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Health Risks and Side Effects of Testosterone Therapy

Last Updated on August 8, 2021 by Max

Introduction.

Many studies suggest the essential role of testosterone in keeping vigorous metabolic processes throughout the body. However, with age, testosterone levels decline, and the levels of sex hormone-binding globulin increase, both trends resulting in decreased bioavailable testosterone with all its benefits. The Baltimore Longitudinal Study of Aging published the rate of hypogonadism (reduced testicular size) as 20% in men over 60 years of age, 30% in men over 70 years, and 50% in men over 80 years of age.

Testosterone replacement therapy is a reasonable treatment that can greatly improve quality-of-life in men suffering from low testosterone. 

But a person who chooses TRT must be aware of all the associated risks. 

TRT is contraindicated in men with prostate and breast cancer. Men on TRT should be watched for side effects such as polycythemia, edema, cardiac and hepatic dysfunction (Osterberg EC et al. 2014).

Health risks of TRT and associated monitoring strategies. 

Any man who has health conditions that exclude TRT should be informed of all the risks. Upon prescribing TRT such possible consequences as aggravation of prostate cancer, worsening the symptoms of benign prostatic hyperplasia, male breast cancer, polycythemia, and an increased risk of obstructive sleep apnea, and an increased risk of arterial plaque build-up should be considered.

Potential risks of TRT and associated monitoring strategies (From Osterberg EC et al. 2014)

Potential RiskSuggested monitoring strategies
Cardiovascular
disease
Baseline blood pressure checks and repeats at 3 and 6 months,
then annually thereafter. For high-risk patients, consider cardiology referral
ErythrocytosisObtain baseline HCT then at 3 and 6 months, then annually thereafter.
If HCT is >54%, stop TRT and restart at a lower dose!*”!
Fluid retentionPatient history and physical exam. Stop TRT if CHF is uncontrolled”
BPHPatient questionnaire and history. Refer to a urologist if:
IPSS+above 19 and stop TRT!
Prostate
cancer
Obtain baseline DRE and serum PSA then again at 3 and 6 months.
Continual monitoring depending on the patient’s race/age.
Refer to a urologist if:
Abnormal DRE;
PSA rises over 4 ng/mL;
IF PSA rises more than 1 ng/mL in the first 6 months;
of TRT or by more than 0.4 ng/mL/year thereafter 4;
If PSA velocity is more than 0.4 ng/mL/year!.
AcnePatient history and physical exam. Dose adjustment
and/or referral to dermatology
HepatoxicityPatient history and physical exam. Liver function tests
are unnecessary in gel, pellet, and IM preparations
InfertilityPatient history and physical exam. Reconsider alternative strategies
if the patient desires to father children
OSABaseline patient history and physical exam and again between 3 and 6 months.!
Consider alternate causes of OSA!
Gynecomastia/
breast cancer
Exclude other etiologies with patient history and physical exam.
Review all medications. Complete hormone evaluation may be necessary.
Medications implicated to cause gynecomastia!
Anti-androgens-finasteride, bicalutamide
Antibiotics-isoniazid, ketoconazole, metronidazole
Antihypertensives-amlodipine, captopril, diltiazem, verapamil, nifedipine
Gl agents-cimetidine, omeprazole
Psychiatric-diazepam, haloperidol, tricyclic
antidepressants
TRT=Testosterone replacement therapy, HCT=Hematocrit, BPH=Benign prostatic hyperplasia, DRE=Digital rectal examination,
CHF=Congestive heart failure, IPSS=International prostate symptom score, PSA=Prostate-specific antigen, IM=Intramuscular,
OSA=Obstructive sleep apnea, Gl=Gastrointestinal.

Endogenous testosterone vs. exogenous testosterone.

Unfortunately, often wishing to show the benefits of TRT therapy, doctors appeal to scientific evidence concerning the effects of endogenous testosterone on human health while deliberately keeping silent about the adverse side effects of testosterone therapy.
It should be noted, for reasons not yet fully understood, these two types of T can sometimes have opposite effects.
In order not to be unfounded, consider an example of the effect of endogenous and exogenous testosterone on the cardiovascular system. The following is a snippet from the post advocating TRT.

