Testosterone Replacement Therapy

Testosterone is a hormone critical to maintaining men’s health. Testosterone levels are highest during adolescence and young adulthood. As we age, testosterone levels decrease over time at a rate of about 1 percent per year after age 30. Low testosterone levels can therefore be the result of the normal aging process; however, it can also be indicative of certain conditions like hypogonadism.

There are several signs of low testosterone. These include:

• Physical changes. These differences may include decreased muscle, decreased bone density, and increased body fat. Additionally, individuals may experience loss of body hair, less energy, or tender breasts.
• Changes in sexual function. This may manifest as having decreased libido, infertility, or less spontaneous erections.
• Emotional changes. Signs can include depression, memory troubles, or decreased motivation and self-esteem.

These symptoms can affect an individual’s health and wellbeing. Likewise, many men want to supplement their testosterone levels to mitigate the issues related to low testosterone. Some men turn to testosterone replacement therapy to do so.

While there are several benefits to testosterone replacement therapy, treatment can also carry a several of risks. It is important to know about the advantages and disadvantages of treatment so that you can make the most informed decision for your health. This article will discuss the benefits of testosterone as well of some of the safety risks associated with supplementation¹.

Efficacy

General benefits

There are several noted benefits of testosterone replacement therapy. These include:

• Improved bone mineral density. Men with hypogonadism tend to be at higher risk of conditions related to bone density, including osteoporosis, osteopenia, and fracture. Testosterone contributes to one’s bone mineral density by increasing osteoblastic activity. However, results from studies evaluating how testosterone replacement therapy affects bone mineral density in men is unclear.
• Increased energy, better mood, and improved quality of life. Men with hypogonadism often experience decreased libido, fatigue, dysphoria, and irritability. Additionally, they may also experience signs of depression. In fact, low testosterone levels correlate with depression in older men. Results from studies evaluating the effect of testosterone replacement therapy on things such as mood and quality of life are mixed, however.
• Improved sexual function and desire. Individuals who have erectile dysfunction (ED) or decreased libido who also have a testosterone deficiency may benefit from testosterone replacement therapy. Long-term data suggests that hypogonadal males on testosterone treatment perceived their libido to be higher than those on placebo. Testosterone has also demonstrated effects in increasing the frequency of sleep-associated erections and sexual acts.
• Cognition. Evidence suggests that there is a correlation between testosterone concentrations and an individual’s cognition. Specifically, it may influence one’s mathematical reasoning or spatial abilities. One study evaluated testosterone treatment in those with Alzheimer’s disease. Treatment appeared to better quality of life, but it did not influence cognition. Other studies, however, have found that there is no relationship.
• Improved muscle strength and mass. Having a more lean body mass can contribute to elevated energy levels and better weight control².

Cardiovascular health

The medical field has largely debated how testosterone can affect cardiovascular (CV) health. On the one hand, certain observations point to its negative effects: estrogen’s protective effects in premenopausal women, the higher incidence of coronary artery disease (CAD) in men, and the link between cardiovascular disease (CVD) related death in those abusing anabolic steroids. However, some data indicates that low testosterone is linked to metabolic conditions such as diabetes, increased adiposity (fat), insulin resistance, and heart attack. Likewise, some researchers hypothesize that maintaining normal testosterone levels has cardiovascular advantages for men. However, the benefits have not been confirmed as evidence is conflicting.  Despite the variation in clinical evidence, the Food and Drug Administration (FDA) and American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) agree that testosterone treatment is safe in those that have low testosterone and are symptomatic. For example, testosterone is a potential treatment option for men experiencing hypogonadism³.

Hypogonadism

Hypogonadism is a clinical condition in which men have low levels of testosterone coupled with symptoms such as low libido, depression, and low bone mineral density. Between two to four million men in the United States experience hypogonadism, however, only five percent receive treatment. Treatment involves replenishing testosterone within normal range, leading to benefits such as improved mood, energy, cognition, sexual function, wellbeing, muscle strength, and bone mineral density⁴.

Prostate cancer

Prostate cancer (PC) is the most commonly experienced cancer in men in the United States. Evidence that high or low testosterone contributes to the development of prostate cancer is mixed. One study evaluated the correlation between testosterone levels and aggressive PC. In 762 subjects, lower testosterone levels were associated with increased aggressiveness of PC and PC-related mortality. Likewise, these findings suggest low testosterone can contribute to aggressive PC and decreased PC-related survival⁵. Other findings suggest otherwise, which will be discussed later in this blog post.

Anemia

Testosterone can increase hemoglobin levels by up to seven percent. It does so by increasing erythropoietin production, thereby improving anemia symptoms in men⁶.

Safety

CV Risk

As aforementioned, some data exists suggesting a correlation between higher testosterone levels and adverse CV-related events. For example, long-term testosterone therapy may cause CV problems such as heart disease-related death, stroke, and heart attack. A study researching testosterone in older men was halted in 2019 due to an increased incidence of heart problems⁷.

In 2015, the FDA released a statement warning about the potential CVD risk with testosterone-containing products. Additionally, the FDA is requiring all new testosterone products to include the potential CVD risk in their labels. The AACE/ACE, however, concluded that research does not support the notion that testosterone either increases or decreases CVD risk. Though evidence is mixed, patients receiving testosterone therapy should be aware of the potential dangers³. However, a researcher panel at an AACE congress stated that the benefits of treating low testosterone levels with testosterone replacement therapy outweigh the risks⁷.

