Endokrynologia Pediatryczna Pediatric Endocrinology

Vol. 5/2006 Nr 1(14)
Endokrynologia Pediatryczna
Pediatric Endocrinology
First-year response to growth hormone (GH) therapy in GH-deficient children
– monitoring of height velocity and insulin-like growth factor-I secretion
Ocena skuteczności leczenia hormonem wzrostu dzieci z somatotropinową
niedoczynnością przysadki na podstawie poprawy tempa wzrastania
i wydzielania insulinopodobnego czynnika wzrostowego-I w pierwszym
roku terapii
Maciej Hilczer, Joanna Smyczyńska, Andrzej Lewiński
Klinika Endokrynologii i Chorób Metabolicznych Uniwersytetu Medycznego w Łodzi, Instytut Centrum Zdrowia Matki Polki w Łodzi
Adres do korespondencji:
Dr n. med. Maciej Hilczer, Klinika Endokrynologii i Chorób Metabolicznych Uniwersytetu Medycznego w Łodzi,
Instytut Centrum Zdrowia Matki Polki w Łodzi, 93–338 Łódź, ul. Rzgowska 281/289, tel. (42) 271-17-15,
e-mail: [email protected]
Key words: growth hormone deficiency, height velocity, insulin-like growth factor-I, growth hormone therapy
Słowa kluczowe: niedobór hormonu wzrostu, tempo wzrastania, insulinopodobny czynnik wzrostowy-I, leczenie hormonem wzrostu
STRESZCZENIE/
STRESZCZENIE/ABSTRACT
Introduction. Improvement of height velocity (HV), related to an increase of insulin-like growth factor-I (IGF-I)
secretion, is the most important index of growth hormone (GH) therapy effectiveness. The aim of the study was an
assessment of the first-year increase of HV, IGF-I secretion and IGF-I to IGF binding protein-3 (IGFBP-3) molar ratio
in children with GH deficiency (GHD). Patients and methods. The analysis comprised 80 children (58 boys) with
short stature, as well as decreased basal IGF-I secretion, divided – according to GH peak in 2 stimulating tests and
in nocturnal spontaneous GH secretion – into the following groups: severe GHD (sGHD), partial GHD (pGHD), and
neurosecretory dysfunction (NSD). All the patients were treated with GH in dose of 0.18 ± 0.02 mg/kg/week for – at
least – 1 year. Before GH application and after 1 year of therapy HV, IGF-I secretion and the IGF-I/IGFBP-3 molar
ratio were compared. Results. There were no significant differences in any of the analysed parameters among the
groups either before the therapy or after 1 year, whereas in all the groups both HV and IGF-I secretion, as well as the
IGF-I/IGFBP-3 molar ratio, were significantly higher (p < 0.0001) after 1 year of GH therapy than before treatment.
Normalisation of previously decreased IGF-I secretion, together with a more than threefold increase of pretreatment
HV, was observed in all the groups after 1 year of GH therapy. In 5 patients, IGF-I in the course of the therapy exceeded
the upper limit of normal range. Conclusions. The effectiveness of treatment was independent of GH secretion in the
stimulating tests. Individualisation of GH dose seems to be necessary both for safety reasons and for optimisation of
the growth-promoting effect.
