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Special Feature |
Unit of Endocrinology (M.T., B.J., A.C., N.L., M.G., C.M., C.P., I.O., P.M., P.R.), Hôpital des Enfants, TSA 70034, 31059 Toulouse Cedex 9, France; Unit of Radiology (P.O., F.J.), Centre Hospitalier Universitaire Rangueil, TSA 50032, 31059 Toulouse Cedex 9, France; and Unit 558 of Epidemiology of Institut National de la Santé et de la Recherche Médicale (C.A.), Hôpital Paule de Viguier, TSA 70034, 31059 Toulouse Cedex 9, France
Address all correspondence and requests for reprints to: Professor M. Tauber, Unit of Endocrinology, Hôpital des enfants, 330 Avenue de Grande Bretagne, BP 3119, 31026 Toulouse Cedex 3, France. E-mail tauber.mt{at}chu-toulouse.fr.
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Abstract |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Therefore, the majority of adolescents having received GH treatment during childhood for GHD do not have severe GHD at completion of growth (2). About 60–70% have normal GH secretion, defined by the cut-off used in childhood (GH peak above 10 µg/liter), and 15% have partial GHD (GH peak between 5 and 10 µg/liter) (9). The latter case is the most frequent in children at initiation of GH treatment, regarding idiopathic and isolated GHD. Conversely, patients with organic GHD more often have complete and persistent GHD with multiple hormone deficiencies.
Beyond the consensus of reevaluating GH secretion at completion of growth, we are currently uncertain as to what to say to patients and what kind of follow-up to offer to those patients whom we did not send to adult endocrinologists because they have either normal GH secretion or "partial GHD."
To answer some of these questions, we performed a prospective study including all GHD patients with a GH peak above 3 µg/liter at completion of GH treatment and followed them for 1 yr.
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Patients and Methods |
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We performed a 1-yr prospective study in GHD patients at completion of growth and 1 yr later. Informed consent was obtained from parents or from subjects more than 18 yr of age.
Among the 96 patients retested, five patients were excluded because they had a GH peak less than 3 µg/liter for two pharmacological tests and organic GHD. We do not have patients with central nervous system malformation, but 18.7% have a pituitary hypoplasia [with a mean value for pituitary height expressed in SD score (SDS) of -4.2 ± 2.2, according to Argyropoulou et al. (10)]. Four patients presented with a combined GHD (one with gonadotropin deficiency, one with hypothyroidism, one with hypothyroidism and gonadotropin deficiency with pituitary height of -7 SDS, and one with corticotropin deficiency with pituitary height of -3.7 SDS). Four patients presented with organic GHD (three had hydrocephaly secondary to spina bifida neonatal meningitis, one with unknown reason, and one patient had acute lymphoid leukemia).
We recorded auxological data [height, weight, body mass index (BMI), waist and hip circumferences, waist-hip ratio], biological data [retesting of GH secretion, serum IGF-I and IGF-binding protein 3 (IGFBP-3)], fasting glycemia and insulinemia, lipid profile [total cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), and lipoprotein(a)], body composition, and intraabdominal and extraabdominal fat mass.
Hormone and biological analysis
GH secretion was reevaluated twice: at completion of treatment with the clonidine-betaxolol test (in 75% of cases), because this was the test most frequently used before starting treatment; and after 1 yr with an insulin tolerance test (ITT) (if not contraindicated) as recommended for the diagnosis of adult GHD (6, 7).
Serum GH was measured using a double-monoclonal immunoradiometric assay (IRMA) (CIS Bio International, ORIS, Gif sur Yvette, France). The interassay coefficient of variation ranged between 2.4% at 3.4 µg/liter and 2.8% at 17 µg/liter. Serum IGF-I was measured by IRMA (Diagnostic System Laboratories Inc., Webster, TX) after acid ethanol extraction, serum IGFBP-3 by IRMA (Diagnostic System Laboratories Inc.), and immunoreactive free insulin by IRMA (Bio-Rad Laboratories, Mions, France). Plasma glucose, TG, and total cholesterol were measured with enzymatic reagents on an automated analyzer (Dade-Behring, Les Ulis, France). HDL cholesterol was assayed after a prior precipitation of apolipoprotein (Apo)B/ApoE-containing lipoproteins with phosphotungstic acid and magnesium (Roche Diagnostics, Meylan, France). LDL cholesterol was calculated according to the Planella equation. Lipoprotein(a) was determined by immunoprecipitation in an automated analyzer (Cobas-Mira; Roche Diagnostics).
