The Interplay of Insulin-Like Growth Factors, Gonadotropins, and Endocrine Disruptors in Ovarian Follicular Development and Function

ABSTRACT

Over the past 20 years, the expression, signaling mechanisms, and roles of members of the insulin-like growth factor (IGF) family (ligands, receptors, binding proteins, and binding protein proteases and their inhibitors) have been elucidated in ovarian follicle function in humans and other species. In vitro studies with human, nonhuman primate, and farm animal granulosa and thecal cells and genetic approaches using mouse knockout models for IGF family members have revealed that IGFs are key intraovarian regulators of follicle growth, selection, atresia, cellular differentiation, and steroidogenesis, oocyte maturation, and cumulus expansion. Some of these actions are synergistic with gonadotropins, although most are not sustainable with IGFs alone and require gonadotropin actions, thereby designating IGFs as “co-gonadotropins.” In the human disorder of polycystic ovarian syndrome, characterized by small antral follicle arrest, the IGF system appears to contribute to the observed resistance to follicle-stimulating hormone action at the level of the granulosa compartment and the persistence of an androgen-dominant milieu in the arrested follicles. Interestingly, recent studies demonstrate that endocrine-disrupting chemicals can compromise IGF activity and signaling in the ovarian follicle, affecting follicle development, steroidogenesis, and oocyte quality. The successful development of a healthy oocyte and appropriate granulosa and theca cell steroidogenesis on a cyclic basis are contingent on multiple factors, including a properly functioning intraovarian IGF system. Disruption of even one component of this system can lead to abnormal follicular development and function and compromised reproductive capacity.

KEYWORDS

Insulin-like growth factors (IGFs) - steroidogenesis - signaling pathways - endocrine disruptors

REFERENCES

• 1 McNatty K P, Reader K, Smith P, Heath D A, Juenguel J L. Control of ovarian follicular development to the gonadotrophin-dependent phase: a 2006 perspective.  Soc Reprod Fertil Suppl. 2007;  64 55-68
• 2 Dupont J, Dunn S E, Barrett J C, LeRoith D. Microarray analysis and identification of novel molecules involved in insulin-like growth factor-1 receptor signaling and gene expression.  Recent Prog Horm Res. 2003;  58 325-342
• 3 Hernandez E R. Regulation of the genes for insulin-like growth factor (IGF) I and II and their receptors by steroids and gonadotropins in the ovary.  J Steroid Biochem Mol Biol. 1995;  53 219-221
• 4 Samani A A, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights.  Endocr Rev. 2007;  28(1) 20-47
• 5 Rose P P, Bogyo M, Moses A V, Fruh K. Insulin-like growth factor II receptor-mediated intracellular retention of cathepsin B is essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus.  J Virol. 2007;  81(15) 8050-8062
• 6 Boldt H B, Conover C A. Pregnancy-associated plasma protein-A (PAPP-A): a local regulator of IGF bioavailability through cleavage of IGFBPs.  Growth Horm IGF Res. 2007;  17(1) 10-18
• 7 Clemmons D R. Role of insulin-like growth factor binding proteins in controlling IGF actions.  Mol Cell Endocrinol. 1998;  140(1–2) 19-24
• 8 Giudice L C. Insulin-like growth factor family in Graafian follicle development and function.  J Soc Gynecol Investig. 2001;  8(1, Suppl) S26-S29
