860
Vol. 12, 860 – 865, September 2003
Cancer Epidemiology, Biomarkers & Prevention
Determinants and Consequences of Major Insulin-like Growth Factor
Components among Full-Term Healthy Neonates
Alkistis Skalkidou,1 Eleni Petridou, Evgenia Papathoma,
Heraklis Salvanos, Simos Kedikoglou, Georgios Chrousos,
and Dimitrios Trichopoulos
Department of Hygiene and Epidemiology, Athens University Medical School
[A. S., E. P., S. K., D. T.] and First Department of Pediatrics, ‘Ag. Sofia’
Children’s Hospital [G. C.], Athens University Medical School, Athens;
Department of Epidemiology, Harvard School of Public Health, Boston,
Massachusetts 02115 [E. P., D. T.]; Department of Neonatology, ‘Alexandra’
Maternity Hospital, Athens [E. P.]; and Department of Neonatology, ‘Marika
Iliadi’ Maternity Hospital, Athens, Greece [H. S.]
Abstract
The purpose of this research was to investigate
determinants of the insulin-like growth factor (IGF)
system among healthy full-term newborns and explore
their relation with anthropometric variables at birth.
Components of the IGF system have been implicated in
the pathogenesis of several forms of cancer, and perinatal
events have been linked to chronic diseases in later life.
Measurements of weight and length, as well as blood
samples, were obtained from 331 healthy full-term
newborns delivered during 1999 in Athens, Greece.
Because the liver is important for IGF production,
newborns were chosen to have bilirubin levels either <8
mg/dl or >12 mg/dl to operationally distinguish them
according to the liver function. IGF-I, IGF-II, and IGF
binding protein-3 were inversely associated with the
presence of neonatal jaundice and blood creatinine, after
controlling for blood protein levels. IGF-I increased
rapidly and significantly over a period of a few days and
was strongly positively associated with both birth weight
and ponderal index. Newborn levels of IGF-I declined
with maternal age. In comparison with first-born
newborns, later-born ones had significantly higher blood
IGF-I levels. We conclude that IGF-I plays a dominant
role in growth during the perinatal period and that all
three studied components of the IGF system are sensitive
to liver and kidney function. These findings provide an
insight into the processes involved in perinatal growth.
Introduction
The IGF2 system plays an important role in the regulation of
cellular proliferation, differentiation, apoptosis, and transfor-
Received 12/30/02; revised 6/2/03; accepted 6/6/03.
The costs of publication of this article were defrayed in part by the payment of
page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1
To whom requests for reprints should be addressed, at Department of Hygiene
and Epidemiology Athens University Medical School, 75 Mikras Asias, Goudi,
Athens 115-27, Greece. Phone: 30-210-746-2105; Fax: 30-210-777-3840; E-mail:
[email protected].
2
The abbreviations used are: IGF, insulin-like growth factor; IGFBP, insulin-like
growth factor binding protein; IRMA, immunoradiometric assay.
mation (1, 2). Components of the IGF system include the
polypeptide ligands IGF-I and IGF-II, which exert their actions
through the interaction with two types of cell membrane receptors, i.e., IGF-IR and IGF-IIR (3), under the regulation of six
binding proteins, i.e., IGFBP-1 through IGFBP-6 (4). IGF-I is
a peptidic growth factor implicated in the proliferation of a wide
variety of cell types (5); IGF-II has similar physiological properties
to those of IGF-I but plays a crucial role during fetal life (6).
Major components of the IGF system in blood have been
associated with cancers of the prostate (7–9), breast (10), colon
(11, 12), lung (13), and with leukemia (14), and a role for IGF-I
in the etiology of these diseases has been postulated. Accumulating epidemiological evidence suggests that individuals with
IGF-I levels in the “high normal” range have increased risk of
common cancers relative to individuals with levels in the “low
normal” range (15). Evidence from in vitro and animal studies
suggests that overexpression of IGF components by cancer cells
may play a significant role in establishing a transformed phenotype in an increasing number of malignancies (16 –20). More
specifically, components of the IGF system may promote cell
cycle progression and inhibition of apoptosis either by directly
associating with other growth factors or indirectly by interacting with other molecular systems, which have an established
role in carcinogenesis and cancer promotion, such as the steroid
hormones and integrins (18). Dietary and other factors may
influence cancer risk via their effects on serum insulin concentrations and on the bioavailability of IGF-I (19). IGF-I has also
been associated with increased cancer cell survival after chemotherapeutic treatment, through inhibition of apoptosis (21).
At the same time, evidence has been accumulated over the role
of intrauterine and perinatal events and conditions in the etiology of such malignancies as childhood leukemia (22, 23),
breast cancer (24, 25), and even prostate cancer (26).
