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Original Studies |
Medical Department M (Endocrinology and Diabetes) (N.V., J.O.L.J., J.S.C.), Aarhus Kommunehospital, Aarhus DK-8000 C, Denmark; Department of Growth and Reproduction (A.J., N.E.S.), Rigshopitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; Center for Clinical Pharmacology (J.O.L.J., J.S.C.), Aarhus University Hospital, Aarhus, Denmark; and Institute of Clinical Experimental Research (H.Ø.), Aarhus University Hospital, Aarhus, Denmark
Address correspondence and requests for reprints to: Nina Vahl, M.D., Medical Department M, Aarhus Kommunehospital, Aarhus DK-8000 C, Denmark. E-mail: nvahl{at}dadlnet.dk
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Abstract |
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In conclusion, discontinuation of GH treatment in GHD patients, during the transition from childhood to adulthood, induces significant and potentially unfavorable changes in IGF-I and body composition, both of which are reversed after resumption of GH treatment. By contrast, continuation of GH therapy results in unaltered IGF-I and body composition. We recommend continuation of GH therapy in these patients, to be undertaken in collaboration between pediatricians and adult endocrinologists.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Most studies have been performed in middle-aged patients with adult-onset (AO) hypopituitarism secondary to pituitary tumors, and studies in patients with childhood-onset GHD (CO-GHD) have been initiated after a prolonged period of discontinued GH treatment (2, 3, 4, 5, 6). After withdrawal of GH treatment in young patients with reconfirmed CO-GHD, an increase in fat mass and a decrease in LBM have been reported after 3 months–1 yr off therapy (7, 8). However, no controlled studies exist, so far, on the effects of continued GH replacement in CO-GHD patients during the transition phase from childhood to adulthood.
The symptoms and signs of GHD seem to be more pronounced in AO-GHD, and this group of patients is also more responsive to GH replacement, both in terms of favorable changes in body composition and quality of life, as well as in frequency of side effects (5, 6).
The reason for these differences is unclear, but it is noteworthy that the two patient groups differ, both in terms of chronological age and underlying disease. It has also been hypothesized that CO patients may gradually have adapted to their disease over the years, in contrast to AO patients most of whom had a normal adult life before their disease.
To elucidate the effects of continuation of GH therapy in adolescents with CO-GHD, we recruited 19 patients, in the transition phase after cessation of linear growth, when discontinuation of GH replacement is normally considered. The study had a randomized, double-blind placebo-controlled design of 1 yr of duration, followed by an open phase of 1 yr, when all patients received GH therapy.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Nineteen subjects with CO-GHD were included in the study. The
diagnosis was reconfirmed by at least one GH-stimulation test performed
within 6 months before study entry (Table 1
). An arginine stimulation test or
insulin-induced hypoglycemia were used. The subjects were off GH
treatment for 1 week before the stimulation test. All subjects had been
treated with GH for at least 3 yr before the start of the study, with a
mean treatment duration of 9.6 yr. The etiology was idiopathic GHD in
13 of the 19 patients. A detailed description of the patients is given
in Table 1. All 19 subjects completed the double-blind phase. Two
subjects withdrew after 21 months: patient no. 18 because of
juxtasellar tumor growth, and patient no. 1 because of lack of
compliance. Both of these patients had received GH since study start.
One subject from the placebo group erroneously received GH for the last
3 months of the first year; and therefore, his data were excluded from
the statistical analyses. Informed written consent was provided from
the subjects before participation. The study was approved by the
regional Ethical Committee and the National Board of Health and was
conducted according to the Declaration of Helsinki and the guidelines
of Good Clinical Practice.
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During the first 12 months, the study had a randomized,
parallel, double-blind, placebo-controlled design. The subsequent 12
months was an open phase, during which all patients received GH. In the
double-blind phase, the patients continued with their regular GH dose
[2.0–5.0 IU/day (
0.006–0.015 µg/day); mean, 3.6 IU/day
( 0.011 µg/day) (Norditropin, Novo Nordisk A/S,
Copenhagen, Denmark)]. Nine subjects received GH, and 10
received placebo. In the open phase, the dose was escalated from 0.5
IU/m2·day (0.0015
µg/m2·day) in the first 2 weeks to 1.0
IU/m2·day (0.003
µg/m2·day) in weeks 3–6 and 2.0
IU/m2·day (0.006
µg/m2·day) from week 7 and onwards. In case
of adverse advents, the dose was reduced by 25%. The patients were
admitted to hospital for 2 days at baseline and after 12 and 24 months,
respectively. In addition, all patients were seen at the outpatient
clinic every 3 months for interviews and physical examination.
