Annika Berggren, Christer Ehrnborg, Thord Rosén, Lars Ellegård, Bengt-Åke Bengtsson, and Kenneth Caidahl

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1 X/05/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 90(6): Printed in U.S.A. Copyright 2005 by The Endocrine Society doi: /jc Short-Term Administration of Supraphysiological Recombinant Human Growth Hormone (GH) Does Not Increase Maximum Endurance Exercise Capacity in Healthy, Active Young Men and Women with Normal GH-Insulin-Like Growth Factor I Axes Annika Berggren, Christer Ehrnborg, Thord Rosén, Lars Ellegård, Bengt-Åke Bengtsson, and Kenneth Caidahl Departments of Clinical Physiology (A.B., K.C.), Endocrinology (C.E., T.R., B.-Å.B.), and Clinical Nutrition (L.E.), Sahlgrenska University Hospital, SE Göteborg, Sweden; and Karolinska Institute (K.C.), SE Stockholm, Sweden Context: Despite the fact that the use of GH as a doping agent in sports is widespread, little is known about its short-term effects. Objective: The objective was to study the effects of GH on exercise capacity. Design: A double-blind, placebo-controlled study was used, with a treatment period of 28 d. Setting: Subjects from general community studied ambulatory at a university hospital. Participants: Thirty healthy active young normal volunteers (15 women and 15 men) were recruited by local announcement, and all completed the study. Intervention: All subjects were randomized to receive a low GH dose (0.033 mg/kg d or 0.1 IU/kg d), a high GH dose (0.067 mg/kg d or0.2 IU/kg d), or placebo. Results: We found no effect of the low or high dosages of GH on maximum oxygen uptake during exercise (mean SE for placebo, to ml/kg min; GH low dose, to ml/kg min; GH high dose, to ml/kg min; not significant by two-way ANOVA). Neither was there any effect on maximum achieved power output during exercise or on blood pressure, heart rate, or the electrocardiographic ST level at rest or during exercise. GH significantly increased total body weight (P 0.028), an effect predominantly ascribed to fluid retention (increased extracellular water volume), whereas muscle mass (as indicated by intracellular water volume) did not change. However, changes in the latter correlated to changes in physical performance, possibly due to different training efforts. Conclusion: Administration of supraphysiological recombinant human GH during a period of 4 wk does not improve power output or oxygen uptake. (J Clin Endocrinol Metab 90: , 2005) Main outcome measures: Power output and oxygen uptake on bicycle exercise were the main outcome measures. GH HAS BEEN used extensively as a doping agent, because it is believed to shorten the time required to obtain a sturdy biceps by bodybuilders or to enhance the performance of cyclists or swimmers. In GH-deficient adults, it has been demonstrated that GH increases protein synthesis and improves muscle performance, including exercise capacity (1 6). Physical training has been shown to change circulating levels of GH and, more inconsistently, IGF-I in normal subjects in relation to improvement in oxygen uptake and muscle strength (7 10). To date, no study has demonstrated a beneficial effect of exogenous GH on exercise capacity in normal active subjects. We therefore investigated First Published Online March 22, 2005 Abbreviations: ECW, Extracellular water volume; ICW, intracellular water volume; rhgh, recombinant human GH; TBW, total body water volume; VO 2, oxygen uptake; VO 2 max, VO 2 at peak exercise. JCEM is published monthly by The Endocrine Society ( endo-society.org), the foremost professional society serving the endocrine community. the effect of high dosages of GH in this type of individual to determine the usefulness of GH as a short-term doping agent. We have evaluated the cardiovascular short-term (28-d) effects of doping doses of recombinant human GH (rhgh) in normal fit subjects as part of the GH-2000 Project, which was aimed at detecting GH abuse in sports (11). Subjects Subjects and Methods Thirty healthy active subjects, who were not professional athletes, were selected. We chose 15 women (mean age, 25 yr; range, yr) and 15 men (mean age, 27 yr; range, yr). None of the subjects was receiving medical treatment or had a previous history of cardiopulmonary, autonomic, or neuromuscular diseases. All subjects were normotensive (blood pressure, 150/90 mm Hg), and physical examination revealed no abnormalities at the time of the study. The exclusion criteria consisted of any disease state. Females underwent a pregnancy test. All subjects were fit, meaning that they had taken part in a minimum of two training sessions a week for at least 1 yr. Informed consent was obtained, 3268

