What are the next steps for a man with hypogonadism on testosterone cypionate (testosterone cypionate) with a rising Prostate-Specific Antigen (PSA) level from 2.01 to 4.5 over the past year, two Prostate Imaging-Reporting and Data System (PI-RADS) lesions on prostate Magnetic Resonance Imaging (MRI), a prostate volume of 70.4 and a PSA density of 0.06?

Management of Rising PSA in a Man on Testosterone Replacement Therapy

You should immediately discontinue testosterone cypionate and proceed with prostate biopsy given the significant PSA rise (2.01 to 4.5 ng/mL over one year) and presence of two PI-RADS lesions on MRI. 1, 2

Immediate Actions Required

Discontinue Testosterone Therapy

• Stop testosterone cypionate immediately due to the substantial PSA increase of >1.0 ng/mL in one year, which meets the threshold for prostate biopsy consideration 3, 1
• The FDA label for testosterone cypionate explicitly warns that "geriatric patients treated with androgens may be at an increased risk of developing prostatic hypertrophy and prostatic carcinoma" 2
• PSA levels are inappropriately low in hypogonadal men and may mask underlying cancer; testosterone replacement unmasks this by raising PSA to more accurate levels 4

Proceed with Prostate Biopsy

• Transrectal ultrasound-guided biopsy with at least 10-12 core samples is mandatory given the combination of rising PSA and PI-RADS lesions 5
• The presence of two PI-RADS lesions on MRI significantly increases cancer probability, even though your PSA density of 0.06 is relatively low 5
• Do not delay biopsy based on a single favorable parameter (PSA density); the constellation of findings (rapid PSA rise + MRI lesions) demands tissue diagnosis 1

Understanding the Clinical Context

PSA Rise Significance

• Your PSA velocity of approximately 2.5 ng/mL per year far exceeds the concerning threshold of ≥0.75 ng/mL per year 5
• A PSA of 4.5 ng/mL falls in the 4.0-10.0 ng/mL range where approximately 25-30% of men harbor prostate cancer 5
• Research demonstrates that patients with PSA <4 ng/mL who experience approximately 20% increases in subsequent PSA measurements have significantly increased prostate cancer risk (adjusted HR = 2.94) 6

Testosterone-PSA Relationship

• While testosterone therapy can modestly increase PSA as a physiologic effect, an increase of >1.0 ng/mL in one year exceeds expected physiologic changes and warrants biopsy 3, 1
• The recommendation to perform biopsy for PSA increases ≥1.0 ng/mL in one year applies specifically to men on testosterone therapy 3
• Your PSA rise of 2.49 ng/mL over one year is more than double this threshold 3, 1

Post-Biopsy Management Algorithm

If Biopsy is Negative

• Maintain testosterone discontinuation for at least 3-6 months 1
• Repeat PSA measurement after testosterone washout to establish new baseline 3, 1
• If PSA remains elevated or continues rising despite testosterone cessation, consider PSMA-PET/CT scan for higher sensitivity detection of small cancer foci 5
• Testosterone levels should be measured to confirm adequate washout (typically returns to baseline within 3-6 months after cessation) 3

If Biopsy Confirms Cancer

• Treatment options depend on cancer grade and stage, including radical prostatectomy, radiation therapy, or active surveillance for low-risk disease 5
• Testosterone therapy is absolutely contraindicated if prostate cancer is diagnosed 2
• The FDA label lists "carcinoma of the prostate" as a contraindication to testosterone cypionate use 2

Critical Pitfalls to Avoid

Do Not Continue Testosterone

• Avoid the temptation to simply monitor PSA while continuing testosterone - this is inappropriate given your PSA velocity and MRI findings 1
• The traditional approach of "PSA monitoring every 3-6 months" applies to men with stable PSA <1.0 ng/mL rise per year, not your clinical scenario 1

Do Not Rely Solely on PSA Density

• While your PSA density of 0.06 is reassuring, MRI has limitations in detecting small or low-grade prostate cancers, and the presence of PI-RADS lesions overrides the favorable PSA density 5
• PSA density should not be used to avoid biopsy when other concerning features are present 5

Do Not Delay Based on Single Measurements

• Confirm the PSA elevation is not laboratory error by repeating measurement, but do not use this as a reason to postpone biopsy given your MRI findings 1
• The combination of rising PSA trend + PI-RADS lesions constitutes sufficient indication for immediate biopsy 5, 1

Monitoring After Resolution

If biopsy is negative and you eventually resume testosterone therapy (only after thorough urologic clearance):

• PSA and digital rectal examination every 3-6 months for the first year, then annually 3, 1
• Immediate biopsy for any PSA increase ≥1.0 ng/mL in one year or abnormal digital rectal examination 3, 1
• Consider concurrent dutasteride use, which has been associated with ability to continue TRT without progression in some studies 7