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Growth Hormone Replacement Therapy in Adults with Growth Hormone Deficiency Improves Maximal Oxygen Consumption Independently of Dosing Regimen or Physical Activity

Lilly Research Laboratories (M.L.H., A.Z., R.L.Q.), Eli Lilly and Co., Indianapolis, Indiana 46285; Departments of Human Services and Medicine (A.W.), University of Virginia, Charlottesville, Virginia 22908; Medical Service (A.R.H.), Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304; Stanford University (A.R.H.), Stanford, California 94305; Research and Medicine Services (G.R.M.), Veterans Affairs Puget Sound Health Care System, Tacoma, Tacoma, Washington 98493; and University of Washington School of Medicine (G.R.M.), Seattle, Washington 98195

Address all correspondence and requests for reprints to: George R. Merriam, M.D., Research (A-151), VA Puget Sound Health Care System, University of Washington School of Medicine, 9600 Veterans Drive SW, Tacoma, Washington 98493. E-mail: merriam{at}u.washington.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Several studies have demonstrated an improvement in aerobic exercise capacity with 6 months of GH replacement in adults with GH deficiency (GHD).

Objective: The objective of the study was to determine whether improvements in aerobic exercise capacity with GH treatment in adults with GHD are related to changes in physical activity or affected by the GH dosing regimen.

Design: This was a randomized, two-arm, parallel, open-label study.

Setting: The study was conducted at five academic medical centers with exercise physiology laboratories.

Subjects: Study subjects were adults (n = 29) with GHD due to hypothalamic-pituitary disease.

Interventions: The intervention was GH replacement therapy, administered either as a fixed body weight-based dosing regimen as an individualized dose titration regimen for 32 wk.

Main Outcome Measures: Maximal oxygen consumption (VO₂ max) and oxygen consumption (VO₂) at the lactate threshold, ventilatory threshold using a cycle ergometry protocol, and weekly energy expenditure (physical activity questionnaire), assessed at baseline and end point, were measured.

Results: In the group as a whole, VO₂ max increased significantly (by 9%) from baseline (19.1± 0.89 ml/kg·min) to end point (21.6 ± 1.23 ml/kg·min, P = 0.010). Compared with baseline, VO₂ max also changed significantly within the individualized dose titration regimen group (+2.5 ± 0.98 ml/kg·min, P =0.034) but not within the fixed body weight-based dosing regimen group (+1.2 ± 0.78 ml/kg·min, P = 0.15), although these changes from baseline were not significantly different between the two groups. VO₂ at lactate threshold, VO₂ at ventilatory threshold, and weekly energy expenditure also did not change.

Conclusions: GH replacement therapy in GH-deficient adults improved VO₂ max similarly with both dosing regimens, without any influence of physical activity. There was no effect on submaximal exercise performance.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Adults with GH deficiency (GHD) have altered body composition, with approximately 7–8% less lean body mass and 7% greater mean body fat mass than their non-GHD peers (1). Exercise capacity is reduced, with average maximal oxygen consumption (VO₂ max) values only 72–82% of those predicted for age, sex, and height (1, 2, 3). Several placebo-controlled studies demonstrated 9–21% improvements in VO₂ max with 6 months of GH treatment (2, 3, 4). These changes were considered clinically relevant because the VO₂ max increased from 79–82% of predicted values at baseline to 96–111% of expected values after GH therapy (2, 4). In contrast, VO₂ max did not increase in two other placebo-controlled trials of 3–6 months duration despite a significant increase in lean body mass (5, 6). The maximal power output and/or the amount of work subjects were able to perform during cycle ergometry also improved significantly compared with placebo in several studies (2, 3, 4, 7).

Improvements in submaximal exercise performance may be measured by changes in the lactate threshold (LT) or ventilatory threshold (VT; sometimes referred to as the anaerobic threshold). There are data indicating that LT and VT do not occur at the same oxygen consumption (VO₂) or power output and that they adapt differently to exercise training (8, 9). Increases in VT were reported with GH replacement in three studies (2, 4, 6), and this change was significant compared with placebo in two of these trials (2, 6). No study has directly assessed the effect of GH treatment on LT in adults with GHD. In addition, there are few data relating improvements in aerobic exercise capacity to possible changes in spontaneous physical activity that might occur with improved health-related quality of life (QoL) as a result of GH treatment (2, 10).

