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Licensed Unlicensed Requires Authentication Published by De Gruyter October 19, 2020

Female adolescents and young women previously treated for pediatric malignancies: assessment of ovarian reserve and gonadotoxicity risk stratification for early identification of patients at increased infertility risk

Francesca Parissone ORCID logo, Rossana Di Paola, Rita Balter, Simone Garzon ORCID logo, Stefano Zaffagnini, Maria Neri, Virginia Vitale, Gloria Tridello and Simone Cesaro ORCID logo



Childhood and adolescent cancer survivors (CACSs) are at risk of adverse reproductive outcomes. Assessment of follicle-stimulating hormone (FSH) levels is the most common test used to diagnose premature ovarian insufficiency (POI) whereas anti-m|llerian hormone (AMH) and antral follicle count (AFC) have been proposed as ovarian reserve markers. We assessed the correlation between these markers and treatment gonadotoxicity risk (GR) in CACSs.


A total of 55 female CACSs were enrolled. GR was graded as low, medium, or high according to classifications based on disease and treatments and on cyclophosphamide equivalent dose score. FSH, AMH, and AFC were determined. POI was defined by amenorrhea and FSH>30 IU/L. For remaining patients, diminished ovarian reserve (DOR) was defined by AMH<5th centile. FSH and AFC cut-offs proposed in the literature as DOR markers were also considered (FSH>10 IU/L or >95th centile; AFC<8 or <5th centile).


Ovarian reserve results to be compromised in 23 (41.8%) patients: 14 with DOR and 9 with an established POI. Results showed GR classifications to be a good predictor of ovarian reserve, with significantly lower AMH and AFC in the high-risk groups. AFC resulted to be directly correlated with AMH (r=0.75, p<0.001).


In CACSs, GR classifications correlate with post-treatment AMH and AFC. These are useful tools in the early identification of young patients with DOR, who may benefit from reproductive and fertility preservation counseling. Further studies are needed to determine the rate and time of progression from DOR to POI in this population.

Corresponding author: Francesca Parissone, Obstetrics and Gynecology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata, P.le Stefani, 1,37126 Verona, Italy, Phone: +390458127147, E-mail:

  1. Research funding: None declared.

  2. Author contributions: FP, SC, RDP for study concepts; FP and SC for study designed; FP, RDP, MN, RB and VV for data collection; FP, GT and SG for quality control of data and algorithms; GT, FP, SZ and SC for data analysis and interpretation; GT for statistical analysis; FP and SG for manuscript preparation; SC, and GT for manuscript editing; RB, SZ and VV for manuscript review; all the authors decided to submit the paper for publication. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  3. Competing interests: None declared.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: All patients and their parents in the case of minors, provided informed consent for the research and for data collection for the purposes of the study, as approved by the institutional review board of Verona. All procedures followed the Italian laws for personal data protection and were in accordance with the tenets of the Helsinki Declaration.


1. ACOG Committee Opinion No. 747. Summary: gynecologic issues in children and adolescent cancer patients and survivors. Obstet Gynecol 2018;132:535-6. in Google Scholar

2. Cancer Statistics ReviewSEER statistics; 1975-2014 SEER n.d. Available from: [Accessed 16 Dec 2019].Search in Google Scholar

3. van Dorp, W, Mulder, RL, Kremer, LCM, Hudson, MM, van den Heuvel-Eibrink, MM, van den Berg, MH, et al. Recommendations for premature ovarian insufficiency surveillance for female survivors of childhood, adolescent, and young adult cancer: a report from the international late effects of childhood cancer guideline harmonization group in collaboration with the pancaresurfup consortium. J Clin Oncol 2016;34:3440-50 in Google Scholar

4. 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;36:2169-80 in Google Scholar

5. Levine, JM, Whitton, JA, Ginsberg, JP, Green, DM, Leisenring, WM, Stovall, M, et al. Nonsurgical premature menopause and reproductive implications in survivors of childhood cancer: a report from the childhood cancer survivor study. Cancer 2018;124:1044-52. in Google Scholar

6. Chemaitilly, W, Li, Z, Krasin, MJ, Brooke, RJ, Wilson, CL, Green, DM, et al. Premature ovarian insufficiency in childhood cancer survivors: a report from the St. Jude lifetime cohort. J Clin Endocrinol Metab 2017;102:2242-50. in Google Scholar

7. Wallace, WHB, Anderson, RA, Irvine, DS. Fertility preservation for young patients with cancer: who is at risk and what can be offered? Lancet Oncol 2005;6:209-18. in Google Scholar

