Logo of jphysiolThe Journal of Physiology SiteMembershipSubmissionJ Physiol
J Physiol. Jan 1, 2011; 589(Pt 1): 7–20.
Published online Oct 4, 2010. doi:  10.1113/jphysiol.2010.198622
PMCID: PMC3021777

The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth

Abstract

Maternal insulin-like growth factors (IGFs) play a pivotal role in modulating fetal growth via their actions on both the mother and the placenta. Circulating IGFs influence maternal tissue growth and metabolism, thereby regulating nutrient availability for the growth of the conceptus. Maternal IGFs also regulate placental morphogenesis, substrate transport and hormone secretion, all of which influence fetal growth either via indirect effects on maternal substrate availability, or through direct effects on the placenta and its capacity to supply nutrients to the fetus. The extent to which IGFs influence the mother and/or placenta are dependent on the species and maternal factors, including age and nutrition. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing degenerative diseases in adult life, understanding the role of maternal IGFs during pregnancy is essential in order to identify mechanisms underlying altered fetal growth and offspring programming.

Amanda Sferruzzi-Perri completed a Bachelor of Science degree with Honours in the School of Molecular and Biomedical Sciences at University of Adelaide, Australia (2001). In 2007, she was awarded her PhD for research into the role of maternal insulin-like growth factors in fetal growth in the Research Centre for Reproductive Health, by the University of Adelaide. In 2008, Amanda received a CJ Martin Biomedical Fellowship from the NH&MRC to investigate the regulation of placental development and function by the IGFs at the University of Cambridge, UK. She is continuing her research through the award of a Next Generation Fellowship from Centre for Trophoblast Research, UK (2010).

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Introduction

The insulin-like growth factors (IGFs) IGF-I and IGF-II are 7.5 kDa single-chained polypeptides that promote growth both before and after birth. They affect the metabolism, mitogenesis and differentiation of a wide variety of cell types, including those of the placenta by binding to IGF receptors (IGF1R and IGF2R), insulin receptor (InsR) and a hybrid IGF1R–InsR receptor. Their bioavailability is influenced by at least six IGF binding proteins (IGFBP-1 to IGFBP-6) that prolong the IGF half-life in the circulation and transport IGFs to their receptors. Together, the IGFs, their receptors and binding proteins form the IGF axis, which is responsive to a range of environmental signals including nutrients, oxygen and hormones, such as growth hormone (GH), cortisol, insulin, thyroid hormones and sex steroids.

Before birth, IGFs are paracrine growth regulators synthesised by multiple fetal tissues, independently of GH. Although IGF-II is the most abundant fetal IGF, deletion of either Igf gene in mice reduces birth weight to 60% of wildtype (Louvi et al. 1997; Fowden, 2003). Effects of IGFs on fetal growth are additive, as deletion of Igf1r, through which both IGFs act, reduces birth weight to a greater extent than deletion of either Igf1 or Igf2 alone (Louvi et al. 1997). Whilst IGF-I appears to regulate fetal growth in response to nutrient availability, IGF-II is thought to provide the constitutive stimulus for feto-placental growth (Fowden, 2003). Circulating IGF-I concentrations rise after birth due primarily to the onset of GH-dependent hepatic synthesis of IGF-I although a variety of other tissues also continue to produce IGF-I. This endocrine IGF-I production drives growth postnatally. In contrast, IGF-II expression declines towards term in association with pre-partum maturation of specific tissues, although IGF-II still circulates in plasma of several species postnatally (Gargosky et al. 1990; Giudice et al. 1993; Sohlstrom et al. 1998; Perry et al. 2002). However, in adult mice, IGF-II is confined to the brain and is not detectable in plasma (Fielder et al. 1990). After postnatal growth is complete, the role of IGFs is less clear. They are thought to be involved in the turnover and growth of adult tissues during physiological conditions, such as wound healing, exercise and pregnancy. This review examines the maternal IGF system during pregnancy and its effects on fetal growth, with particular emphasis on the actions of IGFs on maternal metabolism and nutrient partitioning and on placental growth and function. Since the pattern of fetal growth determines rates of morbidity and mortality at, and long after, birth (Barker, 2004), understanding the role of maternal IGFs during pregnancy may help identify the mechanisms involved in developmental programming of life expectancy.

