Can Testosterone Cause Elevated PSA?
Yes, testosterone replacement therapy (TRT) does cause modest increases in PSA levels, but the typical rise is small (0.30-0.43 ng/ml) and clinically significant elevations warrant investigation for prostate cancer. 1
Expected PSA Changes with TRT
PSA levels do increase with testosterone therapy, but the magnitude matters critically. A meta-analysis demonstrates that men on TRT have statistically higher PSA levels than controls, with a mean difference of 0.154 ng/ml, though this increase is minimal and clinically insignificant in most cases. 2
The route of administration affects PSA response: intramuscular testosterone produces the greatest PSA elevation (mean difference 0.271 ng/ml), while transdermal patches yield the smallest increase. 3, 2
Endogenous testosterone elevation (via clomiphene stimulation) raises PSA levels more than exogenous testosterone administration. 3
Critical Thresholds Requiring Action
Any PSA increase of ≥1.0 ng/ml per year on TRT mandates prostate biopsy, as recommended by the American College of Physicians and other guidelines. 1
The New England Journal of Medicine specifically recommends biopsy for PSA increases of 0.7-0.9 ng/ml, with repeat measurement in 3-6 months and biopsy if any further increase occurs. 1
For men on long-term TRT (≥2 years), a PSA velocity >0.4 ng/ml per year should trigger urologic evaluation and consideration for repeat biopsy. 1, 4
The Hypogonadism-Prostate Cancer Paradox
PSA levels are inappropriately low in hypogonadal men and may mask underlying cancer. 3 This creates a diagnostic challenge:
Among hypogonadal men with normal PSA and digital rectal exam who underwent prostate biopsy before starting TRT, 14% had occult prostate cancer (median age 64 years). 5
In one study of 96 hypogonadal men undergoing biopsy, 47.5% of those not on TRT had prostate cancer, with many being high-grade tumors. 6
The prostate cancer detection rate in TRT trials is only approximately 1%, similar to general population screening rates, despite the high prevalence of occult disease in hypogonadal men. 5, 7
Clinical Algorithm for PSA Monitoring
Baseline assessment before TRT:
- Obtain PSA and digital rectal exam; any abnormality requires biopsy before initiating therapy. 1
- Men with family history of prostate cancer require lower thresholds for biopsy. 1
During TRT:
- Monitor PSA every 3-6 months initially, then every 6-12 months if stable. 5, 8
- Discontinue TRT and perform biopsy if PSA rises ≥1.0 ng/ml in the first year or >0.4 ng/ml per year thereafter. 1, 4
Important Caveats
No men with initial PSA rise on TRT had cancer in one study, but men on long-term TRT (≥2 years) who underwent biopsy had a 24% cancer rate. 6 This suggests early PSA rises may reflect physiologic response, while sustained elevations warrant concern.
Prostate volume increases significantly during the first six months of TRT to levels equivalent to eugonadal men, but this does not correlate with urinary symptoms or cancer risk. 5
In men without prostate cancer, PSA levels remain stable for at least 5 years on TRT, with no significant increases at yearly intervals. 8
Among men who developed prostate cancer on TRT, the mean PSA increase was 1.8 ng/ml at 18 months and 3.2 ng/ml at 36 months—substantially higher than the typical 0.30-0.43 ng/ml increase. 1, 8