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A broadly discussed study from 2013 was the Vigen10 study which has received broad criticism from many professional organizations for its inaccuracy in statistical analysis. This study was a retrospective cohort study of 8709 men in the Veterans Affairs system who underwent angiography over a six-year period and were then followed for any occurrence of myocardial infarction, stroke or death. To qualify for the study these men had to have demonstrated a low testosterone level below 300 ng/dl. Testosterone replacement was not a therapeutic treatment in the study design, but 1223 of the participants received some form of testosterone treatment from their physicians simply by chance. After the first prescription for testosterone was received, this study assumed that it was continued throughout the entire study period. However, 17.6% of the patients received only one prescription for testosterone. The authors reported an increased rate of heart attacks, strokes, and deaths in men receiving testosterone compared to those who did not. The overall event curves showed a 29% increase in CV events among men on testosterone according to the authors. These reported facts were not truly reflected in the analysis but were a misrepresentation obtained through statistical manipulation.
The actual event occurrence simply looking at the raw data are as follows:
No testosterone exposure
Obviously, the group receiving testosterone therapy had a much better prognosis, which is exactly the polar opposite of what was reported by the authors of this study.
Literature in Support of Testosterone Use
Direct-to-consumer advertisements by the pharmaceutical industry prompting men to seek treatment for reduced sex drive, decreased energy, and mood changes has led to a dramatic increase in testosterone prescriptions. Unfortunately, the FDA is looking at old literature and maintaining a stance that testosterone may be dangerous for cardiovascular patients. The FDA put out a statement that men should only receive testosterone therapy if they have documented hypogonadism. This recommendation makes sense and seems prudent, but I would add that as clinicians interested in disease reversal and prevention we need to take a more proactive stance and screen for hypogonadism given the inexpensive and valuable nature of replacement therapy. The time of fearing the boogie man has passed. Science has shown that we needn't fear unproven risks. Testosterone has proven itself to be a most valuable therapy when applied in a sensible manner.
Let's now turn our attention to the ample literature that show testosterone's physiologic impact on cardiovascular and related function.
The 2015 meta-analysis by Corona11 compared five different meta-analysis studies (Calof et al,12 Haddad et al,13 Fernández-Balsells et al,14 Xu et al,9 Corona et al15). Of the five available meta-analyses, four of them did not find any effect of testosterone therapy on CV events, positive or negative. Xu9 was the only study to show any effect on CV events and this has already been discussed above. The Corona study concludes that there is little evidence to support any causal relationship between testosterone replacement therapy and adverse cardiovascular events. This meta-analysis concluded that testosterone therapy could be a new strategy in managing and improving blood glucose and cholesterol, as well as reducing body fat and increasing lean muscle mass. All of which are factors that reduce heart disease risk. In addition, for patients with type 2 diabetes or metabolic syndrome, there was a protective effect of testosterone therapy against major adverse cardiovascular events (MACE).
The paradigm of testosterone increasing CV risk is not only false but dangerous as testosterone is in fact one of the keys to reducing cellular inflammation, guarding against elevated glucose, dilating coronary vessels, and protecting the heart against the progression of atherosclerotic disease.
In 2000, English et al16 conducted a double-blind randomized control trial in an effort to define the effects of low-dose transdermal testosterone therapy on men with chronic stable angina. Men were given transdermal testosterone patch that delivered 5 mg per day. This study concluded that low-dose testosterone therapy has a positive impact on angina threshold, as well as reducing exercise-induced myocardial ischemia in these men. This was one of the first of many studies in the early 21st century to define the positive impacts of testosterone therapy.
