Uh-oh. Just when you guys thought it was safe to go in the water, up from the deep comes this pronouncement from our medical system that testosterone treatments may cause heart attacks and strokes.
The Associated Press said: “Testosterone treatments may increase risks for heart attacks, strokes, and death in older men with low hormone levels and other health problems, a big Veterans Affairs study suggests.”
The article goes on to say, “Men who used testosterone were 30% more likely to have a heart attack or stroke or to die during a three-year period than men with low hormone levels who didn’t take the supplements.”
That sounds pretty bad! Maybe I better stop taking my testosterone injections while there’s still time?
Unfortunately, the pronouncement scared a lot of men out of using their testosterone.
And I received a lot of calls asking me what they should do about the testosterone I prescribed for them? Many of them asking me what I was going to do.
Well, here’s what I did: I read the study.
This study involved 8,799 men who were receiving treatment in the VA system between 2005 and 2011. All of the men had testosterone levels less than 300 ng/dl. This is below the so-called “normal level.” The doctors gave 1,213 of them a testosterone supplement either by injection or by a topical gel. The other 7,486 men did not receive testosterone. Here’s what happened.
In the no testosterone group 9% died, 5.6% had a heart attack, and 6.5% had a stroke. The testosterone group did much better: 5.4% of them died. That’s about half as much. Another 1.8% had a heart attack. That’s about one-third as much. And 2.6% had a stroke. That’s about half as much.
So wait a second, I said to myself. How can it be that the conclusion the authors reached is that testosterone therapy increased risks when the actual numbers tell a completely different story? So for the next hour I went crazy looking for the answer. And wait until you hear what it is.
The numbers I gave you were correct. The men taking the testosterone were about one-half or less likely to die of anything, have a heart attack, or have a stroke than the men not getting any testosterone.
Why Were The Numbers “Adjusted”?
The reason that the conclusion was completely different is that the numbers were “adjusted.” According to the authors, the numbers were changed using “stabilized inverse probability of treatment weighting for any unmeasured cofounders.”
This means that the authors made arbitrary adjustments to the results that were supposed to make them more statistically accurate. I have to tell you that for me, this changes everything. When the results of a study show one thing and then the numbers are “adjusted” so that the results are the exact opposite, I am more than a little skeptical. But there are more reasons to be skeptical of this study than just this.
One of them is that these “adjustments” completely fly in the face of every other study published showing that testosterone replacement saves lives and protects against heart disease.
Do Numbers Lie?
One of these studies is especially interesting. That’s because it used the same study design. And, surprisingly, it also came from the VA. The only difference between the way the researchers analyzed the results in this study and the first study is that they used a different method to adjust the numbers.
In this study, the researchers followed 1,031 men with low testosterone levels for four years. They gave 398 men testosterone supplements by either injection or topical. They just left the other 633 men with their low levels. The overall death rate in the testosterone group was 10.3% compared to the 20.7% death rate of the men not supplemented.
This amounts to one-half the risk – almost the exact same results (before they were adjusted) as the first study! But let’s go back to the first study again. There are some other points I want to make.
After the researchers adjusted the numbers, which initially showed testosterone to cut the risks in half, the results came out completely different. According to the adjusted results, nearly 26% of the men using testosterone either died, had a stroke, or had a heart attack. That’s opposed to only 20% of the men who did not get testosterone.
According to the new numbers, men taking testosterone supplements are in danger. They are 6% more likely to die or have a stroke or heart attack than if they did nothing.
Adjusting for the Truth
So just for kicks, let’s assume the study results are in fact accurate. How could it be possible that men with such low levels of testosterone would be in danger by increasing their levels? Young men have much higher levels and they are in less danger ... not more. On the surface, the idea just doesn’t make sense. Might it have something to do with the overall health of the men in the study?
Unlike most other studies on testosterone, the men in this study were not healthy men. Every single one of them had coronary artery disease, which doctors had proven with coronary angiograms. Some of them had already had a heart attack and some already had stents and angioplasties. Many of them also had high blood pressure, diabetes, obesity, lung disease, sleep apnea, kidney disease, and heart failure.
Previous studies done on healthy men have had completely different outcomes. So why would a man who already has heart disease and any of these other problems be at a greater risk from taking testosterone? I can think of three reasons.
3 Things the Researchers Missed
First, a mistake that many doctors make when they give testosterone to their male patients is that they fail to check estradiol levels. This is a big mistake.
Men, especially older men and men with high blood pressure, obesity, and/or diabetes have an excessive activity of the enzyme aromatase. I have talked about aromatase before. But let me just remind you that this is the enzyme that converts testosterone to the female hormone estradiol.
When men receive testosterone therapy something happens three-to-four months later. Due to the effect of aromatase, it is very common that all that good testosterone they are getting is raising their estradiol levels.
And what does estradiol do? When elevated, it causes blood clotting elements in the blood called platelets to start sticking together. This leads to clot formation. And an increase in clot formation is one of the major reasons for heart attacks and strokes.
There is no indication that any of the men in the study ever even had their estradiol levels checked, much less controlled for. This is a big mistake and could possibly be the key reason for the poor results.
