When is testosterone replacement therapy appropriate for an adult male with symptoms of hypogonadism and a total testosterone level below 300 ng/dL on two separate morning measurements, assuming no contraindications such as prostate cancer, elevated PSA, untreated sleep apnea, uncontrolled cardiovascular disease, or hematocrit >50%?

When to Initiate Testosterone Replacement Therapy

Start testosterone replacement therapy when an adult male has both confirmed biochemical hypogonadism (total testosterone <300 ng/dL on two separate morning measurements) AND specific symptoms of diminished libido or erectile dysfunction, provided no absolute contraindications exist. 1

Diagnostic Requirements Before Starting TRT

Biochemical Confirmation

• Obtain two separate fasting morning total testosterone measurements (8–10 AM) on different days; both values must be <300 ng/dL to confirm hypogonadism 1, 2
• Single measurements are insufficient due to diurnal variation and assay variability 1
• In men with borderline values (231–346 ng/dL) or obesity, measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) to distinguish true from functional hypogonadism 1

Hormone Panel to Guide Treatment

• Measure serum LH and FSH after confirming low testosterone to differentiate primary (elevated LH/FSH) from secondary (low/normal LH/FSH) hypogonadism 1
• This distinction is critical: men with secondary hypogonadism who desire fertility must receive gonadotropin therapy (hCG + FSH), not testosterone, as TRT causes prolonged azoospermia 1
• Check serum prolactin if LH/FSH are low or low-normal; prolactin >1.5× upper limit of normal requires pituitary MRI 1

Qualifying Symptoms

• Primary indications: diminished libido and erectile dysfunction are the only symptoms with proven testosterone responsiveness (standardized mean difference 0.35) 1
• Non-qualifying symptoms: fatigue, low energy, depressed mood, poor concentration, and reduced physical strength show minimal correlation with testosterone levels and negligible improvement with TRT (effect sizes 0.17 for energy, -0.19 for mood) 1
• Do not prescribe TRT for weight loss, athletic performance, or general "anti-aging" purposes—these are not evidence-based indications 1

Absolute Contraindications to TRT

• Active desire for fertility preservation (testosterone suppresses spermatogenesis) 1, 2
• Prostate cancer or PSA >4.0 ng/mL (>3.0 ng/mL in high-risk men) without negative biopsy 1, 2
• Active or treated male breast cancer 1
• Hematocrit >54% or baseline >50% 1
• Untreated severe obstructive sleep apnea 1, 2
• Myocardial infarction or stroke within past 3–6 months 1
• Uncontrolled heart failure 2

Pre-Treatment Baseline Testing

• Hematocrit/hemoglobin (withhold if >54%) 1
• PSA in men >40 years (urologic evaluation if >4.0 ng/mL) 1
• Digital rectal examination to assess for prostate nodules 1
• Fasting glucose and HbA1c to exclude diabetes 1
• Lipid profile 1
• TSH to rule out thyroid dysfunction 1

First-Line Treatment Selection

Preferred Formulation

• Transdermal testosterone gel 1.62% at 40.5 mg daily is first-line due to stable day-to-day levels and lower erythrocytosis risk (15.4%) compared to injectables (43.8%) 1, 3
• Apply to clean, dry skin of shoulders and upper arms (not abdomen, genitals, or chest); cover with clothing once dry 3
• Avoid swimming/showering for minimum 2 hours after application 3

Alternative Formulation

• Intramuscular testosterone cypionate/enanthate 100–200 mg every 2 weeks (or 50–100 mg weekly for more stable levels) is a cost-effective alternative ($156/year vs. $2,135/year for gel) 1
• Peak levels occur days 2–5, return to baseline by days 10–14; measure testosterone midway between injections targeting 500–600 ng/dL 1

Expected Treatment Outcomes

Realistic Benefits

• Small but significant improvement in sexual function and libido (effect size 0.35) 1
• Modest quality-of-life gains confined to sexual domains 1
• Potential improvements in insulin resistance, triglycerides, and HDL cholesterol 1

Minimal or No Benefits

• Little to no effect on physical functioning, muscle strength, or frailty 1
• Negligible improvement in energy/vitality (effect size 0.17) 1
• No meaningful benefit for depressive symptoms (effect size -0.19) 1
• No impact on cognition, memory, or thinking ability 1

Monitoring Protocol

Initial Follow-Up (2–3 Months)

• Measure total testosterone (midway between injections for injectables), hematocrit, and PSA 1
• Assess clinical response, particularly sexual function 1
• Adjust dose if symptoms persist with suboptimal levels 1

Ongoing Monitoring (Every 3–6 Months First Year, Then Annually)

• Repeat testosterone, hematocrit, PSA, and lipid profile 1
• Perform digital rectal examination 1
• Withhold treatment if hematocrit >54%; consider phlebotomy in high-risk cases 1
• Refer to urology if PSA rises >1.0 ng/mL in first 6 months or >0.4 ng/mL/year thereafter 1

Discontinuation Criteria

• Reevaluate at 12 months: discontinue TRT if no improvement in sexual function, as continued therapy offers no benefit and exposes patients to unnecessary risks 1

Special Clinical Scenarios

Obesity-Associated Secondary Hypogonadism

• First-line approach: attempt weight loss through hypocaloric diet (500–750 kcal/day deficit) and structured exercise (≥150 min/week moderate-intensity aerobic + resistance training 2–3×/week) before initiating TRT 1
• Weight loss of 5–10% can significantly increase endogenous testosterone production 1
• If lifestyle modification fails after 3–6 months and symptoms persist, proceed with TRT 1

Men Desiring Fertility

• Gonadotropin therapy (recombinant hCG + FSH) is mandatory for secondary hypogonadism with fertility concerns 1
• Testosterone is absolutely contraindicated as it causes prolonged, potentially irreversible azoospermia 1

Elderly Men or Cardiovascular Risk

• Target mid-range testosterone levels (350–600 ng/dL) rather than upper-normal 1
• Use transdermal formulations preferentially over injectables to minimize erythrocytosis risk 1
• Defer initiation if recent MI/stroke within 3–6 months 1

Critical Pitfalls to Avoid

• Never diagnose hypogonadism on a single testosterone measurement or symptoms alone—require two morning values <300 ng/dL plus qualifying sexual symptoms 1
• Never omit LH/FSH testing after confirming low testosterone—the primary vs. secondary distinction directs treatment and fertility counseling 1
• Never initiate TRT without confirming the patient does not desire fertility—this causes irreversible suppression of spermatogenesis 1
• Never prescribe TRT for fatigue, low energy, or mood complaints in the absence of sexual symptoms—these show no meaningful improvement even with confirmed hypogonadism 1
• Never continue TRT beyond 12 months without documented improvement in sexual function—this exposes patients to risks without benefit 1
• Approximately 20–30% of men receiving TRT do not meet diagnostic criteria for hypogonadism, and nearly 50% never have follow-up testosterone levels checked—strict adherence to diagnostic and monitoring protocols is essential 1