Rat Ovarian Insulin-Like Growth Factor Binding Protein-4: A Hormone-Dependent Granulosa Cell-Derived Antigonadotropin

Abstract

Objective: To assess the in vivo regulation of ovarian insulin-like growth factor binding protein-4 (GFBP-4) mRNA expression by gonadotropins and estrogen.

Methods: Whole varian RNA, obtained from two models of follicular development, was extracted and analyzed by Northern blotting. Immature rats were treated with pregnant mare senum gonadotropin (PMSG) followed 48 hours later with hCG, or alternatively were hypophysectomized and treated with FSH and/or diethylstilbestrol (DES). Localization of IGFBP-4 expression was assessed in the former study by in situ hybridization. Finally, the ability of human IGFBP-4 to antagonize FSH-stimulated progesterone accumulation was assessed in vitro.

Results: The ovarian content of IGFBP-4 transcripts increased threefold (P < .05) at 12 hours after PMSG but was near baseline at 24 and 48 hours. The abundance of IGFBP-4 mRNA increased (P < .05) again at 6 and 24 hours after hCG. The expression of IGFBP-4 was localized to granulosa cells of prenatral (untreated) and small antral (12 hours after PMSG) follicles. No IGFBP-4 expression was noted in large (gonadotropin-primed) antral follicles. Hypophysectomy increased (P < .05) the ovarian content of IGBP-4 mRNA by 1.5-fold, an effect further enhanced (1.8-fold; P < .05) by the provision of FSH and DES. In vitro studies revealed the ability of increasing concentrations (0.01-1 μg/mL) of recombinant human IGFBP-4 to inhibit the FSH-supported accumulation of progesterone.

Conclusion: Increased expression after administration of PMSG, hCG, and FSH/DES suggests that IGFBP-4 is a dynamic and hormonally responsive component of the ovarian cycle. The lack of expression in preovulatory follicles and its antigonadotropic actions in vitro imply that the attenuated expression of IGFBP-4 may constitute a requirement for successful follicular maturation.

Keywords

Insulin-like growth factor binding protein-4 Carrier proteins gonadotropins ovary

References

1. Adashi EY . Intraovarian regulation: The IGF-I example. Reprod Fertil Dev 1992;4:497-504.

2. Hammond JM , Mondschein JS , Samaras SE , Smith SA , Hagen DR . The ovarian insulin-like growth factor system. J Reprod Fertil 1991;43:199-208.

3. Guidice LC . Insulin-like growth factors and ovarian follicular development. Endocr Rev 1992;13:641-669.

4. Ling NC , Liu X-J , Malkowski M , Guo Y-L , Erickson GF , Shimasaki S. Structural and functional studies of insulin-like growth factor binding proteins in the ovary. Growth Regula 1993;3:70-74.

5. Adashi EY . IGFs as determinants of follicular fate. J Soc Gynercol Invest 1995;2:721-726.

6. Nakatani A , Shimasaki S , Erickson GF , Ling N. Tissue-specific expression of four insulin-like growth factor-binding proteins (1,2,3, and 4) in the rat ovary. Endocrinology 1991;129:1521-1529.

7. Ricciarelli E , Hernandez ER , Hurwitz A , et al. The ovarian expression of the antigonadotropic insulin-like growth factor binding protein-2 is theca-interstitial cell-selective: Evidence for hormonal regulation. Endocrinology 1991;129:2266-2268.

8. Ricciarelli E , Hernandez ER , Tedeschi C , et al. Rat ovarian insulin-like growth factor binding protein-3: A growth hormone-dependent theca-interstitial; cell-derived antigonadotropin. Endocrinology 1992;130:3092-3094.

9. Roban RM , Ricciarelli E , Kiefer MC , Resnick CE , Adashi EY . Rat ovarian insulin-like growth factor binding protein-6: A pituitary-dependent theca-interstitial selective spacies with limited antigonadotropic activity. Endocrinology 1993;132:2507-2512.

10.

10. Choi DS , Putowski LT , Fielder PJ , Rosenfield RG , Rohan RM , Adashi EY . Characterization and hormonal regulation of granulosa cell-derived insulin-like growth factor binding protein-4. J Soc Gynecol Invest 1996;3:145-152.

11.

11. Liu X-J , Malkowski M , Guo Y , Erickson GF , Shimasaki S , Ling N. Development of specific antibodies to rat insulin-like growth factor-binding proteins (IGFBP-2 or -6): Analysis of IGFBP production by rat granulosa cells. Endocrinology 1993;132:1176-1183.

12.

12. Ondoa N , Li L , Mickey G , Erickson GF , Shimasaki S. Gonadotropin-releasing hormone overcomes follicle-stimulating hormone's inhibition of insulin-like growth factor-5 synthesis and promotion of its degradation in rat granulosa cells. Mol Cell Endocrinol 1995;110:17-25.

13.

13. Erickson GF , Li D , Sadrkhanloo R , Liu X-J , Shimasaki S , Ling N. Extrapituitary actions of gonadotropin-releasing hormone: Stimulation of insulin-like growth factor-binding protein-4 and atresia. Endocrinology 1994;134:1365-1372.

14.

14. Koistinen R , Huhtala M-L , Stenman U-H , Seppala M. Purification of placental protein PP12 from human amniotic fluid and its comparison with PP12 from placenta by immunological, physicochemical and somatomedin-binding properties. Clin Chim Acta 1987;164:293-303.

15.

15. Tressel TJ , Tatsuno GP , Spratt K , Sommer A. Purification and characterization of human recombinant insulin-like growth factor binding protein 3 expressed in Chinese hamster ovary cells. Biochem Biophys Res Commun 1991;178:625-633.

