It’s difficult for men to be treated for low testosterone levels for a number of reasons. This is true even for men with clinically proven low testosterone levels. The reasons for the reluctance of physicians to treat low testosterone levels in men has to do with the notion that testosterone levels are related to both the onset of prostate cancer, as well as adverse cardiovascular effects. I covered in depth the misinformation concerning the relationship of testosterone to prostate cancer in a recent article in Ironman, and interested readers should refer to that article for the truth about testosterone and prostate cancer onset. In relation to cardiovascular disease, a recent article published in the New England Journal of Medicine suggested that providing testosterone therapy to older men (average age, 74) could rapidly result in adverse cardiovascular outcomes, including increased incidence of both heart attacks and strokes. I also discuss this study and the actual effects of testosterone on heart function in an upcoming edition of my Bodybuilding Pharmacology column, also in Ironman.
While the relationship between testosterone replacement therapy (TRT) and cardiovascular disease (CVD) is specious at best, there is one effect of testosterone that could cause problems in this area. This relates to a thickening of the blood, also known as polycythemia, that can occur when testosterone is provided, particularly in injectable form. For some reason, this side effect is more likely to happen in older men, who are the prime candidates for TRT. It usually occurs when the weekly dose of injectable testosterone exceeds 150 milligrams. The effect is evident by blood tests that reveal an increased hematocrit of the blood. Hematocrit is a measure of the viscosity, or thickness of the blood. Interestingly, one of the primary side effects of blood doping, which involves drug-based increases in the red blood cell content of the blood, is polycythemia. Ironically, when this happens, any athletic edge induced by the increased red blood cell count (which results in increased oxygen delivery to muscle, and therefore, increased endurance) is negated because the blood has now become too thick, which lowers oxygen delivery to tissues, inducing a relative hypoxic (lacking oxygen) state. Testosterone causes a type of natural blood doping because it stimulates the kidneys to produce increased levels of erythropoietin (EPO), which in synthetic form, is used for athletic blood doping. Since EPO works by boosting the synthesis of new red blood cells, it would appear that the higher levels of EPO released by testosterone adminstration could account for the increased blood thickness shown by older men who use injectable forms of testosterone. This is a problem because higher hematocrit levels are linked to increased onset of strokes and heart attacks due to increased clotting activity in the blood.
But a new study found the root cause of higher hematocrit levels in men who use injectable testosterone. The study included both younger (ages 19 to 35) and older (ages 59 to 75) men. These men were provided weekly injections of testosterone enanthate (a long-acting ester of testosterone) in varying doses of 25, 50, 125,300, and 600 milligrams over a course of 20 weeks. The men’s own testosterone production was purposely supressed by providing them with a drug that blocks the secretion of gonadatrophic releasing hormone (GRH), which controls testosterone production in the body. This was done to more precisely determine the effects of the testosterone injections. The men underwent blood tests 5 times over the course of the 20-week study. The study results showed that within one week of getting the testosterone injections at higher doses, a substance called hepcidin was markedly suppressed in the men. The effect was related to the dose of testosterone, and was more likely to occur with the higher doses, above 125 milligrams a week. It also was more pronounced in the older, compared to the younger men in the study, and corresponded to a rise in hemoglobin, or the oxygen-carrying protein in red blood cells. The study concluded that the rise in hematocrit or blood thickness, is related to the supression of hepcidin caused by high dose injectable testosterone. This is probably the most common side effect seen when older men use higher doses of injectable testosterone.
Hepcidin is a 25-amino acid peptide that is produced in the liver. It was discovered in 2000, and is now known to be the master regulator of iron metabolism in the body. It works by directly inhibiting another protein called ferroportin, which works to transport iron out of cells that store the mineral. Ferroportin is present mainly in the cells that line the small intestine, and in immune cells called macrophages. By interfering with the actions of ferroportin, hepcidin reduces iron absorption. When larger doses of injectable testosterone block hepcidin, more iron is released and absorbed into the body. This increased iron, in turn, leads to a greater production of red blood cells, and it is that greater amount of red blood cells that results in the thicker blood or polycythemia that can occur with the testosterone injections. One unanswered question is why this effect of thicker blood with higher dose testosterone injections is more prevalent in older men. One possibility is that older men have lower iron stores than younger men, and this changes when high dose testosterone is used. But that is strictly speculation on my part. The elevated hematocrit effect can be eliminated through either using alternative forms of TRT, such as testosterone creams or gels, or by injecting doses of testosterone that are 125 milligrams or less each week.
Bachman, E, et al. Testosterone suppresses hepcidin in men: A potential mechanism for testosterone-induced erythrocytosis. J Clin Endocrin Metab 2010: in press.
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