0021-972X/05/$15.
00/0 The Journal of Clinical Endocrinology & Metabolism 90(4):2270 –2274
Printed in U.S.A.
Fetal Insulin-Like Growth Factor (IGF)-I, IGF-II, and
Ghrelin in Association with Birth Weight and Postnatal
Growth in Monozygotic Twins with Discordant Growth
Bettina C. Gohlke, Agnes Huber, Kurt Hecher, Rolf Fimmers, Peter Bartmann, and Christian L. Roth
Departments of Pediatrics (B.C.G., C.L.R.), Statistics (R.F.), and Neonatology (P.B.), University of Bonn, 53113 Bonn,
Germany; and Department of Obstetrics and Fetal Medicine (A.H., K.H.), University Clinic Hamburg-Eppendorf,
20246 Hamburg, Germany
Objective: To investigate the relative contribution of genetic
(fetal) vs. environmental (maternal/placental) factors on
growth, we studied monozygotic twins with intertwin birth
weight difference.
Patients and Methods: Twenty-seven twins (15 with discor-
dant growth) who have been treated for severe twin-to-twin
transfusion syndrome by laser coagulation were studied.
Cord blood samples were analyzed for IGF-I, IGF-II, IGF-bind-
ing protein-2, and ghrelin. Intertwin difference (⌬) of birth
weight was correlated to ⌬ of the parameters analyzed. The ⌬
weight after 1 yr was correlated with ⌬ birth weight and all
hormones.
Results: The ⌬ birth weight was positively correlated with
⌬ IGF-I (r ⴝ 0.66; P < 0.0002) and negatively correlated with ⌬
I N MONOCHORIONIC TWIN pregnancies, there are pla-
cental vascular communications between the two fetuses.
In 15% of such pregnancies, there is an imbalance in net flow
between the twins resulting in the twin-twin-transfusion
syndrome (TTTS). The donor becomes hypovolemic, hypo-
tensive, and oliguric, which leads to oligo/anhydramnios
and growth restriction. The recipient, who usually is appro-
priate for gestational age, becomes hyervolemic, hyperten-
sive, and polyuric, leading to polyhydramnios and conges-
tive heart failure (1). With recent advancements in diagnostic
and therapeutic modalities in fetal medicine, the survival rate
of chronic TTTS has improved from less than 10 to 68% (2– 4).
Endoscopic coagulation of the vascular anastomoses respon-
sible for fetofetal transfusion (3, 4) performed during the
second trimenon is a causal treatment option.
Intrauterine growth is regulated by fetal as well as ma-
ternal and environmental factors. Little is known of their
relative contribution and importance because singleton stud-
ies are limited in this regard. Several studies of singleton
pregnancies have shown that various hormones are associ-
ated with birth weight. However, singleton studies fail to
address the question of whether alterations in fetal nutrition
leading to impaired birth weight are due to disturbance in
First Published Online February 1, 2005
Abbreviations: ⌬, Differences; AGA, appropriate birth weight;
IGFBP, IGF binding protein; MZ, monozygotic; SGA, small for gesta-
tional age; TTTS, twin-twin-transfusion syndrome.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the en-
docrine community.
2270
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Copyright © 2005 by The Endocrine Society
doi: 10.1210/jc.2004-1192
IGF-binding protein-2 levels (r ⴝ ⴚ0.68; P < 0.001) but with
neither ⌬ IGF-II nor ⌬ ghrelin. There was a strong intertwin
correlation for all hormones. By comparing the growth in the
first year, we found an overall reduction of the relative weight
difference between the twins of 57%. ANOVA was used to cal-
culate factors for prediction of postnatal catch-up growth.
Besides the birth weight difference (R2 ⴝ 0.84; P < 0.0001), only
ghrelin was of prognostic value for postnatal catch-up growth
(R2 ⴝ 0.94; P ⴝ 0.0035).
Conclusion: These data confirm the importance of IGF-I in
contrast to IGF-II for fetal weight. Additionally, ghrelin seems
to be involved in fetal and probably postnatal growth. (J Clin
Endocrinol Metab 90: 2270 –2274, 2005)
placental transport or in fetal hormone function. Our study
population recruited only monozygotic (MZ) but hemody-
namically dichorionic twins with discordant birth weight.
MZ twinning is a powerful clinical model because of the
identical genetical background, the same maternal nutrition,
and only the individual differences for the fetal environment.
Therefore, they are an excellent model to study the interac-
tion between genetic and environmental factors and their
effects on fetal growth (5, 6).
The IGFs are involved in the regulation of growth during
pregnancy as well as in early embryonic and fetal develop-
ment. In most studies, cord blood IGF-I but not IGF-II con-
centrations correlate with birth weight (7–11). In contrast,
others have shown normal IGF-I (12, 13) and reduced IGF-II
levels in singleton intrauterine growth retardation fetuses
(14, 15). There are only a few studies in twins with interpair
variation in birth weight. Studies in concordant twins sug-
gest that fetal circulating IGF-I levels may be genetically
determined (16).
Ghrelin is a peptide predominantly produced by the stom-
ach, hypothalamus, and adipose tissue (17, 18). It displays
strong GH-releasing action (19). In addition, ghrelin is also
actively synthesized by the placenta (20) and can be detected
in cord blood at 30 wk gestational age, which indicates that
it may play a role in fetal development (21–23). Its various
endocrine and nonendocrine actions have been subjects of
recent scientific work (24). Previous studies indicate that
ghrelin levels are influenced by acute and chronic feeding
state, with increase by fasting and energy restriction (25, 26)
but decrease by food intake and glucose (27–29).
 Gohlke et al. • Fetal IGF-I, -II, and Ghrelin in Monozygotic Twins J Clin Endocrinol Metab, April 2005, 90(4):2270 –2274 2271

