Endokrynologia Pediatryczna Pediatric Endocrinology

Vol. 6/2007 Nr 4(21)
Endokrynologia Pediatryczna
Pediatric Endocrinology
The result of IGF-I and IGFBP-3 generation test as a prognostic factor of
growth hormone (GH) therapy effectiveness in children with short stature
and normal GH secretion in stimulating tests
Wynik testu genracji IGF-I i IGFBP-3 jako czynnik prognostyczny
skuteczności leczenia hormonem wzrostu (GH) u dzieci z niedoborem
wzrostu i prawidłowym wydzielaniem GH w testach stymulacyjnych
1
1
2
Joanna Smyczyńska, 1Maciej Hilczer, 1Renata Stawerska, 2Jolanta Lukamowicz, 1Andrzej Lewiński
Klinika Endokrynologii i Chorób Metabolicznych Uniwersytetu Medycznego w Łodzi, Instytut Centrum Zdrowia Matki Polki w Łodzi
Pracownia Badań Immunochemicznych Zakładu Diagnostyki Laboratoryjnej, Instytut Centrum Zdrowia Matki Polki w Łodzi
Adres do korespondencji:
Joanna Smyczyńska, Klinika Endokrynologii i Chorób Metabolicznych, Instytut „Centrum Zdrowia Matki Polki”, 93-338 Łódź,
ul. Rzgowska 281/289, endo-iczmp@lodz.home.pl
Słowa kluczowe:
hormon wzrostu (GH), insulinopodobny czynnik wzrostowy I (IGF-I), białko wiążące insulinopodobne czynniki wzrostowe typu 3
(IGFBP-3), testy stymulacyjne, test generacji IGF-I i IGFBP-3, leczenie GH
growth hormone (GH), insulin-like growth factor I (IGF-I), insulin-like growth factors binding protein-3 (IGFBP-3), GH stimulating
tests, IGF-I and IGFBP-3 generation test, GH therapy
Key words:
STRESZCZENIE/ABSTRACT
Wprowadzenie: Najważniejszym obwodowym mediatorem działania hormonu wzrostu (GH) jest insulinopodobny
czynnik wzrostowy-I (IGF-I). Stosunek molowy stężeń IGF-I i białka wiążącego IGF typu 3 (IGFBP-3) jest miarą
dostępności biologicznej IGF-I. Test generacji IGF-I wykorzystywany jest w celu oceny wrażliwości na GH.
Cele pracy: ustalenie, czy test generacji IGF-I i IGFBP-3 może mieć znaczenie prognostyczne w odniesieniu do
skuteczności terapii rhGH u dzieci z niedoborem wzrostu. Pacjenci i metody: Analizą objęto 30 dzieci z niedoborem
wzrostu, z prawidłowym wydzielaniem GH w testach stymulacyjnych (GHST) i obniżonym stężeniem IGF-I, u
których wykonano test generacji IGF-I i IGFBP-3 z zastosowaniem ludzkiego rekombinowanego GH (rhGH) przez
7 dni, a następnie włączono terapię rhGH i ponownie oceniono HV oraz stężenie IGF-I i IGFBP-3 po 6 miesiącach
leczenia. Skuteczność terapii porównano z wynikami uzyskanymi u dzieci z izolowanym częściowym niedoborem
GH (pGHD). Wyniki: Uzyskano znamienny (p<0,05) wzrost IGF-I SDS oraz stosunku molowego IGF-I/IGFBP3 w teście generacji z dalszym (nieznamiennym) wzrostem po 6 miesiącach terapii rhGH oraz ponad dwukrotne
przyspieszenie HV. Nie stwierdzono żadnych znamiennych różnic w zakresie ocenianych wskaźników pomiędzy grupą
badaną i dziećmi z pGHD. Wniosek: Wyniki testu generacji IGF-I i IGFBP-3 mogą być czynnikiem prognostycznym
skuteczności terapii rhGH u dzieci z prawidłowymi wynikami GHST, podczas gdy wyniki GHST wydają się nie mieć
decydującego znaczenia dla skuteczności tej terapii. Praca finansowana częściowo ze środków Ministerstwa Nauki i
Informatyzacji, Grant nr 2P05E 030 028. Endokrynol. Ped., 6/2007;4(21):9-18
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Praca oryginalna
Introduction: Insulin-like growth factor-I (IGF-I) is the main peripheral factor of growth hormone (GH) action. The
molar ratio of IGF-I to its binding protein-3 (IGFBP-3) is an index of IGF-I bioavailability. IGF-I generation test is
performed in assessment GH sensitivity. Aims: Evaluation of significance of IGF-I and IGFBP-3 generation test in
prognosing the effectiveness of recombinant human GH (rhGH) therapy in children with short stature. Patients and
methods: The analysis comprised 30 children with short stature, normal results of GH stimulating tests (GHST)
but decreased IGF-I concentration. In all the patients IGF-I and IGFBP-3 generation test was performed with rhGH
application for 7 days and, next, rhGH therapy was applied and HV together with IGF-I and IGFBP-3 concentrations
were assessed after 6 months of treatment. The effects of therapy were compared with those, obtained in children
with isolated non-acquired partial GHD (pGHD). Results: Both IGF-I SDS and IGF-I/IGFBP-3 molar ratio increased
significantly (p<0.05) in generation test and further (insignificantly) during rhGH therapy, together with more than
twofold HV increase. There were no significant differences in any of the assessed parameters between the examined
group of patients and children with pGHD. Conclusion: The results of IGF-I and IGFBP-3 generation test seem to be
a good prognostic factor of the effectiveness of rhGH therapy in short children with normal GHST, while the results
of GHST are of no crucial importance for the responsiveness to treatment. The study was partially supported by funds
from Ministry of Science and Informatisation, Project no 2P05E 030 028. Pediatr. Endocrinol., 6/2007;4(21):9-18
Introduction
Insulin-like growth factor-I (IGF-I) is the main
peripheral factor of growth hormone (GH) action.
