Maternal IGF-1 Research Articles

Regulation of placental amino acid transport in health and disease.

Abnormal fetal growth, i.e., intrauterine growth restriction (IUGR) or fetal growth restriction (FGR) and fetal overgrowth, is associated with increased perinatal morbidity and mortality and is strongly linked to the development of metabolic and cardiovascular disease in childhood and later in life. Emerging evidence suggests that changes in placental amino acid transport may contribute to abnormal fetal growth. This review is focused on amino acid transport in the human placenta, however, relevant animal models will be discussed to add mechanistic insights. At least 25 distinct amino acid transporters with different characteristics and substrate preferences have been identified in the human placenta. Of these, System A, transporting neutral nonessential amino acids, and System L, mediating the transport of essential amino acids, have been studied in some detail. Importantly, decreased placental Systems A and L transporter activity is strongly associated with IUGR and increased placental activity of these two amino acid transporters has been linked to fetal overgrowth in human pregnancy. An array of factors in the maternal circulation, including insulin, IGF-1, and adiponectin, and placental signaling pathways such as mTOR, have been identified as key regulators of placental Systems A and L. Studies using trophoblast-specific gene targeting in mice have provided compelling evidence that changes in placental Systems A and L are mechanistically linked to altered fetal growth. It is possible that targeting specific placental amino acid transporters or their upstream regulators represents a novel intervention to alleviate the short- and long-term consequences of abnormal fetal growth in the future.

P-543 Higher maternal age alters the insulin/IGF system and intracellular lipid metabolism of the endometrium and in the preimplantation embryo – insights from the rabbit model.

Abstract Study question Our aim was to analyse the embryo-maternal-interaction, focusing on the insulin/IGF-system and lipid metabolism on day 6 of pregnancy in reproductive young and old rabbits. Summary answer Advanced maternal age has a decisive effect on maternal and embryonic insulin/IGF-signalling and lipid metabolism, leading to higher embryo loss already during preimplantation period. What is known already The reproductive potential in women declines with age. Molecular and biochemical mechanisms involved in age-related infertility and their impact on embryo-maternal-interaction during early pregnancy are still not completely understood. However, establishment of a successful pregnancy depends on the physiological condition of the mother and a continuous dialogue with the developing embryo. The insulin/IGF-system plays a pivotal role in this embryo-maternal crosstalk, connecting maternal insulin/IGF with embryonic metabolism, cell proliferation and differentiation. Study design, size, duration We used the rabbit as reproductive model to investigate maternal age-related alterations in embryo-maternal-interaction during preimplantation period. Compared to humans, the rabbit shares high similarities in early embryo development, gastrulation and lipid metabolism (DOI: 10.1530/REP-12-0091 and DOI: 10.1093/ajcn/62.2.458S). A total of 50 young (16-20 weeks) and 31 old (<108 weeks) sexually mature, female rabbits were used for analysis at day 6 post coitum. Participants/materials, setting, methods We measured mRNA and protein levels of target genes of the insulin/IGF system and lipid metabolism by quantitative PCR, Western Blot and ELISA. Therefore, maternal blood, endometrium and blastocysts were analysed from reproductive young (16 to 20 weeks) and old (over 108 weeks) rabbits on day 6 of pregnancy. Blastocysts and ovulation points were counted and only blastocysts at the pre-gastrulating stage 1, separated in embryoblast (EB) and trophoblast (TB), were used for further analyses. Main results and the role of chance At day 6 of pregnancy, reproductive old rabbits had a lower amount of embryos. Maternal serum insulin and IGF levels were reduced in reproductive old rabbits, accompanied by a paracrine upregulation of IGF1 and its receptors in the endometrium. Preimplantation blastocysts adapted to hormonal changes by reducing IGF1 and IGF2 levels in both embryonic compartments, EB and TB, while the expression of embryonic IGF receptors was unchanged. Furthermore, an increase of fatty acids metabolism was observed in the ageing endometrium, indicated by the higher level of carnitine palmitoyltransferase I B (CPT1B) and elevated expression of fatty acid binding and transport proteins. These results are in line with lower level of fatty acid synthesis (FASN) in the endometrium from old, gravid rabbits, the key enzyme of fatty acid synthesis. Embryonic fatty acid uptake and b-oxidation were increased in EB and TB, too. The observed changes in embryonic and maternal lipid metabolism are caused by the alterations of the transcription factors cAMP-responsive element binding protein (CREB) and peroxisome proliferator-activated receptor (PPAR) α and γ in endometrium and embryos from reproductive old rabbits. Limitations, reasons for caution Rabbit embryogenesis reflects human development only during blastocysts formation. Therefore, statements are limited to the embryogenesis stages investigated. Wider implications of the findings The results of the current study are in accordance with the common literature, showing that advanced maternal age affects developmental competence of embryos. Our study points out that advanced maternal age alters lipid metabolism and insulin/IGF-signalling, which are two crucial components in embryo-maternal-interaction. Trial registration number not applicable

Maternal, placental, and fetal Insulin-Like Growth Factor-I (IGF-1) and IGF Binding proteins (IGFBPs) in Diabetic pregnancies: Effects on fetal growth and birth size.

