What is the typical dosing regimen for testosterone replacement therapy?

Testosterone Replacement Therapy Dosing

Start with testosterone enanthate or cypionate 50-100 mg intramuscularly weekly, as this provides more stable testosterone levels than biweekly dosing and reduces adverse effects including erythrocytosis and cardiovascular risk. 1, 2

Injectable Testosterone Formulations

Short-Acting Esters (Enanthate/Cypionate)

• Weekly dosing of 50-100 mg intramuscularly is the preferred regimen because it maintains significantly more stable testosterone levels compared to biweekly administration, reducing problematic fluctuations in mood and sexual function. 1, 2
• The alternative biweekly regimen of 100-200 mg every 2 weeks is acceptable but creates supraphysiological peaks at 2-5 days post-injection and often returns to baseline by 10-14 days, causing greater adverse effects. 1, 2, 3
• These injections can be self-administered in the thighs or given by another person in the gluteal region using deep intramuscular technique. 1, 3
• Subcutaneous administration at 50-150 mg weekly is equally effective as intramuscular injection and is increasingly preferred due to easier self-administration, less discomfort, and comparable efficacy across a wide BMI range. 1, 4

Long-Acting Testosterone Undecanoate

• Administer 750 mg intramuscularly initially, followed by 750 mg at 4 weeks, then 750 mg every 10 weeks thereafter. 1, 2
• This formulation must be given as a gluteal intramuscular injection only and provides fewer yearly injections with less fluctuation in testosterone levels. 1
• This represents the most convenient long-term option, requiring only 4 injections per year after the loading phase. 1, 2

Transdermal Formulations

Testosterone Gel

• Start with 40.5-50 mg daily (AndroGel 1.62% = 2 pump actuations; AndroGel 1% = 50-100 mg daily) applied to clean, dry, intact skin of the shoulders and upper arms. 1, 5
• The dose can be adjusted between 20.25 mg (minimum) and 81 mg (maximum) based on serum testosterone levels. 5
• Apply once daily in the morning to the same anatomical sites, avoiding the abdomen, genitals, chest, armpits, or knees. 5
• Critical safety warning: Cover application sites with clothing once dry and avoid contact with women and children due to risk of secondary exposure and virilization. 5
• Patients must avoid swimming, showering, or washing the application site for a minimum of 2 hours after application. 5

Testosterone Patches

• Apply 2-6 mg per 24 hours, but be aware that skin reactions occur in up to 66% of users, significantly limiting tolerability compared to only 5% with gel preparations. 1, 2

Monitoring and Dose Titration Protocol

Initial Monitoring

• Measure testosterone levels at 14 days and 28 days after starting treatment or any dose adjustment, targeting mid-normal values of 450-600 ng/dL. 1, 2, 5
• For injectable formulations, draw levels midway between injections to capture representative trough-to-mid-cycle values, not at peak (2-5 days post-injection). 1, 2
• For transdermal gel, measure pre-dose morning testosterone levels at 2-3 months after initiation or dose change. 1, 5

Dose Adjustment Algorithm

• If testosterone >750 ng/dL: Decrease dose by 20-50 mg (or equivalent) to minimize adverse effects, particularly erythrocytosis. 1, 5
• If testosterone 350-750 ng/dL (target range 450-600 ng/dL): Continue current dose. 1, 2, 5
• If testosterone <350 ng/dL: Increase dose by 20-50 mg (or equivalent). 1, 5
• If maximal transdermal dose fails to achieve adequate levels, switch to intramuscular injection therapy. 1

Long-Term Monitoring

• Once stable levels are achieved, monitor every 6-12 months with testosterone levels, hematocrit/hemoglobin, PSA, and digital rectal examination. 1, 2
• Monitor hematocrit at each visit and reduce dose or temporarily withhold therapy if elevation occurs, as erythrocytosis risk is 43.8% with intramuscular injections versus 15.4% with transdermal patches. 1

Formulation Selection Considerations

Injectable Advantages and Disadvantages

• Advantages: Relatively inexpensive (annual cost $156 for intramuscular vs. $2,135 for transdermal per Medicare data), flexible dosing intervals, and proven efficacy. 1, 2
• Disadvantages: Requires intramuscular injection technique, fluctuating serum testosterone levels (especially with biweekly dosing), and greater cardiovascular risk and erythrocytosis compared to transdermal preparations due to supraphysiological peak levels. 1, 2, 4

Transdermal Advantages and Disadvantages

• Advantages: Easy application, good skin tolerability (gel only), more consistent day-to-day levels, and significantly lower risk of erythrocytosis (dose-dependent: 2.8% at 5 mg/day delivered, increasing to 17.9% at 10 mg/day delivered). 1, 2
• Disadvantages: Higher cost, potential for transfer to partners or children requiring strict adherence to safety precautions, and patches cause unacceptable skin reactions in two-thirds of users. 1, 2

Critical Safety Considerations

Cardiovascular and Hematologic Risks

• Injectable testosterone carries greater cardiovascular risk than transdermal preparations, possibly due to fluctuating testosterone levels creating supraphysiological peaks. 1, 2
• Erythrocytosis occurs more frequently with injectable formulations (43.8%) versus transdermal patches (15.4%), with risk directly related to supraphysiological bioavailable testosterone and estradiol levels. 1
• Assess cardiovascular risk factors before initiating therapy, as testosterone administration may potentially increase cardiovascular events in high-risk patients. 1, 6

Baseline Testing Requirements

• Confirm diagnosis by measuring serum testosterone in the morning on at least two separate days, with both values below normal range. 2
• Obtain baseline PSA, digital rectal examination, hematocrit/hemoglobin, voiding symptoms assessment, sleep apnea history, and optional lipid evaluation. 2

Common Pitfalls to Avoid

• Do not use biweekly dosing when weekly dosing is feasible, as weekly administration provides superior testosterone stability and reduces adverse effects. 1, 2
• Do not allow supraphysiological testosterone levels (>1000 ng/dL) to persist, even if the patient reports feeling well, as this significantly increases erythrocytosis and cardiovascular risk. 1
• Do not forget to prescribe proper injection supplies when prescribing testosterone cypionate vials: 18-gauge needles for drawing, 21-23 gauge 1-1.5 inch needles for injection, 1-3 mL syringes, alcohol prep pads, gauze, bandages, and a sharps container. 1
• Do not overlook fertility counseling, as testosterone replacement therapy greatly compromises fertility due to down-regulation of gonadotropins. 2
• Do not apply transdermal gel to the abdomen, genitals, chest, armpits, or knees, as these sites are not FDA-approved and may alter absorption. 5