The Most Exciting Time for Testosterone - TRAVERSE Results 4 Studies

[madman]

The Most Exciting Time for Testosterone

Primary care physicians may be more comfortable prescribing testosterone to men with low levels after hearing from these expert urologists.

www.medscape.com

Rachel S. Rubin, MD: I am Dr Rachel Rubin, urologist and sexual medicine specialist in the Washington, DC, area. I am so blessed to have with me one of my favorite sexual medicine doctors on earth, Dr Mo Khera, professor of urology at Baylor College of Medicine. He's the president of the Sexual Medicine Society of North America and has been a part of a very big trial — the results of which just came out — all about testosterone, which is what we're going to talk about today.

 

[madman]

This transcript has been edited for clarity.


Rachel S. Rubin, MD: I am Dr Rachel Rubin, urologist and sexual medicine specialist in the Washington, DC, area. I am so blessed to have with me one of my favorite sexual medicine doctors on earth, Dr Mo Khera, professor of urology at Baylor College of Medicine. He's the president of the Sexual Medicine Society of North America and has been a part of a very big trial — the results of which just came out — all about testosterone, which is what we're going to talk about today.


Mohit Khera, MD, MBA, MPH: Thank you, Rachel, for having me on.




Rubin: We have some big news. We're talking about testosterone. Tell us about the very exciting findings that have just come out.


Khera: This is probably the most exciting time for testosterone. We've published the largest randomized, placebo-controlled trial on testosterone and cardiovascular and prostate safety — a landmark trial. The genesis of this trial was cardiovascular concerns. Before 2010, the available studies suggested that testosterone may be protective against cardiovascular disease, with no increased risk for cardiovascular events. Then from 2010 to 2014, four studies came out suggesting an increased risk for cardiovascular events. There are a lot of limitations with these studies; they weren't randomized or placebo-controlled. Still, in September of 2014, the FDA said they wanted to further investigate this. They convened, and two big things came out of that meeting. In 2015, they made a label change on all testosterone products saying that the long-term clinical safety of testosterone cannot be assessed. We need larger trials, and it's inconclusive whether testosterone is safe against cardiovascular disease.

The second big thing was that the FDA required that manufacturers of testosterone products conduct a large clinical trial to show that testosterone is safe. That's why the TRAVERSE trial started, in 2015. The placebo-controlled study involved more than 5200 men who were randomized to get testosterone gel or placebo. They had to have a low testosterone level (< 300 ng/dL), and they had to be symptomatic. The key point was that all of these men either had preexisting cardiovascular disease or at least three out of eight cardiovascular risk factors such as hypertension, diabetes, and metabolic syndrome. The study started in May 2018 and finished in February 2022. I'm very excited today to show you the results of four trials that have already been published.




Rubin: Let's hear it. Start with the big one in The New England Journal of Medicine.


Khera: The "big one" was about cardiovascular risk. The primary endpoint was time to cardiovascular events (myocardial infarction [MI] or stroke). The secondary outcome was risk for high-grade prostate cancer, and the tertiary outcome was any prostate cancer or intervention (medical or surgical) for BPH. All patients received an International Prostate Symptom Score (IPSS) to look for urinary symptoms. The benefit of this study was the other secondary outcomes, such as sexual activity and erectile dysfunction, anemia, diabetes, and bone fracture. Many of these study findings are yet to come out.
Among the men who received testosterone gel, testosterone levels went up by about 148 ng/dL to about 400 ng/dL. Levels in the placebo group went up by about 14 ng/dL at the end — a small increase. The key message is that there was no increased risk of cardiovascular events.

But three things surprised me. One, there was a slight increase in pulmonary embolism (PE) (0.5% in the placebo group vs 0.9% in the testosterone group). Two, men treated with testosterone had an increased risk for atrial fibrillation (2.54% with placebo vs 3.5% in the testosterone group). And three, an increased risk for acute kidney injury was seen (1.5% with placebo vs 2.3% with testosterone treatment). Remember, only the PE was adjudicated; the other outcomes were just self-reported. But it is what it is.

That's the cardiovascular safety study. The second study was the sexual function study, with 1000 patients randomized to testosterone gel or placebo. The primary outcome was an increase in sexual activity. Secondary outcomes were an increase in erectile function and libido. They found that testosterone as monotherapy did not improve erectile function. We already knew that; it's in the American Urological Association (AUA) guidelines. Testosterone as monotherapy does not improve erectile function, but it did significantly improve sexual activity and libido. What is very nice about the study is that testosterone improved libido, and it was sustained for up to 24 months.

