Testosterone Replacement Therapy

Introduction

Testosterone is a hormone that plays a critical role in male sexual health and various physiological processes. Low testosterone levels, also known as hypogonadism, can lead to a range of symptoms and health issues, including decreased libido, erectile dysfunction, reduced muscle mass and strength, mood changes, and osteoporosis. Testosterone replacement therapy (TRT) can restore normal testosterone levels in people with hypogonadism, relieving symptoms and improving overall health and well-being.

TRT has gained attention in recent years due to its potential benefits in improving sexual function, body composition, mood, and overall quality of life. However, the therapy is also associated with potential risks and side effects that need to be carefully considered before initiating treatment.

This article provides a comprehensive overview of TRT, including its benefits, risks, eligibility criteria, and the different ways you can take it.

What is Testosterone Replacement Therapy?

TRT replaces testosterone in people with low testosterone levels due to primary (testicular failure) or secondary (hypothalamic-pituitary dysfunction) hypogonadism. TRT helps restore normal testosterone levels to relieve symptoms associated with hypogonadism, improve overall health and well-being, and prevent or treat complications of hypogonadism [1-8].

TRT can be taken through various methods, including intramuscular injections, transdermal gels or patches, oral tablets or capsules, and subcutaneous pellets. Which method you choose depends on your preferences, lifestyle factors, and medical considerations. Close monitoring and regular adjustments are necessary to maintain normal testosterone levels and monitor potential side effects or adverse reactions [1-8].

It is important to note that TRT should not be taken by people with normal testosterone levels or those seeking to enhance athletic performance or muscle mass beyond normal levels. The therapy is specifically designed for those with hypogonadism who meet the eligibility criteria and have been thoroughly evaluated for potential risks and benefits.

Benefits of Testosterone Replacement Therapy

TRT has been shown to provide numerous benefits for people with hypogonadism.

• Improved sexual function. This is one of the most well-established benefits of TRT. It includes increased libido, enhanced erectile function, and improved sexual satisfaction [9-11, 22].
• Enhanced muscles. TRT may help build muscle mass and strength. It has been shown to improve body composition, and increase physical performance and exercise capacity. Studies have shown that TRT can increase lean muscle mass, muscle strength, and improve waist-to-hip ratio and fat-to-muscle ratio [12-17]. These effects can be particularly helpful for older men with hypogonadism, who may experience age-related declines in muscle mass and strength.
• Stronger bones. TRT can help increase bone mineral density, reduce osteoporosis risk, improve bone remodeling, and decrease fracture risk [18-20]. This is particularly important for men with hypogonadism, who are at increased risk of osteoporosis and fractures due to the role of testosterone in maintaining bone health.
• Improved heart health. TRT has been shown to improve lipid profiles, enhance insulin sensitivity, and improve endothelial function and arterial stiffness [21-23]. However, the research is mixed on the cardiovascular effects of TRT, with some studies suggesting potential risks in certain subgroups of patients.
• Improved mood and cognitive abilities. Cognitive and mood benefits of TRT include improved memory, attention, executive function, mood, and overall well-being [24-26].

Risks and Side Effects of Testosterone Replacement Therapy

While TRT can provide various benefits, it is also associated with potential risks and side effects. Some studies have suggested that there’s an increased risk of cardiovascular events in certain subgroups of patients, particularly those with cardiovascular disease or risk factors. However, other studies have not found a significant association between TRT and cardiovascular risk. The conflicting evidence highlights the need to discuss your personal risks and benefits with your healthcare provider.

TRT may stimulate the growth of the prostate gland, potentially increasing the risk of prostate cancer or benign prostatic hyperplasia (BPH). Close monitoring of prostate-specific antigen (PSA) levels and other signs of prostate issues is essential [33-35]. Men with a history of prostate cancer or elevated PSA levels may not be candidates for TRT due to these potential risks.

TRT may worsen sleep apnea in some men. People should be screened for sleep apnea before and during treatment [36-37].

Erythrocytosis, or increased red blood cell count, is another potential side effect of TRT. The hormone can stimulate the production of red blood cells, increasing the risk of blood clots and other complications. Regular monitoring of hematocrit levels is recommended, and you may need to adjust your dose if levels become too high. Certain medications, like sodium-glucose cotransporter-2 inhibitors (SGLT-2i), can further increase the risk of erythrocytosis when combined with TRT [34-35].

Liver toxicity is a concern with certain forms of testosterone, such as oral testosterone undecanoate [36-37]. People with liver disease or those taking medications that affect liver function may require careful monitoring if they decide to take TRT.

TRT can also lead to temporary infertility in some men by suppressing sperm production. This effect is typically reversible if you stop taking TRT [36-37]. Alternative treatments or sperm banking may be considered for men who wish to preserve fertility while undergoing TRT.

Other potential side effects of TRT include acne, breast enlargement (gynecomastia), fluid retention and edema, mood changes (including irritability and aggression), and decreased testicular size [36-37]. If you have any side effects, you may need to adjust the dose or stop taking TRT.

