IGF-1, also known as somatomedin C, is a 7.6 kDa, 70 amino acid residue peptide, which mediates the actions of growth hormone (GH).1 IGF-1 is synthesized as a prohormone, a polypeptide consisting of A, C, B, D, and E domains.1,2 After post-translational modification, the mature IGF-1 consists of the A, C, B and D domains, and is structurally homologous to IGF-II and insulin. In vivo, IGF-1 is secreted by the liver and several other tissues and is postulated to have mitogenic and metabolic actions at or near the sites of synthesis; this has been termed the paracrine role of IGF-1.1 IGF-1 also appears in the peripheral circulation where it circulates primarily in a high molecular weight tertiary complex with IGF-binding protein-3 (IGFBP-3) and acid-labile subunit (ALS).2,3 A smaller proportion of IGF-1 may circulate in association with other IGF-binding proteins.3 It has been estimated that <5% of plasma IGF-1 circulates unbound.4 In vivo synthesis of IGF-1 is stimulated by GH, and is also dependent on other factors, including adequate nutrition.1,5 IGF-1 may inhibit pituitary production of GH; however, a feedback mechanism has not been completely defined.

In humans, plasma IGF-1 levels are low during fetal and neonatal life, increase gradually during childhood, peak during mid-puberty, and decline gradually through adult life.1,5-7 Average plasma IGF-I levels are slightly higher in females at each age. Maternal plasma levels increase during pregnancy.1 Plasma IGF-1 levels are stabilized by the IGF-binding proteins and there is negligible diurnal variation.5 Plasma IGF-1 levels are low relative to age- and sex-related norms in GH deficiency5-7, malnutrition5,8 and in the syndrome of GH-receptor deficiency (Laron dwarfism).9 Abnormally low levels of plasma IGF-1 have been used as a diagnostic indicator of GH deficiency, although a significant proportion of GH-deficient children may have IGF-1 levels in the normal range, and normal short children may have low IGF-1 levels.1,6,7 Plasma IGF-1 levels may also be used to monitor the short- and long-term in vivo responses to GH treatment.5 Abnormally elevated IGF-1 levels in acromegaly (GH excess) may be used as a diagnostic tool and to monitor treatment.1,5

Assay of plasma IGF-1 is complicated by the presence of IGF-binding proteins, which may sequester IGF-1 in the reaction mixture.1 Various methods have been devised to separate the IGF and IGF-binding proteins prior to assay. Size-exclusion gel chromatography in acid is considered to be optimal1,10, but this procedure is not feasible for routine use. Acidification followed by ethanol precipitation of the IGFBP fraction1,11 gives results which are similar to acid-chromatography. SepPak C-18 cartridges are less convenient11 and give variable results and relatively low recovery.

The Ansh Labs Total IGF-1 Assay uses an acidification and neutralization method to dissociate IGF-1 from all the binding proteins. IGF-1 levels are quantified in the extracted samples using a highly sensitive and specific enzyme-linked immunosorbent assay. Also, a ratio of Bioactive IGF-1 to Total IGF-1 can now be measured in individual subjects using the Ansh Bioactive IGF-1 kit AL-122 along with the Total IGF-1 kit AL-121.

References:
1. Daughaday E, Rotwein P: Insulin like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum and tissue concentrations. Endocrine Rev 10:68-91, 1989.
2. Baxter RC, Martin JL, Beniac VA: High molecular weight insulin-like growth factor binding protein complex. J Biol Chem 264:11843-11848, 1989.
3. Rechler M: Insulin-like growth factor binding proteins. Vit Horm 47:1-114, 1993.
4. Zapf J, Hauri C, Waldvogel M, Froesch ER: Acute metabolic effects and half-lives of intravenously administered insulin-like growth factors I and II in normal and hypophysectomized rats. J Clin Invest 77:1768-1775, 1986.
5. Lee PDK, Rosenfeld RG: Clinical utility of insulin-like growth factor assays. Pediatrician 14:154-161, 1987.
6. Rosenfeld RG, Wilson DM, Lee PDK, Hintz RL: Insulin-like growth factors I and II in evaluation of growth retardation. J Pediatr 109:428-433, 1986.
7. Lee PDK, Wilson DM, Rountree L, Hintz RL, Rosenfeld RG: Efficacy of insulin-like growth factor I levels in predicting the response to provocative growth hormone testing. Pediatr Res 27:45-51, 1990.
8. Soliman AT, Hassan AEHI, Aref MK, Hintz RL, Rosenfeld RG, Rogol AD: Serum insulin-like growth factors I and II concentrations and growth hormone and insulin responses to arginine infusion in children with protein-calorie malnutrition before and after nutritional rehabilitation. Pediatr Res 20:1122-1130, 1986.
9. Guevara-Aguirre J, Rosenbloom AL, Fielder PJ, Diamond FB. Jr, Rosenfeld RG: Growth hormone receptor deficiency in Ecuador: Clinical and biochemical phenotype in two populations. J Clin Endocrinol Metab 76:417-423, 1993.
10. Powell DR, Rosenfeld RG, Baker BK, Liu F, Hintz RL: Serum somatomedin levels in adults with chronic renal failure: the importance of measuring insulin-like growth factor I (IGF-I) and IGF-II in acid-chromatographed uremic serum. J Clin Endocrinol Metab 63:1186-1192, 1986.
11. Underwood LE, Murphy MG: Radioimmunoassay of the somatomedins. IN Patrono C (ed): Radioimmunoassay in Basic and Clinical Pharmacology (Handbook of Experimental Pharmacology vol 82) Springer-Verlag, Heidelberg, 1987, pp 561-574.
12. HHS Publication, 5th ed., 2007. Biosafety in Microbiological and Biomedical Laboratories. Available http://www.cdc.gov/biosafety/publications/bmbl5/BMBL5
13. DHHS (NIOSH) Publication No. 78–127, August 1976. Current Intelligence Bulletin 13 – Explosive Azide Hazard. Available http:// www.cdc.gov/niosh.
14. Kricka L. Interferences in immunoassays – still a threat. Clin Chem 2000; 46: 1037–1038.

