Horm Metab Res 2009; 41(11): 791-798
DOI: 10.1055/s-0029-1231026
Review

© Georg Thieme Verlag KG Stuttgart · New York

Changes in GH/IGF-1 Axis in Intrauterine Growth Retardation: Consequences of Fetal Programming?

S. Setia1 , M. G. Sridhar1
  • 1Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India
Further Information

Publication History

received 22.01.2009

accepted 02.06.2009

Publication Date:
21 July 2009 (online)

Abstract

Fetal growth is a complex process that depends on the genotype and epigenotype of the fetus, maternal nutrition, the availability of nutrients and oxygen to the fetus, intrauterine insults, and a variety of growth factors and proteins of maternal and fetal/placental origin. In the fetus, growth hormone (GH) plays little or no role in regulating fetal growth, and insulin-like growth factors (IGFs) control growth directly independent of fetal GH secretion. Placental growth hormone (PGH) is the prime regulator of maternal serum IGF-1 during pregnancy. Total as well as free PGH and IGFs are significantly lower in pregnancies with intrauterine growth retardation (IUGR). The GH/IGF axis is significantly affected by intrauterine growth retardation and some of these alterations may lead to permanent pathological programming of the IGF axis. Alterations in the IGF axis may play a role in the future occurrence of insulin resistance and hypertension. In this review we focus on the regulation of fetal growth and the role of fetal programming in the late consequences of a poor fetal environment reflected in IUGR.