In GH-sensitive subjects, IGF-I plasma concentration well reflects GH secretion. Conversely, in
case of GH insensitivity, IGF-I level remains low
despite normal or even elevated GH secretion. Both
IGF-I bioavailability and stability of its concentration is determined by binding to specific proteins,
especially – insulin-like growth factors binding
protein-3 (IGFBP-3) [1]. The molar ratio of IGF-I
to IGFBP-3 is considered to be an index of IGF-I
bioavailability [2]. Synthesis of IGFBP-3, similarly
as of IGF-I, is GH-dependent.
Assessment of IGF-I responsiveness to shortterm recombinant human GH (rhGH) administration – known as generation test – has primarily been
established as a diagnostic procedure in the patients
suspected for GH insensitivity [3]. Another possible application of IGF-I generation test is prediction of the efficacy of rhGH therapy. However, the
data concerning relationships between short-term
increase of IGF-I secretion in response to rhGH
administration and long-term effectiveness of the
therapy seem to be rather scarce and non-consistent.
Schwarze et al. [4] stated that an increase of IGF-I
and IGFBP-3 during short-term rhGH administration might be a good predictor of growth response
to the therapy. Similar were the observations of
Kamp et al. [5], concerning IGF-I secretion and
growth response to rhGH therapy. Moreover, the results presented by Lee et al. [6] indicated long-term
stability of IGF-I concentration on the level close
to that achieved during the initial phase of rhGH
therapy. Furthermore, IGF-I increase after rhGH
administration was observed not only in GH-deficient subjects, but also in healthy, normally growing ones [3]. Conversely, Jørgensen et al. [7] stated
that there was no evidence of a correlation between
an increase of IGF-I secretion and improvement
of height velocity (HV) during rhGH therapy, as
positive correlation between short-term increase in
serum IGF-I and HV was found in minority of studies. In the light of the quoted data, it seems very interesting to assess if the results of IGF-I generation
test might be a prognostic factor of the effectiveness
of rhGH therapy, especially in the patients with normal GH secretion in stimulating tests (GHST) but
decreased IGF-I secretion.
Another interesting problem is the relationship
between IGF-I and IGFBP-3 levels during shortand long-term rhGH administration. Tillmann et
al. [8] reported similar increases of both IGF-I and
IGFBP-3 secretion, as well as of IGF-I/IGFBP-3
molar ratio during rhGH therapy. In their study,
however, an increase of neither IGF-I secretion
nor IGF-I/IGFBP-3 molar ratio correlated with 1st
year growth response to the therapy. It should be
mentioned that, in the quoted study, a non-consistent group of patients, including both GH-deficient
and non-GH-deficient subjects, among the former
subgroup – only 15 children with isolated GH deficiency (GHD), was analysed. Other studies on the
relationships between IGF-I and IGFBP-3 secretion
and improvement of HV during rhGH therapy led
to divergent conclusions. Kriström et al. [9] stated
that changes of IGF-I and IGFBP-3 secretion after
rhGH administration might explain 58% of variation in 1st year growth response during the therapy.
Conversely, Lanes and Jakubowicz [10] did not
confirm any correlation between IGF-I and IGFBP-
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3 secretion during rhGH therapy and HV. In our best
knowledge, no data exist, comparing an increase of
IGF-I and IGFBP-3, especially in the aspect of IGFI/IGFBP-3 molar ratio, during short-term rhGH
administration in generation test with that obtained
during long-term rhGH therapy.
