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Endocrine Care |
Department of Pediatrics, Oregon Health Sciences University (C.K.B., K.L.P., R.G.R.), Portland, Oregon 97201; Institute of Endocrinology, Metabolism, and Reproduction (J.G.-A.), Quito, Ecuador; and Queen Mary’s Hospital for Children (C.P.B.), Carshalton, United Kingdom 5M5 1AA
Address all correspondence and requests for reprints to: Caroline K. Buckway, M.D., c/o Ron G. Rosenfeld, M.D., Department of Pediatrics, Oregon Health Sciences University, 707 SW Gaines Road, CDRC-P, Portland, Oregon 97201. E-mail: cbuckway{at}yahoo.com
Abstract
IGF-I generation tests were developed over 20 yr ago and are currently used in differentiating GH insensitivity (GHI) from other disorders characterized by low serum IGF-I. Nevertheless, generation tests have never been adequately characterized, and insufficient normative data are available.
One hundred and ninety-eight subjects [including normal subjects; subjects with GHI, GH deficiency (GHD), and idiopathic short stature (ISS); and heterozygotes for the E180 splice GH receptor mutation] were randomized to self-administration of either a high (0.05 mg/kg·d) or a low (0.025 mg/kg·d) dose of GH for 7 d. After a 2-wk washout period, they received the alternate dose. Samples were collected on d 1, 5, and 8 of each treatment period.
In normal individuals, IGF-I generation was GH dependent at all ages, and little advantage was observed in using the higher dose of GH or extending beyond the d 5 sample. Some GHD patients had IGF-I levels, both baseline and stimulated, that overlapped levels in the verified GHI patients. Subjects heterozygous for the E180 GH receptor splice mutation did not show a decreased responsiveness to GH. ISS patients had low-normal IGF-I levels that did not stimulate beyond the baseline normative ranges for age. These data provide the first large scale effort to provide preliminary normative IGF generation data and evaluate the GH sensitivity of patients with GHI, GHD, and ISS.
PATIENTS WITH EITHER GH deficiency (GHD) or GH insensitivity (GHI) have low serum concentrations of IGF-I, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS). These biochemical markers circulate in serum as a ternary complex and are each GH dependent. Distinguishing patients with a deficiency of GH, insensitivity to GH, or idiopathic short stature (ISS) based upon serum levels of GH or IGF-I has proven to be problematic because biochemical profiles frequently overlap (1). Furthermore, a partial insensitivity to GH has been hypothesized as an etiology of some forms of ISS (2, 3, 4, 5, 6). Although heterozygosity for specific mutations of the GH receptor (GHR) gene can have a dominant negative effect, it is unclear how often such genetic abnormalities result in ISS (7, 8, 9, 10, 11). The E180 splice mutation, causing GHI in the Ecuadorian population studied here, is not one of the mutations shown to have an effect on stature, however (12).
The dose response and time course of IGF-I to GH in hypopituitary patients were first studied over 20 yr ago, using an RIA specific for somatomedin C (SM-C) (13). Rudman et al. (14) were the first to report a 10-d generation test predictive of growth rate in ISS children. One recent study was also able to correlate growth rate in GHD and ISS patients with both generated IGF-I levels and IGFBP-3 levels (15); the investigators were also able to exclude any patients with classic GHI. Several other investigators, however, have not found the IGF generation test helpful in identification or characterization of ISS (16, 17, 18). Furthermore, other initial IGF generation tests confirmed increased levels of stimulated SM-C, both acute and chronic, in response to human GH treatment, but showed a high variability of SM-C levels among GHD patients, with little or no relation to their growth responses (19, 20). Specific criteria have been proposed for the use of IGF generation tests in diagnosing GHI, with GHI defined in part by poor GH-stimulated serum IGF-I concentrations (21).