Due to the myths about testosterone having a negative impact on cardiovascular health, numerous studies were conducted in the early 2000s on testosterone use in patients with heart failure. A double-blind randomized placebo-controlled trial was done by Malkin17 in 2006, looking at patients with moderate heart failure. Again, we see the use of a transdermal patch of testosterone to deliver daily physiologic dose of 5 mg. This study found that testosterone therapy had little consequence in terms of cardiovascular risk but provided an improvement in functional capacity and heart failure symptoms in men treated with testosterone. Later on, in 2009, the Caminiti18 study found that long-acting testosterone therapies (undecanoate) had a plethora of positive outcomes in men with moderately severe CHF, including improved exercise capacity, muscle strength, glucose metabolism, and baroreflex sensitivity (BRS). They employed an IM injection of 1000 mg every six weeks, yielding roughly 20-24 mg per day.
The next few years yielded studies that delved into the use of testosterone therapy in men who were deficient in testosterone. This is likely due to the uptick in commercial advertisements for "Low T" during this time period. In 2012, the Shores19 study concluded that men with low testosterone levels treated with testosterone therapy had a dramatic overall decrease in mortality compared with men who received no testosterone therapy at all. The patients given testosterone therapy (IM testosterone) had a mortality rate of 10.3% compared with 20.7% in untreated men over the length of the study. These men had a high degree of chronic medical morbidity with an average of seven pharmacologically treated medical conditions. They had a 21% prevalence of coronary heart disease and a 38% prevalence of diabetes. This study demonstrates the broad impact appropriate testosterone therapy can have on chronic degenerative disease states.
A study done by Muraleedharan et al.20 in 2013, found that testosterone therapy could improve survival in hypogonadal men with type 2 diabetes. This study was further supported by the Cai21 study which established that testosterone therapy can improve glycemic control and decrease triglyceride levels of hypogonadal men with type 2 diabetes.
One of the most recent studies from 2016 by Haider22 showed impressive impact across many physiologic parameters using sensible testosterone therapy. They treated 77 men with low testosterone levels below 300 ng/dl, using slow release undecanoate testosterone injections every three months. They elevated the testosterone level to an average between 420 to 680 ng/dl. These men were followed over the course of eight years and showed yearly progressive improvements in weight reduction, blood pressure, and HgbA1c measures. There was improvement in all of the cardiometabolic risk factors. The authors concluded that testosterone therapy could be an effective add-on therapy in secondary prevention of cardiovascular events in hypogonadal men with a history of CVD.
For more than 20 years now, we have come to realize that LDL is not the cause of heart disease but rather its oxidation that drives the atherosclerotic process. Oxidized LDL is taken up by macrophages thus driving foam cell formation. This oxidized LDL within plaque is highly immunogenic and creates autoantibodies thus further driving this inflammatory immune process, accelerating the accumulation of LDL and plaque.23-26 Rising autoantibodies to oxidized LDL is predictive for carotid atherosclerosis progression and myocardial infarction. These antibodies are a very reliable predictor of coronary vessel involvement.27
The Barud study28 looked at a host of clinical characteristics and biometric measures and found that testosterone had a consistent inverse correlation with the level of LDL autoantibodies and showed more reliable correlation than lipid levels, age, body weight, or smoking history. Testosterone as an immune modulator is key to reducing coronary risk via its impact as an anti-inflammatory and immune modulating agent.
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Dr. Gary Huber is president of the LaValle Metabolic Institute. He spent 20 years as an emergency medicine physician before joining Jim LaValle in the practice of integrative medicine at LMI. Dr. Huber is an adjunct professor teaching integrative medicine practice at the University of Cincinnati College of Pharmacy as well as a clinical preceptor for pharmacy students. Dr. Huber also lectures on hormone replacement therapies and integrative care for the American Academy of Anti-Aging Medicine for the University of South Florida. He has developed the Metabolic Code Professional Weight Loss Program that has proved very beneficial in reversing metabolic syndrome issues. Dr. Huber has a long-held interest in nutrition and human physiology as they relate to wellness and longevity. He has served as medical director for the Flying Pig Marathon and is presently on the board of directors for Loveland's Amazing Race, a local charity event.