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Endocrine Care |
Research Centre for Endocrinology and Metabolism (J.K., J.S., G.G., B.-Å.B., G.J.) and Department of Rehabilitation Medicine (K.S.S.), Sahlgrenska University Hospital, SE-41345 Göteborg, Sweden
Address all correspondence and requests for reprints to: Josef Koranyi, M.D., Research Centre for Endocrinology and Metabolism, Gröna Stråket 8, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: josef.koranyi{at}medic.gu.se
Abstract
The consequences of GH deficiency may differ if the disease is childhood onset or adulthood onset. In this single-center, prospective study, 21 consecutive adults with childhood onset GH deficiency and 21 adults with adulthood onset GH deficiency, matched for age, gender, body mass index, and number of anterior pituitary hormonal deficiencies, were included. Baseline differences and differences in the responses in body composition, muscle strength, bone mass, and metabolic indices during 5-yr GH replacement were determined. The duration of GH deficiency was longer and serum IGF-I level and body height were lower in the childhood onset patients than in the adulthood onset patients. Body fat (observed/predicted ratio) was increased, and lean mass and muscle strength were decreased, in the childhood onset patients. Total body and lumbar (L2–L4) bone mineral content and bone mineral density were lower in the childhood onset patients. Serum total cholesterol level was higher in the adulthood onset patients. The childhood onset and adulthood onset patients received a similar dose of GH. After adjustment for body weight, however, the dose of GH was higher in the childhood onset patients. The treatment responses were more marked in the childhood onset patients in lean mass, knee extensor strength, left-hand grip strength, and in total body and lumbar (L2–L4) bone mineral content and bone mineral density. The reduction in serum total cholesterol concentration was more marked in the adulthood onset patients. At study end, no differences remained between the two study groups after the correction for body height in the statistical analysis. In conclusion, the baseline analysis suggests more decreased lean mass, muscle strength, and bone mass in the childhood onset patients whereas the lipid profile was more disturbed in the adulthood onset patients. The 5-yr GH replacement eliminated all the anthropodometric and metabolic differences between the two groups.
ADULT GH DEFICIENCY (GHD) IS not a homogenous condition. The clinical presentation may differ depending on the underlying pituitary disease, the severity of GHD, and the presence of other anterior hormonal deficiencies (1, 2). Furthermore, the clinical presentation may differ whether the pituitary disease was acquired in childhood or in adult life. In a study by Attanasio et al. (3), patients with childhood onset (CO) GHD had lower serum IGF-I level, lower body mass index (BMI), higher serum high-density lipoprotein cholesterol (HDL-C) level, and superior quality of life than patients with adulthood onset (AO) GHD. Lower muscle mass (4) and bone mass (5) and enhanced quality of life (6) have been observed in CO patients. Little is known whether the responsiveness to GH treatment differs between CO and AO patients.
The differences between CO and AO patients may be owing to the fact that GH replacement in CO patients was discontinued when final height was reached, whereas peak bone mass and peak muscle strength had still not been attained. Furthermore, baseline differences may also be an effect of lower age and reduced body height in the CO group (7). In a study in which these two groups were closely matched for age, height, and weight, both groups had a similar degree of left ventricular systolic dysfunction (8). In this study, the CO and AO patients were matched for age, number of anterior pituitary hormonal deficiencies, gender, and BMI. A close match for body height was not feasible, however, owing to the considerably lower body height in the CO patients.
In this single-center, prospective study, we compared baseline differences in 21 consecutive adults with CO GHD and in 21 closely matched adults with AO GHD. Furthermore, we investigated the effect of 5 yr of GH replacement therapy in these patients on body composition, muscle strength, bone mass, and metabolic indices.
Subjects and Methods
Patients
Twenty-one consecutive CO patients (age at onset 
20 yr) and 21
matched AO patients (age at onset 
21 yr) were included between 1990
and 1994. All the patients had known pituitary disease or other
pituitary hormonal deficiency (Table 1
).
In the CO group, 13 patients had received GH treatment during
childhood, but it had been discontinued for at least 2 yr before this
study. Eight CO patients had previously not received GH therapy owing
to acceptable body height at onset (n = 6); onset before GH
replacement was established in children (n = 1), and in one
patient the reason was unknown. In the CO and AO groups, 14 and 18
patients had been treated surgically and 5 and 7 patients had received
radiotherapy, respectively. In 17 and 18 of the CO and AO patients,
respectively, the diagnosis of GHD was based on an insulin tolerance
test. In the remaining patients, all with multiple anterior pituitary
deficiencies, the diagnosis was based on a glucagon stimulation test
(n = 1), measurements of 24-h GH secretion (n = 4), or a low
serum IGF-I concentration (n = 2). When required, patients
received adequate and stable therapy with glucocorticoids, thyroid
hormone, gonadal steroids, and desmopressin. However, at entry to the
study, two and four women in the CO and AO groups, respectively, were
not receiving E whereas at study end, one and two women, respectively,
did not receive estrogen replacement. One elderly woman in the CO group
died of pneumonia after 4 yr of GH replacement.
|
This is an ongoing, prospective, open-label treatment trial. The initial target dose of recombinant human GH was 11.9 µg/kg per day (0.25 IU/kg per week). The dose was gradually lowered and individualized when the weight-based dose regimen was abandoned (9). The individualization of the dose of GH was performed with the aim of normalizing serum IGF-I concentration and body composition (estimated by the four-compartment model) in each patient (9).
