A Review of Testosterone Therapy and Effect on Hemoglobin and Hematocrit Levels.

1. What is the cause for Testosterone increasing my hemoglobin levels?

2. What is the best management option if my hematocrit and hemoglobin levels are high while on testosterone replacement therapy?

3. What is Erythrocytosis?

4. What Testosterone formulation has the greatest risk of elevating my hematocrit levels?

Keywords: Erythrocytosis and Testosterone, Phlebotomy, Testosterone and VTE, Testosterone and Cardiovascular Risk, Testosterone and Stroke, Polycythemia and Testosterone Replacement, Hemoglobin and Hematocrit values on Testosterone, Testosterone therapy side effects, Testosterone Cypionate, Testosterone Undecanoate, , Testosterone Enanthate, Testosterone Pellets

Hypogonadism (also known as low testosterone, testosterone deficiency or androgen deficiency) is defined as biochemically having a low testosterone level in combination with specific signs and symptoms. The treatment can be testosterone replacement therapy (TRT). Despite testosterone’s positive and beneficial effects on weight loss, lean muscle growth, decreased low-density lipoprotein (LDL), improved insulin resistance, improved cognition, decrease in waist circumference, improved libido and erectile function there are known risks of therapy. Risks of TRT include increases in estradiol levels, gynecomastia, and erythrocytosis. Erythrocytosis is an increase in red blood cell count that may impart a risk to the cardiovascular system. The following article will review TRT and erythrocytosis and treatment options.

TRT induces an elevation in red blood cell count (RBC). An increase in RBC’s is referred to as erythrocytosis and polycythemia. The increase in RBC’s is measured by a laboratory measurement of hemoglobin (Hgb) and hematocrit (Hct) levels. Hemoglobin is a protein within red blood cells that carries oxygen. Hematocrit is the percentage or proportion of blood volume that is comprised of red blood cells. Blood volume is composed red blood cells, white blood cells, platelets and plasma. It is specifically the red blood cell component of total blood volume that is increased by TRT. Erythrocytosis and polycythemia should not be confused with Polycythemia Vera which is a type of cancer of the bone marrow resulting in an increase in all components of blood volume not only red blood cells.

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Androgen Therapy and Erythrocytosis

Androgen therapy has been used since the 1950’s to stimulate erythropoiesis in patients with low red blood cell volume secondary to a variety of medical conditions including iron deficiency anemia. Kennedy and Gilbertsen in 1957 demonstrated in an observation study of women with breast cancer treated with androgen therapy (100mg testosterone injections three times weekly), significant increases in red blood cell volume. While this regimen of testosterone is supra-physiologic in order to induce erythropoiesis, more standard dosing regimens by men today of 100mg testosterone injection weekly typically increases hemoglobin levels by only 10g/l. Increases in Hct and Hgb levels are often observed by 6 months on intramuscular injections of testosterone and 9 months when testosterone pellets are utilized.

What is the risk of elevated hematocrit levels and increased red blood cell volume induced by testosterone therapy?

Erythrocytosis is clinically diagnosed when the Hgb level is greater than 18.5g/dl and the Hct level is greater than 52%. When Hct levels rises above 52% the red blood cell volume of blood increases, leading to an increase in blood viscosity, reducing venous return and increase platelet adhesiveness. These blood conditions can lead to blood clot formation, stroke, cardiovascular risk and ischemia (1-3)

The potential risk of erythrocytosis induced by testosterone therapy is the increase in blood viscosity and related ischemia (reduced blood flow) which may promote a thromboembolic event (also known as a blood clot or VTE/ Venothromboemoblism ). A blood clot can travel to your lung (known as a pulmonary embolism), a clot could form in your leg (known as a venous blood clot) or a blood clot can travel to your brain, resulting in a stroke. The increase in blood viscosity can also put a strain on your heart and cause ischemia to other parts of the body such as the brain.

