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Original Studies |
Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Institute (A.H., K.H., I.-L.W.-H., M.S., M.T.), S-171 76 Stockholm; and the Department of Primary Health Care, Research and Development Unit, Serafimerlasarettet (A.-L.M.), S-112 83 Stockholm, Sweden
Address all correspondence and requests for reprints to: Dr. Agneta Hilding, Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Hospital, L1:02, S-171 76 Stockholm, Sweden.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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In conclusion, an IGF-I level below -2 SD seems to be of diagnostic value in GHD with onset in childhood or early adulthood, whereas values within normal range are common in patients over 60 yr of age, especially those with pituitary tumors. The outcome of GH replacement therapy may reveal whether the addition of IGF-I as a diagnostic criterion is of predictive value in older patients.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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With attention to differences in etiology and age at onset of GHD, the aim of the present study was to further explore the diagnostic value of serum IGF-I determinations. Moreover, the value of GH replacement therapy is now being explored in elderly patients defined as having GH-deficiency. Accordingly, an extended reference range with healthy older subjects was needed for the comparison of IGF-I values.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The normal range of IGF-I was determined in sera from 448
apparently healthy subjects (247 women and 201 men), aged 20–96 yr,
with an extended number of subjects of older ages compared to that
previously described (9). Thus, the reference range was composed of 229
blood donors, aged 20–71 yr, 128 other healthy subjects, aged 24–84
yr, and 91 healthy elderly individuals, aged 79–96 yr. The subjects
were equally distributed in each decade with respect to number and
gender, except for the ages above 80 yr, where the women were in
majority, probably reflecting the normal sex ratio at that age (Table 1
). The healthy subjects were recruited
among hospital staff and by an advertisement in the local paper. The
elderly individuals were also recruited by information at a
pensioners’ meeting and enquiries to the home service organization
(collected by A.-L.M.). None had diabetes or other endocrine diseases
or had received estrogen therapy. The elderly subjects were living
independently at home. Height and weight were registered in 349
subjects. In women, the mean height was 162.4 cm (range, 140–178 cm),
the mean weight was 64.9 kg (range, 43–100 kg), and the mean body mass
index (BMI) was 24.6 kg/m2 (range, 17.1–37.5
kg/m2). Corresponding values in men were 177.7 cm (range,
161–195 cm), 80.0 kg (range, 58–115 kg), and 25.3 kg/m2
(range, 18.8–32.9 kg/m2).
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One hundred and fifty-two consecutive patients, aged 19–82 yr,
with GHD of various etiologies participated in this study (Table 2). Patients with acromegaly were
excluded. Etiologies referred to as "others" were hypophysitis
(n = 3), intrauterine infection (n = 1), meningoencephalitis
(n = 1), intracranial hemorrhage (n = 1), congenital
lues (n = 1), surgery, not due to pituitary tumor (n =
1), neurosarcoidosis (n = 1), and meningioma (n = 1). One
hundred and seven patients had panhypopituitarism. In 43 patients (20
females and 23 males), GHD was diagnosed before 20 yr of age,
i.e. childhood onset, whereas 109 patients (51 females and
58 males) acquired their GHD as adults. All patients received regular
adequate substitution therapy for pituitary insufficiency, except for
GHD. Cushing’s disease was treated and inactive, and the prolactinoma
patients had normal PRL levels due to either previous treatment or
current medication with dopamine receptor agonists. Twenty patients
with childhood-onset GHD had received previous GH treatment withdrawn
several years before this study. GHD was biochemically defined
according to Consensus Guidelines 1997 (10) as a peak GH response below
3 µg/L to insulin-induced hypoglycemia. When an insulin test was
contraindicated, especially in elderly patients, arginine or glucagon
stimulation tests were performed, with the same cut-off value for GH.
In addition, diurnal GH profiles, sampled every 20 min throughout
24 h using the continuous withdrawal technique (11), were
determined in 58 patients, none with values above 3 µg/L. In fact, in
this patient group, only 4 patients had GH values above 2 µg/L in
stimulation tests or diurnal profiles.
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IGF-I was determined in serum or plasma by RIA after separation of IGFs from IGF-binding proteins (IGFBPs) by acid-ethanol extraction and cryoprecipitation. To minimize interaction of IGFBPs, des(1, 2, 3)-IGF-I was used as the ligand, and high affinity antibodies were employed (12). The detection limit was 8 µg/L. Including the extraction step, the intraassay coefficients of variation (CVs) were 4.3% (at 149 µg/L), 3.9% (at 217 µg/L), and 8.6% (at 526 µg/L), whereas the interassay CVs were 9.6% (at 146 µg/L), 7.7% (at 209 µg/L), and 8.8% (at 317 µg/L), respectively.
