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Original Studies |
Research Center for Endocrinology and Metabolism (G.J., B.-Å.) and Pediatric Growth Research Center (K.A.-W.), Sahlgrenska University Hospital, SE-413–45 Goteborg, Sweden
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 Goteborg, Sweden. E-mail: gudmundur.johannsson{at}medic.gu.se
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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The discontinuation of GH therapy in adolescents with severe GHD continuing into adulthood results over a period of 2 yr in the accumulation of important cardiovascular risk factors that are associated with GHD in adults.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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It has been suggested that the expression of GHD may differ between subjects with childhood-onset and adult-onset disease. One study found that patients with childhood-onset GHD had a lower body mass index, lower waist to hip ratio, lower serum insulin-like growth factor I (IGF-I) concentrations, and higher serum HDL-C concentrations as well as superior scores for quality of life compared with patients with adult-onset GHD (8). More severe consequences of GHD in terms of muscle mass (9) and bone mass (2) have also been suggested in adults with childhood-onset disease than in those with adult-onset disease. This may be an effect of the immediate discontinuation of GH treatment after final height is reached and before peak bone mass and maturation of other tissues have been achieved.
Three small scale trials have studied the consequences of discontinuing GH treatment in adolescents after final height was achieved. The first study demonstrated a reduction in quadriceps muscle strength, muscle size, and muscle fiber area and an increase in the amount of body fat after 12 months without GH treatment in 8 adolescent patients (10). A second study followed 16 adolescent males for 12 weeks after the discontinuation of GH treatment (11). After 12 weeks, the fat mass had increased in the 6 patients with severe GHD, but not in the 10 subjects classified as having normal somatotropic function. A similar finding was reported in 8 adolescents followed for 12 months after GH treatment was stopped (12).
More longitudinal data are needed to establish the long term consequences of GH discontinuation in childhood-onset GHD. The aim of the present study was, therefore, prospectively to follow the consequences of discontinuing GH therapy in adolescents with GHD of childhood onset and short stature. All of the subjects had been receiving long term GH replacement in childhood and were treated for a significant period of time after final height was reached.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Forty adolescent patients receiving GH treatment within clinical trials and 16 healthy control subjects were recruited for the study. The GH-treated subjects were submitted for participation from 14 pediatric clinics. The criteria for inclusion were GHD, idiopathic or organic, and isolated or multiple anterior pituitary hormone deficiencies. The patients had received GH treatment for the past 3 consecutive yr and were otherwise being considered to end GH treatment. Patients who were not considered for inclusion were those who planned to finalize treatment for reasons other than reaching final height, those older than 25 yr at the time of inclusion, pharmacological treatment for psychiatric disease, or mental retardation. Subjects were partly selected for the study so as to have approximately half the subjects with childhood-onset, idiopathic, isolated GHD and half with organic hypothalamic-pituitary disease with or without multiple pituitary hormone deficiencies.
The mean age of the adolescents receiving GH treatment who were
included was 19 yr, with a range of 16–21 yr. The average height
SD score was -2.5 ± 0.31 when GH treatment was
initiated in childhood and -0.67 ± 0.19 when patients were
included in the present study. Most subjects had idiopathic and
isolated GHD, and 12 subjects had organic hypothalamic/pituitary
disease (Table 1
). All patients with
brain neoplasia and acute lymphoblastic leukemia had received
irradiation in the hypothalamic-pituitary area. Patients with other
anterior pituitary hormone deficiencies received, when required, stable
replacement therapy with glucocorticoids (cortisone acetate; mean, 20
mg; range, 15–30 mg/day), thyroid hormone (levothyroxine; mean, 0.1
mg; range, 0.05–0.15 mg/day), and gonadal steroids.
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Study protocol
During a stabilizing period of 3 months, all patients received a standardized GH dose of 0.03 mg/kg·day (0.1 IU/kg·day). After a baseline visit, at which all the physical, laboratory, and body composition examinations were performed, GH treatment was discontinued. The patients were then examined with the same protocol once a year for 2 yr. Between each annual visit, the patients were seen at the home pediatric clinic, where their clinical status was assessed.
One year after GH treatment was stopped, a 24-h GH profile was performed to assess endogenous GH secretion. Six patients with suspected isolated GHD according to low endogenous GH secretion also underwent an insulin tolerance test after the 2-yr follow-up period. 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. The body mass index (BMI) was calculated as body weight in kilograms divided by height in meters squared. Systolic and diastolic blood pressures were measured after 5 min of supine rest using the sphygmanometric cuff method.
