Prostate-specific antigen (
PSA) is a protein produced by the cells of the
prostateThe prostate is a compound tubuloalveolar exocrine gland of the male mammalian reproductive system. Females do not have prostate glands...
gland. PSA is present in small quantities in the
serumBlood plasma is the yellow liquid component of blood, in which the blood cells in whole blood would normally be suspended. It makes up about 55% of the total blood volume. It is mostly water and contains dissolved proteins, glucose, clotting factors, mineral ions, hormones and carbon dioxide...
of normal men, and is often elevated in the presence of
prostate cancerProstate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. The cancer cells may metastasize from the prostate to other parts of the body, particularly the bones and lymph nodes. Prostate cancer may cause pain, difficulty in urinating, problems...
and in other prostate disorders. A blood test to measure PSA is considered the most effective test currently available for the early detection of prostate cancer, but this effectiveness has also been questioned.
Rising levels of PSA over time are associated with both localized and
metastaticMetastasis , or metastatic disease, sometimes abbreviated mets, is the spread of a disease from one organ or part to another non-adjacent organ or part...
prostate cancer (CaP).
Biochemistry
Prostate-specific antigen (PSA), also known as
kallikrein III,
seminin,
semenogelase,
γ-seminoprotein and
P-30 antigen) is a 34 kD
glycoproteinGlycoproteins are proteins that contain oligosaccharide chains covalently attached to their polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
manufactured almost exclusively by the prostate gland; PSA is produced for the ejaculate where it liquifies the
semenSemen is an organic fluid, also known as seminal fluid, that usually contains spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize female ova...
in the seminal coagulum and allows
spermA sperm, from the ancient Greek word σπέρμα and and more commonly known as a sperm cell, is the haploid cell that is the male gamete. It joins an ovum to form a zygote. A zygote is a single cell, with a complete set of chromosomes, that normally develops into an embryo.Sperm cells contribute...
to swim freely. It is also believed to be instrumental in dissolving the cervical mucous cap, allowing the entry of sperm.
It is a
serine proteaseSerine proteases or serine endopeptidases are proteases in which one of the amino acids at the active site is serine....
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
, the
geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
of which is located on the nineteenth
chromosomeA chromosome is an organized structure of DNA and protein that is found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions...
(19q13).
Discovery
The discovery of prostate-specific antigen (PSA) is beset with controversy; as PSA is present in prostatic tissue and semen, it was independently discovered and given different names, thus adding to the controversy. The chronology of the discovery of PSA is reviewed by Rao et al. In 1960, Flocks was the first to experiment with antigens in the prostate and 10 years later Ablin reported the presence of precipitation antigens in the prostate. In 1971, Hara characterized a unique protein in the semen fluid, gamma-seminoprotein. Li and Beling, in 1973, isolated a protein, E1, from human semen in an attempt to find a novel method to achieve fertility control. In 1978, Sensabaugh identified semen-specific protein p30, but proved that it was similar to E1 protein, and that prostate was the source. In 1979, Wang purified a tissue-specific antigen from the prostate ('prostate antigen'). PSA was first measured quantitatively in the blood by Papsidero in 1980, and Stamey carried out the initial work on the clinical use of PSA as a marker of prostate cancer.
Serum PSA
PSA is normally present in the
bloodBlood is a specialized bodily fluid that delivers necessary substances to the body's cells — such as nutrients and oxygen — and transports waste products away from those same cells....
at very low levels. The
reference rangeIn health-related fields, a reference range is a set of values of some measurement that a physician or other health professional can use to interpret a set of results for a particular patient...
of less than 4 ng/mL for the first commercial PSA test, the Hybritech Tandem-R PSA test released in February 1986, was based on a study that found 99% of 472 apparently healthy men had a total PSA level below 4 ng/mL—the upper limit of normal is much less than 4 ng/mL.
Increased levels of PSA may suggest the presence of prostate cancer. However, prostate cancer can also be present in the complete absence of an elevated PSA level, in which case the test result would be a false negative. Obesity has been reported to reduce serum PSA levels. Delayed early detection may partially explain worse outcomes in obese men with early prostate cancer.
