The risks and benefits of TRT have been debated for many years & I was taught in medical school that testosterone replacement was dangerous.

Why does testosterone replacement therapy (TRT) increase polycythemia?

TRT is a beneficial treatment for men with age related testicular hypofunction. The risks and benefits of TRT have been debated for many years and I was taught in medical school that testosterone replacement was dangerous and most often not indicated. The literature does not support what I was taught.

Most of the things that are considered dangerous for men on TRT are, in fact, issues that are more common in men with low and low normal testosterone levels. I’m sure you’ve seen the lawyer commercials regarding the risk of heart attacks, strokes, venous thromboembolism, and prostate cancer. All of those are actually more common in men with lower than optimal testosterone levels. While testosterone will grow a prostate cancer that already exists, it does not cause prostate cancer. Therefore, it is important to screen men for prostate cancer prior to starting TRT.

Dr. Abraham Morgentaler, of Harvard, did a study several years ago showing that in men under 60 years of age with total testosterone levels less than 350, there was a 15% incidence of asymptomatic prostate cancer. Those cancers were of the more aggressive type than prostate cancer found in men over the age of 60. Of course, many men over the age of 60 have total testosterone levels less than 350.

One clear finding is that 2–40% of men will develop polycythemia (aka as erythrocytosis) while on TRT. This is defined as an hematocrit level of >52%. This can happen regardless of the route of administration of testosterone (gels, cream, pellets, or shots) but is more common with testosterone injections. Nevertheless, there is not a clear correlation regarding the risk of adverse events with hematocrit levels above 52%. The average hematocrit for men is 46–47%. If the hematocrit rises to 52% or above, the problem can be corrected by donating blood.

The mechanism of testosterone induced polycythemia involves an upward reset point of erythropoietin levels produced in the kidney. With rising erythropoietin levels, iron levels are reduced in order to produce more red blood cells from bone marrow. Regulation of iron is by hepcidin, a protein made in the liver which also declines under higher erythropoietin levels. This results in a 7–10% rise in the hematocrit. Here is a simple graphic of the mechanism:


(from Erythrocytosis Following Testosterone Therapy in Sexual Medicine Reviews Volume 6, Issue 1, P77–85, January 1, 2018)

If men are monitored appropriately, TRT is a safe way of eradicating the symptoms of suboptimal testosterone concentrations. This includes working closely with a health care professional knowledgable in TRT administration, frequent lab monitoring, and dosing adjustments as indicated. There are those TRT providers that will follow hematocrit but do not worry that much about polycythemia since the association of hematocrit and adverse events is weak. I worked with an internist once that recommended all men donate blood every 3 months since men frequently have too much iron in their blood. Most providers will recommend a blood donation for men on TRT to avoid chronic polycythemia.

The benefits outweigh the risks of TRT for the vast majority of men who meet the criteria for their problematic symptoms. In all the years I’ve worked with TRT, I’ve never seen an adverse event or the development of prostate cancer.

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