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Myth . Testosterone Causes Heart Attacks

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One of the most common myths about testosterone is that it causes heart attacks. Testosterone abuse with synthetic hormones and aromatase inhibitors by athletes and bodybuilders has led to the incorrect assumption that TRT causes heart attacks. There have also been two poorly conducted studies recently that have stated there is an increased risk of heart attacks and potentially death from testosterone replacement. However, contrary to those studies, several studies over the last three decades show that testosterone does not cause heart attacks and death but, in fact, decreases the risk of heart attack, stroke, and death.

Flawed Studies into the Effects of TRT and Heart Attacks

The two poorly conducted studies Vigen et al and Finkle et al were what we call retrospective examinations. They looked at insurance databases to see if people on a testosterone prescription developed a particularly adverse outcome. In this case, they were looking for heart attacks and mortality. The problem with these studies and what makes them a 'Grade D study' (and should be thrown in the garbage) is that they did not check to see that these men even took the testosterone.

Just merely giving them a prescription for testosterone does not mean that they took the medication. Also, only the initial levels of testosterone were examined and never in a laboratory over time. Therefore, we did not know whether they were even at therapeutic levels or even took the testosterone. I would not classify either of these as well-done studies. In a study that examined both these studies, they stated the following:

"New concerns have been raised regarding cardiovascular (CV) risks with testosterone (T) therapy (TTh). These concerns are based primarily on two widely reported retrospective studies. However, methodological flaws and data errors invalidate both studies as credible evidence of risk. One showed reduced adverse events by half in T-treated men but reversed this result using an unproven statistical approach. The authors subsequently acknowledged serious data errors, including nearly 10% contamination of the dataset by women.

The second study mistakenly used the rate of T prescriptions written by healthcare providers to men with recent myocardial infarction (MI) as a proxy for the naturally occurring rate of MI. Numerous studies suggest T is beneficial, including decreased mortality in association with TTh, reduced MI rate with TTh in men with the greatest MI risk prognosis, and reduced CV and overall mortality with higher serum levels of endogenous T.

"Randomized controlled trials have demonstrated benefits of TTh in men with coronary artery disease and congestive heart failure. Improvement in CV risk factors such as fat mass and glycemic control have been repeatedly demonstrated in T-deficient men treated with T. The current evidence does not support the belief that TTh is associated with increased CV risk or CV mortality. On the contrary, a wealth of evidence accumulated over several decades suggests that low serum T levels are associated with increased risk and that higher endogenous T, as well as TTh itself, appear to be beneficial for CV mortality and risk."

Morgentaler A. Testosterone deficiency and cardiovascular mortality. Asian J Androl. 2015;17(1):26-31. doi:10.4103/1008-682X.143248

What Studies Show Cardiovascular Benefits when Taking Testosterone?

There are too many to present in this article. However, we will attempt to present the few that are most impactful.

First, endogenous testosterone levels and other hormones like estradiol are associated with heart disease risk in men. This study:

Muller M, van der Schouw YT, Thijssen JHH, Grobbee DE. Endogenous sex hormones and cardiovascular disease in men. The Journal of clinical endocrinology and metabolism. 2003;88(11):5076-5086.

This study showed that higher testosterone levels, estradiol, and adrenal hormones endogenously had a neutral or beneficial effect on heart attack risk. Meaning that if you naturally have low testosterone, you are more likely to have a heart attack. Conversely, it shows that if you have a naturally higher testosterone level, you are at a decreased risk for heart disease.

"Unlike women, men do not experience an abrupt reduction in endogenous sex hormone production. However, it has become clear that an age-associated decrease in the levels of (bioactive) sex hormones does occur. Whether endogenous sex hormones have an impact on cardiovascular disease has, for many years, remained largely unknown. Still, during the last decade, more attention has been drawn to the importance of testosterone, estrogens, and adrenal androgens in etiology, prevention, and treatment of male cardiovascular disease."

"The purpose of this article is to summarize the evidence currently available on the association between endogenous sex hormones and cardiovascular disease in males. They reviewed published studies dealing with the relationship between circulating levels of sex hormones and cardiovascular disease in males. The studies reviewed in this article suggest that circulating endogenous sex hormones and estrogens have a neutral or beneficial effect on cardiovascular disease in men."