Anastasilakis AD, Koulaxis D, Upadhyay J, Pagkalidou E, Kefala N, Perakakis N, Polyzos SA, Economou F, Mantzoros CS. Free IGF-1, Intact IGFBP-4, and PicoPAPP-A are Altered in Acute Myocardial Infarction Compared to Stable Coronary Artery Disease and Healthy Controls. Horm Metab Res. 2019 Feb;51(2):112-119.

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Babiker A, Al Noaim K, Al Swaid A, et al. Short stature with low insulin-like growth factor 1 availability due to pregnancy-associated plasma protein A2 deficiency in a Saudi family. Clin Genet. 2021;100(5):601-606. doi: 10.1111/cge.14030.

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Becker M, Haluska P, Bale L, Oxvig C, Conover C. A Novel Neutralizing Antibody Targeting Pregnancy-Associated Plasma Protein-A Inhibits Ovarian Cancer Growth and Ascites Accumulation in Patient Mouse Tumorgrafts. Mol Cancer Ther. 2015 Apr;14(4):973-81. Epub 2015 Feb 18.

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Dauber A, Munoz-Calvo MT, Barrios V, Domene HM, Kloverpris S, Serra-Juhe C, Desikan V, Pozo J, Muzumdar R, Martos-Moreno GA, Hawkins F, Jasper HG, Conover CA, Frystyk J, Yakar S, Hwa V, Chowen JA, Oxvig C, Rosenfeld RG, Perez-Jurado LA, Argente J. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol Med. 2016 Mar 31;8(4):363-74.

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Donegan D, Bale LK, Conover CA. PAPP-A in normal human mesangial cells: effect of inflammation and factors related to diabetic nephropathy. J Endocrinol. 2016 Oct;231(1):71-80. doi: 10.1530/JOE-16-0205. Epub 2016 Aug 12. PMID: 27519211.

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Fujimoto M, Khoury JC, Khoury PR, Kalra B, Kumar A, Sluss P, Oxvig C, Hwa V, Dauber A. Anthropometric and biochemical correlates of PAPP-A2, free IGF-I, and IGFBP-3 in childhood. European journal of endocrinology, 182(3), 363–374. https://doi.org/10.1530/EJE-19-0859

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Guercio BJ, Zhang S, Ou FS, et al. . IGF-Binding Proteins, Adiponectin, and Survival in Metastatic Colorectal Cancer: Results From CALGB (Alliance)/SWOG 80405. JNCI Cancer Spectr. 2020 Aug 27;5(1):pkaa074. doi: 10.1093/jncics/pkaa074

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Hjortebjerg R, Rasmussen LM, Gude MF, Irmukhamedov A, Riber LP, Frystyk J, De Mey JGR. Local IGF Bioactivity Associates with High PAPP-A Activity in the Pericardial Cavity of Cardiovascular Disease Patients. J Clin Endocrinol Metab. 2020 Nov 1;105(11):dgaa617. doi: 10.1210/clinem/dgaa617. PMID: 32875328.

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Kazemi M, Jarrett BY, Parry SA, Thalacker-Mercer AE, Hoeger KM, Spandorfer SD, Lujan ME. . Osteosarcopenia in Reproductive-Aged Women with Polycystic Ovary Syndrome: A Multicenter Case-Control Study. J Clin Endocrinol Metab. 2020 Sep 1;105(9):e3400-e3414. doi: 10.1210/clinem/dgaa426

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Kumar A, Kalra B, Chowdavarapu K, Shah S, Savjani G, Oxvig C. Development of IGF-1 ELISA Assays to Measure Free and Total Circulating IGF-1. Poster session presented at the 96th Annual Endocrine Society Meeting; 2014 Jun 21-24; Chicago, IL.

