Gonadorelin

Snapshot: Hexarelin is a synthetic hexapeptide and potent growth hormone secretagogue that selectively activates GHS-R (ghrelin) receptors to simulate endogenous, pulsatile GH release. Preclinical studies suggest potential roles in cardiomyocyte protection under ischemic stress, metabolic and lipid-regulating pathways, skeletal muscle mass preservation, and organ-protective stress-response signalling. What Is Hexarelin? Hexarelin (examorelin) is a synthetic hexapeptide (His-D-2-Methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) belonging to the group of growth hormone secretagogues (GHS) [1]. It was developed as a selective GHS-R ghrelin receptor agonist to enhance the body’s natural growth-hormone output, rather than replace it with exogenous hormone [1]. Through high-affinity receptor binding in the hypothalamus and pituitary, hexarelin activates G-protein coupled signalling, intracellular calcium mobilization, and cAMP-linked pathways that support pulsatile GH release patterns [2]. The peptide incorporates non-natural amino acids including D-2-methyltryptophan, D-phenylalanine, and lysine amide, increasing resistance to enzymatic degradation and improving its pharmacokinetic stability [3]. It is metabolized in the liver with renal elimination and remains analytically detectable for up to 8 hours post-administration [3]. Hexarelin Peptide Benefits In addition to GH signalling, hexarelin is widely used in experimental and preclinical research to study cardiometabolic stress responses, intracellular calcium regulation, oxidative stress and inflammatory markers, and survival-associated pathways in cardiac and skeletal muscle models. Cardiovascular Protection Hexarelin activates two key receptors found directly in cardiac muscle and blood vessels, GHSR-1a receptor and CD36 [4]. Because these receptors are present in heart muscle cells themselves, many of hexarelin’s effects appear to come from local, tissue-level signalling inside the heart, rather than through increasing circulating growth hormone [4]. In many experimental models, hexarelin enhanced myocardial contractility. Hexarelin has been shown to improve intracellular calcium handling and activates downstream kinase pathway (including protein kinase C signalling), resulting in a positive inotropic effect without increasing heart rate or imposing excess hemodynamic load [4]. Hexarelin has also demonstrated cytoprotective effects under stress conditions, including heart failure, ischemia, and toxin exposure [4]. It attenuates cardiomyocyte and endothelial apoptosis, reduces DNA fragmentation, and promotes survival-associated signalling, thereby supporting the preservation of myocardial tissue over time [4]. In ischemic-reperfusion models, hexarelin reduced infarct size and improved recovery of post-ischemic ventricular performance, and heart conduction stabilization [4]. Chronic cardiovascular stress is a driver of fibrotic remodelling, and hexarelin seems to mitigate this process by downregulating collagen I and III expression, reducing profibrotic signaling, and enhancing metalloprotease activity – changes consistent with reduced myocardial stiffness and improved diastolic function [4]. Combined, these findings suggest hexarelin may help the heart contract more efficiently, withstand stress, and recover more efficiently following injury, with actions driven largely by its direct interaction with cardiac receptors [4]. Body Composition & Metabolic Health Hexarelin and related growth-hormone secretagogues have been investigated for their effects on lipid metabolism, insulin-resistance markers, skeletal muscle mass preservation, and cachexia-induced signalling pathways. In a study of healthy older adults, those with higher total fat mass, body fat percentage, BMI or bodyweight showed a smaller growth hormone response after a single dose of hexarelin [5]. Fat mass was the strongest predictor of response, while gender’s predictive effect was not significant once body composition was adjusted [5]. This trend occurred across a continuum, with even moderate increases in body fat linked to reduced GH response. This suggests higher adiposity can blunt GH-sectretagogue signalling [5]. Beyond hormone responsiveness, preclinical research indicates