Prostate-specific antigen

Kallikrein related peptidase 3

Crystallographic structure of human prostate-specific antigen (green/gold cartoon) covalently attached to an substrate acyl intermediate (multicolor sticks, carbon = white, nitrogen = blue, oxygen = red) and an glucosamine–manose disaccharide (spheres, carbon = yellow and oxygen = red).[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols KLK3 ; APS; KLK2A1; PSA; hK3
External IDs OMIM: 176820 MGI: 892021 HomoloGene: 68141 ChEMBL: 2099 GeneCards: KLK3 Gene
EC number 3.4.21.77
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 354 13646
Ensembl ENSG00000142515 ENSMUSG00000060177
UniProt P07288 P15948
RefSeq (mRNA) NM_001030047 NM_010114
RefSeq (protein) NP_001025218 NP_034244
Location (UCSC) Chr 19:
50.85 – 50.86 Mb		 Chr 7:
44.11 – 44.12 Mb
PubMed search

Prostate-specific antigen (PSA), also known as gamma-seminoprotein or kallikrein-3 (KLK3), is a glycoprotein enzyme encoded in humans by the KLK3 gene. PSA is a member of the kallikrein-related peptidase family and is secreted by the epithelial cells of the prostate gland. PSA is produced for the ejaculate, where it liquefies semen in the seminal coagulum and allows sperm to swim freely.[2] It is also believed to be instrumental in dissolving cervical mucus, allowing the entry of sperm into the uterus.[3]

PSA is present in small quantities in the serum of men with healthy prostates, but is often elevated in the presence of prostate cancer or other prostate disorders.[4] The United States Preventive Services Task Force (USPSTF, 2012) does not recommend PSA screening for prostate cancer, noting that the test may result in “overdiagnosis” and “overtreatment” because "most prostate cancer is asymptomatic for life" and treatments involve risks of complications including impotence (erectile dysfunction) and incontinence. The USPSTF concludes "the potential benefit does not outweigh the expected harms."[5] PSA is not a unique indicator of prostate cancer, but may also detect prostatitis or benign prostatic hyperplasia.[6] 30 percent of patients with high PSA have prostate cancer diagnosed after biopsy.

Medical uses

Prostate cancer

Screening

Clinical practice guidelines for prostate cancer screening vary and are controversial due to uncertainty as to whether the benefits of screening ultimately outweigh the risks of overdiagnosis and over treatment.[7] In the United States, 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. The patient needs to be informed of the risks and benefits of PSA testing prior to performing the test (see below). PSA levels between 4 and 10 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 tissue sample for histopathological analysis. In the United Kingdom, the National Health Service (2005) does not mandate, nor advise for PSA test, but allows patients to decide based on their doctor's advice.[8]

A review commissioned by the U.S. Preventive Services Task Force concluded that "Prostate-specific antigen-based screening results in small or no reduction in prostate cancer-specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary,"[5] or more simply, "[t]he potential benefit does not outweigh the expected harms" in patients not already diagnosed or being treated for prostate cancer.

While PSA testing may help 1000 in 1,000,000 avoid death due to prostate cancer, 4000 to 5000 in 1,000,000 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. Of those found to have prostate cancer, frequent overdiagnosis is common because most cases of prostate cancer are not expected to cause any symptoms. Therefore many will experience the side effects of treatment, such as for every 100 men screened, 2.9 will experience erectile dysfunction, 1.8 will suffer urinary incontinence, .2 will have serious cardiovascular events, .1 will suffer pulmonary embolus or deep venous thrombosis, and .1 perioperative death. Since the expected harm relative to risk of death are perceived by patients as minimal, men found to have prostate cancer usually (up to 90% of cases) select to receive treatment.[5]

Risk stratification and staging

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. Criteria for each risk category are as follows:

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 D’Amico criteria, 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.[9] Studies are being conducted into the incorporation of multiparametric MRI imaging results into nomograms that rely on PSA, Gleason grade and tumor stage.[10]

Post-treatment monitoring

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 ng/mL[11] L is generally regarded as evidence of recurrent prostate cancer after a radical prostatectomy; less commonly, it may simply indicate residual benign prostate tissue.

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 it more difficult to interpret the relationship between PSA levels and recurrence/persistence of prostate cancer after radiation therapy. 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 ng/dL above the nadir is the currently accepted definition of prostate cancer recurrence after radiation therapy.

