Testosterone Replacement Therapy: Indications, Evaluation, and Management

When to Initiate Testosterone Replacement Therapy

Testosterone replacement therapy should be initiated only when a patient has both confirmed biochemical hypogonadism (two separate morning total testosterone measurements <300 ng/dL drawn between 8-10 AM) AND specific symptoms—primarily diminished libido and erectile dysfunction. 1, 2

Diagnostic Requirements

Obtain two fasting morning testosterone measurements (8-10 AM) on separate days to confirm persistent hypogonadism, as single measurements are insufficient due to diurnal variation and assay variability 1, 2
Measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) in men with borderline total testosterone (230-350 ng/dL), obesity, or diabetes, as low SHBG can artificially lower total testosterone while free testosterone remains normal 2
Measure serum LH and FSH after confirming low testosterone to distinguish primary hypogonadism (elevated LH/FSH) from secondary hypogonadism (low or low-normal LH/FSH), which has critical treatment implications including fertility preservation 1, 2

Qualifying Symptoms

Primary indication: diminished libido and erectile dysfunction, which show the most reliable improvement with therapy (standardized mean difference 0.35) 1, 2
Secondary symptoms with weaker evidence: reduced muscle mass, decreased bone density, depression, anemia, and diminished sense of vitality 1, 2
Symptoms with minimal or no proven benefit: fatigue, low energy, physical functioning, cognitive complaints, and depressive symptoms (effect sizes too small to be clinically meaningful) 2, 3

Absolute Contraindications

Never initiate testosterone therapy in the following situations:

Active desire for fertility preservation—testosterone causes azoospermia and prolonged suppression of spermatogenesis; use gonadotropin therapy (hCG plus FSH) instead 1, 2
Active or treated male breast cancer 1, 2
Hematocrit >54% at baseline 1, 2
Untreated severe obstructive sleep apnea 2, 4
Recent cardiovascular events (myocardial infarction or stroke within 3-6 months) 2, 3
Active prostate cancer (though this is under debate for men deemed cured) 1

Formulation Selection

First-Line: Transdermal Testosterone Gel

Transdermal testosterone gel 1.62% at 40.5 mg daily is the preferred first-line formulation due to more stable day-to-day testosterone levels and significantly lower risk of erythrocytosis (15.4%) compared to injectable preparations (43.8%). 2, 5

Application: Apply once daily in the morning to clean, dry, intact skin of the shoulders and upper arms (not abdomen, genitals, chest, or axillae) 5
Advantages: Stable testosterone levels, lower erythrocytosis risk, ease of dose titration 2
Disadvantages: Higher annual cost (~$2,135 vs. $156 for injections), risk of secondary exposure to women and children, daily application required 2
Safety precaution: Children and women must avoid contact with unwashed or unclothed application sites; cover site with clothing once dry 5

Second-Line: Intramuscular Testosterone Injections

Testosterone cypionate or enanthate 100-200 mg every 2 weeks (or 50-100 mg weekly) is an effective, safe, and economical alternative. 2, 4

Pharmacokinetics: Peak serum levels occur 2-5 days after injection, with return to baseline by days 10-14 1, 2
Monitoring timing: Measure testosterone levels midway between injections (days 5-7), targeting mid-normal values (500-600 ng/dL) 2
Advantages: Significantly lower cost, infrequent administration 2
Disadvantages: Higher erythrocytosis risk (44% vs. 15% for transdermal), supraphysiologic peaks and subtherapeutic troughs 2, 4

Third-Line: Long-Acting Injectable

Testosterone undecanoate 750 mg initially, repeat at 4 weeks, then every 10 weeks provides fewer yearly injections with more stable levels. 2

Dosing and Titration

Transdermal Gel Dosing Algorithm

Starting dose: 40.5 mg daily (2 pump actuations or one 40.5 mg packet) 5
Dose range: 20.25 mg (minimum) to 81 mg (maximum) daily 5
Titration schedule: Check pre-dose morning testosterone at 14 days and 28 days after starting or dose adjustment 5

Dose adjustment criteria 5:

Testosterone >750 ng/dL: Decrease by 20.25 mg
Testosterone 350-750 ng/dL: Continue current dose
Testosterone <350 ng/dL: Increase by 20.25 mg

Injectable Testosterone Dosing

Standard regimen: 100-200 mg every 2 weeks or 50-100 mg weekly 2, 4
Target levels: Mid-normal range (500-600 ng/dL) measured midway between injections 2
Dose adjustment: If clinical response is suboptimal AND testosterone levels are low-normal or below, increase dose; if response is adequate, no adjustment needed even with low-normal levels 2

Monitoring Protocol

Baseline Evaluation (Before Initiating Therapy)

Testosterone levels: Two morning measurements (8-10 AM), free testosterone by equilibrium dialysis, SHBG 1, 2
Gonadotropins: LH and FSH to distinguish primary from secondary hypogonadism 1, 2
Hematologic: Baseline hematocrit or hemoglobin 1
Prostate assessment (men ≥40 years): PSA level and digital rectal examination; perform prostate biopsy if PSA >4.0 ng/mL or abnormal DRE 1
Clinical assessment: Voiding history, sleep apnea screening 1