Indications to rhGH therapy in short children
with the classic form of GHD, i.e. with decreased
GH secretion after pharmacological stimulation
have been established quite clearly [11, 12]. In
recent years more and more studies reporting good
effectiveness of rhGH therapy in children with – socalled – idiopathic short stature have been published
[13-16]. However, the optimal criteria of both qualification children with short stature to rhGH therapy
and monitoring the effectiveness of treatment have
been the subject of discussion [16-20]. We are convinced that the effects of rhGH administration in
any group of children, qualified to the therapy despite normal results of GHST, should be compared
with that, observed in children with isolated GHD.
Taking into account all the doubts and controversies
concerning the diagnosis of GHD, it seems that if
the efficacy of treatment in any group of children
is similar to that observed in GH-deficient patients,
rhGH application in such children should be fully
justified.
The aim of the study was evaluation of significance of the results of IGF-I and IGFBP-3 generation test in prognosing the effectiveness of rhGH
therapy in children with short stature. The following
analyses have been performed:
1. Assessment of IGF-I and IGFBP-3 concentrations during generation test and after 6 months of
rhGH therapy in children with short stature, normal
results of GHST but decreased IGF-I secretion before the therapy.
2. Comparison of rhGH therapy effectiveness,
evaluated on the ground of changes of IGF-I
secretion and bioavailability (expressed by IGFI/IGFBP-3 molar ratio), followed by improvement
of HV in the examined group of children and in the
patients with isolated, non-acquired GHD.
Patients and methods
The retrospective analysis comprised 30 patients
(26 boys, 4 girls), age 12.6±1.9 years (mean±SD)
with short stature, slow HV, normal results of
GHST and decreased IGF-I serum concentration.
Patient’s height below 3rd centile for age and sex
according to current reference data for Polish children [9] was regarded short. Growing rate was also
assessed with respect to normative data for Polish
children [21]. Growth hormone secretion was assessed in 2 standard pharmacological stimulating
tests – with clonidine in a dose 0,075 mg/m2, orally
and with glucagon 30 μg/kg not exceeding 1 mg,
i.m.; GH peak at least 10 ng/mL in any of GHST
was considered sufficient for exclusion the classic
form of GHD. Plasma IGF-I levels were expressed
as IGF-I standard deviation score (IGF-I SDS) for
age and sex. The cut-off value between normal and
decreased IGF-I secretion was established IGF-I
SDS on the level of –1.0. In every patient, any
chronic diseases that may disturb IGF-I synthesis,
including malabsorption syndrome, undernutrition,
liver diseases, were excluded; all the girls had normal female karyotype.
In all the patients IGF-I and IGFBP-3 generation
test was performed with rhGH administration in a
daily dose 0.033 mg (0.1 IU)/kg for 7 days at 8 p.m.
The observed considerable increase of IGF-I levels
during generation test induced us to carry out additional diagnostic procedures in order to verify both
the previous diagnosis (idiopathic short stature) and
the indications to rhGH therapy in all the patients.
We found decreased GH peak (below 10 ng/mL) either in the repeated 2 GHST (confirming diagnosis
of GHD, in 16 cases) or in the nocturnal profile of
GH secretion (corresponding to diagnosis of neurosecretory dysfunction – NSD, in 10 cases). The remaining subjects (4 children with spontaneous and
stimulated GH secretion exceeding 20 ng/mL) were
suspected for decreased GH sensitivity, but – in all
of them – a significant increase of IGF-I concentration during generation test (over 100% of basal
level) was observed, leading to normalisation of
previously decreased IGF-I secretion. Thus, all the
patients in latter group were considered as probably
secreting GH inactive or with decreased bioactivity
(GHinact). It should be mentioned that an increase
of IGF-I secretion in generation test either exceeding 20 ng/mL [4 wg plakatu] higher than the double
value of coefficient of variation (CV) for the assay
[5,6 wg plakatu].
Next, in all the patients, rhGH therapy in a dose
0.17 mg (0.5 IU)/kg/week was applied and HV
together with IGF-I and IGFBP-3 concentrations
were assessed after 6 months of treatment.
The effects of rhGH therapy (improvement of
both IGF-I secretion and IGF-I/IGFBP-3 molar
ratio, as well as of HV) were compared with those,
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obtained in age- and sex matched group of 24 children (18 boys, 6 girls, age 12.9±2.6 years) with isolated non-acquired partial GHD (pGHD). The diagnosis of pGHD in all the patients from comparative
group was established on the ground of GH peak in
2 stimulating tests in the range of 5-10 ng/mL.
