Iron Metabolism and Ferroptosis in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis

Authors: Fangfang Wang, Tianjing Wang, Leyi Fu, Feng Yun, Ningning Xie, Jue Zhou, Fan Qu

Abstract:

Background: Ferroptosis, a recently discovered form of programmed cell death characterized by iron-dependent lipid peroxidation, may be linked to polycystic ovary syndrome (PCOS). Diseases marked by iron overload have been correlated with ferroptosis. Coincidently, investigations have revealed anomalies in iron metabolism among women with PCOS; however, there were inconsistencies in the evidence. Objective and Rationale: This review aimed to comprehensively explore the potential relationship between ferroptosis and PCOS by investigating the differences in iron metabolism among women with PCOS in comparison to a control group. Additionally, a narrative synthesis was provided on the past research status regarding the association between PCOS and ferroptosis. Methods: A systematic search of the literature was performed using PubMed, Embase, Web of Science from inception up to December 2022. Search terms relating to assisted PCOS, ferroptosis, and iron metabolism were used. PRISMA guidance was followed. RevMan 5.4 was utilized for conducting the meta-analysis, wherein the investigated outcomes included iron status (ferritin, iron, transferrin saturation) and a systemic iron-regulatory hormone (hepcidin). A narrative synthesis was performed to explore the correlation between PCOS and ferroptosis. Results: In the meta-analysis comprising a total of 16 studies, significant differences in serum ferritin levels between the PCOS group and the control group were observed (15 studies, standardized mean difference (SMD): 0.41, 95% CI: 0.22 to 0.59, P<0.01). This indicates elevated serum ferritin levels in PCOS patients compared to women without PCOS. The transferrin saturation in PCOS patients was significantly higher than that in the control group (3 studies, mean difference (MD): 4.39, 95% CI: 1.67 to 7.11, P<0.01). Regarding serum iron (6 studies, SMD: 0.05, 95% CI: -0.24 to 0.33, P=0.75) and serum hepcidin (4 studies, SMD: -0.44, 95% CI: -1.41 to 0.52, P=0.37), no statistically significant differences were observed between the PCOS group and the control group. Other studies have found that ferroptosis is involved in the occurrence and development of PCOS, offering valuable insights for guiding potential treatment measures and prognosis evaluation of PCOS. In addition, ferroptosis is involved in the miscarriage of PCOS-like rats; thus, controlling ferroptosis might improve pregnancy outcomes in PCOS. Conclusions: The observation of a significant elevation in serum ferritin and transferrin saturation levels in women with PCOS may suggest an underlying disturbance in iron metabolism, potentially inducing the activation of ferroptosis. Further research is imperative to elucidate the underlying pathophysiology, providing insights for potential preventive measures and therapeutic strategies. Limitation: There are some limitations as follows: First, due to limited extractable information, we excluded purely abstract publications and non-English publications. Second, the majority of original articles were case-control studies, making it difficult to determine the causal relationship between iron metabolism abnormalities and the onset of PCOS. Third, there is substantial heterogeneity in the definition of PCOS.

Keywords: polycystic ovary syndrome, ferroptosis, iron metabolism, systematic review and meta-analysis