These early single-center studies of GH-deficient adults used fixed GH doses up to 12.5–25 µg/kg·d without adjustments for serum IGF-I levels (2, 3, 4, 5, 6, 7). Individualized GH treatment based on low starting doses and gradual dose titration to normalize serum IGF-I levels results in fewer adverse side effects and similar improvements in body composition and serum lipoproteins, but effects on exercise performance have not been evaluated (11, 12, 13). It is clinically relevant to determine whether individualized GH dosing improves exercise capacity because these regimens, currently recommended by consensus guidelines (14), result in lower GH maintenance doses than were used in the early adult GHD studies that evaluated exercise capacity (11, 12, 13).

The objective of this study was to compare the effects of individualized GH dosing and fixed weight-based GH dosing on maximal (VO₂ max) and submaximal (VO₂ at LT and VT) exercise capacity in adults with GHD. We also sought to determine whether increases in spontaneous physical activity occur during GH replacement therapy.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

This study was conducted in a subset (29 of 387) of adult subjects with GHD enrolled in a randomized study (61 sites in five countries) comparing an individualized GH dosing regimen (ID) with a fixed body weight-based dosing regimen (FD) (11). For the present substudy, the 29 subjects were enrolled at five U.S. centers with the capability to perform exercise testing. The main study and the substudy used the same inclusion and exclusion criteria (11).

Study design

This investigation was a randomized, two-arm, parallel, open-label study carried out in accordance with Good Clinical Practice guidelines, approval of ethical review committees, and signed informed consent of all subjects. The total treatment period was 32 wk, with bimonthly assessments after randomization to therapy. Randomization was carried out centrally within each country at the level of the main study (11). Subjects in the FD arm received GH therapy (Humatrope; Eli Lilly and Co., Indianapolis, IN) at doses of 4.0, 8.0, and 12.0 µg/kg·d for wk 0–16, 16–24, and 24–32, respectively, with dose adjustments for adverse events potentially related to GH therapy (11). Subjects in the ID arm initiated GH therapy at a dose of 200 µg/d for 8 wk, with dose titrations every 8 wk based on an algorithm described previously (11); dose increases were by 200 µg/d increments up to maximal doses of 400, 600, and 800 µg/d for wk 8–16, 16–24, and 24–32, respectively.

Cycle ergometer test

The cycle ergometer test was performed at the screening visit (wk –4), the second baseline visit (wk 0), and at study end point (wk 32). Two baseline measurements were performed to control for any learning effects, either physiological training or improved performance based on developing more familiarity with the exercise protocol. For subjects taking gonadal steroid replacement, women were tested in the first half of the artificial menstrual cycle and men were tested in the middle of their testosterone replacement interval. Exercise tests were performed at least 3 h after consumption of food and after subjects had taken their standard hormone replacement therapy. If the resting blood pressure exceeded 160/100 mm Hg, the exercise test was postponed. An indwelling venous cannula was inserted into a forearm or hand vein before the test to allow periodic blood sampling. An electrically braked cycle ergometer with an adjustable seat height was used; subjects were required to maintain a pedaling frequency of 60–100 rpm throughout the test. The initial power output was 20 W and was increased by 15 W every 3 min until the subject reached volitional exhaustion or could not maintain the required pedaling frequency.

Metabolic data were collected continuously using standard open circuit spirometry. Heart rate was recorded using surface electrocardiography, and electrocardiogram tracings were monitored for clinically significant changes. Blood samples for measurement of blood lactate concentration were obtained before the test (at rest), during the last 15 sec of each 3-min exercise stage, and at termination of the test. The following data were recorded at rest (before start of test), at the end of each 3-min exercise stage, and at the termination of the test: heart rate, blood pressure, power output, VO₂, CO₂ production (VCO₂), expired ventilation (VE), VE/VO₂, VE/VCO₂, respiratory exchange ratio, and blood lactate concentration. The subject’s weight and height measurements were recorded.

Blood lactate measurement

A lactate analyzer was used to determine the whole blood lactate concentration in each blood sample immediately after collection. At four of the five sites, a YSI model 1500L Sport (YSI Inc., Yellow Springs, OH) lactate analyzer was used. At one site (Nashville, TN), a Monarch model 761 (Instrumentation Laboratories, Lexington, MA) was used.

