Comment on “Proteomic Profiling Reveals the Molecular Signatures of Chemotherapy-induced Human Ovarian Damage”

Approximately 1.9 million new cancer cases annually across the globe are diagnosed in women of reproductive age (<50 y), and cancer survivors can often have their quality of life impacted by off-target ovarian toxicity. Chemotherapy can cause damage to the ovaries and have both physical and psychological effects through partial or complete destruction of ovarian follicles, which increases the risk of premature ovarian insufficiency and infertility. Current fertility preservation consists of oocyte, embryo, or ovarian tissue cryopreservation, but developing other methods of ovarian preservation could improve the quality of life and endocrine function of cancer survivors. This study was designed to investigate the mechanisms behind follicle loss in response to chemotherapy through proteomics to target molecular signatures and lay the groundwork for strategies to protect ovarian health during cancer treatment. Data were collected with consent from ovarian cortical biopsies of 10 patients undergoing ovarian tissue cryopreservation for fertility preservation. Methods employed included protein extraction, mass spectrometry, western blotting, histology, immunohistology, an apoptosis assay, and image analysis. Final analysis included 10 patients, with 5 having received first-line chemotherapy treatment before ovarian tissue cryopreservation (OTC) and 5 having OTC before any chemotherapy treatment. Proteomic profiling showed that among 4911 proteins, there were distinct treatment-associated patterns that included partial clustering; the most prominent differences were evident in patients with a shorter timeframe between chemotherapy treatment and OTC. A total of 237 differences were identified, with 162 upregulated proteins and 75 downregulated proteins in chemotherapy patients compared with controls. Dysregulation of proteins was shown to involve immune function, hypoxia, apoptosis, cell cycle, DNA repair capacity, and extracellular matrix (ECM) remodeling. Efforts at validation supported these results. Key cellular processes identified included ovarian cell apoptosis, DNA damage, and oxidative stress; chemotherapy did not significantly impact cell apoptosis, but chemotherapy disproportionately affected primordial follicles compared with growing follicles in terms of DNA damage based on staining protocols. Oxidative stress was also not significantly impacted by chemotherapy. In addition, ovarian fibrosis was not significantly associated with chemotherapy treatment despite increased stromal cell density, and ovarian reserves were not significantly depleted. There were significantly more follicles with abnormal morphology in the chemotherapy group, though follicle density was not affected, meaning this may have a significant impact on fertility. These results indicate that chemotherapy is associated with changes in ovarian function and follicle morphology, though not necessarily through mechanisms previously hypothesized. These results do align with previous literature studying the effect of chemotherapy on other tissues, with both similar mechanisms and results. Future research should validate these findings in a larger cohort to detect more nuanced differences, as well as standardizing first-line chemotherapy treatments to isolate the effects of each type of treatment. In addition, future studies should make an effort to remove confounding due to the timing of treatment with respect to OTC. (Summarized from Grosbois J, Bisteau X, Imbault V, et al. Proteomic profiling reveals the molecular signatures of chemotherapy-induced human ovarian damage. Hum Reprod. 2025;40(12):2395-2408. doi: https://doi.org/10.1093/humrep/deaf203)