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23
JClin Res Ped Endo 2009;(Suppl 1):23–35
DOI: 10.4008/jcrpe.v1i1.21
©2009 Journal of Turkish Pediatric Endocrinology and Diabetes Society
Pubbiz/Probiz Ltd. fiti.
Diagnosis of Growth Hormone Deficiency:
the role of Growth Hormone (GH), Insulin-
Like Growth Factor (IGF-I) and IGF-Binding
Protein (IGFBP-3)
Abdullah Bereket
Marmara University Medical School, Pediatric Endocrinology Department, Istanbul, Turkey
SUPPLEMENT
Keywords:
Growth hormone, growth
hormone deficiency,
insulin-like growth factor I,
insulin-like growth
factor-binding protein 3,
IGF-I, IGFBP-3
Received: 09 October, 2008
Accepted: 22 October, 2008
Corresponding Author:
Abdullah Bereket
Marmara University Medical
School, Pediatric
Endocrinology Department,
Istanbul, Turkey
E-mail:
abereket@e-kolay.net
ABSTRACT
Despite dramatic changes in the treatment of growth hormone (GH) deficiency from cadav-
eric pituitary growth hormone to recombinant human growth hormone, the diagnosis of idio-
pathic growth hormone deficiency remains a challenge for the clinician. The uncertanities in the
cut-off values to describe growth hormone deficiency and reference data for growth hormone
secretion in normally growing children, differences in growth hormone assays over the time,
problems in reproducibility of growth hormone test results all contribute to this vagueness.
However, diagnosing growth hormone deficiency is important to identify children who will ben-
efit most from the GH treatment. GH dependent peptides, insulin-like growth factor I (IGF-I) and
insulin-like growth factor-binding protein 3, (IGFBP-3) are good markers of growth hormone sta-
tus and are useful in diagnosing GH deficiency as well as monitoring efficacy of growth hormone
treatment. An overview of problems in the diagnosis of GH deficiency and the role of IGF-I and
IGFBP-3 in the diagnosis of GH deficiency is provided in this paper.
Conflict of interest: None declared
Since numerous reasons other than GH
deficiency can cause growth retardation,
the diagnosis of GH deficiency in a child
with short stature should never be based
solely on auxological or solely on biochem-
ical-hormonal criteria. The diagnosis should
be reached by a critical evaluation of all the
relevant data brought together. In fact, even
the normal limits for GH response to stimu-
lation tests for endogenous GH secretion
have not yet been fully standardised and
this response is known to be influenced by
factors like age, sex, pubertal stage and
body mass index. Problems with the diag-
nosis of growth hormone deficency based
on GH measurements alone are as follows:
1. The established approach to the diagno-
sis of GH deficiency is based on the
assumption that GH deficient children
have a lower GH response to stimulation
compared to that of normally growing
children. However, many studies have
shown that the maximal response in nor-
mal children can remain below 10, 7 or
even under 5 µg/L. Differences in meth-
ods used for measurement of GH in bio-
logical materials, interlaboratory differ-
ences in cutoff values for normal ranges
arising from differences in methodology,
difficulties inherent in the use of physio-
ISSN: 1308-5727
Online ISSN: 1308-5735
logical stimulation tests as well as the mul-
tiplicity of agents used for pharmacologi-
cal stimulation and the non-standardised
use of sex steroids prior to the testing, all
contribute to the present inadequacies of
the diagnostic criteria.(1, 2, 3, 4)
2. Even if we all agree on a cut-off value,
reproducibility of GH response on GH
stimulation testing is poor. A significantly
large proportion of the so-called GH defi-
cient patients demonstrate normal
response to GH re-testing after the comple-
tion of the treatment. In 25-44% of the indi-
viduals with the diagnosis of GH deficien-
cy during childhood found to have normal
GH levels on spontaneous GH secretion
during sleep or on pharmacological testing
when retested at adulthood.(5, 6)
3. Another area of imprecision comes from the
question of conditions where the normalcy
of GH secretion is evaluated (spontaneous
vs stimulated). Although the best approach
is considered to be the assessment of the
spontaneous GH release, the difficulties
associated with technicalities and the stan-
dardisation of the results in this method as
well as the costs, have restricted its applica-
tion to research procedures only.