Maternal IGF concentrations

Maternal plasma IGFs during pregnancy depend on species and gestational age (Fig. 1). In species like humans, rabbits and guinea pigs, maternal IGF-I concentrations increase in the first half of pregnancy (Fig. 1: Gargosky et al. 1990; Nason et al. 1996; Sohlstrom et al. 1998). In women, IGF-I levels continue to rise throughout pregnancy, whilst in rabbits and guinea pigs, the elevated IGF-I levels decline rapidly from mid-pregnancy onwards (Fig. 1). In the baboon, rhesus monkey, rat and pig, maternal circulating IGF-I concentrations fall during pregnancy to as low as 30% of non-pregnant values (Giudice et al. 1993; Farmer et al. 2000; Van Mieghem et al. 2009). In some species like cattle and sheep, plasma IGF-I is unaltered by pregnancy (Fig. 1: Wallace et al. 1997; Perry et al. 2002; Weber et al. 2007; de Boo et al. 2008). In mice dams, plasma IGF-I at mid-pregnancy is ~70% lower than in virgin and early pregnant females but nothing is known about concentrations in late pregnancy (Travers et al. 1990).

Figure 1
The changes in maternal circulating concentrations of IGF-I (A) and IGF-II (B) during pregnancy expressed as a percentage of the non-pregnant state (represented as the dashed line) with respect to the stage of pregnancy

The IGF-II profile in maternal plasma is more consistent across species than for IGF-I, with an overall rise in concentrations during pregnancy (Fig. 1). In some animals, the increase is marginal, whereas in others like rabbits, there is a 200-fold increment by mid-gestation (Fig. 1: Nason et al. 1996). In rat dams, plasma IGF-II increases with advancing gestation, whereas in women, levels are maintained after the initial elevation, throughout pregnancy (Fig. 1: Gargosky et al. 1990; Van Mieghem et al. 2009). In non-human primates and rabbits, maternal plasma IGF-II declines towards term but remains higher than non-pregnant values (Fig. 1). In cows and guinea pigs, plasma IGF-II concentrations are relatively unresponsive to pregnancy (Sohlstrom et al. 1998; Perry et al. 2002). Irrespective of reproductive state, IGF-II is more abundant than IGF-I in most species studied (Gargosky et al. 1990; Giudice et al. 1993; Nason et al. 1996; Sohlstrom et al. 1998).

Sources of maternal IGFs

There are several potential sources of IGFs during pregnancy. In several species, IGFs are produced by a range of tissues that may increase in mass during pregnancy including the liver, uterus, skeletal muscle and adipose tissue (Peter et al. 1993; Coleman et al. 1994; Sterle et al. 1998; Olausson & Sohlstrom, 2003). Indeed, in women, the increased maternal IGF-I concentration in early–mid pregnancy is thought to reflect growth of maternal tissues (Lof et al. 2005). In rabbits, maternal whole body tissue growth and subsequent tissue mobilisation are associated with elevated and then reduced IGFs in early and late gestation, respectively (Nason et al. 1996). As adipose tissue accounts for a greater proportion of maternal body mass during pregnancy, it may contribute significantly to the circulating pool of IGFs. However, as blood volume rises in parallel with maternal body mass, increased tissue mass is unlikely to be the sole explanation for the rise in maternal IGFs during pregnancy.

Studies performed mainly in the guinea pig have shown that Igf expression is increased in some, but not all, tissues per unit mass during pregnancy (Sohlstrom et al. 1998; Olausson & Sohlstrom, 2003). For instance, there is no increase in Igf mRNA expression by maternal muscle, although its mass is increased. In contrast, Igf mRNA abundance in maternal liver and fat increase early in pregnancy and are maintained until term, especially for Igf1, despite reductions in hepatic and adipose tissue weight during the second half of pregnancy. Furthermore, uterine expression of Igf1 mRNA is reduced during guinea pig pregnancy. Thus, in early pregnancy, an increase in Igf expression by the liver and adipose tissue plus expansion of muscle mass in the mother, may contribute to her elevated plasma IGF-I. In late pregnancy, the reduced liver and fat mass combined with down-regulated uterine Igf1 gene expression may explain the pre-partum decline in plasma IGF-I levels (Sohlstrom et al. 1998; Olausson & Sohlstrom, 2003). In rats, the fall in maternal IGF-I concentration, particularly in the second half of pregnancy, coincides with reduced hepatic Igf1 gene expression (Donovan et al. 1991). In part, the changes in tissue growth and Igf gene expression during pregnancy may relate to the altered maternal endocrine environment. Indeed, somatotropin and steroid hormone concentrations alter during pregnancy and are known to regulate IGF production (Handwerger & Freemark, 2000; Mullis & Tonella, 2008); however, definitive studies are required.