Physical activity questionnaire

To determine whether changes in physical activity occurred during the 32-wk study, a structured interview was conducted by the exercise physiologist with each subject at baseline and at study end point. Subjects were questioned about a variety of physical activities, including activities of daily living, that they performed regularly (at least once a week) over the previous 3 months using the Aerobics Center Longitudinal Study Physical Activity Questionnaire (15, 16). The exercise physiologist used an interview technique to increase accuracy of the assessment (17) and recorded the frequency, intensity, and average duration of these activities. Upon completion of the questionnaire, results were converted to weekly energy expenditure (kilocalories per week), using methods previously described (18), and were recorded at the site.

Body composition measurement

Changes in body fat mass and lean body mass were assessed by dual-energy x-ray absorptiometry (DEXA), performed at baseline and study end point, as previously described (11).

Exercise data analysis

A single experienced exercise physiologist (A.W.), blinded to the treatment group and the visit number, interpreted all of the exercise tests. Maximal power output and VO₂ max were defined as the highest values for power output and VO₂, respectively, attained during the cycle ergometer test.

Power output and VO₂ associated with LT

Blood lactate concentrations were plotted against cycle ergometer power output or VO₂. The power output or VO₂ at LT was defined as the maximum value obtained for each parameter before the curvilinear increase in blood lactate concentration (19). An elevation in blood lactate concentration of at least 0.2 mM (the error associated with the lactate analyzer) above baseline was required for LT determination.

Power output and VO₂ associated with VT

The VT was determined by examining the VE/VO₂ and VE/VCO₂ relationships. The point at which VE/VO₂ increased abruptly in the absence of an increase in VE/VCO₂ was considered the VT (8, 20). Plots of VE/VO₂, VE/VCO₂, and VO₂ vs. power output were used to define the values associated with the VT.

Statistical analysis

A sample size of 20 subjects per treatment group was planned to provide 80% power to detect within-group changes from baseline to end point in VO₂ max of 4 ml/kg·min based on a SD of 6 ml/kg·min, a baseline VO₂ max of 22 ml/min·kg, and a two-sided significance level of 0.05. The actual number of subjects analyzed was 14 in the FD group and 15 in the ID group, although not every subject contributed to each variable.

To determine whether a learning effect was present, results from the screening visit and the second baseline visit were compared using a t statistic. The treatment effect between the second baseline visit and study end point (last observed value) was of primary interest and was measured by the change from baseline to end point. All subjects were included in the analyses. Differences between groups were assessed using an independent groups t test, but the primary analysis was intended to evaluate the overall effect of GH treatment. This was accomplished by pooling the treatment groups and assessing the pooled change with a t statistic. As a secondary analysis of the change, an analysis of covariance was evaluated with baseline age added as a covariate. Demographics and baseline characteristics were evaluated for group differences using an independent-groups t test for continuous variables and Fisher’s exact test for categorical variables. Pearson’s correlation coefficient was used to assess associations. Data are summarized as mean ± SE. Results were considered statistically significant for P 0.05. SAS (version 8.02; SAS Institute, Cary, NC) was used for all analyses.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subject baseline characteristics (Table 1) were similar between groups with the exception of age, with the FD group being older than the ID group (P = 0.010). In the FD group, all subjects (n = 14) completed the protocol. In the ID group (n = 15), three subjects dropped out of the study, leaving 12 subjects who completed the protocol. The reasons for the early discontinuations were an adverse event (tenosynovitis), patient decision, and physician decision.

Serum IGF-I concentrations did not differ significantly between the dosing groups at baseline (FD: 65.1 ± 6.6 µg/liter; ID: 73.4 ± 20.1 µg/liter) or at study end point (FD: 206.5 ± 32.2 µg/liter; ID: 161.2 ± 23.4 µg/liter). The GH dose at study end point was also not significantly different between the FD (0.77 ± 0.09 mg/d) and ID groups (0.58 ± 0.07 mg/d, P = 0.11).

Maximum power output during the cycle ergometer test did not change between the first and second baseline visits in any group (Fig. 1). A significant increase was observed between the second baseline value and study end point in the all-randomized subjects group (+9.3 ± 3.2 W, P = 0.0086) and the FD group (+12.5 ± 4.1 W, P = 0.011) but not in the ID group (+5.0 ± 5.0 W, P = 0.35).

View larger version (15K): [in this window] [in a new window]   FIG. 1. Mean (± SE) maximal power output at the first baseline visit, the second baseline visit, and at study end point for the all-randomized subjects, fixed dosing group, and individualized dosing group. *, P < 0.05 for the change between the second baseline visit and study end point.

