Optimal Free Testosterone Levels for Adult Males
For adult males on testosterone replacement therapy, target mid-normal free testosterone levels of 0.2-0.6 nmol/L (approximately 5.8-17.3 ng/dL), with treatment goals aiming for the middle of this range rather than the extremes. 1
Understanding Free Testosterone Reference Ranges
Normal free testosterone ranges vary by age and measurement method:
- Healthy nonobese men (all ages): 66-309 pg/mL (229-1072 pmol/L or approximately 1.9-8.9 ng/dL) 2
- Young men (19-39 years): 120-368 pg/mL (415-1274 pmol/L or approximately 3.5-10.6 ng/dL) 2
- Clinical guideline reference: 0.2-0.6 nmol/L (5.8-17.3 ng/dL) for treatment monitoring 1
The discrepancy between these ranges reflects different measurement methodologies and populations studied. The most reliable method is equilibrium dialysis performed for 16 hours at 37°C using undiluted serum, which is considered the reference standard. 2
When to Measure Free Testosterone
Free testosterone measurement is essential in specific clinical scenarios, not as a routine first-line test:
- Men with borderline total testosterone levels (280-400 ng/dL) 1, 3
- Patients with obesity, where low SHBG may artificially lower total testosterone while free testosterone remains normal 1, 4
- Men with diabetes or metabolic syndrome 4
- Patients with cirrhosis (use free testosterone index: total testosterone/SHBG ratio <0.3) 1
Total testosterone between 280-350 ng/dL lacks sufficient sensitivity to reliably exclude hypogonadism, and levels must exceed 350-400 ng/dL to reliably predict normal free testosterone. 3
Treatment Targets During Testosterone Replacement Therapy
When monitoring patients on testosterone therapy, the American Urological Association recommends targeting mid-normal free testosterone levels within the 0.2-0.6 nmol/L range. 1 This corresponds to targeting mid-normal total testosterone levels of 500-600 ng/dL (17.3-20.8 nmol/L). 1, 4
Measurement timing is critical for accurate assessment:
- Draw morning samples between 8-10 AM on at least two separate occasions before initiating therapy 1, 4
- For injectable testosterone (cypionate/enanthate), measure levels midway between injections (days 5-7) 1, 4
- Initial monitoring at 2-3 months after treatment initiation or dose changes 1, 4
- Long-term monitoring every 6-12 months once stable 1, 4
Critical Diagnostic Thresholds
The diagnosis of hypogonadism requires both biochemical confirmation and clinical symptoms:
- Frankly low: Total testosterone <8 nmol/L (230 ng/dL) highly supports hypogonadism 5
- Gray zone: 8-12 nmol/L (230-346 ng/dL) requires free testosterone measurement 5
- Likely normal: >12 nmol/L (346 ng/dL) 5
However, total testosterone <280 ng/dL has 91% sensitivity but only 73.7% specificity for predicting low free testosterone, meaning many men with low total testosterone may have normal free testosterone. 3
Age-Related Decline and Clinical Context
Free testosterone exhibits expected age-related decline, with levels negatively associated with age, body mass index, and SHBG levels. 2 Percent free testosterone is lower in middle-aged and older men compared to young men, even after adjusting for SHBG levels. 2
A critical caveat: In men with near-normal total testosterone (250-350 ng/dL), there is no clear relationship between hypogonadal symptoms and free testosterone levels, and symptom-specific free testosterone thresholds cannot be reliably defined. 6 Age remains an important confounder in this population. 6
Monitoring Beyond Free Testosterone
Comprehensive monitoring during testosterone therapy must include:
- Hematocrit monitoring: Withhold treatment if >54% and consider phlebotomy in high-risk cases 1, 4
- PSA monitoring: For men over 40, refer for urologic evaluation if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 1, 4
- Clinical symptom response: Particularly sexual function and libido, which show the most reliable improvement (standardized mean difference 0.35) 1
Common Pitfalls to Avoid
Do not rely on free testosterone measurement alone without confirming low total testosterone on two separate morning measurements. 1, 7 Up to 25% of men receiving testosterone therapy do not meet diagnostic criteria for testosterone deficiency, and nearly half never have their levels checked after starting therapy. 7
Do not expect meaningful improvements in energy, mood, or physical function even with optimized free testosterone levels. The primary proven benefit is improvement in sexual function and libido, with minimal to no effect on physical functioning, depressive symptoms, energy, or cognition. 1, 4
In men with obesity-associated secondary hypogonadism, attempt weight loss through low-calorie diets and regular exercise before initiating testosterone therapy, as this can improve testosterone levels without medication. 4