0021-972X/97/$03.00/0
Journal of Clinical Endocrinology and Metabolism
Copyright © 1997 by The Endocrine Society
Vol. 82, No. 4
Printed in U.S.A.
Growth Hormone (GH) Provocative Retesting of 108
Young Adults with Childhood-Onset GH Deficiency and
the Diagnostic Value of Insulin-Like Growth Factor I
(IGF-I) and IGF-Binding Protein-3*
ANDERS JUUL, KNUD W. KASTRUP, SØREN A. PEDERSEN,
NIELS E. SKAKKEBÆK
AND
Department of Growth and Reproduction, National University Hospital (A.J., N.E.S.), and the
Department of Pediatrics, Hvidovre Hospital, University of Copenhagen (S.A.P.), Copenhagen; and the
Department of Pediatrics, Glostrup Amtssygehus (K.W.K.), Glostrup, Denmark
ABSTRACT
Serum levels of total insulin-like growth factor I (IGF-I) and IGFbinding protein-3 (IGFBP-3) reflect the endogenous GH secretion in
healthy children and exhibit little diurnal variation, which makes
them good diagnostic markers for screening of GH deficiency (GHD)
in short children, although some controversy still exists. In adults, the
diagnostic value of IGF-I and IGFBP-3 suspected of GHD has been
reported in only a few studies.
We performed a GH provocative test, using oral clonidine, in 108
patients who had previously been treated with GH during childhood
(73 men and 35 women). Basal IGF-I and IGFBP-3 levels were compared to those in 1237 healthy controls (312 controls .18 yr) as well
as to peak GH levels. Seventy-nine patients had peak GH values
below a cut-off value of 7.5 mg/L (34 with isolated GHD), whereas 29
patients had a normal GH response (28 with previous isolated GHD),
i.e. 45% of patients treated with GH during childhood because of
isolated GHD had a normal GH response when retested in adulthood.
Multiple regression analysis revealed that peak GH levels were dependent on the degree of hypopituitarism, body mass index, and
duration of disease. IGF-I levels were below 22 SD in 60 of 79 GHD
patients and above 22 SD in 21 of 29 patients with a normal GH
response. IGFBP-3 levels were below 22 SD in 54 of 79 GHD patients
and above 22 SD in 23 of 29 patients with a normal GH response.
Multiple linear regression analysis demonstrated that IGF-I and
IGFBP-3 were significantly dependent on peak GH levels and the
number of other pituitary axes affected. In this analysis, duration of
disease was significantly associated with both IGF-I and IGFBP-3,
whereas body mass index was significantly associated with IGFBP-3,
but not with IGF-I.
We conclude that IGF-I and IGFBP-3 determinations predict the
outcome of a GH provocative test in adults suspected of GHD and
believe that IGF-I as well as IGFBP-3 serum concentrations are
valuable diagnostic parameters in the evaluation of GHD in adults
with childhood-onset disease.
We suggest that children who have been treated with GH should
undergo reassessment of their GH secretory status as young adults
by provocative testing as well as by IGF-related peptides before continued adult GH replacement therapy is considered. However, our
data suggest that it is not necessary to reconfirm GH deficiency by GH
provocative testing in young adults who have two or more pituitary
hormone deficiencies in addition to GHD. (J Clin Endocrinol Metab
82: 1195–1201, 1997)
T
In short, poorly growing children, the diagnosis of GHD
is conventionally achieved by two separate provocative
GH tests, which have been considered the gold standard.
However, proper interpretation of these tests is not trivial
due to the impact of puberty on the GH response (5, 6), the
poor reproducibility of GH response to provocative testing
(7, 8), variability of GH levels according to assay (9, 10),
as well as differences in the GH response according to
stimuli (e.g. oral clonidine, iv arginine or GHRH, insulininduced hypoglycemia, etc.) (11). In adults suspected of
GHD, similar methodological difficulties exist. Furthermore, the degree of abdominal obesity, physical fitness,
age, and gender are major determinants of the stimulated
GH secretion in adults (12) and have to be taken into
account.