The prostate cancer trial came out last week. With 5200 men randomized to testosterone gel or placebo, the primary outcome was high-grade prostate cancer. The secondary outcome was whether their urinary symptoms get worse, meaning their IPSS, need for surgery (eg, TURP), or the need for medication. They found no increased risk in high-grade prostate cancer — no increased risk in any type of prostate cancer. In fact, there were only 23 cancers out of 5200 men (11 in the placebo group and 12 in the treatment group). No significant difference whatsoever. And for the first time, a large study showed no increased risk for worsening of urinary symptoms. Right now, it's on the package insert to be careful if you give someone testosterone because their urinary symptoms may get worse. This study suggests that isn't true at all.

The last study was a small study about anemia, with 815 patients. The primary outcome was whether giving testosterone supplementation, would the anemia improve? At 6 months, they found a significant improvement: 41% in the testosterone patients and 27% in the placebo arm. This is not a novel study. It's been shown in the T trials that if you give testosterone, it can cause erythrocytosis. But in this case, we're actually using this as a beneficial effect. We're trying to help those who have anemia, defined as a hemoglobin level < 12.7 g/dL.

These are the results of the four studies that have come out. We still have three more studies coming out: bone fracture, diabetes, and depression. I'm excited about those. These are very exciting times for testosterone research.




Rubin: Well, there you have it, folks. You've heard huge news. This is groundbreaking research in testosterone therapy. We want to get the word out to the everyday primary care doctors who are seeing these patients all the time with symptoms. What do you think primary care doctors should take away from this data?


Khera: They should realize that testosterone does not increase the risk for heart attack or stroke. In 2015, many clinicians stopped prescribing testosterone when the label changed. If you ask them, they say, I'm concerned that testosterone may cause a heart attack in my patient. Now we know that is not true. We also know that many clinicians are scared that if they give testosterone, it may cause prostate cancer. Now with this large clinical trial, no data suggest that testosterone increases the risk for prostate cancer. This is very consistent with the AUA guidelines. In 2018, they came out suggesting there was no increased risk for prostate cancer in men receiving testosterone. This study only confirms it.

Another important point is that testosterone is not the best treatment for erectile dysfunction as monotherapy. We know it helps if you are giving a PDE-5 inhibitor in conjunction with testosterone. Testosterone does help libido. So in men with low libido, using testosterone as monotherapy may be beneficial.

Finally, testosterone increases the risk of erythrocytosis. In some patients with anemia, this may be beneficial. It's what we saw in the trial as well.




Rubin: You alluded to this, but primary care physicians are always considering risks vs benefits. What do you see as the benefits of testosterone therapy? And what are your patients telling you?


Khera: Great question. The key is that patients who do not have a low testosterone value do not benefit. They have to have a low serum testosterone value. The typical symptoms that improve are energy, sex drive, erectile function, muscle mass, fat deposition, some types of depression, and sleep. Those are the main symptoms that we see in patients. Typically, the lower the testosterone level the patient starts at, the greater the improvement. Not all patients will see improvement in all of these variables, but many patients do.



Rubin: What do you tell the doctor who says, "We'll just work on lifestyle issues first. If we start with lifestyle issues, then maybe if it's bad enough, we can address the testosterone issue"? It's kind of a chicken-or-egg situation. Where do you stand on that?


Khera: I think lifestyle is extremely important. I tell patients that it's not one or the other. We must do both at the same time. What I expect from the patient are four pillars: diet, exercise, sleep, and stress reduction. I don't have a pill on the planet stronger than diet, exercise, sleep, and stress reduction. Nothing. Even if they choose to do one of those and focus on that one, it changes their entire life. So I tell them, you meet me halfway. You focus on diet, exercise, sleep, and stress reduction, and I will focus on optimizing you so that you can change your diet, exercise, sleep, and stress reduction. Together we're a team, but it really works best when both are optimized.




Rubin: Are there any patient populations that make you nervous or contraindications where you say, "I really don't think this is a safe option for you"?


