Target Testosterone Serum Levels for Transgender Individuals on HRT

Transmasculine Hormone Therapy (Trans Men/Transmasculine Individuals)

• The American College of Physicians recommends target testosterone levels should be maintained within the typical cisgender male physiological range of 300-1,000 ng/dL, with trough levels measured immediately before the next scheduled dose 1, 2, 3
• Standard dosing aims for serum testosterone concentrations of 300-1,000 ng/dL, matching the cisgender male reference range 1, 2, 4, 5, 6
• The Endocrine Society suggests dose adjustments should target the mid-normal range to optimize safety and efficacy, although the specific strength of evidence for this recommendation is not provided 3
• Injectable testosterone esters are the most commonly used formulation, typically administered subcutaneously, with a moderate level of evidence supporting their efficacy and safety 1, 2
• Testosterone undecanoate, a long-acting injectable, should be used with caution due to the risk of pulmonary oil microembolism and anaphylaxis, based on high-quality evidence from multiple studies 1, 3
• Hematocrit/hemoglobin levels should be monitored, as testosterone commonly causes erythrocytosis, particularly with injectable formulations, with a high level of evidence supporting this association 3, 4, 5
• Lipid profiles should be monitored, as testosterone may increase triglycerides and LDL cholesterol while decreasing HDL, based on moderate-quality evidence 1, 3
• Blood pressure should be monitored, as testosterone may increase blood pressure, with a low to moderate level of evidence supporting this association 1, 3
• Bone density should be monitored, as inadequate testosterone dosing may negatively impact bone health, although the strength of evidence for this recommendation is not provided 3
• Smoking cessation and weight loss if BMI is elevated are recommended to mitigate the risk of erythrocytosis, based on high-quality evidence from multiple studies 1, 3
• Switching from injectable to transdermal route of administration may help mitigate the risk of erythrocytosis, with a moderate level of evidence supporting this strategy 1, 3

Transfeminine Hormone Therapy (Trans Women/Transfeminine Individuals)

• The Endocrine Society recommends that most individuals achieve testosterone concentrations in the cisgender female reference range through combination estradiol and anti-androgen therapy, with a high level of evidence supporting this approach 5, 6
• Peripheral androgen receptor antagonists, such as spironolactone and bicalutamide, may not necessarily lower testosterone concentrations despite blocking androgen effects, based on moderate-quality evidence 4, 5
• The Endocrine Society recommends avoiding ethinyl estradiol due to its association with higher VTE risk compared to bioidentical estradiol, with a high level of evidence supporting this recommendation 1, 2
• Progestins are not recommended by the Endocrine Society due to increased cardiovascular and breast cancer risk without proven benefit, based on high-quality evidence from multiple studies 2
• Testosterone therapy in trans men shows little to no impact on cardiovascular outcomes despite multiple metabolic risk factors, with a moderate level of evidence supporting this finding 1, 3
• Trans women have an elevated risk of VTE and cardiovascular events compared to cisgender populations, based on moderate-quality evidence 4

Sufficient Masculinization in Trans Males Despite Low Serum Testosterone

Primary Mechanisms Explaining This Phenomenon

• 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 7, 8
• 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 7

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 9
• Sex hormone-binding globulin (SHBG) levels significantly affect the interpretation of total testosterone; low SHBG results in low total testosterone but normal free testosterone 9
• Free testosterone by equilibrium dialysis should be measured when total testosterone appears inadequate despite clinical masculinization 9

Clinical Assessment Algorithm

Step 1: Verify Measurement Accuracy

• Measure free testosterone by equilibrium dialysis, not just total testosterone 9
• Assess SHBG levels to interpret total testosterone appropriately 9

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 9