View larger version (17K): [in this window] [in a new window]   FIG. 2. Mean (± SE) VO2 max at the first baseline visit, the second baseline visit, and at study end point for the all-randomized subjects, fixed dosing group, and individualized dosing group. *, P < 0.05 for the change between the second baseline visit and study end point.

A significant increase in VO₂ at LT (Fig. 3) was observed between the first and second baseline visit in the all-randomized subjects group (+1.52 ± 0.56 ml/kg·min, P = 0.011) and the FD group (+2.15 ± 0.94 ml/kg·min, P = 0.041) but not in the ID group (+0.85 ± 0.54 ml/kg·min, P = 0.14). There were no significant differences in VO₂ at LT between the second baseline visit and study end point in any group.

View larger version (19K): [in this window] [in a new window]   FIG. 3. Mean (± SE) VO2 at LT at the first baseline visit, the second baseline visit, and at study end point for the all-randomized subjects, fixed dosing group, and individualized dosing group. *, P < 0.05 for the change between the first baseline visit and the second baseline visit.

There were no statistically significant changes in weekly energy expenditure results estimated from physical activity questionnaires at baseline and at study end point in either the FD (–1703.81 ± 1631.32 kcal/wk, P = 0.31) or ID groups (–620.23 ± 1026.74 kcal/wk, P = 0.56).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
These data confirm previous findings that GH replacement therapy in adults with GHD improves VO₂ max and maximal power output during cycle ergometer testing (2, 3, 4, 7). We observed a 9.0% increase in VO₂ max, comparable with the 9–21% increases reported in earlier studies of GH-deficient adults (2, 3, 4) and also to the 10–15% increase observed with moderate exercise training programs in the general population (21). When the increase in VO₂ max was expressed per kilogram lean body mass, the change did not reach statistical significance, which is consistent with previous studies using higher doses of GH (2, 3, 4). These are the first data to demonstrate that treatment with the lower GH doses achieved with individualized dosing (0.58 ± 0.07 mg/d at end point) results in similar increases in VO₂ max as reported in the older studies using higher GH doses based on body weight (dose range 1–2 mg/d) (2, 3, 4).

Although LT has been measured during acute exercise in GH-deficient subjects receiving GH (22), this is the first study to measure VO₂ at the LT after months of GH replacement therapy. Three studies have previously evaluated VO₂ at the VT (2, 4, 6), but ours is the first to evaluate this end point with the lower GH doses attained with individualized dosing. We observed a significant increase in VO₂ at LT between the first and second baseline visits in the total group of subjects and the FD group. This suggests that as subjects became more familiar with the testing procedure, they were able to exercise at submaximal levels more economically. However, such an effect was not observed with VO₂ at VT or VO₂ max. Treatment with GH for 32 wk did not have any statistically significant effect on VO₂ at LT or VO₂ at VT, suggesting that the doses of GH treatment used in this study did not impact submaximal exercise performance. These results are in contrast to those reported by Woodhouse et al. (6), who observed a significant increase (18%) in VO₂ at VT but not VO₂ max in adults with GHD treated with GH for 3 months. Compared with the present study, Woodhouse et al. studied younger subjects for a shorter period, used higher GH doses that resulted in greater increases in serum IGF-I (200 vs. 100 µg/liter), and used a different protocol (treadmill) to assess exercise performance (6). Of interest, VO₂ at VT improved with 3 months of exercise training in adults with GHD by similar magnitudes in the absence (+9.4%) or presence (+8.6%) of GH therapy (23). Further research into the effect of GH replacement on submaximal exercise performance is needed.

The fact that GH administration did not affect VO₂ at LT is not surprising. Changes in the LT are related to adaptations within skeletal muscle as a result of exercise training and the response is specific to the muscle groups being trained (24, 25). It is well established that the LT is strongly influenced by fiber type distribution (26, 27). A strong direct relationship exists between oxidative characteristics of the actively recruited muscle and the LT (26). The improvement in the blood lactate response to exercise training, even in the absence of an increase in VO₂ max, is associated with increased oxidative activity of muscle fibers (particularly slow twitch and high oxidative fast twitch) (27). The limited data from studies that examined fiber type adaptation as a result of GH administration in GH-deficient adults indicate little if any effect on the proportion of fiber types (6, 28, 29). In contrast, it is well known that VO₂ max is strongly related to maximal cardiac output (30). Previous investigators have suggested that GH replacement may increase VO₂ max by improving cardiac function (due to increased plasma volume and/or a positive inotropic effect) or by increasing erythrocyte mass (resulting in increased oxygen transport capacity) (2, 10, 31, 32, 33). However, studies investigating the effects of GH replacement on cardiac function in GH-deficient adults have yielded mixed results (4, 31, 32). Thus, further research is needed to confirm these suggested mechanisms.

