PSA: Everything you need to know

What is PSA?

Prostate-Specific Antigen (PSA) is a protein produced by cells in the prostate gland, a small organ below the bladder in people assigned male at birth. While often discussed in the context of cancer, PSA is not a cancer-specific marker. It plays a functional role in semen liquefaction and can be elevated due to multiple prostate conditions, including benign enlargement (BPH), inflammation (prostatitis), infection, or cancer. PSA circulates in the blood in two main forms: "bound" (attached to other proteins) and "free." The ratio of free to total PSA helps distinguish between cancer and non-cancer causes.

When Should PSA Be Measured?

PSA testing serves two primary purposes:

1. Screening: For prostate cancer in asymptomatic individuals. Guidelines vary:
   • General population: Starting at age 50 (Caucasian), or 45 (Black individuals or those with a family history). The USPSTF emphasises shared decision-making due to potential harms.
   • Symptomatic individuals: Regardless of age, if experiencing urinary changes (weak flow, frequency, nocturia), pelvic pain, or erectile dysfunction.
2. Monitoring: Tracking PSA levels over time is important for:
   • Assessing treatment response after prostate cancer therapy (surgery, radiation, hormones).
   • Detecting potential cancer recurrence ("biochemical recurrence").
   • Monitoring individuals with benign conditions like BPH.

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The Power of Early PSA Testing in Prostate Cancer Detection

Research shows that early PSA screening can significantly improve prostate cancer outcomes:

• Men screened with PSA before age 50 have a 40% lower risk of metastatic prostate cancer at diagnosis.
• When detected early (localized stage), the 5-year survival rate exceeds 99%, compared to just 32% for metastatic cases.
• Studies indicate that PSA testing reduces prostate cancer mortality by up to 21% in men aged 55-69 when combined with appropriate follow-up.
• Approximately 1 in 8 men will develop prostate cancer in their lifetime, but early detection through PSA monitoring can lead to less invasive treatments and better long-term survival.

Interpreting PSA Results: What is "High"?

There is no single universal "normal" PSA level. Interpretation considers:

• Age: PSA naturally increases with age as the prostate grows.
• Race/Ethnicity: Black individuals often have higher baseline PSA levels and higher prostate cancer risk.
• Medications: Drugs like 5-alpha-reductase inhibitors (finasteride, dutasteride) lower PSA.
• Prostate Procedures: Recent biopsies, cystoscopy, or urinary catheterization can temporarily elevate PSA.
• Prostate Size: Larger prostates (BPH) produce more PSA.

Common Reference Thresholds (Cisgender Men):

• < 4.0 ng/mL: Traditionally considered "normal," but cancer can exist below this.
• 4.0 – 10.0 ng/mL ("Gray Zone"): Moderate risk of cancer (~25%). Further evaluation with free/total PSA ratio, biomarkers, or MRI is crucial.
• > 10.0 ng/mL: Higher risk of cancer (>50%).

Age-Specific Considerations (Cisgender Men):

Table 1: General Age-Specific PSA Thresholds Prompting Evaluation (Symptomatic or High-Risk Individuals).

The PSA Screening Debate: Pros and Cons

Potential Benefits (Pros):

• Early Detection: Can identify aggressive prostate cancer at an early, potentially curable stage.
• Reduced Mortality: Screening men aged 55-69 may reduce the risk of dying from prostate cancer.
• Monitoring Tool: Essential for tracking known prostate conditions and treatment effectiveness.

Potential Harms (Cons):

• Overdiagnosis: Detects slow-growing cancers that might never cause symptoms or death, leading to unnecessary anxiety and treatment.
• Overtreatment: Treatments (surgery, radiation) have significant side effects (incontinence, erectile dysfunction). Treating insignificant cancers causes avoidable harm.
• False Positives: An elevated PSA without cancer leads to unnecessary biopsies and anxiety.
• False Negatives: A "normal" PSA doesn't guarantee no cancer, potentially providing false reassurance.

The Crucial Role of Shared Decision-Making: Because of these complexities, discussing individual risk factors, values, and preferences with a healthcare provider before PSA screening is paramount. Tools like risk calculators can aid this discussion.

Navigating False Results

• False Positives (Elevated PSA, No Cancer):
  • Causes: BPH, prostatitis, urinary tract infection, recent prostate manipulation (biopsy, catheter), vigorous exercise (e.g., cycling), ejaculation within 48 hours.
  • Impact: Unnecessary anxiety, invasive follow-up tests (biopsy with risks of pain, bleeding, infection).
• False Negatives ("Normal" PSA, Cancer Present):
  • Causes: Some cancers (especially aggressive types) may not produce much PSA; hormone therapy suppressing PSA; individual biological variation.
  • Impact: Delayed diagnosis, potentially missing curable cancer.

