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BRIEF REPORT |
Department of Endocrinology and Diabetes, Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland
Address all correspondence and requests for reprints to: James Gibney, Department of Endocrinology and Diabetes, Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland. E-mail: james.gibney{at}amnch.ie.
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Abstract |
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Design/Methods: A Medline search and examination of reference lists of included studies and relevant review articles identified 11 studies with utilizable, robust data, involving a total of 268 patients. All included studies were randomized, double blind, placebo controlled, and of either parallel or crossover design. Information was retrieved in uniform format, with data pertaining to patient numbers, study design, GH dose, age, IGF-I levels, and the exercise variables maximal oxygen uptake and maximal power output recorded. The data were analyzed using a fixed-effects model, using continuous data measured on different scales. A summary effect measure (ds) was derived for the individual exercise parameters, whereas an overall summary effect was derived from the sum of all studies across different variables; 95% confidence intervals were calculated from the weighted variances of individual study effects.
Results: GH replacement was associated with significant improvement with all studies combined (ds = +0.32, 0.08–0.56), for maximal power output (ds = +0.4, 0.06–0.74), and maximal oxygen uptake (ds = +0.34, 0.07–0.62). There was no association between age or GH dose on the degree of improvement.
Conclusions: There is strong evidence that GH replacement improves exercise performance in GH-deficient patients. This evidence should be considered when decisions are made regarding prescription of GH.
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Introduction |
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Whether GH replacement improves exercise capacity in GHD adults is less clear. Some but not all of the relatively small studies which have addressed this effect have reported improvements in either or both of maximal oxygen uptake (VO2max) (3, 4, 5, 6, 7, 8, 9, 10) and maximum work rate (3, 5, 6, 8, 9, 11, 12) after GH replacement. However, some of these studies used GH doses now known to be supraphysiological, whereas not all demonstrated statistically significant improvements compared with placebo.
This metaanalysis was carried out to clarify whether high-quality evidence exists that GH replacement improves exercise capacity in GHD adults. This is important because whereas GH replacement has clearly been shown to improve certain variables including body composition, cardiovascular risk factors, surrogate cardiovascular end points, and bone mineral density, (13), there is relatively little evidence regarding functional end points, which are more relevant to GHD patients’ quality of life.
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Materials and Methods |
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Original studies were identified using an on-line Medline database comprising the years 1950 to January 2008 inclusive. The search strategy used the terms growth hormone, human growth hormone, hypopituitarism and exercise, exertion, and exercise tolerance. Abstracts and titles were then screened for relevance to the topic and appropriate full-text articles obtained. Further studies were identified from the reference lists of these retrieved articles and several appropriate related review publications. Full details of retrieval protocol and studies retrieved are shown in Fig. 1
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A sole investigator using a uniform information database extracted data. Studies were assessed in terms of design quality and appropriateness for inclusion in the metaanalysis. Appropriate studies for inclusion needed to be of a randomized, placebo-controlled design, either in crossover or parallel format. The lack of control or comparator groups in those studies employing an open or uncontrolled design meant that the data were not able to be included in the statistical analysis and therefore were not appropriate for inclusion. Authors were contacted to clarify data or obtain missing data as required. Data quality was also rated based on that which was presented in the paper, either in text, table, or figure format. In general, data could be included if mean change over the duration of the study along with appropriate SEM or SD were presented in any of those three formats for both placebo and treatment groups.
Statistical analysis
The retrieved studies used four different variables to measure exercise capacity: VO2max, maximal power output, maximal heart rate, and ventilatory threshold (VeT). For the analysis these variables were examined separately, and to maximize study numbers and improve statistical power, all studies were also combined using a solitary variable from each study. The combined variable used was VO2max data when available, or maximal power output when VO2max was not measured in the study. VeT was not used due to the small number of studies reporting this variable (two).
Data analysis was carried out using a fixed-effects model. The analysis used statistical formulae for the derivation of an effect size in each study, in which studies measured exercise capacity on different scales (VO2max, maximum power output, maximal heart rate), as described by Hedges (14) and published by Petitti (15). Analysis required documentation of values for the mean change in both placebo and experimental groups as well as a pooled SD of the effect measure from the study population as a whole. A summary estimate of effect size was then calculated measured in a common metric (ds): this involved the computation of an individual study effect size, the weight of each study, and subsequent computation of the overall summary estimate of effect for the group of studies. Confidence intervals could then be estimated at the 95% significance level for ds using the variances as described by Hedges (14). A test of homogeneity was carried out by deriving a Q statistic from the values of the computation of an individual study effect size, weight of each study, and ds (15). This could then be referred to a 
2 distribution with degrees of freedom equal to the number of studies included minus 1.
Due to the possibility of confounding and differing overall effects, data were initially calculated for all studies combined and then reexamined with studies involving patients with childhood-onset GH deficiency excluded.
Correlation of mean age and GH dose with the overall effect was analyzed using the Pearson product-moment correlation coefficient (VasserStats on-line statistical computation).
