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Assessment of ovarian function after chemotherapy in women with early and locally advanced breast cancer from Serbia

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

Abstract

Purpose

Among harmful effects of chemotherapy is the reduction of ovarian function. The aim was to determine the serum levels of FSH, LH, estradiol and AMH after chemotherapy followed by endocrine therapy in breast cancer patients.

Methods

The study included 40 premenopausal hormone receptor-positive breast cancer patients aged 33–50 years. Anthracycline-based chemotherapy received 14/40 while anthracycline–taxane combination received 26/40 of patients, followed by tamoxifen (30/40) or tamoxifen plus goserelin (10/40). All of them experienced chemotherapy-induced secondary amenorrhea. Hormone levels were determined by ELISA. Statistics included Spearman’s test, Mann–Whitney test and multiple linear regression analysis.

Results

Undetectable AMH levels were observed in 62.5 and 33.3% of patients with time period < 2 and ≥ 2 years from completion of chemotherapy to sample collection. Median levels of hormones for patients treated with anthracycline-based compared to anthracycline–taxane therapy were: 15.5 vs. 22.3 IU/L for FSH; 10.9 vs. 13.6 IU/L for LH; 55.5 vs. 39.5 pg/mL for estradiol; 0.11 vs. 0.11 ng/mL for AMH. The multiple linear regression showed that: women who received goserelin had significantly lower FSH; those with shorter time from completion of chemotherapy to sample collection had significantly higher LH and lower estradiol; younger women had higher AMH levels.

Conclusions

The ovarian function was recovered from chemotherapy-induced secondary amenorrhea with time elapsed since the completion of adjuvant chemotherapy. It may be less disrupted in patients who received anthracycline-based chemotherapy and goserelin plus tamoxifen, as well.

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References

  1. Fleischer RT, Vollenhoven BJ, Weston GC (2011) The effects of chemotherapy and radiotherapy on fertility in premenopausal women. Obstet Gynecol Surv 66:248–254. https://doi.org/10.1097/OGX.0b013e318224e97b

    Article  PubMed  Google Scholar 

  2. Johnston RJ, Wallace WHB (2009) Normal ovarian function and assessment of ovarian reserve in the survivor of childhood cancer. Pediatr Blood Cancer 53:296–302. https://doi.org/10.1002/pbc.22012

    Article  PubMed  Google Scholar 

  3. Henry NL, Xia R, Schott AF et al (2014) Prediction of postchemotherapy ovarian function using markers of ovarian reserve. Oncologist 19:68–74. https://doi.org/10.1634/theoncologist.2013-0145

    Article  CAS  PubMed  Google Scholar 

  4. Lappi M, Borini A (2012) Fertility preservation in women after the cancer. Curr Pharm Des 18:293–302

    Article  CAS  PubMed  Google Scholar 

  5. Bozza C, Puglisi F, Lambertini M et al (2014) Anti-Mullerian hormone: determination of ovarian reserve in early breast cancer patients. Endocr Relat Cancer 21:R51–R65. https://doi.org/10.1530/ERC-13-0335

    Article  CAS  PubMed  Google Scholar 

  6. Zavos A, Valachis A (2016) Risk of chemotherapy-induced amenorrhea in patients with breast cancer: a systematic review and meta-analysis. Acta Oncol 55:664–670. https://doi.org/10.3109/0284186X.2016.1155738

    Article  CAS  PubMed  Google Scholar 

  7. Lass A (2001) Assessment of ovarian reserve—is there a role for ovarian biopsy? Hum Reprod 16:1055–1057

    Article  CAS  PubMed  Google Scholar 

  8. Coccia ME, Rizzello F (2008) Ovarian reserve. Ann N Y Acad Sci 1127:27–30. https://doi.org/10.1196/annals.1434.011

    Article  CAS  PubMed  Google Scholar 

  9. Bernard DJ, Fortin J, Wang Y, Lamba P (2010) Mechanisms of FSH synthesis: what we know, what we don’t, and why you should care. Fertil Steril 93:2465–2485. https://doi.org/10.1016/j.fertnstert.2010.03.034

    Article  CAS  PubMed  Google Scholar 

  10. Vegetti W, Alagna F (2006) FSH and folliculogenesis: from physiology to ovarian stimulation. Reprod Biomed Online 12:684–694