References

  • 1 Bakketeig LS, Butte N, de Onis M, Kramer M, O’Donnell A, Prada JA, Hoffman HJ. Report of the IDECG Working Group on definitions, classifications, causes, mechanisms and prevention of IUGR.  Eur J Clin Nutr. 1998;  52 ((Suppl 1)) S94-S96
  • 2 Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P. International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24-October 1, 2001.  Pediatrics. 2003;  111 1253-1261
  • 3 Mullis PE, Tonella P. Regulation of fetal growth: consequences and impact of being born small.  Best Pract Res Clin Endocrinol Metab. 2008;  22 173-190
  • 4 de Onis M, Blossner M, Villar J. Levels and patterns of intrauterine growth retardation in developing countries.  Eur J Clin Nutr. 1998;  52 ((Suppl 1)) S5-S15
  • 5 Gilbert WM, Danielsen B. Pregnancy outcomes associated with intrauterine growth restriction.  Am J Obstet Gynecol. 2003;  188 1596-1599; , discussion 1599–1601
  • 6 Randhawa R, Cohen P. The role of the insulin-like growth factor system in prenatal growth.  Mol Genet Metab. 2005;  86 84-90
  • 7 Cetin I, Foidart JM, Miozzo M, Raun T, Jansson T, Tsatsaris V, Reik W, Cross J, Hauguel-de-Mouzon S, Illsley N, Kingdom J, Huppertz B. Fetal growth restriction: a workshop report.  Placenta. 2004;  25 753-757
  • 8 Gluckman PD, Hanson MA. Maternal constraint of fetal growth and its consequences.  Semin Fetal Neonatal Med. 2004;  9 419-425
  • 9 Brosens JJ, Pijnenborg R, Brosens IA. The myometrial junctional zone spiral arteries in normal and abnormal pregnancies: a review of the literature.  Am J Obstet Gynecol. 2002;  187 1416-1423
  • 10 Miller HC. Prenatal factors affecting intrauterine growth retardation.  Clin Perinatol. 1985;  12 307-318
  • 11 Voigt HJ, Becker V. Doppler flow measurements and histomorphology of the placental bed in uteroplacental insufficiency.  J Perinat Med. 1992;  20 139-147
  • 12 Catalano PM, Thomas A, Huston-Presley L, Amini SB. Phenotype of infants of mothers with gestational diabetes.  Diabetes Care. 2007;  30 ((Suppl 2)) S156-S60
  • 13 Livshits G, Kato BS, Wilson SG, Spector TD. Linkage of genes to total lean body mass in normal women.  J Clin Endocrinol Metab. 2007;  92 3171-3176
  • 14 Sparks JW. Human intrauterine growth and nutrient accretion.  Semin Perinatol. 1984;  8 74-93
  • 15 Starr ME, Evers BM, Saito H. Age-Associated Increase in Cytokine Production During Systemic Inflammation: Adipose Tissue as a Major Source of IL-6.  J Gerontol A Biol Sci Med Sci. 2009;  64 723-730
  • 16 Enzi G, Zanardo V, Caretta F, Inelmen EM, Rubaltelli F. Intrauterine growth and adipose tissue development.  Am J Clin Nutr. 1981;  34 1785-1790
  • 17 Gluckman PD. Endocrine and nutritional regulation of prenatal growth.  Acta Paediatr Suppl. 1997;  423 153-157 , ; discussion 158
  • 18 Penrose LS. Data on the genetics of birth weight.  Ann Eugen. 1952;  16 378-381
  • 19 Monzavi R, Cohen P. IGFs and IGFBPs: role in health and disease.  Best Pract Res Clin Endocrinol Metab. 2002;  16 433-447
  • 20 Holt RI. Fetal programming of the growth hormone-insulin-like growth factor axis.  Trends Endocrinol Metab. 2002;  13 392-397
  • 21 Humbel RE. Insulin-like growth factors I and II.  Eur J Biochem. 1990;  190 445-462
  • 22 Herington AC. Insulin-like growth factors: biochemistry and physiology.  Baillieres Clin Endocrinol Metab. 1991;  5 531-551
  • 23 Scott CD, Ballesteros M, Madrid J, Baxter RC. Soluble insulin-like growth factor-II/mannose 6-P receptor inhibits deoxyribonucleic acid synthesis in cultured rat hepatocytes.  Endocrinology. 1996;  137 873-878
  • 24 Ferry Jr RJ, Cerri RW, Cohen P. Insulin-like growth factor binding proteins: new proteins, new functions.  Horm Res. 1999;  51 53-67
  • 25 Collett-Solberg PF, Cohen P. Genetics, chemistry, and function of the IGF/IGFBP system.  Endocrine. 2000;  12 121-136