Body composition, muscle strength, and physical fitness
Subcutaneous abdominal fat, intraabdominal (visceral) fat, and muscle and fat area of the right midthigh region were evaluated by computed tomography, with a Somatom Plus-S scanner (Siemens, Erlangen, Holland), as earlier described (9). Percentage body fat and LBM were measured by dual-energy x-ray absorptiometry using a QDR-2000 densitometer (Hologic, Inc., Waltham, MA). Waist-to-hip ratio was calculated. Whole-body bioelectrical impedance analysis was performed with a bioimpedance analyzer (BIA 101/S, RJL Systems, Detroit, MI) and was analyzed by a computer-program provided by the manufacturer. A dynamometer was used to assess the isometric strength of the dominant quadriceps muscle. The torque exerted around the axis of the knee joint during a contraction was electronically measured, and the strength was calculated as the mean of three maximum isometric contractions, each lasting 5 sec. There was an interval of 2 min between contractions.
Exercise capacity was measured on a bicycle ergometer in the morning. The initial workload was 2.9 kilojoules/min, increased by 2.9 kilojoules/min every 3 min until exhaustion.
Quality of life
Quality of life was assessed by a General Health Questionnaire (GHQ), which is a validated self-rated questionnaire of 60 items focusing on disability of normal function, designed also to detect psychiatric disorders (10). According to the manual of the GHQ (11), the 60 items can be subdivided into 6 different groups (general illness, somatic symptoms, sleep disturbance, social dysfunction, anxiety and dysphoria, and severe depression). All items were scored. A high score indicates a low quality of life, and vice versa.
Hormone analyses
A double monoclonal immunofluometric assay (DELFIA, Wallac, Inc., Turku, Finland) was used to measure serum GH. The interassay coefficient of variation in samples varied between 1.7–2.4%, the intraassay coefficient of variation varied between 1.9–3.0% for GH concentrations of 0.27–12.08 µg/L, and the lower detection limit was 0.01 µg/L. Serum insulin-like growth factor (IGF)-I was measured by a noncompetitive time-resolved immunofluometric assay after removal of IGF-binding proteins (IGFBPs) with acid ethanol (12). Serum IGFBP-1 was measured by a commercial assay (Medix Biochemica, Kauniainen, Finland), as was IGFBP-3 (Diagnostic Systems Laboratories, Inc., Webster, TX), and insulin by conventional in-house RIA (13). Plasma total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured by standard enzymatic kits. Low-density lipoprotein (LDL) cholesterol was calculated by the Friedewald’s equation (14) in subjects with triglycerides below 4.5 mmol/L. Blood HbA1c was measured by high-performance liquid chromatography. Serum total T4 (TT4), free T4 (FT4), total T3 (TT3), free T3 (FT3), and total reverse T3 (rT3) were measured by RIAs (15, 16, 17).
Statistical Analyses
Analyses were made on log-transformed data when they were not
normally distributed. Normal distribution was obtained after log
transformation. Data are given as mean ± SE, if not
otherwise stated. In each group, the effect of continuation or
discontinuation of GH replacement was analyzed by one-way ANOVA.
Analyses of treatment effect during the placebo-controlled phase were
performed by comparing delta values (12 months vs. baseline)
between the GH and placebo groups by Student’s t test for
unpaired data. Statistical significance was assumed for
P 
0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The placebo group had more total body fat (kg) than their counterparts (22.7 ± 2.7 vs. 16.2 ± 2.1, P = 0.04). Serum levels of fasting insulin (pmol/L) were also higher in the placebo group (46.4 ± 6.2 vs. 100.3 ± 19.9, P = 0.01). The placebo group tended to have a greater waist circumference (cm) than the GH group at baseline (89.1 ± 3.7 vs. 80.3 ± 2.8, P = 0.07). The hip circumference and the waist-to-hip-ratio were not significantly different. Apart from this, no significant differences were found between the GH- and the placebo-treated groups, with respect to age, IGF-I, fasting glucose, HbA1c, body composition, fitness, hormones, or lipoproteins.
