Testosterone and Heart Disease in Men

Testosterone and anabolic steroids have an extremely jaded history— replete with associations with sports doping, violent crime, and even Nazism. For decades, no public disclosure of any benefit conferred by these drugs was published in professional journals or the media. Instead, public awareness of androgens (testosterone and anabolic steroids) has been colored by laminated posters showing ‘side effects,’ and reports of individuals harmed by anabolic steroid use.

These warnings, well-intentioned as they are, appear to have been premature. In fact, some of the most concerning warnings are inaccurate; some are overstated, while others may be outright false. This does not mean that androgens are harmless and perfectly safe. It simply means that like everything else in life, there is not an absolute answer.

Most college students learn that any test question asking if something is always (or never) ‘true’ is usually ‘false.’ Sadly, that lesson is easily forgotten whenever it serves to influence public opinion.

In part, public officials chose to take a hard line against androgens because the allure of their effect on the male physique (and the accompanying social status) is so powerful and near universal. It is important to realize that the perception of most physicians and politicians is that anabolic steroid users are pursuing vain goals, foreign to the desires of these white-collar professionals. Anabolic steroids are so closely identified with bodybuilding and sports doping that their use is considered pathologic. In fact, there is a movement to more fully define ‘anabolic steroid dependence.’ Dependence is a critical argument in justifying the placement of anabolic steroids in the list of controlled substances.¹

Testosterone’s role in causing prostate cancer has been called to question, and many physicians are grudgingly accepting the arguments countering the classic belief that was elegantly presented by a urologist, Dr. Abraham Morgentaler.² Androgens have long been blamed for episodes of violence and mental instability. In contrast, studies are showing that low testosterone is associated with depression, impaired cognitive function, and other mental health conditions.^3-5

One of the less disputed and more seriously-alleged side effects of androgens is acceleration of atherosclerotic cardiovascular disease (ASCVD).^6,7 This condition is often called ‘plaque buildup.’ Readers old enough to pay attention to advertisements about cholesterol and heart disease will be familiar with pictures showing the inside of an artery (the ‘pipes’ that carry blood from the heart to other tissue). In normal arteries, the pipes are clean and wide open; when atherosclerosis is present, the lumen (the opening, or cross-sectional area) is compromised by LDL (bad) cholesterol building up and blocking the passage of blood. When blood cannot reach an area, oxygen cannot be delivered and the tissue that is supplied by the blocked artery dies. For the affected cells, it’s like being choked to death. When ASCVD affects the arteries that supply the heart, the result is a heart attack.

ASCVD is the leading cause of death in the United States.⁸ Despite its prevalence, it is rare among young and middle-aged adults. Thus, when a small number of case reports was published regarding anabolic steroid users suffering heart attacks or sudden death, the medical profession took notice.⁹ This led researchers to look for an explanation, and they discovered that some anabolic steroid users experienced changes in blood concentrations of cholesterol— a reduction in HDL (good) cholesterol and elevations in LDL (bad) cholesterol and triglycerides (fats)¹⁰— that increased the risk of atherosclerosis.

There is a phenomenon in professional literature that once something is published, it is ‘gospel’ until proven otherwise. Thus, public service announcements and health clinic posters include warnings about heart attacks.

Testosterone’s Role in Good Health

 During the last 20 years, a realization has dawned on clinical science that testosterone has a role in health as well as disease. Life does not occur in a test tube. There are no ‘absolutes,’ and the human body is designed to exist in a continuum. In other words, we live in ranges. At certain points we thrive, but outside of the ‘human range,’ we suffer and eventually die.

A readily-understood example of human range is temperature. People enjoy environmental temperatures between 40ºF and 90ºF, pursuing outdoor recreation and growing bountiful crops. However, when temperatures exceed this range— colder or hotter— humans experience discomfort, injury and eventually death. Even within the human range, there is a smaller range that represents the optimal temperature. While individual opinions may vary, people are most active, productive, and happy when the environmental temperature is near 75ºF. If temperature-related deaths were plotted on a graph, one would see a U-shaped curve, with a significant number of deaths occurring at the extremes (like the cold of outer space or inside a house fire). In the ‘comfort’ zone, temperature-related deaths would be very rare.

Similar ranges exist for physiologic functions. A resting heart rate of 60-80 beats per minute is healthy, as is 6½-8½ hours of sleep, or fasting blood glucose of 60-100 mg per dL.