Introduction: During gestation, IGF1 secretion and availability in the maternal blood and at the maternal-fetal interface is mainly regulated by IGF-binding proteins (IGFBP) such as IGFBP-1 synthesized by the decidua. Data about the interaction between maternal, placental, and fetal IGF1/IGFBP in relation to fetal growth and newborn size during diabetic pregnancy (gestational Diabetes (GDM) and Type 1 DM (T1DM) is not clear. Aim of the study and Methods: We reviewed the research papers published in Pubmed, Google scholar, Research gate, and Scopus in the past 20 years on the relationship between maternal, placental, and fetal/infantile/ IGF1/IGFBP-1 in relation to birth size in pregnancies associated with maternal diabetes. Results: Twenty-eight research papers were selected and reviewed (patients’ number = 1902). In GDM pregnancies, higher maternal IGF1 levels and/or its availability due to lower IGFBP1 levels can increase the size (weight) and functions of the placenta. These include the upregulation of specific placental amino acid transporter isoforms and GLUT-1, stimulation of mTOR signaling which stimulates protein synthesis, increasing mitochondrial functions, and accelerating nutrient transport which significantly contributes to fetal growth and newborn birth size. On the other hand, in pregnant women with T1DM, lower maternal IGF1 is associated with subsequent underweight placenta and lower birthweight.

Insulin like growth factor 1 (IGF-1) and IGF binding proteins in obese pregnant women and their babies: Potential effects on placental function and fetal growth

Introduction: The placenta expresses significant amounts of insulin and IGF1 receptors at distinct locations on both fetal and maternal surfaces. This makes the IGF1 and the insulin receptor accessible to fetal and/or maternal insulin, IGF1 and IGF2. IGFs are involved in the receptor-mediated regulation of placental growth and transport, and placental angiogenesis. Maternal obesity during gestation mediates significant changes in the metabolism of mothers, placentas as well as fetal growth. Objectives: In obese women. the role of the insulin like growth factor system IGFs, IGF receptors, IGF-binding proteins (IGFBPs) and IGFBP proteases during gestation, and their effect on placental growth and fetal anthropometric changes need further clarification. In this update we reviewed the literature on the detected changes in the maternal and fetal IGFs in relation to placental growth and function and to fetal growth and newborn size in pregnant obese mothers. Eighteen research articles fitted the criteria of this update. Results: Twenty-three research papers were including 2817 pregnant obese and non-obese women (controls) and their babies were selected and reviewed. Results showed that obesity and excessive nutrient intake during gestation increase maternal IGF1and decreases IGBP1. Increased maternal IGF1 and/or its availability due to decreased IGFBP1 can increase the size (weight) and development of the placenta, stimulate mTOR signaling which stimulates protein synthesis, mitochondrial function, and upregulate specific placental amino acid transporter isoforms (amino acids transport), GLUT-1, (glucose transport) and possibly lipid transport to the fetus which can induce fetal IGF1 secretion and lead to overgrowth. Conclusions: In obese women during pregnancy, increased level of IGF1 and/or its availability due to decreased IGFBP1 can increase the size (weight) and development of the placenta, stimulate mTOR signaling which stimulates protein synthesis, mitochondrial function, and upregulate placental transport of amino acids, glucose and possibly fatty acids.

The impact of nutritional status and maternal behavior on infant growth

<p><strong>Background: </strong>Maternal behaviour during pregnancy is closely related to the condition of the fetus. Malnutrition in pregnant women can cause Low Birth Weight Babies (LBW) and also a decrease in the level of intelligence. The prevalence of stunting in 2021 decreased by 1.6 from 2019, that shows from 27.7% to 24.4%.</p><p><strong>Objectives:</strong> This study aims to determine the impact of nutritional status and maternal behaviour on infant growth in West Jakarta.</p><p><strong>Methods:</strong> This study was a cross-sectional, starting on July 2017 until January 2018. A total of 66 subjects of pregnant women aged 18-35 years chosen to take part in the study from their 37th weeks of pregnancy to delivery. Drinking alcohol, traditional herbs, medicines, and smoking are indicators of maternal behaviour. Maternal IGF-1 concentrations, body weight, body length, and infant heart rate were indicators of infant growth. Chi-Square test and Independent T-Test were used for the statistical analysis.</p><p><strong>Results:</strong> The subjects showed a mean of 26.0±4.8 years old, body height of 154.0±4.9 cm, body weight in third pregnancy of 66.4±11.3 kg, BMI of 22.6±3.7 kg/m<sup>2</sup>, MUAC of 27.2±3.3 cm, and body temperature of 36.2±1.3°C. Maternal behaviour and nutrional status did not significantly affect infant growth (p≥0.05). However, MUAC was a factor that affected to heart rate in infants (p<0.05).</p><p><strong>Conclusions:</strong> Nutritional status is one of indicator that affects to infant growth; therefore, pregnant women need to more attention to keep their nutritional status, nutritional intake and healthy living behaviour during pregnancy.</p>