Khera: First of all, testosterone is a natural contraceptive. So if a person is trying to conceive or have a child, you absolutely do not want to give them testosterone because it will shut down the sperm count. So that's one population. But based on the TRAVERSE trial, we should at least acknowledge the fact that there was a very slight increased risk for PE. That should be mentioned to patients who have a history of PE. It's also important to let patients know that we still don't have a lot of data on patients with a history of prostate cancer — those who have undergone radical prostatectomy or radiation. With proper counseling, most clinicians feel comfortable prescribing a bit of testosterone to men who have had a history of radical prostatectomy. You still want to do the appropriate counseling.




Rubin: I find that a lot of primary care doctors are fearful. They think testosterone is controversial, and they don't like to talk about it — even some endocrinologists. Why do you think it's so controversial as opposed to, say, thyroid hormone or insulin?


Khera: Clinicians don't get much training on testosterone in medical school. I know I didn't get it until late in my residency or my fellowship. So, there's the discomfort zone. Many of us were ingrained that testosterone causes prostate cancer. In 2000, when I started my residency, we were told that if you give it to a man who has a history of radical prostatectomy, it's like putting fuel on the fire. We were just ingrained that it carried a risk for prostate cancer. Then the cardiovascular risk came up. There were many unknowns. And when there are unknowns, there is controversy. But I think a lot of that controversy has been put to rest with the TRAVERSE trial.
Rubin: The TRAVERSE trial was done with topical testosterone. Do you think the type of testosterone matters, whether it's the injectable or some of the newer oral agents?


Khera: I think it could matter. When it comes to prostate safety, I believe in the prostate saturation model. In patients who are below 250 ng/dL of testosterone, as you raise them above the saturation level, some adverse action can occur. You'll see a rise in PSA. You can see a transient worsening of BPH. But once you have patients above the saturation tipping point, raising them to higher levels doesn't make a difference. So it doesn't matter if they're on a gel or injectable; it's not going to make much of a difference. It could make a difference to cardiovascular health, because higher levels could induce erythrocytosis. Some studies have suggested that the injectable may have be associated with a higher rate of erythrocytosis and cardiovascular concerns than the gel. I'm not saying that it couldn't, but it may not be as transferable when we're talking about cardiovascular risk.



Rubin: Why is testosterone a controlled substance? Why does it make me feel like an opioid-prescribing doctor, that I need to give two-factor authentication and sign my life away every time I prescribe it?


Khera: Because there's a potential for abuse, and it's actually not stated in the package insert. Any product with abuse potential has to be more regulated.




Rubin: Do you think that the label change will happen now that the TRAVERSE trial is out?


Khera: Well, I think it should. It's only fair because this trial was initiated because of concerns that came out in 2010-2014. That's why the label changed. The FDA required a large clinical trial to show that there was no increased cardiovascular risk. So, it makes sense to make that label change at this time.




Rubin: Finally, Dr Khera: Paint a picture for us. We both have many stories of patients who benefit so much from testosterone therapy. Not your classic bodybuilding patient who comes in wanting to abuse testosterone. But tell us the story of that guy who comes in and his life is transformed — his relationships, everything, is better.


Khera: There's a profound effect on the quality of life for many men who initiate testosterone therapy. The typical man is older; remember that roughly 60% of patients who come in who have low testosterone levels will have metabolic syndrome, diabetes, or obesity. That syndrome is there. He now has erectile dysfunction, low libido, and some depression. He has increased fat deposition and decreased muscle mass. He's now having some difficulty in his relationship with his partner because he cannot engage in sexual activity, so he is stressed. When you put these patients on testosterone, many of them could see a significant improvement in their energy. Fat deposition declines and muscle mass improves. They work out, and their erectile function can improve, particularly if they are using a PDE-5 inhibitor in combination therapy. If you watch them over time, these patients are extremely appreciative when they come in, thanking you for making a profound impact on their quality of life.




Rubin: That's why you and I keep showing up to work. This is just been an absolute honor. I am your number-one fan, and we're very excited. Can you give us any hints about the next stage of the TRAVERSE trial? What is it going to show us? Are there any abstracts yet?


Khera: The next one's coming out next month, I believe, and within the next 6 months, we'll have the next three out. Then hopefully we can start taking a deeper dive into some substudies in the dataset to look at other questions. It's a huge, amazing dataset, and there are so many questions that we can answer just by going through that data.


Rubin: Big congratulations. We will be looking for the next data to come out. Thank you so much for joining us today.

