madman
Super Moderator
Abstract
Testosterone stimulates iron-dependent erythropoiesis and suppresses hepcidin. To clarify the role of iron in mediating testosterone's effects on erythropoiesis, we induced iron deficiency in mice by feeding a low iron diet. Iron-replete and iron-deficient mice were treated weekly with testosterone propionate or vehicle for 3 weeks. Testosterone treatment increased red cell count in iron-replete mice, but, surprisingly, testosterone reduced red cell count in iron-deficient mice. Splenic stress erythropoiesis was stimulated in iron-deficient mice relative to iron-replete mice, and further increased by testosterone treatment, as indicated by the increase in red pulp area, the number of nucleated erythroblasts, and expression levels of TfR1, GATA1, and other erythroid genes. Testosterone treatment of iron-deficient mice increased the ratio of early-to-late erythroblasts in the spleen and bone marrow, and serum LDH level, consistent with ineffective erythropoiesis. In iron-deficient mice, erythropoietin levels were higher but erythropoietin-regulated genes were generally downregulated relative to iron-replete mice, suggesting erythropoietin resistance.
Conclusion: Testosterone treatment stimulates splenic stress erythropoiesis in iron-replete as well as iron-deficient mice. However, testosterone worsens anemia in iron-deficient mice because of ineffective erythropoiesis possibly due to erythropoietin resistance associated with iron deficiency. Iron plays an important role in mediating testosterone's effects on erythropoiesis.
4 | DISCUSSION
The findings of the present study offer insight into the role of iron in erythropoiesis and in mediating the mechanisms by which testosterone stimulates erythropoiesis. Our findings indicate that iron availability plays an essential role in mediating the erythropoietic response to testosterone and that testosterone treatment of iron-deficient mice worsens anemia. Testosterone administration of iron-deficient mice was associated with a marked stimulation of stress erythropoiesis in the spleen, as indicated by an increase in spleen size, red pulp area, and the number of erythroblasts in the spleen, as well as increased expression of GATA1, TfR1, and other markers of erythropoiesis. Multiple observations provide evidence that the anemia in iron-deficient mice was worsened by testosterone treatment because of ineffective erythropoiesis. First, there was a substantial expansion of early erythroid progenitors in response to testosterone treatment of iron-deficient mice, as indicated by increased numbers of early erythroblasts as well as increased expression of GATA1, TfR1, and other erythroid genes. Second, there was a maturation block at the polychromatophilic stage, as indicated by a substantially increased ratio of proerythroblasts plus polychromatophilic erythroblasts to orthochromatic erythroblasts in iron-deficient mice treated with testosterone. Finally, there was a loss of erythroid precursors as indicated by fewer late erythroblasts, worsened anemia in spite of evidence of markedly stimulated stress erythropoiesis in the spleen, and increased LDH levels.
Our findings are consistent with a growing body of preclinical as well as clinical studies that suggest that testosterone administration increases hemoglobin and hematocrit by stimulating iron-dependent erythropoiesis. Testosterone suppresses hepcidin transcription in men as well as in mice, upregulates ferroportin, and increases iron availability for erythropoiesis. However, testosterone administration to hepcidin knock out mice is also associated with increases in hemoglobin and hematocrit. Thus, although hepcidin suppression by testosterone increases iron availability for erythropoiesis, hepcidin suppression is not essential for mediating testosterone's effects on erythropoiesis in iron-replete healthy mice. The present study shows that testosterone stimulates erythropoiesis leading to an expansion of early erythropoietic progenitors. In a state of iron deficiency, the expansion of the erythropoietic progenitor pool by testosterone administration is associated with ineffective erythropoiesis, possibly due to a state of erythropoietin resistance induced by iron deficiency. Thus, iron availability, but not hepcidin, is essential for mediating testosterone's effects on erythropoiesis.
Although randomized trials of the effect of testosterone in men with iron deficiency anemia have not been conducted two clinical case reports in humans support our findings. In one open-label trial of 24 patients with advanced breast cancer, who were treated with androgens, four patients had low serum iron at baseline; androgen treatment further decreased serum iron and the expected increase in hemoglobin and hematocrit did not occur in response to androgen administration. Testosterone administration to one female patient with iron deficiency in this case report further decreased serum iron from 30 to 22 ug/dL and hemoglobin from 13.2 to 11.9 gm/dL; the anemia was reversed after testosterone administration was discontinued and iron supplementation was provided. In a second case, the administration of testosterone to an iron-deficient male patient decreased serum iron from 10.8 to 6.0 ug/dL and hemoglobin from 7.5 to 6.0 g/dL (Gardner and Pringle). These case reports support our observations that in an iron-deficient state, testosterone treatment worsens anemia.
These findings have clinical implications. Although testosterone treatment can correct unexplained anemia of aging and anemia of inflammation, it is important to evaluate the cause of anemia and rule out iron deficiency, before starting testosterone treatment because, in these states, testosterone treatment could worsen anemia.
In summary, iron deficiency in mice is associated with ineffective erythropoiesis likely due to erythropoietin resistance. Testosterone treatment of iron-deficient mice worsens anemia by stimulating the expansion of erythropoietic progenitors and ineffective erythropoiesis (Figure 7).