    Article  CAS  PubMed  Google Scholar 

  11. Huhtaniemi I (2015) A short evolutionary history of FSH-stimulated spermatogenesis. Hormones (Athens) 14:468–478. https://doi.org/10.14310/horm.2002.1632

    Google Scholar 

  12. Christensen A, Bentley G, Cabrera R et al (2012) Hormonal regulation of female reproduction. Horm Metab Res 44:587–591. https://doi.org/10.1055/s-0032-1306301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Burger HG (2001) Physiological principles of endocrine replacement: estrogen. Horm Res 56(Suppl 1):82–85

    CAS  PubMed  Google Scholar 

  14. Suzuki S, Brown CM, Wise PM (2006) Mechanisms of neuroprotection by estrogen. Endocrine 29:209–216. https://doi.org/10.1385/ENDO:29:2:209

    Article  CAS  PubMed  Google Scholar 

  15. Visser JA, Schipper I, Laven JSE, Themmen APN (2012) Anti-Müllerian hormone: an ovarian reserve marker in primary ovarian insufficiency. Nat Rev Endocrinol 8:331–341. https://doi.org/10.1038/nrendo.2011.224

    Article  CAS  PubMed  Google Scholar 

  16. Robertson DM (2012) Inhibins and activins in blood: predictors of female reproductive health? Mol Cell Endocrinol 359:78–84. https://doi.org/10.1016/j.mce.2011.05.016

    Article  CAS  PubMed  Google Scholar 

  17. Ben-Aharon I, Shalgi R (2012) What lies behind chemotherapy-induced ovarian toxicity? Reproduction 144:153–163. https://doi.org/10.1530/REP-12-0121

    Article  CAS  PubMed  Google Scholar 

  18. Blumenfeld Z (2012) Chemotherapy and fertility. Best Pract Res Clin Obstet Gynaecol 26:379–390. https://doi.org/10.1016/j.bpobgyn.2011.11.008

    Article  PubMed  Google Scholar 

  19. Meirow D, Biederman H, Anderson RA, Wallace WHB (2010) Toxicity of chemotherapy and radiation on female reproduction. Clin Obstet Gynecol 53:727–739. https://doi.org/10.1097/GRF.0b013e3181f96b54

    Article  PubMed  Google Scholar 

  20. Broer SL, Broekmans FJM, Laven JSE, Fauser BCJM (2014) Anti-Mullerian hormone: ovarian reserve testing and its potential clinical implications. Hum Reprod Update 20:688–701. https://doi.org/10.1093/humupd/dmu020

    Article  CAS  PubMed  Google Scholar 

  21. Peluso C, Fonseca FLA, Rodart IF et al (2014) AMH: an ovarian reserve biomarker in assisted reproduction. Clin Chim Acta 437:175–182. https://doi.org/10.1016/j.cca.2014.07.029

    Article  CAS  PubMed  Google Scholar 

  22. Lutchman Singh K, Muttukrishna S, Stein RC et al (2007) Predictors of ovarian reserve in young women with breast cancer. Br J Cancer 96:1808–1816. https://doi.org/10.1038/sj.bjc.6603814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Anders C, Marcom PK, Peterson B et al (2008) A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer. Cancer Invest 26:286–295. https://doi.org/10.1080/07357900701829777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Reh A, Oktem O, Oktay K (2008) Impact of breast cancer chemotherapy on ovarian reserve: a prospective observational analysis by menstrual history and ovarian reserve markers. Fertil Steril 90:1635–1639. https://doi.org/10.1016/j.fertnstert.2007.09.048

    Article  CAS  PubMed  Google Scholar 

  25. Yu B, Douglas N, Ferin MJ et al (2010) Changes in markers of ovarian reserve and endocrine function in young women with breast cancer undergoing adjuvant chemotherapy. Cancer 116:2099–2105. https://doi.org/10.1002/cncr.25037

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Su HI, Sammel MD, Green J et al (2010) Antimullerian hormone and inhibin B are hormone measures of ovarian function in late reproductive-aged breast cancer survivors. Cancer 116:592–599. https://doi.org/10.1002/cncr.24746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Partridge AH, Ruddy KJ, Gelber S et al (2010) Ovarian reserve in women who remain premenopausal after chemotherapy for early stage breast cancer. Fertil Steril 94:638–644. https://doi.org/10.1016/j.fertnstert.2009.03.045