We evaluated the diagnostic value of insulin-like growth
factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) determinations in relation to the outcome of GH provocative testing using oral clonidine in 108 patients who had previously
been treated with GH in childhood and were reevaluated in
young adulthood.
HE BENEFICIAL effects of GH replacement therapy in
adults with GH deficiency (GHD) have recently become apparent (1, 2), but the criteria to select patients for
replacement therapy remain unclear. Although, adults
with untreated GHD share a number of clinical symptoms,
such as increased body fat, osteopenia, atherogenic lipid
profile, etc. (3), there is no biological end point in adults,
such as poor growth in children, to support the diagnosis.
Consequently, the referral diagnosis of GHD in adults
must include a high index of suspicion; most likely, the
population that will be referred for testing will be adults
previously treated with GH because of pituitary dwarfism
or adults with known or suspected hypothalamic-pituitary
disease (4).
Received October 23, 1996. Revision received December 18, 1996.
Accepted January 6, 1997.
Address all correspondence and requests for reprints to: Anders Juul,
M.D., Department of Growth and Reproduction GR 5064, Rigshospitalet,
Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.
* This work was supported by the Michaelsen Foundation (to A.J.)
and the Danish Medical Research Council (Grants 12–9361 and 12–1376).
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JUUL ET AL.
antecubital vein and centrifuged, and serum was stored at 220 C until
analysis.
Subjects and Methods
Patients
All 251 patients who had been treated with human pituitary-derived
GH (Nanormon, Novo Nordisk, Gentofte, Denmark) until 1988 were
located through the central register at the Danish Health Authorities to
whom application for treatment was originally sent in each case. Files
from 173 patients were available for this study, but data from 65 of these
patients were excluded (5 patients had died, 40 patients were still treated
with GH at the time of the study, 7 had received GH because of hypochondroplasia, and 13 were excluded as they were ,18 yr of age),
leaving 108 patients for further analysis (Table 1). None of these had been
receiving GH replacement for the last 6 months, but were replaced
adequately with other pituitary hormones when needed. Pubertal development was examined in 107 of the patients according to the method
of Tanner (Table 2). The etiologies of the 108 patients varied: idiopathic
(n 5 24; 22.2%), possible birth-related asphyxia (n 5 34; 31.5%), craniopharyngeoma (n 5 9; 8.3%), other intracranial pathology (n 5 19;
17.6%), familiar/genetic (n 5 8; 7.4%), small for gestational age (n 5 6;
5.5%), and other (n 5 8; 7.4%).
The patients were grouped according to their peak GH response
during retesting as either GHD (peak GH, ,7.5 mg/L) or normal (peak
GH above cut-off value). GH provocative testing was performed using
oral clonidine (75 mg/m2 Catapressan, Boehringer Ingelheim, Ingelheim,
Germany), with blood sampling at 230, 0, 30, 60, 90, and 120 min.
Serum analyses
IGF-I. IGF-I was determined in all subjects with a RIA using truncated
IGF-I [des(1–3)-IGF-I] as radioligand as originally described (17) modified by the use of a monoiodinated isomer as tracer [Tyr31-des(1–3)IGF-I] (14). Serum was extracted by acid-ethanol and cryoprecipitated
before analysis to remove interfering binding proteins. Intraassay coefficients of variation (n 5 15) were 5.4% [at bound/free ratio (B/B0) of
0.20], 3.9% (at B/B0 of 0.4), and 10.3% (at B/B0 of 0.7), respectively.
Interassay coefficients of variation (n 5 45) were 10.4% (at B/B0 of 0.2),
8.7% (at B/B0 of 0.4), and 14.1% (at B/B0 of 0.7), respectively.