8. Anderson, RA, Wallace, WHB. Antim|llerian hormone, the assessment of the ovarian reserve, and the reproductive outcome of the young patient with cancer. Fertil Steril 2013;99:1469-75. in Google Scholar PubMed

9. Algarroba, GN, Sanfilippo, JS, Valli-Pulaski, H. Female fertility preservation in the pediatric and adolescent cancer patient population. Best Pract Res Clin Obstet Gynaecol 2018;48:147-57. in Google Scholar PubMed

10. Overbeek, A, van den Berg, MH, van Leeuwen, FE, Kaspers, GJL, Lambalk, CB, van Dulmen-den Broeder, E. Chemotherapy-related late adverse effects on ovarian function in female survivors of childhood and young adult cancer: a systematic review. Canc Treat Rev 2017;53:10-24. in Google Scholar PubMed

11. Green, DM, Nolan, VG, Goodman, PJ, Whitton, JA, Srivastava, D, Leisenring, WM, et al. The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the childhood cancer survivor study. Pediatr Blood Canc 2014;61:53-67. in Google Scholar PubMed PubMed Central

12. La Marca, A, Sunkara, SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update 2014;20:124-40. in Google Scholar

13. Wiweko, B, Prawesti, DMP, Hestiantoro, A, Sumapraja, K, Natadisastra, M, Baziad, A. Chronological age vs. biological age: an age-related normogram for antral follicle count, FSH and anti-mullerian hormone. J Assist Reprod Genet 2013;30:1563-7. in Google Scholar

14. Peqarrubia, J, Fabregues, F, Manau, D, Creus, M, Casamitjana, R, Carmona, F, et al. Initial analysis of variability among basal hormone biomarkers of ovarian reserve. Reprod Biomed Online 2004;8:191-5. in Google Scholar

15. Elchuri, SV, Patterson, BC, Brown, M, Bedient, C, Record, E, Wasilewski-Masker, K, et al. Low anti-m|llerian hormone in pediatric cancer survivors in the early years after gonadotoxic therapy. J Pediatr Adolesc Gynecol 2016;29:393-9. in Google Scholar PubMed

16. La Marca, A, Spada, E, Grisendi, V, Argento, C, Papaleo, E, Milani, S, et al. Normal serum anti-m|llerian hormone levels in the general female population and the relationship with reproductive history. Eur J Obstet Gynecol Reprod Biol 2012;163:180-4. in Google Scholar PubMed

17. Lie Fong, S, Visser, JA, Welt, CK, de Rijke, YB, Eijkemans, MJC, Broekmans, FJ, et al. Serum anti-m|llerian hormone levels in healthy females: a nomogram ranging from infancy to adulthood. J Clin Endocrinol Metab 2012;97:4650-5. in Google Scholar PubMed PubMed Central

18. Ferraretti, AP, La Marca, A, Fauser, BCJM, Tarlatzis, B, Nargund, G, Gianaroli, L, et al. ESHRE consensus on the definition of "poor response" to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod 2011;26:1616-24. in Google Scholar PubMed

19. van der Steeg, JW, Steures, P, Eijkemans, MJC, Habbema, JDF, Hompes, PGA, Broekmans, FJ, et al. Predictive value and clinical impact of basal follicle-stimulating hormone in subfertile, ovulatory women. J Clin Endocrinol Metab 2007;92:2163-8. in Google Scholar PubMed

20. Grisendi, V, Spada, E, Argento, C, Plebani, M, Milani, S, Seracchioli, R, et al. Age-specific reference values for serum FSH and estradiol levels throughout the reproductive period. Gynecol Endocrinol 2014;30:451-5. in Google Scholar PubMed

21. La Marca, A, Spada, E, Sighinolfi, G, Argento, C, Tirelli, A, Giulini, S, et al. Age-specific nomogram for the decline in antral follicle count throughout the reproductive period. Fertil Steril 2011;95:684-8. in Google Scholar PubMed

22. Chung, MK. Correlation coefficient. In: Salkin, NJ, editor. Encyclopedia of measurement and statistics. London: Sage Publications; 2007.Search in Google Scholar

23. van den Berg, MH, Overbeek, A, Lambalk, CB, Kaspers, GJL, Bresters, D, van den Heuvel-Eibrink, MM, et al. Long-term effects of childhood cancer treatment on hormonal and ultrasound markers of ovarian reserve. Hum Reprod 2018;33:1474-88. in Google Scholar PubMed

24. Lie Fong, S, Laven, JSE, Hakvoort-Cammel, FG, Schipper, I, Visser, JA, Themmen, APN, et al. Assessment of ovarian reserve in adult childhood cancer survivors using anti-m|llerian hormone. Hum Reprod 2009;24:982-90. in Google Scholar PubMed

