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Research Centre for Endocrinology and Metabolism (J.S., G.J.) and Department of Rehabilitation Medicine (K.S.S.), Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden
Address all correspondence and requests for reprints to: Johan Svensson, M.D., Research Centre for Endocrinology and Metabolism, Gröna Stråket 8, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: johan.svensson{at}medic.gu.se.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Adults with GHD also have reduced isometric muscle strength, compared with healthy controls (2, 7, 8), and isokinetic muscle strength and the local muscle endurance is reduced or in the lower normal range (7, 8). Replacement with GH increases muscle volume and maximum voluntary isometric and isokinetic strength, changes that in most studies become apparent after approximately 1 yr of therapy (2, 7, 8, 9, 10, 11, 12, 13). The increase in muscle strength during GH replacement is seen regardless whether the GHD is of childhood or adulthood onset; however, the magnitude of the increase in muscle strength may be greater if the disease is of childhood onset (14). In contrast to the other beneficial effects of GH replacement on muscle strength, the local muscle endurance was not increased during 2 yr of GH treatment (7).
In this single center, prospective, open-label study, the effects of 5-yr GH replacement therapy on muscle performance were determined in 109 consecutive adults with adult-onset GHD.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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One hundred nine consecutive adults (61 men and 48 women) with adult-onset pituitary deficiency and with a mean age of 50.0 yr (SEM, 1.1; range, 22–74 yr) were included between 1990 and 1995. All the patients had known pituitary disease or other pituitary hormonal deficiency. The pituitary deficiency was mainly caused by pituitary tumors or their treatment (Table 1
). Nine of the patients had a history of previous Cushing’s disease, and seven patients had a history of previous acromegaly. The mean time from the cure of the previous Cushing’s disease or acromegaly was 15.1 yr (SEM 3.4; range, 5–34) and 11.6 (SEM 2.1; range, 7–24) yr, respectively. Eighty-four of the patients had been treated surgically and 46 of the patients had received radiotherapy. Most patients had multiple anterior pituitary deficiencies (Table 1). Possibly because of late effects of radiotherapy, several patients had more anterior pituitary deficiencies at study end, compared with baseline (Table 1). In 95 patients, the diagnosis of GHD was based on a maximum peak GH response of less than 3 µg/liter during insulin-induced hypoglycemia (blood glucose, 
2.2 mmol/liter). In four patients with at last one additional anterior pituitary hormonal deficiency, the diagnosis of GHD was based on another stimulation test [a maximum GH response 3 µg/liter during a combined GHRH-pyridostigmine stimulation test (n = 3) or < 1.5 µg/liter during a glucagon stimulation test (n = 1)]. In nine patients, all having at least two additional anterior pituitary hormonal deficiencies, the diagnosis was based on measurements of 24-h GH secretion (n = 6) or three consecutive morning GH concentrations less than 0.33 µg/liter (n = 3). In one patient with three additional anterior pituitary hormonal deficiencies, the diagnosis was based on an IGF-I SD score of -2 SD.
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Four patients died during the study period [renal carcinoma (n = 1), pneumonia (n = 1), myocardial infarction (n = 1), and cause of death unknown (n = 1)]. Four patients discontinued the study because of adverse events [prostatic cancer (n = 1), epileptic seizures (n = 2), and angina pectoris (n = 1)] and two patients because of lack of compliance. Four patients were lost to follow-up because they moved to other parts of Sweden or abroad. All patients were, however, retained in the statistical analysis because the last observed value for each variable was carried forward according to the intention-to-treat approach used.
Study protocol
This is an ongoing, prospective, open-label treatment trial of the administration of recombinant human GH in adult patients with GHD. One hundred nine consecutive adult patients with adulthood-onset GHD were treated for 5 yr with GH. The initial target dose of GH in the first 80 patients was 11.9 µg/kg·d (0.25 IU/kg·wk). The dose was gradually lowered and individualized when the weight-based dose regimen was abandoned (15). In the remaining 29 patients, the GH dose was individualized from the beginning (15). The individualization of the dose of GH was performed with the aim of normalizing IGF-I SD score and body composition in each patient (15).
At baseline and after each year of treatment, physical examinations including measurements of body composition and muscle strength were performed. Titration of the dose of GH was performed every third month during the first year and every sixth month thereafter. Body weight was measured in the morning to the nearest 0.1 kg, and body height was measured barefoot to the nearest 0.01 m.
