Early Human Development, 28 (1992) 105-I 10 Elsevier Scientific Publishers Ireland Ltd.

105

EHD 01217

Insulin-like growth factor-l and insulin-like growth factor binding protein-l in early human pregnancy N.C. Wathen,

H.S. Wang, P.L. Cass, D.J. Campbell

and T. Chard

Combined Academic Departments of Obstetrics, Gynaecology and Reproductive Physiology, Homerton Hospital and Saint Bartholomew’s Hospital, West Smithfield, London, EC IA (U.K.) (Received

25 September

1991; revision

received

18 December

1991; accepted

20 December

1991)

Summary

Insulin-like growth factor-l (IGF-1) and insulin-like growth factor binding protein-l (IGFBP-1) were measured in amniotic fluid, extraembryonic coelomic fluid and maternal serum from 23 women with apparently normal first trimester pregnancies prior to termination. The levels of IGF-1 and IGFBP-1 were significantly higher in coelomic fluid than amniotic fluid (IGF-1, P = 0.006; IGFBP-1, P = 0.0008 (paired c-test)). The levels of IGFBP-1 were lower in amniotic fluid than in maternal serum (P = 0.017), a finding in sharp contrast to the situation in the second and third trimesters of pregnancy. There was a significant relation between levels of IGF-1 and IGFBP-1 in amniotic fluid (r = 0.43; P = 0.04) and in coelomic fluid (I = 0.81; P c 0.001) but not in maternal serum. The finding that both the absolute levels of IGFBP-1 and the ratio to IGF-1 were low in amniotic fluid implies that there is a very high level of unbound, biologically active IGF-1 in this compartment in the first trimester. Thus, the regulatory role of IGFBP-1 may change as pregnancy advances. Key words: IGF-1; IGFBP-1; amniotic fluid; extraembryonic

coelom; first trimester

Introduction

The mechanisms controlling human fetal growth are poorly understood. Insulinlike growth factors (IGFs), their receptors and binding proteins may have an imporCorrespondence to: N.C. Wathen, Department Smithfield, London EClA 7BE, U.K.

0378-3782/92/$05.00 0 1992 Elsevier Scientific Printed and Published in Ireland

of Gynaecology,

Publishers

Ireland

Saint

Ltd.

Bartholomew’s

Hospital,

West

106

tant regulatory role in both the fetus [l] and the placenta [2]. In particular, insulinlike growth factor-l (IGF-1) is widely distributed in fetal tissues [3,4] and in the placenta [2]. The peptide is synthesised by tibroblasts and other tissues of mesenchymal origin [4]. It can be detected in fetal blood from the 15th week [5]; levels are low, rising slowly until approximately the 32nd week after which there is a two-fold increase up to term. Levels of IGF-1 are similar in arterial and venous cord serum suggesting that the human fetus synthesises its own IGF-1 [6] and that maternal production is independent. Maternal plasma levels increase during pregnancy, particularly in the third trimester [7,8]. In amniotic fluid, the levels of IGF-I remain the same throughout pregnancy [9]. In the circulation, IGF-1 is noncovalently bound to specific carrier proteins, the insulin-like growth factor binding proteins (IGFBPs). Most IGFBP-1 is synthesised in the decidualised endometrium [lO,l 11. Maternal serum IGFBP-1 levels increase rapidly during pregnancy and remain high until term [ 121. In the second and third trimesters, IGFBP-1 levels in amniotic fluid are lOO-lOOO-fold higher than those in maternal serum [13]. Apart from its function as a carrier protein in the circulation, IGFBP-1 also acts as a modulator of IGF-1 action at a cellular level [14-161. We now report concentrations of IGF-1 and IGFBP-1 in amniotic fluid, extraembryonic coelomic fluid and maternal serum between 8 and 12 weeks of normal pregnancy. The pattern of these compounds in amniotic fluid is totally different from that in late pregnancy. Materials and Methods Twenty-three women with uncomplicated singleton pregnancies in the first trimester gave informed consent for transvaginal ultrasound guided amniocentesis prior to termination of pregnancy under general anaesthesia. Consent was also obtained for the collection of 10 ml of maternal blood at the time of induction of anaesthesia. Transvaginal ultrasound was performed using an Aloka SSD-620 with a 5 MHz vaginal probe giving an effective 60” effective angle of view. Fetal viability was confirmed and the crown rump length (CRL) measured. Using the technique previously described by Wathen et al., 1991 [17], transvaginal amniocentesis was performed so as to obtain separately identified samples of amniotic fluid and extraembryonic coelomic fluid. All samples were stored at -20°C until assayed by radioimmunoassay for IGF-1 [6] and IGFBP-1 [12]. The protocol for this study was approved by the Ethics Committee, Saint Bartholomew’s Hospital, London. Results The concentrations of IGF-1 and IGFBP-1 in matched samples of amniotic fluid, extraembryonic fluid and maternal serum from 23 pregnancies at 8- 12 weeks gestation are shown in Table I and Figs. 1 and 2. Levels of IGF-1 and IGFBP-1 were higher in extraembryonic coelomic fluid than in amniotic fluid (IGF-1, P = 0.006; IGFBP-1, P = 0.0008 (paired t-test)). In amniotic fluid, levels of IGF-1 were higher

