Testosterone Replacement Therapy in Men: Benefits, Risks, and the Right Approach

Testosterone Replacement Therapy in Men: Benefits, Risks, and the Right Approach

Testosterone replacement therapy has become increasingly common, nearly tripling in the last few years, with up to a third of men who are started on replacement not meeting the criteria for low testosterone to begin with. In this blog, we will discuss the ins and outs of low testosterone, including current medical society guidelines regarding treatment, along with the benefits, risks and additional facts surrounding testosterone replacement therapy.

How is Testosterone Deficiency Diagnosed?

Testosterone deficiency is diagnosed by having a low serum total testosterone level ( < 300 ng/dL ), drawn in the early morning ideally between 8 am – 10 am, on two separate occasions, along with typical signs or symptoms of testosterone deficiency.

Symptoms of low testosterone may include fatigue, depression, erectile dysfunction and reduced sex drive, infertility, obesity, gynecomastia (benign enlargement of the male breast tissue), poor concentration and memory, among others. Many of these symptoms are considered non-specific, meaning there are other disorders besides low testosterone that can cause them. Therefore, it is important that your doctor does a thorough history and physical exam, along with the proper diagnostic evaluation prior to diagnosing testosterone deficiency.

There are other conditions that are associated with low testosterone, and should prompt an evaluation for testosterone deficiency if present, even in the absence of the symptoms above. Some examples include unexplained anemia, diabetes mellitus type II, bone density loss (osteopenia or osteoporosis), male infertility, prior chemotherapy, pituitary disorders, HIV, and chronic narcotic use, among others.

Identifying the Cause of Low Testosterone

Testosterone is primarily produced in the testes in men through a feedback loop involving the brain, that sends signals to the pituitary gland, and fluctuations in additional hormones that signal the testes to produce or decrease testosterone production.

Total testosterone can be decreased due to a “primary” defect, where the testes are not able to produce enough testosterone, or a “secondary” defect, where a problem in the brain leads to the testes not being “told” to produce testosterone. There are several additional hormones that may be helpful in the workup, depending on the individual circumstance, and include Luteinizing Hormone, Follicle-Stimulating-Hormone, Prolactin, serum Estradiol, along with semen analysis.

Additional Testing Prior to Treatment

Patients should obtain a baseline measurement of their hemoglobin and hematocrit. This is because testosterone replacement can cause an increase in the hemoglobin and hematocrit, and treatment recommendations may be modified depending on the severity.

Patients over the age of 40 should also have their Prostate-Specific Antigen (PSA) measured prior to beginning testosterone therapy. This is a recommendation from the American Urological Association in order to reduce the risk of prescribing testosterone therapy to men with occult prostate cancer (not yet detected). It should be noted that several cancer society’s report that there is no clear link between testosterone replacement therapy and prostate cancer. A study published in December 2023 by JAMA Network Open confirmed prior research that found that in men with documented low testosterone levels treated with testosterone replacement therapy, there was no increased risk of prostate cancer compared to men not using testosterone replacement therapy.

What are the Possible Benefits of Testosterone Replacement?

In men with low testosterone levels treated with testosterone replacement, clinical trials have shown a statistically significant improvement in erectile function, bone mineral density, lean body mass, anemia, and depressive symptoms.

Indeterminate Benefits

Testosterone replacement therapy has shown indeterminate benefits for the following symptoms that are associated with testosterone deficiency: energy, fatigue, cognitive function, diabetes, quality of life.

Low energy and fatigue are non-specific symptoms that are commonly associated with other conditions such as depression, chronic fatigue and stress. There have been conflicting results in studies as to the potential benefit of testosterone therapy for these symptoms, with at least three randomized controlled trials showing minimal to no benefit. In one study, a questionnaire that assessed patients’ overall impression of change regarding their energy level found that those on testosterone replacement were significantly more likely to rate changes as a little or much better compared to placebo.

Quality of life can be difficult to quantify due to limitations with standardized questionnaires and study method characteristics. At least seven studies have shown no benefits on quality of life in men using testosterone therapy compared to placebo and at least five studies showed there were improvements.

