Clinical Endocrinology (1991) 34,469-475
ADONIS 030006649100081Q
Changes in skeletal muscle and body composition after discontinuation of growth hormone treatment in growth hormone deficient young adults* 0. M. Rutherford, D. A. Jones, J. M. Round,t C. R. BuchananS and M. A. PreeceS Department of Medicine and tChemica1 Pathology, University College and Middlesex School of Medicine, London WCl, and $Department of Growth and Development, Institute of Child Health & Hospitals for Sick Children, Great Ormond Street, London WClN (Received 5 December lgW; returned for revision 3 January 1991;finally revised 24 January 1991;accepted 5 February
strength and size were 101.4%f7.9 and 92.0Y0f9.2 of control. Body fat percentage had increased from 19.5% f 8.6 to 24.1 YOf 9.5. No change was seen in the non-growth hormone deficient group. CONCLUSIONS Although the changes measured were relatively small they suggest a role for GH In the maintenance of muscle integrity and body composition In the young adult with growth hormone deficiency.
1991)
Summary OBJECTiVES The aim of this study was to determine whether there are any changes in skeletal musclestrength and size and body composition foliowing growth hormone (OH) withdrawal in GH deficient young adults. DESIGN A longltudlnai, 1-year, open, uncontrolled study of the changes in skeletal muscle and body composition following OH withdrawal was performed. Endocrinestatus was reassessed at the end of the study period durlng an insulin tolerance test. Some measurements were repeated after 2 years off treatment. PATIENTS Twelve (11 male, one female; age range 14-21) patients who had been diagnosed during childhood as growth hormone deficient took part In the study. Four of the 12 patients were found to have a normal OH response on retesting at the end of the study and their results were anaiysed as a separate group. MEASUREMENTS Quadrlceps and forearm flexor maximum voluntary isometric strength, body fat content and serum IGF-1 were measured at 3-monthly Intervals over 1 year. Every 6 months muscle size was measured from computerized tomography scans and fibre area from quadrlceps needle biopsy samples. RESULTS For the growth hormone deficient group the 12 month quadrlceps strength, size and fibre areas were 94.0% f8.5 (mean f SD), 94.5% f 6.3 and 85.6% f 17.7 respectively of control (baseline) values. Forearm flexor
Correspondence: Dr 0. M. Rutherford, Department of Physiology and Biophysics, St. Mary’s Hospital Medical School, Norfolk Place, London W2 IPG, UK.
* Results presented in part at the 7th International Symposium on Growth and Growth Disorders, Rome, April 1989.
The requirement of growth hormone (GH) for normal growth of the skeleton is well known. In the adult, however, the role for GH following the cessation of linear growth is at present unknown. GH deficient (GHD) adults often complain of ‘weakness’ and ‘fatigue’. This may reflect the metabolic consequences of GH deficiency or result from a reduced muscle strength or size. Anabolic effects of GH have been observed in several groups without GH deficiency, including surgical and bum patients (Liljedahl et al., 1961; Ponting et al., 1988), heaIthy highly conditioned adults during intensive strength training (Crist et al, 1988), and normal and obese subjects during dietary restriction (Clemmons et al., 1987). The potential for treatment of the hypopituitary adult with the recently available biosynthetic GH has highlighted the need to evaluate the anabolic and metabolic requirements for GH in adults. Young GHD adults who are stopping GH treatment received during childhood provide a natural model to observe the effect of GH insufficiency on different body systems. A pilot study several years ago suggested a requirement for GH in the maintenance of muscle size and strength in such patients (Preece et al., 1987). To confirm these findings we have assessed the changes in muscle strength and size, together with body composition, in a small group of these patients for up to 2 years following discontinuation of GH treatment. Methods Patients
Twelve patients who had been diagnosed during childhood, by conventional criteria (Milner & Bums, 1982), as GHD took part in the study (one female, 11 male; age range 14-21 years). GH deficiency was defined as a peak GH of either 469
470 0. M. Rutherford et al.
