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Institute of Endocrinology and Diabetes (S.S., G.D.O., S.P.G., J.W.L., C.T.C.) and Department of Nuclear Medicine (J.N.B.), The Children’s Hospital at Westmead, Westmead, New South Wales 2145, Australia
Address all correspondence and requests for reprints to: Dr. Shubha Srinivasan, Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia. E-mail: shubhas{at}chw.edu.au.
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Abstract |
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Introduction |
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Centripetal obesity in childhood is a significant risk factor for the metabolic syndrome (syndrome X), a cluster of cardiovascular risk factors including insulin resistance, glucose intolerance, dyslipidemia, and hypertension in adulthood (4). Adults with GH deficiency (GHD), both isolated and with hypopituitarism, have features of the metabolic syndrome, including excess abdominal adiposity, insulin resistance, and dyslipidemia (5, 6, 7). This has been implicated in increased cardiovascular mortality (8).
Information on the features of the metabolic syndrome in children with hypopituitarism is limited. Hypercholesterolemia has been described in children with GHD (9, 10). Unlike children with GHD from other causes, hyperinsulinemia is often seen after craniopharyngioma (11) and has been implicated in the growth without GH phenomenon seen in this population (12). As children after craniopharyngioma surgery are generally more overweight due to hypothalamic dysfunction than other children with GHD, we speculated that they would have features of the metabolic syndrome, including insulin resistance.
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Subjects and Methods |
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Nineteen children were diagnosed with craniopharyngioma at our institution over a 13-yr period. Of these, 15 subjects (10 males and five females) consented to participate in the study. The four who did not participate were similar to the study participants. Surgery, with the aim of total removal, was performed at diagnosis in all subjects. The median time since surgery was 5.1 yr (range, 1.8–10.7 yr). Ten subjects underwent more than one surgical resection, and one received adjuvant radiotherapy.
Three of the 15 (20%) subjects were overweight [body mass index (BMI) in the 85th-95th percentile], and eight (53%) were obese (BMI >95th percentile). All subjects were GH deficient on previous stimulation tests. GH was commenced at 4.7 mg/m2·wk if sustained growth failure ensued (5 subjects). Ten subjects had a growth velocity above the 25th percentile for age without GH. T4 was commenced at 75–100 µg/m2·d and hydrocortisone at 5–10 mg/m2·d, and doses were later titrated to response. Twelve of the 15 subjects were reliably receiving T4 replacement at the time of this study, and compliance was poor in three subjects. Thirteen of the 15 subjects were receiving regular hydrocortisone replacement. Eight subjects were prepubertal, one was Tanner stage 2, two were Tanner stage 3, one was Tanner stage 4, and three were Tanner stage 5. Sex steroid replacement was given at appropriate ages in standard incremental regimens (4 subjects). Desmopressin dose and frequency were titrated to control polyuria. No subject had elevated PRL levels (median, 142 mU/liter; range, 14–518).
Controls
Nine subjects (six obese and three overweight) were compared with healthy controls, individually matched for age, sex, BMI, and pubertal stage. Healthy controls had previously presented to the endocrine clinic with a primary concern of overweight or obesity, and no underlying cause for their excess weight gain was found. Appropriate controls could not be found for six subjects, primarily due to their younger age and lower weight.
Ethical considerations
Informed consent was obtained from all parents and subjects or controls. The study was approved by the Royal Alexandra Hospital for Children ethics committee. All subjects and controls were given detailed feedback about the results from the study.
Body composition
Anthropometry. Height, measured to the nearest 0.1 cm, and weight, measured to the nearest 0.1 kg using standard techniques were expressed as SD scores from the age- and sex-specific reference values currently used in Australia (13). Overweight was defined as a BMI between the 85th and 95th percentiles, and obesity as a BMI above the 95th percentile. BMI data are presented as SD scores from the age- and sex-specific reference values currently used in Australia (13) to enable comparative analyses. Waist and hip circumferences were measured to the nearest 0.1 cm using standard techniques. Pubertal status was assessed according to the standards of Tanner and Whitehouse (14).
Dual energy x-ray absorptiometry (DXA). Total body fat, abdominal fat, and lean tissue mass were measured using DXA (Lunar DPX equipped with proprietary Lunar DPX software, version 3.6, Lunar, Madison, WI). Manual analysis, using the regions of interest feature, was performed to gain specific information about the abdominal region as described previously (15). Percent body fat was calculated as DXA-measured fat divided by DXA-measured soft tissue plus bone mineral content. Abdominal fat, using the left abdominal window to exclude any contribution from a fatty liver, was expressed as a percentage of total fat.
