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Regulation of Gonadotropin-Releasing Hormone (GnRH) Receptor-I Expression in the Pituitary and Ovary by a GnRH Agonist and Antagonist

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Abstract

The aim of the current study was to examine the effects of gonadotropin-releasing hormone agonist (GnRH-a) and antagonist (GnRH-ant) on the expression of GnRH receptor-I (GnRHR-I) in pituitary and ovaries in cyclophosphamide (CTX) chemotherapeutic rats and to investigate the possible mechanism of interventions of GnRH-a and GnRH-ant in CTX-induced ovarian damage. In total, 36 female rats were distributed into 6 groups at random: normal saline (NS) group, CTX group, GnRH-a + NS group, GnRH-a + CTX group, GnRH-ant + NS group, and GnRH-ant + CTX group. After the rats were killed, the expression of GnRHR-I messenger RNAs (mRNAs) and proteins in pituitary and ovaries were examined by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot, respectively. The distribution of GnRHR-I in various compartments of the ovaries was observed by immunohistochemistry. Significant downregulation of GnRHR-I mRNA and protein expression in the pituitary were observed after treatment with GnRH-a or GnRH-ant. Moreover, GnRH-ant was more potent for this direct and fast inhibition. In ovary, GnRHR-I expression was significantly downregulated by GnRH-a. Although GnRH-ant slightly decreased the ovarian expression of GnRHR-I mRNA, the protein level was only weakly changed. In the ovarian compartment, GnRHR-ant groups had markedly GnRHR-I expression in early and late growing follicles compared to GnRHR-a groups that exhibited decreased expression of GnRHR-I, especially in late growing follicles. In summary, this study presents evidence for the different regulating effects of GnRH-a and GnRH-ant on the expression of GnRHR-I in pituitary and ovaries, which may provide insight into the mechanism of GnRH-a and GnRH-ant interventions on chemotoxic ovarian damage.

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References

  1. Peng P, Yang DZ, Zheng CY, Mo YQ, He YM, Zhang QX. Effects of gonadotropin releasing hormone analogues on chemotherapy-induced ovarian function damage in rats [in Chinese]. Zhonghua Fu Chan Ke Za Zhi. 2007;42(8):546–550.

    CAS  PubMed  Google Scholar 

  2. Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol. 1996;14(5):1718–1729.

    Article  CAS  Google Scholar 

  3. Goldhirsch A, Gelber RD, Castiglione M. The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients. The International Breast Cancer Study Group. Ann Oncol. 1990;1(3):183–188.

    Article  CAS  Google Scholar 

  4. Moliterni A, Bonadonna G, Valagussa P, Ferrari L, Zambetti M. Cycolophosphamide, methotrexate and fluor-ouracil with and without doborubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes. J Chin Oncol. 1991;9(7):1124–1130.

    CAS  Google Scholar 

  5. Blumenfeld Z, Avivi I, Ritter M, Rowe JM. Preservation of fertility and ovarian function and minimizing chemotherapy-induced gonadotoxicity in young women. J Soc Gynecol Invest. 1999;6(5):229–239.

    Article  CAS  Google Scholar 

  6. Falcon T, Bedaiwy MA. Fertility preservation and pregnancy outcome after maglignancy. Curr Opin Obstet Gynecol. 2005; 17(1):21–26.

    Article  Google Scholar 

  7. Ataya KM, McKanna JA, Weintraub AM, Clark MR, LeMaire WJ. A luteinizing hormone-releasing hormone agonist for the preservation of chemotherapy-induced ovarian follicular loss in rats. Cancer Res. 1985;45(8):3651–3656.

    CAS  PubMed  Google Scholar 

  8. Ortin TT, Shostak CA, Donaldson SS. Gonadal status and reproductive function following treatment for Hodgkin’s disease in childhood: the Stanford experience. Int J Radiat Oncol Biol Phys. 1990;19(4):873–880.

  9. Wallace WH, Shalet SM, Tetlow LJ, Morris-Jones PH. Ovarian function following the treatment of childhood acute lymphoblastic leukaemia. Med Pediatr Oncol. 1993; 21(5):333–339.

    Article  CAS  Google Scholar 

  10. Bokser L, Szende B, Schally AV. Protective effects of D-Trp6-luteinizing hormone-releasing hormone microcapsules against cyclophosphamide-induced gonadotoxicity in female rats. Br J Cancer. 1990;61(6):861–865.

    Article  CAS  Google Scholar 

  11. Ataya K, Ramahi-Ataya A. Reproductive performance of female rats treated with cyclophosphamide and/or LHRH agonist. Reprod Toxicol. 1993;7(3):229–235.