 

Another study showing the same results:

Potenza M, Shimshi M. Male hypogonadism: The unrecognized cardiovascular risk factor. Journal of clinical lipidology. 2008;2(2):71-78.

"Normal levels of male sex hormones are essential to men's health. Many studies demonstrate that hypogonadal men are at higher risk for developing a host of metabolic derangements, including dyslipidemia, type 2 diabetes mellitus, obesity, and hypertension. We examined the most recent studies supporting this notion of hypogonadism as a cardiac risk factor by reviewing all relevant PubMed data.

"Most studies showed an increase in metabolic disorders and cardiac events in hypogonadal men compared to their eugonadal counterparts. Mechanisms explaining this increased risk include adverse cytokine profiles produced by excess adipose (fatty) tissue, abnormal lipid metabolism by understimulated hormone-sensitive lipase, and abnormal cellular respiration leading to insulin resistance."

"In contrast, some studies have not demonstrated such an increased cardiac risk. Conflicting data between studies is expected, given the complexity of testosterone and its metabolic effects. Additionally, the interaction of testosterone with the androgen receptor differs based on an individual genome. Hypogonadism will affect individual men differently because of this genomic variance. The literature points toward true hypogonadism as a major cardiac risk factor. Men at risk of being hypogonadal should be screened and brought back to eugonadism with hormone replacement."

 

Testosterone is Good for the Heart

Now, what happens when you give testosterone to men. This process is complicated, but to simplify it, think about testosterone as being a gateway hormone. As you can see from the previous two studies, testosterone has benefits in protecting the heart by reducing the risk for metabolic syndrome and inflammation. Both of which increase the risk for cardiovascular disease.

Testosterone also reduces subcutaneous and visceral fat (the fat around your organs) and fatty liver.  So, what other benefits does testosterone have? Testosterone, although active, can be considered a prohormone – the precursor to the truly active hormones. So, what are the active hormones that come from testosterone? There are two – dihydrotestosterone (DHT) and estradiol.

Dihydrotestosterone is the active form of testosterone. It is typically 10-100 times more active than testosterone. It gives you the same benefits as testosterone, such as reducing fat by increasing muscle, thus reducing the risk of inflammation and metabolic syndrome. All of this equates to a reduction in heart disease.

When it comes from testosterone, estradiol also protects the heart. Studies show that when you reduce estradiol via an aromatase inhibitor or fat, men have an increased heart disease risk (up to 26%). One way estradiol helps reduce the risk of heart disease is by increasing good fatty acids.  These are the cholesterol molecules you want because they help reverse plaque build-up and thus reduce heart disease.

As a caveat, there is an association of naturally elevated estradiol with heart disease in some studies. Why? Didn't I just tell you that it reduces the risk? Well, first, an association does not necessarily mean causation. Also, having naturally high estradiol is not the same thing as giving testosterone to raise your estradiol. We need to understand the difference.

Estradiol, Testosterone, and Fat

Men who generally have naturally high estradiol are not all making it from testosterone. In fact, they make very little from their testosterone because these men typically have deficient testosterone. So, where are they making it from? Fat. Yes, fat produces estradiol via the action of an enzyme called aromatase. Fat in the cells generally causes an increased aromatase activity, which transforms the estrone in the fat to estradiol.

This increase in estradiol sends a signal to the brain, telling the body to reduce testosterone production because the brain thinks there is an excess of estradiol. Therefore, it must be coming from testosterone. The issue here is not the estradiol. It is the fat that produces it. The estradiol is not bad per se, but the effect it has on your testosterone is. You could say the estradiol is an eyewitness who happened to finger the innocent bystander (testosterone in this case) instead of the culprit (fat).

Therefore, we should block estradiol then by giving an aromatase inhibitor. No, because studies show that if you block estradiol, you will increase the risk for heart attacks even though it will increase testosterone by stopping estradiol conversion. This is the actual reason why steroid abusers use aromatase inhibitors, not because of gynecomastia or being over-emotional. You don't get either from estradiol.

The issue here is the fat, not the estradiol. If you don't do something about the fat, it doesn't matter where the estradiol comes from. Fat kills. It causes heart disease. What about increasing the testosterone by blocking the estradiol? As a result, you can burn the fat with the muscle that the testosterone produces. That would be okay if testosterone didn't depend on estradiol to sensitize your muscle to testosterone.