The purpose of this study was to establish the role of IGF-I
and IGF-II in pre- and perinatal growth of full-term newborns
and to examine their relation to indices of hepatic and renal
function. We determined the serum levels of IGF-I, IGF-II, and
IGFBP-3 in a large group of well-characterized full-term newborns delivered in the Greater Athens region in Greece. Because in pilot studies we observed that IGF-I was inversely
associated with serum bilirubin levels, we chose full-term newborns without clinical jaundice and blood bilirubin levels ⱕ8
mg/dl, or others with clinical jaundice and serum bilirubin
levels ⱖ12 mg/dl. We also measured serum creatinine concentrations in all of the newborns as an index of renal function.
Materials and Methods
During the 1999 calendar year, ⬃10,000 newborns were delivered in the two departments of Obstetrics and Gynecology of
the University of Athens teaching hospitals. These hospitals
mostly admit lower income women from Greece, as well as
from Albania, Poland, Bulgaria, and other eastern European
countries.
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Cancer Epidemiology, Biomarkers & Prevention
To be eligible for the study, a newborn had to be full term
(gestation period ⱖ37 weeks), of Caucasian origin, with a birth
weight of ⱖ2500 g, and apparently healthy, i.e., without serious
signs of disease, need for a neonatal Intensive Care Unit, or
need of a blood transfusion. Newborns were distinguished to
those who were clearly jaundiced (bilirubin ⱖ12 mg/dl) and
clearly nonjaundiced (bilirubin ⱕ8 mg/dl); newborns with intermediate bilirubin levels were not included in this study to
avoid misclassification. In addition, the mother should not
suffer from any chronic disease, such as malignancy, connective tissue disorder, diabetes mellitus (unless it was gestation
related), anemia (unless it was gestation related), major neuropsychiatric disorders (e.g., epilepsy and psychoses), chronic
renal failure, peptic ulcer, ulcerative colitis, bronchial asthma
requiring treatment, or chronic infectious diseases, including
hepatitis B and C. Finally, to secure proper informed consent,
the mother had to be able to communicate adequately in Greek.
The study protocol has been approved by the University of
Athens Medical School Ethical Committee.
All of the eligible newborns that were delivered while two
of the authors (E. P. and H. S.) were the neonatologists on call,
and whose mothers consented to study participation, were enrolled in the study. A total of 60 newborns or their mothers
failed to satisfy the inclusion criteria and were excluded from
the analysis (32 for biomedical exclusion criteria and 28 because they were unable to communicate in Greek or English
and/or explicitly indicate their consent). An additional 243
newborns with bilirubin levels between 8 and 12 mg/dl were
not included in the study to reduce misclassification. Thus,
completed maternal questionnaires as well as infant blood samples were eventually obtained for a total of 331 newborns.
Although it seems to be no apparent circadian or diurnal variation of IGF levels (27), all of the samples were received in
conjunction with routine morning blood taking and no later than
the fifth day of life for bilirubin measurements and/or the
nationally mandated screening for hypothyroidism, phenylketonouria, and G6PD deficiency.
Blood samples were obtained from all of the eligible newborns for masked measurements of the major IGF system components examined in this study (IGF-I, IGF-II, and IGFBP-3), as
well as of renal and liver function variables. IGF-I was run on the
Nichols Advantage Automated Specially System (Nichols Institute, San Juan Capistrano, CA). The sensitivity of the assay is 6
ng/ml. IGF-II was determined by using the DSL-2600 ACTIVE
Non-Extraction Insulin-Like Growth Factor-II Coated-Tube
IRMA kit. The procedure uses a two-site IRMA. The DSL-2600
ACTIVE IGF-II IRMA includes a simple extraction step in which
IGF-II is separated from its binding protein in serum. The IRMA
is a noncompetitive assay in which the analyte to be measured is
“sandwiched” between two antibodies. The sensitivity of the procedure is 12 ng/ml. IGFBP-3 concentrations (in ␮g/ml) were
measured using a commercially available radioimmunoassay kit
(IGFBP-3100T kit; Nichols Institute, San Juan Capistrano, CA).
During a single incubation period radiolabeled IGFBP-3 competes
with unlabeled IGFBP-3 in the test sample, the standards, and the
controls for a limited number of specific antibody binding sites. A
standard curve is prepared using this dose-response relationship,
and test sample and control concentrations are read from the curve.
The sensitivity of the assay is 0.0625 ␮g/ml. No cross-reactivity
with IGF-II, proinsulin, insulin, thyrotropin, or luteinizing hormone was detected.
The data were analyzed through multiple regression.