From the time of the initial studies, however, a standardized protocol has still not been established, nor has normative data in all age groups been collected systematically. Some normative data may be extrapolated from recent investigations, such as from studies searching for markers of GH abuse in athletes, but these data remain limited (22, 23). Additionally, laboratory assays developed over the last several years have simplified IGF extraction methods, using acid/ethanol rather than column chromatography under acidic conditions, and current immunoradiometric assays have improved specificity and sensitivity compared with past RIAs and RRAs (19, 20).
On a large scale, the current study attempts to examine both the dose and duration of GH administration in hopes of establishing a standardized IGF generation protocol using current laboratory technology. Our aim was to examine the GH responsiveness of GHI, GHI heterozygous, GHD, and ISS subjects relative to that in age- and sex-matched normal groups.
Subjects and Methods
Subjects
A total of 198 subjects (male/female ratio, 100:98) from Ecuador were enrolled. These included normal male and female adults and children (n = 72), patients with classic autosomal recessive GHI (n = 22) and their heterozygous relatives (n = 65), patients with GHD (n = 23), and children with ISS (n = 16). The Ecuadorian population is unique in that the largest cohort of GHI patients in the world lives in a geographically isolated area in the southern region of the country, where all GHI patients have the same E180 splice mutation affecting the extracellular portion of the GHR (24, 25). All 198 subjects were genotyped for the E180 splice mutation, as previously described (26, 27). GHD was documented by a GH level less than 10 ng/ml after two stimulation tests (insulin and clonidine). The children with ISS were defined as having a height less than -2 SD with a provocative GH level more than 10 ng/ml. All GHD and ISS subjects were demonstrated to lack the E180 splice mutation, whereas all heterozygous relatives were confirmed genotypically. All GHD subjects were idiopathic, with the exception of 1 who had had a craniopharyngioma. Some subjects with GHD also had other hormone deficiencies, primarily TSH, but all were properly replaced during the tests.
Children with GHD or ISS were excluded if they had a chronic disease, a
history of active malignancy, psychosocial dwarfism, skeletal
dysplasia, or other identifiable syndrome, and female children with GHD
or ISS were documented to have a normal karyotype. Subject
characteristics are shown in Table 1
.
Because normal growth standards for this part of Ecuador are
inadequate, weight and height characteristics have been expressed as
SD scores based on the May 2000 revision of the Centers for
Disease Control growth charts from the National Center for Health
Statistics (28).
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Study design (Fig. 1)
At enrollment, within each diagnostic category the 198 subjects were randomized into 2 groups, differing only by the dosage of GH used initially. Either a low dose (0.025 mg/kg·d) or a high dose (0.05 mg/kg·d) of GH was given for 7 d. Subjects were taught to self-administer sc injections of GH, which were given every evening. Fasting blood samples were drawn on the mornings of d 1, 5, and 8. A 2-wk wash-out period followed, and the subjects then received the other dose of GH, with fasting blood samples again drawn on the mornings of d 1, 5, and 8. Recombinant human GH was provided by Genentech, Inc. (South San Francisco, CA).
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After collection, the specimens were centrifuged, and the sera were stored at -70 C until the assays were run. IGF-I assays were performed using an immunoradiometric assay kit with acid/ethanol extraction. All sera resulting in values over 450 ng/ml were reassayed after diluting the extract 1:4 with the 0 ng/ml standard to assure that values fell within the most appropriate portion of the curve. All assay kits were provided by Diagnostics Systems Laboratories, Inc. (Webster, TX), and have an intraassay coefficient of variation of 1.5–3.4% and an interassay coefficient of variation of 1.5–8.2%. The sensitivity of the IGF-I assay was 5 ng/ml. Normal adult human serum was employed as a standard in all assays.
Statistical analyses
The statistical significance of the normative data was calculated by a two-way, repeated measure ANOVA for the following age groups for both males and females: less than 10, 10–18, 18–40, and more than 40 yr. To isolate which variables differed from the others, a Tukey test was used for pairwise multiple comparison procedures. When comparing specific differences between diagnostic groups, we used an unpaired, two-tailed t test. SigmaStat (SPSS, Inc., Chicago, IL) and InStat (GraphPad Software, Inc., San Diego, CA) software were used for calculations. Values were considered significant at P < 0.05.