Growth hormone concentration was measured
by hGH IMMULITE, DPC assay, calibrated to
WHO IRP 80/505 standard, with the analytical
sensitivity up to 0.01 ng/mL, the calibration range
up to 40 ng/mL, the sensitivity of 0.01 ng/mL, the
intra-assay CV – 5.3-6.5% and the inter-assay CV
– 5.5-6.2%.
Blood samples for IGF-I and IGFBP-3 measurements were collected in morning hours before first
rhGH administration and after 7 daily injections of
rhGH, as well as after 6 months of rhGH therapy, as
described above. Both IGF-I and IGFBP-3 concentration was assessed by IMMULITE, DPC assays.
For IGF-I, WHO NIBSC 1st IRR 87/518 standard
was applied, with analytical sensitivity of the assay
20 ng/mL, the calibration range up to 1600 ng/mL,
the intra-assay CV – 3.1-4.3% and the inter-assay
CV – 5.8-8.4%. For comparison among children
with different age and sex, IGF-I concentrations
were expressed as IGF-I SDS, according to DPC
reference data. The assay for IGFBP-3 assessment
was calibrated to WHO NIBSC Reagent 93/560
standard, with analytical sensitivity 0.02 μg/mL, the
calibration range up to 426 μg/mL, the intra-assay
CV – 3.5-5.6% and the total CV – 7.5-9.9%. For
calculation of IGF-I/IGFBP-3 molar ratio, the following molecular masses were used: 7.5 kDa for
IGF-I and 42.0 kDa for IGFBP-3.
Statistical analysis included comparison of
IGF-I concentrations in particular time points of
the generation test and during rhGH therapy with
use of non-parametric statistical tests, as the distribution of the analysed parameters (assessed with
Kolmogorow-Smirnov test) was not consistent with
normal distribution. Mann-Whitney U test was applied for independent samples and Wilcoxon test for
dependent samples.
Results
An increase of IGF-I secretion during generation
test in the whole analysed group was 166.6±87.3%
of basal value, IGF-I SDS increased significantly
(p<0.05): from -2.07±0.84 to 0.25±0.87. After 6
months of rhGH therapy, further (insignificant)
increase of IGF-I SDS, to 0.42±0.83, was observed.
The molar ratio IGF-I/IGFBP-3 was 0.19±0.06 before rhGH administration, 0.41±0.12 after 7 days
of generation test and 0.44±0.16 after 6 months of
rhGH therapy, being significantly (p<0.05) higher
in both time points during rhGH application than
before treatment. The more than twofold HV increase (from 3.5±0.05 cm/year to 9.2±1.7 cm/year)
was also observed.
There were no significant differences in IGF-I
SDS both before the therapy and after 7 days of
rhGH administration, as well as after 6 months of
the therapy between the subgroups of children included to the study. In all of these subgroups, IGF-I
SDS presented higher in terms of rhGH application
than before the therapy, being similar after 7 days of
generation test and 6 months of treatment. Similarly, IGF-I/IGFBP-3 molar ratio increased more then
twice during rhGH application in all the subgroups
of children, being also similar after 7 days and 6
months of daily injections. Patients’ HV increased
in all the subgroups of children during 6 months
of rhGH therapy, with no significant differences
among them. In children with GHD (diagnosed in
the ground of the repeated GHST) and in those with
NSD, the differences in all the analysed variables
between the values obtained before and during
rhGH application were significant (p<0.05). Unfortunately, the subgroup with disorders of GH activity
(GHinact) was too small to be analysed with statistical tests, however the results in that group presented
quite similar to those obtained in other subgroups.
Interestingly, there were no significant differences
in either IGF-I SDS or IGF-I/IGFBP-3 molar ratio,
or in HV between the whole examined group of patients and the comparative group of children with
pGHD, not only before rhGH application but also
both during generation test and after 6 months of
therapy. The differences in the analysed parameters
between all the studied subgroups considered separately and the comparative group of children with
pGHD presented also insignificant, on the contrary
– the results in children from all the subgroups were
similar to that obtained in the patients with pGHD
The detailed results are presented in Tables I-III and
Figures 1-3.
