Ovarian function compromise in pediatric beta-thalassemia major: a consequence of iron overload-induced mitochondrial and fibrotic damage

STUDY QUESTION: How does iron overload affect ovarian function in pediatric patients with transfusion-dependent beta-thalassemia major? SUMMARY ANSWER: Iron overload in pediatric patients with beta-thalassemia major is strongly associated with decreased ovarian reserve and mitochondrial damage. WHAT IS KNOWN ALREADY: Beta-thalassemia major is a severe blood disorder necessitating frequent blood transfusions, leading to iron overload. Excessive iron causes oxidative stress and damage in various organs, including the ovaries, but its impact on ovarian function in pediatric patients has not been fully explored. STUDY DESIGN, SIZE, DURATION: This study analyzed data from 194 pediatric patients who were treated at The Sixth Affiliated Hospital of Sun Yat-Sen University between January 2021 and January 2024, among whom 138 had beta-thalassemia major. Meanwhile, we conducted experiments using human samples and mouse models of iron overload. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study involved 194 pediatric patients. Clinical assessments measured serum ferritin and ovarian reserve indicators anti-Müllerian hormone (AMH) and antral follicle count. Ovarian tissue from pediatric patients was used for histopathological examination, immunohistochemical (IHC) staining, transmission electron microscopy (TEM), and transcriptome analysis, to investigate the effects of iron overload. For the animal experiments, we utilized 20 newborn female mice to establish an iron overload and control model. These animals underwent comprehensive evaluations, including histopathological examination, TEM, and IHC analyses, to systematically investigate the impact of iron overload on ovarian tissue. MAIN RESULTS AND THE ROLE OF CHANCE: Pubertal pediatric patients with high iron overload had significantly lower AMH, indicating reduced ovarian reserve, accompanied by evident mitochondrial damage and fibrotic remodeling in ovarian tissues, collectively contributing to impaired ovarian function. Decreased AMH and impaired follicular development were also observed in iron-overloaded mice, along with mitochondrial damage and ovarian fibrosis. LARGE SCALE DATA: Transcriptome data are available at China National Center for Bioinformation, reference HRA004373 and HRA013348. LIMITATIONS, REASONS FOR CAUTION: The cross-sectional design limits causality assessment. The sample size for molecular analyses is relatively small, necessitating larger, longitudinal studies to confirm these findings and understand long-term effects. WIDER IMPLICATIONS OF THE FINDINGS: Effective iron management in pediatric patients with beta-thalassemia major is crucial to preserving ovarian function and preventing long-term reproductive issues. These findings can guide clinical practices and therapeutic strategies to mitigate iron overload's adverse effects on ovarian health. In this study, mitochondrial dysfunction may compromise cellular energy production and amplify tissue vulnerability to ischemia-reperfusion injury during transplantation. Additionally, fibrosis-induced structural rigidity may hinder revascularization of transplanted tissue, further reducing success rates. These findings underscore the need to monitor post-transplant survival rates. Further experimental investigations are warranted to explore this critical issue. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Key R&D Program of China (2022YFC2703000); National Natural Science Foundation of China (U24A20662, 82271651); Clinical Research Fund of Guangdong Medical Association (2025SZ-B1001); Postdoctoral Fellowship Program of CPSF (GZC20233216); and Guangdong Basic and Applied Basic Research Foundation (2023A1515110325). The authors declared no competing interests.