Download PDF
Semin Reprod Med 2009; 27(1): 052-061
DOI: 10.1055/s-0028-1108010
© Thieme Medical Publishers

Epidermal Growth Factor-Like Growth Factors in the Follicular Fluid: Role in Oocyte Development and Maturation

Minnie Hsieh1 , A. Musa Zamah1 , Marco Conti1
  • 1Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California
Further Information

Publication History

Publication Date:
05 February 2009 (online)

    Permissions and Reprints

ABSTRACT

The growth and maturation of the ovarian follicle requires the coordinate function of somatic cells and the oocyte. Over the past three decades, numerous growth factors involved in the bidirectional signals between the somatic and germ cells have been identified. A possible function of epidermal growth factor (EGF) signaling at selected stages of follicle maturation had been proposed early on and is supported by many observations of in vitro effects of this growth factor on steroidogenesis, oocyte maturation, and cumulus expansion. However, attempts to link EGF levels in the follicular fluid with the state of follicle and oocyte maturation have been inconclusive. More recently, data generated using mouse genetic models perturbing ovulation and fertility indicate that EGF-like growth factors, rather than EGF itself, accumulate in the follicle at the time of ovulation. EGF-like growth factor mRNA is regulated by the luteinizing hormone surge, and corresponding proteins are detected in the follicle. The EGF-like growth factors amphiregulin, epiregulin, and betacellulin are potent stimulators of oocyte maturation and cumulus expansion, and perturbation of this EGF network in vivo impairs ovulation. Similar findings in species other than the mouse confirm an important physiological role for this network at the time of ovulation. Whether this network also plays a critical role in humans and whether it can be used as a biological marker of follicle development or for the improvement of fertility remains to be determined. This review summarizes the most recent findings on the EGF network during ovulation and the potential clinical applications of manipulating this intercellular communication pathway in the control of fertility.

