Late Effects of Cancer Therapies on Gonadal Function, Fertility, Efficiency of Fertility Preservation Procedures and Pregnancy Outcomes

Fertility preservation (FP) and fertility counselling at the time of diagnosis and throughout follow-up are recommended to improve the quality of life of young patients diagnosed with cancer (Lambertini et al. 2020; Su et al.2025). Indeed, it has been shown that gonadal function, as well as fertility capacity after treatment are crucial aspects for AYA cancer survivors (Letourneau et al.2012). While natural conception can be possible after cancer treatment, cancer-treatment related risk factors for impaired fertility, including a drastically reduced reproductive window, have been identified.

FP techniques are progressing rapidly and have demonstrated their effectiveness in terms of pregnancy chances and live-birth rates. However, it remains difficult to establish firm and evidence-based FP strategies according to a patient's individual factors and cancer treatment. In addition, it remains crucial to carefully balance the risk-benefit of FP procedures and the potential of ovarian/fertility impairment, to examine the efficiency and safety of FP procedures and pregnancies as well as to assess patients' satisfaction regarding FP procedures. Large scale prospective and systematic short- and long-term data on the impact of specific cancer therapies on fertility based on fertility parameters such as ovarian reserve markers, sperm quality and pregnancies hardly exist. Specialized centres and joint regional and national network initiatives have started collecting such data. However, even though these initiatives are of great value and are sufficient to generate data from common cancer diseases such as breast or testicular cancer, rare cancers as well as on novel therapeutics (e.g. anti VEGF or immune therapies) and more complex cancer treatment regimen require large scale data collection initiatives to gain in-depth robust data for appropriate individual fertility-related counselling of female and male AYA patients.

In female cancer patients, it has been shown that serum AMH levels variations may be a direct and real-time indicator of follicular depletion and recovery during and after cancer treatment, as well as it is a non-invasive and reproducible marker (Anderson et al., 2022; Decanter et al., 2021). Systematic follow-up of AMH has been suggested in AYA patients with at least a measurement at baseline and within the 2 years following the end of gonadotoxic treatment (Su et al., 2025; Decanter et al., 2024; von Wolff et al. 2025). In parallel, menstrual function pattern should be regularly analysed as a relevant clinical surrogate and independent variable to determine prevalence of cancer treatment-induced amenorrhea, it's duration and hormonal and clinical signs of potential post treatment premature ovarian insufficiency (POI).

In the FollowAYA study within the PredictAYA project, the investigators therefore aim to set up a large-scale network structure of previously established data collection programmes in specialized centres/networks to evaluate the ovarian toxicity, the prevalence of impaired ovarian function, it's course and/or fertility impairment and POI following specific treatments, identification of predictive markers. Additionally, data on the use of FP and/or subsequent use of artificial reproductive treatment (ART) as well as patients' satisfaction related to these procedures in Europe shall drive the understanding of patient-centric care.

In male cancer patients, the long-term reproductive and endocrine effects of cancer treatment on testicular function remain poorly studied, with existing data based on small cohorts and incomplete clinical characterization. No validated pre-conceptional tests currently exist to guide patients in deciding between natural conception and the use of cryopreserved sperm. Because treatment regimens vary widely even within the same cancer type and incidence rates are relatively low, only a coordinated European effort can generate sufficiently robust data. PredictAYA addresses this need by establishing a harmonized data platform across large male AYA cohorts. Its goals are to develop personalized risk-prediction tools for reproductive and testicular endocrine outcomes, provide evidence-based counselling on FP and future options, and design standardized follow-up protocols enabling early diagnosis and treatment of hypogonadism and infertility. As only limited evidence on sperm DNA damage and epigenetic alterations exist, these aspects will be validated in selected sub-cohorts to assess the frequency and persistence of chemotherapy-induced dysfunction (Farnetani et al. 2023 and 2024, Chan et al. 2023).