Hematocrit elevation with testosterone undecanoate injection vs. testosterone gel

June 2022

The most common side effect of testosterone therapy is elevated hematocrit. In a previous article “Effect of Different Testosterone Preparations on Hematocrit” we summarized the results of a meta-analysis of randomized trials that compared differences in elevations in hematocrit between testosterone preparations that are commonly used for the treatment of hypogonadism.1

Here we present results from a study that aimed to compare hematocrit changes with long-acting intramuscular testosterone undecanoate vs. transdermal gel, in a real-life registry of patients with hypogonadism.2

Key Points

  • Testosterone therapy is associated with a dose-dependent increase in hematocrit.
  • Treatment with testosterone undecanoate injection results in greater elevation of, and higher testosterone levels, compared to testosterone gel.
  • Anemia can be treated more effectively with testosterone undecanoate injection than with testosterone gel.

What is known about testosterone, red blood cell production and hematocrit

A well-documented effect of testosterone therapy is increased red blood cell production and hematocrit. While commonly considered a “side effect”, in fact this is not always bad. For example, testosterone therapy can effectively treat anemia, including unexplained anemia, for which there currently is no treatment, in older men.3

Considering the relatively high prevalence of anemia in patients age ≥60 years at 17%, of which 28% is unexplained anemia,4 a large number of older men benefit from testosterone-induced elevation in red blood cell production and hematocrit.

Furthermore, regardless of presence/absence of anemia, there is no direct evidence for the claim that testosterone-induced hematocrit elevation significantly increases risk of adverse cardiovascular events, as explained below.

 

What this study adds

In a prospective two-arm open registry of 802 men with hypogonadism (median age 40 years), 304 patients received treatment with testosterone undecanoate injection, while 498 patients received testosterone gel.

All venous blood samples were obtained between 08:00 and 12:00 am in the morning. Patients using transdermal gel had to apply testosterone gel 2-4 hours before blood sampling. In patients receiving testosterone undecanoate injections, blood sampling was done prior to the last injection. Follow-up visits after initiation of treatment occurred between treatment week 26-30.

Testosterone levels increased significantly in both testosterone groups, however, treatment with testosterone undecanoate injections resulted in higher testosterone levels.

Increased hematocrit (>50%) was more common among men receiving testosterone undecanoate injection (23%) vs. testosterone gel (5%). Corresponding results were seen for higher values of hematocrit >52% and >54% (9% vs 3% and 2% vs <1%).

Advanced age, higher waist circumference, higher pre-post treatment difference in testosterone, and functional vs classical hypogonadism were associated with higher hematocrit elevations. Attenuated androgen action (longer androgen receptor CAG repeats) was associated with a smaller hematocrit elevation.

Treatment with testosterone undecanoate injections more effectively reduced the prevalence of anemia (hemoglobin ≤12.7 g/dL) than testosterone gel.

 

Commentary

The main finding in the study was that treatment with testosterone gel was associated with a reduced risk of development of high hematocrit >50%, compared to treatment with testosterone undecanoate injection. At face value, this appears to contradict the findings from a previous meta-analysis of randomized controlled trials, which we previously summarized “Effect of Different Testosterone Preparations on Hematocrit”. However, the finding in the present study that testosterone undecanoate injection was associated with a greater elevation in hematocrit than testosterone gel is likely because a higher testosterone level was achieved with testosterone undecanoate injection.

In the present study, at the end of follow-up, the testosterone undecanoate group had 3.3 nmol/L higher testosterone levels than the testosterone gel group. Due to the timing of blood sampling – in the testosterone undecanoate group trough testosterone levels were measured, while in the gel group peak testosterone levels (2 - 4 hours after application of the gel), it is highly likely that the true difference in final testosterone levels was much larger. Support for this comes from a pharmacokinetic study, which showed that 180 days (about 26 weeks) after start of treatment with testosterone gel, testosterone levels peak 2 - 3 hours after application.5 Considering that testosterone has a dose-dependent stimulatory effect on erythropoiesis and hematocrit,6 the finding that the group of men achieving larger elevation in testosterone levels also had a larger elevation in hematocrit, is not surprising.

In cases where there is concern about hematocrit elevation, it is reassuring that high hematocrit in the absence of co-morbidity or acute cardiovascular disease or blood clots, can be managed relatively easy by regular venesection (500 mL), with usually no need to stop the testosterone therapy.7 Reduction in testosterone dose, or in the case of testosterone undecanoate, prolongation of injection intervals 8 (for example from every 12 weeks to every 15 weeks) is another management option.

