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Changes in Non-22-Kilodalton (kDa) Isoforms of Growth Hormone (GH) after Administration of 22-kDa Recombinant Human GH in Trained Adult Males¹

Metabolic Research Unit (J.D.W., R.C.C., J.H.), Department of Medicine, and Statistics Section, Department of Social and Preventative Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane 4102, Australia; Neuroendocrine Unit (M.B., C.J.S.), Department of Medicine, Innenstadt University Hospital, 80336 Munich, Germany; Serviço do Endocrinologia e Metabologia do Hospital de Clínicas da Universidade Federal do Paraná (C.L.B.), 80060-240 Curitiba, Brasil; Research Centre for Endocrinology and Metabolism (P.A.L., L.C., T.R.), Sahlgrenska Hospital, Gothenberg, S-413 45 Sweden; Department of Endocrinology (M.B.), St. Thomas’s Hospital, London SE1 7EH, United Kingdom; Department of Internal Medicine and Cardiovascular Sciences (A.C.), Frederico II University, 80131 Naples, Italy; and Department of Medicine M (Endocrinology and Diabetes) (R.D.), Aarhus University Hospital, Aarhus, 8000 Denmark

Address all correspondence and requests for reprints to: Jennifer D. Wallace, Metabolic Research Unit, University of Queensland, Department of Medicine, Princess Alexandra Hospital, Brisbane 4102, Australia. E-mail: jwallace{at}medicine.pa.uq.edu.au

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
GH is being used by elite athletes to enhance sporting performance. To examine the hypothesis that exogenous 22-kDa recombinant human GH (rhGH) administration could be detected through suppression of non-22-kDa isoforms of GH, we studied seventeen aerobically trained males (age, 26.9 ± 1.5 yr) randomized to rhGH or placebo treatment (0.15 IU/kg/day for 1 week). Subjects were studied at rest and in response to exercise (cycle-ergometry at 65% of maximal work capacity for 20 min). Serum was assayed for total GH (Pharmacia IRMA and pituitary GH), 22-kDa GH (2 different 2-site monoclonal immunoassays), non-22-kDa GH (22-kDa GH-exclusion assay), 20-kDa GH, and immunofunctional GH. In the study, 3 h after the last dose of rhGH, total and 22-kDa GH concentrations were elevated, reflecting exogenous 22-kDa GH. Non-22-kDa and 20-kDa GH levels were suppressed. Regression of non-22-kDa or 20-kDa GH against total or 22-kDa GH produced clear separation of treatment groups. In identical exercise studies repeated between 24 and 96 h after cessation of treatment, the magnitude of the responses of all GH isoforms was suppressed (P < 0.01), but the relative proportions were similar to those before treatment. We conclude: 1) supraphysiological doses of rhGH in trained adult males suppressed exercise-stimulated endogenous circulating isoforms of GH for up to 4 days; 2) the clearest separation of treatment groups required the simultaneous presence of high exogenous 22-kDa GH and suppressed 20-kDa or non-22-kDa GH concentrations; and 3) these methods may prove useful in detecting rhGH abuse in athletes.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
GH is being used by elite athletes in an attempt to enhance athletic performance. Recombinant human GH (rhGH) administration is currently undetectable because there is no approved test. Acute exercise is a potent stimulus for pituitary GH secretion (1). GH measured in the circulation is a heterogeneous mixture of many different isoforms (2). All circulating isoforms of GH in nonpregnant human adults are derived from the GH-N gene on chromosome 17. The 1–191 amino acid, 22-kDa GH comprises more than 70% of circulating isoforms (2). Another major isoform is created by alternate messenger RNA splice-deletion of part of exon 3 (residues 32–46) to produce a 176-amino acid, 20-kDa isoform. Other monomeric, dimeric, oligomeric, and protein-bound molecular isoforms have been identified (2, 3, 4, 5).

We have previously reported that all isoforms that we measured peaked at the end of exercise and decrease with disappearance half-times of 19–25 min after acute endurance-type exercise (5A ). Similar to the nonexercised state, the main component of total GH was 22 kDa, with lesser amounts of 20-kDa, non-22-kDa GH (which includes 20- and 17-kDa GH), and immunofunctional GH (which measures isoforms with the two binding sites necessary for GH receptor dimerization). Others have also shown responses of GH isoforms to acute exercise (6, 7, 8, 9, 10, 11).

