HGH Fragment 176-191 5mg Peptide

HGH Fragment 176-191 is the last sixteen residues of human growth hormone, cut away from the rest of the hormone and made by solid-phase synthesis. Mature hGH is a 191-residue single chain (UniProt P01241); residues 176 to 191 are Phe-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe. The two cysteines are Cys182 and Cys189, which form the smaller of the two native disulfide bonds in hGH, so the fragment carries the intact C-terminal loop of the parent hormone rather than a linear offcut of it.

The region was mapped by Frank Ng's group, first at the University of Melbourne and later at Monash, across roughly twenty-five years of structure-activity work. That work began by asking which part of growth hormone antagonises insulin, and only later reframed the same stretch of sequence as the lipolytic and antilipogenic domain. Metabolic Pharmaceuticals took the reframed version into development in Australia as AOD9401 and then AOD9604.

The compound sold under this name and the compound that carries almost all of the published metabolic data are not the same molecule. That distinction is the single most useful thing to understand about this fragment, and it is covered in detail below.

The defining observation is a negative one: the C-terminal fragment does not work through the growth hormone receptor. In BaF-B03 cells transfected with the hGH receptor, AOD9604 did not compete with radioiodinated hGH for binding and did not drive proliferation, while intact hGH did both (Heffernan et al., International Journal of Obesity, 2001). Anything the fragment does to an adipocyte therefore happens downstream of, or beside, the receptor that mediates the growth-promoting arm of the hormone.

At the enzyme level the fragment reproduces two of the hormone's actions on fat. In isolated rat adipose tissue, AOD9401 (the synthetic hGH 177-191 sequence) stimulated hormone-sensitive lipase, inhibited acetyl-CoA carboxylase and mimicked the effect of intact hGH on diacylglycerol release from adipocytes (Ng et al., Journal of Molecular Endocrinology, 2000). Acetyl-CoA carboxylase catalyses the committed step of de novo fatty acid synthesis, so inhibiting it is what the older literature meant by antilipogenic.

A related fragment effect runs through glucose entry into the fat cell. In adipocytes isolated from genetically obese Zucker rats, synthetic hGH 177-191 reduced both basal and insulin-stimulated uptake of 2-deoxyglucose, and did so more potently than intact hGH at equimolar concentrations (Wijaya and Ng, Biochemistry and Molecular Biology International, 1993). Less glucose entering the adipocyte means less substrate for lipogenesis, which is a plausible part of the antilipogenic result rather than a separate mechanism.

The beta-3 adrenergic receptor is involved but is not the target. Fourteen days of intraperitoneal hGH or AOD9604 in ob/ob mice raised beta-3 adrenergic receptor mRNA in adipose tissue from the suppressed obese level back to the level seen in lean mice. In beta-3 adrenergic receptor knockout mice, chronic treatment with either compound failed to reduce body weight or raise lipolysis, yet a single acute administration of AOD9604 still increased energy expenditure and fat oxidation in those same knockout animals (Heffernan et al., Endocrinology, 2001). The authors concluded that the lipolytic action is not transduced directly by beta-3 adrenergic receptors, and that the receptor upregulation is a permissive change that lets the chronic effect accumulate.

This catalogue lists both compounds, and they are routinely bought as though they were interchangeable. They are two different molecules with two different CAS numbers. HGH Fragment 176-191 is Phe-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe, the native hGH sequence, CAS 66004-57-7. AOD9604 is Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe, CAS 221231-10-3: a tyrosine standing in place of Phe176 at the N-terminus of the same fifteen-residue core. One hydroxyl group, 16 daltons, is the whole chemical difference.

The tyrosine was not cosmetic. It was put there so the peptide could be radioiodinated for tracer and pharmacokinetic work, which is standard practice for peptides that lack a tyrosine of their own, and the substitution then became part of the development candidate. A third designation appears in the same papers: AOD9401 is hGH 177-191, the fifteen-residue core with neither a phenylalanine nor a tyrosine at the front.

Confusion about which is which is not confined to sellers. Review articles on growth hormone axis peptides have printed 'AOD9604 (hGH 176-191)' as a single entry, collapsing the two names onto one molecule. The definition to trust is the one the anti-doping analytical literature uses, because those laboratories have to tell the two apart on a mass spectrometer: Cox and colleagues state it as hGH residues 177-191 with an additional tyrosine at the N-terminus.

The C-terminal region of hGH was not discovered as a fat-loss domain. It was discovered as an insulin antagonist. Ng and Bornstein synthesised six overlapping peptides, hGH 172-191, 176-191, 177-191, 178-191, 179-191 and 180-191, and gave them to normal rats at 5 nmol/kg. The four longest, including 176-191, produced a short-lived rise in blood glucose and a more sustained rise in plasma insulin. The two shortest were inert. A single dose of any peptide containing residues 178 to 191 significantly reduced insulin sensitivity on intravenous insulin tolerance testing (American Journal of Physiology, 1978).

Wade and colleagues then trimmed the other end. Six C-terminally shortened versions of the reduced and S-carbamidomethylated 177-191 peptide were assayed for insulin-antagonistic activity in rats. Truncating to 177-180, 177-185, 177-187 or 177-189 abolished the effect even at a hundred times the active dose, which placed the insulin-antagonistic core at residues 178 to 190 inclusive (Acta Endocrinologica, 1982). The same group's conclusion in 1978 still holds: the peptide needs both the minimum informational sequence and the correct physical configuration, which in practice means the Cys182 to Cys189 loop closed.

The reframing came a decade later. Wu and Ng reported in 1993 that synthetic hGH 177-191 had antilipogenic activity identical to that of intact hGH, and, in the same experiments, no significant lipolytic effect as judged by glycerol release from epididymal fat pads of treated rats. Their reading was that the physiological action of growth hormone on lipid metabolism sits at the level of lipogenesis rather than lipolysis. Natera and colleagues followed in 1994 with long-term hGH 177-191 in ob/ob mice, reporting reduced cumulative body weight gain, reduced adipose tissue mass and inhibited adipose lipogenesis.

Reading the primary papers in order produces an uncomfortable result. The only published in vivo study that administered the 176-191 sequence itself is Ng and Bornstein 1978, and what it reported was hyperglycaemia and reduced insulin sensitivity, not lipolysis.

Every one of the metabolic studies that vendors cite for this product used a different peptide. Wu and Ng 1993, Wijaya and Ng 1993, Natera 1994, Ng 2000 in the Journal of Molecular Endocrinology and Heffernan 2000 in the American Journal of Physiology all used hGH 177-191 or its development designation AOD9401. Ng 2000 in Hormone Research and both 2001 Heffernan papers used AOD9604, the tyrosine analogue. None of them used FLRIVQCRSVEGSCGF.

This is not a reason to dismiss the fragment. A single conservative aromatic residue at the N-terminus of a sixteen-mer whose active core is residues 178 to 190 is unlikely to abolish the activity, and the 1978 series showed that the 176-191 and 177-191 peptides behaved alike in the assay they were run in. It is a reason to be exact about what has and has not been demonstrated for the material in the vial, and to treat any page that presents the AOD9604 rodent data as data on this fragment as having skipped a step.

There is no PubMed-indexed clinical trial of hGH 176-191 in humans. There is no ClinicalTrials.gov registration for AOD9604 or for the fragment under any spelling: a search of the registry returns zero studies. The trials that did happen predate the registration norms that would have captured them and were run by a company that reported through announcements rather than journals.

What exists is a retrospective safety analysis. Stier, Vos and Kenley described six randomised, double-blind, placebo-controlled trials of AOD9604 in the Journal of Endocrinology and Metabolism in 2013: no effect on serum IGF-1, no anti-AOD9604 antibodies in the participants assayed, no withdrawals or serious adverse events attributed to the compound, and a tolerability profile the authors described as indistinguishable from placebo. A companion 2014 paper by Moré and Kenley described the programme as two intravenous and two oral pilot studies plus two Phase 2b efficacy studies in roughly 300 and 500 obese adults, with pig pharmacokinetics giving an intravenous half-life near three minutes, an oral time-to-peak of about 60 minutes and oral bioavailability near 40 percent. Neither paper is indexed in PubMed.

The efficacy story is short. Wilding's 2004 review in Current Opinion in Investigational Drugs records only that Phase 2a trials were under way by February 2002. The larger Phase 2b readout in 2007 did not support continued development for the obesity indication, and the sponsor's own account is that the body weight effect seen in the earlier studies was not reproduced in the final study, which added an intensive diet and exercise programme to both arms. A compound that separates from placebo in sedentary participants and does not separate once both arms are dieting and exercising is a compound whose effect size is small relative to the intervention it would have to compete with.

The Cys182 to Cys189 bond is the handling variable that matters. Oxidised and reduced forms of the same sixteen-mer differ by two daltons, 1,799.1 against 1,801.1, and a certificate of analysis that reports one while the material in the vial is the other is reporting the wrong molecule. Repeated freeze-thaw cycles and prolonged exposure to alkaline aqueous buffer both favour thiol-disulfide exchange, which is why lyophilised material is held sealed and desiccated at -20 °C and aqueous solutions are kept cold and used promptly rather than stored.

Mass spectrometry is the only assay that separates this fragment from AOD9604 cleanly, because the two co-elute closely on reversed-phase HPLC and differ by a single oxygen. A purity figure by HPLC alone says nothing about which of the two sequences was synthesised. Vanhee and colleagues made exactly this point when they characterised AOD9604 in vials seized by the Belgian authorities, using orthogonal methods to establish identity rather than relying on the label (Drug Testing and Analysis, 2014).

Cox and colleagues incubated AOD9604 in human serum and urine and identified six candidate metabolites, of which the nonapeptide CRSVEGSCG was markedly more stable than either the parent peptide or the other fragments, and validated a solid-phase extraction method in urine with a detection limit of 50 pg/mL (Drug Testing and Analysis, 2015). The parent compound clears too fast to be a useful analytical target on its own, and the same short residence time is why the rodent work relied on osmotic pumps and repeated daily administration rather than intermittent dosing.

Both compounds are prohibited in sport at all times. The World Anti-Doping Agency lists growth hormone fragments under section S2.2.3 of the Prohibited List and names AOD-9604 and hGH 176-191 explicitly as examples. They are non-specified substances, which sets the default sanction at the higher end. Orlovius and colleagues showed in 2013 that AOD-9604 does not interfere with the WADA hGH isoform immunoassay, so a negative isoform test says nothing about fragment use; detection requires the dedicated mass spectrometry methods described above.

Neither compound has ever been registered as a medicine in any jurisdiction. In December 2024 the United States Food and Drug Administration's Pharmacy Compounding Advisory Committee reviewed AOD-9604 free base and AOD-9604 acetate for inclusion on the 503A bulk drug substances list and recommended against listing, with the agency's assessment citing incomplete physicochemical characterisation, immunogenicity concerns arising from impurities and aggregates, and an absence of published human exposure data for the routes proposed. The nominations for several peptides including AOD-9604 had been withdrawn earlier that year, and the agency continued its evaluation on its own initiative.

Volta Peptides supplies HGH Fragment 176-191 for laboratory research only. It is not a medicine, not a supplement and not for human or veterinary administration.