Prostate-specific antigen, or PSA, is a glycoprotein enzyme produced by prostate gland. It. It is a marker of prostate cell activity and is present in small quantities in the serum of all healthy men. Blood levels of prostate specific antigen are raised in men having prostatic infection and prostate cancer or other prostatic disorders. It is mainly used as a serum marker for screening and monitoring prostate cancer.
Structure of Prostate Specific antigen
Prostate Specific antigen is a member of the kallikrein-related peptidase family. It is also known as seminin, gamma-seminoprotein or kallikrein-3 (KLK3). It is 34-kD glycoprotein and is encoded by the KLK3 gene on chromosome 19. The mature form of PSA is a single-chain glycoprotein of 237 amino acids. It is a serine protease enzyme manifesting restricted chymotrypsin-like activity.
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PSA is secreted exclusively by the epithelial cells of the prostate gland for the ejaculate. It is one of the most abundant prostate-derived proteins in the seminal fluid. It is a protease whose main function is to break down the high molecular weight protein of the seminal coagulum into smaller polypeptides. Thus it liquefies semen in the seminal coagulum and allows sperm to swim freely. It is also thought to play a role in dissolving cervical mucus, thereby allowing the entry of sperm into the uterus.
< 4.0 ng/ml
Factors Affecting Level of Prostate Specific Antigen
Age and Ethnicity:
The prostate gland increases in size with age and hence produces more Prostate Specific Antigen.
So young men have lower levels as compared to older men. Due to these normal physiological changes with age, the concept of age-adjusted ranges has been proposed.
PSA levels also vary between different races and ethnic groups.
|Reference Range [Prostate Specific Antigen]|
|Age Range (Years)||Asian Americans||African Americans||Caucasians|
|40 to 49||0 to 2.0 ng/mL||0 to 2.0 ng/mL||0 to 2.5 ng/mL|
|50 to 59||0 to 3.0 ng/mL||0 to 4.0 ng/mL||0 to 3.5 ng/mL|
|60 to 69||0 to 4.0 ng/mL||0 to 4.5 ng/mL||0 to 4.5 ng/mL|
|70 to 79||0 to 5.0 ng/mL||0 to 5.5 ng/mL||0 to 6.5 ng/mL|
The use of age-specific Prostate Specific antigen ranges for the detection of prostate cancer is helpful to avoid unnecessary investigations in older men with larger prostate glands.
However a level of 4.0 ng/mL as the highest cutoff of value for all ages is still the most accepted standard. It is considered as the best value that would not miss malignancies at a curable stage and avoid unnecessary prostate biopsies. It also saves unnecessary detection of the clinically insignificant disease.
Infection or inflammation of the prostate gland can cause increased levels.
Pelvic Injury or Trauma to Prostate
Any injury to prostate including prostatic biopsy or surgery can cause increased levels.
Urinary Tract Infection
Infection of the urinary tract can lead to irritation of the prostate which in turn causes increased levels.
Urinary Catheterization or Urinary Tract Surgery
They can also lead to increased PSA levels due to prostatic irritation.
Benign Prostatic Hyperplasia (BPH)
Levels can also be higher in case of benign enlargement of the prostate gland.
Recent ejaculation and having too much sex can both cause a mild and temporary rise in prostate specific antigen. So it is necessary to abstain from sex and ejaculation at least 24 hours before having a test.
Digital Rectal Examination (DRE)
Recent digital rectal examination can also lead to elevated levels. The effect is however not relevant clinically, since significant increase is seen only in patients who already have elevated levels.
Obesity can cause reduced serum prostate specific antigen levels. Poor prognosis in obese men with early prostate cancer is thought to be due to delayed early detection since in the early stages, levels tend to be reduced i.e., within the normal range.
Drugs like 5-alpha reductase blockers (finasteride or dutasteride) which are used to treat BPH also reduce prostate specific antigen levels.
PSA levels are markedly increased in case of prostatic cancer.
How to Detect PSA ?
The test measures the amount of prostate-specific antigen levels in blood.
Prostate specific antigen in serum exists predominantly in three forms
- Free, uncomplexed
- Covalently complexed to α1-antichymotrypsin (PSA-ACT)
- Covalently complexed to α2-macroglobulin (PSA-MG)
Immunoassays available today are able to detect free and PSA-ACT but not PSA-MG.
Therefore total prostate specific antigen as measured by immunoassay refers to the sum of the free and ACT-bound forms.
PSA can also be detected in biopsy samples using immunohistochemistry. Prostatic cancer cells remain positive for this antigen, so it can be used to identify the origin of primary cancer in case of metastasis with unknown primary.
Uses of PSA Levels
Screening for prostate cancer
Prostate specific antigen test has been approved by the U.S. Food and Drug Administration (FDA) for annual screening of prostate cancer in older men (≥50 years).