Few studies have evaluated the relationship between physical activity levels and changes in aerobic exercise capacity during adult GH replacement therapy. Cuneo et al. (2) reported that pedometer recordings did not change significantly in either the GH (23 µg/kg·d) or placebo groups after 6 months, and 7-d physical activity recall also did not differ between groups at 6 months. GH replacement therapy, both with fixed body-weight dosing and individualized dosing, has been reported to improve some aspects of QoL, particularly in subjects with adult-onset GHD and those with a greater degree of QoL impairment (1, 10, 11, 34, 35). In this study, no significant changes in weekly energy expenditure, estimated from physical activity questionnaires, occurred within either the FD or ID groups. The apparent absence of an increase in physical activity during the trial suggests that the improvement in VO₂ max was a direct effect of GH treatment.

Limitations of this study must be considered. The study was not designed with a placebo control group because GH had been approved by the Food and Drug Administration for treating adult GHD. Thus, we cannot exclude the possibility of a placebo effect accounting for the increase in VO₂ max during GH treatment. The lack of statistically significant improvement in VO₂ max in the FD group may be related to an inadequate sample size because we were unable to recruit the planned number of subjects despite using five sites. The exercise data for some subjects were incomplete due to inability to complete a maximal test (i.e. criteria for VO₂ max were not met) or failure of blood sampling. Hyperthermia during exercise in adult GHD may lead to lower voluntary effort (36). Some subjects could not have DEXA performed due to their high body mass index. Estimates of energy expenditure obtained from physical activity questionnaires are not as accurate as those obtained using the doubly labeled water technique (37). Finally, the higher mean age of the FD group, compared with ID group, might be related to the randomization for the overall trial being conducted at the country level rather than at the site level; only five of the 22 U.S. sites participated in this addendum study (11). Nevertheless, the increase in VO₂ max remained statistically significant after correcting for age.

In summary, GH replacement therapy in GH-deficient adults improved VO₂ max similarly with both dosing regimens, without any influence of physical activity. There was no effect on submaximal exercise performance. These results are clinically relevant because they demonstrate that the lower GH doses achieved with individualized dosing regimens now recommended by consensus clinical guidelines will improve aerobic exercise capacity (14).

	Acknowledgments

 
In addition to the writing group, investigators in this study included Michael Carlson (Nashville, TN), Richard Dorin (Albuquerque, NM), and Ping Wang (Irvine, CA). We thank the exercise physiologists and study coordinators at the five sites for their assistance with this study.

	Footnotes

 
This work was supported by Eli Lilly and Co.

Disclosure Summary: M.L.H., A.Z., and R.L.Q. are employees and shareholders of Eli Lilly and Co. A.R.H., G.R.M., and A.W. have received consulting fees from Eli Lilly and Co. A.R.H. and G.R.M. have received research grant support from Eli Lilly and Co.

First Published Online October 23, 2007

Abbreviations: DEXA, Dual-energy x-ray absorptiometry; FD, fixed body weight-based dosing regimen; GHD, GH deficiency; ID, individualized GH dosing regimen; LT, lactate threshold; QoL, quality of life; VCO₂, CO₂ production; VE, expired ventilation; VO₂, O₂ consumption; VO₂ max, maximal oxygen consumption; VT, ventilatory threshold.

Received June 26, 2007.