Table 1 Anthropometric and clinical details for individual subjects. Subjects 9-12 found to be non-GHD at end of study
Patient/sex IF 2M 3M 4M 5M 6M 7M 8M 9M 10 M 11 M 12 M
Age (years)
Height (cm)
Weight (kg)
Body fat
(“/I
Hormone replacement
Years on GH
GH response to ITT at end of study (mU/l)
14 17 20 17 21 17 16 20 18 17 17 18
156.1 170.1 155.0 155.6 169.7 155.3 161.6 171.2 164.1 155.3 166.6 170.8
48.7 46.0 42.0 53.0
30.2 9.5 11.8 23.1 19.0 31.8 10.4 20.0 14.5 18.3 16.4 22.0
GH, E2 GH GH, T4 GH GH, T4, Testo, HC GH GH, T4 GH, T4, Testo GH GH, T4 GH GH
10.0 10.8 13.3 10.3 5.6 9.8 7.5 10.9 7.5 9.1 12.1 4.9
2.8 10.6 40.0 > 40.0 24.0
64.8
74.0 47.2 61.7 51.0 55.6
63.8 67.0
T4, thyroxine; HC, hydrocortisone; Testo, testosterone;E2, oestradiol.
20 mU/1). Quadriceps strength and size and body
composition were remeasured at the end of 2 years off treatment in the GHD group. Patients were advised to maintain their normal level of physical activity throughout the study. Strength measurements
The maximum voluntary isometric strength (MVC) of the quadriceps and forearm flexors was measured using conventional strength testing chairs (Edwards et al., 1977; Jones & Newham, 1985). The best of three MVCs was measured at each test. During the quadriceps manoeuvre a percutaneous twitch superimposition technique (Rutherford et al., 1986) was used to test whether subjects could maximally activate their quadriceps during the isometric contraction. The same technique was not used on the forearm flexors because of methodological difficulties. Muscle size
Quadriceps, forearm flexor (biceps and brachialis) and triceps cross-sectional areas (CSA) were measured from a computerized tomography (CT) X-ray scan taken at half femur height and at the junction of the distal quarter and proximal three-quarters of the upper arm respectively. Scans were performed on a Philips Tomoscan 350 and the images analysed off-line on a locally developed interactive medical imaging package (Grindrod et al., 1983). Muscle area was measured semi-automatically with a contour-following program and manual editing. The coefficient of variation for
Muscle changes in growfh hormone deficiency
repeat scanning of the quadriceps muscle in eight normal subjects scanned 3 months apart was less than 4% (Rutherford, 1986). Estimates of muscle density were made by measuring the mean Hounsfield (HU) number (unit of radiological density) of the forearm flexors and triceps. Similar measurements are more difficult to make on the quadriceps because of the presence of a beam hardening artefact across the centre of the scan leading to spurious HU numbers in areas of the muscle.
66
460
420
- 380
-0
c 54
Z
Fibre areas
IGF-1 assay
Serum IGF-1 concentration was measured by radioimmunoassay, after acid-ethanol extraction, using the polyclonal antibody R557A (Morrell et al., 1989). Sampleswere assayed in triplicate at a single dilution using a working standard of pooled normal adult male reference serum calibrated against the WHO international IGF-1 reference reagent 87/518. The first sample for IGF-1 was taken with the patients on G H treatment at a dose of 4U or 8U (patient 12 only) three times per week. Blood samples were taken 15-20 h after the GH injection of the previous night. All other samples were taken with the patients off GH treatment. Statistics
Results were analysed using Student’s paired t-test or the sign test.
V
m E
Measurement of fibre areas were made from needle biopsy samples taken from the vastus lateralis in five of the patients using the UCH biopsy needle. Cryostat sections were stained for ATPase activity at pH 9.4 to allow for separate measurement of Type 1 and 2 fibre areas. Area measurements were made on a semi-automatic system (Round et d., 1982).
Percentage body fat was estimated from the Siri equation (Siri, 1956) using the sum of four skinfold measurements (triceps, biceps, subscapular and suprailiac).
0 .+
f
F
Sody composition
471
0 VI)
I
340
M
50
e
0
46
300
\
260
0
12
42
\ 0
12
Fig. 1 a, Quadriceps strength and b, cross-sectional area at end of
GH treatment (time 0) and 12 months later for eight GHD patients.
