Prostate-specific antigen#Serum levels

{{Main|Prostate cancer screening}}

Clinical practice guidelines for prostate cancer screening vary and are controversial, in part due to uncertainty as to whether the benefits of screening ultimately outweigh the risks of overdiagnosis and overtreatment.{{cite journal | vauthors = Gomella LG, Liu XS, Trabulsi EJ, Kelly WK, Myers R, Showalter T, Dicker A, Wender R | title = Screening for prostate cancer: the current evidence and guidelines controversy | journal = The Canadian Journal of Urology | volume = 18 | issue = 5 | pages = 5875–5883 | date = October 2011 | pmid = 22018148 }} In the United States, the Food and Drug Administration (FDA) has approved the PSA test for annual screening of prostate cancer in men of age 50 and older.{{medcn|date=July 2020}} The patient is required to be informed of the risks and benefits of PSA testing prior to performing the test.{{medcn|date=July 2020}}

In the United Kingdom, the National Health Service (NHS) {{As of|2018|lc=y}} does not mandate, nor advise for PSA test, but allows patients to decide based on their doctor's advice.{{cite web | url = https://www.nhs.uk/livewell/prostatehealth/pages/psa-test.aspx | title = Should I have a PSA test? | archive-url = https://web.archive.org/web/20180228163153/https://www.nhs.uk/livewell/prostatehealth/pages/psa-test.aspx | archive-date = 28 February 2018| work = NHS Choices | date = 27 February 2018 }} The NHS does not offer general PSA screening, for similar reasons.{{cite web|title=Prostate cancer - PSA testing - NHS Choices|url=http://www.nhs.uk/Conditions/Cancer-of-the-prostate/Pages/Prevention.aspx|publisher=NHS Choices|language=en|date=3 January 2015}}

PSA levels between 4 and 10{{nbsp}}ng/mL (nanograms per milliliter) 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. {{citation needed|date=May 2021}}

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.{{medcn|date=July 2020}}

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).{{Cite web|url=https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/detection.html|title=Can Prostate Cancer Be Found Early?|website=www.cancer.org|language=en|access-date=2020-01-17}} False-positive test results can cause confusion and anxiety in men, and can lead to unnecessary prostate biopsies, a procedure which causes risk of pain, infection, and hemorrhage. False-negative results can give men a false sense of security, though they may actually have cancer.{{medcn|date=July 2020}}

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.{{Failed verification|date=February 2020}} 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.{{cite web |url=http://www.uspreventiveservicestaskforce.org/prostatecancerscreening/prostatecancerscript.pdf |title=Talking With Your Patients About Screening for Prostate Cancer |access-date=2012-07-02 |archive-url=https://web.archive.org/web/20141011150935/http://www.uspreventiveservicestaskforce.org/prostatecancerscreening/prostatecancerscript.pdf |archive-date=11 October 2014 |url-status=dead }}{{cite journal | vauthors = Grossman DC, Curry SJ, Owens DK, Bibbins-Domingo K, Caughey AB, Davidson KW, Doubeni CA, Ebell M, Epling JW, Kemper AR, Krist AH, Kubik M, Landefeld CS, Mangione CM, Silverstein M, Simon MA, Siu AL, Tseng CW | title = Screening for Prostate Cancer: US Preventive Services Task Force Recommendation Statement | journal = JAMA | volume = 319 | issue = 18 | pages = 1901–1913 | date = May 2018 | pmid = 29801017 | doi = 10.1001/jama.2018.3710 | doi-access = free }}{{cite journal | vauthors = Fenton JJ, Weyrich MS, Durbin S, Liu Y, Bang H, Melnikow J | title = Prostate-Specific Antigen-Based Screening for Prostate Cancer: Evidence Report and Systematic Review for the US Preventive Services Task Force | journal = JAMA | volume = 319 | issue = 18 | pages = 1914–1931 | date = May 2018 | pmid = 29801018 | doi = 10.1001/jama.2018.3712 | doi-access = free }}

Men with prostate cancer may be characterized as low, intermediate, or high risk for having/developing metastatic disease or dying of prostate cancer. PSA level is one of three variables on which the risk stratification is based; the others are the grade of prostate cancer (Gleason grading system) and the stage of cancer based on physical examination and imaging studies. D'Amico criteria for each risk category are:{{cite journal | vauthors = D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, Tomaszewski JE, Renshaw AA, Kaplan I, Beard CJ, Wein A | title = Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer | journal = JAMA | volume = 280 | issue = 11 | pages = 969–974 | date = September 1998 | pmid = 9749478 | doi = 10.1001/jama.280.11.969 | doi-access = free }}

