|The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth.|
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|PMID: 20921199 Owner: NLM Status: MEDLINE|
|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.|
|A N Sferruzzi-Perri; J A Owens; K G Pringle; C T Roberts|
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|Type: Journal Article; Research Support, Non-U.S. Gov't; Review Date: 2010-10-04|
|Title: The Journal of physiology Volume: 589 ISSN: 1469-7793 ISO Abbreviation: J. Physiol. (Lond.) Publication Date: 2011 Jan|
|Created Date: 2011-01-12 Completed Date: 2011-04-22 Revised Date: 2013-07-03|
Medline Journal Info:
|Nlm Unique ID: 0266262 Medline TA: J Physiol Country: England|
|Languages: eng Pagination: 7-20 Citation Subset: IM|
|Department of Physiology, Development and Neuroscience, University of Cambridge, Physiology Building, Downing Street, Cambridge CB2 3EG, UK. firstname.lastname@example.org|
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Fetus / blood supply, metabolism*
Maternal Nutritional Physiological Phenomena
Placenta / blood supply, metabolism*
Somatomedins / metabolism*
Journal ID (nlm-ta): J Physiol
Journal ID (publisher-id): tjp
Publisher: Blackwell Publishing Ltd
Journal compilation © 2011 The Physiological Society
Received Day: 26 Month: 8 Year: 2010
Accepted Day: 28 Month: 9 Year: 2010
Print publication date: Month: 1 Year: 2011
Electronic publication date: Day: 04 Month: 10 Year: 2010
Volume: 589 Issue: 1
First Page: 7 Last Page: 20
PubMed Id: 20921199
|The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth|
|A N Sferruzzi-Perri12|
|J A Owens2|
|K G Pringle3|
|C T Roberts2|
1Centre for Trophoblast Research Department of Physiology, Development & Neuroscience, University of CambridgeCambridge, UK
2Research Centre for Reproductive Health, Robinson Institute, University of AdelaideSouth Australia, Australia
3Mothers and Babies Research Centre, University of NewcastleNew South Wales, Australia
|Correspondence: Corresponding author A. N. Sferruzzi-Perri: Department of Physiology, Development and Neuroscience, University of Cambridge, Physiology Building, Downing Street, Cambridge CB2 3EG, UK. Email: email@example.com
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 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).
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).
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).
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.
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.
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).
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.
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.
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.
|Alsat E,Guibourdenche J,Couturier A,Evain-Brion D. Physiological role of human placental growth hormoneMol Cell EndocrinolYear: 19981401211279722179|
|Barker DJ. The developmental origins of adult diseaseJ Am Coll NutrYear: 200423588S595S15640511|
|Butte NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitusAm J Clin NutrYear: 2000711256S1261S10799399|
|Coleman ME,Russell L,Etherton TD. Porcine somatotropin (pST) increases IGF-I mRNA abundance in liver and subcutaneous adipose tissue but not in skeletal muscle of growing pigsJ Anim SciYear: 1994729189248014157|
|Constancia M,Angiolini E,Sandovici I,Smith P,Smith R,Kelsey G,Dean W,Ferguson-Smith A,Sibley CP,Reik W,Fowden A. Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systemsProc Natl Acad Sci U S AYear: 2005102192191922416365304|
