Does testosterone replacement therapy increase chances of heart attack and stroke
As usual, there may be heart attacks and strokes caused by poor treatment
One of my students posted lab results which I reviewed with him and what struck me is that his testosterone levels are very low.
He has had a stroke at some point.
So his doctor said “I don't recommend testosterone replacement therapy to you because it increases the chances of stroke or heart attack.”
There are studies that show this is true.
But the studies are based upon high dosages of esterified testosterone rather than plain testosterone.
Testosterone enanthate, cyprionate, undecanoate, and other esters are not the same as regular physiological testosterone.
And the dosages are generally quite high compared to the normal amount a healthy male produces in the average day.
The average healthy male produces 2 - 5mg per day.1
And yet, typical doses given are as follows.2
Testosterone Undecanoate: 750 mg (3 mL) IM injection followed by 750 mg (3 mL) injected after 4 weeks, then 750 mg (3 mL) every 10 weeks thereafter
Testosterone Enanthate and Cypionate: 50 to 400 mg IM injection every 2 to 4 weeks
Just for example, let’s take the Undecanoate dosage. This amount would equal 25 milligrams per day.
This is 5 times higher than the normal amount produced by a healthy younger man.
I see this all the time. Dosages are much higher than physiological production.
So with that in mind, let’s look at a study.
Researchers studied two groups of men:
1. Ever-TRT Group (got testosterone therapy): 8,808 men, average age 58, 1.4% had heart problems before.
2. Never-TRT Group (didn’t get testosterone): 35,527 men, average age 60, 2% had heart problems before.
They tracked these men for about 3-4 years. Here’s what they found:
• People who didn’t get testosterone therapy had more heart-related issues (about 24 per 1000 years) than those who did get therapy (about 17 per 1000 years).
• Testosterone therapy seemed to lower the risk of heart problems by 33%.
• For strokes, testosterone therapy lowered the risk by 28%.
• For heart attacks and other serious heart issues, it lowered the risk by 34%.
So, testosterone therapy might actually help reduce heart problems for men.
And I believe that if they administered reasonable doses of real testosterone, there would be an even GREATER improvement in men given TRT, over men who are low T and who are not given extra testosterone.
Plus, men given TRT will feel a lot better and experience easier time building muscle mass.
But — the problem is that so many of the studies are done with the very high doses of testosterone replacement therapy.
They're all too typical today.
Therefore, give men too much testosterone, and they may have some problems.
But maybe — if you give men enough testosterone to replace the normal levels, they will experience better health, less cardiovascular disease and fewer strokes.
Let’s investigate this.
Men who are older and who have very low testosterone in their bodies, in other words, how do hypogonadal men do with respect to heart disease and stroke?3
This study used data from the NHANES ongoing study to see if low T was linked to inflammatory markers — namely CRP, and high liver enzymes ALT and AST.
They followed 776 men in Germany who had low T and who did NOT receive TRT for up to 11 years.
These men were 1.8 times more likely to have high CRP levels, showing lots of inflammation. And 1.5 times more likely to have elevated liver ALT enzyme.
As some men were treated with TRT, their CRP and liver enzymes declined.
There are a number of such studies if you really look. Men who have low T should consider TRT that uses responsible reasonable levels of testosterone, not super high levels of esterified testosterone.
It definitely pays to experiment with testosterone replacement therapy done right.
This may involve testosterone and vitamin E co-administered topically. In one rodent study, there was an incredibly protective effect when both T and E were administered together.4
The belly button is an excellent site for this co-administration due to high absorption.
I’ve had very good success personally. I use just a few milligrams mixed with vitamin E liquid and put into my belly button in the morning.
I have found that T levels can remain in the body for the entire day — and this is a physiological dose rather than a huge dose of a esterified testosterone. As a result, it is less likely to down-regulate my natural T production.
https://academic.oup.com/jcem/article-abstract/82/5/1492/2823365
https://www.drugs.com/dosage/testosterone.html
https://journals.sagepub.com/doi/full/10.1177/10742484211032402
https://www.researchgate.net/profile/Adebayo-Opabunmi-2/publication/301645292_Exogenous_Testosterone_and_Vitamin_E_Ameliorates_Diabetes-induced_Necrosis_of_the_Pancreas_Lipid_and_Testicular_Disorders_in_Male_Wistar_Rats/links/652044803ab6cb4ec6c0a8f9/Exogenous-Testosterone-and-Vitamin-E-Ameliorates-Diabetes-induced-Necrosis-of-the-Pancreas-Lipid-and-Testicular-Disorders-in-Male-Wistar-Rats.pdf
The loading dose for testosterone undecanoate is used to shorten the time required to reach steady-state levels due to its extremely long half-life.
You can plot the pharmacokinetics via the various steroidcalc apps available and see that the loading dose never produces a mg released p/d of testosterone above that seen at steady state — it only serves to reduce the time taken to reach steady state.
Accordingly, it's inappropriate to factor the loading dose(s) into your calculation of the average testosterone dose per day.
750mg testosterone undecanoate IM every ten weeks = ~ 10 mg testosterone undecanoate per day.
10mg testosterone undecanoate provides ~ 6mg of actual testosterone after the weight of the ester has been accounted for (your calculations did not factor in ester weight and assumed that 1mg testosterone undecanoate = 1 mg testosterone, which it does not; testosterone undecanoate is approximately 63.15% testosterone by weight).
There is ample data suggesting that young, healthy males can produce up to 8 - 10mg of testosterone daily.
The only study to ever show an increased risk of ASCVD from testosterone replacement was a retrospective analysis of an insurance database that did not even verify whether or not the testosterone was taken, only that it had been, at some point, prescribed at least once. Further, it also compared rates against the general population, not men with low testosterone who went untreated.
Accordingly, if a significant proportion of those men did not start or continue treatment after the first prescription (which is very common when you look at the data on long-term adherence to TRT), all that data shows is that men with low testosterone experience ASCVD at a greater rate than men with normal serum levels, something we already know.
The rest of the data on the topic all show an improvement in cardiovascular health when compared to men with untreated hypogonadism.
With all of the above considered, I'm not sure how one can argue that the way in which testosterone is currently being administered is 'incorrect' or 'unphysiological' given it largely matches endogenous production and the interventional data in humans shows universal benefit.
These are all the same critiques of TRT presented within the Ray Peat community: critiques that don't hold up to scrutiny nor reflect the real-world clinical outcomes seen in actual men on TRT.