Ethical considerations
Informed consent was obtained from all patients. The study was approved by the Ethics Committee at the University of Göteborg and the Swedish Medical Products Agency (Uppsala, Sweden).
Body composition
Dual-energy x-ray absorptiometry (DEXA) (Lunar DPX-L, software version 1.3; Lunar Corp., Madison, WI) was used to measure lean body mass (LBM) and body fat (16). The relative error for LBM was 1.5%.
TBN was measured by in vivo neutron activation with a measurement error of approximately 4% (17, 18). TBK was assessed using a whole-body counter (coefficient of variation, 2.2%).
Measurements of muscle function
Isometric knee-extensor and -flexor strength at knee angles of 60 degrees (
/3 rad) and isokinetic concentric muscle strength at angular velocities of 60 degrees/sec (/3 rad/sec) and 180 degrees/sec( rad/sec) were measured using a Kin-Com dynamometer (Chattecx Co., Chattanooga, TN) (19). Gravity correction was used for isokinetic muscle strength (19). The patients were positioned sitting in the test chair with a hip angle of 90 degrees (/2 rad). The knee-joint axis was approximated to the Kin-Com measuring axis. The lower leg was secured to the Kin-Com shin pad at 3 cm proximal to the insertion of the anterior tibialis muscle with the ankle joint at 90 degrees. The trunk, hip, and thigh were strapped down to avoid involuntary movements. Warming-up submaximal exercise was performed on a bicycle ergometer for 5 min before the muscle tests. The methodological errors in duplicate measurements for isometric muscle strength and isokinetic muscle strength at angular velocities of 60 degrees/sec and 180 degrees/sec were 9%, 8%, and 8% respectively (19).
Right and left hand grip strength was measured using an electronic grip force instrument (AB Detector; Grippit, Göteborg, Sweden), which measures the maximum momentary force and the mean force over a set period of 10 sec in newtons. The methodological error between duplicate determinations was between 4.4% and 9.1% (20).
Local muscle endurance in the quadriceps muscle was measured as the percentage reduction (fatigue index) in peak torque between the first and last three knee extensions in a series of 50 maximal voluntary concentric contractions with an angle of velocity of 180 degrees/sec ( rad/sec). The methodological error was 1.4% from duplicate determinations (21).
Muscle strength values from a normal population
In 1994 and 1995, 144 men and women (age, 40–79 yr), selected at random from the population census of the city of Göteborg, were invited to participate in a study measuring muscle function (22). A physical examination was performed to exclude any orthopedic problems, neurological deficits, and hypertension (22). At least one person of each age was tested (22). The subjects formed 10-yr cohorts: 40–49, 50–59, 60–69, and 70–79 yr for each gender (22). The numbers of men/women tested were 16/19, 20/15, 18/27, and 15/14 in increasing age (22).
Comparisons with the reference population were made by applying a predicted value for muscle function to each GH-deficient patient. The predicted value was obtained by calculating a mean value for each muscle test in each 10-yr cohort of men and women in the reference population. Patients younger than 40 yr of age (11 men and 9 women) were given a predicted value from the cohort of healthy controls aged 40–49 yr, assuming no major change in muscle strength in previous adult age periods (23). This assumption may, however, overestimate the muscle strength in relation to normal in the young GH-deficient men (24). The observed/predicted percentages for each patient were then calculated. Mean body height [1.73 (0.02) m], mean body weight [81.5 (2.5) kg], and mean body mass index [27.2 (0.8) kg/m2] in the reference population were similar as in the present study population.
Biochemical assays
Serum IGF-I concentration was determined by a hydrochloric acid-ethanol extraction RIA using authentic IGF-I for labeling (Nichols Institute Diagnostics, San Juan Capistrano, CA). Interassay and intra-assay coefficients of variation were 5.4% and 6.9%, respectively, at a mean serum IGF-I concentration of 126 µg/liter and 4.6% and 4.7%, respectively, at a mean serum IGF-I concentration of 327 µg/liter. The detection limit of the assay was 13.5 µg/liter. The individual serum IGF-I values were compared with age- and gender-adjusted values obtained from a reference population of 197 men and 195 women (25). The individual IGF-I SD scores could then be calculated as described previously (26).
Statistical methods
All the descriptive statistical results are presented as the mean (SEM). For all variables, within-group differences (in the total study population or subgroups of the study population) were calculated using a one-way ANOVA, with all data obtained from all time points, and with time as the independent variable. Post hoc analysis was performed using a Student-Newman-Keuls test.
