PSA or Prostate Specific Antigen

PSA (Prostate Specific Antigen), also known as kallikrein-3 (KLK3), is a glycoprotein belonging to the serine-type peptidase (kallikrein) family.

Encoded by the KLK3 gene on chromosome 19 (band 19q13.33), this proteolytic enzyme has structural features similar to glandular kallikreins, with ~78% homologies in amino acid sequence. (sources 1, 2, 3).

It is a monomeric protein of approximately 34kDa, composed of approximately 240 amino acids, with approximately 7% of the total weight deriving from carbohydrate groups (glycoprotein).

PSA has a serine-chymotrypsin-like active site, with the catalytic triad His-Asp-Ser, and is regulated by zinc ions and pH changes. (1, 2, 3, 4).

Where and How PSA is Produced

Il PSA è sintetizzato dalle cellule epiteliali luminali della prostate gland nell’uomo e dalle ghiandole parauretrali nella donna.

Its expression is tightly regulated by androgens via the androgen receptor (AR).

Once synthesized, PSA is secreted into the lumen of the prostatic tubules and is present in seminal fluids in very high concentrations (>1mg/mL).

Small quantities enter the bloodstream through the prostatic epithelial barrier, explaining the physiological presence also in the plasma (1, 2, 3).

Physiological Function of PSA

In seminal fluid, PSA acts as a protease, degrading the seminal clot (composed of semenogelin I and II), facilitating sperm liquefaction and motility. It also promotes the dissolution of cervical mucus, facilitating sperm entry into the uterus.

PSA may also act on other targets, such as degrading IGFBP-3, increasing IGF availability, and potentially stimulating cell proliferation (1).

PSA and patient age

Serum PSA levels tend to increase with age. This increase is likely related to the increase in prostate volume that occurs naturally in older men, primarily due to benign prostatic hyperplasia.

A larger gland volume leads to greater PSA production and a larger exchange surface area with the bloodstream. This phenomenon reduces the specificity of the test in older patients, making it necessary to interpret the values ​​based on age and clinical context.

Some protocols propose age-specific reference ranges to improve diagnostic accuracy

PSA in Prostate Pathology

In conditions such as benign prostatic hyperplasia (BPH) and inflammation (prostatitis), serum PSA levels increase in response to increased production or compromised epithelial barrier (1).

In prostate cancer, PSA production and release increase proportionally to tumor mass and its vascular permeability.

Serum values ​​>4ng/mL are considered suspicious, but the diagnosis requires a biopsy, since there are false positives and negatives.

Much of the clinical work revolves around total PSA, but the free fraction or free/total PSA ratio (f/t PSA) also helps improve diagnostic specificity, especially in the “gray zone” (4–10ng/mL) (1).

Over the years, the use of the PSA test in clinics has become increasingly widespread, from screening to the definition of a biochemical recurrence, to the presence of metastases.

PSA is the most widely used biomarker for prostate cancer screening. Studies such as ERSPC and CAP have demonstrated a reduction in PCa-specific mortality (20–31%), with limited absolute benefits and no significant reduction in total mortality (1, 2, 3).

PSA is effective in post-treatment monitoring (surgery, radiotherapy, hormone therapy) and in recurrences (1, 2).

PSA remains a central molecule in the clinical management of prostate cancer, due to its relationship with prostate mass, enzymatic activity, and histotissue damage. However, its use requires integrated and contextualized assessments. Ongoing diagnostic innovations promise to optimize patient selection, avoiding overdiagnosis and enhancing the individualization of treatment strategies.

References:

• Lilja et al., Crystal structure of PSA, J Mol Biol, 2007 [rcsb.org]
• Young et al., Molecular Biology of PSA, SpringerLink, 2008 [link.springer.com]
• Peehl DM, PSA Role and Function, Cancer, 1995 [acsjournal….wiley.com]
• Sofronescu AG, PSA Testing Overview, Medscape, 2025 [emedicine….dscape.com]
• Dahiya et al., Prostate Cancer Biomarkers Review, Clin Transl Oncol, 2024 [link.springer.com]
• Oh C-U & Kang H, Effectiveness and Harms of PSA Screening, Healthcare, 2025 [mdpi.com]