Antenatal dexamethasone therapy and insulin-like growth factor binding protein-1. Table I. Plasma ... potentiation of the mitogenic effects of insulin-like growth.
Human Reproduction vol.13 no.6 pp.1714–1716, 1998
Antenatal dexamethasone therapy does not affect circulating concentrations of insulin-like growth factor binding protein-1
O.Ogueh1,3, F.A.Hills2, T.Chard2 and M.R.Johnson1 1Section
of Obstetrics and Gynaecology, Imperial College School of Medicine at Chelsea and Westminster Hospital, London and 2Reproductive Physiology Laboratory, St Bartholomew’s Hospital, West Smithfield, London, UK 3To
whom correspondence should be addressed at: Section of Obstetrics and Gynaecology, Imperial College School of Medicine at Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK
In animals, dexamethasone administration during pregnancy leads to fetal growth restriction due to enhanced expression of insulin-like growth factor binding protein-1 (IGFBP-1). In humans, there is also a significant inverse correlation between maternal and fetal concentrations of IGFBP-1 and birth weight. During pregnancy, maternal IGFBP-1 is derived from the decidualized endometrium. We have studied the effect of dexamethasone on circulating concentrations of IGFBP-1 in 12 pregnant women who received dexamethasone therapy for fetal lung maturation in anticipation of premature delivery before 34 completed weeks of gestation. Blood samples were collected before dexamethasone administration, at 24 h and 48 h after the course of dexamethasone, and within 24 h of delivery, for the measurement of IGFBP-1. There was no significant change in plasma IGFBP-1 concentrations at 24 and 48 h following dexamethasone therapy, and at delivery (P J 0.666, 0.307 and 0.398, respectively). Therefore, antenatal dexamethasone therapy does not influence decidual synthesis of IGFBP-1. Key words: decidua/dexamethasone/insulin-like growth factor binding protein-1
Introduction It is now well established that administering corticosteroids prior to preterm delivery reduces the incidence of respiratory distress syndrome in the new-born (Liggins and Howie, 1972; Crowley, 1995). The efficacy of neonatal surfactant therapy is also enhanced by antenatal exposure to corticosteroids and there is an associated reduction in the risk of intravascular haemorrhage, necrotizing enterocolitis, neonatal hyperbilirubinaemia and neonatal death (Sinclair, 1994). Therefore, most pregnant women are now given corticosteroids whenever preterm delivery is anticipated. In animals, dexamethasone administration during pregnancy leads to fetal growth restriction due to the enhanced expression of insulin-like growth factor binding protein-1 (IGFBP-1; Price et al., 1992). IGFBP-1 is thought to modulate the paracrine 1714
influence of insulin-like growth factor I (IGF-I) on placental growth and nutrient uptake (Fant et al., 1986), and so to reduce fetal growth (Rutanen et al., 1988; Wang and Chard, 1992). During pregnancy in the human, maternal IGFBP-1 is derived mostly from the decidualized endometrium (Rutanen et al., 1985, 1988). A significant inverse correlation between maternal and fetal concentrations of IGFBP-1 and birth weight has been identified with concentrations being significantly higher in the presence of fetuses that are small for gestational age or in whom there is intrauterine growth restriction (Wang et al., 1991; Hills et al., 1996; Ostlund et al., 1997). Given the animal evidence suggesting that dexamethasone enhances circulating concentrations of IGFBP-1 and leads to growth restriction, this study was performed to examine the effect of antenatal dexamethasone, given to induce fetal lung maturation, on maternal circulating concentrations of IGFBP1. This was thought to be a justifiable investigation in humans given the current trend for repeated administration of dexamethasone, which may have an effect on fetal growth.