  • 26 Kajimura S, Aida K, Duan C. Insulin-like growth factor-binding protein-1 (IGFBP-1) mediates hypoxia-induced embryonic growth and developmental retardation.  Proc Natl Acad Sci USA. 2005;  102 1240-1245
  • 27 Verhaeghe J, Bougoussa M, Van Herck E, de Zegher F, Hennen G, Igout A. Placental growth hormone and IGF-I in a pregnant woman with Pit-1 deficiency.  Clin Endocrinol (Oxf). 2000;  53 645-647
  • 28 Reece EA, Wiznitzer A, Le E, Homko CJ, Behrman H, Spencer EM. The relation between human fetal growth and fetal blood levels of insulin-like growth factors I and II, their binding proteins, and receptors.  Obstet Gynecol. 1994;  84 88-95
  • 29 de Zegher F, Francois I, van Helvoirt M, Van den Berghe G. Clinical review 89: Small as fetus and short as child: from endogenous to exogenous growth hormone.  J Clin Endocrinol Metab. 1997;  82 2021-2026
  • 30 Giudice LC, de Zegher F, Gargosky SE, Dsupin BA, de las Fuentes L, Crystal RA, Hintz RL, Rosenfeld RG. Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth.  J Clin Endocrinol Metab. 1995;  80 1548-1555
  • 31 Woods KA, Camacho-Hubner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene.  N Engl J Med. 1996;  335 1363-1367
  • 32 Woods KA, Camacho-Hubner C, Barter D, Clark AJ, Savage MO. Insulin-like growth factor I gene deletion causing intrauterine growth retardation and severe short stature.  Acta Paediatr Suppl. 1997;  423 39-45
  • 33 Walenkamp MJ, van der Kamp HJ, Pereira AM, Kant SG, van Duyvenvoorde HA, Kruithof MF, Breuning MH, Romijn JA, Karperien M, Wit JM. A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor.  J Clin Endocrinol Metab. 2006;  91 3062-3070
  • 34 Verhaeghe J, Van Bree R, Van Herck E, Laureys J, Bouillon R, Van Assche FA. C-peptide, insulin-like growth factors I and II, and insulin-like growth factor binding protein-1 in umbilical cord serum: correlations with birth weight.  Am J Obstet Gynecol. 1993;  169 89-97
  • 35 Fowden AL, Hill DJ. Intra-uterine programming of the endocrine pancreas.  Br Med Bull. 2001;  60 123-142
  • 36 Fowden AL. Endocrine regulation of fetal growth.  Reprod Fertil Dev. 1995;  7 351-363
  • 37 Economides DL, Proudler A, Nicolaides KH. Plasma insulin in appropriate- and small-for-gestational-age fetuses.  Am J Obstet Gynecol. 1989;  160 1091-1094
  • 38 Setia S, Sridhar MG, Bhat V, Chaturvedula L, Vinayagamoorti R, John M. Insulin sensitivity and insulin secretion at birth in intrauterine growth retarded infants.  Pathology. 2006;  38 236-238
  • 39 Leger J, Noel M, Limal JM, Czernichow P. Growth factors and intrauterine growth retardation. II. Serum growth hormone, insulin-like growth factor (IGF) I, and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects: prospective study from birth to two years of age. Study Group of IUGR.  Pediatr Res. 1996;  40 101-107
  • 40 de Zegher F, Vanderschueren-Lodeweyckx M, Spitz B, Faijerson Y, Blomberg F, Beckers A, Hennen G, Frankenne F. Perinatal growth hormone (GH) physiology: effect of GH-releasing factor on maternal and fetal secretion of pituitary and placental GH.  J Clin Endocrinol Metab. 1990;  71 520-522
  • 41 Thissen JP, Ketelslegers JM, Underwood LE. Nutritional regulation of the insulin-like growth factors.  Endocr Rev. 1994;  15 80-101
  • 42 Setia S, Sridhar MG, Bhat V, Chaturvedula L. Growth hormone in intra-uterine growth retarded newborns.  Indian J Pediatr. 2007;  74 991-994
  • 43 Brown GM, Reichlin S. Psychologic and neural regulation of growth hormone secretion.  Psychosom Med. 1972;  34 45-61
  • 44 Hayek A, Driscoll SG, Warshaw JB. Endocrine studies in anencephaly.  J Clin Invest. 1973;  52 1636-1641
  • 45 Massa G, de Zegher F, Vanderschueren-Lodeweyckx M. Serum growth hormone-binding proteins in the human fetus and infant.  Pediatr Res. 1992;  32 69-72
  • 46 Laron Z. Growth hormone insensitivity (Laron syndrome).  Rev Endocr Metab Disord. 2002;  3 347-355
  • 47 Wit JM, van Unen H. Growth of infants with neonatal growth hormone deficiency.  Arch Dis Child. 1992;  67 920-924