The Gestational Effects of Maternal Appetite Axis Molecules on Fetal Growth, Metabolism and Long-Term Metabolic Health: A Systematic Review.

Increased maternal food intake is considered a normal pregnancy adjustment. However, the overavailability of nutrients may lead to dysregulated fetal development and increased adiposity, with long-lasting effects on offspring in later life. Several gut-hormone molecules regulate maternal appetite, with both their orexigenic and anorectic effects being in a state of sensitive equilibrium. The aim of this manuscript is to systematically review literature on the effects of maternal gut-hormone molecules on fetal growth and metabolism, birth weight and the later metabolic health of offspring. Maternal serum ghrelin, leptin, IGF-1 and GLP-1 appear to influence fetal growth; however, a lack of consistent and strong correlations of maternal appetite axis hormones with birth weight and the concomitant correlation with fetal and birth waist circumference may suggest that these molecules primarily mediate fetal energy deposition mechanisms, preparing the fetus for survival after birth. Dysregulated intrauterine environments seem to have detrimental, sex-dependent effects on fetal energy stores, affecting not only fetal growth, fat mass deposition and birth weight, but also future metabolic and endocrine wellbeing of offspring.

Components of the insulin-like growth factor system in in vivo - and in vitro-derived fetuses of cattle, and the association with growth and development

This experiment was designed to study mechanisms affecting growth of in vivo-derived (IVD) and in vitro-produced (IVP) fetuses of cattle. Day-7 IVD or IVP cattle blastocysts were transferred to recipients, with pregnant females being slaughtered on Days 90 or 180 of gestation or allowed to undergo parturition. Uteri and contents were dissected and physically measured, and maternal and fetal plasma and amniotic and allantoic fluids were collected for IGF-1 and IGF-2 determinations, and IGFBP profile characterization. Transcripts for IGF-1 and IGF-2 mRNA in placental and fetal tissues, and IGF-1r and IGF-2r in placentomes were determined. There was a greater fetal weight in the IVP group, which was associated with greater IGF-1 and IGF-2 concentrations in maternal circulation, and changes in IGFBP profiles within fetal fluids. Day-90 IVP-derived fetuses were longer, had greater organ weights, larger placentomes, less placentome IGF-2r mRNA transcript, and greater maternal IGF-1 and IGF-2 concentrations than controls. On Day 180 and at parturition tissues from IVP-derived fetuses/calves were from larger uteri, with larger placentomes/fetal membranes, fetuses/calves weighed more, had greater fetal hepatic IGF-2 mRNA transcript, had less fetal plasma IGF-1 and greater allantoic IGF-2 concentrations, greater and lesser IGFBP activities in the allantoic and amniotic fluids, respectively, and greater glucose and fructose accumulation in fetal fluids. Components of the IGF system were differentially regulated not only according to the gestation period (Days 90 or 180) and fluid type (maternal or fetal plasma, amniotic or allantoic fluids), but also based on conceptus origin (IVP or IVD) in cattle.

Consecutive measurements show association of IGF-1 with fetal growth in type 1 diabetic pregnancy

