title: Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells.
abstract: 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 mRNA expression, upregulated renal erythropoietin mRNA 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 K562 erythroleukemia cells more than that from vehicle-treated mice. Testosterone administration promoted the association of androgen receptor (AR) with Smad1 and Smad4 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 mRNA stability. In conclusion, testosterone inhibits hepcidin transcription through its interaction with BMP/Smad signaling. Testosterone administration is associated with increased iron incorporation into red blood cells.
authors: Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston Claude D. Pepper Older Americans Independence Center, Boston Medical Center, Boston, MA 02118, USA.
authors: Wen
authors: W
authors: Guo
authors: Eric
authors: E
authors: Bachman
authors: Michelle
authors: M
authors: Li
authors: Cindy N
authors: CN
authors: Roy
authors: Jerzy
authors: J
authors: Blusztajn
authors: Siu
authors: S
authors: Wong
authors: Stephen Y
authors: SY
authors: Chan
authors: Carlo
authors: C
authors: Serra
authors: Ravi
authors: R
authors: Jasuja
authors: Thomas G
authors: TG
authors: Travison
authors: Martina U
authors: MU
authors: Muckenthaler
authors: Elizabeta
authors: E
authors: Nemeth
authors: Shalender
authors: S
authors: Bhasin
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006454:Hemoglobins / Q000096:biosynthesis; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000378:metabolism*; D020014:K562 Cells; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014168:Transferrin / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D019485:Bone Morphogenetic Proteins; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D006454:Hemoglobins; D064451:Hepcidins; D011944:Receptors, Androgen; D051785:Smad Proteins; D014168:Transferrin; D004921:Erythropoietin; D013739:Testosterone; D007501:Iron
references: J Surg Oncol. 1971;3(1):59-65
references: 5093803
references: Blood. 2008 Aug 15;112(4):1503-9
references: 18539898
references: Blood. 2006 Dec 1;108(12):3730-5
references: 16882706
references: Oncogene. 2007 Aug 23;26(39):5741-51
references: 17369855
references: Arch Intern Med. 2006 Jul 10;166(13):1380-8
references: 16832003
references: Cell Metab. 2008 Dec;8(6):502-11
references: 18976966
references: Am J Clin Nutr. 2005 Apr;81(4):814-21
references: 15817857
references: Blood. 2007 May 1;109(9):4038-44
references: 17218383
references: J Clin Endocrinol Metab. 2008 Mar;93(3):914-9
references: 18160461
references: J Lab Clin Med. 1982 Feb;99(2):247-53
references: 7061919
references: AMA J Dis Child. 1959 Sep;98:293-302
references: 14445398
references: J Biochem Biophys Methods. 2004 Mar 31;58(3):239-51
references: 15026210
references: Kidney Int. 1997 Jul;52(1):217-22
references: 9211366
references: Nat Chem Biol. 2008 Jan;4(1):33-41
references: 18026094
references: Blood. 1997 Jan 1;89(1):1-25
references: 8978272
references: Urology. 2010 Jun;75(6):1441-5
references: 20110105
references: Blood. 2010 Apr 29;115(17):3616-24
references: 20053755
references: Nat Genet. 2009 Apr;41(4):482-7
references: 19252486
references: Blood. 2011 Apr 28;117(17):4425-33
references: 21346250
references: Arch Toxicol. 1979 Apr 23;42(1):43-9
references: 454184
references: Gut. 2008 Mar;57(3):374-82
references: 17965061
references: Intern Med J. 2009 Aug;39(8):532-8
references: 19220545
references: J Biol Chem. 2002 Nov 15;277(46):43749-56
references: 12226080
references: Blood. 1975 May;45(5):665-70
references: 47251
references: Lancet. 1947 May 10;1(6454):631-4
references: 20239096
references: J Physiol. 2011 Aug 15;589(Pt 16):3983-94
references: 21690193
references: J Biol Chem. 1985 Nov 25;260(27):14717-21
references: 4055798
references: J Clin Endocrinol Metab. 2010 Jun;95(6):2536-59
references: 20525905
references: J Clin Endocrinol Metab. 2010 Oct;95(10):4743-7
references: 20660052
references: Blood. 2011 Nov 3;118(18):4977-84
references: 21730356
references: Nature. 1965 Apr 17;206(981):270-2
references: 5837677
references: Semin Hematol. 2009 Oct;46(4):387-93
references: 19786207
references: Haematologica. 2012 Jun;97(6):827-34
references: 22207682
references: PLoS One. 2009 Nov 18;4(11):e7875
references: 19924283
references: Arch Biochem Biophys. 1996 Apr 15;328(2):289-94
references: 8645006
references: J Mol Med (Berl). 2009 May;87(5):471-80
references: 19229506
references: Blood. 2011 Nov 10;118(19):5278-82
references: 21876117
references: Eur J Appl Physiol. 2012 Apr;112(4):1391-7
references: 21818622