HGH Fragment 176-191: Side Effects

Safety Notice#

The safety profile of HGH Fragment 176-191 in humans has not been established through controlled clinical trials. The information below is derived primarily from animal studies and should be interpreted accordingly.

Documented Adverse Effects#

Animal Study Safety Data#

We reviewed toxicology data for human growth hormone fragment 176–191 (AOD9604), focusing on acute toxicity (LD50), organ toxicity from repeat‑dose studies, mutagenicity/genotoxicity assays, and dose‑response relationships including NOAEL/LOAEL. Evidence derives from a GLP preclinical package summarized by Moré and Kenley (2014) and associated study descriptions therein (rats: IV 4 weeks; rats: oral 26 weeks; cynomolgus monkeys: oral 39 weeks; in vitro Ames and CHO chromosome aberration assays; in vivo rat bone‑marrow micronucleus), plus accompanying PK/ADME observations (pigs and rats).

Acute toxicity (LD50) • No LD50 values were reported in the accessible preclinical dossier; no acute lethality was observed within the described repeated‑dose studies up to tested dose levels (e.g., rats IV up to 10 mg/kg/day for 28 days; rats oral up to 100 mg/kg/day for 26 weeks; monkeys oral up to 50 mg/kg/day for 39 weeks).

Repeat‑dose organ toxicity • Rats, IV, 4 weeks: Wistar rats (10/sex/group; controls 5/sex) received 0.1, 1, or 10 mg/kg/day IV. No deaths or clinical signs occurred. Females showed reduced body‑weight gain at 1 and 10 mg/kg/day; males at 10 mg/kg/day had reduced thymus mass and cortical width on pathology. No anti‑AOD9604 antibodies were detected. A bone‑marrow micronucleus assessment embedded in this study showed slight increases at some doses (0.1 and 10 mg/kg/day) without a clear dose relationship. • Rats, oral, 26 weeks: Han Wistar rats (12/sex/group) received 0, 0.5, 20, or 100 mg/kg/day by oral gavage. There were no unscheduled deaths or treatment‑related clinical signs. Intermittent laboratory deviations were noted (e.g., lower lymphocytes; modest increases in urea/creatinine/triglycerides; changes in osteocalcin) but lacked consistent dose relationships or corroborating pathology, and were deemed not toxicologically significant. • Cynomolgus monkeys, oral, 39 weeks: Groups of approximately 7/sex received 0, 0.5, 10, or 50 mg/kg/day by oral gavage. No treatment‑related macroscopic or histologic findings were identified. At week 39, treated males exhibited statistically lower covariate liver mass and lower liver glycogen; minimal periportal vacuolation occurred sporadically in both control and treated animals without dose‑dependence. No anti‑AOD9604 antibodies were detected.

Mutagenicity/genotoxicity testing • Ames bacterial reverse‑mutation: Using strains TA1535, TA1537, TA98, TA100, and WP2 uvrA with plate incorporation and pre‑incubation up to 2,000 µg/plate, results were largely negative. A slight, isolated increase in revertants occurred in WP2 uvrA in one pre‑incubation with S‑9 at 200 and 1,000 µg/plate without dose–response and was not reproduced; overall interpretation was non‑mutagenic. • In vitro chromosome aberration (CHO cells): Across concentrations (e.g., 20–200 µg/mL) with and without S‑9, no consistent or biologically meaningful increase in chromosomal aberrations was observed; an isolated increase at 100 µg/mL occurred without a consistent pattern. Polyploidy and cytotoxicity were observed at high/precipitating concentrations. • In vivo bone‑marrow micronucleus (rats): Slight increases in micronucleated erythrocytes were observed at some IV dose levels (0.1 and 10 mg/kg/day) without a monotonic dose–response and without evidence of bone‑marrow cytotoxicity; the overall interpretation was no genotoxicological concern. • Comet assay: Not described in the accessible materials; therefore no conclusion can be drawn for DNA strand‑break assays.