If recurrent prostate cancer is detected by a rise in PSA levels after curative treatment, it 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.

Histology

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.[12]

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. However, in most cases of prostate cancer, the cells remain positive for the antigen, which can therefore 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 PSAP and CD57.[12]

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.[13] PSA is now used to indicate the presence of semen in forensic serology.[14] 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.[15]

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.[16] 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 ng/mL.[17] 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.[16] 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.

Mechanism of action

The physiological function of KLK3 is the dissolution of the coagulum, the sperm entrapping gel composed of semenogelins and fibronectin. Its proteolic 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 ten 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. 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.

Biochemistry

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 3.4.21.77) enzyme, the gene of which is located on the 19th chromosome (19q13) in humans.[18]

History

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.[19]

Flocks was the first to experiment with antigens in the prostate[20] and 10 years later Albin reported the presence of precipitation antigens in the prostate.[21]

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.[22][23]

In 1978, Sensabaugh identified semen-specific protein p30, but proved that it was similar to E1 protein, and that prostate was the source.[24] In 1979, Wang purified a tissue-specific antigen from the prostate ('prostate antigen').[25]

PSA was first measured quantitatively in the blood by Papsidero in 1980,[26] and Stamey carried out the initial work on the clinical use of PSA as a marker of prostate cancer.

Serum levels

PSA is normally present in the blood at very low levels. The reference range 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.[27]

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.[28]

Obesity has been reported to reduce serum PSA levels.[29] Delayed early detection may partially explain worse outcomes in obese men with early prostate cancer.[30] After treatment, higher BMI also correlates to higher risk of recurrence.[31]

PSA levels can be also increased by prostatitis, irritation, benign prostatic hyperplasia (BPH), and recent ejaculation,[32][33] producing a false positive result. Digital rectal examination (DRE) has been shown in several studies[34] 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 ranges for prostate-specific antigen increase with age, as do the usual ranges in cancer:[35]

Age <50 50 - 59 60 - 69 >70 (years)
Cancer No cancer Cancer No cancer Cancer No cancer Cancer No cancer
5th percentile 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

PSA velocity

Risk of prostate cancer in two age groups based on Free PSA as % of Total PSA [36]

Despite earlier findings,[37] recent research suggests that the rate of increase of PSA (e.g. >0.35 ng/mL/yr, the 'PSA velocity'[38]) is not a more specific marker for prostate cancer than the serum level of PSA.[39]

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 prostatectomy.[40] 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.[41]

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[42] 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,[42] i.e., a higher PSA velocity.

Free PSA

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 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 ng/mL.[43] However, both total and free PSA increase immediately after ejaculation, returning slowly to baseline levels within 24 hours.[32]

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. [44] Thus with the introduction of the ratio of free to total PSA, the reliability of the test has improved and measuring the activity of the enzyme could add to the ratio of free to total PSA and further improve the diagnostic value of test.[45] Proteolytically active PSA has been shown to have an anti-angiogenic effect [46] 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. [47] The presence of inactive proenzyme forms of PSA is another potential indicator of disease.[48]

PSA in other biologic fluids and tissues

Concentration of PSA in human body fluids
Fluid PSA (ng/mL)
semen
200,000 - 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 - 0.53

It is now clear that 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.[16]

In women, PSA is found in female ejaculate at concentrations roughly equal to that found in male semen.[49] 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.[50]

Tissue samples can be stained for the presence of PSA in order to determine the origin of malignant cells that have metastasized.[51]

Interactions

Prostate-specific antigen has been shown to interact with protein C inhibitor.[52][53]