Long-term quality control was performed on the DPX using an in-house total body phantom (aluminum and rice) and the Lunar spine phantom. The mean precision for the machine over the period of the study was 0.4% for soft tissue and 1.2% for bone mineral content (16).
Insulin sensitivity
Intravenous glucose tolerance test (IVGTT).
IVGTTs were performed according to the protocol for shortened IVGTTs (17). After an overnight fast, iv glucose (0.3 g/kg in a 25% solution) was given steadily over 1 min. Samples for glucose and insulin were taken at -10, -1, 2, 4, 6, 8, 10, 12, 14, 19, 25, 30, and 40 min. Calculations were made of the glucose disappearance rate (kg; min-1), first phase insulin response (mU/liter-1 min per mmol liter-1), and insulin sensitivity (Si; min-1 per mUL-1 min) from the 40-min test. The glucose disappearance rate was defined as the slope of log glucose concentration between 10 and 40 min after the glucose bolus. The first phase insulin response was defined as the amount of insulin released during the first peak (
area 0–10 min)/unit change in plasma glucose peak above basal. Insulin sensitivity was defined as the kg/unit insulin increased above basal ( area 0–40 min). A lower Si correlates with insulin resistance. Insulin was measured by standard RIA (Phadeseph Insulin RIA, Amersham Pharmacia Biotech, Uppsala, Sweden). Glucose was measured on a Beckman CX5 (Beckman, Fullerton, CA) using a hexokinase method.
Lipid profile
Total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides (TG), and apolipoproteins were measured by standard enzymatic methods. Low density lipoprotein (LDL) cholesterol was calculated using the formula: LDL cholesterol = total cholesterol - TG/2.2 + HDL cholesterol. Free fatty acids (FFA) were measured by an in-house fluoroturbidometric assay (RAHC, Sydney, Australia).
Other assays
IGF-I was measured by a double-antibody RIA (Bioclone Australia Pty. Ltd., Sydney, Australia). Free T4 was measured by two-step RIA (Gamma Coat Free T4, Clinical Assays, Cambridge, MA). PRL was measured by fluoroimmunometric assay (Delfia, Wallac, Finland). Leptin was measured by RIA (Linco Research, Inc., St. Charles, MO).
Statistical methods
Statistical analyses were performed using SPSS (version 10, SPSS, Inc., Chicago, IL). Descriptive data on the craniopharyngioma group are expressed as the mean ± SD for normally distributed data or the median and range for nonparametric data. A t test was used to compare groups with normally distributed data, and Kruskal-Wallis test was used for nonparametric data. Paired data analysis was performed using Wilcoxon’s matched pairs, signed rank test for nonparametric data. P < 0.05 was considered significant.
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Results |
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Characteristics of the 15 craniopharyngioma subjects are shown in Table 1
. Also shown are the characteristics of the nine craniopharyngioma subjects matched to healthy controls and the six who were not matched. Figure 1 shows the BMI SD scores for age for the 15 craniopharyngioma subjects and nine controls.
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Median insulin sensitivity was 1.59 min-1 per mUL-1 min (range, 0.43–4.17). There was no correlation between Si and age, BMI SD score, IGF-I level, GH treatment status, free T4, or pubertal stage.
Craniopharyngioma subjects paired compared with those who were not paired
Subjects who were paired were significantly older, heavier, and at a later stage of puberty than those who were not paired (Table 1
). Fasting TG were significantly higher, the HDL/total cholesterol ratio was significantly lower, and insulin sensitivity was significantly lower in those who were paired compared with those who were not paired. Height SD score, BMI SD score, waist/hip ratio, and ratio of left abdominal fat/total body fat were not different (Table 1).
Paired data analyses
There was no significant difference between subjects and controls for age (13.8 ± 3.5 vs. 13.1 ± 2.9; P = 0.59), height SD score (0.18 ± 1.4 vs. 0.19 ± 1.1; P = 0.31), weight SD score (2.54 ± 1.2 vs. 3.6 ± 2.0; P = 0.14), and BMI SD score (2.24 ± 1.0 vs. 2.59 ± 1.3; P = 0.26). Four of nine individuals in both groups were in Tanner stage 1 or 2 puberty. The waist to hip ratio was higher, although not significantly, in subjects compared with controls (P = 0.07; Table 2).