Follow-Up Monitoring Schedule

Initial phase 1, 2:

1-2 months: Efficacy evaluation with dose adjustment for suboptimal response
2-3 months: Testosterone level, hematocrit, PSA
Every 3-6 months for the first year: Repeat above assessments

Maintenance phase 1, 2:

Annually (once stable): Testosterone level, hematocrit, PSA, digital rectal examination, symptom assessment

Critical Monitoring Parameters

Hematocrit monitoring 1, 2:

Withhold therapy if hematocrit >54%
Consider dose reduction or formulation switch if hematocrit 52-54%
Consider therapeutic phlebotomy in high-risk cases with persistent elevation

PSA monitoring (men ≥40 years) 1:

Perform biopsy or urologic referral if:
- PSA rises above 4.0 ng/mL, OR
- PSA increases >1.0 ng/mL in first 6 months, OR
- PSA increases >0.4 ng/mL per year thereafter
Alternative threshold: Biopsy for PSA increase of 1.0 ng/mL in any year 1

Symptom assessment 1, 2:

Evaluate sexual function, libido, urinary symptoms, sleep apnea, gynecomastia
Discontinue therapy if no improvement in sexual function after 12 months 2

Expected Treatment Outcomes

Proven Benefits

Sexual function and libido: Small but significant improvement (standardized mean difference 0.35) 2, 4
Quality of life: Modest improvements, primarily in sexual function domains 2, 4
Body composition: Increased lean body mass, decreased body fat 4
Bone mineral density: Improved density, reduced osteoporosis risk 4
Metabolic effects: Improvements in fasting glucose, insulin resistance, triglycerides, HDL cholesterol 2
Anemia: Correction of mild anemia associated with hypogonadism 2

Minimal or No Benefit

Physical functioning: Little to no effect (effect size too small) 2, 3
Energy and vitality: Minimal improvement (standardized mean difference 0.17) 2
Depressive symptoms: Less-than-small improvement (standardized mean difference -0.19) 2
Cognition: No meaningful benefit 2, 3

Special Clinical Scenarios

Obesity-Associated Secondary Hypogonadism

Attempt weight loss through low-calorie diets (500-750 kcal/day deficit) and regular exercise (minimum 150 minutes/week moderate-intensity aerobic plus resistance training 2-3 times weekly) BEFORE initiating testosterone therapy, as this can reverse the condition by improving testosterone levels and normalizing gonadotropins. 2

Secondary Hypogonadism with Fertility Concerns

Use gonadotropin therapy (recombinant hCG plus FSH) instead of testosterone replacement, as testosterone causes prolonged and potentially irreversible azoospermia. 2

Regimen: hCG 1,000-2,500 units subcutaneously 2-3 times per week, plus FSH 75-150 units subcutaneously 2-3 times per week if sperm counts remain low after 3-6 months 2
Outcome: Restores both testosterone production and spermatogenesis 2

Men with Cardiovascular Disease

Wait 3-6 months after myocardial infarction or stroke before initiating therapy 2, 3
Target mid-range testosterone levels (350-600 ng/dL) in elderly patients or those with cardiovascular risk factors 2
Use transdermal formulations preferentially to avoid supraphysiologic peaks 2

Men with Diabetes

Measure morning total testosterone even in the absence of hypogonadal symptoms 2
Optimize diabetes management concurrently, considering intensification with GLP-1 receptor agonist or SGLT2 inhibitor for cardiovascular benefits 2

Critical Pitfalls to Avoid

Never diagnose hypogonadism on a single testosterone measurement or symptoms alone—always confirm with two morning measurements and measure gonadotropins 1, 2
Never start testosterone without confirming the patient does not desire fertility—this causes irreversible suppression of spermatogenesis 2
Never use testosterone for weight loss, energy improvement, or athletic performance in eugonadal men—these are not evidence-based indications 2
Never ignore mild erythrocytosis (hematocrit 50-52%) in elderly or cardiovascular patients—even modest elevations increase thrombotic risk 2
Never continue full-dose testosterone when hematocrit exceeds 54%—this is an absolute indication to withhold therapy 1, 2
Never draw testosterone levels at peak (days 2-5) or trough (days 13-14) for injectable formulations—measure midway between injections 2
Never assume age-related decline in young men—always investigate for secondary causes of hypogonadism 2

Management of Common Adverse Effects

Erythrocytosis (Hematocrit >54%)

Algorithm 2:

Withhold testosterone immediately
Consider therapeutic phlebotomy (remove 500 mL every 1-2 weeks until hematocrit <52%) in high-risk patients
Switch from injectable to transdermal formulation when restarting
Reduce dose by 25-50% and target mid-normal testosterone levels (450-600 ng/dL)
Monitor hematocrit every 3 months until stable

Elevated PSA

Perform prostate biopsy or urologic referral if 1:

PSA >4.0 ng/mL, OR
PSA increase >1.0 ng/mL in first 6 months, OR
PSA increase >0.4 ng/mL per year thereafter, OR
Digital rectal examination shows nodule, asymmetry, or increased firmness

When is testosterone replacement therapy indicated, and what are the recommended evaluation, dosing, formulation choices, and monitoring protocols?

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