What are the potential adverse effects of testosterone therapy?

Adverse Effects of Testosterone Therapy

Most Critical Adverse Effect: Erythrocytosis

Erythrocytosis is the most common and clinically significant adverse effect of testosterone therapy, with incidence varying dramatically by formulation—intramuscular injections carry the highest risk at 43.8% of patients experiencing at least one elevated hematocrit (>52%). 1

• Most hematocrit elevations occur within the first three months of therapy 1
• When hematocrit exceeds 54%, immediate intervention is mandatory: dose reduction, temporary discontinuation, therapeutic phlebotomy, or blood donation 1
• Testosterone increases hemoglobin by 0.80 g/dl (95% CI, 0.45 to 1.14) and hematocrit by 3.18% (95% CI, 1.35 to 5.01) 2
• Transdermal formulations cause erythrocytosis in 3-18% of patients, while injectable testosterone affects up to 44% 3

Cardiovascular and Cerebrovascular Effects

The evidence on cardiovascular risk remains uncertain and cannot definitively establish whether testosterone increases or decreases cardiovascular events. 1

• Pooled analysis of 14 trials (n=2415) showed no statistically significant difference in cardiovascular events (Peto OR 1.22, CI 0.66-2.23), though cardiovascular event incidence was 2.3% in testosterone groups versus 1.5% in placebo groups 4
• One high-risk trial (TOM) was stopped early due to excess cardiovascular events (7% in testosterone group vs 1% in placebo) 4
• One retrospective cohort study of veterans with coronary angiography found increased risk for combined endpoint of all-cause mortality, MI, and stroke (hazard ratio 1.29, CI 1.05-1.58) 4
• Fluid retention is uncommon and generally mild, but testosterone should be used cautiously in men with congestive heart failure or renal insufficiency 1, 5

Prostate-Related Effects

There is no evidence linking testosterone therapy to the development of prostate cancer, though monitoring remains essential. 1

• Prostate cancer incidence was less than 1% in trials regardless of treatment group (Peto OR 0.97, CI 0.35-2.69) 4
• 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 1
• Lower urinary tract symptoms occurred in 6.5% of testosterone-treated men versus controls 4
• Patients with benign prostatic hypertrophy may develop acute urethral obstruction 5

Reproductive and Testicular Effects

Down-regulation of gonadotropins causes testicular atrophy and infertility, particularly concerning in young men. 1

• Testicular size and consistency often diminish during therapy 1
• Oligospermia may occur after prolonged administration or excessive dosage 5
• Exogenous testosterone suppresses luteinizing hormone and follicle-stimulating hormone production, reducing testicular sperm production 6

Dermatologic and Local Reactions

Skin reactions vary dramatically by formulation, with transdermal patches causing the highest rates. 1

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

Respiratory Effects

Sleep apnea risk is highest in men receiving higher doses of parenteral testosterone who have other identifiable risk factors. 1

• Assessment for sleep apnea history should be performed at baseline 1
• One retrospective cohort study reported increased risk for obstructive sleep apnea in testosterone-treated men 4

Metabolic Effects

Testosterone causes a small decrease in HDL cholesterol but has minimal other lipid effects. 2

• HDL cholesterol decreases by 0.49 mg/dl (95% CI, -0.85 to -0.13) 2
• Lipid profiles remain largely neutral with physiologic testosterone replacement 3
• In diabetic patients, androgens may decrease blood glucose and therefore insulin requirements 5

Thromboembolic Events

Venous thromboembolism events are rare with testosterone therapy. 4

• Only 0.6% of testosterone-treated patients and 0.5% of placebo patients experienced venous thromboembolism 4
• Observational studies showed no increased risk for pulmonary embolism or deep venous thrombosis 4

Hepatic Effects (Oral Formulations Only)

Oral preparations (excluding testosterone undecanoate) have been reported to cause hepatotoxic effects and neoplasia, including benign and malignant tumors. 1

• The use of oral forms of testosterone in the United States is strongly discouraged 1
• Rare reports exist of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses 5

Serious Adverse Events and Mortality

Overall serious adverse events do not differ between testosterone and placebo groups. 4

• 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) 4
• Withdrawals due to adverse events were similar: 5.1% versus 5.3% (Peto OR 0.92, CI 0.65-1.28) 4
• Pooled mortality analysis showed fewer deaths with testosterone (0.4% vs 1.5%), though evidence certainty is low 4

Other Adverse Effects

• Priapism or excessive sexual stimulation may develop 5
• Patients should report nausea, vomiting, changes in skin color, ankle swelling, or too frequent/persistent erections 5
• Androgens may increase sensitivity to oral anticoagulants, requiring dosage reduction 5

Essential Monitoring Protocol

Baseline assessments must include PSA, digital rectal examination, hematocrit/hemoglobin, and sleep apnea history. 1

• First follow-up at 1-2 months to assess efficacy and early side effects 1
• Subsequent monitoring every 3-6 months for the first year 1
• Annual monitoring thereafter 1
• More frequent hematocrit monitoring may be warranted in high-risk patients 1