(7, 8)
4. GH estimation in the body fluids is
presently carried out by a variety of meth-
ods made available with commercial kits.
These methods include radioimmunoassay
(RIA) which utilizes polyclonal antibodies
or enzyme-linked immunoabsorbant
assay, immunoradiometric assay and lig-
and immunofunctional assay, all of which
utilise monoclonal antibodies. A GH stan-
dard of 2 IU/mg, derived from hypophy-
seal tissue and made available by the
‘National Hormone and Pituitary Program’
(USA), used in the earlier stages of labora-
tory measurement of GH was later
replaced by another standard of 2.6
IU/mg, also of hypophysial origin and
coded as IRP 80/505. In 1998, WHO rec-
ommended the use of recombinant 22-
kDa hGH (human GH), coded 88/624, of
3IU/mg strength, and inclusion of this
standard material in the kits presented to
the market by the industry.(1, 2)
Although these new assays have provided
sensitivity, speed, cost reduction and the
facility of automisation, they have also
brought the endocrinologist face to face with
anumber of problems. The use of polyclon-
al antibodies enabled the detection of all
immunogenic epitopes of GH in the circula-
tion, while the more recent assay kits with
monoclonal antibodies, which do not recog-
nise all components of GH in the circulation,
give lower results for GH levels and necessi-
tate the establishment of new and lower cut-
off (threshold) values. For example, the pre-
viously accepted threshold of 5-7 µg/L should
now become <5 µg/L. However, exactly the
opposite has been recommended and the
threshold has been raised to 10 µg/L. We
believe this is an error and should be correct-
ed. The new assays should be assessed on
samples from normally growing children to
establish the appropriate threshold levels.
Various pharmacological agents are being
used for GH stimulation tests. The sensitivity
of these tests is low.(4) The results obtained
with these pharmacological agents on
healthy children of normal or subnormal
height, using 7 µg/L and 10 µg/L as the lower
limits of normal are shown in Table 1. The
figures indicate the proportion of healthy
children which show values under these cut-
off limits. When the lower limit for GH defi-
ciency is taken as 7.5 µg/L, the sensitivity is
calculated as 73%, the specificity 83%, and
the positive predictive value is 50%.
Stimulation of GH secretion with sex
steroids: The physiological decrease in GH
secretion just before puberty causes difficulty
in differentiating this physiological event from
GH deficiency. Therefore, exogenous sex
steroids has been recommended to be used as
apriming tool prior to the stimulation tests.(9)
Priming with sex steroids can be done at age
10 in prepubertal girls and at age 12 in prepu-
bertal boys. The use of ethynyl oestradiol can
be recommended in both sexes at a single
dose of 20-40 µg/day, given the night before
Diagnosis of Growth Hormone Deficiency
©2009 Journal of Turkish Pediatric Endocrinology and Diabetes Society
24
the test. An alternative approach would be to
administer 20 µg/day ×3days ethynyl oestra-
diol in girls, and 100 mg i.m. testosterone
enanthate in boys in one dose three days
before the test. However, a consensus has not
been reached regarding the use of exogenous
sex steroids or the age at which they should
be given. More data especially on final height
is needed to clarify whether priming is help-
ful in differentiating those children who are
not “really GH deficient” and therefore will
not benefit from GH treatment.
WHICH PATIENTS SHOLUD BE TESTED?
For the clinical diagnosis of GH deficien-
cy, after the elimination of skeletal dysplasias,
genetic diseases such as Turner syndrome,
other endocrinopathies, any chronic or sys-
temic condition that might explain shortness
or growth retardation, the history, physical
findings and auxological data given below
can be taken as signs of GH deficiency.(1)
Clinical findings suggestive of GH
deficiency
Presence of (1) a family history of GH
deficiency or of close consanguinity
between the parents; (2) a history of perina-
tal trauma or of hypoglycemia, prolonged
jaundice, micropenis in the newborn period;
(3) anomalies such as the midline defects;
(4) a history of cranial irradiation, intracra-
nial lesions, head trauma, central nervous
system infections and multiple hypophyseal
hormone deficiency, have been agreed upon
to be suggestive of GH deficiency.
