Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Technology Insight: detecting growth hormone abuse in athletes

Nature Clinical Practice Endocrinology & Metabolism volume 3, pages 769–777 (2007)Cite this article

Abstract

Athletes recognized the performance-enhancing potential of human growth hormone when it became available for treatment of short stature in growth-retarded children. Although no controlled clinical studies have demonstrated a significant benefit in highly trained adults with normal pituitary function, the practice of doping increased with the introduction of recombinant human growth hormone. Evidence of widespread abuse has been gathered by police and customs authorities or provided by former athletes. It has been difficult to develop a test to prove the administration of exogenous growth hormone in athletes because of its specific physiological and biochemical properties. Significant progress has only recently been made, particularly via two differing approaches. The 'marker approach' utilizes characteristic changes in concentrations of pharmacodynamic end points of growth hormone action, for example serum concentrations of insulin-like growth factor I and factors related to bone and soft tissue turnover. The 'isoform approach' detects changes in the molecular isoform composition of circulating growth hormone evoked by the administration of exogenous recombinant growth hormone. The isoform approach was applied at the Olympic Games in Athens in 2004 and in Turin in 2006. Used in a complementary way in an out-of-competition setting, these methods are a powerful tool with which to detect growth hormone abuse in sports.

Key Points

  • Detection of doping with growth hormone (GH) has been difficult because of the physicochemical identity between recombinant human GH (rhGH) and pituitary-derived GH, the short half-life and the pulsatile secretion pattern with highly variable concentrations in normal individuals

  • Two strategies have been developed: the 'marker approach' based on measurement of concentrations of GH-dependent parameters in serum, and the 'isoform approach' based on the detection of changes in the GH isoform spectrum after injection of recombinant GH

  • The marker approach works best with a combination of measurement of insulin-like growth factor I and amino-terminal extension peptide of type III procollagen; changes in the concentrations of these markers after GH administration exceed those seen under physiological conditions

  • The isoform approach utilizes specific immunoassays to detect the relative abundance of the 22 kDa isoform of GH compared with other GH isoforms; injection of rhGH leads, through negative feedback, to a suppression of isoforms other than 22 kDa GH

  • Both methods rely on immunoassays; therefore, the availability and maintenance of the specific antibodies involved is crucial

  • Widespread, out-of-competition use of the tests, probably in a complementary way, will enhance the chances of detecting cheating athletes

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Combination of markers to detect growth hormone (GH) abuse.
Figure 2: Molecular basis of the differential immunoassay approach.

Similar content being viewed by others

References

  1. Duchaine D (1983) Underground Steroid Handbook. Venice, CA: HLR Technical Books

    Google Scholar 

  2. Berggren A et al. (2005) Short-term administration of supraphysiological recombinant human growth hormone (GH) does not increase maximum endurance exercise capacity in healthy, active young men and women with normal GH-insulin-like growth factor I axes. J Clin Endocrinol Metab 90: 3268–3273

    Article  CAS  Google Scholar 

  3. Rennie MJ (2003) Claims for the anabolic effects of growth hormone: a case of the emperor's new clothes? Br J Sports Med 37: 100–105

    Article  CAS  Google Scholar 

  4. Ehrnborg C et al. (2005) Supraphysiological growth hormone: less fat, more extracellular fluid but uncertain effects on muscles in healthy, active young adults. Clin Endocrinol (Oxf) 62: 449–457

    Article  CAS  Google Scholar 

  5. Rickert VI et al. (1992) Human growth hormone: a new substance of abuse among adolescents? Clin Pediatr (Phila) 31: 723–726

    Article  CAS  Google Scholar 

  6. Wanjek B et al. (2007) Doping, drugs and drug abuse among adolescents in the state of Thuringia (Germany): prevalence, knowledge and attitudes. Int J Sports Med 28: 346–353

    Article  CAS  Google Scholar 

  7. World Anti-Doping Agency: Prohibited List [www.wada-ama.org/en/prohibitedlist.ch2] (accessed 18 July 2007)

  8. Abramson FP et al. (1996) Isotopic differences in human growth hormone preparations. Anal Chem 68: 1971–1972

    Article  CAS  Google Scholar 

  9. Andersson C et al. (1996) Isolation and characterization of a trisulfide variant of recombinant human growth hormone formed during expression in Escherichia coli. Int J Pept Protein Res 47: 311–321

    Article  CAS  Google Scholar 

  10. Hepner F et al. (2006) Mass spectrometrical analysis of recombinant human growth hormone norditropin reveals amino acid exchange at M14_V14 rhGH. Proteomics 6: 775–784

    Article  CAS  Google Scholar 

  11. Lasne F and de Ceaurriz J (2000) Recombinant erythropoietin in urine. Nature 405: 635

    Article  CAS  Google Scholar 

  12. De Frutos M et al. (2003) Differences in capillary electrophoresis profiles of urinary and recombinant erythropoietin. Electrophoresis 24: 678–680

