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Simple Summary Cryopreservation of ovarian tissue is a promising technique for fertility preservation in cancer patients at increased risk for subfertility. The International Guideline Harmonization Group recommends ovarian tissue cryopreservation for children and young adults before therapy with cumulative doses of alkylating agent at or above 6000-8000 mg/m(2). A therapy that poses a high risk of subfertility is rarely the first-line therapy and many of the patients have already undergone several regimens of chemotherapy. The aim of our study was to assess the effects of chemotherapy exposures on the quality of cryopreserved ovarian tissue. We confirmed the harmful effects of alkylating agents on xenografted ovarian tissue and suggest that cumulative doses which are not regarded as an indication for fertility preservation in children and young adult may decrease the quality of cryopreserved follicles. Purpose and methods: To elucidate whether previous cancer treatment affects graft recovery and follicle numbers, morphology, and development in grafts, cryopreserved ovarian biopsies obtained from 18 cancer patients aged 1-24 years with and without exposure to chemotherapy were xenografted as 1 mm(3) fragments to immunodeficient mice for 22 weeks with exogenous stimulation. Results: Graft recovery showed no association with chemotherapy exposure, pubertal stage, or leukemia contamination. Total follicle number per recovered graft varied between 0 and 1031 in the chemotherapy-exposed and between 0 and 502 in the non-chemotherapy-exposed group. Atretic follicles formed the largest proportion of the follicle pool in chemotherapy-exposed grafts. Increased atresia correlated with exposure to alkylating agents (mean +/- SD 8866.2 +/- 9316.3 mg/m(2)) but not with anthracyclines, pubertal stage, or leukemia contamination. Conclusion: The observation confirms the harmful effects of alkylating agents on ovarian tissue. Therapy at the median cumulative dose of 8866 mg/m(2) leads to the decreased quality of cryopreserved ovarian follicles in children and young adults.