:Low risk: PSA < 10, Gleason score ≤ 6, AND clinical stage ≤ T2a

:Intermediate risk: PSA 10-20, Gleason score 7, OR clinical stage T2b/c

:High risk: PSA > 20, Gleason score ≥ 8, OR clinical stage ≥ T3

Given the relative simplicity of the 1998 D'Amico criteria (above), other predictive models of risk stratification based on mathematical probability constructs exist or have been proposed to allow for better matching of treatment decisions with disease features.{{cite journal | vauthors = Rodrigues G, Warde P, Pickles T, Crook J, Brundage M, Souhami L, Lukka H | title = Pre-treatment risk stratification of prostate cancer patients: A critical review | journal = Canadian Urological Association Journal | volume = 6 | issue = 2 | pages = 121–127 | date = April 2012 | pmid = 22511420 | pmc = 3328553 | doi = 10.5489/cuaj.11085 | doi-broken-date = 28 November 2024 }}{{dead link|date=November 2016}}

Studies are being conducted into the incorporation of multiparametric MRI imaging results into nomograms that rely on PSA, Gleason grade, and tumor stage.{{cite web| vauthors = Sperling D | title = mpMRI improves the accuracy of the Partin tables and other nomograms|url=http://sperlingprostatecenter.com/mpmri-improves-the-accuracy-of-the-partin-tables-and-other-nomograms/|website=Sperling Prostate Center|access-date=31 March 2016}}

PSA levels are monitored periodically (e.g., every 6–36 months) after treatment for prostate cancer – more frequently in patients with high-risk disease, less frequently in patients with lower-risk disease. If surgical therapy (i.e., radical prostatectomy) is successful at removing all prostate tissue (and prostate cancer), PSA becomes undetectable within a few weeks. A subsequent rise in PSA level above 0.2{{nbsp}}ng/mL{{cite journal | vauthors = Freedland SJ, Sutter ME, Dorey F, Aronson WJ | title = Defining the ideal cutpoint for determining PSA recurrence after radical prostatectomy. Prostate-specific antigen | journal = Urology | volume = 61 | issue = 2 | pages = 365–369 | date = February 2003 | pmid = 12597949 | doi = 10.1016/s0090-4295(02)02268-9 }} L{{Disputed inline|Post-treatment_monitoring:_no_references._Incorrect_units.3F|date=February 2014|reason=Should units be ng/mL?}} is generally regarded as evidence of recurrent prostate cancer after a radical prostatectomy; less commonly, it may simply indicate residual benign prostate tissue.{{Citation needed|date=February 2014}}

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 2.0{{nbsp}}ng/mL{{Disputed inline|Post-treatment_monitoring:_no_references._Incorrect_units.3F|date=February 2014|reason=Should units be ng/mL?}} above the nadir is the currently accepted definition of prostate cancer recurrence after radiation therapy.{{Citation needed|date=February 2014}}

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.{{Citation needed|date=February 2014}}

PSA levels increase in the setting of prostate infection/inflammation (prostatitis), often markedly (> 100).

PSA was first identified by researchers attempting to find a substance in seminal fluid that would aid in the investigation of rape cases.{{Cite journal |vauthors=Hara M, Inorre T, Fukuyama T |title=Some physicochemical characteristics of gamma-seminoprotein, an antigenic component specific for human seminal plasma |journal= Jpn J Legal Med |year=1971 |volume=25 |pages=322–324}} PSA is used to indicate the presence of semen in forensic serology.{{cite journal | vauthors = Gartside BO, Brewer KJ, Strong CL | title = Estimation of Prostate-Specific Antigen (PSA) Extraction Efficiency from Forensic Samples Using the Serateca PSA Semiquant Semiquantitative Membrane Test | journal = Forensic Science Communications | volume = 5 | issue = 2 | date = April 2003| url =https://www.fbi.gov/hq/lab/fsc/backissu/april2003/gartside.htm | access-date = 2008-05-11 |archive-url = https://web.archive.org/web/20080409190231/http://www.fbi.gov/hq/lab/fsc/backissu/april2003/gartside.htm |archive-date = 2008-04-09 |url-status = live }} 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 spermatozoa, it remains useful in identifying semen from vasectomized and azoospermic males.{{cite journal | vauthors = Hochmeister MN, Budowle B, Rudin O, Gehrig C, Borer U, Thali M, Dirnhofer R | title = Evaluation of prostate-specific antigen (PSA) membrane test assays for the forensic identification of seminal fluid | journal = Journal of Forensic Sciences | volume = 44 | issue = 5 | pages = 1057–1060 | date = September 1999 | pmid = 10486959 | doi = 10.1520/JFS12042J }}

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 4{{nbsp}}ng/mL.{{cite journal | vauthors = Hochmeister MN, Budowle B, Rudin O, Gehrig C, Borer U, Thali M, Dirnhofer R | title = Evaluation of prostate-specific antigen (PSA) membrane test assays for the forensic identification of seminal fluid | journal = Journal of Forensic Sciences | volume = 44 | issue = 5 | pages = 1057–1060 | date = September 1999 | pmid = 10486959 | doi = 10.1520/JFS12042J | url = http://journalsip.astm.org/jofs/PAGES/3097.htm | url-status = dead | archive-url = https://web.archive.org/web/20041024194221/http://journalsip.astm.org/jofs/PAGES/3097.htm | archive-date = 2004-10-24 }} 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.

