Chronic iron overload disrupts the reproductive tract and leads to infertility: From a clinical case report to the experimental study of reproduction in female mice

Iron overload is associated with reproductive abnormalities. For example, a case study showed that despite the iron status normalization following phlebotomies and chelation therapy, a woman with juvenile hemochromatosis (JH) continued to exhibit persistent atrophic ovaries, accompanied by prolonged amenorrhea by clinical evaluations. However, the iron overload consequences in the female hypothalamic-pituitary-gonadal (HPG) axis are incompletely understood. Based on the case-report follow-up of a woman diagnosed with JH, this study elucidated the effects of chronic iron overload on the female mouse model, with a special focus on iron-induced consequences in the HPG axis. Female mice were injected with iron (10 mg/mouse/day) five times per week for four weeks, and iron deposits and the reproductive tissues morphology, hormone levels, reactive oxygen species (ROS), and fertility were assessed. Iron-overloaded mice had increased iron levels in serum, hypothalamus, pituitary, ovary, and uterus. Iron-overloaded mice displayed irregular estrous cycles, abnormal folliculogenesis and estrogen levels, reduced corpora lutea and increased atretic follicle numbers. Furthermore, iron overload induced uterine atrophy, along with uterine and ovarian fibrosis. Further iron-overloaded mice increased ROS in the pituitary, ovary and uterus. Positive correlations were found between serum iron levels and ovarian atretic follicles and collagen deposition, and between uterine iron levels and uterine ROS and collagen deposition. In the fertility evaluation, no pups or litters were observed over 90 days in the iron-overloaded mice, suggesting that iron overload causes infertility. Collectively, these findings indicate that chronic iron overload leads to HPG axis abnormalities due to iron accumulation and ROS generation.