Log transformation of IGF-I, IGF-II, and IGFBP-3 was
necessary when these measurements were used as dependent
variables to assure approximate symmetry and, thus, appli-
Table 1 Distribution of 331 newborns by selected demographic, biological,
and social variables, and by presence of jaundice (Athens, 1999/two
university obstetrics departments)
Jaundiced
Nonjaundiced
Variable
Maternal age
⬍25 years
25–34
35⫹
Maternal education
ⱕ9 years
10–12
13–15
16⫹
Ethnic group
Greek or European Union
Other
Maternal body mass index
(before pregnancy)
⬍21 kg/m2
21–24
25⫹
Maternal smoking
(during pregnancy)
No
Yes
Newborn gender
Female
Male
Gestational age
37 weeks
38
39
40
41⫹
Birth order
First
Other
Length
⬍49 cm
49–50.9
51–52.9
53–54.9
55⫹
Birth weight
⬍2750 g
2750–2999
3000–3249
3250–3499
3500–3749
3750⫹
Day blood sample was drawn
⬍3 days
3
4
5
Total
n
%
n
%
66
111
32
31.6
53.1
15.3
39
70
13
32.0
57.4
10.6
73
77
26
33
34.9
36.9
12.4
15.8
37
52
17
16
30.4
42.6
13.9
13.1
122
87
58.4
41.6
70
52
57.4
42.6
62
92
55
29.7
44.0
26.3
50
48
24
41.0
39.3
19.7
176
33
84.2
15.8
84
38
68.9
31.1
82
127
39.2
60.8
78
44
63.9
36.1
31
64
58
48
8
41.8
30.6
27.8
23.0
3.8
11
35
37
31
8
9.0
28.7
30.3
25.4
6.6
130
79
32.2
37.8
73
49
59.8
40.2
27
75
58
36
13
12.9
35.9
27.8
17.2
6.2
8
22
50
34
8
6.6
18.0
41.0
27.9
6.5
18
29
53
43
39
27
8.6
13.9
25.4
20.6
18.6
12.9
16
12
19
33
22
20
13.1
9.8
15.6
27.1
18.0
16.4
6
98
101
4
209
2.9
46.9
48.3
1.9
100.0
1
39
81
1
122
0.8
32.0
66.4
0.8
100.0
cability of parametric techniques. A consequence of the log
transformation is that the adjusted regression coefficients
can be expressed in proportional (percentage) changes of
the dependent variable for a specified increment in each
independent variable.
Results
Table 1 shows the distribution of 331 full-term newborns by
selected demographic and biosocial variables, and presence of
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861
862
Role of the IGF System in Perinatal Growth
Table 2
Mean values (M) and SE of perinatal characteristics and selected compounds of the IGF-system by gender of the newborns and presence of jaundice
Gender
Bilirubin (in mg/dl)
Characteristic
Boys
ⱕ8
M
Maternal age (year)
26.8
Maternal BMI (kg/m2)
23.2
Length (cm)
52.5
Birth weight (gr)
3495
Total blood proteins (g/dl)
6.36
IGF-I (ng/ml)
27.45
IGF-II (ng/ml)
491.7
IGFBP-3 (␮g/ml)
0.81
a
(SE)
Girls
ⱖ12
M
(SE)
(0.79)
27.8
(0.64)
22.9
(0.28)
51.2
(63.1)
3371
(0.10)
5.91
(2.06)
22.99
(13.48) 436.9
(0.05)
0.70
(0.76)
(0.37)
(0.21)
(39.2)
(0.05)
(0.89)
(9.06)
(0.04)
P
ⱕ8
a
M
0.37
28.5
0.75
22.3
0.002
51.2
0.10
3230
0.0001
6.36
0.05
30.07
0.001 500.9
0.10
0.98
(SE)
Total
ⱖ12
M
(SE)
(1.12)
28.5
(0.41)
23.4
(0.23)
50.4
(48.0)
3176
(0.08)
5.95
(1.50)
25.45
(11.57) 437.2
(0.08)
0.76
P
(0.61)
(0.40)
(0.25)
(37.2)
(0.06)
(1.15)
(11.52)
(0.07)
ⱕ8
a
M
(SE)
0.96
27.9
0.05
22.6
0.02
51.7
0.38
3325
0.0001
6.36
0.01
29.13
0.0001 497.6
0.03
0.92
M
ⱖ12
(SE)
(0.77) 28.1
(0.35) 23.1
(0.18) 50.9
(39.7) 3295
(0.06)
5.93
(1.22) 23.96
(8.83) 437.0
(0.05)
0.72
(0.52)
(0.27)
(0.16)
(28.6)
(0.04)
(0.71)
(7.11)
(0.04)
Pa
0.85
0.25
0.003
0.52
0.0001
0.0003
0.0001
0.002
P derived from t test, contrasting mean values of the indicated characteristics between newborns with and without jaundice, within sex group.
jaundice. These results mostly serve descriptive purposes. The
high proportion of newborns with clinical jaundice (63.1%) is
the result of intentional selection, whereas the relatively high
prevalence of maternal smoking during pregnancy (21.5%) is
an unfortunate but well-known phenomenon among Greek
women. Among the jaundiced children, 87 were subsequently
submitted to phototherapy. Table 2 shows mean values and SEs
of some maternal and neonatal variables, as well as of the IGF
hormones by gender and presence of jaundice in the newborn.
