Skip to main content

Advertisement

Log in

Iron and Testosterone: Interplay and Clinical Implications

  • Male Sexual Dysfunction and Disorders (A Pastuszak and T Köhler, Section Editors)
  • Published:
Current Sexual Health Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The purpose of this review is to investigate the crosstalk between testosterone and iron metabolism in men and discuss the clinical implications.

Recent Findings

Testosterone directly regulates body iron levels through inhibition of the master regulator of iron metabolism, hepcidin.

Summary

There is significant overlap between the side effects of exogenous testosterone administration and iron overload. Testosterone increases dietary iron absorption, providing a direct link between the two. As the body is unable to eliminate excess iron, a negative feedback mechanism allowing iron to inhibit testosterone production to maintain body iron homeostasis is proposed. This review discusses the recent data demonstrating the regulation of body iron stores by testosterone, as well as data suggesting testosterone may be reciprocally regulated by iron. Crosstalk between testosterone and iron has significant implications in testosterone deficiency and therapy. Additionally, the regulation of testosterone by iron may indicate a significant role for iron in the development of the hypogonadotropic hypogonadism of aging and chronic disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

Papers of Particular Interest, Published recently, Have Been Highlighted as: • of Importance •• of Major Importance

  1. Garn SM, Ryan AS, Abraham S, Owen G. Suggested sex and age appropriate values for “low” and “deficient” hemoglobin levels. Am J Clin Nutr. 1981;34:1648–51.

    CAS  PubMed  Google Scholar 

  2. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Baltimore longitudinal study of aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore longitudinal study of aging. J Clin Endocrinol Metab. 2001;86:724–31.

    Article  CAS  PubMed  Google Scholar 

  3. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J. Clin. Endocrinol. Metab. Endocrine Society; 2002;87:589–98.

  4. Khera M, Adaikan G, Buvat J, Carrier S, El-Meliegy A, Hatzimouratidis K, et al. Diagnosis and treatment of testosterone deficiency: recommendations from the fourth international consultation for sexual medicine (ICSM 2015). J Sex Med. 2016;13:1787–804.

    Article  PubMed  Google Scholar 

  5. Gabrielsen JS, Najari BB, Alukal JP, Eisenberg ML. Trends in testosterone prescription and public health concerns. Urol Clin North Am. 2016;43:261–71.

    Article  PubMed  Google Scholar 

  6. Evans NA. Current concepts in anabolic-androgenic steroids. Am J Sports Med. 2004;32:534–42.

    Article  PubMed  Google Scholar 

  7. van den Berg P, Neumark-Sztainer D, Cafri G, Wall M. Steroid use among adolescents: longitudinal findings from Project EAT. Pediatrics. American Academy of Pediatrics; 2007;119:476–86.

  8. Maravelias C, Dona A, Stefanidou M, Spiliopoulou C. Adverse effects of anabolic steroids in athletes. A constant threat. Toxicol Lett. 2005;158:167–75.

    Article  CAS  PubMed  Google Scholar 

  9. Jones SD, Dukovac T, Sangkum P, Yafi FA, Hellstrom WJG. Erythrocytosis and polycythemia secondary to testosterone replacement therapy in the aging male. Sex Med Rev. 2015;3:101–12.

    Article  PubMed  Google Scholar 

  10. Koskenkorva-Frank TS, Weiss G, Koppenol WH, Burckhardt S. The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress. Free Radic Biol Med. 2013;65:1174–94.

    Article  CAS  PubMed  Google Scholar 

  11. Anderson CP, Shen M, Eisenstein RS, Leibold EA. Mammalian iron metabolism and its control by iron regulatory proteins. Biochim Biophys Acta. 1823;2012:1468–83.

    Google Scholar 

  12. • Ganz T. Systemic iron homeostasis. Physiol. Rev. American Physiological Society; 2013;93:1721–41. A comprehensive review on the mechanisms regulating iron metabolism.

  13. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of mammalian iron metabolism. Cell. 2010;142:24–38.

    Article  CAS  PubMed  Google Scholar 

  14. Institute of Medicine (US). Panel on micronutrients. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington (DC): National Academies Press (US); 2001.

