Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Estrogen and androgen signaling in the pathogenesis of BPH

Abstract

Estrogens and androgens have both been implicated as causes of benign prostatic hyperplasia (BPH). Although epidemiological data on an association between serum androgen concentrations and BPH are inconsistent, it is generally accepted that androgens play a permissive role in BPH pathogenesis. In clinical practice, inhibitors of 5α-reductase (which converts testosterone to the more potent androgen dihydrotestosterone) have proven effective in the management of BPH, confirming an essential role for androgens in BPH pathophysiology. To date, multiple lines of evidence support a role for estrogens in BPH pathogenesis. Studies of the two estrogen receptor (ER) subtypes have shed light on their differential functions in the human prostate; ERα and ERβ have proliferative and antiproliferative effects on prostate cells, respectively. Effects of estrogens on the prostate are associated with multiple mechanisms including apoptosis, aromatase expression and paracrine regulation via prostaglandin E2. Selective estrogen receptor modulators or other agents that can influence intraprostatic estrogen levels might conceivably be potential therapeutic targets for the treatment of BPH.

Key Points

  • Androgens play a permissive role in the pathogenesis of benign prostatic hyperplasia (BPH)

  • Inhibition of 5α-reductase activity is currently the mainstay of hormonal treatment of BPH

  • Increasing evidence from epidemiological, animal and in vitro studies supports a role for estrogens in the pathogenesis of BPH

  • Estrogen receptors ERα and ERβ mediate proliferative and antiproliferative effects of estrogens on prostate cells, respectively

  • Some androgens are weak ligands for ERs but might have potent agonistic effects on prostate cells because of high tissue concentrations

  • The prevalence of ERα and ERβ in hyperplastic prostate raises the potential of selective estrogen receptor modulators as potential therapeutic agents for BPH

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Biosynthesis and metabolism of the major androgens and estrogens in human prostate.
Figure 2: Schematic representation of human ARs and ERs.
Figure 3: Actions of ER subtypes in the major prostate cell types.

References

  1. Timms, B. G. in Prostate: Basic and Clinical Aspects (ed. Naz, R. K.) 29–52 (CRC Press, Boca Raton, 1997).

    Google Scholar 

  2. Isaacs, J. T. in Testosterone: Action, Deficiency, Substitution (eds Nieschlag, E. & Behre, H. M.) 347–374 (Cambridge University Press, Cambridge, 2004).

    Book  Google Scholar 

  3. Frasier, S. D., Gafford, F. & Horton, R. Plasma androgens in childhood and adolescence. J. Clin. Endocrinol. Metab. 29, 1404–1408 (1969).

    CAS  Article  PubMed  Google Scholar 

  4. Uson, A. C., Paez, A. B. & Uson-Jaeger, J. The natural history and course of untreated benign prostatic hyperplasia. Eur. Urol. 20 (Suppl. 1), 22–26 (1991).

    Article  PubMed  Google Scholar 

  5. McNeal, J. E. Regional morphology and pathology of the prostate. Am. J. Clin. Pathol. 49, 347–357 (1968).

    CAS  Article  PubMed  Google Scholar 

  6. 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).

    CAS  Article  PubMed  Google Scholar 

  7. Isaacs, J. T. & Coffey, D. S. Etiology and disease process of benign prostatic hyperplasia. Prostate Suppl. 2, 33–50 (1989).

    CAS  Article  PubMed  Google Scholar 

  8. Lepor, H. Pathophysiology, epidemiology, and natural history of benign prostatic hyperplasia. Rev. Urol. 6 (Suppl. 9), S3–S10 (2004).

    PubMed  PubMed Central  Google Scholar 

  9. Cunha, G. R. et al. The endocrinology and developmental biology of the prostate. Endocr. Rev. 8, 338–362 (1987).

    CAS  Article  PubMed  Google Scholar 

  10. McNeal, J. E. Origin and evolution of benign prostatic enlargement. Invest. Urol. 15, 340–345 (1978).

    CAS  PubMed  Google Scholar 

  11. Habib, F. K. in Handbook on Benign Prostatic Hyperplasia (ed. Chisholm, G. D.) 19–31 (Raven Press, New York, 1994).

    Google Scholar 

  12. Tutrone, R. F. Jr, Ball, R. A., Ornitz, D. M., Leder, P. & Richie, J. P. Benign prostatic hyperplasia in a transgenic mouse: a new hormonally sensitive investigatory model. J. Urol. 149, 633–639 (1993).

