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Elevated periprostatic androgens, sneaky testosterone and its implications

Nature Reviews Urology (2024)Cite this article

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Abstract

A subset of men with prostate cancer have elevated periprostatic androgens compared with levels in peripheral blood (termed the sneaky T phenomenon), which are associated with poor clinical outcomes after radical prostatectomy. These androgens are of testicular origin and reach the prostate, presumably through venous shunting. Varicocele physiology is accompanied by increased hydrostatic pressure within the pelvic venous system, providing a theoretical mechanistic explanation for the sneaky T phenomenon. These observations suggest a potential role for varicocele in contributing to prostate cancer pathophysiology through sneaky T, which if proved, could be a further indication for varicocele repair. Sneaky T can help to explain the differences in the natural history of benign or malignant prostatic diseases between individuals and could be a tool when deciding on the therapeutic course to take.

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Fig. 1: Interconnected pelvic venous system and its associations with renal and adrenal venous drainage.
Fig. 2: The blood backflow as a result of increased hydrostatic pressure by varicocele diverts blood from gonadal drainage towards prostate tissue.

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References

  1. Wilson, J. D., George, F. W. & Griffin, J. E. The hormonal control of sexual development. Science 211, 1278–1284 (1981).

    Article  CAS  PubMed  Google Scholar 

  2. Deslypere, J. P., Young, M., Wilson, J. D. & McPhaul, M. J. Testosterone and 5 alpha-dihydrotestosterone interact differently with the androgen receptor to enhance transcription of the MMTV-CAT reporter gene. Mol. Cell Endocrinol. 88, 15–22 (1992).

    Article  CAS  PubMed  Google Scholar 

  3. Dai, C., Dehm, S. M. & Sharifi, N. Targeting the androgen signaling axis in prostate cancer. J. Clin. Oncol. 41, 4267–4278 (2023).

    Article  CAS  PubMed  Google Scholar 

  4. Auchus, R. J. & Sharifi, N. Sex hormones and prostate cancer. Annu. Rev. Med. 71, 33–45 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Beveridge, T. S. et al. Retroperitoneal lymph node dissection: anatomical and technical considerations from a cadaveric study. J. Urol. 196, 1764–1771 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ku, S. Y., Gleave, M. E. & Beltran, H. Towards precision oncology in advanced prostate cancer. Nat. Rev. Urol. 16, 645–654 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Winters, S. J. & Troen, P. Testosterone and estradiol are co-secreted episodically by the human testis. J. Clin. Invest. 78, 870–873 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Alyamani, M. et al. Elevated periprostatic venous testosterone correlates with prostate cancer progression after radical prostatectomy. J. Clin. Invest. 133, e171117 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Walsh, T. J. et al. Increased risk of high‐grade prostate cancer among infertile men. Cancer 116, 2140–2147 (2010).

    Article  PubMed  Google Scholar 

  10. Hamada, A., Esteves, S. C. & Agarwal, A. Insight into oxidative stress in varicocele-associated male infertility: part 2. Nat. Rev. Urol. 10, 26–37 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Alsaikhan, B., Alrabeeah, K., Delouya, G. & Zini, A. Epidemiology of varicocele. Asian J. Androl. 18, 179–181 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Liguori, G. et al. Color doppler ultrasound investigation of varicocele. World J. Urol. 22, 378–381 (2004).

    Article  PubMed  Google Scholar 

  13. Jensen, C. F. S. et al. Varicocele and male infertility. Nat. Rev. Urol. 14, 523–533 (2017).

    Article  PubMed  Google Scholar 

  14. Sakamoto, H. & Ogawa, Y. Is varicocele associated with underlying venous abnormalities? Varicocele and the prostatic venous plexus. J. Urol. 180, 1427–1431 (2008).

    Article  PubMed  Google Scholar 

  15. Tilki, D. et al. The complex structure of the smooth muscle layer of spermatic veins and its potential role in the development of varicocele testis. Eur. Urol. 51, 1402–1409 (2007).

    Article  PubMed  Google Scholar 

  16. Gat, Y., Joshua, S., Vuk-Pavlovic, S. & Goren, M. Paying the price for standing tall: fluid mechanics of prostate pathology. Prostate 80, 1297–1303 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Black, C. M. Anatomy and physiology of the lower-extremity deep and superficial veins. Tech. Vasc. Interv. Radiol. 17, 68–73 (2014).

    Article  PubMed  Google Scholar 

  18. Gat, Y., Joshua, S. & Gornish, M. G. Prostate cancer: a newly discovered route for testosterone to reach the prostate : treatment by super-selective intraprostatic androgen deprivation. Andrologia 41, 305–315 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Hoffman, M. A., DeWOLF, W. C. & Morgentaler, A. Is low serum free testosterone a marker for high grade prostate cancer? J. Urol. 163, 824–827 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Morgentaler, A., Bruning, C. O. 3rd & DeWolf, W. C. Occult prostate cancer in men with low serum testosterone levels. JAMA 276, 1904–1906 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Goren, M. & Gat, Y. Varicocele is the root cause of BPH: destruction of the valves in the spermatic veins produces elevated pressure which diverts undiluted testosterone directly from the testes to the prostate. Andrologia 50, e12992 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Canales, B. K. et al. Prevalence and effect of varicoceles in an elderly population. Urology 66, 627–631 (2005).

