The concentration of prostate specific antigen in the blood can help in the assessment and management of early prostate cancer. However, it is important to understand the biology underlying the test. Recent refinements have addressed some of the weaknesses of the test.These include age-related prostate specific antigen reference limits, the free to total prostate specific antigen ratio and prostate specific antigen rates of change including velocity or doubling time. Measuring prostate specific antigen without understanding the underlying biology or without applying these refinements may result in more harm than good.


Prostate specific antigen (PSA) is the name commonly used for a protein that is normally secreted by the healthy prostate gland into semen. PSA is a kallikrein protease whose biological role in semen is to hydrolyse the high molecular weight proteins secreted by the seminal vesicles. This converts the seminal gel to its fluid form to enable spermatozoa to swim free. PSA occurs naturally in semen, but the occasional molecule escapes into the interstitium of the prostate gland and then via the lymphatics to the blood. The PSA concentration in blood is a million times lower than in semen.

The test

A sample of venous blood is needed to measure the concentration of PSA. The result may be affected by mechanical disturbance of the gland such as digital rectal examination, exercise or ejaculation which ideally should be avoided for a day or two before the test. Samples should also be analysed within 24 hours as PSA (especially free PSA) decays in vitro. Although PSA concentrations measured by different laboratory methods are far more comparable today than even five years ago, it is unwise to compare results between laboratories as important differences may still exist.

The rate of PSA changes

A useful refinement in predicting the clinical significance of any prostate cancer is the measurement of the rate of change of PSA concentrations. This is usually referred to as PSA 'velocity', but the 'doubling time' of PSA may be the more appropriate way to assess malignant potential.6

PSA concentrations may double every five years in the early stages of benign prostatic hyperplasia. If the PSA concentration is doubling faster (for example every three years or faster), this is more likely to be due to prostate cancer. When a man has had at least three PSA concentrations, several months apart and they show a rising trend, PSA doubling time can be calculated (see Estimating the rate of change of PSA applies both to PSA 'screening' or monitoring a known cancer.

PSA monitoring in known malignancy

A rising concentration of PSA in a man with prostate cancer suggests that the cancer is progressing. PSA production is typically reduced by prostate cancer treatment (for example antiandrogen therapy), and the nadir can predict clinical outcome. PSA concentrations are ideally undetectable after radical prostatectomy, however men with 'biochemical recurrence' may still not have anything to worry about as a slowly rising PSA indicates their residual tissue may not be an aggressive cancer.7 Watchful waiting should be reserved for men who are not at high risk. Men with low free to total PSA ratios or fast doubling times are at risk and should be considering treatment.8

Medicare Benefits Schedule

All the suggestions made in this article are currently supported by the Medicare Benefits Schedule. At least one free to total PSA ratio can be requested each year when the PSA is above the median. Should the PSA concentrations be above the age-related upper limit, several PSA tests and up to four free to total PSA ratios can be requested within each year.

Further reading

Denham JW, Bender R, Paradice WEJ. It's time to depolarise the unhelpful PSA-testing debate and put into practice lessons from the two major international screening trials. Med J Aust 2010;192:393-6.

Lam QT, Frydenberg M. Strategies for detecting prostate cancer. Common Sense Pathology. 2009 Mar. [cited 2011 Nov 11]

Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter.N Engl J Med 2004;350:2239-46.

Conflict of interest: none declared


  1. Vollmer RT. Predictive probability of serum prostate-specific antigen for prostate cancer: an approach using Bayes rule. Am J Clin Pathol 2006;125:336-42.
  2. Gamé X, Vincendeau S, Palascak R, Milcent S, Fournier R, Houlgatte A. Total and free serum prostate specific antigen levels during the first month of acute prostatitis. Eur Urol 2003;43:702-5.
  3. Sikaris KA, Caldwell G. Age related reference intervals for the Abbott Architect PSA assay [poster abstract]. Proceedings of the Australasian Association of Clinical Biochemists' 45th Annual Scientific Conference. Clin Biochem Rev 2007;28(Suppl):S33.
  4. Hoffman RM, Clanon DL, Littenberg B, Frank JJ, Peirce JC. Using the free-to-total prostate-specific antigen ratio to detect prostate cancer in men with nonspecific elevations of prostate-specific antigen levels. J Gen Intern Med 2000;15:739-48.
  5. Walz J, Haese A, Scattoni V, Steuber T, Chun FK, Briganti A, et al. Percent free prostate-specific antigen (PSA) is an accurate predictor of prostate cancer risk in men with serum PSA 2.5 ng/mL and lower. Cancer 2008;113:2695-703.
  6. Nowroozi MR, Zeighami S, Ayati M, Jamshidian H, Ranjbaran AR, Moradi A, et al. Prostate-specific antigen doubling time as a predictor of Gleason grade in prostate cancer. Urol J 2009;6:27-30.
  7. Tollefson MK, Slezak JM, Leibovich BC, Zincke H, Blute ML. Stratification of patient risk based on prostate-specific antigen doubling time after radical retropubic prostatectomy. Mayo Clin Proc 2007;82:422-7 .
  8. Vollmer RT, Egawa S, Kuwao S, Baba S. The dynamics of prostate specific antigen during watchful waiting of prostate carcinoma: a study of 94 Japanese men. Cancer 2002;94:1692-8.