The role of iron in normal and impaired testicular function

Iron plays a critical role in testicular physiology, impacting spermatogenesis, testosterone production, and overall testicular function. Iron homeostasis is maintained through systemic and cellular regulatory mechanisms, including hepcidin-mediated systemic iron control and the iron-responsive element/iron regulatory protein (IRE/IRP) system at the cellular level. Germ cells require iron for cell divisions and development, while Leydig and Sertoli cells depend on iron for the biosynthesis of testosterone and the maintenance of sperm development, with iron-dependent enzymes playing essential roles in lipid metabolism, DNA synthesis, and mitochondrial function. Iron imbalances, including iron overload and deficiency, significantly impact testicular health. Excess iron accumulation induces oxidative stress, lipid peroxidation, and ferroptosis, contributing to testicular dysfunction. Hereditary hemochromatosis and beta-thalassemia major are associated with disrupted iron metabolism, leading to altered hormonal profiles and impaired spermatogenesis. Conversely, iron deficiency, often linked to dietary insufficiency or inflammatory conditions, can impair testosterone production and sperm quality. Bacterial and viral infections of the testis, such as those caused by Escherichia coli, Zika virus, and HIV, also alter iron metabolism, influencing immune responses and exacerbating testicular inflammation. Additionally, chronic conditions such as obesity and diabetes may disrupt iron regulation and contribute to reproductive dysfunction. Emerging evidence suggests a strong link between ferroptosis and testicular damage, with iron-dependent lipid peroxidation playing a key role in cell death pathways. This review highlights the complexity of iron regulation in the testis, the negative effects of disruptions of iron metabolism on male fertility and reproductive health as well as the gaps in knowledge that currently prevent therapeutic approaches to mitigate infertility associated with iron dysregulation.