See also

References

  1. ↑ PDB: 2ZCK​; Ménez R, Michel S, Muller BH, Bossus M, Ducancel F, Jolivet-Reynaud C, Stura EA (February 2008). "Crystal structure of a ternary complex between human prostate-specific antigen, its substrate acyl intermediate and an activating antibody". J. Mol. Biol. 376 (4): 1021–33. doi:10.1016/j.jmb.2007.11.052. PMID 18187150.
  2. ↑ Balk SP, Ko YJ, Bubley GJ (Jan 2003). "Biology of prostate-specific antigen". Journal of Clinical Oncology 21 (2): 383–91. doi:10.1200/JCO.2003.02.083. PMID 12525533.
  3. ↑ Hellstrom WJG, ed. (1999). "Chapter 8: What is the prostate and what is its function?". American Society of Andrology Handbook. San Francisco: American Society of Andrology. ISBN 1-891276-02-6.
  4. ↑ Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, deKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL (May 1994). "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". The Journal of Urology 151 (5): 1283–90. PMID 7512659.
  5. 1 2 3 "Talking With Your Patients About Screening for Prostate Cancer" (PDF). Retrieved 2012-07-02.
  6. ↑ Velonas VM, Woo HH, dos Remedios CG, Assinder SJ (2013). "Current status of biomarkers for prostate cancer". International Journal of Molecular Sciences 14 (6): 11034–60. doi:10.3390/ijms140611034. PMC 3709717. PMID 23708103.
  7. ↑ Gomella LG, Liu XS, Trabulsi EJ, Kelly WK, Myers R, Showalter T, Dicker A, Wender R (Oct 2011). "Screening for prostate cancer: the current evidence and guidelines controversy". The Canadian Journal of Urology 18 (5): 5875–83. PMID 22018148.
  8. ↑ "Doctors warn on ad hoc screening". BBC News. 2005-08-23.
  9. ↑ Rodrigues, George; Warde, Padraig; Pickles, Tom; Crook, Juanita; Brundage, Michael; Souhami, Luis; Lukka, Himu (17 April 2012). "Pre-treatment risk stratification of prostate cancer patients: A critical review". Canadian Urological Association Journal 6 (2): 121–127. doi:10.5489/cuaj.11085.
  10. ↑ Sperling, MD, Dan. "mpMRI improves the accuracy of the Partin tables and other nomograms". Sperling Prostate Center. Retrieved 31 March 2016.
  11. ↑ Freedland SJ, Sutter ME, Dorey F, Aronson WJ (Feb 2003). "Defining the ideal cutpoint for determining PSA recurrence after radical prostatectomy. Prostate-specific antigen". Urology 61 (2): 365–9. doi:10.1016/s0090-4295(02)02268-9. PMID 12597949.
  12. 1 2 Leong, Anthony S-Y, Cooper, Kumarason, Leong, F Joel W-M (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd. pp. 79–80. ISBN 1-84110-100-1.
  13. ↑ Hara M, Inorre T, Fukuyama T. (1971). "Some physicochemical characteristics of gamma-seminoprotein, an antigenic component specific for human seminal plasma". Jpn J Legal Med. 25: 322–324.
  14. ↑ Bill O. Gartside, Kevin J. Brewer & Carmella L. Strong (April 2003). "Estimation of Prostate-Specific Antigen (PSA) Extraction Efficiency from Forensic Samples Using the Seratecâ PSA Semiquant Semiquantitative Membrane Test". Forensic Science Communications 5 (2). Archived from the original on 2008-04-09. Retrieved 2008-05-11.
  15. ↑ Hochmeister MN, Budowle B, Rudin O, Gehrig C, Borer U, Thali M, Dirnhofer R (Sep 1999). "Evaluation of prostate-specific antigen (PSA) membrane test assays for the forensic identification of seminal fluid". Journal of Forensic Sciences (Eighth International Symposium on Human Identification) 44 (5): 1057–60. PMID 10486959.
  16. 1 2 3 Laux DL, Custis SE. "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" (PDF). Midwestern Association of Forensic Scientists. Retrieved 2008-05-11.
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  23. ↑ Li TS, Beling CG (Oct 1974). "The effect of antibodies to two human seminal plasma-specific antigens on human sperm". Fertility and Sterility 25 (10): 851–6. PMID 4213812.
  24. ↑ Sensabaugh GF (Jan 1978). "Isolation and characterization of a semen-specific protein from human seminal plasma: a potential new marker for semen identification". Journal of Forensic Sciences 23 (1): 106–15. PMID 744956.
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    • Carter HB (May 2004). "Prostate cancers in men with low PSA levels--must we find them?". The New England Journal of Medicine 350 (22): 2292–4. doi:10.1056/NEJMe048003. PMC 3474980. PMID 15163780.
