Home Androgen deprivation decreases prostate specific antigen in the absence of tumor: implications for interpretation of PSA results
Article
Licensed
Unlicensed Requires Authentication

Androgen deprivation decreases prostate specific antigen in the absence of tumor: implications for interpretation of PSA results

  • Judith M. Wenisch , Florian B. Mayr , Alexander O. Spiel , Milko Radicioni , Bernd Jilma EMAIL logo and Petra Jilma-Stohlawetz
Published/Copyright: October 12, 2013
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 52 Issue 3

Abstract

Background: Prostate-specific antigen (PSA) is used as an outcome measure for relapsed disease in prostate cancer. Nonetheless, there are considerable concerns about its indiscriminate use as a surrogate endpoint for cell growth or survival. We hypothesized that treatment with a luteinizing hormone releasing hormone (LHRH) analog would decrease PSA levels even in the absence of malignant disease.

Methods: We determined testosterone and PSA levels in 30 healthy volunteers after a single intramuscular injection of a LHRH depot formulation. Testosterone and PSA levels were quantified by radioimmunoassay and electrochemi-luminescence immunoassay, respectively.

Results: After an initial flare-up during the first 3 days testosterone decreased reaching castration levels in 18 of the 30 young men (60%). After the nadir on day 28, testosterone levels increased to normal again. Changes in PSA paralleled those of testosterone. Castration reduced PSA levels by 29% (95% CI 19%–39%) compared to baseline (p<0.0001).

Conclusions: LHRH superagonists decrease PSA levels by testosterone deprivation. Conferring these findings to tumor patients, decreases in PSA after treatment with LHRH analogs might not only reflect disease regression but also a direct testosterone mediated effect on PSA. Thus, PSA levels should be cautiously interpreted when patients receive hormonal therapy.

Keywords: biomarker; clinical trial; leuprolide; luteinizing hormone releasing hormone (LHRH); prostate specific antigen; testosterone
Corresponding author: Bernd Jilma, MD, Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria, Phone: +43 1 40400 2981, Fax: +43 1 40400 2998, E-mail:

We thank Sabine Schranz, RN for her invaluable contribution.

Conflict of interest statement

Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

References

1. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89–95.10.1067/mcp.2001.113989Search in Google Scholar

2. Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 1989;8:431–40.10.1002/sim.4780080407Search in Google Scholar

3. Diamandis EP. Prostate-specific antigen: a cancer fighter and a valuable messenger? Clin Chem 2000;46:896–900.10.1093/clinchem/46.7.896Search in Google Scholar

4. Zarghami N, Grass L, Sauter ER, Diamandis EP. Prostate-specific antigen in serum during the menstrual cycle. Clin Chem 1997;43:1862–7.10.1093/clinchem/43.10.1862Search in Google Scholar

5. Buyse M, Molenberghs G. Criteria for the validation of surrogate endpoints in randomized experiments. Biometrics 1998;54:1014–29.10.2307/2533853Search in Google Scholar

6. MacGregor JT, Farr S, Tucker JD, Heddle JA, Tice RR, Turteltaub KW. New molecular endpoints and methods for routine toxicity testing. Fundam Appl Toxicol 1995;26:156–73.10.1006/faat.1995.1087Search in Google Scholar

7. Daniels MJ, Hughes MD. Meta-analysis for the evaluation of potential surrogate markers. Stat Med 1997;16:1965–82.10.1002/(SICI)1097-0258(19970915)16:17<1965::AID-SIM630>3.0.CO;2-MSearch in Google Scholar

8. Kontos CK, Scorilas A. Kallikrein-related peptidases (KLKs): A gene family of novel cancer biomarkers. Clin Chem Lab Med 2012;50:1877–91.10.1515/cclm-2012-0247Search in Google Scholar

9. Hoffman RM, Zeliadt SB. The cautionary tale of PSA testing. Arch Intern Med 2010;170:1262–3.10.1001/archinternmed.2010.222Search in Google Scholar

10. Melichar B. Tumor biomarkers: PSA and beyond. Clin Chem Lab Med 2012;50:1865–9.10.1515/cclm-2012-0631Search in Google Scholar

11. Fleming MT, Morris MJ, Heller G, Scher HI. Post-therapy changes in PSA as an outcome measure in prostate cancer clinical trials. Nat Clin Pract Oncol 2006;3:658–67.10.1038/ncponc0664Search in Google Scholar

12. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med 1996;125:605–13.10.7326/0003-4819-125-7-199610010-00011Search in Google Scholar