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Body composition.
There was no significant difference in median total body fat between subjects and controls (Table 2 and Fig. 2A). Abdominal fat, expressed as a percentage of total body fat, was significantly higher in subjects compared with controls (Table 2 and Fig. 2B). Lean tissue mass adjusted for height expressed as an SD score was similar for subjects and controls (median, 0.58; range, -1.1 to 2.03 vs. median, 0.78; range, -1.18 to 2.34; P = 0.59).
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). One of nine subjects and two of nine controls had fasting hyperinsulinemia (fasting insulin, >20 mU/liter). Si was not different between the pairs (Table 2 and Fig. 3A); however, values in both groups were lower than previously published results using this method in healthy adults (mean ± SE, 3.74 ± 0.77 min-1 per mUL-1 min) (17).
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and Fig. 3B), suggesting better glucose tolerance in the craniopharyngioma group. The first phase insulin response was similar in both groups (median, 7.03 mU/liter·min per mmol/liter; range, 3.77–13.10 vs. median, 6.15 mU/liter·min per mmol/liter; range, 3.00–10.12; P = 0.86); these values were reduced compared with those in healthy adults (mean, 16.09; range, 7.06–30.22) (17). Analysis of Si data were not significantly changed when the two subjects not receiving T4 treatment, and the two subjects on GH treatment and their controls were removed.
Lipid profile:
The craniopharyngioma group had a less favorable lipid profile, with significantly higher fasting TG (Table 2 and Fig. 4A) and lower HDL/total cholesterol ratio (Table 2 and Fig. 4B). Apolipoprotein a levels were significantly lower, and apolipoprotein b levels were significantly higher in subjects compared with controls (median, 1.04 mmol/liter; range, 0.88–1.52 vs. 1.28 mmol/liter; range, 0.98–1.73; P = 0.04; and median, 1.19 mmol/liter; range, 0.86–1.85 vs. median, 1.11; range, 0.67–1.45; P = 0.05, respectively). FFA levels were high in both groups; however, there was no difference between subject-control pairs (Table 2).
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Leptin and IGF-I:
Leptin levels were equally high in both groups, with no difference between subject-control pairs (median, 14.38 ng/ml; range, 5.06–38.17 vs. median, 18.54 ng/ml; range, 4.92–21.67; P = 0.59). Paired data analysis showed significantly lower IGF-I levels in craniopharyngioma subjects compared with controls (Table 2).
Subjects treated with GH compared with those not receiving GH
Ten subjects not receiving GH were compared with the five subjects receiving GH. No differences were found for age, anthropometry (height SD score, BMI SD score, and waist to hip ratio), body composition (total body fat, lean tissue mass, and abdominal fat), and metabolic indexes (insulin sensitivity, glucose disposal, TG, HDL/total cholesterol ratio, apolipoproteins, and leptin; data not shown). IGF-I levels were significantly higher in the subjects treated with GH compared with those not receiving GH (median, 21 nmol/liter; range, 15.5–63.3 vs. median, 7.45 nmol/liter; range, 2.1–23.8; P = 0.014).
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Discussion |
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There are few studies looking at the metabolic syndrome in children with GHD. Children with GHD have an adverse lipid profile (9, 10), and GH treatment improves their lipid profile and body composition (10, 19, 20, 21, 22). However, the improvement in LDL cholesterol does not correlate with changes in height or body composition, suggesting that the metabolic and anthropometric mechanisms of GH action are different (20). To our knowledge, our study is the first to detail the increased risk of the metabolic syndrome in children with GHD and hypothalamic obesity after craniopharyngioma surgery.
Excess abdominal adiposity and adverse lipid profile have been demonstrated in adults with panhypopituitarism and isolated GHD (5, 6, 7, 23). In addition, GHD adults are insulin resistant compared with age-, sex-, and BMI-matched controls even after correction for body fat (5). However, the data on lipid profile and FFA levels in adults are conflicting. Some studies have shown higher FFA levels in adults with GHD or hypopituitarism compared with age-, sex-, and BMI-matched controls (7), and others have found significantly lower FFA levels, with no difference in fasting TG levels (5). Another study of adults with panhypopituitarism showed a similar lipid profile to the subjects in our study, with lower HDL cholesterol and higher TG levels (24). Similar to the pediatric population, GH treatment has been shown to improve lipid profile in GHD adults (10, 22, 25, 26, 27).