Another potential source of maternal IGFs is the placenta. In all species studied, the placenta synthesises IGF-II, at least in early pregnancy. In haemochorial placentas of humans, guinea pigs, rhesus monkeys, baboons, rats and mice, IGF-II is produced by the syncytiotrophoblast layer in direct contact with maternal blood (Han & Carter, 2000; Nayak & Giudice, 2003; Sferruzzi-Perri et al. 2006). In rodents, the placenta is likely to be a major IGF-II source as Igf2 gene expression is limited in adult peripheral tissues. In humans, IGF-II is also produced abundantly by the extravillous trophoblasts lining the uterine spiral arteries (Han & Carter, 2000). In contrast to IGF-II, the placenta is an unlikely source of IGF-I as it expresses very little (Han & Carter, 2000). However, the placenta may influence maternal plasma IGF-I indirectly through secreting hormones which modulate IGF-I synthesis in maternal tissues. For instance, human syncytiotrophoblast secretes a variant of growth hormone, placental growth hormone (PGH), which stimulates maternal IGF-I production despite a fall in pituitary GH secretion (Alsat et al. 1998). Similarly, the placenta secretes placental lactogen (PL) into the maternal circulation, which is thought to modulate maternal IGF-I expression, although direct evidence for this is limited (Handwerger & Freemark, 2000; Karabulut et al. 2001).

Changes in maternal circulating IGFs during pregnancy may also be due to post-translational processes. In pregnant women and rats, IGF-II secreted as a biologically inactive pro-peptide undergoes proteolytic cleavage to become active (Qiu et al. 2005, 2007; Van Mieghem et al. 2009). Proteolytic activation increases during pregnancy and correlates with maternal circulating IGF-II concentrations (Qiu et al. 2005, 2007; Van Mieghem et al. 2009). In addition, the expression, covalent modifications and circulating levels of IGFBPs change in the mother during pregnancy and may influence circulating IGF profiles and bioavailability, as reviewed previously (Fielder et al. 1990; Donovan et al. 1991; Giudice et al. 1993; Nason et al. 1996; Sohlstrom et al. 1998; Forbes & Westwood, 2008).

The roles of maternal IGFs in fetal growth regulation

Maternal plasma IGFs correlate positively with fetal growth and birth weight in several species. In mice, cross-breeding experiments between lines selected for high or low plasma IGF-I levels reveal that elevated maternal circulating IGF-I abolishes the normally negative relationship between fetal mass and litter size in late gestation (Gluckman et al. 1992). Experimental manipulations of maternal IGFs by exogenous IGF treatment or elevated endogenous IGF production (via GH infusion) impacts on fetal growth (Table 1). Fetal actions of the IGFs depend on species, the specific treatment regime (length and timing during pregnancy), litter size, maternal age, parity, nutritional state and the time in pregnancy when outcomes were assessed (during or after treatment). Since IGFs and GH do not cross the placenta in significant quantities (Davenport et al. 1990), the effects of the IGFs on fetal growth must occur indirectly through actions on maternal metabolism and nutrient partitioning, and/or placental development and function.