2 Berggren et al. Growth Hormone Administration and Exercise Capacity J Clin Endocrinol Metab, June 2005, 90(6): and the study was approved by the ethics committee at Goteborg University. Exercise electrocardiogram Computerized bicycle exercise electrocardiograms were performed using previously described technology developed at our hospital (12, 13). This includes the consecutive averaging of 10-sec intervals of the electrocardiographic signal. The ST level is measured automatically 60 msec after the end of the QRS complex. The computer program was developed locally and run on a standard personal computer. A bicycle ergometer (RE 820/830, Rodby Innovation AB, Södertälje, Sweden), with automatic load increase was used. Oxygen uptake An ergospirometer Vmax 29c (Sensor Medics Corp., Yorba Linda, CA) was used for gas exchange measurements. This measures tidal volume breath by breath using a flow sensor, i.e. an anemomter based on cooling a heated wire by the gas flow. The stated accuracy is 3%. The mass flow sensor was calibrated with a calibration syringe. Oxygen tension in inspired and mixed expired gas was analyzed using a paramagnetic oxygen sensor. Carbon dioxide tension in inspired and mixed expired gas was analyzed using an infrared absorption sensor; both had a response time less than 130 msec and an accuracy of 0.02% (14, 15). The gas analyzers were calibrated with two calibrated gases containing 16% O 2 and 4.0% CO 2, and 26.0% O 2 and 0.0% CO 2. Oxygen uptake (VO 2 ) and minute ventilation were calculated breath by breath, and we used the mean value for the last 30 sec (16). The VO 2 at peak exercise (VO 2 max) was determined using a bicycle with increasing load. The test was terminated at the point of subjective exhaustion. The minute ventilation, VO 2,O 2 pulse (oxygen pulse VO 2 per heart beat), carbon dioxide production, anaerobic threshold [by V slope method (17)], and respiratory quotient were determined. VO 2 max (peak) was regarded as being achieved if the test met two of the following criteria: 1) respiratory quotient greater than 1.0, 2) heart rate 10 beats/min of age-predicted maximum, and 3) plateau in oxygen uptake with increasing workload. The volunteers were asked to breathe through a mouthpiece connected to a Sensor Medics Vmax 29c metabolic computer. All volunteers breathed room air. IGF-I Serum was stored at 80 C until analysis. Serum IGF-I was measured by RIA with a monoclonal antibody after acid-ethanol extraction, using authentic IGF-I for labeling (Nicholas Institute Diagnostics, San Juan Capistrano, CA) with intraassay coefficients of variation of 10.1%, 6.3%, and 5.7% at serum concentrations of 61.5, 340.8, and g/liter, respectively. The analyses were performed by Per-Arne Lundberg at Sahlgrenska University Hospital (Göteborg, Sweden). Intracellular (ICW) and extracellular (ECW) water volumes ICW and ECW were also determined using multifrequency bioelectrical impedance analysis spectroscopy (18). In short, reactance and resistance were determined with a 4000B Bio-Impedance Spectrum Analyzer (Xitron Technologies, San Diego, CA). The extracellular resistance and the total body water resistance were predicted and combined with body weight, height, and resistivity of ECW and ICW to calculate the total body water volume (TBW) and ECW. ICW was calculated as the ECW subtracted from the TBW (ICW TBW ECW). Protocol After a baseline evaluation, a complete history was obtained, and a physical examination was performed in all subjects. Female subjects underwent a pregnancy test. The subjects were randomized, with an even gender distribution in groups, to placebo (n 10), mg/kg d or 0.1 IU/kg d GH(n 10), or mg/kg d or 0.2 IU/kg d GH(n 10). The treatment was administered for 28 d, and evaluations were performed before and at the end of the treatment period. Evaluations were made in terms of computerized electrocardiography recordings during bicycle exercise test starting at 70 watts with an increase in load of 20 watts each minute. Concomitant sampling and analysis of breathing gases were performed. Systolic and diastolic blood pressures were measured at rest in the supine position and sitting on the bicycle before and after the test. Systolic pressure was measured each minute throughout the test. Blood for analysis of IGF-I was collected at baseline and on d 28 of treatment. Statistical evaluations The data are presented as the mean sd for background variables and the mean