Sex differences in iron overload

Nearly every living organism requires iron due to its roles in DNA synthesis, cellular respiration and oxygen transport. However, iron's ability to generate free radicals makes it toxic at high concentrations. For this reason, the body has an intricate regulatory system that ensures iron's availability while also preventing free radical toxicity. Iron overload can develop when mutations occur to the iron regulatory system, when ineffective erythropoiesis drives excessive dietary iron absorption, or when severe anemia requires chronic blood transfusions. Heart failure due to excessive cardiac iron is the most common cause of lethality in iron overload. The onset of cardiac iron loading most often occurs during puberty. Females exhibit a survival advantage compared to males, but the cause of this is unknown. For this reason, we studied sex differences of iron overload in a mouse model of the disease. We postulated that sex steroids cause an increase in cardiac iron levels and that testosterone increases cardiac iron loading more than estrogen. Effects of sex and hormones were studied via gonadectomy and hormone replacement. Initial experiments found that estrogen increased cardiac iron loading in males compared to castrates (p<0.05); an effect of estrogen on cardiac iron was not observed in females. Since testosterone can be converted into estrogen by the aromatase enzyme, there may be a role for cardiac and/or endothelial aromatase in the generation of male iron overload. Next, cardiac iron transporters were analyzed by RT-PCR in males and females. Both sexes showed a positive relationship between cardiac iron and ferroportin, the only known exporter of cellular iron. However, the relationship was significantly steeper in females than in males (p<0.05). Females may have lower cardiac iron levels than males because of increased iron export rather than decreased iron import. Finally, we observed that ovary-intact females trended towards higher liver iron concentrations than ovariectomized females with estrogen replacement. A follow-up study was therefore performed that investigated the role of progesterone in female iron overload. Progesterone-treated females had significantly increased liver iron concentration compared to ovariectomized females (p<0.05). This could be clinically relevant to female iron overload patients considering progesterone contraceptives. Currently, there is little understanding of progesterone's role in iron homeostasis. Further elucidation of progesterone's effects may help explain differences in male and female iron biology.