When to discontinue testosterone therapy due to elevated hematocrit (Hct) levels?

From the Guidelines

Testosterone therapy should be temporarily stopped when hematocrit levels reach or exceed 54%, as this significantly increases the risk of blood clots and cardiovascular events. This recommendation is based on the American Urological Association (AUA) guideline, which suggests that a hematocrit (Hct) level above 54% warrants intervention, such as dose reduction or temporary discontinuation 1.

When considering the management of elevated hematocrit in patients on testosterone therapy, several key points should be taken into account:

• Prior to commencing testosterone therapy, a baseline measurement of hemoglobin/hematocrit should be performed, and if the Hct exceeds 50%, the etiology should be formally investigated before starting treatment 1.
• While on testosterone therapy, regular monitoring of hematocrit levels is crucial to prevent polycythemia, with particular attention to patients receiving injectable testosterone, which is associated with the greatest treatment-induced increases in hemoglobin/Hct 1.
• If hematocrit levels reach 52-54%, consider reducing the testosterone dose rather than stopping completely, and monitor hematocrit levels closely.
• Once testosterone is paused due to elevated hematocrit, therapeutic phlebotomy may be necessary to quickly reduce hematocrit levels, and the patient should be monitored closely after restarting testosterone at a lower dose.
• Changing from intramuscular injections to transdermal preparations (gels or patches) may be considered when restarting testosterone, as these typically cause less dramatic increases in hematocrit.

It is essential to note that elevated hematocrit occurs because testosterone stimulates erythropoiesis (red blood cell production) in the bone marrow, a normal physiological response, but excessive red cell production increases blood viscosity and thrombotic risk 1. Therefore, staying well-hydrated, avoiding smoking, and maintaining appropriate injection intervals can help minimize hematocrit elevation while on testosterone therapy. If hematocrit repeatedly rises above threshold despite dose adjustments, alternative treatments or regular phlebotomy as part of ongoing testosterone therapy may need to be considered.

From the Research

Hematocrit Threshold for Stopping Testosterone Therapy

• The most common side effect of testosterone therapy is erythrocytosis, and patient-specific factors should be considered when choosing an appropriate dosage and modality 2.
• Providers should decrease or discontinue testosterone therapy if the patient's hematocrit exceeds 54% until the hematocrit normalizes 2.
• Clinical guidelines indicate that hematocrit should be monitored during testosterone replacement therapy, with action taken if a level of 0.54 is exceeded 3.

Association Between Hematocrit and Morbidity/Mortality

• An association between hematocrit and morbidity and mortality appears likely but not proven and may be evident only in patient subgroups 3.
• The consequences of an increased hematocrit may be mediated by alterations in blood viscosity, oxygen delivery, and flow 3.
• Developing polycythemia while on testosterone therapy is an independent risk factor for major adverse cardiovascular events and venous thromboembolic events in the first year of therapy 4.

Management of Erythrocytosis

• All types of testosterone therapies result in statistically significant increases in mean hematocrit when compared with placebo 5.
• Intramuscular testosterone cypionate/enanthate were associated with a significantly higher increase in mean hematocrit compared to patch, but no differences in hematocrit between other formulations were detected 5.
• Therapeutic phlebotomy or venesection is mentioned as a means of reducing hematocrit in patients with testosterone therapy-induced erythrocytosis, but evidence supporting its efficacy or safety is lacking 6.