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J Gerontol A Biol Sci Med Sci. 2014 Jun;69(6):725-35. doi: 10.1093/gerona/glt154. Epub 2013 Oct 24.
Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point.
Bachman E1, Travison TG2, Basaria S3, Davda MN2, Guo W2, Li M2, Connor Westfall J3, Bae H3, Gordeuk V2, Bhasin S4.
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Abstract
BACKGROUND:
The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear.
METHODS:
We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months.
RESULTS:
The 7%-10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range.
CONCLUSIONS:
Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis.
© The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail:
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KEYWORDS:
Erythropoietin; Ferritin.; Hepcidin; Testosterone
PMID: 24158761 PMCID: PMC4022090 DOI: 10.1093/gerona/glt154
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Select item 23399021
2.
Aging Cell. 2013 Apr;12(2):280-91. doi: 10.1111/acel.12052. Epub 2013 Feb 28.
Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells.
Guo W1, Bachman E, Li M, Roy CN, Blusztajn J, Wong S, Chan SY, Serra C, Jasuja R, Travison TG, Muckenthaler MU, Nemeth E, Bhasin S.
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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.
PMID: 23399021 PMCID: PMC3602280 DOI: 10.1111/acel.12052
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Select item 22459616
4.
J Clin Endocrinol Metab. 2010 Oct;95(10):4743-7. doi: 10.1210/jc.2010-0864. Epub 2010 Jul 21.
Testosterone suppresses hepcidin in men: a potential mechanism for testosterone-induced erythrocytosis.
Bachman E1, Feng R, Travison T, Li M, Olbina G, Ostland V, Ulloor J, Zhang A, Basaria S, Ganz T, Westerman M, Bhasin S.
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Abstract
CONTEXT:
The mechanisms by which testosterone increases hemoglobin and hematocrit are unknown.
OBJECTIVE:
The aim was to test the hypothesis that testosterone-induced increase in hematocrit is associated with suppression of the iron regulatory peptide hepcidin.
PARTICIPANTS:
Healthy younger men (ages 19-35 yr; n = 53) and older men (ages 59-75 yr; n = 56) were studied.
METHODS:
Weekly doses of testosterone enanthate (25, 50, 125, 300, and 600 mg) were administered over 20 wk, whereas endogenous testosterone was suppressed by monthly GnRH agonist administration. Blood and serum parameters from each individual were measured at wk 0, 1, 2, 4, 8, and 20. Longitudinal analyses were performed to examine the relationship between hepcidin, hemoglobin, hematocrit, and testosterone while controlling for potential confounders.
RESULTS:
High levels of testosterone markedly suppressed serum hepcidin within 1 wk. Hepcidin suppression in response to testosterone administration was dose-dependent in older men and more pronounced than in young men, and this corresponded to a greater rise in hemoglobin in older men. Serum hepcidin levels at 4 and 8 wk were predictive of change in hematocrit from baseline to peak levels.
CONCLUSION:
Testosterone administration is associated with suppression of serum hepcidin. Greater increases in hematocrit in older men during testosterone therapy are related to greater suppression of hepcidin.
PMID: 20660052 PMCID: PMC3050108 DOI: 10.1210/jc.2010-0864
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Select item 20525906
5.
J Clin Endocrinol Metab. 2010 Jun;95(6):2560-75. doi: 10.1210/jc.2009-2575.
Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis.
Fernández-Balsells MM1, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, Elamin MB, Gallegos-Orozco JF, Wang AT, Erwin PJ, Bhasin S, Montori VM.
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Abstract
CONTEXT:
The risks of testosterone therapy in men remain poorly understood.
OBJECTIVE:
The aim of this study was to conduct a systematic review and meta-analyses of testosterone trials to evaluate the adverse effects of testosterone treatment in men.
DATA SOURCES:
We searched MEDLINE, EMBASE, and Cochrane CENTRAL from 2003 through August 2008. Review of reference lists and contact with experts further identified candidate studies.
STUDY SELECTION:
Eligible studies were comparative, randomized, and nonrandomized and reported the effects of testosterone on outcomes of interest (death, cardiovascular events and risk factors, prostate outcomes, and erythrocytosis). Reviewers, working independently and in duplicate, determined study eligibility.
DATA EXTRACTION:
Reviewers working independently and in duplicate determined the methodological quality of studies and collected descriptive, quality, and outcome data.
DATA SYNTHESIS:
The methodological quality of the 51 included studies varied from low to medium, and follow-up duration ranged from 3 months to 3 yr. Testosterone treatment was associated with a significant increase in hemoglobin [weighted mean difference (WMD), 0.80 g/dl; 95% confidence interval (CI), 0.45 to 1.14] and hematocrit (WMD, 3.18%; 95% CI, 1.35 to 5.01), and a decrease in high-density lipoprotein cholesterol (WMD, -0.49 mg/dl; 95% CI, -0.85 to -0.13). There was no significant effect on mortality, prostate, or cardiovascular outcomes.
CONCLUSIONS:
The adverse effects of testosterone therapy include an increase in hemoglobin and hematocrit and a small decrease in high-density lipoprotein cholesterol. These findings are of unknown clinical significance. Current evidence about the safety of testosterone treatment in men in terms of patient-important outcomes is of low quality and is hampered by the brief study follow-up.
PMID: 20525906 DOI: 10.1210/jc.2009-2575
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Select item 18160461
6.
J Clin Endocrinol Metab. 2008 Mar;93(3):914-9. Epub 2007 Dec 26.
Effects of graded doses of testosterone on erythropoiesis in healthy young and older men.
Coviello AD1, Kaplan B, Lakshman KM, Chen T, Singh AB, Bhasin S.
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Abstract
CONTEXT:
Erythrocytosis is a dose-limiting adverse effect of testosterone therapy, especially in older men.
OBJECTIVE:
Our objective was to compare the dose-related changes in hemoglobin and hematocrit in young and older men and determine whether age-related differences in erythropoietic response to testosterone can be explained by changes in erythropoietin and soluble transferrin receptor (sTfR) levels.
DESIGN:
We conducted a secondary analysis of data from a testosterone dose-response study in young and older men who received long-acting GnRH agonist monthly plus one of five weekly doses of testosterone enanthate (25, 50, 125, 300, or 600 mg im) for 20 wk.
SETTING:
The study took place at a General Clinical Research Center.
PARTICIPANTS:
Participants included 60 older men aged 60-75 yr and 61 young men aged 19-35 yr.
OUTCOME MEASURES:
Outcome measures included hematocrit and hemoglobin and serum erythropoietin and sTfR levels.
RESULTS:
Hemoglobin and hematocrit increased significantly in a linear, dose-dependent fashion in both young and older men in response to graded doses of testosterone (P<0.0001). The increases in hemoglobin and hematocrit were significantly greater in older than young men. There was no significant difference in percent change from baseline in erythropoietin or sTfR levels across groups in either young or older men. Changes in erythropoietin or sTfR levels were not significantly correlated with changes in total or free testosterone levels.
CONCLUSIONS:
Testosterone has a dose-dependent stimulatory effect on erythropoiesis in men that is more pronounced in older men. The testosterone-induced rise in hemoglobin and hematocrit and age-related differences in response to testosterone therapy may be mediated by factors other than erythropoietin and sTfR.
PMID: 18160461 PMCID: PMC2266950 DOI: 10.1210/jc.2007-1692
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