13. Cleutjens KB, van der Korput HA, Ehren-van Eekelen CC, Sikes RA, Fasciana C, Chung LW, et al. A 6-kb promoter fragment mimics in transgenic mice the prostate-specific and androgen-regulated expression of the endogenous prostate-specific antigen gene in humans. Mol Endocrinol 1997;11:1256–65.10.1210/mend.11.9.9974Search in Google Scholar

14. Henttu P, Vihko P. Prostate-specific antigen and human glandular kallikrein: two kallikreins of the human prostate. Ann Med 1994;26:157–64.10.3109/07853899409147884Search in Google Scholar

15. Peehl DM. Prostate specific antigen role and function. Cancer (Suppl) 1995;75:2021–6.10.1002/1097-0142(19950401)75:7+<2021::AID-CNCR2820751644>3.0.CO;2-RSearch in Google Scholar

16. Juul A, Muller J, Skakkebaek NE. Prostate specific antigen in boys with precocious puberty before and during gonadal suppression by GnRH agonist treatment. Eur J Endocrinol 1997;136:401–5.10.1530/eje.0.1360401Search in Google Scholar

17. Vieira JG, Nishida SK, Pereira AB, Arraes RF, Verreschi IT. Serum levels of prostate-specific antigen in normal boys throughout puberty. J Clin Endocrinol Metab 1994;78: 1185–7.10.1210/jcem.78.5.7513717Search in Google Scholar

18. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992;75:1092–8.10.1210/jcem.75.4.1400877Search in Google Scholar

19. Amory JK, Watts NB, Easley KA, Sutton PR, Anawalt BD, Matsumoto AM, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 2004;89:503–10.10.1210/jc.2003-031110Search in Google Scholar

20. Leitner JM, Mayr FB, Spiel AO, Firbas C, Savulsky C, Mis R, et al. The pharmacokinetics and pharmacodynamics of a new sustained-release leuprolide acetate depot compared to market references. Int J Clin Pharmacol Ther 2008;46:407–14.10.5414/CPP46407Search in Google Scholar

21. Stephan C, Klaas M, Muller C, Schnorr D, Loening SA, Jung K. Interchangeability of measurements of total and free prostate-specific antigen in serum with 5 frequently used assay combinations: an update. Clin Chem 2006;52:59–64.10.1373/clinchem.2005.059170Search in Google Scholar

22. Tunn UW, Bargelloni U, Cosciani S, Fiaccavento G, Guazzieri S, Pagano F. Comparison of LH-RH analogue 1-month depot and 3-month depot by their hormone levels and pharmacokinetic profile in patients with advanced prostate cancer. Urol Int 1998;60(Suppl 1):9–16; discussion 7.10.1159/000056540Search in Google Scholar

23. Raina R, Pahalajani G, Agarwal A, Zippe C. Long-term effectiveness of luteinizing hormone-releasing hormone agonist or antiandrogen monotherapy in elderly men with localized prostate cancer (T1-2): A retrospective study. Asian J Androl 2007;9:253–8.10.1111/j.1745-7262.2007.00074.xSearch in Google Scholar

24. Junaidi A, Williamson PE, Trigg TE, Cummins JM, Martin GB. Morphological study of the effects of the GnRH superagonist deslorelin on the canine testis and prostate gland. Reprod Domest Anim 2009;44:757–63.10.1111/j.1439-0531.2008.01066.xSearch in Google Scholar PubMed

25. Keane PF, Timoney AG, Kiely E, Williams G, Stamp G. Response of the benign hypertrophied prostate to treatment with an LHRH analogue. Br J Urol 1988;62:163–5.10.1111/j.1464-410X.1988.tb04299.xSearch in Google Scholar PubMed

26. Vickery BH, McRae GI, Bonasch H. Effect of chronic administration of a highly potent LHRH agonist on prostate size and secretory function in geriatric dogs. Prostate 1982;3: 123–30.10.1002/pros.2990030204Search in Google Scholar PubMed

27. Rick FG, Schally AV, Block NL, Halmos G, Perez R, Fernandez JB, et al. LHRH antagonist Cetrorelix reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia. Prostate 2011;71:736–47.10.1002/pros.21289Search in Google Scholar PubMed

28. Lilja H, Ulmert D, Vickers AJ. Prostate-specific antigen and prostate cancer: Prediction, detection and monitoring. Nat Rev Cancer 2008;8:268–78.10.1038/nrc2351Search in Google Scholar PubMed

29. Ryan CJ, Smith A, Lal P, Satagopan J, Reuter V, Scardino P, et al. Persistent prostate-specific antigen expression after neoadjuvant androgen depletion: An early predictor of relapse or incomplete androgen suppression. Urology 2006;68:834–9.10.1016/j.urology.2006.04.016Search in Google Scholar PubMed