    Article  PubMed  Google Scholar 

  13. Berger, A. P. et al. Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia. Prostate 57, 57–65 (2003).

    CAS  Article  PubMed  Google Scholar 

  14. Isaacs, J. T. Prostate stem cells and benign prostatic hyperplasia. Prostate 68, 1025–1034 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Lin, V. K. et al. Prostatic stromal cells derived from benign prostatic hyperplasia specimens possess stem cell like property. Prostate 67, 1265–1276 (2007).

    CAS  Article  PubMed  Google Scholar 

  16. Siiteri, P. K. & Wilson, J. D. Dihydrotestosterone in prostatic hypertrophy. I. The formation and content of dihydrotestosterone in the hypertrophic prostate of man. J. Clin. Invest. 49, 1737–1745 (1970).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Zhu, Y. S., Katz, M. D. & Imperato-McGinley, J. Natural potent androgens: lessons from human genetic models. Baillieres Clin. Endocrinol. Metab. 12, 83–113 (1998).

    CAS  Article  PubMed  Google Scholar 

  18. Amory, J. K. & Bremner, W. J. Regulation of testicular function in men: implications for male hormonal contraceptive development. J. Steroid Biochem. Mol. Biol. 85, 357–361 (2003).

    CAS  Article  PubMed  Google Scholar 

  19. Farnsworth, W. E. Estrogen in the etiopathogenesis of BPH. Prostate 41, 263–274 (1999).

    CAS  Article  PubMed  Google Scholar 

  20. Morris, P. D., Malkin, C. J., Channer, K. S. & Jones, T. H. A mathematical comparison of techniques to predict biologically available testosterone in a cohort of 1072 men. Eur. J. Endocrinol. 151, 241–249 (2004).

    CAS  Article  PubMed  Google Scholar 

  21. Ho, C. K., Stoddart, M., Walton, M., Anderson, R. A. & Beckett, G. J. Calculated free testosterone in men: comparison of four equations and with free androgen index. Ann. Clin. Biochem. 43, 389–397 (2006).

    CAS  Article  PubMed  Google Scholar 

  22. Gao, W., Bohl, C. E. & Dalton, J. T. Chemistry and structural biology of androgen receptor. Chem. Rev. 105, 3352–3370 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Mhatre, A. N. et al. Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy. Nat. Genet. 5, 184–188 (1993).

    CAS  Article  PubMed  Google Scholar 

  24. Ruizeveld de Winter, J. A. et al. Androgen receptor expression in human tissues: an immunohistochemical study. J. Histochem. Cytochem. 39, 927–936 (1991).

    CAS  Article  PubMed  Google Scholar 

  25. Wilson, C. M. & McPhaul, M. J. A and B forms of the androgen receptor are expressed in a variety of human tissues. Mol. Cell. Endocrinol. 120, 51–57 (1996).

    CAS  Article  PubMed  Google Scholar 

  26. Randall, V. A. Role of 5 alpha-reductase in health and disease. Baillieres Clin. Endocrinol. Metab. 8, 405–431 (1994).

    CAS  Article  PubMed  Google Scholar 

  27. 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).

    CAS  Article  PubMed  Google Scholar 

  28. George, F. W. & Wilson, J. D. Hormonal control of sexual development. Vitam. Horm. 43, 145–196 (1986).

    CAS  Article  PubMed  Google Scholar 

  29. Ozers, M. S. et al. The androgen receptor T877A mutant recruits LXXLL and FXXLF peptides differently than wild-type androgen receptor in a time-resolved fluorescence resonance energy transfer assay. Biochemistry 46, 683–695 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Askew, E. B., Gampe, R. T. Jr, Stanley, T. B., Faggart, J. L. & Wilson, E. M. Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone. J. Biol. Chem. 282, 25801–25816 (2007).

    CAS  Article  PubMed  Google Scholar 

  31. Hsiao, P. W., Thin, T. H., Lin, D. L. & Chang, C. Differential regulation of testosterone vs. 5alpha-dihydrotestosterone by selective androgen response elements. Mol. Cell. Biochem. 206, 169–175 (2000).

