What causes sufficient masculinization in trans males despite low serum testosterone levels during testosterone (hormone replacement therapy)?

Sufficient Masculinization Despite Low Serum Testosterone in Trans Males

When trans males achieve adequate masculinization despite low serum testosterone levels, the most likely explanations are increased androgen receptor sensitivity, adequate free testosterone despite low total testosterone, timing of blood draws relative to dosing (trough vs peak levels), or individual variation in tissue response to androgens.

Primary Mechanisms Explaining This Phenomenon

Androgen Receptor Sensitivity and Tissue Response

• Individual variation in androgen receptor sensitivity can result in adequate masculinization even with lower circulating testosterone levels, as tissue-level androgen effects depend on receptor density and responsiveness rather than serum levels alone 1
• The organizational effects of androgens on target tissues may be sufficient at lower concentrations in some individuals, particularly when therapy is initiated during younger ages 1

Free vs Total Testosterone Considerations

• Low total testosterone with normal free testosterone is a critical distinction - many individuals with low total testosterone have adequate free (bioavailable) testosterone that drives masculinization 1
• Sex hormone-binding globulin (SHBG) levels significantly affect the interpretation of total testosterone; low SHBG (common in obesity or metabolic conditions) results in low total testosterone but normal free testosterone 1
• Free testosterone by equilibrium dialysis should be measured when total testosterone appears inadequate despite clinical masculinization 1

Timing and Pharmacokinetic Factors

• Trough levels measured immediately before the next dose may be misleadingly low while peak levels achieved shortly after administration drive masculinization 2
• The American College of Physicians recommends target testosterone levels of 300-1,000 ng/dL with trough levels measured before the next scheduled dose, but clinical effects depend on the entire dosing interval 2
• Injectable testosterone formulations create significant peak-to-trough variation; patients may experience adequate masculinization from peak levels even when trough measurements are suboptimal 2, 3

Clinical Assessment Algorithm

Step 1: Verify Measurement Accuracy

• Confirm testosterone was drawn at trough (immediately before next dose) for injectable formulations 2
• Measure free testosterone by equilibrium dialysis, not just total testosterone 1
• Assess SHBG levels to interpret total testosterone appropriately 1

Step 2: Evaluate Clinical Masculinization

• Document specific masculinizing effects achieved: cessation of menses, facial/body hair growth, voice deepening, clitoromegaly, muscle mass changes, and body fat redistribution 4, 3
• Both testosterone enanthate and testosterone undecanoate produce desired masculinizing effects even with varying serum levels throughout the dosing interval 3

Step 3: Consider Metabolic Factors

• Body mass index inversely correlates with testosterone levels; higher BMI may result in lower measured testosterone but adequate tissue effects 5
• Increased aromatization in adipose tissue converts testosterone to estradiol, but this does not prevent masculinization and estradiol levels remain in normal male range 5

Management Decisions

When to Maintain Current Therapy

• If clinical masculinization is satisfactory and free testosterone is adequate, do not increase dosing based solely on low total testosterone 1, 2
• Monitor for adequate suppression of menses, progressive virilization, and patient satisfaction with physical changes 4, 3
• Ensure hemoglobin/hematocrit remain within safe ranges, as erythrocytosis indicates adequate androgen effect 2, 6, 3

When to Adjust Therapy

• If free testosterone is truly low and masculinization is inadequate, increase testosterone dose to achieve mid-normal male range (300-1,000 ng/dL) 2
• Consider switching from injectable to transdermal formulations if peak-trough variation is problematic, though this may reduce erythrocytosis risk 2, 6
• Testosterone undecanoate requires fewer injections (6 vs 18 annually) with similar efficacy, potentially improving adherence 3

Important Caveats

Monitoring Considerations

• Hemoglobin and hematocrit typically increase to male reference range within 3 months, serving as a biomarker of adequate androgen effect 6, 3
• Lipid changes (increased LDL and triglycerides, decreased HDL) occur with adequate testosterone therapy regardless of specific serum levels 2, 6, 3
• Estradiol levels decrease significantly with testosterone therapy and remain in normal male range; aromatase inhibitors are unnecessary 5

Common Pitfalls to Avoid

• Do not reflexively increase testosterone dosing based on low trough levels if clinical masculinization is adequate - this increases risks of erythrocytosis and cardiovascular effects without additional benefit 2, 6
• Do not interpret total testosterone in isolation without measuring free testosterone and SHBG 1
• Do not assume inadequate dosing when blood draws are not properly timed relative to injection schedule 2