    Article  PubMed  Google Scholar 

  23. Besiroglu, H., Otunctemur, A., Dursun, M. & Ozbek, E. The prevalence and severity of varicocele in adult population over the age of forty years old: a cross-sectional study. Aging Male 22, 207–213 (2019).

    Article  PubMed  Google Scholar 

  24. Levinger, U., Gornish, M., Gat, Y. & Bachar, G. N. Is varicocele prevalence increasing with age? Andrologia 39, 77–80 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Wishahi, M. M. Detailed anatomy of the internal spermatic vein and the ovarian vein. Human cadaver study and operative spermatic venography: clinical aspects. J. Urol. 145, 780–784 (1991).

    Article  CAS  PubMed  Google Scholar 

  26. Sofikitis, N., Dritsas, K., Miyagawa, I. & Koutselinis, A. Anatomical characteristics of the left testicular venous system in man. Arch. Androl. 30, 79–85 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Iafrate, M. et al. Varicocele is associated with an increase of connective tissue of the pampiniform plexus vein wall. World J. Urol. 27, 363–369 (2009).

    Article  PubMed  Google Scholar 

  28. Li, R., Liu, J., Li, Y. & Wang, Q. Effect of somatometric parameters on the prevalence and severity of varicocele: a systematic review and meta-analysis. Reprod. Biol. Endocrinol. 19, 11 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Zuccolo, L. et al. Height and prostate cancer risk: a large nested case-control study (ProtecT) and meta-analysis. Cancer Epidemiol. Biomark. Prev. 17, 2325–2336 (2008).

    Article  CAS  Google Scholar 

  30. Lophatananon, A. et al. Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium. Br. J. Cancer 117, 734–743 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Emerging Risk Factors Collaboration. Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis. Int. J. Epidemiol. 41, 1419–1433 (2012).

    Article  Google Scholar 

  32. Huggins, C. & Hodges, C. V. Studies on prostatic cancer. Cancer res. 1, 293–297 (1941).

    CAS  Google Scholar 

  33. Tanrikut, C. et al. Varicocele as a risk factor for androgen deficiency and effect of repair. BJU Int. 108, 1480–1484 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Chang, K. H. & Sharifi, N. Prostate cancer-from steroid transformations to clinical translation. Nat. Rev. Urol. 9, 721–724 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Ando, S. et al. Physiopathologic aspects of Leydig cell function in varicocele patients. J. Androl. 5, 163–170 (1984).

    Article  CAS  PubMed  Google Scholar 

  36. Zheng, Y. Q. et al. The effects of artery-ligating and artery-preserving varicocelectomy on the ipsilateral testes in rats. Urology 72, 1179–1184 (2008).

    Article  PubMed  Google Scholar 

  37. Gat, Y., Gornish, M., Heiblum, M. & Joshua, S. Reversal of benign prostate hyperplasia by selective occlusion of impaired venous drainage in the male reproductive system: novel mechanism, new treatment. Andrologia 40, 273–281 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Jarow, J. P., Chen, H., Rosner, T. W., Trentacoste, S. & Zirkin, B. R. Assessment of the androgen environment within the human testis: minimally invasive method to obtain intratesticular fluid. J. Androl. 22, 640–645 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Jarow, J. P., Wright, W. W., Brown, T. R., Yan, X. & Zirkin, B. R. Bioactivity of androgens within the testes and serum of normal men. J. Androl. 26, 343–348 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Han, H. et al. Significant alterations of serum hormone levels in the spermatic vein plexus of patients with varicoceles. Andrologia 48, 1108–1112 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Lima, T. F. N., Patel, P., Blachman-Braun, R., Madhusoodanan, V. & Ramasamy, R. Serum 17-hydroxyprogesterone is a potential biomarker for evaluating intratesticular testosterone. J. Urol. 204, 551–556 (2020).

    Article  PubMed  Google Scholar 

  42. Engels, M. et al. Testicular adrenal rest tumors: current insights on prevalence, characteristics, origin, and treatment. Endocr. Rev. 40, 973–987 (2019).

    Article  PubMed  Google Scholar 

  43. Luo, D. Y., Yang, G., Liu, J. J., Yang, Y. R. & Dong, Q. Effects of varicocele on testosterone, apoptosis and expression of StAR mRNA in rat Leydig cells. Asian J. Androl. 13, 287–291 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Bernstein, A. P. & Najari, B. B. Varicocele treatment and serum testosterone. Androgens: Clin. Res. Ther. 3, 133–137 (2022).

    CAS  Google Scholar 

  45. Tu, H. et al. Low serum testosterone is associated with tumor aggressiveness and poor prognosis in prostate cancer. Oncol. Lett. 13, 1949–1957 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Welén, K., Damber, J.-E. J. R. I. E. & Disorders, M. Androgens, aging, and prostate health. Rev. Endocr. Metab. Disord. 23, 1221–1231 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Roehrborn, C. G. Pathology of benign prostatic hyperplasia. Int. J. Impot. Res. 20, S11–S18 (2008).

