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GNRH agonists and antagonists in rescue for cyclophosphamide-induced ovarian damage: friend or foe?

  • Gynecologic Endocrinology and Reproductive Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

To find out if GnRH agonist (GnRHa) and GnRH antagonist (GnRHant) offer ovarian protection from cyclophosphamide (Cyc) and if AMH expression is affected.

Methods

This experimental study was conducted in Baskent University Animal research laboratory and 66 virgin Wistar albino rats were assigned to six groups. The control group received intraperitoneal saline injection. The GnRHa group had a single dose of leuprolide acetate (1 mg/kg) 28 days prior to saline injection. The GnRHant group had a single dose of cetrorelix acetate (0.1 mg/kg) 1 h prior to saline injection. The Cyc group had a single intraperitoneal dose of Cyc (75 mg/kg). The GnRHa+Cyc group had a single dose of leuprolide acetate (1 mg/kg) 28 days prior to Cyc (75 mg/kg). The GnRHant+Cyc group had single dose of cetrorelix acetate (0.1 mg/kg) 1 h prior to Cyc (75 mg/kg). At day 35, the animals were euthanized, and their ovaries were removed. Primordial follicles were counted and AMH expression was determined. The Kruskal–Wallis, χ 2, or Fisher’s exact test was used where appropriate. p < 0.05 was considered statistically significant.

Results

PMF count was reduced in GnRHant (p < 0.01) and Cyc (p < 0.01) groups. Cyc, GnRHa+Cyc and GnRHant+Cyc groups had similar numbers of PMF. AMH expression was reduced in Cyc, GnRHa+Cyc and GnRHant+Cyc groups (p < 0.01).

Conclusion

Neither GnRHa nor GnRHant can offer protection against Cyc-induced damage. GnRHant itself reduces the number of primordial follicles.

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References

  1. Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M et al (2002) Goserelin versus cyclophosphamide, methotrexate and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 20(24):4628–4635

    Article  CAS  PubMed  Google Scholar 

  2. Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thürlimann B, Senn HJ et al (2005) Meeting highlights: international expert consensus on the primary therapy of early breast cancer. Ann Oncol 16(10):1569–1583

    Article  CAS  PubMed  Google Scholar 

  3. Nygaard R, Clausen N, Siimes MA, Márky I, Skjeldestad FE, Kristinsson JR et al (1991) Reproduction following treatment for childhood leukaemia: a population based prospective cohort study of fertility and offspring. Med Pediatr Oncol 19(6):459–466

    Article  CAS  PubMed  Google Scholar 

  4. Maltaris T, Koelbl H, Seufert R, Kiesewetter F, Beckmann MW, Mueller A et al (2006) Gonadal damage and options for fertility preservation in female and male cancer survivors. Asian J Androl 8(5):515–533

    Article  PubMed  Google Scholar 

  5. Jadoul P, Dolmans MM, Donnez J (2010) Fertility preservation in girls during childhood: is it feasible, efficient and safe and to whom should it be proposed? Hum Reprod Update 16(6):617–630

    Article  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Ataya K, Rao LV, Lawrence E, Kimmel R (1995) Luteinizing hormone-releasing hormone agonist inhibits cyclophosphamide-induced ovarian follicular depletion in rhesus monkeys. Biol Reprod 52(2):365–372

    Article  CAS  PubMed  Google Scholar 

  9. Blumenfeld Z, Avivi I, Linn S, Epelbaum R, Ben-Shahar M, Haim N (1996) Prevention of irreversible chemotherapy-induced ovarian damage in young women with lymphoma by a gonadotrophin-releasing hormone agonist in parallel to chemotherapy. Hum Reprod 11(8):1620–1626

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Clowse MEB, Behera MA, Anders CK, Copland S, Coffman C, Leppert PC et al (2009) Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis. J Womens Health (Larchmt) 18:311–319

    Article  Google Scholar 

  12. Sverrisdottir A, Nystedt M, Johansson H, Fornander T (2009) Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat 117:561–567

    Article  CAS  PubMed  Google Scholar 

  13. Ozcelik B, Turkyilmaz C, Ozgun MT, Serin IS, Batukan C, Ozdamar S et al (2010) Prevention of paclitaxel and cisplatin induced ovarian damage in rats by a gonadotropin-releasing hormone agonist. Fertil Steril 93(5):1609–1614