25. George, SA, Williamson Lewis, R, Schirmer, DA, Effinger, KE, Spencer, JB, Mertens, AC, et al. Early detection of ovarian dysfunction by anti-mullerian hormone in adolescent and young adult-aged survivors of childhood cancer. J Adolesc Young Adult Oncol 2019;8:18-25. in Google Scholar PubMed

26. Lunsford, AJ, Whelan, K, McCormick, K, McLaren, JF. Antim|llerian hormone as a measure of reproductive function in female childhood cancer survivors. Fertil Steril 2014;101:227-31. in Google Scholar PubMed

27. Streuli, I, Fraisse, T, Pillet, C, Ibecheole, V, Bischof, P, de Ziegler, D. Serum antim|llerian hormone levels remain stable throughout the menstrual cycle and after oral or vaginal administration of synthetic sex steroids. Fertil Steril 2008;90:395-400. in Google Scholar PubMed

28. Lambert-Messerlian, G, Plante, B, Eklund, EE, Raker, C, Moore, RG. Levels of antim|llerian hormone in serum during the normal menstrual cycle. Fertil Steril 2016;105:208-13 e1. in Google Scholar PubMed

29. Hehenkamp, WJK, Looman, CWN, Themmen, APN, de Jong, FH, Te Velde, ER, Broekmans, FJM. Anti-m|llerian hormone levels in the spontaneous menstrual cycle do not show substantial fluctuation. J Clin Endocrinol Metab 2006;91:4057-63. in Google Scholar PubMed

30. Practice Committee of the American Society for Reproductive Medicine Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril 2015;103:e44-50. in Google Scholar PubMed

31. Waaseth, M, Bakken, K, Dumeaux, V, Olsen, KS, Rylander, C, Figenschau, Y, et al. Hormone replacement therapy use and plasma levels of sex hormones in the Norwegian women and cancer postgenome cohort - a cross-sectional analysis. BMC Wom Health 2008;8:1. in Google Scholar PubMed PubMed Central

32. van Santen, HM, van den Heuvel-Eibrink, MM, van de Wetering, MD, Wallace, WH. Hypogonadism in children with a previous history of cancer: endocrine management and follow-up. Horm Res Paediatr 2019;91:93-103. in Google Scholar PubMed PubMed Central

33. Nystrvm, A, Mvrse, H, Nordlvf, H, Wiebe, K, Artman, M, Xra, I, et al. Anti-m|llerian hormone compared with other ovarian markers after childhood cancer treatment. Acta Oncol 2019;58:218-24. in Google Scholar PubMed

34. Teede, HJ, Misso, ML, Costello, MF, Dokras, A, Laven, J, Moran, L, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod 2018;33:1602-18. in Google Scholar PubMed PubMed Central

35. Coelho Neto, MA, Ludwin, A, Borrell, A, Benacerraf, B, Dewailly, D, da Silva Costa, F, et al. Counting ovarian antral follicles by ultrasound: a practical guide. Ultrasound Obstet Gynecol 2018;51:10-20. in Google Scholar PubMed

36. Frobisher, C, Glaser, A, Levitt, GA, Cutter, DJ, Winter, DL, Lancashire, ER, et al. Risk stratification of childhood cancer survivors necessary for evidence-based clinical long-term follow-up. Br J Canc 2017;117:1723-31. in Google Scholar PubMed PubMed Central

37. Kutteh, WH, Klosky, JL, Green, DM, Sparrow, CK, Kutteh, MA, Robinson, GW, et al. Ovulation induction and oocyte retrieval for fertility preservation in young adolescents newly diagnosed with medulloblastoma: a case series. J Obstet Gynaecol 2018;38:878-9. in Google Scholar PubMed

38. Group, CO. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers 2008. Version 3.0. http://WwwSurvivor-ShipguidelinesOrg/.Search in Google Scholar

39. Roeca, C, Dovey, S, Polotsky, AJ. Recommendations for assessing ovarian health and fertility potential in survivors of childhood cancer. Maturitas 2019;122:57-9. in Google Scholar PubMed

40. Morin, SJ, Patounakis, G, Juneau, CR, Neal, SA, Scott, RTJr, Seli, E. Diminished ovarian reserve and poor response to stimulation in patients <38 years old: a quantitative but not a qualitative reduction in performance. Hum Reprod 2018;33:1489-98. in Google Scholar PubMed

Supplementary material

The online version of this article offers supplementary material (DOI:

Received: 2020-05-14
Accepted: 2020-08-31
Published Online: 2020-10-19
Published in Print: 2021-01-27

© 2020 Walter de Gruyter GmbH, Berlin/Boston

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