What is the appropriate testosterone replacement therapy regimen and dosage for a 40‑year‑old man weighing 200 lb with a total serum testosterone of approximately 300 ng/dL?

Testosterone Replacement Therapy Dosing for a 40-Year-Old Man with Testosterone 300 ng/dL

Start with testosterone cypionate or enanthate 100–200 mg intramuscularly every 2 weeks, targeting mid-normal serum levels of 500–600 ng/dL measured midway between injections. 1

Diagnostic Confirmation Required First

Before initiating therapy, you must confirm biochemical hypogonadism with two separate fasting morning testosterone measurements (8–10 AM) both showing levels < 300 ng/dL. 1, 2 A single measurement of 300 ng/dL is at the diagnostic threshold and does not definitively confirm hypogonadism—repeat testing is mandatory due to diurnal variation and assay variability. 1, 3

Essential Pre-Treatment Laboratory Work

• LH and FSH to distinguish primary (elevated gonadotropins) from secondary (low/normal gonadotropins) hypogonadism—this distinction is critical for fertility counseling and treatment selection. 1
• Free testosterone by equilibrium dialysis if the patient is obese or has borderline total testosterone, as low SHBG can artificially lower total testosterone while free testosterone remains normal. 1, 3
• Baseline hematocrit/hemoglobin—hematocrit > 54% is an absolute contraindication to starting therapy. 1, 4
• PSA and digital rectal exam in men ≥ 40 years; PSA > 4.0 ng/mL requires urologic evaluation and negative prostate biopsy before initiating therapy. 1
• Prolactin if LH/FSH are low or if loss of libido is prominent, to exclude hyperprolactinemia. 1
• Fasting glucose and HbA1c to screen for diabetes. 1

Confirm Qualifying Symptoms

Testosterone therapy is indicated only for men with confirmed low testosterone and specific sexual symptoms—primarily diminished libido and erectile dysfunction. 1, 3 The evidence shows only small improvements in sexual function (standardized mean difference 0.35) and little to no benefit for fatigue, energy, physical function, mood, or cognition. 1, 5 If the patient's primary complaints are non-sexual (e.g., fatigue, low energy), testosterone therapy is not recommended even with confirmed low testosterone. 1

Recommended Starting Regimen

First-Line: Transdermal Testosterone Gel

Transdermal testosterone gel 1.62% at 40.5 mg daily is the preferred first-line formulation because it provides stable day-to-day testosterone levels and carries a markedly lower risk of erythrocytosis (15.4% incidence) compared with injectable testosterone (43.8% incidence). 1, 4 However, the annual cost is approximately $2,135 versus $156 for intramuscular injections. 1

Cost-Effective Alternative: Injectable Testosterone

If cost is a concern or the patient prefers infrequent dosing, testosterone cypionate or enanthate 100–200 mg intramuscularly every 2 weeks is highly effective. 1, 6 The 200 mg every 2 weeks regimen has been shown to suppress elevated LH to normal and produce serum testosterone concentrations that fluctuate largely within the normal range. 6

• Peak serum levels occur 2–5 days after injection, often transiently exceeding the upper limit of normal. 1, 4
• Levels return to baseline by days 10–14 after injection. 1, 4
• Measure testosterone levels midway between injections (days 5–7) to assess average exposure, targeting 500–600 ng/dL. 1, 2

For a 200-pound (91 kg) man, the expected average serum testosterone concentration with standard dosing is approximately 426–568 ng/dL, as body weight inversely correlates with achieved testosterone levels. 4

Monitoring Schedule

Initial Follow-Up (2–3 Months)

• Measure total testosterone (midway between injections for injectables), hematocrit, and PSA. 1, 2
• Assess clinical response—particularly improvement in libido and erectile function. 1
• Adjust dose if symptoms persist with sub-optimal hormone levels. 1, 2

Ongoing Monitoring (Every 3–6 Months During Year 1, Then Annually)

• Repeat testosterone, hematocrit, PSA, and perform digital rectal examination. 1, 2
• Withhold therapy if hematocrit > 54% and consider phlebotomy in high-risk cases. 1, 4
• Refer to urology if PSA rises > 1.0 ng/mL within the first 6 months or > 0.4 ng/mL per year thereafter. 1

Discontinuation Criteria

Discontinue therapy at 12 months if there is no documented improvement in sexual function, as continued exposure without benefit is not justified. 1, 3

Absolute Contraindications

• Active desire for fertility preservation—testosterone causes prolonged, potentially irreversible azoospermia; use gonadotropin therapy (hCG + FSH) instead. 1, 7, 8
• Hematocrit > 54% at baseline. 1, 4
• Active or treated male breast cancer. 1
• PSA > 4.0 ng/dL without urologic clearance. 1
• Recent cardiovascular event (myocardial infarction or stroke) within the past 3–6 months. 1, 2

Expected Outcomes

• Small but significant improvement in sexual function and libido (standardized mean difference 0.35). 1, 5
• Minimal or no improvement in energy, physical function, mood, or cognition. 1, 5
• Potential metabolic benefits including improved insulin resistance, triglycerides, and HDL cholesterol. 1
• Increased risk of erythrocytosis, especially with injectable formulations (44% vs. 15% with transdermal). 1, 4

Critical Pitfalls to Avoid

• Do not diagnose hypogonadism on a single testosterone measurement—two morning values are required. 1, 3
• Do not initiate therapy without confirming the patient does not desire fertility—this causes irreversible suppression of spermatogenesis. 1, 7
• Do not prescribe testosterone for weight loss, energy enhancement, or athletic performance—these are not evidence-based indications. 1
• Do not omit LH/FSH testing after confirming low testosterone—the distinction between primary and secondary hypogonadism directs therapy and fertility counseling. 1
• Nearly 50% of men on testosterone therapy never have their levels re-checked—this is a dangerous practice pattern. 3, 9
• Up to 25% of men receiving testosterone do not meet diagnostic criteria for testosterone deficiency, highlighting the need for strict adherence to testing protocols. 3, 9