In the present study, we measured IGF-I, IGF-II, IGF bind-
ing protein (IGFBP)-2, and ghrelin concentrations in cord
blood in MZ monochorionic twins and examined its rela-
tionship to birth weight and growth after 1 yr of life.
Patients and Methods
Patients
Twenty-seven women with monochorionic MZ twin pregnancies and
TTTS were studied. The diagnosis of TTTS was made by the combination
of single monochorionic placenta, polyhydramnios and oligohydram-
nios, stuck-twin, and an initial diagnosis before 25 wk gestation. These
fetuses were treated by means of laser coagulation between 17 and 25
wk gestation. All the fetuses were delivered in the local referring
hospital.
Fifteen twin pairs presented with discordant growth [birth weight
difference ⬎ 15%, one twin being small for gestational age (SGA, birth
weight ⬍ ⫺2 sd for gestational age), the other appropriate birth weight
(AGA)], and 12 twin pairs were concordant concerning their growth
(AGA-AGA). All twins were measured regularly at 2, 4, 6, and 12 months
of age. Nineteen twin pairs who were older than 1 yr were analyzed
concerning their postnatal growth.
Collection of samples
Fetal cord blood was obtained from each twin from the umbilical
venous blood from clamped segment of cord at the birth. The samples
were centrifuged, and serum was stored at ⫺70 C until a batch assay was
performed. Informed consent for collection of cord blood samples was
obtained from all parents. The study protocol was approved by the local
ethics committee.
Immunoassays
All hormone concentrations were measured by radioimmunometric
assays using commercially available kits (Mediagnost, Reutlingen, Ger-
many). IGF-I (nanograms per milliliter) was measured by RIA after
employing excess IGF-II to saturate IGFBPs. The detection limit was 0.02
ng/ml. IGF-II (nanograms per milliliter) was measured after separation
from IGFBP by acid chromatography according to Blum and Breier (30).
The detection limit was 0.1 ng/ml. The sensitivity of the IGFBP-2 assay
was 0.2 ng/ml. Interassay variances were 7.4 (IGF-I), 7.9 (IGF-II), and
9.6% (IGFBP-2), respectively. Intraassay variances were 5.6 (IGF-I), 5.4
(IGF-II), and 8.5% (IGFBP-2), respectively. Immunoreactive ghrelin con-
centrations were measured in duplicate using a commercial RIA (Linco
Research, Inc., St. Charles, MO). The antibody used in the assay is a
rabbit polyclonal antibody against full-length octanoylated human
ghrelin. Intra- and interassay coefficients of variation were 3.3 and
17.8%, respectively.
Statistical analysis
Clinical data and hormone concentrations are expressed as medians
and ranges. Delta values (⌬) indicate differences between the twins. For
parametric data, the paired t test was used to compare values within
twin pairs and Student’s t test between groups. Spearman correlation
was calculated between relative intertwin birth weight difference (per-
cent) and ⌬ of the hormones. The percent growth discordance was
defined as the difference in birth weight expressed as a proportion of the
birth weight of the larger twin. Intertwin difference of IGF-I, IGF-II,
IGFBP-2, and ghrelin was expressed in ⌬. Statistical analysis was per-
formed by the SAS system (SAS Institute, Cary, NC). Multiple linear
regression analysis was used to calculate the predictors for weight dif-
ference at birth and after 1 yr.
Results
Comparison of anthropometric data and cord hormone
levels between the discordant SGA-AGA (n ⫽ 15) and con-
cordant AGA-AGA (n ⫽ 12) groups is shown (Table 1). The
birth weight of the AGA twin in the discordant group was
comparable with that of the concordant twin pairs.
IGF-I
In the discordant group, fetal IGF-I concentrations in SGA
twins were significantly lower than those in the AGA cotwin
(P ⬎ 0.01) (Table 1). No difference was observed in the
concordant group (P ⫽ 0.76). Spearman correlation coeffi-
cient (r) between ⌬ birth weight and ⌬ IGF-I was 0.66 (P ⬍
0.001) (Fig. 1A).
IGF-II
Fetal IGF-II levels in recipient and donor twins in both
groups were comparable (P ⫽ 0.79 for discordant twins, P ⫽
0.4 for concordant twins; Table 1). Spearman correlation co-
efficient (r) ⌬ birth weight to ⌬ IGF-II difference was ⫺0.08
(P ⫽ 0.71; Fig. 1B).
IGFBP-2
In the discordant group, fetal IGFBP-2 concentrations in
SGA twins were significantly higher than those in the AGA
cotwin (P ⬍ 0.01; Table 1). Spearman correlation coefficient
(r) of ⌬ birth weight to ⌬ IGFBP-2 was ⫺0.68 (P ⬍ 0.001). The
⌬ IGFBP-2 levels were significantly correlated to ⌬ IGF-I (r ⫽
⫺0.5; P ⫽ 0.01) but not to ⌬ IGF-II.
Ghrelin
Spearman correlation coefficient showed a negative but
not significant correlation between ⌬ birth weight and ⌬
ghrelin levels (r ⫽ ⫺0.39, P ⫽ 0.10).
Correlations among study hormones and between twin pairs
We examined univariate correlations among study hor-
mones and found IGF-I to be negatively correlated to