    Article  CAS  Google Scholar 

  12. Fink G. Gonadotropin secretion and its control. In: Knobil E, Neill JD, et al, eds. The Physiology of Reproduction. New York: Raven; 1988:1349–1377.

    Google Scholar 

  13. Halmos G, Schally AV, Pinski J, Vadillo-Buenfil M, Groot K. Down-regulation of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) in rats by LH-RH antagonist Cetrrelix. Proc Natl Acad Sci U S A. 1996;93(6): 2398–2402.

    Article  CAS  Google Scholar 

  14. Halmos G, Schally AV. Changes in subcellular distribution of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) after treatment with the LH-RH antagonist cetrorelix. Proc Natl Acad Sci U S A. 2002;99(2):961–965.

    Article  CAS  Google Scholar 

  15. Kovacs M, Schally AV, Csernus B, Rekasi Z. Luteinizing hormone-releasing hormone (LH-RH) antagonist Cetrorelix down-regulates the mRNA expression of pituitary receptors for LH-RH by counteracting the stimulatory effect of endogenous LH-RH. Proc Natl Acad Sci U S A. 2001;98(4):1829–1834.

    Article  CAS  Google Scholar 

  16. Kovacs M, Schally AV. Comparison of mechanisms of action of luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix and LHRH agonist triptorelin on the gene expression of pituitary LHRH receptors in rats. Proc Natl Acad Sci U S A. 2001;98(21):12197–12202.

    Article  CAS  Google Scholar 

  17. Horvath JE, Bajo AM, Schally AV, Kovacs M, Herbert F, Groot K. Effects of long-term treatment with the luteinizing hormone-releasing hormone (LHRH) agonist Decapeptyl and the LHRH antagonist Cetrorelix on the levels of pituitary LHRH receptors and their mRNA expression in rats. Proc Natl Acad Sci U S A. 2002;99(23):15048–15053.

    Article  CAS  Google Scholar 

  18. Murase M, Uemura T, Gao M, Inada M, Funabashi T, Hirahara F. GnRH antagonist-induced down-regulation of the mRNA expression of pituitary receptors: comparisons with GnRH agonist effects. Endocr J. 2005;52(1):131–137.

    Article  CAS  Google Scholar 

  19. Leung PC, Cheng CK, Zhu XM. Multi-factorial role of GnRH-I and GnRH-II in the human ovary. Mol Cell Endocrinol. 2003;202(1–2):145–153.

    Article  CAS  Google Scholar 

  20. MeirowD,AssadG,Dor J,RabinoviciJ.The GnRH antagonist cetrorelix reduces cyclophosphamide-induced ovarian follicular destruction in mice. Hum Reprod. 2004;19(6):1294–1299.

  21. Danforth DR, Arbogasta LK, Friedman CI. Acute depletion of murine primordial follicle reserve by gonadotropin-releasing hormone antagonists. Fertil Steril. 2005;83(5):1333–1338.

    Article  CAS  Google Scholar 

  22. Hsueh AJ, Jones PB. Extrapituitary actions of gonadotropin-releasing hormone. Endocr Rev. 1981;2(4):437–461.

    Article  CAS  Google Scholar 

  23. Janssens RM, Brus L, Cahill DJ, Huirne JA, Schoemaker J, Lambalk CB. Direct ovarian effects and safety aspects of GnRH agonists and antagonists. Hum Reprod Update. 2000; 6(5):505–518.

    Article  CAS  Google Scholar 

  24. Trimino E, Pinilla L, Aguilar E. Pituitary-gonadal function in neonatal and adult female rats treated with gonadotropin-releasing hormone agonist and antagonist: short- and long-term effects. Acta Endocrinol (Copenh). 1993;129(3):251–259.

    Article  CAS  Google Scholar 

  25. Kaiser UB, Zhao D, Cardona GR, Chin WW. Isolation and characterization of cDNAs encoding the rat pituitary GnRH receptor. Biochem Biophys Res Commun. 1992;189(3):1163–1169.

    Article  Google Scholar 

  26. Wong H, Anderson WD, Cheng T, Riabowol KT. Monitoring mRNA expression by polymerase chain reaction: the “primer-dropping” method. Anal Biochem. 1994;223(2): 251–258.

    Article  CAS  Google Scholar 

  27. Westergaard CG, Byskov AG, Andersen CY. Morphometric characteristics of the primordial to primary follicle transition in the human ovary in relation to age. Hum Reprod. 2007;22(8): 2225–2231.