Prostate cancer

Lowering testosterone levels in individuals has been shown to be beneficial for existing prostate cancer. Likewise, some physicians are hesitant to prescribe testosterone for men at increased for prostate cancer or men who have been treated for prostate cancer. Their concern is that because prostate concern is androgen-dependent, increased testosterone could cause the progression of tumors. However, no definitive evidence exists suggesting that high levels of testosterone are associated with prostate cancer risk⁴.

Breast cancer

Testosterone is not directly linked to breast cancer. However, it may indirectly contribute to the development of breast cancer. High testosterone levels can affect estrogen, specifically a process called aromatization that produces an active form of estrogen. This process can activate breast tissue receptors, thus elevating one’s risk for male breast cancer.

Like with other conditions, the link between testosterone and breast cancer has not been fully characterized. One retrospective analysis studied 45 men and found that 11 percent developed breast cancer after being on long-term testosterone replacement therapy over 10 years⁶.

Benign prostatic hyperplasia

As previously mentioned, testosterone can affect the prostate, thus causing concern regarding prostate cancer. The relationship between testosterone and the development of benign prostatic hyperplasia (BPH) is an additional concern. Testosterone therapy has been shown to increase the size of the prostate by 12 percent. However, hallmark symptoms of BPH such as lower urinary tract symptoms (LUTS) and urinary retention did not worsen in those taking testosterone⁶.

Polycythemia

Polycythemia is a blood disorder. It can increase one’s risk of adverse vascular events such as a heart attack, stroke, and deep vein thrombosis. Few studies exist evaluating testosterone’s effect on the development of polycythemia. However, polycythemia is a potential side effect of testosterone replacement therapy. Though testosterone can be beneficial in men with anemia, research indicates it can cause polycythemia in greater than 20 percent of men treated with testosterone replacement therapy.

The increased risk of polycythemia warrants a baseline complete blood count (CBC) and continuous CBC monitoring throughout testosterone therapy. If a patient’s hematocrit (HCT) increases more than 54 percent while on treatment, one should discontinue testosterone until this level normalizes. If testosterone is re-initiated, it should be done at a lower dose with continued monitoring⁶.

Obstructive sleep apnea

Obstructive sleep apnea (OSA) is a potential risk related to testosterone replacement therapy, but evidence is mixed. If starting testosterone, individuals should be aware of typical OSA symptoms, including signs such as fatigue or snoring. Testosterone may also worsen OSA symptoms in those that have pre-existing OSA. Likewise, OSA is a potential contraindication to testosterone replacement therapy⁶.

Deciding to pursue treatment

Testosterone therapy carries a wide variety of benefits, but there are still a number of potential risks. Much research needs to be done to address the potential correlations. Likewise, the decision to undergo testosterone treatment is one to be made between you and your doctor.

Additionally, it is important to consider the various symptoms of low testosterone and if you are addressing these issues without medication. For example, symptoms such as low libido and fatigue could be attributed to things such as diet, exercise, and sleep habits. Addressing these factors first may help to improve symptoms or eliminate the need for testosterone therapy⁸.

References

1. Testosterone therapy: Potential benefits and risks as you age. (n.d.). Mayo Clinic. Retrieved November 15, 2022, from https://www.mayoclinic.org/healthy-lifestyle/sexual-health/in-depth/testosterone-therapy/art-20045728
2. Bassil, N., Alkaade, S., & Morley, J. E. (2009). The benefits and risks of testosterone replacement therapy: A review. Therapeutics and Clinical Risk Management, 5, 427–448.
3. Elagizi, A., Köhler, T. S., & Lavie, C. J. (2018). Testosterone and cardiovascular health. Mayo Clinic Proceedings, 93(1), 83–100. https://doi.org/10.1016/j.mayocp.2017.11.006
4. Ramasamy, R., Fisher, E. S., & Schlegel, P. N. (2012). Testosterone replacement and prostate cancer. Indian Journal of Urology : IJU : Journal of the Urological Society of India, 28(2), 123–128. https://doi.org/10.4103/0970-1591.98449
5. Tu, H., Gu, J., Meng, Q. H., Kim, J., Strom, S., Davis, J. W., He, Y., Wagar, E. A., Thompson, T. C., Logothetis, C. J., & Wu, X. (2017). Low serum testosterone is associated with tumor aggressiveness and poor prognosis in prostate cancer. Oncology Letters, 13(3), 1949–1957. https://doi.org/10.3892/ol.2017.5616
6. Osterberg, E. C., Bernie, A. M., & Ramasamy, R. (2014). Risks of testosterone replacement therapy in men. Indian Journal of Urology : IJU : Journal of the Urological Society of India, 30(1), 2–7. https://doi.org/10.4103/0970-1591.124197
7. Elagizi, A., Köhler, T. S., & Lavie, C. J. (2018). Testosterone and cardiovascular health. Mayo Clinic Proceedings, 93(1), 83–100. https://doi.org/10.1016/j.mayocp.2017.11.006
8. Is testosterone therapy safe? Take a breath before you take the plunge. (2014, February 1). Harvard Health. https://www.health.harvard.edu/mens-health/is-testosterone-therapy-safe-take-a-breath-before-you-take-the-plunge

Author

David J. Bauder, PA-C David Bauder, PA-C, is a certified physician assistant and the assistant medical director at Weight Loss and Vitality in Manassas and Alexandria, Virginia, Washington, DC; and Gaithersburg, MD. He enjoys helping patients optimize their physical and mental health to improve their overall well-being. He earned his physician assistant degree from the University of Texas Health Science Center at San Antonio. Afterward, he gained admission into the reputable graduate program for physician assistant studies at the University of Nebraska Health Science Center in Omaha. David has over 26 years of experience working as a physician assistant. He’s practiced in podiatry, family medicine, emergency medicine, general surgery, urgent care, and functional medicine.