Application of the Athlete Biological Passport approach to the detection of growth hormone doping

2021 ◽  
Author(s):  
Tristan Equey ◽  
Antoni Pastor ◽  
Rafael de la Torre Fornell ◽  
Andreas Thomas ◽  
Sylvain Giraud ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Outcome Measure ◽  
High Dose ◽  
Serum Samples ◽  
Open Label ◽  
Recreational Athletes ◽  
Biological Passport ◽  
Individual Profiles ◽  
Cessation Of Treatment ◽  
Different Doses

Abstract Context Because of its anabolic and lipolytic properties, growth hormone (GH) use is prohibited in sport. Two methods based on population derived decision limits are currently used to detect human GH (hGH) abuse: the hGH Biomarkers Test and the Isoforms Differential Immunoassay. Objective Test the hypothesis that longitudinal profiling of hGH biomarkers through application of the Athlete Biological Passport (ABP) has the potential to flag hGH abuse. Design IGF-1 and P-III-NP distributions were obtained from 7 years of anti-doping data and applied as priors to analyse individual profiles from an hGH administration study in recreational athletes. Setting Academic and anti-doping laboratories. Elite (n=11,455) and recreational athletes (n=35). Intervention(s) An open-label, randomized, single site, placebo-controlled administration study was carried out with individuals randomly assigned to 4 arms: placebo, or 3 different doses of recombinant hGH. Main Outcome Measure(s) Serum samples were analyzed for IGF-1, P-III-NP, and hGH isoforms and the performance of a longitudinal, ABP-based approach was evaluated. Results An ABP-based approach set at a 99% specificity level flagged 20/27 individuals receiving hGH treatment, including 17/27 individuals after cessation of the treatment. ABP sensitivity ranged from 12.5-71.4 % across the hGH concentrations tested following 7 days of treatment, peaking at 57.1-100 % after 21 days of treatment, and was maintained between 37.5-71.4 % for the low and high dose groups one week after cessation of treatment. Conclusions These findings demonstrate that longitudinal profiling of hGH biomarkers can provide suitable performance characteristics for use in anti-doping programs.

scholarly journals Pharmacokinetics and pharmacodynamics of GH: dependence on route and dosage of administration

2007 ◽  
Vol 156 (6) ◽  
pp. 647-653 ◽  
Author(s):  
Alexandra Keller ◽  
Zida Wu ◽  
Juergen Kratzsch ◽  
Eberhard Keller ◽  
Werner F Blum ◽  
...  
Keyword(s):  
Pharmacokinetic Parameters ◽  
High Dose ◽  
Open Label ◽  
Igf Binding Proteins ◽  
Trained Subjects ◽  
Routes Of Administration ◽  
Igf Binding ◽  
Serum Gh ◽  
Different Doses ◽  
Igfbp 3

Objective: Pharmacokinetic and pharmacodynamic data after recombinant human GH (rhGH) administration in adults are scarce, but necessary to optimize replacement therapy and to detect doping. We examined pharmacokinetics, pharmacodynamics, and 20 kDa GH after injection of rhGH at different doses and routes of administration. Design: Open-label crossover study with single boluses of rhGH. Methods: Healthy trained subjects (10 males, 10 females) received bolus injections of rhGH on three occasions: 0.033 mg/kg s.c., 0.083 mg/kg s.c., and 0.033 mg/kg i.m. Concentrations of 22 and 20 kDa GH, IGF-I, and IGF-binding proteins (IGFBP)-3 were measured repeatedly before and up to 36 h after injection. Results: Serum GH maximal concentration (Cmax) and area under the time-concentration curve (AUC) were higher after i.m. than s.c. administration of 0.033 mg/kg (Cmax 35.5 and 12.0 μ g/l; AUC 196.2 and 123.8). Cmax and AUC were higher in males than in females (P < 0.01) and pharmacodynamic changes were more pronounced. IGFBP-3 concentrations showed no dose dependency. In response to rhGH administration, 20 kDa GH decreased in females and remained suppressed for 14–18 h (low dose) and 30 h (high dose). In males, 20 kDa GH was undetectable at baseline and throughout the study. Conclusions: After rhGH administration, pharmacokinetic parameters are mainly influenced by route of administration, whereas pharmacodynamic variables and 20 kDa GH concentrations are determined mainly by gender. These differences need to be considered for therapeutic use and for detection of rhGH doping.