TABLE 1. Median and range of study anthropometric indices and hormones in the discordant and in the concordant group

Discordant group (n ⫽ 15) Concordant group (n ⫽ 12)

SGA-donor AGA-recipient P AGA-donor AGA-recipient P
Gestational age at 34 (31–38) 36 (32–37)
delivery (wk)
Birth weight (g) 1600 (710 –2280) 2130 (1330 –2900) ⬍0.01 2040 (1410 –2890) 2110 (1410 –3060) 0.76
IGF-I (ng/ml) 35 (6 – 81) [19.5] 65 (25–93) [20.9] ⬍0.002 43 (13–70) [16.4] 49 (9 –58) [15.6] 0.79
IGF-II (ng/ml) 296 (165– 415) [49] 302 (198 – 406) [63.3] 0.79 298 (250 – 454) [58.2] 291 (205–398) [49.2] 0.4
IGFBP-2 (ng/ml) 1250 (566 –2684) [696.1] 855 (513–1332) [263.2] ⬍0.01 827 (650 –3457) [1195.7] 873 (563–3457) [738.4] 0.54
Ghrelin (ng/ml) 1109 (660 –1701) [338.8] 1060 (870 –1916) [270] 0.06 1109 (836 –2696) [626] 1055 (921–3234) [830] 0.43
Data expressed as median (range) [SD].