Background: Abnormal fetal growth can lead to adverse outcomes in pregnancy as well in later postnatal life and is more prevalent in diabetic pregnancies. These are usually associated with large for gestational age neonates, an issue that has already been broadly examined. On the other side, diabetes in pregnancy can also relate to intrauterine growth restriction and small for gestational age neonates. During pregnancy, maternal IGF-1 is secreted excessively and additionally produced by placenta, which regulates transport of nutrients to the fetus acting through an IGF-receptor and accordingly affects its growth. As type 1 diabetes carries a higher risk of adverse events associated with fetal growth there is a natural focus on possible links between IGF-1 and fetal growth. Aim: The present study investigated the time-course relationship between the maternal serum IGF-1 and the birthweight as an obstetrical outcome in type 1 diabetic pregnancies with various levels of background risk. Methods: 130 pregnant women with type 1 diabetes were consecutively recruited for measurement of growth factors, genes affecting coagulation, evaluated for diabetes status, and perinatal outcome. The birthweight z-score was computed and grouped into tertiles for analysis of association with repeated measurements of IGF-1. Diurnal blood pressure was measured by monitor. Retinopathy grade was evaluated by two specialists independently, blinded of the clinical data. Blood samples for IGF-1 during pregnancy were drawn from week 6 and every 4th week until week 30, then every 2 nd week. Genomic DNA was extracted from peripheral blood. Results: The median of the lowest tertile of birthweight z-score was 0.4 (-1 - +1.3) and included more women with micro/macroalbuminuria than the middle and upper tertile; however, ¾ had normoalbuminuria and no further sign of surplus vasculopathy compared to the other tertile groups. The lowest birthweights were associated with a lower rise in IGF-1 from week 22 to 32. Neither glycemic control, genetics, grade of retinopathy, renal function nor vascular resistance indices in diurnal blood pressure were different between the tertile groups. Conclusion: Our main finding is that lower IGF-1 levels are associated with subsequent lower birthweight in diabetic pregnancy and is displayed markedly at the end of 2nd trimester. We hypothesize that the relative low birthweight, despite being within the limits of appropriate for gestational age may display inappropriate growth if not outright growth-restriction. We were able to discern different levels of growth at a critical point in pregnancy where ultrasound may pick up different levels of growth patterns and optimized care can be commenced.

Decreased maternal serum adiponectin and increased insulin-like growth factor-1 levels along with increased placental glucose transporter-1 expression in gestational diabetes mellitus: Possible role in fetal overgrowth

IntroductionThe placental glucose transporter – 1 (GLUT-1) is involved in the transplacental glucose transport to the fetus. GLUT-1 expressions are increased in diabetic pregnancies and associated with altered fetal growth. However, the factors regulating the GLUT-1 expressions are largely unknown. We hypothesised that maternal adipokines and insulin-like growth factor-1 (IGF1) modulate the placental expressions of GLUT-1 through the activation of insulin/IGF-1 signalling which may contribute to a fetal overgrowth in GDM. MethodsMaternal blood, cord blood and placental samples were collected from GDM and control pregnant women (CPW). The biochemical parameters, IGF1, adipokines, and high sensitive C- reactive protein were measured. We analysed the placental expressions of GLUT-1 and proteins related to insulin/IGF-1 signalling - insulin receptor –β, insulin receptor substrate – 1, phosphatidylinositol-3-kinase p110α, phospho Akt-1, phospho extracellular signal-regulated kinase 1/2, and nuclear factor-κB p65 in GDM and CPW. ResultsIncreased maternal IGF-1 and decreased adiponectin levels were found in the GDM women. Maternal IGF-1 levels were positively correlated, whereas adiponectin levels were negatively correlated with the birth weight of GDM newborns. Increased phosphorylation of Akt and ERK 1/2 was found in the placenta of GDM women. Placental expressions of GLUT-1 were significantly higher in the GDM women and positively correlated to the maternal IGF-1 levels in the GDM group. DiscussionDecreased maternal adiponectin and increased IGF-1 levels might have caused increased GLUT-1 expression via the increased activation of insulin/IGF-1 signalling in the placenta of GDM women which might have influenced the fetal growth.

Association of placental nutrient sensing pathways with birth weight.

Birth weight (BW) is an important indicator for newborn health. Both high and low BW is associated with increased risks for adult metabolic diseases. AMPK (AMP-activated protein kinase), mTOR (mechanistic target of rapamycin), and insulin/IGF1 (insulin-like growth factor 1) pathways may function as placental sensors of maternal hormonal and nutritional status. However, the physiological role of these pathways in placenta has not been completely elucidated. To evaluate expression and activation of AMPK, mTOR, and insulin/IGF1 pathways and its association with placental weight (PW), BW, and maternal hormonal and metabolic status, we performed a cross-sectional study in placentas from non-obese mothers with SGA (n = 17), AGA (n = 19) and LGA (n = 10) newborns. We analyzed placental expression of total and phosphorylated key proteins from the AMPK, mTOR and insulin/IGF1 pathways. Maternal and cord blood hormones were determined by ELISA. AMPK and LKB1 activation correlated negatively with PW and BW, cord leptin, and pregestational BMI. Placental SIRT1 inversely correlated with BW, cord leptin, neonatal HOMA-IR, and maternal IGF1. PGC1α correlated negatively with PW and BW. Phosphorylated mTOR positively correlated with maternal glucose, PW and BW. IGF1R was lower in SGA. No changes in p-IGF1R, INSRb, total AKT or p-AKT were found, and pPDK1 was lower in SGA and LGA. These results suggest that placental AMPK, insulin/IGF1, and mTOR pathways may influence fetal growth, perhaps regulating placental physiology, even in metabolically healthy pregnancies. Our study highlights these nutrient sensing pathways as potential molecular mechanisms modulating placental adaptations and, thus, long-term metabolic health.