• 9 Balasubramanian K, Lavoie H A, Garmey J C, Stocco D M, Veldhuis J D. Regulation of porcine granulosa cell steroidogenic acute regulatory protein (StAR) by insulin-like growth factor I: synergism with follicle-stimulating hormone or protein kinase A agonist.  Endocrinology. 1997;  138(1) 433-439
• 10 Davoren J B, Hsueh A J. Insulin enhances FSH-stimulated steroidogenesis by cultured rat granulosa cells.  Mol Cell Endocrinol. 1984;  35(2–3) 97-105
• 11 Urban R J, Garmey J C, Shupnik M A, Veldhuis J D. Insulin-like growth factor type I increases concentrations of messenger ribonucleic acid encoding cytochrome P450 cholesterol side-chain cleavage enzyme in primary cultures of porcine granulosa cells.  Endocrinology. 1990;  127(5) 2481-2488
• 12 Veldhuis J D, Kolp L A, Toaff M E, Strauss III J F, Demers L M. Mechanisms subserving the trophic actions of insulin on ovarian cells. In vitro studies using swine granulosa cells.  J Clin Invest. 1983;  72(3) 1046-1057
• 13 Veldhuis J D, Rodgers R J. Mechanisms subserving the steroidogenic synergism between follicle-stimulating hormone and insulin-like growth factor I (somatomedin C). Alterations in cellular sterol metabolism in swine granulosa cells.  J Biol Chem. 1987;  262(16) 7658-7664
• 14 Pellegrini S, Fuzzi B, Pratesi S et al.. In-vivo studies on ovarian insulin-like growth factor I concentrations in human preovulatory follicles and human ovarian circulation.  Hum Reprod. 1995;  10(6) 1341-1345
• 15 Bondy C A, Chin E, Zhou J. Significant species differences in local IGF-I and -II gene expression.  Adv Exp Med Biol. 1993;  343 73-77
• 16 Vendola K, Zhou J, Wang J, Bondy C A. Androgens promote insulin-like growth factor-I and insulin-like growth factor-I receptor gene expression in the primate ovary.  Hum Reprod. 1999;  14(9) 2328-2332
• 17 Vendola K, Zhou J, Wang J et al.. Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary.  Biol Reprod. 1999;  61(2) 353-357
• 18 Baker J, Hardy M P, Zhou J et al.. Effects of an Igf1 gene null mutation on mouse reproduction.  Mol Endocrinol. 1996;  10(7) 903-918
• 19 Liu J L, Yakar S, LeRoith D. Conditional knockout of mouse insulin-like growth factor-1 gene using the Cre/loxP system.  Proc Soc Exp Biol Med. 2000;  223(4) 344-351
• 20 Kadakia R, Arraztoa J A, Bondy C, Zhou J. Granulosa cell proliferation is impaired in the Igf1 null ovary.  Growth Horm IGF Res. 2001;  11(4) 220-224
• 21 Zhou J, Bievre M, Bondy C A. Reduced GLUT1 expression in Igf1 − / − null oocytes and follicles.  Growth Horm IGF Res. 2000;  10(3) 111-117
• 22 Dierich A, Sairam M R, Monaco L et al.. Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance.  Proc Natl Acad Sci U S A. 1998;  95(23) 13612-13617
• 23 Abel M H, Wootton A N, Wilkins V et al.. The effect of a null mutation in the follicle-stimulating hormone receptor gene on mouse reproduction.  Endocrinology. 2000;  141(5) 1795-1803
• 24 Sasaki N, Rees-Jones R W, Zick Y, Nissley S P, Rechler M M. Characterization of insulin-like growth factor I-stimulated tyrosine kinase activity associated with the beta-subunit of type I insulin-like growth factor receptors of rat liver cells.  J Biol Chem. 1985;  260(17) 9793-9804
• 25 Ludwig T, Eggenschwiler J, Fisher P et al.. Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds.  Dev Biol. 1996;  177(2) 517-535
• 26 Khamsi F, Roberge S, Yavas Y et al.. Recent discoveries in physiology of insulin-like growth factor-1 and its interaction with gonadotropins in folliculogenesis.  Endocrine. 2001;  16(3) 151-165