KEYWORDS

Epidermal growth factor (EGF) - EGF-like factors - oocyte - follicular fluid

REFERENCES

  • 1 Eppig J J. Oocyte-somatic cell communication in the ovarian follicles of mammals.  Semin Dev Biol. 1994;  5(1) 51-59
    PubMedGoogle Scholar
  • 2 Tsafriri A, Dekel N. Molecular mechanisms in ovulation. In: Findlay JK Molecular Biology of the Female Reproductive System. San Diego, CA; Academic Press 1994: 207-258
    Google Scholar
  • 3 Adashi E Y. Endocrinology of the ovary.  Hum Reprod. 1994;  9(5) 815-827
    PubMedGoogle Scholar
  • 4 Diaz F J, Wigglesworth K, Eppig J J. Oocytes determine cumulus cell lineage in mouse ovarian follicles.  J Cell Sci. 2007;  120(Pt 8) 1330-1340
    CrossrefPubMedGoogle Scholar
  • 5 Eppig J J. Intercommunication between mammalian oocytes and companion somatic cells.  Bioessays. 1991;  13(11) 569-574
    CrossrefPubMedGoogle Scholar
  • 6 Richards J S, Russell D L, Ochsner S, Espey L L. Ovulation: new dimensions and new regulators of the inflammatory-like response.  Annu Rev Physiol. 2002;  64 69-92
    CrossrefPubMedGoogle Scholar
  • 7 Tsafriri A, Reich R. Molecular aspects of mammalian ovulation.  Exp Clin Endocrinol Diabetes. 1999;  107(1) 1-11
    PubMedGoogle Scholar
  • 8 Conti M, Andersen C B, Richard F et al.. Role of cyclic nucleotide signaling in oocyte maturation.  Mol Cell Endocrinol. 2002;  187(1–2) 153-159
    CrossrefPubMedGoogle Scholar
  • 9 Dekel N. Protein phosphorylation/dephosphorylation in the meiotic cell cycle of mammalian oocytes.  Rev Reprod. 1996;  1(2) 82-88
    PubMedGoogle Scholar
  • 10 Schultz R M. From egg to embryo: a peripatetic journey.  Reproduction. 2005;  130(6) 825-828
    CrossrefPubMedGoogle Scholar
  • 11 Clarke H G, Hope S A, Byers S, Rodgers R J. Formation of ovarian follicular fluid may be due to the osmotic potential of large glycosaminoglycans and proteoglycans.  Reproduction. 2006;  132(1) 119-131
    CrossrefPubMedGoogle Scholar
  • 12 Shalgi R, Kraicer P F, Soferman N. Gases and electrolytes of human follicular fluid.  J Reprod Fertil. 1972;  28(3) 335-340
    PubMedGoogle Scholar
  • 13 Shalgi R, Kraicer P, Rimon A, Pinto M, Soferman N. Proteins of human follicular fluid: the blood-follicle barrier.  Fertil Steril. 1973;  24(6) 429-434
    PubMedGoogle Scholar
  • 14 Manarang-Pangan S, Menge A C. Immunologic studies on human follicular fluid.  Fertil Steril. 1971;  22(6) 367-372
    PubMedGoogle Scholar
  • 15 Andersen M M, Kroll J, Byskov A G, Faber M. Protein composition in the fluid of individual bovine follicles.  J Reprod Fertil. 1976;  48(1) 109-118
    PubMedGoogle Scholar
  • 16 Wang T H, Chang C L, Wu H M et al.. Insulin-like growth factor-II (IGF-II), IGF-binding protein-3 (IGFBP-3), and IGFBP-4 in follicular fluid are associated with oocyte maturation and embryo development.  Fertil Steril. 2006;  86(5) 1392-1401
    CrossrefPubMedGoogle Scholar
  • 17 Thierry van Dessel H J, Chandrasekher Y, Yap O W et al.. Serum and follicular fluid levels of insulin-like growth factor I (IGF-I), IGF-II, and IGF-binding protein-1 and -3 during the normal menstrual cycle.  J Clin Endocrinol Metab. 1996;  81(3) 1224-1231
    CrossrefPubMedGoogle Scholar
  • 18 Beg M A, Ginther O J. Follicle selection in cattle and horses: role of intrafollicular factors.  Reproduction. 2006;  132(3) 365-377
    CrossrefPubMedGoogle Scholar