Between-group differences (men vs. women, gonadotrophin-deficient men on testosterone treatment vs. gonadotrophin-sufficient men, gonadotrophin-deficient women on estrogen treatment vs. gonadotrophin-deficient women without estrogen treatment, and comparisons between age groups) were calculated by a one-way ANOVA, with all data obtained from all time points, and with gender, testosterone treatment, estrogen treatment, and age group, respectively, as the independent variable. To eliminate for baseline differences, data were transformed as percentage change or change from baseline before the analyses of between-group differences.
All analyses were performed using an intention-to-treat approach (based on the last observation carried forward principle). Correlations were calculated using Pearson’s linear regression coefficient. A two-tailed P of 0.05 or less was considered significant.
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Results |
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The mean dose of GH decreased during the first 2–3 yr of the study (Table 2). The mean IGF-I SD score increased from -1.54 at baseline to 1.53 at study end (Table 2). Body weight was unchanged during the 5 yr (Table 2). The GH therapy induced a sustained reduction in body fat and a sustained increase in lean mass, as measured using DEXA (Table 2). TBN was increased as compared with baseline at 1–4 yr of GH treatment but not at 5 yr (Table 2). TBN/TBK ratio was unaffected by the GH treatment during the first 4 yr, whereas after 5 yr, TBN/TBK ratio was decreased (Table 2).
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There was a sustained increase in isometric knee flexor strength, concentric knee flexor strength at an angular velocity of 60 degrees/sec, and peak right-hand grip strength (Table 3). A transient increase was observed in concentric knee flexor and extensor strength at angular velocities of 180 degrees/sec, and average 10-sec right-hand grip strength (Table 3). Isometric knee extensor strength, concentric knee extensor strength at an angular velocity of 60 degrees/sec, and left-hand grip strength were unchanged during the study period (Table 3). The fatigue index, expressed as the percentage reduction in torque at 50 repeated isokinetic knee extensions, was increased by GH replacement therapy (Table 3).
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After correction for age and gender using observed/predicted value ratios, a sustained increase was observed in most muscle strength variables (Table 4). The observed/predicted ratios for knee flexor strength at an angular velocity of 180 degrees/sec and concentric knee extensor strength at 60 degrees/sec were only transiently increased (Table 4). At study end, knee flexor and extensor strength was 96–104% and hand grip strength was 84–90% of predicted values (Table 4). After correction for age and gender, the fatigue index was not significantly different from the baseline value at 5 yr (Table 4).
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The dose of GH (milligrams/day) was similar in both genders (data not shown). Adjusted for body weight, the mean dose of GH was, however, higher in women at all times during the 5-yr period except at baseline (data not shown). The increase in IGF-I SD score was, however, more marked in men (Fig. 1A). In men, TBN was increased at 1–4 yr of GH replacement, whereas in women, TBN was decreased at study end (Fig. 1B). There was no gender difference in the response in TBK (Fig. 1C). There was a tendency toward a gender difference in the response in TBN/TBK ratio (Fig. 1D). The responses in other body composition measurements were similar between men and women.
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and 3). Hand grip strength was not normalized in either men or women (data not shown). The fatigue index was similar in both genders both at baseline and study end, and no gender difference was found in the treatment response.
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Gonadotrophin-deficient men (all on testosterone replacement; n = 50) had, as measured by DEXA, lower total body fat both at baseline (P < 0.05) and study end (P < 0.05) as compared with the gonadotrophin-sufficient men (n = 11) (data not shown). There was no baseline difference between gonadotrophin-deficient and gonadotrophin-sufficient men in any other variable measured in this study (including muscle strength). The treatment response after 5 yr was similar in all variables measured (data not shown).
There was no baseline difference in any variable measured in this study including muscle strength between gonadotrophin-deficient women on estrogen treatment (n = 24) and gonadotrophin-deficient women not receiving estrogen treatment (n = 20) (data not shown). [A baseline comparison vs. gonadotrophin-sufficient women was not meaningful because of the low number of patients in this group (n = 4).] The treatment response was similar in all variables measured between gonadotrophin-deficient women on estrogen treatment and gonadotrophin-deficient women without estrogen treatment (data not shown).
