HGH Fragment 176-191

HGH Fragment 176-191 (AOD-9604) is a modified synthetic peptide fragment derived from the C-terminal region of human growth hormone (amino acids 176-191) that was developed to isolate the fat-reducing properties of HGH without its growth-promoting or insulin-antagonistic effects. This peptide stimulates lipolysis (fat breakdown) and inhibits lipogenesis (fat formation) by upregulating beta-3 adrenergic receptors in adipose tissue, which enhances fat oxidation and energy expenditure. While preclinical studies in rodents demonstrated significant reductions in body weight and fat mass, human clinical trials showed mixed results, with some short-term trials showing modest weight loss (2.6 kg over 12 weeks) but larger long-term trials failing to demonstrate statistically significant efficacy, leading to termination of its development as an approved obesity treatment in 2007. Despite not receiving regulatory approval for weight loss, the peptide has shown excellent safety and tolerability profiles across multiple clinical trials involving over 900 participants, with emerging research exploring potential applications in cartilage regeneration and osteoarthritis treatment.

Fat Loss and Lipolytic Activity

HGH Fragment 176-191 demonstrates significant fat-reducing effects through selective activation of lipolysis in adipose tissue. In preclinical studies, chronic administration of AOD-9604 reduced body weight gain by over 50% in obese Zucker rats compared to controls (15.8 ± 0.6 vs. 35.6 ± 0.8 g) over 19 days of treatment ^[1][3]. The peptide increased fat oxidation and plasma glycerol levels in obese mice following 14 days of chronic intraperitoneal administration ^[2][4]. Importantly, the lipolytic effects correlated with increased expression of beta-3 adrenergic receptor (β3-AR) RNA in adipose tissue, with both human GH and AOD-9604 elevating the repressed levels of β3-AR RNA in obese mice to levels comparable with lean mice ^[4]. Studies in β3-AR knockout mice confirmed that the lipolytic actions are mediated through this receptor pathway, as long-term treatment failed to produce weight changes in knockout mice that were observed in wild-type controls ^[4].

Metabolic Benefits Without Growth Hormone Side Effects

Unlike full-length human growth hormone, HGH Fragment 176-191 provides metabolic benefits without adverse effects on glucose metabolism or IGF-1 levels. Multiple studies confirmed that AOD-9604 showed no adverse effect on insulin sensitivity in treated animals, as measured by euglycemic clamp testing ^[1][3]. The peptide did not stimulate production of IGF-1 in any of the systems studied and had no effect on serum IGF-1 levels in human clinical trials ^[6]. While full-length HGH caused hyperglycemia and reduced insulin secretion, AOD-9604 avoided these untoward effects ^[2]. Six randomized, double-blind, placebo-controlled human trials involving 893 participants demonstrated that AOD-9604 had no harmful effects on carbohydrate metabolism, insulin resistance, decreased glucose tolerance, or increased IGF-1 levels ^[6].

Cartilage Regeneration and Joint Health

Emerging research suggests potential benefits for cartilage regeneration and osteoarthritis treatment. In a rabbit osteoarthritis model, intra-articular injections of AOD-9604 enhanced cartilage regeneration, with combined AOD-9604 and hyaluronic acid injections proving more effective than either treatment alone ^[5]. The combination therapy produced significantly better gross morphological and histopathological scores and resulted in significantly shorter lameness periods compared to control groups ^[5]. In vitro studies demonstrated that AOD-9604 enhances differentiation of adipose mesenchymal stem cells into bone, promotes proteoglycan and collagen production in isolated bovine chondrocytes, and promotes differentiation of myoblasts ^[5]. These findings suggest potential therapeutic applications beyond fat loss, including joint health and tissue regeneration.