Here’s a Second Problem
Testosterone is an anabolic hormone. That’s one of the major reasons why it’s so good for men as they get older. Anabolic hormones build up tissues. Specifically lean body mass like bone, muscles (including the heart muscle), ligaments, tendons, and skin.
But anabolic hormones also build up the blood. They cause an increase in the immune cells and also the red blood cells. And that could lead to a problem.
When a man gets testosterone, his red blood cell count will increase – sometimes by a lot. And if the blood count increases too much, a bad thing happens. The blood gets too thick and viscous and it can’t circulate well.
Normally, in most men, a slight increase in the blood count does not matter. But in this group of men who already have a significant decrease in their circulation, it might make the difference between life and death.
The authors of the study did consider this fact. They did not include men whose red blood cell count was over 50%. However, for unhealthy men, even a higher red blood cell count below 50% might be excessive. I carefully monitor the red blood cell count of all my patients on testosterone and I want it to be no higher than 48%.
The Last Problem Is a Real Pet Peeve of Mine
The last thing is a mistake that doctors commonly make when deciding who needs testosterone replacement and who doesn’t. And that is that they rely too much on laboratory tests. You cannot determine whether or not a man can benefit from testosterone replacement simply because he has low blood levels.
Some men with normal levels of testosterone need replacement. And others with low levels don’t. This is a very important point and is extremely misunderstood. Here’s why simply looking at a hormone level is a poor way to decide who needs that hormone.
Hormones are signaling molecules. They signal cells to start and stop certain processes. But they don’t do that by actually entering the cell. They do it by interacting with hormone receptor molecules on the surface of the cell. Every hormone has certain special receptor molecules on the surface of cells that it can interact with. So when a testosterone molecule approaches a cell, it has to find a testosterone receptor molecule on the surface of the cell. When it finds it, the hormone can bind onto it and interact with it.
This interaction is what stimulates changes in the interior of the cell. So you can see that there is more than just the hormone itself that is responsible for the effects of the hormone. The other determining factor is the number of receptors for that hormone on the surface of the cells.
When a cell decides it needs the effect of a particular hormone, it increases the number of receptors on its surface. When it decides it needs less of the hormone effect, it decreases the number of receptors.
This is why testing for testosterone levels is so misleading. A man may have low levels of testosterone but high levels of the testosterone receptors. In that case, he doesn’t need any testosterone replacement.
On the other hand, another man may have normal levels of testosterone, but a low number of receptors. In that case, he needs testosterone replacement despite the fact that his levels are in the normal range. This is why there is such an incredibly wide range of values for the normal range.
And here’s the problem. We have no way to test for how many testosterone receptors a man has. So how should a doctor determine if a man needs testosterone or not? It’s not that hard.
Your Body Determines the Need
If a man needs testosterone, he will have symptoms and signs and conditions indicating it. The primary symptoms are decreased libido, moodiness, depression, erectile dysfunction, cognitive decline, weight gain, decreased stamina, weakness, loss of muscle mass, aches and pains, and poor recovery from exercise.
Common signs and conditions are decreased bone density, muscle loss, sagging muscles, loss of body hair, hair thinning, heart disease, diabetes, and sleep apnea.
Of course, not all men with testosterone deficiency will have all of these symptoms and signs. But if a man has enough of them, the next part of determining if he needs testosterone replacement is to give it to him for three months and see what happens.
If his symptoms go away or become significantly better, it’s obvious that he needs the hormone. If they don’t, then it’s clear that he doesn’t. Your doctor can use testosterone blood levels to help adjust the dose over time, but they are useless to determine if a man needs the hormone or not.
What Doctors Should Do
So doctors need to pay attention to what they are doing when they dish out testosterone. First of all, they should forget blood levels (or any other levels for that matter) and determine who needs testosterone based on signs, symptoms, conditions, and a clinical trial. Otherwise many men will be getting the hormone when they shouldn’t, and others will not be getting it when they should be.
Second, any man on testosterone replacement needs to have his red blood cell count (hematocrit) and his estradiol levels checked on a regular basis. The hematocrit should never be above 48% and the estradiol levels should always be less than the upper limit of normal and less than one-twentieth of the testosterone levels.
Lastly, and this is extremely important, men on testosterone therapy need to be in the gym pumping iron for at least one hour three times a week. Why? Because this creates a demand for testosterone and their cells will maintain a good number of receptors. Without the resistance training, their cells will decrease the number of testosterone receptors after they are taking the hormone for a few months and the effects will decrease.
You can find a doctor trained in male hormone replacement at www.a4m.com.
Shores, M.M., N.L. Smith, and C.W. Forsberg. “Testosterone treatment and mortality in men with low testosterone.” J Clin Endocrinol Metab, 2012 June;97(6):2050-8.
Tanner, Lindsey. “Testosterone treatments linked with heart risks,” Associated Press, November 05, 2013.
Vigen, R., C. O’Donnell, A. Baron, et al. “Association of testosterone therapy on men with mortality, myocardial infarction, and stroke in men with low testosterone levels.” JAMA, 2013;310(17):1829-1836.