Two different assays have over time been used to determine serum or plasma levels of GH. First, a RIA with polyclonal antibodies was used, and the separation was performed with a second antibody (13). The detection limit was 0.2 µg/L, and the intra- and interassay CVs were 3.0% and 10%, respectively. Later a commercially available kit, a two-site fluoroimmunometric GH assay based on two monoclonal antibodies, was used (DELFIA hGH, Wallac, Inc., Turku, Finland) with a detection limit of 0.04 µg/L. The intra- and interassay CVs were 5.0% and 8%, respectively. Standards used in the different assays were both calibrated against the WHO First International Reference Preparation 80/505. The equation for the linear regression line comparing the two methods is: y = 1.01x + 0.32 (r = 0.97), where x is the DELFIA, and y is the RIA.
Study protocol
Serum samples for the determination of IGF-I were taken in the morning after an overnight fast in all subjects, except for the blood donors, who had had their regular morning meal. However, levels of IGF-I seem to be unaffected by meals, as in most studies (14, 15, 16, 17) no diurnal variation has been found in healthy subjects.
The ethics committee of the Karolinska Hospital approved the study, and the subjects gave informed consent.
Statistics
Results are presented as the mean ± SEM if not otherwise stated. Unpaired t test or Mann-Whitney rank sum test assessed the comparability of two groups. Correlation coefficients were determined from simple and multiple least linear regression analysis. The nonnormally distributed serum IGF-I values were log transformed before analysis to more closely approximate a Gaussian distribution. The age-dependent reference range for serum IGF-I concentrations was calculated by simple least linear regression analysis; the regression line represents the mean, and the prediction interval is represented by ±2 SD, where SD is the residual deviation of the regression errors. The value of acceptance for statistical significance was set at P < 0.05. Statistical analyses were performed using SigmaStat for Windows (Jandel Scientific GmbH, Erkarth, Germany).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Serum levels of IGF-I in healthy subjects were age dependent,
declining with age (r = -0.774; P < 0.001;
n = 448; Fig. 1 and Table 1
). A
logarithmic scale was used on the y-axis because the
transformed data of IGF-I approximated a normal distribution more
closely. The equation for the regression line in women was:
10log [IGF-I (µg/L)] = 2.585 - 0.00715
x age (yr) (r = -0.768; P < 0.001); the
equation in men was: 10log [IGF-I (µg/L)] = 2.566
- 0.00647 x age (yr) (r = -0.775; P <
0.001). No significant difference was found between the slopes. Thus,
an age-dependent reference range (geometrical mean ± 2
SD) in healthy subjects, independent of gender, was
calculated based on the equation for the regression line in all
subjects: 10log [IGF-I (µg/L)] = 2.581 -
0.00693 x age (yr), with SD = 0.120. The variation
(SD) was constant for ages between 20–80 yr, although it
increased at ages above 80 yr. However, a common regression line for
all ages was calculated. Thus, the prediction interval became slightly
larger in ages younger than 80 yr than if the subjects older than 80 yr
were excluded.
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). In multiple regression analysis, when
age was taken into account, the relation was still significant if women
and men were calculated together. However, only a small increase in the
r2 value, from 0.516 to 0.533, was observed in the
multivariate correlation compared to the univariate correlation between
IGF-I and age. Body weight correlated positively to IGF-I in men
(r = 0.224; P = 0.007) and in all subjects (r
= 0.241; P < 0.001; Table 3), but the relation
disappeared when age was taken into account. Exclusively in women an
inverse relationship was found between IGF-I and BMI (r = -0.161;
P = 0.021), which was also lost when age was
considered.
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Compared to the age-dependent reference range in healthy subjects,
the majority (76%) of GHD patients had IGF-I values below -2
SD (Fig. 2). When all
patients were included, no correlation was found between levels of
IGF-I and age (r = 0.134; P = 0.100). The number
of patients with IGF-I values within the normal range increased with
increasing age: 4% for ages 20–39 yr (n = 48), 30% for ages
40–59 yr (n = 61), and 40% for ages above 60 yr (n = 43).
Mean IGF-I was lower in women than in men (57 ± 4 µg/L
vs. 81 ± 5 µg/L; P < 0.001), also
when corrected for age; IGF-I-SD was -5.0 ± 0.3 in
women and -3.3 ± 0.3 in men (P < 0.001). For
all patients (n = 152), only five had serum IGF-I levels above -2
SD for 20-yr-old healthy individuals (159 µg/L); one had
craniopharyngioma, two had nonsecreting pituitary adenomas, one had
Cushing’s disease, and one had idiopathic GHD.