Mitigation Strategies: Repeating the PSA test if an initial result is elevated (especially if no risk factors/symptoms), considering PSA velocity (rate of change over time), using adjunctive tests (free PSA, newer biomarkers, MRI).

Beyond PSA: Useful Biomarkers and Tests

PSA is often the first step. Other tools improve specificity and help avoid unnecessary biopsies:

1. Free PSA (%fPSA): Measures the percentage of PSA not bound to proteins. A lower %fPSA suggests a higher likelihood of cancer. Used primarily in the "gray zone" (PSA 4-10 ng/mL).
2. Prostate Health Index (PHI): Combines total PSA, free PSA, and [-2]proPSA into a single score. Better than PSA or %fPSA alone at predicting significant cancer. Note: Calibration in Black men requires more study.
3. 4Kscore Test: Measures four different kallikrein proteins in the blood to calculate the risk of finding aggressive (Gleason Grade Group ≥2) cancer on biopsy.
4. Urine Biomarkers (e.g., PCA3, TMPRSS2:ERG, ExoDX, SelectMDx): Detect prostate cancer-related RNA or other markers in urine collected after a digital rectal exam (DRE). Helpful for deciding on repeat biopsy.
5. Multiparametric MRI (mpMRI): Imaging scan that provides detailed pictures of the prostate. A PI-RADS score helps assess cancer likelihood. Can guide targeted biopsies and help some men avoid immediate biopsy if low risk.

Table 2: Key Biomarkers Used Alongside PSA

PSA interpretation can be significantly enhanced when tested alongside other biomarkers, including Thyroid Stimulating Hormone (TSH), Free Thyroxine (FT4), Free Triiodothyronine (FT3), Albumin, Bilirubin, Gamma GT, Alanine Transferase (ALT), Alkaline Phosphatase (ALP), Total Protein, and Globulin. These additional tests help rule out non-prostate-related conditions that may influence PSA levels, such as liver dysfunction, metabolic disorders, or hormonal imbalances. For example, thyroid dysfunction (indicated by abnormal TSH, FT4, or FT3) can affect prostate cell activity, while liver enzymes (Gamma GT, ALT, ALP) and proteins (Albumin, Globulin) may signal systemic inflammation or metabolic stress that could indirectly elevate PSA. By analyzing these biomarkers together, clinicians can better distinguish between benign conditions (e.g., prostatitis, BPH) and aggressive prostate cancer, reducing unnecessary biopsies and improving diagnostic accuracy.

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PSA in Transgender Women and Non-Binary Individuals with Prostates

This population remains at risk for prostate cancer, though GAHT significantly lowers PSA levels and likely reduces overall risk. Key considerations:

• Profound PSA Suppression: Estrogen therapy and androgen blockers (or orchiectomy) drastically reduce testosterone, shrinking the prostate and lowering PSA. Median levels are often far below 1.0 ng/mL (e.g., 0.02 ng/mL in one large study) – potentially fiftyfold lower than cisgender men.
• Current Reference Intervals Unreliable: Standard cis-male PSA thresholds (e.g., 4.0 ng/mL) are far too high for this population. A PSA above 1.0 ng/mL in someone on long-term GAHT or post-orchiectomy should be considered potentially significant and warrants investigation, even if it falls within the "normal" cis-male range.
• Screening Recommendations Lack Clarity: There are no universally accepted guidelines. Screening is generally not routinely offered to all. It should be considered individually, especially for those over 50 (or 45 if Black or family history), with symptoms (urinary changes, pelvic pain), or significant genetic/family risk. Screening before starting GAHT provides a baseline.
• Diagnostic Challenges: Digital rectal exams (DRE) can be performed transvaginally post-vaginoplasty. Biopsies may also be performed transvaginally or transperineally. Interpreting MRI might be different due to prostate atrophy from hormones.
• Barriers to Care: Lack of provider knowledge, patient fear of discrimination or gender dysphoria triggered by discussing prostate health or undergoing exams, and misgendering in medical settings are significant hurdles. Creating inclusive environments and provider education are critical.

Practical Tips for Transgender/Non-Binary Individuals:

• Be aware you have a prostate and remain at risk.
• Discuss prostate health and screening with your affirming provider or a knowledgeable urologist.
• If you choose PSA screening, ensure your provider uses appropriate, lower thresholds for interpretation.
• Advocate for yourself: Share information like this article or guidelines if needed.
• Seek care from LGBTQ+-affirming providers or clinics (e.g., UK's UCATS service).

