Effect of Different Testosterone Preparations on Hematocrit

December 2021

Testosterone therapy effectively stimulates production of red blood cells (erythropoiesis), which in turn may lead to elevated levels of hemoglobin and hematocrit.1 This is a sought after effect when treating anemia, including unexplained anemia.2 However, as a safety measure, clinical guidelines recommend monitoring and avoidance of excessive elevations in hemoglobin and hematocrit (≥54%) - also known as secondary erythrocytosis - in men who are receiving testosterone therapy.3-7

Here we summarise the results of a study that analysed differences in elevations in hematocrit between testosterone preparations that are commonly used for the treatment of hypogonadism.8

KEY POINTS

  • Testosterone therapy with testosterone undecanoate injection causes less elevation in hematocrit than other commonly used preparations, such as gels and testosterone enanthate/cypionate injections.
  • Testosterone undecanoate injection is a long-acting preparation that is ideal for long-term testosterone therapy from both a practical (only requiring 4 injections per year) and safety perspective, causing the smallest hematocrit elevation.

What is known about testosterone and hematocrit

Erythrocytosis is the presence of too many red blood cells.9 Several different parameters are used to diagnose erythrocytosis in a blood sample; number of red blood cells, hemoglobin concentration and hematocrit.9 Testosterone-induced elevation in hemoglobin and hematocrit may lead to erythrocytosis, generally defined clinically as hemoglobin > 17.5 g/dL or hematocrit > 54% in males,10 although this definition varies.11

The most concerning risks associated with increased hematocrit are venous thromboembolism and major adverse cardiovascular events.12-15 It is well documented that patients with essential thrombocythemia and polycythemia vera, in whom elevated hematocrit is a hallmark, have significantly increased risk of thrombosis and cardiovascular events.14 However, there is no direct evidence that the increased hematocrit observed with testosterone therapy carries the same risk.1,15,16

The increase in hematocrit observed with testosterone therapy is dose-dependent,17,18 and more pronounced in older men (60-75 years old) than in young men (19-35 years old).18 Additionally, different testosterone preparations (short-acting testosterone injections, long-acting testosterone injections, gel, capsule etc.) have varying pharmacokinetics, which in turn affects the magnitude of the hematocrit elevation to varying degrees.1,19 A review of studies that reported elevations in hematocrit after testosterone therapy with different testosterone preparations pointed out that compared to other commonly available testosterone preparations, long-acting testosterone undecanoate injection has a significantly lower risk of causing excessive elevation in hematocrit.17 For more information, see “Hematocrit elevation following testosterone therapy – does it increase risk of blood clots?

As of this writing, no large randomized controlled trials have compared the effects of different testosterone preparations head-to-head. Therefore, to evaluate testosterone preparations against one another, network meta-analysis is used, which is a statistical technique for comparing the effects of multiple treatment arms against one another across several studies.20

What this study adds

The present study was a network meta-analysis of randomized controlled trials that compared various testosterone preparations - gel, patch, oral testosterone undecanoate, testosterone undecanoate injection and testosterone enanthate/cypionate injection - against placebo and one another. The aim of the study was to quantify and compare the magnitude of increase in hematocrit between the different testosterone preparations.

A total of 29 placebo-controlled randomized trials (including a total of 3,393 men) met inclusion criteria for analysis of mean hematocrit change after testosterone therapy. Randomized controlled trial data for the following formulations of testosterone were pooled via network meta-analysis: gel, patch, oral testosterone undecanoate, long-acting testosterone injection (intramuscular testosterone undecanoate) and short-acting testosterone injection (intramuscular testosterone enanthate and cypionate).

Results showed that all types of testosterone preparations significantly increased mean hematocrit levels compared to placebo, however, the magnitude of the increase was different for each testosterone preparation, as illustrated in the figure.

Figure: Elevation in hematocrit during testosterone therapy with different testosterone preparations.8

Elevation in hematocrit during testosterone therapy with different testosterone preparations.