|Costine BA,Inskeep EK,Wilson ME. Growth hormone at breeding modifies conceptus development and postnatal growth in sheepJ Anim SciYear: 20058381081515753335|
|Davenport ML,Clemmons DR,Miles MV,Camacho-Hubner C,D’Ercole AJ,Underwood LE. Regulation of serum insulin-like growth factor-I (IGF-I) and IGF binding proteins during rat pregnancyEndocrinologyYear: 1990127127812861696882|
|de Boo HA,Eremia SC,Bloomfield FH,Oliver MH,Harding JE. Treatment of intrauterine growth restriction with maternal growth hormone supplementation in sheepAm J Obstet GynecolYear: 2008199559.e551559.e55918599015|
|Donovan SM,Giudice LC,Murphy LJ,Hintz RL,Rosenfeld RG. Maternal insulin-like growth factor-binding protein messenger ribonucleic acid during rat pregnancyEndocrinologyYear: 1991129335933661720094|
|Fang J,Furesz TC,Lurent RS,Smith CH,Fant ME. Spatial polarization of insulin-like growth factor receptors on the human syncytiotrophoblastPediatr ResYear: 1997412582659029648|
|Farmer C,Palin MF,Sorensen MT. Mammary gland development and hormone levels in pregnant Upton-Meishan and large white giltsDomest Anim EndocrinolYear: 20001824125110764979|
|Fielder PJ,Thordarson G,Talamantes F,Rosenfeld RG. Characterization of insulin-like growth factor binding proteins (IGFBPs) during gestation in mice: effects of hypophysectomy and an IGFBP-specific serum protease activityEndocrinologyYear: 1990127227022801699743|
|Forbes K,Westwood M. The IGF axis and placental function. a mini reviewHorm ResYear: 20086912913718219215|
|Forbes K,Westwood M,Baker PN,Aplin JD. Insulin-like growth factor I and II regulate the life cycle of trophoblast in the developing human placentaAm J Physiol Cell PhysiolYear: 2008294C1313C132218400990|
|Fowden AL. The insulin-like growth factors and feto-placental growthPlacentaYear: 20032480381213129676|
|Gargosky SE,Moyse KJ,Walton PE,Owens JA,Wallace JC,Robinson JS,Owens PC. Circulating levels of insulin-like growth factors increase and molecular forms of their serum binding proteins change with human pregnancyBiochem Biophys Res CommunYear: 1990170115711631697167|
|Gargosky SE,Owens JA,Walton PE,Owens PC,Wallace JC,Ballard FJ. Administration of insulin-like growth factor-I, but not growth hormone, increases maternal weight gain in late pregnancy without affecting fetal or placental growthJ EndocrinolYear: 19911303954001719115|
|Gatford KL,De Blasio MJ,Roberts CT,Nottle MB,Kind KL,van Wettere WHEJ,Smits RJ,Owens JA. Responses to maternal GH or ractopamine during early-mid pregnancy are similar in primiparous and multiparous pregnant pigsJ EndocrinolYear: 200920314315419654144|
|Gatford KL,Owens JA,Campbell RG,Boyce JM,Grant PA,De Blasio MJ,Owens PC. Treatment of underfed pigs with GH throughout the second quarter of pregnancy increases fetal growthJ EndocrinolYear: 200016622723410856901|
|Giudice LC,Dsupin BA,De las Fuentes L,Gargosky SE,Rosenfeld RG,Zelinski-Wooten MB,Stouffer RL,Fazleabas AT. Insulin-like growth factor binding proteins in sera of pregnant nonhuman primatesEndocrinologyYear: 1993132151415267681762|
|Gluckman PD,Morel PC,Ambler GR,Breier BH,Blair HT,McCutcheon SN. Elevating maternal insulin-like growth factor-I in mice and rats alters the pattern of fetal growth by removing maternal constraintJ EndocrinolYear: 1992134R1R31500836|
|Hamilton GS,Lysiak JJ,Han VK,Lala PK. Autocrine-paracrine regulation of human trophoblast invasiveness by insulin-like growth factor (IGF)-II and IGF-binding protein (IGFBP)-1Exp Cell ResYear: 19982441471569770358|
|Han VK,Carter AM. Spatial and temporal patterns of expression of messenger RNA for insulin-like growth factors and their binding proteins in the placenta of man and laboratory animalsPlacentaYear: 20002128930510833363|
