Markers of Iron Flux during Testosterone-Mediated Erythropoiesis in Older Men with Unexplained or Iron-Deficiency Anemia

Abstract

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.

© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

The effect of treatment with testosterone or placebo on hemoglobin in men in The Testosterone Trials who had unexplained anemia (top) or iron deficiency anemia (bottom). The values are means and 95% confidence intervals. P values are based on adjusted mean differences.

Figure 2.

The effect of treatment with testosterone or placebo in men who had unexplained anemia or iron deficiency anemia on hepcidin, ferritin, transferrin, and soluble transferrin receptor. Values are means and 95% confidence intervals. P values are based on adjusted mean differences.

Figure 3.

Correlation of the change in hemoglobin with the change in hepcidin during testosterone treatment of older hypogonadal men with unexplained anemia (top panel) and with iron deficiency anemia (bottom panel).