IGF-1

The native 70-amino-acid growth factor that carries out much of growth hormone's action; its recombinant form, mecasermin, is FDA-approved for severe primary IGF-1 deficiency, while the research market mostly sells engineered analogs instead.

Also referenced as: Mecasermin, Increlex, IGF-I, Insulin-like growth factor 1, Somatomedin C, rhIGF-1

Also appears in: GH axis

What is IGF-1?

Insulin-like growth factor 1 is a naturally occurring 70-amino-acid single-chain polypeptide cross-linked by three disulfide bridges. Its structure is openly homologous to proinsulin — residues 1-29 correspond to the insulin B chain and residues 42-62 to the A chain, joined by a shortened 12-residue connecting peptide (Rinderknecht & Humbel, Journal of Biological Chemistry, 1978;253:2769-2776). It is produced chiefly by the liver under growth hormone stimulation, and it is the molecule through which much of growth hormone’s growth-promoting activity is actually delivered.

The recombinant, sequence-identical version is a prescription drug called mecasermin: 70 amino acids expressed in E. coli, approved by the FDA on August 30, 2005 for growth failure in children with severe primary IGF-1 deficiency. That approval is what places this compound in the “FDA Approved” band, and it is narrow — two rare pediatric growth indications, not a general anabolic license.

Where the research-peptide market is concerned, a distinction matters more than anything else on this page: a vial labeled “IGF-1” is usually not the native molecule. The two engineered analogs — IGF-1 LR3 and IGF-1 DES, each profiled separately on this site — dominate that catalog, and neither is the approved drug. The key considerations below set out exactly how they differ.

How it works

• IGF1R signaling. IGF-1 binds the type 1 IGF receptor, a receptor tyrosine kinase, which autophosphorylates and recruits substrates including IRS-1 and Shc; these drive the PI3K-Akt and Ras-MAPK pathways, producing cell proliferation, differentiation, protein synthesis, and survival signaling (Hakuno & Takahashi, Journal of Molecular Endocrinology, 2018;61:T69-T86). Because IGF-1 and insulin are structurally related, IGF-1 also retains lower-affinity cross-reactivity with the insulin receptor, which contributes to the hypoglycemia seen with therapeutic dosing.
• Binding proteins govern its availability. Almost none of the circulating pool is free. IGF-1 travels bound to a family of six IGF-binding proteins, mostly in a ternary complex with IGFBP-3 and the acid-labile subunit, which shields it from clearance and greatly extends its circulating half-life relative to free hormone (Rajaram et al., Endocrine Reviews, 1997;18:801-831). This carrier system is the reason the market’s analogs exist: both are designed to escape it.
• It mediates growth hormone’s action, but not only from the bloodstream. Purified IGF-I alone stimulates growth in hypophysectomized rats (Schoenle et al., Nature, 1982;296:252-253). Yet mice with the liver igf1 gene deleted lose most of their circulating IGF-I and still grow normally in body weight, body length, and femoral length (Yakar et al., Proceedings of the National Academy of Sciences, 1999;96:7324-7329) — evidence that locally produced, autocrine/paracrine IGF-1 does much of the work that the circulating pool was once credited with.
• Muscle effects in animals are local-delivery effects. Infusing IGF-I directly into one rat tibialis anterior via an implanted catheter produced a muscle roughly 9% heavier than the untreated contralateral side, with higher total protein and DNA content (Adams & McCue, Journal of Applied Physiology, 1998;84:1716-1722), and localized Igf-1 transgene expression sustained hypertrophy and regeneration in aged mouse muscle (Musarò et al., Nature Genetics, 2001;27:195-200). Both are targeted-tissue models; neither tests systemic injection in humans.

Research status

Approved indications. Mecasermin is indicated for growth failure in pediatric patients 2 years of age and older with severe primary IGF-1 deficiency, or with growth hormone gene deletion who have developed neutralizing antibodies to growth hormone. The label defines severe primary IGF-1 deficiency by three criteria together: height standard deviation score at or below -3.0, basal IGF-1 standard deviation score at or below -3.0, and normal or elevated growth hormone. It is explicitly not indicated for secondary IGF-1 deficiency from growth hormone deficiency, malnutrition, hypothyroidism, or chronic corticosteroid use.

The supporting long-term dataset is Chernausek et al. (Journal of Clinical Endocrinology & Metabolism, 2007;92:902-910), which followed 76 children with growth hormone insensitivity treated with rhIGF-I for up to 12 years at 60-120 µg/kg twice daily. Mean height velocity rose from 2.8 cm/year at baseline to 8.0 cm/year in the first treatment year (P < 0.0001), fell in subsequent years but stayed above baseline for up to 8 years. Adverse events were common: hypoglycemia in 49% of subjects, injection-site lipohypertrophy in 32%, and tonsillar or adenoidal hypertrophy in 22%.

A second product, mecasermin rinfabate (rhIGF-1 complexed with rhIGFBP-3), was approved on December 12, 2005 for the same growth indication under a different sponsor, and later left the U.S. market following patent litigation with the sponsor of the mecasermin product — a commercial outcome, not a safety withdrawal.