Table 1
The impact of elevated maternal plasma IGF-I, IGF-II or GH treatment on the mother and offspring

Maternal metabolism and nutrient partitioning

In rat dams, positive nitrogen balance during early pregnancy is correlated with circulating IGF concentrations (Palmer et al. 1996; Nakago et al. 1999). Elevating maternal IGF-I by IGF-I or GH administration in the second half of rat pregnancy stimulated growth of maternal tissue without an affect on fetal growth (Table 1: Gargosky et al. 1991; Woodall et al. 1999). In addition, reducing maternal IGF-I in the second half of pregnancy using antibodies against GH, repartitioned maternal muscle protein to growth of the rat pup (Palmer et al. 1996). This suggests that, in rats, declining maternal IGF-I concentrations in late pregnancy may limit maternal anabolic activity to divert substrates to the gravid uterus. A similar decline in maternal IGF-I occurs in guinea pigs during late pregnancy although levels remain higher than pre-pregnancy (Sohlstrom et al. 1998). Elevating maternal plasma IGF-I in early guinea pig pregnancy increases uptake of amino acid and glucose by maternal visceral organs, reduces maternal adiposity and increases fetal growth, near term long after cessation of treatment (Sohlstrom et al. 2001; Sferruzzi-Perri et al. 2006, 2007a,b). Overall, these studies indicate that maternal IGF-I is important in resource allocation between maternal tissues and the growing conceptus but that its endocrine actions are dependent on species and gestational age.

In pigs, in which plasma IGF-I is lower in pregnant than non-pregnant states, elevating endogenous IGF-I during the first half of pregnancy by maternal GH administration increased growth of maternal tissues (Table 1: Kelley et al. 1995; Sterle et al. 1995; Okere et al. 1997; Rehfeldt et al. 2001; Schneider et al. 2002; Gatford et al. 2009). In some of these studies, elevating plasma IGF-I in pig mothers was also associated with increased plasma concentrations of glucose, insulin and free fatty acids and enhanced fetal growth and/or survival (Table 1). These studies suggest that maternal IGF-I may drive fetal growth by promoting maternal insulin resistance and thus increasing substrate availability for the gravid uterus. Certainly, maternal IGF-I appears to have the most beneficial effects on fetal development when maternal nutrient supply is limited. For instance, elevating maternal IGF-I endogenously enhances maternal back fat loss during pregnancy and increases fetal growth in undernourished pigs (Gatford et al. 2000).

In sheep, elevating plasma IGF-I by maternal GH treatment in early pregnancy increases maternal nutrient concentrations and sometimes increases fetal weight at the expense of maternal tissue mass (Table 1: Stelwagen et al. 1994; Jenkinson et al. 1999; Wallace et al. 2004; Costine et al. 2005; Koch et al. 2010). However, in later pregnancy, increasing maternal circulating IGF-I appears to have no immediate effect on maternal body composition or fetal weight (Harding et al. 1997). The extent of IGF-I actions on the mother is dependent on gestational age, maternal age and nutrition, and whether the pregnancy is a singleton or twin (Table 1: Costine et al. 2005; Wallace et al. 2006a; Kenyon et al. 2007; Wright et al. 2008; Koch et al. 2010). Like the pig, maternal IGF-I may have most benefit on ovine fetal growth in adverse maternal environments. For instance, in the over-nourished adolescent ewe when there is increased competition for substrates by still-growing maternal tissues, GH treatment and elevated IGF-I between days 95 to 125 of pregnancy, reduces maternal adiposity and increases fetal growth (Wallace et al. 2006b). Furthermore, increasing maternal plasma IGF-I endogenously in late ovine pregnancy, shifts maternal metabolism in favour of the conceptus by increasing maternal plasma insulin, glucose and free fatty acids. This partially prevents the fetal growth restriction caused by placental embolization (de Boo et al. 2008).

Compared to IGF-I, there is less information about the role of endocrine IGF-II in maternal metabolism and substrate partitioning (Table 1). In guinea pigs, elevating maternal IGF-II in early to mid pregnancy did not affect maternal body composition, whilst uptake of amino acids by maternal visceral organs was increased and fetal growth enhanced near term (Sferruzzi-Perri et al. 2006, 2007a,b). In contrast to native IGF-II, treatment of guinea pig dams with a synthetic analogue of IGF-II that selectively binds to IGF2R (Leu27–IGF-II), reduced maternal adiposity in late pregnancy without effects on substrate uptake by maternal tissues (Sferruzzi-Perri et al. 2008). The effects of Leu27–IGF-II on maternal body composition were similar to those of IGF-I, suggesting that some IGF-I-specific effects may be due to displacement of endogenous IGF-II from the IGF2R and its subsequent interaction with IGF1R and the InsR. In rats, IGF-II treatment in mid to late pregnancy increased maternal blood volume expansion without impacting on fetal growth (Table 1: Van Mieghem et al. 2009). Thus, maternal endocrine IGF-II may influence fetal growth by regulating maternal metabolic and cardiovascular adaptations to pregnancy; however, further studies are warranted.

