Could low testosterone could be associated with heart disease?

The (not so) short answer:

Heart disease is the leading cause of death among men in the U.S..  It’s important for men to have a clear understanding of how testosterone (or lack of) could affect their health.  In this article I present much of the available information about how low testosterone appears to affect cardiovascular (CV) health.

To answer the question: Yes, it appears that low T has an association with heart disease. However, the link between the two is a little murky.

Some argue that low T is merely a symptom of poor health.  Because weight gain suppresses testosterone and causes CV problems, some theorize that T is just an innocent bystander.  Others think that as testosterone levels decline, the risk for metabolic changes that lead to obesity and CV issues increases.

This confusion is also reflected in the research.  While much of the research indicates men with low testosterone are more likely to have heart disease, some studies have shown no association at all.  The media adds to this confusion by publishing poorly researched articles based on ineptly designed studies.  For some examples of this, check out my report Is Testosterone Therapy Safe for Your Heart? and this article that appeared in The Guardian (this researcher actually believes we should lower men’s T levels to preserve their health).

So does having low T directly cause heart disease or is it just an innocent bystander?

My Opinion:

It is probably a combination of both.  Testosterone plays a significant role in metabolism and body composition.  As we age testosterone levels naturally decrease, as does our activity level.  The lower testosterone and activity levels, typically lead to a gradual increase in body fat.  Higher levels of body fat lead to an increase in estrogen, which contributes to suppressing testosterone production.  Next, is a vicious cycle of increased body fat and further testosterone suppression.  On top of this, testosterone is necessary for the maintenance of lean muscle. The less testosterone we have the harder it becomes to hold onto muscle.  The less muscle we have, the fewer calories we burn, which leads to further weight gain.  To make things even worse, fat accumulation effects gene expression which desensitizes cells to insulin.  This means your muscle cells can’t bring in sugars as well, and they are more likely to be stored as fat.  So as we age it gets more and more difficult to remain healthy and keep weight off.  The more body fat we carry (particularly visceral fat), the higher the risk for CV disease.

The development of heart disease is an extremely complicated area of medicine and there are multiple factors that contribute.  The research shows that diet, genetics, level of exercise, stress, smoking, obesity, diabetes, high blood pressure, degree of inflammation and cholesterol levels all play a role.  Complicating matters T influences many of those things I just listed.  When evaluating studies regarding testosterone and CV disease we need to keep in mind that the are many intertwined variables at play.  While testosterone seems to play a role, it is only a piece of the puzzle.

Below is just some of the vast amount of research in this area.  I have tried to provide key pieces of the puzzle, so you can come to an informed decision of your own.

** Please note that testosterone therapy is not FDA approved to treat heart disease.  The research presented here should not be interpreted as an endorsement for TRT to treat cardiovascular problems.  This is simply a review of the available studies.  If you have heart disease you should consult with your doctor about treatment options. 

putting the puzzle together

#1 Androgen deprivation therapy (ADT):

The first clue to understanding of the effect of low testosterone on heart disease is to examine what happens when doctors suppress testosterone to zero.  Androgen deprivation therapy (ADT), is a treatment for aggressive prostate cancer.  Medications are given that completely shut down testosterone production.  A large study in 2006 showed a 44% increased risk of diabetes, a 16% increased risk of coronary heart disease, an 11% increased risk of heart attack and a 16% increased risk of sudden cardiac death, in men receiving ADT!  A similar trend was seen in a study by D’Amico et al. and a second study by D’Amico.  Newer studies have shown that the risk may only be seen in individuals with cardiovascular risk factors or prior heart disease and not the total population (1) (2).

What is clear is that ADT causes metabolic changes that lead to elevated insulin, elevated cholesterol, decreased lean muscle and increased fat.  The American College of Cardiology states, “although data are still inconclusive, it appears that ADT does increase cardiovascular risk, particularly among individuals with prior cardiovascular disease or cardiac risk factors”.

I think we can confidently draw the conclusion that the elimination of testosterone is harmful.