It should be noted that the direct relationship between TRT and an elevation in Hct and subsequent risk for VTE has not been investigated through prospective randomized clinical trials. Much of the data is retrospective and observational in nature, yet precautions are still recommended by many professional guideline statements from the endocrine and urologic societies.

To Learn more about the risk of blood clot formation on testosterone therapy

and FDA labeling click here.

How does testosterone replacement therapy (TRT) cause an increase in red blood cell volume? What is the pathophysiology of TRT and elevated RBC’s?

There are several different theories how TRT causes an increase in red blood cell volume. The first is testosterone’s ability to increase erythropoietin (EPO). EPO is a protein produced by the kidney and directly stimulates the bone marrow to make more red blood cells. It is hypothesized that testosterone stimulates EPO release from the kidney.

Another mechanism for testosterone induced erythrocytosis centers around the suppression of hepcidin. Hepcidin regulates iron utilization in the body and iron is a key component of red blood cells. Bachman et al. theorized that testosterone causes suppression of hepcidin leading to an increase in iron absorption for erythrocytosis to occur.

What type of testosterone formulation poses the greatest risk for erythrocytosis?

Thera are a variety of testosterone replacement formulations including short and long acting intramuscular injections (Testosterone Cypionate, Testosterone Undecanoate, Testosterone Enanthate), Testosterone Pellets, Testosterone transdermal Cream/Gel, Nasal Testosterone and Oral Testosterone. Of these formulations, short acting IM testosterone injections have the highest incidence of erythrocytosis. The incidence of erythrocytosis secondary to testosterone injections approach 40-60%. Recent studies theorize that the large fluctuations in testosterone levels associated with IM injections is more supra-physiologic and causes a large spike in androgen levels resulting in increased hematocrit levels. This spike is less apparent with transdermal testosterone and testosterone pellets, where more steady state testosterone levels are achieved.

Table 1 (4) : Testosterone Formulations & Erythrocytosis Percentage

Testosterone Enanthate & Cypionate 66.7%

Testosterone Undecanoate 7%

Transdermal Testosterone (Testim ®, Androgel ® 1.62%) 12.8%

Testosterone Pellets 35.1%

What is the best treatment for erythrocytosis induced by testosterone replacement therapy?

5 main options for men on TRT who have elevated Hct levels.

1. Interruption of TRT

2. Phlebotomy

3. Temporary reduction in dosage

4. Must consider evaluation of cause of Hct/Hgb

5. Consider changing testosterone delivery method to more stable/consistent delivery such as topical transdermal testosterone gel or cream.

For patients who are on testosterone replacement therapy and a measured hematocrit (Hct) level is greater than 50% the following is recommended. A physician should consider withholding TRT until the etiology of the elevated Hct is investigated. The rise in Hct could be secondary to polycythemia vera, sleep apnea, high altitude or tobacco use among others.

If the measured Hct level is greater than or equal to 54% this demands intervention. A patient can stop TRT and obtain further assessment, as recommended by the Endocrine Society Guidelines. Dose adjustments of testosterone can be optimally lowered. Second, and a more preferred method is phlebotomy. A patient can donate blood to remove excess red blood cell volume and continue on therapy after medical investigation. Phlebotomy and blood donation are often free in many states and provides a quick and cost-effective solution.

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1. Guyton AC, Richardson TQ. Effect of hematocrit on venous return. Circ Res. 1961;9:157–64.

2. Hellem AJ, Borchgrevink CF, Ames SB. The role of red cells in hemostasis: the relation between hematocrit, bleeding time and platelet adhesiveness. Br J Haematol. 1961;7:42–50.

3. Wells RE, Jr, Merrill EW. Influence of flow properties of blood upon viscosity-hematocrit relationships. J Clin Invest. 1962;41:1591–8.

4. (Table 1) Samuel et al, Erythrocytosis Following Testosterone Therapy. Sex Med Rev. 2019 Jan1.

5. Nieschlag et al. Testosterone. Action. Deficiency. Substitution. Fourth Edition published 2012. Cambridge University Press.