Prostate Specific Antigen (PSA)

Prostate specific antigen (PSA) is a protein produced by both normal and cancerous cells of the prostate gland. The PSA test measures the level of PSA in the blood and can help detect prostate cancer in men who have no symptoms. However, the PSA test is not perfect and has some limitations and controversies. In this blog post, we will discuss some of the important aspects of PSA testing, such as age-specific PSA levels, free and bound PSA, diagnostic value of PSA, and controversies surrounding PSA screening.

Human prostate specific antigen with bound substrate from complex with antibody. Source.

Age-specific PSA levels

It is normal for all men to have some PSA in their blood, but the amount tends to increase with age. Therefore, some experts have suggested using age-specific PSA ranges to interpret the results of the PSA test. For example, one study proposed the following age-specific PSA ranges for men with no prostate cancer symptoms: 

  • 40 to 49 years: 0 to 2.5 ng/mL 
  • 50 to 59 years: 0 to 3.5 ng/mL 
  • 60 to 69 years: 0 to 4.5 ng/mL 
  • 70 to 79 years: 0 to 6.5 ng/mL

Using age-specific PSA ranges may help reduce unnecessary biopsies and overdiagnosis of prostate cancer in older men who have higher PSA levels due to benign prostate enlargement or inflammation. However, age-specific PSA ranges may also miss some cases of aggressive prostate cancer in younger men who have lower PSA levels. Therefore, age-specific PSA ranges are not widely accepted or used in clinical practice.

Free and bound PSA

PSA exists in two forms in the blood: free PSA and bound PSA. Free PSA is not attached to any other protein, while bound PSA is attached to a protein called alpha-1-antichymotrypsin (ACT). The ratio of free PSA to total PSA (free plus bound) can provide additional information about the risk of prostate cancer. 

Generally, men with prostate cancer tend to have lower free PSA levels and lower free-to-total PSA ratios than men with benign prostate conditions. For example, one study found that men with a free-to-total PSA ratio of less than 10% had a 56% chance of having prostate cancer, while men with a ratio of more than 25% had only an 8% chance.

The free-to-total PSA ratio can help reduce unnecessary biopsies in men who have elevated total PSA levels but low risk of prostate cancer based on their free-to-total PSA ratio. However, the free-to-total PSA ratio is not a definitive test and cannot replace biopsy for confirming or ruling out prostate cancer.

Diagnostic value of PSA

The main purpose of the PSA test is to help detect prostate cancer in men who have no symptoms. However, the PSA test is not very specific for prostate cancer, meaning that it can be elevated by other factors besides prostate cancer, such as benign prostate enlargement, inflammation, infection, ejaculation, or certain medications. Therefore, a high PSA level does not necessarily mean that a man has prostate cancer, and a low PSA level does not necessarily mean that he does not.

The diagnostic value of the PSA test depends on several factors, such as the cut-off point used to define an abnormal result, the age and race of the man, his family history of prostate cancer, his previous biopsy results, and his coexisting medical conditions. There is no universal consensus on what cut-off point should be used to recommend biopsy for men with elevated PSA levels. Some experts suggest using a cut-off point of 4 ng/mL, while others suggest using lower or higher cut-off points depending on the individual risk factors.

The diagnostic value of the PSA test can also be improved by using other tests or methods, such as digital rectal examination (DRE), transrectal ultrasound (TRUS), magnetic resonance imaging (MRI), or biomarkers such as PCA3 or PHI. These tests or methods can help identify suspicious areas in the prostate that may need biopsy or rule out areas that are unlikely to harbor cancer.

Controversies surrounding PSA screening

PSA screening is the use of the PSA test to check for prostate cancer in men who have no symptoms. The goal of PSA screening is to find prostate cancer early when it is more likely to be cured by treatment. However, there are also potential harms associated with PSA screening, such as overdiagnosis, overtreatment, false-positive results, false-negative results, complications from biopsy or treatment, and psychological distress.

Overdiagnosis means finding prostate cancers that are slow-growing and unlikely to cause any problems during a man's lifetime. Overtreatment means treating these cancers with surgery or radiation that may not improve survival but may cause side effects such as urinary incontinence, erectile dysfunction, or bowel problems. False-positive results mean having a high PSA level but no prostate cancer, which may lead to unnecessary anxiety and biopsy. 

False-negative results mean having a low PSA level but prostate cancer, which may delay diagnosis and treatment. Complications from biopsy or treatment mean having bleeding, infection, pain, or other problems from the procedures. Psychological distress means having fear, worry, or depression from the uncertainty or consequences of PSA screening.


The benefits and harms of PSA screening are not clear-cut and may vary depending on the individual characteristics and preferences of each man. Therefore, most professional organizations recommend that men who are considering PSA screening should discuss the potential benefits and harms with their doctors and make an informed decision based on their own values and preferences. 

Some organizations also recommend that men who are at higher risk of prostate cancer, such as Black men, men with a family history of prostate cancer, or men with certain genetic mutations, should start PSA screening earlier or more frequently than the general population.

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Further Reading

  1. Cózar JM, Hernández C, Miñana B, Morote J, Alvarez-Cubero MJ. The role of prostate-specific antigen in light of new scientific evidence: An update in 2020. Actas Urol Esp (Engl Ed). 2021 Jan-Feb;45(1):21-29. PMID: 33408046.
  2. Balk SP, Ko Y-J, Bubley GJ. Biology of prostate-specific antigen. J Clin Oncol. 2003 Jan 15;21(2):383-91. PMID: 12525533.
  3. Kim DW, Chen M-H, Wu J, Huland H, Graefen M, Tilki D, D'Amico AV. Prostate-specific antigen levels of ≤4 and >4 ng/mL and risk of prostate cancer-specific mortality in men with biopsy Gleason score 9 to 10 prostate cancer. Cancer. 2021 Jul 1;127(13):2222-2228. PMID: 34101827.

Disclaimer: This blog post is intended solely for informational purposes. It is not meant to serve as medical advice. For professional medical guidance, please consult your doctor.


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