What is the target serum total testosterone range for replacement therapy in adult men with documented hypogonadism?

Target Serum Total Testosterone Range for Replacement Therapy

For adult men with documented hypogonadism receiving testosterone replacement therapy, target mid-normal serum total testosterone concentrations of 450–600 ng/dL, measured at the appropriate time relative to dosing. 1, 2, 3

Therapeutic Target Range

• The goal is to achieve total testosterone levels in the middle tertile of the normal reference range (450–600 ng/dL), which optimizes clinical response while minimizing adverse effects such as erythrocytosis. 1, 3

• The broader acceptable physiologic range is 300–1,000 ng/dL, but targeting mid-normal values (450–600 ng/dL) is strongly preferred over aiming for upper-normal concentrations. 1, 3

• Use the minimal dosing necessary to drive testosterone levels into this 450–600 ng/dL target range; supraphysiologic levels (>1,000 ng/dL) markedly increase the risk of erythrocytosis and other adverse events. 1, 2

Timing of Testosterone Measurement by Formulation

Injectable Testosterone (Enanthate or Cypionate)

• Measure serum testosterone midway between injections (e.g., days 5–7 for weekly dosing or days 7–10 for bi-weekly dosing), targeting 500–600 ng/dL at this midpoint. 1, 2, 3

• Peak serum levels occur 2–5 days after injection and often transiently exceed the upper limit of normal; measuring at the peak will show supraphysiologic levels that do not reflect average exposure and may lead to inappropriate dose reduction. 1, 2

• Testosterone returns to baseline by days 10–14 after injection; measuring at the trough may show falsely low levels and prompt unnecessary dose escalation. 1, 2

Transdermal Testosterone (Gel or Patch)

• Levels can be measured at any time after 2–3 months of stable therapy, as transdermal preparations provide more consistent day-to-day testosterone concentrations compared with injectable formulations. 1, 3

• Peak values occur approximately 6–8 hours after gel application, but the relatively stable pharmacokinetics make timing less critical than with injectables. 3

Oral Testosterone Undecanoate

• Measure testosterone levels 4–6 hours after the morning dose to capture representative steady-state concentrations; target the same mid-normal range of 450–600 ng/dL. 1

Monitoring Schedule

• Initial assessment at 2–3 months after treatment initiation or any dose change to confirm that target levels (450–600 ng/dL) are being achieved. 1, 2, 3

• Repeat every 3–6 months during the first year to ensure stability and assess for adverse effects (hematocrit, PSA). 1, 2

• Once stable levels are confirmed on a given dose, monitoring every 6–12 months is typically sufficient for long-term management. 1, 2, 3

Dose Adjustment Algorithm

• If clinical response is adequate and testosterone is 450–600 ng/dL, no dose adjustment is needed even if the level is in the low-normal range. 1, 2

• If clinical response is suboptimal AND testosterone levels are low-normal or below target, increase the dose and recheck in 2–3 months. 1, 2

• If testosterone exceeds 1,000 ng/dL (supraphysiologic), reduce the dose by approximately 50 % to minimize erythrocytosis risk and recheck in 2–3 months. 1, 2

• If maximal recommended transdermal doses fail to achieve adequate serum testosterone (≥450 ng/dL), consider switching to intramuscular injection therapy for more reliable absorption. 1, 2

Clinical Outcomes and Expectations

• Testosterone therapy produces a small but statistically significant improvement in sexual function and libido (standardized mean difference ≈0.35) when target levels are achieved. 1

• There is little to no clinically meaningful effect on energy, vitality, physical functioning, depressive symptoms, or cognition, even when testosterone is normalized to 450–600 ng/dL. 1

• If the patient experiences no improvement in sexual function after 12 months despite achieving target testosterone levels, discontinue therapy to avoid unnecessary long-term exposure to potential risks without benefit. 1

Safety Thresholds and Monitoring

• Hematocrit must be checked at every follow-up visit; withhold testosterone if hematocrit exceeds 54 % and consider therapeutic phlebotomy in high-risk patients. 1, 2

• Injectable testosterone carries a markedly higher erythrocytosis risk (≈44 % of users) compared with transdermal preparations (≈15 %), largely due to supraphysiologic peak levels. 1, 2

• In men ≥40 years, monitor PSA at baseline and periodically during treatment; refer to urology if PSA rises >1.0 ng/mL within the first 6 months or >0.4 ng/mL per year thereafter. 1, 2

Common Pitfalls to Avoid

• Do not measure testosterone at the peak (days 2–5 post-injection), as supraphysiologic levels do not reflect average exposure and will lead to inappropriate dose reductions. 1, 2

• Do not measure at the trough (days 13–14 post-injection), as levels may have returned to baseline or below, prompting unnecessary dose escalation. 1, 2

• Do not target upper-normal testosterone levels (>700 ng/dL), as this increases adverse event risk without additional clinical benefit. 1, 2

• Do not continue therapy if sexual function has not improved after 12 months, even if testosterone levels are normalized, as the primary indication for treatment is sexual dysfunction. 1