By: Amanda Bernett, DO
Editor’s Note: Amanda Bernett, DO, wrote this article during her final year of medical school while completing the FACTS elective. She summarizes findings from Mao et al.’s review, “Iron: A Double-Edged Sword of Female Reproductive Health,” examining iron metabolism, ferroptosis, and their implications for female reproductive health. Like the reproductive biomarkers tracked through FABMs, iron status can offer valuable insight into factors that may influence fertility and overall health.
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Introduction
Iron is essential to life. Its ability to reversibly gain and lose electrons allows it to drive enzymatic redox reactions critical to cellular respiration, DNA repair, oxygen transport, and antioxidant defense. Iron is integral to hemoglobin, myoglobin, cytochromes, nitric oxide synthase, and ribonucleotide reductase. Yet this same redox activity can make iron toxic in excess as it catalyzes the formation of reactive oxygen species (ROS) and oxidative damage [1].
Along with manganese, zinc, and copper, iron is a vital trace element in female fertility. It supports ovarian function, endometrial development, placental growth, and fetal oxygenation. Still, both iron deficiency and iron overload have been implicated in infertility, adverse pregnancy outcomes, and gynecologic disease. Emerging research on ferroptosis—an iron-dependent form of regulated cell death—suggests that iron metabolism may play a central role in reproductive physiology and pathology.
“Iron is a vital trace element in female fertility. It supports ovarian function, endometrial development, placental growth, and fetal oxygenation.”
Iron Metabolism and Ferroptosis
Dietary iron exists as heme iron and non-heme (inorganic) ferric iron (Fe³⁺). Non-heme iron must first be reduced to its ferrous form (Fe²⁺) before absorption by intestinal epithelial cells. It is stored in these cells in ferritin form when the body has sufficient iron levels or exported to the blood via ferroportin—the body’s only known iron exporter—when iron or oxygen concentrations are low. Iron in cells can come from diet but can also come from degradation of old proteins (e.g. old erythrocytes degraded by macrophages). Systemic iron balance is tightly regulated by hepcidin, a hepatic hormone that reduces iron export into the blood when stores are high.
When intracellular iron accumulates, excess ferrous iron participates in Fenton reactions that generate lipid reactive oxygen species (ROS). If antioxidant defenses—particularly glutathione peroxidase 4 (GPX4)—are overwhelmed, ferroptosis occurs. In reproductive tissues, ferroptosis has been linked to granulosa cell function, oocyte maturation, trophoblast invasion, and endometrial decidualization. Dysregulation of this pathway may contribute to infertility and gynecologic disease.
Iron Deficiency vs. Overload in Pregnancy
Pregnancy substantially increases iron demand to support maternal blood volume expansion, placental development, and fetal growth. A singleton pregnancy requires approximately 500–800 mg of maternal iron, though much more is required in the third trimester.
Maternal iron deficiency anemia is associated with preterm birth, intrauterine growth restriction, low birth weight, and perinatal mortality. Iron deficiency has been linked to thrombocytosis and an increased risk of vascular thrombosis in the mother. It has also been found to impair fetal brain development and may lead to long-term neurocognitive effects. In mild deficiency, iron is preferentially shunted to the fetus; however, moderate to severe deficiency compromises the entire maternal-placental-fetal unit.
“Maternal iron deficiency anemia is associated with preterm birth, intrauterine growth restriction, low birth weight, and perinatal mortality…It has also been found to impair fetal brain development and may lead to long-term neurocognitive effects.”
While iron supplementation benefits iron-deficient mothers, excessive supplementation in iron-replete women may increase risks such as gestational hypertension, as well as adverse offspring metabolic outcomes (e.g. increased risk for Type I Diabetes) and cognitive development. These findings suggest reconsideration of the universally accepted iron regimen during pregnancy and emphasize the importance of individualized assessment for iron supplementation.
Iron Overload and Reproductive Disorders
Polycystic Ovary Syndrome, now known as Polyendocrine Metabolic Ovarian Syndrome (PMOS)
PMOS is characterized by hyperandrogenism, ovulatory dysfunction, and metabolic abnormalities. Women with PMOS frequently exhibit elevated serum ferritin levels, even in the absence of hereditary hemochromatosis. Proposed mechanisms include reduced menstrual blood loss due to oligo-ovulation, chronic low-grade inflammation, and altered hepcidin signaling in insulin resistance.
Excess iron may exacerbate oxidative stress within ovarian tissue, impair granulosa cell function, and disrupt follicular maturation. Ferroptosis has been proposed as a mechanistic link between iron overload and ovarian dysfunction, though human data remain limited. This emerging pathway may explain how metabolic and inflammatory disturbances intersect with reproductive outcomes.
Endometriosis
Endometriosis involves the presence of endometrial-like tissue outside the uterine cavity. Retrograde menstruation introduces hemoglobin into the peritoneal cavity where macrophage degradation of erythrocytes releases free iron. Over time, this leads to localized iron accumulation.
Elevated iron concentrations promote oxidative stress and inflammatory signaling, potentially contributing to chronic pelvic pain and infertility. At the cellular level, altered dysregulation of ferroptosis may allow ectopic endometrial cells to survive in an iron-rich environment, perpetuating lesion persistence.
Endometrial Cancer and Ovarian Cancer
Iron-mediated oxidative stress has also been implicated in gynecologic malignancies. Cancer cells often alter iron uptake and storage to support rapid proliferation. While iron can promote mutagenic oxidative damage, induction of ferroptosis is being explored as a potential therapeutic strategy—highlighting iron’s complex role in tumor biology.
Premature Ovarian Failure
Iron overload conditions, including transfusion-dependent anemias and hereditary hemochromatosis, have long been linked to gonadal dysfunction. Excess iron deposition in ovarian tissue may accelerate follicular atresia through oxidative injury and mitochondrial dysfunction. Experimental models suggest ferroptosis pathways may contribute to early ovarian senescence.
Summary
Iron is a double-edged sword in female reproductive health. Adequate levels are essential for ovulation, implantation, placental development, and fetal growth. Yet, both deficiency and overload can impair reproductive outcomes through oxidative stress and ferroptosis-mediated injury.
These findings challenge one-size-fits-all iron supplementation strategies and underscore the need for individualized assessment of iron status in women of reproductive age. As understanding of iron metabolism deepens, targeted modulation of iron balance may represent an emerging frontier in fertility preservation and women’s health.
“These findings challenge one-size-fits-all iron supplementation strategies and underscore the need for individualized assessment of iron status in women of reproductive age.”
The reviewed article offers a comprehensive synthesis of molecular, animal, and clinical evidence linking iron metabolism to reproductive health. However, much of the mechanistic data derives from experimental models. Direct causal relationships in humans remain under investigation. Large prospective studies are needed to clarify optimal iron thresholds for fertility and pregnancy outcomes.
REFERENCES
[1] Mao R, Yin D, Lv W, et al. Iron: A double-edged sword of female reproductive health. J Trace Elem Med Biol. 2026;93:127808. doi:10.1016/j.jtemb.2025.127808
ABOUT THE AUTHOR
Amanda Bernett is a fifth-year osteopathic medical student and osteopathic manipulative medicine scholar at Chicago College of Osteopathic Medicine in Downers Grove, IL. She completed her undergraduate education at Northwestern University in Evanston, IL. She is interested in holistic approaches to wellness in primary care and hopes to promote comprehensive education and treatment of the female reproductive system and women’s health.
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