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Research Centre for Endocrinology and Metabolism (G.J., B.-Å.B.), Department of Clinical Nutrition (L.Hu., L.Ha.), and Department of Rehabilitation Medicine (K.S.S., G.G.), Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden
Abstract
The postpubertal period and the early years of adulthood may be of importance for continuing tissue maturation of importance in adulthood and aging. An example of this is the peak bone mass. This study has evaluated the importance of GH for lean mass and muscle strength in adolescents and young adults. GH treatment was discontinued in 40 adolescents aged 16–21 yr with GH deficiency of childhood onset. Measurements of isometric and isokinetic knee-extensor and flexor strength, handgrip strength, lean body mass, fat-free mass, and total body nitrogen were performed annually for 2 yr. Two hundred fifty healthy adolescents were randomly selected for prospective measurements of lean mass and handgrip strength between the ages of 17 and 21 yr. In the adolescents with continuing GH deficiency, lean body mass decreased, compared with the patients defined as having sufficient endogenous GH. The isometric strength in knee flexors increased in the sufficient endogenous GH group and was unchanged in the GH deficiency group during the 2 yr off GH treatment (between group, P < 0.05). The mean and peak handgrip strength increased on average by 9–15% in the group with sufficient endogenous GH and was unchanged in those with GH deficiency (P < 0.05). Lean body mass and handgrip strength (both, P < 0.001) increased in both the healthy boys and girls who were followed for 4 yr with a more marked increase in the boys. The mean increase in handgrip between the age of 17 and 21 yr was 7–9%. The increased lean mass and improved muscle performance seen in healthy adolescents did not occur in adolescents with GH deficiency. These findings suggest that GH is of importance for the maturation of lean mass and muscle strength in adolescents and young adults.
DURING PUBERTY, LEVELS of sex steroids and GH increase markedly and interact in a complex manner (1). During this period longitudinal bone and tissue growth reaches its peak (2, 3). Whether the influence of GH and sex steroids can explain all features of the pubertal development is not known.
The postpubertal period and the early years of adulthood may be of importance for tissue maturation with slower changes than during puberty but of importance for adulthood and aging. The best example of this is the peak bone mass that occurs sometime between the postpubertal years and the third to fourth decade of life (2, 4, 5), which is of importance for the bone density and fracture risk in adults. That GH may be of importance for the attainment of peak bone mass is supported by reduced bone mineral density in young adults with childhood-onset GH deficiency (6).
Cross-sectional studies indicate that peak muscle strength occurs between 20 and 30 yr of age (7, 8). Indirect evidence that GH may be of importance in this development is the reduced muscle mass and strength found in young adults with GH deficiency (9). Moreover, there is an association between the increase in lean body mass and bone mass in children (10). Both the continuing consolidation of bone and maturation of muscle in young adults are therefore of importance in the decision of whether to continue GH replacement during the transition between childhood and adulthood in adolescents with GH deficiency.
The aim of this prospective trial was to study the longitudinal development of muscle strength and lean tissue in adolescents and the impact of GH on these measurements. Adolescents discontinuing GH treatment since childhood were followed for 2 yr, and a large cohort of healthy control adolescents was followed annually for 4 yr.
Subjects and Methods
Patients
Forty adolescent patients on GH-promoting treatment were
recruited for the study as previously described (11). In
short, the criteria for inclusion were GH deficiency of childhood
onset. They should have received GH treatment for the past three
consecutive years and were otherwise being considered to end treatment.
Most subjects had idiopathic and isolated GH deficiency and 12 subjects
had organic hypothalamic/pituitary disease (Table 1
). Patients with other anterior
pituitary hormone deficiencies received, when required, stable
replacement therapy with glucocorticoids (7), thyroid
hormone (12), and gonadal steroids (10). The
mean daily dose of cortisone acetate and T4 was
21 mg (range 15–20) and 0.12 mg (range 0.05–0.2), respectively. All
other hormone replacement was kept stable 3 months before entering the
study and throughout the study period. There was no patient in the
hypopituitary group that had visual impairment or a physical
disability that could impair on daily physical activity.
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On the basis of the results of the GH secretion assessments, the subjects were retrospectively classified into two groups as previously described (11): a GH-deficient (GHD) group in which continued severe adult GHD was identified, and a GH-sufficient (GHS) group. Thus, 21 patients were classified as GHD and 19 as GHS. These two patient groups were similar in terms of the average daily dose of GH during the past 2 yr before entering the study. The period of GH treatment was, however, longer in the GHD group (9 yr; range 4–15 vs. 7 yr; range 3–16 yr; P = 0.04) and the prospective evaluation of age at onset of puberty was somewhat lower in the GHD group (13 vs. 14 yr).
