Journal of Assisted Reproduction and Genetics

, Volume 36, Issue 2, pp 341–348 | Cite as

Chemotherapy-related damage to ovarian reserve in childhood cancer survivors: interpreting the evidence

  • Edgardo SomiglianaEmail author
  • Monica Terenziani
  • Francesca Filippi
  • Alice Bergamini
  • Fabio Martinelli
  • Giorgia Mangili
  • Fedro Peccatori
  • Paolo Vercellini
Fertility Preservation


Chemotherapy during childhood damages ovarian reserve and can affect future fertility. However, recent large epidemiological studies showed that the detrimental impact on fertility is less severe if women seek for pregnancy at a younger age. To explain this observation, we hypothesize that the detrimental effects of previous chemotherapy on the ovarian reserve may be attenuated in young adults for two main reasons. Firstly, recent evidence showed that the amount of ovarian reserve is not a critical factor for effective natural conceptions. Provided that the residual ovarian reserve allows regular ovulatory cycles, the chances of pregnancy are similar in women with intact or reduced ovarian reserve. Secondly, ovarian reserve depletion appears to be a phenomenon that is inversely related to the residual ovarian reserve rather than to age. From a mathematical perspective, this kind of regulation intrinsically attenuates the effects of an early loss of a significant amount of primordial follicles. In conclusion, the detrimental effects of chemotherapy on natural fertility may be less severe if women with a history of chemotherapy during childhood seek for pregnancy early. This information should be part of the counseling.


Ovarian reserve Chemotherapy Infertility Childhood cancer Survivor 


Compliance with ethical standards

Conflict of interest

Edgardo Somigliana received during the last 3 years grants of research from Ferring and Merck-Serono. All the other authors do not have any financial disclosure to declare.


