Side effects of TRT

Medical Q&A [Moderated]
1

I’ve seen a massive increase in ads for TRT and influencers are becoming a lot more liberal with their promotion.

In your aritcle Low Testosterone: Causes, Diagnosis, and Management 
you mention “true testosterone deficiency” WRT CVD, do you mean primary hypogonadism? Or anyone who reaches clinically low levels?

Second, do you think the side effects are perhaps not yet as commonly known? i.e. do you expect more data to show worrying trends in the future?

A recent video I watch on the Medlife crisis channel mentioned he has seen multiple st elevation myocardial infarctions in men taking TRT with otherwise normal BP and cholesterol

As practitioners, is it common that you see men who are worried about their testosterone change their lifestyle? sleep, stress, weight management? Or is it an uphill battle against wellness influencers/clinics?

2

you mention “true testosterone deficiency” WRT CVD, do you mean primary hypogonadism? Or anyone who reaches clinically low levels?

No, this is not restricted to primary hypogonadism, but clinical hypogonadism in general.

Second, do you think the side effects are perhaps not yet as commonly known? i.e. do you expect more data to show worrying trends in the future?

No, I do not – particularly when it is appropriately dosed, as this leads to appropriate physiologic levels. Of course with surpaphysiological dosing, side effects and toxicities are expected and well-characterized.

A recent video I watch on the Medlife crisis channel mentioned he has seen multiple st elevation myocardial infarctions in men taking TRT with otherwise normal BP and cholesterol

I have not seen the video, but I would not weigh these anecdotes higher than data from randomized trials. Among his anecdotes, I would also be curious as to whether they were appropriately diagnosed with testosterone deficiency/hypogonadism in the first place, and then whether the testosterone dosing they were receiving was leading to appropriate physiological levels.

Regardless, even if this all looks good, we also know that cardiovascular disease is very common, while there is also an increasing prevalence of people receiving testosterone therapy – and just through sheer prevalence, there is going to be some overlap in these groups. While these can be hypothesis-generating observations, they do not inform causality. That is where we need higher quality randomized trial data to differentiate whether the incidence/risk of cardiovascular events among those appropriately diagnosed and treated to physiological levels is higher than those who are left untreated. As of now, this does not appear to be the case; and in fact, we also know that more severe and prolonged testosterone deficiency itself increases the risk of cardiovascular events, perhaps best characterized among those receiving androgen deprivation therapy.

As practitioners, is it common that you see men who are worried about their testosterone change their lifestyle? sleep, stress, weight management? Or is it an uphill battle against wellness influencers/clinics?

I see and work with lots of people in this realm, and there is a wide range of variation among them. Some, more motivated and aggressive on the lifestyle front. Others, less so.

3

Here is the video in the case you are interested:

However he does mention that they did not have levels considered deficient prior to starting but were claiming their use as replacement therapy. I am noticing that people are often conflating TRT with low dose steroid use.

How do you feel about the rise in advertisements and these functional medical clinics? I am not sure how they diagnose, but did see one in the UK that flagged you as “likely having low testosterone” even if you answer no to all symptoms but said yes to “low mood”.

Do you feel like they (the clinics) are a net benefit, i.e. more people getting treated or a net negative, i.e. more people using low dose steroid cycles. If the side effects are well-documented, is it even an issue if someone uses testosterone, if in smaller quantities?

With all of the ads, I just hear all of the positives, which of course are similar to what those using steroids talk of. I am having quite a few clients either use TRT or desire to do so, mainly because they feel like it’s a fix for energy and body comp. They almost always get it, and their energy and body comp almost always improves.

I would imagine that if there was some laws/guidelines within medical practice (I am unsure) that would require someone to have multiple hypo readings then the advertising wouldn’t be an issue. But if it’s moreso based on symptoms (which I believe is a big factor rather than numbers) then a lot more men could be essentially just doing a cycle rather than TRT (but I guess it’s a grey area).

4

If someone does not have clinical hypogonadism / testosterone deficiency that would benefit from restoration/replacement to physiologic levels, the picture gets a lot murkier.

