What are the adverse effects of testosterone (T) replacement therapy?

From the Guidelines

Testosterone supplementation is not associated with an increased risk of mortality, cardiovascular events, prostate cancer, or pulmonary embolism, according to the most recent and highest quality study available 1. The potential side effects of testosterone supplementation include acne, fluid retention, and increased red blood cell production, but the evidence from 20 observational studies with a mean follow-up ranging from 0.73 to 10.3 years showed no consistent differences in harms according to transdermal versus intramuscular formulations 1. Some key points to consider when evaluating the side effects of testosterone supplementation include:

• The lack of increased risk for mortality, cardiovascular events, prostate cancer, or pulmonary embolism 1
• The potential for skin reactions at application sites with topical forms, and pain or bruising with injections
• The importance of regular monitoring through blood tests to check hormone levels, red blood cell counts, cholesterol, and prostate health markers
• The variation in risk and severity of side effects based on dosage, administration method, individual sensitivity, age, and pre-existing health conditions
• The need for patients to be aware of the potential benefits and harms of testosterone treatment, including the improvement of symptoms such as lack of energy, decreased strength and endurance, and deterioration in work performance 1.

From the FDA Drug Label

ADVERSE REACTIONS The following adverse reactions in the male have occurred with some androgens: Endocrine and urogenital: Gynecomastia and excessive frequency and duration of penile erections. Oligospermia may occur at high dosages. Skin and appendages: Hirsutism, male pattern of baldness, seborrhea, and acne Fluid and electrolyte disturbances: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates. Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function tests, rarely hepatocellular neoplasms and peliosis hepatis (see WARNINGS) Hematologic: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia. Nervous system: Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia. Allergic: Hypersensitivity, including skin manifestations and anaphylactoid reactions. Miscellaneous: Inflammation and pain at the site of intramuscular injection.

The side effects of testosterone supplementation include:

• Endocrine and urogenital: Gynecomastia, excessive frequency and duration of penile erections, and oligospermia at high dosages
• Skin and appendages: Hirsutism, male pattern of baldness, seborrhea, and acne
• Fluid and electrolyte disturbances: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates
• Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function tests, hepatocellular neoplasms, and peliosis hepatis
• Hematologic: Suppression of clotting factors, bleeding, and polycythemia
• Nervous system: Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia
• Allergic: Hypersensitivity and anaphylactoid reactions
• Miscellaneous: Inflammation and pain at the site of intramuscular injection 2

From the Research

Side Effects of Testosterone Supplementation

• The potential side effects of testosterone supplementation include worsening symptoms of benign prostatic hypertrophy, liver toxicity, hyperviscosity, erythrocytosis, worsening untreated sleep apnea or severe heart failure 3
• Testosterone replacement therapy (TRT) may also stimulate prostate cancer, although no evidence currently supports this risk 3
• Other possible risks associated with TRT include polycythemia, peripheral edema, cardiac and hepatic dysfunction 4
• The use of clomiphene citrate, a medication used to treat hypogonadism or infertility, has been shown to significantly increase testosterone levels without changing prostate-specific antigen (PSA) or hematocrit (Hct) values 5
• A Bayesian network meta-analysis found that testosterone therapy does not lead to abnormal PSA changes and increased risk of prostate cancer in patients with hypogonadism or low testosterone level 6

Specific Administration Methods

• Intramuscular injection of testosterone has been shown to be effective in minimizing prostate cancer cases and resulting in fewer prostate biopsy cases compared to other formulations 6
• Transdermal testosterone patches have been found to be an effective mode of delivery, with safety data indicating no negative effect on the prostate 7
• Testogel, a hydroalcoholic gel containing 1% testosterone, has been shown to be effective and successful in restoring normal hormonal values and correcting signs and symptoms of hypogonadism 7

Monitoring and Precautions

• Men on TRT should be monitored for side effects such as polycythemia, peripheral edema, cardiac and hepatic dysfunction 4
• Patients with untreated prostate and breast cancer should not receive TRT 4
• Regular laboratory evaluations should be scheduled to monitor the effects of testosterone supplementation, although routine assessment of PSA and Hct may not be necessary 5