    Article  PubMed  Google Scholar 

  48. Chughtai, B. et al. Benign prostatic hyperplasia. Nat. Rev. Dis. Prim. 2, 16032 (2016).

    Article  Google Scholar 

  49. Berry, S. J., Coffey, D. S., Walsh, P. C. & Ewing, L. L. The development of human benign prostatic hyperplasia with age. J. Urol. 132, 474–479 (1984).

    Article  CAS  PubMed  Google Scholar 

  50. Page, S. T. et al. Dihydrotestosterone administration does not increase intraprostatic androgen concentrations or alter prostate androgen action in healthy men: a randomized-controlled trial. J. Clin. Endocrinol. Metab. 96, 430–437 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. van der Sluis, T. M. et al. 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 (2012).

    Article  PubMed  Google Scholar 

  52. Dai, C. et al. Direct metabolic interrogation of dihydrotestosterone biosynthesis from adrenal precursors in primary prostatectomy tissues. Clin. Cancer Res. 23, 6351–6362 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Carson, C. III & Rittmaster, R. The role of dihydrotestosterone in benign prostatic hyperplasia. Urology 61, 2–7 (2003).

    Article  PubMed  Google Scholar 

  54. Kim, I. Y. et al. Modulation of sensitivity to transforming growth factor-beta 1 (TGF-beta 1) and the level of type II TGF-beta receptor in LNCaP cells by dihydrotestosterone. Exp. Cell Res. 222, 103–110 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. Foster, C. S. Pathology of benign prostatic hyperplasia. Prostate Suppl. 9, 4–14 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Griffiths, K., Morton, M. S. & Nicholson, R. I. Androgens, androgen receptors, antiandrogens and the treatment of prostate cancer. Eur. Urol. 32, 24–40 (1997).

    CAS  PubMed  Google Scholar 

  57. Isaacs, J. T. Antagonistic effect of androgen on prostatic cell death. Prostate 5, 545–557 (1984).

    Article  CAS  PubMed  Google Scholar 

  58. Niu, Y. et al. Proliferation and differentiation of prostatic stromal cells. BJU Int. 87, 386–393 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Kim, E. H., Brockman, J. A. & Andriole, G. L. The use of 5-alpha reductase inhibitors in the treatment of benign prostatic hyperplasia. Asian J. Urol. 5, 28–32 (2018).

    Article  CAS  PubMed  Google Scholar 

  60. Thirumalai, A. et al. Stable intraprostatic dihydrotestosterone in healthy medically castrate men treated with exogenous testosterone. J. Clin. Endocrinol. Metab. 101, 2937–2944 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Parsons, J. K., Palazzi-Churas, K., Bergstrom, J. & Barrett-Connor, E. Prospective study of serum dihydrotestosterone and subsequent risk of benign prostatic hyperplasia in community dwelling men: the Rancho Bernardo Study. J. Urol. 184, 1040–1044 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Trifiro, M. D. et al. Serum sex hormones and the 20-year risk of lower urinary tract symptoms in community-dwelling older men. BJU Int. 105, 1554–1559 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Kristal, A. R. et al. Serum steroid and sex hormone-binding globulin concentrations and the risk of incident benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am. J. Epidemiol. 168, 1416–1424 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Schatzl, G. et al. High-grade prostate cancer is associated with low serum testosterone levels. Prostate 47, 52–58 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Kratzik, C. et al. Lower serum total testosterone is associated with lymph node metastases in a radical prostatectomy cohort study. Anticancer Res. 31, 3615–3618 (2011).

    CAS  PubMed  Google Scholar 

  66. Li, X. et al. BMX controls 3betaHSD1 and sex steroid biosynthesis in cancer. J. Clin. Invest. 133, e163498 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Waltering, K. K. et al. Increased expression of androgen receptor sensitizes prostate cancer cells to low levels of androgens. Cancer Res. 69, 8141–8149 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Chen, C. D. et al. Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 10, 33–39 (2004).

    Article  PubMed  Google Scholar 

  69. Titus, M. A., Schell, M. J., Lih, F. B., Tomer, K. B. & Mohler, J. L. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin. Cancer Res. 11, 4653–4657 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Montgomery, R. B. et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 68, 4447–4454 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Stanbrough, M. et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 66, 2815–2825 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Nishiyama, T., Hashimoto, Y. & Takahashi, K. The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer. Clin. Cancer Res. 10, 7121–7126 (2004).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, FL, USA

    Masoud Bitaraf, Ranjith Ramasamy, Sanoj Punnen & Nima Sharifi

  2. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Sanoj Punnen & Nima Sharifi

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All authors researched data for the article. All authors contributed substantially to discussion of the content. All authors wrote the article. M.B., R.R. and N.S. reviewed and/or edited the manuscript before submission.

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Bitaraf, M., Ramasamy, R., Punnen, S. et al. Elevated periprostatic androgens, sneaky testosterone and its implications. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-024-00878-8

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