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). In contrast,
among patients with adult-onset GHD, 34% had IGF-I levels within the
normal range for age (Fig. 3B). The mean IGF-I was 48 ± 4 µg/L
in childhood-onset GHD patients and 78 ± 4 µg/L in adult-onset
GHD patients (P < 0.001), corresponding to -6.2
± 0.3 and -3.2 ± 0.2 SD scores (P
< 0.001), respectively, so a difference in age was also observed
(34 ± 2 vs. 55 ± 1 yr; P <
0.001). In both groups, patients with panhypopituitarism were in the
majority (70%). Similar age-corrected IGF-I levels were found in
panhypopituitarism and partial pituitary insufficiency; the mean IGF-I
SD score was -6.4 ± 0.4 vs. -5.8 ±
0.5 (P = 0.443) in patients with childhood-onset GHD
and -3.5 ± 0.3 vs. -2.6 ± 0.4
(P = 0.075) in adult-onset GHD patients.
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). IGF-I concentrations were within the
normal range in 4 of 25 (16%) craniopharyngiomas, in 20 of 57 (35%)
nonsecreting pituitary adenomas, in 5 of 15 (33%) prolactinomas, and
in 6 of 12 (50%) Cushing’s disease patients. In patients with
idiopathic GHD, corresponding values were 1 of 16 (6%), and in
patients treated with radiation, not due to pituitary tumor,
corresponding values were 1 in 9 (11%). All patients with Sheehan’s
syndrome (n = 5) as well as all patients with GHD due to trauma
(n = 3) had IGF-I values below -2 SD for age in
healthy subjects. In patients with GHD of other etiologies (n =
10), all had IGF-I values below -2 SD.
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summarizes relationships between IGF-I and age, body height,
body weight, and BMI in the GHD patients. Despite previous GH treatment
in 20 of 43 patients with childhood-onset GHD, they were shorter than
those with adult-onset GHD (167.4 ± 1.5 vs. 172.0
± 0.9 cm; P = 0.009), mainly due to differences in
height among the males. Body weight and BMI did not differ
significantly between childhood-onset GHD and adult-onset GHD. Positive
correlations were found between levels of IGF-I and body height. A
relationship to body weight was observed in the whole GHD patient group
and in the subgroup with adult-onset GHD, which disappeared when body
height was added in the regression analysis. No correlation was found
between serum levels of IGF-I and BMI. In the subgroup of patients who
acquired GHD as adults and had IGF-I levels within normal range, a
significant negative correlation to age was found, probably due to the
age-related cut-off value at -2 SD. In this group, levels
of IGF-I were not related to body height, body weight, or BMI.
Furthermore, in adult-onset GHD patients, no difference in BMI was
found between those with IGF-I levels within the normal range and those
with subnormal serum IGF-I concentrations (27.2 ± 0.7
vs. 26.7 ± 0.7). |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The finding of normal IGF-I levels in patients assumed to have GHD due to GH unresponsiveness in a provocation test raises several questions. Firstly, is the GH peak level after provocation test a reliable index of endogenous GH production? The GH responses to insulin-induced hypoglycemia and arginine have low reproducibility (23, 24), and age-related reference values are lacking. GH secretion as well as the peak response to most provocative tests decrease with increasing age in healthy individuals (25). The peak GH response to arginine was below 3 µg/L in about 20% of healthy subjects over 60 yr of age (18). Thus, at least 20% of our older patients with pituitary disorders could have remaining GH production, which fulfills their requirements for age and results in a normal IGF-I SD score. Secondly, a cause of the discrepancy between GH response and IGF-I levels is obesity, which is characterized by normal serum IGF-I in the presence of low GH secretion (8). However, no difference in BMI was found between patients with normal and subnormal IGF-I levels, and as in the healthy subjects, no correlation was found between IGF-I and BMI. This is in contrast to the report by Svensson et al. (7), who found higher BMI values in patients with IGF-I levels within normal range. Thirdly, can another hormone replace GH as stimulator of IGF-I expression? Insulin, which is suggested to be involved in GH-regulated IGF-I production (26), was not measured in the present study, but no relationship was found between insulin and IGF-I in a previous study based on 23 GHD patients (9). Yet in a larger material of adult GHD patients, IGF-I correlated positively to insulin (7). It is not known whether GHD patients with normal and subnormal IGF-I levels in relation to age differ concerning GH-dependent signs such as body composition. The observation of similar IGF-I SD scores in partial and total hypopituitarism indicates that the finding of normal IGF-I values among GHD patients is probably real. GH is assumed to be the first anterior pituitary hormone to be affected by surgery, radiation, or mass lesion of the hypothalamic-pituitary region. Thus, in multiple pituitary insufficiency, the probability of GHD being present is high (8).
The overlap of IGF-I levels between GHD patients and healthy subjects in our study was less pronounced than that observed in previous studies, in which IGF-I values within normal range were found in 48–70% of GHD patients with mainly adult onset of disease (4, 5, 6, 7). Moreover, in GHD patients over 60 yr of age, the percentage of those with normal IGF-I levels has been reported to be 2-fold higher than that in our study (18). Possible reasons for the fewer GHD patients with normal IGF-I in the present study could be the selection of healthy subjects for the reference range, the statistical analysis employed setting up the reference values, the IGF-I method, inclusion of GHD patients with childhood-onset disease, and/or the causes of GHD.