Auxological findings suggestive of
GH deficiency
Auxological findings accepted by the
Growth Hormone Society (GHS) and the
European Society of Paediatric Endocrinology
(ESPE) as suggestive of a diagnosis of GH
deficiency and which need to be confirmed
by further investigation include:
1. Extreme shortness (height for age < -3
SD) without an explanatory reason
2. Medium shortness (height for age
between -2 SD and -3 SD) with
a) a growth velocity less than 25th per-
centile or, in children > 2 years of
age, a decrease of > 0.5 SDS in height
noted after one year of follow-up
b) apredicted height value lower than
the target height by 1.5 SD (approxi-
mately 9-10 cm)
3. Without shortness of stature, a slow
growth velocity of (< 2 SD or < 5 p) over
1year or of < 1.5 SD over two years.
Estimation of target height
There are two equations which can be
used for this calculation:
Bereket A.
JClin Res Ped Endo 2009;(Suppl 1):23–35 25
Table 1: GHresponse to pharmacological stimulation in healthy children of normal and subnormal height, calculated
with 7 µg/L and <10 µg/L as cut-off limits.4
Pharmacological agent Max (min) Mean (range) <7 µg/L <10 µg/L
Pyridostigmin 60 13.5 (2.5-35) 15% 36%
Insulin 90 13.2 (2.7-46) 23.7% 49.1%
Arginine 45 16.7 (4.4-45.5) 12.6% 32.9%
Clonidine 60 13.1 (4.5-56.5) 10.1% 23.2%
L-Dopa 45 13 (1.9-40) 23.6% %36.4%
Glucagon 120 16.9 (1.9-49.5) 10% 35%
GHRH 30 28.8 (2.7-102) 8.9% 14.9%
Pyridostigmin+GHRH 30 47 (19-106) 0 0
Arginine+GHRH 45 61 (19-120) 0 0
GHRH: GH releasing hormone ; Max: maximum
1. Target Height for Boys = (Mother’s Height+Father’s Height)/2+6.5
Target Height for Girls = (Mother’s Height+Father’s Height)/2–6.5
2. Midparental Height SDS = (Mother’s Height SDS+Father’s Height SDS)/1.6
DIAGNOSIS OF GH DEFICIENCY IN THE
NEWBORN
In both preterm and term newborns,
GH levels in the first days of life are >20
µg/L.10-11 IGF-I values, are relatively low,
but it has been shown that in infancy,
IGF-I values lower than -2 SD for age are
suggestive of GH deficiency. In newborns
with micropenis, hypoglycemia, birth trau-
ma or a family history of GH deficiency, a
value of 20 µg/L or below by routine GH
estimation (using polyclonal antibodies)
can be accepted as indicative of GH defi-
ciency.
IGF-I AND IGFBP-3 IN GH DEFICIENCY
Changes in the levels of growth
factors with age
In healthy children serum IGF-I and
IGFBP-3 levels well reflect the endogenous
24-hour GH secretion. These levels have been
recognised as useful clinical parameters since
they show very little diurnal change and
remain stable.(12, 13, 14, 15, 16, 17, 18, 19)
Insulin and IGF-I are the two main fac-
tors responsible for growth in the early
postnatal period. Studies have shown that
birth weight, placental weight and gesta-
tional age correlate positively with the cord
blood IGF-I levels. In preterms, cord blood
IGF-I, IGFBP-3 and the acid-labile subunit
(ALS) levels are lower than in term new-
borns.(10, 20, 21)
In the early neonatal period, serum
IGF-I levels are closely associated with
nutritional state. This association weakens
but remains through childhood and adult-
hood. The levels fall during periods of
inadequate nutrition and rise with rever-
sion to normal nutrition.(22)
The fundamental factors influencing
growth are nutrition during the infancy
period, primarily GH and also other hor-
mones during childhood, and in addition to
these, sex steroids during the pubertal peri-
od. In late infancy and early childhood,
serum IGF-I and IGFBP-3 levels become
GH dependent.