se for the study measures. The significance of differences between treatment groups was evaluated by ANOVA for changes from baseline to 28 d treatment values. Post hoc test (Bonferroni) was applied in the case of significant group differences. Due to low numbers, possible gender differences were not statistically tested, but are graphically illustrated in Figs. 3 and 4. Pearson s correlation coefficients were computed to evaluate relationships between changes in IGF-I, ICW, or ECW and changes in measures of exercise capacity. Results The demographic, metabolic, and cardiorespiratory findings are listed in Tables 1 and 2. There were no drop-outs from the study. The 30 subjects completed 1 month of treatment. Transient fluid retention and increased sweating were reported side effects (Table 3). We reduced the dose for two of the subjects. There was no change in height, but the body weight was significantly altered; GH treatment caused an increase in weight (Table 1). This increase in weight could be explained by an increase in ECW, and neither correlated to VO 2 max or power output. In contrast, individual changes in ICW correlated to VO 2 max (r 0.41; P 0.05) and power output (r 0.45; P 0.02), but changes in ICW were not attributable to GH treatment. Thus, ICW did not differ significantly between treatment groups (Table 1), and there was no significant relation to changes in IGF-I, whereas changes in ECW were strongly related to changes in IGF-I (r 0.66; P ). No significant alteration was found in heart rate or blood pressure at rest, although there was a tendency toward differences in diastolic blood pressure between groups, with lower values in the high GH group compared with placebo and low GH groups (Table 1). In the placebo group, IGF-I did not change during treatment. IGF-I rose by 67% in the low dose group and more markedly (135%) in the high dose GH group (Table 1). We found no relationship between changes in IGF-I and changes in oxygen uptake or maximum achieved power output. Neither at rest nor during exercise was there a significant difference in the electrocardiographic ST level between treatment groups (Table 2). There was no significant difference between the groups in maximum heart rate response to treatment. We saw no effect of treatment on systolic blood pressure at maximum exercise, nor was there any difference between groups in O 2 pulse, carbon dioxide production, anaerobic threshold, or maximum expired volume. Importantly, we found no effect by low or high dosages of GH on maximum achieved power output during exercise. Some individuals in each group displayed a slight increase in achieved power output (Fig. 1). There was no effect on maximum oxygen uptake (Table 2); the individual response of weight-adjusted VO 2 is shown in Fig. 2. The individual gender response is illustrated in Figs. 1 and 2. No systematic

3 3270 J Clin Endocrinol Metab, June 2005, 90(6): Berggren et al. Growth Hormone Administration and Exercise Capacity TABLE 1. Background variables Variable Occasion Placebo (n 10) Low GH (n 10) High GH (n 10) P value (by ANOVA) Height (m) Baseline month Change Weight (kg) Baseline month Change a Heart rate (beats/min) Baseline month Change SBP (mm Hg) Baseline month Change DBP (mm Hg) Baseline month Change IGF-I ( g/liter) Baseline month Change a a ECW (kg) Baseline month Change a ICW (kg) Baseline month Change Values are the mean SD. DBP, Diastolic blood pressure; SBP, systolic blood pressure. a Significantly different from placebo. difference in gender response was noted, and the lack of such is also illustrated by the average values in Figs. 3 and 4. Discussion In the present study, short-term GH administration did not cause any increase in maximum power output or maximum oxygen uptake despite the administration of supraphysiological doses of GH and an increase in circulating IGF-I. Thus, high doses of GH do not appear to improve aerobic exercise capacity or oxygen uptake in active normal subjects. There is no published evidence that GH leads to an improvement in aerobic exercise capacity in non-gh-deficient subjects (19). On the contrary, Lange et al. (20) suggested that a single relevant GH dose in combination with bicycling exaggerate plasma lactate and may be associated with a reduction in aerobic exercise capacity. A recent study of acute GH administration before exercise demonstrated no effect on total work, caloric expenditure, blood lactate, or perceived exertion, but a lower exercise oxygen consumption (21). Animals treated with GH do not appear to improve their muscle