What are the criteria for initiating testosterone replacement therapy in men, the preferred formulations and dosing, and the recommended baseline and follow‑up monitoring?

Testosterone Replacement Therapy: Comprehensive Clinical Guide

Diagnostic Criteria for Initiating TRT

Testosterone replacement therapy should only be initiated when BOTH biochemical hypogonadism AND specific qualifying symptoms are confirmed. 1

Biochemical Confirmation Requirements

• Two separate morning total testosterone measurements (drawn between 8-10 AM) must both be <300 ng/dL to establish hypogonadism 1, 2
• Single measurements are insufficient due to diurnal variation and assay variability 1
• In men with obesity or borderline total testosterone, measure free testosterone by equilibrium dialysis (gold standard) or calculate using validated formulas, as low SHBG can artificially lower total testosterone while free testosterone remains normal 1

Distinguish Primary from Secondary Hypogonadism

• Measure serum LH and FSH after confirming low testosterone 1
• Elevated LH/FSH with low testosterone = primary (testicular) hypogonadism 1
• Low or low-normal LH/FSH with low testosterone = secondary (hypothalamic-pituitary) hypogonadism 1
• This distinction is critical because men with secondary hypogonadism who desire fertility must receive gonadotropin therapy (hCG + FSH), not testosterone, which causes azoospermia 1

Qualifying Symptoms That Justify Treatment

Primary symptoms with proven benefit:

• Diminished libido 3, 1
• Erectile dysfunction 3, 1

Secondary symptoms with weaker evidence:

• Diminished sense of vitality or energy 3
• Depressed mood 3
• Reduced muscle mass and bone density 3

Critical caveat: Testosterone therapy produces little to no meaningful improvement in physical functioning, energy/vitality, or cognition, even in confirmed hypogonadism 1. The standardized mean difference for sexual function is only 0.35, and for depressive symptoms only -0.19 1.

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Absolute Contraindications to TRT

Never initiate testosterone therapy in men with: 1

• Active desire for fertility preservation (testosterone causes prolonged, potentially irreversible azoospermia)
• Active or treated male breast cancer
• Prostate cancer (though evidence is evolving)
• Hematocrit >54%
• Untreated severe obstructive sleep apnea
• Recent cardiovascular events within 3-6 months (myocardial infarction, stroke)
• Severe/decompensated heart failure

The European Association of Urology explicitly recommends against testosterone therapy in eugonadal men (normal testosterone levels), even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength. 1

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Preferred Formulations and Dosing

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 compared to injectable preparations (15.4% vs 43.8%). 1, 4

Application instructions: 4

• 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
• Cover application site with clothing once dry
• Avoid swimming/showering for minimum 2 hours after application
• Wash hands thoroughly with soap and water immediately after application

Dose adjustment range: 4

• Minimum: 20.25 mg (1 pump actuation)
• Starting: 40.5 mg (2 pump actuations)
• Maximum: 81 mg (4 pump actuations)

Critical safety warning: Children and women must never touch unwashed or unclothed application sites, as secondary exposure causes virilization in children (early puberty, genital enlargement) and unwanted hair growth in women. 4

Second-Line: Intramuscular Testosterone Injections

Testosterone cypionate or enanthate 100-200 mg intramuscularly every 2 weeks (or 50-100 mg weekly for more stable levels). 1

Advantages: 3

• Low cost ($156/year vs $2,135/year for transdermal)
• High peak serum levels

Disadvantages: 3, 1

• Pain of injection
• "Roller coaster" effect with alternating symptomatic benefit and return to baseline
• Significantly higher risk of erythrocytosis (43.8% vs 15.4% for transdermal)
• Peak levels occur days 2-5, return to baseline by days 10-14

Third-Line: Oral Testosterone Undecanoate

Testosterone undecanoate 200 mg orally twice daily (morning and evening) with food. 5

Dose adjustment range: 5

• Minimum: 100 mg once daily in morning
• Maximum: 400 mg twice daily

Critical FDA boxed warning: Testosterone undecanoate can cause blood pressure increases that increase risk of major adverse cardiovascular events (MACE), including non-fatal MI, stroke, and cardiovascular death. 5 Due to this risk, use only for hypogonadism associated with structural or genetic etiologies. 5

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Target Testosterone Levels

Target mid-normal range: 450-600 ng/dL (or 500-600 ng/dL). 1, 2

• Do NOT target upper-normal levels, as this increases erythrocytosis risk without additional benefit 1
• The goal is normalization of testosterone levels combined with improvement in symptoms 2
• If patients do not experience symptomatic relief after reaching target levels, discontinue testosterone therapy 2

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Baseline Testing Before Initiating TRT

Required baseline assessments: 1

• Two morning total testosterone measurements (8-10 AM on separate days)
• Free testosterone by equilibrium dialysis (if total testosterone borderline or patient has obesity/diabetes)
• LH and FSH (to distinguish primary vs secondary hypogonadism)
• Hematocrit or hemoglobin (hematocrit >54% is absolute contraindication)
• PSA level in men >40 years (PSA >4.0 ng/mL requires urologic evaluation and negative biopsy before starting)
• Digital rectal examination in men >40 years (to assess for palpable prostate nodules)
• Fasting glucose (to exclude diabetes)
• Lipid panel (baseline for monitoring)

Additional testing in secondary hypogonadism: 1

• Serum prolactin (to evaluate for hyperprolactinemia)
• Consider pituitary MRI if prolactin elevated or other pituitary dysfunction suspected

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Follow-Up Monitoring Schedule