You need estradiol for your muscles to respond to testosterone. So, how do you reduce heart disease in men who have a naturally high estradiol level from fat? You give estradiol in the form of testosterone. By doing so, you increase muscle and reduce fat, and, as a result, reduce estradiol from fat. As a result, you should never block estradiol because you put men at risk for heart disease. Testosterone, DHT, and estradiol all equally protect you against heart disease.

Take Hormone Assessment Now

 

Due to so much misinformation floating around regarding heart attacks and testosterone therapy, we have compiled a comprehensive list of studies to show the truth. Testosterone replacement therapy does not increase the risk of heart attacks, low testosterone does!

Tivesten A, Vandenput L, Labrie F, et al. Low serum testosterone and estradiol predict mortality in elderly men. The Journal of clinical endocrinology and metabolism. 2009;94(7):2482-2488

Conclusions: Elderly men with low serum testosterone and estradiol have increased risk of mortality, and subjects with low values of both testosterone and estradiol have the highest risk of mortality.

Ärnlöv J, Pencina MJ, Amin S, et al. Endogenous sex hormones and cardiovascular disease incidence in men. Annals of Internal Medicine. 2006;145(3):176-184

In the community-based sample, a higher serum estradiol level was associated with lower risk for CVD events in older men. The findings are consistent with the hypothesis that endogenous estrogen has vasculoprotective influences in men.

Shono N, Higaki Y, Mori M, Nishizumi M. Physiological levels of estradiol correlate with lipid / lipoprotein profiles in healthy men. Environmental health and preventive medicine. 1999;4(2):81-86.

These results suggest that higher levels of E2 and DHEA-S, at least in physiological concentrations, are related to the favorable lipid and lipoprotein levels in men.

D’Amico AV, Denham JW, Crook J, et al. Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(17):2420-2425. Accessed October 30, 2020

The use of AST (androgen suppression therapy) is associated with earlier onset of fatal MIs in men age 65 years or older who are treated for 6 months compared with men who are not treated with AST.

Lai J, Zhou D, Xia S, et al. Reduced testosterone levels in males with lone atrial fibrillation. Clinical cardiology. 2009;32(1):43-46.

Reduced testosterone levels may be associated with susceptibility to lone AF in men.

Giri S, Thompson PD, Taxel P, et al. Oral estrogen improves serum lipids, homocysteine and fibrinolysis in elderly men. Atherosclerosis. 1998;137(2):359-366.

We conclude that oral estrogen in men reduces homocysteine, fibrinogen, and PAI-1 concentrations and favorably influences VLDL, LDL and HDL subclass levels without increasing markers of thrombotic risk.

Hak AE, Witteman JCM, de Jong FH, Geerlings MI, Hofman A, Pols HAP. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. The Journal of clinical endocrinology and metabolism. 2002;87(8):3632-3639. Accessed October 30, 2020.

In conclusion, we found an independent inverse association between levels of testosterone and aortic atherosclerosis in men.

Malkin CJ, Pugh PJ, West JN, van Beek EJR, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. European heart journal. 2006;27(1):57-64.

Testosterone replacement therapy improves functional capacity and symptoms in men with moderately severe heart failure.

Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. The Journal of clinical endocrinology and metabolism. 2004;89(7):3313-3318.

In conclusion, testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol. Twenty of these men had established coronary disease, and because total cholesterol is a cardiovascular risk factor, and proinflammatory cytokines mediate the development and complications associated with atheromatous plaque, these properties may have particular relevance in men with overt vascular disease.

Marin P. Holmang S, Jonsson L, et al. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes Relat Metab Disord. 1992 Dec; 16 (12): 991-997.

Testosterone treatment was followed by a decrease in visceral fat.

Insulin resistance decreased.

Diastolic blood pressure and serum cholesterol decreased with testosterone treatment.

Insulin sensitivity improved.

Testosterone treatment … gives beneficial effects on well-being and the cardiovascular and diabetes risk profile, results similar to those observed after hormonal replacement therapy in postmenopausal women.

Ginsberg TB, Cavalieri TA. Androgen deficiency in the aging male: The beginning, the middle, and the ongoing. Clinical Geriatrics. 2008 April: 25-28.

Low testosterone levels in the aging male may contribute to the development of several comorbid conditions.

Examples of these conditions are myocardial infarction, coronary atherosclerosis, type 2 diabetes, obesity, hypertension, and osteoporosis.

Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. European journal of endocrinology. 2006;154(6):899-906.