At baseline and after each year of treatment, physical examinations including measurements of body composition, muscle strength, and bone mass were performed. In addition, dose titration was performed by visits 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. Systolic and diastolic blood pressures were measured using the sphygmomanometric cuff method.
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 Corp., Madison, WI; software version 1.3) was used to measure lean body mass (LBM) and body fat (BFDEXA) (10). The relative error for LBM was 1.5%.
Body cell mass (BCM), extracellular water (ECW), and body fat (BF) were estimated using a four-compartment model based on total body potassium and total body water assessments (11). Total body potassium was assessed using a whole-body counter [coefficient of variation (CV) = 2.2%], and total body water was determined by the isotope dilution of tritiated water (CV = 3.2%). Normative values for the four-compartment model were from body composition studies of 476 healthy individuals (11). An individual observed/predicted value ratio could then be calculated for BCM (BCM%), ECW (ECW%) and BF (BF%).
Total body nitrogen was measured by in vivo neutron activation with a measurement error of approximately ± 4% (12, 13).
Measurements of muscle function
Isometric knee-extensor and -flexor strength at knee angles of
60 degrees (
/3 rad) and 180 degrees (rad), and isokinetic
concentric muscle action 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)
(14). The methodological errors in duplicate measurements
for isometric muscle strength and isokinetic muscle strength at 60
degrees/sec and 180 degrees/sec were 9%, 8%, and 8%, respectively
(14). Right and left handgrip strength was measured using
an electronic grip force instrument (Grip-It) as described previously
(15). The methodological error between duplicate
determinations was between 4.4% and 9.1% (15).
Bone mineral content (BMC) and bone mineral density (BMD)
DEXA (Lunar Corp. DPX-L, software version 1.3) was used to measure BMC and apparent BMD (BMC/area), as described previously (10). The CV between measurements were 0.4%, 0.5%, and 0.6% for total body apparent BMD, lumbar (L2–L4) spine apparent BMD, and femur neck apparent BMD. The apparent BMD was determined using the DPX-L software program (Lunar Corp.). Volumetric BMD in lumbar (L2–L4) spine was calculated as described previously [volumetric density = BMC/(area 1.5)] (16).
Biochemical assays
Serum IGF-I level was measured using RIA after acid-ethanol extraction (Nichols Institute Diagnostics, San Juan Capistrano, CA). Age- and sex-adjusted IGF-I values were obtained from a reference population (17). The individual IGF-I SD scores could then be calculated (1).
Total cholesterol (TC) and triglyceride (TG) concentrations were determined using enzymatic methods (Roche Molecular Biochemicals, Mannheim, Germany). The within-assay CV for TC and TG determinations were 0.9% and 1.1%, respectively. HDL-C levels were determined after the precipitation of apoB-containing lipoproteins with MgCl2 and heparin (18). Low-density cholesterol (LDL-C) concentration was calculated according to Friedewald’s formula adjusted to Systeme Internationale units (19). Serum insulin was determined by RIA (Phadebas, Pharmacia Biotech, Uppsala, Sweden), and blood glucose was measured with the glucose-6-phosphate dehydrogenase method (Kebo Lab, Stockholm, Sweden). Serum HbA1c was determined by high-pressure liquid chromatography (Waters Corp., Milford, MA).
Statistical methods
The descriptive statistical results are shown as the mean (SEM). Between-group differences during the 5-yr period were determined using a one-way ANOVA of the percent change from baseline at all time points (onset category as the independent variable). Between-group P values at baseline and study end were determined using one-way ANOVA. Within-group P values (5 yr vs. baseline) were determined using one-way ANOVA, followed by Newman-Keuls post hoc test. All analyses were performed using an intention-to-treat approach based on the carry-forward principle. A two-tailed P less than 0.05 was considered significant.
Results
Both the CO and AO groups consisted of 14 men and 7 women. The two
study groups were matched groupwise with regard to number of anterior
pituitary hormonal deficiencies (Table 1
). The CO and the AO groups
were matched groupwise with respect to age [31.2 (3.0, range
17.1–61.0) vs. 32.3 (1.2, range 21.7–41.9) yr] and BMI
[25.8 (1.4, range 15.7–37.1) vs. 26.5 (1.0, range
20.2–40.0) kg/m2]. The duration of GHD was,
however, longer in the CO group [19.0 (3.1, range 1.1–44.0)
vs. 3.6 (0.8, range 0.2–13.7) yr; P <
0.001].