“Of considerable interest is the association between blood testosterone and cardiovascular events such as heart attack and stroke. In a revealing new study, researchers identified 2,416 men (aged 69-81 years) who were not on any kind of testosterone-affecting treatment. These men were subjected to a battery of blood tests that included total testosterone and estradiol (estrogen).

The first observation was that men with increasing levels of testosterone had a decreased prevalence of diabeteshypertension, and body fat mass. Compared to men with the highest testosterone levels, those with low testosterone were twice as likely to have a history of cardiovascular disease. It was also observed that men with the highest testosterone levels were the most physically active.

This large group of men was followed for an average of 5.1 years. Men in the highest quartile of total testosterone (above 550 ng/dL) had a 30% lower risk of cardiovascular events. Any level of total testosterone below 550 ng/dL resulted in significantly increased risk, thus helping to establish a minimal baseline as to where total testosterone should be to guard against heart attack or stroke.

This finding showed that it did not matter if these men’s total testosterone was very low (below 340 ng/dL) or moderately low (up to 549 ng/dL)…they all had a similar increased risk for suffering a cardiovascular event. Only when total testosterone exceeded 550 ng/dL did cardiovascular risk plummet.

This finding remained consistent for cerebrovascular disease incidence, where men with the highest total testosterone (Quartile 4) had a 24% reduced risk of transient ischemic attack or full-blown stroke

The conclusions by the researchers who conducted this study were:

“Higher serum testosterone levels are associated with a reduced risk of fatal and non-fatal cardiovascular events in community-dwelling elderly men.” (Ohlsson C, et al. 2011). 

All the above is a demonstration of the great benefits of the testosterone that our body produces naturally. But is it true when it comes to the exogenous testosterone that we take on the TRT? Unfortunately, not. You can find a handful of well-organized research showing a positive correlation between TRT and cardiovascular events. Just to mention one of them is a recent report by Peter J Snyder and colleagues (2018). These Testosterone Trials (TTrials) were a set of seven placebo-controlled, double-blind trials involving 788 men, of a mean age of 72. The trials lasted 12 months.

In the Cardiovascular Trial, testosterone treatment much increased the coronary artery noncalcified plaque volume. Noncalcified plaque is a plaque directly related to the risk of fatal cardiovascular events.  

Also, an accepted side-effect of TRT is polycythemia- a condition when your hematocrit (relative volume of red blood cells) or hemoglobin is elevated in the blood. These excess cells thicken your blood, slowing its flow, which may cause serious cardiovascular problems, such as blood clots.

As you can see from these two examples, the effects of high testosterone levels in older people are completely different, depending on whether testosterone is endogenous or exogenous. Therefore, the use of research results related to natural, endogenous T for the promotion of TRT is at least misleading.

In addition, the flamboyant portrayal of the ease of accessibility of testosterone benefits, while keeping the related risks hidden, is appealing to younger people as well. Young or middle-aged men (under 50), instead of making some effort and changing their lifestyle and thereby spurring testosterone production naturally, are also tempting to easily increase their testosterone levels with TRT. Often, these guys even don’t realize what kind of trap they are getting into.

The following is a typical ask for help you can find on social networks:
“I just returned from the hospital, I had an angiogram where they found 3 main arteries over 80 % blocked and put 3 stents. I had another angiogram in 2019 with stents. My Cardiologist and Endocrinologist both insist for I stop TRT as they both said that one of the main causes of my plaque build-up in my arteries is due to TRT. I started TRT in 2017 and since then every 2 years I am having Plaque build-up. I am very active I work out at the gym with weight and cardio 2 Hours 5-6 times per week, I watch my diet and eat healthy with low carbs more protein. Has anyone on TRT experienced any plaque build-up in their arteries? I will really appreciate any comments. Thanks in advance.”

I’ve included this message from a Facebook group here, (I hope there is nothing illegal here) to show, how people going to TRT do not imagine the possible risks associated with it.