It should be no surprise that the same holds true for testosterone. There is a strong body of evidence supporting the claim that low serum (blood) testosterone concentration in men predisposes one to a higher risk of numerous conditions of poor physical and/or mental health, as well as premature death.^11,12 Though it is less clear due to ethical and safety considerations, the suggestion that supraphysiologic testosterone use may increase the risk of harm or premature death in a dose-related manner is not without merit (i.e., more is not better). Unfortunately, a lack of research, as well as the number of different drugs generically classified as anabolic steroids, the diversity in dosing patterns, use of adjunct drugs, and failure to account for pre-existing disease will delay the emergence of a clinical understanding of optimal testosterone therapy.

Thus, the general understanding among physicians and policymakers is that testosterone negatively affects cardiovascular health by promoting ASCVD. Fortunately, there are a number of physicians and clinical scientists who continue to explore the relationship. Among them are Drs. T. Hugh Jones and Farid Saad, who recently reviewed the effects of testosterone on ASCVD risk factors and mediators in the journal Atherosclerosis.¹³

Jones and Saad looked at the association of low testosterone with markers of ASCVD, conditions associated with ASCVD, and the effect of testosterone replacement therapy. It is important to note that they did not look at the effect of supraphysiologic testosterone— concentrations most athletes and bodybuilders use to promote muscle growth and strength. So, what did they discover?

Low testosterone concentration in males is unhealthy— there is little question of that. Men with low testosterone concentration are at greater risk of CHD (coronary heart disease, plugging of the arteries that supply the heart muscle), confirmed by a special type of X-ray called coronary angiography, and episodes of heart attacks or angina (chest pain). When hypogonadal (low testosterone) men are treated with testosterone, positive changes are noted that are associated with a lower risk of future CHD. These include reductions in visceral obesity and insulin resistance, improved lipid (cholesterol and fat) and inflammation labs, and better exercise tolerance.¹³

An increased risk of a heart attack is related to a number of conditions— smoking, hypertension, high LDL cholesterol, unhealthy diet/exercise, abdominal obesity, and diabetes.¹⁴ Several of these conditions are lifestyle-based. In 1981, a constellation of health problems was described as the ‘Metabolic Syndrome.’ The syndrome includes abdominal obesity, high triglycerides (blood fat) and cholesterol, low HDL cholesterol, hypertension (high blood pressure), and high fasting glucose (blood sugar taken prior to breakfast).¹⁵ Not all of these conditions need to be present for a person to be classified as having the Metabolic Syndrome. Due in part to the changing lifestyle noted from the 1970s to now, these conditions— both individually and as part of the Metabolic Syndrome— are increasingly common. Coincidentally, the average testosterone concentration in men has been falling over the same period.¹⁶

Shrinking Testosterone, Bigger Stomachs

Is falling testosterone a coincidence?^17,18 Consider that the highest rate of heart attack occurs in men who are at greatest risk of having a low testosterone concentration due to age-related decline. Taking a closer look at the conditions that predispose a person to an increased risk of heart disease, it becomes clear that testosterone has a protective role in preventing ASCVD— at least within the normal physiologic range.

Obesity adversely affects one’s health, but this is particularly true with regard to cardiovascular health. Studies that analyzed the relationship between testosterone and obesity discovered that there is an inverse (opposite) relationship.^19,20 This means that generally speaking, the higher one’s testosterone, the less likely he will be obese. Conversely, the more obese a man is, the lower his testosterone would be. Even more convincing is the data showing that a low testosterone concentration correlates with elevated abdominal obesity, percentage of body fat, and insulin levels. High insulin levels promote fat storage and inhibit fat loss.

Body fat and testosterone have a ‘chicken and the egg’ relationship. Sometimes, it is impossible to determine which came first— and therefore, which causes the other. Testosterone stimulates receptors on and within the fat cell that reduce fat storage, increase the breakdown and release of stored fat, and divert fat cell precursors (stem cell-like cells) to become muscle cells rather than fat cells.²¹

When the results of a study are reported by the media, conflicting conclusions can be made. By focusing on a single effect, especially when discussing a globally-acting hormone like testosterone, the net effect is often clouded. It brings to mind the adage of not being able to see the forest for the trees— a folksy way of reminding people to keep looking at the ‘big picture.’

