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Prostate-specific antigen ( PSA), also known as gamma-seminoprotein or kallikrein-3 ( KLK3), P-30 antigen, is a glycoprotein enzyme encoded in humans by the KLK3 gene. PSA is a member of the kallikrein-related protease family and is secreted by the epithelium of the prostate gland in men and the paraurethral glands in women.
PSA is produced for the ejaculate, where it liquefies semen in the seminal coagulum and allows spermatozoon to swim freely. It is also believed to be instrumental in dissolving cervical mucus, allowing the entry of sperm into the uterus. (1999). 9781891276026, American Society of Andrology. ISBN 9781891276026
PSA is present in small quantities in the Blood plasma of men with healthy prostates, but is often elevated in the presence of prostate cancer or other prostate disorders. PSA is not uniquely an indicator of prostate cancer, but may also detect prostatitis or benign prostatic hyperplasia.
In the United Kingdom, the National Health Service (NHS) does not mandate, nor advise routine PSA testing, but allows patients over 50 to request a test based on their doctor's advice, in an "informed choice programme called prostate cancer risk management for healthy men". The charity Prostate Cancer UK, however, recommend men discuss PSA testing from the age of 45.
PSA levels between 4 and 10 ng/mL (nanograms per millilitre) are considered to be suspicious, and consideration should be given to confirming the abnormal PSA with a repeat test. If indicated, prostate biopsy is performed to obtain a tissue sample for histopathological analysis.
While PSA testing may help 1 in 1,000 avoid death due to prostate cancer, 4 to 5 in 1,000 would die from prostate cancer after 10 years even with screening. This means that PSA screening may reduce mortality from prostate cancer by up to 25%. Expected harms include anxiety for 100–120 receiving false positives, biopsy pain, and other complications from biopsy for false positive tests.
Use of PSA screening tests is also controversial due to questionable test accuracy. The screening can present abnormal results even when a man does not have cancer (known as a false-positive result), or normal results even when a man does have cancer (known as a false-negative result). False-positive test results can cause confusion and anxiety in men, and can lead to unnecessary prostate biopsy, a procedure which causes risk of pain, infection, and bleeding. False-negative results can give men a false sense of security, though they may actually have cancer.
Of those found to have prostate cancer, overtreatment is common because most cases of prostate cancer are not expected to cause any symptoms due to low rate of growth of the prostate tumor. Therefore, many will experience the side effects of treatment, such as for every 1000 men screened, 29 will experience erectile dysfunction, 18 will develop urinary incontinence, two will have serious cardiovascular events, one will develop pulmonary embolus or deep venous thrombosis, and one perioperative death. Since the expected harms relative to risk of death are perceived by patients as minimal, men found to have prostate cancer usually (up to 90% of cases) elect to receive treatment.
Following radiation therapy of any type for prostate cancer, some PSA levels might be detected, even when the treatment ultimately proves to be successful. This makes interpreting the relationship between PSA levels and recurrence/persistence of prostate cancer after radiation therapy more difficult. PSA levels may continue to decrease for several years after radiation therapy. The lowest level is referred to as the PSA nadir. A subsequent increase in PSA levels by 2.0ng/mL above the nadir is the currently accepted definition of prostate cancer recurrence after radiation therapy.
Recurrent prostate cancer detected by a rise in PSA levels after curative treatment is referred to as a "biochemical recurrence". The likelihood of developing recurrent prostate cancer after curative treatment is related to the pre-operative variables described in the preceding section (PSA level and grade/stage of cancer). Low-risk cancers are the least likely to recur, but they are also the least likely to have required treatment in the first place.
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 positive results and conclusively state that semen is present. While traditional tests such as crossover electrophoresis 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 4ng/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.
More significantly, PSA remains present in prostate cells after they become malignant. Prostate cancer cells generally have variable or weak staining for PSA, due to the disruption of their normal functioning. Thus, individual prostate cancer cells produce less PSA than healthy cells; the raised serum levels in prostate cancer patients is due to the greatly increased number of such cells, not their individual activity. In most cases of prostate cancer, though, the cells remain positive for the antigen, which can then be used to identify metastasis. Since some high-grade prostate cancers may be entirely negative for PSA, however, histological analysis to identify such cases usually uses PSA in combination with other antibodies, such as prostatic acid phosphatase and CD57.
Further regulation is achieved through pH variations. Although its activity is increased by higher pH, the inhibitory effect of zinc also increases. The pH of semen is slightly alkaline and the concentrations of zinc are high. On ejaculation, semen is exposed to the acidic pH of the vagina, due to the presence of lactic acid. In fertile couples, the final vaginal pH after coitus approaches the 6-7 levels, which coincides well with reduced zinc inhibition of PSA. At these pH levels, the reduced PSA activity is countered by a decrease in zinc inhibition. Thus, the coagulum is slowly liquefied, releasing the sperm in a well-regulated manner.
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, Mitsuwo 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.
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. After treatment, higher BMI also correlates to higher risk of recurrence.
PSA levels can be also increased by urinary tract infection, prostatitis, irritation, benign prostatic hyperplasia (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 4.0ng/mL. PSA levels are higher during the summer than during the rest of the year.
The "normal" for prostate-specific antigen increase with age, as do the usual ranges in cancer (per associated table).
| 0.4 !rowspan=3 | ng/mL or μg/L |
| 4.0–9.0 | |
| 7.7–13 |
However, the PSA rate of rise may have value in prostate cancer prognosis. Men with prostate cancer whose PSA level increased by more than 2.0ng per milliliter during the year before the diagnosis of prostate cancer have a higher risk of death from prostate cancer despite undergoing radical prostatectomy. PSA velocity (PSAV) was found in a 2008 study to be more useful than the PSA doubling time (PSA DT) to help identify those men with life-threatening disease before start of treatment.
Men who are known to be at risk for prostate cancer and decide to plot their PSA values as a function of time (i.e., years) may choose to use a semi-log plot. An exponential growth in PSA values appears as a straight line(Archived by WebCite® at ) on a semi-log plot, so that a new PSA value significantly above the straight line signals a switch to a new and significantly higher growth rate (i.e., a higher PSA velocity).
| + Concentration of PSA in human body fluids ! Fluid | PSA (ng/mL) |
In women, PSA is found in female ejaculate at concentrations roughly equal to that found in male semen. Other than semen and female ejaculate, 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.
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