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Circulating sex steroids and prostate cancer: introducing the time-dependency theory

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Abstract

Purpose

We sought whether serum total testosterone (tT), estradiol (E2), tT/E2 ratio, and sex hormone-binding globulin (SHBG) significantly fluctuate throughout time in men with prostate cancer (PCa).

Methods

Circulating hormones were measured in a cohort of 631 candidates for radical prostatectomy. Hormone levels were analyzed according to either patient age, stratified into quartiles, or body mass index (BMI). Linear regression analyses tested the association between sex steroids and continuously coded patient age and BMI values.

Results

No significant differences were found among age quartiles regarding serum tT levels and tT/E2 ratio. Conversely, E2 and SHBG levels significantly increased throughout time (all, p ≤ 0.001). Total T did not linearly change according to continuously coded patient age; in contrast, E2 and SHBG linearly increased (all, p ≤ 0.001), whereas tT/E2 decreased (p = 0.016) with aging. Rate of hypogonadism significantly increased with aging (p = 0.04). Total T, T/E2 ratio, and SHBG linearly decreased along with BMI increases (all p ≤ 0.02), whereas serum E2 did not significantly change. Rate of hypogonadism significantly increased with BMI increases (p < 0.001).

Conclusions

In contrast with longitudinal studies in the general male population, these data indirectly suggest that serum tT levels could be stable over time in PCa patients. This finding led to formulation of a “time-dependency theory”, which postulates that the endocrine biology of prostate tissue is dependent on the exposure time at a given concentration of sex steroid, which, in turn, fluctuates throughout the lifespan of the individual.

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References

  1. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB (2002) Age trends in the level of serum testosterone and other hormones in middleaged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 87:589–598. doi:10.1210/jc.87.2.589

    Article  PubMed  CAS  Google Scholar 

  2. Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O’Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huhtaniemi IT, EMAS Group (2010) Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 363:123–135. doi:10.1056/NEJMoa0911101

    Article  PubMed  CAS  Google Scholar 

  3. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S (2010) Adverse events associated with testosterone administration. N Engl J Med 363:109–122. doi:10.1056/NEJMoa1000485

    Article  PubMed  CAS  Google Scholar 

  4. Isbarn H, Pinthus JH, Marks LS, Montorsi F, Morales A, Morgentaler A, Schulman C (2009) Testosterone and prostate cancer: revisiting old paradigms. Eur Urol 56:48–56. doi:org/10.1016/j.eururo.2009.03.088

    Article  PubMed  CAS  Google Scholar 

  5. Ellem SJ, Risbridger GP (2010) Aromatase and regulating the estrogen: androgen ratio in the prostate gland. J Steroid Biochem Mol Biol 118:246–251. doi:10.1016/j.jsbmb.2009.10.015

    Article  PubMed  CAS  Google Scholar 

  6. Prins GS, Korach KS (2008) The role of estrogens and estrogen receptors in normal prostate growth and disease. Steroids 73:233–244. doi:10.1016/j.steroids.2007.10.013

    Article  PubMed  CAS  Google Scholar 

  7. Morgentaler A, Traish AM (2009) Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol 55:310–320. doi:10.1016/j.eururo.2008.09.024

    Article  PubMed  Google Scholar 

  8. Endogenous Hormones and Prostate Cancer Collaborative Group, Roddam AW, Allen NE, Appleby P, Key TJ (2008) Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst 100:170–183. doi:10.1093/jnci/djm323

    Article  PubMed  CAS  Google Scholar 

  9. Imamoto T, Suzuki H, Fukasawa S, Shimbo M, Inahara M, Komiya A, Ueda T, Shiraishi T, Ichikawa T (2005) Pretreatment serum testosterone level as a predictive factor of pathological stage in localized prostate cancer patients treated with radical prostatectomy. Eur Urol 47:308–312. doi:10.1016/j.eururo.2004.11.003

    Article  PubMed  CAS  Google Scholar 

  10. Isom-Batz G, Bianco FJ Jr, Kattan MW, Mulhall JP, Lilja H, Eastham JA (2005) Testosterone as a predictor of pathological stage in clinically localized prostate cancer. J Urol 173:1935–1937. doi:10.1097/01.ju.0000158040.33531.e7

    Article  PubMed  CAS  Google Scholar 

  11. Salonia A, Abdollah F, Capitanio U, Gallina A, Suardi N, Briganti A, Zanni G, Ferrari M, Castiglione F, Clementi MC, Rigatti P, Montorsi F (2012) Preoperative sex steroids are significant predictors of early biochemical recurrence after radical prostatectomy. World J Urol [Epub ahead of print]. doi:10.1007/s00345-012-0856-7

  12. Salonia A, Abdollah F, Capitanio U, Suardi N, Briganti A, Gallina A, Colombo R, Ferrari M, Castagna G, Rigatti P, Montorsi F (2012) Serum sex steroids depict a nonlinear U-shaped association with high-risk prostate cancer at radical prostatectomy. Clin Cancer Res 18:3648–3657. doi:10.1158/1078-0432.CCR-11-2799

    Article  PubMed  CAS  Google Scholar 

  13. Foley R, Marignol L, Keane JP, Lynch TH, Hollywood D (2011) Androgen hypersensitivity in prostate cancer: molecular perspectives on androgen deprivation therapy strategies. Prostate 71:550–557. doi:10.1002/pros.21266

    Article  PubMed  CAS  Google Scholar 

  14. Hofland J, van Weerden WM, Dits NF, Steenbergen J, van Leenders GJ, Jenster G, Schröder FH, de Jong FH (2010) Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer. Cancer Res 70:1256–1264. doi:10.1158/0008-5472.CAN-09-2092

