Is the hematopoietic effect of testosterone mediated by erythropoietin? the results of a clinical trial in older men.

The prevalence of anaemia is higher in older individuals where it has been recognized as an independent predictor of disability and mortality (1-2). Anaemia is often multifactorial (1). One of the causes of anemia is the decline of testosterone levels in both sexes (1). In older subjects low testosterone levels are predictors of anemia (3), which is consistent with the known stimulatory effect of testosterone on erythropoiesis (4). However, there are several mechanisms underlying the erythropoietic effect of testosterone (4). One of the most common has been considered the stimulating effect on erythropoietin levels (5). However this ‘‘dogma’’ has not been confirmed in more recent studies using injectable testosterone (6). Aim of the Study: To test the effects of transdermal testosterone on haemoglobin and erythropoietin levels in older men with low-normal levels of testosterone. Methods: 108 men[65 years old were selected according to serum testosterone concentration C 1 SD below the mean for normal young men (\475 ng/dL) and randomized to receive a testosterone patch or placebo in a double blind fashion for 36 months. Ninety-six subjects completed 36 months of treatment. The present analysis was performed on 70 men, 42 in the testosterone treatment group and 28 in placebo group who had sufficient sera remaining for assays of testosterone, haemoglobin, erythropoietin, and creatinine. Total testosterone was assessed by electrochemiluminescence immunoassay with minimum detective concentration (MDC) of 2 ng/dl and interassay coefficients of variation (CV) less than 10%. Erythropoietin was assessed by ELISA with MDC of 2.5 mIU/ml and interassay CV less than 10%. Changes within groups from baseline to treatment end were evaluated with paired t tests. Finally the association between treatment and change of haemoglobin and erythropoietin over time was examined with random coefficient analyses. Treatment status and time point (T0-T1) were entered as fixed factors; subjects were treated as a random factor and a random intercept was estimated. To test whether the changes in hemiglobin and erythropoietin levels were different according to testosterone levels at treatment-by-T1 an interaction term was entered in the same models. Results: The mean age ± SD of the 70 subjects population at baseline was 71.8 ± 4.9 years. The testosterone and placebo groups did not differ at baseline in terms of age, haemoglobin, and erythropoietin. The testosterone-treated group had lower baseline testosterone and BMI than the placebo group but neither was quite statistically significant (p = 0.06 and p = 0.16, respectively). As expected,36 months testosterone treatment was associated with an increase in testosterone levels (from 488.20 ± 230.53 to 689.41 ± 307.26) that was statistically significant (p = 0.0003). The delta change in testosterone levels was 201.21 and 22.73 in testosterone and placebo group, respectively. Testosterone therapy for 36 months induced an increase in haemoglobin levels of about 1 g/dL (from 14.72 ± 1.02 to 15,53 ± 1.36).The delta change in haemoglobin levels was 0.81 and - 0.06 in testosterone and placebo group, respectively. During the treatment period, participants on testosterone therapy, as compared to those on placebo, had a steeper increase of haemoglobin levels (Treatment-by-T1: b ± SE 0.86 ± 0.31, p = 0.01). Testosterone therapy for 36 months did not induce any significant increase in EPO levels (from 15.24 ± 19.32 to 15.40 ± 17.47). No significant change was also found in placebo group. The change in EPO levels during treatment did not differ between subjects on testosterone and those on placebo. The difference between 2 groups was not statistically significant (Treatment-by-T1: beta ± SE = -0.24 ± 2.16, p = 0.91). Conclusion: Transdermal testosterone treatment for 36 months in older men significantly increased haemoglobin but not erythropoietin levels. Other mechanisms should be explored to explain the hematopoietic effect of testosterone.