Target Free Testosterone Levels for Adult Males on Testosterone Replacement Therapy
Your Understanding is Correct
You are absolutely right—the normal reference range for free testosterone is typically 0.2-0.6 nmol/L (approximately 5.8-17.3 ng/dL), and treatment targets should aim for mid-normal values within this range, not the higher total testosterone values often discussed. 1
The confusion arises because most clinical guidelines and studies primarily reference total testosterone levels rather than free testosterone when discussing treatment targets and diagnostic thresholds.
Understanding the Different Testosterone Measurements
Total Testosterone vs. Free Testosterone
- Total testosterone includes both protein-bound (to SHBG and albumin) and free testosterone, with normal ranges typically cited as 10.4-35 nmol/L (300-1000 ng/dL) 2
- Free testosterone represents only the unbound, biologically active fraction (approximately 2-3% of total), with normal ranges of 0.2-0.6 nmol/L or 5.8-17.3 ng/dL 1, 3
- Bioavailable testosterone includes free testosterone plus albumin-bound testosterone 2
When to Measure Free Testosterone
- Free testosterone by equilibrium dialysis should be measured in men with borderline total testosterone levels, particularly those with obesity, as SHBG alterations can affect total testosterone without true hypogonadism 1, 3
- Men with obesity and low total testosterone due solely to low SHBG typically have normal free testosterone levels and do not require testosterone replacement 3
- Free testosterone measurement is essential when total testosterone falls in the "grey zone" between 8-12 nmol/L (231-346 ng/dL) 4
Treatment Targets During Testosterone Replacement Therapy
For Total Testosterone Monitoring
- Target mid-normal total testosterone levels of 500-600 ng/dL (17.3-20.8 nmol/L) during treatment 1, 3
- Most trials enrolled men with baseline total testosterone ≤10.4 nmol/L (300 ng/dL), with some using even lower thresholds of <9.54 nmol/L (275 ng/dL) 2
- For injectable testosterone (cypionate/enanthate), measure levels midway between injections (days 5-7), targeting these mid-normal values 1
For Free Testosterone Monitoring
- When monitoring free testosterone specifically, target mid-normal free testosterone levels within the 0.2-0.6 nmol/L range 1, 3
- Free testosterone by equilibrium dialysis on at least two separate morning measurements (8-10 AM) should confirm frankly low levels before initiating therapy 3
- In men with cirrhosis, use free testosterone index (total testosterone/SHBG ratio <0.3) to define hypogonadism 1
Clinical Context for Mental Health Disorders
Expected Psychiatric Benefits Are Minimal
- Testosterone therapy produces only minimal improvements in depressive symptoms with a standardized mean difference of -0.19, which is considered "less-than-small" 2
- Critically, most men in these trials did not have baseline depression, limiting applicability to psychiatric populations 2
- No differences were found in cognitive function across multiple studies using various assessment scales 2
- Energy and vitality improvements are barely distinguishable from placebo (SMD 0.17), with effect sizes too small to be clinically meaningful 2, 1
Primary Indication Remains Sexual Function
- The primary proven benefit of testosterone therapy is improvement in sexual function and libido (SMD 0.35), not mood or energy 2
- If your patient lacks sexual symptoms as the primary complaint, realistic expectations must be set that improvements in mood, energy, or cognition are unlikely to be substantial 1
Association Between Hypogonadism and Depression
- Observational data shows hypogonadal men have increased incidence of diagnosed depression (21.7% vs 7.1% over 2 years) with an adjusted hazard ratio of 4.2 5
- Low testosterone levels (<2.5 ng/mL or approximately 0.07 nmol/L free testosterone) predict incident depression, particularly in men aged 50-65 with high medical morbidity 6
- However, treatment trials have not consistently demonstrated that testosterone repletion improves depressive symptoms, suggesting the relationship may be correlational rather than causal 7
Monitoring Algorithm
Initial Monitoring (First 3 Months)
- Measure testosterone levels at 2-3 months after treatment initiation or any dose change 1, 3
- For injectable testosterone, measure midway between injections 1
- Monitor hematocrit—withhold treatment if >54% and consider phlebotomy in high-risk cases 1, 3
Long-Term Monitoring (After Stabilization)
- Once stable levels are confirmed, monitoring every 6-12 months is typically sufficient 1, 3
- Continue periodic hematocrit monitoring throughout treatment 1, 3
- For men over 40, monitor PSA levels with urologic referral if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 1
Critical Pitfall to Avoid
Do not assume that achieving higher testosterone levels will produce better psychiatric outcomes. The evidence shows that even with confirmed biochemical hypogonadism and appropriate testosterone replacement achieving mid-normal levels, improvements in mood, energy, and cognition remain minimal at best 2, 1. The target should be physiologic replacement to mid-normal ranges (whether measuring total or free testosterone), not supraphysiologic levels, as higher levels increase risks without additional psychiatric benefit.