Possible Risks

Low testosterone levels are associated with an increased risk of heart attacks, stroke, and possibly cardiovascular-related death. However, studies that have evaluated for a cardiovascular benefit or harm in men on testosterone replacement have found inconsistent results. Some studies suggest there is an increased risk of major adverse cardiovascular events on testosterone replacement, while others suggest a decreased risk or a more neutral effect.

Based on several studies suggesting an increased risk of cardiovascular events, the FDA required the addition of a warning to testosterone products about a possible increased risk of heart attack or stroke in patients using testosterone therapy. However, the American Urological Association recommends to counsel patients that the current scientific literature does not definitively demonstrate that testosterone therapy increases risk.

In 2014, the FDA also required the addition of a warning about the possible association between testosterone therapy and venothrombolic events such as deep vein thrombosis (DVT) or pulmonary embolism (PE), based on anecdotal cases and not peer-reviewed literature. Since then, at least four large observational studies were performed with none showing an increased risk of venothrombolic events with testosterone therapy.

Testosterone replacement therapy is associated with decreased sperm counts, or no sperm at all seen in semen. This is because exogenous testosterone (from testosterone replacement) also lowers the level of Follicle-Stimulating Hormone (FSH), which is responsible for stimulating sperm production. In many cases, this can be reversed once testosterone replacement has been stopped. Men who are diagnosed with testosterone deficiency and are interested in preserving their current fertility should undergo an additional assessment of their reproductive health status prior to initiating treatment.

Treatment of Testosterone Deficiency

The American Urological Association recommends that men with testosterone deficiency should be counseled that lifestyle modifications, such as weight loss in the setting of excess weight, along with increased physical activity, may increase total testosterone levels and/or reduce signs and symptoms associated with testosterone deficiency. They also recommend that men with mild testosterone deficiency and whose weight is above the recommended range and/or who are physically inactive should consider lifestyle modifications followed by reassessment of testosterone levels, signs, and symptoms before deciding to initiate testosterone replacement.

The goal of testosterone replacement therapy is to normalize the total testosterone level, combined with an improvement in symptoms or signs. The American Urological Association recommends that doctors use the smallest dose necessary to bring testosterone levels to the normal physiological range of 450 – 600 ng/dL, which is about the middle tertile of the normal range. This range was felt to be sufficient to resolve any symptoms that are truly associated with testosterone deficiency. Patients should have their signs/symptoms re-evaluated within three months after beginning treatment to determine if any dosing adjustments are required. Dose escalation into the supraphysiological range is not recommended as it has not been shown to achieve greater efficacy of symptoms, and there is data showing an increased risk of serious adverse events.

Types of Testosterone Replacement

Testosterone gels are a popular recommendation as they typically result in normal and relatively stable serum testosterone levels. Occasional skin irritation may occur but typically does not lead to discontinuation of therapy. Topical preparations have the potential to result in transference to others, and patients are advised to apply the medication only to suggested areas, wash hands after applying, cover with clothing and follow other recommendations to reduce the risk of transference.

Intramuscular testosterone offers a biologically effective treatment that doesn’t require daily administration. Some disadvantages include having to do an intramuscular injection every one to three weeks and the resultant fluctuations in the serum testosterone concentration, which may result in fluctuations in symptoms including energy, libido, and mood.

There is an extra-long-acting intramuscular testosterone formulation that is typically dosed at 10 weeks apart for maintenance. This preparation has been associated with rare cases of pulmonary oil microembolism (POME), 1.5 cases per 10,000 injections, as well as anaphylaxis, 0.4 cases per 10,000 injections. These injections are required to be administered in an office or hospital setting by a trained and registered health care provider and the patient must be monitored for 30 minutes afterwards for adverse reactions.

Oral preparations that include methyltestosterone are not typically recommended, as these preparations are not felt to be completely effective in producing virilization (masculine features), and there have been reports of liver side effects.

A newer oral formulation of testosterone undecanoate has shown promising results as being an effective treatment with a safety profile relatively consistent with other approved products, and no evidence of liver toxicity. A study published in 2020 found that it was associated with a mean increase in systolic blood pressure of 3 to 5 mmHg.