scholarly journals Some experiments relating to artificial immunity in enzootic pneumonia of pigs

1969 ◽  
Vol 67 (3) ◽  
pp. 465-476 ◽  
Author(s):  
R. F. W. Goodwin ◽  
Ruth G. Hodgson ◽  
P. Whittlestone ◽  
Rosemary L. Woodhams
Keyword(s):  
Experimental Infection ◽  
Technical Assistance ◽  
Agricultural Research ◽  
High Dose ◽  
Serum Samples ◽  
Enzootic Pneumonia ◽  
Agricultural Research Council ◽  
Indirect Haemagglutination ◽  
Gel Diffusion ◽  
Different Doses

SUMMARYHysterectomy-produced, colostrum-deprived pigs were injected twice with formalinized antigen prepared from the J strain of Mycoplasma suipneumoniae; the first injection was with Freund's adjuvant and the second injection without adjuvant. The immunity of these animals was tested by inoculating them intranasally with different doses of lung suspension prepared from cases of enzootic pneumonia. Two of the pigs were not killed shortly after infection, but were kept and challenged with enzootic pneumonia in order to compare the serology of experimentally-injected animals with the serology of the immune state following the experimentally-induced disease.In a second main experiment, a pregnant sow was injected twice with nonformalinized antigen without adjuvant, and her litter was subsequently exposed to the disease at 7 days of age after suckling naturally from birth.There was no evidence to suggest that the injections had protected the pigs in the first experiment against a high dose of infection, but they may have given some protection against low doses. The piglets suckled by the injected sow were not protected against two different doses of infection.Serum samples taken at different stages were examined by the metabolic inhibition (MI) test, the indirect-haemagglutination (IHA) test, the complement fixation (CF) test and the gel-diffusion precipitin test, using M. suipneumoniae as antigen.Serum samples taken before injection in the first experiment were all negative in the MI test and they became positive after the injections of antigen. However, 1 the highest MI titres obtained were not associated with obvious immunity; nor was the development of true immunity after experimental infection associated with a change in MI titre.In the first experiment, substantial IHA titres (over 20,000) were recorded by 14 days after the second injection of antigen. Again, there was no correlation between the IHA titres and the area of pneumonia following experimental infection. In the sow experiment, IHA titres developed after the first injection and increased after the second; a high IHA titre occurred in the colostrum and titres of 320 or more were present in the piglets 7 days after birth.The CF titres appeared earlier than the IHA titres but did not increase so markedly thereafter. Once more, there was no correlation between the titre before infection and the area of pneumonia afterwards.In the gel-diffusion test, precipitins were demonstrated in all the post-injection serum samples tested, most of the samples being positive after the first injection. Precipitins were also demonstrated in the colostrum of the injected sow and in her uninjected litter at 7 days of age.From these experiments it was concluded that, as judged by the development of pneumonic lesions and in marked contrast to the known immunizing effect of the disease itself, injections of antigen given in this manner had little or no protective effect against the dose levels of infection used. Nevertheless, the titres obtained in the MI, IHA and CF tests were comparable with those obtained earlier in pigs that were strongly immune, which provides further evidence for the suggestion that these tests do not measure protective immunity.Miss Elaine Repworth provided technical assistance. Most of the expenses of this work, including the salary of two of the authors (R. G. H. and R. L. W.) were met by a grant from the Agricultural Research Council.

scholarly journals High-Sensitivity Chemiluminescence Immunoassays for Detection of Growth Hormone Doping in Sports

2009 ◽  
Vol 55 (3) ◽  
pp. 445-453 ◽  
Author(s):  
Martin Bidlingmaier ◽  
Jennifer Suhr ◽  
Andrea Ernst ◽  
Zida Wu ◽  
Alexandra Keller ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Single Injection ◽  
Recombinant Human Growth Hormone ◽  
Human Growth ◽  
High Sensitivity ◽  
High Dose ◽  
Recreational Athletes ◽  
Before And After ◽  
Sandwich Type ◽  
Preferential Recognition