Table 2 Group mean quadriceps strength as percentage of baseline value at 3 , 6 , 9 and 12 months
Months off
GH treatment
Mean
SD
n
3 6 9 12
97.8 96.2 94.8 94.0
4.8 4.9 8.6 8.5
8 8 6 8
patients reported any change in their level of activity over the study period. The results are presented first for the eight patients considered at the end of the year to be GHD, followed by results for the patients with normal GH secretion during the ITT. Body composition
Results
All the patients completed the study; one patient selfreported a feeling of weakness at the end of the year. The majority of the patients had relatively sedentary occupations and did not take part in regular physical exercise. None of the
Body fat increased from 19.5%+8.6 to 24.1%f9.5
(P
ADONIS 030006649100081Q
Changes in skeletal muscle and body composition after discontinuation of growth hormone treatment in growth hormone deficient young adults* 0. M. Rutherford, D. A. Jones, J. M. Round,t C. R. BuchananS and M. A. PreeceS Department of Medicine and tChemica1 Pathology, University College and Middlesex School of Medicine, London WCl, and $Department of Growth and Development, Institute of Child Health & Hospitals for Sick Children, Great Ormond Street, London WClN (Received 5 December lgW; returned for revision 3 January 1991;finally revised 24 January 1991;accepted 5 February
strength and size were 101.4%f7.9 and 92.0Y0f9.2 of control. Body fat percentage had increased from 19.5% f 8.6 to 24.1 YOf 9.5. No change was seen in the non-growth hormone deficient group. CONCLUSIONS Although the changes measured were relatively small they suggest a role for GH In the maintenance of muscle integrity and body composition In the young adult with growth hormone deficiency.
1991)
Summary OBJECTiVES The aim of this study was to determine whether there are any changes in skeletal musclestrength and size and body composition foliowing growth hormone (OH) withdrawal in GH deficient young adults. DESIGN A longltudlnai, 1-year, open, uncontrolled study of the changes in skeletal muscle and body composition following OH withdrawal was performed. Endocrinestatus was reassessed at the end of the study period durlng an insulin tolerance test. Some measurements were repeated after 2 years off treatment. PATIENTS Twelve (11 male, one female; age range 14-21) patients who had been diagnosed during childhood as growth hormone deficient took part In the study. Four of the 12 patients were found to have a normal OH response on retesting at the end of the study and their results were anaiysed as a separate group. MEASUREMENTS Quadrlceps and forearm flexor maximum voluntary isometric strength, body fat content and serum IGF-1 were measured at 3-monthly Intervals over 1 year. Every 6 months muscle size was measured from computerized tomography scans and fibre area from quadrlceps needle biopsy samples. RESULTS For the growth hormone deficient group the 12 month quadrlceps strength, size and fibre areas were 94.0% f8.5 (mean f SD), 94.5% f 6.3 and 85.6% f 17.7 respectively of control (baseline) values. Forearm flexor
Correspondence: Dr 0. M. Rutherford, Department of Physiology and Biophysics, St. Mary’s Hospital Medical School, Norfolk Place, London W2 IPG, UK.
* Results presented in part at the 7th International Symposium on Growth and Growth Disorders, Rome, April 1989.
The requirement of growth hormone (GH) for normal growth of the skeleton is well known. In the adult, however, the role for GH following the cessation of linear growth is at present unknown. GH deficient (GHD) adults often complain of ‘weakness’ and ‘fatigue’. This may reflect the metabolic consequences of GH deficiency or result from a reduced muscle strength or size. Anabolic effects of GH have been observed in several groups without GH deficiency, including surgical and bum patients (Liljedahl et al., 1961; Ponting et al., 1988), heaIthy highly conditioned adults during intensive strength training (Crist et al, 1988), and normal and obese subjects during dietary restriction (Clemmons et al., 1987). The potential for treatment of the hypopituitary adult with the recently available biosynthetic GH has highlighted the need to evaluate the anabolic and metabolic requirements for GH in adults. Young GHD adults who are stopping GH treatment received during childhood provide a natural model to observe the effect of GH insufficiency on different body systems. A pilot study several years ago suggested a requirement for GH in the maintenance of muscle size and strength in such patients (Preece et al., 1987). To confirm these findings we have assessed the changes in muscle strength and size, together with body composition, in a small group of these patients for up to 2 years following discontinuation of GH treatment. Methods Patients
Twelve patients who had been diagnosed during childhood, by conventional criteria (Milner & Bums, 1982), as GHD took part in the study (one female, 11 male; age range 14-21 years). GH deficiency was defined as a peak GH of either 469
470 0. M. Rutherford et al.
