When choosing testosterone replacement, what factors (age, lifestyle, comorbidities, patient preferences, adherence ability, contraindications such as prostate cancer, sleep apnea, cardiovascular disease, elevated hematocrit, and cost/insurance) should guide the decision between a topical gel and an intramuscular injection?

Choosing Between Topical and Injectable Testosterone: A Clinical Decision Framework

For most patients initiating testosterone replacement therapy, transdermal gel is the preferred first-line formulation due to stable testosterone levels and a 3-fold lower risk of erythrocytosis (15.4% vs 43.8%), which directly impacts cardiovascular morbidity and mortality. 1

Primary Decision Point: Erythrocytosis Risk

The single most important factor distinguishing these routes is the dramatically different risk of erythrocytosis:

• Injectable testosterone (cypionate/enanthate): 43.8% develop hematocrit >52% 1, 2
• Transdermal patches/gels: 15.4% develop erythrocytosis 1, 2
• Mechanism: Intramuscular injections create supraphysiologic peaks followed by subtherapeutic troughs, causing prolonged exposure to both extremes and stimulating excessive erythropoiesis 1

This 3-fold difference in erythrocytosis risk is not trivial—elevated hematocrit increases blood viscosity and directly worsens cardiovascular outcomes, particularly in older men or those with existing vascular disease. 1

Patient-Specific Selection Algorithm

Choose Transdermal Gel When:

• Cardiovascular risk factors present: elderly patients, diabetes, hypertension, known coronary artery disease 1
• Age >60 years: higher baseline cardiovascular risk makes stable levels critical 1
• Baseline hematocrit 48-50%: already approaching the threshold where treatment must be withheld 1
• Patient prioritizes convenience and ease of use: 71% of patients prefer gels for these reasons 3, 4
• Patient can afford higher cost: annual cost $2,135 vs $156 for injections 3

Choose Injectable Testosterone When:

• Cost is the primary barrier: injections cost $156/year vs $2,135 for transdermal 3
• Patient has significant skin reactions to adhesives or topical preparations 1
• Patient preference after informed discussion: 53% of patients choose injections primarily due to lower cost 3, 4
• No cardiovascular risk factors and hematocrit <45%: lower baseline risk makes the erythrocytosis risk more acceptable 1

Critical Monitoring Differences

Injectable Testosterone Monitoring:

• Hematocrit at EVERY visit—withhold if >54%, consider phlebotomy 1
• Testosterone levels measured midway between injections (days 5-7), targeting 500-600 ng/dL 1, 5
• Peak levels occur days 2-5, return to baseline by days 10-14—this fluctuation causes mood/energy/libido swings in some men 1, 5

Transdermal Gel Monitoring:

• Hematocrit periodically (every 6-12 months once stable)—still 15.4% risk 1
• Testosterone levels can be measured anytime after 2-3 months of stable therapy 1
• Stable day-to-day levels minimize mood/energy fluctuations 1, 6

Practical Considerations Beyond Efficacy

Lifestyle Factors:

• Gel requires daily application to shoulders/upper arms, must avoid skin-to-skin contact with partners/children for 2-6 hours 7
• Injections require technique (deep gluteal IM) but only every 2-4 weeks 8
• Gel users must wash application site before anticipated skin contact 7
• Injection users experience "roller coaster" testosterone levels—some men tolerate this poorly 1, 6

Adherence Considerations:

• TRT discontinuation rates are 30-62% across all formulations 3
• Gel adherence depends on daily routine—missed doses immediately affect levels 1
• Injection adherence depends on clinic access or self-injection comfort 9

Common Pitfalls to Avoid

Do not ignore erythrocytosis risk in older men or those with cardiovascular disease—even "mild" elevations (hematocrit 50-52%) increase thrombotic risk in this population. 1

Do not assume all patients can afford transdermal preparations—the 13-fold cost difference ($2,135 vs $156 annually) is a legitimate barrier that drives 35% of injection users' choice. 3

Do not measure testosterone at peak (days 2-5) or trough (days 13-14) in injection users—only midpoint values (days 5-7) reflect average exposure. 1, 5

Do not start injections in men with baseline hematocrit >48%—they will almost certainly exceed 54% and require treatment interruption. 1

Expected Outcomes Are Identical

Both routes produce the same modest improvements in sexual function (standardized mean difference 0.35) and quality of life, with little to no effect on energy, physical function, mood, or cognition. 3, 1, 5 The choice between formulations does not alter efficacy—it alters safety profile and practical feasibility.

Special Populations

Men with diabetes or metabolic syndrome:

• Prefer transdermal—these patients already have elevated cardiovascular risk and benefit from stable levels 1

Men with obesity-associated hypogonadism:

• Attempt weight loss first (can improve testosterone without medication), then use transdermal if TRT needed 1, 5

Men with baseline hematocrit 48-50%:

• Transdermal is mandatory—injectable testosterone will push them over 54% 1

Men with severe financial constraints:

• Injectable testosterone is the only feasible option at $156/year 3

The Bottom Line

Start with transdermal gel in most patients—particularly those over 60, with cardiovascular risk factors, or with baseline hematocrit >45%—because the 3-fold lower erythrocytosis risk (15.4% vs 43.8%) directly reduces cardiovascular morbidity. 1 Reserve injectable testosterone for patients where cost is prohibitive or who have documented intolerance to topical preparations, and monitor hematocrit aggressively at every visit. 1 The efficacy is identical; the safety profile is not. 3, 1, 6, 2