Body composition
Body composition was determined using dual energy x-ray absorptiometry with a whole-body scanner (Lunar DPX-L, Lunar Corp., Madison, WI). Total body fat (TBF) and lean body mass (LBM) were analyzed using the Lunar 1.31 software version. Because we do not have French standard references on body composition parameters during childhood and adolescence, we chose to use the data from Sendsen et al. (11) and Boot et al. (12). TBF and LBM were first expressed as percentages of total body weight, and after log transformation, SDS were calculated from curves of Boot et al. (12).
Extraabdominal and intraabdominal fat
Extraabdominal (sc) fat and intraabdominal (visceral) fat were evaluated by computed tomography (CT) with a Somatom Plus-S scanner (Siemens, Erlangen, Germany), as previously described (11). A 10-cm-long lateral scout view (140 kV; 111 mA) was obtained in the caudocranial direction, starting from the iliac crests. A single cross-sectional scan (120 kV; 240 mA; rotation time, 0.75 sec) was performed through the L4–L5 intervertebral discs. The area of pixels with attenuation values ranging between -130 and -70 Hounsfield units was considered to represent the total fat area. A line outlining the ip tissue was traced with a cursor; the area of pixels within this region and with the same attenuation values enabled us to evaluate visceral fat. The sc area was regarded as the total fat area minus the visceral fat. Results are expressed in square centimeters.
Bone mineral density (BMD)
The BMD was determined using dual x-ray absorptiometry, as described (see Body composition). SDS were calculated from standard curves of Boot et al. (13).
Statistical analysis
The Jarque-Bera test was used to determine whether variable distributions were normal or skewed.
For variables with a normal distribution (final height, height gain, waist, hip, waist-hip ratio, BMD, IGF-I, IGFBP-3, and metabolic data), descriptive results are presented as the mean ± SE. The t test for unpaired samples was used to analyze the differences between the four groups, and the t test for paired samples was used to analyze the differences between baseline and 1 yr within the four groups of subjects.
For variables with a skewed distribution (BMI, TBF, LBM, intraabdominal fat, and extraabdominal fat), descriptive results are presented as the median and the interquartile range. The Mann-Whitney U test was used to analyze the differences between the four groups, and the Wilcoxon test was used to analyze the differences between baseline and 1 yr within the four groups of subjects.
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Results |
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We report here only the data of 91 patients (51 boys and 40 girls) treated for GHD, with normal GH secretion or with partial GHD at reevaluation, and compare their evolution.
Auxological data at the start of treatment are summarized in Table 1
. Mean chronological age was 12.0 ± 3.7 yr in boys and 9.9 ± 3.0 yr in girls; mean bone age was 10.3 ± 3.2 yr in boys and 8.7 ± 2.7 yr in girls. Mean SDS for height according to the French growth charts (14) was -2.4 ± 0.8 for boys and -2.6 ± 0.6 for girls; and the mean z-score for BMI according to the French BMI curves (15) was -0.21 ± 1.46 for boys and -0.19 ± 1.52 for girls.
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According to recent French recommendations, normal GH secretion was defined by at least two tests above 20 mIU/liter (or 11.8 µg/liter according to the internal standard; group 1, n = 46). We subsequently expressed the values of GH in micrograms per liter.