There is some controversy as it is being argued whether the benefits of screening ultimately outweigh the risks of over diagnosis and over treatment. This is because some prostate cancers detected in early stages never progress further so as to endanger the life of the patient.
Diagnosing and treating such cases would do more harm than good resulting in anxiety, biopsy pain and other potential complications occurring due to biopsy. The side effects of treatment include erectile dysfunction, urinary incontinence, serious cardiovascular events, pulmonary embolus or deep venous thrombosis.
In spite of this, PSA testing remains a valuable screening tool for prostate cancer.
It has helped to reduce cancer mortality by up to 25%.
Marker for Disease Progression and Risk Stratification
Increasing levels of PSA is an indicator of the aggressiveness of the disease and could imply spread of the disease to other organs. For the purpose of risk stratification, prostate cancer patients are classified as low-risk, intermediate-risk, or high-risk. This classification is based on three parameters – PSA level, histological grade of prostate cancer on biopsy (Gleason score) and the stage of cancer based on physical examination and imaging studies. High-risk patients have a higher chance of developing metastasis and have a higher mortality.
D’Amico Criteria for prostate cancer risk stratification groups:
Low-risk: PSA < 10 ng/ml, Gleason score ≤ 6, Stage ≤ T2a
Intermediate-risk: PSA 10-20 ng/ml, Gleason score 7, Stage T2b/c
High-risk: PSA > 20 ng/ml, Gleason score ≥ 8, Stage ≥ T3
Post-treatment monitoring of Prostate Cancer
After treatment, PSA monitoring is used for determining the success of treatment and for detecting early signs of cancer recurrence. Periodic monitoring every 6 months to 1 year depending upon the risk categorization of the patient is recommended.
After radical prostatectomy, PSA level should drop to undetectable levels — zero nanograms per milliliter (ng/ml) — since the entire gland has been removed. Any detectable PSA level indicates a residual or recurrent prostate cancer.
If the patient has been treated with radiotherapy, the PSA levels may or may not drop to undetectable levels. If some normal prostate tissue does not undergo radioablation, it will still produce some amount of PSA and thus low levels of PSA may be detected in such patients. If however, the value continues to rise or levels are above 1 or 2 ng/ml 12 to 18 months following completion of radiation treatment, there is a chance that cancer has spread outside the gland or the radiation treatment has not been successful in eradicating the entire cancerous tissue.
PSA levels may continue to decrease for several years after radiation therapy. The lowest level is referred to as the PSA nadir.
Recurrence of cancer which is detected by rising PSA level in blood after completion of treatment is called Biochemical recurrence.
Free and Bound
PSA circulates in the body in two ways: either bound to other proteins or on its own as free form. While PSA test measures the total of both free and bound, the free-PSA test measures the percentage of unbound PSA only.
Men with a total prostate specific antigen in borderline zone and a free prostate specific antigen greater than 25% are more likely to have a benign condition, making biopsy unnecessary. Men with a total value in the same range and a free PSA below 10% have a higher chance of cancer and should undergo a biopsy.
The rate at which the PSA rises over a period of time is called PSA velocity. PSA velocity over a year should be less than 0.75 ng/mL. For example, a baseline PSA level of 0.5 ng/mL will be considered normal for a man of any age. But if after one year the level rises to 2.5 ng/mL, this indicates a high PSA velocity and could indicate an underlying prostate cancer. PSA velocity is thus a more specific test than a 4.0 ng/mL cutoff.
The antigen increases more rapidly in men with prostate cancer than in healthy men. High velocity is also a measure of aggressiveness of cancer. Accurately measuring velocity requires three serial readings, ideally with the same assay, obtained over at least a 12- to 24-month period
It is calculated by dividing the prostate specific antigen level by prostate volume.
As the size of the prostate gland affects the PSA level, this parameter is a better measure of the amount of enzyme secreted by the prostate gland. A PSA density of 0.18 or less is considered to be normal.
How to manage the patient post PSA testing
Levels below 4 ng/ml are considered normal and no further testing is usually required. However, a small but significant number of people with prostate cancer can present with a level of less than 4.0 ng/mL. Therefore in the presence of risk factors like family history of prostate cancer, ethnicity along with PSA density and velocity, the patient may be advised to undergo a biopsy even with low values.
Levels above 10 ng/ml are usually seen in malignancies and require prostatic biopsy for confirmation of diagnosis.
Levels between 4 and 10 ng/mL are considered to be borderline. In these patients, levels of free and bound PSA should be determined.
Due to unique pathobiology of prostate cancer, structural model of prostate-specific antigen could be used as target for prostate cancer therapy. Such targeting would require the identification of highly selective inhibitor-binding sites. Research is being carried out to develop selective inhibitors which could be useful tools for the targeted treatment and imaging of prostate cancer in future.