  1. 1.
    Madanat LM, Malila N, Dyba T, Hakulinen T, Sankila R, Boice JD Jr, et al. Probability of parenthood after early onset cancer: a population-based study. Int J Cancer. 2008;123(12):2891–8.CrossRefGoogle Scholar
  2. 2.
    Reulen RC, Zeegers MP, Wallace WH, Frobisher C, Taylor AJ, Lancashire ER, et al. Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study. Cancer Epidemiol Biomark Prev. 2009;18(8):2239–47.CrossRefGoogle Scholar
  3. 3.
    Stensheim H, Cvancarova M, Møller B, Fosså SD. Pregnancy after adolescent and adult cancer: a population-based matched cohort study. Int J Cancer. 2011;129(5):1225–36.CrossRefGoogle Scholar
  4. 4.
    Pivetta E, Maule MM, Pisani P, Zugna D, Haupt R, Jankovic M, et al. Marriage and parenthood among childhood cancer survivors: a report from the Italian AIEOP Off-Therapy Registry. Haematologica. 2011;96(5):744–51.CrossRefGoogle Scholar
  5. 5.
    Brämswig JH, Riepenhausen M, Schellong G. Parenthood in adult female survivors treated for Hodgkin’s lymphoma during childhood and adolescence: a prospective, longitudinal study. Lancet Oncol. 2015;16:667–75.CrossRefGoogle Scholar
  6. 6.
    Chow EJ, Stratton KL, Leisenring WM, Oeffinger KC, Sklar CA, Donaldson SS, et al. Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol. 2016;17:567–76.CrossRefGoogle Scholar
  7. 7.
    Armuand G, Skoog-Svanberg A, Bladh M, Sydsjö G. Reproductive patterns among childhood and adolescent cancer survivors in Sweden: a population-based matched-cohort study. J Clin Oncol. 2017;35(14):1577–83.CrossRefGoogle Scholar
  8. 8.
    Anderson RA, Brewster DH, Wood R, Nowell S, Fischbacher C, Kelsey TW, et al. The impact of cancer on subsequent chance of pregnancy: a population-based analysis. Hum Reprod. 2018;33(7):1281–90.CrossRefGoogle Scholar
  9. 9.
    van Dorp W, Haupt R, Anderson RA, Mulder RL, van den Heuvel-Eibrink MM, van Dulmen-den Broeder E, et al. Reproductive function and outcomes in female survivors of childhood, adolescent, and young adult cancer: a review. J Clin Oncol. 2018;36(21):2169–80.CrossRefGoogle Scholar
  10. 10.
    Morgan S, Anderson RA, Gourley C, Wallace WH, Spears N. How do chemotherapeutic agents damage the ovary? Hum Reprod Update. 2012;18:525–35.CrossRefGoogle Scholar
  11. 11.
    Wallace WH, Kelsey TW, Anderson RA. Fertility preservation in pre-pubertal girls with cancer: the role of ovarian tissue cryopreservation. Fertil Steril. 2016;105:6–12.CrossRefGoogle Scholar
  12. 12.
    Oktem O, Kim SS, Selek U, Schatmann G, Urman B. Ovarian and Uterine functions in female survivors of childhood cancers. Oncologist. 2018;23:214–24.CrossRefGoogle Scholar
  13. 13.
    Kalich-Philosoph L, Roness H, Carmely A, Fishel-Bartal M, Ligumsky H, Paglin S, et al. Cyclophosphamide triggers follicle activation and “burnout”; AS101 prevents follicle loss and preserves fertility. Sci Transl Med. 2013;5:185ra62.CrossRefGoogle Scholar
  14. 14.
    Meirow D, Dor J, Kaufman B, Shrim A, Rabinovici J, Schiff E, et al. Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury. Hum Reprod. 2007;22(6):1626–33.CrossRefGoogle Scholar
  15. 15.
    De Vos M, Smitz J, Woodruff TK. Fertility preservation in women with cancer. Lancet. 2014;384:1302–10.CrossRefGoogle Scholar
  16. 16.
    Donnez J, Dolmans MM. Fertility preservation in women. N Engl J Med. 2017;377:1657–65.CrossRefGoogle Scholar
  17. 17.
    Mertes H. Let’s not forget that many prepubertal girls do have other options besides ovarian tissue cryopreservation. Hum Reprod. 2015;30:2011–3.CrossRefGoogle Scholar
  18. 18.
    Filippi F, Meazza C, Paffoni A, Raspagliesi F, Terenziani M, Somigliana E. Egg freezing in childhood and young adult cancer survivors. Pediatrics. 2016;138:e20160291.CrossRefGoogle Scholar
  19. 19.
    te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update. 2002;8:141–54.CrossRefGoogle Scholar
  20. 20.
    Eijkemans MJ, van Poppel F, Habbema DF, Smith KR, Leridon H, te Velde ER. Too old to have children? Lessons from natural fertility populations. Hum Reprod. 2014;29:1304–12.CrossRefGoogle Scholar