Materials and methods A longitudinal study was performed on 12 pregnant women who received dexamethasone therapy for fetal lung maturation in anticipation of premature delivery before 34 completed weeks of gestation, but who were not in labour. The obstetric problems that threatened premature birth were preterm rupture of membranes (n 5 4) and antepartum haemorrhage due to placenta praevia (n 5 4) and of unknown origin (n 5 4). These women served as their own controls. A standard regimen of dexamethasone (David Bull Laboratories, Mulgrave, Victoria, Australia) that comprised two doses of 12 mg intramuscular injections at 12 h intervals was administered to all women. The number of women (n 5 12) was chosen on the basis of an earlier study by Miell et al. (1993) who reported a mean baseline serum IGFBP-1 concentration of 42.9 6 8.2 µg/l, and demonstrated that it fell by a mean difference of 14.9 µg/l following short-term dexamethasone administration; this was statistically significant (P , 0.001; Miell et al., 1993). Power calculations showed that a study demonstrating a comparable difference would require a total group size of 10 with an α of 0.05 and a β of 0.2. All women gave informed consent to the study, which was approved by the Riverside Research Ethics Committee. Blood samples were collected before starting the dexamethasone therapy, at 24 and 48 h after completing therapy, and within 24 h of delivery. The samples were collected between 0800 and 2200 to avoid the nocturnal peak of circulating IGFBP-1 (Baxter and Cowell, 1987). Samples were centrifuged at 1560 g for 30 mins to separate plasma, which was stored at –20°C until analysed in a single batch. Measurement of IGFBP-1 was as described by Wang et al. (1991). Statistical analysis was performed using the Statistics Package for Social Sciences (SPSS). Changes in IGFBP-1 levels from pre-therapy values were © European Society for Human Reproduction and Embryology
Antenatal dexamethasone therapy and insulin-like growth factor binding protein-1
Table I. Plasma levels of insulin-like growth factor binding protein-1 before and after dexamethasone therapy Two-tailed P value (Z value)a
Mean (range) Pre-therapy (a)
Post 24 h (b)
Post 48 h (c)
At delivery (d)
a versus b
a versus c
a versus d
178.75 (44–422)
171.83 (53–430)
206.25 (46–339)
250.29 (159–430)
0.666 (0.431)
0.307 (1.019)
0.398 (0.845)
aWilcoxon
matched-pairs signed-ranks test.
assessed by Wilcoxon matched-pairs signed-ranks test separately for each post-therapy stage.
Results The mean (6 SD) age of subjects was 33.2 6 5.3 (range 24– 40) years; parity ranged from zero to four. The median gestational age at administration of the first dose of dexamethasone was 29 (range 23–33) weeks. The median gestational age at delivery was 34 (range 25–41) weeks, with a median interval between dexamethasone therapy and delivery of 18 (range 2– 117) days. The mean birth weight was 2.345 6 0.859 kg and the mean birth weight percentile was 60 6 26. There was no significant change in plasma concentrations of IGFBP-1 at 24 and 48 h following dexamethasone therapy, and at delivery (P 5 0.666, 0.307 and 0.398, respectively) (Table I). Discussion Serum concentrations of IGFBP-1 increase rapidly during pregnancy and reach a peak at 12–13 weeks of gestation; thereafter they remain high but without significant change until term (Wang et al., 1991; Hills et al., 1996). The bulk of the maternal circulating IGFBP-1 in pregnancy is believed to result from synthesis by the decidualized endometrium (Rutanen et al., 1985; Bell, 1989). IGFBP-1 is thought to act systemically, or locally, to modulate the mitogenic actions of IGF-1 on placental growth and secondarily on fetal growth (Wang and Chard, 1992). Indeed, Miell et al. (1997) assessed IGFBP-1 concentrations in early pregnancy in maternal