The relatively low serum IGF-I and
IGFBP-3 levels at birth start increasing dur-
ing childhood and reach maximal levels in
adolescence and fall thereafter to prepuber-
tal levels in adulthood.(23)
During childhood IGF-I levels increase
slowly and show each year a parallelism
with the growth rate of the following
year.(23, 24) Longitudinal studies have
shown that serum IGF-levels maintain this
parallelism until the attainment of the maxi-
mal growth velocity. Thereafter, despite the
fall in postpubertal growth rate, IGF-I levels
have been observed to remain high.
Therefore, the correlation between the IGF-
Ilevels and the growth rate is marked only
in prepubertal children.(25, 26)
In both sexes, the increase in sex
steroids during puberty results in higher
GH secretion. Alongside with this increase
in GH secretion, an increase in GH sensitiv-
ity also contributes to the increase in IGF-I
and IGFBP-3 levels.(13) Peak IGF-I and
IGFBP-3 levels are reached approximately 2
years after the attainment of peak height
velocity.(27, 28)
Although serum IGF-I and IGFBP-3
determinations are very useful in evaluat-
ing growth disorders, a reliable normative
data is needed for optimal benefit of these
diagnostic tools. Since IGF-I levels vary
with age, sex and puberty, a large sample
is needed to determine normative values.
There are differences in reported refer-
ence values for normal ranges due to dif-
ferences in populations studied and differ-
ences in assay methods used. Values
obtained in a study using the immunora-
diometric assay (IRMA) method (DSL
assay kits) carried out on healthy school
children in Istanbul in order to determine
the reference range for IGF-I levels in
Turkey are presented in Tables 2-7 and
Figures 2-5 below. These data have made
possible the calculation of IGF-I SDS and
IGFBP-3 SDS values.
(28, 29)
Diagnosis of Growth Hormone Deficiency
©2009 Journal of Turkish Pediatric Endocrinology and Diabetes Society
26
Bereket A.
JClin Res Ped Endo 2009;(Suppl 1):23–35 27
THE DIAGNOSTIC SIGNIFICANCE OF
IGF-I AND IGFBP-3
In the diagnosis of GH deficiency
The conditions which affect the GH-IGF
axis and the relative changes of serum GH,
IGF-I ve IGFBP-3 levels are given in Table 8.
Low IGF-I levels in GH deficiency have
been shown in many studies. While IGF-I
levels were found to be lower than -2 SD
Table 2: Change in serum mean, standard deviation (SD) and standard deviation score (SDS) IGF-I levels in healthy
girls with age.
IGF-I(*) IGF-I
SD SD
Age N Mean SD -1 1 Mean -2 2
417 11.7 3.2 75 220 140 30 330
5 6 13.8 3.7 110 280 180 50 400
6 17 15.3 2.1 140 340 225 70 480
7 28 15.8 3.9 170 390 270 90 545
8 41 17.2 3.8 210 455 320 120 620
9 30 18.5 3.4 260 520 370 160 680
10 33 20.3 3.7 320 580 430 220 740
11 46 23.1 3.2 380 630 500 280 780
12 32 24.0 1.6 440 670 545 340 805
13 39 24.1 1.9 470 690 580 380 820
14 31 24.5 2.1 485 705 590 390 830
15 24 24.1 2.8 480 700 585 385 830
16 28 24.1 2.7 465 680 580 375 805
17 7 23.0 1.7 455 640 545 360 750
*Square-root transformation has been utilised to normalise the data
Table 3: Change in serum mean, standard deviation (SD) and standard deviation score (SDS) IGF-I levels in healthy
boys with age.