I don’t love them, particularly when they do not take a rigorous approach to accurate diagnosis.

However, I don’t know what the “net” effect is. I think there is a simultaneous issue of both over-treatment and under-treatment, just among different clinical populations. Lots of folks with obvious, significant risk factors and symptoms of clinical hypogonadism are undiagnosed and untreated, while many people with unequivocally normal levels are offered testosterone therapy – more often by these types of shady clinics. With that said, if someone goes through a full informed consent process and is appropriately monitored over time, I still have a hard time getting overly worked up about this.

There is a big difference between “laws” (which I would not be in favor of), and “guidelines” (which already exist, but are poorly followed).

As discussed in the article, it is not “moreso” based on symptoms than labs, but rather both symptoms and labs. And not all symptoms are weighted equally in this context, either – as they have varying specificity & predictive value for testosterone deficiency.

5

@Austin_Baraki

I recently had my testosterone tested (Testosterone, Total, MS was the name of the test). Levels were fine. I wanted to see where I was now as a baseline so if, later, I started having symptoms I’d know if it’d changed a lot.

Anyway, my GP mentioned they’d be very hesitant to proscribe HRT in the future as I have ASCVD and a prior cardiac event.

Does your risk estimate change for people who’ve had a cardiac event or is it the same/similar to the general population?

6

Here is a different way to think about this:

Given that you have ASCVD and a prior cardiac event, are they recommending actively suppressing your testosterone levels?

I assume not – which means they’re perfectly comfortable with your current testosterone levels.

That being the case, if you were to develop confirmed clinical hypogonadism that was not easily remediable through other means, why would they be uncomfortable simply restoring your levels to where they already are at present?

The TRAVERSE trial recently examined men with existing cardiovascular disease or who were at high risk of CV events. Like all studies it has certain limitations (beyond what we have time to get into here currently), but it is informative, and led to the FDA changing labeling of testosterone products: https://www.nejm.org/doi/full/10.1056/NEJMoa2215025

Finally, according to the current AUA Guidelines:

The currently available literature does not provide enough evidence to offer clear guidance on the use of testosterone therapy in men with existing, stable atherosclerotic CVD and/or a remote history of a myocardial infarction or a cerebrovascular accident. It is the opinion of the Panel that testosterone therapy, with close monitoring to ensure appropriate dosing and safety surveillance, may be considered in these patients after a three to six month waiting period. Clinicians should counsel patients on the association between low testosterone and the increased risk of cardiovascular events, as well as the ill-defined cardiovascular risks and benefits of testosterone therapy in the testosterone deficient patient.

This recommendation is supported by a recent review of studies that evaluate cardiovascular risk associated with testosterone therapy, most of which have excluded men who had a history of a cardiovascular event within the preceding three to six months.194, 229, 386 In the recent Testosterone and TOM Trials,194, 229 participants were excluded if they had a myocardial infarction or a cerebrovascular accident within the previous 3 months, had a history of unstable angina, New York Heart Association class III or IV congestive heart failure, a systolic blood pressure >160 mm Hg, or a diastolic blood pressure >100 mm Hg.194, 229

In the absence of long-term RCTs evaluating whether testosterone therapy results in cardiovascular benefit or harm, the decision to use testosterone therapy in such patients should be based on a shared decision-making approach between clinicians and patients.

7

That makes sense.

Just finished an interesting interview on Attia’s podcast with Carol Hooven.

Except in cases of clear hypogonadism, she seemed skeptical of any objective improvement of symptoms like ED, libido, or body composition in subjects who are already within normal ranges, but then do HRT to get to the upper end.

She seemed to imply their root cause might be environmental (stress, sleep, diet, obesity, etc) and improvement could be placebo effects. She said control based studies did not show significant changes across these symptoms with hormonal treatment of subjects squarely within normal ranges.

She wasn’t absolutist or anything, just skeptical in a “I’d need to see better evidence of this” way.

8

Right; these symptoms are non-specific – meaning they can be caused by a lot of other things, too. So, if you have these symptoms and normal blood levels, the next step is often to look elsewhere for alternative causes/contributors, rather than just trying testosterone therapy anyway.

