Role of GnRH Agonists for Fertility Preservation in Breast Cancer

  • Cynthia Villarreal-Garza
  • Edna A. Lopez-Martinez
  • Hatem A. AzimJr


A large fraction of young breast cancer patients are concerned about their chances of future fertility. Chemotherapy often results in premature ovarian failure, particularly in women over the age of 35. Recent trials have suggested that concomitant administration of gonadotropin-releasing hormone agonists (GnRHa) with chemotherapy reduces the risk of premature ovarian failure. This option is currently endorsed by several international and local guidelines, and in some countries it is being covered by healthcare insurance as well. In this chapter, we discuss the clinical data supporting the use of GnRHa in early breast cancer for ovarian protection and fertility preservation.


Breast cancer Fertility Ovarian function LHRH analogs LHRHa GnRHa Young Premenopausal 


  1. 1.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer; 2013.. Scholar
  2. 2.
    Collins LC, Marotti JD, Gelber S, Cole K, Ruddy K, Kereakoglow S, et al. Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer. Breast Cancer Res Treat. 2012;131(3):1061–6.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Partridge AH, Hughes ME, Ottesen RA, Wong YN, Edge SB, Theriault RL, et al. The effect of age on delay in diagnosis and stage of breast cancer. Oncologist. 2012;17(6):775–82.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Poggio F, Levaggi A, Lambertini M. Chemotherapy-induced premature ovarian failure and its prevention in premenopausal breast cancer patients. Expert Rev Quality Life Cancer Care. 2016;1(1):5e7.CrossRefGoogle Scholar
  5. 5.
    ESHRE Guideline Group on POI, Webber L, Davies M, et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016;31(5):926–37.CrossRefGoogle Scholar
  6. 6.
    Sawe BE. Countries with the oldest average mother’s age at first birth. 15 Aug. 2016.
  7. 7.
    Mathews TJ, Hamilton BE. Mean age of mothers is on the rise: United States, 2000–2014. NCHS Data Brief. 2016;232:1e8.. Scholar
  8. 8.
    Partridge AH, Gelber S, Peppercorn J, et al. Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol. 2004;22(20):4174–83.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Villarreal-Garza C, Aguila C, Magallanes-Hoyos MC, et al. Breast cancer in young women in Latin America: an unmet, growing burden. Oncologist. 2013;18(12):1298–306.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Villarreal-Garza C, Platas A, Bargalló-Rocha JE, et al. Cáncer de mama en mujeres jóvenes: Experiencia en el Instituto Nacional de Cancerología. Rev Mex Mastol. 2015;5(1):12–7.Google Scholar
  11. 11.
    Ruddy KJ, Gelber SI, Tamimi RM, Ginsburg ES, Schapira L, Come SE, et al. Prospective study of fertility concerns and preservation strategies in young women with breast cancer. J Clin Oncol. 2014;32(11):1151e6.CrossRefGoogle Scholar
  12. 12.
    Letourneau JM, Ebbel EE, Katz PP, et al. Pretreatment fertility counseling and fertility preservation improve quality of life in reproductive age women with cancer. Cancer. 2012;118:17 10–7.CrossRefGoogle Scholar
  13. 13.
    Villarreal-Garza C, Martinez-Cannon BA, Platas A, et al. Fertility concerns among breast cancer patients in Mexico. Breast. 2017;33:71–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Litton JK. Breast cancer and fertility. Curr Treat Options Oncol. 2012;13:137–45.PubMedCrossRefGoogle Scholar
  15. 15.
    Paluch-Shimon S, Pagani O, Partridge AH, et al. ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3). Breast. 2017;35:203–17.CrossRefGoogle Scholar
  16. 16.
    Oktay K, Harvey BE, Partridge AH, et al. Fertility preservation in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2018;36(19):1994–2001.CrossRefGoogle Scholar
  17. 17.
    Lambertini M, Goldrat O, Barragan-Carrillo R, et al. Viable options for fertility preservation in breast cancer patients: a focus in Latin America. Rev Invest Clin. 2017;69:103–13.PubMedGoogle Scholar
  18. 18.
    Lambertini M, Goldrat O, Clatot F, et al. Controversies about fertility and pregnancy issues in young breast cancer patients: current state of the art. Curr Opin Oncol. 2017;29:243–52.PubMedCrossRefGoogle Scholar
  19. 19.
    Gründker C, Emons G. Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer. Reprod Biol Endocrinol. 2003;1:65.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Chapman RM, Sutcliffe SB. Protection of ovarian function by oral contraceptives in women receiving chemotherapy for Hodgkin’s disease. Blood. 1981;58:849–51.PubMedCrossRefGoogle Scholar