• 27 Sekar N, Garmey J C, Veldhuis J D. Mechanisms underlying the steroidogenic synergy of insulin and luteinizing hormone in porcine granulosa cells: joint amplification of pivotal sterol-regulatory genes encoding the low-density lipoprotein (LDL) receptor, steroidogenic acute regulatory (StAR) protein and cytochrome P450 side-chain cleavage (P450scc) enzyme.  Mol Cell Endocrinol. 2000;  159(1–2) 25-35
• 28 Eimerl S, Orly J. Regulation of steroidogenic genes by insulin-like growth factor-1 and follicle-stimulating hormone: differential responses of cytochrome P450 side-chain cleavage, steroidogenic acute regulatory protein, and 3beta-hydroxysteroid dehydrogenase/isomerase in rat granulosa cells.  Biol Reprod. 2002;  67(3) 900-910
• 29 Costrici N, Lunenfeld B, Pariente C et al.. Induction of aromatase in human granulosa cells by both follicle stimulating hormone and insulin-like growth factor-I involves tyrosine phosphorylation.  Gynecol Endocrinol. 1994;  8(3) 183-189
• 30 Erickson G F, Garzo V G, Magoffin D A. Insulin-like growth factor-I regulates aromatase activity in human granulosa and granulosa luteal cells.  J Clin Endocrinol Metab. 1989;  69(4) 716-724
• 31 Erickson G F, Magoffin D A, Cragun J R, Chang R J. The effects of insulin and insulin-like growth factors-I and -II on estradiol production by granulosa cells of polycystic ovaries.  J Clin Endocrinol Metab. 1990;  70(4) 894-902
• 32 Kanzaki M, Hattori M A, Horiuchi R, Kojima I. Co-ordinate actions of FSH and insulin-like growth factor-I on LH receptor expression in rat granulosa cells.  J Endocrinol. 1994;  141(2) 301-308
• 33 Safi M, Onagbesan O M, Bruggeman V et al.. Regulation of inhibin alpha- and beta(A)-subunit messenger ribonucleic acid levels by gonadotropins and IGF-I in cultured chicken granulosa cells.  Gen Comp Endocrinol. 2003;  131(2) 159-167
• 34 Schoenfelder M, Einspanier R. Expression of hyaluronan synthases and corresponding hyaluronan receptors is differentially regulated during oocyte maturation in cattle.  Biol Reprod. 2003;  69(1) 269-277
• 35 Chen L, Mao S J, Larsen W J. Identification of a factor in fetal bovine serum that stabilizes the cumulus extracellular matrix. A role for a member of the inter-alpha-trypsin inhibitor family.  J Biol Chem. 1992;  267(17) 12380-12386
• 36 Yoshioka S, Ochsner S, Russell D L et al.. Expression of tumor necrosis factor-stimulated gene-6 in the rat ovary in response to an ovulatory dose of gonadotropin.  Endocrinology. 2000;  141(11) 4114-4119
• 37 Salustri A, Garlanda C, Hirsch E et al.. PTX3 plays a key role in the organization of the cumulus oophorus extracellular matrix and in in vivo fertilization.  Development. 2004;  131(7) 1577-1586
• 38 Kobayashi H, Sun G W, Hirashima Y, Terao T. Identification of link protein during follicle development and cumulus cell cultures in rats.  Endocrinology. 1999;  140(8) 3835-3842
• 39 Minegishi T, Hirakawa T, Kishi H et al.. A role of insulin-like growth factor I for follicle-stimulating hormone receptor expression in rat granulosa cells.  Biol Reprod. 2000;  62(2) 325-333
• 40 Sun G W, Kobayashi H, Suzuki M, Kanayama N, Terao T. Follicle-stimulating hormone and insulin-like growth factor I synergistically induce up-regulation of cartilage link protein (Crtl1) via activation of phosphatidylinositol-dependent kinase/Akt in rat granulosa cells.  Endocrinology. 2003;  144(3) 793-801
• 41 Wasielak M, Bogacki M. Apoptosis inhibition by insulin-like growth factor (IGF)-I during in vitro maturation of bovine oocytes.  J Reprod Dev. 2007;  53(2) 419-426
• 42 Demeestere I, Gervy C, Centner J et al.. Effect of insulin-like growth factor-I during preantral follicular culture on steroidogenesis, in vitro oocyte maturation, and embryo development in mice.  Biol Reprod. 2004;  70(6) 1664-1669