Glucosamine Supplementation in Premating Drinking Water Improves Within-Litter Birth Weight Uniformity of Rats Partly through Modulating Hormone Metabolism and Genes Involved in Implantation.

Within-litter birth weight variation in multiparous animals has become a big issue due to high incidence of low birth weight neonates, which gives rise to high preweaning mortality and morbidity. Foetus with various birth weights is the outcome of diverse embryos competence which is affected by oocyte quality. Glucosamine (GlcN) has been reported to be involved in oocyte maturation; however, its effect on pregnant outcomes remains unknown. The present study was conducted to investigate the effects of premating GlcN supplementation via drinking water on within-litter birth weight variation and its underlying mechanism. Fifty eight Sprague-Dawley female rats were randomly assigned to one of two groups with normal drinking water or drinking water supplemented with 0.5 mM GlcN from six to eight weeks old. Variation of within-litter birth weight in the GlcN group was 5.55%, significantly lower compared with 8.17% in the control group. Birth weight was significantly increased in the GlcN group (2.27 ± 0.06) compared with the control group (2.08 ± 0.04). Both absolute and relative weights of the ovary at the end of GlcN treatment were higher in the GlcN group than in the control group (P < 0.05). In the GlcN group, there were more successfully implanted blastocysts (13.38 ± 0.63 and 15.75 ± 0.59 in the control and treatment group, respectively) with more uniform distribution along the two uterine horns compared with the control group. Besides, gene expressions of Alk3 and Bmp2 were increased in the implantation sites, while IGF-1 and Mucin-1 were decreased significantly in rats administrated with GlcN. Maternal progesterone, estradiol, and IGF-1 concentrations on D 19.5 were significantly increased, while insulin and total cholesterol levels were significantly decreased in contrast with control dams. In summary, the administration of 0.5 mM GlcN solution before mating reduced within-litter birth weight variation, accompanied with increased fetal weight. Further investigation indicated that the improved outcome of pregnancy results at least partly from the increased ovary weights of the rats, the homogeneous embryo developmental competence, the enhanced receptivity of the uterine environment, and the adjusted maternal hormone levels.

Increased maternal serum placental growth hormone variant in pregnancies complicated by otosclerosis.

To investigate the potential role of maternal serum concentrations of placental growth hormone variant (GH-V), insulin-like growth factor (IGF) 1 and 2, and IGF-binding proteins (IGFBP) 1 and 3 in pregnancies complicated by otosclerosis. Otosclerosis cases (n=22) and age, ethnicity-matched controls (n=22) were selected in a nested case-control study. Maternal serum hormone concentrations at 26 and 34weeks of gestation were determined by enzyme-linked immunosorbent assay (ELISA). Concentrations of all measured hormones except IGFBP-1 were increased as gestation progressed. Maternal serum GH-V concentrations at 26 and 34weeks of gestation were significantly increased in the otosclerosis group, when compared to the control group (2.53±0.17ng/ml vs. 1.78±0.19ng/ml, P=0.036; 4.34±0.31ng/ml vs. 3.12±0.18ng/ml, P<0.001, respectively). Maternal serum IGF-1 concentrations at 34weeks in otosclerotic patients were significantly higher than in the controls (589.1±21.4ng/ml vs. 499.7±17.8ng/ml, P<0.001). The increase of IGF-1 was not observed at 26weeks of gestation. Serum IGF-2, IGFBP-1 and IGFBP-3 at either 26 or 34weeks were unaltered between the two groups. Maternal serum concentrations of GH-V and IGF-1 were altered in pregnancy complicated by otosclerosis, suggesting that the GH-IGF axis may contribute to the development of this condition during pregnancy.