Effects of age
Patients in the upper age quartile [mean age 64.5 yr (range 59.6–73.7)] had lower baseline body weight (P < 0.05), TBN (P < 0.05), and TBK (P < 0.05) values than patients in the lowest age quartile [mean age 34.3 yr (range 21.7–42.2)] (data not shown). Body mass index, TBN/TBK ratio, and total body fat and lean mass as measured by DEXA, were similar between the two groups at baseline. Serum IGF-I concentration (P < 0.01) and all variables reflecting muscle strength (except for the fatigue index) were lower at baseline in patients in the upper age quartile. IGF-I SD score and all observed/predicted ratios (muscle strength corrected for age and gender) were, however, similar between the two groups at baseline. The treatment response after 5 yr was similar in the two groups in all variables measured (data not shown).
Correlation analysis
Baseline isometric knee extensor strength, average 10-sec right-hand and left-hand grip strength, and fatigue index were negatively correlated with the percentage change in these variables at study end (r = -0.20, P < 0.05; r = -0.25, P < 0.05; r = -0.23, P < 0.05; and r = -0.63, P < 0.001, respectively). In other variables reflecting muscle strength, the baseline absolute values were not correlated with the percentage change in the variables after 5 yr. However, inverse correlations were observed between all baseline ratios of observed/predicted muscle strength (muscle strength corrected for age and gender) and the percentage change at study end in the variables. This means that those patients with the lowest observed/predicted muscle strength had the greatest response to treatment. The baseline observed/predicted value ratio and the percentage change at study end in the fatigue index also showed a strong negative correlation (r = -0.60, P < 0.001). Therefore, the patients with highest observed/predicted fatigue index had the lowest increase in the fatigue index.
At baseline, serum IGF-I concentration was positively correlated with all muscle strength variables except for the fatigue index (data not shown). At study end, the percentage change in serum IGF-I concentration was not correlated with the percentage change in any variable reflecting muscle strength. The absolute change in serum IGF-I concentration was, however, positively correlated with the absolute changes in isometric knee flexor strength (r = 0.24, P < 0.05), isometric knee extensor strength (r = 0.20, P < 0.05), and average 10-sec right-hand grip strength (r = 0.20, P < 0.05).
Baseline age was not correlated with the percentage change at study end in any variable reflecting muscle performance (data not shown).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The 5 yr of GH treatment increased, as previously found in studies with shorter duration (2, 7, 8, 9, 10, 11, 12, 13), isometric (60 degrees) and isokinetic (60 degrees/sec) knee flexor strength. The effects on isometric (60 degrees) and isokinetic (60 degrees/sec) knee extensor strength were less marked than isometric/isokinetic knee flexor strength as also previously observed (7). Right- and left-hand grip strength, compared with predicted values, was lower than knee flexor and extensor strength both at baseline and study end. This is in line with the previous finding that GH replacement therapy induced a greater increase in proximal than distal muscle mass (27). A larger effect by GH on proximal leg muscle strength than hand grip strength could therefore be anticipated.
GH replacement has been shown to increase well-being and physical activity (6, 28). In the present study, the physical activity level of the patients was not measured, but a possible increase in physical activity might have contributed to the increase in muscle strength. It has been suggested that the strength in proximal leg muscle groups may be more affected by physical activity level and exercise than hand grip strength (29, 30, 31). It could therefore be speculated that a possible increase in physical activity in this study could, at least partly, explain the differences in the response to GH replacement in different muscle groups.
In this study, as previously observed in a 2-yr trial (7), GH replacement induced a sustained increase in the quadriceps fatigue index, suggesting a decrease in the local muscle endurance. However, after correction for age and gender, this effect disappeared at the end of the present study. The fatigue index is less affected by age than most other variables reflecting muscle performance (22). This suggests that only a part of the decline in quadricep muscle endurance was due to aging in this study. Other factors, such as initial water retention or possible metabolic changes in the muscles (7), may also be of importance for the transient decline in quadriceps muscle endurance.
The maximum effect on muscle performance was observed after 2–3 yr of GH replacement. The lowering of the dose of GH during the first years of this study could explain the tendency toward a decrease in muscle strength during the last 2–3 yr of the study. However, a reduction in muscle strength of approximately 7% would be expected during a 5-yr period in the reference population (22). Therefore, the increased age of the patients during the present study could contribute to the tendency toward a decline in muscle strength between yr 2 and yr 5 of follow-up. In support of this, knee flexor and extensor strength was normalized in the total study population (
100% of predicted) already after 2 yr of therapy and then maintained at a level of approximately 100% of predicted throughout the study period.
