What are the comparative side effects of testosterone patches (transdermal testosterone) versus intramuscular (IM) injections (testosterone cypionate or enanthate) in a male patient with hypogonadism?

Comparative Side Effects: Testosterone Patches vs. IM Injections

Intramuscular testosterone injections carry a significantly higher risk of erythrocytosis (43.8% vs. 15.4%) compared to transdermal patches, making patches the safer choice for most hypogonadal men despite their higher cost and potential for skin irritation. 1

Key Side Effect Differences

Erythrocytosis Risk (Most Critical for Morbidity/Mortality)

• IM injections produce erythrocytosis in 43.8% of patients versus only 15.4% with transdermal patches—a nearly 3-fold higher risk that directly impacts cardiovascular morbidity and mortality 1
• The elevated hematocrit risk with injections stems from supraphysiologic testosterone peaks (days 2-5 post-injection) followed by subtherapeutic troughs, creating prolonged exposure to both extremes 1
• Hematocrit >54% requires treatment discontinuation and potential phlebotomy, with blood viscosity increases potentially aggravating coronary, cerebrovascular, or peripheral vascular disease—particularly dangerous in elderly patients 1

Cardiovascular Safety Concerns

• Evidence suggests IM injections may carry higher cardiovascular event risk than transdermal preparations due to time spent in both supratherapeutic and subtherapeutic ranges between injections 1
• The FDA required labeling changes in 2015 regarding possible increased risk of heart attack and stroke with testosterone preparations, with some data specifically implicating injections over gels for cardiovascular events, hospitalizations, and deaths 1
• However, multiple professional societies support testosterone use when appropriately indicated, noting that safety concerns may reflect high-risk patient populations rather than the formulation itself 1

Formulation-Specific Side Effects

Transdermal Patches:

• Skin irritation at patch application site (common, may require discontinuation) 1, 2
• Issues with patch adherence to skin 1
• No risk of inadvertent transfer to others (unlike gels) 1
• Stable testosterone levels minimize mood/energy fluctuations 1, 2

IM Injections:

• Requires intramuscular injection technique (thighs for self-injection, gluteal when administered by others) 1
• Fluctuating serum testosterone with peaks and valleys causing mood/sexual function shifts in some men 1, 3
• Peak levels 2-5 days post-injection often transiently exceed upper normal limit 4
• Return to baseline by days 10-14, potentially causing symptom recurrence 4

Shared Side Effects (No Difference Between Formulations)

• Lipid profile effects: Both formulations show neutral effects on HDL cholesterol and total cholesterol/HDL ratio at physiologic doses 1
• Prostate effects: Benign prostatic hyperplasia exacerbation is rare with both; prostate cancer risk remains theoretical and unproven 1
• Testicular atrophy and infertility: Common with both formulations due to suppression of hypothalamic-pituitary-gonadal axis 1
• Other systemic effects: Sleep apnea, gynecomastia, acne, and fluid retention occur with both delivery methods 1

Clinical Decision Algorithm

Choose Transdermal Patches when:

• Patient has cardiovascular risk factors (elderly, diabetes, hypertension, known CAD) 1
• Patient has chronic obstructive pulmonary disease or conditions predisposing to elevated hematocrit 1
• Patient requires stable day-to-day testosterone levels for mood/energy stability 1, 2
• Patient can tolerate potential skin irritation and higher cost 1, 2

Choose IM Injections when:

• Cost is a primary concern ($156.24/year vs. $2,135.32/year for transdermal) 2
• Patient has history of significant skin reactions to adhesives 1
• Patient prefers infrequent dosing (every 2 weeks) over daily application 1
• Patient has low baseline cardiovascular risk and normal hematocrit 1

Critical Monitoring Requirements

For IM Injections:

• Measure testosterone midway between injections (days 5-7), targeting 500-600 ng/dL 1, 4
• Monitor hematocrit at each visit—withhold if >54% and consider phlebotomy 1, 4
• Check levels 2-3 months after initiation, then every 6-12 months once stable 1, 4

For Transdermal Patches:

• Measure testosterone anytime (peak occurs 6-8 hours post-application) 1
• Monitor hematocrit periodically (lower risk but still necessary) 1
• Assess application site for skin reactions at each visit 1, 2

For Both Formulations:

• Monitor PSA in men >40 years—refer if increase >1.0 ng/mL in first 6 months or >0.4 ng/mL/year thereafter 4
• Perform digital rectal examination to assess prostate 4
• Reassess symptoms at 12 months—discontinue if no improvement in sexual function 4

Common Pitfalls to Avoid

• Never draw testosterone levels at peak (days 2-5) for IM injections—this shows supraphysiologic levels leading to inappropriate dose reduction 4
• Never ignore hematocrit monitoring with IM injections—the 43.8% erythrocytosis rate makes this non-negotiable 1
• Never assume patches eliminate erythrocytosis risk entirely—15.4% still develop elevated hematocrit requiring monitoring 1
• Never continue therapy beyond 12 months without documented symptom improvement—prevents unnecessary exposure to risks without benefit 4