PSA is produced in the epithelial cells of the prostate, and can be demonstrated in biopsy samples or other histological specimens using immunohistochemistry. Disruption of this epithelium, for example in inflammation or benign prostatic hyperplasia, may lead to some diffusion of the antigen into the tissue around the epithelium, and is the cause of elevated blood levels of PSA in these conditions.{{cite book | vauthors = Leong AS, Cooper K, Leong FJ | year = 2003 | title = Manual of Diagnostic Cytology | edition = 2nd | publisher = Greenwich Medical Media, Ltd. | pages = 79–80 | isbn = 978-1-84110-100-2 }}

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.

The physiological function of KLK3 is the dissolution of the coagulum, the sperm-entrapping gel composed of semenogelins and fibronectin. Its proteolytic action is effective in liquefying the coagulum so that the sperm can be liberated. The activity of PSA is well regulated. In the prostate, it is present as an inactive pro-form, which is activated through the action of KLK2, another kallikrein-related peptidase. In the prostate, zinc ion concentrations are 10 times higher than in other bodily fluids. Zinc ions have a strong inhibitory effect on the activity of PSA and on that of KLK2, so that PSA is totally inactive.{{cite journal | vauthors = Hara M, Kimura H | title = Two prostate-specific antigens, gamma-seminoprotein and beta-microseminoprotein | journal = The Journal of Laboratory and Clinical Medicine | volume = 113 | issue = 5 | pages = 541–548 | date = May 1989 | pmid = 2654306 | url = https://www.translationalres.com/article/0022-2143(89)90023-1/fulltext#%20 }}

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.{{citation needed|date=May 2021}}

Prostate-specific antigen (PSA, also known as kallikrein III, seminin, semenogelase, γ-seminoprotein and P-30 antigen) is a 34-kD glycoprotein produced almost exclusively by the prostate gland. It is a serine protease ({{EC number|3.4.21.77}}) enzyme, the gene of which is located on the 19th chromosome (19q13) in humans.{{cite journal | vauthors = Lilja H | title = Biology of prostate-specific antigen | journal = Urology | volume = 62 | issue = 5 Suppl 1 | pages = 27–33 | date = November 2003 | pmid = 14607215 | doi = 10.1016/S0090-4295(03)00775-1 }}

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.{{cite journal | vauthors = Rao AR, Motiwala HG, Karim OM | title = The discovery of prostate-specific antigen | journal = BJU International | volume = 101 | issue = 1 | pages = 5–10 | date = January 2008 | pmid = 17760888 | doi = 10.1111/j.1464-410X.2007.07138.x | s2cid = 27307190 }}

Flocks was the first to experiment with antigens in the prostate{{cite journal | vauthors = Flocks RH, Boatman DL, Hawtrey CE | title = Tissue specific isoantigens in the dog prostate | journal = Investigative Urology | volume = 10 | issue = 3 | pages = 215–220 | date = November 1972 | pmid = 4629646 }} and 10 years later Ablin reported the presence of precipitation antigens in the prostate.{{cite journal | vauthors = Ablin RJ, Soanes WA, Gonder MJ | title = Immunologic studies of the prostate. A review | journal = International Surgery | volume = 52 | issue = 1 | pages = 8–21 | date = July 1969 | pmid = 4977978 }}

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.{{cite journal | vauthors = Li TS, Beling CG | title = Isolation and characterization of two specific antigens of human seminal plasma | journal = Fertility and Sterility | volume = 24 | issue = 2 | pages = 134–144 | date = February 1973 | pmid = 4631694 | doi = 10.1016/S0015-0282(16)39496-1 }}{{cite journal | vauthors = Li TS, Beling CG | title = The effect of antibodies to two human seminal plasma-specific antigens on human sperm | journal = Fertility and Sterility | volume = 25 | issue = 10 | pages = 851–856 | date = October 1974 | pmid = 4213812 | doi = 10.1016/S0015-0282(16)40691-6 | doi-access = free }}