strength, and acromegalic patients may have functionally weak muscles even though they are outwardly hypertrophied (22). The use of anabolic steroids in an effort to improve athletic performance has been well documented (23). Among body builders and athletes, there is also a belief that supraphysiological doses of GH will enhance their physical appearance and performance (Committee on the Judiciary, U.S. Senate: Drug Misuse: Anabolic Steroids and Human Growth Hormone). The same document states that anecdotal reports suggest that GH may actually be preferred to anabolic steroids, because it is not easily detectable with current drug-testing protocols. In the current study, as expected, we found increased levels of IGF-I in our treated groups, but we found no correlation between IGF-I and VO 2 or maximum achieved power output. This accords with the lack of correlation between peak weight corrected VO 2 and endogenous IGF-I or IGFBP-3 demonstrated by Eliakim et al. (10) in normal male subjects. Although plasma IGF-I levels not invariably reflect IGF-I bioactivity, they are in some studies related to peak VO 2 (8, 9). However, these studies did not evaluate the effect of supraphysiological levels of GH and IGF-I on VO 2 and the way they affect maximum power. Instead, VO 2 was more of a correlate for fitness, and because GH increases during exertion, it is likely to be related to VO 2 (24). A correlation between endogenous GH and VO 2 in healthy young adults has been ascribed to degree of fitness (25), but age seems to be a concomitant factor for relationships to the GH-IGF-I axis (25, 26). The achieved peak VO 2 has been found to be more closely related to the 24-h integrated serum GH concentration in male than in female subjects (25), whereas no gender difference was found in its age-dependent relation to a single measure of IGF-I (26). During exercise, the stimulation of GH secretion seems to be greater in women than in men (24). In contrast, we previously demonstrated in the current study

4 Berggren et al. Growth Hormone Administration and Exercise Capacity J Clin Endocrinol Metab, June 2005, 90(6): TABLE 2. Measures of exercise reaction Variable Occasion Placebo (n 10) Low GH (n 10) High GH (n 10) P value (by ANOVA) STV5 rest ( V) Baseline month Change STV5 max ( V) Baseline month Change Power output (watts) max Baseline month Change SBP max (mm Hg) Baseline month Change Heart rate max (beats/min) Baseline month Change VO 2 max (liter/min) Baseline month Change VO 2 max (ml/kg min) Baseline month Change O 2 pulse max (ml/beat) Baseline month Change VCO 2 max (liter/min) Baseline month Change VO 2 at AT (liter/min) Baseline month Change VE max (liter/min) Baseline month Change Values are the mean SE. AT, Anaerobic threshold; SBP, systolic blood pressure; VE, volume expired (minute ventilation). population that, in terms of IGFBP-3, male subjects are more responsive than females to exogenous GH (11). Although the study lacks statistical power to test gender differences, we did not note any tendency to such with regard to maximum aerobic exercise capacity in response to supraphysiological GH treatment. In the current study we did not evaluate all aspects of physical performance, e.g. maximum voluntary muscle strength and flexibility. However, it has been shown that in healthy subjects, even in highly trained power athletes, muscle strength does not improve after GH administration (27 29). Supraphysiological doses of rhgh may also suppress the exercise-stimulated endogenous circulating levels of GH (30) and evoke equivocal effects on the already enhanced muscle protein synthesis induced by the training itself (29, 31). In contrast, replacement therapy in GH deficiency improves reduced ventilatory function and oxygen uptake (32, 33). Furthermore, a beneficial effect of GH replacement has been noted on exercise capacity and perceived maximum power output (1, 6, 33), changes normally related to an increase in muscle mass and lean body mass (1, 2, 6). However, an increase in muscle protein synthesis may not necessarily cause an increase in muscle strength (34). Moreover, it has been demonstrated that GH-deficient adults benefit from TABLE 3. Side effects in the three treatment groups Placebo Low GH High GH Transient fluid retention Increased sweating Muscle pain after exercise FIG. 1. Maximum power output at baseline (B) and after 28 d of treatment (1 mth) in the placebo group and in the low dose GH group (0.033 mg/kg d or 0.1 IU/kg d) and the high dose GH group (0.067 mg/kg d or 0.2 IU/kg d). E, Males; F, females.