Healthy population
A cohort study of a representative group of 1244 adolescents, 620 boys and 624 girls, was performed in 1994 in Göteborg, Sweden. Data were originally collected to gather baseline information on iron status in Swedish adolescents before the general iron fortification of white wheat flour was removed. Adolescents, 15–16 yr old in different socioeconomic areas in Göteborg, were selected to be representative for the population according to a socioeconomic index. Information about food habits and health status in this population will be presented elsewhere.
From the original study group of 1244 adolescents, a subgroup of 250 boys and girls was randomly selected for further measurements. Out of this subgroup, 237 (95%) adolescents (137 girls and 100 boys) agreed to participate (12). This group was followed annually for 4 yr between the age of 17 and 21 yr with measurements of DXA and handgrip strength.
Methods
Muscle function. Knee-extensor and flexor strength for
isometric contraction at a knee angle of 60 degrees (
g/3 rad), for
isokinetic concentric muscle action at angular velocities of 180
degrees/sec ( g rad/sec) and local muscle endurance in quadriceps
was measured using a Kin-Com dynamometer (Chattecx Co.,
Chattanooga, TN) as previously described (13). The
methodological error for duplicate measurements for isometric muscle
strength, isokinetic muscle strength at an angular velocity of 180
degrees/sec, and local muscle endurance was 9%, 8%, and 1.4%,
respectively (14).
Right and left handgrip strength was measured using an electronic grip force measurement instrument (Grippit, AB Detector, Göteborg, Sweden), which measures the maximum momentary force and the mean force over a set period of 10 sec in Newton using the same method and set-up as previously described (15). The methodological error between duplicate determinations has been shown to be 4.4–9.1% (16). Verbal instructions were given to encourage maximal force production. All measurements in patients (M.H.) and controls (S.L.) were performed by the same study technician.
Body composition. Body weight was measured in the morning to the nearest 0.1 kg with the subject wearing indoor clothing, and body height was measured barefoot to the nearest 0.01 m.
Lean body mass was determined using DXA. The Lunar Corp.-DPX-L (Lunar Corp., Madison, WI) was used in the patients and the 2000 Plus (Hologic, Inc., Waltham, MA) in the controls. Precision error (1 SD) on the Lunar Corp.-DPX-L as determined from double examinations of 10 healthy subjects was 0.7% for lean body mass.
Total body potassium was measured by counting the emission of 1.46 MeV
radiation from the naturally occurring 40K
isotope in a high-sensitive 3
whole-body counter with a
coefficient of variation of 2.2%. Body cell mass was calculated on the
assumption that there is a constant intracellular potassium/nitrogen
ratio of 3 mmol of potassium per gram of nitrogen and a protein content
equal to 25% of the body cell mass.
Total body nitrogen was measured by in vivo neutron activation. This method is based on the capture of low-energy (thermal) neutrons by N nuclei. A Cf source was used to produce the neutrons. The patients were irradiated from below by a 15 cm x 50 cm rectangular neutron field. The measurement error is approximately ±4%.
Ethics
Informed consent was obtained from all patients. The Ethics Committee at the Faculty of Medicine, Göteborg University, approved the study.
Statistical analysis
All descriptive statistical results are presented as the mean and SEM or the mean and a 95% confidence interval. A two-stage method was used for statistical analysis (17), which means that the repeated measurements from each patient were reduced to one summary variable, reflecting the within-individual change with time. In the present study, the coefficient of the slope (ß) for the estimated individual regression line was chosen as the summary variable, using each effect variable as a dependent and time as an independent variable. A t test was used to test effect of treatment and differences among subgroups of patients. Correlations were sought by calculating Pearson’s linear correlation coefficient. Significance was obtained if the two-tailed P value was 0.05 or less.
Results
Four patients were not followed for 2 yr. One man was not interested in further investigations after the baseline visit, and two women and one man with severe GHD withdrew from the study as a result of psychological symptoms. Fifteen healthy controls with only one baseline measurement at the age of 16 yr were excluded from the analysis.
Patients discontinuing GH
Body weight increased in the GHS patient group from 64.7 ±
2.7 at baseline to 68.1 ± 3.5 kg after 2 yr (P <
0.01) and not in the patients with continuing GHD into adulthood. This
increase was associated with unchanged fat-free mass, lean body mass
(Fig. 1A) and total body nitrogen in the
GHS group. In the GHD group, however, fat-free mass decreased from
56.2 ± 2.3 at baseline to 51.6 ± 2.2 kg (P
= 0.009) at 2 yr, lean body mass decreased from 50.7 ± 1.9 to
46.9 ± 1.7 kg (P = 0.002) (Fig. 1A), and total
body nitrogen decreased from 1.95 ± 0.10 to 1.64 ± 0.06 kg
(P = 0.009). The mean individual time response in these
measurements were different between the two patient groups (fat-free
mass, P = 0.04; lean body mass, P =
0.03, and total body nitrogen, P = 0.009).