hexarelin may support metabolic resilience and cellular protection [6]. In models of chemically induced pancreatic beta-cell damage, hexarelin reduced mitochondrial injury, oxidative stress, and activation of cell-death pathways, while preserving beta-cell structure and insulin levels [6]. These findings suggest a potential role in protecting beta-cell mass under oxidative and metabolic stress conditions [6]. Additional animal models have shown improvements in glucose and insulin tolerance, lowered liver and plasma triglycerides, and enhanced fat-cell differentiation and lipid handling [7]. These improvements occurred without increases in total body weight and were accompanied by a shift toward lower fat mass and higher lean mass, despite increased food intake [7]. These effects may relate, in part, to CD36-linked lipid metabolism pathways [7]. Organ Protection Research across cardiac, metabolic, and skeletal muscle systems indicates that hexarelin may exert organ-protective effects. It is thought these effects occur through activation of survival- and stress-response pathways, modulation of fibrosis and remodelling signals, stabilization of intracellular calcium dynamics, and protection of mitochondrial function under metabolic or toxic stress [8, 9, 10, 6]. These effects are currently described within experimental frameworks and mechanistic investigations, rather than clinical outcome studies. 1 Carpino, P. A. (2002) Recent developments in ghrelin receptor (GHS-R1a) agonists and antagonists. Expert Opin. Ther. Pat., Informa Healthcare 12, 1599–1618 2 Imbimbo, B. P., Mant, T., Edwards, M., Amin, D., Dalton, N., Boutignon, F., et al. (1994) Growth hormone-releasing activity of hexarelin in humans. A dose-response study. Eur. J. Clin. Pharmacol., Springer 46, 421–425 3 Ghigo, E., Arvat, E., Gianotti, L., Imbimbo, B. P., Lenaerts, V., Deghenghi, R., et al. (1994) Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man. J. Clin. Endocrinol. Metab., The Endocrine Society 78, 693–698 4 Mao, Y., Tokudome, T. and Kishimoto, I. (2014) The cardiovascular action of hexarelin. J. Geriatr. Cardiol. 11, 253–258 5 Rahim, A., O’Neill, P. and Shalet, S. M. (1998) The effect of body composition on hexarelin-induced growth hormone release in normal elderly subjects. Clin. Endocrinol. (Oxf.), Wiley 49, 659–664 6 Zhao, Y., Zhang, X., Chen, J., Lin, C., Shao, R., Yan, C., et al. (2016) Hexarelin protects rodent pancreatic Β-cells function from cytotoxic effects of streptozotocin involving mitochondrial signalling pathways in vivo and in vitro. PLoS One, Public Library of Science (PLoS) 11, e0149730 7 Mosa, R., Huang, L., Wu, Y., Fung, C., Mallawakankanamalage, O., LeRoith, D., et al. (2017) Hexarelin, a growth hormone secretagogue, improves lipid metabolic aberrations in nonobese insulin-resistant male MKR mice. Endocrinology, Endocrinology 158, 3174–3187 8 Guan, C., Li, C., Shen, X., Yang, C., Liu, Z., Zhang, N., et al. (2023) Hexarelin alleviates apoptosis on ischemic acute kidney injury via MDM2/p53 pathway. Eur. J. Med. Res., Springer Science and Business Media LLC 28, 344 9 Rossoni, G., De Gennaro Colonna, V., Bernareggi, M., Polvani, G. L., Müller, E. E. and Berti, F. (1998) Protectant activity of hexarelin or growth hormone against postischemic ventricular dysfunction in hearts from aged rats. J. Cardiovasc. Pharmacol., Ovid Technologies (Wolters Kluwer Health) 32, 260–265 10 Zambelli, V., Rizzi, L., Delvecchio, P., Bresciani, E., Rezoagli, E., Molteni, L., et al. (2021) Hexarelin modulates lung mechanics, inflammation, and fibrosis in acute lung injury. Drug Target Insights, Aboutscience Srl 15, 26–33

