Is TRT Safe? Here's What a Big New Study Says

Testosterone Replacement Therapy: The Final Verdict

One month the medical establishment says TRT is safe. The next month they say it’s going to kill you. Which is it? Finally, some answers.

Is TRT Safe? The Final Verdict

In 2016, the FDA hurriedly issued some new warnings about the serious adverse health outcomes associated with testosterone replacement therapy (TRT). Their statement, a dictum to drug companies to shore up the labeling on testosterone packaging, contained the following warnings:

“Reported serious adverse outcomes include heart attack, heart failure, stroke, depression, hostility, aggression, liver toxicity, and male infertility.”

Oh my, fire and brimstone coming down from the skies! Rivers and seas boiling! The dead rising from the grave! Human sacrifice, dogs and cats living together!

Sorry for being so glib about this whole issue, but I’ve spent most of my professional career studying testosterone and its effects and Boss, I gets tired having to repeatedly whack the head of this particular mole.

But the FDA didn’t stop with a warning. They also restricted testosterone approval to cases of hypogonadism caused by documented pituitary or testicular disease, specifically excluding age-related drops in the hormone, i.e., testosterone replacement therapy.

Many doctors and patients bought into the announcement. They stopped prescribing/using TRT. The vitality of patients lagged and their muscle mass waned. Libidos flagged and so did erections. Wives and sexual partners in general bought lots more batteries for their personal devices while casting lascivious glances at phallic squashes at the grocery store.

Fortunately for all those people, a solid meta-study (a study that combines results from previous separate but related studies) was just published and it implies responsible TRT is not only safe but might also exhibit “reverse causality,” i.e., TRT might actually lower the risks of cardiovascular events instead of raising them.

So, What Made This Study Different?

Use-Testosterone-for-Heart-Health

The aim of Jemma Hudson and her 37-member team of researchers was to “provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyze subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD.”

They cast their database nets into the turbulent information sea and pulled in 9,871 citations. After excluding duplicates and those that were deemed irrelevant, they kept 225 and tossed the rest back in. Of these, only 35 (comprising 5,601 participants) of them were deemed suitable for inclusion in their study.

After painstakingly teasing the data apart, they found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism.

The Specifics

Testosterone-Testing-Is-Completely-Bogus

Of the 35 studies that comprised their catch, 17 of them provided those individual data sets I mentioned in the previous chunk of text. (These types of studies are particularly valuable because they incorporate placebo groups.) These 17 studies included 1,750 men who’d been using TRT and 1681 who were in the placebo group.

The mean age was 65 and the mean BMI was 30 (definitely portly, to be kind). Many had diabetes, angina, or had experienced previous myocardial infarction. The mean duration of testosterone replacement was 9.5 months (the range was 12 weeks to 3 years).

Here’s a rundown of some of their findings:

  • 82% of the studies addressed mortality. The testosterone group reported fewer deaths from any cause than the placebo group, but the difference didn’t reach statistical significance.
  • 76% of the studies provided data on cardiovascular or cerebrovascular (loss of blood flow to the brain) events. The testosterone group reported slightly more (120) deaths than the placebo group (110), but again, it didn’t reach statistical significance.
    That being said, post hoc (after the fact) sensitivity analyses (an examination of how changes in methods, models, or values of unmeasured variables affected results) implied that the risk of cardiovascular or cardiocerebral events went down after TRT was brought into what’s considered a high-normal range.
  • Both serum total cholesterol and triglycerides were significantly lower in the testosterone groups, although, as is usually the case, TRT appeared to modestly lower levels of HDL more than the placebo group.
  • There appeared to be no difference in the blood pressure between the two groups. The same was true for glucose sensitivity or A1C (a measure of average blood sugar over the previous three months).
  • Hemoglobin and hematocrit were higher in the TRT groups and the number was statistically relevant. This is to be expected, though, as testosterone therapy suppresses hepcidin, a regulator of iron levels, and iron levels directly influence red blood cell production. However, only 5 cases of deep-vein thrombosis were reported in the testosterone groups, compared to 7 in the placebo group.
  • Lastly, there was no difference in the groups as far as incidence of prostate cancer.