Safety Profile and Clinical Tolerability

AOD-9604 demonstrated an excellent safety and tolerability profile across multiple clinical trials. Six randomized, double-blind, placebo-controlled studies showed that AOD-9604's safety profile was indistinguishable from placebo ^[6]. No treatment-related serious adverse events or study withdrawals occurred in any trials, and no anti-AOD-9604 antibodies were detected in any participants ^[6]. The most commonly reported adverse effects were mild, with headache (6 instances), fatigue (4), and dizziness (3) being most frequent, all equally distributed between AOD-9604 and placebo groups ^[6]. Non-clinical studies revealed no evidence of genotoxicological or toxicological concerns, with the no-observed-adverse-effect level (NOAEL) for rats at ≥100 mg/kg/day and for cynomolgus monkeys at 50 mg/kg/day ^[6].

Clinical Safety Profile

HGH Fragment 176-191 (AOD-9604) has demonstrated excellent safety and tolerability in human clinical trials. Between 2001 and 2007, six randomized, double-blind, placebo-controlled trials involving approximately 893-900 healthy, clinically obese adults evaluated the peptide's safety across dosing ranges from 25-400 µg/kg intravenously to 0.25-54 mg orally, with administration periods up to 24 weeks ^[6]. The overall safety profile was described as "indistinguishable from placebo" with no treatment-related serious adverse events or study withdrawals ^[6]. The most frequently reported adverse effects were mild in intensity, including headache (6 cases), fatigue (4), hypoglycemia unspecified (3), dizziness (3), nasopharyngitis (2), and cough (2), with single instances of lethargy, tonsillitis, abdominal pain, injection site reactions, sore throat, injection site bruising, seasonal rhinitis, anorexia, and injection site pain ^[6]. Critically, none of the adverse events were of severe intensity, and the incidence was equally distributed between various concentrations of AOD-9604 and placebo treatment groups ^[6].

Absence of Growth Hormone-Related Side Effects

A key safety advantage of HGH Fragment 176-191 is the absence of adverse effects typically associated with full-length human growth hormone. AOD-9604 did not result in any growth hormone-related adverse effects, specifically showing no effect on serum IGF-1 levels throughout clinical trials ^[6]. Unlike full-length HGH, AOD-9604 demonstrated no negative effects on carbohydrate metabolism, glucose tolerance, or insulin sensitivity ^[1][3][6]. No anti-AOD-9604 antibodies were detected in any patients selected for antibody assay, indicating no immunogenic concerns ^[6]. Studies confirmed that while full-length HGH induced hyperglycemia and reduced insulin secretion, AOD-9604 avoided these metabolic disturbances ^[2]. The peptide's selective action on adipose tissue without affecting the growth hormone receptor prevents the systemic effects associated with traditional HGH therapy ^[4].

Non-Clinical Toxicology

Comprehensive non-clinical safety studies revealed no evidence of genotoxicological or toxicological concerns regarding AOD-9604 safety ^[6]. Multiple genotoxicity assays including Ames testing, chromosomal aberration assays, and micronucleus testing showed no evidence of genotoxic activities . Chronic toxicity studies demonstrated that the peptide was generally safe after chronic oral application in animal models . The no-observed-adverse-effect level (NOAEL) for rats under chronic conditions was determined to be at least 100 mg/kg/day, while for cynomolgus monkeys, chronic dose levels up to 50 mg/kg/day were considered as NOAEL ^[6]. Extended toxicity studies in rats (6 months) and cynomolgus monkeys (9 months) confirmed the substance was safe with sustained administration .

Pharmacokinetics and Metabolism

Pharmacokinetic studies revealed that AOD-9604 has a very short half-life of approximately 3 minutes following intravenous administration in humans, with rapid degradation kinetics . The peptide demonstrated good oral absorption (approximately 40% oral bioavailability in rat radiography studies) and was rapidly broken down in the body, with the major degradation pathway involving sequential N-terminal amino acid removal . Studies in pigs confirmed that AOD-9604 was well absorbed when administered orally and distributed similarly across organs regardless of administration route (oral or injection) . The rapid metabolism and clearance contribute to the peptide's safety profile by limiting systemic exposure and accumulation.