Testosterone and Red Blood Cell Count. What is Secondary Erythrocytosis?

Greetings,

One of the most common concerns associated with testosterone therapy is an increase in red blood cells, also known as secondary erythrocytosis. This condition, which often leads to the term "thick blood," can prompt concerns about heart attacks, strokes, or blood clots. However, these fears may be based on misunderstandings or misinterpretations of the science behind testosterone's effects.

Origins of the Concern

When a patient undergoing testosterone therapy exhibits higher red blood cell counts, increased hemoglobin, and hematocrit, some doctors mistakenly associate this with Polycythemia Vera (PV), a type of bone marrow cancer. PV is characterized by uncontrolled red blood cell, white blood cell, and platelet production, often leading to a higher risk of blood clots. The blood clotting tendency in PV is caused by both the abnormal blood cells and the vascular changes that make the blood vessels more likely to clot. The treatment for PV often involves blood donations to manage the risk of thrombosis.

However, this is quite different from secondary erythrocytosis caused by testosterone therapy. In secondary erythrocytosis, there is an increase in red blood cells, but it does not come with the same harmful characteristics found in PV. Testosterone stimulates red blood cell production by influencing erythropoietin, hematopoietic progenitor cells, and reducing hepcidin. Secondary erythrocytosis is also common in other conditions such as smoking, sleep apnea, and chronic obstructive pulmonary disease (COPD), or in people living at high altitudes.

The True Risk of Secondary Erythrocytosis

Despite the concern, there is no evidence from randomized controlled trials or prospective studies linking secondary erythrocytosis with an increased risk of thrombosis. Guidelines suggest monitoring hematocrit levels after starting testosterone therapy, and if the levels exceed 54%, it may be advised to adjust the testosterone dosage, stop therapy, or conduct blood donation. However, this threshold of 54% is not based on conclusive studies showing harm, but rather on the general reference range for hematocrit in healthy males.

For example, in regions like Bolivia, where people live at high altitudes, the normal hematocrit range can be much higher—45% to 61%—without any increased risk of blood clotting. Similarly, many men use testosterone therapy without physician supervision, and there is no evidence of widespread adverse cardiovascular events like heart attacks or strokes in these populations.

Addressing the Misconception of Increased Blood Viscosity

Some believe that increased red blood cells from secondary erythrocytosis will thicken the blood and impede circulation, increasing the risk of thrombosis. However, studies measuring blood viscosity in laboratory settings using viscometers are not representative of how blood behaves in the human circulatory system. In reality, blood vessels are flexible, and the blood flows rapidly, reducing the viscosity. Additionally, the body adjusts to secondary erythrocytosis by enlarging the vascular bed, reducing peripheral resistance, and increasing cardiac output, which ensures optimal oxygen delivery even with higher hematocrit levels.

The Protective Effects of Testosterone

Testosterone has several effects that may actually protect against blood clotting. It improves vascular reactivity, acts as a vasodilator, and increases nitric oxide. Additionally, testosterone decreases pro-coagulant substances, improves red blood cell membrane fluidity and deformability, and lowers levels of lipoprotein(a), all of which contribute to cardiovascular health.

The Issue with Blood Donations

Although blood donation is sometimes recommended to manage high hematocrit levels, a study found that for men on testosterone therapy who donated blood, many still had persistently elevated hematocrit levels, even after repeated donations. This suggests that blood donation alone may not be a reliable way to maintain hematocrit levels within a safe range for men undergoing testosterone therapy. Additionally, too frequent blood donations will lead to iron deficiecy anemia which will lead to worse symptoms.

Long-Term Safety of Testosterone Therapy

Testosterone therapy has been in clinical use since 1937, and numerous randomized controlled trials have demonstrated its safety. To date, there is no conclusive evidence linking testosterone therapy to an increased risk of major adverse cardiovascular events, such as heart attacks or strokes.

Hope this alleviates the fear of high hematocrit with testosterone replacement therapy.