What The Team Had To Say About All That

Unlike most studies, Hudson’s group was pretty confident in its assertions. Most research papers hem and haw until the cows either come home of their own volition or were brought there by a random sequence of events, perhaps precipitated by some unknown or hitherto unrealized reasons. More research is needed on these cows and their homeward tendencies.

You get the idea. Anyhow, her group punctuated their findings by writing the following:

"The most frequently recorded cardiovascular event categories in the identified trials were arrhythmia, coronary heart disease, heart failure, cerebrovascular events, and myocardial infarction. We have also identified and reported frequencies of stable angina, peripheral vascular disease, aortic aneurysm, and aortic dissection, which have not been reported by any previous meta-analysis.

“None of the cardiovascular event subtypes were significantly more common in patients assigned to testosterone treatment than in patients assigned to placebo.”

And later in the paper, the group doubles down, even getting a little cocky:

“We have conducted the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism. Testosterone treatment did not increase cardiovascular event risk in the short term to medium term. So there.”

Okay, I added the “so there,” but I could sense that’s what they were itching to add.

Roll Up This Paper And Thump Your Doctor On The Head With It

The-Top-3-Myths-About-Testosterone

Here’s where I put on my grown-up, Robin Hood-style hat with a feather attached and do a little of my own hemming and hawing. While the data compiled by Hudson and her colleagues was comforting, I need to remind everyone that the mean duration of TRT was 9.5 months. It’s possible that being on testosterone for longer periods, say years, might have some different effects on cardiovascular health or overall health.

No one knows for sure. Additionally, the research they compiled used sane, standard dosages of TRT, not amounts that require a syringe barrel that’s as big as a turkey baster.

Still, this study is a good one to toss at your physician if they push their glasses up against their nose and start wagging their forefinger at you and begin droning on about how testosterone replacement therapy will turn you into a dead man walking.

Reference

Reference

  1. Hudson j et al. **Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.**Lancet Healthy Longev. 2022 Jun;3(6):e381-e393. PubMed.
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There is no data that says a man with age related low-T can’t benefit from TRT, in fact studies are already showing it does, especially related to bone density.

The leading experts on testosterone say there is no data that currently shows TRT causes heart attacks.

I wonder where the FDA is getting their data.

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Ok, so it does appear to kill you, in-fact may help in certain areas. Riddle me this. How does TRT effect BPH? If you have early signs will it make it worse?

My understanding is it has to do with DHT, which is converted from T.

Maybe this is the right answer.

Testosterone Replacement Therapy and LUTS/BPH. What is the Evidence?- Beyond the Abstract

July 13, 2016

An FDA mandated warning on all testosterone products states that testosterone replacement therapy (TRT) in men with benign prostate hyperplasia (BPH) “increases the risk of worsening signs and symptoms of BPH”. This warning appears to be based off the commonly held notion that prostate growth is proportional to testosterone levels, despite evidence to the contrary. In this review article we explored BPH/LUTS and its interplay with testosterone. This included an overview of the physiology of testosterone interactions with the prostate and lower urinary tract, as well as a review of literature pertaining to TRT’s effects on LUTS/BPH.

In terms of physiology, testosterone actually appears to be beneficial for the prevention of LUTS/BPH.1,2 Studies have suggested three major contributors to LUTS/BPH: nitric oxide deficiency, autonomic hypertonicity, and pelvic atherosclerosis. Among other things, these entities result in pelvic ischemia and chronic hypoxia of the bladder and prostate, which has been associated with LUTS/BPH.3-6 Sharing a similar pathway with phosphodiesterase-5 (PDE-5) inhibitors, testosterone has been shown to alleviate this hypoxia by modulating cGMP-mediated nitric oxide production.7-10