    Article  CAS  Google Scholar 

  13. Lasne F et al. (2002) Detection of isoelectric profiles of erythropoietin in urine: differentiation of natural and administered recombinant hormones. Anal Biochem 311: 119–126

    Article  CAS  Google Scholar 

  14. Sasaki H et al. (1987) Carbohydrate structure of erythropoietin expressed in Chinese hamster ovary cells by a human erythropoietin cDNA. J Biol Chem 262: 12059–12076

    CAS  PubMed  Google Scholar 

  15. Rice KG et al. (1992) Quantitative mapping of the N-linked sialyloligosaccharides of recombinant erythropoietin: combination of direct high-performance anion-exchange chromatography and 2-aminopyridine derivatization. Anal Biochem 206: 278–287

    Article  CAS  Google Scholar 

  16. Lasne F (2003) Double-blotting: a solution to the problem of nonspecific binding of secondary antibodies in immunoblotting procedures. J Immunol Methods 276: 223–226

    Article  CAS  Google Scholar 

  17. Van Cauter E et al. (1992) A quantitative estimation of growth hormone secretion in normal man: reproducibility and relation to sleep and time of day. J Clin Endocrinol Metab 74: 1441–1450

    CAS  PubMed  Google Scholar 

  18. Hartman ML et al. (1991) Temporal structure of in vivo growth hormone secretory events in humans. Am J Physiol 260: E101–E110

    CAS  PubMed  Google Scholar 

  19. Kanaley JA et al. (1999) Obesity attenuates the growth hormone response to exercise. J Clin Endocrinol Metab 84: 3156–3161

    CAS  PubMed  Google Scholar 

  20. Richter SD et al. (1996) Time kinetics of the endocrine response to acute psychological stress. J Clin Endocrinol Metab 81: 1956–1960

    CAS  PubMed  Google Scholar 

  21. Pritzlaff CJ et al. (1999) Impact of acute exercise intensity on pulsatile growth hormone release in men. J Appl Physiol 87: 498–504

    Article  CAS  Google Scholar 

  22. Wideman L et al. (2002) Growth hormone release during acute and chronic aerobic and resistance exercise: recent findings. Sports Med 32: 987–1004

    Article  Google Scholar 

  23. Eliakim A et al. (2001) Fitness, training, and the growth hormone-insulin-like growth factor I axis in prepubertal girls. J Clin Endocrinol Metab 86: 2797–2802

    CAS  PubMed  Google Scholar 

  24. Kraemer WJ et al. (1999) Effects of heavy-resistance training on hormonal response patterns in younger vs. older men. J Appl Physiol 87: 982–992

    Article  CAS  Google Scholar 

  25. Kraemer WJ and Ratamess NA (2005) Hormonal responses and adaptations to resistance exercise and training. Sports Med 35: 339–361

    Article  Google Scholar 

  26. Ho KY et al. (1988) Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. J Clin Invest 81: 968–975

    Article  CAS  Google Scholar 

  27. Anderson SM et al. (2001) Short-term estradiol supplementation augments growth hormone (GH) secretory responsiveness to dose-varying GH-releasing peptide infusions in healthy postmenopausal women. J Clin Endocrinol Metab 86: 551–560

    CAS  PubMed  Google Scholar 

  28. Veldhuis JD et al. (2004) Short-term testosterone supplementation relieves growth hormone autonegative feedback in men. J Clin Endocrinol Metab 89: 1285–1290

    Article  CAS  Google Scholar 

  29. Armanini D et al. (2002) Growth hormone and insulin-like growth factor I in a Sydney Olympic gold medallist. Br J Sports Med 36: 148–149

    Article  CAS  Google Scholar 

  30. Parker ML et al. (1962) Studies on human growth hormone. II. The physiological disposition and metabolic fate of human growth hormone in man. J Clin Invest 41: 262–268

    Article  CAS  Google Scholar 

  31. Holl RW et al. (1993) Diurnal variation in the elimination rate of human growth hormone (GH): the half-life of serum GH is prolonged in the evening, and affected by the source of the hormone, as well as by body size and serum estradiol. J Clin Endocrinol Metab 77: 216–220

    CAS  PubMed  Google Scholar 

  32. Veldhuis JD et al. (2002) Impact of experimental blockade of peripheral growth hormone (GH) receptors on the kinetics of endogenous and exogenous GH removal in healthy women and men. J Clin Endocrinol Metab 87: 5737–5745

    Article  CAS  Google Scholar 

  33. Ho KY et al. (1989) The pharmacokinetics, safety and endocrine effects of authentic biosynthetic human growth hormone in normal subjects. Clin Endocrinol (Oxf) 30: 335–345