Pediatr. Endocrinol., 5/2005;1(14):9-14
Vol. 5/2006, Nr 1(14)
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Endokrynol. Ped., 5/2006;1(14):9-14
Wstęp. Poprawa tempa wzrastania (HV) związana ze zwiększeniem wydzielania insulinopodobnego czynnika
wzrostowego-I (IGF-I) stanowi najważniejszy wskaźnik skuteczności leczenia hormonem wzrostu (GH). Cel
pracy. Ocena skuteczności leczenia GH dzieci z niedoborem GH (GHD) na podstawie poprawy tempa wzrastania
oraz wzrostu wydzielania insulinopodobnego czynnika wzrostowego-I i stosunku molowego IGF-I do jego białka
wiążącego typu 3 (IGFBP-3) w pierwszym roku terapii. Pacjenci i metody. Analizą objęto 80 dzieci (58 chłopców)
z niedoborem wzrostu podzielonych w zależności od wydzielania GH w testach stymulacyjnych i po zaśnięciu na
grupy: ciężki GHD (sGHD), częściowy GHD (pGHD), zaburzenia neurosekrecyjne (NSD). Terapię GH w dawce 0,18
± 0,02 mg/kg/tydzień prowadzono przez okres co najmniej 1 roku. Przed rozpoczęciem terapii oraz po roku leczenia
oceniono: HV, wydzielanie IGF-I i stosunek molowy IGF-I/IGFBP-3. Wyniki. Nie stwierdzono znamiennych różnic
pomiędzy poszczególnymi grupami pacjentów w zakresie wszystkich analizowanych parametrów zarówno przed
leczeniem, jak i po roku terapii. We wszystkich grupach pacjentów HV, wydzielanie IGF-I oraz stosunek IGF-I/
IGFBP-3 były znamiennie wyższe po roku terapii niż przed leczeniem. U pięciu pacjentów stężenie IGF-I podczas
terapii przekroczyło górną granicę wartości prawidłowych. Wnioski. Skuteczność leczenia GH była podobna we
wszystkich grupach, niezależnie od wydzielania GH w testach stymulacyjnych. Indywidualizacja dawek GH wydaje
się konieczna ze względów bezpieczeństwa oraz dla optymalizacji promocji wzrastania. Endokrynol. Ped., 5/2006;1(14):9-14
Introduction
Subjects and methods
Improvement of height velocity (HV) in order
to achieve normal final height is the main goal of
growth hormone (GH) therapy in children with GH
deficiency (GHD), being the most important index
of GH therapy effectiveness.
Insulin-like growth factor-I (IGF-I) is the main
peripheral mediator of growth hormone (GH) action. Kamp et al. [1] have showed that IGF-I generation during the therapy with high dose of GH
determines the growth response to GH. The insulin-like growth factor binding protein-3 (IGFBP-3)
is the main carrier protein of IGF-I in serum. The
bioavailability of IGF-I is dependent on the IGF-I to
IGFBP-3 molar ratio [2]. In GH-deficient adult patients, monitoring of GH therapy with IGF-I assessment is a routine practice and GH dose is adjusted
in order to maintain IGF-I serum concentration within normal range for age and sex [3]. However, in
children, IGF-I and IGFBP-3 concentrations have
not been routinely assessed during GH therapy and
the recommended GH doses are not dependent on
IGF-I level [4]. Monitoring of IGF-I and IGFBP-3
secretion in children treated with GH is important
not only for optimising the therapy effectiveness but
also for safety reasons [5]. In adults, the increased
IGF-I concentration, especially in combination with
low IGFBP-3 level may be associated with an increased risk of cancer development [6, 7].
The analysis comprised 80 GH-deficient children (58 boys, 22 girls) who were treated with GH
for, at least, 12 months. Patients’ height at diagnosis
was below the third centile for age and sex, according to national reference data [8], and was expressed as a height SD score (hSDS). All the patients
fulfilled other auxological criteria of qualifying to
GH assessment (including decreased height velocity and delayed bone age), according to current standards [9].
The diagnosis of GHD was based on decreased
GH secretion in 2 standard stimulating tests (i.e.