In 1978, Sensabaugh identified semen-specific protein p30, but proved that it was similar to E1 protein, and that prostate was the source.{{cite journal | vauthors = Sensabaugh GF | title = Isolation and characterization of a semen-specific protein from human seminal plasma: a potential new marker for semen identification | journal = Journal of Forensic Sciences | volume = 23 | issue = 1 | pages = 106–115 | date = January 1978 | pmid = 744956 | doi = 10.1520/JFS10659J }} In 1979, Wang purified a tissue-specific antigen from the prostate ('prostate antigen').{{cite journal | vauthors = Wang MC, Valenzuela LA, Murphy GP, Chu TM | title = Purification of a human prostate specific antigen | journal = Investigative Urology | volume = 17 | issue = 2 | pages = 159–163 | date = September 1979 | pmid = 89106 }}

PSA was first measured quantitatively in the blood by Papsidero in 1980,{{cite journal | vauthors = Kuriyama M, Wang MC, Papsidero LD, Killian CS, Shimano T, Valenzuela L, Nishiura T, Murphy GP, Chu TM | title = Quantitation of prostate-specific antigen in serum by a sensitive enzyme immunoassay | journal = Cancer Research | volume = 40 | issue = 12 | pages = 4658–4662 | date = December 1980 | pmid = 6159971 }} and Stamey carried out the initial work on the clinical use of PSA as a marker of prostate cancer.

PSA is normally present in the blood at very low levels. The reference range of less than 4{{nbsp}}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{{nbsp}}ng/mL.{{cite news | vauthors = Gina K |date=May 30, 2004 |title=It Was Medical Gospel, but It Wasn't True |work=The New York Times |page=47 |url=https://www.nytimes.com/2004/05/30/weekinreview/it-was-medical-gospel-but-it-wasn-t-true.html }}{{cite journal | vauthors = Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA | title = Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter | journal = The New England Journal of Medicine | volume = 350 | issue = 22 | pages = 2239–2246 | date = May 2004 | pmid = 15163773 | doi = 10.1056/NEJMoa031918 | s2cid = 3747157 | doi-access = free }}{{cite journal | vauthors = Carter HB | title = Prostate cancers in men with low PSA levels--must we find them? | journal = The New England Journal of Medicine | volume = 350 | issue = 22 | pages = 2292–2294 | date = May 2004 | pmid = 15163780 | pmc = 3474980 | doi = 10.1056/NEJMe048003 }}{{cite book |vauthors=Myrtle JF, Klimley PG, Ivor L, Bruni JF |year=1986 |chapter=Clinical utility of prostate specific antigen (PSA) in the management of prostate cancer |title=Advances in Cancer Diagnostics |location=San Diego |publisher=Hybritech Inc}}{{cite book |vauthors=Myrtle JF, Ivor L |year=1989 |chapter=Measurement of Prostate-Specific Antigen (PSA) in Serum by a Two-Site Immunometric Method (Hybritech Tandem-R/Tandem-E PSA) |veditors=Catalona WJ, Coffey DS, Karr JP |title=Clinical Aspects of Prostate Cancer. Assessment of New Diagnostic and Management Procedures. Proceedings of a workshop of the Prostate Cancer Working Group of the National Cancer Institute's Organ Systems Program, held October 16–19, 1988 at Prout's Neck, Maine, U.S.A. |location=New York |publisher=Elsevier |isbn=978-0-444-01514-3 |pages=161–71}}{{cite book |author=Myrtle JF |year=1989 |chapter=Normal Levels of Prostate-Specific Antigen (PSA) |veditors=Catalona WJ, Coffey DS, Karr JP |title=Clinical Aspects of Prostate Cancer. Assessment of New Diagnostic and Management Procedures. Proceedings of a workshop of the Prostate Cancer Working Group of the National Cancer Institute's Organ Systems Program, held October 16–19, 1988 at Prout's Neck, Maine, U.S.A. |location=New York |publisher=Elsevier |isbn=978-0-444-01514-3 |pages=183–9}}{{cite journal | vauthors = Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, Petros JA, Andriole GL | title = Measurement of prostate-specific antigen in serum as a screening test for prostate cancer | journal = The New England Journal of Medicine | volume = 324 | issue = 17 | pages = 1156–1161 | date = April 1991 | pmid = 1707140 | doi = 10.1056/NEJM199104253241702 | doi-access = free }}{{cite journal | vauthors = Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, DeKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL, Waters WB, MacFarlane MT, Southwick PC | title = Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men | journal = The Journal of Urology | volume = 151 | issue = 5 | pages = 1283–1290 | date = May 1994 | pmid = 7512659 | doi = 10.1016/S0022-5347(17)35233-3 }}