  • 19 Spicer L J, Santiago C A, Davidson T R, Bridges T S, Chamberlain C S. Follicular fluid concentrations of free insulin-like growth factor (IGF)-I during follicular development in mares.  Domest Anim Endocrinol. 2005;  29(4) 573-581
    CrossrefPubMedGoogle Scholar
  • 20 Hammond J M, Hsu C J, Klindt J, Tsang B K, Downey B R. Gonadotropins increase concentrations of immunoreactive insulin-like growth factor-I in porcine follicular fluid in vivo.  Biol Reprod. 1988;  38(2) 304-308
    CrossrefPubMedGoogle Scholar
  • 21 Lee A, Christenson L K, Stouffer R L, Burry K A, Patton P E. Vascular endothelial growth factor levels in serum and follicular fluid of patients undergoing in vitro fertilization.  Fertil Steril. 1997;  68(2) 305-311
    CrossrefPubMedGoogle Scholar
  • 22 Ferrari B, Pezzuto A, Barusi L, Coppola F. Follicular fluid vascular endothelial growth factor concentrations are increased during GnRH antagonist/FSH ovarian stimulation cycles.  Eur J Obstet Gynecol Reprod Biol. 2006;  124(1) 70-76
    CrossrefPubMedGoogle Scholar
  • 23 Artini P G, Monti M, Fasciani A et al.. Correlation between the amount of follicle-stimulating hormone administered and plasma and follicular fluid vascular endothelial growth factor concentrations in women undergoing in vitro fertilization.  Gynecol Endocrinol. 1998;  12(4) 243-247
    CrossrefPubMedGoogle Scholar
  • 24 Kawano Y, Zeineh Hasan K, Fukuda J, Mine S, Miyakawa I. Production of vascular endothelial growth factor and angiogenic factor in human follicular fluid.  Mol Cell Endocrinol. 2003;  202(1–2) 19-23
    PubMedGoogle Scholar
  • 25 Ginther O J, Gastal E L, Gastal M O, Checura C M, Beg M A. Dose-response study of intrafollicular injection of insulin-like growth factor-I on follicular fluid factors and follicle dominance in mares.  Biol Reprod. 2004;  70(4) 1063-1069
    PubMedGoogle Scholar
  • 26 Barboni B, Turriani M, Galeati G et al.. Vascular endothelial growth factor production in growing pig antral follicles.  Biol Reprod. 2000;  63(3) 858-864
    CrossrefPubMedGoogle Scholar
  • 27 Seifer D B, Feng B, Shelden R M, Chen S, Dreyfus C F. Brain-derived neurotrophic factor: a novel human ovarian follicular protein.  J Clin Endocrinol Metab. 2002;  87(2) 655-659
    CrossrefPubMedGoogle Scholar
  • 28 Seifer D B, Lambert-Messerlian G, Schneyer A L. Ovarian brain-derived neurotrophic factor is present in follicular fluid from normally cycling women.  Fertil Steril. 2003;  79(2) 451-452
    CrossrefPubMedGoogle Scholar
  • 29 Wu Y T, Tang L, Cai J et al.. High bone morphogenetic protein-15 level in follicular fluid is associated with high quality oocyte and subsequent embryonic development.  Hum Reprod. 2007;  22(6) 1526-1531
    CrossrefPubMedGoogle Scholar
  • 30 Su Y Q, Wu X, O'Brien M J et al.. Synergistic roles of BMP15 and GDF9 in the development and function of the oocyte-cumulus cell complex in mice: genetic evidence for an oocyte-granulosa cell regulatory loop.  Dev Biol. 2004;  276(1) 64-73
    CrossrefPubMedGoogle Scholar
  • 31 Yan C, Wang P, DeMayo J et al.. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function.  Mol Endocrinol. 2001;  15(6) 854-866
    CrossrefPubMedGoogle Scholar
  • 32 Dong J, Albertini D F, Nishimori K et al.. Growth differentiation factor-9 is required during early ovarian folliculogenesis.  Nature. 1996;  383(6600) 531-535
    CrossrefPubMedGoogle Scholar
  • 33 Elvin J A, Clark A T, Wang P, Wolfman N M, Matzuk M M. Paracrine actions of growth differentiation factor-9 in the mammalian ovary.  Mol Endocrinol. 1999;  13(6) 1035-1048
