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Original Studies |
Endocrine Sciences Research Group, University of Manchester (M.S.G., P.E.C.), Manchester, United Kingdom M13 9PT; the Department of Endocrinology, Christie Hospital National Health Service Trust (A.A.T., S.M.S.), Withington, Manchester, United Kingdom M20 4BX; the Department of Geriatric Medicine, South Manchester University Hospitals National Health Service Trust (P.A.O.), Manchester, United Kingdom M20 8LR; and the Department of Medicine, University of Virginia Health Sciences Center (M.O.T.), Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Dr. Peter E. Clayton, Endocrine Sciences Research Group, Department of Medicine, University of Manchester, Oxford Road, Manchester, United Kingdom M13 9PT. E-mail: peter.clayton{at}man.ac.uk
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Abstract |
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AUCGH, sIGF-I, and sIGFBP-3 were significantly lower in GHD subjects than in controls. Total uGH24 was lower in GHD subjects, but tuIGF-I24 and tuIGFBP-324 excretion were not different in the two groups. AUCGH provided the best separation between GHD and control subjects, whereas there was substantial overlap for sIGF-I, sIGFBP-3, and tuGH24. In both groups sIGF-I was correlated to sIGFBP-3 (GHD, r = 0.75; controls, r = 0.65; both P < 0.01), whereas tuIGF-I24 was not correlated to tuIGFBP-324 in either group. Moreover, tuIGF-I24 and tuIGFBP-324 were not related to their respective serum concentrations in either group. Total uGH24 was correlated with AUCGH only in controls (r = 0.54; P < 0.05). These data demonstrate that urinary GH and urinary and serum IGF-I and IGFBP-3 are not suitable diagnostic markers for GHD in elderly subjects.
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Introduction |
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Subjects and Methods |
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Twenty GHD patients [15 men and 5 women; age, 61.1–83.4 yr; body mass index (BMI), 23.7–37.3 kg/m2] and 19 sex- and BMI-matched control subjects (12 men and 7 women; age, 60.8–87.5 yr; BMI, 20.1–37.0 kg/m2) were studied. GH deficiency in the patients was due to a mass lesion, pituitary surgery, radiotherapy, or a combination of these insults. The median duration of GH deficiency was 7.8 yr (range, 4.0–20.8 yr). Pathological diagnoses of the patients have been described in detail previously (7). However, in this study only those subjects with a GH peak less than 3 ng/mL in response to arginine stimulation were included (median, 0.002 ng/mL; range, 0.002–2.6 ng/mL) (8). All control subjects had a GH peak greater than 3 ng/mL after arginine stimulation (median, 10.7 ng/mL; range, 3.32–42.3 ng/mL). Patients with ACTH (n = 14) and TSH (n = 13) deficiencies were receiving standard hormone replacement. Ten of the 13 men with gonadotropin deficiency were receiving testosterone replacement, whereas none of the female patients or controls was receiving estrogen replacement. GH secretion was assessed by 24-h profile, and IGF-I and IGFBP-3 were determined in a single morning, fasted serum sample. Urine was collected over the same 24-h period and was stored at -20 C in the presence of 250 µL 10% BSA-10% sodium azide.
Serum assays
sGH was determined using the Nichols Luma Tag chemiluminescent immunometric assay (Nichols Institute, San Juan Capistrano, CA) with enhanced sensitivity (9). The detection limit was 0.002 ng/mL, with intra- and interassay coefficients of variation (CVs) of 9.8–11.7% and 6.6–10.4%, respectively. Results were expressed as area under the GH profile (AUCGH; minutes per ng/mL). IGFBP-3 was measured by specific RIA with intra- and interassay CVs of 3.6–5.6% and 4.2–7.2%, respectively, and a detection range of 0.6–50 ng/mL (10). IGF-I was measured using a specific IGFBP-blocked RIA (10). Intra- and interassay CVs were 4.0–5.7% and 5.2–7.4%, respectively, and the detection range was 0.8–25 ng/mL.
Urine assays
uGH was measured by immunoradiometric assay after dialysis, as previously described (11). The detection range was 0.78–100 pg/mL, and the intra- and interassay CVs were 6.6–8.8% and 8.8–10%, respectively. uIGFBP-3 was measured by RIA with intra- and interassay CVs of 1.9–2.6% and 6.2–9.2% respectively, and a detection range of 0.9–50 ng/mL (10). uIGF-I was measured in undiluted acidified urine (10). Intra- and interassay CVs were 2.1–4.4% and 5.1–10.1%, respectively, and the detection range was 0.26–6.25 ng/mL. Urinary creatinine (uCrt) was measured using a semiautomated alkaline picrate method (12). Urine results were expressed as total amounts excreted in 24 h (tuGH24, nanograms; tuIGFBP-324, micrograms; tuIGF-I24, nanograms; tuCrt24, millimoles).
Statistical analysis
Total uGH24, AUCGH, and tuIGFBP-324 were not normally distributed and were log10 transformed before parametric statistical analysis. Differences between groups were assessed by independent samples t test, and relationships between variables were assessed by Pearson correlation.
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Results |
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AUCGH was significantly lower in GHD subjects than in
controls (Table 1
and Fig. 1A). There was a significant sex
difference in AUCGH in controls [men, 847.2 (476.4,
1506.6) min/ng·mL; women, 1905.4 (1132.4, 3206.3) min/ng·mL;
P < 0.01]. When GHD and controls were compared within
the sexes, all GHD subjects had an AUCGH below the range of
their respective controls. uGH excretion was significantly lower in GHD
subjects than in controls (Table 1 and Fig. 1B) and was below the
detection limit of the assay in 6 patients and 1 control. In controls,
tuGH24 was lower in men than in women [men, 2.1 (0.3,
14.8) ng; women, 13.9 (6.6, 29.6) ng; P < 0.05].