|Handwerger S,Freemark M. The roles of placental growth hormone and placental lactogen in the regulation of human fetal growth and developmentJ Pediatr Endocrinol MetabYear: 20001334335610776988|
|Harding JE,Evans PC,Gluckman PD. Maternal growth hormone treatment increases placental diffusion capacity but not fetal or placental growth in sheepEndocrinologyYear: 1997138535253589389520|
|Harding JE,Liu L,Evans PC,Gluckman PD. Insulin-like growth factor 1 alters feto-placental protein and carbohydrate metabolism in fetal sheepEndocrinologyYear: 1994134150915148119193|
|Hiden U,Maier A,Bilban M,Ghaffari-Tabrizi N,Wadsack C,Lang I,Dohr G,Desoye G. Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancyDiabetologiaYear: 20064912313116344925|
|Hills FA,Elder MG,Chard T,Sullivan MH. Regulation of human villous trophoblast by insulin-like growth factors and insulin-like growth factor-binding protein-1J EndocrinolYear: 200418348749615590975|
|Holmes R,Montemagno R,Jones J,Preece M,Rodeck C,Soothill P. Fetal and maternal plasma insulin-like growth factors and binding proteins in pregnancies with appropriate or retarded fetal growthEarly Hum DevYear: 1997497179179534|
|Irving JA,Lala PK. Functional role of cell surface integrins on human trophoblast cell migration: regulation by TGF-β, IGF-II, and IGFBP-1Exp Cell ResYear: 19952174194277535237|
|Jenkinson CM,Min SH,Mackenzie DD,McCutcheon SN,Breier BH,Gluckman PD. Placental development and fetal growth in growth hormone-treated ewesGrowth Horm IGF ResYear: 19999111710207503|
|Kabir-Salmani M,Shiokawa S,Akimoto Y,Sakai K,Iwashita M. The role of α5β1-integrin in the IGF-I-induced migration of extravillous trophoblast cells during the process of implantationMol Hum ReprodYear: 200410919714742693|
|Kanai-Azuma M,Kanai Y,Kurohmaru M,Sakai S,Hayashi Y. Insulin-like growth factor (IGF)-I stimulates proliferation and migration of mouse ectoplacental cone cells, while IGF-II transforms them into trophoblastic giant cells in vitroBiol ReprodYear: 1993482522618439614|
|Karabulut AK,Layfield R,Pratten MK. Growth promoting effects of human placental lactogen during early organogenesis: a link to insulin-like growth factorsJ AnatYear: 200119865166211465858|
|Karl PI. Insulin-like growth factor-1 stimulates amino acid uptake by the cultured human placental trophoblastJ Cell PhysiolYear: 199516583887559811|
|Kelley RL,Jungst SB,Spencer TE,Owsley WF,Rahe CH,Mulvaney DR. Maternal treatment with somatotropin alters embryonic development and early postnatal growth of pigsDomest Anim EndocrinolYear: 19951283947621681|
|Kenyon PR,Blair HT,Breier BH,Gluckman PD. The influence of maternal IGF-1 genotype on birthweight and growth rate of lambsNZ J Agricultural ResearchYear: 200750291297|
|Kim J,Song G,Gao H,Farmer JL,Satterfield MC,Burghardt RC,Wu G,Johnson GA,Spencer TE,Bazer FW. Insulin-like growth factor II activates phosphatidylinositol 3-kinase-protooncogenic protein kinase 1 and mitogen-activated protein kinase cell signaling pathways, and stimulates migration of ovine trophectoderm cellsEndocrinologyYear: 20081493085309418339715|
|Kniss DA,Shubert PJ,Zimmerman PD,Landon MB,Gabbe SG. Insulin like growth factors. Their regulation of glucose and amino acid transport in placental trophoblasts isolated from first-trimester chorionic villiJ Reprod MedYear: 1994392492568040840|
|Koch JM,Wilmoth TA,Wilson ME. Periconceptional growth hormone treatment alters fetal growth and development in lambsJ Anim SciYear: 2010881619162520118428|