5 3272 J Clin Endocrinol Metab, June 2005, 90(6): Berggren et al. Growth Hormone Administration and Exercise Capacity FIG. 2.VO 2 max at baseline (B) and after 28 d of treatment (1 mth) in the same three study groups as those described in Fig. 1 (for symbols, see Fig. 1). resistance training even without replacement therapy (35, 36). Effects other than muscular, from administered GH as well as from training, may be important for work performance. In addition to its direct effects on cardiac and pulmonary muscles in GH deficiency, GH replacement is known to have profound effects on fuel metabolism (37), erythropoiesis, and total blood volume (38), but studies of such effects in healthy trained subjects are lacking. Previous findings by Deyssig et al. (27) do not suggest a muscle strength performance-enhancing effect by low dose GH administration in already trained adults. Probably due to the comparatively low dose, they achieved no total body weight gain after GH treatment, in contrast to our results. However, the weight gain after GH administration in our study was at least partly caused by an increase in ECW and not muscle mass. This could explain why we found no evidence of a positive effect on maximum aerobic exercise capacity in the present study despite the use of a high GH dosage. Small changes in ICW, independent of GH treatment, might be due to different physical exercise habits; some individuals in the various groups may have made an effort to improve their test results. An indication of this is the approximately 10-watt higher power output in each group on the second occasion. FIG. 4. Average oxygen consumption ( SE) in the same three study groups as those described in Fig. 1. F, Female; M, male. Thus, we saw no beneficial effects of rhgh administration on aerobic exercise capacity in active healthy subjects, only water retention. This indicates that only untoward effects can be anticipated from GH abuse (39, 40). Rather, we suggest that a normal level of GH is required for maximum muscle performance to be achieved. The improvement produced by GH substitution in GH deficiency (1) and the comparatively poor exercise performance in acromegalics (22) support this theory. Acknowledgments This study was performed in connection with the GH-2000 antidoping project, a research program performed within the competitive EU BioMed2 Research Program, initiated by the International Olympic Committee and the European Union. We are grateful to Elisabeth Aspenlid, Ann-Christin Karlsson, Ingrid Hansson, Sigrid Lindstrand, and Lena Wirén for technical assistance. Received June 24, Accepted March 15, Address all correspondence and requests for reprints to: Dr. Kenneth Caidahl, Karolinska University Hospital, N2:01, SE Stockholm, Sweden. kencai@ki.se. This work was supported by the Swedish Heart-Lung Foundation, the Swedish Medical Research Council (14231), Göteborg University, the Göteborg Medical Society, and the Sahlgrenska Foundation. References FIG. 3. Average maximum power output ( SE) in the same three study groups as those described in Fig. 1. F, Female; M, male. 1. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH 1991 Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance. J Appl Physiol 70: Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH 1991 Growth hormone treatment in growth hormone-deficient adults. I. Effects on muscle mass and strength. J Appl Physiol 70: Johannsson G, Grimby G, Sunnerhagen KS, Bengtsson BA 1997 Two years of growth hormone (GH) treatment increase isometric and isokinetic muscle strength in GH-deficient adults. J Clin Endocrinol Metab 82: Jorgensen JO, Pedersen SA, Thuesen L, Jorgensen J, Ingemann-Hansen T, Skakkebaek NE, Christiansen JS 1989 Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet 1: Christiansen JS, Jorgensen JO, Pedersen SA, Muller J, Jorgensen J, Moller J, Heickendorf L, Skakkebaek NE 1991 GH-replacement therapy in adults. Horm Res 36(Suppl 1): Johannsson G, Bengtsson BA, Andersson B, Isgaard J, Caidahl K 1996 Longterm cardiovascular effects of growth hormone treatment in GH-deficient adults. Preliminary data in a small group of patients. Clin Endocrinol (Oxf) 45: Eliakim A, Brasel JA, Mohan S, Barstow TJ, Berman N, Cooper DM 1996

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