IGFBP-3. Serum concentrations of IGFBP-3 were measured by a RIA,
previously described by Blum et al. (18). Reagents for the IGFBP-3 RIA
were obtained from Mediagnost (Tubingen, Germany). Intraassay coefficients of variation (n 5 17) were 2.3% (at B/B0 of 0.3), 2.4% (at B/B0
of 0.4), and 5.9% (at B/B0 of 0.8), respectively. Interassay coefficients of
variation (n 5 144) were 10.7% (at B/B0 of 0.5) and 7.6% (at B/B0 of 0.8),
respectively.
Serum GH was determined by a commercially available RIA (Pharmacia, Uppsala, Sweden).
Statistical procedures
Controls
5–20 yr old (n 5 1038). Healthy children and adolescents in four different
primary schools and one grammar school in the Copenhagen area participated in this study. Serum procollagens, IGF-I and IGFBP-3 levels in
these healthy subjects have previously been reported (13–15).
20 –70 yr (n 5 199). Hospital employees and medical students participated as controls. None had acute or chronic diseases, and none was
taking any medication (including oral contraceptives). These results
have previously been reported (16).
There was a total of 312 healthy subjects over 18 yr of age.
Blood sampling
Serum levels of IGF-I and IGFBP-3 was determined in a basal blood
sample from all 108 individuals and compared to the peak GH value
during the GH provocative test. Blood samples were drawn from an
sd scores were calculated for IGF-I and IGFBP-3 based on previously
reported normative data (14, 15).
Results
GH provocative testing in 108 adults suspected of GHD
Seventy-nine (54 men and 25 women) of the 108 patients
who were reevaluated had a peak GH response less than 7.5
mg/L (GHD). Thirty-four of these had isolated GHD, and 45
had multiple pituitary deficiency of varying degree. Twentynine patients had a normal GH response to oral clonidine (28
with previous isolated GHD). Consequently, 28 of 62 patients
(45%) who were treated during childhood because of isolated
GHD had a normal GH response when retested in adulthood.
TABLE 1. Description of patients according to their GH responses during GH provocative retesting
Peak GH
Cut-off value
n
Males/females
Age (yr)
Age at diagnosis (yr)
Adult ht (SD score)
Adult BMI (SD score)
IGF-I (SD score)
IGFBP-3 (SD score)
,3 mg/L
3–7.5 mg/L
,7.5 mg/L
$7.5 mg/L
68
47/21
25.8 (0.8)
12.4 (0,7)
22.2 (0.2)
0.5 (0.3)
23.2 (0.2)
24.1 (0.3)
11
7/4
22.5 (1,3)
12.3 (1,0)
22.5 (0.4)
0.5 (0.6)
21.6 (0.6)
21.6 (0.9)
79
54/25
25.4 (0.7)
12.3 (0,6)
22.2 (0.2)
0.5 (0.3)
22.9 (0.2)
23.7 (0.3)
29
19/10
22.2 (0,7)a
12.1 (0,7)
22.2 (0.2)
20.7 (0.3)
21.2 (0.2)a
20.6 (0.3)a
Statistically significant difference between patients with peak GH greater than 7.5 mg/L and less than 7.5 mg/L (by Students unpaired t
test, P , 0.001).
a
TABLE 2. Sexual maturation in 108 patients previously treated with GH, who were reexamined as young adults
n
Boys
Eugonadal
Hypogonadal
Girls
Eugonadal
Hypogonadal
72
48
24
35
23
12
Pubic hair stage
(I/II/III/IV/V)
Genital/breast stage
(I/II/III/IV/V)
Testicular vol
[mL; mean (SD)]
Range
(mL)
0/0/1/6/41
0/0/2/11/11
0/0/1/5/42
0/0/3/10/11
18,8 (5,5)
4,0 (3,1)
7–30
1–13
0/1/2/4/16
1/2/6/2/12
1/0/7/3/12
0/0/7/4/1
VALUE OF IGF-I AND IGFBP-3 IN DIAGNOSIS OF GHD
One patient with secondary hypothyroidism had a normal
GH response when reevaluated, whereas in the presence of
2 or more additional hormone deficiencies, all patients had
a pathological GH response during retesting (Fig. 1 and Table
3). Multiple linear regression analysis revealed that peak GH
levels were significantly dependent on duration of disease,
1197
degree of hypopituitarism, age, and body mass index (r 5
0.41; P , 0.0001).