|Kveragas CL,Seerley RW,Martin RJ,Vandergrift WL. Influence of exogenous growth hormone and gestational diet on sow blood and milk characteristics and on baby pig blood, body composition and performanceJ Anim SciYear: 198663187718873546238|
|Lacey H,Haigh T,Westwood M,Aplin JD. Mesenchymally-derived insulin-like growth factor provides a paracrine stimulus for trophoblast migrationBMC Dev BiolYear: 20022511972897|
|Liu L,Harding JE,Evans PC,Gluckman PD. Maternal insulin-like growth factor-I infusion alters feto-placental carbohydrate and protein metabolism in pregnant sheepEndocrinologyYear: 19941358959008070384|
|Lof M,Olausson H,Bostrom K,Janerot-Sjoberg B,Sohlstrom A,Forsum E. Changes in basal metabolic rate during pregnancy in relation to changes in body weight and composition, cardiac output, insulin-like growth factor I, and thyroid hormones and in relation to fetal growthAm J Clin NutrYear: 20058167868515755839|
|Louvi A,Accili D,Efstratiadis A. Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic developmentDev BiolYear: 199718933489281335|
|McKinnon T,Chakraborty C,Gleeson LM,Chidiac P,Lala PK. Stimulation of human extravillous trophoblast migration by IGF-II is mediated by IGF type 2 receptor involving inhibitory G protein(s) and phosphorylation of MAPKJ Clin Endocrinol MetabYear: 2001863665367411502794|
|Maruo T,Murata K,Matsuo H,Samoto T,Mochizuki M. Insulin-like growth factor-I as a local regulator of proliferation and differentiated function of the human trophoblast in early pregnancyEarly PregnancyYear: 1995154619363236|
|Mullis P-E,Tonella P. Regulation of fetal growth: Consequences and impact of being born smallBest Pract Res Clin Endocrinol MetabYear: 20082217319018279787|
|Nakago S,Funakoshi T,Ueda Y,Maruo T. Regulation of circulating levels of IGF-I in pregnant rats: changes in nitrogen balance correspond with changes in serum IGF-I concentrationsJ EndocrinolYear: 199916337337710556788|
|Nason KS,Binder ND,Labarta JI,Rosenfeld RG,Gargosky SE. IGF-II and IGF-binding proteins increase dramatically during rabbit pregnancyJ EndocrinolYear: 19961481211308568459|
|Nayak NR,Giudice LC. Comparative biology of the IGF system in endometrium, decidua, and placenta, and clinical implications for foetal growth and implantation disordersPlacentaYear: 20032428129614626217|
|Okere C,Hacker RR,Werchola G. Relationships between serum IGF-I concentrations and piglet development or neonatal viability following porcine somatotropin (pST) and insulin administration to gestating giltsTheriogenologyYear: 1997471403141216728086|
|Olausson H,Sohlstrom A. Effects of food restriction and pregnancy on the expression of insulin-like growth factors-I and -II in tissues from guinea pigsJ EndocrinolYear: 200317943744514656213|
|Palmer RM,Thom A,Flint DJ. Repartitioning of maternal muscle protein towards the foetus induced by a polyclonal antiserum to rat GHJ EndocrinolYear: 19961513954008994384|
|Perry VEA,Norman ST,Daniel RCW,Owens PC,Grant P,Doogan VJ. Insulin-like growth factor levels during pregnancy in the cow are affected by protein supplementation in the maternal dietAnim Reprod SciYear: 20027211012106961|
|Peter MA,Winterhalter KH,Boni-Schnetzler M,Froesch ER,Zapf J. Regulation of insulin-like growth factor-I (IGF-I) and IGF-binding proteins by growth hormone in rat white adipose tissueEndocrinologyYear: 1993133262426317694843|
|Pringle KG,Roberts CT. New light on early post-implantation pregnancy in the mouse: roles for insulin-like growth factor-II (IGF-II)?PlacentaYear: 20072828629716824595|