There is a statistically significant inverse association between
blood bilirubin levels and the levels of both IGF-I and IGF-II in
all infants (boys: P ⫽ 0.05 for IGF-I and P ⫽ 0.001 for IGF-II,
girls: P ⫽ 0.01 for IGF-I and P ⫽ 0.0001 for IGF-II). In
addition, length and total blood protein levels are inversely
associated with the existence of jaundice and bilirubin levels
(boys: P ⫽ 0.002 for length and P ⫽ 0.0001 for blood protein
levels, girls: P ⫽ 0.02 for length and P ⫽ 0.0001 for blood
protein levels).
Tables 3–5 show mutually adjusted proportional
changes of IGF-I (Table 3), IGF-II (Table 4), and IGFBP-3
(Table 5) per indicated increments of the independent variables. Because changes in IGF-I and IGF-II are controlled
for the IGFBP-3 values, the findings of the regression analyses reasonably approximate the corresponding changes of
the unbound, biologically active, free compounds of these
hormones. As expected, there are strong positive associations of both IGF-I and IGF-II with IGFBP-3 (P ⫽ 0.0001
and P ⫽ 0.004, respectively).
The data in Tables 3–5 show that the presence of jaundice
is inversely associated with the values of both IGF-I and IGF-II
(P ⫽ 0.06 and P ⫽ 0.002, respectively). There is also a
statistically significant positive association of birth weight and
ponderal index (birth weight over the cube of the birth length)
with the value of IGF-I (P ⫽ 0.0001 and P ⫽ 0.04, respectively). The respective associations for IGF-II are not statistically
significant. In addition, high levels of creatinine are strongly
associated with low levels of IGF-I and IGF-II (P ⫽ 0.0001 and
P ⫽ 0.003, respectively). With respect to IGFBP-3, the observed pattern in Table 5 reflects the positive association of this
compound with both IGF-I and IGF-II (P ⫽ 0.0001 and P ⫽
0.004, respectively).
Of the 331 women included in the study, 8 have developed
gestational diabetes, and among their newborns 6 were jaundiced and 2 nonjaundiced. Our primary intention was not to
exclude these women, because of the uncertainty surrounding
the role of gestational diabetes in the processes underlying the
studied associations. Nevertheless, inclusion of gestational diabetes in the models presented in Tables 3–5 did not reveal any
significant or suggestive association of this condition with
Table 3 Multiple regression-derived estimates of change, percent, of IGF-I
per indicated increment of predictor variables and corresponding 95% CI
among 331 studied newborns
Variable
Maternal age
Maternal BMI (before
pregnancy)
Maternal smoking
(during
pregnancy)
Gender
Gestational age
Birth order
Total blood proteins
Creatinine
Jaundice
Days from birth to
blood draw
IGFBP-3
Category or Proportional
increment change (%)
⬍25 years
25–34
35⫹
4 kg/m2
9.6
Baseline
⫺14.9
⫺2.4
No
Baseline
Yes
Female
Male
1 week
First
Other
1 g/dl
1 mg/dl
Yes
No
1 day
5.5
Baseline
⫺6.3
2.3
Baseline
10.2
4.1
⫺69.3
⫺8.7
Baseline
9.7
1 SD
18.6
95% CI (%)
P
(two tailed)
⫺0.5
20.8
0.06
⫺25.1
⫺7.7
⫺3.4
3.2
0.01
0.38
⫺4.8
16.9
0.31
⫺13.9
⫺1.5
2.1
6.3
0.14
0.24
0.7
⫺2.8
⫺78.6
⫺17.0
20.6
11.5
⫺55.9
0.4
0.04
0.25
0.0001
0.06
4.1
15.7
0.0006
10.1
27.7
0.0001
Additionally introduced variables
Model 1
Birth weight
250 g
Model 2
Length
1 cm
Model 3
Birth ponderal index 1 kg/m3
Model 4
Length
1 cm
Birth ponderal index 1 kg/m3
6.5
3.4
9.7
0.0001
1.8
⫺0.1
3.8
0.06
1.4
0.03
2.9
0.04
4.2
3.1
1.9
1.4
6.5
4.8
0.0004
0.0003
IGF-I, IGF-II, or IGFBP-3, nor did it affect to a noticeable
extent the other regression coefficients in the respective models. We have also added in the models indicated in Tables 3–5
weight gain during pregnancy. A 5-kg increment in weight gain
was associated with an increase of 3.7% of IGF-I, 1.2% of
IGF-II, and 6.7% for IGFBP-3; however, none of these differences was statistically significant nor did the introduction of
weight gain into the models depicted in Tables 3–5 substantially affect the other regression coefficients in the respective
models.