#2 Low t and increased artery thickness:

Doctors use the term “intimal-media thickening” to describe the thickness of arteries.  Thickening of the artery is a hallmark of atherosclerosis and is often used as a proxy for CV disease.  In the drawing above, the lumen is the open space where blood flows.  The two inner layers are called the “Media” and “Intima”.  The development of atherosclerosis begins with damage to the skin-like lining of the blood vessel called the endothelium.  When this layer is damaged it allows cholesterol and fat particles to become incorporated into the intima and media layers of the artery.  The particles can then be attacked by immune cells and shortly after, the wall of the artery thickens.  Thickening of the artery wall can be measured by ultrasound and helps doctors to predict the presence of atherosclerosis and the increased risk for cardiovascular events.

low testosterone is associated with increased artery thickness

Many studies (listed at the bottom of this article), including the famous Rotterdam Study, have shown an inverse relationship between testosterone levels and intimal-media thickness.  That means men with lower testosterone levels tend to have thicker arteries and men with higher testosterone levels tend to have less thickening. What is less clear, is whether low testosterone levels somehow cause increased intima-media thickness or if they are simply a side effect.  It could be that narrower arteries have a more difficult time allowing blood flow to the testes and areas of the brain responsible for testosterone production.  Others believe that lower testosterone levels lead to other metabolic changes that can affect the health of the blood vessels.

So who is correct?

A study by Van Den Beld et al. provides some insight.  The researchers showed that the association between testosterone levels and intima-media thickness is independent of existing atherosclerosis.  To say that another way, they showed that thickening of the carotid artery occurred with lower levels of testosterone even if a man did not have extensive atherosclerosis.  According to this study it seems that testosterone may play a direct role in the development of atherosclerosis.

The next question is how significant a role does testosterone play?

Free Testosterone Level vs. Intimal-Media Thickness

While we don’t know the exact answer yet, a 2003 study examined the relationship between artery thickness and the actual level of free testosterone.  What they found is represented in the graph above.  They report that the degree on intima-media thickness is inversely associated with the level of free testosterone.  Put more simply, the lower the free testosterone level a man had the more likely he was to have increased thickness of his arteries.  The thin black line represents an average of all of the dots and you a can clearly see the relationship between free T and artery thickness.

While there is still controversy whether low testosterone directly influences the development of CV disease, the studies we reviewed certainly point us in that direction.  Other studies have taken a more direct direct approach to examine how testosterone levels influence the severity of heart disease.

#3 Testosterone levels are Associated with Coronary Artery Calcium build up

A special heart scan called a coronary artery calcium scan (CAC), uses a CT scan of the heart to measure calcium build up.  Calcium deposits in the arteries are highly correlated with plaque build up, that can lead to a heart attack.  A CAC scan is essentially a look into the future to help understand your heart attack risk in the coming years.  The higher the CAC score the greater the risk.

A study by Park et al. using men with an average age of 53, showed an inverse relationship between bioavailable testosterone levels (unbound testosterone) and CAC scores.  That means low testosterone levels were an independent risk factor for increased CAC scores. Even when the researchers controlled for other factors that can affect CV disease such as age, smoking status, body mass, blood pressure the relationship did not go away.  This led the researchers to conclude, “our findings indicate that bioavailable testosterone is inversely associated with the degree of subclinical coronary artery calcification in non-obese men.”

A later study from 2015 by Lai et al. showed similar results.  They examined men over 65 and found that men with the highest CAC scores tended to have lower total testosterone levels.  They also found difference was also independent of other risk factors.

The world famous Framingham Heart Study, found that free and total testosterone were also negatively associated with CAC scores.  This means that as testosterone decreased, CAC scores increased. This was similar to the prior studies. However, once the researchers controlled for other risk factors the negative association was no longer significant.  This may be explained by the age difference in the men in these studies. The subjects in the Framingham study were younger than the men in the previous studies.  The average age was 49 in the Framingham study, while two other studies had an average age of 53 and 65 respectively.  Since CV disease takes time to develop, perhaps if the men were watched over a longer period, the association may have become pronounced.

#4 testosterone levels may influence the severity of cardiovascular disease

Four small studies have examined the relationship between testosterone levels and the severity of cardiovascular disease.  While each of these studies had relatively few subjects, each of them clearly showed the same trend.  The lower the levels of testosterone the more severe the level of cardiovascular disease.

