Diagnosing Hypogonadism: Both Total and Free Testosterone Should Be Measured
For diagnosing hypogonadism in adult males, you should measure both total testosterone AND free testosterone (by equilibrium dialysis or calculation), particularly when total testosterone is borderline (280-400 ng/dL) or in men with obesity, diabetes, or conditions affecting sex hormone-binding globulin (SHBG). 1
Why Both Tests Are Essential
Total Testosterone Alone Misses Many Cases
- 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 2
- In men presenting with erectile dysfunction, 17.2% have normal total testosterone but low free testosterone, meaning they would be misdiagnosed if only total testosterone were checked 3
- Among men over 60 years with erectile dysfunction, 26.3% have normal total testosterone but low calculated free testosterone, primarily due to elevated SHBG with aging 3
- Total testosterone measurement misdiagnoses hypogonadism in 8.4% of men with sexual symptoms when free testosterone is not assessed 4
Free Testosterone Provides Superior Diagnostic Accuracy
- Free testosterone correlates better with clinical symptoms of androgen deficiency (age, erectile dysfunction, low libido, hematocrit, BMI) compared to total testosterone, which only correlates with BMI and low libido 4
- In men with borderline total testosterone levels, only 24.7% actually have confirmed hypogonadism when free testosterone is measured, preventing unnecessary treatment 4
- Measuring free testosterone by equilibrium dialysis is essential in men with obesity, as they frequently have low total testosterone due solely to low SHBG while maintaining normal free testosterone levels 1
The Diagnostic Algorithm
Step 1: Initial Morning Testing (8-10 AM)
- Draw morning total testosterone between 8 AM and 10 AM on two separate occasions to confirm persistent hypogonadism, as single measurements are insufficient due to assay variability 1, 5
- Simultaneously measure free testosterone by equilibrium dialysis AND sex hormone-binding globulin, especially in men with obesity, diabetes, or age >60 years 1, 5
- Normal total testosterone range is 300-800 ng/dL, with hypogonadism defined as <300 ng/dL (some guidelines use <275-350 ng/dL) 1, 5
Step 2: Interpret Results Based on Clinical Context
If total testosterone is clearly low (<280 ng/dL):
- Free testosterone measurement still adds value, as 91% sensitivity means 9% of cases could still have normal free testosterone 2
- Proceed with hypogonadism workup if free testosterone confirms deficiency 1
If total testosterone is borderline (280-400 ng/dL):
- Free testosterone measurement is mandatory, as total testosterone in this range is not sensitive enough to exclude hypogonadism 2, 3
- This is the most critical scenario where free testosterone changes management 4
If total testosterone is normal (>400 ng/dL) but symptoms persist:
- Still measure free testosterone in men >60 years, those with obesity, diabetes, or elevated SHBG, as up to 17-26% may have low free testosterone despite normal total testosterone 3, 6
Step 3: Confirm Type of Hypogonadism
- If testosterone levels are subnormal on repeat testing, measure serum LH and FSH to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism 1, 5
- Low or low-normal LH/FSH with low testosterone indicates secondary hypogonadism 5
- Elevated LH/FSH with low testosterone indicates primary hypogonadism 5
Critical Populations Requiring Free Testosterone
Men with Obesity
- Obesity causes low SHBG, which artificially lowers total testosterone while free testosterone may remain normal 1
- Increased aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback, suppressing pituitary LH secretion 1
- Free testosterone by equilibrium dialysis is essential to distinguish true hypogonadism from low SHBG-related decreases 1, 5
Men Over 60 Years
- Aging increases SHBG levels, creating discordance between total and free testosterone 3
- 52.5% of men over 60 have elevated SHBG, and 26.3% have normal total testosterone but low free testosterone 3
- Current guidelines that rely solely on total testosterone miss over one-quarter of hypogonadal men in this age group 3
Men with Diabetes
- In men with diabetes who have symptoms of hypogonadism, measure both morning total testosterone AND free or bioavailable testosterone when total testosterone is near the lower limit of normal 1, 5
- Free testosterone measurement is particularly important as diabetes affects SHBG levels 1
Common Pitfalls to Avoid
- Never diagnose or exclude hypogonadism based on total testosterone alone when levels are 280-400 ng/dL, as this range has poor sensitivity and specificity 2, 3
- Never skip free testosterone measurement in men over 60 years presenting with sexual dysfunction, as aging dramatically increases the prevalence of normal total/low free testosterone 3
- Never use analog immunoassay methods for free testosterone measurement—only equilibrium dialysis or calculated free testosterone (using total testosterone, SHBG, and albumin) are reliable 1
- Never assume obesity-related low total testosterone represents true hypogonadism without confirming low free testosterone, as many obese men have normal free testosterone despite low total testosterone 1
Treatment Implications
- Treatment with testosterone replacement should only be considered when morning free testosterone by equilibrium dialysis is frankly low on at least 2 separate assessments 1
- Men with low total testosterone but normal free testosterone due to low SHBG should not receive testosterone therapy 1
- In men with confirmed low free testosterone, testosterone replacement produces small but significant improvements in sexual function (standardized mean difference 0.35), but little to no effect on physical functioning, energy, vitality, or cognition 5