    CrossrefPubMedGoogle Scholar
  • 34 Duffy D M. Growth differentiation factor-9 is expressed by the primate follicle throughout the periovulatory interval.  Biol Reprod. 2003;  69(2) 725-732
    CrossrefPubMedGoogle Scholar
  • 35 Westergaard L G, Andersen C Y. Epidermal growth factor (EGF) in human preovulatory follicles.  Hum Reprod. 1989;  4(3) 257-260
    PubMedGoogle Scholar
  • 36 Goud P T, Goud A P, Qian C et al.. In-vitro maturation of human germinal vesicle stage oocytes: role of cumulus cells and epidermal growth factor in the culture medium.  Hum Reprod. 1998;  13(6) 1638-1644
    CrossrefPubMedGoogle Scholar
  • 37 Park J Y, Su Y Q, Ariga M et al.. EGF-like growth factors as mediators of LH action in the ovulatory follicle.  Science. 2004;  303(5658) 682-684
    CrossrefPubMedGoogle Scholar
  • 38 Ashkenazi H, Cao X, Motola S et al.. Epidermal growth factor family members: endogenous mediators of the ovulatory response.  Endocrinology. 2005;  146(1) 77-84
    PubMedGoogle Scholar
  • 39 Sekiguchi T, Mizutani T, Yamada K et al.. Expression of epiregulin and amphiregulin in the rat ovary.  J Mol Endocrinol. 2004;  33(1) 281-291
    CrossrefPubMedGoogle Scholar
  • 40 Freimann S, Ben-Ami I, Dantes A, Ron-El R, Amsterdam A. EGF-like factor epiregulin and amphiregulin expression is regulated by gonadotropins/cAMP in human ovarian follicular cells.  Biochem Biophys Res Commun. 2004;  324(2) 829-834
    CrossrefPubMedGoogle Scholar
  • 41 Lindbloom S M, Farmerie T A, Clay C M, Seidel Jr G E, Carnevale E M. Potential involvement of EGF-like growth factors and phosphodiesterases in initiation of equine oocyte maturation.  Anim Reprod Sci. 2008;  103(1–2) 187-192
    PubMedGoogle Scholar
  • 42 Fru K N, Cherian-Shaw M, Puttabyatappa M, VandeVoort C A, Chaffin C L. Regulation of granulosa cell proliferation and EGF-like ligands during the periovulatory interval in monkeys.  Hum Reprod. 2007;  22(5) 1247-1252
    CrossrefPubMedGoogle Scholar
  • 43 Hsieh M, Lee D, Panigone S et al.. Luteinizing hormone-dependent activation of the epidermal growth factor network is essential for ovulation.  Mol Cell Biol. 2007;  27(5) 1914-1924
    CrossrefPubMedGoogle Scholar
  • 44 Richards J S, Russell D L, Ochsner S et al.. Novel signaling pathways that control ovarian follicular development, ovulation, and luteinization.  Recent Prog Horm Res. 2002;  57 195-220
    CrossrefPubMedGoogle Scholar
  • 45 Matzuk M M. Revelations of ovarian follicle biology from gene knockout mice.  Mol Cell Endocrinol. 2000;  163(1–2) 61-66
    CrossrefPubMedGoogle Scholar
  • 46 Hsueh A J. Paracrine mechanisms involved in granulosa cell differentiation.  Clin Endocrinol Metab. 1986;  15(1) 117-134
    CrossrefPubMedGoogle Scholar
  • 47 Sanderson M P, Dempsey P J, Dunbar A J. Control of ErbB signaling through metalloprotease mediated ectodomain shedding of EGF-like factors.  Growth Factors. 2006;  24(2) 121-136
    CrossrefPubMedGoogle Scholar
  • 48 Yarden Y, Sliwkowski M X. Untangling the ErbB signalling network.  Nat Rev Mol Cell Biol. 2001;  2(2) 127-137
    CrossrefPubMedGoogle Scholar
  • 49 Holbro T, Hynes N E. ErbB receptors: directing key signaling networks throughout life.  Annu Rev Pharmacol Toxicol. 2004;  44 195-217
    CrossrefPubMedGoogle Scholar
  • 50 Prenzel N, Zwick E, Daub H et al.. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF.  Nature. 1999;  402(6764) 884-888