  21. 21.
    Navot D, Rosenwaks Z, Margalioth EJ. Prognostic assessment of female fecundity. Lancet. 1987;2:645–7.CrossRefGoogle Scholar
  22. 22.
    Hagen CP, Vestergaard S, Juul A, Skakkebæk NE, Andersson AM, Main KM, et al. Low concentration of circulating antimullerian hormone is not predictive of reduced fecundability in young healthy women: a prospective cohort study. Fertil Steril. 2012;98:1602–8.CrossRefGoogle Scholar
  23. 23.
    Streuli I, de Mouzon J, Paccolat C, Chapron C, Petignat P, Irion OP, et al. AMH concentration is not related to effective time to pregnancy in women who conceive naturally. Reprod BioMed Online. 2014;28:216–24.CrossRefGoogle Scholar
  24. 24.
    Somigliana E, Lattuada D, Colciaghi B, Filippi F, La Vecchia I, Tirelli A, et al. Serum anti-Mullerian hormone in subfertile women. Acta Obstet Gynecol Scand. 2015;94:1307–12.CrossRefGoogle Scholar
  25. 25.
    Steiner AZ, Pritchard D, Stanczyk FZ, Kesner JS, Meadows JW, Herring AH, et al. Association between biomarkers of ovarian reserve and infertility among older women of reproductive age. JAMA. 2017;318:1367–76.CrossRefGoogle Scholar
  26. 26.
    Greenwood EA, Cedars MI, Santoro N, Eisenberg E, Kao CN, Haisenleder DJ, et al. Antimüllerian hormone levels and antral follicle counts are not reduced compared with community controls in patients with rigorously defined unexplained infertility. Fertil Steril. 2017;108(6):1070–7.CrossRefGoogle Scholar
  27. 27.
    Daan NM, Hoek A, Corpeleijn E, Eijkemans MJ, Broekmans FJ, Fauser BC, et al. Reproductive characteristics of women diagnosed with premature ovarian insufficiency. Reprod BioMed Online. 2016;32:225–32.CrossRefGoogle Scholar
  28. 28.
    Letourneau JM, Ebbel EE, Katz PP, Oktay KH, McCulloch CE, Ai WZ, et al. Acute ovarian failure underestimates age-specific reproductive impairment for young women undergoing chemotherapy for cancer. Cancer. 2012;118:1933–9.CrossRefGoogle Scholar
  29. 29.
    Oktem O, Oktay K. A novel ovarian xenografting model to characterize the impact of chemotherapy agents on human primordial follicle reserve. Cancer Res. 2007;67:10159–62.CrossRefGoogle Scholar
  30. 30.
    Soleimani R, Heytens E, Darzynkiewicz Z, Oktay K. Mechanisms of chemotherapy-induced human ovarian aging: double strand DNA breaks and microvascular compromise. Aging. 2011;3:782–93.CrossRefGoogle Scholar
  31. 31.
    Oktem O, Oktay K. Quantitative assessment of the impact of chemotherapy on ovarian follicle reserve and stromal function. Cancer. 2007;110:2222–9.CrossRefGoogle Scholar
  32. 32.
    McLaughlin M, Kelsey TW, Wallace WH, Anderson RA, Telfer EE. Non-growing follicle density is increased following adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy in the adult human ovary. Hum Reprod. 2017;32:165–74.Google Scholar
  33. 33.
    Lie Fong S, Laven JS, Hakvoort-Cammel FG, Schipper I, Visser JA, Themmen AP, et al. Assessment of ovarian reserve in adult childhood cancer survivors using anti-Müllerian hormone. Hum Reprod. 2009;24:982–90.CrossRefGoogle Scholar
  34. 34.
    Gracia CR, Sammel MD, Freeman E, Prewitt M, Carlson C, Ray A, et al. Impact of cancer therapies on ovarian reserve. Fertil Steril. 2012;97:134–40.CrossRefGoogle Scholar
  35. 35.
    Dillon KE, Sammel MD, Ginsberg JP, Lechtenberg L, Prewitt M, Gracia CR. Pregnancy after cancer: results from a prospective cohort study of cancer survivors. Pediatr Blood Cancer. 2013;60:2001–6.CrossRefGoogle Scholar
  36. 36.
    El-Shalakany AH, Ali MS, Abdelmaksoud AA, Abd El-Ghany S, Hasan EA. Ovarian function in female survivors of childhood malignancies. Pediatr Hematol Oncol. 2013;30:328–35.CrossRefGoogle Scholar
  37. 37.
    Krawczuk-Rybak M, Leszczynska E, Poznanska M, Zelazowska-Rutkowska B, Wysocka J. Anti-müllerian hormone as a sensitive marker of ovarian function in young cancer survivors. Int J Endocrinol. 2013;2013:125080.CrossRefGoogle Scholar