    Google Scholar 

  15. Wu X-G, Wang Y, Wu Q, Cheng W-H, Liu W, Zhao Y, et al. HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression. Blood. American Society of Hematology; 2014;124:1335–43.

  16. Garry PJ, Koehler KM, Simon TL. Iron stores and iron absorption: effects of repeated blood donations. Am J Clin Nutr. 1995;62:611–20.

    CAS  PubMed  Google Scholar 

  17. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. American Society for Clinical Investigation; 2004;113:1271–6.

  18. Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood. American Society of Hematology; 2002;100:3776–81.

  19. Rostoker G, Vaziri ND, Fishbane S. Iatrogenic iron overload in dialysis patients at the beginning of the 21st century. Drugs. Springer International Publishing; 2016;76:741–57.

  20. Gabrielsen JS, Gao Y, Simcox JA, Huang J, Thorup D, Jones D, et al. Adipocyte iron regulates adiponectin and insulin sensitivity. J. Clin. Invest. American Society for Clinical Investigation; 2012;122:3529–40.

  21. Carrero JJ, Bárány P, Yilmaz MI, Qureshi AR, Sonmez A, Heimbürger O, et al. Testosterone deficiency is a cause of anaemia and reduced responsiveness to erythropoiesis-stimulating agents in men with chronic kidney disease. Nephrol. Dial. Transplant. Oxford University Press; 2012;27:709–15.

  22. Rotter I, Kosik-Bogacka DI, Dołęgowska B, Safranow K, Kuczyńska M, Laszczyńska M. Analysis of the relationship between the blood concentration of several metals, macro- and micronutrients and endocrine disorders associated with male aging. Environ Geochem Health. 2016;38:749–61.

    Article  CAS  PubMed  Google Scholar 

  23. Shin YS, You JH, Cha JS, Park JK. The relationship between serum total testosterone and free testosterone levels with serum hemoglobin and hematocrit levels: a study in 1221 men. Aging Male. 2016;19:209–14.

    Article  CAS  PubMed  Google Scholar 

  24. Waalen J, Löhneysen von K, Lee P, Xu X, Friedman JS. Erythropoietin, GDF15, IL6, hepcidin and testosterone levels in a large cohort of elderly individuals with anaemia of known and unknown cause. European Journal of Haematology. Blackwell Publishing Ltd; 2011;87:107–16.

  25. Ferrucci L, Maggio M, Bandinelli S, Basaria S, Lauretani F, Ble A, et al. Low testosterone levels and the risk of anemia in older men and women. Arch Intern Med American Medical Association. 2006;166:1380–8.

    Article  CAS  Google Scholar 

  26. Fernández-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, et al. Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab Endocrine Society. 2011;95:2560–75.

    Article  Google Scholar 

  27. Zhang LT, Shin YS, Kim JY, Park JK. Could testosterone replacement therapy in hypogonadal men ameliorate anemia, a cardiovascular risk factor? An observational, 54-week cumulative registry study. J Urol. 2016;195:1057–64.

    Article  CAS  PubMed  Google Scholar 

  28. Strum SB, McDermed JE, Scholz MC, JOHNSON H, TISMAN G. Anaemia associated with androgen deprivation in patients with prostate cancer receiving combined hormone blockade. BJU Int. Blackwell Science Ltd; 1997;79:933–41.

  29. Nilsson-Ehle H, Jagenburg R, Landahl S, Svanborg A. Blood haemoglobin declines in the elderly: implications for reference intervals from age 70 to 88. Eur J Haematol. 2000;65:297–305.

    Article  CAS  PubMed  Google Scholar 

  30. Dallman PR. Changing iron needs from birth through adolescence. Nestle nutrition workshop series (USA). Nestle nutrition workshop series (USA); 1992;30:29–38.

  31. Anttila R, Cook JD, Siimes MA. Body iron stores in relation to growth and pubertal maturation in healthy boys. Br J Haematol. 1997;96:12–8.