Methods
Blood samples were drawn in the morning after an overnight fast. The serum concentration of IGF-I was determined by a hydrochloric acid-ethanol extraction RIA using authentic IGF-I for labeling (Nichols Institute Diagnostics, San Juan Capistrano, CA) with within-assay coefficients of variation (CV) of 2.5% and 4.2% at serum concentrations of 125 and 345 µg/L, respectively. The IGF-binding protein-3 (IGFBP-3) concentration in serum was determined by RIA (Nichols Institute Diagnostics), with total CVs of 6.2% and 5.7% at serum concentrations of 2.05 and 3.49 mg/L, respectively.
The GH secretory status was assessed by 24-h GH measurements from repeated 30-min blood sampling using a withdrawal pump. Serum GH was determined by a polyclonal antibody-based immunoradiometric assay (Pharmacia Biotech, Uppsala, Sweden) using IRP 80/505 as standard. The detection limit of the assay was 0.1 µg/L, and the total CV was 5.3% for a serum pool of 6.6 µg/L. The GH area under the curve, the mean 24-h GH concentration, and the GH maximum peak concentration from the 24-h GH measurements were calculated using the Pulsar program.
Free T4 was determined by a luminometric labeled antibody immunoassay (MAB Free T4, Kodak Clinical Diagnostics Ltd., Amersham Pharmacia Biotech, Aylesbury, UK), and free T3 was analyzed by a ligand analog RIA (Amerlex M, Kodak Clinical Diagnostics). Serum insulin was determined by RIA (Phadebas, Pharmacia Biotech), and blood glucose was measured using the glucose-6-phosphate dehydrogenase method (Kebo Lab, Stockholm, Sweden). Hemoglobin A1c was determined by high pressure liquid chromatography (Waters Corp., Massachusetts).
Serum total cholesterol (TC) and triglyceride concentrations were determined with fully enzymatic methods (Roche Molecular Biochemicals, Mannheim, Germany). The within-assay CVs for TC and triglyceride determinations were 0.9% and 1.1%, respectively. Apolipoprotein (apo) B concentrations were determined with an immunoturbidometric assay (UniKit Roche, Hoffman-LaRoche Inc., Nutley, NJ) with a within-assay CV of 1.9%. HDL-C was determined after the precipitation of apo B-containing lipoproteins with MgCl2 and heparin. The LDL-C concentration was calculated according to Friedewald’s formula adjusted to Systeme International units. The lipoprotein(a) [Lp(a)] concentration was determined with a RIA (Pharmacia Biotech). This Lp(a) assay was standardized against an electroimmunoassay. The within-assay CV for the Lp(a) assay was 4.4%.
Body composition was determined using bioelectrical impedance analysis (BIA) and dual energy x-ray absorptiometry (DXA). DXA was performed using a whole body scanner (Lunar DPX-L, Lunar Corp., Madison, WI). Total body fat (BF) and lean body mass (LBM) were analyzed using the 1.31 software version. Precision errors (1 SD) on the scanner used (system number 7156), as determined from double examinations of 10 healthy subjects, were 1.7% for BF and 0.7% for LBM. The results are presented as the percentages of BF and LBM of body weight (BF% and LBM%). DXA can be used to estimate fat in specific anatomical regions (13), and in this study an abdominal region (trunk) was defined to assess abdominal fat mass. BIA was measured in the supine position (BIA-101 equipment, RJL System, Inc., Detroit, MI). The resistance was measured using a 50-kHz, 800-µamp and principally reflects the extracellular fluid volume (14). The BIA measurements had a day to day CV of 1.7%.
Ethics
Informed consent was obtained from all patients. The study was approved by the ethics committee at the University of Goteborg.
Statistical analysis
All descriptive statistical results are presented as the
mean ± SEM. The overall within-group effect of
discontinuing GH treatment was analyzed using a one-way ANOVA for
repeated measurements. Student’s t test was used to analyze
the differences between baseline and 2 yr between groups of subjects.
Correlations were sought by calculating Pearson’s linear correlation
coefficient. Because of the highly skewed distribution of the serum
concentration of Lp(a), the descriptive results of Lp(a) are presented
as the median and 25th and 75th percentiles, and a logarithmic
transformation of the Lp(a) concentration was used before other
statistical analyses. Significance was obtained if two-tailed
P 
0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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24-h GH secretion and classification of subjects
Severe GHD into adulthood was defined as: 1) another anterior pituitary hormone deficiency associated with a spontaneous GH peak of less than 3 µg/L (17 subjects); 2) an organic hypothalamic/pituitary disease associated with a GH peak of less than 3 µg/L during an insulin tolerance test (3 subjects); and 3) in the absence of an organic hypothalamic/pituitary disease, a GH peak of less than 3 µg/L during 2 GH stimulation tests (1 subject).
