Prostate-specific antigen

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Prostate-specific antigen
Prostate-specific antigen
Surface model of PSA with substrate fragment according to PDB  2ZCK

Existing structural data : 1pfa , 2psa , 2zch , 2zck , 2zcl , 3QUM

Properties of human protein
Mass / length primary structure 237 amino acids
Identifier
Gene names KLK3  ; PPE
External IDs
Enzyme classification
EC, category 3.4.21.77 ,  serine protease
MEROPS S01.162
Response type hydrolysis
Substrate Semenogelin -Tyr - + - Xaa-
Products Fission products
Orthologue
human House mouse
Entrez 354 13646
Ensemble ENSG00000142515 ENSMUSG00000060177
UniProt P07288 P15948
Refseq (mRNA) NM_001030047 NM_010114
Refseq (protein) NP_001025218 NP_034244
Gene locus Chr 19: 50.85 - 50.86 Mb Chr 7: 44.11 - 44.12 Mb
PubMed search 354 13646

The prostate-specific antigen ( PSA for short , also semenogelase or kallikrein-3 ) is an enzyme that is added to the ejaculate as a physiological secretion product of the prostatic ducts and serves to liquefy the semen coagulum . In female ejaculate there is PSA formed by the paraurethral glands . It is a typical serine protease whose substrate is the protein Semenogelin-1 .

PSA is produced by the glandular epithelium of the prostate or the paraurethral glands and is found in high concentrations in seminal plasma (up to 3 mg / ml). The production is controlled by androgens . The PSA was first isolated from the seminal plasma in 1979 by Wang. PSA is found in very small amounts in other tissues, such as the mammary glands, thyroid glands, salivary glands, lungs, testicles and the uterus .

PSA is a laboratory parameter that is often used in prostate cancer diagnostics. It is specific for the prostate, but not for a tumor disease, but can also be used in the case of inflammation, for example in the case of a urinary tract infection , benign prostate enlargement , urinary retention or, sometimes for several days, after any mechanical stress in the pelvic area, e.g. from sport, v . a. Bicycling, sex, or medical procedures such as digital rectal exam (DRE), transrectal prostate ultrasound , or urinary catheters , may be increased.

A PSA test for the possible early detection of prostate cancer was no longer recommended in 2018 by the responsible specialist societies because of the associated disadvantages, but only after special consideration in individual cases. In contrast, the PSA test continued to be regarded as the most important diagnostic tool for monitoring the progress of prostate cancer treatment.

The prostate-specific antigen (PSA) was described as a protein for the first time in 1984 by Pollen (1984) also in the female organism , in the periurethral glands , the female prostate ( prostate feminina ). In both sexes, the gene expression for the PSA protein is subject to hormonal regulation via steroid receptors for androgens , gestagens , glucocorticoids and mineralocorticoids , all of which have a stimulating effect.

biosynthesis

In order to ramp up the production of the enzyme, androgens first bind to the androgen receptor in the cell nuclei of PSA-producing cells in the prostate epithelium. The activated receptor acts as a transcription factor to a promoter of KLK3 - gene coding for PSA coded . In humans, the gene is on chromosome 19 and extends over 5850 base pairs and five exons . After transcription , mRNA with 1464 bases is produced. This is translated into a precursor protein with 261 amino acids . A post-translational modification results in the end product with 237 amino acids.

The prostate-specific antigen has so far been found in various organs and their tissues, such as the endometrium, the pancreas, the salivary glands and also in the amniotic fluid, saliva and liquor. However, the main producer in the female organism is the mammary gland ( glandula mammaria ).

PSA concentration in the blood

The measurement of the PSA concentration in the blood serum is called a PSA test. The PSA can be bound to serum proteins in the serum or be present free in the serum. There is no fixed normal range of the PSA value. German professional societies generally see a need for further clarification from a value of 4 ng / ml. The PSA value results from the balance of how much gets into the blood and how quickly it is broken down or excreted. Both are very different in different healthy men. It is influenced, among other things, by the amount of prostate tissue, which usually increases with age, or by medication, diseases or irritation of the prostate. Anything that mechanically stresses the prostate (also indirectly through stress in the pelvic area, for example through sport, especially cycling, sex or medical measures such as digital rectal examination (DRE), transrectal prostate ultrasound or urinary catheter ) can significantly increase the values. Some medications, as well as removal of prostate tissue, can also lower the values ​​significantly.

Free and bound PPE

PSA is in free (fPSA) and bound form (complexed to chymotrypsin and macroglobulin; complexed PSA or cPSA ). Both together are measured as the total PSA (total PSA or tPSA) . Total PSA is determined using conventional assays . The proportion of fPSA and cPSA can be measured separately. The half-life of the bound PSA is 48-72 hours. It is metabolized in the liver . Free PSA has a half-life of two to three hours and is eliminated via the kidneys.

Prostate Cancer Detection

A high PSA level is usually associated with changes in the prostate. The higher the PSA value, the higher the likelihood that an illness is present. A distinction must be made between benign and malicious changes. The PSA can be increased in benign prostate enlargement, the so-called benign prostatic hyperplasia (BPH), as well as in inflammation , the so-called prostatitis , or the (less common) prostate infarction.

