Growth hormone in sportsBaumann; Growth Hormone Doping in Sports: GH is believed jn be widely employed in sports as a performance-enhancing substance. Its use in horrmone competition is banned by the World Anti-Doping Agency, and athletes are required to submit to testing for GH exposure. 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. It human growth hormone definition in sport a longer window of opportunity 1—2 wk but is less specific and presents a variety of technical challenges.
Growth hormone in sports - Wikipedia
Baumann; Growth Hormone Doping in Sports: 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.
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. It has a longer window of opportunity 1—2 wk but is less specific and presents a variety of technical challenges. 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.
The use of GH as a performance-enhancing agent is believed to be widespread among both professional athletes and adolescents participating in sports 1 — 4. A detailed time line of the use of GH in sports is presented in Holt et al. This review critically evaluates the scientific underpinnings of GH use in sports, with particular emphasis on strategies and methods of detection of exogenous GH administration.
GH is a pituitary polypeptide hormone with anabolic and growth-promoting activity. Both its structure and function are species-specific. This review will only discuss hGH because animal GH are not pertinent in the context of doping in humans.
The human genome contains five GH-related genes, located in the GH gene cluster on chromosome 17q These multiple genes are believed to have arisen by gene duplication. Each of the five genes in the cluster is composed of five exons and four introns. The GH-N gene is expressed in pituitary somatotrope cells and, to a minor extent, in lymphocytes, whereas GH-V and CS genes are expressed in the placenta.
In the absence of pituitary or placental GH gene expression, there is no detectable GH in blood, and the clinical features of severe GH deficiency ensue. The main product of the GH-N gene is a amino acid, 22, molecular weight mol wt , single chain, simple unmodified protein with two disulfide bridges Fig.
It is also the recombinant GH available for therapeutic use and for doping purposes. It has amino acids and a mol wt of 20, A third isoform This form has not been shown to be expressed in significant amounts under normal physiological conditions. Primary structure of hGH and its isoforms. The sequence indicated by the bold line from residue 32 to 46 is deleted in 20K-GH. The black dot at the amino terminus denotes the acyl probably acetyl group in N-acylated GH.
The two asterisks denote the deamidated residues in desamido-GH forms. The amino acid designations next to the main chain denote the residues that are changed in placental GH GH-V.
The tree structure at residue indicates the glycosylation site in glycosylated GH-V. Its sequence differs from that of 22K-GH at 13 amino acid positions. It contains a consensus sequence for N-glycosylation at position and exists as both a glycosylated and a nonglycosylated form. The GH-V gene does not produce significant amounts of a 20K variant 11 , GH-V is exclusively produced by the placenta and during pregnancy progressively supplants GH-N in the maternal circulation 13 , It has similar somatogenic activity as GH-N but has reduced lactogenic activity 15 — CS is also produced by the placenta in considerable amounts.
GH is not a single protein, but consists of several molecular variants isoforms. A detailed treatise on GH isoforms has recently been published 18 ; a synopsis tailored to the purposes of the current review follows Table 2. It has a propensity to dimerize, and its dimer is enriched compared to the 22K-GH-dimer 19 , 21 , Recombinant 20K-GH has been produced pharmaceutically 23 but was never developed for therapeutic use.
Whether it is available for illicit use is currently unknown. Proteolytically cleaved GH forms are not considered native forms GH isoforms also exist as an oligomeric series of at least up to pentameric GH, with both covalent disulfide-linked and noncovalently associated oligomers. Homo- as well as heterooligomers composed of the described monomeric forms have been described.
Oligomers are present in the pituitary, are secreted as such, and circulate in blood 21 , 22 , 28 , The tertiary structure of monomeric 22K-GH and 20K-GH is a four-helix, antiparallel, twisted bundle characteristic of the cytokine family of proteins Crystal structures have not been obtained for the other GH isoforms, but it is likely that they retain the same overall conformation.
Part of helix 1 and the loop between helices 1 and 2 with its embedded minihelix are missing in 20K-GH GH action is initiated by its binding to the GHR in target tissues.
