Growth hormone doping in sports: a critical review of use and detection strategies.

GH is believed to be widely employed in sports as a performance-enhancing substance. Its use in athletic competition is banned by the World Anti-Doping Agency, and athletes are required to submit to testing for GH exposure. Detection of GH doping is challenging for several reasons including identity/similarity of exogenous to endogenous GH, short half-life, complex and fluctuating secretory dynamics of GH, and a very low urinary excretion rate. The detection test currently in use (GH isoform test) exploits the difference between recombinant GH (pure 22K-GH) and the heterogeneous nature of endogenous GH (several isoforms). Its main limitation is the short window of opportunity for detection (~12-24 h after the last GH dose). A second test to be implemented soon (the biomarker test) is based on stimulation of IGF-I and collagen III synthesis by GH. It has a longer window of opportunity (1-2 wk) but is less specific and presents a variety of technical challenges. GH doping in a larger sense also includes doping with GH secretagogues and IGF-I and its analogs. The scientific evidence for the ergogenicity of GH is weak, a fact that is not widely appreciated in athletic circles or by the general public. Also insufficiently appreciated is the risk of serious health consequences associated with high-dose, prolonged GH use. This review discusses the GH biology relevant to GH doping; the virtues and limitations of detection tests in blood, urine, and saliva; secretagogue efficacy; IGF-I doping; and information about the effectiveness of GH as a performance-enhancing agent.

Growth hormone isoforms.

Human growth hormone (GH) is a heterogeneous protein hormone consisting of several isoforms. The sources of this heterogeneity reside at the level of the genome, mRNA splicing, post-translational modification and metabolism. The GH gene cluster on chromosome 17q contains 2 GH genes (GH1 or GH-N and GH2 or GH-V) in addition to 2(-3) genes encoding the related chorionic somatomammotropin. Alternative mRNA splicing of the GH1 transcript yields two products: 22K-GH (the principal pituitary GH form) and 20K-GH. Post-translationally modified GH forms include N(alpha)-acylated, deamidated and glycosylated monomeric GH forms, as well as both non-covalent and disulfide-linked oligomers up to at least pentameric GH. GH fragments generated in the course of peripheral metabolism may be measured in immunoassays for GH. The GH-N gene is expressed in the pituitary, the GH-V gene in the placenta. Secretion of pituitary GH forms is pulsatile under control from the hypothalamus, whereas secretion of placental GH-V is tonic and rises progressively in maternal blood during the 2nd and 3rd trimester. Pituitary GH forms are co-secreted during a secretory pulse; no isoform-specific stimuli have been identified. There are minor differences in somatogenic and metabolic bioactivity among the GH isoforms, depending on species and assay system used. Both 20K-GH and GH-V have poor lactogenic activity. Oligomeric GH forms have variably diminished bioactivity compared to monomeric forms. GH isoforms cross-react in most immunoassays, but assays specific for 22K-GH, 20K-GH and GH-V have been developed. The metabolic clearance of 20K-GH and GH oligomers is delayed compared to that of 22K-GH. The heterogeneous mixture of GH isoforms in blood is further complicated by the presence of two GH-binding proteins, which form complexes with GH; isoform proportions also vary depending on the lag time from a secretory pulse because of different half-lives. GH forms excreted in the urine reflect monomeric GH isoforms in blood, but constitute only a minute fraction of the GH production rate. The heterogeneity of GH is one important reason for the notorious disparity among assay results. It also presents an opportunity for distinguishing endogenous from exogenous GH.

Growth hormone (GH) replacement therapy in adult-onset gh deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial.

Adult GH deficiency (AGHD) is characterized by an altered body composition, an atherogenic lipid profile, decreased exercise capacity, and diminished quality of life. We performed a randomized, double-blind, placebo-controlled, multicenter study in 166 subjects with AGHD to assess the effects of GH on these outcomes. GH was initiated at 0.0125 mg/kg.d, increased to 0.025 mg/kg.d as tolerated, or decreased to 0.00625 mg/kg.d for 12 months. Primary measures of efficacy included body composition, strength and endurance, and quality of life. Additional parameters included serum IGF-I concentrations, serum lipids, and bone mineral density. After 12 months, 79% of subjects remained on GH 0.0125 mg/kg.d, whereas 21% received 0.00625 mg/kg.d. GH-treated men and women demonstrated significant decreases in total body and trunk fat and increases in lean body mass over baseline. In GH-treated men, mean IGF-I SD scores exceeded age-adjusted normal ranges, whereas similar doses produced a smaller response in women. GH treatment was associated with significant improvements in total cholesterol and low-density lipoprotein (P < 0.05 for all). No significant treatment effects were observed in strength and endurance, quality of life, or bone mineral density. GH treatment was generally well tolerated. Subjects with AGHD should receive individualized GH therapy to maintain IGF-I between the mean value and +2 SD and improve body composition and cardiovascular risk factors.