The Effect of Sports Injury on Insulin-Like Growth Factor-I and Type 3 Procollagen: Implications for Detection of Growth Hormone Abuse in Athletes

Erotokritou‐Mulligan, Ioulietta; Bassett, E. Eryl; Bartlett, Christiaan; Cowan, David; McHugh, Cathy; Seah, Rick; Curtis, Benjamin L.; Wells, Victoria; Harrison, Kate; Sönksen, Peter H.; Holt, Richard

doi:10.1210/jc.2007-2801

Cited by 36 publications

(28 citation statements)

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“…Although the outcome was inconclusive, it appears that the most likely reason for the 57% increase in P-III-P was two untreated soft tissue injuries that were not disclosed to the research staff. 7 Nevertheless, this unexpectedly large value had only a trivial effect on the intra-individual variability estimate (estimated difference approximately 0AE2%). In contrast to the small within-subject variability, the inter-individual variability for IGF-I varied between 44-71% while that for P-III-P varied from 31-58%.…”

Section: Igf-i (Ngmentioning

confidence: 93%

“…4 The GH-2000 detection method provides high sensitivity and specificity 4 and has been validated in an independent GH administration study. 5 In addition, ethnicity 6 and sporting injuries 7 do not affect the reliability of the test. A limitation of all anti-doping tests based on measurements made at a single point in time is that training intensity and volume vary considerably during the season, and these may affect the values on which these tests are based.…”

Section: Introductionmentioning

confidence: 99%

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The use of growth hormone (GH)‐dependent markers in the detection of GH abuse in sport: Physiological intra‐individual variation of IGF‐I, type 3 pro‐collagen (P‐III‐P) and the GH‐2000 detection score

Erotokritou‐Mulligan

Bassett

Cowan

et al. 2010

Clinical Endocrinology

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Summary Background Growth Hormone is abused by athletes for its lipolytic and anabolic properties. Its use is prohibited by the World Anti‐Doping Agency. The GH‐2000 project developed a methodology to detect its abuse using the concentrations of two GH‐dependent biomarkers, IGF‐I and type 3 procollagen (P‐III‐P). The sensitivity of this method may be improved by considering intra‐individual variability. Aim The aim of this study was to examine the intra‐individual variability of IGF‐I, P‐III‐P and the GH‐2000 score. Subjects and methods IGF‐I, P‐III‐P and GH‐2000 score were evaluated in four longitudinal studies involving 303 elite and 78 amateur athletes. Samples were collected over a period of up to 12 months from a total of 238 men and 143 women aged between 17 and 53 years (mean 24·2). Results The four studies showed good agreement with no apparent difference in within‐individual variation between amateur and elite athletes. The intra‐individual variability for IGF‐I ranged between 14–16% while the variability for P‐III‐P was 7–18%. No athlete tested positive for growth hormone during any of the studies. The overall mean intra‐individual variability of the GH‐2000 score was less than 0·6 units in all studies. Conclusions The high stability of marker levels suggests that concentrations are largely genetically determined. Adopting a test based on the concept of an athlete’s ‘passport’ or ‘profiling’ would take advantage of this and most likely increase the sensitivity of the test. These data also provide strong evidence that a positive test result for GH abuse would not occur as a result of chance variability.

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Section: Igf-i (Ngmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

The use of growth hormone (GH)‐dependent markers in the detection of GH abuse in sport: Physiological intra‐individual variation of IGF‐I, type 3 pro‐collagen (P‐III‐P) and the GH‐2000 detection score

Erotokritou‐Mulligan

Bassett

Cowan

et al. 2010

Clinical Endocrinology

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“…Both of these markers rise in response to GH administration in a dose-dependent manner (5,6). As these markers are largely unaffected by other regulators of GH secretion, such as exercise or injury, and remain elevated beyond the discontinuation of GH, the test provides a means of detecting exogenous GH administration for a longer period after the last dose of GH (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

The GH-2004 project: the response of IGF1 and type III pro-collagen to the administration of exogenous GH in non-Caucasian amateur athletes

Holt

Erotokritou‐Mulligan

McHugh

et al. 2010

European Journal of Endocrinology

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Context: The GH-2000 team proposed a method based on IGF1 and type III pro-collagen (P-III-P) to detect exogenously administered GH. As previous studies involved predominantly white European athletes, it is important to assess whether the response of these markers to recombinant human GH (rhGH) differs with ethnicity. Objective: To examine the response of serum IGF1 and P-III-P and GH-2000 score to rhGH in non-Caucasian amateur athletes. Design: Double-blind placebo-controlled rhGH administration study. Setting: Wellcome Trust Clinical Research Facility, Southampton General Hospital. Subjects: The study included 31 male and 14 female amateur athletes of different ethnicities. Intervention: The subjects were assigned to treatment with placebo or 0.1 IU/kg per day (low dose) or 0.2 IU/kg per day (high dose) rhGH for 28 days. Blood was collected weekly during treatment and on days 35, 42 and 84 during the washout period. Serum IGF1 and P-III-P were measured, and GH-2000 score was calculated. Results: IGF1, P-III-P and GH-2000 score rose in response to both low-and high-dose GH in both men and women. When compared with the Caucasian volunteers of the previous GH-2000 study, mean baseline and placebo-treated P-III-P and GH-2000 score were lower in GH-2004 men and women. Post-GH, however, peak IGF1 or P-III-P did not differ between studies but the peak GH-2000 score was lower in GH-2004 men. There was no difference between studies in the maximal change in IGF1, P-III-P and GH-2000 score in response to GH in either gender. Conclusions: These data do not support a significant ethnic effect on the peak or maximal response to rhGH.

