What are the recommended steps to initiate testosterone replacement therapy in a male with confirmed hypogonadism, including diagnostic criteria, baseline labs, contraindications, first‑line formulations, dosing, and monitoring?

Initiating Testosterone Replacement Therapy for Male Hypogonadism

Testosterone replacement therapy should be initiated only when a man has both confirmed biochemical hypogonadism—defined as two separate fasting morning total testosterone measurements (8–10 AM) below 300 ng/dL—and specific symptoms of testosterone deficiency, particularly diminished libido and erectile dysfunction. 1, 2, 3, 4

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Diagnostic Confirmation

Biochemical Testing Requirements

• Obtain two separate fasting morning total testosterone measurements between 8:00 AM and 10:00 AM on different days; a single measurement is insufficient due to diurnal variation and assay variability. 1, 2, 3, 4
• Both values must be < 300 ng/dL to establish biochemical hypogonadism. 1, 2, 4
• Measure free testosterone by equilibrium dialysis (gold standard) or calculate it using a validated formula in men with borderline total testosterone (231–346 ng/dL) or in those with obesity, where low SHBG may artificially lower total testosterone while free testosterone remains normal. 1, 2, 4
• Measure serum LH and FSH after confirming low testosterone to differentiate primary hypogonadism (elevated LH/FSH) from secondary hypogonadism (low or low-normal LH/FSH); this distinction is critical for treatment selection and fertility counseling. 1, 4

Qualifying Symptoms

• Primary symptoms that justify treatment: diminished libido and erectile dysfunction—these are the only symptoms with proven responsiveness to testosterone therapy. 1, 4
• Symptoms with minimal or no proven benefit: fatigue, low energy, depressed mood, reduced physical function, and cognitive complaints show little to no improvement with testosterone therapy, even when hypogonadism is confirmed. 1, 4
• Do not initiate therapy based on symptoms alone without biochemical confirmation; symptoms are nonspecific and overlap with many other conditions. 1, 5, 4

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Baseline Laboratory and Clinical Assessments

Mandatory Pre-Treatment Tests

• Hematocrit or hemoglobin: document baseline values; hematocrit > 54% is an absolute contraindication to starting therapy. 1, 4
• Prostate-specific antigen (PSA) in men > 40 years: PSA > 4.0 ng/mL (or > 3.0 ng/mL in high-risk men such as African Americans or those with a first-degree relative with prostate cancer) requires urologic evaluation and documented negative prostate biopsy before initiating therapy. 1, 4
• Digital rectal examination to assess for palpable prostate nodules or induration. 1, 4
• Fasting glucose and HbA1c to exclude diabetes. 1
• Lipid profile as part of baseline metabolic assessment. 1
• TSH to exclude thyroid dysfunction that can mimic hypogonadal symptoms. 1

Additional Testing in Secondary Hypogonadism

• Serum prolactin: measure in all men with low testosterone and low/normal LH-FSH; if prolactin exceeds 1.5 × the upper limit of normal, order a pituitary MRI to exclude prolactinoma. 1, 4
• Pituitary MRI is indicated when total testosterone < 150 ng/dL with LH/FSH < 1.5 IU/L (regardless of prolactin level), or when visual field defects or anosmia are present. 1

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Absolute Contraindications

Do not initiate testosterone therapy in men with any of the following: 1, 4

• Active desire for fertility preservation (testosterone causes prolonged azoospermia; use gonadotropin therapy instead)
• Breast or prostate cancer
• Palpable prostate nodule or induration
• PSA > 4.0 ng/mL (or > 3.0 ng/mL in high-risk men) without further urologic evaluation
• Hematocrit > 54%
• Untreated severe obstructive sleep apnea
• Uncontrolled heart failure
• Myocardial infarction or stroke within the past 3–6 months
• Thrombophilia

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First-Line Formulations and Dosing

Transdermal Testosterone Gel (Preferred First-Line)

Transdermal testosterone gel 1.62% is the preferred first-line formulation due to more stable day-to-day testosterone levels and a markedly lower risk of erythrocytosis (≈15%) compared with injectable preparations (≈44%). 1, 6, 3

• Starting dose: 40.5 mg of testosterone (2 pump actuations or one 40.5 mg packet) applied once daily in the morning to the shoulders and upper arms. 6, 3
• Dose range: can be adjusted between 20.25 mg (1 pump actuation) and 81 mg (4 pump actuations or two 40.5 mg packets). 6, 3
• Application instructions: apply to clean, dry, intact skin of the shoulders and upper arms only; do not apply to the abdomen, genitals, chest, armpits, or knees. 3
• Safety precautions: patients must wash hands immediately with soap and water after application, cover the application site with clothing once dry, and wash the site thoroughly before any skin-to-skin contact with others (especially children and women) to prevent secondary exposure. 3