• 43 Quirk S M, Cowan R G, Harman R M, Hu C L, Porter D A. Ovarian follicular growth and atresia: the relationship between cell proliferation and survival.  J Anim Sci. 2004;  82(Suppl) E40-E52
• 44 Xin X, Hou Y T, Li L et al.. IGF-I increases IGFBP-5 and collagen alpha1(I) mRNAs by the MAPK pathway in rat intestinal smooth muscle cells.  Am J Physiol Gastrointest Liver Physiol. 2004;  286(5) G777-G783
• 45 Hunzicker-Dunn M, Maizels E T. FSH signaling pathways in immature granulosa cells that regulate target gene expression: branching out from protein kinase A.  Cell Signal. 2006;  18(9) 1351-1359
• 46 Salvador L M, Park Y, Cottom J et al.. Follicle-stimulating hormone stimulates protein kinase A-mediated histone H3 phosphorylation and acetylation leading to select gene activation in ovarian granulosa cells.  J Biol Chem. 2001;  276(43) 40146-40155
• 47 Weck J, Mayo K E. Switching of NR5A proteins associated with the inhibin alpha-subunit gene promoter after activation of the gene in granulosa cells.  Mol Endocrinol. 2006;  20(5) 1090-1103
• 48 Falender A E, Lanz R, Malenfant D, Belanger L, Richards J S. Differential expression of steroidogenic factor-1 and FTF/LRH-1 in the rodent ovary.  Endocrinology. 2003;  144(8) 3598-3610
• 49 Kwintkiewicz J, Cai Z, Stocco C. Follicle-stimulating hormone-induced activation of Gata4 contributes in the up-regulation of Cyp19 expression in rat granulosa cells.  Mol Endocrinol. 2007;  21(4) 933-947
• 50 Gillio-Meina C, Hui Y Y, LaVoie H A. Expression of CCAAT/enhancer binding proteins alpha and beta in the porcine ovary and regulation in primary cultures of granulosa cells.  Biol Reprod. 2005;  72(5) 1194-1204
• 51 Yazawa T, Mizutani T, Yamada K et al.. Involvement of cyclic adenosine 5′-monophosphate response element-binding protein, steroidogenic factor 1, and Dax-1 in the regulation of gonadotropin-inducible ovarian transcription factor 1 gene expression by follicle-stimulating hormone in ovarian granulosa cells.  Endocrinology. 2003;  144(5) 1920-1930
• 52 Sekar N, Veldhuis J D. Involvement of Sp1 and SREBP-1a in transcriptional activation of the LDL receptor gene by insulin and LH in cultured porcine granulosa-luteal cells.  Am J Physiol Endocrinol Metab. 2004;  287(1) E128-E135
• 53 LaVoie H A, Garmey J C, Veldhuis J D. Mechanisms of insulin-like growth factor I augmentation of follicle-stimulating hormone-induced porcine steroidogenic acute regulatory protein gene promoter activity in granulosa cells.  Endocrinology. 1999;  140(1) 146-153
• 54 Manna P R, Chandrala S P, King S R et al.. Molecular mechanisms of insulin-like growth factor-I mediated regulation of the steroidogenic acute regulatory protein in mouse Leydig cells.  Mol Endocrinol. 2006;  20(2) 362-378
• 55 Manna P R, Wang X J, Stocco D M. Involvement of multiple transcription factors in the regulation of steroidogenic acute regulatory protein gene expression.  Steroids. 2003;  68(14) 1125-1134
• 56 Stocco D M, Clark B J, Reinhart A J et al.. Elements involved in the regulation of the StAR gene.  Mol Cell Endocrinol. 2001;  177(1–2) 55-59
• 57 Urban R J, Shupnik M A, Bodenburg Y H. Insulin-like growth factor-I increases expression of the porcine P-450 cholesterol side chain cleavage gene through a GC-rich domain.  J Biol Chem. 1994;  269(41) 25761-25769
• 58 Stocco C, Kwintkiewicz J, Cai Z. Identification of regulatory elements in the Cyp19 proximal promoter in rat luteal cells.  J Mol Endocrinol. 2007;  39(4) 211-221