    Article  PubMed  Google Scholar 

  28. Anderson RA, Rosendahl M, Kelsey TW, Cameron DA (2013) Pretreatment anti-Müllerian hormone predicts for loss of ovarian function after chemotherapy for early breast cancer. Eur J Cancer 49:3404–3411. https://doi.org/10.1016/j.ejca.2013.07.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hamy A-S, Porcher R, Cuvier C et al (2014) Ovarian reserve in breast cancer: assessment with anti-Müllerian hormone. Reprod Biomed Online 29:573–580. https://doi.org/10.1016/j.rbmo.2014.07.008

    Article  CAS  PubMed  Google Scholar 

  30. Tiong V, Rozita AM, Taib NA et al (2014) Incidence of chemotherapy-induced ovarian failure in premenopausal women undergoing chemotherapy for breast cancer. World J Surg 38:2288–2296. https://doi.org/10.1007/s00268-014-2542-y

    Article  CAS  PubMed  Google Scholar 

  31. Bala J, Seth S, Dhankhar R, Ghalaut VS (2016) Chemotherapy: impact on anti-Müllerian hormone levels in breast carcinoma. J Clin Diagn Res 10:BC19–BC21. https://doi.org/10.7860/JCDR/2016/15933.7328

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Liem GS, Mo FKF, Pang E et al (2015) Chemotherapy-related amenorrhea and menopause in young chinese breast cancer patients: analysis on incidence, risk factors and serum hormone profiles. PLoS One 10:e0140842. https://doi.org/10.1371/journal.pone.0140842

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ben-Aharon I, Granot T, Meizner I et al (2015) Long-term follow-up of chemotherapy-induced ovarian failure in young breast cancer patients: the role of vascular toxicity. Oncologist 20:985–991. https://doi.org/10.1634/theoncologist.2015-0044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Long J-P, Wan F, Zhang F et al (2016) DTC chemotherapy regimen is associated with higher incidence of premature ovarian failure in women of reproductive age with breast cancer. Eur Rev Med Pharmacol Sci 20:1087–1092

    PubMed  Google Scholar 

  35. Berliere M, Duhoux FP, Dalenc F et al (2013) Tamoxifen and ovarian function. PLoS One 8:e66616. https://doi.org/10.1371/journal.pone.0066616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Montemurro F, Del Mastro L, De Laurentiis M, Puglisi F (2016) Endocrine therapy in premenopausal women with breast cancer: a critical appraisal of current evidence. Expert Rev Anticancer Ther 16:211–218. https://doi.org/10.1586/14737140.2016.1128327

    Article  CAS  PubMed  Google Scholar 

  37. Senkus E, Kyriakides S, Ohno S et al (2015) Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 26:v8–v30. https://doi.org/10.1093/annonc/mdv298

    Article  PubMed  Google Scholar 

  38. Klijn JG, Blamey RW, Boccardo F et al (2001) Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 19:343–353. https://doi.org/10.1200/JCO.2001.19.2.343

    Article  CAS  PubMed  Google Scholar 

  39. Barbakadze L, Kristesashvili J, Khonelidze N, Tsagareishvili G (2015) The correlations of anti-mullerian hormone, follicle-stimulating hormone and antral follicle count in different age groups of infertile women. Int J Fertil Steril 8:393–398

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Lee JE, Yoon SH, Kim HO, Min EG (2015) Correlation between the serum luteinizing hormone to folliclestimulating hormone ratio and the anti-Müllerian hormone levels in normo-ovulatory women. J Korean Med Sci 30:296. https://doi.org/10.3346/jkms.2015.30.3.296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rama Raju G, Chavan R, Deenadayal M et al (2013) Luteinizing hormone and follicle stimulating hormone synergy: a review of role in controlled ovarian hyper-stimulation. J Hum Reprod Sci 6:227. https://doi.org/10.4103/0974-1208.126285

    Article  Google Scholar 

  42. Lambalk CB, van Disseldorp J, de Koning CH, Broekmans FJ (2009) Testing ovarian reserve to predict age at menopause. Maturitas 63:280–291. https://doi.org/10.1016/j.maturitas.2009.06.007