Carcinoma can be present at any PSA value. The positive predictive value, i.e. the probability of actually predicting prostate cancer correctly, is 25–35% for PSA values ​​between 4 ng / ml and 10 ng / ml, and 50–80% for values ​​above 10 ng / ml. In two-thirds of tumors in an organ-limited stage, the PSA value does not rise above 10 ng / ml. When prostate cancer is first diagnosed, every fifth patient has a PSA below 4 ng / ml. According to biopsies, 60% of these carcinomas have a Gleason score of (maximum) 6, an indication of a less aggressive form.

The definition of a limit value, to make the best distinction between benign and malignant change to allow the prostate, is difficult. There is a balance between too many false-positive results (these men do not have cancer and a punch biopsy of the prostate is unnecessarily performed) and too many false-negative results (these men have cancer; however, it is not recognized).

Age-dependent limit values, for which slightly lower limit values ​​apply to younger patients and slightly higher ones to older patients, improve the situation somewhat. Other options include observing the PSA density (PSA concentration depending on the prostate volume) and the PSA velocity (rate of increase of the PSA). It should be noted that only values ​​that have been determined with the same test system should be compared.

PSA quotient

The proportion of free PSA (PSA quotient) in the presence of prostate cancer is smaller than in healthy men. The lower this ratio is, the higher the probability of prostate cancer being present. The same problems arise when defining a limit value as above. 20% is an example of a frequently used limit value.

There are currently more than 100 test systems for PSA / FPSA on the market. Each test system has its own limit value for the PSA quotient with the same sensitivity and specificity for the detection or exclusion of prostate cancer.

Screening / early detection

The aim of PSA screening is to increase life expectancy through the early detection of prostate cancer. Whether this goal can be achieved is controversial and in any case has not yet been proven. Those who die of prostate cancer in Germany are even three years older than the average male death age. Furthermore, of the men over 50 who died of natural causes, a third did not die of prostate cancer even though they had prostate cancer. Men aged 70 and over die from prostate cancer, not from it.

According to a Finnish study, men who participated in PSA screening three times four years apart reported a false positive result in 12.5% ​​of the cases. In the three different screening rounds, the proportion of false positive results fluctuated between 3.3 and 12.1%. Between a quarter and a third of the men didn't want to know anything about the PSA test after a false positive result.

According to the interdisciplinary S3 guideline for the early detection, diagnosis and treatment of the various stages of prostate cancer from April 2018, a PSA test is expressly not generally recommended as a preventive measure. Men over 45 should only be informed by specialists about this measure as a possibility, including the advantages and disadvantages and the limits of the meaningfulness of the test. General practitioners, on the other hand, should not even address the possibility of their own accord, but only address it if the patient asks. In this case, the risks, such as overdiagnosis and overtreatment, should be presented in natural numbers and also graphically.

In December 2019, the Institute for Quality and Efficiency in Health Care (IQWiG) published a preliminary report under the heading: Prostate cancer screening using a PSA test . The following conclusions were drawn:

“Prostate cancer screening using a PSA test harms significantly more men through overdiagnosis than it does men. In summary, it is therefore stated that the benefits of prostate cancer screening using the PSA test do not outweigh the damage. "

"PSA should never be used to regularly test all men over 50, as those who are likely to benefit from it want," says the discoverer of the PSA. He continued: “I would never have dreamed that my discovery 40 years ago would result in such a profit-driven disaster for the healthcare sector. Medicine should face reality and stop the inappropriate use of PSA testing. That would save billions of dollars and save millions of men from unnecessary and debilitating treatments. "

For general problems with screening examinations and the early detection of diseases see there.

Payment of the cost of the PSA measurement

Due to the low level of safety of the PSA test described above, its use in healthy men in Germany is not a service provided by the statutory health insurances for early disease detection, but rather has to be paid for as an individual health service . In Austria, the health insurance companies cover the costs from the age of 50, and the examination is an obligatory part of the urological check-up. In men with an increased risk of cancer or accelerated cancer growth risk, e.g. If, for example, prostate cancer or testosterone is administered, regular monitoring of the PSA value is considered necessary. The measurement is then paid for by the health insurance company in Germany.

Complementary investigations

Prostate cancer palpable findings

The tactile finding, which is referred to as a digital rectal examination of the prostate, proves cancer in 1.45 to 3.3% of the cases in the screening population . The detection rate of prostate cancer using PSA determination within the screening population is 4.6%. If both methods are combined, the detection rate increases to 5.8%. It is worth mentioning in this context that even the experienced examiner can only digitally feel carcinomas from a size of 7 mm.

PCA3 test

  • PCA3 for further clarification, which is sensible and gentle in certain cases, after the PSA determination and before the biopsy using a urine sample if prostate carcinoma is suspected.

PSA measurement after prostate cancer therapy

The importance of the PSA test for follow-up after treatment of prostate cancer is undisputed. The introduction of the PSA determination has pushed back all other methods of looking for recurrences.