Results
Normative data (Fig. 2 and Table 2)
A total of 72 normal subjects, with an equal male/female
distribution, were enrolled; 38 subjects were less than 18 yr of age,
and 34 subjects were more than 18 yr of age. In these and subsequent
patient groups, subjects are divided by gender and by age. Thus, even
with a total of 198 subjects studied, the subject number in each group
was often small, and the normal ranges presented should be viewed as
preliminary. In all normal subgroups serum IGF-I concentrations were GH
dependent, with significant elevation by d 5 and 8 compared with
baseline, using either the low or high dose of GH (all
P < 0.001, except males 18–40 yr of age,
P = 0.007, and females < 10 yr of age,
P = 0.015). The magnitude of elevation of IGF-I on d 8
relative to d 5 was not significantly different in any age group, nor
was the degree of elevation seen with the high dose relative to the low
dose in any age group, with the exception of females over age 40 yr
(P = 0.028). Table 2 provides the mean IGF-I levels for
each age and gender group; data are presented graphically, showing
ranges ± 1 SD and means of the IGF-I levels
in Fig. 2.
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and Table 2
)Seven male and 15 female subjects were confirmed to be homozygous for the E180 splice mutation, affecting the extracellular portion of the GHR. As previously reported, baseline serum IGF-I concentrations were strikingly low and appeared to show little response to either low or high dose GH (29). However, there were 5 subjects of the 22 with IGF-I elevations greater than 15 ng/ml. Absolute increases from baseline of GH-stimulated IGF-I levels in these 5 subjects ranged from 16–63 ng/ml. These IGF-I increases of more than 15 ng/ml occurred in 7 (4 low dose, 3 high dose) of the 10 IGF generation tests performed on these 5 GHI patients and occurred by d 5 in all but 1 of the tests. The sensitivity of the IGF-I generation test is, therefore, only 77% (17 of 22 GHI patients with a maximum IGF-I value of <15 ng/ml).
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and Table 2)Twenty-three patients were enrolled; all but six were under the age of 18 yr. All GHD subjects had low baseline serum IGF-I concentrations for age (< 5–125 ng/ml). Although most GHD subjects were able to generate IGF-I levels into the normal baseline ranges, many could not achieve stimulated IGF-I concentrations equivalent to the baseline levels observed in normal subjects even with 7 d of high dose GH. Six subjects were considered poor responders to GH, defined as an inability to generate IGF-I levels above 100 ng/ml on either d 5 or 8 of the treatment week. Of these subjects, one actually had less than a 15 ng/ml increase in IGF-I in response to GH; therefore, the specificity of the IGF-I generation test is 97%. Compliance with the GH injections was confirmed by history and by documentation of significant rises in their serum IGFBP-3 and/or ALS concentrations (data not shown).
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and Table 2)
A total of 65 subjects heterozygous for the E180 splice mutation,
confirmed by molecular diagnosis, completed the study. As shown in Fig. 6, the vast majority of baseline and
stimulated IGF-I concentrations fall within the observed ranges for the
normal individuals. There were no significant differences found when
comparing the changes in IGF generation of the heterozygotes to the
age-matched normal subjects. However, in some groups, such as females
less than 10 yr of age and males 10–18 yr of age, there were
insufficient numbers of heterozygous subjects to perform statistical
analyses. Also, a few males in the more than 40 yr group had lower
IGF-I responses to both low and high dose GH than the age-matched
normal subjects. In these heterozygous patients, other undiagnosed
comorbid conditions potentially affecting IGF generation, such as liver
disease, or noncompliance with the study regimen cannot be excluded.