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)In the GHD adolescents, the isometric strength in knee extensors and knee flexors did not change during the 2-yr period after GH treatment was discontinued. The concentric muscle strength during knee flexion at an angular velocity of 180 degrees/sec decreased and a similar tendency for concentric knee extension at an angular velocity of 180 degrees/sec was found. The GHS adolescents increased their isometric knee flexor strength during the 2-yr period with a similar tendency for the isometric knee extensors. A between-group difference in the mean individual change with time was observed in isometric knee flexors and a similar tendency was observed in concentric knee flexion strength at an angular velocity of 180 degrees/sec (P = 0.08) demonstrating improved muscle strength in the GHS group, compared with the GHD group. The local muscle endurance expressed as the fatigue index tended to deteriorate in both groups during the period of observation.
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). Thus, the mean and peak handgrip
increased on average by 9–15% in the GHS group and was unchanged in
the adolescents with continuing GHD. In the GHD group, the change in lean body mass correlated with the changes in isometric knee extensor strength (r = 0.66; P = 0.003), isokinetic knee extension (r = 0.86; P < 0.001), and flexion strength (r = 0.62; P = 0.006). Similar correlations were observed in the GHS group with an additional correlation between the change in lean body mass and isometric knee extensor strength (r = 0.70; P < 0.001). A correlation between the changes in lean body mass and handgrip strength was seen in the GHD subjects (r = 0.62 to 0.65; P < 0.01) and not in the GHS group.
Healthy adolescents
The healthy group of adolescents was followed over a period of 4
yr (Table 3). During that period of time,
the body weight increased. This increase was partly explained by an
increase in lean mass (Fig. 1A). Moreover, the handgrip strength, both
measured as peak torque (Fig. 1B) and mean torque over a period of 10
sec, increased. The mean increase between the age of 17 and 21 yr was
7–9%. Similar results were found whether analyzing the changes
between 19 and 21 yr or when the entire period was included.
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). No correlation was seen between the
increase in lean body mass and the increase in handgrip strength in the
girls, whereas positive correlations were observed in the boys (r
= 0.25–0.33; P < 0.05).
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Adolescents with childhood-onset GHD and continued severe GHD into adulthood lost body nitrogen and lean body mass with unchanged muscle strength when GH replacement was discontinued. Prospective data from a large group of randomly selected healthy adolescents at similar ages as the patients demonstrated, however, increased lean body mass and muscle strength. The expected improvement in muscle performance with time therefore did not occur in adolescents with GHD.
The highest daily GH production rate is seen in late puberty, and after the age of 18–25 yr, there is an exponential fall in the mean 24-h GH secretion continuing into middle years of life with an accompanying fall in serum IGF-I levels (18). This fall in GH levels has been postulated to be of importance for the sarcopenia of aging (19). This has, however, been questioned because short-term GH treatment of healthy aging volunteers has not been able to restore muscle function (20, 21). This trial has addressed the question of whether GH is of importance for muscle mass and function in early adulthood.
This is the first prospective long-term study of muscle strength in young adulthood. It demonstrates continuing increase in handgrip strength in both boys and girls between 19 and 21 yr of age, which is in agreement with previous cross-sectional studies, which suggested that peak isometric and dynamic muscle strength occurs in the ages between 20 and 30 yr (7, 8). In boys there is a marked increase in muscle strength through the years of puberty, whereas girls experience an almost linear increase in muscular strength with chronological age, until about 15 yr of age (3, 22) despite a marked increase in the GH secretion during puberty. Our data suggest that there is a further slow increase into the second decade of life in both females and males. This increase did not occur in the adolescents who continued to lack GH into adulthood, which indicates that GH is of importance for the continuing increase in muscle mass and muscle strength after puberty. That the increase in lean body mass and handgrip strength was more marked in the young men than in the women suggests that sex steroids or the interplay between sex steroids and GH is still of importance in early adulthood.
The peak gain in muscle mass and the peak gain in muscle strength occur within 1 yr of peak height velocity, supporting the role of sex steroids and GH on development of muscle mass and function (3). In a cross-sectional study of children and young adults aged 4–26 yr, lean body mass increased until the age of 16.6 and 13.4 yr in males and females, respectively (23). This is in contrast with this longitudinal study that shows a continuing increase of lean body mass in both healthy boys and girls between 19 and 21 yr of age. Muscle strength is closely associated with muscle mass (24) although neural activation, contractile properties, and force transmission is also of importance for the individual variation in muscle strength. These properties are, however, not affected by puberty (25). In our study a close correlation was found between the increase in lean body mass and the increase in muscle strength, suggesting in the analogy with the changes in muscle mass and strength in puberty that peak muscle mass and peak muscle strength are achieved at a similar age.