Using these criteria, 21 patients were classified as having severe GHD
into adulthood, whereas 19 patients were classified as GH sufficient
(GHS). These 2 patient groups were similar in terms of age, body
height, the proportions of men and women, and age at the start of GH
treatment in childhood (Table 1
). The period of GH treatment was longer
in the GHD group (9 yr; range, 4–15 yr) than in the GHS group (7 yr;
range, 3–16 yr; P = 0.03), and the prospective
evaluation of age at onset of puberty was somewhat lower in the GHD
group (13 vs. 14 yr; P = 0.04). The average
daily doses of GH during the past 2 yr before entering the study were
0.03 ± 0.004 and 0.04 ± 0.004 mg/kg·day in the GHD and
GHS groups, respectively (P = 0.2). In the GHD group, 5
patients had 1 additional anterior pituitary hormone deficiency, and 12
patients 2–3 additional anterior pituitary hormone deficiencies; 4 had
isolated GHD.
The GHS patients did not differ from the healthy control subjects in
terms of 24-h mean GH secretion and 24-h maximum GH secretion. The GHD
subjects had, however, markedly lower GH secretion than both the GHS
group and the healthy controls (Table 1).
Serum IGF-I and IGFBP-3
Before discontinuing GH treatment, serum IGF-I concentrations were
markedly higher in both patient groups than in the healthy matched
controls (Table 2 and Fig. 1). Serum IGF-I concentrations decreased
in all groups during the 2-yr observation period. In the adolescents
with severe GHD, the reduction in serum IGF-I was more marked than in
the GHS group and the controls. At 2 yr, the serum IGF-I level was,
therefore, lower in the GHD group than in both GHS patients and
controls. In subjects with sufficient GH secretion, the baseline serum
IGF-I concentration was higher than in the GHD patients and was higher
than in both the GHD group and the controls after 2 yr without GH
treatment. The reduction in serum IGF-I was positively correlated with
the mean 24-h endogenous GH secretion (P = 0.57 and
P = 0.001), demonstrating the largest reduction in
serum IGF-I concentration in subjects with the lowest endogenous GH
reserve.
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During the 2 yr without treatment, serum levels of IGFBP-3 only
decreased in the GHD group. At 2 yr, the levels of serum IGFBP-3 were
therefore lower in the GHD group than in both the GHS and control
groups. Glucose metabolism, blood pressure, and lipoproteins
Blood glucose levels did not change in the patients taken off GH
treatment or in the controls during the 2 yr of observation. The level
of hemoglobin A1c and serum insulin concentration
decreased in both patient groups, whereas no changes were seen in the
control group (Table 2). No changes occurred in the serum
concentrations of free T4 and free
T3.
Systolic blood pressure only decreased in the GHS group in response to
the discontinuation of GH treatment. In the GHD group, diastolic blood
pressure demonstrated a transient reduction 1 yr after GH treatment was
stopped, whereas after 2 yr of observation, diastolic blood pressure
had increased (Table 2).
Before GH treatment was stopped, serum concentrations of total C,
LDL-C, and apo B were higher in the GHD group than in both the GHS
group and the control subjects (Table 3
and Fig. 2). After the discontinuation of
GH treatment, the serum levels of these lipids increased in both
patient groups, but not in the controls. The changes in serum levels of
total C, LDL-C, and apo B did not, however, differ among the three
groups during the 2-yr period of observation. After 2 yr, the serum
levels were therefore still higher in the GHD group than in the GHS and
control subjects.
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).
The slight reduction in HDL-C observed in the GHD group therefore
resulted in a significantly different overall change in this group of
patients compared with levels in both the GHS and control groups (Fig. 3). In the GHD group, serum triglyceride
levels were higher than those in controls at baseline and then
decreased in response to the discontinuation of GH treatment. Serum
Lp(a) levels were similar in all study groups throughout the study. A
reduction in the Lp(a) concentration occurred after GH treatment was
stopped in the GHD group, but not in the other two study groups.
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Body composition
After the discontinuation of GH treatment and during the 2-yr
observation period, BMI increased in both controls and the GHS group
(Table 4). The BMI did not, however,
differ significantly between the groups throughout the study. The LBM%
decreased and the BF% increased in both patient groups during the 2 yr
without GH treatment (Table 4). A similar tendency was found in the
healthy controls. The loss of LBM% and the gain in BF% in both
patient groups was more marked than in the healthy controls (Fig. 4). Before the discontinuation of GH
treatment, the amount of total BF% and truncal fat increased in the
GHD group compared with levels in both GHS and control subjects.