    Article  CAS  Google Scholar 

  34. Flanagan DE et al. (1997) Urinary growth hormone following exercise to assess growth hormone production in adults. Clin Endocrinol (Oxf) 46: 425–429

    Article  CAS  Google Scholar 

  35. Leger J et al. (1995) The wide variation in urinary excretion of human growth hormone in normal growing and growth hormone-deficient children limits its clinical usefulness. Horm Res 44: 57–63

    Article  CAS  Google Scholar 

  36. Albini CH et al. (1988) Quantitation of urinary growth hormone in children with normal and abnormal growth. Pediatr Res 23: 89–92

    Article  CAS  Google Scholar 

  37. Saugy M et al. (1996) Detection of human growth hormone doping in urine: out of competition tests are necessary. J Chromatogr B Biomed Appl 687: 201–211

    Article  CAS  Google Scholar 

  38. Saugy M et al. (2006) Human growth hormone doping in sport. Br J Sports Med 40 (Suppl 1): i35–i39

    Article  Google Scholar 

  39. World Anti-Doping Agency: World Anti-Doping Code—International Standard for Laboratories Version 4.0 August 2004 [http://www.wada-ama.org/rtecontent/document/lab_aug_04.pdf] (accessed 18 July 2007)

  40. Wallace JD et al. (1999) Responses of the growth hormone (GH) and insulin-like growth factor axis to exercise, GH administration, and GH withdrawal in trained adult males: a potential test for GH abuse in sport. J Clin Endocrinol Metab 84: 3591–3601

    CAS  PubMed  Google Scholar 

  41. Le Roith D et al. (2001) The somatomedin hypothesis: 2001. Endocr Rev 22: 53–74

    Article  CAS  Google Scholar 

  42. Wallace JD et al. (2000) Responses of markers of bone and collagen turnover to exercise, growth hormone (GH) administration, and GH withdrawal in trained adult males. J Clin Endocrinol Metab 85: 124–133

    CAS  PubMed  Google Scholar 

  43. Burman P et al. (1997) Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women. J Clin Endocrinol Metab 82: 550–555

    CAS  PubMed  Google Scholar 

  44. Dall R et al. (2000) The effect of four weeks of supraphysiological growth hormone administration on the insulin-like growth factor axis in women and men. GH-2000 Study Group. J Clin Endocrinol Metab 85: 4193–4200

    CAS  PubMed  Google Scholar 

  45. Longobardi S et al. (2000) Growth hormone (GH) effects on bone and collagen turnover in healthy adults and its potential as a marker of GH abuse in sports: a double blind, placebo-controlled study. The GH-2000 Study Group. J Clin Endocrinol Metab 85: 1505–1512

    CAS  PubMed  Google Scholar 

  46. Eliakim A et al. (1996) Physical fitness, endurance training, and the growth hormone-insulin-like growth factor I system in adolescent females. J Clin Endocrinol Metab 81: 3986–3992

    CAS  PubMed  Google Scholar 

  47. Harrela M et al. (1996) Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3. J Clin Invest 98: 2612–2615

    Article  CAS  Google Scholar 

  48. Juul A et al. (1995) Serum levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation. J Clin Endocrinol Metab 80: 2534–2542

    CAS  PubMed  Google Scholar 

  49. Bang P et al. (1990) Exercise-induced changes in insulin-like growth factors and their low molecular weight binding protein in healthy subjects and patients with growth hormone deficiency. Eur J Clin Invest 20: 285–292

    Article  CAS  Google Scholar 

  50. Hopkins NJ et al. (1994) Changes in circulating insulin-like growth factor-binding protein-1 (IGFBP-1) during prolonged exercise: effect of carbohydrate feeding. J Clin Endocrinol Metab 79: 1887–1890

    CAS  PubMed  Google Scholar 

  51. Hornum M et al. (1997) Exercise-induced changes in circulating growth factors with cyclic variation in plasma estradiol in women. J Appl Physiol 82: 1946–1951

    Article  CAS  Google Scholar 

  52. Schwarz AJ et al. (1996) Acute effect of brief low- and high-intensity exercise on circulating insulin-like growth factor (IGF) I, II, and IGF-binding protein-3 and its proteolysis in young healthy men. J Clin Endocrinol Metab 81: 3492–3497

    CAS  PubMed  Google Scholar 

  53. Powrie JK et al. (2007) Detection of growth hormone abuse in sport. Growth Horm IGF Res 17: 220–226

    Article  CAS  Google Scholar 

  54. Rigamonti AE et al. (2005) Growth hormone abuse: methods of detection. Trends Endocrinol Metab 16: 160–166

    Article  CAS  Google Scholar 

  55. Healy ML et al. (2005) Toward the development of a test for growth hormone (GH) abuse: a study of extreme physiological ranges of GH-dependent markers in 813 elite athletes in the postcompetition setting. J Clin Endocrinol Metab 90: 641–649

