What are the adverse effects of Testosterone Replacement Therapy (TRT)?

From the Guidelines

Testosterone Replacement Therapy (TRT) is associated with several adverse effects, including erythrocytosis, fluid retention, benign prostatic hyperplasia, and prostate cancer, although the evidence for these risks is not always consistent or conclusive.

Adverse Effects of TRT

• Erythrocytosis: a wide range of risk, depending on the mode of administration, with 3-18% risk with transdermal administration and up to 44% with injection, requiring monitoring 1
• Fluid retention: rarely of clinical significance 1
• Benign prostatic hyperplasia: rarely of clinical significance 1
• Prostate cancer: controversial, with an unknown level of risk, requiring long-term monitoring 1
• Cardiovascular disease: existing evidence suggests a neutral or possible beneficial effect, although definitive assessment of long-term effects requires prospective, large-scale, placebo-controlled studies 1 ### Other Potential Risks
• Lipid alterations: most studies show no change with physiologic replacement doses, although supraphysiologic doses of androgens may lower high-density lipoprotein (HDL) levels 1
• Sleep apnea: infrequent 1
• Gynecomastia: rare, usually reversible 1
• Skin reactions: high incidence with patch (up to 66%), low incidence with gel (5%), rare with injections 1
• Acne or oily skin: infrequent 1
• Testicular atrophy or infertility: common, especially in young men, usually reversible with cessation of treatment 1 ### Monitoring and Recommendations
• Regular monitoring of hematocrit, lipid profiles, and prostate-specific antigen (PSA) levels is recommended for men undergoing TRT 1
• Men with a history of cardiovascular disease, prostate cancer, or sleep apnea should be carefully evaluated and monitored before initiating TRT 2, 3

From the Research

Adverse Effects of Testosterone Replacement Therapy (TRT)

The adverse effects of TRT can be categorized into several areas, including:

• Cardiovascular risks: Studies have suggested an increased risk of cardiovascular events among groups of men prescribed TRT 4. However, the evidence is not conclusive, and more well-designed trials are needed to establish the relationship between TRT and cardiovascular risks.
• Prostate health risks: While TRT may increase serum prostate-specific antigen levels in some men, it has not been shown to increase the risk of prostate cancer 5, 6. However, TRT should not be administered to individuals with active evidence of untreated prostate cancer, except under rare circumstances.
• Hematologic risks: TRT may result in erythrocytosis in some men, which can increase the risk of cardiovascular events 5, 6. Regular monitoring of hematocrit levels is recommended, and therapeutic phlebotomy may be indicated if the hematocrit exceeds 52% 6.
• Liver dysfunction risks: Older oral forms of TRT can affect liver function, and therefore, transdermal, newer oral forms, and injectables are generally favored in men with a history of liver disease 6.
• Other risks: TRT may also be associated with other adverse effects, such as gynecomastia, peripheral edema, and polycythemia 7, 6.

Management of Adverse Effects

The management of adverse effects associated with TRT is critical to maximize benefit and minimize risks. This includes:

• Regular monitoring of hematocrit levels, blood pressure, and prostate-specific antigen levels 5, 6.
• Therapeutic phlebotomy if the hematocrit exceeds 52% 6.
• Use of aromatase inhibitors and tamoxifen to manage gynecomastia 6.
• Avoiding TRT in individuals with active evidence of untreated prostate cancer, except under rare circumstances 6.
• Using transdermal, newer oral forms, and injectables in men with a history of liver disease 6.