Initial Monitoring Phase

At 2-3 months after treatment initiation or dose change: 1, 2

• Testosterone level:
  • For injectable testosterone: measure midway between injections (days 5-7 after injection), targeting 500-600 ng/dL 1
  • For transdermal testosterone: measure 4-6 hours after morning application 1
  • For oral testosterone undecanoate: measure 3-5 hours after morning dose 5
• Hematocrit (withhold treatment if >54%) 1
• PSA in men >40 years 1
• Assess symptomatic response, particularly sexual function 1

Long-Term Monitoring (Once Stable)

Every 6-12 months: 1, 2

• Testosterone level (targeting 450-600 ng/dL)
• Hematocrit (withhold if >54%, consider phlebotomy if persistently elevated)
• PSA in men >40 years (refer to urology if increase >1.0 ng/mL in first 6 months or >0.4 ng/mL/year thereafter)
• Digital rectal examination
• Lipid panel
• Blood pressure (especially for oral testosterone undecanoate)
• Assess symptomatic response

Reevaluate at 12 months: If no improvement in sexual function, discontinue testosterone therapy to prevent unnecessary long-term exposure without benefit. 1

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Management of Erythrocytosis on TRT

Erythrocytosis is the most common serious adverse effect of testosterone therapy, occurring in 2.8-43.8% of patients depending on formulation. 1

Risk by Formulation

• Injectable testosterone enanthate: 43.8% 1
• Transdermal nonscrotal patches: 15.4% 1
• Transdermal gel (dose-dependent): 2.8-17.9% 1
• Scrotal patches: 5.5% 1

Management Algorithm Based on Hematocrit Level

Hematocrit 50-52%: 1

• Continue current therapy with closer monitoring (every 3 months)
• Consider dose reduction if trending upward

Hematocrit 52-54%: 1

• Reduce testosterone dose by 25-50%
• Consider switching from injectable to transdermal formulation

Hematocrit >54%: 1

• Withhold testosterone therapy immediately
• Consider therapeutic phlebotomy in high-risk patients (elderly, cardiovascular disease)
• Remove 500 mL blood every 1-2 weeks until hematocrit <52%
• Monitor iron studies to avoid iron deficiency

If hematocrit remains persistently elevated (>52%) despite dose reduction and formulation change, reevaluate whether patient is experiencing meaningful clinical benefit from testosterone. 1

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Special Clinical Scenarios

Obesity-Associated Secondary Hypogonadism

First-line approach: Weight loss through lifestyle modification BEFORE initiating testosterone. 1

• Implement hypocaloric diet with 500-750 kcal/day restriction 1
• Prescribe structured physical activity: minimum 150 minutes/week moderate-intensity aerobic exercise plus resistance training 2-3 times weekly 1
• Weight loss of 5-10% can significantly increase endogenous testosterone production 1
• Repeat morning testosterone measurements after 3-6 months of lifestyle intervention 1

If testosterone remains low after adequate weight loss trial, then consider TRT. 1

Men Desiring Fertility

Testosterone therapy is ABSOLUTELY CONTRAINDICATED in men seeking fertility preservation. 1

For secondary hypogonadism with fertility concerns: 1

• First-line: Gonadotropin therapy (recombinant hCG plus FSH)
• hCG stimulates testosterone production
• FSH stimulates spermatogenesis
• This approach restores both testosterone levels AND fertility potential
• Combined hCG + FSH produces better outcomes than hCG alone

For primary hypogonadism: Testosterone therapy is the only option, but it permanently compromises fertility. 1

Elderly Men with Cardiovascular Risk Factors

Use caution and target mid-range testosterone levels (350-600 ng/dL). 1

• Avoid testosterone therapy within 3-6 months of MI, stroke, or cardiovascular event 1, 5
• Prefer transdermal formulations over injectable (more stable levels, lower erythrocytosis risk) 1
• Monitor blood pressure closely, especially with oral testosterone undecanoate 5
• Consider lower starting doses and slower titration 1

Men with Diabetes

Optimize diabetes management concurrently with TRT. 1

• Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c (reduction ~0.37%) 1
• Consider intensifying diabetes therapy with GLP-1 receptor agonist or SGLT2 inhibitor for cardiovascular benefits 1
• Continue statin therapy as indicated 1
• Monitor for hypoglycemia, as testosterone may decrease insulin requirements 5

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Common Pitfalls to Avoid

Never diagnose hypogonadism on a single testosterone measurement – two morning values are required. 1

Never rely on symptoms alone without biochemical confirmation – symptoms are nonspecific. 1

Never omit LH/FSH testing once low testosterone is confirmed – the distinction between primary and secondary hypogonadism directs therapy and fertility counseling. 1

Never start testosterone without confirming the patient does not desire fertility – this causes irreversible suppression of spermatogenesis. 1

Never use testosterone therapy for weight loss, energy improvement, or athletic performance – these are not evidence-based indications. 1

Never ignore mild erythrocytosis (hematocrit 50-52%) in elderly patients or those with cardiovascular disease – even modest elevations increase thrombotic risk. 1

Never continue full-dose testosterone when hematocrit exceeds 54% – this is an absolute indication to withhold therapy. 1

Never draw testosterone levels at peak (days 2-5 for injectable) or trough (days 13-14) – measure midway between injections for accurate assessment. 1

Never assume age-related decline in young men – always investigate for secondary causes of hypogonadism. 1

Approximately 20-30% of men receiving testosterone in the United States do not have documented low testosterone levels before treatment initiation – this violates evidence-based guidelines. 1