Table 1 Anthropometric and clinical details for individual subjects. Subjects 9-12 found to be non-GHD at end of study
Patient/sex IF 2M 3M 4M 5M 6M 7M 8M 9M 10 M 11 M 12 M
Age (years)
Height (cm)
Weight (kg)
Body fat
(“/I
Hormone replacement
Years on GH
GH response to ITT at end of study (mU/l)
14 17 20 17 21 17 16 20 18 17 17 18
156.1 170.1 155.0 155.6 169.7 155.3 161.6 171.2 164.1 155.3 166.6 170.8
48.7 46.0 42.0 53.0
30.2 9.5 11.8 23.1 19.0 31.8 10.4 20.0 14.5 18.3 16.4 22.0
GH, E2 GH GH, T4 GH GH, T4, Testo, HC GH GH, T4 GH, T4, Testo GH GH, T4 GH GH
10.0 10.8 13.3 10.3 5.6 9.8 7.5 10.9 7.5 9.1 12.1 4.9
2.8 10.6 40.0 > 40.0 24.0
64.8
74.0 47.2 61.7 51.0 55.6
63.8 67.0
T4, thyroxine; HC, hydrocortisone; Testo, testosterone;E2, oestradiol.
20 mU/1). Quadriceps strength and size and body
composition were remeasured at the end of 2 years off treatment in the GHD group. Patients were advised to maintain their normal level of physical activity throughout the study. Strength measurements
The maximum voluntary isometric strength (MVC) of the quadriceps and forearm flexors was measured using conventional strength testing chairs (Edwards et al., 1977; Jones & Newham, 1985). The best of three MVCs was measured at each test. During the quadriceps manoeuvre a percutaneous twitch superimposition technique (Rutherford et al., 1986) was used to test whether subjects could maximally activate their quadriceps during the isometric contraction. The same technique was not used on the forearm flexors because of methodological difficulties. Muscle size
Quadriceps, forearm flexor (biceps and brachialis) and triceps cross-sectional areas (CSA) were measured from a computerized tomography (CT) X-ray scan taken at half femur height and at the junction of the distal quarter and proximal three-quarters of the upper arm respectively. Scans were performed on a Philips Tomoscan 350 and the images analysed off-line on a locally developed interactive medical imaging package (Grindrod et al., 1983). Muscle area was measured semi-automatically with a contour-following program and manual editing. The coefficient of variation for
Muscle changes in growfh hormone deficiency
repeat scanning of the quadriceps muscle in eight normal subjects scanned 3 months apart was less than 4% (Rutherford, 1986). Estimates of muscle density were made by measuring the mean Hounsfield (HU) number (unit of radiological density) of the forearm flexors and triceps. Similar measurements are more difficult to make on the quadriceps because of the presence of a beam hardening artefact across the centre of the scan leading to spurious HU numbers in areas of the muscle.
66
460
420
- 380
-0
c 54
Z
Fibre areas
IGF-1 assay
Serum IGF-1 concentration was measured by radioimmunoassay, after acid-ethanol extraction, using the polyclonal antibody R557A (Morrell et al., 1989). Sampleswere assayed in triplicate at a single dilution using a working standard of pooled normal adult male reference serum calibrated against the WHO international IGF-1 reference reagent 87/518. The first sample for IGF-1 was taken with the patients on G H treatment at a dose of 4U or 8U (patient 12 only) three times per week. Blood samples were taken 15-20 h after the GH injection of the previous night. All other samples were taken with the patients off GH treatment. Statistics
Results were analysed using Student’s paired t-test or the sign test.
V
m E
Measurement of fibre areas were made from needle biopsy samples taken from the vastus lateralis in five of the patients using the UCH biopsy needle. Cryostat sections were stained for ATPase activity at pH 9.4 to allow for separate measurement of Type 1 and 2 fibre areas. Area measurements were made on a semi-automatic system (Round et d., 1982).
Percentage body fat was estimated from the Siri equation (Siri, 1956) using the sum of four skinfold measurements (triceps, biceps, subscapular and suprailiac).
0 .+
f
F
Sody composition
471
0 VI)
I
340
M
50
e
0
46
300
\
260
0
12
42
\ 0
12
Fig. 1 a, Quadriceps strength and b, cross-sectional area at end of
GH treatment (time 0) and 12 months later for eight GHD patients.
Table 2 Group mean quadriceps strength as percentage of baseline value at 3 , 6 , 9 and 12 months
Months off
GH treatment
Mean
SD
n
3 6 9 12
97.8 96.2 94.8 94.0
4.8 4.9 8.6 8.5
8 8 6 8
patients reported any change in their level of activity over the study period. The results are presented first for the eight patients considered at the end of the year to be GHD, followed by results for the patients with normal GH secretion during the ITT. Body composition
Results
All the patients completed the study; one patient selfreported a feeling of weakness at the end of the year. The majority of the patients had relatively sedentary occupations and did not take part in regular physical exercise. None of the
Body fat increased from 19.5%+8.6 to 24.1%f9.5
(P