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 2272 J Clin Endocrinol Metab, April 2005, 90(4):2270 –2274 Gohlke et al. • Fetal IGF-I, -II, and Ghrelin in Monozygotic Twins

TABLE 2. Spearman correlation coefficient between the various

study hormones

⌬ Birth
⌬ IGF-I ⌬ IGF-II ⌬ IGFBP-2 ⌬ Ghrelin
weight
⌬ Birth weight 1.000 0.67 ⫺0.08 ⫺0.68 ⫺0.39
P ⫽ 0.0002 P ⫽ 0.71 P ⫽ 0.001
⌬ IGF-I 1.000 0.26 ⫺0.53 ⫺0.17
P ⫽ 0.2 P ⫽ 0.015
⌬ IGF-II 1.000 ⫺0.14 0.05
P ⫽ 0.81
⌬ Ghrelin 1.000

twins with discordant weight at birth did not show a sig-

nificant reduction of relative weight difference.
ANOVA revealed a strong correlation between relative
weight difference, at the age of 1 yr to (⌬ 1 yr) and relative
birth weight difference (R2 ⫽ 0.84; P ⬍ 0.0001) (Fig. 4). Step-
wise regression showed that the only factor with a further
association to weight difference at 1 yr was ⌬ ghrelin level
(R2 ⫽ 0.94; P ⬍ 0.0035).

FIG. 1. A, Correlation between percent birth weight difference and

intertwin difference of IGF-I (⌬ IGF-I) levels in cord blood (n ⫽ 27) (r ⫽
0.66; P ⬍ 0.001). Correlation line and 95% confidence interval are
shown. B, Correlation between percent birth weight difference and
intertwin difference of IGF-II (⌬ IGF-II) levels in cord blood (n ⫽ 27)
(r ⫽ ⫺0.08; P ⫽ 0.71). Correlation line and 95% confidence interval
are shown.

IGFBP-2 (r ⫽ ⫺0.53; P ⬍ 0.01). There was no correlation

among the other hormones at birth. Table 2 shows Spearman
correlation coefficients among all measured hormones.
For all hormones a highly significant intertwin correlation
was found (IGF-I and IGF-II are shown, Fig. 2, A and B).

Longitudinal data
Nineteen twin pairs were analyzed concerning their post-
natal weight and length development, and an overall reduc-
tion of 57.1% of relative weight difference was observed.
Single data are shown in Fig. 3. Three of the nine pairs of
FIG. 2. Correlation for IGF-I levels (r ⫽ 0.49; P ⬍ 0.009) (A) and
IGF-II levels (r ⫽ 0.58; P ⬍ 0.0014) (B) among all 27 twin pairs is
shown.