  21. 21.
    Li M, Huang H, Liang Y, Tan J, Lin D. Effect of Zoladex administered before chemotherapy on menstruation of patients with breast cancer. Chin J Clin Oncol. 2008;35:905–7.Google Scholar
  22. 22.
    Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat. 2009;117:561–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Gerber B, von Minckwitz G, Stehle H, Reimer T, Felberbaum R, Maass N, et al. Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study. J Clin Oncol. 2011;29:2334–41.PubMedCrossRefGoogle Scholar
  24. 24.
    Sun J, Ren Y, Li W. Effect of Zoladex administered before chemotherapy on menstruation of patients with breast cancer. China Disabil Med. 2011;19:15–6.. n.dGoogle Scholar
  25. 25.
    Munster PN, Moore AP, Ismail-Khan R, Cox CE, Lacevic M, Gross-King M, et al. Randomized trial using gonadotropin-releasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol. 2012;30:533–8.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Elgindy EA, El-Haieg DO, Khorshid OM, Ismail EI, Abdelgawad M, Sallam HN, et al. Gonadatrophin suppression to prevent chemotherapy-induced ovarian damage: a randomized controlled trial. Obstet Gynecol. 2013;121:78–86.PubMedCrossRefGoogle Scholar
  27. 27.
    Jiang FY, Zhang QQ, Zeng J. Protective effect of GnRHa on chemotherapy Induced ovarian damage in breast cancer patients. Shandong Med J. 2013;53(8):16–8.Google Scholar
  28. 28.
    Karimi-Zarchi M, Forat-Yazdi M, Vafaeenasab MR, Nakhaie-Moghadam M, Miratashi-Yazdi A, Teimoori S, et al. Evaluation of the effect of GnRH agonist on menstrual reverse in breast cancer cases treated with cyclophosphamide. Eur J Gynaecol Oncol. 2014;35:59–61.PubMedGoogle Scholar
  29. 29.
    Song G, Gao H, Yuan Z. Effect of leuprolide acetate on ovarian function after cyclophosphamide-doxorubicin-based chemotherapy in premenopausal patients with breast cancer: results from a phase II randomized trial. Med Oncol. 2013;30:667.PubMedCrossRefGoogle Scholar
  30. 30.
    Del Mastro L, Boni L, Michelotti A, Gamucci T, Olmeo N, Gori S, et al. 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. 2011;306:269–76.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Lambertini M, Boni L, Michelotti A, Gamucci T, Scotto T, Gori S, et al. Ovarian suppression with triptorelin during adjuvant breast cancer chemotherapy and long-term ovarian function, pregnancies, and disease-free survival: a randomized clinical trial. JAMA. 2015;314:2632–40.CrossRefGoogle Scholar
  32. 32.
    Moore HCF, Unger JM, Phillips K-A, Boyle F, Hitre E, Porter D, et al. Final analysis of the prevention of early menopause study (POEMS)/SWOG intergroup S0230. JNCI J Natl Cancer Inst. 2019;111(2):djy185.CrossRefGoogle Scholar
  33. 33.
    Leonard RCF, Adamson DJA, Bertelli G, Mansi J, Yellowlees A, Dunlop J, et al. GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: the Anglo Celtic Group OPTION trial. Ann Oncol. 2017;28:1811–6.CrossRefGoogle Scholar
  34. 34.
    Zhang Y, Ji Y, Li J, Lei L, Wu S, Zuo W, et al. Sequential versus simultaneous use of chemotherapy and gonadotropin-releasing hormone agonist (GnRHa) among estrogen receptor (ER)-positive premenopausal breast cancer patients: effects on ovarian function, disease-free survival, and overall survival. Breast Cancer Res Treat. 2018;168:679–86.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril. 2009;91:694–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Lambertini M, Ceppi M, Poggio F, Peccatori FA, Azim HA, Ugolini D, et al. Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies. Ann Oncol. 2015;26:2408–19.CrossRefGoogle Scholar
  37. 37.
    Bai F, Lu Y, Wu K, Chen Q, Ding L, Ge M, et al. Protecting effects of gonadotropin releasing hormone agonist on chemotherapy-induced ovarian damage in premenopausal breast cancer patients: a systematic review and meta-analysis. Breast Care. 2017;12:48–52.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Munhoz RR, Pereira AAL, Sasse AD, Hoff PM, Traina TA, Hudis CA, et al. Gonadotropin-releasing hormone agonists for ovarian function preservation in premenopausal women undergoing chemotherapy for early-stage breast cancer: a systematic review and metaanalysis. JAMA Oncol. 2016;2:65–73.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Lambertini M, Moore HCF, Leonard RCF, Loibl S, Munster P, Bruzzone M, et al. Gonadotropin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in premenopausal patients with early breast cancer: a systematic review and meta-analysis of individual patient-level data. J Clin Oncol. 2018;36:1981–90.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Shen Y-W, Zhang X-M, Lv M, Chen L, Qin T-J, Wang F, et al. Utility of gonadotropinreleasing hormone agonists for prevention of chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a systematic review and meta-analysis. OncoTargets Ther. 2015;8:3349–59.CrossRefGoogle Scholar
