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

J Clin Endocrinol Metab. 2020 Nov 1;105(11):3396-3403. doi: 10.1210/clinem/dgaa521.


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: NCT00799617.

Keywords: anemia; erythropoiesis; hepcidin; hypogonadism; iron; testosterone.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Anemia, Iron-Deficiency / blood
  • Anemia, Iron-Deficiency / drug therapy*
  • Erythropoiesis / drug effects*
  • Hemoglobins / analysis*
  • Hormone Replacement Therapy
  • Humans
  • Hypogonadism / blood
  • Hypogonadism / drug therapy*
  • Male
  • Testosterone / administration & dosage
  • Testosterone / therapeutic use*
  • Treatment Outcome


  • Hemoglobins
  • Testosterone

Associated data