    Article  CAS  Google Scholar 

  56. Wright NM et al. (1995) Greater secretion of growth hormone in black than in white men: possible factor in greater bone mineral density—a clinical research center study. J Clin Endocrinol Metab 80: 2291–2297

    CAS  PubMed  Google Scholar 

  57. Nelson AE et al. (2006) Influence of demographic factors and sport type on growth hormone-responsive markers in elite athletes. J Clin Endocrinol Metab 91: 4424–4432

    Article  CAS  Google Scholar 

  58. Abellan R et al. (2006) Effect of physical fitness and endurance exercise on indirect biomarkers of recombinant growth hormone misuse: insulin-like growth factor I and procollagen type III peptide. Int J Sports Med 27: 976–983

    Article  CAS  Google Scholar 

  59. Kurdy NM (2000) Serology of abnormal fracture healing: the role of PIIINP, PICP, and BsALP. J Orthop Trauma 14: 48–53

    Article  CAS  Google Scholar 

  60. Baumann G (1999) Growth hormone heterogeneity in human pituitary and plasma. Horm Res 51 (Suppl 1): 2–6

    CAS  PubMed  Google Scholar 

  61. Popii V and Baumann G (2004) Laboratory measurement of growth hormone. Clin Chim Acta 350: 1–16

    Article  CAS  Google Scholar 

  62. Nakamoto JM et al. (1986) Suppression of the growth hormone (GH) response to clonidine and GH-releasing hormone by exogenous GH. J Clin Endocrinol Metab 62: 822–826

    Article  CAS  Google Scholar 

  63. Leung KC et al. (2002) Physiological and pharmacological regulation of 20-kDa growth hormone. Am J Physiol Endocrinol Metab 283: E836–E843

    Article  CAS  Google Scholar 

  64. Wu Z et al. (1999) Detection of doping with human growth hormone. Lancet 353: 895

    Article  CAS  Google Scholar 

  65. Bidlingmaier M et al. (2000) Test method: GH. Baillieres Best Pract Res Clin Endocrinol Metab 14: 99–109

    Article  CAS  Google Scholar 

  66. Wu Z et al. (2002) Development of human growth hormone (hGH) isoform specific antibodies and their use in a possible test to detect hGH-doping in sports. Abstract P3-527 presented at the 84th Meeting of the Endocrine Society: 2002 June 19–22, San Francisco, CA

  67. Hashimoto Y et al. (2000) Exogenous 20K growth hormone (GH) suppresses endogenous 22K GH secretion in normal men. J Clin Endocrinol Metab 85: 601–606

    Article  CAS  Google Scholar 

  68. Ishikawa M et al. (1999) Serum levels of 20-kilodalton human growth hormone (GH) are parallel those of 22-kilodalton human GH in normal and short children. J Clin Endocrinol Metab 84: 98–104

    Article  CAS  Google Scholar 

  69. Wallace JD et al. (2001) Changes in non-22-kilodalton (kDa) isoforms of growth hormone (GH) after administration of 22-kDa recombinant human GH in trained adult males. J Clin Endocrinol Metab 86: 1731–1737

    CAS  PubMed  Google Scholar 

  70. Wallace JD et al. (2001) The response of molecular isoforms of growth hormone to acute exercise in trained adult males. J Clin Endocrinol Metab 86: 200–206

    CAS  PubMed  Google Scholar 

  71. Keller A et al. (2007) Pharmacokinetics and pharmacodynamics of GH: dependence on route and dosage of administration. Eur J Endocrinol 156: 647–65355

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medizinische Klinik – Innenstadt (Medical Department), M Bidlingmaier is Head of the Endocrine Research Laboratories, Klinikum der Universität, Ludwig-Maximilians University, Munich, Germany.,

    Martin Bidlingmaier

  2. CJ Strasburger is Division Chief and Professor of Clinical Endocrinology, Department of Medicine, Campus Mitte at the Charitè Universitätsmedizin Berlin, Germany.,

    Christian J Strasburger

Authors
  1. Martin Bidlingmaier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian J Strasburger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Bidlingmaier.

Ethics declarations

Competing interests

Martin Bidlingmaier received research grants from the World Anti-Doping Agency (WADA) and holds stock in the CMZ-Assay GmbH, Berlin, Germany, which is involved in the production of assay kits to measure growth hormone. Christian J Strasburger is recipient of research grants from the World Anti-Doping Agency (WADA) and formerly from the International Olympic Committee (IOC) and holds stock in the CMZ-Assay GmbH, Berlin, Germany, which is involved in the production of assay kits to measure growth hormone.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bidlingmaier, M., Strasburger, C. Technology Insight: detecting growth hormone abuse in athletes. Nat Rev Endocrinol 3, 769–777 (2007). https://doi.org/10.1038/ncpendmet0644

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpendmet0644

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing