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Department of Endocrinology (R.D.M., S.M.S.), Christie Hospital, Manchester M20 4BX, United Kingdom; and Clinical Radiology (J.E.A.), Imaging Science and Biomedical Engineering, the University of Manchester, Manchester M13 9PL, United Kingdom
Address all correspondence and requests for reprints to: Professor S. M. Shalet, Department of Endocrinology, Christie Hospital National Health Service Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom. E-mail: stephen.m.shalet{at}man.ac.uk.
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Abstract |
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GHD adults (n = 30, peak GH < 3 µg/liter) were of shorter stature than the controls. Body mass index was not significantly increased, but waist/hip ratio (0.885 vs. 0.818, P = 0.001) and skinfold thickness (78.2 vs. 59.6 mm, P = 0.003) were greater than control subjects. Bioimpedance analysis revealed these patients to have reduced lean body mass (LBM) (44.4 vs. 51.2 kg, P = 0.023) and increased fat mass (FM) (25.7 vs. 18.4 kg, P = 0.039). Dual-energy x-ray absorptiometry (DXA) analysis of body composition confirmed reduced LBM (43.6 vs. 50.6 kg, P = 0.010) and increased FM (26.0 vs. 19.2 kg, P = 0.015). The excess FM was observed to be primarily truncal in distribution. Similarly, GHI adults were of shorter stature but with increased waist/hip ratio (0.871 vs. 0.818, P = 0.006) and skinfold thickness (80.8 vs. 59.6 mm, P = 0.003), compared with controls. Bioimpedance analysis revealed a reduction in LBM (44.9 vs. 51.2 kg, P = 0.020). DXA studies confirmed the reduced LBM (45.0 vs. 50.6 kg, P = 0.041) and additionally noted an increase in percent FM (32.9 vs. 27.4%, P = 0.019). All measures of body composition in the GHI patients were intermediate between those of the controls and GHD patients. Serum leptin levels were significantly elevated in both the GHD (41.5 vs. 20.7 ng/ml, P = 0.009) and GHI (36.7 vs. 20.7 ng/ml, P = 0.022) adults, compared with healthy controls. The excess FM observed using DXA in the GHD and GHI adults equated to 6.5 kg (8%) and 3.5 kg (5.5%), respectively, relative to healthy controls.
In summary, we have shown that adults with GHI have abnormalities of body composition characteristic of GHD. The degree of abnormality of body composition lies between that of healthy subjects and GHD adults and correlates with the IGF-I level. Any future trials of GH replacement in patients with GHI must await further studies to establish the exact impact of this relative deficiency on the broad spectrum of biological end points influenced by GH status.
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Introduction |
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In childhood a peak GH response of less than 5–7 µg/liter to insulin-induced hypoglycemia is taken as consistent with a diagnosis of GH insufficiency, this level having been validated against the height velocity both pre- and post-GH therapy (16). The observed improvement in height velocity during GH replacement therapy in children with partial GHD is greater than in short normal children, although less than in children with severe GHD (16, 17). Extrapolating from studies in childhood, it is foreseeable that a similar group of patients with partial GHD exists within the adult hypopituitary population. In our unit, the median peak GH response to insulin-induced hypoglycemia in healthy subjects was 36 µg/liter, none of the subjects failing to achieve a peak GH response of greater than 7 µg/liter (18). Therefore, a peak GH response to insulin-induced hypoglycemia of 3–7 µg/liter in hypopituitary adults may thus be interpreted as consistent with a diagnosis of partial GHD (GH insufficiency) in the context of known or putative disease of the hypothalamic-pituitary disease.
Whether this lesser degree of GHD has a significant biological impact has not been fully established. Initial studies from Colao et al. (19, 20), defining GH status of hypopituitary adults according to their peak GH response to the arginine-GHRH test, suggested adults with partial GHD have normal bone mineralization (19) but elevated serum total and low-density lipoprotein cholesterol levels (20). We therefore initially studied hypopituitary adults according to their GH status, defined by the insulin tolerance test (ITT), to establish the impact on regional and overall body composition.
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Subjects and Methods |
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The study cohort comprised 62 adults with a history of pituitary disease and 30 age- and sex-matched controls. The patient cohort was subdivided according to their GH secretory status into subgroups defined as GH deficient (GHD), GH insufficient (GHI), and GH replete (GHR). The GH stimulation test of choice was the ITT (n = 57 of 62). Where the ITT was contraindicated and to confirm the patient’s GH secretory status, patients underwent alternate GH stimulation tests using arginine (n = 29), glucagon (GST, n = 9), or GHRH plus arginine (n = 20). All patients were required to undergo two tests of GH reserve to confirm their GH secretory status, except in the setting of panhypopituitarism and a peak GH response to the ITT of less than 0.33 µg/liter (21), or a normal GH reserve (peak GH > 7 µg/liter). GHD was defined as a peak GH response of less than 3 µg/liter to all stimulation tests undertaken (15). GHI was defined by the highest peak GH response to a stimulation test within the range of 3–7 µg/liter and GHR as a peak GH response of more than 7 µg/liter to at least one stimulation test. Respective values for the diagnosis of GHD, GHI, and GHR when using the GHRH plus arginine test were less than 9, 9–21, and greater than 21 µg/liter, respectively (20, 22).
The GHD subgroup included 30 patients (15 female) with a mean age of 34.2 ± 10.8 yr, of whom 16 had childhood-onset pituitary disease. Fifteen of the patients were gonadotropin deficient, eight ACTH deficient, and six TSH deficient. Eight patients received GH replacement during childhood to optimize final height. The mean peak GH response to the primary GH stimulation test was 0.8 ± 0.6 µg/liter (ITT, n = 28; GST, n = 2), and mean fasting serum IGF-I was 207 ± 117 ng/ml. Twenty-four patients were defined as GHI (12 female) with a mean age of 31.5 ± 13.2 yr. Thirteen were of childhood onset, six of whom had received GH replacement therapy to aid linear growth during childhood. Of the GHI patients, two were gonadotropin deficient, two ACTH deficient, and two TSH deficient. The mean peak GH level after stimulation was 3.7 ± 1.2 µg/liter (ITT, n = 22; GST, n = 2), and fasting IGF-I was 295 ± 104 ng/ml. Of the total patient cohort, eight patients (two female) with a mean age of 26.9 ± 8.4 yr, were defined as GHR. Three were of childhood onset, and one had received GH replacement during childhood. One patient was gonadotropin deficient. Mean peak GH response to the primary GH stimulation test was 10.3 ± 6.2 µg/liter (ITT, n = 7; GST, n = 1) and fasting IGF-I was 352 ± 138 ng/ml. None of the patients had received GH replacement therapy in the 12 months before their inclusion in the study. Thirty age- and sex-matched control subjects (mean age of 30.9 ± 11.5 yr, 15 female) were additionally studied. Mean fasting IGF-I was 373 ± 123 ng/ml. There was no significant difference in age between the control and patient groups.
Study protocol
All studies were conducted after an overnight fast. Blood was drawn for measurement of fasting serum leptin. Height was measured to the nearest 0.5 cm using a wall-mounted stadiometer. Waist circumference was measured between the lower rib superiorly and iliac crest inferiorly and taken as the smallest circumferential distance. Hip circumference was measured at the level of the anterior superior iliac spines. Arm circumference was measured halfway between the head of the humerus and olecranon process. Skin thickness was measured using Harpenden skinfold calipers over the biceps, triceps, immediately below the scapula, and immediately superior to the iliac crest in the sagittal plane. Measurement of height, waist, hip, arm circumference, and skin thickness was performed by a single observer (R.D.M.). Weight, total body fat mass (FM, kilograms), percent FM (%FM), and lean body mass (LBM, kilograms) were estimated using a bioelectrical impedance monitor (Tanita TBF-305, Uxbridge, UK). The Tanita TBF-305 uses pressure contact foot-pad dual electrodes, providing leg-to-leg measurement of conductance at a frequency of 50 Hz. FM, LBM, and %FM were calculated according to gender. Calculation of body mass index and waist/hip ratio (WHR) were derived from the anthropometric data. Regional and total FM, %FM, and LBM were additionally measured using dual-energy x-ray absorptiometry (DXA). Ethical approval for this study was granted by the South Manchester Local Research Ethics Committee, and written informed consent was obtained from each subject.
DXA
Whole-body scanning (23) was performed on a 4500 Acclaim scanner (Hologic Inc., Bedford, MA). All jewelry and outer clothing were removed, and the patients were scanned wearing a cotton gown. Patients were positioned supine on the scanning table, with arms internally rotated and hands prone on the scanning table with fingers together. The legs were positioned straight on the table with the feet taped together and extended as much as possible. Before commencing the scan, it was ensured that all parts of the body were inside the boundary of the scanned field that is marked out on the mattress of the scanning table. The short-term precision of whole-body DXA in the unit for bone mineral content is 0.92%, FM is 1.75%, and lean (muscle) mass is 0.56%.
Assays
IGF-I was determined, after acid-alcohol extraction, by an immunoradiometric assay using a commercially available kit (Diagnostic Systems Laboratories, Inc., Webster, TX). Sensitivity was 0.8 ng/ml, and intraassay coefficients of variation (CVs) at 9.3, 55.3, and 263.6 ng/ml were 3.4, 3.0, and 1.5%, respectively. Interassay CVs at 10.4, 53.8, and 255.9 ng/ml were 8.2, 1.5, and 3.7% respectively.
Serum leptin levels were measured using a commercially available immunoradiometric assay (Diagnostic Systems Laboratories, Inc.). Intraassay CVs at 2.7, 13.5, and 73.6 ng/ml were 3.7, 4.9, and 2.6%, respectively. Interassay CVs at 2.8, 14.3, and 73.8 ng/ml were 6.6, 5.3, and 3.7%, respectively.
Data analysis
All data are presented as mean ± SD. Differences across the groups were studied using one-way ANOVA or one-way ANOVA on ranks for parametric and nonparametric data sets, respectively. Differences between groups were examined using a t test or rank sum test. Correlations between serum IGF-I levels and the various measures of body composition were investigated using Pearson’s or Spearman’s test.
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Results |
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No difference in height was detected between the controls and GHR patients (Table 1
). The GHI patients were significantly shorter in stature than the controls (1.64 vs. 1.71 m, P = 0.008), whereas the GHD patients were of shorter stature than both the controls and GHR patients (1.62 vs. 1.71 m, P = 0.0003; and 1.62 vs. 1.69 m, P = 0.035, respectively). No difference in weight or body mass index was detected among the four study groups. Waist circumference was greater in the GHD patients, compared with controls (87.6 vs. 80.1 cm, P = 0.03); however, no differences were detected in waist measurement between the remaining study groups, and no significant differences in hip circumference among groups were observed. WHR was significantly greater in both the GHD and GHI subgroups, compared with the controls (0.885 vs. 0.818, P = 0.001; and 0.871 vs. 0.818, P = 0.006, respectively). There were no differences in arm circumference among the four groups.
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Regional skin thickness at the biceps, triceps, subscapular, and suprailiac areas was significantly greater in the GHD subjects than the controls (11.3 vs. 8.4 mm, P = 0.05; 21.1 vs. 15.6 mm, P = 0.02; 22.4 vs. 16.8 mm, P = 0.003; and 23.4 vs. 18.8 mm, P = 0.001, respectively) (Table 2). Additionally, GHD patients when compared with the GHR patients had significantly greater skinfold thickness in the triceps and subscapular regions (21.1 vs. 13.5 mm, P = 0.035; and 22.4 vs. 15.5, P = 0.031). Similar to findings for the GHD subgroup, the GHI patients were also shown to have significantly greater skinfold thickness at the biceps (11.6 vs. 8.4 mm, P = 0.008; and 11.6 vs. 7.5 mm, P = 0.038), triceps (21.3 vs. 15.6 mm, P = 0.017; and 21.3 vs. 13.5 mm, P = 0.022), and suprailiac (27.7 vs. 18.8 mm, P = 0.0003; and 27.7 vs. 18.5 mm, P = 0.013) regions, compared with the controls and GHR groups, respectively.
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Bioimpedance analysis
LBM measured by bioelectrical impedance was lower in the GHD and GHI adults, compared with controls (44.4 vs. 51.2 kg, P = 0.023; and 44.9 vs. 51.2 kg, P = 0.020, respectively) (Table 3). In contrast, FM was significantly greater in the GHD, but not the GHI, adults, compared with controls (25.7 vs. 18.4 kg, P = 0.039). The %FM was also significantly greater in the GHD adults, compared with controls (34.5 vs. 26.1%, P = 0.020). The %FM for the GHI adults was intermediate in value to that seen in GHD adults and controls and was not significantly different from either group.
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DXA was used to examine regional, subtotal (excluding the head), and total FM and LBM (Table 4). In the upper limbs, both GHD and GHI adults had significantly greater FM than controls (3.3 vs. 2.2 kg, P = 0.005; and 3.0 vs. 2.2 kg, P = 0.018, respectively); however, there was no significant difference among the four study groups in LBM. In the lower limb, there was no significant difference in FM among the study groups; however, LBM was significantly lower in both the GHD and GHI adults, compared with the control group (13.8 vs. 16.4 kg, P = 0.006; and 14.6 vs. 16.4 kg, P = 0.048, respectively). In the trunk, GHD adults were observed to have increased FM (12.0 vs. 8.3 kg, P = 0.003) and reduced LBM (21.9 vs. 25.4 kg, P = 0.009), compared with the controls. GHI adults had reduced truncal LBM, compared with controls (22.4 vs. 25.4 kg, P = 0.026), and a FM intermediate to the value seen in GHD patients and healthy controls.
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A significant correlation between measures of FM (R = 0.94, P < 0.0001) using bioimpedance and DXA was observed for the cohort overall. A similarly highly significant relationship was also observed for LBM (R = 0.86, P < 0.0001).
Serum leptin
Serum leptin levels were significantly elevated in both the GHD (41.5 ± 34.9 vs. 20.7 ± 16.2 ng/ml, P = 0.009) and GHI (36.7 ± 26.2 vs. 20.7 ± 16.2 ng/ml, P = 0.022) adults, compared with the healthy controls.
IGF-I and body composition
Using serum IGF-I as a marker for GH status, IGF-I was observed to correlate with the sum of skinfold thickness (R = –0.26, P = 0.013), bioimpedance FM and %FM (R = –0.33, P = 0.0014; and R = –0.33, P = 0.0014), bioimpedance LBM (R = 0.22, P = 0.037), DXA truncal FM (R = –0.35, P = 0.0008; Fig. 1), DXA total FM and %FM (R = –0.31, P = 0.0033; and R = –0.34, P = 0.0012), and serum leptin (R = –0.33, P = 0.0014).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the current study, we subgrouped hypopituitary adults according to their GH status to patients with severe GHD (peak GH < 3 µg/liter), GHI (peak GH 3–7 µg/liter), and patients who were GHR (peak GH > 7 µg/liter). All but five patients underwent the ITT, and all patients were subject to two stimulation tests unless panhypopituitary accompanied by a peak GH of less than 0.33 µg/liter to the initial stimulation test or GHR. These strict criteria for division of the patients to their respective GH strata were applied to avoid inappropriate classification of patients that may result from the inherent intraindividual variability of standard GH stimulation tests.
Examination of the body composition of these patients using anthropometry, skinfold thickness, bioimpedance, and DXA confirmed that GHD adults have reduced LBM and excess FM in keeping with the published literature (1, 2, 26, 27). FM in the GHD adults was 6.5 kg greater than healthy age- and sex-matched control subjects; equating to an 8% excess body fat in the GHD adults. Regional analysis of body composition by DXA demonstrated the majority of the excess FM in GHD adults to be truncal, whereas the deficit in LBM (
7 kg) was located primarily within the trunk and lower limbs. The regional DXA findings are independently supported by the anthropometric data, which show an increased WHR, accompanied by no significant difference in arm circumference when comparing GHD adults with controls.
The novel finding of this study, however, concerns the patients with GHI for whom the impact of a lesser degree of GH deficiency on body composition has never been defined. We have shown that patients with GHI have an abnormal body composition with increased FM and reduced LBM, as classically described for patients with severe GHD. The observed abnormalities in the GHI patients included an increased WHR; increased skinfold thickness over the biceps, triceps, and suprailiac regions; and an increase in the sum of the regional skinfolds; and reduced LBM measured by bioimpedance analysis. Regional DXA revealed an increase in FM of the upper limbs and reduced LBM of the lower limbs and trunk. Total body DXA showed an overall increased percentage FM, as well as a reduction in LBM. As would be predicted from the pediatric growth data for patients with partial GH deficiency, the degree of variance in body composition from a state of normal health in patients with adult GHI was less than that observed in patients with severe GHD.