Discussion
Both IGF-I and IGFBP-3 generation tests are
considered sensitive and specific markers of GH
sensitivity [25]. The results of these tests, especially of IGF-I generation test, seem to be also valu-
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Table I. IGF-I SDS before and after rhGH administration in all the analysed subgroups of children and in the
comparative group
Tabela I. Wartości IGF-I SDS przed i podczas stosowania rhGH w poszczególnych grupach badanych dzieci i w grupie
porównawczej
group
IGF-I SDS
studied (whole)
GHD (repeated
tests)
NSD
GHinact
comparative
(pGHD)
-2.07±0.84a,b
-2.05±0.89c,d
-1.89±0.67e,f
-2.67±0.73
-2.20±0.98g
after 7 days
of generation test
0.25±0.87a
0.17±0.77c
0.75±0.64e
-0.70±0.84
not assessed
after 6 months
of therapy
0.42±0.83b
0.41±0.79d
0.69±0.83f
-0.23±0.60
0.58±0.93g
before rhGH
application
a-g – significant differences (p<0.05)
Table II. IGF-I/IGFBP-3 molar ratio before and after rhGH administration in the analysed subgroups of children
and in the comparative group
Tabela II. Stosunek molowy stężeń IGF-I/IGFBP-3 przed i podczas stosowania rhGH w poszczególnych grupach
badanych dzieci i w grupie porównawczej
group
IGF-I/IGFBP-3
molar ratio
studied (whole)
GHD (repeated
tests)
NSD
GHinact
comparative
(pGHD)
0.19±0.06a,b
0.18±0.04c,d
0.20±0.06e,f
0.19±0.08
0,22±0,12g
after 7 days
of generation test
0.41±0.12a
0.47±0.10c
0.45±0.64e
0.43±0.20
not assessed
after 6 months
of therapy
0.44±0.16b
0.46±0.15d
0.46±0.17f
0.35±0.07
0,58±0,93g
before rhGH
application
a-g – significant differences (p<0.05)
Table III. Height velocity before and after rhGH administration in the analysed subgroups of children and in the
comparative group
Tabela III. Tempo wzrastania przed i podczas stosowania rhGH w poszczególnych grupach badanych dzieci i w grupie
porównawczej
group
HV [cm/year]
studied (whole)
GHD (repeated
tests)
NSD
GHinact
comparative
(pGHD)
before rhGH
application
3.5±0.5a
3.5±0.5b
3.3±0.6c
3.8±03d
3.5±1.1e
after 6 months
of therapy
9.2±1.7a
8.9±1.5b
9.6±02.0c
8.9±0.7d
10.1±2.3e
a-e – significant differences (p<0.05)
able measure of potential responsiveness to rhGH
therapy [20]. It was shown that in both healthy and
GH-deficient individuals, in terms of rhGH administration, IGF-I secretion was dependent on rhGH
dose [20]. Surprisingly, in both obese and tall children GH responsiveness in generation test tended to
be greater than in both healthy, normally-growing
controls and short children, being similar in the
latter two groups despite a lower baseline IGF-I in
short children [26.]. Our observations, concerning
the group of children with short stature and either
normal or decreased GH secretion after pharmaco13
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a-i – significant differences (p<0.05)
Fig. 1. IGF-I SDS before and after rhGH administration in all the analysed subgroups of children
and in the comparative group
Ryc. 1. Wartości IGF-I SDS przed i podczas stosowania rhGH w poszczególnych grupach badanych dzieci
i w grupie porównawczej
logical stimulation, also indicate that the increase
of IGF-I concentration during rhGH administration
may be not dependent on GH secretory status. However, it should be mentioned that GH secretion was
assessed on the ground of the results of GHST, that
may not very well reflect real GH secretion under
physiological conditions, due to some limitations
of their credibility [17, 27-29]. The same problem
occurred in current study, as in more than 50% patients (i.e. in 16 out of 30 children) with previously
normal results of GHST the same tests repeated
proved GHD.
Another important problem constitutes the reproducibility of IGF-I and IGFBP-3 generation tests.
Unfortunately, the results of studies on that issue are
not consistent, indicating either good reproducibility
in patterns of IGF-I and IGFBP-3 secretion in dur-
ing generation test [25] or – conversely – the poor
reproducibility of this diagnostic procedure [30]. As
a matter of fact, that issue was not directly a subject
of our study, however, significant increase of IGF-I
secretion was observed during both generation test
and rhGH therapy with no statistical difference
between the results obtained after 7 days and after
6 months of rhGH therapy. The latter observation
speaks for the stability of the effect of rhGH administration on IGF-I synthesis and – indirectly – for a
good reproducibility of changes in IGF-I synthesis
in terms of rhGH administration. This finding seems
to be important especially in the aspect of prediction of the effectiveness of rhGH therapy in short
children with unclear diagnosis of GHD, like most
of those, included to current study.
The crucial issue in qualifying such patients to
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a-i – significant differences (p<0.05)
Fig. 2. IGF-I/IGFBP-3 molar ratio before and after rhGH administration in the analysed subgroups of children and in
the comparative group
Ryc. 2. Stosunek molowy stężeń IGF-I/IGFBP-3 przed i podczas stosowania rhGH w poszczególnych grupach
badanych dzieci i w grupie porównawczej
rhGH therapy – more essential than an impact of
treatment on IGF-I synthesis – seems to be the effect on growing rate. In the light of the limitations
of clinical utility of GHST, the studies on short-term
tests useful in prediction the effectiveness of rhGH
therapy have special value. Unfortunately, the results of such studies lead to divergent conclusions,
either confirming the significance of generation
test as a strong predictor of the growth response to
rh GH therapy [4] or – conversely – denying any
relationships between IGF-I and the effects of GH
therapy [7]. According to our results, a good IGF-I
response to rhGH administration may be a strong
predictor of long-term effects of this treatment. It
should be mentioned, however, that all the children
subjected to the therapy had decreased basal IGF-I
level, increasing well during generation test.