TABLE

I

The concentrations of IGF-I and IGFBP-1 in 23 matched coelomic fluid and serum at 8-12 weeks gestation. Amniotic fluid IGF-I (p&l) Median

samples

of amniotic

Extraembryonic coelomic fluid

273.0

364.0

fluid, extraembryonic

Serum

98.0

Range 10th centile 90th centile IGFBP-I (pg/l)

203.0-413.0 225.4 323.9

158.0-840.0 168.04 676.91

35.0-158.0 45.5 142.8

Median Range 10th centile 90th centile

1.5 5.0-270.0 5.0 89.7

500.0 11.0-3100.0 23.3 2440.0 I

17.0- 135.0 40.9 120.0

64.0

loo0

. . 500 .

7 + . .

:

-&-

:

i

IGF-1 f

I@

:

::

100

50

20

Amniotic fluid

Extra embryonic coelomic fluid

Serum

Fig. 1. Levels of IGF-I in 23 matched samples of amniotic fluid, extraembryonic maternal serum in the first trimester of pregnancy. The median levels are indicated

coelomic fluid and by horizontal bars.

108

300C

1OOC

. : -t

IGFBP-1 clsn

. .

.

. . :

.

0.

100 -

.

I

t ?

: : :

.

I .

10

Arnh~tic

Extra embryonic coelomic fluid

Serum

Fig. 2. Levels of IGFBP-1 in 23 matched samples of amniotic fluid, extraembryonic maternal serum in the first trimester of pregnancy. The median levels are indicated

coelomic fluid and by horizontal bars.

than in maternal serum (P < 0.0001); in contrast, amniotic fluid IGFBP-1 levels were lower than in maternal serum (P = 0.017). The ratio of median levels of IGF-l:IGFBP-1 in amniotic fluid was 36.4:1 and in extraembryonic coelomic fluid was 0.73:1. There was a significant linear correlation between levels of IGF-1 and IGFBP-1 in amniotic fluid (r = 0.43; p = 0.04) and in extraembryonic coelomic fluid (r = 0.81; P < 0.001). No correlation was found between levels of IGF-I and IGFBP-1 in maternal serum. Over the period of pregnancy investigated, there was

109

no relation between CRL and levels of IGF-1 or IGFBP-1 in amniotic fluid, extraembryonic coelomic fluid or maternal serum. Discussion

Little is known about the source or function of extraembryonic coelomic fluid in the human fetus. Here we show that both IGF-1 and IGFBP-1 levels are higher in extraembryonic coelomic fluid than in amniotic fluid, a phenomenon similar to that already observed with other placental and decidual products, namely human chorionic gonadotrophin [17], human placental lactogen and placental protein 14 (Wathen et al., unpublished data). The fact that levels of IGF-1 and IGFBP-1 are higher in coelomic fluid than amniotic fluid cannot be explained by any obvious anatomical relationship. It is possible that the difference might be due to differences in clearance rates in the two compartments. However, the concentrations of IGFBP-1 in both compartments are very low when compared with the second and third trimesters when levels in amniotic fluid are lOO-lOOO-fold higher than in maternal serum (131. Thus the synthesis of IGFBP-1 by the amnion and chorion which occurs in the second and third trimesters [ 181 may not occur in the first trimester. The finding that both the absolute levels of IGFBP-1 and the ratio to IGF-1 were notably low in amniotic fluid (Fig. 1 and Table I) may have considerable biological significance. This difference is even more striking when the results are expressed on a molar basis (median IGFBP-I level in amniotic fluid is 0.21 nmol/l; IGF-1 36 nmol/l). The growth promoting properties of IGF-1 are mediated via an autocrine or paracrine effect [2], i.e. they act at or close to their site of production. Moreover, IGFBP-1 has a modulating effect on IGF-1 at a cellular level [14,15], including the interface between the decidua and the placenta [16]. Thus the very low ratio of IGFBP-1 to IGF-1 in amniotic fluid samples implies that there is a very high level of unbound, biologically active IGF-1. This suggests that IGFBP-1 may have a specific regulatory role in the growth of the fetus or its surrounding membranes, the nature of which may change as pregnancy advances. References Chard, T. (1989): Review - Hormonal control of growth in the fetus, J. Endocrinol., 123, 3-9. Fant, M., Munro, H. and Moses, A.C. (1986): An autocrine/paracrine role for insulin-like growth factors in the regulation of human placental growth. J. Clin. Endocrinol. Metab., 63 (2), 499-505. Hill, D.J., Clemmons, D.R., Wilson, S., Han, V.K.N., Strain, A.J. and Milner, R.D.G. (1989): Immunological distributon of one form of insulin-like growth factor (IGF)-binding protein and IGF peptides in human fetal tissues. J. Mol. Endocrinol., 2, 31-38. Han, V.K.M., D’Ercole, A.J. and Lund, P.K. (1987): Cellular localisation of somatomedin (insulinlike growth factor) messenger RNA in the human fetus. Science, 236, 193-197. Ashton, I.K., Zapf, J., Einschenk, I. and MacKenzie, I.Z. (1985): Insulin like growth factors (IGF) I and 2 in human fetal plasma and relationship to gestational age and fetal size during midpregnancy. Acta. Endocrinol., 110, 558-563. Wang, H.S., Lim, J., English, J., Irvine, L. and Chard, T. (1991): The concentration growth factor-l and insulin-like growth factor binding protein-l in human umbilical delivery: relation to fetal weight. J. Endocrinol., 129, 459-464.

