New technologies and ways of manipulating the GH-IGF axis are emerging. Gene doping, GH secretagogues, rhIGF-I, and rhIGF-I/recombinant human IGF-I–binding protein 3 (rhIGFBP-3) complex are already in circulation. Certain genotypes confer athletic advantages, and transmission of a genetic code with or without the aid of a vector, such as a virus, allows incorporation of the DNA into target tissues where expression of that gene can leads to enhanced local production of an anabolic substance such as IGF-I. This confers target tissue specificity without altering systemic concentrations of the product and is thus not detected by blood or urine testing. Detection requires tissue biopsy, which would not be feasible in the sporting setting.
Proof-of-concept experiments have been undertaken in animals in which injection of a recombinant adeno-associated virus genetically manipulated to induce myocyte overexpression of IGF-I in young mice induced a 15% increase in muscle mass and a 14% increase in muscle strength without inducing a systemic increase in IGF-I (16).
Challenges of Detecting GH Abuse
Important considerations in GH measurement for antidoping include the amino acid sequence identity between the main fraction of pituitary-derived GH and recombinant GH, the heterogeneous nature of GH, the presence of GH-binding proteins in plasma, the potential cross-reactivity with homologous polypeptide hormones (i.e., prolactin), the heterogeneous immunoreactivity of (monoclonal) antibodies used for commercial immunoassays, and the short half-life in circulation.
Detection of abuse with GH poses many challenges. Unlike many substances of abuse, such as synthetic anabolic steroids, GH is a naturally occurring substance; thus, demonstration of exogenous administration must rely on detecting concentrations exceeding established reference intervals and the exclusion of a pathologic cause such as acromegaly. Possible solutions include repeat testing after a period of known abstinence and detailed clinical examination and investigation. Detection is hampered by the fact that recombinant and endogenous GH have identical amino acid sequences.
Physiologic challenges include a pulsatile release pattern, a short half-life of 20 min, and increased concentrations 2 h after exercise (17)(18). Although researchers can perform repeated sampling over a 24-h period to overcome the issue of pulsatility, this is not feasible in the sporting setting (19).
Traditional drug testing in sport has involved urinary sampling, but it is not viable for rhGH detection because neither GH itself nor markers of GH, which are also peptides, are secreted into the urine in sufficient and reliable quantities (20). Consequently, blood sampling is required for the detection of GH abuse. This is minimally invasive and has been accepted for use in competitive events for blood doping and erythropoietin detection.