GH peak in both tests below 10 ng/mL) – one with
clonidine and the other with glucagon. Clonidine
was administered in a dose of 0.15 mg/m2, p.o.,
glucagon – in a dose of 30 μg/kg i.m. (not exceeding 1 mg). Blood samples for GH estimation
were collected every 30 min from 0 to 120 min in
the test with clonidine, and at 0, 90, 120, 150 and
180 min in the test with glucagon. The concentrations of GH were measured by the two-site chemiluminescent enzyme immunometric assay (hGH
IMMULITE, DPC) for the quantitative measurement of human GH, 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 coefficient of variation (CV) of 5.3–6.5% and the inter-assay CV of 5.5–6.2%. Both tests were performed in patients who were admitted to the hospital
at least one day before the test, fasting, in morning
hours. At least one-day interval was maintained
between the two different tests, performed during
the same evaluation. The diagnosis of neurosecretory dysfunction (NSD) was established in patients
Aims
The aim of the study was an assessment of the
increase of HV, IGF-I secretion and of the IGF-I/IGFBP-3 molar ratio in short children with GHD during the first year of GH therapy.
10
Hilczer M. et al. – First-year response to growth hormone (GH) therapy in GH-deficient children...
with normal GH secretion in stimulating tests, decreased basal IGF-I concentration and decreased
spontaneous nocturnal GH secretion.
In all the patients basal serum IGF-I and IGFBP-3
concentrations were assessed at 0 min of the first of
the two performed stimulating tests. Serum IGF-I
concentration was assessed by a solid-phase, enzyme-labelled chemiluminescent immunometric
assay, (IMMULITE, DPC), calibrated to WHO
NIBSC 1st IRR 87/518 standard, with analytical
sensitivity of 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 SD score (IGF-I SDS),
according to DPC reference data. Serum IGFBP-3
was assessed by a solid-phase, enzyme-labelled
chemiluminescent immunometric assay, (IMMULITE, DPC), calibrated to WHO NIBSC Reagent 93/
560 standard, with analytical sensitivity of 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 the 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.
The patients were divided into the following
groups: a) severe GHD (sGHD – GH peak in stimulating tests below 5 ng/mL), b) partial GHD
(pGHD – GH peak in stimulating tests between 5–10 ng/mL), c) neurosecretory dysfunction
(NSD – GH normal peak in stimulating tests, while below10 ng/mL at night, together with decreased
IGF-I concentration with respect to reference values for age and sex).
The therapy with GH in a dose of 0.18 ± 0.02 mg/
kg/week (mean ± SD) was performed for, at least, 1
year. In all the patients with multiple pituitary hormone deficiency, confirmed by appropriate diagnostic procedures, an appropriate substitutive therapy
was applied and continued together with GH application. Thyroid function was assessed before GH therapy and every 6 months. In all the patients free thyroxine concentration was within normal range.
After one year of GH therapy, patient’s height
was assessed again, together with measurement of
IGF-I and IGFBP-3 concentrations. The following
parameters were calculated and compared: height
velocity before the therapy and in the 1st year of treatment, IGF-I SDS and the IGF-I/IGFBP-3 molar
ratio before and after 1 year of treatment.
Statistical analysis included non-parametric tests:
Kruskall-Wallis’ test for independent samples for the
assessment of differences among the groups in particular time points and Wilcoxon’s test for dependent
samples for comparison of the same parameter in the
same group before GH therapy and after 1 year.
Results
There were no significant differences in any of
the analysed parameters among the groups, either
before the therapy or after 1 year, whereas in all the
groups, both HV and IGF-I secretion, as well as the
IGF-I/IGFBP-3 molar ratio, were significantly higher (p<0.0001) after 1 year of GH therapy than
before treatment. Normalisation of previously decreased IGF-I secretion, together with a more than
threefold increase of pretreatment HV, was observed in all the groups after 1 year of GH therapy.
The effectiveness of treatment was independent of
GH secretion in the stimulating tests.
