimetic (G-7039, [1-Nal4]G-7039 and ipamorelin) families in order to test locations for the insertion of fluorine-18 for PET imaging. The peptidomimetic G-7039 was found to be the most suitable for 18F-radiolabelling as its non-radioactive 4-fluorobenzoylated analogue ([1-Nal4,Lys5(4-FB)]G-7039), had both a high binding affinity (IC50 = 69 nM) and promising in vitro efficacy (EC50 = 1.1 nM). Prosthetic group radiolabelling of the precursor compound [1-Nal4]G-7039 using N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) delivered the PET probe [1-Nal4,Lys5(4-[18F]-FB)]G-7039 in an average decay-corrected radiochemical yield of 48%, a radio-purity ≥ 99% and an average molar activity of >34 GBq/μmol. This compound could be investigated as a PET probe for the detection of diseases that are characterised by overexpression of the ghrelin receptor.
Quick links (PubMed)
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