    Article  CAS  PubMed  Google Scholar 

  32. Kuiri-Hänninen T, Sankilampi U, Dunkel L. Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty. Horm Res Paediatr. Karger Publishers; 2014;82:73–80.

  33. Dallman PR, Siimes MA, Stekel A. Iron deficiency in infancy and childhood. Am. J. Clin. Nutr. American Society for Nutrition; 1980;33:86–118.

  34. •• Bachman E, Feng R, Travison T, Li M, Olbina G, Ostland V, et al. Testosterone suppresses hepcidin in men: a potential mechanism for testosterone-induced erythrocytosis. J. Clin. Endocrinol. Metab. Endocrine Society; 2010;95:4743–7. Initial paper to report that testosterone regulates hepcidin expression in men.

  35. •• Bachman E, Travison TG, Basaria S, Davda MN, Guo W, Li M, et al. Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. J. Gerontol. A Biol. Sci. Med. Sci. Oxford University Press; 2014;69:725–35. Second paper to demonstrate the effect of testosterone on hepcidin as well as the effect on erythropoietin.

  36. Dhindsa S, Ghanim H, Batra M, Kuhadiya ND, Abuaysheh S, Green K, et al. Effect of testosterone on hepcidin, ferroportin, ferritin and iron binding capacity in patients with hypogonadotropic hypogonadism and type 2 diabetes. Clin. Endocrinol. (Oxf). 2016;85:772–80.

  37. Beggs LA, Yarrow JF, Conover CF, Meuleman JR, Beck DT, Morrow M, et al. Testosterone alters iron metabolism and stimulates red blood cell production independently of dihydrotestosterone. Am J Physiol Endocrinol Metab. 2014;307:E456–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hero M, Wickman S, Hanhijärvi R, Siimes MA, Dunkel L. Pubertal upregulation of erythropoiesis in boys is determined primarily by androgen. J Pediatr. 2005;146:245–52.

    Article  CAS  PubMed  Google Scholar 

  39. • Latour C, Kautz L, Besson-Fournier C, Island M-L, Canonne-Hergaux F, Loréal O, et al. Testosterone perturbs systemic iron balance through activation of epidermal growth factor receptor signaling in the liver and repression of hepcidin. Hepatology. 2014;59:683–94. This paper demonstrates that EGFR signaling is necessary for testosterone inhibition of hepcidin signaling

    Article  CAS  PubMed  Google Scholar 

  40. Guo W, Li M, Bhasin S. Testosterone supplementation improves anemia in aging male mice. J. Gerontol. A Biol. Sci. Med. Sci. Oxford University Press; 2014;69:505–13.

  41. • Guo W, Bachman E, Li M, Roy CN, Blusztajn J, Wong S, et al. Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells. Aging Cell. 2013;12:280–91. This paper demonstrates that androgen receptor signaling is necessary for testosterone to inhibit hepcidin signaling

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pinto JP, Ribeiro S, Pontes H, Thowfeequ S, Tosh D, Carvalho F, et al. Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPalpha. Blood. American Society of Hematology; 2008;111:5727–33.

  43. Liu Q, Davidoff O, Niss K, Haase VH. Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis. J. Clin. Invest. American Society for Clinical Investigation; 2012;122:4635–44.

  44. Guo W, Schmidt PJ, Fleming MD, Bhasin S. Effects of testosterone on erythropoiesis in a female mouse model of anemia of inflammation. Endocrinology. 2016;157:2937–46.

    Article  CAS  PubMed  Google Scholar 

  45. Charbonnel B, Chupin M, Le Grand A, Guillon J. Pituitary function in idiopathic haemochromatosis: hormonal study in 36 male patients. Acta Endocrinol. 1981;98:178–83.

    CAS  PubMed  Google Scholar 

  46. Safarinejad MR. Evaluation of semen quality, endocrine profile and hypothalamus-pituitary-testis axis in male patients with homozygous beta-thalassemia major. J Urol. 2008;179:2327–32.

    Article  CAS  PubMed  Google Scholar 

  47. Kim MK, Lee JW, Baek KH, Song KH, Kwon HS, Oh KW, et al. Endocrinopathies in transfusion-associated iron overload. Clin. Endocrinol. (Oxf). 2013;78:271–7.

