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An Overview of Testosterone Replacement Therapy (TRT)

TRT for low testosterone

DISCLAIMER: All content is for informational and educational purposes only. Please consult your physician for personalized medical advice.

Testosterone replacement therapy (TRT) is something that everyone is talking about nowadays. Its rise in popularity is partially due to influential figures, such as Joe Rogan, who talk about how amazing they feel since starting TRT. While it is certainly true that TRT can be extremely beneficial and helpful in the right context, using exogenous hormones can be dangerous in the wrong context. Unfortunately, its rise in popularity has led to an increase in the amount of TRT being prescribed by generic “hormone clinics” that are possibly out to make a quick buck and may be negatively affecting young men.

The purpose of this article is to simply provide an overview of TRT, what it is, and who it’s for, as well as discussing some potential side effects of using TRT.

What is TRT?

Testosterone Replacement Therapy, commonly known as TRT, is a medical treatment designed to supplement or replace the body's natural testosterone levels. As you probably know, testosterone is a crucial hormone responsible for various functions in the body, including the development of male sexual characteristics, maintaining muscle mass, and bone density, and contributing to overall well-being [1]. While TRT has been used for decades to treat testosterone deficiency in men, its recent surge in popularity has garnered significant attention.

TRT involves the administration of exogenous testosterone through various methods, such as topical gels, injections, patches, or pellets implanted under the skin. The therapy aims to bring low testosterone levels back to a healthy range, alleviating symptoms associated with low testosterone and potentially improving a person's quality of life.

It’s important to highlight that the main purpose of TRT is to bring testosterone levels back to a normal, healthy, range and not to increase them to supraphysiological levels. The main difference between the two is the dose of testosterone being used. The latter requires a much higher dose and is not considered TRT, but is pursued by bodybuilders and other physique athletes looking to push their testosterone levels beyond the natural range.

Who is TRT for?

Testosterone Replacement Therapy (TRT) is primarily intended for individuals diagnosed with hypogonadism; a condition characterized by insufficient testosterone production in the body. Hypogonadism can manifest at different stages of life and can have various underlying causes, which determine whether TRT is a suitable treatment option.

While hypogonadism results in lower testosterone, the cause can be multifactorial. Hypogonadism can be classified into two main types: primary and secondary hypogonadism.

Primary Hypogonadism: This form of hypogonadism results from direct dysfunction in the testes, leading to reduced testosterone production. It can be caused by factors such as genetic conditions, testicular injury, or infection.

Secondary Hypogonadism: This type of hypogonadism originates from issues in the hypothalamus or pituitary gland, which regulate testosterone production in the testes. In secondary hypogonadism, the testes may actually still have the ability to produce testosterone, however, they are not receiving the signal to do so from the hypothalamus. Secondary hypogonadism can be due to factors like certain medications, tumors, or other medical conditions affecting the brain's endocrine control centers.

TRT may be an appropriate treatment for individuals diagnosed with primary hypogonadism, since the reason they’re not producing testosterone is due to testicular dysfunction. In such cases, TRT helps replenish testosterone levels, alleviating symptoms and restoring hormonal balance.

However, TRT may not be the best choice for individuals diagnosed with secondary hypogonadism, since the issue lies in the brain's endocrine control centers (hypothalamus or pituitary gland). If the brain's signaling mechanisms are impaired, administering exogenous testosterone can help increase testosterone concentrations, but it does not address the root cause of the issue. Instead, treatment may involve addressing the underlying cause or, in some cases, using alternative hormone therapies.

Symptoms of Hypogonadism (low testosterone)

Hypogonadism can manifest differently depending on several factors. In males, the common symptoms of hypogonadism include:

  • Reduced Libido: A decrease in sex drive and a lack of interest in sexual activities.
  • Erectile Dysfunction: Difficulty achieving or maintaining erections during sexual arousal.
  • Fatigue: Persistent feelings of tiredness and lack of energy.
  • Decreased Muscle Mass: Loss of muscle bulk and strength.
  • Infertility: Impaired sperm production, leading to fertility issues.
  • Mood Changes: Increased irritability, depression, or difficulty concentrating.
  • Gynecomastia: Enlargement of breast tissue in males.
  • Decreased Body Hair: Thinning of facial and body hair.
  • Osteoporosis: Reduced bone density, increasing the risk of fractures.

While none of these symptoms directly indicate that a man is hypogonadal, if you’re experiencing a combination of these symptoms, it may be a good idea to discuss them with your physician [2].

How do I know if I have low testosterone?