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Kumar A, Kalra B, Chowdavarapu K, Shah S, Savjani G, Oxvig C. Development of IGF-1 ELISA Assays to Measure Free and Total Circulating IGF-1. Presented at 98th Annual Endocrine Society Meeting; 2016 Apr 1-3; Boston, MA

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Kumar A, Kalra B, Kommareddy V, Chowdavarapu K, Mistry S, Savjani G, Oxvig C. Development of Well Characterized ELISAs for Bound and Unbound Insulin-Like Growth Factors and their Binding Proteins. Poster presented at 98th Annual Endocrine Society Meeting; 2016 Apr 1-3; Boston, MA.

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Legro R, Dodson W, Estes S, Kunselman A, Coutifaris C, Dokras A. Effect of Weight Loss and Hormonal Suppression Alone and in Combination on Bioactive Gut and Ovarian Peptide Hormones in Women with Polycystic Ovary Syndrome. Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, MON-233, https://doi.org/10.1210/js.2019-MON-233

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Martín-Rivada Á, Guerra Cantera S, Campillo-Calatayud A, Andrés-Esteban EM, Sánchez Holgado M, Martos-Moreno GÁ, Pozo J, Güemes M, Soriano-Guillén L, Pellicer A, Oxvig C, Frystyk J, Chowen JA, Barrios V, Argente J. Pappalysins and Stanniocalcin and Their Relationship With the Peripheral IGF Axis in Newborns and During Development. J Clin Endocrinol Metab. 2022 Sep 28;107(10):2912-2924. doi: 10.1210/clinem/dgac453. PMID: 35902207.

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Panagiotou G, Papakonstantinou E, Vagionas A, Polyzos SA, Mantzoros CS. Serum Levels of Activins, Follistatins, and Growth Factors in Neoplasms of the Breast: A Case-Control Study. J Clin Endocrinol Metab. 2019 Feb 1;104(2):349-358.

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Pellikaan K, Elizabeth M, Hokken-Koelega ACS, van den Berg SA, de Graaff-Herder L. Reference intervals for bioavailable IGF-I values in Dutch healthy children, adolescents, and young adults. J Endocr Soc. 2023;7(Supplement_1). doi:10.1210/jendso/bvad114.1422.

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Polyzos SA, Perakakis N, Boutari C, Kountouras J, Ghaly W, Anastasilakis AD, Karagiannis A, Mantzoros CS. Targeted Analysis of Three Hormonal Systems Identifies Molecules Associated with the Presence and Severity of NAFLD. J Clin Endocrinol Metab. 2020 Mar 1;105(3):e390–400. doi: 10.1210/clinem/dgz172. PMID: 31690932; PMCID: PMC7112980.

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Richard Legro, William Dodson, Stephanie Estes, Allen Kunselman, Christos Coutifaris, Anuja Dokras, MON-233 Effect of Weight Loss and Hormonal Suppression Alone and in Combination on Bioactive Gut and Ovarian Peptide Hormones in Women with Polycystic Ovary Syndrome, Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, MON–233, https://doi.org/10.1210/js.2019-

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Shah A, Dodson WC, Kris-Etherton PM, Kunselman AR, Stetter CM, Gnatuk CL, Estes SJ, Allison KC, Sarwer DB, Sluss PM, Coutifaris C, Dokras A, Legro RS. Effects of Oral Contraception and Lifestyle Modification on Incretins and TGF-ß Superfamily Hormones in PCOS. J Clin Endocrinol Metab. 2021 Jan 1;106(1):108-119. doi: 10.1210/clinem/dgaa682. PMID: 32968804; PMCID: PMC7765645

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Shulman DS, Merriam P, Choy E, et al. Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma. Cancer Med. 2023;12:15207-15216. doi: 10.1002/cam4.6208.

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Vicente Barrios, Álvaro Martín-Rivada, Gabriel Á Martos-Moreno, Sandra Canelles, Francisca Moreno-Macián, Carmen De Mingo-Alemany, Maurizio Delvecchio, Roberta Pajno, Danilo Fintini, Julie A Chowen, Jesús Argente, Increased IGFBP Proteolysis, IGF-I Bioavailability, and Pappalysin Levels in Children With Prader-Willi Syndrome, The Journal of Clinical Endocrinology & Metabolism, Volume 109, Issue 9, September 2024, Pages e1776–e1786, https://doi.org/10.1210/clinem/dgad754

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