    CAS  Article  PubMed  Google Scholar 

  32. Klinge, C. M. Estrogen receptor interaction with co-activators and co-repressors. Steroids 65, 227–251 (2000).

    CAS  Article  PubMed  Google Scholar 

  33. Katzenellenbogen, B. S. & Korach, K. S. A new actor in the estrogen receptor drama--enter ER-beta. Endocrinology 138, 861–862 (1997).

    CAS  Article  PubMed  Google Scholar 

  34. Martin, C. et al. CYP7B generates a selective estrogen receptor beta agonist in human prostate. J. Clin. Endocrinol. Metab. 89, 2928–2935 (2004).

    CAS  Article  PubMed  Google Scholar 

  35. Wendel, E. F., Brannen, G. E., Putong, P. B. & Grayhack, J. T. The effect of orchiectomy and estrogens on benign prostatic hyperplasia. J. Urol. 108, 116–119 (1972).

    CAS  Article  PubMed  Google Scholar 

  36. Stone, N. N. & Clejan, S. J. Response of prostate volume, prostate-specific antigen, and testosterone to flutamide in men with benign prostatic hyperplasia. J. Androl. 12, 376–380 (1991).

    CAS  PubMed  Google Scholar 

  37. Gann, P. H. et al. A prospective study of plasma hormone levels, nonhormonal factors, and development of benign prostatic hyperplasia. Prostate 26, 40–49 (1995).

    CAS  Article  PubMed  Google Scholar 

  38. Roberts, R. O. et al. Serum sex hormones and measures of benign prostatic hyperplasia. Prostate 61, 124–131 (2004).

    CAS  Article  PubMed  Google Scholar 

  39. Rohrmann, S. et al. Serum sex steroid hormones and lower urinary tract symptoms in Third National Health and Nutrition Examination Survey (NHANES III). Urology 69, 708–713 (2007).

    Article  PubMed  Google Scholar 

  40. 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 

  41. Ansari, M. A., Begum, D. & Islam, F. Serum sex steroids, gonadotrophins and sex hormone-binding globulin in prostatic hyperplasia. Ann. Saudi Med. 28, 174–178 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Jin, B., Conway, A. J. & Handelsman, D. J. Effects of androgen deficiency and replacement on prostate zonal volumes. Clin. Endocrinol. (Oxf.) 54, 437–445 (2001).

    CAS  Article  Google Scholar 

  43. Jin, B., Turner, L., Walters, W. A. & Handelsman, D. J. The effects of chronic high dose androgen or estrogen treatment on the human prostate [corrected]. J. Clin. Endocrinol. Metab. 81, 4290–4295 (1996).

    CAS  PubMed  Google Scholar 

  44. Becker, H., Kaufmann, J., Klosterhalfen, H. & Voigt, K. D. In vivo uptake and metabolism of 3H-testosterone and 3H-5 -dihydrotestosterone by human benign prostatic hypertrophy. Acta Endocrinol. (Copenh.) 71, 589–599 (1972).

    CAS  Article  Google Scholar 

  45. Habib, F. K., Lee, I. R., Stitch, S. R. & Smith, P. H. Androgen levels in the plasma and prostatic tissues of patients with benign hypertrophy and carcinoma of the prostate. J. Endocrinol. 71, 99–107 (1976).

    CAS  Article  PubMed  Google Scholar 

  46. Ghanadian, R. & Puah, C. M. Relationships between oestradiol-17 beta, testosterone, dihydrotestosterone and 5 alpha-androstane-3 alpha, 27 beta-diol in human benign hypertrophy and carcinoma of the prostate. J. Endocrinol. 88, 255–262 (1981).

    CAS  Article  PubMed  Google Scholar 

  47. Walsh, P. C., Hutchins, G. M. & Ewing, L. L. Tissue content of dihydrotestosterone in human prostatic hyperplasis is not supranormal. J. Clin. Invest. 72, 1772–1777 (1983).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Krieg, M., Weisser, H. & Tunn, S. Potential activities of androgen metabolizing enzymes in human prostate. J. Steroid Biochem. Mol. Biol. 53, 395–400 (1995).