IGF-I(*) IGF-I
SD SD
Age N Mean SD -1 1 Mean -2 2
4 20 10.0 3.2 50 180 100 15 270
5 7 11.2 3.4 70 220 130 30 325
6 19 13.9 3.2 100 260 170 45 380
7 25 14.5 3.2 120 300 200 60 420
8 28 15.7 2.3 140 340 230 70 480
9 39 15.4 4.0 160 380 260 80 540
10 41 16.6 3.1 190 440 300 100 610
11 37 18.5 4.3 230 510 350 130 700
12 31 19.6 4.7 280 580 415 180 780
13 38 22.9 2.5 340 640 480 240 830
14 48 24.1 3.2 405 700 540 290 880
15 41 25.1 2.9 450 740 580 330 910
16 26 25.0 2.8 470 750 600 350 910
17 28 23.7 2.8 475 740 600 355 890
*Square-root transformation has been utilised to normalise the data
Diagnosis of Growth Hormone Deficiency
©2009 Journal of Turkish Pediatric Endocrinology and Diabetes Society
28
Table 4: Change in serum mean, standard deviation (SD) and standard deviation score (SDS) of IGFBP-3 levels in
healthy girls with age.
IGFBP-3 IGFBP-3
SD SD
Age N Mean SD -1 1 Mean -2 2
414 4291 457 3650 5000 4300 2950 5650
5 6 4635 1157 3750 5350 4550 2950 6150
6 16 4654 806 3900 5600 4750 3050 6400
7 25 4917 793 4100 5750 4950 3250 6600
8 37 5150 860 4300 5950 5100 3450 6750
9 31 5062 758 4500 6150 5300 3700 6950
10 33 5505 821 4700 6350 5500 3950 7200
11 45 5763 793 4900 6450 5700 4150 7250
12 30 5916 659 5050 6550 5800 4300 7350
13 37 6047 778 5100 6600 5850 4350 7350
14 30 5580 779 5050 6550 5800 4350 7300
15 29 5863 822 5000 6400 5700 4350 7100
16 28 5455 523 4900 6150 5550 4350 6800
17 11 5346 539 4800 5900 5350 4350 6400
Table 5: Change in serum mean, standard deviation (SD) and standard deviation score (SDS) IGFBP-3 levels in healthy
boys with age.
IGFBP-3 IGFBP-3
SD SD
Age N Mean SD -1 1 Mean -2 2
4 20 4040 755 3550 4700 4100 2950 5300
5 8 4557 315 3600 4900 4250 2950 5600
6 16 4208 870 3650 5150 4400 2900 5900
7 22 4417 886 3700 5350 4550 2900 6200
8 26 4547 927 3850 5600 4750 3000 6500
934 4971 805 4100 5850 4950 3200 6750
10 39 5141 927 4350 6100 5225 3400 7000
11 37 5578 910 4550 6350 5450 3650 7200
12 29 5631 925 4700 6450 5600 3850 7350
13 36 5932 686 4800 6550 5700 4000 7350
14 44 5617 807 4900 6450 5650 4050 7300
15 35 5566 952 4750 6350 5575 4000 7150
16 26 5294 623 4650 6200 5490 3950 6950
17 29 5348 745 4550 6000 5450 3850 6700
of the mean value for respective age in 82%
of patients with GH deficiency, these val-
ues were found to be within normal limits
in 68% of short children with no GH defi-
ciency.
(30)
In 203 boys of low stature, Juul
et al.
(31)
have found that IGF- I values of -
2SD below the mean had a positive pre-
dictive value of 57%. In children younger
than 10 years, IGF-I estimation is more use-
ful than estimation of GH in pointing to
subnormality in GH stimulation tests
(Figure 13). An IGF-I value of -2.5 SD gives
the optimal limit for discriminating GH
deficiency from idiopathic low stature.
(31)
Bereket A.
JClin Res Ped Endo 2009;(Suppl 1):23–35 29
Table 6: Calculation of IGF-I z-score (SDS) according to the Tanner scoring.