IGF-I and IGFBP-3 in adults suspected of GHD
Serum IGF-I and IGFBP-3 levels in 79 patients with GHD
and 29 patients with a normal GH response are shown in Fig.
2, and mean values are shown in Tables 2 and 3. IGF-I as well
as IGFBP-3 serum levels (sd score) significantly decreased
with increasing degree of hypopituitarism (Fig. 3; all P ,
0.001, by ANOVA). In patients with isolated GHD, IGF-I and
IGFBP-3 predicted a subnormal peak GH after provocative
testing in 17 of 34 (50%) and 18 of 34 (47%) patients, respectively (Fig. 4).
Diagnostic value of IGF-I compared to IGFBP-3
FIG. 1. Peak GH levels during GH provocative testing (clonidine)
according to degree of hypopituitarism in 108 adults previously
treated during childhood with GH.
IGF-I levels were below 22 sd in 60 of 79 GHD patients
and above 22 sd in 21 of 29 patients with normal GH
responses. IGFBP-3 levels were below 22 sd in 54 of 79
GHD patients and above 22 sd in 23 of 29 patients with
normal GH responses. Sensitivities and specificities are
given in Table 4.
IGF-I and IGFBP-3 serum levels correlated significantly
with peak GH levels (r 5 0.41 and r 5 0.48, respectively; both
P , 0.001). The effect of varying the peak GH cut-off value
TABLE 3. The number of patients grouped according to their GH responses during retesting as well as to their IGF-I and IGFBP-3 levels
n
IGHD
MPD
All
62
46
108
GH
IGF-I
,7.5 mg/L
$7.5 mg/L
34
45
79
28
1
29
IGHD, Isolated GH deficiency; MPD, multiple pituitary deficiency.
FIG. 2. Serum levels of IGF-I (top panels) and IGFBP-3 (bottom panels) in 108
patients classified as either GHD (peak
GH, ,7.5 mg/L; F) or patients with a
normal GH response (E). Males are
shown to the left (females to the right).
Lines represent the 95% prediction intervals for IGF-I and IGFBP-3 and are
derived from Refs. 14 –16.
,22
24
44
68
SD
IGFBP-3
$22
38
2
40
SD
,22SD
21
39
60
$22
41
7
48
SD
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JUUL ET AL.
FIG. 4. Peak GH levels vs. IGF-I SD score (top panel) and IGFBP-3 SD
score (bottom panel) in 62 patients previously treated with GH because of isolated GHD who were reevaluated as young adults. The
dotted lines represent the two cut-off values corresponding to 7.5 mg/L
(for peak GH) and to 22 SD score (for IGF-I and IGFBP-3).
TABLE 4. Comparison of the diagnostic value of IGF-I and
IGFBP-3 in 108 patients grouped as GHD (peak GH, ,7.5 mg/L) or
with a normal GH response (.7.5 mg/L)
Sensitivity
Specificity
Predictive value of positive test
Predictive value of negative test
Test accuracy
IGF-I
IGFBP-3
75,90
72,00
88,20
52,50
75,00
68,40
79,00
90,00
47,90
71,30
Sensitivity, percentage of GHD patients with value below the cutoff; specificity, percentage of patients with normal GH response with
value above the cut-off; predictive value of positive test, percentage of
values below the cut-off that represent GHD patients; predictive
value of negative test, percentage of values above the cut-off that
represent patients with normal GH; test accuracy: (GHD ,22 SD 1
normal GH . 22 SD)/all.