Intramuscular Testosterone Injections (Cost-Effective Alternative)

Intramuscular testosterone cypionate or enanthate is a cost-effective alternative (annual cost ≈$156 vs. ≈$2,135 for transdermal gel) but carries a higher risk of erythrocytosis. 1, 6

• Starting dose: 100–200 mg every 2 weeks or 50–100 mg weekly (weekly dosing provides more stable levels). 1, 6
• Administration: can be self-administered in the thighs or given by another person in the gluteal region. 6
• Monitoring timing: measure testosterone levels midway between injections (days 5–7 for weekly dosing, days 7–10 for bi-weekly dosing), as peak levels occur at days 2–5 and return to baseline by days 10–14. 1, 6

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Target Testosterone Levels

• Target mid-normal serum testosterone concentrations of 450–600 ng/dL during treatment to optimize clinical response while minimizing adverse effects. 1, 6, 4
• The broader acceptable range is 300–1,000 ng/dL, but mid-normal values are preferred. 6

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Monitoring Schedule

Initial Follow-Up (First Year)

• 2–3 months after initiation or any dose change: measure serum testosterone (timed appropriately for the formulation), hematocrit, and PSA; evaluate clinical response and adjust dose if symptoms persist with suboptimal levels. 1, 6, 4
• Every 3–6 months during the first year: repeat testosterone, hematocrit, PSA, lipid profile, and perform digital rectal examination. 1, 4

Long-Term Monitoring (After First Year)

• Every 6–12 months once stable: continue the same panel (testosterone, hematocrit, PSA, lipid profile, digital rectal examination). 1, 6, 4

Safety Thresholds and Actions

• Withhold testosterone if hematocrit rises > 54%; consider therapeutic phlebotomy in high-risk individuals. 1, 4
• Refer to urology if PSA increases > 1.0 ng/mL within the first 6 months or > 0.4 ng/mL per year thereafter, or if a palpable prostate nodule or induration develops. 1, 4
• Discontinue therapy at 12 months if there is no documented improvement in sexual function, as this is the primary indication with proven benefit. 1

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Expected Treatment Outcomes

• Small but statistically significant improvement in sexual function and libido (standardized mean difference ≈0.35). 1, 4
• Little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition, even with confirmed hypogonadism. 1, 4
• Modest improvements in metabolic parameters (insulin resistance, triglycerides, HDL cholesterol) may occur. 1
• Modest improvements in bone mineral density may be observed. 1

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Special Considerations

Fertility Preservation

• Testosterone therapy is absolutely contraindicated in men desiring fertility because it suppresses spermatogenesis and causes prolonged, potentially irreversible azoospermia. 1, 4
• For men with secondary hypogonadism who desire fertility, use gonadotropin therapy (recombinant hCG plus FSH) instead, which restores both testosterone production and spermatogenesis. 1

Obesity-Associated Secondary Hypogonadism

• Attempt weight loss through a hypocaloric diet (≈500–750 kcal/day deficit) and structured exercise (≥150 min/week moderate-intensity aerobic activity plus resistance training 2–3 times/week) before initiating testosterone therapy; a 5–10% weight loss can markedly increase endogenous testosterone. 1

Cardiovascular Risk

• The 2023 TRAVERSE trial (5,246 men, mean follow-up 21.7 months) found no significant difference in the incidence of major adverse cardiac events or nonfatal stroke between transdermal testosterone gel and placebo in men 45–80 years with confirmed hypogonadism and preexisting or high risk of cardiovascular disease. 7
• Initiation or continuation of transdermal testosterone therapy in men 45–80 years with confirmed hypogonadism is reasonable and does not increase the risk of stroke. 7

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Common Pitfalls to Avoid

• Do not diagnose hypogonadism on a single testosterone measurement or on symptoms alone; require two fasting morning values < 300 ng/dL plus specific sexual symptoms. 1, 2, 4
• Do not omit LH and FSH testing after confirming low testosterone; the primary vs. secondary distinction guides therapy and fertility counseling. 1, 4
• Do not initiate testosterone without confirming the patient does not desire fertility, as this can cause prolonged azoospermia. 1, 4
• Do not prescribe testosterone for weight loss, general energy enhancement, or athletic performance; these are not evidence-based indications. 1
• Do not test testosterone outside of morning hours (8–10 AM), as this increases false-positive rates. 1, 2
• Do not use direct immunoassays for free testosterone in men with abnormal SHBG; use equilibrium dialysis or calculate the free androgen index. 1
• Approximately 25–30% of men receiving testosterone therapy do not meet formal diagnostic criteria for hypogonadism, highlighting the need for strict adherence to testing protocols. 1
• Nearly 50% of men on testosterone therapy never have their levels re-checked, representing a significant safety gap. 1