Effect of Different Testosterone Preparations on Blood Thickness

December 2021

Testosterone treatment effectively stimulates production of red blood cells, 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, medical guidelines recommend monitoring and avoidance of excessive elevations in hemoglobin and hematocrit (≥54%) in men who are receiving testosterone treatment.^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 treatment with long-acting testosterone undecanoate injection causes less elevation in hematocrit than other commonly used preparations, such as gels and short-acting testosterone injections.
Testosterone undecanoate injection is a long-acting preparation that is ideal for long-term testosterone treatment 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

Increased production of red blood cells and elevated levels of hemoglobin and hematocrit is a natural response to testosterone treatment. In most men, the elevation stays within the normal range. It is when levels rise too high that concern may arise. Excess red blood cells thicken the blood and slow down blood flow, which may cause serious problems, such as blood clots and ensuing complications.

The threshold used to define what is too high varies, but levels of hemoglobin higher than 17.5 g/dL and hematocrit above 54% are commonly deemed to be too high.⁹^,¹⁰

The most concerning risk associated with increased hematocrit is blood clots.¹¹^-¹⁴

It is well documented that patients with thrombocythemia (a disease in which the bone marrow produces too many platelets) and polycythemia vera (a type of blood cancer that causes the bone marrow to produce too many red blood cells), in whom elevated hematocrit is a hallmark, have a greatly increased risk of blood clots.¹³ However, there is no direct evidence that the increased hematocrit observed with testosterone treatment carries the same risk.¹^,¹⁴^,¹⁵

The increase in hematocrit observed with testosterone treatment is dose-dependent,¹⁶^,¹⁷ and more pronounced in older men (60-75 years old) than in young men (19-35 years old).¹⁷ Additionally, different testosterone preparations (short-acting testosterone injections, long-acting testosterone injections, testosterone gel, testosterone capsule etc.) affect the magnitude of the hematocrit elevation to varying degrees.¹^,¹⁸

A review of studies that reported elevations in hematocrit after testosterone treatment 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.¹⁶ For more information, see “Hematocrit elevation following testosterone therapy – does it increase risk of blood clots?”

As of this writing, no large studies 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 groups against one another across several studies.¹⁹

What this study adds

The present study was a network meta-analysis of studies 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 studies (including a total of 3,393 men) met inclusion criteria for analysis of mean hematocrit change after testosterone treatment. Data for the following testosterone preparations were analysed: 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 increased 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 treatment with different testosterone preparations.⁸

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, 16, 18} For patients who are at increased risk of venous thromboembolism, such as older men, and 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

It is important to know that the commonly used threshold for defining what constitutes excessive elevation in hematocrit (≥54%)^3-7 was arbitrarily set based on population distribution, not on physiological outcomes.²⁰ Hence, the implications of a hematocrit >54% in men without thrombophilia or a history of venous thromboembolism, is unknown. Although there is no doubt that testosterone increases production of red blood cells and elevates levels of hemoglobin and hematocrit,¹ the link between testosterone-induced hematocrit elevation and subsequent risk of blood clots remains doubtful.

Support for this comes from meta-analyses of many studies, which showed that despite a higher incidence of elevated hematocrit in men receiving testosterone treatment compared to placebo, no difference in adverse events were reported.^{9, 21} 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, and is linked to reduced propensity of the blood to form blood clots.^{22, 23}

Nevertheless, due to current lack of scientific data on a possible link between testosterone-induced hematocrit elevation and blood clots, it is prudent to follow clinical guideline recommendations. During testosterone treatment, if hematocrit rises to ≥54%, blood donation is recommended, as it effectively reduces hematocrit.³ Aspirin may also be useful for prevention of blood clots.^{20, 24, 25}

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 treatment, 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.^{26, 27}

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