What are the differences in trough levels and mid-cycle therapeutic ranges for testosterone in transgender males undergoing hormone therapy?

Testosterone Therapeutic Ranges for Transgender Males

For transgender males on testosterone therapy, trough levels should be maintained at 300-1,000 ng/dL (measured immediately before the next scheduled dose), while mid-cycle levels should target the mid-normal range of approximately 400-700 ng/dL to optimize both safety and efficacy. 1, 2, 3

Trough Level Targets

• Trough testosterone levels must be maintained between 300-1,000 ng/dL, representing the physiological range for cisgender males, as recommended by the American College of Physicians and Endocrine Society 1, 2, 3
• Trough measurements should be obtained immediately before the next scheduled testosterone dose to capture the lowest serum concentration in the dosing cycle 1, 3
• These trough targets apply regardless of testosterone formulation (injectable, transdermal gel, or patch), though timing of measurement varies by preparation 1

Mid-Cycle Therapeutic Ranges

• The Endocrine Society specifically recommends targeting the mid-normal range (approximately 400-700 ng/dL) to optimize safety and efficacy 2, 3
• Mid-cycle levels (Cavg) of 561 ng/dL (±259 ng/dL) were achieved in clinical trials with dose-adjusted testosterone therapy 4
• Peak levels (Cmax) should generally remain below 1,500 ng/dL to avoid supraphysiologic dosing and associated adverse effects 2, 4

Key Differences Between Trough and Mid-Cycle Monitoring

Trough levels serve as the primary safety threshold (ensuring adequate dosing without going subtherapeutic), while mid-cycle levels guide dose optimization (preventing supraphysiologic exposure that increases adverse effects without additional benefit) 1, 2, 3

When to Measure Each:

• Trough levels: Measure before the next dose for all formulations; this is the standard monitoring approach for dose adjustments 1, 3
• Mid-cycle levels: Useful when trough levels are adequate but clinical response is suboptimal, or when peak toxicity is suspected 4

Practical Dosing Algorithm Based on Levels

If Trough <300 ng/dL:

• Increase testosterone dose by one increment (typically 20.25 mg for gel formulations or adjust injection frequency/dose for injectables) 4
• Recheck trough level in 2-4 weeks 5

If Trough 300-1,000 ng/dL but <400 ng/dL:

• Consider modest dose increase if clinical masculinization is inadequate 2, 3
• Critical caveat: Check free testosterone and SHBG before increasing dose, as some individuals achieve adequate masculinization with lower total testosterone if free testosterone is normal 3

If Trough 400-700 ng/dL (Mid-Normal Range):

• Maintain current dose - this is the optimal target range 2, 3
• Continue routine monitoring every 3 months during first year, then every 6-12 months 5

If Trough >750 ng/dL or Mid-Cycle >1,500 ng/dL:

• Decrease dose to reduce risk of erythrocytosis, lipid abnormalities, and other adverse effects 2, 4
• Monitor hematocrit closely, as values >50% require dose reduction or temporary discontinuation 1, 2

Critical Monitoring Parameters Tied to Testosterone Levels

• Hematocrit/hemoglobin: Increases to male reference range within 3 months; erythrocytosis risk is dose-dependent and more common with injectable formulations 1, 2, 6
• Lipid profile: Testosterone may increase triglycerides and LDL while decreasing HDL, particularly at higher serum levels 1, 2
• Liver enzymes: Transient elevations possible; AST increased by mean of 4.3 U/L in studies 2, 6
• Blood pressure: May increase with testosterone therapy, requiring monitoring 1, 2

Common Pitfalls to Avoid

Do not increase testosterone dose based solely on low total testosterone if clinical masculinization is satisfactory - measure free testosterone by equilibrium dialysis and SHBG, as low SHBG can result in low total testosterone with adequate free testosterone 3

Avoid supraphysiologic dosing (trough >1,000 ng/dL or mid-cycle >1,500 ng/dL consistently) as this increases adverse effects without additional virilization benefit 2, 4

Do not use reference ranges for cisgender males or females for all laboratory values - while testosterone and SHBG can use cisgender male ranges, estradiol, LH, FSH, AMH, and DHEAS require transgender-specific reference intervals 7

Formulation-Specific Considerations

• Injectable testosterone esters (cypionate/enanthate): Most commonly used; measure trough immediately before next injection (typically every 1-2 weeks) 1, 5
• Transdermal preparations: More stable levels with less peak-trough variation; may reduce erythrocytosis risk compared to injectables 1, 2
• Testosterone undecanoate: Long-acting injectable; use with caution due to pulmonary oil microembolism and anaphylaxis risk 1, 3

Timeline for Dose Adjustments

• Initial dose titration should occur at Days 14,28, and 42 after starting therapy based on trough levels 4
• After achieving stable dosing, monitor every 3 months during the first year 5
• Once stable on therapy for >1 year, monitoring can extend to every 6-12 months 5
• Maximum virilization effects typically achieved after 3-5 years of therapy, though most changes occur within 6 months 5