Selected auxological data and height velocity in
particular groups of patients before GH therapy and
during the 1st year of therapy are presented in Table
I. Patients’ height velocity before GH therapy and in
the 1st year of treatment is compared in Figure 1. Secretion of IGF-I and the IGF-I/IGFBP-3 molar ratio
in particular groups of patients in the same time po-
Table I. Selected auxological data in particular groups of patients before GH therapy and after 1 year of treatment
Tabela I. Wybrane wskaźniki auksologiczne w poszczególnych grupach pacjentów przed leczeniem GH i po roku terapii
n
age [years]
hSDS
total
80
12.0 ± 2.3
sGHD
16
pGHD
NSD
HV [cm/year]
before GH therapy
in 1st year of therapy
-2.20 ± 0.60
3.4 ± 0.8a
11.0 ± 2.3a
10.7 ± 2.7
-2.53±0.78
3.4 ± 0.7b
11.4 ± 2.9b
49
12.4 ± 2.2
-2.10 ± 0.53
3.3 ± 1.0c
10.8 ± 2.2c
15
12.0 ± 1.7
-2.17 ± 0.51
3.5 ± 0.5d
11.2 ± 2.1d
a-d – significant differences (p < 0.0001)
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Endokrynol. Ped., 5/2006;1(14):9-14
Figure 1. Comparison of height velocity before GH therapy and
in 1st year of treatment in particular groups of patients
Rycina 1. Porównanie tempa wzrastania przed leczeniem
GH i w pierwszym roku terapii w poszczególnych grupach
pacjentów
ints is compared in Table II and illustrated in Figures 2 and 3.
No significant correlations were found between
the improvement of HV in the 1st year of GH therapy and either IGF-I secretion or the IGF-I/IGFBP-3
molar ratio (both before and during treatment).
In 6 patients (3 – with sGHD, 1 – with pGHD and
2 – with NSD), IGF-I SDS after 1 year of GH therapy was still below the normal range (i.e. below – 2.0).
Nevertheless, in all of them, the observed improvement of IGF-I secretion was considerable (IGF-I SDS
increase ranged from 0.63 to 2.65). The improvement
of HV was only slightly worse in that subgroup of patients than the parameter in question, observed in the
remaining patients (HV range: 3.3–3.8 cm/year before the therapy and 8.2–10.6 cm/year during 1st year
of treatment). In 5 patients (4 with sGHD and 1 with
NSD) IGF-I SDS after 1 year of GH therapy exceeded the upper limit of normal range (i.e. +2.0).
Table II. Serum IGF-I concentration and IGF-I/IGFBP-3 molar ratio in particular groups of patients
Tabela II. Stężenie IGF-I w surowicy i stosunek molowy IGF-I/IGFBP-3 w poszczególnych grupach pacjentów
IGF-I [SDS]
IGF-I/IGFBP-3
n
before
GH therapy
after 1 year
of GH therapy
before
GH therapy
after 1 year
of GH therapy
total
80
-2.40 ± 1.07a
0.40 ± 1.07a
0.22 ± 0.12e
0.47 ± 0.22e
sGHD
16
-2.71 ± 1.22b
0.34 ± 1.52b
0.22 ± 0.13f
0.48 ± 0.21f
pGHD
49
-2.37 ± 1.06c
0.48 ± 1.17c
0.23 ± 0.15g
0.50 ± 0.31g
NSD
15
-2.19 ± 0.94d
0.17 ± 1.40d
0.21 ± 0.09h
0.43 ± 0.17h
a-h – significant differences (p < 0.0001)
Figure 2. Comparison of IGF-I SDS before GH therapy and
after 1 year of treatment in particular groups of patients
Rycina 2. Porównanie wartości IGF-I SDS przed leczeniem
GH i po roku terapii w poszczególnych grupach pacjentów
12
Figure 3. Comparison of IGF-I/IGFBP-3 molar before GH therapy
and after 1 year of treatment in particular groups of patients
Rycina 3. Porównanie stosunku molowego IGF-I/IGFBP-3
przed leczeniem GH i po roku terapii w poszczególnych
grupach pacjentów
Hilczer M. et al. – First-year response to growth hormone (GH) therapy in GH-deficient children...