serum and embryological fluid, and found maternal serum to contain mainly phosphorylated isoforms of IGFBP-1 whereas IGFBP1 in coelomic fluid was almost exclusively non-phosphorylated. Phosphorylated IGFBP-1 is inhibitory to the bioactivity of IGF-1 (Jones et al., 1991, 1993), hence, these data suggest a mechanism whereby circulating maternal IGFBP-1 suppresses fetal growth. The presence of significant quantities of nonphosphorylated IGFBP-1 in coelomic fluid would allow potentiation of the mitogenic effects of insulin-like growth factors (IGF) in the early human gestational sac (Miell et al., 1997). Price and colleagues (1992) administered a daily intraperitoneal injection of 100 µg dexamethasone for 5 days to rats, beginning on gestational day 15 (term 5 22 days), and showed fetal concentrations of IGFBP-1 to be significantly higher than in controls. They concluded that increased IGFBP-1 concentrations may be important in the aetiology of dexamethasone-induced fetal growth retardation (Price et al., 1992). In
the present study we have demonstrated that dexamethasone administered to pregnant women in whom premature delivery is anticipated does not affect maternal concentrations of IGFBP-1, possibly due to the relatively shorter duration and lower dosage of dexamethasone administration than was used by Price et al. (1992). Miell and colleagues (1993) studied the effect of short-term dexamethasone treatment on the serum concentrations of IGF and their binding proteins in men, and showed suppression of IGFBP-1 concentrations after dexamethasone administration. They suggested that this effect was due to a dexamethasoneinduced rise in insulin levels, as IGFBP-1 concentrations are known to be inversely related to those of insulin (Holly et al., 1988; Suikkari et al., 1989). Also, dexamethasone has been shown to inhibit production of IGFBP-1 in human fetal liver explants (Lewitt and Baxter, 1989). Indeed, in the nonpregnant state, the predominant source of IGFBP-1 is the liver (Hossenlopp et al., 1987; Scharf et al., 1996). In contrast, in the non-pregnant rat, dexamethasone elicits a rise in both serum IGFBP-1 and hepatic IGFBP-1 mRNA concentrations (Luo et al., 1990). The conflicting results in the non-pregnant state may be due to a species difference in the response to dexamethasone. In humans, differences between males and pregnant females may be due to the fact that in males the liver is the predominant source of circulating IGFBP-1, while in females it is produced by the decidua. Alternatively, such differences may be due to variations in regulatory mechanisms of IGFBP-1 production during pregnancy. The lack of change in plasma concentrations of IGFBP-1 following antenatal dexamethasone therapy suggests that the drug does not influence decidual synthesis of IGFBP-1. Such lack of effect may explain the fact that, in contrast to animal studies, there is no evidence of fetal growth retardation following antenatal dexamethasone therapy in humans (Lamont et al., 1983), a view supported by our finding of a mean birth weight centile of 60. While this is reassuring, further studies are required to see whether repeated dexamethasone dosage to women in whom the threat of premature delivery persists might have a different outcome. References Baxter, R.C. and Cowell, C.T. (1987) Diurnal rhythm of growth hormoneindependent binding protein for insulin-like growth factors in human plasma. J. Clin. Endocrinol. Metab., 65, 432–440. Bell, S.C. (1989) Decidualization and insulin-like growth factor (IGF) binding protein: implications for its role in stromal cell differentiation and the decidual cell in haemochorial placentation. Hum. Reprod., 4, 125–130. Crowley, P. (1995) Antenatal corticosteroid therapy: a meta-analysis of randomised trials, 1972–94. Am. J. Obstet. Gynecol., 173, 322–335.