Increased placental IGF-1/mTOR activity in macrosomia born to women with gestational diabetes

AimsNewborns of women with gestational diabetes mellitus (GDM) are susceptible to be macrosomic, even if the blood glucose levels are in normal ranges. The underlying mechanisms are largely unknown. We tested the hypothesis that placental insulin like growth factor(IGF)-I and mammalian target of rapamycin (mTOR) signaling is activated and amino acid transporter expression is increased in women with GDM who give birth to macrosomic babies. Methods50 Chinese pregnant women with GDM whose blood glucose levels were controlled within normal range were recruited and their placental tissues were collected. 23 women gave birth to macrosomia and 27 women gave birth to babies with normal birth weight. We determined the phosphorylation of key signaling molecules (including Akt, IRS-1, S6K1, 4E-BP-1, and AMPKα) in the placental IGF-I and mTOR signaling pathways. We also measured the protein expression of the amino acid transporter systems A in placenta. ResultsBirth weights (range 2500–4400 g) were positively correlated to maternal IGF-1 (P < 0.05). The activity of placental IGF-I and mTOR signaling was positively correlated (P < 0.05), whereas AMPKα phosphorylation was inversely (P < 0.05) correlated to birth weight. Protein expression of the system A isoform sodium-dependent neutral amino acid transporter (SNAT) 1 were positively correlated to birth weight (P < 0.05). ConclusionsUp-regulation of placental amino acid transporters may contribute to more macrosomic babies in women with GDM. Activation of IGF-I and mTOR signaling pathways might involve in this effect.

Maternal and umbilical cord blood level of macrophage migration inhibitory factor and insulin like growth factor in Sudanese women with preeclampsia

Preeclampsia is a health concern and it is the main cause of maternal and perinatal mortality. The macrophage migration inhibitory factor (MIF) and insulin-like growth factor-I (IGF-I) are factors associated with preeclampsia. A case-control (45 women in each arm) study was conducted at Saad Abualila Maternity Hospital (Khartoum, Sudan). The cases were of women who had preeclampsia, and the controls were healthy pregnant women. The clinical and obstetrical characteristics were gathered using a questionnaire and MIF and IGF-I levels were measured by ELISA. The cases and the controls (45 in each arm) were matched in their basic data. In comparison with the healthy controls, while the median (interquartile range) of the maternal MIF [8.221 (7.334–8.820) vs. 3.717 (2.385–4.883) ng/mL, p < .001] was significantly higher, the levels of the maternal IGF-1 [1.250 (0.670–1.980) vs. 1.939 (1.056–2.752), ng/mL, p < .001] were significantly lower in the women with preeclampsia. There was no significant difference in the cord levels of both the MIF and IGF-1 between the cases and controls. In linear regression, preeclampsia was the only factor that was significantly associated with the log of the maternal MIF (−0.338 ng/mL, p < .001), IGF-1 (0.293 ng/mL, p = .005) and cord MIF (−0.340 ng/mL, p < .001) levels.Impact statementWhat is already known on this subject? Macrophage migration inhibitory factor (MIF) has a pivotal role in pro-inflammatory processes during pregnancy/labour and its levels have been correlated with preeclampsia. Insulin like factors are produced in the liver under the stimulation of the growth hormones; they stimulate cell differentiation proliferations. IGF-I may be implicated in the pathogenesis of the adverse effects of preeclampsia (mainly the birth weight).What do the results of this study add? The current study showed a significantly higher level of MIF and lower level IGF-1 in the women with preeclampsia. Thus, both MIF and IGF-1 might have a role in the pathogeneses of preeclampsia.What are the implications of these findings for clinical practice and/or further research? MIF and IGF might be used as reliable markers to detect preeclampsia. These markers might be used as preventive or therapeutic elements for preeclampsia.

Growth hormone deficiency and pregnancy: any role for substitution?

Growth hormone (GH) is not approved for use during conception and pregnancy. Nevertheless, data from the clinical care practice reveal that most women concieve on GH replacement therapy (GHRT), and more than half continue on GHRT also during pregnancy. GH stimulates the hypothalamic-pituitary-gonadal axis at all levels, and there is evidence that GH deficiency impacts the morphology of reproductive organs, onset of puberty, ovarian function and fertility. Patients with hypopituitarism often conceive using assisted reproductive techniques and several studies support the benefit of GH supplementation for achieving fertility in women with GH deficiency. During gestation the GH system is regulated by the placental growth hormone, which increases continuously with the growth of placenta and stimulates maternal IGF-1 levels, leading to a concomitant decline in pituitary GH secretion. GHRT regimens that aim to mimic the pathophysiology of GH/IGF-1 concentrations during pregnancy continue GHRT during the first trimester, gradually reduce GH dose during the second trimester and stopp GHRT at the beginning of the third trimester. Pregnancy outcomes were not found to be related to GHRT treatment patterns during pregnancy, but female patients with childhood-onset hypopituitarism have lower fertility rates and less positive pregnancy outcomes. Although current guidelines recommend against GHRT during pregnancy, GHRT might be needed for achieving fertility and satisfactory pregnancy outcomes are reported following the decision of patients and physicians for adapting the GHRT dose during pregnancy.

Placental control of metabolic adaptations in the mother for an optimal pregnancy outcome. What goes wrong in gestational diabetes?

