What are the risks associated with testosterone therapy?

Risks of Testosterone Therapy

Testosterone therapy carries significant risks including cardiovascular events, erythrocytosis, prostate effects, and infertility, requiring careful patient selection and monitoring. 1, 2

Cardiovascular Risks

• Current evidence is inconsistent regarding whether testosterone therapy increases or decreases cardiovascular events (myocardial infarction, stroke, cardiovascular death, all-cause mortality) 1
• Patients must be counseled that the relationship between testosterone therapy and cardiovascular events remains uncertain 1, 2
• Patients on testosterone therapy should report any cardiovascular symptoms such as chest pain, shortness of breath, or dizziness during follow-up visits 1
• Fluid retention may occur and can be problematic in patients with pre-existing cardiac, renal, or hepatic disease 3

Venous Thromboembolism

• Post-marketing reports have identified venous thromboembolic events including deep vein thrombosis and pulmonary embolism in patients using testosterone products 3
• If a venous thromboembolic event is suspected, testosterone therapy should be discontinued immediately 3
• FDA required pharmaceutical companies to add warnings regarding VTE to product labeling, though observational studies have not consistently shown an association 1

Hematologic Effects

• Erythrocytosis (elevated red blood cell count) is a common side effect with varying risk by administration route: 3-18% with transdermal formulations and up to 44% with injections 2, 4
• Regular monitoring of hemoglobin and hematocrit is essential to detect polycythemia, especially in patients receiving high doses 3
• Increased hemoglobin (weighted mean difference of 0.80 g/dl) and hematocrit (weighted mean difference of 3.18%) are well-documented effects 4

Prostate Effects

• Clinicians should inform patients that there is no definitive evidence linking testosterone therapy to the development of prostate cancer 1
• Patients with testosterone deficiency and history of prostate cancer should be informed of inadequate evidence to quantify risk-benefit ratio 1
• Testosterone therapy in men with in-situ prostate cancer on active surveillance or previously treated prostate cancer should be approached with caution 1
• Prostate biopsy should be considered for PSA increases of ≥1.0 ng/ml in one year 1, 2

Hepatic Effects

• Prolonged use of high doses of androgens has been associated with peliosis hepatis and hepatic neoplasms including hepatocellular carcinoma 3
• Oral testosterone preparations should be avoided due to hepatotoxicity risk 1, 2
• If cholestatic hepatitis with jaundice appears or liver function tests become abnormal, testosterone should be discontinued 3

Sleep Apnea

• Testosterone therapy has been associated with exacerbation of existing sleep apnea or development of new sleep apnea 1, 2
• This risk is particularly significant in men with other identifiable risk factors for sleep apnea 1, 2
• Testosterone appears to contribute to sleep-disordered breathing through central mechanisms rather than anatomical changes in the airway 1

Reproductive Effects

• Testicular size and consistency often diminish during testosterone therapy 1
• Fertility is greatly compromised during testosterone therapy due to down-regulation of gonadotropins 1, 2
• Exogenous testosterone should not be prescribed to men who are currently trying to conceive 1

Other Effects

• Skin reactions vary by formulation: up to 66% with patches, 5% with gels 1, 2
• Intramuscular injections can cause local pain, soreness, bruising, erythema, swelling, nodules, or furuncles 1
• Gynecomastia may develop and occasionally persist in patients being treated for hypogonadism 3
• Small decrease in high-density lipoprotein cholesterol (weighted mean difference of -0.49 mg/dl) has been observed 4

Monitoring Recommendations

• Baseline assessment should include cardiovascular risk evaluation, PSA and digital rectal examination, hematocrit/hemoglobin, and assessment for sleep apnea 2
• First follow-up at 1-2 months to assess efficacy, then every 3-6 months for the first year, then annually 2, 5
• Target testosterone levels should be in the middle tertile of the normal reference range (450-600 ng/dL) 1
• Consider prostate biopsy for PSA increases of ≥1.0 ng/ml in one year 1, 2

Key Pitfalls to Avoid

• Failing to recognize that testosterone therapy can exacerbate fluid retention in patients with heart failure 3
• Inadequate monitoring of hematocrit, which can lead to hyperviscosity and increased thrombotic risk 2, 4
• Using oral testosterone preparations which carry higher hepatotoxicity risk 1, 3
• Overlooking the potential exacerbation of sleep apnea, particularly in patients with existing risk factors 1, 2