• 59 Monte D, DeWitte F, Hum D W. Regulation of the human P450scc gene by steroidogenic factor 1 is mediated by CBP/p300.  J Biol Chem. 1998;  273(8) 4585-4591
• 60 Liu Z, Simpson E R. Steroidogenic factor 1 (SF-1) and SP1 are required for regulation of bovine CYP11A gene expression in bovine luteal cells and adrenal Y1 cells.  Mol Endocrinol. 1997;  11(2) 127-137
• 61 Ahlgren R, Suske G, Waterman M R, Lund J. Role of Sp1 in cAMP-dependent transcriptional regulation of the bovine CYP11A gene.  J Biol Chem. 1999;  274(27) 19422-19428
• 62 Ahlgren R, Simpson E R, Waterman M R, Lund J. Characterization of the promoter/regulatory region of the bovine CYP11A (P-450scc) gene. Basal and cAMP-dependent expression.  J Biol Chem. 1990;  265(6) 3313-3319
• 63 Basile A, Sica A, d'Aniello E et al.. Characterization of the promoter for the human long pentraxin PTX3. Role of NF-kappaB in tumor necrosis factor-alpha and interleukin-1beta regulation.  J Biol Chem. 1997;  272(13) 8172-8178
• 64 Yamada Y, Itano N, Zako M et al.. The gene structure and promoter sequence of mouse hyaluronan synthase 1.  Biochem J. 1998;  330(Pt 3) 1223-1227
• 65 Cataldo N A, Giudice L C. Insulin-like growth factor binding protein profiles in human ovarian follicular fluid correlate with follicular functional status.  J Clin Endocrinol Metab. 1992;  74(4) 821-829
• 66 Giudice L C. Growth factor action on ovarian function in polycystic ovary syndrome.  Endocrinol Metab Clin North Am. 1999;  28(2) 325-339 vi
• 67 Jones J I, Clemmons D R. Insulin-like growth factors and their binding proteins: biological actions.  Endocr Rev. 1995;  16(1) 3-34
• 68 Qin Q P, Christiansen M, Oxvig C et al.. Double-monoclonal immunofluorometric assays for pregnancy-associated plasma protein A/proeosinophil major basic protein (PAPP-A/proMBP) complex in first-trimester maternal serum screening for Down syndrome.  Clin Chem. 1997;  43(12) 2323-2332
• 69 Sinosich M J, Porter R, Sloss P, Bonifacio M D, Saunders D M. Pregnancy-associated plasma protein A in human ovarian follicular fluid.  J Clin Endocrinol Metab. 1984;  58(3) 500-504
• 70 Sinosich M J, Seppala M, Saunders D M, Grudzinskas J G. Pregnancy-associated plasma protein-A and placental protein 5 in human seminal plasma.  Ann N Y Acad Sci. 1985;  442 287-292
• 71 Tsakok F H, Koh S, Chua S E et al.. Prognostic significance of the new placental proteins in trophoblastic disease.  Br J Obstet Gynaecol. 1983;  90(5) 483-486
• 72 Qin X, Byun D, Lau K H, Baylink D J, Mohan S. Evidence that the interaction between insulin-like growth factor (IGF)-II and IGF binding protein (IGFBP)-4 is essential for the action of the IGF-II-dependent IGFBP-4 protease.  Arch Biochem Biophys. 2000;  379(2) 209-216
• 73 Conover C A, Faessen G F, Ilg K E et al.. Pregnancy-associated plasma protein-a is the insulin-like growth factor binding protein-4 protease secreted by human ovarian granulosa cells and is a marker of dominant follicle selection and the corpus luteum.  Endocrinology. 2001;  142(5) 2155
• 74 Overgaard M T, Nyegaard M, Su Y Q et al.. Lack of functional PAPP-A compromises female fertility. Paper presented at: The Endocrine Society annual meeting June 24–27, 2006 Boston, MA;
• 75 Overgaard M T, Glerup S, Boldt H B et al.. Inhibition of proteolysis by the proform of eosinophil major basic protein (proMBP) requires covalent binding to its target proteinase.  FEBS Lett. 2004;  560(1–3) 147-152
• 76 Glerup S, Boldt H B, Overgaard M T et al.. Proteinase inhibition by proform of eosinophil major basic protein (pro-MBP) is a multistep process of intra- and intermolecular disulfide rearrangements.  J Biol Chem. 2005;  280(11) 9823-9832
