Managing Elevated Hematocrit in Testosterone Therapy: Risks, Studies, and Guidelines

Introduction

Testosterone replacement therapy (TRT) has become a common treatment for men with hypogonadism, aiming to restore normal testosterone levels and alleviate associated symptoms. However, one of the notable side effects of TRT is an increase in hematocrit levels, which can elevate the risk of cardiovascular events. Understanding the implications of elevated hematocrit and implementing appropriate management strategies are crucial for patient safety.

Understanding Hematocrit and Its Significance

Hematocrit refers to the percentage of red blood cells (RBCs) in the blood. Normal hematocrit levels typically range from 38.3% to 48.6% for men. Elevated hematocrit levels, particularly above 54%, can increase blood viscosity, leading to a higher risk of thrombotic events such as stroke, myocardial infarction, and venous thromboembolism.

Testosterone Therapy and Its Impact on Hematocrit

Testosterone stimulates erythropoiesis, the production of RBCs, by increasing erythropoietin levels and suppressing hepcidin. This effect can lead to elevated hematocrit levels in men undergoing TRT. The degree of hematocrit increase can vary based on the dosage, formulation, and individual patient factors.

Key Studies Highlighting Risks of Elevated Hematocrit in TRT

The TRAVERSE trial was a large-scale, randomized, placebo-controlled study involving 5,246 men with hypogonadism and preexisting or high risk of cardiovascular disease. The study found that hematocrit levels ≥54% occurred significantly more often in the testosterone group compared to the placebo group. Elevated hematocrit was associated with an increased risk of venous thromboembolism and other adverse cardiovascular events. 

The T Trials were a set of seven coordinated trials involving 790 men aged 65 years or older with low testosterone levels. One of the findings was that testosterone therapy led to an average increase in hematocrit of 2.5–3.0% over 12 months. Some participants exceeded hematocrit levels of 54%, necessitating dose adjustments or discontinuation of therapy. 

This retrospective cohort study analyzed data from 8,709 men with low testosterone levels. The study found that testosterone therapy was associated with increased risks of myocardial infarction, stroke, and death, particularly in patients with rising hematocrit levels. 

A comprehensive meta-analysis of 51 randomized controlled trials revealed that testosterone therapy significantly increased the risk of polycythemia (hematocrit >52–54%). The risk ratio for developing polycythemia was 3.69 in men treated with testosterone compared to placebo.

Endocrine Society Clinical Practice Guidelines

The Endocrine Society's 2018 Clinical Practice Guidelines provide clear recommendations for monitoring and managing hematocrit levels in men undergoing TRT:

• Baseline Assessment: Measure hematocrit levels before initiating therapy.

• Monitoring: Reassess hematocrit at 3–6 months after starting therapy and annually thereafter.

• Management: If hematocrit exceeds 54%, consider reducing the testosterone dose or discontinuing therapy until levels normalize.

Risk Factors for Elevated Hematocrit in TRT

Several factors can increase the likelihood of hematocrit elevation in men on testosterone therapy:

• Dosage and Formulation: Higher doses and certain formulations, such as intramuscular injections, are more likely to elevate hematocrit levels.

• Age: Older men may have a heightened erythropoietic response to testosterone.

• Smoking: Smoking can independently raise hematocrit levels.

• Altitude: Living at high altitudes can lead to naturally higher hematocrit levels.

• Dehydration: Reduced plasma volume can falsely elevate hematocrit readings.

Management Strategies for Elevated Hematocrit

Reducing the testosterone dose is often the first step in managing elevated hematocrit. Lowering the dose can decrease erythropoiesis and bring hematocrit levels back within the normal range.

Switching from intramuscular injections to transdermal gels or patches may result in a more stable testosterone level and a lower risk of hematocrit elevation.

In cases where hematocrit remains elevated despite dose adjustments, therapeutic phlebotomy can be employed to reduce hematocrit levels quickly. This procedure involves the removal of blood to decrease RBC mass.

Regular monitoring of hematocrit levels is essential. Additionally, addressing modifiable risk factors such as smoking cessation, ensuring adequate hydration, and managing sleep apnea can help control hematocrit levels.

Conclusion

While testosterone replacement therapy offers significant benefits for men with hypogonadism, it is not without risks. Elevated hematocrit levels are a notable concern, increasing the potential for serious cardiovascular events. Clinicians must remain vigilant, adhering to established guidelines for monitoring and managing hematocrit levels to ensure patient safety. Through appropriate dosing, choice of formulation, and regular monitoring, the benefits of TRT can be realized while minimizing associated risks.

References

1. Cardiovascular Safety of Testosterone-Replacement Therapy. New England Journal of Medicine. 2023. (ursahealthconsortium.org)

2. The Testosterone Trials. Verywell Health. 2017. (verywellhealth.com)

3. Deaths and Cardiovascular Events in Men Receiving Testosterone. JAMA. 2013. (jamanetwork.com)

4. Adverse Effects of Testosterone Therapy in Adult Men: A Systematic Review and Meta-Analysis. The Journal of Clinical Endocrinology & Metabolism. 2010. (academic.oup.com)

5. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. 2018. (endocrine.org)

6. Therapeutic Phlebotomy for Testosterone-Induced Polycythemia. American Journal of Clinical Pathology. 2019. (academic.oup.com)