PSA levels can be also increased by prostate infection, irritation,
benign prostatic hyperplasiaBenign prostatic hyperplasia also known as benign prostatic hypertrophy , benign enlargement of the prostate , and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate in middle-age and elderly men...
(BPH), and recent ejaculation, producing a false positive result. Digital rectal examination (DRE) has been shown in several studies to produce an increase in PSA. However, the effect is clinically insignificant, since DRE causes the most substantial increases in patients with PSA levels already elevated over 4.0 ng/mL.
The "normal"
reference rangeIn health-related fields, a reference range is a set of values of some measurement that a physician or other health professional can use to interpret a set of results for a particular patient...
s for prostate-specific antigen increase with age, as do the usual ranges in cancer:
| Age | | <50 | | 50 - 59 | | 60 - 69 | | >70 | (years) |
|---|
| |
Cancer |
No cancer |
Cancer |
No cancer |
Cancer |
No cancer |
Cancer |
No cancer |
|
| 5th percentile A percentile is the value of a variable below which a certain percent of observations fall. So the 20th percentile is the value below which 20 percent of the observations may be found...
|
0.4 |
0.3 |
1.2 |
0.3 |
1.7 |
0.3 |
2.3 |
0.4 |
(ng/mL) |
| 95th percentile |
163.0 |
2.5 |
372.5 |
4.7 |
253.2 |
8.3 |
613.2 |
17.8 |
Despite earlier findings, recent research suggests that the rate of increase of PSA (the
PSA velocity) is not a more specific marker for prostate cancer. However, the PSA rate of rise may have value in prostate cancer prognosis. Men with prostate cancer whose PSA level increased by more than 2.0 ng per milliliter during the year before the diagnosis of prostate cancer have a higher risk of death from prostate cancer despite undergoing
radical prostatectomyRadical retropubic prostatectomy is a surgical procedure in which the prostate gland is removed through an incision in the abdomen. It is most often used to treat individuals who have early prostate cancer. Radical retropubic prostatectomy can be performed under general, spinal, or epidural...
.
Most PSA in the blood is bound to serum proteins. A small amount is not protein bound and is called
free PSA. In men with prostate cancer the ratio of free (unbound) PSA to total PSA is decreased. The risk of cancer increases if the free to total ratio is less than 25%. (See graph at right.) The lower the ratio the greater the probability of prostate cancer. Measuring the ratio of free to total PSA appears to be particularly promising for eliminating unnecessary
biopsiesA biopsy is a medical test involving the removal of cells or tissues for examination. It is the removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
in men with PSA levels between 4 and 10 ng/mL. However, both total and free PSA increase immediately after ejaculation, returning slowly to baseline levels within 24 hours.
PSA in other biologic fluids & tissues
Concentration of PSA in human body fluids
| Fluid |
PSA (ng/mL) |
| semen |
200,000 to 5.5 million |
| amniotic fluid |
0.60-8.98 |
| breast milk |
0.47-100 |
| saliva |
0 |
| female urine |
0.12-3.72 |
| female serum |
0.01-.53 |
It is now clear that the term prostate-specific antigen is a misnomer. It is neither an antigen nor specific to the prostate. Although present in large amounts in prostatic tissue and semen, it has been detected in other body fluids and tissues.
Other than semen, the greatest concentrations of PSA in biological fluids are detected in breast milk and amniotic fluid. Low concentrations of PSA have been identified in the urethral glands, endometrium, normal breast tissue and salivary gland tissue. PSA also is found in the serum of women with breast, lung, or uterine cancer and in some patients with renal cancer.
Tissue samples can be stained for the presence of PSA in order to determine the origin of malignant cells that have metastasized.
Screening
The U.S. Food and Drug Administration (FDA) has approved the PSA test for annual screening of prostate cancer in men of age 50 and older. PSA levels between 4 and 10 ng/mL (nanograms per milliliter) are considered to be suspicious and should be followed by rectal
ultrasoundDiagnostic sonography is an ultrasound-based diagnostic imaging technique used to visualize subcutaneous body structures including tendons, muscles, joints, vessels and internal organs for possible pathology or lesions. Obstetric sonography is commonly used during pregnancy and is widely...
imaging and, if indicated,
prostate biopsyProstate biopsy is a procedure in which small samples are removed from a man's prostate gland to be tested for the presence of cancer. It is typically performed when the scores from a PSA blood test rise to a level that is associated with the possible presence of prostate cancer.The procedure,...