On a case by case basis it may still be reasonable to offer a trial of therapy to see if someone responds, but I tend to agree that if someone does not have clinical hypogonadism/testosterone deficiency, I would not expect life-changing effects by taking their levels from a “lower, but non-deficient range” to a “middle” or “upper, non-supraphysiologic range”

9

Is there research on this or is this your observations as it’s quite interesting but I can see how that would play out especially with optimizer type individuals.

If someone had a WNR range testosterone, but that decreased over time but still WNR but also presented with non specific symptoms (low mood, energy) would this be a scenario you would be comfortable with prescribing treatment? Anecdotally, I have seen middle aged (35+) clientele fall into this bracket and seek treatment.

10

Edit: I believe you answered the second part of the above question in your response to the other poster.

11

Is there research on this or is this your observations as it’s quite interesting but I can see how that would play out especially with optimizer type individuals.

As cited in the article, there is evidence indicating that:

  • 1 in 4 patients have no testosterone level measured prior to starting therapy

  • 1 in 3 patients who are treated don’t meet diagnostic criteria for low testosterone

  • 1 in 2 patients don’t have blood levels rechecked after starting testosterone therapy

On the other hand, current Endocrine Society guidelines advise screening in patients with conditions that put them at high risk of testosterone deficiency, including:

Pituitary disease

Use of medications affecting T

HIV-associated weight loss

Kidney disease on dialysis

Moderate-severe COPD

Diabetes mellitus

Anabolic steroid withdrawal

Infertility

Osteoporosis, low-trauma fracture

Low libido or erectile dysfunction

In practice, I rarely see this done – outside of patients with established pituitary disease, and perhaps in occasional cases of erectile dysfunction.

To your second question:

In general, prescribing treatment would not be my immediate choice for patients with those types of vague symptoms and unequivocally normal testosterone levels, as it would be malpractice to go that route without ruling out other (potentially more ominous) causes first, such as undiagnosed iron deficiency.

12

Appreciate it, and final question related. I know there has been some evidence to show that WNR hypertrophy seems to be more closely linked with androgen receptor density than blood hormone levels. Why is it then that older people struggle to build muscle compared to younger? Does androgen receptor density decrease with age too or is it other factors such as recovery etc? Typically you’ll hear it’s as a result of lowering T levels.

13

I think it’s intuitive that a process as complex as muscle gain would be related to multiple factors, not just one thing like testosterone or AR density.

Even the evidence on AR density is mixed & controversial, from the original 2018 paper that popularized this idea, to a more recent paper that did not show similar relationship. Ultimately this research is pretty deep in the weeds and not worth worrying about from a practical standpoint as a coach or lifter, though.

So yes, the spectrum of training responsiveness, “anabolic sensitivity” vs. “resistance” is mediated by numerous factors – most of which are not actually related to age itself, but rather to things that that are either intrinsic (like genetics), or that tend to correlate with aging, like the accumulation of medical comorbidities, insulin resistance, cardiovascular disease, etc. Testosterone of course can play a role, especially when clinically deficient, but even this is also commonly affected by the accumulation of medical conditions. A super healthy, active, untrained older adult with favorable genetics might realistically build more muscle from training compared with a less healthy/active younger person with less favorable genetics.

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14

Appreciate you sharing that, I was still referencing the older paper. Not covered in the article, but are both of these considered Testosterone Replacement Therapy or Low dose steroid use?

Case Study A
Increasing testosterone through medication from clinically low levels (<264) to high but WNR (1000+), yet beyond what was normal for that individual.

Case Study B
Increasing testosterone through medication from non-clinically low levels (>264) but perhaps some general symptoms to high but WNR (1000+), yet beyond what was normal for that individual.

I have seen this a lot with clients, even as recent as yesterday (case study B) and I am trying to understand long-term health side effects. I understand you’ve covered side effects in the article and I’ve looked at the research articles but admittedly not all the criteria within each study design.

It’s typically, slightly older male, but as young as 30’s, with low end but WNR testosterone and is sold the idea that using gel/jabs but keeping to the higher end of population level WNR is TRT and therefore safe.