In the aspect of predicting of rhGH therapy effectiveness, the observations of changes in IGFBP-3
secretion during both generation test and long-term
rhGH administration seem to be no less important
than assessment of IGF-I levels. Derandeliler et al.
[31] proved that in the patients with GHD, diagnosed
on the ground of pharmacological tests, an adequate
IGFBP-3 response in generation test predicted the
poor HV during rhGH therapy. In our study the increase of IGF-I secretion was much higher than that
of IGFBP-3, leading to doubling the IGF-I/IGFBP3 molar ratio. Our results concerning the effects of
rhGH administration on IGF-I/IGFBP-3 molar ratio
are consistent with those, presented by Tillmann
et al. [8]. It seems that a considerable increase of
IGFBP-3 secretion during rhGH application may
worsen the bioavailability of IGF-I.
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a-e – significant differences (p<0.05)
Fig. 3. Height velocity before and after rhGH administration in the analysed subgroups of children and in the
comparative group
Ryc. 3. Tempo wzrastania przed i podczas stosowania rhGH w poszczególnych grupach badanych dzieci i w grupie
porównawczej
A relatively short observation of growing rate
during rhGH therapy makes impossible to establish
final conclusions concerning the realtionships between the results of IGF-I and IGFBP-3 generation
test and the effectiveness of rhGH therapy. The obtained results, however, seem to be promising and
indicate the necessity of further studies on the effects of treatment in the observed group of patients,
possibly to completion of linear growing. The more
detailed studies of individual responsiveness to
long-term rhGH administration in the patients subjected to IGF-I and IGFBP-3 generation test may be
useful in optimising indications to growth-promoting rhGH therapy in short children.
The last observation resulting from our study
that should be stressed is the similar growth response to rhGH therapy in the examined group of
children with the effects observed in the patients
with pGHD. Thus, it may be impossible to distinguish between good and poor responders to rhGH
therapy basing on the results of GHST. This observation confirms the lack of evidence for diagnosing GHD and – consistently – qualifying children
to rhGH therapy only on the basis of the results of
GHST [19, 27] and are consistent with the results of
our previous studies [32]. In 2002 a very interesting discussion on that problem took place among
Carel et al. [33, 34], Saenger [35] and Loche et al.
[36]. Many doubts, concerning both reliability of
diagnosis of GHD based on GHST and the efficacy
of rhGH therapy in such patients had been widely
presented, however with no agreement among the
authors. The conclusions led rather to tightening
than to widening indications to rhGH therapy in
children. However, it should be re-called that in recent years similar effectiveness of rhGH therapy in
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Smyczyńska J. i inni – The result of IGF-I and IGFBP-3 generation test as a prognostic factor of growth hormone (GH) therapy effectiveness...
short children with normal and subnormal results of
GHST has been documented [13-16].
It seems that further studies on the diagnostic
tools that may be useful in predicting growth response to rhGH therapy can be even more important
than optimising and standardisation the tests used
for assessment of GH secretion. In the patients with
organic abnormalities in pituitary region (including
pituitary hypoplasia and neoplastic processes), GH
secretion is undoubtedly very low [37-40]. In the
patients with such abnormalities excluded, not only
GH secretion but also GH sensitivity, as well as
both IGF-I secretion and its bioavailability should
be taken into account while qualifying or disquali-
fying to rhGH therapy.
At least twofold increase of IGF-I secretion,
leading to normalisation of its serum concentration,
together with similar increase of IGF-I/IGFBP-3
molar ratio during generation test seem to be a
good prognostic factor of the effectiveness of rhGH
therapy in short children with normal results of
GHST. Further observations of such patients up to
final height seem necessary to fully assess the significance of these preliminary observations. Conversely, the results of GHST themselves seem not
to be of crucial importance for the responsiveness
to rhGH therapy in short children with decreased
IGF-I secretion.
PIŚMIENNICTWO/REFERENCES
[1]
Rosenfeld R.G., Lamson G., Pham H. et al.: Insulin-like growth factor binding proteins. Recent Prog. Horm. Res., 1990:46,
99-164.
[2] Juul A., Dalgaard P., Blum W.F. et al.: Serum levels of insulin-like growth factor (IGF) binding protein 3 (IGFBP-3) in healthy
infants, children and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal
maturation. J. Clin. Endocrinol. Metab., 1995:80, 2534-2542.