Accepted October 17, 2007.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Simpson H, Savine R, Sönksen P, Bengtsson BÅ, Carlsson L, Christiansen JS, Clemmons D, Cohen P, Hintz R, Ho K, Mullis P, Robinson I, Strasburger C, Tanaka T, Thorner M 2002 Growth hormone replacement therapy for adults: into the new millennium. Growth Horm IGF Res 12:1–33[CrossRef][Medline]
2. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sönksen PH 1991 Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance. J Appl Physiol 70:695–700[Abstract/Free Full Text]
3. Whitehead HM, Boreham C, McIlrath EM, Sheridan B, Kennedy L, Atkinson AB, Hadden DR 1992 Growth hormone treatment of adults with growth hormone deficiency: results of a 13-month placebo controlled cross-over study. Clin Endocrinol (Oxf) 36:45–52[Medline]
4. Nass R, Huber RM, Klauss V, Muller OA, Schopohl J, Strasburger CJ 1995 Effect of growth hormone (hGH) replacement therapy on physical work capacity and cardiac and pulmonary function in patients with hGH deficiency acquired in adulthood. J Clin Endocrinol Metab 80:552–557[Abstract]
5. Rodriguez-Arnao J, Jabbar A, Fulcher K, Besser GM, Ross RJM 1999 Effects of growth hormone replacement on physical performance and body composition in GH deficient adults. Clin Endocrinol (Oxf) 51:53–60[CrossRef][Medline]
6. Woodhouse LJ, Asa SL, Thomas SG, Ezzat S 1999 Measures of submaximal aerobic performance evaluate and predict functional response to growth hormone (GH) treatment in GH-deficient adults. J Clin Endocrinol Metab 84:4570–4577[Abstract/Free Full Text]
7. Jørgensen JO, Pedersen SA, Thuesen L, Jorgensen J, Ingemann-Hansen T, Skakkebæk NE, Christiansen JS 1989 Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet 8649:1221–1225
8. Gaesser GA, Poole DC 1986 Lactate and ventilatory thresholds: disparity in time course of adaptations to training. J Appl Physiol 61:999–1004[Abstract/Free Full Text]
9. Berry MJ, Stoneman JV, Weyrich AS, Burney B 1991 Dissociation of the ventilatory and lactate thresholds following caffeine ingestion. Med Sci Sports Exerc 23:463–469
10. Woodhouse LJ, Mukherjee A, Shalet SM, Ezzat S 2006 The influence of growth hormone status on physical impairments, functional limitations, and health-related quality of life in adults. Endocr Rev 27:287–317[Abstract/Free Full Text]
11. Hoffman AR, Strasburger CJ, Zagar A, Blum WF, Kehely A, Hartman ML 2004 Efficacy and tolerability of an individualized dosing regimen for adult growth hormone replacement therapy in comparison with fixed body weight-based dosing. J Clin Endocrinol Metab 89:3224–3233[Abstract/Free Full Text]
12. Johannsson G, Rosen T, Bengtsson B-Å 1997 Individualized dose titration of growth hormone (GH) treatment during GH replacement in hypopituitary adults. Clin Endocrinol (Oxf) 47:571–581[CrossRef][Medline]
13. Drake WM, Coyte D, Camacho-Hubner C, Jivanji NM, Kaltsas G, Wood DF, Trainer PJ, Grossman AB, Besser GM, Monson JP 1998 Optimizing growth hormone replacement therapy by dose titration in hypopituitary adults. J Clin Endocrinol Metab 83:3913–3919[Abstract/Free Full Text]
14. Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Shalet SM, Vance ML, Endocrine Society’s Clinical Guidelines Subcommittee 2006 Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 91:1621–1634[Abstract/Free Full Text]
15. Kohl HW, Blair SN, Paffenbarger Jr RS, Macera CA, Kronenfeld JJ 1988 A mail survey of physical activity habits as related to measured physical fitness. Am J Epidemiol 127:1228–1239[Abstract/Free Full Text]
16. Blair SN 1997 Aerobics Center Longitudinal Study Physical Activity Questionnaire. Med Sci Sports Exerc 29:S10–S14
17. Sallis JF, Haskell WL, Wood PD, Fortmann SP, Rogers T, Blair SN, Paffenbarger Jr RS 1985 Physical activity assessment methodology in the Five-City Project. Am J Epidemiol 121:91–106[Abstract/Free Full Text]