Measurement of total or 22-kDa GH as a means of detecting exogenous rhGH administration is unlikely to succeed, given the identical amino acid structure of exogenous rhGH and endogenous 22-kDa GH, the substantial (but variable) GH response to exercise, and the rapid half-life of endogenous GH. Supraphysiological doses of rhGH should induce insulin-like growth factor-I (IGF-I)-mediated negative feedback to reduce pituitary GH secretion (12, 13, 14, 15). We hypothesized that suppression of non-22-kDa GH isoforms may represent a means of detecting exogenous 22-kDa GH.

	Materials and Methods

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The details of the study have been reported previously (5A, 16, 17). Briefly, after informed consent for studies approved by Guy’s and St. Thomas’s Hospital’s ethics committee (London, UK), we studied young (age, 18–40), well trained [maximal oxygen uptake (VO₂max) > 45 mL·kg^-1·min^-1], healthy males. After a screening maximal exercise test (visit 1), subjects were randomized to undergo rest and exercise studies (visits 2 and 3) in random order. Subjects were rerandomized to receive either rhGH (Genotropin, Pharmacia & Upjohn, Inc., Stockholm, Sweden) or identical placebo treatment in a parallel, double-blind study. The dose was 0.15 IU·kg^-1·day^-1, self-administered by sc abdominal injection for 7 days. Identical exercise testing protocols were repeated after the final dose of rhGH or placebo (visit 4), and 24, 48, and 96 h later (visits 5, 6, and 7, respectively).

The exercise protocol commenced after a 3-h fast. Each subject presented at an identical time in the late afternoon or early evening. The first six doses were administered at 2000 h, with the seventh dose 3 h before commencement of the visit 4 protocol. At T = -60 min, a venous cannula was inserted using local anesthetic. Subjects rested in a semirecumbent position throughout, except for the period of exercise (T = 0–30 min). Venous samples were collected at -30, 0, 15, 30, 45, 60, 75, 90, and 120 min. Blood was allowed to clot; and serum was separated in a refrigerated centrifuge, snap frozen, and stored at -80 C until assayed. Subjects drank 250 mL water immediately after exercise and again at T = 60, to replace predicted sweat loss. Exercise testing was performed using an electromagnetically braked cycle ergometer (Lode Excalibur Sport, Grunningen, Holland) and Medical Graphics CPX-D Cardiopulmonary Exercise Testing System (Medical Graphics, Birmingham, UK). The screening VO₂max test started at 1.5 W·kg^-1 body weight and smoothly ramped by 25 W·min^-1 until exhaustion, using a cadence of 80 rev·min^-1. The submaximal exercise protocol used in visits 2–7 was identical, consisting of three consecutive stages: 5 min each at 1 and 2 W·kg^-1 and 20 min at 65% of the workload achieved at VO₂max (corresponding to approximately 80% VO₂max).

Assays

The details of the assays have previously been reported (5A ). All samples from each individual were assayed in the one assay run, where possible. Total serum GH (total GH) was assayed using a polyclonal immunoradiometric assay (IRMA, Pharmacia & Upjohn, Inc., Uppsala, Sweden). The assay had 100% cross-reactivity with 22-kDa, deaminated 22-kDa, dimeric 22-kDa, and 20-kDa GH isoforms. 22-kDa GH was measured by a 2-site, monoclonal antibody, time-resolved fluroimmunoassay (Delphia hGH assay, Wallac, Inc. Oy, Turku, Finland). Cross-reactivity with 20-kDa GH was less than 0.001%. Non-22-kDa GH was measured with the 22-kDa GH exclusion assay [22-kDa GHEA (18)]. Sera were stripped of 22-kDa GH monomers and dimers (but not 20-kDa, 17-kDa, or 5-kDa GH) with a specific monoclonal antibody (MCB) and magnetic beads, then reassayed with the Pharmacia IRMA to quantitate non-22-kDa GH isoforms. Samples beyond visit 4 were not processed for this assay. Pituitary GH (Pit-GH) and recombinant or 22-kDa GH (rhGH) were assayed simultaneously in two sandwich-type immunoassays. The Pit-GH assay was permissive in recognizing preferentially pituitary GH consisting of a wide variety of molecular isoforms, including 22-kDa; 20-kDa; and acidic, fragmented, and modified forms of GH. The rhGH assay preferentially recognized recombinant 22-kDa GH (19). 20-kDa GH was assayed with antibodies kindly provided by Mitsui Pharmaceuticals, Tokyo, Japan (20), with modifications. The method involved monoclonal antibody D05 and biotinylated monoclonal antibody 7D5 in a solid-phase fluorometric sandwich assay. The immunofunctional GH assay (GH-IFA) measured isoforms possessing both receptor binding sites, i.e. those capable of biological signaling via GH receptor dimerization (21).