[3] Buckway C.K., Guevara-Aguirre J., Pratt K.L. et al.: The IGF-I generation test revisited: a marker of GH sensitivity. J. Clin.
Endocrinol. Metab., 2001:86, 5176-5183.
[4] Schwarze C.P., Wollmann H.A., Binder G. et al.: Short-term increments of insulin-like growth factor I (IGF-I) and IGFbinding protein-3 predict the growth response to growth hormone (GH) therapy in GH-sensitive children. Acta Paediatr.
Suppl., 1999:88, 200-208.
[5] Kamp G.A., Zwinderman A.H., Van Doorn J. et al.: Biochemical markers of growth hormone (GH) sensitivity in children with
idiopathic short stature: individual capacity of IGF-I generation after high-dose treatment determines the growth response to
GH. Clin. Endocrinol. (Oxf)., 2002:57, 312-325.
[6] Lee P.D., Durham S.K., Martinez V. et al.: Kinetics of insulin-like growth factor (IGF) and IGF-binding protein responses to a
single dose of growth hormone. J. Clin. Endocrinol. Metab., 1997:82, 2266-2274.
[7] Jørgensen J.O.L., Hansen T.K., Conceicao F.L. et al.: Short-term tools to measure responsiveness to growth hormone
replacement. Horm. Res., 2001:55 (Suppl. 2), 40-43.
[8] Tillmann V., Patel L., Gill M.S., et al.: Monitoring serum insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3),
IGF-I/IGFBP-3 molar ratio and leptin during growth hormone treatment for disordered growth. Clin. Endocrinol. (Oxf)., 2000:
53, 329-336.
[9] Kriström B., Jansson C., Rosberg S. et al.: Growth response to growth hormone (GH) treatment relates to serum insulinlike growth factor I (IGF-I) and IGF binding protein-3 in short children with various GH secretion capacities: Swedish Study
Group for Growth Hormone Treatment. J. Clin. Endocrinol. Metab., 1997:82, 2889-2898.
[10] Lanes R., Jakubowicz S.: Is insulin-like growth factor-1 monitoring useful in assessing the response to growth hormone of
growth hormone-deficient children? J. Pediatr., 2002:141, 606-610.
[11] Saggese G., Ranke M.B., Saenger P. et al.: Diagnosis and treatment of growth hormone deficiency in children and
adolescents: towards a consensus. Horm. Res., 1998:50, 320-340.
[12] GH Research Society: Consensus guidelines for the diagnosis and treatment of growth hormone deficiency in childhood
and adolescence: summary statement of the GH Research Society. J. Clin. Endocrinol. Metab., 2000:85, 3990-3993.
[13] Hintz R.L.: Growth hormone treatment of idiopathic short stature: clinical studies. Growth Horm. IGF Res., 2005:15 (Suppl.
A), S6-8.
[14] Kemp S.F.: Growth hormone treatment of idiopathic short stature: history and demographic data from the NCGS. Growth
Horm. IGF Res. 2005:15, (Suppl A), S9-12.
[15] Kemp S.F., Kuntze J., Attie K.M. et al.: Efficacy and safety results of long-term growth hormone treatment of idiopathic short
stature. J. Clin. Endocrinol. Metab., 2005:90, 5247-5253.
[16] Ranke M.B., Lindberg A., Price D.A. et al.: Age at Growth Hormone Therapy Start and First-Year Responsiveness to
Growth Hormone Are Major Determinants of Height Outcome in Idiopathic Short Stature. Horm. Res., 2007:68, 53-62.
17
Endokrynologia 21.indd
17
2008-01-11, 15:27
Praca oryginalna
Endokrynol. Ped., 6/2007;4(21):9-18
[17] Rosenfeld R.G., Albertsson-Wikland K., Cassorla F. et al.: Diagnostic controversy: the diagnosis of childhood growth hormone
deficiency revisited. J. Clin. Endocrinol. Metab., 1995:80, 1532-1540.
[18] Rosenfeld R.G.: Biochemical diagnostic strategies in the evaluation of short stature: the diagnosis of insulin-like growth factor
deficiency. Horm. Res., 1996:46, 170-173.
[19] Badaru A., Wilson D.M.: Alternatives to growth hormone stimulation testing in children. Trends Endocrinol. Metab., 2004:15,
252-258.
[20] Rosenfeld R.G., Buckway C., Selva K. et al.: Insulin-like growth factor (IGF) parameters and tools for efficacy: the IGF-I
generation test in children. Horm. Res., 2004:62 (Suppl. 1), 37-43.