 

[madman]

*Rubin: That's why you and I keep showing up to work. This is just been an absolute honor. I am your number-one fan, and we're very excited. Can you give us any hints about the next stage of the TRAVERSE trial? What is it going to show us? Are there any abstracts yet?


*Khera: The next one's coming out next month, I believe, and within the next 6 months, we'll have the next three out. Then hopefully we can start taking a deeper dive into some substudies in the dataset to look at other questions. It's a huge, amazing dataset, and there are so many questions that we can answer just by going through that data.

 

[madman]

TRT and Cardiovascular Disease

Testosterone replacement therapy and cardiovascular disease (2022) Jeremy M. Auerbach and Mohit Khera The use of testosterone therapy has a complex history of apprehension and questions regarding its safety. Despite an eventual consensus that testosterone therapy was safe and effective...

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TRT and the Prostate

Testosterone Treatment and the Risk of Prostate Adverse Events (2022) Jason A. Levy, DO, MS, Arthur L. Burnett, MD, MBA, Adrian S. Dobs, MD, MHS INTRODUCTION Definition Hypogonadism is a clinical syndrome that results from failure of the testis to produce physiologic concentrations of...

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[madman]

Is TRT safe in men who are at high risk for cardiovascular disease?

Dr. Khera breaking it down! Is testosterone replacement therapy safe in men who are at high risk for cardiovascular disease? Ask a Sexpert! Dr. Mohit Khera explains this topic in our latest edition of this video series.

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[madman]

New and emergent preparations for male hypogonadism treatment

ABSTRACT Introduction The specific role of testosterone (T) replacement therapy in patients with late-onset hypogonadism is still conflicting. Several available preparations have been developed to restore either fertility and normal testosterone (T) levels (secondary hypogonadism) or just T...

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TRAVERSE/CVD

*However, it should be recognized that the long-term CV safety of TRT still represents a conflicting issue. One of the most recent meta-analyses showed that TRT does not increase short-term or medium-term CV risk in men with hypogonadism [69]. The same study emphasized the paucity of data evaluating TRT-related long-term CV safety. In addition, although the TRAVERSE study did not report any differences in MACE risk after 2 years of treatment, a mild, although significant, increased risk of arrhythmias, and atrial fibrillation, in particular, as well as of venous thromboembolism, has been reported in the active arm when compared to placebo [23]. The high (>60%) dropout observed during the study and the lack of formal adjudication of the latter events, which were secondary endpoints (venous thromboembolism) and investigator-reported (arrhythmias), represent crucial bias in the data interpretation [23].

 

[Seagal]

"Among the men who received testosterone gel, testosterone levels went up by about 148 ng/dL to about 400 ng/dL."
Many here believe 400 ng/dL is low T. Please do keep in mind that more might not be better, it rather could be worse.

 

[Systemlord]

"Among the men who received testosterone gel, testosterone levels went up by about 148 ng/dL to about 400 ng/dL."
Many here believe 400 ng/dL is low T. Please do keep in mind that more might not be better, it rather could be worse.

A lot of men would not get full symptom improvement at 400 ng/dL.

 

[Nelson Vergel]

I still have questions.

 

[Seagal]

https://www.nejm.org/doi/full/10.1056/NEJMoa1000485

Participants were stratified according to age (65 to 75 years or older than 75 years) and were randomly assigned to receive 10 g of a transdermal gel containing either placebo or 100 mg of testosterone (Testim 1%,23 Auxilium Pharmaceuticals), to be applied once daily for 6 months. Two weeks after randomization was performed, the dose was adjusted if the average of two testosterone measurements was less than 500 ng per deciliter (17.4 nmol per liter), in which case the dose was increased to 15 g daily, or more than 1000 ng per deciliter (34.7 nmol per liter), in which case the dose was decreased to 5 g daily.

 

[madman]

https://www.nejm.org/doi/full/10.1056/NEJMoa1000485

Participants were stratified according to age (65 to 75 years or older than 75 years) and were randomly assigned to receive 10 g of a transdermal gel containing either placebo or 100 mg of testosterone (Testim 1%,23 Auxilium Pharmaceuticals), to be applied once daily for 6 months. Two weeks after randomization was performed, the dose was adjusted if the average of two testosterone measurements was less than 500 ng per deciliter (17.4 nmol per liter), in which case the dose was increased to 15 g daily, or more than 1000 ng per deciliter (34.7 nmol per liter), in which case the dose was decreased to 5 g daily.