Thirty patients had discordant stimulation tests, one peak being less than 11.8 µg/liter and the other above 11.8 µg/liter. For 21 patients, the first test was less than 11.8 µg/liter and the second test was normal (group 2, n = 21), and for nine patients it was the opposite, with a normal test at discontinuation of GH treatment and a low GH peak 1 yr later (group 3, n = 9). Finally, partial GHD was defined by two tests less than 11.8 µg/liter (group 4, n = 15). Table 2 summarizes the results of GH testing.
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Mean final height expressed in SDS at completion of treatment was -1.2 ± 0.9; and mean height gain expressed in SDS during GH treatment was 1.2 ± 0.8. During the year after completion of treatment, mean height gain, in centimeters, was 1.2 ± 1.5. For all these data we did not find any significant differences between the four groups.
Anthropometric data
At completion of treatment, the median of BMI expressed in z-score was 0 in group 1, 0.37 in group 2, 0.04 in group 3, and 0.6 in group 4. Group 1 is statistically lower than group 4 (P = 0.03). After 1 yr, BMI was 0.13 in group 1, 0.78 in group 2, 0.31 in group 3, and 0.83 in group 4. Group 1 remains statistically different from group 4 (P = 0.03). The values did not change significantly after 1 yr within each group, except for group 1 (P = 0.02) (Table 3).
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The waist-hip ratio did not differ between the four groups, whether boys and girls were considered together or separately.
Body composition
After completion of GH treatment, TBF is significantly higher in groups 4 and 2 than in group 1 (P = 0.01 and P = 0.03, respectively), and LBM is significantly lower in group 4 than in group 1 (P = 0.01) (Fig. 1). Moreover, TBF increases significantly during the year after completion of GH treatment, from 1.1–1.5 SDS (P = 0.03) in group 4 and from 0.3–0.4 SDS (P = 0.04) in group 3, whereas LBM decreases from -1.0 to -1.4 SDS (P = 0.03) in group 4, and from -0.6 to -1.4 SDS (P = 0.04) in group 3 (Table 3
). There were no significant changes in body composition during the year without treatment in groups 1 and 2.
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Intraabdominal and extraabdominal fat
Intraabdominal and extraabdominal fat were measured by CT scan at cessation of treatment and 1 yr after (Table 3). Because no reference values were available, we analyzed boys and girls separately. There was no difference in the intraabdominal fat between the four groups and no evolution during the year after cessation of GH treatment.
In the extraabdominal fat, there was no statistically significant difference between the four groups in girls. In boys, extraabdominal fat is significantly higher in group 4 than in group 2 at cessation of treatment (P = 0.005); after 1 yr, extraabdominal fat is significantly higher in groups 4 and 2 than in group 1 (P = 0.03 and 0.02, respectively). There was a trend to increase of extraabdominal fat mass in groups 3 and 4 during the year without GH, although it was not significant.
BMD
BMD expressed in SDS according to reference curves from Boot et al. (13) was not significantly different between the four groups at either evaluation and was not modified after 1 yr (Table 3).
IGF-I and IGFBP-3 levels
IGF-I levels were expressed in SDS according to the reference curves established by Diagnostic System Laboratories, Inc. Before discontinuation of treatment, only 41 patients had IGF-I evaluation: 18 in group 1, 12 in group 2, two in group 3, and nine in group 4. Data are missing for technical reasons or for other reasons without any specific bias. Mean IGF-I SDS was 0.4 ± 0.9 and was not significantly different between the four groups (data not shown).
After 4 wk without GH treatment, mean IGF-I SDS decreased to 0.1 ± 0.9 and was stable after 1 yr at -0.1 ± 0.8. There was no significant difference between the four groups at either evaluation (data not shown).
IGFBP-3 levels were expressed in SDS according to the reference curves established by Diagnostic System Laboratories, Inc. IGFBP-3 SDS were not significantly different between the four groups at completion of treatment and after 1 yr (data not shown).
Metabolic data
Glycemia (n = 79) and fasting insulin (n = 45) levels were not significantly different between the four groups at either evaluation (data not shown).