[21] Romer T.E., Walczak M., Wiśniewski A. et al.: Dzieci z zaburzonym procesem wzrastania, kwalifikowane w Polsce do
leczenia hormonem wzrostu. Pediatria Praktyczna, 2001:9, 41-54.
[22] Tetlow L.J., Clayton P.: Tests and normal values in pediatric endocrinology. [in]: Clinical Pediatric Endocrinology. [ed.] Brook
C., Clayton P., Brown R. Blackwell Publishing, 2005, 523-564.
[23] Blair J.C., Camacho-Hubner C., Miraki Moud F. et al.: Standard and low-dose IGF-I generation tests and spontaneous growth
hormone secretion in children with idiopathic short stature. Clin. Endocrinol. (Oxf), 2004:60, 163-168.
[24] Cotterill A.M., Camacho-Hubner C., Duquesnoy P. et al.: Changes in serum IGF-I and IGFBP-3 concentrations during the
IGF-I generation test performed prospectively in children with short stature. Clin. Endocrinol. (Oxf), 1998:48, 719-724
[25] Selva K.A., Buckway C.K., Sexton G. et al.: Reproducibility in patterns of IGF generation with special reference to idiopathic
short stature. Horm. Res., 2003:60, 237-246.
[26] Bouhours-Nouet N., Gatelais F., Boux de Casson F. et al.: The insulin-like growth factor-I response to growth hormone is
increased in prepubertal children with obesity and tall stature. J. Clin. Endocrinol. Metab., 2007:92, 629-635.
[27] Loche S., Bizzarri C., Maghnie M. et al.: Results of early reevaluation of growth hormone secretion in children with apparent
growth hormone deficiency. J. Pediatr., 2002:140, 445-449.
[28] Hilczer M., Smyczyńska J., Stawerska R. et al.: Stability of insulin like growth factor-I concentration despite divergent
results of repeated growth hormone stimulating tests indicates poor reproducibility of test results. Endocrine Regul., 2006:
40, 8-16.
[29] Hilczer M., Smyczyńska J., Lewiński A.: Limitations of clinical utility of growth hormone stimulating tests in diagnosing
children with short stature. Endocrine Regul., 2006:40, 69-75.
[30] Jorge A.A., Souza S.C., Arnhold I.J. et al.: Poor reproducibility of IGF-I and IGF binding protein-3 generation test in children
with short stature and normal coding region of the GH receptor gene. J. Clin. Endocrinol. Metab., 2002:87, 469-472.
[31] Darendeliler F., Ocal C., Bas F.J.: Evaluation of insulin-like growth factor (IGF)-I and IGF binding protein-3 generation test in
short stature. Pediatr. Endocrinol. Metab., 2005:18, 443-452.
[32] Hilczer M., Smyczyńska J., Lewiński A.: First-year response to growth hormone (GH) therapy in GH-deficient children
– monitoring of height velocity and insulin-like growth factor-I secretion. Pediatric Endocrinol., 2006:5, 9-14.
[33] Carel J.C., Ecosse E., Nicolino M. et al.: Adult height after long-term treatment with recombinant growth hormone for
idiopathic isolated growth hormone deficiency: observational follow-up study of the French population based registry. Br.
Med. J., 2002:325, 70-73.
[34] Carel J.C., Ecosse E., Coste J.: Ignore the evidence and keep going wrong. Letter to the editor. Br. Med. J., 2002:325,
1037.
[35] Saenger P.: Growth hormone in growth hormone deficiency. Br. Med. J., 2002:325, 58-59.
[36] Loche S., Maghnie M., Cappa M.: Deficiency cannot be diagnosed solely on the results of stimulation tests. Br. Med. J., 2002:
235, 1037.
[37] Bozzola M., Adamsbaum C., Biscaldi I. et al.: Role of magnetic resonance imaging in the diagnosis and prognosis of growth
hormone deficiency. Clin. Endocrinol. (Oxf.), 1996:45, 21-26.
[38] Tillmann V., Tang V.W., Price D.A. et al.: Magnetic resonance imaging of the hypothalamic-pituitary axis in the diagnosis of
growth hormone deficiency. J. Pediatr. Endocrinol. Metab., 2000:13, 1577-1583.
[39] Bressani N., di Natale B., Pellini C. et al.: Evidence of morphological and functional abnormalities in the hypothalamus of
growth deficient children: A combined magnetic resonance imaging and endocrine study. Horm. Res., 1990:34, 189-192.
[40] Hilczer M., Szalecki M., Smyczyńska J. et al.: Growth hormone (GH) secretion and pituitary size in children with short
stature. Efficacy of GH therapy in GH-deficient children, depending on the pituitary size. Neuroendocrinol. Lett., 2005:26,
475-480.
18
Endokrynologia 21.indd
18
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