Increased Hematocrit Linked to Reduced Death in Men Receiving Testosterone Therapy
Real-world evidence studies have shown that men with hypogonadism who receive long-term treatment with testosterone undecanoate injection for up to 12 years have a significant reduction in mortality.1-3 Yet, testosterone therapy increases hematocrit, which theoretically could increase risk of fatal cardiovascular events.4
Here we summarise the results of a study that aimed to specifically examine the relationship between hematocrit and all-cause mortality in men receiving long-term treatment with testosterone undecanoate injection.5,6
What is known about testosterone, hematocrit and mortality
The link between elevated hematocrit and cardiovascular disease (especially venous thromboembolism) is uncertain.4,7 While some population studies suggest that high hematocrit is associated with increased risk of venous thromboembolism,8 cardiovascular disease and all-cause mortality,9 this can be explained by the presence of other medical conditions that cause both a high hematocrit and venous thrombosis or cardiovascular disease.7 For example, in the Scottish Heart Health Extended Cohort Study, hematocrit was significantly associated with cardiovascular disease events and mortality, however after adjusting for lipids, blood pressure, type 2 diabetes, smoking status, family history of cardiovascular disease and fibrinogen, the association disappeared.10
There is a paucity of data on the ratio between hemoglobin and hematocrit. In most individuals, hematocrit (expressed as a percentage) is about 3 times the hemoglobin value (expressed in g/dL).
Changes in hemoglobin, hematocrit and the hemoglobin/hematocrit ratio during testosterone therapy, and how these changes are associated with various outcomes, such as mortality, requires further understanding.
What this study adds
To gain a better understanding of the clinical impact of increased hematocrit during testosterone therapy in men with hypogonadism, the present study investigated the relationship between baseline hematocrit, change in hematocrit over time, and all-cause mortality in 737 men who had been diagnosed with functional hypogonadism (serum total testosterone ≤12.1 nmol/L and symptoms of testosterone deficiency).
Testosterone therapy with testosterone undecanoate injection was started in 353 men, whereas the remaining 384 men who declined testosterone therapy served as a control group. Change in hematocrit, hemoglobin and hematocrit/hemoglobin ratio after 12, 48, 72, and 96 months of treatment with testosterone undecanoate injection was analysed, as well as mortality.
As expected, results showed that hematocrit significantly increased (+4% at month 96) in men receiving testosterone therapy, with most of the increase occurring during the first 48 months, as illustrated in figure 1. At final assessment (month 96) mean hematocrit was 49% (range 47-51%). No subject had hematocrit above 52%. There was no change in hematocrit in men not receiving testosterone therapy.
Figure 1: Change in hematocrit at 12, 48, 72 and 96 months in men receiving testosterone therapy vs. untreated men.5
From Strange RC, König CS, Ahmed A, et al. Testosterone Therapy: Increase in Hematocrit is Associated with Decreased Mortality. Androgens: Clinical Research and Therapeutics. 2021/12/01 2021;2(1):150-159.
HCT, hematocrit; TTh, testosterone therapy
TTh group = 353 men
Untreated group: 384 men
Among men receiving testosterone therapy, a surprising finding was that those who died during the follow-up had significantly (p=0.021) lower hematocrit than men who survived, and baseline hematocrit and change in hematocrit were inversely associated with mortality, even after adjustment for age. Men with final hematocrit above 49% up to 52% suffered lower mortality than men with hematocrit 46-49%. The higher the baseline hematocrit and the greater the increase in hematocrit during testosterone therapy (up to 52%), the lower the risk of mortality. Results were the same when the group of testosterone-treated men was stratified by type 2 diabetes prevalence. This suggests that the mortality risk reduction occurs even at relatively higher hematocrit levels up to 52%.
Interestingly, the hematocrit/hemoglobin ratio increased significantly at all time points (p < 0.0001) compared to baseline), possibly due to increased red blood cell life span, as suggested by the investigators of the T4DM study.
The present study showed that increased hematocrit (up to 52% at final assessment) was independently associated with reduced mortality.5 This confirms the current clinical guideline recommendation of using 54% as a threshold for change in management of men receiving testosterone therapy (e.g. dose reduction or therapeutic phlebotomy).11-15 It should be kept in mind that dehydration can cause a temporary elevation in hematocrit,16 and therefore a high hematocrit reading should be confirmed in a second blood test, ensuring the patient is in a well hydrated state, before action is taken.
The finding that the hematocrit elevation stabilized at month 48 is reassuring.5 This is congruent with results from another long-term real-world evidence study, in which treatment with testosterone undecanoate injection for 10 years increased hematocrit by 3.6%.3
Meta-analyses of randomized controlled trials which showed that despite a higher incidence of elevated hematocrit in men receiving testosterone therapy compared to placebo, no difference in clinical adverse events were reported.17,18 The present study provides reassurance regarding the safety of testosterone therapy, and suggests that long-term treatment with testosterone undecanoate injection can reduce mortality even in the context of relatively high hematocrit levels. Support for this comes from other long-term real-world evidence studies showing that despite increases in hematocrit, there was no increased risk for venous thromboembolism, myocardial infarction, stroke, or mortality.2,19
A possible reason for the lack of adverse effects of testosterone-induced elevation of hematocrit in men receiving testosterone therapy could be that the association between testosterone therapy and increased hemoglobin and hematocrit may be mediated by other mechanisms besides erythropoiesis. For example, it has been shown that testosterone therapy may increase red blood cell lifespan.20 In healthy subjects, there is a loss of 20% of erythrocyte hemoglobin, a phenomenon that increases during the second half of red blood cell life span.21,22 In the context of increased red blood cell life span, the loss of hemoglobin would increase, which in turn would increase the hematocrit/hemoglobin ratio. This could impact not only the accuracy of HbA1c - for more information see our report of the T4DM study23 - but possibly also the link between hematocrit and adverse outcomes. For example, the increased red blood cell lifespan during testosterone therapy may occur as a result of beneficial testosterone-induced modification of the composition and fluidity of red blood cell membranes, contributing to improvement in blood rheology and possibly reduced thrombosis risk.24 If this is the case, an increased hematocrit/hemoglobin ratio could be a marker for beneficial outcomes in the context of hematocrit elevation during testosterone therapy.
In contrast to the present study, where no subject receiving treatment with testosterone undecanoate injection experienced hematocrit above 52%, in the T4DM study23 22% of subjects (106 men) in the testosterone group had at least one reading of hematocrit ≥54%, compared to 1% (6 men) in the placebo group. A possible explanation for this is that the T4DM study was conducted in Australia, where the prevalence of dehydration due to hot weather is relatively common, which may have contributed to rising hematocrit to ≥54%. In contrast, the registry study was conducted in Germany, where dehydration prevalence due to hot weather is likely non-existent. Another possible explanation is that blood testing for measurement of hematocrit was done at different time points between injections.
More studies, both randomized controlled trials and real-world evidence studies, are needed to further investigate the association between hematocrit and mortality, and whether testosterone-induced hematocrit elevation is a cause of concern or just an innocent bystander.7
For related research, see:
Hematocrit elevation following testosterone therapy – does it increase risk of blood clots?