    Article  CAS  PubMed  Google Scholar 

  43. Rosendahl M, Andersen CY, la Cour Freiesleben N et al (2010) Dynamics and mechanisms of chemotherapy-induced ovarian follicular depletion in women of fertile age. Fertil Steril 94:156–166. https://doi.org/10.1016/j.fertnstert.2009.02.043

    Article  CAS  PubMed  Google Scholar 

  44. Anderson RA, Themmen APN, Qahtani AA et al (2006) The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer. Hum Reprod 21:2583–2592. https://doi.org/10.1093/humrep/del201

    Article  CAS  PubMed  Google Scholar 

  45. Zhao J, Liu J, Chen K et al (2014) What lies behind chemotherapy-induced amenorrhea for breast cancer patients: a meta-analysis. Breast Cancer Res Treat 145:113–128. https://doi.org/10.1007/s10549-014-2914-x

    Article  CAS  PubMed  Google Scholar 

  46. Badawy A, Elnashar A, El-Ashry M, Shahat M (2009) Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril 91:694–697. https://doi.org/10.1016/j.fertnstert.2007.12.044

    Article  CAS  PubMed  Google Scholar 

  47. Clowse MEB, Behera MA, Anders CK et al (2009) Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis. J Women’s Heal 18:311–319. https://doi.org/10.1089/jwh.2008.0857

    Article  Google Scholar 

  48. Del Mastro L, Catzeddu T, Boni L 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. https://doi.org/10.1093/annonc/mdj029

    Article  PubMed  Google Scholar 

  49. Lambertini M, Ceppi M, Poggio F et al (2015) 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 26:mdv374. https://doi.org/10.1093/annonc/mdv374

    Article  Google Scholar 

  50. Moore HCF, Unger JM, Phillips K-A et al (2015) Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. N Engl J Med 372:923–932. https://doi.org/10.1056/NEJMoa1413204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Shen YW, Zhang XM, Lv M et al (2015) Utility of gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a systematic review and meta-analysis. Onco Targets Ther 8:3349. https://doi.org/10.2147/OTT.S95936

    Article  PubMed  PubMed Central  Google Scholar 

  52. 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. https://doi.org/10.1007/s10549-009-0313-5

    Article  CAS  PubMed  Google Scholar 

  53. Magon N (2011) Gonadotropin releasing hormone agonists: expanding vistas. Indian J Endocrinol Metab 15:261. https://doi.org/10.4103/2230-8210.85575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Mrs Jasna Popovic-Basic for her excellent technical assistance. This study was financially supported by the Grant no. III 41023 and OI 175068 of the Ministry of Education and Science of Serbia.

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Authors and Affiliations

  1. Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11 000, Belgrade, Serbia

    Emina Malisic, Jelena Milovanovic & Natasa Todorovic-Rakovic

  2. Department of Medical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11 000, Belgrade, Serbia

    Snezana Susnjar

  3. Department of Obstetrics and Gynecology, Faculty of Medicine, Clinical Center of Serbia, University of Belgrade, Višegradska 26, 11 000, Belgrade, Serbia

    Vesna Kesic

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  1. Emina Malisic
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  2. Snezana Susnjar
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Contributions

EM: Protocol/project development, data analysis, Manuscript writing. SS: Protocol/project development, data analysis, manuscript editing. JM: Data collection, data analysis, manuscript editing. NTR: Data collection, data analysis, manuscript editing. VK: Protocol/project development, manuscript editing.

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Correspondence to Emina Malisic.

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The authors declare no conflict of interests.

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All procedures performed in study were in accordance with the ethical standards of the Ethics Committee of the Institute for Oncology and Radiology of Serbia and with the 1964 Helsinki declaration and its later amendments.

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Informed consent was obtained from all individual participants included in the study.

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Malisic, E., Susnjar, S., Milovanovic, J. et al. Assessment of ovarian function after chemotherapy in women with early and locally advanced breast cancer from Serbia. Arch Gynecol Obstet 297, 495–503 (2018). https://doi.org/10.1007/s00404-017-4581-8

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  • DOI: https://doi.org/10.1007/s00404-017-4581-8

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