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Cancer Epidemiology, Biomarkers & Prevention
Table 4 Multiple regression-derived estimates of change, percent, of IGF-II
per indicated increment of predictor variables and corresponding 95% CI
among 331 studied newborns
Category or Proportional
increment change (%)
Variable
Maternal age
Maternal BMI (before
pregnancy)
Maternal smoking
(during pregnancy)
Gestational age
Birth order
Total blood proteins
Creatinine
Jaundice
Days from birth to
blood draw
IGF BP-3
P
(two tailed)
1.3
⫺4.8
7.9
0.68
Maternal age
Baseline
3.5
⫺0.3
⫺4.7
⫺3.9
12.4
3.3
0.42
0.86
No
Baseline
Maternal BMI (before
pregnancy)
Maternal smoking
(during pregnancy)
1 SD
7.4
⫺6.8
6.5
0.91
Gender
⫺4.9
⫺0.8
6.2
4.2
0.86
0.18
Gestational age
Birth order
0.23
0.002
0.003
0.002
Total blood proteins
Creatinine
Jaundice
⫺9.0
2.3
2.7
12.3
⫺44.6 ⫺11.5
⫺14.7 ⫺3.6
⫺0.9
6.1
0.15
2.3
12.7
0.004
Additionally introduced variables
Model 1
Birth weight
Model 2
Length
Model 3
Birth ponderal index
Model 4
Length
Birth ponderal index
Variable
⬍25
years
25–34
35⫹
4 kg/m2
Yes
⫺0.4
Female Baseline
Male
0.5
1 week
1.7
First
Baseline
Other
⫺3.5
1 g/dl
7.4
1 mg/dl ⫺30.0
Yes
⫺9.3
Baseline
1 day
2.5
Gender
95% CI (%)
Table 5 Multiple regression-derived estimates of change, percent, of IGFBP-3
per indicated increment of predictor variables and corresponding 95% CI
among 331 studied newborns
250 g
1.65
⫺0.31
3.65
0.10
1 cm
0.4
⫺0.83
1.65
0.52
1 kg/m3
0.5
⫺0.42
1.39
0.29
1 cm
1 kg/m3
1.1
0.9
⫺0.38
⫺0.16
2.59
2.02
0.15
0.09
Discussion
We have evaluated levels of IGF-I, IGF-II, and IGFBP-3 in
relation to physiological parameters of the newborn. In some of
these relationships, the studied factors are likely to affect the
levels of the IGF components, whereas in others the IGF system
may be responsible for changes in the variables under investigation. Although an attempt is made to assess the direction of
causality, the emphasis is in the interpretability of the findings
from a clinical point of view.
Among the variables that are likely to affect the levels of
the studied IGF components, maternal age is inversely associated with the levels of IGF-I. There are several reports indicating that the levels of IGF-I among adults decline with age (28,
29), and it is likely that the lower values of IGF-I among
newborns with older mothers is a reflection of this phenomenon. It is of interest that no pattern of decline with maternal age
is evident for IGF-II, whereas the nonsignificant decline with
maternal age for IGFBP-3 is brought about by the corresponding reduction of IGF-I, because these two biochemical variables
are strongly correlated.
There is a suggestion that firstborn children, in comparison
to later born children, have lower levels of IGF-I, but similar
levels of IGF-II and IGFBP-3. In a previously reported study,
correlations between serum IGF components and size at birth
were stronger in nonprimiparous than in primiparous pregnancies (30). Moreover, even within a few days after birth, IGF-I
is increasing sharply with age, ⬃10% per day, whereas no
Days from birth to
blood draw
Category or Proportional
increment change (%)
⬍25 years
25–34
35⫹
4 kg/m2
12.6
Baseline
⫺14.6
4.0
No
Baseline
Yes
Female
Male
1 week
First
Other
1 g/dl
1 mg/dl
Yes
No
1 day
9.1
Baseline
⫺8.8
6.8
Baseline
5.2
14.4
⫺60.1
⫺18.6
Baseline
0.5
95% CI (%)
P
(two tailed)
⫺4.8
33.0
0.16
⫺31.5
⫺5.5
6.4
14.4
0.16
0.43
⫺8.5
30.2
0.33
⫺21.3
0.01
5.6
14.1
0.22
0.05
⫺10.0
1.7
⫺78.4
⫺30.8
22.8
28.7
⫺26.4
⫺4.2
⫺8.2
10.1
0.91
0.52
0.02
0.003
0.01
Additionally introduced variables
Model 1
Birth weight
250 g
Model 2
Length
1 cm
Model 3
Birth ponderal index 1 kg/m3
Model 4
Length
1 cm
Birth ponderal index 1 kg/m3
5.98
0.65
11.6
0.03
3.5
0.1
6.9
0.04
⫺0.03
⫺2.4
2.4
0.98
5.0
1.9
0.9
⫺0.9
9.2
4.9
0.02
0.19
similar trend is evident with respect to IGF-II and IGFBP-3
(31). As it has been reported in earlier studies (32, 33), boys
have lower levels of IGF-I and IGFBP-3 than girls, although in
our investigation the differences have not reached statistical
significance.