    • Myrtle JF, Klimley PG, Ivor L, Bruni JF (1986). "Clinical utility of prostate specific antigen (PSA) in the management of prostate cancer". Advances in Cancer Diagnostics. San Diego: Hybritech Inc.
    • Mytrle JF, Ivor L (1989). "Measurement of Prostate-Specific Antigen (PSA) in Serum by a Two-Site Immunometric Method (Hybritech Tandem-R/Tandem-E PSA)". In Catalona WJ, Coffey DS, Karr JP (eds.). 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. New York: Elsevier. pp. 161–71. ISBN 0-444-01514-0.
    • Mytrle JF (1989). "Normal Levels of Prostate-Specific Antigen (PSA)". In Catalona WJ, Coffey DS, Karr JP (eds.). 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. New York: Elsevier. pp. 183–9. ISBN 0-444-01514-0.
    • Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, Petros JA, Andriole GL (Apr 1991). "Measurement of prostate-specific antigen in serum as a screening test for prostate cancer". The New England Journal of Medicine 324 (17): 1156–61. doi:10.1056/NEJM199104253241702. PMID 1707140.
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  28. ↑ Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA (May 2004). "Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter". The New England Journal of Medicine 350 (22): 2239–46. doi:10.1056/NEJMoa031918. PMID 15163773.
  29. ↑ 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 (Nov 2007). "Obesity-related plasma hemodilution and PSA concentration among men with prostate cancer". JAMA 298 (19): 2275–80. doi:10.1001/jama.298.19.2275. PMID 18029831.
  30. ↑ Robert Dreicer (2007-11-20). "Why do obese men have lower PSA concentrations?". Journal Watch (New England Journal of Medicine) 2007 (1120): 1. Retrieved 2008-04-27.
  31. ↑ Cao Y, Ma J (Apr 2011). "Body mass index, prostate cancer-specific mortality, and biochemical recurrence: a systematic review and meta-analysis". Cancer Prevention Research 4 (4): 486–501. doi:10.1158/1940-6207.CAPR-10-0229. PMC 3071449. PMID 21233290.
  32. 1 2 Herschman JD, Smith DS, Catalona WJ (Aug 1997). "Effect of ejaculation on serum total and free prostate-specific antigen concentrations". Urology 50 (2): 239–43. doi:10.1016/S0090-4295(97)00209-4. PMID 9255295.
  33. ↑ Nadler RB, Humphrey PA, Smith DS, Catalona WJ, Ratliff TL (Aug 1995). "Effect of inflammation and benign prostatic hyperplasia on elevated serum prostate specific antigen levels". The Journal of Urology 154 (2 Pt 1): 407–13. doi:10.1016/S0022-5347(01)67064-2. PMID 7541857.
  34. ↑ Crawford ED, Schutz MJ, Clejan S, Drago J, Resnick MI, Chodak GW, Gomella LG, Austenfeld M, Stone NN, Miles BJ (1992). "The effect of digital rectal examination on prostate-specific antigen levels". JAMA 267 (16): 2227–8. doi:10.1001/jama.267.16.2227. PMID 1372943.
    Chybowski FM, Bergstralh EJ, Oesterling JE (Jul 1992). "The effect of digital rectal examination on the serum prostate specific antigen concentration: results of a randomized study". The Journal of Urology 148 (1): 83–6. PMID 1377290.
    Collins GN, Martin PJ, Wynn-Davies A, Brooman PJ, O'Reilly PH (May 1997). "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". The Journal of Urology 157 (5): 1744–7. doi:10.1016/S0022-5347(01)64849-3. PMID 9112518.
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  35. ↑ Connolly D, Black A, Murray L, Gavin A, Keane P (2007). "798 Population Based Age-Specific Reference Ranges for PSA". European Urology Supplements 6 (2): 222. doi:10.1016/S1569-9056(07)60793-3.
  36. ↑ Catalona W, Partin A, Slawin K, Brawer M, Flanigan R, Patel A, Richie J, deKernion J, Walsh P, Scardino P, Lange P, Subong E, Parson R, Gasior G, Loveland K, Southwick P (1998). "Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial". JAMA 279 (19): 1542–7. doi:10.1001/jama.279.19.1542. PMID 9605898.
  37. ↑ Carter HB, Pearson JD, Metter EJ, Brant LJ, Chan DW, Andres R, Fozard JL, Walsh PC (1992). "Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease". JAMA 267 (16): 2215–20. doi:10.1001/jama.267.16.2215. PMC 3461837. PMID 1372942.
  38. ↑ "PSA Velocity Does Not Improve Prostate Cancer Detection". 13 Apr 2011. Retrieved 25 April 2015.
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