    Article  CAS  PubMed  Google Scholar 

  14. Tan SJ, Yeh Y, Shang W, Wua G, Liu J, Chen C (2010) Protective effect of a gonadotropin-releasing hormone analogue on chemotherapeutic agent-induced ovarian gonadotoxicity: a mouse model. Eur J Obstet Gynecol Reprod Biol 149(2):182–185

    Article  CAS  PubMed  Google Scholar 

  15. Meirow D, Assad G, Dor J, Rabinovici J (2004) The GnRH antagonist cetrorelix reduces cyclophosphamide-induced ovarian follicular destruction in mice. Hum Reprod 19(6):1294–1299

    Article  CAS  PubMed  Google Scholar 

  16. Lemos CN, Reis FM, Pena GN, Silveira LC, Camargos AF (2010) Assessment of fertility protection and ovarian reserve with GnRH antagonist in rats undergoing chemotherapy with cyclophosphamide. Reprod Biol Endocrinol 18(8):51

    Article  Google Scholar 

  17. Meirow D, Lewis H, Nugent D, Epstein M (1999) Subclinical depletion of primordial follicular reserve in mice treated with cyclophosphamide: clinical importance and proposed accurate investigative tool. Hum Reprod 14(7):1903–1907

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  20. Dogan E, Saygili U, Posaci C, Tuna B, Caliskan S, Altunyurt S et al (2004) Regression of endometrial explants in rats treated with the cyclooxygenase-2 inhibitor rofecoxib. Fertil Steril 82:1115–1120

    Article  CAS  PubMed  Google Scholar 

  21. Schwahn M, Nagaraja NV, Derendorf H, Derendorf H (2000) Population pharmacokinetic/pharmacodynamic modeling of cetrorelix, a novel LH-RH antagonist, testosterone in rats and dogs. Pharm Res 17:328–335

    Article  CAS  PubMed  Google Scholar 

  22. Celik-Ozenci C, Akkoyunlu G, Korgun ET, Savas B, Demir R (2004) Expressions of VEGF and its receptors in rat corpus luteum during interferon alpha administration in early and pseudopregnancy. Mol Reprod Dev 67:414–423

    Article  CAS  PubMed  Google Scholar 

  23. Warne GL, Fairley KF, Hobbs JB, Martin FI (1973) Cyclophosphamide-induced ovarian failure. N Engl J Med 289(22):1159–1162

    Article  CAS  PubMed  Google Scholar 

  24. Jarrell JF, Bodo L, Young Lai EV, Barr RD, O’Connell GJ (1991) The short-term reproductive toxicity of cyclophosphamide in the female rat. Reprod Toxicol 5(6):481–485

    Article  CAS  PubMed  Google Scholar 

  25. Letterie GS (2004) Anovulation in the prevention of cytotoxic-induced follicular attrition and ovarian failure. Hum Reprod 19(4):831–837

    Article  CAS  PubMed  Google Scholar 

  26. Ben-Aharon I, Bar-Joseph H, Tzarfaty G, Kuchinsky L, Rizel S, Stemmer SM et al (2010) Doxorubicin-induced ovarian toxicity. Reprod Biol Endocrinol 4(8):20

    Article  Google Scholar 

  27. Bedaiwy MA, Abou-Setta AM, Desai N, Hurd W, Starks D, El-Nashar SA et al (2011) Gonadotropin-releasing hormone analog cotreatment for preservation of ovarian function during gonadotoxic chemotherapy: a systematic review and meta-analysis. Fertil Steril 95(3):906–914

    Article  CAS  PubMed  Google Scholar 

  28. Waxman JH, Ahmed R, Smith D, Wrigley PF, Gregory W, Shalet S et al (1987) Failure to preserve fertility in patients with Hodgkin’s disease. Cancer Chemother Pharmacol 19:159–162

    Article  CAS  PubMed  Google Scholar 

  29. Chen H, Li J, Cui T, Hu L (2011) Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy induced premature ovarian failure in premenopausal women. Cochrane Database Syst Rev (11):CD008018

  30. Del Mastro L, Boni L, Michelotti A, Gamucci T, Olmeo N, Gori S et al (2011) Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial. JAMA 306(3):269–276