The notion of prostatic growth being proportional to testosterone levels likely stems from the sentinel papers of Huggins et al in the 1940s, in which castration resulted in prostate cancer regression and T administration caused prostate growth.11 Of note, this landmark study was comprised of only one patient, and involved prostate cancer rather than normal prostatic tissue, which may have influenced the results. More recent evidence suggests a saturation model to prostatic growth, with androgen receptors becoming saturated at near castrate levels.12 This makes sense given that prostate volume has been shown to increase with time regardless of testosterone levels. As such, men continue to have prostate growth despite waning bioavailable T with age, and young men do not see a spike in prostatic growth with high T levels seen in early adulthood (Figure 1). It is also worth noting that increasing prostate size does not correlate with worsening LUTS/BPH, as has been shown by numerous studies.13,14 Thus the antiquated idea of testosterone fueling prostatic growth still should have no bearing on urinary symptoms.

Figure 1: Graph of bioavailable T, SHBG, and prostate volume with age. Note increasing prostatic volume increase despite lowering levels of bioavailable T.

Graph created with raw data from St. Sauver et al and Muller et al.

Finally, to date there are multiple studies that have shown there to be no relationship between TRT and worsening LUTS/BPH. On the contrary, some studies have suggested improvements of LUTS with TRT, likely through the mechanisms mentioned above. It is the authors’ opinion that TRT is not a risk factor for LUTS/BPH and the warning set forth by the FDA likely needs reevaluation.

Written by: Wesley Baas and Tobias S. Köhler, Division of Urology, Southern Illinois University School of Medicine, Springfield, IL, USA.

Wasn’t this in response to all those commercials with old dudes claiming to turn the clocks by by going on androgel? IMO that’s a failure of our medical establishment and laws concerning what pharma can and can’t say in a TV ad.

All of the studies from 1900s show that T was beneficial. these f insurance companies and pharmaceutical companies are the ones suppressing the data. the government does not and will not ever make good decisions for society. they are not a business. they do not have our best in mind at all.

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The DHT in the prostate is not effected by the rest of the bodies DHT levels. Its having its own enviornment or whatever you would call it.

Again, the studies are out there, but doctors are hand fed the studies to continue with prostate surgeries and status quo.

Imagine if the truth came out. how many doctors pharmaceutical and hospitols would lose revenue due to the fact that their current procedures are not needed.

Same with T. It lowers diabettees/ stops it from becoming a serious issue and will reverse for men who start TRT. You will fix your cholestoral issues and blood pressure… libido issues. imagine how mcuh revenue is lost when many men in the world would realize that they just have a low T problem and dont need to spend hundreds or thousands on all these damn pharmacetuicals they prescribe us. instead a 30% vial of cypionate does the trick.

some shite man.

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TRT saved my life, otherwise I be close to dead by now!

Five years ago my legs were freezing cold to the touch, heart palpitating hard simply getting up out of a chair.

Now medicare isn’t going to be milked for a small fortune. I’m going to need less healthcare as time goes on and may finally have no need for diabetes medicines.

Medicare wins, I win and my providers and pharmaceutical companies lose.

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thats great to hear man. congratulations. i wish western mediicnce would stop doing this to men and woman. its a disaster of a system today. no cures, just symptom supression.

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There were plenty of earlier studies, mostly flawed, that “seemed to,” at first glance, make TRT look scary. One, in 2014, found that younger guys with a history of heart disease who started T therapy had a two to three-fold increase in the risk of myocardial infarction. Further, they found that guys over 65 who started TRT had a two-fold increase in cardiovascular disease regardless of their cardiovascular history. As I’d expect, they didn’t find any increased risk in younger men without a history of heart disease. But the first NCIS moments come when you see that the study didn’t bother to look at or consider testosterone levels before or after the study. Neither did they consider post-therapy red blood cell counts or estrogen levels. Most of the “TRT bad” studies had similar flaws, but they were out there.

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I’m working on an article right now about that subject. There’s a theory out there, one that I want to believe, that hormonal imbalances aren’t the primary cause of BPH. Instead, it has to do with vitamin K deficiency. In a nutshell, a deficiency of vitamin K causes varicoceles near the prostate. These cause retrograde blood flow from the testes to the prostate gland, causing a 130-fold increase in free testosterone in the veins near the prostate. Stay tuned.