16.

16. Kiefer MC , Schmid C , Waldvogel M , et al. Characterization of recombinant human nsulin-like growth factor binding proteins 4, 5, and 6 produced in yeast. J Biol Chem 1992;267:12692-12699.

17.

17. Hurwitz A , Ricciarelli E , Botero L , Rohan RM , Hernandez ER , Adashi EY . Endocrine- and autocrine-mediated regulation of rat ovarian (theca-interstitial) interleukin-1β gene expression: Gonadotropin-dependent preovulatory acquisition. Endocrinology 1991;129:3247-3249.

18.

18. Shimasaki S , Uchiyama F , Shimonaka M , Ling N. Molecular cloning of the cDNAs encoding a novel insulin-like growth factor-binding protein from rat and human. Mol Endocrinol 1990;4:1451-1458.

19.

19. Harpold MM , Evans RM , Salditt-Georgieff M , Darnell JE . Production of mRNA in Chinese hamster cells: Relationships of the rate of synthesis to the cytoplasmic concentration of nine specific mRNA sequences. Cell 1979;17:1025-1035.

20.

20. Park O-K , Mayo KE . Transient expression of progesterone receptor messenger RNA in ovarian granulosa cells after the preovulatory luteinizing hormone surge. Mol Endocrinol 1991;5:967-978.

21.

21. Camp T , Rahal JO , Mayo KE . Cellular localization and hormonal regulation of follicle-stimulating hormone and luteinizing hormone receptor messenger RNAs in the rat ovary. Mol Endocrinol 1991;5:1405-1417.

22.

22. Suzuki K , Olvera J , Wool IG . Primary structure of rat ribosomal protein S2: A ribosomal protein with arginine-glycine tandem repeats and RGGF motifs that are associated with nucleolar localization and binding to ribonucleic acids. J Biol Chem 1991;266:20007-20010.

23.

23. Heller DL , Gianola KM , Leinwand LA . A highly conserved mouse gene with a propensity to form pseudogenes in mammals. Mol Cell Biol 1988;8:2797-2803.

24.

24. Adashi EY , Resnick CE , Hernandez ER , Hurwitz A , Rosenfeld R. Ovarian granulosa cell-derived insulin-like growth factor (IGF) binding proteins: Release of low molecular weight, high-affinity IGF-selective species. Mol Cell Endocrinol 1990;74:175-184.

25.

25. Gibori G , Antczak A , Rothchild I. The role of estrogen in the regulation of luteal progesterone secretion in the rat after day 12 of pregnancy. Endocrinology 1977;100:1483-1491.

26.

26. Andashi EY , Resnick CE , Ricciarelli E , et al. Local tissue modification of follicle stimulating hormone action. In: Genazzani AR , Petraglia F , eds. Hormones in gynecological endcrinology. Lancaster, England: The Parthenon Publishing Group, 1992;255-261.

27.

27. Mason HD , Willis D , Holly JMP , Cwyfan-Hughes SC , Seppala M , Franks S. Inhibitory effects of insulin-like growth factor-binding proteins on steroidogenesis by human grfanulosa cells in culture. Mol Cell Endocrinol 1992;89:R1-R4.

28.

28. Ui M , Shimonaka M , Shimasaki S , Ling N. An insulin-like growth factor-binding protein in ovarian follicular fluid blocks follicle-stimulating hormone-stimulated steroid production by ovarian granulossa cells. Endocrinology 1989;125:912-916.

29.

29. Bicsak TS , Shimonaka M , Malkowsi M , Ling N. Insulin-like growth factor-binding protein (IGFBP) inhibition of granulosa cell function: Effect on cyclic adenosine 3',5'-monophosphate, deoxyribonculeic acid synthesis, and comparison with the effect of an IGF-I antibody. Endocrinology 1990;126:2184-2189.

30.

30. Bicsak TS , Ling N , DePaolo LV . Ovarian intrabursal administration of insulin-like growth factor-binding protein inhibits follicle rupture in gonadotropin-treated immature female rats. Biol Reprod 1991;44:599-603.

31.

31. Erickson GF , Nakatani A , Ling N , Shimasaki S. Cyclic changes in insulin-like growth factor-binding protein-4 messenger ribonucleic acid in the rat ovary. Endocrinology 1992;130:625-636.

32.

32. Giudice LC , Milki AA , Milkowski DA , Danasouri IE . Human granulosa cells contain messenger ribonucleic acid encoding insulin-like growth factor-binding proteins (IGFBPs) and secret IGFBPs in culture. Fertil Steril 1991;56:475-480.

33.

33. Adashi EY , Resnick CE , Hernandez ER , Hurwitz A , Rosenfeld R. Follicle-stimulating hormone inhibits and constitutive release of insulin-like growth factor binding proteins by cultured rat ovarian granulosa cells. Endocrinology 1990;126:1305-1307.

34.

34. Adashi EY , Resnick CE , Hurwitz A , Ricciarelli E , Hernandez ER , Rosenfeld RG . Ovarian granulosa cell-derived insulin-like growth factor binding proteins: Modulatory role of follicle-stimulating hormone. Endocrinology 1991;128:754-760.

35.

35. Hsueh AJ , Billig H , Tsafriri R. Ovarian follicle atresia: A hofmonally controlled apoptotic process. Endocr Rev 1994;15:707-724.

36.

36. Van Dessel THJHM , Chandrasekher Y , Yap OWS , et al. Serum and follicular fluid levels of insulin-like growth factor 1 (IGF-1), IGF-II, and IGF-binding protein-1 and -3 during the normal menstrual cycle. J Clin Endocrinol Metab 1996;81:1224-1231.