Discussion
The factors determining growth response to GH
therapy in GH-deficient children have not been precisely identified, so far. In the study of Cole et al.
[10], 10 factors including auxological data and GH
secretion have explained only 42% of the variance
of the 1st year growth response to GH therapy, however only 9.9% of total variance have been explained by GH peak in stimulating tests. Unfortunately, IGF-I and IGFBP-3 secretion has not been assessed in that study. The prediction model of Ranke et al. [11] explained 61% of the variation in the
1st year growth response to GH therapy. After exclusion of GH peak in stimulating tests from the model,
45% of the growth rate variation was still explained.
Moreover, the differences between the two models
were relevant only in cases with severe GHD. We
have documented similar growth response in all the
analysed groups of patients, independently from
either decreased or normal GH secretion in stimulating tests. However, in our study, the prediction
model was not performed due to too small number
of patients, including children in different stages of
puberty at therapy onset.
The data concerning the relationships between
an increase of IGF-I and IGFBP-3 and improvement of height velocity are not consistent. Kriström
et al. [12] have stated that 58% of the variation in
the 1st year growth response to GH therapy might
be explained by baseline serum levels of IGF-I and
IGFBP-3, together with IGF-I increase in response
to GH administration. Tillmann et al. [4] have not
confirmed the correlation between the growth rate
during GH therapy and IGF-I and IGFBP-3 concentrations. Lanes and Jakubowicz [13] have reported
the lack of correlation between an increase of IGF-I
secretion and improvement of HV in the patients
treated with GH. Recently, Ranke et al. [14] have
found a negative correlation between HV in the
initial phase of GH treatment and IGF-I SDS before
GH therapy together with the lack of correlation
between HV during the therapy and the increase of
IGF-I secretion. In our material no correlation has
been found between IGF-I and IGFBP-3 secretion
and HV during GH therapy. Moreover, both the
increase of IGF-I concentration and of the IGF-I/
IGFBP-3 ratio, as well as the improvement of HV
were similar in particular groups of patients, independently from either decreased or normal GH secretion in stimulating tests before the therapy onset.
In most of our patients the increase of IGF-I secretion during GH therapy led to the normalisation of
IGF-I serum concentration. However, in individual
cases, IGF-I concentration during the therapy did
not achieve the lower limit of normal range, while
in few other patients, it exceeded the upper limit
for age and sex. Similar were the observations of
Ranke et al. [15]. These observations speak for the
need of individualised GH dosing in children with
GHD. The increased IGF-I concentrations and the
IGF-I/IGFBP3 ratio (i.e. relatively high IGF-I and
low IGFBP-3 concentration) may be associated
with adverse effects, including cancer development
[4–6]. Individual dose adjustment may improve the
effectiveness of GH therapy [5], however, IGF-I
and IGFBP-3 gain during GH therapy have not
always been correlated with the improvement of
height velocity [16]. Moreover, in some patients
with high GH-sensitivity, smaller than routinely
applied GH doses may be sufficient [17]. Further
studies are required on the relationships among GH
dose, IGF-I secretion and growth rate [14, 16]. Our
analysis presented in this paper, was performed as a
retrospective study, therefore the doses of GH were
not adjusted with reference to IGF-I and IGFBP-3
secretion, as it was not a routine practice at that
time. The same problem has been reported in other
studies. Juul et al. have stated that, in most patients
with regularly measured IGF-I concentration during
GH therapy, the dose of GH has not been adjusted,
according to IGF-I level [18]. The authors postulate
standardization of therapeutic procedures in GHD,
including not only auxological evaluation but also
IGF-I assessment for GH dose adjustment.
In our opinion, individualising GH dose in children in order to maintain IGF-I and IGFBP-3 serum
concentrations within the normal range, seems to be
necessary.
The study was partially supported by funds from the Medical University of Lodz, project no. 502-11-185.
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