Outside deficiency, the record is largely negative:

• ALS. An early North American trial of 266 patients over 9 months reported 26% slower functional decline on the higher dose of 0.10 mg/kg/day (P = 0.01) (Lai et al., Neurology, 1997;49:1621-1630). A parallel European trial of 183 patients at 0.1 mg/kg/day for 9 months found no significant difference on its primary Appel ALS rating scale endpoint (Borasio et al., Neurology, 1998;51:583-586). The question was settled by a Phase 3 trial (NCT00035815) randomizing 330 patients across 20 centers to 0.05 mg/kg subcutaneously twice daily or placebo for two years: no difference in the primary manual muscle testing endpoint, and none in tracheostomy-free survival or ALSFRS-R decline (Sorenson et al., Neurology, 2008;71:1770-1775).
• Rett syndrome. A placebo-controlled crossover trial in 30 girls with classic Rett syndrome, two 20-week periods separated by a 28-week washout, found no significant improvement; several measures — the Kerr severity scale, an ADAMS depressed-mood subscale, and EEG parameters — moved in the direction of worsening (O’Leary et al., Annals of Clinical and Translational Neurology, 2018;5:323-332).
• Complications of extreme prematurity. A Phase 2 trial infusing rhIGF-1/rhIGFBP-3 in 121 infants born at 23-27 weeks (NCT01096784) missed its primary endpoint of retinopathy of prematurity severity, but showed a reduction in severe bronchopulmonary dysplasia (21.3% versus 44.9%, P = .04) (Ley et al., The Journal of Pediatrics, 2019;206:56-65). A larger Phase 2 study of the same complex, now coded OHB-607, is ongoing — active but no longer recruiting, with 295 infants enrolled and severe bronchopulmonary dysplasia or death by 36 weeks postmenstrual age as its primary endpoint (NCT03253263).
• Muscle and physique use. There is no controlled human trial of rhIGF-1 as a muscle-building agent in healthy adults. Registered IGF-1 studies in muscle-relevant conditions have been small: a Phase 1/2 trial in Duchenne muscular dystrophy (NCT01207908, 44 participants) completed with results posted, and a Phase 1 study in HIV metabolic disease (NCT01329744, 16 participants) was terminated — neither established a functional benefit. IGF-1 LR3 and IGF-1 DES have no registered human trials of any kind.

Common dosage forms

• Prescription rhIGF-1 is supplied as a clear, colorless 40 mg/4 mL (10 mg/mL) solution in a multiple-dose glass vial preserved with benzyl alcohol, for subcutaneous injection. The label directs dosing within roughly 20 minutes before or after a meal or snack because of the hypoglycemia risk, and states that it must not be given intravenously. Benzyl alcohol is why the label does not recommend use in infants, citing the risk of “gasping syndrome” in neonates and infants given benzyl alcohol-preserved drugs.
• Research-market vials are lyophilized powder labeled in micrograms or milligrams for reconstitution. In practice these are almost always the LR3 or DES analog rather than the native sequence, and listings frequently read only “IGF-1” without naming the actual variant — so the format itself does not tell you which molecule is in the vial.
• Oral, sublingual, and topical products marketed as IGF-1 — including deer antler velvet extracts — cannot deliver an intact, active 70-amino-acid disulfide-bonded protein systemically. Like other proteins of this size, IGF-1 is not orally bioavailable.

Key considerations

• Approved status is narrow, and the contraindications are specific. Mecasermin is a prescription biologic for two rare pediatric growth conditions. The label contraindicates it in patients with closed epiphyses, in those with malignant neoplasia or a history of malignancy, and in known hypersensitivity to mecasermin. “FDA Approved” on this profile describes the native recombinant molecule in those indications only; it says nothing about the analogs sold as research chemicals.
• The documented safety signals are real and clinically monitored. Labeling and long-term data describe severe hypoglycemia including hypoglycemic seizures, tonsillar and adenoidal hypertrophy leading to sleep apnea, intracranial hypertension, slipped capital femoral epiphysis during rapid growth, progression of existing scoliosis, injection-site lipohypertrophy, and post-marketing reports of neoplasms — benign, malignant, and unspecified. Approved use involves funduscopic examination and periodic monitoring for these; unsupervised use involves neither.
• The IGF axis carries a cancer-risk signal from both directions of the epidemiology. A meta-regression analysis found higher circulating IGF-I associated with increased risk of prostate cancer and premenopausal breast cancer, with modest effect sizes varying by site (Renehan et al., The Lancet, 2004;363:1346-1353). At the opposite extreme, an Ecuadorian cohort with growth hormone receptor deficiency and correspondingly very low IGF-1 was followed for 22 years and showed one non-lethal malignancy and no diabetes, versus 17% cancer and 5% diabetes prevalence in controls (Guevara-Aguirre et al., Science Translational Medicine, 2011;3:70ra13). These are association data about endogenous IGF-1 levels, not measured outcomes of injecting rhIGF-1 — but they are the context behind the neoplasia contraindication.
• Four different molecules share the “IGF” shorthand. Native IGF-1 (and its sequence-identical recombinant form, mecasermin) is the approved one. IGF-1 LR3 is Long [Arg3]-IGF-I: a 13-residue N-terminal extension plus substitution of arginine for glutamate at position 3, a design that lowers IGF-binding-protein affinity and makes it more potent than native IGF-I in cells that secrete IGFBPs — while actually being less potent than native IGF-I in cells that secrete none (Francis et al., Journal of Molecular Endocrinology, 1992;8:213-223). IGF-1 DES is des(1-3)IGF-I, truncated by the first three residues, achieving the same IGFBP escape by a different route. MGF (mechano growth factor, IGF-1Ec) is a splice variant, not IGF-1 itself. And IGF-1 is not growth hormone — it is downstream of it.
• The muscle-growth rationale outruns the human evidence, and the compound is banned in sport. The anabolic case rests on local-delivery animal models, while the largest systemic human trial in a muscle-wasting disease showed no functional benefit over two years, and systemic dosing is dose-limited by hypoglycemia. IGF-1 and its analogs are prohibited at all times under section S2 of the World Anti-Doping Agency Prohibited List (peptide hormones, growth factors, related substances and mimetics), alongside growth hormone and the growth hormone secretagogues.