    PubMedGoogle Scholar
  • 51 Eden J A, Jones J, Carter G D, Alaghband-Zadeh J. Follicular fluid concentrations of insulin-like growth factor 1, epidermal growth factor, transforming growth factor-alpha and sex-steroids in volume matched normal and polycystic human follicles.  Clin Endocrinol (Oxf). 1990;  32(4) 395-405
    PubMedGoogle Scholar
  • 52 Barreca A, Minuto F, Volpe A et al.. Insulin-like growth factor-I (IGF-I) and IGF-I binding protein in the follicular fluids of growth hormone treated patients.  Clin Endocrinol (Oxf). 1990;  32(4) 497-505
    CrossrefPubMedGoogle Scholar
  • 53 Reeka N, Berg F, Brucker C. Presence of transforming growth factor alpha and epidermal growth factor in human ovarian tissue and follicular fluid.  Hum Reprod. 1998;  13(8) 2199-2205
    CrossrefPubMedGoogle Scholar
  • 54 Hofmann G E, Scott Jr R T, Brzyski R G, Jones Jr H W. Immunoreactive epidermal growth factor concentrations in follicular fluid obtained from in vitro fertilization.  Fertil Steril. 1990;  54(2) 303-307
    PubMedGoogle Scholar
  • 55 Ozornek M H, Bielfeld P, Krussel J S et al.. Epidermal growth factor and leukemia inhibitory factor levels in follicular fluid. Association with in vitro fertilization outcome.  J Reprod Med. 1999;  44(4) 367-369
    PubMedGoogle Scholar
  • 56 Hsu C J, Holmes S D, Hammond J M. Ovarian epidermal growth factor-like activity. Concentrations in porcine follicular fluid during follicular enlargement.  Biochem Biophys Res Commun. 1987;  147(1) 242-247
    CrossrefPubMedGoogle Scholar
  • 57 Das K, Phipps W R, Hensleigh H C, Tagatz G E. Epidermal growth factor in human follicular fluid stimulates mouse oocyte maturation in vitro.  Fertil Steril. 1992;  57(4) 895-901
    PubMedGoogle Scholar
  • 58 McWilliam R, Leake R E, Coutts J R. Growth factors in human ovarian follicle fluid and growth factor receptors in granulosa-luteal cells.  Int J Biol Markers. 1995;  10(4) 216-220
    PubMedGoogle Scholar
  • 59 Dekel N, Sherizly I. Epidermal growth factor induces maturation of rat follicle-enclosed oocytes.  Endocrinology. 1985;  116(1) 406-409
    PubMedGoogle Scholar
  • 60 Downs S M, Daniel S A, Eppig J J. Induction of maturation in cumulus cell-enclosed mouse oocytes by follicle-stimulating hormone and epidermal growth factor: evidence for a positive stimulus of somatic cell origin.  J Exp Zool. 1988;  245(1) 86-96
    CrossrefPubMedGoogle Scholar
  • 61 Downs S M. Specificity of epidermal growth factor action on maturation of the murine oocyte and cumulus oophorus in vitro.  Biol Reprod. 1989;  41(2) 371-379
    CrossrefPubMedGoogle Scholar
  • 62 De La Fuente R, O'Brien M J, Eppig J J. Epidermal growth factor enhances preimplantation developmental competence of maturing mouse oocytes.  Hum Reprod. 1999;  14(12) 3060-3068
    CrossrefPubMedGoogle Scholar
  • 63 Smitz J, Cortvrindt R, Hu Y. Epidermal growth factor combined with recombinant human chorionic gonadotrophin improves meiotic progression in mouse follicle-enclosed oocyte culture.  Hum Reprod. 1998;  13(3) 664-669
    CrossrefPubMedGoogle Scholar
  • 64 Ben-Yosef D, Galiani D, Dekel N, Shalgi R. Rat oocytes induced to mature by epidermal growth factor are successfully fertilized.  Mol Cell Endocrinol. 1992;  88(1–3) 135-141
    CrossrefPubMedGoogle Scholar
  • 65 Boland N I, Gosden R G. Effects of epidermal growth factor on the growth and differentiation of cultured mouse ovarian follicles.  J Reprod Fertil. 1994;  101(2) 369-374
