What is the next step in managing a patient with low free testosterone levels despite normal total testosterone levels?

Management Recommendation

This patient meets criteria for testosterone deficiency based on persistently low free testosterone levels (3.0 and 3.8 pg/mL, both well below the normal range of 6.6-18.1 pg/mL) despite borderline-normal total testosterone, and should be initiated on testosterone replacement therapy after appropriate counseling and baseline assessments. 1

Diagnostic Confirmation

This patient has confirmed testosterone deficiency with two separate measurements showing:

• Total testosterone levels that are borderline-low (316 and 391 ng/dL, with 300 ng/dL being the typical diagnostic threshold) 2
• Persistently low free testosterone (3.0 and 3.8 pg/mL) that is approximately 50% below the lower limit of normal, which is the more clinically relevant measurement 3

The discordance between borderline-normal total testosterone and clearly low free testosterone suggests low sex hormone-binding globulin (SHBG), commonly seen with obesity, insulin resistance, or metabolic syndrome. 4

Pre-Treatment Mandatory Assessments

Before initiating testosterone therapy, the following must be completed:

• Measure PSA in this 66-year-old patient to exclude occult prostate cancer; if elevated, obtain a second confirmatory PSA before proceeding 1
• Measure baseline hemoglobin/hematocrit; withhold therapy if Hct exceeds 50% until etiology is investigated 1
• Assess cardiovascular risk factors including dyslipidemia, hypertension, diabetes, and smoking status 1
• Counsel regarding fertility: exogenous testosterone will suppress spermatogenesis and cause oligospermia or azoospermia, though this is less relevant for a 66-year-old 1, 5

Required Patient Counseling

Cardiovascular risk counseling is mandatory: inform the patient that current evidence cannot definitively state whether testosterone therapy increases or decreases cardiovascular events (myocardial infarction, stroke, cardiovascular death), though untreated low testosterone is associated with increased cardiovascular risk. 1

Additional counseling points:

• Lifestyle modifications (weight loss, increased physical activity) can increase testosterone levels and should be implemented concurrently with therapy 1
• Expected benefits include improvements in erectile function, libido, anemia, bone mineral density, lean body mass, and depressive symptoms 1
• Instruct patient to report chest pain, shortness of breath, dizziness, or loss of consciousness during follow-up 1

Treatment Initiation Strategy

Target testosterone levels to the middle tertile of normal range (450-600 ng/dL) using minimal effective dosing. 1, 6

Formulation selection considerations:

• Intramuscular injections avoid absorption variability and may be more reliable for patients with metabolic factors affecting SHBG 6
• Transdermal preparations (gels/patches) show variable absorption, particularly in patients with obesity or rapid metabolism 6
• Never prescribe 17-alpha-alkylated oral testosterone given availability of safer alternatives 1

Monitoring Protocol

Recheck testosterone levels 2-3 months after initiation to allow steady-state levels:

• For injectable testosterone, measure midway between injections, targeting 500-600 ng/dL 6
• Measure both total and free testosterone 6
• If Hct exceeds 54% on therapy, reduce dose or temporarily discontinue; injectable testosterone carries the highest risk of polycythemia 1

Once stable testosterone levels achieved:

• Monitor every 6-12 months with testosterone levels and symptom assessment 6
• Continue PSA monitoring using shared decision-making approach per AUA Early Detection guidelines 1

Critical Contraindications and Timing Considerations

Do not initiate testosterone if the patient:

• Is actively trying to conceive 1
• Has had a cardiovascular event within the past 3-6 months 1
• Has Hct >50% at baseline 1

Addressing Underlying Metabolic Factors

Given the pattern of low free testosterone with borderline-normal total testosterone:

• Aggressively address obesity, insulin resistance, and metabolic syndrome as these lower SHBG and increase testosterone clearance 4
• Weight loss can significantly increase SHBG levels and improve the free testosterone ratio 4
• These interventions should be concurrent with, not instead of, testosterone therapy 1

If Inadequate Response After Dose Optimization

If symptoms persist despite achieving target testosterone levels (450-600 ng/dL), or if testosterone remains low despite dose escalation:

• Reassess for factors lowering SHBG: obesity, insulin resistance, liver disease, hypothyroidism 6
• Consider measuring LH and FSH to distinguish primary from secondary hypogonadism if not previously done 6
• Stop testosterone therapy if patient achieves target levels but has no symptomatic improvement, as continued therapy is not indicated 1