|Qiu Q,Basak A,Mbikay M,Tsang BK,Gruslin A. Role of pro-IGF-II processing by proprotein convertase 4 in human placental developmentProc Natl Acad Sci U S AYear: 2005102110471105216040806|
|Qiu Q,Jiang J-Y,Bell M,Tsang BK,Gruslin A. Activation of endoproteolytic processing of insulin-like growth factor-II in fetal, early postnatal, and pregnant rats and persistence of circulating levels in postnatal lifeEndocrinologyYear: 20071484803481117628003|
|Rehfeldt C,Kuhn G,Nurnberg G,Kanitz E,Schneider F,Beyer M,Nurnberg K,Ender K. Effects of exogenous somatotropin during early gestation on maternal performance, fetal growth, and compositional traits in pigsJ Anim SciYear: 2001791789179911465366|
|Roberts CT,Owens JA,Sferruzzi-Perri AN. Distinct actions of insulin-like growth factors (IGFs) on placental development and fetal growth: lessons from mice and guinea pigsPlacentaYear: 2008294247|
|Roos S,Lagerlof O,Wennergren M,Powell T,Jansson T. Regulation of amino acid transporters by glucose and growth factors in cultured primary human trophoblast cells is mediated by mTOR signalingAm J Physiol Cell PhysiolYear: 2009297C723C72319587219|
|Schneider F,Kanitz E,Gerrard DE,Kuhn G,Brüssow KP,Nürnberg K,Fiedler I,Nürnberg G,Ender K,Rehfeldt C. Administration of recombinant porcine somatotropin (rpST) changes hormone and metabolic status during early pregnancyDomest Anim EndocrinolYear: 20022345547412457954|
|Sferruzzi-Perri AN,Owens JA,Pringle KG,Robinson JS,Roberts CT. Maternal insulin-like growth factors-I and -II act via different pathways to promote fetal growthEndocrinologyYear: 20061473344335516556757|
|Sferruzzi-Perri AN,Owens JA,Standen P,Roberts CT. Maternal insulin-like growth factor-II promotes placental functional development via the type 2 IGF receptor in the guinea pigPlacentaYear: 20082934735518339421|
|Sferruzzi-Perri AN,Owens JA,Standen P,Taylor RL,Heinemann GK,Robinson JS,Roberts CT. Early treatment of the pregnant guinea pig with IGFs promotes placental transport and nutrient partitioning near termAm J Physiol Endocrinol MetabYear: 2007a292E668E67617062842|
|Sferruzzi-Perri AN,Owens JA,Standen P,Taylor RL,Robinson JS,Roberts CT. Early pregnancy maternal endocrine IGF-I programs the placenta for increased functional capacity throughout gestationEndocrinologyYear: 2007b1484362437017525121|
|Siler-Khodr TM,Forman J,Sorem KA. Dose-related effect of IGF-I on placental prostanoid releaseProstaglandinsYear: 1995491147792387|
|Smith S,Francis R,Guilbert L,Baker PN. Growth factor rescue of cytokine mediated trophoblast apoptosisPlacentaYear: 20022332233011969343|
|Sohlstrom A,Fernberg P,Owens JA,Owens PC. Maternal nutrition affects the ability of treatment with IGF-I and IGF-II to increase growth of the placenta and fetus, in guinea pigsGrowth Horm IGF ResYear: 20011139239811914027|
|Sohlstrom A,Katsman A,Kind KL,Roberts CT,Owens PC,Robinson JS,Owens JA. Food restriction alters pregnancy-associated changes in IGF and IGFBP in the guinea pigAm J PhysiolEndocrinol MetabYear: 1998274E410E416|
|Soos MA,Field CE,Siddle K. Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinityBiochem JYear: 19932904194268452530|
|Stelwagen K,Grieve DG,Walton JS,Ball JL,McBride BW. Effect of bovine somatotropin administration during the last trimester of gestation on maternal growth, and fetal and placental development in primigravid ewesAnim ProdYear: 1994588794|
|Sterle JA,Boyd C,Peacock JT,Koenigsfeld AT,Lamberson WR,Gerrard DE,Lucy MC. Insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein-2 and pregnancy-associated glycoprotein mRNA in pigs with somatotropin-enhanced fetal growthJ EndocrinolYear: 19981594414509834461|
