What is the significance of total prostate-specific antigen (PSA) and free PSA levels, and how are they interpreted in men over 50?

Understanding Total PSA and Free PSA Levels

Total PSA measures all forms of prostate-specific antigen in blood (both free and protein-bound), while free PSA measures only the unbound fraction; the free-to-total PSA ratio (percent free PSA) is FDA-approved to distinguish prostate cancer from benign conditions in men with total PSA 4–10 ng/mL, with a ratio ≤25% indicating higher cancer risk and warranting biopsy. 1

What is Total PSA?

Total PSA represents the sum of all molecular forms of PSA circulating in the blood 2:

• 60–90% is bound to protease inhibitors, primarily alpha-1-antichymotrypsin (PSA-ACT complex) 1, 3
• 5–40% circulates as free (unbound) PSA 1, 3
• A small fraction is bound to alpha-2-macroglobulin, but this cannot be measured by conventional assays because the PSA antigenic sites are "caged" by the protein 1

Total PSA is not cancer-specific—it is elevated by prostate cancer, benign prostatic hyperplasia (BPH), prostatitis, recent ejaculation, urinary catheterization, and prostate trauma 4, 3.

What is Free PSA?

Free PSA is the fraction of PSA that circulates unbound to any protease inhibitor 1. Men with prostate cancer have significantly lower percentages of free PSA compared to men with benign prostatic conditions 1, 5.

Clinical Interpretation: The Free-to-Total PSA Ratio

The percent free PSA (%fPSA = [free PSA ÷ total PSA] × 100) is the key diagnostic tool 1:

FDA-Approved Indication

• Approved for men with total PSA 4–10 ng/mL (the "diagnostic gray zone") to differentiate cancer from benign disease 1
• A 25% cutoff detects 95% of prostate cancers while avoiding 20% of unnecessary biopsies 1

Risk Stratification by Percent Free PSA 6

%Free PSA	Cancer Risk	Recommended Action
<10%	High risk (>30% probability)	Strongly recommend immediate biopsy
10–15%	Intermediate-high risk	Biopsy preferred
15–25%	Intermediate risk	Individualize decision; consider PSA velocity and other factors
>25%	Low risk	Consider annual surveillance (repeat PSA, DRE) instead of immediate biopsy

Practical Algorithm for Total PSA 4–10 ng/mL 6

1. Measure free/total PSA ratio before any biopsy decision
2. If ratio <10% → Proceed directly to prostate biopsy
3. If ratio 10–25% → Calculate PSA velocity (if ≥3 values over 18 months available); if velocity >0.75 ng/mL/year, proceed to biopsy 1, 6
4. If ratio >25% → Offer annual surveillance with repeat PSA and digital rectal examination

Critical Pre-Test Considerations

Rule out prostatitis first 4, 6:

• Prostatitis causes dramatic PSA elevations that can confound interpretation 1, 4
• Treat empirically with antibiotics if suspected
• Recheck PSA 4–6 weeks after complete symptom resolution 4

Avoid confounding factors 4:

• Wait ≥2 weeks (preferably 6–8 weeks) after ejaculation, urinary catheterization, or prostate manipulation before testing 4
• Use the same laboratory and assay for serial measurements—different assays are not interchangeable 4, 7, 8

Account for medications 4:

• 5α-reductase inhibitors (finasteride, dutasteride) reduce PSA by approximately 50% after 6–12 months 4, 6

Common Pitfalls to Avoid

• Do not ignore the free PSA ratio in the 4–10 ng/mL range—it is the single best tool to reduce unnecessary biopsies while maintaining cancer detection 1, 6
• Do not use a single PSA measurement to make decisions—confirm elevation with repeat testing using the same laboratory 4, 6
• Do not proceed to biopsy without first excluding prostatitis—men with very high PSA velocity are more likely to have prostatitis than cancer 1, 4
• Do not apply the free PSA ratio to men with total PSA >10 ng/mL—these men should proceed directly to biopsy regardless of the ratio 6
• Do not forget digital rectal examination—any palpable abnormality mandates biopsy regardless of PSA level 6

PSA Velocity as an Adjunct

PSA velocity (rate of change over time) enhances interpretation 1, 6:

• Requires ≥3 measurements over 18–24 months 1, 6
• >0.75 ng/mL/year is suspicious for cancer when baseline PSA is 4–10 ng/mL 1, 6
• >0.35 ng/mL/year predicts high-risk cancer 10–20 years before diagnosis 1, 6
• Most useful in younger men (<50 years) who have less benign prostatic enlargement 1, 6