  • A drop in increased values ​​into the reference range indicates a remission of the disease. After radical prostatectomy , patients with PSA values ​​below the measurement limit are considered to be free of recurrences. The PSA controls should be carried out every three months in the first year, then every six months for another four years.
  • Following radiation therapy of the prostate, there may be a (single or multiple) temporary increase in PSA one to five years after treatment, the cause of which is not yet understood and which is known as PSA bounce .
  • In the case of primary hormonal treatment of prostate cancer, the PSA values ​​allow an assessment of the success within the first half of the year. The controls should be continued accordingly closely in order to be able to develop individual treatment strategies after a possible increase.

Tumor progression after therapy without an increase in PSA is extremely rare. The increase itself usually precedes the clinical manifestation of a relapse by years. If, after radical prostate removal , the PSA increases again and none of the usually recommended treatments are carried out, the average time from the start of the PSA increase to the formation of metastases with symptoms is eight years.

literature

Web links

Individual evidence

  1. ↑ Florian Wimpissinger: The female prostate - fact or myth? Urology, 2/07, p. 19
  2. ↑ Samuel Salama, Florence Boitrelle, Amélie Gauquelin, Lydia Malagrida, Nicolas Thiounn, Pierre Desvaux: Nature and Origin of “Squirting” in Female Sexuality . In: The Journal of Sexual Medicine . tape 12 , no. 3 , March 2015, p. 661-666 , doi : 10.1111 / jsm.12799 .
  3. ^ MC Wang et al .: Purification of a human prostato specific antigen. Investig Urol (Berl) 17/2/ 1979 . Pp. 159-163; PMID 89106 .
  4. ↑ GM Yousef, EP Diamandis: The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr Rev 2001; 22: pp. 184-204, doi: 10.1210 / edrv.22.2.0424 (free full text).
  5. ↑ Pollen JJ, Dreilinger A: Immunohistochemical identification of (…) PSA in female periurethral glands. Urology, (1984) 23: 303-304
  6. ↑ Black M, Giai M, Yu H, Diamandis EP: Serum total and free Prostate-specific antigen for breast cancer diagnosis in women. Clin Cancer Res, (2000) 6 (2): 467-473
  7. ↑ Zarghami N, Grass L, Diamandis EP: Steroid hormon regulation of PSA gene expression in breast cancer. Br J Cancer, (1997) 75: 579-588
  8. ↑ Prostate-specific antigen.  In: Online Mendelian Inheritance in Man . (English).
  9. ↑ ENSEMBL entry
  10. ↑ Clements J, Mukhtar A: Glandular kallikreins and PSA are expressed in the human endometrium. J Clin Endocrinol Metab, (1994) 78: 1536-1539
  11. ↑ Elgamal AA, Ectors NL, Sunardi-Widyaputra S et al: Detection of PSA in pancreas and salivary glands: a potential impact on prostate cancer overestimation. J Urol, (1996) 156: 464-468
  12. ↑ Mannello F, Bianchi G, Gazzanelli G: Immunoreactivity of PSA in plasma and saliva of healthy women. Clin Chem, (1996) 42: 1110-1111
  13. ↑ Melegos DN, Freedman MS, Diamandis EP: PSA in cerebrospinal fluid. Clin Chem, (1997) 43: 855
  14. ↑ PSA screening cancer information service KID, German Cancer Research Center, PSA determination , on the knowledge page of Takeda Pharma Sales, Author: Hubert E. Weiß, November 7, 2011 (last change 2014)
  15. ^ Controversy about PSA screening for prostate cancer ( Memento from February 23, 2004 in the Internet Archive )
  16. ↑ Often a taboo: The Risks of Early Cancer Detection ( Memento from December 5, 2003 in the Internet Archive )
  17. ↑ GE Hanks, PT Scardino: Does screening for prostate cancer make sense? Sci Am 275/3/ 1996 p 114-115; PMID 8701279 .
  18. ↑ TP Kilpelainen, TLJ Tammela, L. et al .: Maattanen False-positive screening results in the Finnish prostate cancer screening trial . In: Br J Cancer . . doi : 10.1038 / sj.bjc.6605512 .
  19. ↑ Interdisciplinary guideline of quality S3 for early detection, diagnosis and therapy of the different stages of prostate cancer , leading professional society: Deutsche Gesellschaft für Urologie e. V. (Ed.), Version 5.0, 2018,
  20. ↑ Prostate cancer screening using PSA test , IQWiG, December 20, 2019.
  21. ↑ Richard Ablin. The author is a professor of immunobiology and pathology at the University of Arizona and discovered PSA 40 years ago. 2010, The New York Times, quoted in Süddeutsche Zeitung, Der große Prostata-Errtum, March 12, 2010, p. 16
  22. ↑ Interdisciplinary guideline of quality S3 for early detection, diagnosis and therapy of the different stages of prostate cancer , leading professional society: Deutsche Gesellschaft für Urologie e. V. (Ed.), Version 5.0, 2018,