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.{{cite journal | vauthors = Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA | title = Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter | journal = The New England Journal of Medicine | volume = 350 | issue = 22 | pages = 2239–2246 | date = May 2004 | pmid = 15163773 | doi = 10.1056/NEJMoa031918 | s2cid = 3747157 | doi-access = free }}

Obesity has been reported to reduce serum PSA levels.{{cite journal | vauthors = Bañez LL, Hamilton RJ, Partin AW, Vollmer RT, Sun L, Rodriguez C, Wang Y, Terris MK, Aronson WJ, Presti JC, Kane CJ, Amling CL, Moul JW, Freedland SJ | title = Obesity-related plasma hemodilution and PSA concentration among men with prostate cancer | journal = JAMA | volume = 298 | issue = 19 | pages = 2275–2280 | date = November 2007 | pmid = 18029831 | doi = 10.1001/jama.298.19.2275 | doi-access = free }} Delayed early detection may partially explain worse outcomes in obese men with early prostate cancer.{{cite journal | vauthors = Dreicer R | title = Why do obese men have lower PSA concentrations? | journal = Journal Watch | date = 2007-11-20 | url = http://oncology-hematology.jwatch.org/cgi/content/full/2007/1120/1 | access-date = 2008-04-27 | volume = 2007 | issue = 1120 | pages = 1 | archive-url = https://web.archive.org/web/20080217021312/http://oncology-hematology.jwatch.org/cgi/content/full/2007/1120/1 | archive-date = 2008-02-17 | url-status = dead }} After treatment, higher BMI also correlates to higher risk of recurrence.{{cite journal | vauthors = Cao Y, Ma J | title = Body mass index, prostate cancer-specific mortality, and biochemical recurrence: a systematic review and meta-analysis | journal = Cancer Prevention Research | volume = 4 | issue = 4 | pages = 486–501 | date = April 2011 | pmid = 21233290 | pmc = 3071449 | doi = 10.1158/1940-6207.CAPR-10-0229 }}

PSA levels can be also increased by prostatitis, irritation, benign prostatic hyperplasia (BPH), and recent ejaculation,{{cite journal | vauthors = Herschman JD, Smith DS, Catalona WJ | title = Effect of ejaculation on serum total and free prostate-specific antigen concentrations | journal = Urology | volume = 50 | issue = 2 | pages = 239–243 | date = August 1997 | pmid = 9255295 | doi = 10.1016/S0090-4295(97)00209-4 | s2cid = 46329694 }}{{cite journal | vauthors = Nadler RB, Humphrey PA, Smith DS, Catalona WJ, Ratliff TL | title = Effect of inflammation and benign prostatic hyperplasia on elevated serum prostate specific antigen levels | journal = The Journal of Urology | volume = 154 | issue = 2 Pt 1 | pages = 407–413 | date = August 1995 | pmid = 7541857 | doi = 10.1016/S0022-5347(01)67064-2 }} producing a false positive result. Digital rectal examination (DRE) has been shown in several studies{{cite journal | vauthors = Crawford ED, Schutz MJ, Clejan S, Drago J, Resnick MI, Chodak GW, Gomella LG, Austenfeld M, Stone NN, Miles BJ | title = The effect of digital rectal examination on prostate-specific antigen levels | journal = JAMA | volume = 267 | issue = 16 | pages = 2227–2228 | year = 1992 | pmid = 1372943 | doi = 10.1001/jama.267.16.2227 }}{{cite journal | vauthors = Chybowski FM, Bergstralh EJ, Oesterling JE | title = The effect of digital rectal examination on the serum prostate specific antigen concentration: results of a randomized study | journal = The Journal of Urology | volume = 148 | issue = 1 | pages = 83–86 | date = July 1992 | pmid = 1377290 | doi = 10.1016/S0022-5347(17)36517-5 }}{{cite journal | vauthors = Collins GN, Martin PJ, Wynn-Davies A, Brooman PJ, O'Reilly PH | title = The effect of digital rectal examination, flexible cystoscopy and prostatic biopsy on free and total prostate specific antigen, and the free-to-total prostate specific antigen ratio in clinical practice | journal = The Journal of Urology | volume = 157 | issue = 5 | pages = 1744–1747 | date = May 1997 | pmid = 9112518 | doi = 10.1016/S0022-5347(01)64849-3 }}{{cite journal | vauthors = Tarhan F, Orçun A, Küçükercan I, Camursoy N, Kuyumcuoğlu U | title = Effect of prostatic massage on serum complexed prostate-specific antigen levels | journal = Urology | volume = 66 | issue = 6 | pages = 1234–1238 | date = December 2005 | pmid = 16360449 | doi = 10.1016/j.urology.2005.06.077 }} 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{{nbsp}}ng/mL. PSA levels are higher during the summer than during the rest of the year.{{cite journal | vauthors = Salama G, Noirot O, Bataille V, Malavaud S, Rebillard X, Villers A, Malavaud B | collaboration = French arm of the ERSPC study | title = Seasonality of serum prostate-specific antigen levels: a population-based study | journal = European Urology | volume = 52 | issue = 3 | pages = 708–714 | date = September 2007 | pmid = 17174467 | doi = 10.1016/j.eururo.2006.11.042 | author8 = French arm of the ERSPC study }}{{cite journal | vauthors = Dobson R | title = Summer PSA tests may lead to more biopsies | journal = BMJ | volume = 335 | issue = 7614 | pages = 276 | date = August 2007 | pmid = 17690355 | pmc = 1941861 | doi = 10.1136/bmj.39297.475694.DB }}