To diagnose hypogonadism, healthcare professionals perform blood tests to measure the levels of total testosterone in the bloodstream. The diagnosis is not solely based on the absolute testosterone value but also on the presence of symptoms associated with hypogonadism such as loss of libido, mood changes, and erectile dysfunction, amongst others. Different medical organizations may have slightly varying guidelines, but generally, morning total testosterone levels below 300-350 ng/dL (nanograms per deciliter) are considered low and may prompt further investigation for hypogonadism.

While total testosterone is used as the “standard” to diagnose hypogonadism, it doesn’t paint the entire picture of what’s going on physiologically. Some medical organizations also look at what’s called free testosterone in addition to total testosterone concentrations. While total testosterone tells us the overall amount of testosterone that’s present in the bloodstream, free testosterone tells us how much of that testosterone is actually available for different physiological functions. To understand why this is the case, you need to understand the role and function of a protein called sex hormone binding globulin (SHBG).

What is sex hormone binding globulin (SHBG)?

SHBG is a protein produced by the liver that acts as a carrier for sex hormones, including testosterone and estrogen. When testosterone is released into the bloodstream, a significant portion of it binds to SHBG, forming a testosterone-SHBG complex. Testosterone bound to SHBG is inactive. However, it is the free testosterone, the portion of testosterone that remains unbound to SHBG, that is readily available to interact with various tissues and organs and have a physiological effect, including sexual health, muscle mass, bone density, mood, and energy levels.

In cases where SHBG levels are elevated, a greater proportion of testosterone becomes bound, resulting in reduced free testosterone levels. This scenario can occur even when total testosterone levels appear normal. As a consequence, an individual may experience symptoms of hypogonadism due to insufficient bioavailable testosterone, despite having seemingly adequate total testosterone concentrations. Similarly, a person could have low total testosterone, yet have adequate free testosterone because their SHBG concentrations are low.

By assessing free testosterone levels alongside total testosterone, your doctor can obtain a more accurate picture of your hormonal status and identify whether testosterone deficiency is genuinely contributing to your symptoms. This comprehensive approach ensures that individuals receive appropriate diagnosis and treatment to help them make a more informed decision about potential treatments for their condition.

What are the potential risks of TRT?

TRT has a ton of conferred health benefits for individuals with low testosterone including improved blood lipids, improved muscle mass, improved blood pressure, and improvements in sexual function [3], amongst others. There are some risks that have been identified in the literature that also important to discuss. Truthfully, the list of potential side effects goes on and on including things like acne, aggression, and joint pain. That being said, we are just going to focus on the side effects that can pose a serious threat to your health like cardiovascular risks, prostate complications, and infertility. The truth is that unfortunately, most of the evidence isn’t extremely robust and there is a lot of conflicting evidence.

Cardiovascular disease (CVD):

One of the concerns people have with TRT is that it may affect cardiovascular health. Low testosterone is actually associated with an increased risk of cardiovascular events [4], which would suggest that TRT might reduce the risk of CVD. However, there is conflicting evidence on this topic. Most of the data investigating the effects of TRT on CVD seem no show a neutral effect, while others show that there might be a potential detrimental effect [5]. For example, two meta-analysis found that TRT has no effect on cardiovascular events [6][7], while a 2013 meta-analysis found that TRT increased cardiovascular events [8]. That being said, the authors of two reviews [3][5] have pointed out that there are a number of methodological issues with the studies that show potential risks that many of the studies included in this meta-analysis, which put to question their findings. Read the review by Traish et al., [3] for a deeper explanation of this topic, but these methodological flaws combined with the abundance of data showing no effect of TRT on CVD indicates that, when used safely, TRT does not seem to pose any negative cardiovascular effects.

Infertility:

Another potential risk of using TRT is the possibility of infertility. Testosterone production in the testes stimulates spermatogenesis, which is the production of new sperm. Men who are hypogonadal already have a higher risk of infertility due to decreased testosterone production. That being said, there are different treatments that are effective for reversing infertility in hypogonadal men [8]. However, using TRT can increase the risk of infertility because exogenous testosterone decreases the production of endogenous testosterone (the testosterone your body makes itself). Since the production of sperm happens locally in the testes, where testosterone is produced, TRT decreases sperm production due to the fact that it inhibits endogenous production of testosterone in the testes [10]. Although fertility may be recovered through a combination of other hormonal therapies as well as the cessation of TRT [11], it is recommended for men to either start TRT after their reproductive years are over, or perhaps, freeze healthy sperm prior to starting TRT if they desire to have children in the future.