    Article  Google Scholar 

  28. Felig Philip, Frohman Lawrence A. Endocrinology and Metabolism. 4th ed. New York, NY: McGraw-Hill; 2001.

    Google Scholar 

  29. Norwitz ER, Cardona GR, Jeong KH, et al. Identification and characterization of the gonadotropin-releasing hormone receptor. Mol Cell Endocrinol. 1992;6:1163–1169.

    Google Scholar 

  30. Bussenot I, Azoulay Barjonet C, Parinoud J. Modulation of the steroido-genesis of cultured human granulosa-lutein cells by gonadotropin-releasing hormone analogs. J Cin Endocrinol Metab. 1993;76(5):1376–1379.

    CAS  Google Scholar 

  31. Roth C, Leonhardt S, Seidel C, Luft H, Wuttke W, Jarry H. Comparative analysis of different puberty inhibiting mechanisms of two GnRH agonist and the GnRH antagonist cetrocelix using a female rat model. Pediatr Res. 2000;48(4): 468–474.

    Article  CAS  Google Scholar 

  32. Roth C, Schricker M, Lakomek M, et al. Autoregulation of the gonadotropin-releasiong hormone (GnRH) system during puberty: effects of antagonistic versus agonistic GnRH analogs in a female rat model. J endocrinol. 2001;169(2):361–405.

    Article  CAS  Google Scholar 

  33. Bauer-Dantoin AC, Jameson JL. Gonadotropin-releasing hormone receptor messenger ribonucleic acid expression in the ovary during the rat estrous cycle. Endocrinology. 1995; 136(10):4432–4438.

    Article  CAS  Google Scholar 

  34. Whitelaw PF, Eidne KA, Sellar R, Smyth CD, Hillier SG. Gonadotropin-releasing hormone receptor messenger ribonucleic acid expression in rat ovary. Endocrinology. 1995;136(1): 172–179.

    Article  CAS  Google Scholar 

  35. Hsueh AJ, Jones PB. Extrapituitary actions of gonadotropin-releasing hormone. Endocr Rev. 1981;2(4):437–461.

    Article  CAS  Google Scholar 

  36. Takekida S, Deguchi J, Samoto T, et al. Comparative analysis of the effects of gonadotropin-releasing hormone agonist on the proliferative activity, apoptosis, and steroidogenesis in cultured porcine granulosa cell at varying stages of follicular growth. Endocrine. 2000 Feb;12(1):61–7.

  37. Takekida S, Matsuo H, Maruo T. GnRH agonist action on granulosa cells at varying follicular stages. Mol Cell Endocrinol. 2003;202(1–2):155–164.

    Article  CAS  Google Scholar 

  38. Hillensjo T, LeMaire WJ. Gonadotropin-releasing hormone agonist stimulate meiotic maturation of follicle-enclosed rat oocytes in vitro. Nature. 1980;287(5778):145–146.

    Article  CAS  Google Scholar 

  39. Parinaud J, Beaur A, Bourreau E, Vieitez G, Pontonnier G. Effects of a luteinizing hormone-releasing hormone agonist (Buserelin) on steroidogenesis of cultured human preovulatory granulosa cells. Fertil Steril. 1988;50(4):597–602.

    Article  CAS  Google Scholar 

  40. Nathwani PS, Kang SK, Cheng KW, Choi KC, Leung PC. Regulation of gonadotropin-releasing hormone and its receptor gene expression by 17beta-estradiol in cultured human granulosa-luteal cells. Endocrinology. 2000;141(5): 1754–1763.

    Article  CAS  Google Scholar 

  41. Vänänen JE, Tong BL, Vänänen CM, Chan IH, Yuen BH, Leung PC. Interaction of prostaglandin F2 alpha and gonadotropin-releasing hormone on progesterone and estradiol production in human granulosa-luteal cells. Biol Reprod. 1997;57(6):1346–1353.

    Article  Google Scholar 

  42. Irusta G, Parborell F, Peluffo M, et al. Steroidogenetic acute regulatory protein in ovarian follicles of gonadotropin-stimulated rats is regulated by a gonadotropin-releasing hormone agonist. Biol Reprod. 2003;68(5):1577–1583.

    Article  CAS  Google Scholar 

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Correspondence to DongZi Yang PhD.

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Mo, Y., Peng, P., Zhou, R. et al. Regulation of Gonadotropin-Releasing Hormone (GnRH) Receptor-I Expression in the Pituitary and Ovary by a GnRH Agonist and Antagonist. Reprod. Sci. 17, 68–77 (2010). https://doi.org/10.1177/1933719109348026

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