Estrogens Iron Out the Details: A Novel Direct Pathway for Estrogen Control of Iron Homeostasis

The importance of estrogens and iron to physiology and disease has been known for decades, and their levels are intentionally manipulated throughout human life whether by doctor’s prescriptions or over-the-counter natural supplements. An important and often overlooked detail is that these two factors interact. This interaction largely consists of estrogen effects on menstrual blood flow, a major source of iron loss in premenopausal women (1, 2). However, in a recent publication in Endocrinology, the lab of Xi Huang describes a direct mechanism of interaction between estrogens and hepcidin, the peptide hormone that regulates iron transport and homeostasis. Specifically, they observed that estrogen can decrease the expression of hepcidin mRNA by an estrogen response element half-site upstream in the hepcidin promoter (3). Iron is an essential trace element that is required for human life and tightly regulated in the plasma between 10–30 M (4). Iron homeostasis is maintained by altering the absorption of iron from the gut and the release of iron from storage in hepatocytes and macrophages. A key regulator of these processes is hepcidin, a 25-amino acid peptide hormone produced by the liver to inhibit iron transport by binding and inhibiting the cellular iron exporter, ferroportin. A brief schematic of the role of hepcidin in iron homeostasis is shown in Fig. 1. The levels of hepcidin are regulated in a homeostatic manner so that high iron levels raise hepcidin to decrease iron absorption and lower the rate of release from storage cells (4, 5). The reproductive axis in women affects iron homeostasis in part through menstrual blood flow. Because iron is tightly conserved with low levels of excretion, menstrual blood flow represents a significant source of iron loss from the body (1, 2). Premenopausal nonpregnant women are often deficient in iron, and postmenopausal women have higher levels of iron (3) and a much lower recommended daily allowance of iron intake (1). Iron levels are also raised in women who take oral contraceptives (6, 7). Although this effect may be due to smaller volume of menstrual blood flow, a similar effect occurs in rats that do not lose blood with menses (8). The recent study by Yang et al. (3) describes a mechanism by which estradiol could increase iron absorption and iron release from storage cells. Specifically, the authors describe a functional estrogen response element (ERE) half-site in the human hepcidin promoter, and they observe that 24 h after estradiol treatment, hepcidin mRNA are decreased both in vitro in human liver cells and in vivo in mice. An estrogen antagonist (ICI 182,780) prevented the estradiol-induced decrease and, independent of estradiol treatment, caused an increase in hepcidin mRNA that indicates that the estrogen receptor may have ligandindependent effects on hepcidin expression. It remains to be seen whether the effect of estradiol on hepcidin expression is robust enough to substantially alter iron homeostasis in vivo. Although the magnitude of the effect on hepcidin mRNA was substantial (up to 50% in HuH7 cells), the estradiol-induced decrease in liver hepcidin mRNA did not correspond with an effect on serum iron concentration in mice. However, all measurements were taken only 24 h after estradiol injection (3). Therefore, it is possible that an effect would have been observed with chronic estradiol treatment. Because hepcidin is the principal regulator of iron distribution as well as absorption, it’s also possible that the effects may alter tissue distribution without a change in serum iron levels. In humans, the relationship between exogenous estrogen treatment and iron homeostasis is not clear. Women using oral contraceptives have higher levels of iron (6, 7),