The "normal" reference ranges for prostate-specific antigen increase with age, as do the usual ranges in cancer (per associated table).{{cite journal | vauthors = Connolly D, Black A, Murray L, Gavin A, Keane P | year = 2007 | title = 798 Population Based Age-Specific Reference Ranges for PSA |journal=European Urology Supplements |volume=6 |issue=2 |pages=222 |doi=10.1016/S1569-9056(07)60793-3}}{{cite journal| vauthors = Luboldt HJ, Schindler JF, Rübben H |title=Age-Specific Reference Ranges for Prostate-Specific Antigen as a Marker for Prostate Cancer|journal=EAU-EBU Update Series|volume=5|issue=1|year=2007|pages=38–48|issn=1871-2592|doi=10.1016/j.eeus.2006.10.003}}

Despite earlier findings,{{cite journal | vauthors = Carter HB, Pearson JD, Metter EJ, Brant LJ, Chan DW, Andres R, Fozard JL, Walsh PC | title = Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease | journal = JAMA | volume = 267 | issue = 16 | pages = 2215–2220 | year = 1992 | pmid = 1372942 | pmc = 3461837 | doi = 10.1001/jama.267.16.2215 }} recent research suggests that the rate of increase of PSA (e.g. >0.35{{nbsp}}ng/mL/yr, the 'PSA velocity'{{cite web |url=http://www.cancer.gov/cancertopics/types/prostate/research/psa-velocity-detection |title=PSA Velocity Does Not Improve Prostate Cancer Detection |date=13 April 2011| access-date=25 April 2015 }}) is not a more specific marker for prostate cancer than the serum level of PSA.{{cite journal | vauthors = Carter HB | title = Assessing risk: does this patient have prostate cancer? | journal = Journal of the National Cancer Institute | volume = 98 | issue = 8 | pages = 506–507 | date = April 2006 | pmid = 16622114 | doi = 10.1093/jnci/djj155 | doi-access = free }}

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{{nbsp}}ng per milliliter during the year before the diagnosis of prostate cancer have a higher risk of death from prostate cancer despite undergoing radical prostatectomy.{{cite journal | vauthors = D'Amico AV, Chen MH, Roehl KA, Catalona WJ | title = Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy | journal = The New England Journal of Medicine | volume = 351 | issue = 2 | pages = 125–135 | date = July 2004 | pmid = 15247353 | doi = 10.1056/NEJMoa032975 | doi-access = free }} 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.{{cite journal | vauthors = Loeb S, Kettermann A, Ferrucci L, Landis P, Metter EJ, Carter HB | title = PSA doubling time versus PSA velocity to predict high-risk prostate cancer: data from the Baltimore Longitudinal Study of Aging | journal = European Urology | volume = 54 | issue = 5 | pages = 1073–1080 | date = November 2008 | pmid = 18614274 | pmc = 2582974 | doi = 10.1016/j.eururo.2008.06.076 }}

Men who are known to be at risk for prostate cancer, and who 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{{cite web|title=Semi-Log Transformations of Data |url=http://wmueller.com/precalculus/families/semilog.html |access-date=4 March 2016 |url-status=bot: unknown |archive-url=https://web.archive.org/web/20160224083006/http://wmueller.com/precalculus/families/semilog.html |archive-date=24 February 2016 }}(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.

Image:Free PSA bar graph.svg

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) The lower the ratio is, the greater the probability of prostate cancer. Measuring the ratio of free to total PSA appears to be particularly promising for eliminating unnecessary biopsies in men with PSA levels between 4 and 10{{nbsp}}ng/mL.{{cite journal | vauthors = Catalona WJ, Smith DS, Ornstein DK | title = Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination. Enhancement of specificity with free PSA measurements | journal = JAMA | volume = 277 | issue = 18 | pages = 1452–1455 | date = May 1997 | pmid = 9145717 | doi = 10.1001/jama.277.18.1452 }} However, both total and free PSA increase immediately after ejaculation, returning slowly to baseline levels within 24 hours.