The GHR is a plasma membrane-resident receptor of the cytokine receptor class I superfamily It is expressed ubiquitously and is particularly abundant in the liver 32 , The two GHR exist in a predimerized form; binding of GH leads to a conformational change of the dimer followed by signal transduction 35 — The GHR signals through several intracellular phosphorylation cascades, of which the JAK2-Stat5b pathway is particularly important for its growth-promoting activity 37 , Animal GH do not bind to the prolactin receptor, although in some species e.
This property is the basis for the commercial use of bovine GH in the dairy industry. Table 3 lists the principal biological activities of GH. Of particular interest to the athlete are its anabolic and lipolytic activities. From these properties alone it has been assumed that GH must be an ergogenic, performance-enhancing substance. The various GH isoforms have qualitatively similar bioactivities in humans reviewed in Ref.
The reduced diabetogenic activity attributed to 20K-GH based on some rodent data has not been confirmed in human subjects Among the monomeric forms, their in vivo bioactivity appears to be similar in both qualitative and quantitative terms. Oligomeric GH forms generally have reduced bioactivity compared with GH monomers as assessed by in vitro assays; there is only limited information about their bioactivity in vivo GH is secreted from the pituitary gland in a pulsatile fashion under dual hypothalamic control by GHRH stimulatory and somatostatin inhibitory.
Ghrelin, derived from the stomach and possibly the hypothalamus, plays at best a minor role in physiological GH secretion.
The largest pulses generally occur at night and are associated with stage IV slow wave sleep, typically in the early phases of the sleep cycle. This difference is attributable to an estrogen effect Diurnal profiles of plasma GH concentrations.
Patterns representative for men left and women right are shown. Note the logarithmic ordinate, which serves to highlight the lower range of GH fluctuations. The solid black bars indicate sleep periods. Basal plasma growth hormone levels in man: J Clin Endocrinol Metab Cosecretion of GH isoforms. Physiological and pharmacological regulation of kDa growth hormone.
Am J Physiol Endocrinol Metab E—E, 62 , with permission. Obesity attenuates GH secretion; undernutrition and physical fitness enhance it 45 — Acute physiological stimuli for GH release are sleep, exercise, stress, and fasting 46 , 48 — The GH response to exercise has been well-documented and reviewed in detail 51 — GH inhibits its own secretion through both short loop autofeedback 56 , 57 and long loop IGF-I-mediated feedback 58 , 59 Fig. Feedback regulation occurs both at the hypothalamic principal site of GH autofeedback and pituitary levels main but not exclusive site of IGF-I feedback.
Additional feedback regulation of GH secretion occurs through metabolic factors elicited by GH action e. Minus signs denote inhibitory action, the plus sign denotes stimulatory action. Collagen markers produced by tissues in response to GH are added for the purposes of this review, although they are not strictly part of the GH-IGF axis. Growth hormone binding proteins. With respect to GH isoform secretion, there is no evidence for differential regulation of isoforms.
Rather, it appears that all isoforms are cosecreted during a secretory burst 60 — 63 Fig. A major portion of the metabolic clearance of monomeric GH occurs in the kidney, with efficient glomerular filtration followed by extensive degradation in the proximal tubule 64 — Other sites of metabolic clearance are the liver and other tissues, where GH is cleared via GHR-mediated cellular uptake and intracellular degradation.
There is little quantitative information available on this process and how it is distributed among organs; the liver is thought to be an important site because the GHR is abundantly expressed in that organ. I for discussion of GH-binding proteins 67 , Estimates for free and bound GH are 11 and 27 min, respectively It is not clear whether this property is due to its tendency for dimer formation, thereby slowing renal clearance, to its lower affinity for the GHR, or both.
Similarly, the clearance of oligomeric GH forms is also slower than that of monomeric GH; with reported plasma half-lives of 19, 27, and 45 min for monomeric, dimeric, and oligomeric GH, respectively Because of the differences in clearance rates, the relative proportions of GH isoforms in blood change over time, with relative accumulation of the more slowly cleared forms This is the main reason for the observation that 20K-GH and oligomeric GH forms tend to be proportionately higher in blood than in the pituitary After sc injection, a plasma peak is achieved at 4 h, the half-life is 3.
After im injection, the values are similar to those after sc administration, except that the peak is reached earlier at 2 h and the half-life is 4. It should be noted that half-lives after sc or im administration are not true half-lives, but represent a combination of continued absorption and elimination kinetics.