Abstract Background: Recombinant human growth hormone (rhGH) is abused in sports, but adequate routine doping tests are lacking. Analysis of serum hGH isoform composition has been shown to be effective in detecting rhGH doping. We developed and validated selective immunoassays for isoform analysis with potential utility for screening and confirmation in doping tests. Methods: Monoclonal antibodies with preference for pituitary hGH (phGH) or rhGH were used to establish 2 pairs of sandwich-type chemiluminescence assays with differential recognition of rhGH (recA and recB) and phGH (pitA and pitB). We analyzed specimens from volunteers before and after administration of rhGH and calculated ratios between the respective rec- and pit-assay results. Results: Functional sensitivities were &lt;0.05 μg/L, with intra- and interassay imprecision ≤8.4% and ≤13.7%, respectively. In 2 independent cohorts of healthy subjects, rec/pit ratios (median range) were 0.84 (0.09–1.32)/0.81 (0.27–1.21) (recA/pitA) and 0.68 (0.08–1.20)/0.80 (0.25–1.36) (recB/pitB), with no sex difference. In 20 recreational athletes, ratios (median SD) increased after a single injection of rhGH, reaching 350% (73%) (recA/pitA) and 400% (93%) (recB/pitB) of baseline ratios. At a moderate dose (0.033 mg/kg), mean recA/pitA and recB/pitB ratios remained significantly increased for 18 h (men) and 26 h (women). After high-dose rhGH (0.083 mg/kg), mean rec/pit ratios remained increased for 32 h (recA/pitA) and 34 h (recB/pitB) in men and were still increased after 36 h in women. Conclusions: Using sensitive chemiluminescence assays with preferential recognition of phGH or rhGH, detection of a single injection of rhGH was possible for up to 36 h.

Bioavailability and bioactivity of three different doses of nasal growth hormone (GH) administered to GH-deficient patients: comparison with intravenous and subcutaneous administration

1996 ◽  
Vol 135 (3) ◽  
pp. 309-315 ◽  
Author(s):  
Torben Laursen ◽  
Birgitte Grandjean ◽  
Jens OL Jørgensen ◽  
Jens S Christiansen
Keyword(s):  
Growth Hormone ◽  
Metabolic Response ◽  
Serum Insulin ◽  
Subcutaneous Administration ◽  
Absolute Bioavailability ◽  
High Dose ◽  
Gh Treatment ◽  
Significant Difference ◽  
Igf I ◽  
Different Doses

