Free vs Total Testosterone in Middle-Aged to Older Males
Key Diagnostic Difference
In middle-aged to older males with potential hypogonadism, free testosterone measurement is essential because total testosterone alone misses approximately 17-26% of cases where men have normal total testosterone but low free testosterone due to elevated sex hormone-binding globulin (SHBG), particularly in men over 60 years. 1, 2
Understanding the Biochemical Distinction
Total Testosterone
- Represents the sum of all testosterone in circulation: bound to SHBG (60-70%), bound to albumin (30-40%), and unbound/free (1-3%) 3
- Measured using standard immunoassays in most clinical laboratories 4
- Can be falsely reassuring in older men with elevated SHBG, who may have symptomatic hypogonadism despite "normal" total levels 1, 5
Free Testosterone
- Represents only the biologically active, unbound fraction available to tissues 3, 5
- Should be measured by equilibrium dialysis (gold standard) or calculated using total testosterone, SHBG, and albumin concentrations 4, 3
- More accurately reflects true androgen status, especially when SHBG is elevated 5, 2
Clinical Significance in Older Men
The SHBG Problem
- SHBG increases progressively with age, particularly after age 60 years 1, 2
- Among men over 60 presenting with erectile dysfunction, 52.5% have elevated SHBG and 26.3% have normal total testosterone with low free testosterone 1
- Elevated SHBG binds more testosterone, reducing the free fraction despite normal total levels 5
Missed Diagnoses with Total Testosterone Alone
- In men with sexual symptoms, total testosterone measurement alone misdiagnoses hypogonadism in 8.4% of cases 5
- The frequency of normal total testosterone with low free testosterone is 17.2% overall in men presenting with erectile dysfunction 1
- In men over 60 years specifically, this rises to 26.3% 1
When to Measure Free Testosterone
Primary Indications
- Morning total testosterone levels between 231-346 ng/dL (borderline range) - free testosterone confirms true hypogonadism in only 24.7% of these cases 3, 5
- Men over 60 years with hypogonadal symptoms - age-related SHBG elevation makes free testosterone essential 1, 2
- Obesity or diabetes - conditions associated with altered SHBG levels 4, 3
Measurement Method
- Free testosterone by equilibrium dialysis is the gold standard 4, 3
- Calculated free testosterone using the Vermeulen formula (requires total testosterone, SHBG, and albumin) is an acceptable alternative 4, 3, 2
- Direct immunoassay methods for free testosterone are unreliable and should be avoided 3
Diagnostic Thresholds
Total Testosterone
- Low testosterone defined as <300 ng/dL (some guidelines use 275-350 ng/dL) 3, 6
- Requires two separate morning measurements (8-10 AM) to confirm 4, 3
Free Testosterone
- Low free testosterone defined as <6.5 ng/dL (or <63 pg/mL depending on assay) 1, 5
- Correlates better with clinical symptoms than total testosterone 5, 2
Clinical Correlations
Free Testosterone Shows Stronger Associations
- Free testosterone levels correlate significantly with age, hematocrit, gonadotropins, BMI, erectile dysfunction, and low libido 5
- Total testosterone correlates only with BMI and low libido 5
- Free testosterone exhibits a clear negative correlation with age, while total testosterone does not 2
Practical Algorithm for Diagnosis
Step 1: Initial Screening
- Measure morning total testosterone (8-10 AM) on two separate occasions 4, 3
- If total testosterone <300 ng/dL → confirmed biochemical hypogonadism 3
- If total testosterone >346 ng/dL → hypogonadism unlikely (but consider free testosterone if age >60 years) 3, 1
Step 2: Borderline Cases (Total Testosterone 231-346 ng/dL)
- Always measure free testosterone by equilibrium dialysis or calculate using SHBG and albumin 4, 3
- Measure SHBG simultaneously to understand binding status 3, 5
- If free testosterone <6.5 ng/dL → confirmed hypogonadism despite borderline total testosterone 1, 5
Step 3: Special Populations Requiring Free Testosterone
- All men over 60 years with hypogonadal symptoms, regardless of total testosterone level 1
- Men with obesity (BMI >30) - increased aromatization and altered SHBG 3
- Men with diabetes - altered SHBG metabolism 4, 3
- Men with liver disease - elevated SHBG 4
Critical Pitfalls to Avoid
- Never rely on total testosterone alone in men over 60 years - you will miss 26.3% of cases with true biochemical hypogonadism 1
- Never use direct immunoassay methods for free testosterone - these are inaccurate and unreliable 3
- Never diagnose hypogonadism based on symptoms alone without biochemical confirmation - symptom questionnaires lack specificity 3
- Never assume borderline total testosterone (231-346 ng/dL) confirms hypogonadism - only 24.7% have low free testosterone 5
Treatment Implications
When Free Testosterone Clarifies Diagnosis
- Men with normal total testosterone but low free testosterone have symptomatic hypogonadism that warrants treatment consideration 1, 5
- These patients show similar clinical and biochemical parameters of androgen deficiency as those with low total testosterone 5
- Treatment decisions should be based on both biochemical confirmation (low free testosterone) and specific symptoms, particularly diminished libido and erectile dysfunction 3