The loss of lean body mass in the GHD group was expected and in accordance with two previous smaller trials also demonstrating unchanged isometric quadriceps strength 12 months (26) and 2 yr (27) after GH treatment was discontinued in young adults with GH deficiency. In our study, both the large control group and the patients defined as having sufficient GH secretion demonstrated a small longitudinal increase in lean body mass and muscle strength that may be of importance for the attainment of peak muscle strength. Such changes did not occur in the GHD group suggesting that the presence of GH is needed for normal maturation of muscle mass and muscle function in the postpubertal years and in early adulthood.
Bone mass is associated with muscle mass both in children (10) and adults (28). The increase in muscle mass and muscle strength may therefore be of importance in the attainment of peak bone mass, which in turn affects the fracture risk in adults. Adequate levels of GH during puberty and the years thereafter may therefore influence peak bone mass, both through direct actions on bone and indirect through muscle mass and muscle strength.
Similar results were obtained for isometric and isokinetic muscle strength during knee extension and knee flexion although not as clear as for handgrip strength. Some data indicate that muscle groups may mature differently. For example, no clear adolescent spurt occurs in trunk strength and abdominal muscle endurance whereas this is observed in upper and lower body strength (3). Other plausible explanations are that the methodological error in the measurement of handgrip strength is lower and that handgrip is less influenced by environment and physical activity than lower body muscle strength.
We cannot exclude the possibility that the changes seen in lean body mass and muscle strength were indirect through different changes in physical activity among the study groups. A study of 1,069,556 18-yr-old boys from the Military Service Conscription Registry in Sweden demonstrated increased body weight and decreased physical performance between the years 1969 and 1994 (Hulthén, L., personal communication) that does not support increased physical activity in the GH sufficient group and healthy controls. Also, the tendency for increased fatigue index in both patient groups suggests that different physical activity in the patients group is not responsible for the findings in this study. We know, however, that GHD affects well-being (29) and may cause a more sedentary lifestyle (30).
This study demonstrates that young adults/adolescents with GHD lose lean body mass and do not gain muscle strength, compared with healthy subjects in the same age, when their GH treatment is discontinued. This clearly suggests that GH in adolescence and in young adulthood is of importance for the maturation of muscle mass and muscle strength, which in turn may be of importance for the attainment of peak muscle strength and peak bone mass. Whether reduced GH secretion may explain the loss of bone mass and lean mass in aging remains to be proven. Our observation is of importance for adolescents with continuing GHD into adulthood whom usually discontinue GH treatment at final height.
Acknowledgments
We are indebted to Sigrid Lindstrand at the Research Center for Endocrinology and Metabolism for invaluable contribution during the testing of the healthy adolescents and to Marita Hedberg of the Department of Rehabilitation Medicine for excellent assistance during the muscle tests of the patients. We also acknowledge the important contribution of Ingrid Hansson, Lena Wirén, and Anne Rosén and of the Research Center for Endocrinology and Metabolism.
The Swedish Study Group for Growth Hormone Treatment in Children was responsible for referring the GH-treated children into this study. This group consists of: Kerstin Albertsson-Wikland, Jan Alm, Stefan Aronson, Jan Gustafsson, Lars Hagenäs, Anders Häger, Sten Ivarsson, Berit Kriström, Claude Marcus, Christian Moëll, Karl-Olof, Nilsson, Martin Ritzén, Torsten Tuvemo, Ulf Westgren, Otto Westphal, and Jan Åman.
Footnotes
Address all correspondence and requests for reprints to: Gudmundur Johannsson, M.D., Ph.D., Research Center for Endocrinology and Metabolism, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.
This work was supported by grants from the Swedish Medical Research Council (Project No. 11621).
Abbreviations: DXA, Dual-energy x-ray absorptiometry; GHD, GH deficiency; GHS, GH sufficiency.
Received March 26, 2001.
Accepted June 18, 2001.
References
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  S. Radovick and S. DiVall Approach to the Growth Hormone-Deficient Child during Transition to Adulthood J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1195 - 1200. [Abstract] [Full Text] [PDF]
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 J. Svensson, G. Johannsson, A. Iranmanesh, K. Albertsson-Wikland, J. D Veldhuis, and B.-A. Bengtsson GH secretory pattern in young adults who discontinued GH treatment for GH deficiency and decreased longitudinal growth in childhood. Eur. J. Endocrinol., July 1, 2006; 155(1): 91 - 99. [Abstract] [Full Text] [PDF]
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0.05; ***, P < 0.001,
compared with the GHD group.