Laursen T, Grandjean B, Jørgensen JOL, Christiansen JS. Bioavailability and bioactivity of three different doses of nasal growth hormone (GH) administered to GH-deflcient patients: comparison with intravenous and subcutaneous administration. Eur J Endocrinol 1996;135:309–15. ISSN 0804–4643 The current mode of growth hormone (GH) replacement therapy is daily subcutaneous (sc) injections given in the evening. This schedule is unable to mimic the endogenous pulsatile pattern of GH secretion, which might be of importance for the induction of growth and other GH actions. The present study was conducted in order to study the pharmacokinetics of different doses of GH following intranasal (IN) administration and the biological activity of GH after IN administration as compared with sc and intravenous (iv) delivery. Sixteen GH-deficient patients were studied on five different occasions. On three occasions GH was administered intranasally in doses of 0.05, 0.10 and 0.20IU/kg, using didecanoyl-l-α-phosphatidylcholine as an enhancer. On the other two occasions the patients received an sc injection (0.10IU/kg) and an iv injection (0.015IU/kg) of GH, respectively. The nasal doses and the sc injection were given in random order in a crossover design. In a double-blinded manner the subjects received the three nasal doses as one puff in each nostril. The patients received no GH treatment between the five studies or during the last week before the start of each study. Intravenous administration produced a short-lived serum GH peak value of 128.12 ± 6.71 μg/l. Peak levels were 13.98±1.63 μg/l after sc injection and 3.26±0.38. 7.07±0.80 and 8.37± 1.31 μg/l, respectively, after the three nasal doses. The peak values of the 0.05 and the 0.20IU/kg nasal doses were significantly different (p = 0.007). The mean levels obtained by the low nasal dose were significantly lower than those obtained with the medium (p < 0.001) and the high dose (p < 0.001). while there was no significant difference between the medium and the high doses. The absolute bioavailability of GH following sc relative to iv administration was 49.5%. The bioavailabilities of the nasal doses were: 7.8% (0.05 IU), 8.9% (0.10 IU) and 3.8% (0.20 IU). Serum insulin-like growth factor I (IGF-I) levels increased significantly after sc administration only. Mean levels were significantly higher after sc administration as compared with the iv and all three nasal does (p < 0.001). Serum IGF binding protein 3 (IGFBP-3) levels remained unchanged on all five occasions. Mean serum IGFBP-1 levels were significantly lower after sc GH injection than after administration of the iv (p < 0.001) and the three nasal doses (p < 0.005). Subcutaneous GH administration resulted in significantly higher levels of serum insulin and blood glucose (p < 0.001). In conclusion, the bioavailability of nasal GH was low (3.8–8.9%). An iv bolus injection of, on average, 1 IU of GH induced no metabolic response. Only sc GH administration induced increased levels of IGF-I, insulin and glucose. These data reveal that a closer imitation of the physiological GH pulses than achieved by sc GH administration is of limited importance for the induction of a metabolic response to GH. Torben Laursen, Medical Department M (Diabetes & Endocrinology), Aarhus Kommunehospital, DK-8000 Aarhus C. Denmark

scholarly journals The proteomic signature of recombinant Growth Hormone in recreational athletes

2021 ◽  
Author(s):  
Max Esefeld ◽  
Antoni Pastor ◽  
Rafael de la Torre ◽  
Osquel Barroso ◽  
Reid Aikin ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Serum Proteins ◽  
Human Growth ◽  
Biological Processes ◽  
Protein Markers ◽  
Serum Samples ◽  
Recombinant Growth Hormone ◽  
Recreational Athletes ◽  
Protein Levels ◽  
New Biomarkers

Abstract Objectives Administration of human growth hormone (hGH) is prohibited in competitive sport and its detection in an athlete’s sample triggers an adverse analytical finding. However, the biological processes that are modulated by recombinant hGH are not well characterized and associated blood serum proteins may constitute new biomarkers for hGH misuse. Methods Thirty-five recreational athletes were enrolled in a study to investigate the time- and dose-dependent response of serum protein levels to recombinant hGH administration. Participants were randomized into four groups, receiving one of three different doses of recombinant hGH or a placebo. Bio samples were collected at 22 time points over a period of 13 weeks, starting four weeks prior to treatment, three weeks of treatment, and six weeks’ follow-up. A total of 749 serum samples was analyzed for 1,305 protein markers using the SOMAscan® proteomics platform. Results We identified 66 proteins that significantly associated with recombinant hGH administration and dosage, including well known hGH targets, such as IGF1, but also previously unknown hGH-related proteins (e.g.: protease inhibitors, WFIKKN1, and chemokines, CCL2). Network analysis revealed changes in specific biological pathways, mainly related to the immune system and glucose metabolism. Conclusion Our analysis suggests that hGH administration is impacting biological processes more strongly than previously acknowledged. Some of the proteins were dysregulated even after hGH treatment and could potentially be developed into biomarkers for hGH misuse. Moreover, our findings suggest new roles for hGH associated proteins in the etiology of hGH related diseases and may indicate new risks that may be associated with hGH misuse.

scholarly journals A Stereological Study of the Toxic Effects of Cerium Oxide during Pregnancy on Kidney Tissues in Neonatal NMRI Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Afsaneh Nemati ◽  
Vahideh Assadollahi ◽  
Ilaria Peluso ◽  
Abolfazl Abbaszadeh ◽  
Mandana Beigi-boroujeni ◽  
...  
Keyword(s):  
Cerium Oxide ◽  
Serum Levels ◽  
Control Group ◽  
High Dose ◽  
Serum Samples ◽  
Antioxidant Power ◽  
Nmri Mice ◽  
Ferric Reducing Antioxidant Power ◽  
The Mean ◽  
Different Doses