As pregnancy progresses the placental syncytiotrophoblast increasingly assumes control of maternal glucose homeostasis through the release and counter-balancing effects of placental lactogen (PL) and placental variant growth hormone (GH-V). While local actions of these hormones on placental growth and function are likely to exist, each also exerts indirect actions to ensure fetal nutritional availability through modulation of the maternal insulin/insulin-like growth factor axis. Peripheral insulin resistance results from the increasing levels of GH-V in the maternal circulation and is counter-balanced by an increase in insulin availability through an expansion of maternal pancreatic β-cell mass. GH-V also increases maternal IGF-1 synthesis leading to enhanced placental growth and nutrient transporter activity. Maternal obesity and the presence of diabetes in pregnancy is associated with a disrupted balance in the placental expression of PL and GH-V. Several parallel mechanisms are likely to contribute to the increasing maternal β-cell mass as gestation progresses, including a reactivation of β-cell proliferation, an expansion of subsequent differentiation of resident β-cell progenitors, and α-to β-cell trans-differentiation. Each of these pathways could potentially be modulated during pregnancy to increase β-cell mass and prevent the onset of gestational diabetes.

Maternal serum placental growth hormone, insulin-like growth factors and their binding proteins at 20 weeks' gestation in pregnancies complicated by gestational diabetes mellitus.

To investigate whether maternal serum concentrations of placental growth hormone (GH-V), insulin-like growth factor (IGF) 1 and 2, and IGF binding proteins (IGFBP) 1 and 3 were altered in pregnancies complicated by gestational diabetes mellitus (GDM). In a nested case-control study, GDM cases (n=28) and matched controls (n=28) were selected from the Screening for Pregnancy Endpoints (SCOPE) biobank in Auckland, New Zealand. Maternal serum hormone concentrations at 20 weeks of gestation were determined by enzyme-linked immunosorbent assay (ELISA). There was no significant difference in maternal serum GH-V concentration in the GDM group compared to the control group (1.64 ± 0.11 ng/ml vs. 1.38 ± 0.10 ng/ml, p=0.079). However, GDM cases who delivered large for gestational age (LGA) babies had significantly higher serum GH-V concentrations compared to non-diabetic control cases. Maternal IGF-1 concentrations in GDM pregnancies were significantly higher than in controls (275.7 ± 11.5 ng/ml vs. 218.5 ± 11.1 ng/ml, p <0.001). Maternal IGFBP-1 concentrations were significantly lower in GDM pregnancies than in controls (41.04 ± 3.42 ng/ml vs. 67.58 ± 6.17 ng/ml, p <0.001). There were no significant differences in serum IGF-2 and IGFBP-3 concentrations between groups. Concentrations of IGF-1 and IGFBP-1 in maternal serum were altered in GDM pregnancies compared to controls, suggesting that the IGF axis plays a role in the development of this condition. GH-V may be associated with macrosomia as increased maternal GH-V was observed in GDM cases who delivered LGA babies.

Insulin-like growth factor I and its binding protein-3 are regulators of lactation and maternal responsiveness

Adaptation to motherhood includes maternal behaviour and lactation during the postpartum period. The major organizing centres of maternal behaviour and lactation are located in the hypothalamic medial preoptic area (MPOA) and the arcuate nucleus, respectively. Insulin-like growth factor I (IGF-I) is an effector of the growth hormone axis; however, its function in the brain is largely unexplored. We identified increased maternal IGF binding protein-3 (IGFBP-3) expression in preoptic rat microarray data and confirmed it by RT-PCR. In situ hybridization histochemistry showed markedly elevated IGFBP-3 expression in the MPOA and the arcuate nucleus in rat dams. Prolonged intracerebroventricular injection of IGF-I or antagonism of brain IGFBP-3 with an inhibitor (NBI-31772) using osmotic minipumps increased pup retrieval time, suggesting reduced maternal motivation. Suckling-induced prolactin release and pup weight gain were also suppressed by IGF-I, suggesting reduced lactation. In addition, IGF-I-induced tyrosine hydroxylase expression and its specific phosphorylation in tuberoinfundibular dopaminergic neurons suppress prolactin secretion. Thus, IGF-I may inhibit both behavioural and lactational alterations in mothers. Neurons in the MPOA and arcuate nuclei express IGFBP-3 during the postpartum period to neutralize IGF-I effects. IGFBP-3 can prevent the blockade of maternal behaviour and lactation exerted by IGF-I, suggesting a novel modulatory mechanism underlying the behavioural and hormonal effects during central maternal adaptations.