The positive association between total blood proteins and
the three studied IGF components, which was significant for
IGF-II and IGFBP-3, may be a reflection of variable hemoconcentration. In contrast, the strong inverse associations between
the three studied components on the one hand and bilirubin and
creatinine levels on the other, are likely to reflect underlying
pathophysiologic processes, impaired liver and kidney function, respectively. Because IGF-I is mainly produced in the
liver, its reduction may signal transient or permanent hepatic
malfunction as it has also been reported in the adult (34). With
respect to the kidney, the fact that IGF-I is not only produced
in this organ, but also contributes to its development, provides
biological plausibility to our findings (35). It is of interest that
the total serum protein was significantly lower in the jaundiced
group, as has been reported previously (36).
The IGF system is crucial for growth and this is reflected
in the strong association of IGF-I with birth weight, ponderal
index and birth length. The pattern of associations, presented in
Tables 3–5, confirm that IGF-I is more important than IGF-II or
IGFBP-3 with respect to growth during the perinatal period.
The effect of IGF-I concerns both length and ponderal index at
birth. Several earlier investigations have pointed out the positive association between IGF-I and birth weight (37– 41). The
positive association between IGF-I and birth length has been
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863
864
Role of the IGF System in Perinatal Growth
evaluated in fewer investigations and was generally reported as
weaker than the relation between IGF-1 and birth weight
(40, 41).
Among the advantages of the present investigation are the
use of standardized methods for both biochemical and clinical
measurements, and restriction of the study to healthy full-term
newborns, a process that minimizes the influence of confounding factors that may be involved in prematurity or prenatal
pathology. The study was moderately large because of cost
constraints, but earlier investigations of similar objectives were
generally of smaller size (38, 42). The study subjects were
Greek women of lower income or migrant women from eastern
European countries, but results were virtually identical among
Greek and other women and did not change when educational
status was controlled for.
In conclusion, our study design in a relatively large sample
of healthy full-term newborns allowed us to document a dominant role of IGF-I in pre- and perinatal growth. Moreover, our
study points out that liver dysfunction and kidney immaturity
are reflected in reduced levels of all three of the studied components of the IGF system. These findings provide an insight
into the processes involved in perinatal growth and point out a
possible pathophysiological link between perinatal events and
conditions, and adult life diseases, notably cancer.
References
1. Valentinis, B., and Baserga, R. IGF-I receptor signalling in transformation and
differentiation. Mol. Pathol., 54: 133–137, 2001.
2. Niesler, C. U., Urso, B., Prins, J. B., and Siddle, K. IGF-I inhibits apoptosis
induced by serum withdrawal, but potentiates TNF-␣-induced apoptosis, in
3T3–L1 preadipocytes. J. Endocrinol., 167: 165–174, 2000.
3. Rechler, M. M., and Nissley, S. P. Insulin-like growth factor (IGF)/somatomedin receptor subtypes: structure, function, and relationships to insulin receptors
and IGF carrier proteins. Horm. Res., 24: 152–159, 1986.
4. Collett-Solberg, P. F., and Cohen, P. Genetics, chemistry, and function of the
IGF/IGFBP system. Endocrine, 12: 121–136, 2000.
5. Laron, Z. Insulin-like growth factor 1 (IGF-1): a growth hormone. Mol.
Pathol., 54: 311–316, 2001.
6. Lighten, A. D., Hardy, K., Winston, R. M., and Moore, G. E. Expression of
mRNA for the insulin-like growth factors and their receptors in human preimplantation embryos. Mol. Reprod. Dev., 47: 134 –139, 1997.
7. Cohen, P. Serum insulin-like growth factor-I levels and prostate cancer riskinterpreting the evidence. J. Natl. Cancer Inst., 90: 876 – 879, 1998.
8. Chan, J. M., Stampfer, M. J., Giovannucci, E., Gann, P. H., Ma, J., Wilkinson,
P., Hennekens, C. H., and Pollak, M. Plasma insulin-like growth factor-I and
prostate cancer risk: a prospective study. Science (Wash. DC), 279: 563–566,
1998.
9. Wolk, A., Mantzoros, C. S., Andersson, S. O., Bergstrom, R., Signorello,
L. B., Lagiou, P., Adami, H. O., and Trichopoulos, D. Insulin-like growth factor
1 and prostate cancer risk: a population-based, case-control study. J. Natl. Cancer
Inst., 90: 911–915, 1998.
10. Hankinson, S. E., Willett, W. C., Colditz, G. A., Hunter, D. J., Michaud,
D. S., Deroo, B., Rosner, B., Speizer, F. E., and Pollak, M. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet, 351:
1393–1396, 1998.
11. Manousos, O., Souglakos, J., Bosetti, C., Tzonou, A., Chatzidakis, V.,
Trichopoulos, D., Adami, H. O., and Mantzoros, C. IGF-I and IGF-II in relation
to colorectal cancer. Int. J. Cancer, 24: 15–17, 1999.