The Controversy of At-Home PSA Tests

Several companies sell kits allowing individuals to collect a finger-prick blood sample at home for PSA analysis (rapid or lab-based). While convenient, significant concerns exist:

• Lack of Pre-Test Counseling: Users miss vital discussions about risks, benefits, limitations, and implications of results.
• Interpretation Challenges: Rapid tests often use a simplistic "Positive/Negative" based on 4.0 ng/mL, ignoring age, race, medications, and symptoms. Lab results provide a number but lack context.
• False Reassurance/Alarm: A "negative" rapid test doesn't rule out cancer; a "positive" or elevated lab result causes anxiety but might be due to benign causes.
• Need for Clinical Follow-Up: An abnormal home test still requires confirmation and discussion with a healthcare provider.
• Quality Concerns: While some labs are accredited, quality control can vary.
  Recommendation: If concerned about prostate cancer, consult a healthcare provider for PSA testing. This ensures appropriate counseling, accurate interpretation, and timely follow-up. Home tests are not a substitute for professional medical care.

Conclusion: PSA – A Valuable, Imperfect Tool

Prostate-Specific Antigen remains a cornerstone of prostate health assessment, crucial for early cancer detection in some and managing known conditions in others. However, it is not a perfect test. Understanding its limitations – including false positives/negatives, overdiagnosis risks, and the profound impact of gender-affirming hormone therapy – is essential for both patients and providers.

The future lies in personalized risk assessment. This involves combining PSA with novel biomarkers, advanced imaging like MRI, clinical factors (age, race, family history), and shared decision-making. For transgender women and non-binary individuals with prostates, increased awareness, provider education, and research into population-specific thresholds are urgently needed to ensure equitable care.

References

1. Hall, R., Ball, R., Bancroft, E., Eeles, R. & Berner, A.M. (2025) 'Systematic review of PSA reference intervals in the gender diverse population with prostates', BJU International [Epub ahead of print]. Available at: https://www.urotoday.com/recent-abstracts/urologic-oncology/prostate-cancer/161495-systematic-review-of-psa-reference-intervals-in-the-gender-diverse-population-with-prostates.html (Accessed: 25 June 2025).
2. [Anonymous] (2025) 'Prostate-Specific Antigen and Prostate Cancer in Gender-Affirming Hormone Therapy for Transgender or Nonbinary Individuals', International Journal of Radiation Oncology, Biology, Physics, 121(3), pp. 761-767. doi:10.1016/j.ijrobp.2024.09.039.
3. [Author(s) Not Listed] (2023) 'Concerns regarding prostate cancer screening guidelines', Prostate Cancer and Prostatic Diseases, 27(4), pp. 591–593. doi:10.1038/s41391-023-00765-0.
4. Ma, S.J. et al. (2021) 'Prostate Cancer Screening Patterns Among Sexual and Gender Minority Individuals', European Urology, 79(5), pp. 588-592. doi:10.1016/j.eururo.2020.11.009.
5. Prostate Cancer UK (2024) 'The pros and cons of PSA self-test kits for prostate cancer'. Available at: https://prostatecanceruk.org/about-us/news-and-views/2024/12/the-pros-and-cons-of-psa-self-test-kits-for-prostate-cancer (Accessed: 25 June 2025).
6. [Anonymous] (2025) 'Prostate-Specific Antigen and Prostate Cancer in Gender-Affirming Hormone Therapy for Transgender or Nonbinary Individuals', Clinical Investigation [Abstract]. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0360301624034096 (Accessed: 25 June 2025).
7. [Anonymous] (2025) 'Systematic review of PSA reference intervals in the gender diverse population with prostates', BJU International [Epub ahead of print]. doi:10.1111/bju.16825.
8. Cedars-Sinai (2024) 'Improving Prostate Cancer Screening for Transgender Women'. Available at: https://www.cedars-sinai.org/newsroom/improving-prostate-cancer-screening-for-transgender-women/ (Accessed: 25 June 2025).
9. Prostate Cancer UK (2025) 'How prostate cancer is diagnosed in trans women'. Available at: https://prostatecanceruk.org/prostate-information-and-support/prostate-tests/prostate-cancer-diagnosis-in-trans-women (Accessed: 25 June 2025).
10. WebMD (2024) 'Prostate Cancer in Nonbinary and Trans People'. Available at: https://www.webmd.com/prostate-cancer/prostate-cancer-nonbinary-trans-people (Accessed: 25 June 2025).