This week a new study in the Journal of the American Medical Association discusses the association of testosterone therapy with the risks of death, heart attack and stroke in men with low testosterone levels. There are multiple issues with the current study that must be considered before men get scared off testosterone therapy as women were scared off potentially beneficial hormone replacement therapy.
First, we must consider that the study showed an association but the authors admit that this study certainly does not prove that testosterone therapy caused the adverse outcomes seen in the study. Multiple prior studies have shown that testosterone therapy may protect against heart disease and decrease mortality. In another study published in June, 2012 in the Journal of Clinical Endocrinology and Metabolism that also examined veterans the authors concluded that testosterone treatment resulted in a 39% decreased mortality risk versus men not treated with testosterone. Importantly, many studies have shown that men with lower testosterone levels are at a higher risk of mortality. A 2007 study also in the Journal of Clinical Endocrinology and Metabolism studied 794 men aged 50-91yo for over 11 years and showed that men with testosterone levels in the lowest quartile were 40% more likely to die than those with higher levels. In this study low testosterone also predicted increased risk of cardiovascular disease. Another study in Diabetes shows that low testosterone is associated with an increased risk of type 2 diabetes which is closely associated with cardiovascular disease risk.
So, the important question here is why testosterone therapy was associated with increased risks in this study when lower testosterone levels are clearly associated with increased risks of death and disease whereas higher levels of testosterone are associated with protection against cardiovascular disease and mortality? There are multiple reasons for this outcome. In this study, the authors mention that only 60% of the patients had an additional testosterone level checked after starting treatment. Without follow up testing it would be impossible to know if therapeutic increases in testosterone were achieved with the testosterone treatment.
There are several risk factors of testosterone replacement therapy that were not addressed in this study and do not tend to be addressed by doctors who prescribe testosterone hormone therapy. Testosterone therapy may cause increased concentration of red blood cells (erythrocytosis). A study published in the journal, Therapeutics and Clinical Risk Management regarding risks and benefits of testosterone replacement therapy states that elevations in hemoglobin (concentration of red blood cells) may have bad outcomes because the blood can become thick which could exacerbate vascular disease. The study authors state that the treatment for this increase in concentration of red blood cells is either dose adjustment and/or periodic phlebotomy (drawing off blood as in blood donation). It would be necessary to periodically measure testosterone levels and levels of red blood cells to make sure that the testosterone dosing is not excessive and to make sure that a patient is not developing high levels of red blood cells. This was not mentioned in this study and presumably was not done since a large number of patients never even had follow up testosterone level testing. Regular monitoring of red blood cells and making necessary adjustments to dosing or recommending phlebotomy may help to decrease any risks of testosterone therapy associated with erythrocytosis.
There are other levels that must be followed when one is placed on testosterone therapy. One of the most important is estradiol (estrogen). Testosterone is known to convert to estrogen readily in men through a process called aromatization. A study in the Journal of Clinical Endocrinology and Metabolism in 2009 showed that testosterone treated men readily convert testosterone to estrogen in a dose dependent manner which means the higher the dose of testosterone, the higher the level of estrogen. A study in the Journal of the American Medical Association also in 2009 showed that men with heart disease with both low levels of estrogen and high levels of estrogen had increased mortality. Since estrogen levels were not assessed in the men in the current JAMA study, it is impossible to know whether subjects had high or low estrogen levels. The prior research states that estrogen levels must be kept in a middle range for optimal survival. Studies show that optimal estrogen levels also protect men from osteoporosis and protect their cognitive function as well. For testosterone therapy to produce optimal results, levels of estrogens must be assessed on an ongoing basis to assure that levels are not too high which may increase risk of cardiovascular disease and mortality. High levels of estrogen in men can also be associated with gynecomastia or development of increased male breast tissue. Any nipple tingling or breast growth in men on testosterone therapy should prompt an investigation for an elevated estrogen level.
Testosterone converts to another hormone known as dihydrotestosterone (DHT). DHT was also studied in the previously mentioned Journal of Clinical Endocrinology and Metabolism study. The more testosterone a man receives the more his DHT level will rise. Researchers in 2004 published in the journal Endocrinology that the hormone DHT enhances some of the early stages in atherosclerosis. With testosterone therapy it is possible for excess levels of DHT to be produced. Again, men given testosterone therapy were not monitored for high DHT levels which may have put them at additional, unnecessary risk for cardiovascular disease. High DHT levels can also be associated with symptoms of benign prostatic hypertrophy (benign growth of the prostate) and male pattern baldness.
In conclusion, testosterone therapy should not be taken lightly, but when managed properly can elevate testosterone levels which is associated with a lower risk of cardiovascular disease and a lower mortality risk. This elevation of testosterone can be accomplished safely only when additional monitoring is undertaken. This additional monitoring should include assessment of hemoglobin and hematocrit (red blood cells), estrogen levels and dihydrotestosterone levels. Dosage adjustments, therapeutic phlebotomy (blood drawing) and possibly additional medications to control levels of estrogen and DHT may be necessary for optimal testosterone therapy. Consider consulting a hormone specialist who is knowledgeable in this area to experience optimal results.