Prostate health:

Mechanistically, testosterone is involved in the function and growth of the prostate gland. There is some evidence showing that exogenous testosterone may increase the levels of prostate-specific antigen, or PSA [5][12], which is a molecule associated with the development of prostate cancer. According to the American Cancer Society, individuals with a PSA above 10 ng/mL are at a 50% increased risk of prostate cancer. That being said, all of the data is not unanimous. There are data showing that TRT does not seem to increase PSA levels in both hypogonadal or eugonadal men undergoing TRT [13]. The differences in results between these studies may be due to the method of TRT administration being used, the population studied, as well as other methodological differences. Nonetheless, since there are some data showing that TRT may increase PSA levels, androgen deprivation is a commonly used therapy in individuals who have prostate cancer. That being said, when looking at hardcore outcome data, it does not seem that TRT increases risk of prostate cancer compared to individuals who are not on TRT. A 2005 meta-analysis found that while individuals on TRT are 11 times more likely to have a prostate biopsy, the number of individuals with prostate cancer was not different between TRT and placebo [7]. A 2003 study showed that TRT does not seem to increase the risk of prostate cancer even in individuals who are already at risk for developing prostate cancer [14]. Overall, the data do not suggest that using TRT in a safe fashion will increase the risk of prostate cancer. If you want to read more on this topic, make sure to check out this review by Ramasamy et al., [15].

Conclusion

Starting hormone replacement therapy is a personal decision that should be thought through carefully and discussed with your medical doctor. If you are experiencing several of the symptoms associated with hypogonadism, it may be a good idea to talk to your doctor and have your testosterone levels checked.

The main contraindication would be if you’re planning on, or would like to, have children in the near future. In such cases, it’s likely best to postpone TRT after your reproductive years are over or freezing your sperm for later use.

Overall, TRT is safe when used correctly and can drastically improve quality of life in individuals who have low testosterone levels. Most of the “serious risks” associated with TRT, such as cardiovascular disease and prostate cancer, do not seem to be strongly substantiated by the currently available evidence. Of course, this assumes that you are using TRT to simply increase your testosterone levels to a normal, healthy physiological range. This would not be the case if you’re using TRT to increase your testosterone levels to supraphysiological levels.

References

1. Bassil, N., S. Alkaade, and J.E. Morley, The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag, 2009. 5(3): p. 427-48.

2. Kumar, P., et al., Male hypogonadism: Symptoms and treatment. J Adv Pharm Technol Res, 2010. 1(3): p. 297-301.

3. Traish, A.M., Testosterone therapy in men with testosterone deficiency: are the benefits and cardiovascular risks real or imagined? Am J Physiol Regul Integr Comp Physiol, 2016. 311(3): p. R566-73.

4. Tambo, A., M.H. Roshan, and N.P. Pace, Testosterone and Cardiovascular Disease. Open Cardiovasc Med J, 2016. 10: p. 1-10.

5. Grech, A., J. Breck, and J. Heidelbaugh, Adverse effects of testosterone replacement therapy: an update on the evidence and controversy. Ther Adv Drug Saf, 2014. 5(5): p. 190-200.

6. Fernández-Balsells, M.M., et al., Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab, 2010. 95(6): p. 2560-75.

7. Calof, O.M., et al., Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci, 2005. 60(11): p. 1451-7.

8. Xu, L., et al., Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med, 2013. 11: p. 108.

9. Prior, M., et al., Fertility induction in hypogonadotropic hypogonadal men. Clin Endocrinol (Oxf), 2018. 89(6): p. 712-718.

10. Desai, M.S., et al., A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility. Cell, 2016. 167(5): p. 1339-1353.e21.

11. Crosnoe, L.E., et al., Exogenous testosterone: a preventable cause of male infertility. Transl Androl Urol, 2013. 2(2): p. 106-13.

12. Osterberg, E.C., A.M. Bernie, and R. Ramasamy, Risks of testosterone replacement therapy in men. Indian J Urol, 2014. 30(1): p. 2-7.

13. Grober, E.D., et al., Correlation between simultaneous PSA and serum testosterone concentrations among eugonadal, untreated hypogonadal and hypogonadal men receiving testosterone replacement therapy. Int J Impot Res, 2008. 20(6): p. 561-5.

14. Rhoden, E.L. and A. Morgentaler, Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia. J Urol, 2003. 170(6 Pt 1): p. 2348-51.

15. Ramasamy, R., E.S. Fisher, and P.N. Schlegel, Testosterone replacement and prostate cancer. Indian J Urol, 2012. 28(2): p. 123-8.

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