    PubMed  Google Scholar 

  31. Blumenfeld Z, Shapiro D, Shteinberg M, Avivi I, Nahir M (2000) Preservation of fertility and ovarian function and minimizing gonadotoxicity in young women with systemic lupus erythematosus treated by chemotherapy. Lupus 9:401–405

    Article  CAS  PubMed  Google Scholar 

  32. Matsumoto M, Shinohara O, Ishiguro H, Shimizu T, Hattori K, Ichikawa M et al (1999) Ovarian function after bone marrow transplantation performed before menarche. Arch Dis Child 80:452–454

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Thibaud E, Rodriguez-Macias K, Trivin C, Espérou H, Michon J, Brauner R (1998) Ovarian function after bone marrow transplantation during childhood. Bone Marrow Transplant 21:287–290

    Article  CAS  PubMed  Google Scholar 

  34. Del Mastro L, Catzeddu T, Boni L, Bell C, Sertoli MR, Bighin C et al (2006) Prevention of chemotherapy induced menopause by temporary ovarian suppression with goserelin in young, early breast cancer patients. Ann Oncol 17:74–78

    Article  PubMed  Google Scholar 

  35. Knauff EA, Eijkemans MJ, Lambalk CB, ten Kate-Booij MJ, Hoek A, Beerendonk CC, Dutch Premature Ovarian Failure Consortium et al (2009) Anti-Mullerian hormone, inhibin B, and antral follicle count in young women with ovarian failure. J Clin Endocrinol Metab 94(3):786–792

    Article  CAS  PubMed  Google Scholar 

  36. Licciardi FL, Liu HC, Rosenwaks Z (1995) Day 3 estradiol serum concentrations as prognosticators of ovarian stimulation response and pregnancy outcome in patients undergoing in vitro fertilization. Fertil Steril 64:991–994

    CAS  PubMed  Google Scholar 

  37. Das M, Shehata F, Son WY, Tulandi T, Holzer H (2012) Ovarian reserve and response to IVF and in vitro maturation treatment following chemotherapy. Hum Reprod 27(8):2509–2514

    Article  CAS  PubMed  Google Scholar 

  38. Choi JH, Choi KC, Auersperg N, Leung PC (2006) Differential regulation of two forms of gonadotropin-releasing hormone messenger ribonucleic acid by gonadotropins in human immortalized ovarian surface epithelium and ovarian cancer cells. Endocr Relat Cancer 13(2):641–651

    Article  CAS  PubMed  Google Scholar 

  39. Bhartiya D, Sriraman K, Gunjal P, Modak H (2012) Gonadotropin treatment augments postnatal oogenesis and primordial follicle assembly in adult mouse ovaries? J Ovarian Res 5(1):32

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Dong M, Huang L, Wang W, Du M, He Z, Mo Y et al (2011) Regulation of AMH and SCF expression in human granulosa cells by GnRH agonist and antagonist. Pharmazie 66(6):436–439

    CAS  PubMed  Google Scholar 

  41. Yu Ng EH, Chi Wai Chan C, Tang OS, Shu Biu Yeung W, Chung Ho P (2004) Effect of pituitary down regulation on antral follicle count, ovarian volume and stromal blood flow measured by three-dimensional ultrasound with power Doppler prior to ovarian stimulation. Hum Reprod 19:2811–2815

    Article  PubMed  Google Scholar 

  42. Maman E, Prokopis K, Levron J, Carmely A, Dor J, Meirow D (2009) Does controlled ovarian stimulation prior to chemotherapy increase primordial follicle loss and diminish ovarian reserve? An animal study. Hum Reprod 24(1):206–210

    Article  CAS  Google Scholar 

  43. Stanislaus D, Ponder S, Ji TH, Conn PM (1998) Gonadotropin-releasing hormone receptor couples to multiple G proteins in rat gonadotrophs and in GGH3 cells: evidence from palmitoylation and overexpression of G proteins. Biol Reprod 59(3):579–586

    Article  CAS  PubMed  Google Scholar 

  44. Andersen CY, Byskov AG (2006) Estradiol and regulation of anti-Mullerian hormone, inhibin-A, and inhibin-B secretion: analysis of small antral and preovulatory human follicles’ fluid. J Clin Endocrinol Metab 91:4064–4069