The PSA test in 1994 failed to differentiate between prostate cancer and benign prostate hyperplasia (BPH) and the commercial assay kits for PSA did not provide correct PSA values.{{cite journal | vauthors = Wu JT | title = Assay for prostate specific antigen (PSA): problems and possible solutions | journal = Journal of Clinical Laboratory Analysis | volume = 8 | issue = 1 | pages = 51–62 | year = 1994 | pmid = 7513021 | doi = 10.1002/jcla.1860080110 | s2cid = 13179006 }} Thus with the introduction of the ratio of free-to-total PSA, the reliability of the test has improved. Measuring the activity of the enzyme could add to the ratio of free-to-total PSA and further improve the diagnostic value of test.{{cite web | url = http://www.sbir.gov/sbirsearch/detail/12931 |title=A bioelectronic assay for PSA activity }} Proteolytically active PSA has been shown to have an anti-angiogenic effect {{cite journal | vauthors = Mattsson JM, Valmu L, Laakkonen P, Stenman UH, Koistinen H | title = Structural characterization and anti-angiogenic properties of prostate-specific antigen isoforms in seminal fluid | journal = The Prostate | volume = 68 | issue = 9 | pages = 945–954 | date = June 2008 | pmid = 18386289 | doi = 10.1002/pros.20751 | s2cid = 30095129 }} and certain inactive subforms may be associated with prostate cancer, as shown by MAb 5D3D11, an antibody able to detect forms abundantly represented in sera from cancer patients.{{cite journal | vauthors = Stura EA, Muller BH, Bossus M, Michel S, Jolivet-Reynaud C, Ducancel F | title = Crystal structure of human prostate-specific antigen in a sandwich antibody complex | journal = Journal of Molecular Biology | volume = 414 | issue = 4 | pages = 530–544 | date = December 2011 | pmid = 22037582 | doi = 10.1016/j.jmb.2011.10.007 }}

The presence of inactive proenzyme forms of PSA is another potential indicator of disease.{{cite journal | vauthors = Mikolajczyk SD, Catalona WJ, Evans CL, Linton HJ, Millar LS, Marker KM, Katir D, Amirkhan A, Rittenhouse HG | title = Proenzyme forms of prostate-specific antigen in serum improve the detection of prostate cancer | journal = Clinical Chemistry | volume = 50 | issue = 6 | pages = 1017–1025 | date = June 2004 | pmid = 15054080 | doi = 10.1373/clinchem.2003.026823 | doi-access = free }}

PSA exists in serum in the free (unbound) form and in a complex with alpha 1-antichymotrypsin; research has been conducted to see if measurements of complexed PSA are more specific and sensitive biomarkers for prostate cancer than other approaches.{{cite journal | vauthors = Mikolajczyk SD, Marks LS, Partin AW, Rittenhouse HG | title = Free prostate-specific antigen in serum is becoming more complex | journal = Urology | volume = 59 | issue = 6 | pages = 797–802 | date = June 2002 | pmid = 12031356 | doi = 10.1016/S0090-4295(01)01605-3 }}{{cite journal | vauthors = Naya Y, Okihara K | title = Role of complexed PSA in the early detection of prostate cancer | journal = Journal of the National Comprehensive Cancer Network | volume = 2 | issue = 3 | pages = 209–212 | date = May 2004 | pmid = 19795605 | doi = 10.6004/jnccn.2004.0019 | doi-access = free }}

The term prostate-specific antigen is a misnomer: it is an antigen but is not specific to the prostate. Although present in large amounts in prostatic tissue and semen, it has been detected in other body fluids and tissues.{{cite report | vauthors = Laux DL, Custis SE |title=Forensic Detection of Semen III. Detection of PSA Using Membrane Based Tests: Sensitivity Issues with Regards to the Presence of PSA in Other Body Fluids |publisher=Midwestern Association of Forensic Scientists |url=http://mafs.net/pdf/forensicdetectionsemen3.pdf |access-date=2008-05-11 |url-status=dead |archive-url=https://web.archive.org/web/20050827025155/http://mafs.net/pdf/forensicdetectionsemen3.pdf |archive-date=2005-08-27 }}