 

While excessively high hematocrit of >54% theoretically could increase risk for blood clots (venous thromboembolism), the European Association of Urology (EAU) notes that there is no direct evidence that an increase of hematocrit up to and including 54% causes any adverse effects in men without blood clotting disorders.7 If hematocrit exceeds 54% there is a testosterone independent, but weak associated rise in cardiovascular events and mortality.7 For more information about testosterone therapy, hematocrit elevation and risk of blood clots, see “Hematocrit elevation following testosterone therapy – does it increase risk of blood clots?

 

It is important to point out that for men with anemia, especially unexplained anemia, increased red blood cell production and hematocrit elevation with testosterone therapy, is a beneficial effect. Unequivocal evidence for this comes from the Testosterone Trials, which showed that in older men with low testosterone levels, testosterone treatment significantly increased hemoglobin levels of those with unexplained anemia, as well as those with anemia from known causes.3 In fact, this finding led to the recommendation that measurement of testosterone levels might be considered in men 65 years or older who have unexplained anemia and symptoms of low testosterone levels.3 In accordance with this, the present study showed that testosterone undecanoate injection more effectively treated anemia than testosterone gel.2 Further support comes from a real-life evidence study conducted in patients receiving medical care at an urology practice, which showed that treatment with testosterone undecanoate injection effectively reduced the prevalence of anemia.9 For more information about this study, see “Could testosterone therapy in hypogonadal men ameliorate anemia, a cardiovascular risk factor?

 

In addition to being an effective treatment of anemia, a recent study showed that in men receiving long term treatment with testosterone undecanoate injection, high hematocrit up to 52% was associated with reduced all-cause mortality. For more information, see “Increased Hematocrit Linked to Reduced Death in Men Receiving Testosterone Therapy

 

An analysis of erythrocyte membrane composition in men after testosterone therapy showed beneficial changes in composition and fluidity of erythrocyte membranes, which could improve blood rheology and reduce thrombosis risk.10 It is possible that this contributes, at least partly, to the lack of direct association between testosterone therapy-induced hematocrit elevation and adverse cardiovascular events.

References

  • 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. Return to content
  • Zitzmann M, Cremers JF, Krallmann C, Kliesch S. The HEAT-Registry (HEmatopoietic Affection by Testosterone): comparison of a transdermal gel vs long-acting intramuscular testosterone undecanoate in hypogonadal men. The aging male : the official journal of the International Society for the Study of the Aging Male. Dec 2022;25(1):134-144. Return to content
  • Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial. JAMA internal medicine. Apr 1 2017;177(4):480-490. Return to content
  • Michalak SS, Rupa-Matysek J, Hus I, Gil L. Unexplained anemia in the elderly - a real life analysis of 981 patients. Archives of medical science : AMS. 2020;16(4):834-841. Return to content
  • Swerdloff RS, Wang C, Cunningham G, et al. Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J Clin Endocrinol Metab. Dec 2000;85(12):4500-10. Return to content
  • Coviello AD, Kaplan B, Lakshman KM, Chen T, Singh AB, Bhasin S. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab. Mar 2008;93(3):914-9. Return to content
  • Salonia A, Bettocchi C, Carvalho J, et al. EAU Guidelines on Sexual and Reproductive Health (available at https://d56bochluxqnz.cloudfront.net/documents/full-guideline/EAU-Guidelines-on- Sexual-and-Reproductive-Health-2022_2022-03-29-084141_megw.pdf accessed May 29, 2022). Return to content
  • Abildgaard J, Petersen JH, Bang AK, et al. Long-term testosterone undecanoate treatment in the elderly testosterone deficient male: An observational cohort study. Andrology. Feb 2022;10(2):322-332. Return to content
  • Zhang LT, Shin YS, Kim JY, Park JK. Could Testosterone Replacement Therapy in Hypogonadal Men Ameliorate Anemia, a Cardiovascular Risk Factor? An Observational, 54-Week Cumulative Registry Study. J Urol. Apr 2016;195(4 Pt 1):1057-64. Return to content
  • Angelova P, Momchilova A, Petkova D, Staneva G, Pankov R, Kamenov Z. Testosterone replacement therapy improves erythrocyte membrane lipid composition in hypogonadal men. The aging male : the official journal of the International Society for the Study of the Aging Male. Sep 2012;15(3):173-9. Return to content