The largest of these studies examined 803 men and categorized them into 3 groups according to their testosterone levels.  They then looked at something called a Gensini score.  A Gensini score is commonly used to quantify the amount of blockage seen during an angiography (process of injecting dye into heart vessels).  A higher Gensini score means more severe blockage.  The researchers found that the Gensini scores were significantly lower in men with testosterone levels in the top third, compared to the lowest third.

The other 3 studies are listed below.  These studies and the others presented previously show that there is growing evidence supporting an inverse relationship between the degree of testosterone deficiency and the severity of coronary artery disease.

1. An Assessment of the Correlations Between Endogenous Sex Hormone Levels and the Extensiveness of Coronary Artery Disease…
2. Low Testosterone Levels are Associated with Coronary Artery Disease in Male Patients with Angina
3. The Association of Hypotestosteronemia with Coronary Artery Disease in Men

In a review article by the American Heart Association they state, “these findings suggest that normal physiologic testosterone levels may help to protect men from the development of atherosclerosis.”  Again, we cannot say in absolute terms that testosterone protects against heart disease, but in the coming years new research may show this to be the case.

#5 Testosterone’s relationship to obesity

The statistics on obesity levels in America are shocking.  Approximately 72% of Americans are either obese or overweight.  It is well know that obesity is a major risk factor for the development of cardiovascular (CV) disease.That means almost 3 out of every 4 people has serious potential to develop heart problems.

What is less well known, is that where we store fat appears to be the critical factor in the development of CV issues. Visceral fat (also called abdominal obesity) is a major risk factor for elevated cholesterol levels, lower glucose tolerance, insulin resistance, systemic inflammation, high blood pressure, type 2 diabetes, and all-cause mortality.

Our bodies store fat in essentially two different compartments.  The fat under the skin is called subcutaneous fat.  The fat that is stored within the body cavity (around our organs) is called visceral fat.  When it comes to cardiovascular disease, it has been shown that visceral fat is much more dangerous than subcutaneous fat.  Multiple studies have shown an accumulation of visceral fat increases the metabolic risk factors for CV disease.  Since this fat accumulates around the internal organs waist circumference typically correlates well with the amount of visceral fat present.

The following are the best studies to date, that show indicate an association between low testosterone and obesity:

The Tromoso Study:

This study done in 2003, showed a strong correlation between low testosterone levels and increase waist circumference (visceral fat).  What was most surprising, was that men with the lowest T levels had the highest waist circumference despite relatively low overall obesity.  To say it another way, men with low T were more likely to have higher levels of visceral fat, when compared to men with normal T levels. Earlier studies by Seidell et al. and Tsai et al. showed similar results.  These studies seem to indicate testosterone plays a role in where fat gets stored.  Low testosterone appears to have a significant role in visceral fat accumulation.

The Mauras et al. Study:

In my opinion, this very small study published in 1998 is one of the the most interesting.  The researchers took 6 young healthy men (avg. age 23) and used a medication to suppress their testosterone production to near zero (31 ng/dL).  The researchers measured all types of biomarkers, but what they found with regards to fat accumulation was the most astounding.  After just 10 days of T suppression, the men’s body fat percentage increased from 19.2% to 22.2%.  If this wasn’t bad enough their fat free mass (i.e. muscle), decreased from 124.3 pounds to 119.6 pounds.  So, in just 10 days these men lost 5 pounds of muscle and gained 3% body fat!  Luckily for these subjects, the researchers did not extend the length of the study.  Unfortunately, the researchers did not measure visceral fat in this study.

The Bhasin et al. Study:

Similar to the previous study, the researchers in this study took 61 healthy men and completely suppressed their testosterone production.  They then injected testosterone enanthate in various doses (25, 50, 125, 300, or 600 mg), for 20 weeks.  Their calorie intake and energy expenditure were standardized, to prevent diet or exercise from becoming a factor.  After the 20 weeks, the researchers found that whole body fat mass was inversely related to testosterone levels.  Men given the 20 mg and 50 mg testosterone doses, actually gained fat mass (6.8 and 7.7 pounds).  Men who received 300 and 600 mg had a significant reduction in fat (1.1 and 2.2 pounds).  Most importantly they found that visceral fat mass decreased significantly at doses above 125 mg of testosterone.

can loosing fat increase my testosterone levels?

