Does testosterone therapy cause Benign Prostatic Hyperplasia (BPH) and elevated Prostate-Specific Antigen (PSA) levels?

Does Testosterone Therapy Cause BPH and Elevated PSA?

Testosterone therapy does not cause benign prostatic hyperplasia (BPH) or clinically significant elevations in PSA levels in men being treated for hypogonadism. 1, 2

Effect on Benign Prostatic Hyperplasia

Testosterone replacement therapy is safe and does not worsen lower urinary tract symptoms (LUTS) or significantly increase prostate volume, except in men with severe pre-existing symptoms. 2

• Multiple prospective studies have consistently failed to demonstrate exacerbation of voiding symptoms attributable to BPH during testosterone supplementation. 1
• Complications such as urinary retention have not occurred at higher rates than in placebo-controlled groups. 1
• While prostate volume measured by ultrasonography does increase during the first six months of therapy to levels equivalent to men without hypogonadism, this does not translate into worsening urinary symptoms. 1
• Urine flow rates, post-void residual volumes, and prostate voiding symptoms remain unchanged in clinical studies, explained by the poor correlation between prostate volume and urinary symptoms. 1

Important caveat: Individual men may occasionally experience increased voiding symptoms with testosterone therapy, though this is uncommon. 1

Effect on PSA Levels

Testosterone therapy produces minimal to no clinically significant increases in PSA levels. 3

Magnitude of PSA Changes

• A systematic review and meta-analysis of 739 patients receiving testosterone replacement showed a mean PSA increase of only 0.154 ng/mL compared to controls. 3
• In clinical trials of testosterone gel 1.62%, the mean change in PSA was 0.14 ng/mL during the 182-day double-blind period. 4
• Intramuscular testosterone administration produces slightly higher PSA increases (0.271 ng/mL) compared to other routes, but this remains minimal. 3

Clinical Significance

• The rate of elevated PSA levels after treatment is similar between testosterone-treated patients and controls (odds ratio 1.02). 3
• In testosterone gel trials, 11.1% of patients had increased PSA reported as an adverse event, but most did not meet clinically significant thresholds. 4
• There is no compelling evidence that men with higher testosterone levels are at greater risk of prostate cancer, and prostate cancer becomes more prevalent exactly when testosterone levels naturally decline. 1

Monitoring Recommendations

All men on testosterone therapy require systematic PSA monitoring regardless of BPH status. 1, 2

Baseline Evaluation

• Perform digital rectal examination. 1
• Measure baseline PSA and testosterone levels. 1
• Document baseline voiding history using standardized questionnaires. 1
• Perform prostate biopsy if baseline PSA >4.0 ng/mL or digital rectal examination is abnormal. 1

Follow-up Schedule

• Monitor every 3-6 months for the first year, then annually thereafter. 1, 2
• Repeat PSA testing, digital rectal examination, and assessment of urinary symptoms at each visit. 1

Thresholds for Urologic Referral

• PSA rises above 4.0 ng/mL. 1
• PSA increases by >1.0 ng/mL during the first 6 months of treatment. 1
• PSA increases by >0.4 ng/mL per year after the first 6 months. 1
• For PSA increases of 0.7-0.9 ng/mL, repeat testing in 3-6 months and perform biopsy if further increase occurs. 1
• Any change on digital rectal examination (nodule, asymmetry, increased firmness). 1

Underlying Pathophysiology

Emerging evidence suggests that low testosterone, rather than high testosterone, may actually contribute to BPH development. 5

• Inflammation is a key driver of BPH development, and low testosterone with hyperestrogenism (common in metabolic syndrome) may favor prostate inflammation. 5
• Treating hypogonadism could potentially produce relief from LUTS and limit prostatic inflammation. 5
• This contradicts historical assumptions that higher testosterone drives prostatic growth. 5