I am writing in response to a letter by Dr. Joshua Kra (“Testosterone Benefits Questionable” March 11, 2021) regarding the use of testosterone therapy. I appreciate that Dr. Kra read my article (“Testosterone: Benefits and Misconceptions” March 4, 2021) and took the time to respond. He expressed concern that the elevated red blood cell count caused by testosterone may be a risk for increased blood clots. That would suggest that there would be increased cardiovascular disease and increased risk of venous blood clots.
There are a few negative studies with regard to cardiac disease, which is why the FDA applied that label about possible increased cardiac risk that Dr. Kra pointed out. It should be clarified that several medical societies found those studies to be flawed and misleading, and the preponderance of studies show that there is cardiac benefit with testosterone replacement with no increased blood clots in arteries or veins. With regard to venous clot, a case-controlled study of 30,572 men showed no association between testosterone therapy and risk of venous clot.
Dr. Kra noted that the risk of clotting in polycythemia vera is not related to the platelet count. However, strong evidence suggests that the increased risk of clotting is platelet-mediated, even if not directly related to the platelet count as it can also be due to platelet dysfunction. In either case, the fact is that with polycythemia vera there is increased risk of clotting, while with testosterone-induced erythrocytosis there is no strong evidence of increased clotting risk. As noted, the preponderance of evidence shows cardiac benefit from testosterone replacement.
It was also noted by Dr. Kra that the mechanism of increased red blood cells is unknown. Actually, research proves direct stimulation of red blood progenitor cells in the bone marrow. While this may be so, the main point is that the increase is physiologic and does not translate into an increased risk for clotting, which is the main clinical concern.
What Dr. Kra is missing is that millions of people who live at high altitude throughout the world have increased red blood counts (physiologic erythrocytosis) due to the hypoxia of high altitude. There is no adverse effect or increased risk of blood clots to having elevated red blood counts from living at high altitude and the same applies to the erythrocytosis from testosterone.
Lastly, Dr. Kra recommends that blood counts should be monitored and that is based on current guidelines. I agree with this but disagree that testosterone should be stopped if rising above a set level as there are hundreds of randomized controlled studies that demonstrate no increase in blood clots with testosterone administration. Studies show that over 50% of patients treated with testosterone develop this increased red blood cell count termed erythrocytosis. However, no randomized control trial demonstrates any increased risk of blood clots in hundreds of studies.
As noted, there are numerous benefits of taking testosterone including improved cardiac health, reduced visceral fat with weight loss, and many studies suggesting improved insulin resistance reversal of diabetes. It would be unfortunate to prevent someone benefiting from testosterone because of erythrocytosis when the erythrocytosis has not been shown to have negative consequences among millions of men treated with testosterone as well as millions of people living at high altitude.
Dr. Kra is correct in that elevated red blood cell counts and elevated platelet counts with polycythemia vera cause
increased risk of blood clots. However, it is incorrect that testosterone-induced erythrocytosis causes blood clots as evidenced by hundreds of studies demonstrating no blood clots or harm in the physiologic erythrocytosis induced by testosterone. A recent paper published in a hematology journal stated that secondary polycythemia (erythrocytosis) from testosterone, COPD, or from high altitude do not require phlebotomy as it has not been shown to be harmful. Thus, elevated red blood count (erythrocytosis) is not a reason to discontinue testosterone.