Eligibility Criteria for Testosterone Replacement Therapy

Certain symptoms can lead to a diagnosis of low testosterone, or hypogonadism, and make you a candidate for TRT [38].

According to the Endocrine Society Clinical Practice Guideline, symptoms of testosterone deficiency include decreased libido, erectile dysfunction, decreased energy, decreased muscle mass and strength, and depression.

A diagnosis also includes blood tests that show low total testosterone levels, defined as less than 300 ng/dL (10.4 nmol/L) for younger adults or less than 200 ng/dL (6.9 nmol/L) for older adults. The tests are usually repeated at least twice to confirm low levels [38].

Recent studies suggest that the traditional thresholds for diagnosing hypogonadism may be too high, with the lower limit of normal potentially being 3-4 nmol/L lower than published ranges [39]. This highlights the importance of considering individual factors and symptoms in addition to serum testosterone levels when being evaluated for TRT.

Age is another consideration. The therapy is typically recommended for adult men aged 18 and above who meet the diagnostic criteria for hypogonadism. There is no upper age limit for TRT, as long as the potential benefits outweigh the risks, which may increase with age. However, older men may require more careful monitoring and dose adjustments due to age-related changes in metabolism and sensitivity to testosterone. TRT is not recommended for adolescents, as the effects of long-term therapy on growth and development are not well-established [38].

Certain medical conditions may prevent you from getting TRT. The treatment is not recommended for people with a history of prostate cancer, an elevated prostate-specific antigen (PSA) level, or a history of breast cancer. Men with severe lower urinary tract symptoms, such as those associated with benign prostatic hyperplasia (BPH), may not be good candidates for TRT. However, recent studies have found that mild urinary tract symptoms are not worsened by TRT and may even improve in men with the metabolic syndrome [40-41]. Men with untreated obstructive sleep apnea are generally excluded from TRT, as it may worsen the condition [38].

Other factors that may influence TRT eligibility include having cardiovascular disease or risk factors, liver disease, polycythemia, and taking medications that may interact with testosterone.

Methods and Administration of Testosterone Replacement Therapy

Testosterone replacement therapy can be taken through various methods, each with its own plusses and minuses. The choice depends on individual preferences, lifestyle factors, and medical considerations, and may require trying different options to find the optimal approach for each patient.

• Intramuscular injections of testosterone cypionate or enanthate are commonly used. It’s administered into the gluteal or deltoid muscles every 2-4 weeks [1-8]. Injections provide a rapid increase in serum testosterone levels, followed by a gradual decline over the dosing interval. This method may be preferred by men who want less frequent shots or have difficulty with daily application of transdermal formulations. However, injections may be associated with fluctuations in testosterone levels and may require more frequent monitoring and dose adjustments.
• Transdermal patches, such as Androderm and Testoderm, are applied daily, allowing continuous absorption of testosterone through the skin. Patches provide a more consistent delivery of testosterone compared to injections but may cause skin irritation or allergic reactions in some patients.
• Topical gels, including AndroGel, Testim, and Fortesta, are applied daily to the shoulders, arms, or abdomen, providing consistent delivery of testosterone. Proper application technique is important to prevent transfer of testosterone to others through skin contact [1-8].
• Buccal and sublingual tablets, like Striant®, are placed under the tongue or between the gum and cheek, allowing direct absorption of testosterone into the bloodstream [1-8]. This method provides a convenient and discreet option for patients who prefer oral administration but may be associated with gum or mouth irritation in some cases.
• Testosterone pellets are surgically implanted under the skin, slowly releasing testosterone over several months, offering a long-acting and consistent delivery option [1-8]. Pellets require a minor surgical procedure for insertion and removal and may be preferred by men who don’t want to bother with daily or weekly treatments.

When first starting TRT, you’ll be given a starting dose based on baseline testosterone levels, symptoms, and overall health. Your healthcare provider will gradually increase the dose, while monitoring improvements in your symptoms and for side effects [1-8].

Regular monitoring of serum testosterone levels, hematocrit, PSA, and other markers help ensure that testosterone levels remain within the therapeutic range and to detect any potential adverse effects. It may be necessary to adjust the dose [1-8].

Conclusion

Testosterone replacement therapy is a well-established treatment for people with hypogonadism, and is designed to restore normal testosterone levels and improve overall health and well-being. TRT has numerous benefits, including improved sexual function, enhanced muscle mass and strength, better body composition, stronger bone health, improved cardiovascular health, and cognitive and mood enhancements.

However, TRT may have risks and side effects, such as cardiovascular risks, prostate issues, sleep apnea, erythrocytosis, liver toxicity, infertility, and other side effects. Careful patient selection based on eligibility criteria, close monitoring, can help ensure safe and effective use of TRT.

Healthcare providers should work closely with men to develop individualized treatment plans that optimize the benefits of TRT while minimizing potential risks and side effects.

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