In adult men with documented low serum testosterone, when is testosterone replacement therapy indicated and what evaluation, contraindications, formulation options, and monitoring are recommended?

Testosterone Replacement Therapy for Low Testosterone

Testosterone replacement therapy (TRT) should be initiated only in men with both confirmed biochemical hypogonadism (two separate morning testosterone levels <300 ng/dL) and specific symptoms—primarily diminished libido and erectile dysfunction—as these are the only outcomes with proven benefit. 1, 2

Diagnostic Confirmation Required Before Treatment

Laboratory Testing Algorithm

• Measure morning total testosterone (8-10 AM) on two separate occasions to confirm persistent levels below 300 ng/dL, as single measurements are unreliable due to diurnal variation and assay variability 2, 3
• Measure free testosterone by equilibrium dialysis in men with borderline total testosterone, obesity, or diabetes, where SHBG abnormalities may mask true hypogonadism 2, 4
• Measure LH and FSH after confirming low testosterone to distinguish primary (elevated LH/FSH) from secondary (low/low-normal LH/FSH) hypogonadism, as this distinction is critical for treatment selection and fertility counseling 2, 4

Qualifying Symptoms for Treatment

• Primary indications: Diminished libido and erectile dysfunction are the only symptoms with moderate-certainty evidence for improvement (standardized mean difference 0.35) 1
• Symptoms with minimal/no benefit: Fatigue, low energy, depressed mood, reduced physical function, and cognitive complaints show little to no improvement even with confirmed hypogonadism 1

Absolute Contraindications to Testosterone Therapy

Do not initiate TRT in men with: 2, 5, 4

• Active desire for fertility preservation (testosterone causes prolonged azoospermia)
• Active or treated male breast cancer or prostate cancer
• Hematocrit >54%
• Untreated severe obstructive sleep apnea
• Recent cardiovascular events within 3-6 months
• Severe/decompensated heart failure

Treatment Selection Algorithm

First-Line: Transdermal Testosterone Gel

Transdermal testosterone gel 1.62% at 40.5 mg daily is the preferred initial formulation due to more stable day-to-day testosterone levels and significantly lower erythrocytosis risk (15.4% vs 43.8% with injectable) 2, 5

Application instructions: 5

• Apply once daily in the morning to clean, dry, intact skin of shoulders and upper arms only
• Do not apply to abdomen, genitals, chest, armpits, or knees
• Wash hands immediately with soap and water after application
• Cover application sites with clothing after gel dries
• Wash application sites thoroughly before any skin-to-skin contact with others

Alternative: Intramuscular Testosterone

Testosterone cypionate or enanthate 100-200 mg every 2 weeks is a cost-effective alternative (annual cost $156 vs $2,135 for transdermal) but carries higher erythrocytosis risk 2, 6

Monitoring timing for injectable: Measure testosterone levels midway between injections (days 5-7), targeting mid-normal values of 500-600 ng/dL, as peak levels occur days 2-5 and return to baseline by days 10-14 2

Special Population: Men Desiring Fertility Preservation

Testosterone is absolutely contraindicated—use gonadotropin therapy (hCG plus FSH) instead for men with secondary hypogonadism who desire fertility, as this stimulates the testes directly without suppressing spermatogenesis 2, 4

Monitoring Requirements During Treatment

Initial Monitoring (First 3 Months)

• Testosterone levels at 2-3 months after initiation or dose change, targeting mid-normal range (450-600 ng/dL) 2, 4
• Hematocrit at each visit—withhold treatment if >54% and consider phlebotomy in high-risk cases 2, 4
• PSA in men over 40 years—refer for urologic evaluation if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 2

Long-Term Monitoring (After Stabilization)

• Testosterone levels every 6-12 months once stable 2, 4
• Hematocrit monitoring at each visit, as erythrocytosis risk persists throughout treatment 2
• Clinical symptom response assessment, particularly sexual function, at 12 months—discontinue if no improvement 2

Expected Treatment Outcomes

Proven Benefits (Moderate-Certainty Evidence)

• Small but significant improvement in sexual function and libido (SMD 0.35) 1
• Modest quality of life improvements, primarily driven by sexual function domains 1

Minimal or No Benefits (Low-Certainty Evidence)

• Physical function: SMD 0.14, clinically insignificant 1
• Energy and vitality: SMD 0.17, barely distinguishable from placebo 1
• Depressive symptoms: SMD -0.19, less-than-small improvement 1
• Cognitive function: No meaningful benefit demonstrated 1

Critical Management Pitfalls to Avoid

Never initiate testosterone without: 2

• Confirming the patient does not desire fertility (causes irreversible azoospermia)
• Documenting two separate morning testosterone measurements <300 ng/dL
• Measuring LH/FSH to distinguish primary from secondary hypogonadism
• Assessing for absolute contraindications, particularly hematocrit >54%

Never diagnose hypogonadism based on: 2, 3

• Symptoms alone without biochemical confirmation
• Single testosterone measurement
• Nonspecific symptoms (fatigue, low energy) in the absence of sexual dysfunction

Never continue testosterone beyond 12 months without documented improvement in sexual function, as this exposes patients to potential cardiovascular and hematologic risks without proven benefit 2

Special Clinical Scenarios

Obesity-Associated Secondary Hypogonadism

Attempt weight loss through hypocaloric diet (500-750 kcal/day deficit) and structured exercise (150 minutes/week moderate-intensity aerobic plus resistance training 2-3 times weekly) before initiating TRT, as this can reverse the condition by improving testosterone levels naturally 2

Borderline Testosterone (231-346 ng/dL)

Consider a 4-6 month trial of TRT after careful discussion of risks and benefits, with continuation only if clinical benefit is demonstrated and testosterone remains consistently low on repeat testing 2

Cardiovascular Disease

Target mid-range testosterone levels (350-600 ng/dL) and use transdermal formulations preferentially in elderly patients or those with cardiovascular risk factors, as injectable testosterone produces supraphysiologic peaks associated with higher cardiovascular risk 2

Erythrocytosis Management Algorithm

• Hematocrit 50-52%: Continue with closer monitoring, consider dose reduction if trending upward 2
• Hematocrit 52-54%: Reduce testosterone dose by 25-50%, consider switching from injectable to transdermal 2
• Hematocrit >54%: Withhold testosterone immediately, consider therapeutic phlebotomy (remove 500 mL every 1-2 weeks until <52%) in high-risk patients 2