What is the recommended starting dose and dosing schedule of testosterone cypionate for testosterone replacement therapy in an adult male, and how should it be titrated and monitored?

Testosterone Cypionate Dosing for TRT

Start testosterone cypionate at 50–100 mg intramuscularly weekly (or 100–200 mg every 2 weeks), targeting mid-normal testosterone levels of 450–600 ng/dL measured midway between injections. 1

Initial Dosing Regimen

• The FDA-approved dosing range is 50–400 mg every 2–4 weeks for hypogonadal males, though weekly dosing provides superior testosterone stability. 2
• Weekly administration of 50–100 mg produces more stable serum testosterone concentrations compared to biweekly dosing, minimizing the "roller-coaster" effect of supraphysiologic peaks and subtherapeutic troughs. 1
• Biweekly dosing of 100–200 mg remains clinically effective but creates greater fluctuation, with testosterone peaking at days 2–5 and returning to baseline by days 10–14 after each injection. 1, 3

Pharmacokinetic Rationale

• Peak serum testosterone occurs 2–5 days post-injection, often transiently exceeding the upper limit of normal, while levels return to baseline by days 10–14. 3, 4
• Weekly dosing reduces the magnitude of these fluctuations, keeping testosterone in the physiologic range for a greater proportion of the dosing interval. 1
• The supraphysiologic peaks associated with less frequent dosing are directly linked to increased risk of erythrocytosis (approximately 43.8% with intramuscular injections vs. 15.4% with transdermal preparations). 1, 3

Dose Titration Protocol

• Measure testosterone levels 2–3 months after treatment initiation or any dose change, drawn midway between injections (days 5–7 for weekly dosing, days 7–10 for biweekly). 1, 3
• Target mid-normal testosterone concentrations of 450–600 ng/dL at the midpoint measurement—not at peak or trough. 1, 3
• If clinical response is adequate, no dose adjustment is needed even if levels are low-normal; conversely, if symptoms persist and testosterone is suboptimal, increase the dose. 3
• Once stable levels are achieved, monitor every 6–12 months with testosterone, hematocrit, and PSA (in men >40 years). 1, 3

Alternative Formulations

• Transdermal testosterone gel (1.62% at 40.5 mg daily or 1% at 50–100 mg daily) is preferred first-line due to more stable day-to-day levels and markedly lower erythrocytosis risk (15.4% vs. 43.8%). 1
• Testosterone undecanoate 750 mg initially, repeated at 4 weeks, then every 10 weeks provides the fewest injections with minimal fluctuation but requires gluteal administration only. 1
• Subcutaneous testosterone cypionate or enanthate 50–150 mg weekly is an effective alternative to intramuscular injection, achieving therapeutic levels across a wide BMI range with less discomfort and easier self-administration. 1, 5

Mandatory Monitoring

• Hematocrit must be checked at baseline and every 3–6 months during the first year, then annually; withhold therapy if hematocrit exceeds 54% and consider therapeutic phlebotomy in high-risk cases. 1, 3
• PSA and digital rectal examination are required in men >40 years at baseline and periodically; refer to urology if PSA rises >1.0 ng/mL in the first 6 months or >0.4 ng/mL per year thereafter. 1, 3
• Testosterone levels should be measured midway between injections—not at peak (days 2–5) or trough (days 13–14)—to avoid inappropriate dose adjustments. 1, 3

Critical Safety Considerations

• Injectable testosterone carries greater cardiovascular risk than transdermal preparations, possibly due to fluctuating levels and time spent in supraphysiologic and subtherapeutic ranges. 1
• Erythrocytosis occurs in approximately 44% of men receiving intramuscular testosterone, significantly higher than the 15% rate with transdermal formulations. 1, 3
• Elevated hematocrit increases blood viscosity and can exacerbate coronary, cerebrovascular, and peripheral vascular disease, particularly in elderly patients. 1, 3

Common Pitfalls to Avoid

• Do not draw testosterone levels at peak (days 2–5), as supraphysiologic values will prompt inappropriate dose reduction. 3
• Do not draw levels at trough (days 13–14), as low values may lead to unnecessary dose escalation. 3
• Do not continue full-dose testosterone when hematocrit exceeds 54%—this is an absolute indication to withhold therapy. 1, 3
• Do not initiate testosterone without confirming the patient does not desire fertility, as exogenous testosterone suppresses spermatogenesis and causes prolonged azoospermia. 1, 3

Expected Clinical Outcomes

• Testosterone therapy produces small but significant improvements in sexual function and libido (standardized mean difference 0.35). 1, 3
• There is little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition, even in confirmed hypogonadism. 1, 3
• Reevaluate at 12 months and discontinue if no improvement in sexual function is documented, to avoid unnecessary long-term exposure without benefit. 1, 3