  41. 41.
    Yang B, Shi W, Yang J, Liu H, Zhao H, Li X, et al. Concurrent treatment with gonadotropin-releasing hormone agonists for chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a meta-analysis of randomized controlled trials. Breast. 2013;22:150–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Wang C, Chen M, Fu F, Huang M. Gonadotropin-releasing hormone analog cotreatment for the preservation of ovarian function during gonadotoxic chemotherapy for breast cancer: a meta-analysis. PLoS One. 2013;8:e66360.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Silva C, Caramelo O, Almeida-Santos T, Ribeiro Rama AC. Factors associated with ovarian function recovery after chemotherapy for breast cancer: a systematic review and meta-analysis. Hum Reprod. 2016;31:2737–49.PubMedCrossRefGoogle Scholar
  44. 44.
    Azim HA Jr, Davidson NE, Ruddy KJ. Challenges in treating premenopausal women with endocrine-sensitive breast cancer. Am Soc Clin Oncol Educ Book. 2016;35:23–32.PubMedCrossRefGoogle Scholar
  45. 45.
    Lambertini M, Cinquini M, Moschetti I, et al. Temporary ovarian suppression during chemotherapy to preserve ovarian function and fertility in breast cancer patients: a GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology. Eur J Cancer. 2017;71:25e33.Google Scholar
  46. 46.
    Lambertini M, Di Maio M, Pagani O, et al. The BCY3/BCC 2017 survey on physicians’ knowledge, attitudes and practice towards fertility and pregnancy-related issues in young breast cancer patients. The Breast. 2018;42:41–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Villarreal-Garza CM, Barragan-Carillo R, Bargallo-Rocha JE, et al. Physicians’ knowledge and attitudes towards fertility preservation in Mexican young breast cancer patients. Cancer Res. 2018;78(4 Suppl). P6-11-09.Google Scholar
  48. 48.
    Biglia N, Torrisi R, D’Alonzo M, Codacci Pisanelli G, Rota S, Peccatori FA. Attitudes on fertility issues in breast cancer patients: an Italian survey. Gynecol Endocrinol. 2015;31(6):458e64.CrossRefGoogle Scholar
  49. 49.
    Lambertini M, Fontana V, Massarotti C, et al. Prospective study to optimize care and improve knowledge on ovarian function and/or fertility preservation in young breast cancer patients: Results of the pilot phase of the PREgnancy and FERtility (PREFER) study. The Breast. 2018;41:51–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Snyder KA, Pearse W. Discussing fertility preservation options with patients with cancer. JAMA. 2011;306:202–3.PubMedCrossRefGoogle Scholar
  51. 51.
    Duffy CM, Allen SM, Clark MA. Discussions regarding reproductive health for young women with breast cancer undergoing chemotherapy. J Clin Oncol. 2005;23:766–73.PubMedCrossRefGoogle Scholar
  52. 52.
    Rashedi AS, De Roo SF, Ataman LM, et al. Survey of fertility preservation options available to patients with cancer around the globe. J Glob Oncol. 2018;4:1–16.PubMedCrossRefGoogle Scholar
  53. 53.
    Cohen L, Hamer J, Helwig C, et al. Formal evaluation of PYNK: breast cancer program for young women-the patient perspective. Curr Oncol Tor Ont. 2016;23:e102–8.CrossRefGoogle Scholar
  54. 54.
    Villarreal-Garza C, Castro-Sanchez A, Platas A, et al. “Joven & Fuerte”: program for young women with breast cancer in Mexico—initial results. Rev Invest Clin. 2017;69:223–8.PubMedGoogle Scholar
  55. 55.
    Villarreal-Garza C, Platas A, Bargallo-Rocha JE, et al. Characterization of young Mexican patients with breast cancer who underwent oocyte/embryo preservation. The Breast. 2018;41:S9.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Cynthia Villarreal-Garza
    • 1
    • 2
    • 3
  • Edna A. Lopez-Martinez
    • 1
    • 3
  • Hatem A. AzimJr
    • 1
  1. 1.Hospital Zambrano Hellion—Breast Cancer CenterTecnologico de Monterrey, School of MedicineMonterreyMexico
  2. 2.Research and Breast Cancer DepartmentInstituto Nacional de CancerologiaMexico CityMexico
  3. 3.Joven & Fuerte, Program for Young Women with Breast Cancer in MexicoMexico CityMexico

Personalised recommendations