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“…A multinational team, the GH-2000, has proposed the combined application of IGF-I and P3NP for detection of rhGH doping (13,15,16). P3NP levels rise after a bone fracture or soft tissue muscle injury (9,(33)(34)(35). P3NP response to rhGH administration may be affected by the age, gender, and stage of pubertal maturation, whereas ethnicity has only a small effect (6,17,36).…”

Section: Discussionmentioning

confidence: 99%

“…The N-and C-terminal extensions of procollagen III are removed by specific proteinases during final stages of collagen synthesis and released into circulation in stoichiometric amounts (4). P3NP, a product of this proteolytic cleavage during collagen synthesis in connective tissue, can be measured in the human serum, and its circulating concentrations have been described in children, healthy adults, acromegalics, and athletes (5)(6)(7)(8)(9). P3NP levels are responsive to exercise, testosterone, and GH (6, 10 -14) and are being explored as a marker of GH doping in sports (5, 6, 10, 12, 14 -17).…”

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confidence: 99%

N-Terminal Propeptide of Type III Procollagen as a Biomarker of Anabolic Response to Recombinant Human GH and Testosterone

Meikle¹

2010

Yearbook of Endocrinology

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Context:Biomarkers that predict musculoskeletal response to anabolic therapies should expedite drug development. During collagen synthesis in soft lean tissue, N-terminal propeptide of type III procollagen (P3NP) is released into circulation. We investigated P3NP as a biomarker of lean body mass (LBM) and muscle strength gains in response to testosterone and GH.Design: Community-dwelling older men received GnRH agonist plus 5 or 10 g testosterone gel plus 0, 3, or 5 g recombinant human GH daily. P3NP levels were measured at baseline and wk 4, 8, 12, and 16.LBMandappendicularskeletalmusclemass(ASM)weremeasuredbydual-energyx-rayabsorptiometry. Results:One hundred twelve men completed treatment; 106 underwent serum P3NP measurements. P3NP levels were higher at wk 4 than baseline (6.61 Ϯ 2.14 vs. 4.51 Ϯ 1.05, P Ͻ 0.0001) and reached plateau by wk 4 in men receiving testosterone alone. However, wk 8 P3NP levels were higher than wk 4 levels in men receiving testosterone plus recombinant human GH. Increases in P3NP from baseline to wk 4 and 16 were significantly associated with gains in LBM (r ϭ 0.26, P ϭ 0.007; r ϭ 0.53, P Ͻ 0.001) and ASM (r ϭ 0.17, P ϭ 0.07; r ϭ 0.40, P Ͻ 0.0001). Importantly, for participants receiving only testosterone, P3NP increases at wk 4 and 16 were related to muscle strength gains (r ϭ 0.20, P ϭ 0.056 and r ϭ 0.36, P ϭ 0.04). In stepwise regression, change in P3NP explained 28 and 30% of the change in ASM and LBM, respectively, whereas change in testosterone but not IGF-I and age provided only small improvements in the models. Conclusion:Early changes in serum P3NP levels are associated with subsequent changes in LBM and ASM during testosterone and GH administration. Serum P3NP may be a useful early predictive biomarker of anabolic response to GH and testosterone. The past decade has witnessed substantial pharmaceutical and academic investment in the development of function promoting anabolic therapies that improve physical function and health-related outcomes (1). The leading function promoting anabolic molecules that are under development, androgens, myostatin inhibitors, and GH, are potential promyogenic agents that are expected to improve physical function primarily by increasing skeletal muscle mass. Considering the enormous resources required for conducting large efficacy trials, serum biomar-

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The Effect of Sports Injury on Insulin-Like Growth Factor-I and Type 3 Procollagen: Implications for Detection of Growth Hormone Abuse in Athletes

Abstract: Although there was a rise in P-III-P after injury, this was insufficient to invalidate the GH-2000 detection method based on IGF-I and P-III-P concentrations.

Cited by 36 publications

References 10 publications

The use of growth hormone (GH)‐dependent markers in the detection of GH abuse in sport: Physiological intra‐individual variation of IGF‐I, type 3 pro‐collagen (P‐III‐P) and the GH‐2000 detection score

The use of growth hormone (GH)‐dependent markers in the detection of GH abuse in sport: Physiological intra‐individual variation of IGF‐I, type 3 pro‐collagen (P‐III‐P) and the GH‐2000 detection score

The GH-2004 project: the response of IGF1 and type III pro-collagen to the administration of exogenous GH in non-Caucasian amateur athletes

N-Terminal Propeptide of Type III Procollagen as a Biomarker of Anabolic Response to Recombinant Human GH and Testosterone

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