Dose‑response relationships, NOAEL/LOAEL • Rats, IV, 4 weeks: Body‑weight gain reductions in females at 1–10 mg/kg/day and thymic changes in males at 10 mg/kg/day indicate some threshold for systemic effects with daily IV dosing; a formal NOAEL/LOAEL was not explicitly designated in the accessible text. • Rats, oral, 26 weeks: No toxicologically significant, dose‑related organ pathology up to 100 mg/kg/day; the narrative indicates a NOAEL at least 100 mg/kg/day under the study conditions. • Cynomolgus monkeys, oral, 39 weeks: No dose‑related organ pathology up to 50 mg/kg/day; findings (e.g., lower covariate liver mass/glycogen in males) lacked dose dependence. The narrative supports a NOAEL at least 50 mg/kg/day. • Exposure considerations: Extremely rapid IV clearance (t1/2 ~3–4 min in pigs) and rapid plasma degradation likely limit systemic exposure; oral administration produced measurable exposure in pigs and rats with extensive first‑pass degradation and tissue localization (pancreas, pineal, thyroid, liver, kidney cortex).

Key study summary table

Conclusions Within the accessible preclinical dossier, AOD9604 did not demonstrate mutagenic or clastogenic activity in standard Ames and CHO chromosome aberration assays, and in vivo micronucleus findings were slight and inconsistent without a dose–response, leading to an overall assessment of no genotoxic concern. Repeat‑dose studies showed no treatment‑related organ pathology in 26‑week rat oral and 39‑week cynomolgus oral studies at doses up to 100 and 50 mg/kg/day, respectively; a NOAEL was at least equal to the highest doses tested in those studies. An IV 4‑week rat study noted reduced female body‑weight gain at 1–10 mg/kg/day and thymic changes at 10 mg/kg/day, indicating some dose‑related systemic effects under daily IV administration. No LD50 was reported in the accessible sources, and no acute lethality was observed at the reported dose ranges. Limitations include lack of explicit acute LD50 testing results, absence of Comet assay data, and incomplete numeric details for some clinical pathology and immunogenicity outputs in the public summary.

Human Safety Reports#

Human reports summarized in secondary sources describe six clinical trials (intravenous and oral; including two phase IIb trials in obese adults) in which AOD‑9604 was generally well tolerated. Reported adverse events were typically mild—headache, fatigue, and injection‑site reactions—and were comparable to placebo. No changes in glucose tolerance or serum IGF‑1 were reported in these summaries. However, numerical frequencies (%) and severity grading were not available in the accessible excerpts of the primary reports; a dedicated safety/tolerability paper is cited but not retrieved here.

Details by evidence domain.

• Rats, 28‑day IV toxicity (0.1, 1, 10 mg/kg/day): No deaths or clinical toxicity. Females exhibited reduced body‑mass gain at 1 and 10 mg/kg/day; males had reduced thymus mass at 10 mg/kg/day. Slight increase in micronucleus formation at 0.1 and 10 mg/kg without a dose–response; anti‑AOD‑9604 antibodies not detected. No numerical incidence (%) reported.
• Rats, 6‑month oral gavage (0.5–100 mg/kg/day): No unscheduled deaths. Laboratory deviations included decreased lymphocytes in females at 0.5/20/100 mg/kg/day and increased urea (0.5/20/100) plus increased creatinine and triglycerides at 100 mg/kg/day in males; investigators judged these not dose‑related and without toxicological importance. No frequencies reported.
• Cynomolgus monkeys, up to 9‑month oral dosing (≤50 mg/kg/day): No treatment‑related clinical signs, ECG, ophthalmic, hematologic/biochemical, urinary, or histopathologic abnormalities. Minor findings included statistically lower liver glycogen and minimal periportal vacuolation inconsistently across groups, considered minor and not clearly drug‑related; no immunogenicity detected. No frequencies reported.
• Genotoxicity assays: Ames negative up to 2,000 µg/plate; CHO chromosomal assay largely negative with a single significant aberration at 100 µg/mL in one harvest; in vivo micronucleus showed slight increases at 0.1 and 10 mg/kg without dose–response. High‑concentration in vitro cytotoxicity/precipitation noted; overall judged non‑genotoxic.
• Human trials (summarized): Six trials (IV and oral; phase IIb cohorts ~300 and ~500 participants) report AOD‑9604 was safe and well tolerated; adverse events generally mild (headache, fatigue, injection‑site reactions), with no deterioration in glucose tolerance or IGF‑1; frequencies and severity grading not available in accessible excerpts.

Limitations. The accessible human data are secondary summaries that do not provide numerical adverse‑event frequencies or severity grading. The dedicated human safety paper (Stier et al., 2013) is referenced but not retrieved here; thus, precise incidence rates cannot be reported from the present context.

Conclusion. In animals, AOD‑9604 demonstrates a benign safety profile at high repeated doses, with isolated, generally mild and non–dose‑related findings (reduced body‑mass gain, thymus mass reduction, transient laboratory changes) and negative genotoxicity overall. In humans, short‑term trials report mild adverse events comparable to placebo and no effects on glucose tolerance or IGF‑1, but frequency and severity grading were not extractable from available summaries. Future work should consult the primary clinical safety reports to quantify AE rates and grades.

Contraindications#

Summary of known/reported information

• Contraindications: No explicit clinical contraindications were identified in the available safety/metabolism review or obesity pharmacotherapy reviews for AOD-9604. The cited clinical and preclinical programs reported it as safe and well tolerated, but did not publish formal contraindication lists.
• Drug–drug interactions: No formal drug–drug interaction (DDI) studies or reported clinical DDIs were found. Available reviews and trial summaries did not report metabolism-based interactions or interaction testing.
• Mechanism and PK points relevant to interactions: AOD-9604 is a C‑terminal hGH fragment that promotes lipolysis and inhibits lipogenesis. In systems studied it did not stimulate IGF‑1 production, and in contrast to full-length hGH, it did not induce insulin resistance in reported experiments. It is orally bioavailable but undergoes rapid enzymatic degradation with very short IV half‑life and rapid clearance, suggesting a low likelihood of CYP-mediated pharmacokinetic interactions.

Theoretical (mechanism-based) interactions and precautions Given the absence of published DDI studies, the following potential interactions are inferred from pharmacology and physiology and should be considered precautionary:

• Antidiabetic agents (insulin, sulfonylureas) and GLP‑1 receptor agonists: Because AOD‑9604 exerts metabolic effects without inducing insulin resistance, concurrent use with glucose-lowering therapies could theoretically augment glycemic effects. Monitor glucose closely when initiating or adjusting AOD‑9604 in patients on insulin or insulin secretagogues; hypoglycemia risk may increase if weight loss or improved insulin sensitivity occurs.
• Systemic corticosteroids: Glucocorticoids promote hyperglycemia and lipogenesis, potentially opposing the lipolytic/antilipogenic actions of AOD‑9604 and destabilizing glycemic control. Monitor weight, glycemia, and metabolic markers if combined.
• Sympathomimetics/beta‑agonists: These can increase lipolysis and metabolic rate; combined use may produce additive metabolic and cardiovascular effects (tachycardia, tremor) in sensitive patients; use caution in cardiovascular disease.
• Thyroid hormone: Thyroid replacement or suppression therapy alters basal metabolic rate; co‑administration may enhance catabolism and necessitate clinical monitoring of thyroid status and symptoms. This is a pharmacodynamic consideration; no PK interaction is expected.
• Lipid‑lowering drugs (statins, fibrates): AOD‑9604 affects lipid handling in preclinical studies; additive effects on lipid profile are possible, but PK interactions are unlikely. Monitor lipids to assess combined efficacy.
• Anticoagulants (warfarin/DOACs) and other narrow therapeutic index drugs: No mechanism suggests a PK interaction because AOD‑9604 is rapidly degraded as a peptide and is not a CYP modulator. However, given the absence of formal DDI studies, adopt routine monitoring when therapy is started or stopped.

Precautionary contraindications and populations

• Although explicit contraindications were not found, general peptide hormone precautions are reasonable: avoid use in pregnancy/lactation and active malignancy unless under specialist oversight; data are limited and efficacy for weight loss was not established in pivotal trials.

Mechanistic distinctions from full-length hGH

• Unlike hGH, AOD‑9604 did not stimulate IGF‑1 production in the systems studied and did not induce insulin resistance, suggesting that hGH-specific contraindications related to IGF‑1 excess (e.g., acromegaly risk) are not applicable; nonetheless, the clinical evidence base remains limited.

Clinician guidance

• In the absence of established contraindications or DDIs, manage AOD‑9604 conservatively: review comorbidities, monitor glucose in patients with diabetes or on insulin/secretagogues, monitor weight, lipids, and cardiovascular symptoms when combined with sympathomimetics or thyroid hormone, and apply heightened vigilance with narrow therapeutic index drugs due to the lack of formal interaction studies.

Embedded summary table

Evidence Gaps#

• Human adverse event data is limited to anecdotal reports
• Systematic adverse event monitoring has not been conducted
• Drug interaction studies are incomplete
• Long-term safety profiles are unknown

Related Reading#

• HGH Fragment 176-191 overview and research guide
• HGH Fragment 176-191 dosing protocols
• HGH Fragment 176-191 risks and legal status