Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells
Open accessAbstract
Summary: Testosterone administration increases hemoglobin levels and has been used to treat anemia of chronic disease. Erythrocytosis is the most frequent adverse event associated with testosterone therapy of hypogonadal men, especially older men. However, the mechanisms by which testosterone increases hemoglobin remain unknown. Testosterone administration in male and female mice was associated with a greater increase in hemoglobin and hematocrit, reticulocyte count, reticulocyte hemoglobin concentration, and serum iron and transferrin saturation than placebo. Testosterone downregulated hepatic hepcidin m RNA expression, upregulated renal erythropoietin m RNA expression, and increased erythropoietin levels. Testosterone‐induced suppression of hepcidin expression was independent of its effects on erythropoietin or hypoxia‐sensing mechanisms. Transgenic mice with liver‐specific constitutive hepcidin over‐expression failed to exhibit the expected increase in hemoglobin in response to testosterone administration. Testosterone upregulated splenic ferroportin expression and reduced iron retention in spleen. After intravenous administration of transferrin‐bound 58 Fe, the amount of 58 Fe incorporated into red blood cells was significantly greater in testosterone‐treated mice than in placebo‐treated mice. Serum from testosterone‐treated mice stimulated hemoglobin synthesis in K 562 erythroleukemia cells more than that from vehicle‐treated mice. Testosterone administration promoted the association of androgen receptor ( AR ) with S mad1 and S mad4 to reduce their binding to bone morphogenetic protein ( BMP )‐response elements in hepcidin promoter in the liver. Ectopic expression of AR in hepatocytes suppressed hepcidin transcription; this effect was blocked dose‐dependently by AR antagonist flutamide. Testosterone did not affect hepcidin m RNA stability. In conclusion, testosterone inhibits hepcidin transcription through its interaction with BMP / S mad signaling. Testosterone administration is associated with increased iron incorporation into red blood cells.
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Serum sTR concentration reflects total erythroid activity and iron status and reflects plasma iron turnover and erythroid transferrin uptake if iron deficiency is not present.
“Serum sTR concentration reflects total erythroid activity and iron status and has been shown to reflect plasma iron turnover and erythroid transferrin uptake if iron deficiency is not present (22,25).”
From Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point (2014) · cites this paper as [25]
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“Besides, differences in sex hormones may also explain the gender difference in iron deficit, since estrogen hormones have shown to stimulate hepcidin synthesis [134], while testosterone promotes an inhibition of hepcidin [135,136].”
BackgroundIkeda, Y., Watanabe, H., Shiuchi, T., Hamano, H., Horinouchi, Y., Imanishi, M., Goda, M., Zamami, Y., Takechi, K., Izawa-Ishizawa, Y., et al. (2020) · Diabetologia · doi:10.1007/s00125-020-05153-0 · Cited by 53 · see citing works
- Authors
- Guo, W., Bachman, E., Li, M., Roy, C. N., Blusztajn, J., Wong, S., Chan, S. Y., Serra, C., Jasuja, R., Travison, T. G., Muckenthaler, M. U., Nemeth, E., & Bhasin, S.
- Affiliations
- Boston University (US)
- Johns Hopkins University (US)
- Woods Hole Oceanographic Institution (US)
- Brigham and Women's Hospital (US)
- Heidelberg University (DE)
- University of California, Los Angeles (US)
- Corresponding author
- Guo, Wen
- Bhasin, Shalender
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2013-02-28
- Volume
- 12
- Issue
- 2
- Pages
- 280-291
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC3602280
- OpenAlex
- W2012598190
- Cited by
- 192
- References
- 38
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 3 · 2023: 13 · 2022: 16 · 2021: 6 · 2020: 22 · 2019: 14 · 2018: 11 · 2017: 23 · 2016: 15 · 2015: 16 · 2014: 16 · 2013: 9
- FWCI
- 13.38
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Centre National de la Recherche Scientifique
- National Institutes of Health (5p30ag031679-15)
- National Institute on Aging (U01AG014369, R21AG037859, R01AG037193, P30-AG031679, 1UO1AG14369)
- National Heart, Lung, and Blood Institute (K08HL096834)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082722, R01DK056690)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- testosterone, hepcidin, erythropoiesis, erythrocytosis, iron incorporation, erythropoietin, BMP/Smad signaling, androgen receptor, Smad1, SMAD4, iron retention, anemia of chronic disease, hypogonadism, hemoglobin synthesis, flutamide
- MeSH terms
- Animals, Erythrocytes, Erythropoietin, Female, Gene Expression Regulation, Hemoglobins, Humans, Iron, Liver, Male, Mice, Transgenic, Receptors, Androgen, Spleen, Testosterone, Transcription, Genetic, Transferrin, Signal Transduction, Bone Morphogenetic Proteins, K562 Cells, Hepatocytes, Antimicrobial Cationic Peptides, Mice, Smad Proteins, Hepcidins
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