Tanner Score αα(SE) ββ(SE) SD PNr
Boys
I7.94 (0.997) 0.82 (0.108) 3.95 <0.0001 198 0.479
II 14.53 (4.642) 0.44 (0.381) 3.12 0.258 32 0.206
III 7.96 (6.692) 1.01 (0.507) 3.66 0.058 25 0.384
IV 25.40 (5.599) -0.07 (0.396) 2.68 0.858 41 -0.029
V27.08 (3.119) -0.16 (0.197) 2.64 0.428 113 -0.075
Girls
I8.09 (1.101) 1.0 (0.143) 3.75 <0.0001 123 0.536
II 14.96 (4.764) 0.36 (0.464) 3.00 0.442 21 0.177
III 15.24 (4.532) 0.632 (0.410) 3.12 0.130 44 0.232
IV 20.52 (2.554) 0.290 (0.204) 2.28 0.159 67 0.174
V25.96 (2.205) -0.128 (0.147) 2.33 0.386 114 -0.082
Y=
β
x Age (year) +
α
IGF-I z-score= (IGF-1 SQR –Y)/SD
E.g.: 12- year old girl; Tanner score III; IGF-I = 400 ng/mL
√IGF-I = IGF-I SQR = 20
Y = 0.632 x 12 + 15.24 = 22.82
IGF-I z-score= (20-22.82)/3.12= -0.904
Table 7: Calculation of IGFBP-3 z-score (SDS) according to Tanner scoring.
Tanner Score αα(SE) ββ(SE) SD PNr
Boys
I3518 (234) 140 (25) 929 <0.0001 187 0.378
II 2710 (1100) 251 (91) 803 0.010 30 0.463
III 7083 (1354) -97 (104) 742 0.357 26 -0.188
IV 10934 (1538) -352 (109) 803 0.003 35 -0.489
V6926 (939) -93 (59) 778 0.117 108 -0.152
Girls
I3948 (318) 111 (40) 780 0.007 114 0.250
II 4216 (1371) 133 (132) 699 0.326 20 0.231
III 4100 (1076) 129 (97) 776 0.191 44 0.201
IV 7129 (816) -51 (65) 801 0.429 66 -0.099
V7540 (674) -96 (45) 717 0.033 119 -0.196
Y=
β
x Age (year) +
α
IGFBP-3 z-score = (IGFBP-3 –Y)/SD
E.g.: 12-year old boy; Tanner score III; IGFBP-3 = 6000 ng/mL
Y = -97 x 12 + 7083 = 5919
IGFBP-3 z-score = (6000-5919)/742= 0.109
Table 8: Laboratory findings in conditions affecting the GH-IGF axis
Condition GH IGF-I IGFBP-3 Growth
GH deficiency Variable Low Low Decreased
GH resistance Normal/High Low Low Decreased
IGF deficiency Variable Low Low/Normal Decreased
Acromegaly High High High Increased
LGA Variable High High Increased
SGA Low Low Low Decreased
LGA: High birth weight for gestational age
SGA: Low birth weight for gestational age
The diagnostic value of estimating IGF-I
and IGFBP-3 changes according to the cut-
off limits taken, Rikken et al.(32) have
demonstrated in a study with 96 children
that when a cut-off limit of -0.83 SD was
taken for IGF-I, the sensitivity and the speci-
ficity of the estimations for detecting GH
deficiency were 92% and 47%, respectively.
If the IGF-I cut-off limit was taken as -1 SD,
the percentages of GH deficiency and idio-
pathic low stature detected became 88 and
46, respectively. In other studies taking the
IGF-I limit at -2 SD, the specificity and the
sensitivity of detecting GH deficiency varied
between 47% and 80% and 61% and 91%,
respectively.(33, 34, 35, 36, 37, 38, 39, 40)
Blum et al. in 1990 have stated that the
sensitivity and the specificity of measuring
IGFBP-3 were 97% and 95%, respectively,
and that estimating IGFBP-3 was more use-
ful than measuring IGF-I for the diagnosis
of GH deficiency. However, in subsequent
studies these high levels of specificity and
sensitivity were not demonstrable and the
reported sensitivities varied between 15%
and 98% and the corresponding specificities
Diagnosis of Growth Hormone Deficiency
© 2009 Journal of Turkish Pediatric Endocrinology and Diabetes Society
30
IGF-I
AGE (year)
Mean
± 1 SD
± 2 SD
1000
800
600
400
200
0
2 4 6 8 10 12 14 16 18
Figure 2: Change in serum IGF-I levels in healthy
Turkish girls with age.