  • 48 Barsh GS, Seeburg PH, Gelinas RE. The human growth hormone gene family: structure and evolution of the chromosomal locus.  Nucleic Acids Res. 1983;  11 3939-3958
  • 49 Barrera-Saldana HA, Seeburg PH, Saunders GF. Two structurally different genes produce the same secreted human placental lactogen hormone.  J Biol Chem. 1983;  258 3787-3793
  • 50 Scippo ML, Frankenne F, Hooghe-Peters EL, Igout A, Velkeniers B, Hennen G. Syncytiotrophoblastic localization of the human growth hormone variant mRNA in the placenta.  Mol Cell Endocrinol. 1993;  92 R7-R13
  • 51 Mirlesse V, Frankenne F, Alsat E, Poncelet M, Hennen G, Evain-Brion D. Placental growth hormone levels in normal pregnancy and in pregnancies with intrauterine growth retardation.  Pediatr Res. 1993;  34 439-442
  • 52 Eriksson L, Frankenne F, Eden S, Hennen G, von Schoultz B. Growth hormone secretion during termination of pregnancy. Further evidence of a placental variant.  Acta Obstet Gynecol Scand. 1988;  67 549-552
  • 53 Lacroix MC, Guibourdenche J, Frendo JL, Muller F, Evain-Brion D. Human placental growth hormone – a review.  Placenta. 2002;  23 ((Suppl A)) S87-S94
  • 54 Alsat E, Guibourdenche J, Couturier A, Evain-Brion D. Physiological role of human placental growth hormone.  Mol Cell Endocrinol. 1998;  140 121-127
  • 55 Patel N, Alsat E, Igout A, Baron F, Hennen G, Porquet D, Evain-Brion D. Glucose inhibits human placental GH secretion, in vitro.  J Clin Endocrinol Metab. 1995;  80 1743-1746
  • 56 Hauguel-de Mouzon S, Leturque A, Alsat E, Loizeau M, Evain-Brion D, Girard J. Developmental expression of Glut1 glucose transporter and c-fos genes in human placental cells.  Placenta. 1994;  15 35-46
  • 57 Caufriez A, Frankenne F, Hennen G, Copinschi G. Regulation of maternal insulin-like growth factor I by placental growth hormone in pregnancy. Possible action of maternal IGF-I on fetal growth.  Horm Res. 1994;  42 62-65
  • 58 Chowen JA, Evain-Brion D, Pozo J, Alsat E, Garcia-Segura LM, Argente J. Decreased expression of placental growth hormone in intrauterine growth retardation.  Pediatr Res. 1996;  39 736-739
  • 59 Papadopoulou E, Sifakis S, Giahnakis E, Fragouli Y, Karkavitsas N, Koumantakis E, Kalmanti M. Increased human placental growth hormone at midtrimester pregnancies may be an index of intrauterine growth retardation related to preeclampsia.  Growth Horm IGF Res. 2006;  16 290-296
  • 60 Mittal P, Hassan SS, Espinoza J, Kusanovic JP, Edwin S, Gotsch F, Erez O, Than NG, Mazaki-Tovi S, Romero R. The effect of gestational age and labor on placental growth hormone in amniotic fluid.  Growth Horm IGF Res. 2008;  18 174-179
  • 61 Laron Z. Insulin-like growth factor-I treatment of children with Laron syndrome (primary growth hormone insensitivity).  Pediatr Endocrinol Rev. 2008;  5 766-771
  • 62 Laron Z. Insulin-like growth factor-I (lGF-l): safety and efficacy.  Pediatr Endocrinol Rev. 2004;  2 ((Suppl 1)) 78-85
  • 63 Eremia SC, de Boo HA, Bloomfield FH, Oliver MH, Harding JE. Fetal and amniotic insulin-like growth factor-I supplements improve growth rate in intrauterine growth restriction fetal sheep.  Endocrinology. 2007;  148 2963-2972
  • 64 de Boo HA, Eremia SC, Bloomfield FH, Oliver MH, Harding JE. Treatment of intrauterine growth restriction with maternal growth hormone supplementation in sheep.  Am J Obstet Gynecol. 2008;  199 559 , e1–e9
  • 65 Fowden AL, Giussani DA, Forhead AJ. Intrauterine programming of physiological systems: causes and consequences.  Physiology (Bethesda). 2006;  21 29-37
  • 66 Han VK, Carter AM. Control of growth and development of the feto-placental unit.  Curr Opin Pharmacol. 2001;  1 632-640
  • 67 Fernandez-Twinn DS, Ozanne SE. Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome.  Physiol Behav. 2006;  88 234-243
  • 68 Wells JC. The thrifty phenotype hypothesis: thrifty offspring or thrifty mother?.  J Theor Biol. 2003;  221 143-161