  48. Taddesse A, Woldie IL, Khana P, Swerdlow PS, Chu J-W, Abrams J, et al. Hypogonadism in patients with sickle cell disease: central or peripheral? Acta Haematol. Karger Publishers; 2012;128:65–8.

  49. Hagag AA, Badraia IM, Elfarargy MS, El-Enein AMA. Study of male sex hormone levels in male Egyptian children with beta-thalassemia: correlation with iron load. Endocr Metab Immune Disord Drug Targets. 2016;16:124–30.

    Article  CAS  Google Scholar 

  50. Bergeron C, Kovacs K. Pituitary siderosis. A histologic, immunocytologic, and ultrastructural study. Am. J. Pathol. American Society for Investigative Pathology; 1978;93:295–309.

  51. Noetzli LJ, Panigrahy A, Mittelman SD, Hyderi A, Dongelyan A, Coates TD, et al. Pituitary iron and volume predict hypogonadism in transfusional iron overload. Am. J. Hematol. Wiley Subscription Services, Inc., A Wiley Company; 2012;87:167–71.

  52. Singer ST, Killilea D, Suh JH, Wang ZJ, Yuan Q, Ivani K, et al. Fertility in transfusion-dependent thalassemia men: effects of iron burden on the reproductive axis. Am J Hematol. 2015;90:E190–2.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Bronspiegel-Weintrob N, Olivieri NF, Tyler B, Andrews DF, Freedman MH, Holland FJ. Effect of age at the start of iron chelation therapy on gonadal function in beta-thalassemia major. N Engl J Med. 1990;323:713–9.

    Article  CAS  PubMed  Google Scholar 

  54. Chatterjee R, Katz M. Reversible hypogonadotrophic hypogonadism in sexually infantile male thalassaemic patients with transfusional iron overload. Clin. Endocrinol. (Oxf). 2000;53:33–42.

  55. McDermott JH, Walsh CH. Hypogonadism in hereditary hemochromatosis. J. Clin. Endocrinol. Metab. Endocrine Society; 2005;90:2451–5.

  56. Siemons LJ, Mahler CH. Hypogonadotropic hypogonadism in hemochromatosis: recovery of reproductive function after iron depletion. J. Clin. Endocrinol. Metab. The Endocrine Society; 1987;65:585–7.

  57. Atkin SL, Burnett HE, Green VL, White MC, Lombard M. Expression of the transferrin receptor in human anterior pituitary adenomas is confined to gonadotrophinomas. Clin. Endocrinol. (Oxf). 1996;44:467–71.

  58. Schümann K. Safety aspects of iron in food. Ann Nutr Metab. 2001;45:91–101.

    Article  PubMed  Google Scholar 

  59. Greenberg SR. The pathogenesis of hypophyseal fibrosis in aging: its relationship to tissue iron deposition. J Gerontol. 1975;30:531–8.

    Article  CAS  PubMed  Google Scholar 

  60. Noetzli LJ, Panigrahy A, Hyderi A, Dongelyan A, Coates TD, Wood JC. Pituitary iron and volume imaging in healthy controls. AJNR Am J Neuroradiol. American Society of Neuroradiology; 2012;33:259–65.

  61. Vuppalanchi R, Troutt JS, Konrad RJ, Ghabril M, Saxena R, Bell LN, et al. Serum hepcidin levels are associated with obesity but not liver disease. Obesity (Silver Spring). 2014;22:836–41.

  62. Jiang F, Sun Z-Z, Tang Y-T, Xu C, Jiao X-Y. Hepcidin expression and iron parameters change in Type 2 diabetic patients. Diabetes Res Clin Pract. 2011;93:43–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joseph Scott Gabrielsen.

Ethics declarations

Conflict of Interest

Joseph S. Gabrielsen has declared no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Male Sexual Dysfunction and Disorders

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gabrielsen, J.S. Iron and Testosterone: Interplay and Clinical Implications. Curr Sex Health Rep 9, 5–11 (2017). https://doi.org/10.1007/s11930-017-0097-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11930-017-0097-2

Keywords

Navigation