An increase in the amount of truncal fat was observed in all of the
study groups, but this increase was more marked in the GHD group than
in the controls (Fig. 4). As a result, 2 yr after GH treatment was
stopped, the LBM% had decreased, and the BF% and the amount of
truncal fat had increased in the GHD group compared with those in the
GHS and control subjects.
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). The change in body
resistance was more marked in the GHD than in the other two groups.
After 2 yr, body resistance had increased in the GHD group compared
with the others, thereby indicating a reduction in extracellular fluid
volume and fat-free mass in this group. |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A large percentage of patients with short stature and GHD in childhood do not have severe GHD into adulthood (15). One consistent finding, however, is that subjects with organic hypothalamic-pituitary disease, an additional anterior pituitary hormone deficiency, and postirradiation GHD in childhood will most likely remain severely GH deficient into adulthood (16, 17). This experience was used in the classification of subjects in this trial. It is, however, a small risk that the five patients with only one additional anterior pituitary hormone deficiency were wrongly classified, as there is a small proportion of such patients who will not have severe GHD (18). The use of peak 24-h GH levels will, however, minimize that risk, as GH-deficient adults may have a lower peak that does not overlap with the peak 24-h GH concentration in normal subjects (19).
We can only speculate about whether the GH levels in all of the subjects who were not classified as GH deficient are sufficient for their future health and well-being. Using previously defined criteria for severe GHD in adults, the mean 2-yr changes in the patients with severe GHD were different from those in the subjects who did not fulfill those criteria. In addition, the GH-sufficient patients had mean and peak 24-h GH concentrations similar to those in the control group. Furthermore, the GH-sufficient group and the controls displayed longitudinal changes in terms of lipoproteins and body composition similar to those reported in large cross-sectional cohorts of healthy subjects of similar age (20, 21), indicating only that the endogenous GH secretion in the GH-sufficient group was adequate.
There is limited knowledge about GH replacement therapy during the transition between childhood and adulthood, during which there is a steep decline in the GH secretion (22). The elevated serum IGF-I levels in both patient groups at baseline compared with the controls indicate that the average replacement dose of GH when entering the study was too high and that the longitudinal changes may therefore be inappropriately large in both patient groups. The duration of the study and the comparison between both patient groups and with the levels and the longitudinal changes in the controls should minimize any inappropriate interpretation of the between-group effects in this trial. The slightly higher serum IGF-I concentration in the GH-sufficient group might be influenced by their more recent onset of puberty than the GHD group, but not by different doses of GH during the last 2 yr before entering the trial. Subjects with multiple pituitary hormone deficiencies could not explain why the GH-deficient group had increased total body fat and abdominal obesity at baseline compared with the groups with preserved GH secretion (data not shown). This suggests that an inappropriate replacement therapy with other hormones was not responsible for this difference.
GH-deficient adults have increased secretion rate and reduced clearance rate of very low density lipoprotein (VLDL)-apo B (23), explaining their increased serum concentrations of LDL-C and apo B (5). Abdominal obesity, particularly when combined with insulin resistance and hyperinsulinemia, increases VLDL-apo B secretion from the liver (24). The increased VLDL-apo B secretion in GHD is therefore most likely explained by their abdominal obesity (1) and insulin resistance (25). Short term GH treatment increases the VLDL-apo B clearance rate (26). This is probably an effect of both induced action of the hepatic LDL receptor by GH (27) and increased removal of triglycerides from the VLDL particle by enhanced lipoprotein lipase activity in muscle (28). Before GH treatment was discontinued and throughout the study period, the levels of serum total C, LDL-C, and apo B were increased in the GH-deficient subjects compared with those in both groups with more preserved GH secretion. In accordance with previous studies (29, 30), this could not be explained by differences in serum concentrations of IGF-I, insulin, or body composition among the study groups. An association was found, however, between the increase in serum concentrations of LDL-C and apo B and the gain in abdominal adiposity during the 2 yr after terminating GH treatment. The increased levels of total C, LDL-C, and apo B in the GH-deficient compared with the other two study groups, therefore, remain unexplained. Probably, however, it depends on the balanced and complex effect on VLDL metabolism by insulin sensitivity, abdominal adiposity, genetic factors, and GH status.