Total cholesterol and TG values (n = 81) were not significantly different in the four groups at completion of GH treatment and 1 yr after; and neither were LDL cholesterol, HDL cholesterol, or ApoA1 and ApoB levels.
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Discussion |
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Conversely, group 3, defined by a normal GH peak at completion of treatment and by a low GH peak 1 yr after, strongly raises the question of an evolutive endocrine status. If this is not the case, could we suggest that GH treatment could restore GH secretion in these patients at least for a while? Interestingly, two patients underwent a clonidine test after 1 yr with a low GH peak of 0.6 and 8.7 µg/liter, showing that the type of testing in this group does not explain the discrepancy. Moreover, this group had a similar evolution to that of the partial GHD group (group 4) with a significant increase in body fat and a decrease of LBM. The existence of such patients (10% of the retested population) supports the need for repeating GH reevaluation and for prolonged follow-up of these patients. Interestingly, we noticed in this study that partial GHD adolescents are already fatter than the GH-sufficient patients at completion of treatment.
This study also stressed that anthropometric measurements are not sufficiently accurate to monitor body composition changes in this population because the evolution of BMI and waist-hip ratio was not significant after 1 yr. The increase in TBF associated with the decrease in LBM after 1 yr without treatment strongly suggests that these changes are due to low GH levels. Moreover, these changes did not occur in the GH-sufficient group or in group 2, supporting a causative effect of GHD.
A recent prospective study in GHD adolescents clearly showed the same abnormalities in body composition after 1 yr and also after 2 yr of discontinuation of GH treatment in the GHD group alone, and not in the GH-sufficient group (16). GHD secretion was not analyzed by provocative tests but by 24-h GH secretion, and we could not distinguish partial and complete GHD. In the present study, abdominal fat analyzed by CT scan did not significantly increase in partial GHD adolescents, although there was an increasing trend after 1 yr, whereas visceral fat did not change. The lack of significance could be due to the low number of patients studied. This observation tends to confirm the abnormalities previously reported in severe GHD adolescents (3) and corrected by the resumption of GH therapy. This point was different from what is observed in patients with adult GHD, in whom visceral fat mass is relatively more increased than sc fat (17, 18, 19).
However, BMD was not modified after 1 yr of treatment, as previously described (20). The values around -1 SDS could suggest that the references from Boot et al. (13), which we used, were not appropriate. We observed no marked metabolic changes in the partial GHD group, no significant increase of TG levels or insulin after 1 yr of GH treatment, and we did not measure blood pressure accurately in these patients. These latter features were not observed in adolescents with severe GHD in previous studies (5, 16). This suggests that they appear later in the course of the metabolic syndrome due to GHD, as they were described in adults with CO-GHD but were less severe than in adults with AO-GHD (21). This difference could be explained by the age of the patients (25–30 yr in CO-GHD vs. 50–60 yr in AO-GHD), by the duration of GHD, or by an additional effect of age on GHD (22). Therefore, our study confirms that alterations of body composition rapidly occur during the first year without GH treatment in partial GHD adolescents and perhaps even sooner after the completion of treatment (3 or 6–9 months), because it has been reported that body composition was rapidly modified when GH was started in GHD children (23, 24). These findings raise several questions: 1) What is the course of these abnormalities in partial GHD patients over time, and therefore what follow-up should we offer them (25)? Are they, in the same way as severe GHD adults, at high risk of cardiovascular morbidity due to their altered body composition, these changes being the first and silent signs of an ongoing process leading to metabolic abnormalities and later on syndrome X (26, 27)? and 2) Will all of these patients need GH treatment, or at least those with the most severe changes in body composition?
Long-term follow-up for these adolescents should be pursued with sequential GH retesting and careful evaluation of body composition, metabolic features, and cardiovascular status, in close collaboration with adult endocrinologists during and after the so-called transition period.
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Acknowledgments |
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Footnotes |
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Received March 6, 2003.
Accepted June 14, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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, Group 1;
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group 2;
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group 3; 
, group 4. B, Evolution of TBF and LBM during the year without GH.