Placental development and function

Maternal endocrine IGFs may also affect fetal growth via placental actions. In addition to transporting nutrients, the placenta may modulate fetal development by secreting hormones, either into the umbilical circulation to directly affect fetal metabolism and growth, or into the maternal circulation to alter maternal metabolism and substrate availability for placental transfer. The placenta expresses IGF1R, IGF2R and InsR in several species and IGF1R–InsR hybrid in the human placenta (Zhou & Bondy, 1992; Soos et al. 1993; Fang et al. 1997; Hiden et al. 2006; Sferruzzi-Perri et al. 2006; Pringle & Roberts, 2007). More specifically, in women and guinea pigs, the IGF and insulin receptors are localised to the syncytiotrophoblast layer bathed in maternal blood (Fang et al. 1997; Hiden et al. 2006; Sferruzzi-Perri et al. 2006). This permits endocrine regulation of placental growth and function by maternal IGFs (Table 2).

Table 2
The impact of IGFs on placental growth and function in vitro and in vivo

IGF-I and IGF-II prevent apoptosis and enhance proliferation and migration in human placental villous explants, primary trophoblast cultures or trophoblast cell lines from early pregnancy and term (Table 2: Irving & Lala, 1995; Hamilton et al. 1998; McKinnon et al. 2001; Lacey et al. 2002; Smith et al. 2002; Hills et al. 2004; Kabir-Salmani et al. 2004; Qiu et al. 2005; Forbes et al. 2008). Similarly, IGF-I stimulates proliferation and migration, whilst IGF-II promotes differentiation of murine ectoplacental cone trophoblast in culture (Kanai-Azuma et al. 1993). Furthermore, IGF-II promotes migration of ovine trophoblast cells in vitro (Kim et al. 2008).

In guinea pigs, maternal plasma IGF-I and IGF-II correlate positively with placental surface area for exchange and negatively with barrier thickness (Roberts et al. 2008). Treatment of guinea pig dams with either IGF in early to mid pregnancy increases fetal weight near term (Sferruzzi-Perri et al. 2006). Whilst there was no sustained effect of either IGF on placental weight, IGF-II increased the volume and surface area of the exchange region in late gestation (Table 2: Sferruzzi-Perri et al. 2006). Development of the placental exchange region was further enhanced when the IGF2R-selective synthetic analogue, Leu27–IGF-II was administered maternally (Sferruzzi-Perri et al. 2008). This suggests that maternal IGF-II in early gestation may act, in part, via the IGF2R to enhance functional development of the placenta.

In addition to stimulating placental growth, maternal endocrine IGFs may influence fetal growth by altering activity of the placental nutrient transporters. Both IGF-I and IGF-II stimulate glucose and amino acid uptake in human trophoblast in vitro (Kniss et al. 1994; Karl, 1995; Roos et al. 2009). In the late pregnant ewe, acute maternal IGF-I treatment alters placental metabolic function, which suggests enhanced glucose and lactate delivery to the fetus (Liu et al. 1994). In guinea pigs, elevated maternal plasma IGF-I or IGF-II during early to mid pregnancy increases placental capacity to deliver glucose and/or amino acids to the fetus in late gestation (Table 2: Sferruzzi-Perri et al. 2006, 2007a,b). Placental substrate transfer was increased in late gestation, partly due to enhanced expression of nutrient transporters by IGF-I in mid pregnancy and improved development of the exchange region by IGF-II in late pregnancy (Sferruzzi-Perri et al. 2006, 2007b). In culture, IGF-I prevents the release of the vaso-constrictors prostaglandin E and F, and thromboxane, by the term human placenta (Table 2: Siler-Khodr et al. 1995). In vivo, these effects could influence utero-placental blood flow and substrate transfer in late gestation. Indeed, reduced maternal circulating IGF-I or increased maternal circulating inactive pro-IGF-II in women, are associated with abnormal placental blood flows and small for gestational age and growth-restricted babies (Holmes et al. 1997; Qiu et al. 2005).