  • 69 Roberts CT, Owens JA, Carter AM, Harding JE, Austgulen R, Wlodek M. Insulin-like growth factors and foetal programming – a workshop report.  Placenta. 2003;  24 ((Suppl A)) S72-S75
  • 70 Vaessen N, Janssen JA, Heutink P, Hofman A, Lamberts SW, Oostra BA, Pols HA, van Duijn CM. Association between genetic variation in the gene for insulin-like growth factor-I and low birthweight.  Lancet. 2002;  359 1036-1037
  • 71 Barker DJ. Intrauterine programming of adult disease.  Mol Med Today. 1995;  1 418-423
  • 72 Hales CN, Barker DJ. The thrifty phenotype hypothesis.  Br Med Bull. 2001;  60 5-20
  • 73 Hales CN, Desai M, Ozanne SE, Crowther NJ. Fishing in the stream of diabetes: from measuring insulin to the control of fetal organogenesis.  Biochem Soc Trans. 1996;  24 341-350
  • 74 Gluckman PD, Hanson MA. The consequences of being born small – an adaptive perspective.  Horm Res. 2006;  65 ((Suppl 3)) 5-14
  • 75 Gluckman PD, Hanson MA, Spencer HG, Bateson P. Environmental influences during development and their later consequences for health and disease: implications for the interpretation of empirical studies.  Proc Biol Sci. 2005;  272 671-677
  • 76 Hattersley AT, Tooke JE. The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease.  Lancet. 1999;  353 1789-1792
  • 77 Vaessen N, Heutink P, Janssen JA, Witteman JC, Testers L, Hofman A, Lamberts SW, Oostra BA, Pols HA, van Duijn CM. A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction.  Diabetes. 2001;  50 637-642
  • 78 Jones RH, Ozanne SE. Fetal programming of glucose-insulin metabolism.  Mol Cell Endocrinol. 2009;  297 4-9
  • 79 Sridhar MG, Setia S, John M, Bhat V, Nandeesha H, Sathiyapriya V. Oxidative stress varies with the mode of delivery in intrauterine growth retardation: association with Apgar score.  Clin Biochem. 2007;  40 688-691
  • 80 Luo ZC, Fraser WD, Julien P, Deal CL, Audibert F, Smith GN, Xiong X, Walker M. Tracing the origins of “fetal origins” of adult diseases: programming by oxidative stress?.  Med Hypotheses. 2006;  66 38-44
  • 81 Mathers JC. Early nutrition: impact on epigenetics.  Forum Nutr. 2007;  60 42-48
  • 82 Bertram CE, Hanson MA. Prenatal programming of postnatal endocrine responses by glucocorticoids.  Reproduction. 2002;  124 459-467
  • 83 Larnkjaer A, Ingstrup HK, Schack-Nielsen L, Hoppe C, Mølgaard C, Skovgaard M, Juul A, Michaelsen KF. Early programming of the IGF-I axis: Negative association between IGF-I in infancy and late adolescence in a 17-year longitudinal follow-up study of healthy subjects.  Growth Horm IGF Res. 2009;  19 82-86
  • 84 Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis.  Diabetologia. 1992;  35 595-601
  • 85 Woods KA, van Helvoirt M, Ong KK, Mohn A, Levy J, de Zegher F, Dunger DB. The somatotropic axis in short children born small for gestational age: relation to insulin resistance.  Pediatr Res. 2002;  51 76-80
  • 86 Jaquet D, Vidal H, Hankard R, Czernichow P, Levy-Marchal C. Impaired regulation of glucose transporter 4 gene expression in insulin resistance associated with in utero undernutrition.  J Clin Endocrinol Metab. 2001;  86 3266-3271
  • 87 Vehaskari VM, Aviles DH, Manning J. Prenatal programming of adult hypertension in the rat.  Kidney Int. 2001;  59 238-245
  • 88 Nwagwu MO, Cook A, Langley-Evans SC. Evidence of progressive deterioration of renal function in rats exposed to a maternal low-protein diet in utero.  Br J Nutr. 2000;  83 79-85
  • 89 Drake AJ, Walker BR. The intergenerational effects of fetal programming: non-genomic mechanisms for the inheritance of low birth weight and cardiovascular risk.  J Endocrinol. 2004;  180 1-16

Correspondence

Dr. S. Setia

Senior Resident

Department of Biochemistry

Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER)

Pondicherry 605 006

India

Phone: +91/96/268 806 12

Phone: +91/41/322 727 63

Fax: +91/41/322 720 67

Email: sajita.setia@gmail.com

    >