In a male patient with confirmed testosterone deficiency (low serum testosterone and hypogonadal symptoms) and no contraindications such as prostate cancer, untreated sleep apnea, uncontrolled heart failure, or elevated hematocrit, should testosterone replacement be administered via intramuscular injection?

Should Testosterone Replacement Be Given Intramuscularly?

Yes, intramuscular testosterone injections (cypionate or enanthate) are FDA-approved, effective, and remain a standard route of administration for testosterone replacement therapy in hypogonadal men, though transdermal preparations are often preferred as first-line due to more stable testosterone levels and lower risk of erythrocytosis. 1, 2

Route Selection Algorithm

First-Line: Transdermal Preparations

• Transdermal testosterone gel (1.62% at 40.5 mg daily) is the preferred initial formulation because it provides stable day-to-day testosterone levels and carries a significantly lower risk of erythrocytosis (15.4%) compared to intramuscular injections (43.8%). 3, 4
• Transdermal patches are an alternative but cause skin reactions (erythema or pruritus) in up to 66% of users, compared to only 5% with gels. 1, 5

When to Choose Intramuscular Injections

• Cost is a primary concern: Annual cost of IM testosterone is $156 versus $2,135 for transdermal preparations—a 13-fold difference. 3, 4
• Patient preference for less frequent dosing: IM injections require administration every 2-3 weeks rather than daily application. 3
• Significant skin reactions to transdermal preparations: If patches or gels cause intolerable dermatitis. 5, 4
• Patient preference: Some patients prefer injections despite the higher erythrocytosis risk. 3

Intramuscular Administration Details

FDA-Approved Dosing

• Testosterone cypionate or enanthate: 50-400 mg every 2-4 weeks is the FDA-approved range, with typical dosing of 100-200 mg every 2 weeks or 50 mg weekly. 3, 2
• Peak serum testosterone occurs 2-5 days after injection, with return to baseline by days 10-14. 1, 3

Subcutaneous Alternative to Traditional IM

• Subcutaneous injection is an effective and increasingly popular alternative to traditional intramuscular injection, using the same testosterone esters (cypionate or enanthate) at similar doses (50-150 mg weekly). 6, 7
• Subcutaneous administration is easier to self-administer, causes less discomfort, and produces comparable pharmacokinetics and serum testosterone levels to IM injections. 6, 7
• Among patients who switched from IM to subcutaneous, 91% (20/22) had a marked preference for subcutaneous, and none preferred IM. 6

Monitoring for IM Injections

• Measure testosterone levels midway between injections (days 5-7), targeting mid-normal values of 500-600 ng/dL. 3
• Monitor hematocrit at each visit—withhold treatment if >54% and consider phlebotomy in high-risk cases. 1, 3
• First follow-up at 1-2 months, then every 3-6 months for the first year, then yearly. 1, 3

Critical Safety Differences Between Routes

Erythrocytosis Risk

• Injectable testosterone produces erythrocytosis in 43.8% of patients versus 15.4% with transdermal patches—a nearly 3-fold higher risk that directly impacts cardiovascular morbidity. 4
• The elevated hematocrit risk stems from supraphysiologic testosterone peaks followed by subtherapeutic troughs, creating prolonged exposure to both extremes. 4
• Elevated blood viscosity can exacerbate coronary, cerebrovascular, or peripheral vascular disease, particularly in older adults. 1

Testosterone Level Fluctuations

• IM injections cause fluctuating serum testosterone with peaks and valleys, leading to mood and sexual function shifts in some men. 4
• Transdermal preparations minimize these fluctuations by maintaining stable levels. 4

Local Reactions

• IM injections can cause local pain, soreness, bruising, erythema, swelling, nodules, or furuncles at injection sites. 1
• Subcutaneous injections cause minor and transient local reactions in only 14% (9/63) of patients. 6

Clinical Efficacy: No Difference by Route

The evidence shows no differences in clinical outcomes between intramuscular and transdermal testosterone formulations. 1

• Both routes produce small but significant improvements in sexual function and libido (standardized mean difference 0.35). 1, 3
• Both have little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition. 1, 3
• No clinical trial directly compared IM versus transdermal formulations for patient-centered outcomes. 1

Common Pitfalls to Avoid

• Do not draw testosterone levels at the peak (days 2-5) after IM injection, as this will show supraphysiologic levels and may lead to inappropriate dose reduction. 3
• Do not draw levels at the trough (days 13-14), as testosterone may have returned to baseline, potentially leading to unnecessary dose escalation. 3
• Do not ignore mild erythrocytosis (hematocrit 50-52%) in elderly patients or those with cardiovascular disease, as even modest elevations increase blood viscosity and thrombotic risk. 3
• Do not continue full-dose testosterone when hematocrit exceeds 54%—this is an absolute indication to withhold therapy. 1, 3
• Do not use weekly dosing exceeding standard practice, as this increases the risk of supraphysiologic levels and erythrocytosis. 3

Special Populations

Elderly or Cardiovascular Risk Factors

• Choose transdermal patches when patients have cardiovascular risk factors (elderly, diabetes, hypertension, known CAD) due to lower erythrocytosis risk. 4
• Target mid-range testosterone levels (350-600 ng/dL) rather than upper-normal in these patients. 3

Obesity-Associated Hypogonadism

• Attempt weight loss through low-calorie diets and regular exercise before initiating testosterone, as this can improve testosterone levels without medication. 3

Fertility Concerns

• Testosterone therapy (any route) is absolutely contraindicated in men seeking fertility preservation, as it suppresses spermatogenesis and causes azoospermia. 3
• Use gonadotropin therapy (hCG plus FSH) instead for men with secondary hypogonadism who desire fertility. 3