T = testosterone

From Nackeeran S, Kohn T, Gonzalez D, White J, Ory J, Ramasamy R. The Effect of Route of Testosterone on Changes in Hematocrit: A Systematic Review and Bayesian Network Meta-Analysis of Randomized Trials. J Urol. Jan 2022;207(1):44-51

Commentary

This study is the first network meta-analysis to investigate the effect of different testosterone preparations on hematocrit in men with hypogonadism.8 It shows that while all types of testosterone preparations should be expected to increase hematocrit to some degree, the risk of excessive elevation in hematocrit is highest for oral testosterone undecanoate (capsules) and short-acting testosterone injections.

This is consistent with previous studies showing that short-acting injectable testosterone is associated with greater risk of erythrocytosis compared with other formulations.1,17,19 For patients who are at increased risk of venous thromboembolism, such as those with thrombophilia (familial or acquired) or a history of venous thromboembolism, it is prudent to choose a testosterone preparation that has the smallest impact on hematocrit.1

To identify patients who are at increased risk of venous thromboembolism, screening has been recommended, by measuring Factor V Leiden and Prothrombin mutations, Factors VIII and XI.21,22 This will allow for a more accurate stratification of risk in susceptible patients.23

It is important to know that the commonly used threshold for defining what constitutes excessive elevation in hematocrit (≥54%)3-7 was arbitrary set based on population distribution, not on physiological outcomes.24 Hence, the clinical significance of a hematocrit > 54% in men without thrombophilia or a history of venous thromboembolism, is unknown. Although there is no doubt about the erythrogenic effect of androgens that leads to an increase in levels of hemoglobin and hematocrit,1 the association between testosterone-induced erythrocytosis and subsequent risk of venous thromboembolism remains doubtful.

Support for this comes from 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.10,25 The lack of increase in cardiovascular events with elevated hematocrit may be due to the fact that testosterone acts as a vasodilator and has anti-atherosclerotic effects.26,27 Importantly, higher testosterone levels have been associated with higher levels of tissue plasminogen activator (a protein involved in the breakdown of blood clots) and lower levels of several pro-thrombotic mediators, such as fibrinogen, clotting factor VII and plasminogen activator inhibitor-1. It is hoped that the currently ongoing TRAVERSE (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men) study, a randomised double-blind placebo-controlled trial of testosterone therapy in 6000 men that aims to investigate the effect of testosterone therapy on major adverse cardiovascular events in men with testosterone deficiency will provide more clarity on the speculated association between testosterone-induced hematocrit elevation and venous thromboembolism. The results from this study are forthcoming (ClinicalTrials.gov Identifier: NCT03518034, available at https://clinicaltrials.gov/ct2/show/NCT03518034 )

Nevertheless, due to current lack of scientific data from randomized controlled trials on the link between testosterone-induced hematocrit elevation and cardiovascular outcomes, it is prudent to follow clinical guideline recommendations. During testosterone therapy, if hematocrit rises to ≥54%, starting regular therapeutic phlebotomy is recommended.3 Aspirin may also be useful for prevention of venous thromboembolism.24,28,29

In the present study, testosterone undecanoate injection and testosterone patch had the lowest risk of causing excessive hematocrit elevation (≥54%). However, because patch commonly causes skin irritation, it is not a good option for long-term testosterone therapy, which most men with hypogonadism need. In contrast, testosterone undecanoate injection, which only needs administration every 3 months (after an initial loading interval of 6 weeks), has high long-term adherence and is commonly preferred among patients.30,31 For more information, see:

Testosterone replacement therapy with Nebido shows superior long-term adherence compared to gels and short-acting testosterone injectables. For more information, see:

Hypogonadism treatment with testosterone undecanoate injection has best long-term adherence https://www.nebido.com/hcp/research-news/hypogonadism-treatment-with-testosterone-undecanoate-injection-has-best-long-term-adherence

Testosterone replacement therapy with Nebido shows superior long-term adherence compared to gels and short-acting testosterone injectables https://www.nebido.com/hcp/research-news/testosterone-undecanoate-injection-treatment-superior-long-term-adherence-compared-to-gels-and-short-acting-testosterone-injections

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