Prostate specific antigen (PSA)

PSA is a protein released by the prostate gland. PSA is a kallikrein-family serine protease that has been commonly used to screen men for prostate cancer. It’s also used to monitor recurrence and therapy response after initial treatment.

PSA is developed in both normal and cancerous prostate tissue. PSA is generated as a proantigen (proPSA) by the secretory cells that line the prostate glands and secreted into the lumen, where the propeptide moiety is extracted to generate active PSA, in normal circumstances. Active PSA may be proteolyzed to produce inactive PSA, of which a small amount reaches the bloodstream and circulates unbound (free PSA). Active PSA can also enter the bloodstream directly, where it is quickly bound to alpha-1-antichymotrypsin (ACT) and alpha-2-macroglobulin.

The majority of free PSA in the serum in men with a normal prostate represents the mature protein that has been inactivated by internal proteolytic cleavage. Prostate cancer patients, on the other hand, have a lower level of free PSA.


PSA is a 7 percent carbohydrate-containing single-chain glycoprotein. It contains 237 amino acid residues and four carbohydrate sidechains and has a molecular weight of 28,430 Da. On chromosome 19, KLK3, the complete PSA gene, can be located. It is mostly made up of epithelial cells found in the acini and ducts of the prostate gland. The prostatic duct lumina secretes PSA. PSA, as part of the seminal coagulum’s liquefaction process, cleaves seminal vesicle-specific proteins into a slew of low-molecular-weight proteins in seminal blood. PSA has activity similar to chymotrypsin and trypsin. The PSA promoter is activated by androgens, progestins, and glucocorticoids.

Fig: Crystal structure of human prostate specific antigen complexed with an activating antibody.

The majority of PSA is bound to two protease inhibitors: (1) α1-antichymotrypsin (ACT) (MW, 100,000 Da) and (2) α2-macroglobulin (AMG); free PSA is only a minor portion (MW, 28,430 Da). PSA-AMG is sterically inhibited, and most immunoassays test both free and ACT complexed PSA. PSA is enzymatically active in about 60% to 70% of human seminal fluid, with the rest inactive. Free PSA comes in three separate molecular forms that are inactive: (1) BPSA, (2) pPSA, and (3) iPSA.

BPSA is a degraded version of free PSA with two peptide bond cleavages at Lys 145 and Lys 183. BPSA is found in the transition zone of the prostate in tissue and leads to free PSA in BPH serum.


PSA has a two-compartment metabolic clearance rate, with half-lives of 1.2 and 0.75 hours for free PSA and total PSA, respectively, and half-lives of 22 and 33 hours respectively. Because of this long half-life, it can take at least 2 to 3 weeks for serum PSA levels to return to baseline following such procedures, such as transrectal biopsy, transurethral resection of the prostate, and radical prostatectomy.

PSA levels are also raised by benign prostatic conditions like BPH and prostatitis. Although the DRE has no clinically significant effects on serum PSA concentrations in most patients, it can cause a twofold increase in some. Inhibitors of 5-reductase, such as finasteride, are used to treat BPH and cause a 50% reduction in PSA levels; as a result, the results should be adjusted. There has been significant physiological variation in serum PSA concentrations (up to 30%).

Normal range

(serum level of <4 ng/mL)

Clinical Application

Prostate cancer is associated with a lower percentage of free PSA in the serum compared to PSA values observed in benign conditions.

Early Detection of Prostate Cancer

PSA testing has limitations in terms of early prostate cancer screening and diagnosis. PSA is only specific for prostatic tissue, not for cancer. As a result, serum PSA is raised not only by prostate cancer, but also by BPH and other prostate-related conditions. BPH is a prevalent disease in men 50 years and older, and studies have shown that PSA levels in patients with BPH are close to those associated with early prostatic cancer but statistically distinct.

Any type of perineal trauma can raise PSA levels in the blood. Minor transient elevations caused by prostate massage and digital rectal examination (DRE) may be clinically insignificant. Mechanical manipulation of the prostate, such as cystoscopy, prostate biopsy, or transurethral resection of the prostate (TURP), may have a greater impact on PSA levels in the blood. Serum PSA levels have been reported to rise dramatically after intense bicycle riding, but this is not a clear finding. For 48 to 72 hours after ejaculation, sexual activity may trigger a minor increase in PSA (usually in the 0.4 to 0.5 ng/mL range).

The greater the sensitivity, but the lower the specificity, the higher the cutoff value. In men with prostate cancer, free PSA could be useful for risk stratification. A lower free-to-total PSA ratio has been linked to a more severe type of prostate cancer.

False positive PSA results

It’s possible to get falsely positive PSA test results, which may lead to uncertainty about the diagnosis of prostate cancer. Men who were falsely positive for one PSA screening test, on the other hand, were more likely to be diagnosed with prostate cancer in the future.

Nonetheless, the presence of heterophilic antibody in the serum is the most common cause of false PSA elevation. In fact, the presence of heterophilic antibody in the specimen can result in false elevations of not only PSA but also other tumor markers. Because of the interference of heterophilic antibodies, falsely elevated PSA can lead to inadequate and unnecessary prostate cancer care.

Free to Total PSA ratio

PSA is first formed as proPSA, and in men with prostate cancer, this type is more likely to leak into their bloodstream. [-2]proPSA is an unbound isoform of proPSA that may be more prevalent in men with prostate cancer. Based on this finding, interest in using the ratio of [-2]proPSA to free PSA (expressed as percent [-2]proPSA or percent [-2]proPSA) for prostate cancer screening is increasing.

In comparison to PSA values found in benign conditions, prostate cancer is associated with a lower percentage of free PSA in the serum. When total PSA is in the normal range (4 ng/mL), the percentage of free PSA has been used to increase the sensitivity of cancer detection, as well as the specificity of cancer detection when total PSA is in the “gray zone” (4.1 to 10 ng/mL).

There is no absolute free/total cutoff that can fully distinguish prostate cancer from BPH, as there is with PSA. In men with prostate cancer, free PSA may be useful for risk stratification. A lower free-to-total PSA ratio could be linked to a more severe type of prostate cancer. Prostate biopsy remains the gold standard for final diagnosis of prostatic diseases.


  1. Clinical Chemistry, Immunology and Laboratory Quality Control , Elsevier
  2. Tietz fundamentals of clinical chemistry and molecular diagnostics, 7th edition
  3. RCSB Protein Data Bank

Leave a Comment