Impact of TRT on Adverse Cardiovascular Events in Men with Low Testostosterone: Evaluation of Physiological and Supraphysiological T Levels

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madman

Super Moderator


Abstract

Introduction


Sustained treatment with elevated levels of exogenous testosterone (T) has been linked to various adverse events, particularly concerning cardiovascular risks. However, there is currently a lack of sufficient literature that comprehensively describes the overall safety profile of supraphysiologic testosterone levels.


Objective

To compare the safety profiles and rates of polycythemia, venous thromboembolism (VTE), major adverse cardiac events (MACE), deep vein thrombosis (DVT), myocardial infarction (MI), and stroke between hypogonadism patients treated with testosterone replacement therapy (TRT) at physiological and supraphysiological testosterone levels.

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Methods

We identified patients with hypogonadism (<300 ng/dL) who underwent testosterone replacement therapy (TRT) at our institution through electronic medical record review. Patients lacking records of their first encounter, documented medical history, sufficient follow-up, or post-TRT adverse event data were excluded from the analysis. Supraphysiological testosterone levels were defined as >1000 ng/dL. The included patients were retrospectively analyzed using two-way nonparametric testing for continuous variables and chi-square and Fisher exact tests for categorical variables (α = 0.05).


Results

From a cohort of 537 men diagnosed with hypogonadism, we included 184 patients who underwent testosterone replacement therapy (TRT). Among these patients, 135 (73.4%) were treated to achieve physiological testosterone levels, with a median level of 468.0 ng/dL (interquartile range, IQR = 308.0-644.5), while 49 patients (26.6%) were treated to attain supraphysiologic testosterone levels, with a median level of 1552 ng/dL (IQR = 1279-1700). Before initiating TRT, there was no significant difference in testosterone levels between the two groups (p = 0.11). Moreover, no significant differences were found between the groups in terms of a history of diabetes mellitus (DM; p = 0.422) or prostate cancer (p = 0.29). However, significant differences were observed in the history of hypertension (HTN; p = 0.003) and hyperlipidemia (HLD; p = 0.006), with more patients in the physiologic testosterone group having a diagnosis of HTN and HLD prior to treatment. Regarding adverse events, there were more cases of polycythemia in the supraphysiologic testosterone group compared to the physiologic testosterone group (p < 0.001; 35.4% vs. 7.0%). Interestingly, there was no significant difference in the rate of other adverse events after TRT between the two groups, including venous thromboembolism (VTE; p = 0.285), major adverse cardiovascular events (MACE; p = 0.768), deep vein thrombosis (DVT; p > 0.999), myocardial infarction (MI; p = 0.562), and stroke (p > 0.999).


Conclusions

Despite widespread concerns, these findings suggest that although patients treated to achieve supraphysiologic testosterone levels had a higher incidence of polycythemia, there were no significant differences in the rates of other adverse events after TRT between patients treated to attain physiological versus supraphysiologic testosterone levels.
 
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FunkOdyssey

Seeker of Wisdom
Despite widespread concerns, these findings suggest that although patients treated to achieve supraphysiologic testosterone levels had a higher incidence of polycythemia, there were no significant differences in the rates of other adverse events after TRT between patients treated to attain physiological versus supraphysiologic testosterone levels.
File that under "Let 'er rip, bro!"
 

Nelson Vergel

Founder, ExcelMale.com
All cause mortality was associated with higher T levels, although heart related deaths were not statistically significant.

 

FunkOdyssey

Seeker of Wisdom
All cause mortality was associated with higher T levels, although heart related deaths were not statistically significant.

Yeah I saw that, higher mortality but not heart related deaths. So what was killing them then?
 

Nelson Vergel

Founder, ExcelMale.com
Yeah I saw that, higher mortality but not heart related deaths. So what was killing them then?
Good question.

We saw from the TRASVERSE trial that men on TRT had more fractures than those on placebo. TRT increases bone density, so my opinion is that men on TRT are more active and this higher activity leads to more fractures.
Men with high T levels may have higher mortality due to more activity. Big assumption that I really don't know if it is true.
 

Seagal

Active Member
What I really don't understand is the fact that most of these studies seem to only look at TT instead of FT. Isn't this a huge confounding factor?
 

Nelson Vergel

Founder, ExcelMale.com
What I really don't understand is the fact that most of these studies seem to only look at TT instead of FT. Isn't this a huge confounding factor?
Free T by equilibrium dialysis is the only trusted test and many research sites do not have access to it. Total T is OK with cheaper tests that use immunoassays. That is the main reason why large cohort studies with multiple sites do not track free T.

 

Guided_by_Voices

Well-Known Member
Good question.

We saw from the TRASVERSE trial that men on TRT had more fractures than those on placebo. TRT increases bone density, so my opinion is that men on TRT are more active and this higher activity leads to more fractures.
Men with high T levels may have higher mortality due to more activity. Big assumption that I really don't know if it is true.
I think a more likely explanation is that it's just random variation due to a small sample size. There were only 75 men in the >1000 T level group. In the total study 1 out of 12 men died, so if the risk were even, that would imply that around 6 would die in the high T group, but with such a small sample size randomness could account for significantly larger number. They didn't say how many in the high T group died although a bigger statistical brain than mine could likely derive the number, but it would have to be really high to be confident the T was an issue. In theory the p value of .007 says it is unlikely to be random but without knowing the actual numbers and cause of death it is hard to say.

Another factor is that if the high T group included those on other anabolics, uncontrolled high-blood pressure could have been the issue.
 

Nelson Vergel

Founder, ExcelMale.com

Mastodont

Active Member
This review concerns me :


I invited Dr Ramasamy for an interview
Hope you get him on, pretty sure that those who get elevated hct are also more likely to get blood pressure on trt, even if not directly, more like correlation not causation.
 

madman

Super Moderator

Limitations​

This was a retrospective claims database analysis extracted from electronic medical records, and as such we lack important granularity from the data. We were not able to assess pre- and post-TTh levels or confirm that men used the prescriptions for testosterone that were given or the type of testosterone prescribed. This hypothesis will need to be further tested in a clinical-based setting.
 

Wilson7

Active Member
Good question.

We saw from the TRASVERSE trial that men on TRT had more fractures than those on placebo. TRT increases bone density, so my opinion is that men on TRT are more active and this higher activity leads to more fractures.
Men with high T levels may have higher mortality due to more activity. Big assumption that I really don't know if it is true.
They didn't have baseline iDXA data, it may well be as they mentioned in the article, higher activity following HRT and they may have lower BMD and are at higher risk of fractures because of low T and likely E2, compounded with less activity.
 

Wilson7

Active Member

Limitations​

This was a retrospective claims database analysis extracted from electronic medical records, and as such we lack important granularity from the data. We were not able to assess pre- and post-TTh levels or confirm that men used the prescriptions for testosterone that were given or the type of testosterone prescribed. This hypothesis will need to be further tested in a clinical-based setting.
The question is, is it the increased HCT, or is there something else going on (genetic predisposition with increased T independent of increased HCT or combined risk factors) that is driving this. Nadeem et al, 2013 showed that secondary polycythemia in COPD patients (HCT 53.5% vs 43.6%) was not a driver of VTE, but when combined with higher BMI (obesity) it was.
 
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