Statistics

Effects of rhGH treatment on the exercise-induced changes in molecular isoforms of GH were assessed by split-plot, repeat-measures ANOVA using a general linear model (7.5 for Windows, SPSS, Inc., Chicago, IL), with within-subject factors being condition (visit) and time point, and the between-subject factor being treatment (rhGH or placebo) and study order (the sequence of the randomized rest or exercise studies at visits 2 or 3). No order effects were seen in any analyses. Data for non-22-kDa GH percent were log-transformed before analysis, to restore a normal distribution. Differences between treatment groups before intervention; the difference in treatment responses, between groups, to visit 4 (pretreatment exercise visit vs. visit 4); and differences in delayed hormone responses (pretreatment exercise visit vs. visits 5–7) were analyzed individually. Bonferroni correction for multiple primary comparisons altered only one result (indicated by asterisk in Results). In the case of a significant difference in delayed responses, post hoc ANOVA was used to compare pretreatment with later visits. Linear regression analysis was applied to the relationships between total GH, 22-kDa GH or GH-IFA, and non-22-kDa GH and 20-kDa GH. Results were reported as mean ± SEM. Assays measured in mass units were converted to Système Internationale units (1 mg = 2.6 U).

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
As previously reported (5A, 16, 17), the characteristics of the 17 male subjects included: age, 26.9 ± 1.5 yr; height, 176.9 ± 1.1 cm; weight, 73.9 ± 2.2 kg; body mass index, 23.6 ± 0.6 kg/m²; percent fat mass, 17.3 ± 1.1; waist-to-hip ratio, 0.84 ± 0.02; and VO₂max, 4.09 ± 0.09 L/min or 56 ± 1.2 mL/min·kg. There were no statistically significant differences between those randomized to the 2 treatment groups, with respect to physical characteristics or pretreatment serum GH isoform responses to acute exercise (see Table 1).

View larger version (16K): [in this window] [in a new window]   Figure 1. The response of molecular isoforms of GH to acute endurance-type exercise. Data represent only visit 4 (i.e. 3 h after the final sc injection of either rhGH (solid symbols and lines) or placebo (open symbols and dotted lines) administration: a, 22-kDa GH; b, 20-kDa GH; c, non-22-kDa GH. Data represent mean ± SEM.

View larger version (43K): [in this window] [in a new window]   Figure 2. Individual responses of ratios of molecular isoforms of GH to acute endurance-type exercise at visit 4. Placebo- (left) and rhGH-treated group responses to non-22-kDa GH:total GH (a), rhGH:pit-GH (b), and 20-kDa GH:GH-IFA (c). Please note the differing scales.

View larger version (18K): [in this window] [in a new window]   Figure 3. Regression analysis of 20-kDa GH vs. GH-IFA (a), 20-kDa GH vs. 22-kDa GH (b), and non-22-kDa:total GH (%) vs. total GH (c). For a and b, data represent normal or untreated individuals (i.e. data at all time points from the placebo group from rest and exercise studies from visits 2–7 and rhGH groups from before intervention for either visit 2 or 3, open circles); and rhGH group at visit 4 (i.e. 3 h after the last dose, solid squares), visit 5 (open triangles), visit 6 (open diamonds), and visit 7 (double crosses). For c, data represent untreated individuals (open diamonds, only to visit 4), and rhGH group at visit 4 (solid squares).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

We made five key observations of the study, 3 h after the treatment last dose. First, the dose of rhGH was supraphysiological, doubling serum IGF-I concentrations. Second, a marked reduction in exercise-induced endogenous pituitary GH secretion was evidenced by the suppressed non-22-kDa and 20-kDa GH responses. Third, exogenous 22-kDa rhGH was recorded as elevated serum total GH, 22-kDa GH, and GH-IFA concentrations. Fourth, the gradual decline in these analytes during that study reflected the sc absorption of the exogenous rhGH. Fifth, the exercise-induced increments in these same analytes were suppressed, most likely reflecting a transient reduction in clearance of the exogenous 22-kDa GH (i.e. caused by reduced hepatic and renal blood flow) rather than a true secretory response (16). We speculate that the doubling of serum total and free IGF-I (16) in the rhGH-treated group would have provided a strong negative feedback inhibitory signal to pituitary GH secretion.

