The insulin-like growth factor (IGF) family plays an important role in follicle development, dominant follicle growth and steroidogenesis, and follicular atresia. Insulin-like growth factor (IGF)-II is the primary IGF in human ovary, acting as a mediator of gonadotropin action. IGF-II stimulates granulosa steroidogenesis, and its actions, along with those of follicle-stimulating hormone (FSH), are inhibited by IGF binding protein (IGFBP)-4. At the time of follicle selection, in the estrogen-dominant follicle, granulosa IGF-II synthesis increased dramatically. Simultaneously, in the selected follicle, IGFBP-4, an inhibitor of IGF-II action and abundant within androgen-dominant follicles, is proteolyzed by a specific IGFBP-4 protease, resulting in decreased affinity of IGFBP-4 for IGF-II. The IGFBP-4 protease has recently been identified in human ovary as pregnancy-associated plasma protein-A (PAPP-A). In the Graafian follicle, IGF-II bioavailability is increased to act as a mediator of FSH action, by increased synthesis of this peptide and concomitant decrease in an inhibitor of its actions by proteolysis of IGFBP-4.
1. Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor binding protein superfamily. Endocrine Rev1992;20:761-787.
2.
2. Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LC. The insulin-related ovarian regulatory system in health and disease. Endocrine Rev1992;20:535-582.
3.
3. El-Roeiy A, Chen X, Roberts VJ, LeRoith D, Roberts CT, Yen SSC. Expression of insulin-like growth factor-I (IGF-I) and IGF-II and the IGF-I, IGF-II, and insulin receptor genes and localization of the gene products in the human ovary. J Clin Endocrinol Metab1993;77:1411-1418.
4.
4. El-Roeiy A, Chen X, Roberts VJ, Shimasaki S, Ling N, LeRoith D, et al. Expression of the genes encoding the insulin-like growth factors, 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 Metab1994;78:1488-1496.
5.
5. Zhou J, Bondy C. Anatomy of the human ovarian insulin-like growth factor system. Biol Reprod1993;48:467-470.
6.
6. Yuan W, Giudice LC. Insulin-like growth factor-II mediates the steroidogenic and growth promoting actions of follicle stimulating hormone on human ovarian pre-antral follicles in vitro. J Clin Endocrinol Metab1999;84:1479-1482.
7.
7. Chandrasekher YA, Yuan W, Faessen GH, Clark CA, Giudice LC. Synergistic regulation of insulin-like growth factor binding protein (IGFBP)-4 proteolysis by IGF-II and follicle stimulating hormone (FSH) in human ovarian granulosa cells in vitro. J Clin Endocrinol Metab (In Press).
8.
8. Gomez E, Tarin JJ, Pellicer MD. Oocyte maturation in humans: The role of gonadotropins and growth factors. Fertil Steril1993;60:40-46.
9.
9. Chun S-Y, Billig H, Tilly JL, Furuta I, Tsafriri A, Hsueh AJW. Gonadotropin suppression of apoptosis in cultured preovulatory follicles: mediatory role of endogenous insulin-like growth factor-I. Endocrinology1994;135:1845-1853.
10.
10. Van Dessel HJHM, Chandrasekher YA, Yap OWS, Lee PDK, Hintz RL, Faessen GHJ, et al. Serum and follicular fluid levels of IGF-I, IGF-II, and IGF binding protein-1 (IGFBP-1) and IGFBP-3 during the normal menstrual cycle. J Clin Endocrinol Metab1996;81:1224-1231.
11.
11. Cataldo NA, Giudice LC. Insulin-like growth factor binding protein profiles in human ovarian follicular fluid correlate with follicular functional status. J Clin Endocrinol Metab1992;74:821-829.
12.
12. Schuller AGP, Lindenbergh-Kortleve DJ, Pache TD, Zwarthoff EC, Fauser BCJM, Drop SLS. Insulin-like growth factor binding protein-2, 28 kDa and 24 kDa IGF-BP levels are decreased in fluid of dominant follicles, obtained from normal and polycystic ovaries. Regul Peptides1993;48;157-163.
13.
13. San Roman GA, Magoffin DA. Insulin-like growth factor binding proteins in healthy and atretic follicles during natural menstrual cycles. J Clin Endocrinol Metab1993;76:625-632.
14.
14. Mason HD, Cwyfan-Hughes S, Holly JMP, Franks S. Potent inhibition of human ovarian steroidogenesis by insulin-like growth factor binding protein-4 (IGFBP-4). J Clin Endocrinol Metab1998;83:284-287.
15.
15. Iwashita M, Kudo Y, Takeda Y. Effect of follicle stimulating hormone and insulin-like growth factors on proteolysis of insulin-like growth factor binding protein-4 in human granulosa cells. Mol Hum Reprod1998;4:401-405.
16.
16. Chandrasekher YA, Van Dessel HJHM, Fauser BCJM, Giudice LC. Estrogen- but not androgen-dominant human ovarian follicular fluid contains an IGFBP-4 protease. J Clin Endocrinol Metab1995;80:2734-2739.
17.
17. Rivera GM, Chandrasekher YA, Evans ACO, Giudice LC, Fortune JE. A role for insulin-like growth factor binding protein-4 (IGFBP-4) proteolysis in establishment of ovarian follicle dominance in cattble. Biol Reprod (In Press).
18.
18. Besnard N, Pisselet C, Monniaux D, Monget P. Proteolytic activity degrading insulin-like growth factor-binding protein-2, -3, -4, and -5 in healthy growing and atretic follicles in the pig ovary. Biol Reprod1997;56:1050-1058.
19.
19. Mazerbourg S, Zapf J, Bar RS, Brigstock DR, Lalou C, Binoux M, Monget P. Insulin-like growth factor binding protein-4 proteolytic degradation in ovine preovulatory follicles: studies of underlying mechanisms. Endocrinology1999;140:4175-4184.
20.
20. Conover CA, Oxvig C, Overgaard MT, Christiansen M, Giudice LC. Evidence that the insulin-like growth factor binding protein-4 protease in human ovarian follicular fluid is pregnancy associated plasma protein-A. J Clin Endocrinol Metab1999;84:4742-4745.
21.
21. Oxvig C, Sand O, Kristensen T, Gleich GJ, Sottrup-Jensen L. Circulating human pregnancy-associated plasma protein-A is disulfide-bridged to the proform of eosinophil major basic protein. J Biol Chem1993;268:12243-12246.
22.
22. Bonno M, Kephart GM, Carlson CM, Loegering DA, Vernof KK, Gleich GJ. Expression of eosinophil-granulosa major basic protein messenger ribonucleic acid in placental X cells. Lab Invest1994;70:234-241.
23.
23. Brambati B, Macintosh MC, Teisner B, Maguiness S, Shrimanker K, Lanzani A, et al. Low maternal serum levels of pregnancy associated plasma protein A (PAPP-A) in the first trimester in association with abnormal fetal karyotype. Br J Obstet Gynaecol1993;100:324-326.
24.
24. Kristensen T, Oxvig C, Sand O, Moller NPH, Sottrup-Jensen L. Amino acid sequence of human pregnancy-associated plasma protein-A derived from cloned cDNA. Biochemistry1994;33:1592-1598.
25.
25. Lawrence JB, Oxvig C, Overgaard MT, Sottrup-Jensen L, Gleich GJ, Hays LC, et al. The insulin-like growth factor-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Proc Natl Acad Sci USA1999;96:3149-3153.