Serum IGF-I, IGFBP-1, and IGFBP-3
In the placebo group, serum IGF-I (µg/L) decreased at 12
months and increased significantly at 24 months [baseline: 422.0
± 56.8; 12 months: 147.8 ± 33.4 (P < 0.001); 24
months: 452.1 ± 75.6 (P = 0.001)] (Fig. 1). The levels of IGFBP-1 (µg/L)
increased after 12 months of placebo and decreased again after GH
[baseline: 2.34 ± 0.63; 12 months: 4.92 ± 1.61
(P = 0.12); 24 months: 3.14 ± 1.64
(P = 0.4)]. The IGFBP-3 levels (µg/L) decreased
after 12 months of placebo and increased subsequently during the open
GH phase [baseline: 3526 ± 209; 12 months: 2596 ± 269
(P = 0.002); 24 months: 3394 ± 335
(P = 0.02)]. Serum IGF-I, IGFBP-1, and IGFBP-3
remained unchanged in the GH group throughout the study [data not
shown, except for IGF-I (Fig. 1)]. Concerning IGF-I, the difference in
delta values from 0–12 months was significant (P =
0.003), demonstrating an effect of GH-discontinuation on IGF-I in the
first 12 months.
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In the placebo group, TBF (kg) increased significantly after
placebo, and a subsequent decrease after open GH treatment approached
significance [baseline: 22.68 ± 2.67; 12 months: 26.49 ±
2.51 (P = 0.01); 24 months: 21.02 ± 2.57
(P = 0.065)] (Fig. 2).
LBM was unchanged after 1 yr of placebo treatment; but during the
following year of open GH treatment, LBM (kg) rose significantly
[baseline: 50.85 ± 5.88; 12 months: 52.36 ± 4.86
(P = 0.12); 24 months: 60.70 ± 5.59
(P = 0.006)] (Fig. 2).
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A small, nonsignificant decrease in muscle mass of the thigh
(cm2/10 mm) was seen after placebo, followed by a
significant increase after open GH treatment [baseline: 121.3 ±
11.2; 12 months: 118.2 ± 11.7 (P = 0.12); 24
months: 130.0 ± 10.9 (P = 0.002)] (Fig. 3). Fat mass of the thigh
(cm2/10 mm) increased after 12 months and
decreased nonsignificantly after 24 months in the placebo group
[baseline: 84.1 ± 9.7; 12 months: 104.9 ± 13.6
(P = 0.007); 24 months: 98.9 ± 16.1
(P = 0.3)] (Fig. 3). A significant decrease after 12
months and an increase after 24 months in muscle to fat ratio were
observed [baseline: 1.66 ± 0.27; 12 months: 1.33 ± 0.24
(P = 0.02); 24 months: 1.69 ± 0.36
(P = 0.02)] (Fig. 3).
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No significant changes were seen in the GH treated group in any of the body composition estimates. Differences in delta values of TBF were significant after 12 months (P = 0.04), indicating an effect on TBF of GH-discontinuation. No significant difference in delta values was observed concerning any of the other body composition estimates.
Muscle strength and exercise
No significant changes in muscle strength or exercise capacity
were observed in either group after either 12 or 24 months (Table 2).
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In the placebo group, the resistance (ohms) increased
nonsignificantly after 12 months and decreased significantly again
after 24 months, when GH replacement was resumed [baseline: 569.6
± 36.9; 12 months: 586.8 ± 38.5 (P = 0.2); 24
months: 535.0 ± 31.2 (P = 0.002)] (Table 3). No significant changes were seen in
the GH group. A true treatment effect of discontinuation of GH could
not be confirmed because differences in delta values after 1 yr were
nonsignificant.
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). Lipoproteins and triglyceride
No significant changes were observed in total cholesterol, HDL
cholesterol, LDL cholesterol, or triglycerides after 12 or 24 months in
either the placebo- or the GH-treated group, except for an increase in
HDL cholesterol in the GH group from 12 to 24 months (Table 4).