These data may also simply reflect the small number of subjects in
these groups. The limitation of small subject numbers may also be an
explanation for a more robust IGF-I response to GH seen in some
heterozygous males between 18 and 40 yr of age relative to their
age-matched normal subjects, merely reflecting a larger range of normal
values. Thus, at least within the limits of the 2 GH dosages employed,
no evidence of insensitivity to GH could be observed in the E180 splice
heterozygotes.
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and Table 2)Sixteen children with ISS participated in the investigation; all were documented to lack the E180 splice mutation of the GHR gene and to have stimulated GH concentrations greater than 10 ng/ml. Although baseline serum IGF-I concentrations in these subjects fall predominantly within the age-matched ranges of the normal children from Ecuador, most lie within the lower half of these normal ranges or occasionally below. Similarly, GH-stimulated IGF-I concentrations increase, albeit none to levels greater than baseline normative ranges. As a group, these subjects could be described as having low-normal baseline and GH-stimulated IGF-I concentrations.
Discussion
Like other endocrine stimulation tests, the IGF generation test measures hormonal production in response to stimulation by a pituitary trophic factor. It is presumed on the basis of recent conditional knockout studies that increments in serum IGF-I represent primarily hepatic production, but this has yet to be proven definitively in man (30). Whatever the source(s) of serum IGF-I, this stimulation test has the potential to assess the ability of an individual to respond to a 4- to 7-d course of GH by elevations of serum concentrations of IGF-I as well as other GH-dependent peptides, such as IGFBP-3 and ALS.
Although IGF generation tests have been available for over 20 yr (13, 14), major limitations have included variability in protocols for administration of GH, timing of samples, differences in IGF assay methodologies, and lack of adequate normative data (15). The latter is particularly problematic, given the well documented age-related variability in IGF-I concentrations (1, 31) as well as gender-related differences in responsiveness to exogenous GH (32).
The current study included 72 normal subjects, with an equal distribution of males and females. This constitutes a relatively large number of normal subjects for such a protocol, although once these subjects are subdivided by gender and age, the numbers in some groups are small, as in females under age 10 yr (n = 3). The dosages of GH employed (0.025 and 0.05 mg/kg·d) relate to current pediatric practice norms, but clearly reflect a relatively high dose for adults. The number of injection days (n = 7) and the timing of sampling (d 1, 5, and 8) are arbitrary and partially reflect historical precedent. Despite these caveats, a number of points are readily apparent from the data available. 1) Little advantage is gained by using the higher dosage of GH, probably reflecting the fact that both 0.025 and 0.05 mg/kg·d represent supraphysiological doses of GH even in the pediatric and adolescent populations. 2) Little advantage is gained by using d 8 rather than the earlier d 5 time point. In particular, there was no evidence that GHD, ISS, or GHI subjects were more likely to show a normal response to the higher dosage or longer duration of GH therapy. It is possible that longer trials of GH administration might have uncovered differences in responsiveness, although one prior report in GHD subjects indicated that the acute IGF response to GH was highly predictive of the chronic response (d 5 vs. 6 month IGF-I, r = 0.80, P < 0.001) (20).
In the normal subjects serum IGF-I concentrations were GH dependent in all age groups, with significant elevations over baseline at both d 5 and 8 and with both the 0.025 and 0.05 mg/kg·d doses of GH. Although the study did not specifically focus on an aging population, the IGF-I responsiveness of both males and females more than 40 yr of age was in the same range as in subjects 18–40 yr old. Lieberman et al. (33) reported a 36% lower IGF-I response to GH in older vs. younger males, but this was not observed in our population. Although additional IGF-I generation data in normal aging adults are clearly necessary, our findings suggest that the decrease in IGF-I commonly observed in aging is not attributable to reduced GH responsiveness.