GH dose, IGF-I SD score, and blood pressure
The mean dose of GH (mg/d) was gradually lowered in both groups
during the first 2–3 yr (Table 2). Serum
IGF-I concentration was lower at baseline in the CO patients but
similar in the two groups at study end (Table 2). Body height was lower
in the CO patients both at baseline [168.9 (2.1) vs. 176.3
(2.0) cm, respectively; P < 0.05] and at study end
[170.7 (2.4) vs. 177.0 (2.0) cm, respectively;
P < 0.05; data not shown]. Body weight, BMI,
waist:hip ratio, and systolic and diastolic blood pressures were
similar in the CO and AO patients both at baseline and at study end
(data not shown).
|
Lean mass was lower at baseline in the CO group than in the
AO group, as measured by DEXA and the four-compartment model
(Table 3). Baseline BF%
(observed/predicted values ratio) was higher in the CO patients (Table 3). The increase in lean mass was more marked in the CO group (Table 3). After 5 yr, there were no differences between the CO and AO groups
in any variable reflecting body composition (Table 3).
|
Knee extensor muscle strength was lower in the CO group at
baseline (Fig. 1). The increase in knee
extensor strength was greater in the CO patients (Fig. 1). After 5 yr
of GH replacement, isometric and concentric knee extensor strength did
not differ statistically between the two groups (Fig. 1).
|
). The CO patients increased
their left-hand grip strength more than the AO patients (Table 4).
After 5 yr, no significant differences remained in knee flexor
and handgrip strength between the two study groups (Table 4).
|
Baseline total body BMC, apparent BMD (BMC/area), and t
score were lower in the CO group as measured by DEXA (Table 5). The increases in total body BMC and
apparent BMD were more marked in the CO patients (Table 5). At study
end, total BMC and apparent BMD were similar in the two study groups,
whereas total body t score was still lower in the CO group
(Table 5). BMC, apparent BMD, and t score in femur neck were
similar in the two groups both at baseline and at study end (Table 5).
|
). The
increases in lumbar (L2–L4) BMC and apparent BMD were greater in the
CO patients (Fig. 2). After 5 yr, lumbar (L2–L4) BMC and lumbar
t score were still lower in the CO patients, whereas lumbar
apparent BMD did not differ statistically between the two groups (Fig. 2). The volumetric BMD in lumbar (L2–L4) spine was similar in the two
groups both at baseline and at study end, although the treatment
response was greater in the CO patients (Fig. 2D).
|
Metabolic indices
Baseline serum TC concentration was higher in the AO group. The
reduction in serum TC concentration was more marked in the AO patients
(Fig. 3). At study end, all lipid
concentrations measured were similar in the two groups (Fig. 3). Blood
glucose, serum insulin, and serum HbA1c concentration were similar in
the two groups, both at baseline and at study end (data not shown).
|
Using body height as a covariant, the baseline differences in BF% (P < 0.01), BCM% (P < 0.01), isometric knee extensor (60 degrees) strength (P < 0.05), lumbar (L2–L4) BMC (P < 0.05), total body BMD (P < 0.05), total body t score (P < 0.05), lumbar (L2–L4) BMD (P < 0.05), lumbar t score (P < 0.05), and serum TC concentration (P < 0.05) remained, whereas other baseline differences lost their statistical significance. The same baseline differences remained when duration of hypopituitarism was used as a covariant. Using both body height and duration of hypopituitarism as covariants, the baseline differences in BF% (P < 0.01), BCM% (P < 0.001), lumbar (L2–L4) BMC (P < 0.05), and serum TC concentration (P < 0.05) remained.
At study end, the differences between the two groups in total body t score and in lumbar (L2–L4) BMC, t score, and bone area lost significance if body height was used as a covariant.
Discussion
This study reveals marked differences in the baseline characteristics of CO and AO patients. The CO patients were shorter; had increased BF (observed/predicted ratio); and decreased serum IGF-I concentration, LBM, muscle strength, and bone mass. Serum TC was higher in the adults with AO GHD. The treatment responses were more marked in the CO patients in lean body mass, knee extensor strength, left-hand grip strength, and in total body and lumbar (L2–L4) BMC and BMD, whereas a reduction in serum TC concentration was observed only in the AO patients. After 5 yr of GH therapy, no differences remained between the two study groups after correction for body height in the statistical analysis.