However, when the sex difference was taken into account,
tuGH24 failed to differentiate between the 2 groups.
Excluding the 1 control subject with undetectable uGH, 9 of 15 male and
4 of 5 female patients had tuGH24 levels below the range of
controls. The total amount of uCrt excreted over 24 h was
identical in the 2 groups (Table 1).
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sIGFBP-3 and sIGF-I were significantly lower in GHD subjects
than in controls (Table 1
and Fig. 1, C and E). However, there was a
substantial overlap between the 2 groups; only 3 of 20 and 6 of 20 GHD
subjects had IGF-I and IGFBP-3 concentrations, respectively, below the
range of the controls. uIGF-I was below the limit of detection of the
assay in 5 GHD and 2 control subjects, whereas uIGFBP-3 was within the
detection range for all samples. There was, however, no difference in
tuIGFBP-324 or tuIGF-I24 excretion between GHD
and control subjects (Table 1 and Fig. 1, D and F), with complete
overlap between the 2 groups. A sex difference was observed only for
tuIGF-I24 in controls (men, 630.5 ± 401.2 ng; women,
215.1 ± 181.2 ng; P < 0.01). When patients and
controls were compared within the sexes, there remained complete
overlap between the 2 groups.
Correlation analysis
There was a significant correlation between sIGF-I and sIGFBP-3 in both control and GHD subjects (controls, r = 0.65; GHD, r = 0.75; both P < 0.01), but there was no relationship in either group between AUCGH and sIGF-I or sIGFBP-3. In controls, but not GHD subjects, AUCGH was inversely correlated with both tuIGF-I24 (r = -0.51; P < 0.05) and tuIGFBP-324 (r = -0.63; P < 0.01). In addition, although neither tuIGF-I24 nor tuIGFBP-324 correlated with their respective serum concentrations, tuGH24 was significantly correlated with AUCGH in controls (r = 0.54; P < 0.05). There was also a significant negative correlation between tuGH24 and tuIGF-I24 in controls (r = -0.61; P < 0.01).
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Discussion |
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The subjects included in this study, both GHD and controls, were defined by their responses to a GH stimulation test. A peak GH concentration below 3 ng/mL indicated severe GHD (2). All control subjects had a peak GH above 3 ng/mL, and thus, the arginine test was used as the standard against which the other tests were compared. This allowed us to judge the urine tests in two distinct groups. Integrated GH secretion measured by an ultrasensitive assay provided the best discrimination between the groups, in agreement with that reported by Baum et al. (13). Although sIGF-I and sIGFBP-3 concentrations were significantly lower in GHD subjects than in controls, there was considerable overlap between the two groups. A similar result was obtained by Hoffman et al. (1), and the narrow age range of our subjects suggests that comparison with age-related normal ranges would not provide further discrimination. The results for tuGH24 were similar to those obtained by Bates et al. (5) in subjects over 60 yr of age, in that tuGH24 was significantly lower in GHD subjects, but there was a substantial overlap with the controls. In contrast, neither tuIGF-I24 nor tuIGFBP-324 excretion could discriminate between GHD and controls, with no difference in levels between the two groups.
No significant correlations among sIGF-I, sIGFBP-3, and GH secretion were found in either controls or GHD subjects. Others have noted the lack of relationship between the IGF axis and GH in healthy elderly (14) and GHD subjects (13). We have previously shown in children that both tuIGF-I and tuIGFBP-3 were correlated with tuGH, with their respective serum concentrations, and with each other (10). However, none of these relationships could be demonstrated in the elderly, either GHD or control subjects. The only relationship that remained was that of tuGH24 excretion and AUCGH in controls, suggesting a role for uGH measurements in physiological studies of the normal elderly population.
An unexpected finding of this study was the negative correlation between AUCGH and tuIGFBP-3 and tuIGF-I in controls. This may be related to the existence of proteases that act on both IGF-I and IGFBP-3. Proteolysis of IGFBP-3 generates two fragments (15) that are recognized equally by the IGFBP-3 RIA used in this study (10). An inverse relationship between IGFBP-3 proteolytic activity and GH status has been described (16). Thus, low GH levels would be associated with the production of IGFBP-3 fragments, which are rapidly cleared through the kidney, generating the inverse correlation between tuIGFBP-324 and AUCGH. IGF-I proteolysis in the serum generates a truncated form of IGF-I, des(1, 2, 3)-IGF-I, which can be detected in urine (17). Des(1, 2, 3)-IGF-I undergoes increased renal clearance due to a reduced affinity for IGFBPs and can be detected by the uIGF-I assay used in this study (10). There is some evidence that the protease may be GH dependent (18) and could therefore account for the inverse relationship between AUCGH and tuIGF-I24 and tuGH24 and tuIGF-I24. The lack of these relationships in the GHD subjects may be due to the severity of GHD, which generates a very restricted range of GH levels.
This study has demonstrated that neither uGH, uIGF-I, nor uIGFBP-3 is capable of discriminating between GHD subjects and healthy elderly adults. Furthermore, neither tuIGF-I nor tuIGFBP-3 levels reflect their serum concentrations and thus are not suitable noninvasive surrogates for serum measurements. uGH excretion does, however, correlate with its serum concentration in controls and may have a role in physiological studies in healthy elderly subjects.
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Acknowledgments |
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Footnotes |
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Received January 8, 1998.
Revised March 10, 1998.
Accepted March 24, 1998.
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References |
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