Adverse Events Associated with Testosterone Administration (2010)​

​

TESTOSTERONE DOSE AND ADHERENCE

After adjustment of the testosterone dose to achieve the target range, 29 men in the testosterone group received 5 g of the testosterone gel daily, 61 received 10 g, and 16 received 15 g. Adherence, as assessed by a count of the unused gel tubes, was greater than 90% in both groups.




LABORATORY AND PHYSIOLOGICAL DATA

The mean (±SD) testosterone levels were 574±403 ng per deciliter (19.9±14.0 nmol per liter) in the testosterone group (after adjustment of the dose to achieve the target range) and 292±160 ng per deciliter (10.1±5.6 nmol per liter) in the placebo group. In the testosterone group, as compared with the placebo group, there was a significant increase in hemoglobin and hematocrit levels and a significant decrease in high-density lipoprotein cholesterol and low-density lipoprotein cholesterol levels (Table 1 in the Supplementary Appendix). Changes in blood pressure did not differ significantly between the testosterone and placebo groups (change in systolic pressure, −2.9±12.9 mm Hg vs. −4.6±14.8 mm Hg; change in diastolic pressure, −1.3±7.1 mm Hg vs. −1.3±7.8 mm Hg).

​

Discussion

In this study of older men with low testosterone levels and limitations in mobility, random assignment to daily application of a testosterone gel, as compared with a placebo gel, was associated with a greater frequency of adverse events, particularly cardiovascular, respiratory, and dermatologic events. The divergence between the groups in the incidence of cardiovascular adverse events was maintained over the 6-month intervention period and did not diminish during the 3-month observation phase that followed the intervention period. The increased cardiovascular risk in the testosterone group was seen with all three definitions of cardiovascular events, and the increase persisted after adjustment for baseline risk factors. The increased risk was also evident in sensitivity analyses adjusted for baseline mobility status and Short Physical Performance Battery score and in sensitivity analyses performed after the exclusion of subjects whose eligibility deviated from the planned criteria. The pattern of adverse cardiovascular events associated with testosterone therapy was considered by the data and safety monitoring board to be of sufficient concern to warrant termination of the trial.


The generalizability of our data about the safety of testosterone therapy is limited by several factors. First, cardiovascular events were not a planned primary or secondary outcome, and therefore, a structured evaluation of cardiovascular events was not performed, a factor that may have influenced the ascertainment of events. Most of the cardiovascular-related events were verified from medical records or by direct examination. Second, the sample, although larger than those in most previous trials, was small, and the number of adverse events was small. The results of individual small trials may not be confirmed in large trials,28, and trials that have been stopped early tend to overestimate treatment differences. Third, the clinical characteristics of our study population differ from those of most other populations in which testosterone therapy has been administered in a clinical setting or as part of a clinical trial. Men who were younger than 65 years of age and men with severe hypogonadism were excluded from the trial. Participants had substantial limitations in mobility and a high prevalence of chronic conditions, including preexisting heart disease, obesity, diabetes, and hypertension. Frail elderly men with limitations in mobility are more likely to have clinical and subclinical cardiovascular disease than are those who do not have limitations in mobility.29,30

Previous studies provide very limited data to either reinforce or contradict the findings in this study with respect to the effects of testosterone therapy in older men with limited mobility. Meta-analyses of previous trials of testosterone therapy have not shown significant increases in cardiovascular risk with testosterone therapy, although nonsignificant increases have been noted among participants of all ages,31-33 as well as among older men.31,33 The trials in these meta-analyses were limited by inadequate methods of ascertaining adverse events or the poor quality of data on adverse events, by the small numbers of events or the small numbers of older participants, or by intervention periods that were shorter than the 6-month intervention in this trial. Some epidemiologic studies have shown that low testosterone levels are an independent risk factor for death from cardiovascular causes and from all causes.34-37 However, differences between the effects of endogenous hormones and those of pharmacologic hormonal therapy, as well as differences in the duration of exposure to testosterone, could contribute to the apparent discrepancies between these epidemiologic data and the results of our trial.