IGFs enhance placental secretion of hormones including progesterone, human chorionic gonadotrophin and PL in vitro (Maruo et al. 1995). In addition, IGF-II simulates the differentiation of hormone-producing cells in murine and ovine trophoblast in vitro and the development of the endocrine trophospongial zone of the rat placenta, in vivo (Kanai-Azuma et al. 1993; Kim et al. 2008; Van Mieghem et al. 2009). IGF-induced changes in placental hormone production may influence fetal growth directly or indirectly. For instance, PL secreted into the umbilical circulation promotes secretion of growth promoting hormones, such as insulin and IGF-I and IGF-II in the fetus, whilst in the mother, PL and progesterone induce maternal insulin resistance, favouring glucose delivery to the fetus for growth (Butte, 2000; Handwerger & Freemark, 2000; Karabulut et al. 2001). Thus, maternal endocrine IGFs may influence fetal growth by altering placental development, hormone secretion and substrate transport.

Conclusions and perspectives

IGFs in the maternal circulation are emerging as important regulators of fetal growth via their actions on both the mother and the placenta (Fig. 2). They influence maternal tissue growth and metabolism and, thereby, modulate nutrient availability for conceptus growth. They also regulate placental morphogenesis, substrate transport and hormone secretion, which influence fetal growth either via indirect effects on maternal substrate availability, or through direct impacts on fetal nutrient supply and its endocrine environment (Fig. 2). In turn, changes in fetal growth, metabolism and endocrine state induced by the actions of maternal plasma IGFs may signal back to the placenta to alter its phenotype further (Harding et al. 1994; Constancia et al. 2005). Overall, maternal IGF-I and IGF-II may have complementary but overlapping roles in optimising fetal nutrient acquisition for growth and survival. Maternal IGF-I appears to act predominantly on maternal tissues to influence substrate availability, whereas maternal IGF-II acts on the placenta to influence substrate delivery to the fetus (Fig. 2). The relative balance of IGF actions on the mother and placenta in regulating fetal growth depends not only on the abundance of the two IGFs, but also on the species, stage of pregnancy, and age and nutritional state of the mother. Maternal IGF administration may, therefore, have benefits to the food and livestock industry by providing a means of improving animal productivity; however, further studies are warranted. Furthermore, in animal models of intrauterine growth, elevating maternal IGF concentrations appears to improve fetal growth, suggesting the possibility for clinical translation (Gatford et al. 2000; Wallace et al. 2006b; de Boo et al. 2008). Before this approach could be used therapeutically to improve fetal growth in compromised human pregnancies, further studies are required to identify the potential long-term effects on both the mother and her offspring with respect to tissue growth and endocrine function. Furthermore, little is known about the regulation of IGF synthesis or the identity of molecular mediators of IGF actions on the placenta and mother. Thus, future research could aim to antagonise IGFs actions and/or their specific receptors and determine the effect/s on pregnancy and postnatal outcomes, so that perhaps IGF-I or IGF-II may be targeted specifically to the placenta and/or particular maternal tissues. Moreover, researchers could explore therapeutic options of increasing endogenous IGF synthesis, perhaps by nutritional means. Since maternal IGF treatment is likely to be most efficacious in early gestation, before the onset of impaired fetal growth, an additional focus should be developing better methods for identifying pregnancies at risk of intrauterine growth restriction.

Figure 2
The proposed actions of maternal circulating IGFs on the mother and placenta that drive fetal growth

Acknowledgments

We would like to acknowledge the financial support provided by the National Health & Medical Research Council of Australia for a CJ Martin Biomedical Fellowship awarded to A.S-P. We would also like to thank the reviewers of this manuscript for their critical comments and helpful advice.

Glossary

Abbreviations

AIB
amino isobutyric acid
CR
crown–rump
D
day of pregnancy
GH
growth hormone
hCG
human chorionic gonadotropin
hPL
human placental lactogen
IGF
insulin-like growth factor
IGFBP
IGF binding protein
P
postnatal day
PL
placental lactogen

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