Fat cells do not just store and release fat— they also communicate with the body by releasing unique messenger molecules. After all, it is important for the body to know if stored energy is too low to survive a long winter— or too high, making it difficult to be able to forage, labor, fight or flee. Two of these messengers, called adipocytokines, are resistin and adiponectin. Resistin increases insulin resistance and inflammation (two traits leading to type 2 diabetes, ASCVD, etc). Testosterone therapy on hypogonadal men with type 2 diabetes had no effect on resistin levels.²² Adiponectin appears to play a protective role, and its concentration rises as fat is lost. Oddly, adiponectin levels were higher in hypogonadal men than men with normal testosterone of the same weight. Testosterone treatment reduced visceral obesity (the fat around the organs in the gut, which is believed to be particularly harmful), but also reduced adiponectin. One would have expected the opposite; researchers thought that testosterone reduced the number of fat cells, reducing the production of adiponectin. It is just as important to acknowledge studies that show no effect or even negative effects associated with testosterone, to gain a full understanding of the hormone’s effects.

Insulin resistance and type 2 diabetes are important factors to consider in determining one’s risk for a heart attack. Again, when looking at groups of people, it is clear that testosterone has an inverse relationship with insulin resistance and type 2 diabetes.²³ In fact, low testosterone is often a precursor to the development of type 2 diabetes.²⁴ As testosterone decreases, insulin resistance increases, forcing the body to maintain a higher insulin concentration to shuttle nutrients into muscle and other tissue. As insulin levels remain elevated long term, fat loss is inhibited and fat gain results. Treating type 2 diabetics with testosterone reduces blood sugar and insulin resistance, demonstrating a beneficial effect in a condition affecting many men— and potentially reducing the risk of heart attack in those suffering from the condition.^25,26

Another marker, hemoglobin A1C (HA1C), was reduced during testosterone therapy. Recently, a collaboration of professional agencies jointly changed how diabetes is diagnosed. From the onset, diagnosing diabetes was dependent upon fasting blood sugar and a more specific test called the oral glucose tolerance test. These tests looked at how the body handled sugar in the short term. Now, clinicians are being urged to look at long-term blood sugar control measuring HA1C.²⁷

Testosterone Therapy Has Many Benefits

There does not appear to be just one effect leading to the improvements seen with testosterone therapy— rather, a multitude of effects. Testosterone appears to reduce insulin resistance by reducing visceral fat, which decreases inflammation and fatty acid delivery to the liver—reducing body fat, and improving mitochondrial function (the powerhouse of the cell).¹³ As testosterone concentration drops, its inhibitory effect of fat cells also drops, allowing body fat to increase. Unfortunately, this leads into a vicious cycle as fat cells contain an enzyme called aromatase, which converts testosterone to estrogen.²⁸ Not only does estrogen increase fat storage, but along with two adipocytokines (chemical messengers released by fat cells) and the hormone leptin, it reduces the sensitivity of the body to low testosterone— causing the body to fail to increase testosterone production from the testicles, as levels fall. This results in yet lower testosterone status, feeding the cycle toward greater obesity and insulin resistance.¹³

The strongest argument against testosterone has been its effect on cholesterol, raising the total amount of cholesterol while lowering the amount of HDL (good) cholesterol. However, there is more to the story than appears on the surface. Within the physiologic range, total cholesterol and LDL (bad) cholesterol both are reduced as testosterone concentration goes up.^29,30

The relationship between testosterone and HDL cholesterol is less clear. HDL has been shown to be highest in those whose testosterone is in the top 25 percent of the physiologic range. However, other studies have shown the opposite. The confusion seems to rise from the variability of the people studied and the dose of testosterone used, if given as therapy.¹³ It appears that supraphysiologic dosing (using amounts greater than the body would naturally produce) produces changes that are unhealthy in a dose-dependent manner.³¹ Once again, the health benefits of testosterone appear to reside within the ‘human range.’ Exactly where the best benefits are located in that range is a topic that should be of great interest to the health professions.