What is LGF-LR3 peptide? Insulin-like Growth Factor 1 Long Arg3 (IGF-1 LR3) is a synthetic analog of human IGF-1, a naturally occurring peptide hormone that plays a critical role in growth, repair, and metabolic regulation. Structurally, IGF-1 LR3 consists of 83 amino acids, whereas native IGF-1 has 70 amino acids. IGF-1 LR3 has two additional key modifications: the substitution of arginine for glutamic acid at position 3, and the addition of a 13–amino acid extension at the N-terminus [1]. LGF These alterations significantly extend its half-life and reduce its binding affinity to IGF-binding proteins, enhancing its biological availability in circulation. LGF-LR3 benefits Anabolic benefits By activating IGF-1 receptors, LGF-LR3 can initiate various intracellular signaling pathways, including PI3K/Akt/mTOR and MAPK/ERK, which are central to [2, 3]: Cell proliferation Differentiation Protein synthesis, including in skeletal muscles IGF-1 stimulates satellite cell activation and differentiation, key processes for muscle hypertrophy and repair following injury or intensive exercise [4]. However, these effects have yet to be studied in LGF-LR3 specifically. LGF-LR3 enhances amino acid uptake, which can theoretically increase protein synthesis, and promotes the fusion of myoblasts into mature muscle fibers, contributing to muscle growth. An animal study examined whether infusion of IGF-1 LR3 could improve growth and metabolic parameters in fetuses affected by placental insufficiency and fetal growth restriction (FGR) [5]. Fourteen fetal sheep were divided into two groups: one receiving IGF-1 LR3 infusion (1.17  μg/kg·h) and a control group receiving only the vehicle over one week. Glucose-stimulated insulin secretion (GSIS) tests were performed at the end of the treatment period to assess β-cell function. Results showed: No significant difference in body weight between IGF-1 LR3-treated and control fetuses after one week of treatment. Baseline and post-treatment plasma insulin, glucose, and GSIS remained unchanged. IGF-1 LR3 treatment led to a significant decrease in circulating amino acid concentrations (p = 0.02). IGF-1 LR3 did not enhance fetal growth or insulin dynamics in growth-restricted fetuses under these experimental conditions. The observed decline in amino acid levels suggested possible increased tissue uptake or utilization, suggesting higher metabolic demand without adequate substrate availability. Supplemental amino acids, glucose, or oxygenation may be necessary to optimize IGF-1-mediated growth responses in FGR scenarios. Brain health and cognition IGF-1 LR3 has drawn increasing interest for its neuroprotective and cognitive-enhancing potential, reflecting the broader role of IGF signaling in the central nervous system (CNS). Endogenous IGF-1 is widely expressed in both neurons and glial cells [6]. A study in 5XFAD mice (a transgenic model that rapidly develops amyloid-β (Aβ) pathology of Alzheimer’s disease) evaluated whether intranasal LR3-IGF-1 could mitigate cognitive decline and reduce AD-related pathology [7]. Wild-type and 5XFAD mice were treated intranasally with LR3-IGF-1 or vehicle solution from 3 to 10 months of age. Results showed that LR3-IGF-1 treatment: Did not significantly improve cognitive performance in 5XFAD mice despite long-term treatment. Altered Aβ plaque morphology by reducing filamentous (toxic) plaques and increasing inert, less harmful forms. Enhanced Aβ1–42 uptake by microglia and upregulated genes related to actin remodeling and endocytosis, indicating improved microglial clearance function. Improved body composition, suggesting systemic anabolic activity. Although LR3-IGF-1 did not prevent cognitive decline, it produced measurable benefits in amyloid plaque remodeling and microglial function, implying a partial neuroprotective effect at the cellular level. While human data remain limited, these findings point to IGF-1 LR3 as a promising anti-aging agent for the brain. Energy metabolism and glucose regulation IGF-1 LR3 plays a pivotal role in energy balance and glucose metabolism, closely mirroring the physiological actions of insulin. An animal study explored how short-term exposure to IGF-1 LR3 affects insulin secretion dynamics [8]. Ten fetal sheep were infused intravenously for 90 minutes with either IGF-1 LR3 (n = 5) or vehicle control (n = 5). Results showed that: Plasma insulin levels dropped approximately 66% during IGF-1 LR3 infusion (p < 0.0001). Isolated islets from IGF-1 LR3-treated fetuses displayed normal insulin release when exposed to glucose or potassium chloride, indicating recovery of β-cell function. Acute IGF-1 LR3 infusion transiently suppressed insulin secretion in vivo, without damaging β-cells. This suggests that the inhibitory effects are reversible and may have therapeutic use for intrauterine growth restriction (IUGR) or metabolic modulation during development.

