Comments for:

Iron regulation by hepcidin
Ningning Zhao, … , An-Sheng Zhang, Caroline A. Enns
Ningning Zhao, … , An-Sheng Zhang, Caroline A. Enns
Published June 3, 2013
Citation Information: J Clin Invest. 2013;123(6):2337-2343. https://doi.org/10.1172/JCI67225.
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Science in Medicine

Iron regulation by hepcidin

Abstract

Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physiologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulation of hepcidin is found in many disease states, such as the anemia of chronic disease, iron refractory iron deficiency anemia, cancer, hereditary hemochromatosis, and ineffective erythropoiesis, such as β-thalassemia. Thus, the regulation of hepcidin is the subject of interest for the amelioration of the detrimental effects of either iron deficiency or overload.

Authors

Ningning Zhao, An-Sheng Zhang, Caroline A. Enns

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Testosterone Regulates Hepcidin

Submitter: Joshua Yarrow | jfyarrow@ufl.edu

Authors: Luke A. Beggs1,3, Stephen E. Borst2,3, Joshua F. Yarrow1,3

Malcom Randall VA Medical Center

Published June 24, 2013

1Malcom Randall VA Medical Center Research Service, 2Geriatrics Research, Education, and Clinical Center (GRECC), Gainesville, FL, 3Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL

To the Editor:

In the June 3rd edition of JCI, Zhao et al. (1) review the regulation of iron metabolism by hepcidin. The authors correctly state that erythropoietic stimuli [e.g., hypoxia or synthetic erythropoietin (EPO)] suppress hepcidin and alter iron homeostasis. In this regard, the sex-steroid hormone testosterone is also a potent stimulus for erythropoiesis, as evidenced by 1) a 5- to 13-fold higher prevalence of anemia in older men with low testosterone when compared to their eugonadal counterparts (2) and 2) a nearly 4-fold greater risk for polycythemia that occurs in hypogonadal men receiving testosterone replacement therapy (3). However, the increase in hematocrit that results from testosterone administration occurs independently of changes in circulating EPO (4); suggesting that other factors mediate androgen-induced erythropoiesis. This observation raises an intriguing question: Is hepcidin a mediator of testosterone-induced erythropoiesis?

To this effect, testosterone administration rapidly and dose-dependently suppresses circulating hepcidin in men , with higher-than-replacement doses suppressing hepcidin >50% within 7 days (5). This hepcidin suppression precedes the androgen-induced increase in hematocrit/hemoglobin and occurs to a greater magnitude in older vs. younger men. Interestingly, the testosterone-induced elevation in hematocrit is also more robust in older vs. younger men and occurs without an increase in circulating EPO (4). Furthermore, testosterone suppresses hepcidin mRNA expression in mice co-administered with an anti-EPO antibody, demonstrating an EPO-independent mechanism of hepcidin suppression that occurs via direct interactions between liganded androgen receptors and the bone morphogenic protein (BMP)/Smad pathways (6). Importantly, testosterone-induced hepcidin suppression was associated with ferroportin upregulation, resulting in decreased splenic iron retention and increased iron incorporation into red blood cells (6). As such, androgen-induced hepcidin suppression is a biologically and clinically significant effect that represents an EPO-independent pathway through which testosterone influences iron metabolism and erythropoiesis.

References

  1. Zhao N, Zhang A, Enns CA. Iron regulation by hepcidin. J Clin Invest. 2013; 123(6):2337–2343.
  2. Ferrucci L, et al. Low testosterone levels and the risk of anemia in older men and women. Arch Intern Med. 2006; 166(13): 1380-1388.
  3. Calof OM, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. 2005; 60(11): 1451-1457.
  4. Coviello AD, et al. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab. 2008; 93: 914-919.
  5. Bachman E, et al. Testosterone suppresses hepcidin in men: a potential mechanism for testosterone-induced erythrocytosis. J Clin Endocrinol Metab. 2010; 95: 4743-4747.
  6. Guo W, et al. Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells. Aging Cell. 2013; 12: 280-291.

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