  38. 38.
    Johnson LN, Sammel MD, Dillon KE, Lechtenberg L, Schanne A, Gracia CR. Antimüllerian hormone and antral follicle count are lower in female cancer survivors and healthy women taking hormonal contraception. Fertil Steril. 2014;102:774–81.CrossRefGoogle Scholar
  39. 39.
    Akar B, Doğer E, Çakıroğlu Y, Çorapçıoğlu F, Sarper N, Çalışkan E. The effect of childhood cancer therapy on ovarian reserve and pubertal development. Reprod BioMed Online. 2015;30:175–80.CrossRefGoogle Scholar
  40. 40.
    Thomas-Teinturier C, Allodji RS, Svetlova E, Frey MA, Oberlin O, Millischer AE, et al. Ovarian reserve after treatment with alkylating agents during childhood. Hum Reprod. 2015;30:1437–46.CrossRefGoogle Scholar
  41. 41.
    Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod. 1992;7:1342–6.CrossRefGoogle Scholar
  42. 42.
    Scheffer GJ, Broekmans FJ, Dorland M, Habbema JD, Looman CW, te Velde ER. Antral follicle counts by transvaginal ultrasonography are related to age in women with proven natural fertility. Fertil Steril. 1999;72:845–51.CrossRefGoogle Scholar
  43. 43.
    Hanson B. Questioning the construction of maternal age as a fertility problem. Health Care Women Int. 2003;24:166–76.CrossRefGoogle Scholar
  44. 44.
    Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA. A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause. Hum Reprod. 2008;23:699–708.CrossRefGoogle Scholar
  45. 45.
    Rosen MP, Sternfeld B, Schuh-Huerta SM, Reijo Pera RA, McCulloch CE, Cedars MI. Antral follicle count: absence of significant midlife decline. Fertil Steril. 2010;94:2182–5.CrossRefGoogle Scholar
  46. 46.
    Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS One. 2010;5(1):e8772.CrossRefGoogle Scholar
  47. 47.
    Kelsey TW, Anderson RA, Wright P, et al. Data-driven assessment of the human ovarian reserve. Mol Hum Reprod. 2012;18:79–87.CrossRefGoogle Scholar
  48. 48.
    Wallace WH, Smith AG, Kelsey TW, Nelson SM, Wallace WH. Fertility preservation for girls and young women with cancer: population-based validation of criteria for ovarian tissue cryopreservation. Lancet Oncol. 2014;15:1129–36.CrossRefGoogle Scholar
  49. 49.
    Mills M, Rindfuss RR, McDonald P, te Velde E, ESHRE Reproduction and Society Task Force. Why do people postpone parenthood? Reasons and social policy incentives. Hum Reprod Update. 2011;17:848–60.CrossRefGoogle Scholar
  50. 50.
    van Dijk M, van den Berg MH, Overbeek A, Lambalk CB, van den Heuvel-Eibrink MM, Tissing WJ, et al. Reproductive intentions and use of reproductive health care among female survivors of childhood cancer. Hum Reprod. 2018;33(6):1167–74.CrossRefGoogle Scholar
  51. 51.
    Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. 2011;26:1768–74.CrossRefGoogle Scholar
  52. 52.
    Kelsey TW, Wright P, Nelson SM, Anderson RA, Wallace WH. A validated model of serum anti-müllerian hormone from conception to menopause. PLoS One. 2011;6(7):e22024.CrossRefGoogle Scholar
  53. 53.
    Zamah AM, Stephenson MD. Antimüllerian hormone and miscarriage: fifty shadesof gray. Fertil Steril. 2018;109:1008–9.CrossRefGoogle Scholar
  54. 54.
    Lyttle Schumacher BM, Jukic AMZ, Steiner AZ. Antimüllerian hormone as a risk factor for miscarriage in naturally conceived pregnancies. Fertil Steril. 2018;109(6):1065–71.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Clinical Sciences and Community HealthUniversità degli Studi di MilanoMilanItaly
  2. 2.Obstet-Gynecol DepartmentFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly
  3. 3.Infertility UnitFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly
  4. 4.Pediatric Oncology UnitFondazione IRCCS National Cancer InstituteMilanItaly
  5. 5.Obstet-Gynecol DepartmentSan Raffaele Scientific InstituteMilanItaly
  6. 6.Gynecologic Oncology UnitFondazione IRCCS National Cancer InstituteMilanItaly
  7. 7.Fertility and Procreation Unit, Division of Gynaecologic OncologyEuropean Institute of OncologyMilanItaly

Personalised recommendations