In studies between 24 and 96 h after the last treatment dose, three additional findings were noted. First, the preexercise measures of exogenous 22-kDa GH (i.e. assays for total GH, 22-kDa GH, and GH-IFA) fell to very low concentrations, consistent with the disappearance of the sc injected rhGH (22). Therefore, we suggest that all GH isoforms measured during this period reflected endogenous secretion. Second, the exercise-induced increments of all isoforms was suppressed for up to 96 h after the cessation of rhGH administration. Serum IGF-I concentrations returned toward pretreatment levels by the final study, suggesting the IGF-I-induced negative feedback was responsible for the delayed recovery of pituitary GH secretion. Third, the relative proportions of isoforms produced in response to exercise returned to normal, which suggests that pituitary secretion and systemic isoform processing were qualitatively normal.

In terms of developing a workable test of exogenous 22-kDa rhGH administration, GH molecular isoforms offer three approaches: concentrations, ratios, and regressions of combinations. Suppression of serum concentrations of endogenous GH, i.e. non-22-kDa GH and 20-kDa GH, might seem useful. 20-kDa GH responses were undetectable in five out of eight individuals, and the differences between treatment groups were highly significant at visit 4. In isolation, however, suppressed GH isoform concentrations have low specificity, because of the wide interindividual variation in GH responses to exercise (1). The 22-kDa GH-exclusion assay for non-22-kDa GH at visit 4 revealed incompletely suppressed values, perhaps because of inefficiency of 22-kDa GH extraction at very high total GH concentrations (18) or the presence of degradation products of 22-kDa rhGH, generated either before or after administration (23).

Ratios of suppressed endogenous (in relation to elevated exogenous) rhGH GH isoforms offered more promise. For example, 20-kDa GH:GH-IFA ratio reflected the best of the ratios considered (see Fig. 2). The closest individual values in the two treatment groups were an order of magnitude apart. Limitations of this approach include assay sensitivity, specificity, and detection limits. The utility of the non-22-kDa GH:total GH ratio was hampered by specificity problems. Furthermore, these ratios change after exercise (5A ; Figs. 1 and 2), necessitating extensive, time-specific, normative data in elite athletes. The rhGH:pit GH ratio avoided the assay sensitivity problem, by comparing high concentrations of both a specific rhGH and permissive pit-GH assay. This approach had high specificity and warrants further investigation to address the overlap in one rhGH-treated individual.

Regression analysis, similar to the ratio approach, also compared 20-kDa GH or non-22-kDa GH against total or 22-kDa GH concentrations. The first advantage of this approach was an increase in statistical power by including all untreated time points. The rhGH group, 3 h after the last dose, was between 3 and 5 SDs from the untreated mean. Because 3, 4, and 5 SDs encompass 99.73, 99.99366, and 99.99994% of normal values, the probability of a false positive in an untreated individual in this study would be 1 in 370, 15,772, or 1,666,666, respectively. The second advantage of regressions was the avoidance of reliance on a specific time point for sample collection, a feature of potentially great practical importance.

Detection of exogenous rhGH administration by measuring molecular isoforms of GH was therefore reliable, 3 h (but not 24 h or more) after the last dose. None of the ratios or regressions permitted separation of the two treatment groups beyond visit 4. This underscores the necessity of having both high serum 22-kDa or total GH concentrations (representing exogenous rhGH) and suppression of endogenous GH production. Spontaneous GH secretion has been shown to return to normal, 48 h after cessation of 12 months of rhGH treatment, in children with idiopathic short stature (24); but prolonged rhGH abuse by athletes may theoretically further delay recovery in endogenous GH secretion. Our current study did not define the exact duration of robust detection of rhGH administration, but we predict detection to be unaltered by prolonged rhGH abuse, given the method’s reliance on the presence of circulating rhGH.

Markers of GH actions [the IGF and IGF-BP system and markers of bone and collagen turnover (16, 17, 25)] may permit detection of rhGH administration for several days. Sensitivity has not been fully defined, but it is likely to be lower than for the GH isoform approach. Molecular isoforms of GH currently seem to have the advantage of greater statistical power but the disadvantage of a shorter window of sensitivity. Unannounced, out-of-competition testing, using markers of GH action as a screening test, and subsequent testing with molecular isoforms may prove to be useful in deterring GH abuse.

	Acknowledgments

 
We thank all members of the GH2000 team for support and encouragement and Zida Wu for assay development.

	Footnotes

 
¹ Funded in part by grants from the International Olympic Committee and the European Union (BIOMED 2 Project Number BMH4 CT950678). The development of the pit-GH and rhGH assays was supported by a grant from the Bundesministerium für Sportwissenschaft, Cologne, Germany (VF 0408/08/02/98). This paper was presented, in part, at the Annual Scientific Meeting of the Endocrine Society of Australia, Melbourne, Australia, 1999.

Received June 8, 2000.

Revised December 15, 2000.

Accepted December 28, 2000.

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