30. Etzioni RD, Howlader N, Shaw PA, Ankerst DP, Penson DF, Goodman PJ, et al. Long-term effects of finasteride on prostate specific antigen levels: Results from the prostate cancer prevention trial. J Urol 2005;174:877–81.10.1097/01.ju.0000169255.64518.fbSearch in Google Scholar PubMed

31. Byrnes CA, Liss CL, Tenover JL, Lippert MC, Gillenwater JY. Combined analysis of two multicenter studies of finasteride 5 mg in the treatment of symptomatic benign prostatic hyperplasia. Prostate Cancer Prostatic Dis 1997; 1:26–31.10.1038/sj.pcan.4500202Search in Google Scholar PubMed

32. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215–24.10.1056/NEJMoa030660Search in Google Scholar PubMed

33. Thalmann GN, Sikes RA, Chang SM, Johnston DA, von Eschenbach AC, Chung LW. Suramin-induced decrease in prostate-specific antigen expression with no effect on tumor growth in the LNCaP model of human prostate cancer. J Natl Cancer Inst 1996;88:794–801.10.1093/jnci/88.12.794Search in Google Scholar PubMed

34. Scher HI, Mazumdar M, Kelly WK. Clinical trials in relapsed prostate cancer: Defining the target. J Natl Cancer Inst 1996;88:1623–34.10.1093/jnci/88.22.1623Search in Google Scholar PubMed

35. Collette L, Burzykowski T, Schroder FH. Prostate-specific antigen (PSA) alone is not an appropriate surrogate marker of long-term therapeutic benefit in prostate cancer trials. Eur J Cancer 2006;42:1344–50.10.1016/j.ejca.2006.02.011Search in Google Scholar PubMed

36. D′Amico AV, Moul JW, Carroll PR, Cote K, Sun L, Lubeck D, et al. Intermediate end point for prostate cancer-specific mortality following salvage hormonal therapy for prostate-specific antigen failure. J Natl Cancer Inst 2004;96: 509–15.10.1093/jnci/djh086Search in Google Scholar PubMed

37. Jilma B, Eichler HG, Koppl C, Weber B, Pidlich JP, Ferenci P, et al. Effects of testosterone suppression on serum levels of hepatitis B surface antigen and HBV-DNA in men. Liver 1998;18:162–5.10.1111/j.1600-0676.1998.tb00144.xSearch in Google Scholar PubMed

38. Ulmert D, Vickers AJ, Scher HI, Becker C, Iversen P, Frankel D, et al. Rapid elimination kinetics of free PSA or human kallikrein-related peptidase 2 after initiation of gonadotropin-releasing hormone-antagonist treatment of prostate cancer: Potential for rapid monitoring of treatment responses. Clin Chem Lab Med 2012;50:1993–8.10.1515/cclm-2011-0967Search in Google Scholar PubMed PubMed Central

39. Bjork T, Schalken J, Wittjes W, Ljungberg B, Lilja H. Similar rates of exponential decrease in serum concentrations of free prostate-specific antigen (PSA), PSA complexed to alpha-1-antichymotrypsin, and human glandular kallikrein 2 (hK2) in prostate cancer patients treated with GnRH-analogues. Prostate 2001;47:14–20.10.1002/pros.1042Search in Google Scholar PubMed

Received: 2013-07-12
Accepted: 2013-09-19
Published Online: 2013-10-12
Published in Print: 2014-03-01