    Article  PubMed  CAS  Google Scholar 

  15. Green F, Page D, Fleming I (2002) American joint committee on cancer staging manual, 6th edn. Sprinter, New York

    Google Scholar 

  16. Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, Thompson IM, Weidner W, Wu FC, International Society of Andrology, International Society for the Study of Aging Male, European Association of Urology, European Academy of Andrology, American Society of Andrology (2009) Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol 55:121–130. doi:10.1016/j.eururo.2008.08.033

    Article  PubMed  Google Scholar 

  17. National Institutes of Health, National Heart, Lung, and Blood Institute (1998) Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults—the evidence report. Obes Res 6(suppl):51S–210S

    Google Scholar 

  18. Mohr BA, Guay AT, O’Donnell AB, McKinlay JB (2005) Normal, bound and nonbound testosterone levels in normally ageing men: results from the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf) 62:64–73. doi:10.1111/j.1365-2265.2004.02174.x

    Article  CAS  Google Scholar 

  19. Miller LR, Partin AW, Chan DW, Bruzek DJ, Dobs AS, Epstein JI, Walsh PC (1998) Influence of radical prostatectomy on serum hormone levels. J Urol 160:449–453

    Article  PubMed  CAS  Google Scholar 

  20. De Nunzio C, Carluccini A, Cicione A, Squillacciotti S, Trucchi A, Cantiani A, Leonardo C, Tubaro A (2011) Prostate cancer does not influence androgen levels: a radical prostatectomy cohort study. Urol Int 86:161–166. doi:10.1159/000322964

    Article  PubMed  Google Scholar 

  21. Lackner JE, Maerk I, Koller A, Bieglmayer C, Marberger M, Kratzik C, Schatzl G (2008) Serum inhibin-not a cause of low testosterone levels in hypogonadal prostate cancer? Urology 72:1121–1124. doi:10.1016/j.urology.2008.01.066

    Article  PubMed  Google Scholar 

  22. Ellem SJ, Wang H, Poutanen M, Risbridger GP (2009) Increased endogenous estrogen synthesis leads to the sequential induction of prostatic inflammation (prostatitis) and prostatic pre-malignancy. Am J Pathol 175:1187–1199. doi:10.2353/ajpath.2009.081107

    Article  PubMed  CAS  Google Scholar 

  23. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H (2007) Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab 92:405–413. doi:10.1210/jc.2006-1864

    Article  PubMed  CAS  Google Scholar 

  24. Sinnecker GH, Hiort O, Nitsche EM, Holterhus PM, Kruse K (1997) Functional assessment and clinical classification of androgen sensitivity in patients with mutations of the androgen receptor gene. German Collaborative Intersex Study Group. Eur J Pediatr 156:7–14. doi:10.1007/s004310050542

    Article  PubMed  CAS  Google Scholar 

  25. Imamoto T, Suzuki H, Yano M, Kawamura K, Kamiya N, Araki K, Komiya A, Nihei N, Naya Y, Ichikawa T (2008) The role of testosterone in the pathogenesis of prostate cancer. Int J Urol 15:472–480. doi:10.1111/j.1442-2042.2008.02074.x

    Article  PubMed  CAS  Google Scholar 

  26. Heracek J, Hampl R, Hill M, Starka L, Sachova J, Kuncova J, Eis V, Urban M, Mandys V (2007) Tissue and serum levels of principal androgens in benign prostatic hyperplasia and prostate cancer. Steroids 72:375–380. doi:10.1016/j.steroids.2007.01.004

    Article  PubMed  CAS  Google Scholar 

  27. van der Sluis TM, Meuleman EJ, van Moorselaar RJ, Bui HN, Blankenstein MA, Heijboer AC, Vis AN (2012) Intraprostatic testosterone and dihydrotestosterone. Part II: concentrations after androgen hormonal manipulation in men with benign prostatic hyperplasia and prostate cancer. BJU Int 109:183–188. doi:10.1111/j.1464-410X.2011.10652.x

    Article  PubMed  Google Scholar 

  28. Suzuki K, Nishiyama T, Hara N, Yamana K, Takahashi K, Labrie F (2007) Importance of the intracrine metabolism of adrenal androgens in androgen-dependent prostate cancer. Prostate Cancer Prostatic Dis 10:301–306. doi:10.1038/sj.pcan.4500956

    Article  PubMed  CAS  Google Scholar 

  29. Mostaghel EA, Page ST, Lin DW, Fazli L, Coleman IM, True LD, Knudsen B, Hess DL, Nelson CC, Matsumoto AM, Bremner WJ, Gleave ME, Nelson PS (2007) Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res 67:5033–5041. doi:10.1158/0008-5472.CAN-06-3332

    Article  PubMed  CAS  Google Scholar 

  30. van der Sluis TM, Vis AN, van Moorselaar RJ, Bui HN, Blankenstein MA, Meuleman EJ, Heijboer AC (2012) Intraprostatic testosterone and dihydrotestosterone. Part I: concentrations and methods of determination in men with benign prostatic hyperplasia and prostate cancer. BJU Int 109:176–182. doi:10.1111/j.1464-410X.2011.10651.x

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors thank Dragonfly Editorial for reviewing the language in this manuscript.

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The authors declare that they have no conflict of interest.

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Correspondence to Andrea Salonia.

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Salonia, A., Abdollah, F., Capitanio, U. et al. Circulating sex steroids and prostate cancer: introducing the time-dependency theory. World J Urol 31, 267–273 (2013). https://doi.org/10.1007/s00345-012-1009-8

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  • DOI: https://doi.org/10.1007/s00345-012-1009-8

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