What initial dose and titration schedule should be used for testosterone replacement therapy, and how should it be monitored?

Testosterone Replacement Therapy: Initial Dosing and Monitoring

Initial Dose Selection

For most hypogonadal men, transdermal testosterone gel should be initiated at 40.5 mg daily (AndroGel 1.62%, 2 pump actuations) applied to the shoulders and upper arms, as this formulation provides stable physiologic testosterone levels with lower risk of adverse effects compared to injectable preparations. 1, 2

Alternative Injectable Dosing (if transdermal not suitable)

• Testosterone enanthate or cypionate: Start at 50-100 mg weekly via intramuscular or subcutaneous injection 1
• Weekly dosing provides more stable levels than the traditional 100-200 mg every 2 weeks regimen 1
• Testosterone undecanoate: 750 mg initially, then 750 mg at 4 weeks, followed by 750 mg every 10 weeks (gluteal IM only) 1

Rationale for Transdermal First-Line

Transdermal preparations are preferred because they minimize fluctuations in testosterone levels that occur with injectable formulations 3. Injectable testosterone carries significantly higher risk of erythrocytosis (43.8% vs 15.4% with patches) and potentially greater cardiovascular risk due to supraphysiological peaks and subtherapeutic troughs between injections 1, 3.

Titration Schedule

Initial Monitoring Phase

• Measure testosterone levels at 2-3 months after treatment initiation 3, 1, 4
• Repeat testosterone measurement 2-3 months after any dose adjustment 3, 1
• Target mid-normal testosterone levels of 450-600 ng/dL 1, 4

Timing of Blood Draw

• For injectable formulations: Measure testosterone midway between injections to capture representative levels 3, 1
• For transdermal preparations: Can measure at any time, though peak occurs 6-8 hours after application 3

Dose Adjustment Algorithm

If testosterone level >750 ng/dL: Decrease dose by 20.25 mg daily (transdermal) or reduce injectable dose by 25-50% 2, 1

If testosterone level 350-750 ng/dL: Continue current dose 2

If testosterone level <350 ng/dL: Increase dose by 20.25 mg daily (transdermal) or increase injectable dose incrementally 2, 1

Long-Term Monitoring

• Once stable therapeutic levels achieved, monitor every 6-12 months 3, 1, 4

Comprehensive Monitoring Protocol

Baseline Assessment (Before Initiating Therapy)

• Morning testosterone levels on at least 2 separate days (both must be low to confirm hypogonadism) 2, 3
• Digital rectal examination 3
• Prostate-specific antigen (PSA) 3
• Hematocrit or hemoglobin 3
• Voiding symptoms assessment (standardized questionnaire) 3
• Sleep apnea history 3
• Perform prostate biopsy if PSA >4.0 ng/mL or abnormal digital rectal exam 3

Follow-Up Monitoring Schedule

At 1-2 months: Assess efficacy and symptom improvement 3

At 2-3 months and after dose changes:

• Testosterone level 3, 1, 4
• Hematocrit/hemoglobin 3
• PSA 3

Every 3-6 months during first year, then annually:

• Testosterone level 3
• Hematocrit/hemoglobin 3
• PSA 3
• Digital rectal examination 3
• Urinary symptoms 3
• Sleep apnea symptoms 3

PSA Monitoring Thresholds for Prostate Biopsy

Perform biopsy or urologic referral if:

• PSA rises above 4.0 ng/mL 3
• PSA increases by >1.5 ng/mL/year 3
• PSA increases by >0.75 ng/mL/year over 2 years 3
• Digital rectal exam shows nodule, asymmetry, or increased firmness 3

Critical Safety Considerations

Absolute Contraindications

• Breast carcinoma in men 2
• Known or suspected prostate cancer 2
• Pregnancy (testosterone causes fetal harm) 2
• Men currently trying to conceive (suppresses spermatogenesis) 4

Cardiovascular Precautions

• Do not initiate testosterone therapy within 3-6 months of cardiovascular events (myocardial infarction, stroke) 4
• Counsel overweight/obese patients regarding concurrent weight loss programs due to cardiovascular risks 4
• Injectable formulations may carry higher cardiovascular risk than transdermal preparations 3, 4

Erythrocytosis Management

Monitor hematocrit at every visit during first year 3. Erythrocytosis risk is dose-dependent and formulation-dependent:

• Injectable testosterone: 43.8% incidence 1
• Transdermal patches: 15.4% incidence 1
• Transdermal gel (low dose): 2.8% incidence 1

If hematocrit becomes elevated: Reduce dose or temporarily withhold therapy 1

Secondary Exposure Prevention (Transdermal Only)

• Application sites must be covered with clothing after gel dries 2
• Wash application site with soap and water before anticipated skin-to-skin contact 2
• Children must avoid contact with unwashed or unclothed application sites 2
• Virilization has been reported in children secondarily exposed to testosterone gel 2

Common Pitfalls to Avoid

Do not use alkylated oral testosterone due to hepatotoxicity risk 4

Do not continue therapy if no symptom improvement after 3-6 months despite achieving target testosterone levels—discuss cessation as there is no benefit without clinical response 4

Do not measure testosterone during rebound periods after stopping therapy, as values will not reflect true baseline 4

Do not assume all gel formulations are interchangeable—1.62% gel delivers more testosterone per gram than 1% gel, requiring different dosing 1

Do not forget to prime the pump before first use (3 actuations discarded) 2

Do not apply transdermal testosterone to abdomen, genitals, chest, armpits, or knees—only shoulders and upper arms 2

Avoid swimming or showering for minimum 2 hours after transdermal application 2