What is the recommended initial treatment for testosterone replacement therapy, comparing topical testosterone gel (AndroGel (testosterone)) and testosterone injections (testosterone cypionate (Depo-Testosterone) or testosterone enanthate (Delatestryl))?

Testosterone Gel vs. Injection for Testosterone Replacement Therapy

Testosterone gel is recommended as the initial treatment for testosterone replacement therapy over injections due to more stable serum testosterone levels and lower risk of cardiovascular events and erythrocytosis. 1

Comparison of Formulations

Testosterone Gel

• Provides more stable day-to-day testosterone levels without the peaks and valleys seen with injections 1
• Available as 1% and 1.62% formulations with typical dosing of 50-100 mg/day 1
• Applied to skin of back, abdomen, upper thighs, and upper arms 1
• Advantages include easy application and good skin tolerability 1
• Disadvantages include potential for transfer to partners or children through skin contact and higher cost compared to injections 1, 2
• Reaches steady-state testosterone levels within 24 hours of application 3

Testosterone Injections

• Available as testosterone cypionate or enanthate at 100-200 mg every 2 weeks or 50 mg weekly 1
• Administered intramuscularly in the thigh or gluteal muscle 1, 4
• Advantages include lower cost, flexible dosing, and no risk of interpersonal transfer 1
• Disadvantages include fluctuating testosterone levels with peaks and valleys, and requirement for intramuscular injection 1

Safety Considerations

Cardiovascular Risk

• FDA required labeling changes in 2015 to inform about possible increased risk of heart attack and stroke with testosterone preparations 1
• Evidence suggests testosterone injections are associated with greater risk of cardiovascular events, hospitalizations, and deaths compared to gels 1
• Safety concerns with injections may be related to time spent in both supratherapeutic and subtherapeutic ranges between injections 1

Erythrocytosis Risk

• Injections are associated with significantly higher risk of erythrocytosis than topical preparations 1
• Studies show 43.8% of patients receiving intramuscular testosterone had at least one elevated hematocrit value compared to 15.4% with transdermal patches 1
• Erythrocytosis with injections is associated with supraphysiologic levels of bioavailable testosterone 1
• Gel preparations show lower rates of erythrocytosis: 2.8% with 5 mg/day patches, 11.3% with 50 mg/day gel, and 17.9% with 100 mg/day gel 1

Monitoring Recommendations

For All Testosterone Formulations

• Confirm diagnosis of hypogonadism with morning testosterone concentrations measured on at least two separate days 4
• Monitor testosterone levels 2-3 months after treatment initiation and after any dose change 1
• Once stable levels are confirmed, monitoring every 6-12 months is typically sufficient 1
• Monitor hematocrit/hemoglobin and PSA levels regularly 5

Formulation-Specific Monitoring

• For injections: measure testosterone levels midway between injections, targeting mid-normal values (500-600 ng/dL) 1, 5
• For gels: levels can be measured at any time, understanding that peak values occur 6-8 hours after application 1

Clinical Decision Algorithm

1. First-line recommendation: Testosterone gel

   • Best for patients concerned about stable hormone levels and minimizing cardiovascular risk 1
   • Preferred for elderly patients due to lower risk of erythrocytosis and cardiovascular events 3
   • Consider if patient has history of or risk factors for cardiovascular disease 1

2. Consider testosterone injections if:

   • Cost is a significant concern for the patient 1
   • Patient has difficulty with daily application regimens 1
   • Risk of transfer to partners/children is high and cannot be mitigated 1, 2
   • Patient strongly prefers less frequent administration 1

3. Weekly rather than biweekly injections if using injectable form

   • Provides more stable serum testosterone levels 5
   • Reduces time spent in supratherapeutic and subtherapeutic ranges 1

Common Pitfalls and Caveats

• Secondary exposure with gel formulations can cause virilization in women and children - patients must be counseled about proper application and precautions 2
• Fluctuating testosterone levels with injections may contribute to mood swings and other adverse effects 1, 6
• Erythrocytosis risk with testosterone therapy requires regular monitoring of hematocrit, especially with injections 1
• Both formulations can cause testicular atrophy and reduced fertility during therapy 5