FIG. 3. Serum levels of IGF-I (top panel), IGFBP-3 (middle panel),
and body mass index (bottom panel; expressed as the SD score) according to degree of hypopituitarism in 79 GHD patients (peak GH,
,7.5 mg/L) compared to 29 patients with normal GH responses.
between 1–10 mg/L on the sensitivity and specificity of IGF-I
and IGFBP-3 sd scores is shown in Fig. 5. The combined use
of these parameters improved the diagnostic value, as shown
in Fig. 6.
Factors influencing the diagnostic parameters in adults
with GHD
Multiple linear regression analyses revealed that the peak
GH response and the degree of hypopituitarism played a
significant role for both parameters, whereas body mass index played a role for IGFBP-3 only (see Table 5).
Discussion
We found that 29 of 108 (27%) individuals who received
GH replacement in childhood showed a normal GH response
VALUE OF IGF-I AND IGFBP-3 IN DIAGNOSIS OF GHD
1199
FIG. 5. Effect of varying the peak GH
cut-off value during GH provocative
test between 1–10 mg/L on sensitivity
(top panel), specificity (middle panel),
and test accuracy (bottom panel) for
IGF-I and IGFBP-3 (at three different
cut-off values). The dashed lines represent the chosen peak GH cut-off value of
7.5 mg/L.
FIG. 6. Comparison of the diagnostic value of IGF-I vs. IGFBP-3 in
all 108 patients who were classified as either GHD (peak GH, ,7.5
mg/L; F) or normal (E). The lines represent the lower limit (22 SD) for
the analyses.
after provocative retesting with oral clonidine in young
adulthood. Forty-five percent of those subjects who were
initially diagnosed as having isolated GHD had a normal
peak GH response to clonidine, and all patients with 2 or
more additional pituitary hormone deficiencies had a subnormal GH response at reassessment. This is in accord with
previous studies in which it has been shown that 30 – 40% of
patients who received GH replacement in childhood showed
a normal GH response at reassessment after completion of
GH therapy (7, 19 –21), but in these studies the percentage of
normal GH responses during adult retesting was not related
to the number of additional hormone deficiencies. We suggest that patients who have been treated with GH during
childhood because of isolated GHD should undergo reassessment of their GH secretory status in young adulthood
before continued adult GH replacement therapy is considered. Our finding of significantly lower peak GH levels in
patients with additional hormonal deficiencies compared to
patients with isolated GHD is in accord with the findings in
patients with adult-onset GHD (22, 23).
A large number of clinical trials have been carried out since
1989 of GH replacement therapy in GHD adults, who have
been diagnosed using various provocative tests (insulin tol-
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JUUL ET AL.
TABLE 5. Multiple linear regression analysis of factors of importance for IGF-I and IGFBP-3 as dependent variables in 108 adults
reevaluated for GH deficiency
Variables
IGF-I
IGFBP-3
Beta (T)
P
Beta (T)
P
Duration of disease
Degree of hypopituitarism
Peak GH level
BMI
Age
Sex
20.31 (24.23)
20.34 (24.36)
0.30 (3.77)
0.08 (1.16)
20.11 (21.17)
20.02 (20.23)
0.0001
0.0000
0.0003
0.2492
0.2437
0.8186
20.19 (22.36)
20.36 (24.69)
0.33 (4.31)
0.14 (2.05)
20.15 (21.78)
0.05 (0.84)
0.0204
0.0000
0.0000
0.0430
0.0773
0.4033
r, P
0.69, ,0.0001
erance test, arginine, GHRH, clonidine, and glucagon). In the
present study we used clonidine, which is an a-adrenergic
agonist that stimulates GH secretion (24, 25). The peak GH
response to oral clonidine is dependent on age (26), obesity,
and physical fitness (12, 27). Vahl et al. found that 50% of
healthy young adults (aged 27–34 yr) had peak GH levels
below the arbitrary cut-off value of 3 mg/L (12). This poor
specificity may argue against using clonidine as a diagnostic
test in adults. On the other hand, poor specificity has recently
been described for the insulin tolerance test (8), which has
been regarded as the most reliable provocative test in the
diagnosis of GHD in adults (28), leaving unanswered the
question of which test to use. Furthermore, varying biochemical criteria for patient selection have been described during
the last 6 or 7 yr. Definition of maximal GH response to a
stimulus varies enormously from 0.5–10 mg/L (1, 2, 29 –34).
