Context: Testosterone treatment of hypogonadal men improves their hemoglobin, but the mechanism is not understood.
Objective: To investigate possible mechanisms by which testosterone stimulates erythropoiesis in hypogonadal older men with unexplained or iron-deficiency anemia.
Design: The Anemia Trial of The Testosterone Trials, a placebo-controlled study in older, hypogonadal men.
Setting: Twelve academic medical centers.
Participants: A total of 95 hypogonadal men (testosterone < 275 ng/mL) ≥65 years with anemia (hemoglobin < 12.7 g/dL). They were classified as having unexplained (n = 58) or iron deficiency anemia (n = 37).
Intervention: Testosterone or placebo gel for 1 year.
Main outcome measures: Markers of iron metabolism during the first 3 months of treatment.
Results: Testosterone replacement significantly (P < 0.001) increased hemoglobin in the 58 men who had unexplained anemia (adjusted mean difference 0.58 g/dL; 95% confidence interval, 0.31-0.85). Testosterone replacement tended to increase hemoglobin in the 37 men who had iron deficiency (0.38 g/dL; -0.19, 0.95), but the response was more variable and not statistically significant (P = 0.19). In men with unexplained anemia, testosterone replacement suppressed hepcidin (-8.2 ng/mL; -13.7, -2.7; P = 0.004) and ferritin (-19.6 µg/L; -32.8, -6.3; P = 0.004), but in men with iron deficiency, testosterone replacement did not. The decrease in hepcidin was moderately correlated with the increase in hemoglobin in the men with unexplained anemia (correlation coefficient -0.35, P = 0.01) but not in those with iron deficiency anemia (correlation coefficient -0.07, P = 0.73).
Conclusions: Testosterone replacement of older hypogonadal men with unexplained anemia stimulates erythropoiesis associated with increased iron mobilization. This effect appears to be attenuated by iron deficiency.
Trial registration: ClinicalTrials.gov NCT00799617.
Keywords: anemia; erythropoiesis; hepcidin; hypogonadism; iron; testosterone.
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