In women, PSA is found in female ejaculate at concentrations roughly equal to that found in male semen.{{cite journal | vauthors = Wimpissinger F, Stifter K, Grin W, Stackl W | title = The female prostate revisited: perineal ultrasound and biochemical studies of female ejaculate | journal = The Journal of Sexual Medicine | volume = 4 | issue = 5 | pages = 1388–93; discussion 1393 | date = September 2007 | pmid = 17634056 | doi = 10.1111/j.1743-6109.2007.00542.x }} 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.{{Cite web | vauthors = Brosman SA | work = eMedicine | title = Prostate-Specific Antigen |publisher=WebMD |url= http://www.emedicine.com/med/TOPIC3465.HTM#section~CharacteristicsofProstateSpecificAntigen|access-date=2008-05-11}}

Tissue samples can be stained for the presence of PSA in order to determine the origin of malignant cells that have metastasized.{{cite journal | vauthors = Chuang AY, DeMarzo AM, Veltri RW, Sharma RB, Bieberich CJ, Epstein JI | title = Immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma | journal = The American Journal of Surgical Pathology | volume = 31 | issue = 8 | pages = 1246–1255 | date = August 2007 | pmid = 17667550 | doi = 10.1097/PAS.0b013e31802f5d33 | s2cid = 11535862 }}

Prostate-specific antigen has been shown to interact with protein C inhibitor.{{cite journal | vauthors = Christensson A, Lilja H | title = Complex formation between protein C inhibitor and prostate-specific antigen in vitro and in human semen | journal = European Journal of Biochemistry | volume = 220 | issue = 1 | pages = 45–53 | date = February 1994 | pmid = 7509746 | doi = 10.1111/j.1432-1033.1994.tb18597.x }}{{cite journal | vauthors = Kise H, Nishioka J, Kawamura J, Suzuki K | title = Characterization of semenogelin II and its molecular interaction with prostate-specific antigen and protein C inhibitor | journal = European Journal of Biochemistry | volume = 238 | issue = 1 | pages = 88–96 | date = May 1996 | pmid = 8665956 | doi = 10.1111/j.1432-1033.1996.0088q.x | doi-access = free }}

Prostate-specific antigen interacts with and activates the vascular endothelial growth factors VEGF-C and VEGF-D, which are involved in tumor angiogenesis and in the lymphatic metastasis of tumors.{{cite journal | vauthors = Jha SK, Rauniyar K, Chronowska E, Mattonet K, Maina EW, Koistinen H, Stenman UH, Alitalo K, Jeltsch M | title = KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D | journal = eLife | volume = 8 | pages = –44478 | date = May 2019 | pmid = 31099754 | pmc = 6588350 | doi = 10.7554/eLife.44478 | doi-access = free }}

• Tumor markers

{{Reflist|30em}}

{{Refbegin | 2}}

• {{cite journal | vauthors = De Angelis G, Rittenhouse HG, Mikolajczyk SD, Blair Shamel L, Semjonow A | title = Twenty Years of PSA: From Prostate Antigen to Tumor Marker | journal = Reviews in Urology | volume = 9 | issue = 3 | pages = 113–123 | year = 2007 | pmid = 17934568 | pmc = 2002501 }}
• {{cite journal | vauthors = Henttu P, Vihko P | title = Prostate-specific antigen and human glandular kallikrein: two kallikreins of the human prostate | journal = Annals of Medicine | volume = 26 | issue = 3 | pages = 157–164 | date = June 1994 | pmid = 7521173 | doi = 10.3109/07853899409147884 }}
• {{cite journal | vauthors = Diamandis EP, Yousef GM, Luo LY, Magklara A, Obiezu CV | title = The new human kallikrein gene family: implications in carcinogenesis | journal = Trends in Endocrinology and Metabolism | volume = 11 | issue = 2 | pages = 54–60 | date = March 2000 | pmid = 10675891 | doi = 10.1016/S1043-2760(99)00225-8 | s2cid = 25806934 }}
• {{cite journal | vauthors = Lilja H | title = Biology of prostate-specific antigen | journal = Urology | volume = 62 | issue = 5 Suppl 1 | pages = 27–33 | date = November 2003 | pmid = 14607215 | doi = 10.1016/S0090-4295(03)00775-1 }}

{{Refend}}

• {{cite web | work = National Cancer Institute | url = https://www.cancer.gov/types/prostate/psa-fact-sheet | title = The Prostate-Specific Antigen (PSA) Test: Questions and Answers | date = 21 March 2022 }}
• {{MeshName|Prostate-Specific+Antigen}}
• {{PDBe-KB2|P07288|Prostate-specific antigen}}

{{Tumor markers}}

{{Serine endopeptidases}}

{{Enzymes}}

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{{DEFAULTSORT:Prostate Specific Antigen}}

Category:Andrology

Category:Biomarkers

Category:Blood tests

Category:EC 3.4.21

Category:Prostate cancer

Category:Tumor markers

Category:Urology