18. Ainsworth BE, Haskell WL, Leon AS, Jacobs Jr DR, Montoye HJ, Sallis JF, Paffenbarger Jr RS 1993 Compendium of physical activities: classification of energy costs of human physical activities. Med Sci Sports Exerc 25:71–80
19. Weltman A, Seip RL, Snead D, Weltman JY, Haskvitz, Evans WS, Veldhuis JD, Rogol AD 1992 Exercise training at and above the lactate threshold in previously untrained women. Int J Sports 13:257–263
20. Shimizu M, Myers J, Buchanan N, Walsh D, Kraemer M, McAuley P, Froelicher VF 1991 The ventilatory threshold: method, protocol, and evaluator agreement. Am Heart J 122:509–516[CrossRef][Medline]
21. Pollock ML, Gaesser GA, Butcher JD, Després JP, Dishman RK, Franklin BA, Ewing Garber C 1998 ACSM Position Stand: the recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness, and flexibility in adults. Med Sci Sports Exerc 30:975–991
22. Kanaley JA, Dall R, Moller N, Nielsen SC, Christiansen JS, Jensen MD, Jørgensen JO 2004 Acute exposure to GH during exercise stimulates the turnover of free fatty acids in GH-deficient men. J Appl Physiol 96:747–753[Abstract/Free Full Text]
23. Thomas SG, Esposito JG, Ezzat S 2003 Exercise training benefits growth hormone (GH)-deficient adults in the absence or presence of GH treatment. J Clin Endocrinol Metab 88:5734–5738[Abstract/Free Full Text]
24. Yoshida, T, Suda Y, Takeuichi N 1982 Endurance training regimen based on arterial blood lactate: effects on anaerobic threshold. Eur J Appl Physiol 49:223–230[CrossRef]
25. Pierce EF, Weltman A, Seip RL, Snead D 1990 Effects of specificity of training on lactate threshold and VO₂ peak. Int J Sports Med 11:267–272[Medline]
26. Ivy JL, Withers RT, Van Handel PJ, Elger DH, Costill DL 1980 Muscle respiratory capacity and fiber type as determinants of the lactate threshold. J Appl Physiol 48:523–527[Abstract/Free Full Text]
27. Sjödin B, Jacobs I, Svedenhag J 1982 Changes in onset of blood lactate accumulation (OBLA) and muscle enzymes after training at OBLA. Eur J Appl Physiol 49:45–57[CrossRef]
28. Whitehead HM, Gilliland JS, Allen IV, Hadden DR 1989 Growth hormone treatment in adults with growth hormone deficiency: effect on muscle fibre size and proportions. Acta Paediatr Scand 356(Suppl):65–67
29. Cuneo RC, Salomon F, Wiles CM, Round JM, Jones D, Hesp R, Sönksen PH 1992 Histology of skeletal muscle in adults with GH deficiency: comparison with normal muscle and response to GH treatment. Horm Res 37:23–28[Medline]
30. Rowell L 1974 Human cardiovascular adjustments to exercise and thermal stress. Physiol Rev 54:75–159[Free Full Text]
31. Ter Maaten JC, De Boer H, Kamp O, Stuurman L, Van der Veen EA 1999 Long-term effects of growth hormone (GH) replacement in men with childhood-onset GH deficiency. J Clin Endocrinol Metab 84:2373–2380[Abstract/Free Full Text]
32. Colao A, Marzullo P, Di Somma C, Lombardi G 2001 Growth hormone and the heart. Clin Endocrinol (Oxf) 54:137–154[CrossRef][Medline]
33. Christ ER, Cummings MH, Westwood NB, Sawyer BM, Pearson TC, Sönksen PH, Russell-Jones DL 1997 The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency. J Clin Endocrinol Metab 82:2985–2990[Abstract/Free Full Text]
34. Holmes SJ, Shalet SM 1995 Factors influencing the desire for long-term growth hormone replacement in adults. Clin Endocrinol (Oxf) 43:151–157[Medline]
35. Attanasio AF, Lamberts SWJ, Matranga AMC, Birkett MA, Bates PC, Valk NK, Hilsted J, Bengtsson B-Å, Strasburger CJ 1997 Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. J Clin Endocrinol Metab 82:82–88[Abstract/Free Full Text]
36. Juul A, Hjortskov N, Jepsen LT, Nielsen B, Halkjær-Kristensen J, Vahl N, Jørgensen JOL, Christiansen JS, Skakkebæk NE 1995 Growth hormone deficiency and hyperthermia during exercise: a controlled study of sixteen GH-deficient patients. J Clin Endocrinol Metab 80:3335–3340[Abstract]
37. Lamonte MJ, Ainsworth BE 2001 Quantifying energy expenditure and physical activity in the context of dose response. Med Sci Sports Exerc 33(6 Suppl):S370–S378

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