It is not likely that the adverse cardiovascular events seen in the TOM trial are a consequence of an unusual protocol for testosterone administration (Table 4 in the Supplementary Appendix). The upper limit of the testosterone threshold used for inclusion in the trial is not dissimilar to that used in most other trials.16-19,38-47 The testosterone doses in this trial may have been higher than those that are typically used in clinical practice48 and were higher than the doses used in some previous trials17,18,39-42 but were similar to those in other trials.16,21,43-46 The average testosterone concentrations during the intervention period among men in our testosterone group were in the middle of the normal range for young men; these levels were higher than those in some testosterone trials17,18,39-42 but did not differ from levels reported in other trials.16,19,21,43-46

The cardiovascular adverse events reported in the TOM trial were diverse and may have variable clinical importance. The lack of a consistent pattern in these events and the small number of overall events suggest the possibility that the differences detected between the two trial groups may have been due to chance alone. The results of several separate analyses were consistent with the initial observation of a significant difference, but these analyses were not entirely independent of one another. In interpreting these findings, it is essential to recognize the role that chance may have played in the outcomes we observed.

The diversity of cardiac adverse events also renders the events less susceptible to a single mechanistic explanation. Testosterone causes salt and water retention,49-51, particularly in older men,14 and this could contribute to edema, hypertension, and congestive heart failure, although there are some trials in which testosterone has been administered in men with congestive heart failure.39,40 Testosterone and associated increases in estradiol may promote inflammation, coagulation, and platelet aggregation.52 The use of anabolic steroids has been associated with left ventricular hypertrophy and systolic and diastolic dysfunction.53,54 Changes in plasma lipid levels would not account for the rapid divergence in rates of cardiovascular adverse events.Testosterone therapy was associated with significant improvements in leg-press and chest-press strength and in stair-climbing power with a load. Inferences regarding efficacy are limited because of the attenuation of statistical power owing to the early termination of the trial.








Listen to Dr. Khurram and Dr. Khera (3:55-21:17).

Testosterone and Cardiovascular Disease (Traverse Trial)

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*4 articles suggesting increased CV risk with T

 

[Sergel]

I still have questions.

I had a lot of palpitations when I was flying high... never had any hematocrit issues, but man, anxiety and palpitations at night were really strong.... Lowering my dose fixed all of those symptoms.

 

[madman]

Testosterone Therapy and the Risk of Cardiovascular Disease

Abstract The debate over the cardiovascular (CV) implications of testosterone therapy (TT) have resulted in diverging safety recommendations and clinical guidelines worldwide. This narrative review synthesizes and critically evaluates long-term studies examining the effects of TT within the...

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4. Conclusion

The therapeutic approach for TT for symptomatic hypogonadism and low testosterone levels associated with aging, obesity, and systemic illness presents challenges. These conditions are intricately linked with CVD outcomes and may confound the relationship between low testosterone and CVD. Although observational studies suggest an association between low testosterone and increased risk of CVD, results from testosterone supplementation are inconsistent. RCTs indicate that short-term TT at standard replacement is not associated with increased CVD risk. Nevertheless, the cardiovascular sub-study of T Trials observed increases in NCP and CAC, signaling the need for further investigation into potential long-term implications of TT.

The TRAVERSE trial, a landmark study unique in its capacity to evaluate CVD events, contributes valuable insights into the short-term safety of TT at lower physiological levels. However, the long-term effects and implications of mid to high physiological testosterone levels are not yet fully understood. The trials’ limitations — achievement of only low-normal testosterone levels, high discontinuation rates, brief follow-up period, and high loss to follow-up rate — suggest that the findings should be interpreted with caution. It is important to avoid generalizing the safety of TT based on these results alone and to approach the extrapolation of TRAVERSE’s conclusions to higher dosages or longer-term therapy with caution.

The decision to initiate TT requires a nuanced approach, which must account for current gaps in evidence regarding CV safety. A personalized assessment and management of CVD risk factors is essential for older men with known CVD. The CV effects of exogenous testosterone, when given to maintain physiological levels, remain to be fully explored. In this regard, an important question remains the identification of male patients with symptomatic hypogonadism who may benefit from TT. This topic continues to be the subject of ongoing debate. Hopefully, future trials will provide clarity on whether TT confers beneficial, neutral, or adverse cardiovascular effects in middle-aged and older men. Until definitive evidence surfaces, clinical practice should exercise caution and prioritize individualized care with informed discussions regarding the potential CV implications of TT.