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Leaving aside the findings of the study, which are important and relevant, the larger issue for me is that I’d rather not have the government, notoriously prone to error (understatement), telling me what to do out of one side of its mouth, while championing those women who want to become men and who then are free to shoot up with supraphysiological dosages at will. Then again, logic and consistency were never hallmarks of government.

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Thanks for this. I’ve previously referred to that paper from the 1940’s that started all the prostate mythology about testosterone – based on one patient!

Could very well be!

I’m not sure it’s a conspiracy. Remember what Mark Twain said, “Two men can keep a secret, if one of them is dead.” I’m thinking it’s more likely because medical “truths,” once they take root, can be hard to kill.

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Whoa! Let’s hear more about this, if you feel like it.

That’s understandable and relatable. Still, I’m not sure I’d feel comfortable in a world where businesses got to make whatever drugs they wanted with no oversight at all.

I’m age 66, have been and still am bodybuilding no-AAS for over fifty years since beginning in 1971 at age 15.
However, while I’ve done it without AAS, technically I’ve been on AAS for the past seven years, since at age 59 I began TRT, at the standard prescribed 100/mg/week dosage.

I’d tracked my T levels regularly since about age 50, when I began noticing a decrease in recovery ability, libido, and energy despite maintaining the same training (with modifications to adapt to my accumulated joint wear due to aging as well as to my contractor-roofer job-incurred injuries), resting, and nutritional program I’d used for decades, and despite carrying no more than about 12% bodyfat for nine months out of every year. When my T had dropped about 300 ng/dL from its former normal of about 850 ng/dL, I was prescribed TRT, and been self-injecting ever since. My overall heath condition returned to my previous normal in energy, recovery, and libido. [And, noooo - - I didn’t suddenly increase muscle mass beyond what I’d had at age 50. In fact, even on TRT, I don’t carry quite as much muscle mass as I did in my prime, naturally, at age 25. At 100 mg/week, most guys aren’t getting anywhere near the 300 to (usually more like) 600 mg/week required, depending on genetic response, to induce substantial hypertrophy.]

Except for exactly the one common issue this new study stated, high hematocrit, everything else has continued to test as healthy during my seven years on TRT

One potential side effect not mentioned and perhaps not commonly known regarding the long-term use of TRT is, since TRT does restore, improve, and maintain libido, paradoxically, erectile dysfunction.

In this form of ED, it’s not the ability to achieve an erection that’s an issue, but, the ability to sustain an erection.

Erections being a matter of adequate blood flow, and ED being due to impaired blood flow, the issue that can develop during long-term TRT is due to the inevitable atrophy of the testicles. The testicles on us human males normally serve as a sort of one-way valve which prevents blood from seeping out of the penis during an erection. Apparently, when the testicles lose mass, as they will due to essentially being taken off-line by the chronic negative feedback in the HPG axis which exogenous testosterone causes, that loss of their volume allows blood to seep back out of the penis. Consequently, erection can flag. (One popular reference which discusses this ED among long-term AAS users is Llewellyn’s “Anabolics”; in my 2017 copy of his 11th Edition; on page 51, he discusses “Testicular Atrophy” then on page 63, last paragraph of the left column, he discusses the venous leakage caused by that atrophy and the consequent erection dysfunction.)

I’ve experienced it myself, beginning about four years into my seven years of TRT.

The simple resolve, at least for me, is low dose prescription tadalafil (generic Cialis). That seems to compensate for the leakage allowed by the failure of the testicles to act as a “stopper”.

Just, so those new to TRT or who’ve been using TRT awhile are aware, and are informed, in case they experience this side-effect…

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Interesting! I didn’t know that. However, inability to maintain an erection might also have to do with atherosclerosis and age-related inelasticity of the blood vessels. As I often state, erections are the canary in the coal mine of cardiovascular health. I’m not suggesting this is the case with you, but I did want to mention it so that other plus-60 guys are at least aware of it.

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