Yes, absolutely and it has been studied.  Weight loss has been shown to increase testosterone levels.

A study published in 2015 looked at this.  The study put 44 obese men on a restricted calorie diet and aerobic exercise for 12 weeks.  They found that the average total testosterone level increased by 25 ng/dL (a mild increase).

Another study put 437 overweight men on a reduced calorie diet, this time for 12 months.  These men saw their T levels increase by 15%.  On average the men’s their total testosterone increased from 417 to 460 ng/dL (normal range 350 to 1000).

A study by Camacho et al. also showed a positive increase in testosterone levels with weight loss.  The researchers report that a 10% decrease in weight lead to a 85 ng/dL increase in testosterone levels.  They also found that a 10% increase in weight, led to a similar decrease in testosterone levels.

So, it does appear that diet and exercise can have a positive effect on testosterone levels, however the improvement appears to be somewhat modest, at least according to these studies.

Summary

As you can see testosterone plays a role in body composition, metabolism and the development of cardiovascular disease.  Testosterone therapy should not be viewed as a cure for a poor diet and lack of exercise, but having optimal levels certainly evens the playing field.

A quote from an article appearing an editorial piece from the American Diabetes Association sums this up well: “Data suggest that serum testosterone levels in the range that is mid-normal for healthy young men are consistent with an optimal cardiovascular risk profile at any age and that testosterone concentrations either above or below the physiologically normal male range may increase the risk of atherosclerotic heart disease.”

studies showing association between atherosclerosis and low testosterone:

1. Low Levels of Endogenous Androgens Increase the Risk of Atherosclerosis in Elderly Men: The Rotterdam Study
2. Endogenous Hormones and Carotid Atherosclerosis in Elderly Men
3. Association Between Serum Testosterone Concentration and Carotid Atherosclerosis in Men With Type 2 Diabetes
4. Free Testosterone Levels Are Associated with Intima-Media Thickness of the Common Carotid Artery in Overweight and Glucose-Tolerant Young Adult Men
5. Increased Carotid Atherosclerosis in Andropausal Middle-Aged Men
6. Low Testosterone Levels are Associated with Athersoclerosis in Men
7. Endogenous Testosterone and the Prospective Association with Carotid Atherosclerosis in Men: The Tromso Study
8. Endogenous Sex Hormone and Progression of Carotid Atherosclerosis in Elderly Men
9. Male Hypogonadism: The Unrecognized Cardiovascular Risk Factor

Studies Showing lower testosterone levels lead to more severe atherosclerosis:

1. Increased Carotid Atherosclerosis in Andropausal Middle-Aged Men
2. Endogenous Hormones and Carotid Atherosclerosis in Elderly Men
3. Association Between Serum Testosterone Concentration and Carotid Atherosclerosis in Men with Type 2 Diabetes
4. Free Testosterone Levels are Negatively Associated with ITM Thickness of the Common Carotid Artery in Obese Glucose-Tolerant Young Adult Men
5. Low Testosterone Levels are Associated with Athersoclerosis in Men
6. An Assessment of Correlations Between Endogenous Sex Hormones and Extensiveness of Coronary Heart Disease…
7. Low Testosterone Levels are Associated with Coronary Artery Disease in Male Patients with Angina
8. Testosterone is Negatively Associated with the Severity of Coronary Artery Sclerosis in Men

Other studies/Links showing the link between low testosterone and cardiovascular disease:

1. Hypogonadism as a Risk Factor for Cardiovascular Mortality in Men: A Meta-Analytic Study
2. Normalization of Testosterone Levels is Associated with Reduced Incidence of Myocardial Infarction and Mortality in Men
3. Testosterone and Cardiovascular Health – Mayo Clinic Proceedings
4. Testosterone and the Cardiovascular System –  A Comprehensive Review of the Clinical Literature