Markers of obesity and growth in preeclamptic and normotensive pregnant women

The objective of the study was to analyse leptin, IGF-1, Apo A, lipoproteins, haem oxygenase-1 (HO-1) in maternal sera and venous umbilical cord sera of newborn babies of 25 preeclamptics (group II), and 25 normotensive pregnant women (group I) as markers of obesity and growth in preeclamptic and normotensive pregnant women. Apo A I and II levels were estimated by competitive immunoassay using direct chemiluminiscence technology. Haem oxygenase-1 (HO-1), leptin and IGF-1 were analysed by ELISA. Maternal and cord blood levels of homocysteine, folic acid, lipid profile (namely, total cholesterol, triglycerides, LDL-C, VLDL-C and HDL-C), Haem oxygenase 1 were higher in preeclamptic women as compared to normotensive pregnant women. Serum and cord blood Apo A-I and Apo B, leptin levels, IGF-I were lower in preeclamptic women as compared to normotensive pregnant. The findings of high serum HO-1 levels in maternal and cord blood in preeclampsia supports the role of oxidative stress and excessive inflammatory response in the pathogenesis of preeclampsia. It seems likely that IGF-1 and leptin play a central role in controlling foetal growth. There is increasing evidence that the foundations of life-long health are, in part, laid in the uterus. Findings of present study suggest that alterations in biochemical markers of growth and obesity occur in mothers and foetuses and modifications of uterine environment can be of help to prevent future cardiovascular risk.Impact statementPreeclampsia has been reported to be associated with an increased risk of later life cardiovascular disease. However, information regarding how obesity increases the risk of preeclampsia is limited. Atherogenic milieu occurring during pregnancy persists into adulthood and foetal growth retardation is strongly associated with adult atherosclerosis.There is conflicting evidence regarding alterations of IGFs in preeclamptic pregnancies and deficit in circulating and cord blood IGF-1 levels in intrauterine growth restricted newborns and a correlation between IGF-1 levels and birth weight have been reported. Leptin is a predictor of cardiovascular risk independent of insulin resistance. Emerging evidence supports an important role for the haem oxygenase system (HO-1) in the maintenance of a healthy pregnancy, especially during pathological challenge.Conflicting data are available regarding HO-1, leptin and IGF –1 in preeclamptic mothers. The extent to which they mediate foetal growth and developmental abnormalities remains to be clarified.Serum IGF-1 levels were significantly decreased in preeclamptics and maternal IGF-1 showed a strong inverse correlation with leptin levels. High serum HO-1 levels in maternal and cord blood in preeclampsia were observed in the present study.Findings of the present study suggest that alterations in biochemical markers of growth and obesity occur in mothers and foetuses and modifications of the uterine environment can be of help to prevent future cardiovascular risk.

Influence of dietary -arginine supplementation of sows during late pregnancy on piglet birth weight and sow and litter performance during lactation.

Two experiments were conducted to determine the effect of feeding supplemental -Arg during late pregnancy on piglet birth weight and preweaning performance. In Exp. 1, 97 gilts and sows were allotted (gestation d 93) to receive a control diet (CON; 19.8 g standardized ileal digestible [SID] Arg/d) or the CON + 1.0% -Arg (ARG; 46.6 g SID Arg/d). Gilts and sows were weighed on gestation d 93 and 110, 48 h after farrowing, and at weaning. Data, including number born alive, number weaned, individual birth and weaning weight, and placenta weight, were recorded. Blood samples were collected on d 93 and 110 and analyzed for plasma IGF-1, insulin, and blood urea nitrogen concentration. In a second experiment, 383 sows in a commercial research farm were allotted to receive CON or ARG. An -Arg premix was provided daily by top dress beginning at gestation d 81 (±0.1 d) and fed for an average of 35 d (±0.2 d). Sows received 2.73 kg feed/d with CON sows provided 17 g SID Arg/d and ARG sows receiving a total of 44 g SID Arg/d. Litter birth weight was recorded and average birth weight was computed. In a subset of 82 sows, individual birth weights were recorded. In Exp. 1, there was a tendency for greater late pregnancy maternal BW gain ( = 0.06) in ARG compared with CON. A tendency for a parity × treatment interaction was observed for late pregnancy BW gain, with first litter sows fed ARG gaining the most, gilts fed ARG intermediate, and all other treatments gaining the least ( = 0.10). No differences between treatment groups were observed for maternal plasma IGF-1, insulin, and urea nitrogen and in progeny performance to weaning ( > 0.28). In Exp. 2, piglet birth weight was more effectively tested because of the large number of multiparous sows involved. There was a tendency for individual birth weight to decline in ARG compared with CON ( < 0.08), but birth weight distribution between <0.80 and >2.8 kg was similar. No other differences were observed ( > 0.18). In conclusion, late pregnancy supplementation with -Arg had no effect on number of pigs born alive, piglet birth weight, or lactation performance.