In this study, a preserved responsiveness to GH replacement was observed in all age groups. The response in muscle strength (percentage change from baseline) to GH replacement therapy was similar in the eldest quartile as in the youngest quartile of the GHD patients, and no relation was found between baseline age and the responses in muscle performance after 5 yr. The baseline muscle strength in isometric knee extensor strength and average 10-sec right-hand and left-hand grip strength was negatively related with the percentage change in the variable after 5 yr. If age and gender were corrected for, however, inverse relationships were found among all baseline observed/predicted ratios of muscle strength and the percentage change in the muscle strength variables after 5 yr of treatment. Although this could be due to regression toward the mean, it may suggest that patients with low baseline muscle strength in relation to normative data had the greatest response in muscle strength. This, as well as the normalization of knee flexor and extensor strength, could suggest that GH could only increase muscle strength toward that predicted for age and gender. This observation therefore suggests that GH replacement in adults can normalize, but not supranormalize (rejuvenate), muscle performance in all age groups.
At baseline, serum IGF-I concentration was positively correlated with all muscle strength variables except for the fatigue index. This is in line with previous observations that GH as well as IGF-I is of importance for muscle morphology, function, and metabolism (7, 32). No correlation was found in the present study between the percentage change in serum IGF-I concentration and the percentage change in any measure of muscle function. The absolute change in serum IGF-I concentration was, however, positively correlated with the absolute change in some measures of muscle strength. These positive correlations may suggest that the increase in muscle strength by GH was partly mediated by the increase in circulating IGF-I.
In the present study, as measured by DEXA, the gonadotrophin-deficient men (all on testosterone replacement) had lower total body fat, both at baseline and study end, than the gonadotrophin-sufficient men. Testosterone treatment decreases body fat and increases LBM (33), and administration of testosterone in supraphysiological doses has been shown to increase muscle strength (34). There was, however, no baseline difference in any measure of muscle strength between gonadotrophin-deficient and gonadotrophin-sufficient men in this study, and the treatment response in muscle strength was similar between these two groups. This suggest that the increase in muscle strength observed in the GHD men was induced by the GH replacement therapy and not by supraphysiological testosterone treatment.
The treatment response in all variables reflecting muscle performance was similar in both genders. Muscle strength was, however, lower in women than men throughout the study also after correction for age and gender. At study end, knee flexor and extensor strength were 100% or more of predicted in men, whereas only isometric knee flexor strength was fully normalized in women. Suboptimal estrogen replacement therapy could be of importance because it has been suggested that estrogen status affects muscle strength (35). In the present study, 55% and 61% of the estrogen-deficient women received estrogen therapy at study start and study end, respectively. However, we could not detect any difference in baseline muscle strength or the treatment responses in muscle strength between gonadotrophin-deficient women with or without estrogen therapy. The lower age- and gender-adjusted muscle strength in women may therefore be an effect of the severe androgen deficiency seen in hypopituitary women (36, 37).
In the GHD women, TBN was decreased at study end. Oral estrogen replacement therapy might reduce protein synthesis during GH treatment (38). We could, however, not detect any difference in the treatment response in TBN or any other variable measured in this study between gonadotrophin-deficient women with or without estrogen therapy (data not shown). TBN reflects total body protein (6, 39), whereas TBK reflects body cell mass (6, 40). The observed decrease in TBN/TBK ratio in women is therefore likely to reflect decreased extracellular proteins in relation to intracellular proteins at study end, which is probably of less importance for muscle strength.
In conclusion, the results of this single-center, prospective, open-label study showed that long-term GH replacement therapy in adults induced a sustained increase and normalization of isometric and isokinetic knee flexor and extensor strength. After 2–3 yr of treatment, an influence of age on muscle performance could be detected indicating that age-related decline in muscle strength may occur, independent of GH/IGF-I. In agreement with previous data, women had fewer anabolic effects of treatment than men but demonstrated a similar response in muscle performance. Finally, proximal muscle groups may respond more markedly to GH treatment than more distal muscles.
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Acknowledgments |
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Footnotes |
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Abbreviations: DEXA, Dual-energy x-ray absorptiometry; GHD, GH deficiency; LBM, lean body mass; TBK, total body potassium; TBN, total body nitrogen.
Received June 10, 2002.
Accepted February 10, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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