12. Ma, J., Pollak, M. N., Giovannucci, E., Chan, J. M., Tao, Y., Hennekens,
C. H., and Stampfer, M. J. Prospective study of colorectal cancer risk in men and
plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3.
J. Natl. Cancer Inst., 91: 620 – 625, 1999.
13. Yu, H., Spitz, M. R., Mistry, J., Gu, J., Hong, W. K., and Wu, X. Plasma
levels of insulin-like growth factor-I and lung cancer risk: a case-control study.
J. Natl. Cancer Inst., 91: 151–156, 1999.
14. Petridou, E., Dessypris, N., Spanos, E., Mantzoros, C., Skalkidou, A., Kalmanti, M., Koliouskas, D., Kosmidis, H., Panagiotou, J. P., Piperopoulou, F.,
Tzortzatou, F., and Trichopoulos, D. Insulin-like growth factor-I and binding
protein-3 in relation to childhood leukaemia. Int. J. Cancer, 80: 494 – 496, 1999.
15. Burroughs, K. D., Howe, S. R., Okubo, Y., Fuchs-Young, R., LeRoith, D.,
and Walker, C. L. Dysregulation of IGF-I signaling in uterine leiomyoma. J.
Endocrinol., 172: 83–93, 2002.
16. Wang, Y. Z., and Wong, Y. C. Sex hormone-induced prostatic carcinogenesis
in the noble rat: the role of insulin-like growth factor-I (IGF-I) and vascular
endothelial growth factor (VEGF) in the development of prostate cancer. Prostate,
35: 165–177, 1998.
17. Norstedt, G., Levinovitz, A., Moller, C., Eriksson, L. C., and Andersson, G.
Expression of insulin-like growth factor I (IGF-I) and IGF-II mRNA during
hepatic development, proliferation and carcinogenesis in the rat. Carcinogenesis
(Lond.), 9: 209 –213, 1988.
18. Moschos, S. J., and Mantzoros, C. S. The role of the IGF system in cancer:
from basic to clinical studies and clinical applications. Oncology, 63: 317–332,
2002.
19. Sandhu, M. S., Dunger, D. B., and Giovannucci, L. Insulin, insulin-like
growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and
colorectal cancer. J. Natl. Cancer Inst., 94: 972–980, 2002.
20. Rosen, C. J., and Pollak, M. Circulating IGF-I: New Perspectives for a New
Century. Trends Endocrinol. Metab., 10: 136 –141, 1999.
21. Dunn, S. E., Hardman, R. A., Kari, F. W., and Barrett, J. C. Insulin-like
growth factor 1 (IGF-1) alters drug sensitivity of HBL100 human breast cancer
cells by inhibition of apoptosis induced by diverse anticancer drugs. Cancer Res.,
57: 2687–2693, 1997.
22. McKinney, P. A., Juszczak, E., Findlay, E., Smith, K., and Thomson, C. S.
Pre-and perinatal risk factors for childhood leukaemia and other malignancies: a
Scottish case control study. Br. J. Cancer, 80: 1844 –1851, 1999.
23. Cnattingius, S., Zack, M. M., Ekbom, A., Gunnarskog, J., Linet, M., and
Adami, H. O. Prenatal and neonatal risk factors for childhood lymphatic leukemia. J. Natl. Cancer Inst. 87: 908 –914, 1995.
24. Michels, K. B., Trichopoulos, D., Robins, J. M., Rosner, B. A., Manson, J. E.,
Hunter, D. J., Colditz, G. A., Hankinson, S. E., Speizer, F. E., and Willett, W. C.
Birthweight as a risk factor for breast cancer. Lancet, 348: 1542–1546, 1996.
25. Sanderson, M., Williams, M. A., Malone, K. E., Stanford, J. L., Emanuel, I.,
White, E., and Daling, J. R. Perinatal factors and risk of breast cancer. Epidemiology, 7: 34 –37, 1996.
26. Ekbom, A., Hsieh, C. C., Lipworth, L., Wolk, A., Ponten, J., Adami, H. O.,
and Trichopoulos, D. Perinatal characteristics in relation to incidence of and
mortality from prostate cancer. BMJ, 313: 337–341, 1996.
27. Daughaday, W. H., and Rotwein, P. Insulin-like growth factors I and II.
Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr. Rev., 10: 68 –91, 1989.
28. Maccario, M., Ramunni, J., Oleandri, S. E., Procopio, M., Grottoli, S.,
Rossetto, R., Savio, P., Aimaretti, G., Camanni, F., and Ghigo, E. Relationships
between IGF-I and age, gender, body mass, fat distribution, metabolic and
hormonal variables in obese patients. Int. J. Obes. Relat. Metab. Disord., 23:
612– 618, 1999.
29. Lukanova, A., Toniolo, P., Akhmedkhanov, A., Hunt, K., Rinaldi, S., Zeleniuch-Jacquotte, A., Haley, N. J., Riboli, E., Stattin, P., Lundin, E., and Kaaks, R.
