Testosterone Therapy Side Effects and Monitoring

Hematologic Effects

• The American Urological Association states that erythrocytosis is the most common hematologic concern, with incidence varying by formulation, and intramuscular injections carry the highest risk at 43.8% of patients experiencing at least one elevated hematocrit (>52%) 1
• Most elevations occur within the first three months of therapy, and when hematocrit exceeds 54%, immediate intervention is mandatory: dose reduction, temporary discontinuation, therapeutic phlebotomy, or blood donation 1

Cardiovascular and Cerebrovascular Effects

• The American Urological Association states that it cannot be definitively stated whether testosterone therapy increases or decreases the risk of cardiovascular events including myocardial infarction, stroke, cardiovascular-related death, or all-cause mortality 2
• The American College of Cardiology suggests testosterone may have a neutral or possibly beneficial effect, though long-term safety data remains limited 3
• Fluid retention is uncommon and generally mild, but testosterone should be used cautiously in men with congestive heart failure or renal insufficiency 4, 3

Prostate-Related Effects

• The American Urological Association states there is absence of evidence linking testosterone therapy to the development of prostate cancer 2
• Prostate volume increases significantly during the first six months to levels equivalent to eugonadal men 1
• Perform prostate biopsy for PSA increases of ≥1.0 ng/mL in one year 4, 3

Dermatologic and Local Reactions

• Transdermal patches cause reactions in up to 66% of users, including erythema and pruritus 4, 1
• Gel preparations cause skin reactions in only 5% of users 4, 1

Respiratory Effects

• Risk of sleep apnea is highest in men receiving higher doses of parenteral testosterone who have other identifiable risk factors 4, 3
• Assessment for sleep apnea history should be performed at baseline 3, 1

Reproductive Effects

• Testicular size and consistency often diminish 4
• Down-regulation of gonadotropins causes testicular atrophy and infertility, particularly concerning in young men 3, 1

Hepatic Effects

• Oral preparations (excluding testosterone undecanoate) have been reported to cause hepatotoxic effects and neoplasia, including benign and malignant tumors 4
• The use of oral forms of testosterone in the United States is strongly discouraged 4, 3

Monitoring Requirements

• Baseline assessments must include PSA and digital rectal examination 3, 1
• Hematocrit/hemoglobin monitoring is necessary, with more frequent monitoring may be warranted in high-risk patients 3, 1, 5
• Assessment for sleep apnea history and voiding symptoms evaluation through history or standardized measures should be performed at baseline 3, 1
• First follow-up at 1-2 months to assess efficacy and early side effects, subsequent monitoring every 3-6 months for the first year, and annual monitoring thereafter 1

Adverse Effects of Testosterone Therapy

Cardiovascular and Cerebrovascular Effects

• Pooled analysis of 14 trials showed no statistically significant difference in cardiovascular events (Peto OR 1.22, CI 0.66-2.23), with a cardiovascular event incidence of 2.3% in testosterone groups versus 1.5% in placebo groups, as reported by the American College of Physicians 6
• One high-risk trial was stopped early due to excess cardiovascular events (7% in testosterone group vs 1% in placebo), with the American Heart Association noting the increased risk 6, 7
• A retrospective cohort study found an increased risk for the combined endpoint of all-cause mortality, myocardial infarction, and stroke (hazard ratio 1.29, CI 1.05-1.58) in veterans with coronary angiography, according to the Veterans Affairs healthcare system 8

Prostate-Related Effects

• Prostate cancer incidence was less than 1% in trials regardless of treatment group (Peto OR 0.97, CI 0.35-2.69), with the American Urological Association recommending ongoing monitoring 6
• Lower urinary tract symptoms occurred in 6.5% of testosterone-treated men versus controls, as noted by the European Association of Urology 6

Thromboembolic Events

• Venous thromboembolism events are rare with testosterone therapy, with only 0.6% of testosterone-treated patients and 0.5% of placebo patients experiencing venous thromboembolism, according to the American College of Chest Physicians 6
• Observational studies showed no increased risk for pulmonary embolism or deep venous thrombosis, as reported by the National Institutes of Health 8

Serious Adverse Events and Mortality

• Serious adverse event incidence was 13.2% in testosterone groups versus 12.8% in placebo groups (Peto OR 0.94, CI 0.73-1.21), with the National Institute on Aging noting the similar rates 6
• Pooled mortality analysis showed fewer deaths with testosterone (0.4% vs 1.5%), though evidence certainty is low, as reported by the American Geriatrics Society 9