Subcutaneous testosterone pellets can be implanted into the buttocks, lower abdominal wall, or thigh using a local anesthetic. Adverse events include pellet extrusion, infection, and fibrosis (tissue thickening and scarring). There is limited data on the serum testosterone concentrations during treatment and pellets are not routinely recommended compared to other formulations.  

Ongoing Monitoring

Patients on testosterone replacement should have follow up bloodwork to evaluate their response, and make adjustments as needed to maintain a therapeutic level. The specific timeline will depend on various factors including the formulation of testosterone.

For example, patients on topical gels and patches should have their total testosterone re-checked between two to four weeks after beginning treatment. However, patients on long-acting subcutaneous pellets will require an initial measurement between two to four weeks after initial implant. This is to determine if the number of inserted pellets need to be increased or decreased to achieve the appropriate therapeutic level. Patients should then be re-tested after ten to twelve weeks again.

Once in the maintenance phase, it is recommended to re-check serum testosterone levels every six to twelve months. The hemoglobin and hematocrit are also recommended to be followed every six to twelve months in order to maintain hematocrit levels below 54%. This is because erythrocytosis, or having a high concentration of red blood cells, is a common adverse effect of testosterone replacement, and the risk of blood clots increases when the hematocrit rises.

Why Does It Seem Like Everyone Is On Testosterone Replacement Now?

Marketing. There has been a striking increase in the inappropriate use of testosterone therapy in healthy, middle-aged and older men. This has largely been driven by online or cash-pay clinics who promise an improvement in non-specific symptoms such as low energy and mood, poor memory and concentration, and decreased sexual performance, while providing testosterone replacement outside of the recommended medical guidelines.

As discussed earlier, testosterone is primarily produced in the testes in men through a feedback loop involving the brain, that sends signals to the pituitary gland. Subsequent fluctuations in additional hormones signal the testes to increase or decrease testosterone production. If you start taking additional testosterone, the brain sends signals that cause the testes to decrease or stop producing testosterone. It may then be difficult to stop supplemental testosterone treatment due to the prolonged period of hypogonadism (reduced production of sex hormones including testosterone) while this feedback loop recovers.

A clinical practice guideline for testosterone therapy in men with hypogonadism published in May 2018 reported that supplemental testosterone withdrawal, after an extended period of high dose treatment, was associated with marked suppression of the bodies own testosterone production and severe symptoms of hypogonadism. The body’s ability to re-initiate testosterone at a therapeutic level may take weeks to months, depending on the dose and duration of prior testosterone replacement use. A small minority of men may never recover normal endogenous (made by the body) testosterone production and require ongoing replacement therapy.  

Final Thoughts

Testosterone replacement therapy can offer significant benefits for men with clinically diagnosed testosterone deficiency. The decision to pursue treatment should be based on a thorough evaluation, including proper diagnostic testing, an assessment of symptoms, and consideration of underlying conditions that may affect testosterone levels.

It’s crucial that men seeking testosterone therapy work closely with their doctor to ensure they meet the criteria for testosterone replacement and understand the potential risks. Moreover, lifestyle changes, such as weight loss and increased physical activity, should be considered as part of a comprehensive approach to managing testosterone deficiency, particularly for those with milder cases. With careful monitoring, including regular bloodwork and symptom evaluation, testosterone replacement can be beneficial for many men, but it should always be used in accordance with established medical guidelines. As the growing trend of testosterone therapy continues, it is important for patients to remain informed and cautious, avoiding unnecessary or inappropriate use driven by marketing or anecdotal claims.

Florida Direct Primary Care

At Florida Direct Primary Care, we develop individualized treatment plans that promote overall health and wellness, tailored to each patient’s unique health needs and goals. If you’re in the St. Augustine area and looking for a primary care, sports medicine, or obesity medicine doctor, contact us to learn more about the practice. Visit FloridaDPC.com, email us at info@FloridaDPC.com, or call 904-650-2882.

This web site is provided for educational and informational purposes only and does not constitute the provision of medical advice or professional services. The information provided should not be used for diagnosing or treating individual health problems or diseases. Those seeking medical advice should consult with a licensed physician.

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