Prostate specific antigen

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PSA falls short of being a satisfactory test for cancer of the prostate for screening a general population. That has resulted in controversy and different recommendations for screening individuals internationally. The situation is evolving as knowledge is accumulated.

PSA is a serine protease belonging to the kallikrein family. It is single-chain glycoprotein coded for at 19q13.4. It is produced by prostate cells and excreted into prostatic fluid where its physiological role is to help the seminal coagulum to dissolve by proteolysis.

Normal levels 0.1-4.0 ng/ml, though it is better to think of age-specific ranges rather than absolute cut-off values. There is an overlap between normal, benign disease and malignant disease. Attempts have been made to increase the diagnostic utility of PSA in several ways:

  • PSA velocity - monitoring the rate of increase over a period of time)
  • PSA density - amount of PSA produced relative to the volume of prostate as measured ultrasonographically).
  • PSA fractions - measuring free PSA versus PSA bound to α-2-macroglobulin

None of these PSA-derivatives, however, have had significant uptake in clinical practice in the UK.

Contents

Limitations

History

Several proteins found only in seminal fluid were described in 1971. PSA was was subsequently isolated and characterised in 1973.[3] It was named PSA in 1979 and prior to that had also been referred to as gamma seminoprotein [4] and p30 [5]. One of its earliest intended uses was as a forensic tool in rape cases. [6]

Physiology

Androgen responsive elements exist in the proximal promoter region of the PSA gene. In females PSA is present at very low concentrations which is modified by corticosteroids. Interestingly higher levels are found in female hirsutism[7].

Levels in normal males are associated with

  • Individual genetics - explains 45% of variability
  • Individual parameters which unhappily only explain 23% of variability so far[8]:
    • Age
    • Transitional zone volume of prostate gland and TZ were retained in the final model. The proportion of variability in total PSA explained by these 2 factors, however, was below 24%. In contrast, estimates of heritability showed that approximately 45% of the variability in total PSA could be explained by inherited factors

PSA has a half-life in the body of about 3 days.[9]

Genetics

In man it is part of a 13 kallikrein-related gene complex with 5 pseudogenes and 5 exons.

Screening

Screening increases prostate cancer detection with more localized and low-grade tumors being detected. No significant effect on prostate cancer mortality and all cause mortality appeared likely in the short term.[10][11] Longer term population studies suggest mortality may be reduced by PSA based screening[12] but randomised controlled trial evidence of benefit is in short supply, and still being sought or accumulated. The ERSPC (European Randomised Study of Screening for Prostate Cancer) randomised >160,000 men to a screening arm vs no active screening and showed a 29% reduction in prostate cancer mortality, as well as a 42% relative risk reduction of metastatic disease, at 11 years.[13] [14]. A proposal to withdraw former positive screening recommendations in the USA proved controversial during 2011[15].

See Also

References

  1. Eastham JA, Riedel E, Scardino PT, Shike M, Fleisher M, Schatzkin A, Lanza E, Latkany L, Begg CB; Polyp Prevention Trial Study Group. Variation of serum prostate-specific antigen levels: an evaluation of year-to-year fluctuations. JAMA. 2003 May 28;289(20):2695-700.
  2. Chang SL, Harshman LC, Presti JC. Impact of common medications on serum total prostate-specific antigen levels: analysis of the National Health and Nutrition Examination Survey. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010 Sep 1; 28(25):3951-7.(Link to article – subscription may be required.)
  3. One of the original papers isolation and characterising PSA. Li TS, Beling CG. Isolation and characterization of two specific antigens of human seminal plasma. Fertil Steril. 1973 Feb;24(2):134-44.
  4. Hara M, Koyanagi Y, Inoue T, Fukuyama T. [Some physico-chemical characteristics of " -seminoprotein", an antigenic component specific for human seminal plasma. Forensic immunological study of body fluids and secretion. VII] Nippon Hoigaku Zasshi. 1971 Jul;25(4):322-4. Japanese.
  5. Sensabaugh GF. Isolation and characterization of a semen-specific protein from human seminal plasma: a potential new marker for semen identification. J Forensic Sci. 1978 Jan;23(1):106-15.
  6. Graves HC, Sensabaugh GF, Blake ET. Postcoital detection of a male-specific semen protein. Application to the investigation of rape. N Engl J Med. 1985 Feb 7;312(6):338-43.
  7. Melegos DN, Yu H, Ashok M, Wang C, Stanczyk F, Diamandis EP. Prostate-specific antigen in female serum, a potential new marker of androgen excess. The Journal of clinical endocrinology and metabolism. 1997 Mar; 82(3):777-80.
  8. Bansal A, Murray DK, Wu JT, Stephenson RA, Middleton RG, Meikle AW. Heritability of prostate-specific antigen and relationship with zonal prostate volumes in aging twins. The Journal of clinical endocrinology and metabolism. 2000 Mar; 85(3):1272-6.
  9. http://radiology.rsnajnls.org/cgi/content/abstract/184/1/271
  10. Lumen N, Fonteyne V, De Meerleert G, Ost P, Villeirs G, Mottrie A, De Visschere P, De Troyer B, Oosterlinck W. Population screening for prostate cancer: An overview of available studies and meta-analysis. International journal of urology : official journal of the Japanese Urological Association. 2011 Nov 22.(Epub ahead of print) (Link to article – subscription may be required.)
  11. Orsted DD, Nordestgaard BG, Jensen GB, Schnohr P, Bojesen SE. Prostate-Specific Antigen and Long-Term Prediction of Prostate Cancer Incidence and Mortality in the General Population. European urology. 2011 Nov 12.(Epub ahead of print) (Link to article – subscription may be required.)
  12. van Leeuwen PJ, Connolly D, Gavin A, Roobol MJ, Black A, Bangma CH, Schröder FH. Prostate cancer mortality in screen and clinically detected prostate cancer: estimating the screening benefit. European journal of cancer (Oxford, England : 1990). 2010 Jan; 46(2):377-83.(Link to article – subscription may be required.)
  13. The ERSPC (European Randomised Study of Screening for Prostate Cancer) Overview and trial site: http://www.erspc-media.org/ Paper: subscription may be required: Prostate Cancer Mortality Reduction by Prostate-Specific Antigen–Based Screening Adjusted for Nonattendance and Contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC) Monique J. Roobola et al European Urology Volume 56, Issue 4, October 2009, Pages 584–591 http://www.sciencedirect.com/science/article/pii/S0302283809007684
  14. Djulbegovic M, Beyth RJ, Neuberger MM, Stoffs TL, Vieweg J, Djulbegovic B, Dahm P. Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials. BMJ (Clinical research ed.). 2010; 341:c4543.(Epub)
  15. Brett AS, Ablin RJ. Prostate-Cancer Screening - What the U.S. Preventive Services Task Force Left Out. The New England journal of medicine. 2011 Oct 26.(Epub ahead of print) (Link to article – subscription may be required.)
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