Individuals with high blood pressure (hypertension) are also at greater risk of a heart attack. Given the direction of this article, it should be of no surprise that once again, low testosterone is associated with hypertension, which resolves with treatment in many subjects.³² In keeping with the theme of the human range, supraphysiologic testosterone (or other anabolic steroids) may also increase blood pressure dangerously.³³

Inflammation is a major component of ASCVD. As LDL cholesterol embeds itself into an artery wall, it attracts inflammatory cells which cause it to form a crusty plaque— think of a pimple. This plaque can grow until it blocks all blood flow, or it can burst like John Belushi’s re-enactment of a zit explosion in the movie “Animal House.” If the plaque bursts, platelets and clotting agents rush to shut down blood flow, causing an immediate blockage. The inflammation is dependent upon chemical messengers to create the ‘crustiness’ and damage the artery wall. In a setting of low testosterone, the conditions are pro-inflammation; treatment with testosterone reduces the inflammatory signal.¹³ In fact, testosterone has even been provided prior to coronary stenting (placing a tube in the arteries of the heart to re-open an area of blockage).³⁴

A general marker of inflammation is a protein called CRP. Ideally, CRP concentration would be inverse to testosterone (high CRP when testosterone is low, and vice versa). Unfortunately, published studies are not in agreement.¹³ However, in men with prostate cancer who are chemically castrated (their testosterone production is blocked with drugs), CRP levels increase.³⁵

The size of an artery’s opening not only depends on how ‘clean’ the insides are, but also on how much the artery can expand or dilate. Most readers will be familiar with the claims of supplements that increase nitric oxide (NO). NO causes the arteries to open up, increasing blood flow. The ability of arteries to open is called ‘vasoreactivity.’ As the heart works harder or suffers from a lack of oxygen due to ASCVD, the arteries need to open up to provide oxygen to the working heart muscle. When this need is not met, the heart suffers damage and people feel chest pain called angina. Testosterone was originally used to treat angina over 60 years ago.¹³ Low testosterone is also associated with low vasoreactivity in other arteries, such as those feeding the penis during an erection. Testosterone therapy has been shown to be an effective treatment of erectile dysfunction, even in some men who do not respond to Viagra-like drugs.³⁶

Not only does the artery need to function, it also needs to repair itself. The artery repairs itself when healing precursor cells attach to damaged areas. These cells decrease in number as a person ages and as testosterone concentration decreases.^13,37 Test tube studies show that these healing cells generate under the influence of testosterone; a clinical study in healthy men with normal testosterone showed that testosterone treatment increased the activity and growth of these cells.³⁸

Contrary to the evidence in this review, there are also unforeseen concerns relating to androgen use, especially in excess, as well as in addition to other anabolic hormone (i.e. GH, IGF-1, insulin, etc). In addition to injury to the blood vessels, the heart may also be directly injured by hormonal imbalance/excess, resulting in a condition known generally as cardiomyopathy.³⁹

The failure to search for the benefits of testosterone has delayed the advent of an inexpensive and relatively safe therapy for a number of ills facing the male members of mankind. As has been shown in this review by Jones and Saad, low testosterone, even low-normal testosterone, may predispose adult men to a greater risk of ASCVD or other cardiovascular events. Where a man’s testosterone concentration should be to confer the greatest health benefit is still undetermined, but it appears that the top 25 percent of the ‘normal’ range is healthier than the lower third.

Is it reasonable to assume that men should target a testosterone concentration near the top of the ‘human range?’ Not from a clinical or scientific point of view, as that question has not been fully explored. However, is it proper for the medical profession to restrict testosterone therapy only to men who are dramatically below the normal range? What about restricting treatment to ‘barely correcting’ within the physiologic range?⁴⁰

In the reactive culture of American policy, physicians and state boards are choosing to err on the side of caution, restricting testosterone replacement to the bare minimum. If the spirit of the Hippocratic oath is to be adhered to, that being to do no harm, the cautionary guidelines relating to testosterone therapy may be violating this most basic edict.

What does this mean to bodybuilders and athletes who use testosterone to provide a supraphysiologic concentration to enhance muscle growth? The failure to study this, despite decades on awareness of the use of these agents, reflects poorly on U.S. policymakers. It is reasonable to assume that a similar increase in adverse effects would be present in a dose-related manner. What is the optimal concentration of testosterone for a man with regard to health? It is unknown at this time, but early suggestions support investigating the range of 700-1,000 ng/dL; as opposed to the 300-400 ng/dL that is state-of-the-art therapy. As to anabolic steroids other than testosterone, it is impossible to say what added benefits or risks they may offer, as they are chemically different from testosterone.

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