• 77 Glerup S, Kloverpris S, Laursen L S et al.. Cell surface detachment of pregnancy-associated plasma protein-A requires the formation of intermolecular proteinase-inhibitor disulfide bonds and glycosaminoglycan covalently bound to the inhibitor.  J Biol Chem. 2007;  282(3) 1769-1778
• 78 Poretsky L, Cataldo N A, Rosenwaks Z, Giudice L C. The insulin-related ovarian regulatory system in health and disease.  Endocr Rev. 1999;  20(4) 535-582
• 79 Rhoton-Vlasak A, Gleich G J, Bischof P, Chegini N. Localization and cellular distribution of pregnancy-associated plasma protein-a and major basic protein in human ovary and corpora lutea throughout the menstrual cycle.  Fertil Steril. 2003;  79(5) 1149-1153
• 80 Sabuncu T, Vural H, Harma M, Harma M. Oxidative stress in polycystic ovary syndrome and its contribution to the risk of cardiovascular disease.  Clin Biochem. 2001;  34(5) 407-413
• 81 Adler V, Yin Z, Tew K D, Ronai Z. Role of redox potential and reactive oxygen species in stress signaling.  Oncogene. 1999;  18(45) 6104-6111
• 82 el-Roeiy A, Chen X, Roberts V J et al.. Expression of the genes encoding the insulin-like growth factors (IGF-I and II), the IGF and insulin receptors, and IGF-binding proteins-1–6 and the localization of their gene products in normal and polycystic ovary syndrome ovaries.  J Clin Endocrinol Metab. 1994;  78(6) 1488-1496
• 83 Magoffin D A, San Roman G A, Muderspach L I. Insulin-like growth factor binding proteins in a natural pre-ovulatory follicle from a woman with polycystic ovary syndrome.  Hum Reprod. 1995;  10(9) 2248-2252
• 84 Peng X, Maruo T, Samoto T, Mochizuki M. Comparison of immunocytologic localization of insulin-like growth factor binding protein-4 in normal and polycystic ovary syndrome human ovaries.  Endocr J. 1996;  43(3) 269-278
• 85 Pocar P, Brevini T A, Fischer B, Gandolfi F. The impact of endocrine disruptors on oocyte competence.  Reproduction. 2003;  125(3) 313-325
• 86 Propper C R. The study of endocrine-disrupting compounds: past approaches and new directions.  Integr Comp Biol. 2005;  45(1) 194-200
• 87 Minegishi T, Hirakawa T, Abe K, Kishi H, Miyamoto K. Effect of IGF-1 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the expression of LH receptors during cell differentiation in cultured granulosa cells.  Mol Cell Endocrinol. 2003;  202(1–2) 123-131
• 88 Holloway A C, Petrik J J, Younglai E V. Influence of dichlorodiphenylchloroethylene on vascular endothelial growth factor and insulin-like growth factor in human and rat ovarian cells.  Reprod Toxicol. 2007;  24(3–4) 359-364
• 89 Mlynarcikova A, Kolena J, Fickova M, Scsukova S. Alterations in steroid hormone production by porcine ovarian granulosa cells caused by bisphenol A and bisphenol A dimethacrylate.  Mol Cell Endocrinol. 2005;  244(1–2) 57-62
• 90 Kwintkiewicz J, Giudice L C. Endocrine disruptor bisphenol A induces expression of peroxisome proliferator-activated receptor which contributes to down-regulation of FSH stimulated aromatase expression and estradiol production in human granulosa KGN cells. Paper presented at: The Society for the Study of Reproduction annual meeting May 27–30, 2008 Kona, HI;
• 91 Kwintkiewicz J, Giudice L C. Endocrine disruptor bisphenol A (BPA) reduces FSH stimulated cyp19 expression and downstream estradiol production in human granulosa KGN cells. Paper presented at: The Society for Gynecologic Investigation annual meeting March 23–29, 2008 San Diego, CA;