The increased serum triglyceride levels in the GH-deficient group compared with controls at baseline and the reduction in serum triglyceride levels in response to terminating GH treatment is in contrast with observations that GH-deficient adults have increased serum triglyceride concentrations (4). Statistically, however, increased serum IGF-I concentration, increased serum insulin level, and increased abdominal adiposity could explain this increased serum triglyceride concentration at baseline. GH has profound lipolytic actions on visceral fat, increasing the availability of free fatty acids to the liver, which together with GH per se increase VLDL secretion from the liver (31). Moreover, abdominal obesity combined with hyperinsulinemia increase hepatic VLDL secretion more markedly than abdominal obesity alone (24), and patients with acromegaly have increased serum levels of triglycerides, which normalize in response to successful adenomectomy (32). Prolonged periods of inappropriately high GH levels and increased serum IGF-I and insulin concentration may therefore, together with increased adiposity, explain this contrasting finding for triglyceride levels in this study.
Two years after GH treatment was discontinued, the patients with severe GHD persisting into adulthood developed an increase in the amount of body fat and an increase in abdominal fat mass, and their elevated levels of total, LDL-C, and apo B concentrations increased further compared with those in subjects with more preserved endogenous GH secretion and healthy controls. Moreover, the reduction in HDL-C concentration contrasted with the increase observed in the GH-sufficient group and the controls. Although a reduction occurred in serum insulin and Lp(a) levels in the GHD group after stopping GH treatment, the levels of insulin and Lp(a) did not differ from the levels seen in the controls during the study, making these changes less important. Two years after GH treatment was discontinued, the GH-deficient group was therefore characterized by metabolic features previously well known from cross-sectional studies of adult patients with GHD (33, 34).
Abdominal obesity is an important risk factor for cardiovascular morbidity and mortality in both men and women (35, 36). Moreover, high concentrations of LDL-C and low levels of HDL-C are associated with a high incidence of cardiovascular morbidity and mortality (37). Intima-media thickness is an important surrogate variable for the progression of atherosclerosis and its manifestations (38, 39). Young adults with GHD of childhood onset have increased intima-media thickness of the common carotid arteries (40), which is normalized by GH replacement therapy (41). This finding together with the great importance of the total cholesterol level in early adult life for cardiovascular disease in midlife (42) demonstrate the significance of the metabolic consequences of discontinuing GH treatment in adolescents with severe GHD persisting into adult life. The overall cardiovascular risk profile at baseline together with the metabolic deterioration observed during the 2 yr without GH treatment in the GH-deficient adolescents may therefore be of major importance for their future cardiovascular health.
The increase in cardiovascular mortality seen in long term survivors of childhood neoplasia (43) may be explained in part by neuroendocrine aberrations. This particularly applies to children who have received cranial irradiation. They may develop features of the metabolic syndrome, with an increase in body weight, abdominal obesity, hyperinsulinemia, and low serum HDL-C concentrations (44). These are all characteristics that can be explained by the high prevalence of GHD found in these subjects (45). The eight subjects in this trial with GHD as an effect of previous neoplasia and radiation therapy did not differ from the 13 subjects with other causes of GHD (data not shown). This suggests that the metabolic consequences of GHD found in this trial were an effect of the hormone deficiency rather than its cause.
The increase in BF% and the decreases in LBM% and extracellular fluid volume observed when GH treatment was stopped were expected from previous small scale, short term trials of the discontinuation of GH treatment in adolescents (10, 11, 12). What is, however, clearly demonstrated in this trial is that the loss of LBM and the increase in BF are more marked in subjects with severe GHD compared with those with preserved GH secretion.
Two years after discontinuing GH treatment for GHD in childhood and short stature, subjects with severe GHD continuing into adulthood accumulated metabolic features that may disadvantageously affect their future cardiovascular health. Although it has not been proven that GH replacement therapy in adults saves lives, it is clear that the treatment improves the overall metabolic profile in GH-deficient adults (1, 46). Adolescents with severe GHD continuing into adulthood should, therefore, be considered for GH replacement therapy continuing into adult life.
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Acknowledgments |
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Footnotes |
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2 Participants in the Swedish Study Group for Growth Hormone
Treatment in Children: 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.
Received February 3, 1999.
Revised May 6, 1999.
Accepted July 7, 1999.
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M. Tauber, B. Jouret, A. Cartault, N. Lounis, M. Gayrard, C. Marcouyeux, C. Pienkowski, I. Oliver, P. Moulin, P. Otal, et al. Adolescents with Partial Growth Hormone (GH) Deficiency Develop Alterations of Body Composition after GH Discontinuation and Require Follow-Up J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5101 - 5106. [Abstract] [Full Text] [PDF]
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P < 0.05 compared with the GHS group.
