By Gary Huber, DO, AOBEM, and Andrew Comb, RPh
The practice of medicine in America is such an interesting beast. Much like the current political environment where there is such deep divide, we find similar camps in medicine where instead of a united review and discussion of the literature we either fall far left or far right on given issues. If we look back in history at the treatment of heart disease in this country, we see a once absolute belief that LDL cholesterol is “bad” and credited as the lone cause of heart disease, acquired from eating too much fat. Then the science catches up and disproves this belief more than 20 years ago; and yet still to this day, a majority of clinicians and even cardiologists still cling to this outdated paradigm. I detail this in an article published in March 2016, and you can review this in full detail in my library at www.huberpm.com.
And so it seems that testosterone has fallen to a similar fate. I published an article in February 2017 (www.huberpm.com) detailing the history of testosterone over time and the current societal lifestyle trends that cause its erosion in modern populations. This has become a hot issue as greater numbers of men are suffering from an escalating rate of hypogonadism at the same time that the FDA is trying to limit testosterone use and availability. The overwhelming evidence that proper testosterone levels are key to good cardiovascular health is being lost due to a few poorly constructed and executed studies that have received undue notoriety. It is my hope here to explore the current science and put to rest any unease that testosterone could in any way contribute to greater cardiovascular risk. Let’s move beyond myth and engage our love of science to drive intelligent decision making.
Interesting to note that more than one study has explored the idea that a proven scientific fact can take 10 to 20 years before it becomes common knowledge in the medical community. The Morris study(1) in 2011 reported that it takes 17 years post publication to alter a previously set medical paradigm. Testosterone has a tainted history. Huggins’ research in the 1960s proclaimed that testosterone was the cause of prostate cancer. This has since been disproved, and we generally accepted that testosterone is not a causative factor; but it took more than 40 years to erase that error. Methyl-Testosterone use back in 1935 created increased occurrence of liver cancer which even today leaves some uninformed clinicians with suspicion regarding the safety of modern bioidentical testosterone. Making matters worse is the fact that both medical school and pharmacy school training is seriously devoid of any detailed education in the proper physiology and proper use of bioidentical hormones. Many physicians still confuse drugs with hormones despite holding polar differences in effect.
Many physicians take on the task of using bioidentical hormones armed only with the information provided by the pharmaceutical companies. This invites another problem as the pharmaceutical companies have never studied the absorptive path of topical testosterone. None of the current topical testosterone manufacturers have any literature to demonstrate testosterone’s absorptive rate, yet they have all made claims that it absorbs at a standard 10% rate. No company anywhere at any time has ever published literature demonstrating that they tested tissue levels after applying their product. These companies have no idea how their product moves through human physiology nor how it impacts metabolic byproducts such as dihydrotestosterone or estradiol; yet these same companies are the ones instructing uninitiated doctors on the use of this powerful endocrine agent. The Basaria study,(2) published in the New England Journal of Medicine, is a great example of this. Subjects were given 100 mg of topical testosterone as a starting point and then doses were increased from there. The human body on average only makes 10 mg of testosterone per day, so why were these men being given supra-physiological doses, ten times the normal daily production?
A look at the literature should provide a clue as to the absorptive rates of testosterone despite it having never been actually tested. In the Chang(3) study, women scheduled for lumpectomy were given one of four treatments: placebo, progesterone, estradiol, or progesterone plus estradiol topically for 11 to 13 days prior to procedure. The procedure was intentionally scheduled to be done prior to ovulation on day 11-13 of the menstrual cycle when progesterone would be at its lowest level. On the day of the surgical procedure, serum level for progesterone and estradiol were measured and compared to actual biopsied tissue levels. The plasma levels of progesterone were <1 ng/dl in all of the patient groups. Tissue levels however showed quite a different result. In patients receiving placebo or estradiol the progesterone level ranged between 0.6 to 2.1 ng/gram. But in the patients receiving progesterone, the average level of progesterone found in the tissue was 53.5 ng/gram. That’s roughly a 50-fold difference while the serum showed no elevation of any kind. This clearly demonstrates that progesterone is moving through the body by lymph flow, diffusion, and arterial spread but is not being reflected in the venous return. Therefore, we cannot use serum measures to assess topical steroid use.
This finding is confirmed with a look at the Du4 study, which gave topical progesterone to women and tracked levels in the serum, saliva, and capillary blood over 24 hours. Again, we saw that whole blood and serum levels remain relatively unchanged while spikes were seen in both the saliva and capillary blood specimens. It would seem apparent that hormone movement through the body is being facilitated by lymphatic and arterial spread that is being metabolized by the cells into metabolites other than the parent compound and thus not being detected in the venous sample.
Yes, these are studies of progesterone not testosterone, but testosterone is a slightly smaller molecule than progesterone, is lipophilic like all of the steroid hormones and would be expected to move in identical fashion to progesterone. Given this knowledge how can we expect serum measures such as those used in the Basaria study to accurately reflect true physiology?
Topical hormones are absorbed, distributed, and metabolized differently than our endogenous hormones. There is a peak and trough effect that is not like our endogenous hormones. There is metabolism of parent compounds into metabolites, yet we are searching for the parent compound in venous blood and ignoring its metabolite.
If you were to follow the estradiol, DHT and testosterone metabolite levels in the venous blood of patients receiving the high dose topical testosterone given by the Basaria(2) study, you would see dramatic elevations; but these were not tested. It needs to be considered that this supra-physiologic dosing of testosterone may in fact cause tachyphylaxis, which may lead to adverse events. Bottom line, there is no evidence to support the notion that testosterone absorbs at a 10% rate, and then to assume we can track its movement through venous sampling is to ignore multiple physiologic principles.