What Is Ipamorelin Peptide and What Is It Used For? Ipamorelin is a synthetic pentapeptide that stimulates the pituitary to release growth hormone (GH). Since its discovery in 1998, it has gained a lot of attention as the first selective GH secretagogue. It stimulates GH release without affecting other pituitary hormones such as adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, and prolactin. Ipamorelin has primarily been researched preclinically for muscle gain and weight loss, as well as for counteracting corticosteroid side effects and postoperative complications [1]. Ipamorelin Benefits Ipamorelin has an intriguing mechanism of action that mimics some aspects of ghrelin (hunger hormone). It’s a selective agonist, which activates the ghrelin receptor pathway [2]. This interaction activates GH release from the pituitary gland, essentially initiating anabolic processes, including: Appetite regulation Fat metabolism and lipolysis Energy utilization on the whole In rodents, ipamorelin increases appetite, hunger, and caloric intake, suggesting that it may be helpful in patients with cachexia or other conditions where weight gain is beneficial [3]. However, in humans, its effect on appetite appears to vary between individuals. Bodybuilding and Muscle Growth Ipamorelin-induced GH may act on muscles through insulin-like growth factor-1 (IGF-1) to increase muscle protein synthesis, inhibit protein degradation, stimulate satellite cell activity, and counteract myostatin signals [4]. In rats treated with glucocorticoid (GC), ipamorelin significantly increased maximum muscle tension and the rate of periosteal bone formation by fourfold [5]. These findings suggest that ipamorelin may mitigate the decline in muscle strength and bone formation typically observed in GC-treated rats. In young rats, chronic administration of ipamorelin does not lead to desensitization of the GH response, helping to increase body weight. However, chronic administration of ipamorelin on pituitary cell culture did lead to a dampened GH response over time, suggesting a desensitization response [6]. Bone Health GH is essential for linear body growth during childhood, bone remodeling throughout life, and bone preservation in aging adults. GH and its downstream effector IGF-1 are central to skeletal growth and homeostasis. They activate osteoblasts and increase calcium storage and bone collagen. In adult rats, 12 weeks of continuously administered ipamorelin significantly increased body weight, bone mineral content, and femur and vertebra L6 bone volume [6]. Another rat study found that ipamorelin increased linear growth rate and body weight in a dose-dependent manner. However, the ipamorelin treatment did not alter levels of IGF-1, IGFBPs, or serum markers of bone formation or resorption [7]. Body Weight The effect of ipamorelin on weight has been paradoxical. Although GH is a crucial hormone for weight loss, most rodent studies found that ipamorelin assists with weight and body fat gain. Ipamorelin has been shown to exert effects beyond muscle mass regulation. Experimental studies demonstrated that it significantly increased insulin secretion (p < 0.04) from the pancreas in both normal and diabetic rats. These findings suggest that ipamorelin may influence glucose metabolism and insulin-dependent anabolic processes [8]. Gut Health and Pain Ipamorelin demonstrated gastrointestinal effects that are mediated through activating ghrelin receptors. In a rodent model of postoperative ileus, a painful bowel paralysis after surgery, ipamorelin was shown to accelerate gastric emptying by enhancing gastric contractility [9]. A clinical trial on 114 patients who had undergone bowel resection surgery compared twice-daily ipamorelin administration with placebo to assess its effects on shortening the time to the first solid meal. Although there was no statistically significant difference between ipamorelin and the placebo, no safety concerns were observed [10]. Ipamorelin Side Effects In a Phase 2 placebo-controlled trial, ipamorelin had lower but nonsignificant differences in incidents of side effects than placebo (87.5% in the ipamorelin group vs. 94.8% in the placebo group) [10]. Adverse effects observed in this trial included headache, gastrointestinal symptoms, and injection site reactions. The study did not report severe side effects specific to ipamorelin. The one report of risk for immunogenicity was linked to a production-related impurity in an IV administration [11].