    Article  CAS  PubMed  Google Scholar 

  45. Durlinger AL, Gruijters MJ, Kramer P, Karels B, Ingraham HA, Nachtigal MW et al (2002) Anti-Müllerian hormone inhibits initiation of primordial follicle growth in the mouse ovary. Endocrinology 143:1076–1084

    CAS  PubMed  Google Scholar 

  46. Baarends WM, Uilenbroek JT, Kramer P, Hoogerbrugge JW, van Leeuwen EC, Themmen AP et al (1995) Anti-Müllerian hormone and anti-Müllerian hormone type II receptor messenger ribonucleic acid expression in rat ovaries during postnatal development, the estrous cycle and gonadotropin-induced follicle growth. Endocrinology 136:4951–4962

    CAS  PubMed  Google Scholar 

  47. Durlinger AL, Visser JA, Themmen AP (2002) Regulation of ovarian function: the role of anti-Müllerian hormone. Reproduction 124(5):601–609

    Article  CAS  PubMed  Google Scholar 

  48. Jeppesen JV, Anderson RA, Kelsey TW, Christiansen SL, Kristensen SG, Jayaprakasan K et al (2013) Which follicles make the most anti-Mullerian hormone in humans? Evidence for an abrupt decline in AMH production at the time of follicle selection. Mol Hum Reprod 19(8):519–527. doi:10.1093/molehr/gat024

    Article  CAS  PubMed  Google Scholar 

  49. Wunder DM, Guibourdenche J, Birkhauser MH, Bersinger NA (2008) Anti-Mullerian hormone and inhibin B as predictors of pregnancy after treatment by in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril 90:2203–2210

    Article  CAS  PubMed  Google Scholar 

  50. Browne HN, Moon KS, Mumford SL, Schisterman EF, Decherney AH, Segars JH et al (2011) Is anti-Müllerian hormone a marker of acute cyclophosphamide-induced ovarian follicular destruction in mice pretreated with cetrorelix? Fertil Steril 96(1):180–186

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Winkler N, Bukulmez O, Hardy DB, Carr BR (2010) Gonadotropin releasing hormone antagonists suppress aromatase and anti-Müllerian hormone expression in human granulosa cells. Fertil Steril 94(5):1832–1839

    Article  CAS  PubMed  Google Scholar 

  52. Ethics Committee of the American Society for Reproductive Medicine (2005) Fertility preservation and reproduction in cancer patients. Fertil Steril 83:1622–1628

    Article  Google Scholar 

  53. Lee SJ, Schover LR, Partridge AH, Patrizio P, Wallace WH, Hagerty K et al (2006) American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 24:2917–2931

    Article  PubMed  Google Scholar 

  54. Yano T, Yano N, Matsumi H, Morita Y, Tsutsumi O, Schally AV et al (1997) Effect of luteinizing hormone-releasing hormone analogs on the rat ovarian follicle development. Horm Res 48(3):35–41

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank veterinary surgeon Didem Bacanlı and her team for support during the experiments and Cağla Sarıturk for statistical analysis.

Conflict of interest

We have no financial relationship with the drug companies. We have full control of all primary data and that we agree to allow the journal to review their data if requested. We declare no conflict of interest.

Ethical standard

The study was approved by the Baskent University Animal Care and Use Committee (DA 11/02). The manuscript does not contain clinical studies or patient data.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Baskent University, Ankara, Turkey

    Huriye A. Parlakgumus, Esra B. Kilicdag & Bulent Haydardedeoglu

  2. Department of Pathology, Baskent University, Ankara, Turkey

    Filiz A. Bolat

  3. Department of General surgery, Baskent University, Ankara, Turkey

    Alper Parlakgumus

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  1. Huriye A. Parlakgumus
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  2. Esra B. Kilicdag
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Correspondence to Huriye A. Parlakgumus.

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Parlakgumus, H.A., Kilicdag, E.B., Bolat, F.A. et al. GNRH agonists and antagonists in rescue for cyclophosphamide-induced ovarian damage: friend or foe?. Arch Gynecol Obstet 291, 1403–1410 (2015). https://doi.org/10.1007/s00404-014-3564-2

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  • DOI: https://doi.org/10.1007/s00404-014-3564-2

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