Why do we have these differences?

It can be assumed that a drop in testosterone levels, whether due to age or due to illness or lifestyle, leads to a cascade of other changes that we cannot yet take into account. If you manage to raise your testosterone levels through exercise, lifestyle changes, and diet, then it naturally raises the complex of concomitant changes, restoring harmony and balance in the body.

It’s quite another stuff when you increase your testosterone levels with TRT. Your elevated T levels no longer fit into the changed structure of the complex relationships of other biologically active components and hence all the health benefits of testosterone cannot be fully manifested. On the contrary, imbalanced relationships can lead to unexpected adverse effects, as in the case of the cardiovascular system.

The explanation sounds somewhat mechanistic, I couldn’t find any scientific data on the issue. However, I believe that we must be very careful when we disrupt the balance and hormones of important components such as testosterone, so as not to turn it from an element of youth into a factor of destruction of our body.

The main results of the TRT trials in older men. 

Returning to TTrials, I would like to dwell on the results of the study in more detail since this was the first comprehensive and credible study aimed at determining the effectiveness of increasing the testosterone levels of older men with low testosterone. The study included the following trials: Sexual Function, Physical Function, Vitality, Cognitive Function, Anemia, Bone, and Cardiovascular diseases. T treatment increased the mean testosterone level from unequivocally low at baseline to mid normal for young men after 3 months and maintained that level until month 12. 

  1. Testosterone treatment substantially increased sexual activity in old men. TRT treatment resulted in the raises of total and free testosterone and estradiol levels, which in turn improved sexual activity as increased libido and sexual desire but not erectile function
  2. In the  Physical Function Trial, testosterone did not increase the distance walked in 6 minutes in men whose walk speed was slow. However, in all TTrials, testosterone did increase the distance walked so it can be concluded that testosterone treatment for older men with low testosterone does improve walking, although to a small degree.  
  3. In the Vitality Trial testosterone did not increase energy but slightly improved mood and depressive symptoms.
  4. In the Cognitive Function Trial, testosterone did not improve cognitive function
  5. In the Anemia Trial, testosterone increased hemoglobin. However, this side effect of T often may have adverse consequences resulting in thickening of the blood and increasing the risks of blood clots. 
  6. In the Bone Trial, testosterone improved bone mineral density and the estimated strength of the spine and hip. 
  7. In the Cardiovascular Trial, testosterone raised the coronary artery noncalcified plaque volume hence increasing the risk of fatal cardiovascular events.  

Concerning the risks associated with prostate cancer and CVD, the follow-up period of 12 months was too short to draw any conclusions. The study authors conclude: “Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial of a much larger number of men for a much longer period would be necessary to determine whether testosterone increases cardiovascular or prostate risk.”

Conclusions.

It’s no secret that human health has long become the most convertible to money object. The hormonal system is very sensitive to chronic diseases, including cancer, cardiovascular and autoimmune diseases, which are the scourge of our time. Therefore, it is not surprising how rapidly the number of clinics focused on the correction of hormonal balance, in particular, testosterone replacement therapy (TRT), has been growing recently.

Be aware of all the risks associated with the TRT before making the final decision. Make sure to constantly monitor the possible adverse side effects if you have chosen TRT to improve the quality of your life.

YOUR EXPERIENCE OR POINT OF VIEW EXPRESSED IN THE COMMENT IS VERY HELPFUL AND ENCOURAGING THE AUTHOR THE BEST WAY

Literature.

  • Osterberg EC, Bernie AM, Ramasamy R. Risks of testosterone replacement therapy in men. Indian J Urol. 2014;30(1):2-7. doi:10.4103/0970-1591.124197.
  • Ohlsson C, et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol. 2011 Oct 11;58(16):1674-81. doi: 10.1016/j.jacc.2011.07.019. PMID: 21982312.
  • Snyder PJ, Bhasin S, Cunningham GR, et al. Lessons From the Testosterone Trials. Endocr Rev. 2018;39(3):369-386. doi:10.1210/er.2017-00234.
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