Baseline serum IGF-I level and LBM were lower, and BF (observed/predicted ratio) was higher in the CO patients, although age, gender, BMI, and number of pituitary hormonal deficiencies were similar in the two study groups. This could suggest that the CO patients experienced more severe consequences as a result of their GHD. One reason for this could be the longer duration of hypopituitarism in the CO group because it is known that serum IGF-I level is inversely related to the duration of hypopituitarism (1). However, it could be argued that, owing to their smaller size, CO patients are less able to produce IGF-I. In support of this, the baseline difference in serum IGF-I level lost its significance when body height was accounted for.
Baseline quadriceps and handgrip muscle strength were lower in the CO patients, although these differences could be explained by differences in body height and duration of hypopituitarism. As shown in other studies (20, 21, 22, 23, 24), GH replacement therapy increased isometric (60 degrees) knee flexor muscle strength in both groups, whereas the effect on isometric (60 degrees) and isokinetic (60 degrees/sec) knee extensor strength was less marked in the AO patients. Muscle strength was therefore similar in the two study groups at study end.
BMC, apparent BMD (BMC/area), and t score in lumbar (L2–L4) spine were lower in the CO patients at baseline. These differences could not be fully explained by the lower body height and the longer duration of hypopituitarism in the CO patients. One reason for this could be that the CO patients had not been able to reach peak bone mass during adolescence. The increases in lumbar (L2–L4) BMC and apparent BMD were more marked in the CO patients and, after 5 yr, bone mass was similar in the two groups after correction for body height.
In rodents, GH treatment increases the apparent BMD (BMC/area) as measured by DEXA (25, 26), whereas no effect is seen on volumetric BMD (BMC/volume) as measured by Archimedes’ principle or computed tomography (26, 27, 28). The difference in the treatment responses in terms of apparent and volumetric BMD are anticipated because DEXA does not account for the increase in bone mass perpendicular to the DEXA image. Therefore, when the volumes of bones are increased by GH owing to increased bone formation, this may in itself result in increased apparent BMD as measured by DEXA. In the present study, we accounted for this by calculating the volumetric BMD for lumbar (L2–L4) spine (16). It is interesting to note that we were unable to find any baseline difference in the volumetric lumbar (L2–L4) spine BMD. The present data therefore suggest that BMC is decreased in CO patients and that DEXA measurements overestimate the between-group difference in lumbar (L2–L4) apparent BMD, possibly owing to the smaller body size of CO patients.
Baseline serum TC was higher in the AO patients, and there was also a tendency toward higher baseline serum LDL-C and TG in the AO patients. The treatment response in serum TC was more marked in the AO patients, and at study end, there was no difference in any lipid concentration measured. The baseline difference in TC is not likely to be explained by other baseline differences. BMI, waist:hip ratio, age, and sex ratio were similar in the two groups, and the percentage of body fat was even lower in AO patients. The reason for the baseline difference in TC is unknown, but it has been suggested that in CO patients, developmental adaptations to GH deficiency may occur in childhood life, directing to alternatives for the metabolism of lipoproteins (3).
The differences in the baseline characteristics of CO and AO patients in this study were of a type similar to those previously observed by Attanasio et al. (3). The CO patients appeared to be somatically underdeveloped, with decreased lean body mass, muscle strength, and bone mass, whereas AO patients have more marked lipid abnormalities. In our study, no differences were observed between CO and AO patients after 5 yr of treatment, when body height was accounted for. All features of both CO GHD and AO GHD can therefore be normalized with long-term GH replacement therapy.
In conclusion, this study reveals marked differences in the baseline characteristics of patients with CO and AO GHD, even after the adjustment of confounding factors such as age and body height. The anabolic effect of GH on lean tissue and bone mass was more marked in the CO patients, whereas the reduction in serum TC concentration was of greater significance in the AO patients. After 5 yr of GH replacement therapy, no difference remained between the two study groups. The features of both CO and AO GHD can, therefore, be normalized by long-term GH replacement therapy.
Acknowledgments
We are indebted to Marita Hedberg of the Department of Rehabilitation Medicine for excellent technical assistance during the muscle tests and to Lena Wirén, Anne Rosén, Ingrid Hansson, and Sigrid Lindstrand of the Research Center for Endocrinology and Metabolism for skillful technical support.
Footnotes
This work was supported by grants from the Swedish Medical Research Council (No. 11621) and the chair of Göteborg. This work was presented in part at the 82nd Annual Meeting of The Endocrine Society, Toronto, Canada, June 21–24, 2000.
Abbreviations: AO, Adulthood onset; BCM, body cell mass; BF, body fat; BMC, bone mineral content; BMD, bone mineral density; BMI; body mass index; CO, childhood onset; CV, coefficient of variation; DEXA, dual-energy x-ray absorptiometry; ECW, extracellular water; GHD, GH deficiency; HDL-C, high-density lipoprotein cholesterol; LBM, lean body mass; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride.
Received February 7, 2001.
Accepted June 16, 2001.
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