1715
O.Ogueh et al. 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, 499–505. Hills, F.A., English, J. and Chard, T. (1996) Circulating levels of IGF-I and IGF-binding protein-1 throughout pregnancy: relation to birthweight and maternal weight. J. Endocrinol., 148, 303–309. Holly, J.M.P., Biddlecombe, R.A., Dunger D.B. et al. (1988) Circadian variation of GH-dependent IGF-binding protein in diabetes mellitus and its relationship to insulin. Clin. Endocrinol., 29, 667–675. Hossenlopp, P., Seurin, D., Segovia, B. et al. (1987) Heterogeneity of insulinlike growth factor binding proteins between structure and affinity. 2. Forms released by human and rat liver in culture. Eur. J. Biochem., 170, 133–142. Jones, J.L., D’Ercole, J., Carnacho-Hubner, C. et al. (1991) Phosphorylation of IGFBP-1 in cell culture and in vivo effects on affinity for IGF-1. Proc. Natl Acad. Sci. USA, 88, 7481–7485. Jones, J.L., Busby, W.H., Wright, G. et al. (1993) Human IGFBP-1 is phosphorylated on three serine residues: effects of site directed mutagenesis of the major phosphoserine. Growth Regul., 1, 37–40. Lamont, R.F., Dunlop, P.D., Levene, M.I. et al. (1983) Use of glucocorticoids in pregnancies complicated by severe hypertension and proteinuria. Br. J. Obstet. Gynaecol., 90, 199–202. Lewitt, M.S. and Baxter, R.C. (1989) Regulation of growth hormoneindependent insulin-like growth factor-binding protein (BP-28) in cultured human fetal liver explants. J. Clin. Endocrinol. Metab., 69, 246–252. Liggins, G.C. and Howie, R.N. (1972) A controlled trial of antepartum glucocorticoid treatment for prevention of respiratory distress syndrome in premature infants. Paediatrics, 50, 515–525. Luo, J., Reid, R.E. and Murphy, L.J. (1990) Dexamethasone increases hepatic insulin-like growth factor binding protein-1 (IGFBP-1) mRNA and serum IGFBP-1 concentrations in the rat. Endocrinology, 127, 1456–1462. Miell, J.P., Taylor, A.M., Jones J. et al. (1993) Effect of dexamethasone on immunoreactive and bioreactive insulin-like growth factors (IGFs) and IGFbinding proteins in normal male volunteers. J. Endocrinol., 136, 525–533. Miell, J.P., Jauniaux, E., Langford, K.S. et al. (1997) Insulin-like growth factor binding protein concentration and post-translational modification in embryological fluid. Mol. Hum. Reprod., 3, 343–349. Ostlund, E., Bang, P., Hagenas, L. et al. (1997) Insulin-like growth factor I in fetal serum obtained by cordocentesis is correlated with intrauterine growth retardation. Hum. Reprod., 12, 840–844. Price, W.A., Stiles, A.D., Moats-Staats, B.M. et al. (1992) Gene expression of insulin-like growth factors (IGFs), the type 1 IGF receptor, and IGFbinding proteins in dexamethasone-induced fetal growth retardation. Endocrinology, 130, 1424–1432. Rutanen, E.M., Koistinen, R., Wahlstrom, T. et al. (1985) Synthesis of placental protein 12 by human decidua. Endocrinology, 116, 1304–1309. Rutanen, E.M., Pekonen, F. and Makinen, T. (1988) Soluble 34K binding protein inhibits the binding of insulin-like growth factor I to its cell receptors in human secretory phase endometrium: evidence for autocrine/paracrine regulation of growth factor action. J. Clin. Endocrinol. Metab., 66, 173–180. Scharf, J., Ramadori, G., Braulke, T. et al. (1996) Synthesis of insulin-like growth factor binding proteins and of the acid-labile subunit in primary cultures of rat hepatocytes, of Kupffer cells, and in cocultures: regulation by insulin, insulin-like growth factor, and growth hormone. Hepatology, 23, 818–827. Sinclair, J. (1994) Discussion of Crowley’s meta-analysis of randomised controlled trials of antenatal corticosteroids for prevention of respiratory distress syndrome. In Report of the Consensus Development Conference on the Effects of Corticosteroids for Fetal Maturation on Perinatal Outcomes. National Institutes of Health, Bethesda, pp. 95–96. Suikkari, A., Koivisto, V.A., Koistinen, R. et al. (1989) Dose-response characteristics for suppression of low molecular weight plasma insulin-like growth factor binding protein by insulin. J. Clin. Endocrinol. Metab., 68, 135–140. Wang, H.S. and Chard, T. (1992) The role of insulin-like growth factor-I and insulin-like growth factor-binding protein-1 in the control of human fetal growth. J. Endocrinol., 132, 11–19. Wang, H.S., Perry, L.A., Kanisius, J. et al. (1991) Purification and assay of insulin-like growth factor-binding protein-1: measurement of circulating levels throughout pregnancy. J. Endocrinol., 128, 161–168. Received on November 17, 1997; accepted on March 3, 1998
1716