of insulin-like cord serum at

110 I

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9 10 11

12 13

14

15 16 17

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Wilson D.M., Bennet, A., Adamson, G.D., Nagashima, R.J., Liu, F., DeNatale, M.L., Hintz, R.L. and Rosentield, R.G. (1982): Somatomedins in pregnancy: A cross-sectional study of insulin-like growth factors 1 and 11 and somatomedin peptide content in normal human pregnancies. J. Clin. Endocrinol. Metab., 55 (3), 858-861. Wang, H.S., Perry, L.A., Kanisius, J., Iles, R.K., Holly, J.M.P. and Chard, T. (1991): Purification and assay of insulin-like growth factor binding protein-l: measurement of circulation levels throughout pregnancy. J. Endocrinol., 128, 161-168. Merimee, T.I., Grant, M. and Tyson, J.E. (1984): Insulin-like growth factors in amniotic fluid. J. Clin. Endocrinol. Metab., 59, 752-755. Rutanen, E.M., Menabawey, M., Isaka, K., Bohn, H. and Chard,T. (1986): Synthesis of placental protein 12 by decidua from early pregnancy. J. Clin. Endocrinol. Metab., 63, 675-679. Bell, SC. (1989): Decidualisation and insulin-like growth factors (IGF) binding protein: implication for its role in stromal cell differentiation and the decidual cell in haemochorial placentation. Hum. Reprod., 4, 125-130. Wang, H.S. and Chard, T. (1991): The role of insulin-like growth factor-l and insulin-like growth factor binding protein-l in the control of human fetal growth. J. Endocrinol., (in press). Rutanen, E-M., Hans, B. and Seppala, M. (1982): Radioimmunoassay of placental protein 12: levels in amniotic fluid, cord blood, and serum of healthy adults, pregnant women and patients with trophoblastic disease. Am. J. Obstet. Gynecol., 144 (4) 460-463., Ritvos, O., Ranta, T., Jalkanen, J., Suikkari, A., Voutilainen, R., Bohn, H. and Rutanen, E. (1988): Insulin-like growth factor (IGF) binding protein from human decidua inhibits the binding and biological action of IGF-1 in cultured choriocarcinoma cells. Endocrinology, 122 (3) 2150-2157. Elgin, R.E., Busby, W.H. and Clemmons, D.R. (1987): An insulin-like growth factor (IGF) binding protein enhances the biological response to IGF-1. Proc. Natl. Acad. Sci. U.S.A., 81, 3254-3258. Pekonen, F., Suikkari, A., Makinen, T. and Rutanen, E. (1988): Different insulin-like growth factor binding species in human placenta and decidua. J. Clin. Endocrinol. Metab., 67 (6), 1250-1257. Wathen, N.C., Cass, P.L., Kitau, M.J. and Chard, T. (1991): Human chorionic gonadotrophin and alphafetoprotein levels in matched samples of amniotic fluid, extraembryonic coelomic fluid and maternal serum in the first trimester of pregnancy. Prenat. Diagn., I 1, 145- 15 1. Rutanen, E-M., Koistinen, R., Wahlstrom, T., Bohn, H. and Seppala, M. (1984): The content of placenta protein 12 in decidua and fetal membranes is greater than placenta. Br. J. Obstet. Gynaecol., 9 I, 1240-44.

Insulin-like growth factor-1 and insulin-like growth factor binding protein-1 in early human pregnancy.

Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-1 (IGFBP-1) were measured in amniotic fluid, extraembryonic coelom...
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