A cross-sectional study of IGF-I determinants in women. Eur. J. Cancer Prev., 10:
443– 452, 2001.
30. Ong, K., Kratzsch, J., Kiess, W., Costello, M., Scott, C., and Dunger, D. Size
at birth and cord blood levels of insulin, insulin-like growth factor I (IGF-I),
IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and the soluble IGF-II/
mannose-6-phosphate receptor in term human infants. The ALSPAC Study Team.
Avon Longitudinal Study of Pregnancy and Childhood. J. Clin. Endocrinol.
Metab., 85: 4266 – 4269, 2000.
31. Orbak, Z., Darcan, S., Coker, M., and Goksen, D. Maternal and fetal serum
insulin-like growth factor-I (IGF-I) IGF binding protein-3 (IGFBP-3), leptin
levels and early postnatal growth in infants born asymmetrically small for
gestational age. J. Pediatr. Endocrinol. Metab., 14: 1119 –1127, 2001.
32. Maffeis, C., Moghetti, P., Vettor, R., Lombardi, A. M., Vecchini, S., and Tato,
L. Leptin concentration in newborns’ cord blood: relationship to gender and growthregulating hormones. Int. J. Obes. Relat. Metab. Disord., 23: 943–947, 1999.
33. Garnett, S., Cowell, C. T., Bradford, D., Lee, J., Tao, C., Petrauskas, V., Fay,
R., and Baur, L. A. Effects of gender, body composition and birth size on IGF-I
in 7- and 8-year-old children. Horm. Res., 52: 221–229, 1999.
34. Stuver, S. O., Kuper, H., Tzonou, A., Lagiou, P., Spanos, E., Hsieh, C. C.,
Mantzoros, C., and Trichopoulos, D. Insulin-like growth factor 1 in hepatocellular
carcinoma and metastatic liver cancer in men. Int. J. Cancer, 87: 118 –121, 2000.
35. Doublier, S., Amri, K., Seurin, D., Moreau, E., Merlet-Benichou, C., Striker,
G. E., and Gilbert, T. Overexpression of human insulin-like growth factor binding
protein-1 in the mouse leads to nephron deficit. Pediatr. Res., 49: 660 – 666, 2001.
36. Oski, F. A. Physiologic jaundice. In: W. H. Tauesch, R. A. Ballard, and
M. H. Avery (eds.) Schauffer and Avery’s Diseases of the Newborn, Ed. 6, pp.
753–757. Philadelphia: W. B. Saunders Company, 1991.
Downloaded from cebp.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer Research.
Cancer Epidemiology, Biomarkers & Prevention
37. Christou, H., Connors, J. M., Ziotopoulou, M., Hatzidakis, V., Papathanassoglou, E., Ringer, S. A., and Mantzoros, C. S. Cord blood leptin and insulin-like
growth factor levels are independent predictors of fetal growth. J. Clin. Endocrinol. Metab., 86: 935–938, 2001.
38. Ochoa, R., Zarate, A., Hernandez, M., Galvan, R., and Basurto, L. Serum
leptin and somatotropin components correlate with neonatal birth weight. Gynecol. Obstet. Investig., 52: 243–247, 2001.
39. Vatten, L. J., Odegard, R. A., Nilsen, S. T., Salvesen, K. A., and Austgulen,
R. Relationship of insulin-like growth factor-I and insulin-like growth factor
binding proteins in umbilical cord plasma to preeclampsia and infant birth weight.
Obstet. Gynecol., 99: 85–90, 2002.
40. Yang, S. W., and Kim, S. Y. The relationship of the levels of leptin,
insulin-like growth factor-I and insulin in cord blood with birth size, ponderal
index, and gender difference. J. Pediatr. Endocrinol. Metab., 13: 289 –296, 2000.
41. Yang, S. W., and Yu, J. S. Relationship of insulin-like growth factor-I,
insulin-like growth factor binding protein-3, insulin, growth hormone in cord
blood and maternal factors with birth height and birthweight. Pediatr. Int., 42:
31–36, 2000.
42. Coutant, R., Boux de Casson, F., Douay, O., Mathieu, E., Rouleau, S.,
Beringue, F., Gillard, P., Limal, J. M., and Descamps, P. Relationships between
placental GH concentration and maternal smoking, newborn gender, and maternal
leptin: possible implications for birth weight. J. Clin. Endocrinol. Metab., 86:
4854 – 4859, 2001.
Downloaded from cebp.aacrjournals.org on June 17, 2017. © 2003 American Association for Cancer Research.
865
Determinants and Consequences of Major Insulin-like
Growth Factor Components among Full-Term Healthy
Neonates
Alkistis Skalkidou, Eleni Petridou, Evgenia Papathoma, et al.
Cancer Epidemiol Biomarkers Prev 2003;12:860-865.
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