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In the placebo group, a significant decrease in fasting glucose (mmol/L) was observed after 12 months, followed by a significant increase after 24 months [baseline: 5.1 ± 0.2; 12 months: 4.9 ± 0.2 (P = 0.05); 24 months: 5.3 ± 0.2 (P = 0.03)]. Serum insulin (pmol/L) decreased nonsignificantly after 12 months and rose again nonsignificantly after 24 months in the placebo group [baseline: 100.3 ± 19.9; 12 months: 64.9 ± 8.6 (P = 0.08); 24 months: 131.6 ± 46.0 (P = 0.16)]. No change was observed in HbA1c after placebo, but the increase when GH was resumed approached significance [baseline: 0.0486 ± 0.001; 12 months: 0.0489 ± 0.001 (P = 0.6); 24 months: 0.0503 ± 0.001 (P = 0.07)]. No significant changes were seen in the GH group in fasting glucose, serum insulin, or HbA1c after 12 or 24 months. Because a nonsignificant increase in serum insulin (pmol/L) was seen after 12 months in the GH group [baseline: 46.4 ± 6.2; 12 months: 57.1 ± 14.1 (P = 0.5); 24 months: 66.4 ± 14.2 (P = 0.2)], the differences in delta values after 1 yr became significant (P = 0.04). There were no differences in delta values after 1 yr, concerning fasting glucose or HbA1c.
Thyroid hormones
In the placebo group, serum levels of FT3
(pmol/L) decreased significantly after 12 months and rose
nonsignificantly after 24 months [baseline: 5.64 ± 0.39; 12
months: 5.04 ± 0.39 (P = 0.02); 24 months:
5.24 ± 0.57 (P = 0.8)]. Levels of
TT4 (nmol/L) increased significantly after
placebo, and the decrease when GH was resumed approached significance
[baseline: 149.3 ± 10.5; 12 months: 166.0 ± 11.3
(P = 0.03); 24 months: 149.6 ± 11.7
(P = 0.09)]. There were no significant changes in
either FT3 or TT4 in the GH
group and no differences in delta values after 1 yr (Table 3).
Quality of life
There was no effect on total score or subscores of general illness, somatic symptoms, sleep disturbance, social dysfunction, anxiety and dysphoria, or severe depression, according to the GHQ after 12 months in either group. After 24 months, the placebo-treated group tended to have a lower total score, indicating a better quality of life when GH was resumed [baseline: 45.1 ± 4.7; 12 months: 50.5 ± 6.9 (P = 0.5); 24 months: 38.3 ± 3.5 (P = 0.07)]. There were no differences in delta values after 1 yr.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The observed changes in body composition after discontinuation of GH for 12 months are in agreement with two earlier studies on the effects of GH withdrawal in patients with CO-GHD for 3 and 12 months, respectively (7, 8). Likewise, the decrease in fat mass and increase in LBM and muscle mass when GH replacement was resumed are in accordance with several studies of the effects of GH in adult patients of both AO (1) and CO (3, 4, 6, 18, 19, 20, 21). The lack of an increase in muscle strength and exercise capacity in the placebo group when GH was resumed in our study disagrees with earlier studies (2, 19, 21); but this could be explained by the longer mean times of discontinuation with GH, which were 6.4 yr (2, 21) and 7 yr (19), respectively, as opposed to 1 yr in the present study.
It is generally observed that GH administration in patients with GHD exerts beneficial effects on lipoproteins, resulting in a lowering of total and LDL cholesterol (6, 22, 23, 24, 25, 26, 27, 28). Those studies, however, comprise GHD of AO or mixed AO and CO. The present study, on the other hand, is in accordance with a study in CO-GHD (6) in which no effect of GH on lipoproteins was recorded.
GH administration in GHD patients, as well as in obese women, has been reported to induce a decline in circulating T4 levels secondary to stimulation of peripheral conversion of T4 to T3 (29, 30). The same studies demonstrated significant increments in FT3 after administration of GH to the patients. This is compatible with the findings in the present study, where discontinuation of GH resulted in an increase in TT4 and a decrease in FT3.