The treatment of women with bioidentical hormones has typically engaged levels of hormone replacement that are on par with physiologic hormone production. A woman makes roughly 380 mcg of estradiol mid-cycle and about 250 mcg in the mid-luteal phase. Typical treatment doses of estradiol deliver 250 to 500 mcg of estradiol per day, which is close to and consistent with physiologic levels. Progesterone production in a cycling female ranges from 1 to 25 mg depending on the luteal timing, and we typically replace progesterone at a dose of 20 to 40 mg, so once again nearly consistent with physiologic production. The results of these treatments show obvious physiologic and clinical benefit for these women as studies have shown clear reduction in cardiovascular events, better bone density, and improvements in cognitive and neurologic function. So why is it that when we go to treat men we abandon the lessons learned about physiologic hormone replacement and hormone movement in tissue and insist upon using 10 times the physiologic dose of testosterone? There is no science to support such high dosing and absolutely no studies done to demonstrate tissue levels of testosterone when exposed to such high doses.
The Literature
As we look to explore the history of testosterone’s relationship with heart disease in the literature, we can see that epidemiologic studies from 20 years ago have consistently shown an inverse correlation between the endogenous testosterone level and major risk factors of atherosclerosis, as well as the presence and extent of coronary artery disease.(5-7) Despite this history, a prior study by Gluud(8) in 1986 set a truly bad example by using an extremely high dose of a non-approved oral micronized testosterone that led to serum levels ranging from 4,000 to 21,000 ng/dl, a value 20 times the upper range of normal. The study included 221 men with cirrhosis who were treated with 600 mg of oral testosterone. Despite this toxic dose of testosterone in an ill group of men, there was only one myocardial infarction reported. The authors chose to label any bleeding event as a cardiovascular event. The most frequently observed cause of death in this study was bleeding from esophageal varices, which is not surprising given that this was a group of cirrhotic patients. Despite this poorly constructed study, it is cited as one of the examples of the dangers of testosterone by later studies such as the metanalysis by Xu(9).
The meta-analysis by Xu(9) in 2013 gives the impression to the medical community that it is a consensus statement as it claims to offer review of 27 studies. The authors of this meta-analysis specifically included only studies in which one or more cardiovascular (CV) events were reported, so any study without a reported CV event was excluded. Obviously, this selection process exaggerates the apparent rate of events, and misrepresents differences in event rates between groups. In addition, 2 out of the 27 studies contributed nearly 35% of all CV events in the testosterone arm. These two studies were the Basaria study and the 1986 Copenhagen (Gluud) study(8), both of which have already been cited as poorly designed and poorly executed studies.
The Basaria(2) study received a lot of notoriety as it appeared in the NEJM, but the study design was seriously flawed. When changing the hormonal milieu of the body, the cellular physiology may take as long as 12 weeks to fully reach steady state as binding proteins and hormones go through homeostatic adjustments. Despite this, the design of the Basaria study chose to test patients a mere two weeks after the introduction of topical testosterone. They also elected to start the original dosing of testosterone at 100 mg daily which represents 10 times physiologic dosing. They only measured serum levels which has already been discussed above; and if serum levels did not reach their desired level of >500 mg/dl then the dose was further increased to 150 mg daily. They did not elect to monitor any testosterone metabolites such as DHT or estradiol, which would one might expect to be abnormally high given the use of supra-physiologic doses of testosterone.
A total of 209 men (mean age, 74 years) completed the Basaria study. Baseline measures showed a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. This group of men had poor mobility and significant levels of chronic disease such that risk for CV events was already high at the onset. The authors make the claim that during the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with five in the placebo group, had what the authors report as “cardiovascular-related adverse events.”
This study had several flaws in addition to its lack of power with only 209 participants:
Men in the testosterone group had higher baseline risk compared to the control group (more hypertensive patients, more patients with hyperlipidemia) for cardiovascular events.
o A greater percentage of the testosterone group was on statin therapy.
Cardiovascular-related events were reported in patients receiving higher doses of testosterone with abnormally high serum levels:
o Four subjects with testosterone levels higher than 1000 ng per deciliter,
o Five subjects with testosterone levels of 500 to 1000 ng per deciliter.
Cardiovascular events were not a planned primary or secondary outcome, so there was no structured evaluation of cardiovascular events.
o In fact, there was only one myocardial infarction reported for the entire study.
Clinical characteristics of the study population differ from those of most populations being considered for testosterone therapy:
o Men who were younger than 65 years of age and men with severe hypogonadism were excluded from the trial.
Participants had substantial limitations in mobility and a high prevalence of chronic conditions, including preexisting heart disease, obesity, diabetes, and hypertension.
o Frail, elderly men with limitations in mobility are more likely to have clinical and subclinical cardiovascular disease.
The testosterone doses in this trial were higher than those that are typically used in clinical practice.
The lack of a consistent pattern in the cardiovascular events and the small number of overall events suggest the possibility that the differences detected between the two trial groups may have been due to chance alone.
What was not highlighted was that the men in the testosterone group reported dramatic improvement in strength, stair climbing ability, and stamina.
A broadly discussed study from 2013 was the Vigen(10) 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:
7486 Patients 1223 Patients
Event No testosterone exposure Received testosterone
Myocardial Infarction 420 (5.6%) 23 (1.9%)
Cerebrovascular accident 486 (6.5% 33 (2.7%)
Death 681 (9.1%) 67 (5.5%)
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
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 al(15). Of the five available meta-analyses, four of them did not find any effect of testosterone therapy on CV events, positive or negative. Xu(9) 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 al(16) 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 Malkin(17) 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 Caminiti(18) 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 Shores(19) 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 Cai(21) 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 Haider(22) 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 study(28) 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.
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.
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.
References
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