For diagnostic purposes, the IGF generation test should differentiate between GHD and GHI. All subjects with GHI in our study have the same mutation (E180 splice), affecting synthesis of the extracellular domain of the GHR. Five of the 22 subjects studied, however, had GH-stimulated increases in serum IGF-I in excess of the 15 ng/ml level defined in the diagnostic criteria for classic GHI (21). Thus, although the specificity of the test is 97%, the sensitivity of the test is only 77%. These results cannot be explained by assay variability, as all samples for each subject were assayed together, nor can there be any question of the diagnosis, given that all subjects had classical phenotypic and biochemical features of GHI, as well as confirmed homozygosity for the E180 splice mutation. A pubertal rise in serum IGF-I in GHI patients has been noted previously, presumably reflecting a direct effect of sex steroids on IGF-I production (29); whether sex steroids also affect GH sensitivity is uncertain. In any case, it appears that the maximum serum IGF-I of 15 ng/ml as a diagnostic criterion for GHI must be reexamined; alternatively, a lower GH dosage might result in sharper discrimination between GHI and GHD, although such modifications may further blur the distinction between GHI and GHD, given that some GHD patients show limited IGF-I responsiveness (see below).
Six of the GHD subjects failed to attain serum IGF-I concentrations
above 100 ng/ml on either d 5 or 8 of GH treatment with either GH
dosage. Most noteworthy is the observation of a surprising degree of
overlap in IGF-I generation between the GHD and GHI subjects in both
baseline and stimulated IGF-I concentrations (Fig. 7). This clear overlap was observed
between GHD and GHI subjects, even though all GHD subjects had been
proven to lack the E180 splice mutation and had been shown to have both
low baseline IGF-I and IGFBP-3 concentrations as well as provocative GH
levels less than 10 ng/ml. Although detailed evaluation of serum
IGFBP-3 and ALS concentrations in these subjects is pending, a clear
rise in both parameters was observed, sufficient to exclude the
unlikely possibility of noncompliance. GHD patients with low or modest
rises in serum IGF-I during GH therapy may require careful monitoring
to assure that their growth response on treatment is appropriate.
Indeed, long-term data correlating growth responses with IGF-I
concentrations are sorely lacking.
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In this light, the results in children with ISS are of particular interest. As previously reported (4), such children tend to have serum IGF-I concentrations in the lower portion of the normal range, or below the lower limits of normal. Interestingly, these subjects also failed, in general, to raise their serum IGF-I concentrations in response to GH; many did not even attain levels within the baseline normal range. These results can be clearly distinguished from those observed in the subjects who were heterozygous for the E180 splice mutation, suggesting that although the latter group had normal GH sensitivity, a subset of children with ISS has some degree of GH resistance. Although this may not necessarily be the result of mutations of the GHR gene, it theoretically can result from subtle postreceptor mechanisms (39, 40, 41).
The results presented in this report probably constitute the largest body of data to date on IGF-I generation in normal subjects, as well as patients with various growth defects. It is, nevertheless, clear that these studies must be extended to a larger number of subjects with normal stature and with various defects of the GH-IGF axis if we are to be able to correlate biochemical and clinical phenotypes in a meaningful manner.
Acknowledgments
We thank Ms. Efi Tjoeng for her assistance with data formatting and statistical analyses, and Dr. Gary Sexton for his assistance with statistical analyses.
Footnotes
This work was supported by Genentech Center for Clinical Research and Education (to R.G.R.), NIH Grants CA-58110 and DK-51513 (to R.G.R.) and 5T32-HD-07497 (to C.K.B.), and USPHS Grant 5M01-RR-00334 (to G.S.).
Abbreviations: ALS, Acid-labile subunit; GHD, GH deficiency, GH-deficient; GHI, GH insensitivity; GHR, GH receptor; IGFBP, IGF-binding protein; ISS, idiopathic short stature; SM-C, somatomedin C.
Received April 23, 2001.
Accepted July 26, 2001.
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)
assayed in GHI patients, subdivided into age groups and superimposed on
normal box-whisker graphs as defined in Fig. 1
), showing overlap between the two groups.