Testosterone and cardiovascular disease

Over the past few years, testosterone replacement therapy (TRT) has gone from fringe to mainstream.

TRT doesn’t mean the type of anabolic steroids that bodybuilders use.

Testosterone replacement in this context means treating “Low T,” the epidemic of low testosterone levels that are impacting an increasingly large number of men.

Over the past few years, this issue has received varying amounts of press, and I wouldn’t be surprised if it crossed your radar.

And, no, 2023 is not the end of men, even if societal testosterone levels are declining.

But I have been seeing this increasingly in my clinical practice, and so I read the recent article on the cardiovascular safety of testosterone therapy (TRAVERSE trial) published in NEJM with great interest.

The group with low testosterone is not a homogeneous population

The reference range of normal levels for testosterone range from 300-1000 ng/dL, which is a pretty large range.

And this doesn’t even get into a discussion of the difference between free and bound testosterone, which further complicates things.

Testosterone levels probably change with age, going down as we get older.

Even though someone with a testosterone level of 300 and someone with a testosterone level of 1000 are both in the normal range, they likely have very different physiologic experiences related to sex hormone levels.

A wide range introduces a lot of confusion in making a true diagnosis of who has low T, not to mention the way that reference ranges change over time in response to changes across a population.

Based on the patients that I’ve seen, I’m convinced that a lot of doctors that treat low T don’t actually have much of an idea of what they’re doing.

The cardiac safety of testosterone has not been well studied

Despite the increasing popularity of TRT, before TRAVERSE we didn’t have much in the way of large randomized trials looking at the safety of testosterone therapy.

The prior data had conflicting information, with some studies suggesting increased cardiac risk from TRT while others suggested TRT reduced cardiac risk.

And the anecdotal evidence from the bodybuilder community (the most well-publicized exogenous testosterone users) suggested the possibility of risk.

I’ve certainly seen patients in my clinical practice with anabolic steroid induced cardiomyopathy or testosterone related heart attack to due increased viscosity (at least partly mediated by increase in red blood cells).

So enter TRAVERSE, a study designed to help us guide regular patients with low testosterone on the cardiac safety of TRT.

Before we discuss TRAVERSE, just know that this isn’t an article on the benefits of TRT

Despite its increasing ubiquity, there’s considerable doubt on the effectiveness of testosterone replacement therapy.

While low testosterone levels are associated with lots of negative symptoms - depression, low libido, difficulty maintaining muscle mass, decreased functional capacity, poor sleep, the list goes on - there isn’t great evidence that replacing testosterone makes all that much better compared to just using a placebo.

After all, a lot of what influences testosterone levels is the same type of lifestyle stuff that makes people feel better.

If you want to naturally raise testosterone, you need to eat enough protein, lift weights, stay aerobically active, sleep well, reduce stress, and, especially, lose body fat.

And so I suspect that low testosterone is often a proxy for unhealthy lifestyle - too much junkfood, too little exercise, too much body fat, and too much TV.

There are certainly a subset of people who will have a massive quality of life benefit from TRT, but getting a prescription for testosterone cypionate isn’t a magical elixir for everyone who has a single blood test demonstrating low T.

TRAVERSE doesn’t actually tell us much, unfortunately

The top line result looks promising for the safety of TRT:

If you look at each of the individual endpoints, you see there isn’t much difference anywhere, although there is the suggestion that testosterone therapy may be linked to blood clots (look at venous thromboembolic events near the bottom) that warrants further follow up:

And the headlines suggest that testosterone therapy is totally safe:

But the reality is that TRAVERSE doesn’t actually answer many questions.

Look at the levels of testosterone achieved in the T group versus placebo:

Most people who treat patients in this realm will tell you that a testosterone level of 350 ng/dL (which is what they achieved in the TRT group) isn’t all that great.

Patients on exogenous testosterone will shoot for way higher levels in treatment.

So TRAVERSE looks at a small increase in testosterone that is less than what is targeted in most treatment and finds no major change in cardiovascular risk.

Ultimately, TRT is an area of medicine where the questions exceed the answers

The unknowns here are pretty extensive.

• What happens when TRT leads to higher testosterone levels?

• What are the long term consequences (4 years isn’t much time when it comes to cardiovascular disease)?

• How much does TRT actually help compared to a placebo?

• Is there a dose dependent risk in blood clots?

• How do you figure out who really needs TRT versus who will have testosterone levels raised to normal levels by eating better, working out more, and getting some sleep?

But there are a few things I feel comfortable making educated guesses on.

Do I think that supplementing low testosterone levels is safe from a cardiac perspective?

Probably.

Do I think that there are some patients who will benefit from TRT from a quality of life perspective?

Absolutely.

But do most of the people on TRT benefit?

I doubt it.

This is an area of medicine where I suspect that a lot of the people offered TRT are being kind of ripped off.

I’ve seen some really smart, well-off patients who I think are being scammed by doctors who offer a diagnosis and treatment plan (if you pay cash) after a single non-diagnostic blood test and some vague symptoms.

Whenever there’s a gray area in medicine - amorphous symptoms, complicated diagnostics, overlap between true medical condition versus lifestyle effect - there is necessarily going to be some difficulty in separating the wheat from the chaff.

When we get more data, I’ll weigh in with more concrete thoughts, but for now, my overall perception is that when it comes to TRT, the risks are fairly low and so are the benefits.