. PSA is false positive-prone (7 out of 10 men in this category will still not have prostate cancer) and false negative-prone (2.5 out of 10 men with prostate cancer have no elevation in PSA). Recent reports indicate that refraining from ejaculation 24 hours or more prior to testing will improve test accuracy.
Post-Treatment Monitoring
Each year, up to 70,000 men in the U.S. will have a "biochemical recurrence," a rising PSA level after failed definitive therapy. The ideal salvage therapy for these men is not clear and includes salvage local therapies and systemic approaches, of which the mainstay is hormonal therapy. Treatment needs to be individualized based on the individual's risk of progression as well as the likelihood of success and the risks of the treatment.
Forensic identification of semen
PSA was first identified by researchers attempting to find a substance in seminal fluid that would aid in the investigation of rape cases. PSA is now used to indicate the presence of
semenSemen is an organic fluid, also known as seminal fluid, that usually contains spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize female ova...
in forensic
serologySerology is the scientific study of blood serum. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
. The semen of adult males has PSA levels far in excess of those found in other tissues; therefore, a high level of PSA found in a sample is an indicator that semen may be present. Because PSA is a biomarker that is expressed independently of
spermatozoaA sperm, from the ancient Greek word σπέρμα and and more commonly known as a sperm cell, is the haploid cell that is the male gamete. It joins an ovum to form a zygote. A zygote is a single cell, with a complete set of chromosomes, that normally develops into an embryo.Sperm cells contribute...
, it remains useful in identifying semen from
vasectomizedVasectomy is a minor surgical procedure wherein the vasa deferentia of a man are severed, and then tied or sealed in a manner such to prevent sperm from entering the seminal stream .-Types:...
and
azoospermicAzoospermia is the medical condition of a male not having any measurable level of sperm in his semen. It is associated with very low levels of fertility.Azoospermia has two forms:...
males.
It is important to note that PSA can also be found at low levels in other body fluids, such as urine and breast milk, thus setting a high minimum threshold of interpretation to rule out
false positiveIn statistics, the terms type I error and type II error are used to describe possible errors made in a statistical decision process...
results is necessary to conclusively state that semen is present. While traditional tests such as crossover
electrophoresisElectrophoresis is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric field caused clay particles...
have a sufficiently low sensitivity to detect only seminal PSA, newer diagnostics tests developed from clinical prostate cancer screening methods have lowered the threshold of detection down to 4 ng/mL. This level of antigen has been shown to be present in the peripheral blood of males with prostate cancer, and rarely in female urine samples and breast milk. No studies have been performed to assess the PSA levels in the tissues and secretions of pre-pubescent children. Therefore, the presence of PSA from a high sensitivity (4 ng/mL) test cannot conclusively identify the presence of semen, so care must be taken with the interpretation of such results.
Interactions
Prostate-specific antigen has been shown to
interactProtein-protein interactions involve not only the direct-contact association of protein molecules but also longer range interactions through the electrolyte, aqueous solution medium surrounding neighbor hydrated proteins over distances from less than one nanometer to distances of several tens of...
with
Protein C inhibitorProtein C inhibitor is a serine protease inhibitor which limits the expression of protein C.-Interactions:Protein C inhibitor has been shown to interact with Prostate specific antigen, Protein C and PLAU....
.
See also
- False positive/False negative
In statistics, the terms type I error and type II error are used to describe possible errors made in a statistical decision process...
- Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. The cancer cells may metastasize from the prostate to other parts of the body, particularly the bones and lymph nodes. Prostate cancer may cause pain, difficulty in urinating, problems...
- Prostate cancer screening
Prostate cancer screening is an attempt to identify individuals with prostate cancer in a broad segment of the population—those for whom there is no reason to suspect prostate cancer. There are two methods used: One is the digital rectal examination , in which the examiner inserts a gloved,...
- Tumor markers
External links