The number of individuals of different ages constituting the reference intervals is essential for improving the sensitivity and specificity of serum IGF-I levels (27). In the reference group of apparently healthy individuals, including ages from 20–96 yr, a linear inverse correlation was found between logarithmically transformed IGF-I levels and age. Thus, the normal mean value of serum IGF-I in a 90-yr-old individual corresponds to -4 SD of healthy young adults, 20 yr of age. A decline in serum IGF-I in adults with increasing age is well known from previous studies, based on smaller number of subjects and/or individuals less than 70 yr of age (9, 28, 29, 30, 31, 32). The use of logarithmically transformed data when evaluating the normal reference values was primarily due to nonnormal distribution of serum IGF-I values in the healthy subjects. The transformation results in a more narrow variation around the mean at low levels of IGF-I compared to high levels of IGF-I in terms of arithmetic values. As calculated from the regression analysis, the normal range for age constitutes an extensive variation around the mean; the -2 SD value is 57% of the mean, and the mean is 57% of the +2 SD value. For ages above 80 yr, the individual variations are greater, which might be due to varying levels of nutritional status and physical activity (33). Although apparently healthy, some were more physically active than others, and undernutrition cannot be ruled out among the elderly. No significant gender difference was found between the slopes of the regression lines, which is in agreement with the reports by Nyström et al. (32) and Juul et al. (30), but in contrast to those by Yamamoto et al. (28), Landin-Wilhelmsson et al. (29), and Kitano et al. (31). This discrepancy might be explained by a larger group in the present study and, as suggested by Nyström et al. (32), a wider range of age. Other explanations could be that the healthy individuals in the present study were not recruited from a population registry, and the analysis of IGF-I was performed by a method minimizing the interference of IGFBPs (12). This could be of importance in GHD patients, because they have high IGFBP-1/IGF-I ratios compared to healthy subjects (9).
Serum IGF-I levels were below -2 SD in all of our patients with childhood-onset GHD, where the original selection of children was based on retarded growth. When adult patients with childhood-onset GHD were reevaluated in a previous study, 7% had normal IGF-I levels (1). In both studies the included patients were selected by GH stimulation tests, with the exception of higher GH cut-off values in the study by De Boer et al. (1). Thus, in the present study serum IGF-I concentrations completely separated GHD patients with childhood-onset disease from healthy subjects and can be recommended for use in the reevaluation of the GHD diagnosis made during childhood. In contrast, IGF-I levels above -2 SD were found in 34% of the patients with adult-onset GHD; five were even within the normal range for young healthy adults. The mean IGF-I SD score was significantly higher in the adult-onset GHD patients, as previously observed by others (2, 8). In addition, a gender difference was found, with normal IGF-I levels being more common in men than in women with GHD.
The differences in IGF-I levels between childhood- and adult-onset GHD as well as the finding of fewer patients with normal IGF-I than in previous studies might be influenced by the underlying etiologies. Idiopathic hypopituitarism and craniopharyngioma dominated among childhood-onset GHD, whereas pituitary tumors, such as nonsecreting pituitary adenoma, prolactinoma, and Cushing’s disease, dominated in patients with adult-onset GHD. In fact, the majority (86%) of patients over 60 yr of age, in which 40% had normal IGF-I levels, were diagnosed with hypothalamic-pituitary tumors. It cannot be excluded that apart from GH, an additional pituitary factor can regulate IGF-I expression.
In conclusion, in the identification of adult patients suitable for GH replacement therapy, measurement of serum IGF-I can be used as a diagnostic tool in younger adult patients. However, the IGF-I SD score seems less reliable in elderly patients, especially in patients with hypothalamic-pituitary tumors, partly due to the age-dependent decrease in IGF-I levels in healthy subjects. Nevertheless, it is still the treatment outcome that could ascertain which patients are GH deficient and thus most likely to respond to and benefit from GH replacement therapy.
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Acknowledgments |
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Footnotes |
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Received October 30, 1998.
Revised February 24, 1999.
Accepted March 11, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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R. Fernholm, M. Bramnert, E. Hägg, A. Hilding, D. J. Baylink, S. Mohan, and M. Thorén Growth Hormone Replacement Therapy Improves Body Composition and Increases Bone Metabolism in Elderly Patients with Pituitary Disease J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4104 - 4112. [Abstract] [Full Text]
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, Women (n = 71); 
, men (n = 81). The normal range for
age (the geometrical mean ± 2 SD) is indicated.
, patients with partial pituitary
insufficiency. The normal range for age (the geometrical mean ± 2
SD) is indicated.