We did not find significant differences in metabolic parameters and body composition between the five craniopharyngioma subjects treated with GH and the 10 subjects not treated with GH. However, paired data analysis showed minor improvements in the lipid profile of the craniopharyngioma subjects when the subjects receiving GH and their pairs were removed from the analysis. This suggests that either the worst-affected cases are receiving GH or that GH has an adverse effect on lipid profile, contrary to other published data (10, 19, 20, 22). The small numbers in our study do not enable us to draw any definite conclusions about the role of GH treatment in children and adolescents after craniopharyngioma surgery.
The craniopharyngioma subjects had significantly higher kg values than their controls, suggesting better glucose tolerance. As kg reflects insulin-dependent (Si) and insulin-independent processes, and Si values were similar in subjects and controls, we postulate that the higher glucose disposal rate seen in our subjects is due to more efficient insulin-independent glucose uptake. In healthy adults, insulin-dependent glucose uptake and insulin-independent glucose uptake contribute equally to glucose disposal (28). In adults with type 2 diabetes, although the total glucose uptake is decreased compared with that in healthy controls, the proportional contribution of insulin-independent glucose uptake increases significantly (28). We speculate that this mechanism may be present in our subjects, as their Si is decreased secondary to obesity. Furthermore, the higher glucose disposal resulting in better glucose tolerance in the craniopharyngioma subjects could be a result of GHD consistent with data in prepubertal children with GHD and hypoglycemia (29, 30). The exact mechanism of higher glucose disposal in relation to GHD after craniopharyngioma surgery remains to be elucidated.
Obesity related to hypothalamic injury after surgery for craniopharyngioma can be one of the most distressing outcomes in this population. In our series, 53% of subjects were obese, and 27% were overweight, similar to previously published data (2, 3). Hyperinsulinemia is often associated with obesity in this population and has been postulated to contribute to the growth without GH phenomenon (12). Although two thirds of our subjects postcraniopharyngioma surgery demonstrated growth without GH treatment, only one subject had fasting hyperinsulinemia. Neither hyperinsulinemia, leptin, nor PRL could explain the growth without GH treatment in our subjects.
We used the 40-min IVGTT as a simple tool to measure insulin sensitivity. This method is reliable in a diverse range of glucose tolerance and insulin sensitivity and correlates well with the clamp (r2= 0.85) and minimal model (r2= 0.87) (17). This test has been used in studies with adults; however, there are no normative data from this methodology in children across different ages and stages of puberty. Although we were able to use the 40-min IVGTT to demonstrate reduced Si in several subjects and controls, we were unable to demonstrate a significant difference between subject-control pairs. This may be due to the small numbers in our study. Additional limitations to our study relate to the heterogeneity of craniopharyngioma subjects as well as difficulties in finding controls. Individually matched controls for age, sex, BMI, and pubertal stage were found for nine cases. However, we were unable to recruit matched controls for six subjects who were of younger age and lower weight.
Obesity is associated with the metabolic syndrome and cardiovascular morbidity. After craniopharyngioma removal, children and adolescents are at risk of excess weight gain, and together with GHD, this increases the likelihood of abdominal adiposity and dyslipidemia. As a result, they could be at higher risk of atherogenic complications from the metabolic syndrome compared with BMI-matched healthy controls. Further studies assessing predictors of abdominal adiposity and dyslipidemia after craniopharyngioma surgery are required. As these patients progress into adulthood, they should be monitored for features of the metabolic syndrome, including insulin resistance, type 2 diabetes mellitus, dyslipidemia, and hypertension with a view to appropriate treatment.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMI, Body mass index; DXA, dual energy x-ray absorptiometry; FFA, free fatty acid; GHD, GH deficiency; HDL, high density lipoprotein; IVGTT, iv glucose tolerance test; kg, glucose disappearance rate; LDL, low density lipoprotein; Si, insulin sensitivity; TG, triglycerides.
Received March 13, 2003.
Accepted September 22, 2003.
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, controls (n = 9). Of note, six craniopharyngioma subjects and five controls had a BMI SD score greater than 2.33 (99th percentile).
, Data from individuals; •, mean; error bars, 95% confidence intervals. A, Percent total body fat. No difference between subjects and controls (P = 0.51). B, Left abdominal fat/total body fat percentages. Subjects had significantly higher abdominal fat compared with controls (P = 0.008).