Adults with CO-GHD exhibit social phobia, a decreased self-esteem, a closed attitude towards social relationships, a pessimistic attitude tending towards depression, and a sense of detachment from the outside world, which lead to a below-average rate of marriage and an above-average rate of unemployment (31, 32, 33, 34). It is, however, unknown whether these psychological disorders also prevail in adolescents who discontinue GH replacement. In several (35, 36, 37, 38), but not all (39, 40) studies, improvements in quality of life have been observed after GH replacement in AO-GHD. However, part of the improvement might be attributed to a placebo effect (37). We found no significant changes in quality of life in our study, but a near-significant improvement was detected in the placebo group after subsequent open GH treatment.
Recently, a heterogeneity between CO- and AO-GHD was demonstrated in a large double-blind, placebo-controlled study (6). The two groups differed not only in baseline data of body composition, hormones, and quality of life but also in the response to GH treatment and in number of side effects. The group with CO-GHD had been off GH therapy for at least 2 yr before the study start, indicating that the clinical manifestations of GHD need more time to develop.
From Fig. 1, it seems that baseline levels of serum IGF-I vary
considerably in the GH group (90–580 µg/L), in contrast to the
placebo group, even though this difference was nonsignificant. The
variation in baseline IGF-I could suggest compliance problems in the GH
group, and the decrease in serum IGF-I after 1 yr in three of the
subjects supports this notion. This could explain why some of the
differences between the two groups, after the first year, are rather
small. In the placebo group, serum IGF-I levels, after the first year,
declined to approximately 150 µg/L, which is lower than in healthy
postpubertal subjects (41). These relatively high levels of IGF-I
could, however, explain why the changes in some of the variables were
less pronounced than expected, and this could suggest that it takes
more time to develop the full clinical picture of adult GHD. In an
earlier study, it was observed that levels of IGF-I in adult patients
are inversely correlated to duration of GHD (42), which could help to
explain why our younger subjects (mean age, 20.2 ± 0.7 yr) have
higher levels of IGF-I than the subjects in the study by Attanasio
et al. (6). Furthermore, they had been off GH for 2 yr, as
opposed to 1 yr in our study.
The patients in the present study continued their regular GH dose, which is considerably higher, compared with currently recommended replacement doses in AO patients. Even though we have not obtained a reference level of IGF-I specific for this group, it seems plausible that supraphysiological IGF-I levels were reached in some of the patients. A reduction of the replacement dose based on serial IGF-I measurements should therefore be considered.
The number of adverse events that could be related to withdrawal or resumption of GH were very few. One subject in the placebo group had a feeling of extreme tiredness, but the same was also observed in two subjects from the GH group. Two subjects in the placebo group developed peripheral edemas when GH was resumed, whereas none in the GH-treated group experienced any side effects in this period. The periphereral edemas were small and transient, and one of the two patients did not want a reduction in the GH dose because she felt more energetic at the same time. None of the other established side effects of GH, such as arthralgia and carpal tunnel syndrome, were reported in this study. This confirms earlier studies in which adverse events are seen more commonly in subjects with AO than with CO-GHD (5, 6, 43).
In conclusion, withdrawal of GH treatment in young adults with CO-GHD does lead to several unfavorable changes that all revert after renewed GH therapy. The results are less pronounced, compared with studies in AO patients, but the number of side effects in our patients was also less. It is recommended that continuation of GH therapy in transition-phase patients with reconfirmed GHD should be conducted in collaboration between pediatricians and adult endocrinologists, with particular awareness of GH dosage and potential compliance problems.
Received September 15, 1999.
Revised January 28, 2000.
Accepted February 2, 2000.
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L. Hulthen, B.-A. Bengtsson, K. S. Sunnerhagen, L. Hallberg, G. Grimby, and G. Johannsson GH Is Needed for the Maturation of Muscle Mass and Strength in Adolescents J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4765 - 4770. [Abstract] [Full Text] [PDF]
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W. M. Drake, S. J. Howell, J. P. Monson, and S. M. Shalet Optimizing GH Therapy in Adults and Children Endocr. Rev., August 1, 2001; 22(4): 425 - 450. [Abstract] [Full Text] [PDF]
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