Editing Prostate-specific antigen (section)

==Serum levels==

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.<ref name="Gina-2004">{{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 }}</ref><ref name="Thompson-2004">{{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 }}</ref><ref name="Carter-2004">{{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 }}</ref><ref name-"Myrtle-1986">{{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}}</ref><ref name="Myrtle-1989">{{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}}</ref><ref name="Myrtle-1989b">{{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}}</ref><ref name="Catalona-1991">{{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 }}</ref><ref name="Catalona-1994">{{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 }}</ref>

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 [[Type I and type II errors|false negative]].<ref>{{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 }}</ref>

[[Obesity]] has been reported to reduce serum PSA levels.<ref>{{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 }}</ref> Delayed early detection may partially explain worse outcomes in obese men with early prostate cancer.<ref>{{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 }}</ref> After treatment, higher BMI also correlates to higher risk of recurrence.<ref>{{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 }}</ref>

PSA levels can be also increased by [[prostatitis]], irritation, [[benign prostatic hyperplasia]] (BPH), and recent ejaculation,<ref name="Herschman-1997">{{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 }}</ref><ref name="Nadler-1995">{{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 }}</ref> producing a [[false positive]] result. Digital [[rectal examination]] (DRE) has been shown in several studies<ref name="Crawford-1992">{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref> 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.<ref>{{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 }}</ref><ref>{{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 }}</ref>

The "normal" [[reference range]]s for prostate-specific antigen increase with age, as do the usual ranges in cancer (per associated table).<ref name="Connolly-2007">{{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}}</ref><ref name="Luboldt-2007">{{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}}</ref>

{| class="wikitable"
! Age !!colspan=2| 40 - 49 !!colspan=2| 50 - 59 !!colspan=2| 60 - 69 !!colspan=2| 70-79 !! years
|-
| ||style="background: Salmon"| Cancer ||style="background: PaleGreen"| No cancer ||style="background: Salmon"| Cancer ||style="background: PaleGreen"| No cancer ||style="background: Salmon"| Cancer ||style="background: PaleGreen"| No cancer ||style="background: Salmon"| Cancer ||style="background: PaleGreen"| No cancer ||
|-
| 5th [[percentile]] ||style="background: Salmon"| 0.4<ref name="Connolly-2007"/> ||style="background: PaleGreen"| 0.3<ref name="Connolly-2007"/> ||style="background: Salmon"| 1.2<ref name="Connolly-2007"/> ||style="background: PaleGreen"| 0.3<ref name="Connolly-2007"/> ||style="background: Salmon"| 1.7<ref name="Connolly-2007"/> ||style="background: PaleGreen"| 0.3<ref name="Connolly-2007"/> ||style="background: Salmon"| 2.3<ref name="Connolly-2007"/> ||style="background: PaleGreen"| 0.4<ref name="Connolly-2007"/>
!rowspan=3| ng/mL or μg/L
|-
| 95th percentile<br />Non-[[African-American]] ||style="background: Salmon" rowspan=2| 163.0<ref name="Connolly-2007"/> ||style="background: PaleGreen"| 1.2 - 2.9<ref name="Luboldt-2007"/> ||style="background: Salmon" rowspan=2| 372.5<ref name="Connolly-2007"/> ||style="background: PaleGreen"| 2.07 - 4.7<ref name="Luboldt-2007"/> ||style="background: Salmon" rowspan=2| 253.2<ref name="Connolly-2007"/> ||style="background: PaleGreen"| 2.8 - 7.2 ||style="background: Salmon" rowspan=2| 613.2<ref name="Connolly-2007"/> ||style="background: PaleGreen"| 4.0 - 9.0<ref name="Luboldt-2007"/>
|-
| 95th percentile<br />[[African-American]] ||style="background: PaleGreen"| 2.4 - 2.7<ref name="Luboldt-2007"/> ||style="background: PaleGreen"| 4.4 - 6.5<ref name="Luboldt-2007"/> ||style="background: PaleGreen"| 6.7 - 11<ref name="Luboldt-2007"/> ||style="background: PaleGreen"| 7.7 - 13<ref name="Luboldt-2007"/>
|}

===PSA velocity===

Despite earlier findings,<ref>{{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 }}</ref> recent research suggests that the rate of increase of PSA (e.g. >0.35{{nbsp}}ng/mL/yr, the 'PSA velocity'<ref>{{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 }}</ref>) is not a more specific marker for prostate cancer than the serum level of PSA.<ref>{{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 }}</ref>

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 retropubic prostatectomy|radical prostatectomy]].<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref>

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<ref name="SemiLog">{{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 )</ref> 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,<ref name="SemiLog"/> i.e., a higher PSA velocity.

===Free PSA===

[[Image:Free PSA bar graph.svg|thumb|300px|Risk of prostate cancer in two age groups based on ''Free PSA'' as % of Total PSA<ref>{{cite journal | vauthors = Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, Richie JP, deKernion JB, Walsh PC, Scardino PT, Lange PH, Subong EN, Parson RE, Gasior GH, Loveland KG, Southwick PC | title = Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial | journal = JAMA | volume = 279 | issue = 19 | pages = 1542–1547 | date = May 1998 | pmid = 9605898 | doi = 10.1001/jama.279.19.1542 }}</ref>]]
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 [[Biopsy|biopsies]] in men with PSA levels between 4 and 10{{nbsp}}ng/mL.<ref>{{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 }}</ref> However, both total and free PSA increase immediately after ejaculation, returning slowly to baseline levels within 24 hours.<ref name="Herschman-1997"/>

===Inactive PSA===

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.<ref name="Wu-1994">{{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 }}</ref> 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.<ref>{{cite web | url = http://www.sbir.gov/sbirsearch/detail/12931 |title=A bioelectronic assay for PSA activity }}</ref> Proteolytically active PSA has been shown to have an anti-angiogenic effect <ref name="Mattsson-2008">{{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 }}</ref> 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.<ref name="Stura-2011">{{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 }}</ref>
The presence of inactive proenzyme forms of PSA is another potential indicator of disease.<ref name="Mikolajczyk-2004">{{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 }}</ref>

===Complexed PSA===

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.<ref name="Mikolajczyk-2002">{{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 }}</ref><ref name="Naya-2004">{{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 }}</ref>