Iron cardiomyopathy is the leading cause of death in transfusional iron overload, and men have twice the mortality of women. Since the prevalence of cardiac iron overload increases rapidly in the second decade of life, we postulated that there are steroid-dependent sex differences in cardiac iron uptake. To test this hypothesis, we manipulated sex steroids in mice having constitutive iron absorption (homozygous hemojuvelin knockout); this model mimics the myocyte iron deposition observed in humans. At four weeks of age, female mice were ovariectomized (OVX) and male mice were castrated (OrchX). Female mice received an estrogen implant (OVX+E) or a cholesterol control (OVX), while male mice received an implant containing testosterone (OrchX+T), dihydrotestosterone (OrchX+DHT), estrogen (OrchX+E), or cholesterol (OrchX). All animals received a high iron diet for eight weeks. OrchX, OVX and OVX+E mice all had similar cardiac iron loads. However, OrchX+E males had a significant increase in cardiac iron concentration compared to OrchX (p<0.01), while OrchX+T and OrchX+DHT only trended higher (p<0.06 and p<0.15, respectively). Hormone treatments did not impact liver iron concentration in either sex. When data were pooled across hormone therapies, liver iron concentration was 25% greater in males than females (p<0.01). In summary, we found that estrogen increased cardiac iron loading in male mice, but not in females. Male mice loaded 25% more hepatic iron than female mice, irrespective of the hormone treatment.
展开▼