©2014 by Walter de Gruyter Berlin Boston

Articles in the same Issue

  1. Masthead
  2. Masthead
  3. Editorial
  4. Point of care testing: evolving scenarios and innovative perspectives
  5. Review
  6. Point-of-care testing: where is the evidence? A systematic survey
  7. Mini Review
  8. Vulnerability of point-of-care test reagents and instruments to environmental stresses: implications for health professionals and developers
  9. Opinion Paper
  10. Twenty-five years of idiopathic calcium nephrolithiasis: has anything changed?
  11. Genetics and Molecular Diagnostics
  12. Optimizing the purification and analysis of miRNAs from urinary exosomes
  13. General Clinical Chemistry and Laboratory Medicine
  14. Extensive study of human insulin immunoassays: promises and pitfalls for insulin analogue detection and quantification
  15. Absorptive chemistry based extraction for LC-MS/MS analysis of small molecule analytes from biological fluids – an application for 25-hydroxyvitamin D
  16. Evaluation of 3-epi-25-hydroxyvitamin D3 cross-reactivity in the Roche Elecsys Vitamin D Total protein binding assay
  17. Quantification of linezolid in serum by LC-MS/MS using semi-automated sample preparation and isotope dilution internal standardization
  18. Comparison of two immunoassays for measurement of faecal calprotectin in detection of inflammatory bowel disease: (pre)-analytical and diagnostic performance characteristics
  19. Reference Values and Biological Variations
  20. Reference change values to assess changes in concentrations of biomarkers of exposure in individuals participating in a cigarette-switching study
  21. Reference values of fetal serum β2-microglobulin in the Chinese: evaluation of its clinical usefulness
  22. Cancer Diagnostics
  23. Gut neuroendocrine tumor blood qPCR fingerprint assay: characteristics and reproducibility
  24. Androgen deprivation decreases prostate specific antigen in the absence of tumor: implications for interpretation of PSA results
  25. Radioimmunoassay of free plasma metanephrines for the diagnosis of catecholamine-producing tumors
  26. Infectious Diseases
  27. Plasma endothelial cell-specific molecule-1 (ESM-1) in management of community-acquired pneumonia
  28. A soluble form of the macrophage-related mannose receptor (MR/CD206) is present in human serum and elevated in critical illness
  29. Letters to the Editor
  30. Evaluation of a JAK2 V617F quantitative PCR to monitor residual disease post-allogeneic hematopoietic stem cell transplantation for myeloproliferative neoplasms
  31. Is magnetic resonance imaging really innocent?
  32. Clinical sample stability and measurement uncertainty
  33. A specific and sensitive activated partial thromboplastin time (APTT)-based factor VIII inhibitor screening assay
  34. Evaluating the inappropriateness of repeated laboratory testing in a teaching hospital of South Italy
  35. Could kidney glomerular filtration impairment represent the “Achilles heel” of HE4 serum marker? A possible further implication
https://doi.org/10.1515/cclm-2013-0535
Keywords for this article
biomarker; clinical trial; leuprolide; luteinizing hormone releasing hormone (LHRH); prostate specific antigen; testosterone

Articles in the same Issue

  1. Masthead
  2. Masthead
  3. Editorial
  4. Point of care testing: evolving scenarios and innovative perspectives
  5. Review
  6. Point-of-care testing: where is the evidence? A systematic survey
  7. Mini Review
  8. Vulnerability of point-of-care test reagents and instruments to environmental stresses: implications for health professionals and developers
  9. Opinion Paper
  10. Twenty-five years of idiopathic calcium nephrolithiasis: has anything changed?
  11. Genetics and Molecular Diagnostics
  12. Optimizing the purification and analysis of miRNAs from urinary exosomes
  13. General Clinical Chemistry and Laboratory Medicine
  14. Extensive study of human insulin immunoassays: promises and pitfalls for insulin analogue detection and quantification
  15. Absorptive chemistry based extraction for LC-MS/MS analysis of small molecule analytes from biological fluids – an application for 25-hydroxyvitamin D
  16. Evaluation of 3-epi-25-hydroxyvitamin D3 cross-reactivity in the Roche Elecsys Vitamin D Total protein binding assay
  17. Quantification of linezolid in serum by LC-MS/MS using semi-automated sample preparation and isotope dilution internal standardization
  18. Comparison of two immunoassays for measurement of faecal calprotectin in detection of inflammatory bowel disease: (pre)-analytical and diagnostic performance characteristics
  19. Reference Values and Biological Variations
  20. Reference change values to assess changes in concentrations of biomarkers of exposure in individuals participating in a cigarette-switching study
  21. Reference values of fetal serum β2-microglobulin in the Chinese: evaluation of its clinical usefulness
  22. Cancer Diagnostics
  23. Gut neuroendocrine tumor blood qPCR fingerprint assay: characteristics and reproducibility
  24. Androgen deprivation decreases prostate specific antigen in the absence of tumor: implications for interpretation of PSA results
  25. Radioimmunoassay of free plasma metanephrines for the diagnosis of catecholamine-producing tumors
  26. Infectious Diseases
  27. Plasma endothelial cell-specific molecule-1 (ESM-1) in management of community-acquired pneumonia
  28. A soluble form of the macrophage-related mannose receptor (MR/CD206) is present in human serum and elevated in critical illness
  29. Letters to the Editor
  30. Evaluation of a JAK2 V617F quantitative PCR to monitor residual disease post-allogeneic hematopoietic stem cell transplantation for myeloproliferative neoplasms
  31. Is magnetic resonance imaging really innocent?
  32. Clinical sample stability and measurement uncertainty
  33. A specific and sensitive activated partial thromboplastin time (APTT)-based factor VIII inhibitor screening assay
  34. Evaluating the inappropriateness of repeated laboratory testing in a teaching hospital of South Italy
  35. Could kidney glomerular filtration impairment represent the “Achilles heel” of HE4 serum marker? A possible further implication
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 19.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/cclm-2013-0535/html
Scroll to top button