    PubMedGoogle Scholar
  • 66 Buccione R, Vanderhyden B C, Caron P J, Eppig J J. FSH-induced expansion of the mouse cumulus oophorus in vitro is dependent upon a specific factor(s) secreted by the oocyte.  Dev Biol. 1990;  138(1) 16-25
    CrossrefPubMedGoogle Scholar
  • 67 Lorenzo P L, Liu I K, Carneiro G F, Conley A J, Enders A C. Equine oocyte maturation with epidermal growth factor.  Equine Vet J. 2002;  34(4) 378-382
    CrossrefPubMedGoogle Scholar
  • 68 Prochazka R, Srsen V, Nagyova E, Miyano T, Flechon J E. Developmental regulation of effect of epidermal growth factor on porcine oocyte-cumulus cell complexes: nuclear maturation, expansion, and F-actin remodeling.  Mol Reprod Dev. 2000;  56(1) 63-73
    CrossrefPubMedGoogle Scholar
  • 69 Prochazka R, Kalab P, Nagyova E. Epidermal growth factor-receptor tyrosine kinase activity regulates expansion of porcine oocyte-cumulus cell complexes in vitro.  Biol Reprod. 2003;  68(3) 797-803
    PubMedGoogle Scholar
  • 70 Lorenzo P L, Illera M J, Illera J C, Illera M. Enhancement of cumulus expansion and nuclear maturation during bovine oocyte maturation in vitro by the addition of epidermal growth factor and insulin-like growth factor I.  J Reprod Fertil. 1994;  101(3) 697-701
    PubMedGoogle Scholar
  • 71 Lonergan P, Carolan C, Van Langendonckt A et al.. Role of epidermal growth factor in bovine oocyte maturation and preimplantation embryo development in vitro.  Biol Reprod. 1996;  54(6) 1420-1429
    CrossrefPubMedGoogle Scholar
  • 72 Rieger D, Luciano A M, Modina S et al.. The effects of epidermal growth factor and insulin-like growth factor I on the metabolic activity, nuclear maturation and subsequent development of cattle oocytes in vitro.  J Reprod Fertil. 1998;  112(1) 123-130
    PubMedGoogle Scholar
  • 73 Pang Y, Ge W. Epidermal growth factor and TGF{alpha} promote zebrafish oocyte maturation in vitro: potential role of the ovarian activin regulatory system.  Endocrinology. 2002;  143(1) 47-54
    CrossrefPubMedGoogle Scholar
  • 74 Park K W, Iga K, Niwa K. Exposure of bovine oocytes to EGF during maturation allows them to develop to blastocysts in a chemically-defined medium.  Theriogenology. 1997;  48(7) 1127-1135
    CrossrefPubMedGoogle Scholar
  • 75 Goff A, Yang Z, Cortvrindt R, Smitz J, Miron P. Protein synthesis during maturation of bovine oocytes, effect of epidermal growth factor.  Reprod Domest Anim. 2001;  36(1) 19-24
    CrossrefPubMedGoogle Scholar
  • 76 Singh B, Meng L, Rutledge J M, Armstrong D T. Effects of epidermal growth factor and follicle-stimulating hormone during in vitro maturation on cytoplasmic maturation of porcine oocytes.  Mol Reprod Dev. 1997;  46(3) 401-407
    CrossrefPubMedGoogle Scholar
  • 77 Conti M, Hsieh M, Park J Y, Su Y Q. Role of the epidermal growth factor network in ovarian follicles.  Mol Endocrinol. 2006;  20(4) 715-723
    PubMedGoogle Scholar
  • 78 Espey L LRJ. Temporal and spatial patterns of ovarian gene transcription following an ovulatory dose of gonadotropin in the rat.  Biol Reprod. 2002;  67(6) 1662-1670
    CrossrefPubMedGoogle Scholar
  • 79 Shimada M, Hernandez-Gonzalez I, Gonzalez-Robayna I, Richards J S. Paracrine and autocrine regulation of epidermal growth factor-like factors in cumulus oocyte complexes and granulosa cells: key roles for prostaglandin synthase 2 and progesterone receptor.  Mol Endocrinol. 2006;  20(6) 1352-1365
    PubMedGoogle Scholar