Testosterone replacement therapy reduces insulin resistance and improves glycaemic control in hypogonadal men with type 2 diabetes. Improvements in glycaemic control, insulin resistance, cholesterol and visceral adiposity together represent an overall reduction in cardiovascular risk.

Haider A, Yassin A, Haider KS, et al. Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy: observational, real-life data from a registry study. Vascular Health & Risk Management. 2016;12:251-261.

In this study, we investigated the effects of long-term testosterone therapy up to 8 years in hypogonadal men with a history of cardiovascular disease.

Cardiometabolic parameters such as lipid pattern, glycemic control, blood pressure, heart rate, and pulse pressure all improved significantly and sustainably.

No patient suffered a major adverse cardiovascular event during the full observation time.

Testosterone therapy appears to be effective in achieving sustained improvements in all cardiometabolic risk factors and may be effective as an add-on measure in the secondary prevention of cardiovascular events in hypogonadal men with a history of cardiovascular disease.

Cardiovascular benefits of testosterone therapy have been shown in interventional studies, including benefits in men with congestive heart failure, cardiac ischemia/angina, including a reduction in carotid intima-media thickness.

Most studies identified an inverse association between serum testosterone concentration and all-cause or cardiovascular mortality.

Recently, Corona et al analyzed a large number of published studies for the benefits and risk of testosterone therapy and concluded that there was no evidence of increased cardiovascular risk with testosterone therapy but protective effects in men with metabolic disorders and suggested that testosterone therapy has benefits on cardiometabolic function.

It must be emphasized that several recent studies showed a reduced incidence of myocardial infarction, stroke, and mortality in men treated with testosterone, achieving physiological testosterone levels.

Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. The Journal of clinical endocrinology and metabolism. 2012;97(6):2050-2058. 

This is the first study to specifically examine the association between testosterone treatment and mortality in men with low testosterone levels. Testosterone treatment was associated with decreased mortality in an observational cohort of middle-aged male veterans with low total testosterone levels and high chronic medical morbidity.

Rezanezhad B, Borgquist R, Willenheimer R, Elzanaty S. The Association between Serum Testosterone and Risk Factors for Atherosclerosis. Current urology. 2019;13(2):101-106.

These results suggest an inverse association between testosterone levels and risk factors for atherosclerosis.

In addition, randomized control studies reported beneficial effects of testosterone replacement therapy on insulin resistance and lipid metabolism and reduction in waist circumference, fasting blood glucose, and biomarkers of atherosclerosis in hypogonadal men with metabolic syndrome.

Gooren IJ. Toorians AW. Significance of oestrogens in male (patho)physiology. Ann Endocrinol. 2003. Apr;64(2):126-35

Oestrogens appear to have significant effects in the male biological system. Favorable effects have been noted on bone, brain and cardiovascular physiology.

Effects on the cardiovascular system include those on lipid profiles, fat distribution, endocrine factors produced by the vascular wall.

Circulating E2 levels in young men are bout 70 plus or minus 15 pmol/L which is equivalent to the levels in the early follicular phase in women.

HENCE THIS IS WHY WE DON’T BLOCK ESTRADIOL AND ALSO TRY TO GET LEVELS TO 75-100 PMOL/L

Giri S, Thompson PD, Taxel P, et al. Oral estrogen improves serum lipids, homocysteine and fibrinolysis in elderly men. Atherosclerosis. 1998 Apr;137(2) 359-66.

We conclude that oral estrogen in men reduces homocysteine, fibrinogen, and PAI-1 concentrations and has favorable influences on VLDL, LDL, and HDL subclass levels without increasing markers of thrombotic risk.

Blakemore J, Naftolin F. Aromatase: Contributions to Physiology and Disease in Women and Men. Physiology (Bethesda, Md). 2016;31(4):258-269

Concerns have been raised regarding cardiovascular complications of aromatase inhibitors and mood disturbances.

References:

Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9:e85805.

Vigen R, O’Donnell CI, Barón AE, Grunwald GK, Maddox TM, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310:1829–36.

English KM, Mandour O, Steeds RP, Diver MJ, Jones TH, Channer KS. Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms. Eur Heart J. 2000;21(11):890-894. doi:10.1053/euhj.1999.1873

Huo, Samantha, et al. Treatment of Men for "Low Testosterone": A Systematic Review, Plos One, September 21, 2016.