IGF-1
AGE (year)
Mean
± 1 SD
± 2 SD
1000
800
600
400
200
02 4 6 8 10 12 14 16 18 20
Figure 3: Change in serum IGF-I levels of healthy
Turkish boys with age
IGFBP-3
AGE (year)
Mean
± 1 SD
± 2 SD
8000
7000
6000
5000
4000
3000
20002 4 6 8 10 12 14 16 18 20
IGFBP-3
AGE (year)
Mean
± 1 SD
± 2 SD
8000
7000
6000
5000
4000
3000
20002 4 6 8 10 12 14 16 18 20
Figure 4: Change in serum IGFBP-3 levels of
healthy Turkish girls with age
Figure 5: Change in serum IGFBP-3 levels in
healthy Turkish boys with age
varied between 50% and 98%.(42, 43, 44)
After the publication of the reference
curves for IGF-I and IGFBP-3 values over
the age range 0 to 6 years, it was seen that
the lower limits of IGF-I levels were very
close to the estimated IGF-I values whereas
this was not the case with IGFBP-3. Thus,
theoretically IGFBP-3 has a diagnostic
superiority over IGF-I for the 0 to 6-year
age group and this hypothesis has been
supported by other studies demonstrating
the diagnostic superiority of IGFBP-3 esti-
mations in prepubertal children as com-
pared to those in older children.(24, 31, 33)
In most patients with GH deficiency IGF-
I and IGFBP-3 levels are low and rise to nor-
mal after treatment. IGF-I and IGFBP-3 can
be used in evaluation of response to treat-
ment as well as in the follow-up of GH defi-
cient patients, regardless of etiology. The
follow up of IGF-I and IGFBP-3 levels theo-
retically will help to predict the growth
response as well as assessing the efficacy of
GH replacement and patient compliance to
the treatment. In patients receiving GH
replacement, positive correlations between
the z-scores of IGF-I and IGFBP-3 and the
increase in height have been shown. In GH
replacement dose adjustment IGF-I values
specific for age and sex must be taken into
consideration.
In recent years, it has been argued that
both from the points of view of effectiveness
and long term safety, the adjustment of the
GH replacement dose be made according to
IGF-I and IGFBP-3 values.(45) The advan-
tages and disadvantages of the criteria used
in adjusting the GH replacement dose are
shown in Table 10.
The targeted IGF-I z-scores in different
stages of the replacement therapy for opti-
mal benefits are shown in Table 11.
Bereket A.
J Clin Res Ped Endo 2009;(Suppl 1):23–35 31
1000
800
600
400
200
0
04 8 12 16 20
1000
800
600
400
200
0
0 4 8 12 16 20
1000
800
600
400
200
0
0 4 8 12 16 20
1000
800
600
400
200
0
0 4 8 12 16 20
IGF-I (µg/L)
NORMAL GH RESPONSE
GHD GHD
NORMAL GH RESPONSE
Age (years)
Figure 6: Serum IGF-I values in patients presenting with low stature. The upper panel gives results of GH
response to stimulation tests in children with normal GH response and the lower panel gives results on GH
deficient children.31
Diagnosis of Growth Hormone Deficiency
© 2009 Journal of Turkish Pediatric Endocrinology and Diabetes Society
32
Table 9: The diagnostic sensivity and specificity of IGF-I ve IGFBP-3 estimations as compared to the results of the GH
stimulation tests in children suspected with GH deficiency.
