The Impact of Iron Overload and Ferroptosis on Reproductive Disorders in Humans: Implications for Preeclampsia

Abstract

Iron is an essential element for the survival of most organisms, including humans. Demand for iron increases significantly during pregnancy to support growth and development of the fetus. Paradoxically, epidemiologic studies have shown that excessive iron intake and/or high iron status can be detrimental to pregnancy and is associated with reproductive disorders ranging from endometriosis to preeclampsia. Reproductive complications resulting from iron deficiency have been reviewed elsewhere. Here, we focus on reproductive disorders associated with iron overload and the contribution of ferroptosis—programmed cell death mediated by iron-dependent lipid peroxidation within cell membranes—using preeclampsia as a model system. We propose that the clinical expressions of many reproductive disorders and pregnancy complications may be due to an underlying ferroptopathy (elemental iron-associated disease), characterized by a dysregulation in iron homeostasis leading to excessive ferroptosis.

Role of ferroptosis induced by a high concentration of calcium oxalate in the formation and development of urolithiasis

“…Ferroptosis, as a regulated cell death phenomenon, was first reported in 2012, and is a type of iron-dependent lipid peroxidation ( 5 ). With the advancements in research, ferroptosis has been reported to play a role in the development of blood diseases, neurological diseases, respiratory diseases, cardiovascular diseases, reproductive system diseases and tumors ( 28 - 32 ). However, the related reports of the role of ferroptosis in urinary system diseases have mainly focused on renal failure and renal tumors ( 18 , 22 ), and to date, there is no relevant report available on the topic of urolithiasis, at least to the best of our knowledge.…”

Ferroptosis: Biochemistry and Biology in Cancers

“…Cells undergoing ferroptosis cannot be rescued by chemical or genetic inhibitors of apoptosis or necroptosis, which indicates that ferroptosis is a distinct form of cell death ( 4 ). Ferroptosis has been investigated in many human diseases, such as neurodegenerative diseases [including Parkinson’s disease ( 5 , 6 ), Alzheimer’s disease ( 7 , 8 ), Friedreich’s ataxia ( 9 ), and Huntington’s disease ( 10 )], organ injury [including hepatic damage ( 11 , 12 ), brain injury ( 13 – 15 ), spinal cord injury ( 16 , 17 ), and kidney injury ( 18 – 20 )], organ fibrosis ( 21 – 23 ), cardiovascular diseases ( 24 , 25 ), and gynecological diseases ( 26 – 28 ). Recently, an increasing number of studies on ferroptosis have been conducted in diverse cancers as ferroptosis is gradually being recognized as a potential form to eliminate cancer cells.…”

Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

“…Iron can serve as an essential signaling molecule that modulates diverse physiological processes, and iron homeostasis is required for the normal growth and development of the placenta and fetus during pregnancy (13, 63). An extensive body of evidence indicates that while iron deficiency is linked to abnormal pregnancy (13) and increased risk of fetal death (64), iron overload is associated with the manifestation of PCOS (65). Previous findings by Kim and colleagues indicate that increased circulating iron levels are associated with metabolic abnormalities, including HAIR, in PCOS patients (66).…”

“…For example, suppression of glutathione (GSH) biosynthesis and subsequent inhibition or degradation of glutathione peroxidase 4 (Gpx4) activity, disturbed balance of iron homeostasis, and activation of the mitogen-activated protein kinase (MAPK) signaling pathways all contribute to regulate the initiation and execution of ferroptosis (6, 7, 10, 11). However, little is known about the role of ferroptosis (13) in comparison with other forms of programmed cell death such as apoptosis (14, 15) in female reproduction.…”