|Sterle JA,Cantley TC,Lamberson WR,Lucy MC,Gerrard DE,Matteri RL,Day BN. Effects of recombinant porcine somatotropin on placental size, fetal growth, and IGF-I and IGF-II concentrations in pigsJ Anim SciYear: 199573298029858617668|
|Travers MT,Madon RJ,Vallance AJ,Barber MC. Circulating concentrations and hepatic expression of IGF-1 during pregnancy and lactation in the mouseBiochem Soc TransYear: 19901812682088909|
|Van Mieghem T,van Bree R,Van Herck E,Deprest J,Verhaeghe J. Insulin-like growth factor-II regulates maternal hemodynamic adaptation to pregnancy in ratsAm J Physiol Regul Integr Comp PhysiolYear: 2009297R1615R162119776249|
|Wallace JM,Da Silva P,Aitken RP,Cruickshank MA. Maternal endocrine status in relation to pregnancy outcome in rapidly growing adolescent sheepJ EndocrinolYear: 19971553593689415070|
|Wallace JM,Luther JS,Milne JS,Aitken RP,Redmer DA,Reynolds LP,Hay WW Jr. Nutritional modulation of adolescent pregnancy outcome–a reviewPlacentaYear: 2006a27S61S6816442614|
|Wallace JM,Matsuzaki M,Milne J,Aitken R. Late but not early gestational maternal growth hormone treatment increases fetal adiposity in overnourished adolescent sheepBiol ReprodYear: 2006b7523123916687645|
|Wallace JM,Milne JS,Aitken RP. Maternal growth hormone treatment from day 35 to 80 of gestation alters nutrient partitioning in favor of uteroplacental growth in the overnourished adolescent sheepBiol ReprodYear: 2004701277128514695907|
|Weber WJ,Wallace CR,Hansen LB,Chester-Jones H,Crooker BA. Effects of genetic selection for milk yield on somatotropin, insulin-like growth factor-I, and placental lactogen in Holstein cowsJ Dairy SciYear: 2007903314332517582117|
|Woodall SM,Breier BH,Johnston BM,Bassett NS,Barnard R,Gluckman PD. Administration of growth hormone or IGF-I to pregnant rats on a reduced diet throughout pregnancy does not prevent fetal intrauterine growth retardation and elevated blood pressure in adult offspringJ EndocrinolYear: 1999163697710495409|
|Wright CD,Orbus RJ,Regnault TRH,Anthony RV. Effects of early gestation GH administration on placental and fetal development in sheepJ EndocrinolYear: 2008198919918430766|
|Zhou J,Bondy C. Insulin-like growth factor-II and its binding proteins in placental developmentEndocrinologyYear: 1992131123012401380437|
|AIB||amino isobutyric acid|
|D||day of pregnancy|
|hCG||human chorionic gonadotropin|
|hPL||human placental lactogen|
|IGF||insulin-like growth factor|
|IGFBP||IGF binding protein|
[Figure ID: fig01]
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 data presented are from the following references: Gargosky et al. 1990; Giudice et al. 1993; Nason et al. 1996; Wallace et al. 1997; Sohlstrom et al. 1998; Farmer et al. 2000; Perry et al. 2002; Weber et al. 2007; de Boo et al. 2008; Van Mieghem et al. 2009.
[Figure ID: fig02]
The proposed actions of maternal circulating IGFs on the mother and placenta that drive fetal growth
Circulating IGFs influence maternal tissue growth and metabolism and thereby modulate nutrient availability for conceptus growth. Maternal IGFs also regulate placental morphogenesis, substrate transport and hormone secretion, which influence fetal growth by indirect effects on maternal substrate availability, or by direct impacts on placental capacity to supply nutrients to the fetus and the fetal endocrine environment. These actions of plasma IGFs on the mother and placenta influence fetal growth, metabolism and endocrine state, which in turn, may signal back to the placenta to alter its phenotype.