Thus, apart from different selection criteria of patients (complete GHD vs. GHD with minor GH secretory capacity), a
lack of standardization of GH assays contributes to this variation. These findings strongly argue for each laboratory to
construct its own cut-off values (10).
Serum levels of total IGF-I and IGFBP-3 reflect the endogenous GH secretion in healthy children and exhibit little
diurnal variation, which makes them good diagnostic markers for screening of GHD in short children. In adults, the
diagnostic value of IGF-I and IGFBP-3 suspected of GHD has
been reported in a few studies (23, 35– 40) and has recently
been questioned (28). Pulsatile GH secretion increases in
puberty and declines with increasing age in adulthood (41–
43). Similarly, IGF-I (14, 44 – 46) and IGFBP-3 (15, 16, 18)
increase in puberty and decline with increasing age, partly
due to sex steroids (43), physical fitness (47), and adiposity
(46). Consequently, extensive age-related normative data for
these two analyses are mandatory, but often lacking. In the
present study of 79 adults with childhood-onset GHD, the
diagnostic sensitivity of IGF-I and IGFBP-3 determinations
was 75.9% and 68.4%, respectively, giving predictive values
of a positive test (ability to correctly identify patients with
GHD) of 88.2% and 90.0% for IGF-I and IGFBP-3, respectively. Our findings regarding the diagnostic value of total
IGF-I are in accord with those of other studies in GHD adults
(23, 35–37), but in contrast to those of Hoffman et al. (28), who
found an extremely poor diagnostic value for IGF-I (sensitivity of 39%). This discrepancy may be due to the fact that
these researchers (28) studied a relatively small group of
patients (n 5 23) with GHD of adult onset, who may represent a different population of patients compared to our
0.73, ,0.0001
patients who have childhood-onset GHD. Some patients
with childhood-onset GHD never reach final sexual maturation (or with a substantial delay), which may affect the
diagnostic value of IGF-I and IGFBP-3. Finally, we found that
serum levels of both IGF-I and IGFBP-3 in GHD adults were
dependent on the degree of GHD in accordance with previous findings for IGF-I (35). In addition, body mass index
played a significant role for IGFBP-3 levels. Manipulating the
cut-off limits for GH and IGF, respectively, yielded the highest degree of concordance between the GH provocative test
and IGF-I/IGFBP-3 levels using a cut-off value for GH of
approximately 3– 4 mg/L and cut-off values of 22.0 and 21.0
sd for IGF-I and IGFBP-3, respectively.
We conclude that a subnormal IGF-I or IGFBP-3 serum
level in most cases predicts a subnormal GH response to
provocative testing using oral clonidine in adult patients
who are suspected of having GHD. IGF-I and IGFBP-3 levels
were dependent on the duration of GHD, the number of
additional hormonal deficits, and peak GH levels. Consequently, we believe that they are valuable tools in the evaluation of adult GHD. We suggest that children who have
been treated with GH should undergo reassessment of their
GH secretory status as young adults before continued adult
GH replacement therapy is considered. However, our data
suggest that it is not necessary to reconfirm GHD by GH
provocative testing in young adults who have two or more
pituitary hormone deficiencies in addition to GHD.
Acknowledgments
We are grateful to Ulla Højelse, Brian Vendelboe, and Kirsten
Jørgensen for their skilled technical assistance.
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