Should I stop testosterone (testosterone replacement therapy) in a patient with mildly elevated Prostate-Specific Antigen (PSA) levels and symptoms of nocturia (nocturnal urination) while on testosterone therapy?

Management of Mildly Elevated PSA in a Patient on Testosterone Therapy

Do not stop testosterone therapy based solely on a PSA of 4.05 ng/mL; instead, confirm the elevation with a repeat PSA in 3-6 weeks while continuing testosterone, and simultaneously evaluate for other causes of PSA elevation and nocturia. 1, 2

Immediate Assessment Steps

Confirm the PSA elevation before making treatment decisions:

• Repeat PSA measurement in 3-6 weeks to account for laboratory variability (which can range 20-25%) and confirm this is a true elevation rather than assay variation 1
• Continue testosterone therapy during this confirmation period, as stopping prematurely may unnecessarily disrupt treatment 3
• Perform digital rectal examination (DRE) to assess for palpable prostatic abnormalities that might indicate cancer risk 1, 2

Evaluate alternative explanations for the mildly elevated PSA:

• A PSA of 4.05 ng/mL is only marginally above the traditional 4.0 ng/mL threshold and does not automatically indicate malignancy 1
• Benign prostatic hyperplasia (BPH), which commonly causes nocturia, can elevate PSA levels and may be the primary issue here 4, 5
• Prostatitis or subclinical inflammation can also elevate PSA, though routine antibiotic trials for PSA 4-10 ng/mL without overt infection evidence show no clear benefit 6

Understanding the Testosterone-PSA Relationship

The evidence does not support routine discontinuation of testosterone for mild PSA elevations:

• The FDA labeling for testosterone gel states that men with known or suspected prostate cancer should not use testosterone, but a PSA of 4.05 ng/mL does not establish cancer diagnosis 7
• Testosterone therapy itself can modestly increase PSA levels as part of its physiologic effects, and this does not necessarily indicate malignancy 3
• Clinical trial eligibility criteria for rising PSA states require testosterone levels ≥150 ng/dL to be maintained, suggesting that testosterone presence is expected during PSA monitoring 1

Addressing the Nocturia

The nocturia may be unrelated to prostate cancer and more likely represents BPH:

• In patients with lower urinary tract symptoms suggestive of BPH, 94% have nocturia frequency of more than 2 times per night, and 76.5% have nocturnal polyuria 4
• Nocturia in BPH patients is significantly related to evening fluid intake and is often poorly responsive to medical therapy alone 4, 5
• Alpha-blockers (like tamsulosin) improve overall BPH symptoms but show minimal improvement in nocturia specifically, with only a net reduction of 0.3 episodes over placebo 5

Recommended Management Algorithm

Follow this stepwise approach:

1. Week 0-3: Continue testosterone therapy unchanged while repeating PSA and performing DRE 1, 2

2. Week 3-6: If repeat PSA confirms elevation (remains >4.0 ng/mL):

   • Calculate PSA velocity: an increase of ≥0.75 ng/mL per year in patients with PSA 4-10 ng/mL warrants closer attention 1
   • For younger patients or those with PSA <4.0 ng/mL baseline, a PSA velocity of ≥0.4 ng/mL per year is more concerning 1
   • Monitor hematocrit/hemoglobin to assess for testosterone-induced erythrocytosis, which poses thrombotic risk 3

3. If PSA remains 4-10 ng/mL with normal DRE:

   • Continue testosterone therapy with PSA monitoring every 3-6 months for the first year 2
   • Consider prostate biopsy if PSA increases by ≥1.0 ng/mL in one year or if DRE becomes abnormal 2
   • Address nocturia as a separate BPH symptom with behavioral modifications (limiting evening fluids) and potentially alpha-blocker therapy 4, 5

4. If PSA shows concerning velocity (rising >20% between measurements):

   • Patients with PSA <4 ng/mL who show approximately 20% increase have significantly increased prostate cancer risk (adjusted HR 2.94) 8
   • This scenario would warrant prostate biopsy consideration regardless of testosterone status 2, 8

Critical Pitfalls to Avoid

Do not reflexively stop testosterone without proper evaluation:

• Stopping testosterone based on a single mildly elevated PSA creates unnecessary treatment disruption and patient anxiety 3
• The PSA of 4.05 ng/mL does not meet criteria for "rising PSA" which requires three determinations showing progressive elevation 1
• Some prostate cancers present with low PSA levels, so PSA alone is insufficient for decision-making 9

Do not attribute all symptoms to testosterone therapy:

• Nocturia is extremely common in aging men with BPH (present in 96.5% of BPH patients) and is not specifically caused by testosterone 5
• The nocturia likely represents underlying BPH that requires separate evaluation and management 4

Do not delay biopsy if truly indicated:

• If repeat PSA confirms elevation and shows concerning velocity, or if DRE is abnormal, proceed to biopsy rather than simply monitoring 2
• The traditional PSA threshold of 4.0 ng/mL has sensitivity of only 20% for cancer detection, so clinical judgment incorporating PSA trends and DRE findings is essential 1