The impact of elevated maternal plasma IGF-I, IGF-II or GH treatment on the mother and offspring
|Gestational age (days) at||Outcomes for|
|Maternal treatment||Species||Treatment||Study (% of term)||Offspring||Mother||References|
|IGF-I||Mouse||D1–19||D19 (95%)||↓ maternal constraint||↔ fetal weight litter size and fetal weight were no longer negatively associated||(Gluckman et al. 1992)|
|Rat||D10–21||D21 (95%)||↑ weight gain during pregnancy||↔ fetal weight or viability||(Gargosky et al. 1991; Woodall et al. 1999)|
|Guinea pig||D20–37||D40 (57%)||↔ weight gain, food efficiency, body composition ↔ circulating metabolites||↓ litter size by 27%↑ fetal weight by 6%||(Sohlstrom et al. 2001)|
|D20–38||D35 (50%) and D62 (90%)||On D35 and D63: ↑ tissue glucose and AIB uptake On D62: ↓ 30–50% adiposity||On D35 and D62: ↑ fetal weight by 15–17% On D62: ↑ fetal viability ↑ plasma a-amino nitrogen ↓ circulating cholesterol||(Sferruzzi-Perri et al. 2006, 2007a,b)|
|IGF-II||Rat||D16–22||D22 (100%)||↑ plasma volume expansion ↔ body weight||↔ fetal weight||(Van Mieghem et al. 2009)|
|Guinea pig||D20–37||D40 (57%)||↔ weight gain, food efficiency ↔ circulating metabolites ↑ interscapular fat mass||↑ fetal weight by 7%||(Sohlstrom et al. 2001)|
|D20–38||D35 (50%) and D62 (90%)||On D62: ↔ weight or body composition ↑ tissue AIB uptake ↔ circulating metabolites||On D62: ↑ fetal viability ↑ fetal weight by 11% ↑ circulating a-amino nitrogen||(Sferruzzi-Perri et al. 2006, 2007a,b)|
|Leu27 IGF-II||Guinea pig||D20–38||D62 (90%)||↔ weight gain ↓ adiposity by 10–30% ↔ tissue uptake of glucose or AIB ↔ circulating metabolites||↔ fetal viability ↑ fetal weight by 11% ↑ circulating a-amino nitrogen ↓ circulating cholesterol ↓ circulating fatty acids||(Sferruzzi-Perri et al. 2008)|
|GH||Rat||D10–20||D20 (90%)||↑ weight gain||↔ fetal weight or body composition ↔ postnatal growth||(Woodall et al. 1999)|
|GH||Pig||D10–27||D28 (25%)||↔ body weight ↑ lean body mass ↑ circulating insulin, glucose and free fatty acids||↑ fetal weight of runts||(Rehfeldt et al. 2001; Schneider et al. 2002)|
|D25–50||D50 (45%)||↑ weight gain in sows ↔ weight gain in gilts In both sows and gilts: ↓ circulating urea||In both sows and gilts: ↑ fetal weight by 11%||(Gatford et al. 2009)|
|D28–40||D41 (35%), P1 (100%)||↑ weight on D41 but ↓ by D105||↑ embryonic survival ↔ fetal weight ↑ fetal and postnatal CR length||(Kelley et al. 1995; Sterle et al. 1995)|
|D30–70||D113 (100%)||ND||↔ fetal weight ↔ fetal viability||(Okere et al. 1997)|
|D97–115||D113 (100%)||↑ circulating glucose ↑ circulating insulin ↑ circulating fatty acids||↔ birth weight||(Kveragas et al. 1986)|
|Sheep||D7–30 Singleton and twin pregnancies||P1 (100%)||ND||In singleton but not twin pregnancies: ↑ birth weights by 10%||(Costine et al. 2005; Koch et al. 2010)|
|D35–55 Only twin pregnancies||D55 (37%)||↔ weight gain||↔ fetal weight||(Wright et al. 2008)|
|D70–84 or D98–112 Singleton and twin pregnancies||D85 (56%) or D113 (75%)||↔ energy intake ↑ uterine weight ↑ circulating insulin ↑ circulating fatty acids ↑ circulating glucose||D70–84: ↔ fetal weight D98–112: ↑ fetal weight by 9–11% (similar impacts on singles and twins)||(Jenkinson et al. 1999)|
|D35–80||D81 (54%)||↔ food intake ↔ weight gain ↓ adiposity by ∼20%↑ liver mass ↑ circulating insulin, glucose and fatty acids ↓ circulating leptin||↔ fetal weight||(Wallace et al. 2004)|
|GH||Sheep||D97–124||D125 (83%), P1 (100%)||↔ weight gain ↓ proportion of body fat||↔ fetal weight||(Stelwagen et al. 1994)|
|D125–134||D134 (90%)||↔ energy intake ↔ body weight ↓ circulating urea ↑ circulating insulin||↔ fetal weight||(Harding et al. 1997)|
AIB, amino isobutyric acid; CR, crown–rump; D, day of pregnancy; ND, not determined; P, postnatal day. For studies in sheep, pregnancies were singleton or otherwise stated. Average gestational length in days in: mice, 20; rats, 22; guinea pigs, 70; pigs, 112 and sheep, 150.