Age group (yrs) Stim. test GH lower limit Sensitivity Specificity
IGF-I
Rosenfeld et al. 1–18 ARG+ITT 7 ng/ml 82% (56/68) 68% (30/44)
Lee et al. 8.9±4.4 CLO, L-DOPA 7 ng/ml 81% (13/16) 53% (71/133)
Blum et al. 11.2 [0.25–34.4] ARG, ITT 10 ng/ml 96% (127/132) 54% (70/130)
Smith et al. 0.2–18.0 ITT, ARG 1 ng/ml 86% (49/57) 70% (16/23)
Cianfarani et al. 8.1±1.8 ARG, CLO 8 mU/l 69% (11/16) 80% (8/10)
Hasegawa et al. ND ARG, ITT 10 ng/ml 88% (52/59) 79% (81/103)
Nunez et al. 10.7±2.4 ARG, ITT, L-DOPA 7 ng/ml 50% (8/16) 81% (60/74)
Juul and Skakkebæk 12.7 [1.1–19.9] ARG, CLO 15 mU/l 69% (42/61) 77% (110/142)
Tillman et al. 7.9±3.4 Clinical Diagn.* 34% (20/58) 72% (78/109)
Rikken et al. 7.5±3.5 Not known 20 mU/l 61% (36/59) 78% (24/32)
Hall et al. ND Not known 20 mU/l 82% (18/22) 62% (29/62)
Mitchell et al. 0.9–25.4 ITT, GLU 13.5 mU/l 62% (92/148) 47% (69/147)
Bussieres et al. 4.7 [2.9–18.8] ORN, GLU, AITT 10 ng/ml 84% (36/43) 57% (39/68)
Ranke et al. 6.8 (1.0) AITT 10 ng/ml 75% (140/187) 50% (102/205)
IGFBP-3
Blum et al. 11.2 [0.25–34.4] ARG+ITT 10 ng/ml 97% (128/132) 95% (123/130)
Smith et al. 0.2–18.0 ITT, ARG 1 ng/ml 93% (53/57) 57% (13/23)
Hasegawa et al. ND ARG, ITT 5 ng/ml 90% (53/59) 70% (71/103)
Cianfarani et al. 8.1± 1.8 ARG, CLO 8 mU/l 50% (8/16) 90% (9/10)
Nunez et al. 10.7±2.4 ARG, ITT, L-DOPA 7 ng/ml 31% (5/16) 85% (63/74)
Juul and Skakkebæk 12.7 [1.1–19.9] ARG, CLO 15 mU/l 61% (37/61) 85% (121/142)
Tillman et al. 7.9±3.4 Clinical Diagn.* 34% (20/58) 72% (78/109)
Rikken et al. 7.5±3.5 Not Known 20 mU/l 63% (37/59) 84% (27/32)
Mitchell et al. 0.9–25.4 ITT, GLU 13.5 mU/l 15% (22/148) 98% (147/150)
Ranke et al.55 6.8 (1.0) AITT 10 ng/ml 67% (140/187) 50% (102/205)
ARG, arginin; ITT, insulin tolerance test; CLO, clonidine; L-DOPA, L-dopamine; GLU, glucagon; ORN, ornithine; AITT, arginine and ITT combination;
* According to the clinical diagnosis (organic hypopituitarism or stalk lesion seen at MRI)
Table 10: Advantages and disadvantages of criteria used in GH replacement therapy.
Standard dose On body weight basis On IGF level On growth rate basis
Advantage Simple Easy Optimal growth Most important criterion
Tried in adults Tried Safe Economical
Noninvasive
Disadvantage Variable results Disregards individual Requires laboratory Safety?
GH sensitivity facilities Requires a minimum time of
6 months for evaluation
Table 11: The targeted IGF-I z-score values for optimal benefits from treatment
Growth phase Catch-up Continuity of Puberty Transition to
growth growth adulthood
Aim of Treatment Maximum height Maintenance of height SDS Optimising final Body composition
correction height
Targeted IGF-I +2 to +3 SDS -1 to +1 SDS +1 to +2SDS 0 to +1 SDS
Z score If short
+2 to 3 SDS
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