Testosterone stimulates iron-dependent erythropoiesis and suppresses hepcidin. To clarify the role of iron in mediating testosterone's effects on erythropoiesis, we induced iron deficiency in mice by feeding a low iron diet. Iron-replete and iron-deficient mice were treated weekly with testosterone propionate or vehicle for 3 weeks. Testosterone treatment increased red cell count in iron-replete mice, but, surprisingly, testosterone reduced red cell count in iron-deficient mice. Splenic stress erythropoiesis was stimulated in iron-deficient mice relative to iron-replete mice, and further increased by testosterone treatment, as indicated by the increase in red pulp area, the number of nucleated erythroblasts, and expression levels of TfR1, GATA1, and other erythroid genes. Testosterone treatment of iron-deficient mice increased the ratio of early-to-late erythroblasts in the spleen and bone marrow, and serum LDH level, consistent with ineffective erythropoiesis. In iron-deficient mice, erythropoietin levels were higher but erythropoietin-regulated genes were generally downregulated relative to iron-replete mice, suggesting erythropoietin resistance.
Conclusion: Testosterone treatment stimulates splenic stress erythropoiesis in iron-replete as well as iron-deficient mice. However, testosterone worsens anemia in iron-deficient mice because of ineffective erythropoiesis possibly due to erythropoietin resistance associated with iron deficiency. Iron plays an important role in mediating testosterone's effects on erythropoiesis.
4 | DISCUSSION
The findings of the present study offer insight into the role of iron in erythropoiesis and in mediating the mechanisms by which testosterone stimulates erythropoiesis. Our findings indicate that iron availability plays an essential role in mediating the erythropoietic response to testosterone and that testosterone treatment of iron-deficient mice worsens anemia. Testosterone administration of iron-deficient mice was associated with a marked stimulation of stress erythropoiesis in the spleen, as indicated by an increase in spleen size, red pulp area, and the number of erythroblasts in the spleen, as well as increased expression of GATA1, TfR1, and other markers of erythropoiesis. Multiple observations provide evidence that the anemia in iron-deficient mice was worsened by testosterone treatment because of ineffective erythropoiesis. First, there was a substantial expansion of early erythroid progenitors in response to testosterone treatment of iron-deficient mice, as indicated by increased numbers of early erythroblasts as well as increased expression of GATA1, TfR1, and other erythroid genes. Second, there was a maturation block at the polychromatophilic stage, as indicated by a substantially increased ratio of proerythroblasts plus polychromatophilic erythroblasts to orthochromatic erythroblasts in iron-deficient mice treated with testosterone. Finally, there was a loss of erythroid precursors as indicated by fewer late erythroblasts, worsened anemia in spite of evidence of markedly stimulated stress erythropoiesis in the spleen, and increased LDH levels.
Our findings are consistent with a growing body of preclinical as well as clinical studies that suggest that testosterone administration increases hemoglobin and hematocrit by stimulating iron-dependent erythropoiesis. Testosterone suppresses hepcidin transcription in men as well as in mice, upregulates ferroportin, and increases iron availability for erythropoiesis. However, testosterone administration to hepcidin knock out mice is also associated with increases in hemoglobin and hematocrit. Thus, although hepcidin suppression by testosterone increases iron availability for erythropoiesis, hepcidin suppression is not essential for mediating testosterone's effects on erythropoiesis in iron-replete healthy mice. The present study shows that testosterone stimulates erythropoiesis leading to an expansion of early erythropoietic progenitors. In a state of iron deficiency, the expansion of the erythropoietic progenitor pool by testosterone administration is associated with ineffective erythropoiesis, possibly due to a state of erythropoietin resistance induced by iron deficiency. Thus, iron availability, but not hepcidin, is essential for mediating testosterone's effects on erythropoiesis.
Although randomized trials of the effect of testosterone in men with iron deficiency anemia have not been conducted two clinical case reports in humans support our findings. In one open-label trial of 24 patients with advanced breast cancer, who were treated with androgens, four patients had low serum iron at baseline; androgen treatment further decreased serum iron and the expected increase in hemoglobin and hematocrit did not occur in response to androgen administration. Testosterone administration to one female patient with iron deficiency in this case report further decreased serum iron from 30 to 22 ug/dL and hemoglobin from 13.2 to 11.9 gm/dL; the anemia was reversed after testosterone administration was discontinued and iron supplementation was provided. In a second case, the administration of testosterone to an iron-deficient male patient decreased serum iron from 10.8 to 6.0 ug/dL and hemoglobin from 7.5 to 6.0 g/dL (Gardner and Pringle). These case reports support our observations that in an iron-deficient state, testosterone treatment worsens anemia.
These findings have clinical implications. Although testosterone treatment can correct unexplained anemia of aging and anemia of inflammation, it is important to evaluate the cause of anemia and rule out iron deficiency, before starting testosterone treatment because, in these states, testosterone treatment could worsen anemia.
In summary, iron deficiency in mice is associated with ineffective erythropoiesis likely due to erythropoietin resistance. Testosterone treatment of iron-deficient mice worsens anemia by stimulating the expansion of erythropoietic progenitors and ineffective erythropoiesis (Figure 7).
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