The impact of IGFs on placental growth and function in vitro and in vivo
|Treatment||Species||Treatment (txt)||Analysis day||Placental outcome||References|
|IGF-I||Mouse||In vivo: maternal txt D1–19||D19||↔ weight||(Gluckman et al. 1992)|
|In vitro: primary ectoplacental cone trophoblast||1st trimester||↑ proliferation ↑ migration||(Kanai-Azuma et al. 1993)|
|Rat||In vivo: maternal txt D10–21||D21||↔ weight||(Gargosky et al. 1991; Woodall et al. 1999)|
|Guinea pig||In vivo: maternal txt D20–37||D40||↑ weight by 10%||(Sohlstrom et al. 2001)|
|In vivo: maternal txt D20–38||D35 and D62||↔ weight or structure ↑ transfer of glucose and AIB||(Sferruzzi-Perri et al. 2006, 2007a,b)|
|Sheep||In vivo: maternal txt for 4 h on ∼D132||D132||↑ lactate production||(Liu et al. 1994)|
|Human||In vitro: villous explants||1st trimester||↑ trophoblast proliferation ↑ extravillous trophoblast migration ↓ trophoblast apoptosis||(Maruo et al. 1995; Lacey et al. 2002; Forbes et al. 2008)|
|In vitro: villous explants||1st trimester||↑ secretion of hCG and hPL||(Maruo et al. 1995),|
|In vitro: primary trophoblast||1st trimester||↑ proliferation ↑ migration ↑ invasion||(Hamilton et al. 1998; Hills et al. 2004; Kabir-Salmani et al. 2004)|
|In vitro: primary villous trophoblast||1st trimester and term||↑ glucose and amino acid uptake||(Kniss et al. 1994; Karl, 1995; Roos et al. 2009)|
|In vitro: villous explants||Term||↓ release of vasoconstrictors||(Siler-Khodr et al. 1995)|
|In vitro: primary villous and syncytialised trophoblast||Term||↓ TNFα- and IFNγ-induced apoptosis||(Smith et al. 2002)|
|IGF-II||Mouse||In vitro: primary ectoplacental cone trophoblast||1st trimester||↑ differentiation into giant cells||(Kanai-Azuma et al. 1993)|
|Rat||In vivo: maternal txt D16–22||D22||↑ 29% volume of junctional zone||(Van Mieghem et al. 2009)|
|Sheep||In vitro: primary mononuclear trophoblast||1st trimester||↑ migration||(Kim et al. 2008)|
|Guinea pig||In vivo: maternal txt D20–37||D40||↑ weight by 9%||(Sohlstrom et al. 2001)|
|In vivo: maternal txt D20–38||D35 and D62||↔ weight ↓ area and proportion of the interlobium ↑ labyrinthine area, proportion and volume ↑ surface area for exchange ↔ thickness of the trophoblast barrier for exchange ↑ transfer of glucose||(Sferruzzi-Perri et al. 2006, 2007a,b)|
|IGF-II||Human||In vitro: villous explants||1st trimester||↑ trophoblast proliferation ↑ syncytial regeneration ↑ extravillous trophoblast cell migration ↓ trophoblast apoptosis||(Lacey et al. 2002; Forbes et al. 2008)|
|In vitro: primary trophoblast||1st trimester||↑ proliferation ↑ migration ↑ invasion||(Irving & Lala, 1995; Hamilton et al. 1998; McKinnon et al. 2001; Hills et al. 2004; Qiu et al. 2005)|
|In vitro: primary villous trophoblast||1st trimester and term||↑ glucose and amino acid uptake||(Kniss et al. 1994; Karl, 1995)|
AIB, amino isobutyric acid; D, day of pregnancy; hCG, human chorionic gonadotropin; hPL, human placental lactogen; txt, treatment.
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