  • 80 Panigone S, Hsieh M, Fu M, Persani L, Conti M. Luteinizing hormone signaling in preovulatory follicles involves early activation of the epidermal growth factor receptor pathway.  Mol Endocrinol. 2008;  22(4) 924-936
    PubMedGoogle Scholar
  • 81 Ben-Ami I, Freimann S, Armon L et al.. PGE2 up-regulates EGF-like growth factor biosynthesis in human granulosa cells: new insights into the coordination between PGE2 and LH in ovulation.  Mol Hum Reprod. 2006;  12(10) 593-599
    CrossrefPubMedGoogle Scholar
  • 82 Negishi H. Regulation of amphiregulin, EGFR-like factor expression by hCG in cultured human granulosa cells.  Acta Obstet Gynecol Scand. 2007;  86(6) 706-710
    CrossrefPubMedGoogle Scholar
  • 83 Rimon E, Sasson R, Dantes A, Land-Bracha A, Amsterdam A. Gonadotropin-induced gene regulation in human granulosa cells obtained from IVF patients: modulation of genes coding for growth factors and their receptors and genes involved in cancer and other diseases.  Int J Oncol. 2004;  24(5) 1325-1338
    PubMedGoogle Scholar
  • 84 Feuerstein P, Cadoret V, Dalbies-Tran R et al.. Gene expression in human cumulus cells: one approach to oocyte competence.  Hum Reprod. 2007;  22(12) 3069-3077
    CrossrefPubMedGoogle Scholar
  • 85 Inoue Y, Miyamoto S, Fukami T et al.. Amphiregulin is much more abundantly expressed than transforming growth factor-alpha and epidermal growth factor in human follicular fluid obtained from patients undergoing in vitro fertilization-embryo transfer.  Fertil Steril. 2008;  , Epub ahead of print
    PubMedGoogle Scholar
  • 86 Lemos-Gonzalez Y, Rodriguez-Berrocal F J, Cordero O J, Gomez C, Paez de la Cadena M. Alteration of the serum levels of the epidermal growth factor receptor and its ligands in patients with non-small cell lung cancer and head and neck carcinoma.  Br J Cancer. 2007;  96(10) 1569-1578
    CrossrefPubMedGoogle Scholar
  • 87 Gutman G, Barak V, Maslovitz S et al.. Regulation of vascular endothelial growth factor-A and its soluble receptor sFlt-1 by luteinizing hormone in vivo: implication for ovarian follicle angiogenesis.  Fertil Steril. 2008;  89(4) 922-926
    CrossrefPubMedGoogle Scholar
  • 88 Artini P G, Monti M, Matteucci C et al.. Vascular endothelial growth factor and basic fibroblast growth factor in polycystic ovary syndrome during controlled ovarian hyperstimulation.  Gynecol Endocrinol. 2006;  22(8) 465-470
    CrossrefPubMedGoogle Scholar
  • 89 Hammadeh M E, Fischer-Hammadeh C, Hoffmeister H et al.. Relationship between cytokine concentrations (FGF, sICAM-1 and SCF) in serum, follicular fluid and ICSI outcome.  Am J Reprod Immunol. 2004;  51(1) 81-85
    CrossrefPubMedGoogle Scholar
  • 90 Arici A, Oral E, Bahtiyar O et al.. Leukaemia inhibitory factor expression in human follicular fluid and ovarian cells.  Hum Reprod. 1997;  12(6) 1233-1239
    CrossrefPubMedGoogle Scholar
  • 91 Li M G, Ding G L, Chen X J et al.. Association of serum and follicular fluid leptin concentrations with granulosa cell phosphorylated signal transducer and activator of transcription 3 expression in fertile patients with polycystic ovarian syndrome.  J Clin Endocrinol Metab. 2007;  92(12) 4771-4776
    CrossrefPubMedGoogle Scholar

Marco ContiM.D. 

Professor and Director, Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Reproductive Sciences, University of California

San Francisco, 513 Parnassus, HSW 1656, San Francisco, CA 94143-0556

Email: ContiM@obgyn.ucsf.edu