GH replacement therapy has been shown to produce beneficial effects on growth in children with a peak GH response to insulin-induced hypoglycemia of 2.5–5 µg/liter (i.e. partial GHD) (16, 17). The observed improvement in height velocity in children with partial GHD was greater than in short normal children, although less than those children with severe GHD (16, 17). In our GHI patients, the excess FM and %FM was in the region of 3.5 kg and 5.5%, respectively, whereas LBM was around 5.5 kg lower than the age- and sex-matched controls. In keeping with the intermediate body composition data of the GHI patients, serum leptin levels were also observed to be between levels in the healthy controls and GHD adults. Furthermore and finally, support is given to the observation that body composition abnormalities in the GHI patients are intermediate to those of the GHD and healthy subjects by the correlation between IGF-I or the peak stimulated GH level and the various measures of body composition. Of note is that only four of the GHI patients had deficiencies of other anterior pituitary hormones, supporting the hypothesis that the observed abnormalities in body composition are a consequence of GHI.
During the assessment of GH status in the hypopituitary patients, eight subjects with a history of pituitary disease were found to be GHR on the basis of the GH stimulation tests. Although this group was limited numerically, they are of interest because no differences in body composition were observed between them and the healthy controls. In fact, the mean value for all measures of body composition of the healthy controls and GHR patients showed remarkable similarity. Additionally, although no significant difference was detected in the DXA total body %FM and FM/LBM ratio of GHI and GHD adults, the GHR patients had significantly lower %FM and FM/LBM ratio than the GHD adults. These data suggest that in patients who achieve a peak GH level of more than 7 µg/liter to insulin-induced hypoglycemia, any relative and subtle impairment of GH status imparts a negligible impact on body composition.
To date little is known about the impact of GHI on the adult hypopituitary patient. Using arginine plus GHRH to assess GH status, Colao et al. (19, 20) correlated the degree of GH reserve with abnormalities of the lipid profile and bone mineral density (19, 20). Patients were stratified to four groups according to a peak GH response to the arginine-GHRH test of less than 9.0, 9.1–27.0, 27.1–49.5, and more than 49.5 µg/liter, representing very severe GHD, severe GHD, partial GHD, and not GHD, respectively. Although it is difficult to directly compare results of different GH stimulation tests, the patients with a peak GH response to the arginine-GHRH test of 27.1–49.5 correspond best to the GHI group of the current study characterized using insulin-induced hypoglycemia. Total cholesterol and low-density lipoprotein cholesterol levels were significantly higher in the very severe, severe, and partial GHD groups, compared with the healthy controls. Total cholesterol was, however, significantly higher in the very severe and severe GHD groups than in the partial GHD group, although no differences in low-density lipoprotein cholesterol among these three groups was reported. Triglyceride and high-density lipoprotein levels in the partial GHD group were not significantly different from those in the control group (20). In a second study Colao et al. (19) observed no difference in bone mineral density t-scores at the lumbar spine or femoral neck between patients with partial GHD and either patients with very severe GHD or healthy controls (19). Furthermore, no difference in bone turnover markers was reported between patients with partial GHD and healthy controls.
In summary, we have shown adults with GH insufficiency, defined by a peak GH response to insulin-induced hypoglycemia of 3–7 µg/liter, to have abnormalities of body composition characteristic of GHD. These abnormalities include an increase in total fat mass of around 3.5 kg and reduction of LBM of around 5.5 kg. The increase in FM was predominantly distributed within the trunk. The degree of abnormality of body composition is intermediate between that of healthy subjects and GHD adults and correlated with the IGF-I level. Thus, patients biochemically defined as having GHI may have a number of physiological sequelae as a consequence of their GH status. The overall impact on a host of biological end points needs to be carefully defined before trials of GH replacement are considered in patients with GHI.
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Acknowledgments |
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Footnotes |
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Abbreviations: CV, Coefficient of variation; DXA, dual-energy x-ray absorptiometry; FM, fat mass; %FM, percent FM; GHD, GH deficiency; GHI, GH insufficiency; GHR, GH replete; GST, glucagon stimulation test; ITT, insulin tolerance test; LBM, lean body mass; WHR, waist/hip ratio.
Received April 29, 2003.
Accepted December 18, 2003.
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