What are the side effects of testosterone therapy?

Side Effects of Testosterone Therapy

Testosterone therapy carries several well-documented side effects, with erythrocytosis being the most common hematologic concern, cardiovascular effects remaining controversial but likely neutral, and prostate cancer risk not definitively established despite ongoing monitoring requirements.

Hematologic Effects

Erythrocytosis (elevated red blood cell count) is the most common and clinically significant side effect, 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
• Transdermal gels show intermediate risk: 11.3% at 50 mg/day and 17.9% at 100 mg/day 1
• Transdermal patches have the lowest incidence at 2.8% 1
• Most 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

Cardiovascular and Cerebrovascular Effects

The relationship between testosterone therapy and cardiovascular events remains controversial, with current evidence suggesting a neutral effect:

• 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
• Recent meta-analysis of 13 studies (3,120 participants) showed no difference in cardiovascular/cerebrovascular events between testosterone (7.5%) and placebo (7.2%) groups (odds ratio 1.07,95% CI 0.81-1.42) 3
• The American College of Cardiology suggests testosterone may have a neutral or possibly beneficial effect, though long-term safety data remains limited 4
• Fluid retention is uncommon and generally mild, but testosterone should be used cautiously in men with congestive heart failure or renal insufficiency 2, 4

Prostate-Related Effects

Prostate monitoring is required despite lack of definitive evidence linking testosterone to prostate cancer:

• 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
• Multiple studies show no exacerbation of voiding symptoms or increased urinary retention rates compared to placebo 1
• Prospective studies show only 1.1% cancer incidence, similar to the general population 1
• Perform prostate biopsy for PSA increases of ≥1.0 ng/mL in one year 2, 4
• If PSA rises by 0.7-0.9 ng/mL, repeat measurement in 3-6 months and perform biopsy for any further increase 2

Dermatologic and Local Reactions

Skin reactions vary dramatically by formulation:

• Transdermal patches cause reactions in up to 66% of users, including erythema and pruritus 2, 1
• Gel preparations cause skin reactions in only 5% of users 2, 1
• Intramuscular injections commonly cause local pain, soreness, bruising, erythema, swelling, nodules, or furuncles 2, 1
• Acne and oily skin may occur with all formulations 2

Respiratory Effects

Sleep apnea may be exacerbated or newly develop during testosterone therapy:

• Risk is highest in men receiving higher doses of parenteral testosterone who have other identifiable risk factors 2, 4
• Upper-airway dimensions are unaffected, suggesting central mechanisms rather than anatomical airway changes 2
• Assessment for sleep apnea history should be performed at baseline 4, 1

Reproductive Effects

Fertility will be greatly compromised during testosterone therapy:

• Testicular size and consistency often diminish 2
• Down-regulation of gonadotropins causes testicular atrophy and infertility, particularly concerning in young men 4, 1
• These effects are due to suppression of the hypothalamic-pituitary-gonadal axis 2

Hepatic Effects

Hepatotoxicity is primarily limited to oral testosterone preparations:

• Oral preparations (excluding testosterone undecanoate) have been reported to cause hepatotoxic effects and neoplasia, including benign and malignant tumors 2
• The use of oral forms of testosterone in the United States is strongly discouraged 2, 4
• Intramuscular injections and transdermal preparations do not appear associated with hepatic dysfunction, and routine liver function monitoring is unnecessary 2
• The FDA has contraindicated oral testosterone undecanoate for age-related hypogonadism due to demonstrated increases in blood pressure 4

Miscellaneous Effects

• Breast tenderness and swelling occur in a small number of men 2
• Gynecomastia is rare and usually reversible 4
• Increased body hair may occur 2

Abuse-Related Adverse Reactions

When testosterone is abused at supratherapeutic doses, serious adverse reactions occur:

• Cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident 5
• Hepatotoxicity and serious psychiatric manifestations including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression 5
• Transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility in men 5
• Withdrawal symptoms upon abrupt discontinuation include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism 5

Monitoring Requirements

Baseline assessments must include:

• PSA and digital rectal examination 4, 1
• Hematocrit/hemoglobin 4, 1
• Assessment for sleep apnea history 4, 1
• Voiding symptoms evaluation through history or standardized measures 4, 1

Follow-up monitoring schedule:

• 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 6

Critical Pitfalls to Avoid

• Inadequate monitoring of hematocrit can lead to hyperviscosity and increased thrombotic risk 6
• Failing to assess for sleep apnea before initiation, particularly in men with other risk factors 4, 1
• Using oral testosterone preparations due to hepatotoxicity risk 2, 4
• Overlooking the impact on fertility, especially in younger men desiring future children 4, 1
• Not counseling patients about lifestyle modifications (weight loss, increased physical activity) as concurrent treatment strategy 2