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 Gohlke et al. • Fetal IGF-I, -II, and Ghrelin in Monozygotic Twins
FIG. 3. Relative weight difference of all twin pairs at birth, 2 months,
4 months, 6 months, and 1 yr. Circles represent the pairs of twins with
concordant birth weight (⬍10%, n ⫽ 10), triangles those with discor-
dant birth weight (difference ⬎ 15%, n ⫽ 9)
Discussion
Based on our data of IGF-I, IGF-II, IGFBP-2, and ghrelin in
venous cord blood from MZ monochorionic twins with birth
weight difference, the following conclusions can be drawn.
In accordance with most published data (7–11) and in
contrast to Bajoria et al. (5), we found a strong correlation of
IGF-I levels and birth weight. Among the group of discor-
dant twins, the normally grown twin, in all but one case, had
significantly higher cord serum IGF-I levels than the growth-
restricted cotwin. There was no significant intertwin differ-
ence in the cord blood IGF-I levels in the concordant twin
pairs. These data demonstrate that IGF-I is important in the
FIG. 4. Correlation between weight difference at 1 yr and birth
weight difference only of all twins (R2 ⫽ 0.84, P ⬍ 0.0001). Correlation
line and 95% confidence interval are shown.
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J Clin Endocrinol Metab, April 2005, 90(4):2270 –2274 2273
regulation of fetal growth, and its mechanism appears to be,
at least in part, through an endocrine action. There is also
evidence that the weight difference between twins suffering
from chronic TTTS cannot be explained only by the transfer
of blood and nutrients along the placental vascular anasto-
moses. Although all our patients had a laser coagulation of
the connecting vessels, more than half of the twins presented
with discordant birth weight.
In addition, we found a strong intertwin correlation for
IGF-I for all twin pairs, confirming the underlying genetic
influence on the IGF-I level (31).
In IGF-II a strong intertwin correlation was found, but it
was not related to fetal weight or length in our study pop-
ulation. IGF-II may play a role as a fetal somatomedin during
earlier periods of human intrauterine life.
IGFBP-2 is one of the major IGFBPs in the fetus (32). It is
known to correlate negatively to birth weight, indicating an
antagonistic regulatory mechanism for the effect of IGF. Al-
ternatively, IGFBP-2 levels might be up-regulated in the
presence of low IGF-I levels. In disease states it has been
shown that if IGF-I levels were suppressed, IGFBP-2 levels
were elevated (33).
Umbilical cord blood concentrations of ghrelin were in-
versely related to birth weight. This is in accordance with
very recent data demonstrating that cord ghrelin concentra-
tions were higher in SGA neonates, compared with AGA/
large-for-gestational-age neonates (22, 23, 34). A similar in-
verse relationship is found in patients with anorexia nervosa
having higher and obese patients having lower ghrelin levels
than controls (25, 26, 29). We cannot add information about
change of ghrelin concentrations throughout gestation due to
our small patient numbers.
The source(s) of circulating ghrelin in fetuses remains un-
clear. It could originate from the placenta (20), the stomach
(17), or other fetal organ tissues (35) that are known to syn-
thesize ghrelin during early fetal life. Our study population
recruited only MZ but hemodynamically dichorionic twins
after laser coagulation. We suggest that the SGA fetus itself
had developed a compensatory mechanism to the negative
energy balance, and the increased ghrelin level would be an
indication of an adaptive response.
The most important predictor for catch-up growth be-
tween the discordant twin pairs was the relative weight
difference at birth, a greater difference at birth being asso-
ciated with greater weight difference after 1 yr. Although
IGF-I was positively associated with birth weight, it was not
of additional prognostic value for the weight development
during the first year of life. Further information was received
only by including intertwin difference of ghrelin. SGA twins
with a high ghrelin concentration had a better chance for
catching up of weight after 1 yr. We suggest that higher
ghrelin concentrations remained high throughout the first
year of life, leading to an increased appetite and different
satiety regulation in those patients followed by rapid post-
natal catch-up growth. This is in accordance with recent
findings of Iniguez et al. (36). They observed a significantly
smaller glucose-induced drop in ghrelin concentrations in
1-yr-old infants born SGA who had experienced catch-up
growth, compared with those who had not, and proposed
 2274 J Clin Endocrinol Metab, April 2005, 90(4):2270 –2274
that higher postprandial ghrelin concentrations may have
resulted in greater weight gain early in life.
In conclusion, our data confirm the importance of IGF-I vs.
IGF-II for fetal weight development, although IGF-I levels
were significantly higher in the AGA twin, compared with
the SGA cotwin, whereas these levels were similar in the
AGA twin pairs. Furthermore, this demonstrates the strong
contribution of the uterine environment for IGF-I. However,
a significant intertwin correlation was found for both growth
factors, showing also the genetic influence on IGF-I and -II.
Furthermore, our data show that ghrelin is negatively cor-
related to birth weight difference with higher levels in the
lighter twin. Birth weight difference was the strongest predictor
for weight difference after 1 yr, but prediction of catch-up
growth was dependent on ghrelin levels with high cord blood
ghrelin associated with improved catch-up growth than lower
levels. These data confirm the importance of both genetic and
intrauterine factors in early human development.
Acknowledgments
The authors are grateful to E. Maslak for her excellent technical
assistance in the laboratory.
Received June 22, 2004. Accepted January 21, 2005.
Address all correspondence and requests for reprints to: Dr. B.
Gohlke, Zentrum für Kinderheilkunde, der Universität Bonn, Adenauer-
allee 119, 53113 Bonn, Germany. E-mail: gohlke-bonn@t-online.de.
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