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Results |
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Within the remaining studies, eight measured VO2max (3, 4, 5, 6, 7, 8, 9, 10), seven measured maximal power output (either as watts or kilojoules) (3, 5, 6, 8, 9, 11, 12), nine measured maximal heart rate (although only three contained data usable in the analysis) (3, 4, 5, 6, 7, 8, 11, 12, 30), and two measured VeT (8, 10). The total number of patients pooled from the studies was 268: 208 in studies measuring VO2max; 138 in those measuring maximal power output; and 56 in those included studies measuring maximal heart rate. Table 1 summarizes the patient characteristics and study design of the included studies as well as those excluded and the reasons for their exclusion. Figure 2 shows raw data as presented in the included studies, showing variability in the combined variable across studies.
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Tests for homogeneity, a measure of the similarity of the individual effect measures and thence the accuracy or applicability of the summary effect measure, revealed heterogeneity of effect in the combined variable set (Q = 2.68, P = 0.012) and maximum power data (Q = 0.92, P = 0.012). Homogeneity was not disproved for the data sets of VO2max and maximum heart rate (Q = 2.51, P = 0.74 and Q = 2.19, P = 0.4, respectively).
Removal of the data sets from studies including primarily or solely childhood-onset disease resulted in little change in effect sizes and confidence intervals for all four variable groups but improved the homogeneity of the combined variable group, with subsequent inability to reject the homogeneity hypothesis (Q = 2.19, P = 0.05). Other variables retained similar Q statistics and P values (Table 2).
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Discussion |
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These data are important because whereas the effects of GH replacement on body composition, cardiovascular risk factors, and bone mineral density have been clearly demonstrated there is a paucity of high-quality evidence regarding functional end points. An important role for GH during exercise was first postulated more than 40 yr ago when it was demonstrated that the exercise-induced increase in plasma GH levels preceded an increase in free fatty acids, and it was suggested that through its lipolytic effect GH might exert a glycogen-sparing effect (31). Subsequent studies in GHD adults have confirmed that administration of GH augments lipolysis during exercise, whereas other effects of GH, which are potentially important during exercise include increased cardiac output and red cell mass (increasing oxygen delivery to exercising muscle), increased muscle strength, reduced body fat, and improved thermoregulation (1).
Assessment of exercise performance was carried out in some of the earliest studies of GH replacement in GHD adults, with some evidence provided that GH replacement improves VO2max and maximum work rate (6, 9, 12, 28). However, supraphysiological doses of GH were used, not all studies demonstrated improvement compared with placebo, and one demonstrated no improvement compared with baseline. Most of the later studies using lower doses demonstrated positive effects of GH replacement, although one demonstrated no improvement compared with exercise training (8). It is likely that at least some of the differences in findings of these studies reflected low statistical power to detect significant improvements.
As with any study using metaanalytical techniques, some qualifications are necessary. First, the magnitude of benefit gained is difficult to extrapolate from these figures because the summary effects are calculated in a common metric with units of SD, which will vary from study to study; the result simply states that statistically there is a significant positive difference between treatment groups. Second, interpretation is limited by the strength of the original data available. Small patient numbers within studies leads to larger intrastudy variation, and thus, the likelihood of larger interstudy variation upon calculation of the summary effect. Heterogeneity of individual effects makes interpretation of the summary effect measure more difficult, as is the case with the combined variable and maximal power output results in this analysis. This does not invalidate the findings, however, but should prompt analysis of possible reasons underlying the degree of heterogeneity. It is interesting that removal of studies investigating childhood-onset-GHD patients improved the level of homogeneity within the combined variable group to the point of significance; study numbers and variable study design are likely to be major contributing factors to the residual level of heterogeneity seen. Finally, it should be noted that there is evidence that GH replacement influences clinically relevant exercise-related variables other than VO2max and maximum power output, which could not be included in this analysis. In particular, reduction in O2 consumption relative VeT has been shown to correlate strongly with reduced fatigue after GH replacement (10). Further studies are needed to clarify these effects.
The lack of influence of initial IGF-I levels or age on exercise capacity improvement is interesting because it would be expected that a lower IGF-I, in particular, may be a marker for a greater potential benefit with GH replacement. The small study sizes, however, are likely to contribute partly to the lack of correlation with inadequate power to detect an effect.
In summary, these data provide strong support for a significant positive effect of GH replacement on exercise capacity in patients with GH deficiency. This evidence is potentially important when GH replacement is under consideration both at an individual and a population level.
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Footnotes |
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First Published Online August 12, 2008
Abbreviations: ds, Summary estimate of effect size was then calculated measured in a common metric; GHD, GH deficient; VeT, ventilatory threshold; VO2max, maximum ability to take in and use oxygen.
Received June 9, 2008.
Accepted August 6, 2008.
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References |
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This article has been cited by other articles:
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  J. Svensson and B.-A. Bengtsson Safety aspects of GH replacement Eur. J. Endocrinol., November 1, 2009; 161(S1): S65 - S74. [Abstract] [Full Text] [PDF]
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