Background. Both antioxidant and prooxidant activities have been previously reported for cerium oxide (CeO2). The aim of this study was to investigate the effects of CeO2 at different doses on changes in kidney tissues and markers in neonatal mice. Methods. We randomly divided 30 pregnant NMRI mice into five groups (n=6 per group)—a control group and four groups treated with intraperitoneal (i.p.) administration of different doses of CeO2 (10, 25, 80, or 250 mg/kg body weight (bw)) on gestation days (GD) 7 and GD14. At the end of the treatment period, we analyzed the kidney tissues and serum samples. The levels of two serum redox markers, malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP), were determined. Data were analyzed using one-way ANOVA and Tukey’s test, and a P value of <0.05 was considered significant. Results. The mean total volumes of the renal corpuscle, glomeruli, and Bowman’s capsule membranes significantly increased, and there was a significant decrease in the mean total volume of Bowman’s space in the high-dose CeO2 group compared to that in the control group. No statistically significant differences existed in the serum levels of MDA and FRAP in the treated and control groups. Conclusion. Our results suggest that high doses of CeO2 impair fetal renal development in pregnant mice, which results in kidney damage. Therefore, CeO2 administration during pregnancy could have dose-dependent adverse effects on the developing kidneys in neonates.

scholarly journals A Multicentric, Open-Label, Randomized, Comparative Clinical Trial of Two Different Doses of Expanded hBM-MSCs Plus Biomaterial versus Iliac Crest Autograft, for Bone Healing in Nonunions after Long Bone Fractures: Study Protocol

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Enrique Gómez-Barrena ◽  
Norma G. Padilla-Eguiluz ◽  
Cristina Avendaño-Solá ◽  
Concepción Payares-Herrera ◽  
Ana Velasco-Iglesias ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bone Healing ◽  
Iliac Crest ◽  
Bone Fractures ◽  
Primary Objective ◽  
Long Bone ◽  
High Dose ◽  
Open Label ◽  
Secondary Objective ◽  
Different Doses

ORTHOUNION is a multicentre, open, comparative, three-arm, randomized clinical trial (EudraCT number 2015-000431-32) to compare the efficacy, at one and two years, of autologous human bone marrow-derived expanded mesenchymal stromal cell (hBM-MSC) treatments versus iliac crest autograft (ICA) to enhance bone healing in patients with diaphyseal and/or metaphysodiaphyseal fracture (femur, tibia, and humerus) status of atrophic or oligotrophic nonunion (more than 9 months after the acute fracture, including recalcitrant cases after failed treatments). The primary objective is to determine if the treatment with hBM-MSCs combined with biomaterial is superior to ICA in obtaining bone healing. If confirmed, a secondary objective is set to determine if the dose of 100 × 106 hBM-MSCs is noninferior to that of 200 × 106 hBM-MSCs. The participants (n=108) will be randomly assigned to either the experimental low dose (n=36), the experimental high dose (n=36), or the comparator arm (n=36) using a central randomization service. The trial will be conducted in 20 clinical centres in Spain, France, Germany, and Italy under the same clinical protocol. The confirmation of superiority for the proposed ATMP in nonunions may foster the future of bone regenerative medicine in this indication. On the contrary, absence of superiority may underline its limitations in clinical use.

Antiviral Effect of High-Dose Ivermectin in Adults with COVID-19: A Pilot Randomised, Controlled, Open Label, Multicentre Trial

2020 ◽  
Author(s):  
Alejandro Krolewiecki ◽  
Adrián Lifschitz ◽  
Matías Moragas ◽  
Marina Travacio ◽  
Ricardo Valentini ◽  
...  
Keyword(s):  
Multicentre Trial ◽  
Antiviral Effect ◽  
High Dose ◽  
Open Label ◽  
Randomised Controlled
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