Abstract Context Many female survivors of adolescent and young adult cancers (AYA survivors) have shortened reproductive lifespans. However, the timing and duration of ovarian function after cancer treatment are largely unknown. Objective To model the trajectory of ovarian function over two decades following cancer treatment and evaluate how trajectories vary by treatment gonadotoxicity and age. Design In a prospective cohort, AYA survivors aged 18-39 at variable times since cancer treatment completion provided dried blood spots (DBS) every 6 months for up to 18 months. Anti-Müllerian hormone (AMH) levels were measured using the Ansh DBS AMH enzyme-linked immunosorbent assay. The mean AMH trajectory was modeled for the entire cohort and separately by treatment gonadotoxicity and age using functional principal components analysis. Results 763 participants, mean (standard deviation) enrollment age 33.3 (4.7) and age at cancer diagnosis 25.9 (5.7) years, contributed 1905 DBS samples. The most common cancers were breast (26.9%), lymphoma (24.8%), and thyroid (18.0%). AMH trajectories differed among survivors by treatment gonadotoxicity (low, moderate, or high) (P < 0.001). Following low or moderately gonadotoxic treatments, AMH levels increased over 2-3 years and plateaued over 10-15 years before declining. In contrast, following highly gonadotoxic treatment, AMH levels were lower overall and declined shortly after peak at 2-3 years. Younger age at treatment was associated with higher trajectories, but a protective effect of younger age was not observed in survivors exposed to highly gonadotoxic treatments (Pinteraction < 0.001). Conclusions In this large AYA survivor cohort, timing and duration of ovarian function strongly depended on treatment gonadotoxicity and age at treatment. The findings provide novel, more precise information to guide reproductive decision-making.

Context While stages of reproductive aging for women in the general population are well described by STRAW+10 criteria, this is largely unknown for female adolescent and young adult cancer survivors (AYA survivors). Objective To evaluate applying STRAW+10 criteria in AYA survivors using bleeding patterns with and without endocrine biomarkers, and assess how cancer treatment gonadotoxicity is related to reproductive aging stage. Design The sample (n=338) included AYA survivors from the Window Study cohort. Menstrual bleeding data and dried blood spots for AMH and FSH measurements (Ansh DBS ELISAs) were utilized for reproductive aging stage assessment. Cancer treatment data were abstracted from medical records. Results Among participants, mean age 34.0±4.5 and at a mean of 6.9±4.6 years since cancer treatment, the most common cancers were lymphomas(31%), breast(23%), and thyroid(17%). Twenty-nine percent was unclassifiable by STRAW+10 criteria, occuring more frequently in the first 2 years from treatment . Most unclassifiable survivors exhibited bleeding patterns consistent with the menopausal transition, but had reproductive phase AMH and/or FSH levels. For classifiable survivors (48% peak reproductive, 30% late reproductive, 12% early transition, 3% late transition, 7% post-menopause), endocrine biomarkers distinguished among peak, early and late stages within the reproductive and transition phases. Gonadotoxic treatments were associated with more advanced stages. Conclusions We demonstrate a novel association between gonadotoxic treatments and advanced stages of reproductive aging. Without endocrine biomarkers, bleeding pattern alone can misclassify AYA survivors into either more or less advanced stages. Moreover, a large proportion of AYA survivors exhibited combinations of endocrine biomarkers and bleeding patterns that do not fit STRAW+10 criteria, suggesting the need for modified staging for this population.

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