    CAS  Article  PubMed  Google Scholar 

  49. Labrie, F. et al. Intracrinology: role of the family of 17 beta-hydroxysteroid dehydrogenases in human physiology and disease. J. Mol. Endocrinol. 25, 1–16 (2000).

    CAS  Article  PubMed  Google Scholar 

  50. Masai, M. et al. Immunohistochemical study of androgen receptor in benign hyperplastic and cancerous human prostates. Prostate 17, 293–300 (1990).

    CAS  Article  PubMed  Google Scholar 

  51. Chodak, G. W. et al. Nuclear localization of androgen receptor in heterogeneous samples of normal, hyperplastic and neoplastic human prostate. J. Urol. 147, 798–803 (1992).

    CAS  Article  PubMed  Google Scholar 

  52. El-Alfy, M. et al. Localization of type 5 17beta-hydroxysteroid dehydrogenase, 3beta-hydroxysteroid dehydrogenase, and androgen receptor in the human prostate by in situ hybridization and immunocytochemistry. Endocrinology 140, 1481–1491 (1999).

    CAS  Article  PubMed  Google Scholar 

  53. Olapade-Olaopa, E. O. et al. Androgen receptor protein expression in prostatic tissues in black and Caucasian men. Prostate 59, 460–468 (2004).

    CAS  Article  PubMed  Google Scholar 

  54. Pelletier, G. Expression of steroidogenic enzymes and sex-steroid receptors in human prostate. Best Pract. Res. Clin. Endocrinol. Metab. 22, 223–228 (2008).

    CAS  Article  PubMed  Google Scholar 

  55. Giovannucci, E. et al. The CAG repeat within the androgen receptor gene and benign prostatic hyperplasia. Urology 53, 121–125 (1999).

    CAS  Article  PubMed  Google Scholar 

  56. Mitsumori, K. et al. Androgen receptor CAG repeat length polymorphism in benign prostatic hyperplasia (BPH): correlation with adenoma growth. Prostate 41, 253–257 (1999).

    CAS  Article  PubMed  Google Scholar 

  57. Bousema, J. T. et al. Polymorphisms in the vitamin D receptor gene and the androgen receptor gene and the risk of benign prostatic hyperplasia. Eur. Urol. 37, 234–238 (2000).

    CAS  Article  PubMed  Google Scholar 

  58. Andersson, S. & Russell, D. W. Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases. Proc. Natl Acad. Sci. USA 87, 3640–3644 (1990).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Andersson, S., Berman, D. M., Jenkins, E. P. & Russell, D. W. Deletion of steroid 5 alpha-reductase 2 gene in male pseudohermaphroditism. Nature 354, 159–161 (1991).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Jenkins, E. P., Andersson, S., Imperato-McGinley, J., Wilson, J. D. & Russell, D. W. Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase. J. Clin. Invest. 89, 293–300 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. Thigpen, A. E., Cala, K. M. & Russell, D. W. Characterization of Chinese hamster ovary cell lines expressing human steroid 5 alpha-reductase isozymes. J. Biol. Chem. 268, 17404–17412 (1993).

    CAS  PubMed  Google Scholar 

  62. Levy, M. A. et al. Cloning, expression and functional characterization of type 1 and type 2 steroid 5 alpha-reductases from Cynomolgus monkey: comparisons with human and rat isoenzymes. J. Steroid Biochem. Mol. Biol. 52, 307–319 (1995).

    CAS  Article  PubMed  Google Scholar 

  63. Wilson, J. D., Griffin, J. E. & Russell, D. W. Steroid 5 alpha-reductase 2 deficiency. Endocr. Rev. 14, 577–593 (1993).

    CAS  PubMed  Google Scholar 

  64. Thigpen, A. E. et al. Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression. J. Clin. Invest. 92, 903–910 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Walsh, P. C. et al. Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N. Engl. J. Med. 291, 944–949 (1974).

    CAS  Article  PubMed  Google Scholar 

  66. Imperato-McGinley, J. et al. Prostate visualization studies in males homozygous and heterozygous for 5 alpha-reductase deficiency. J. Clin. Endocrinol. Metab. 75, 1022–1026 (1992).

    CAS  PubMed  Google Scholar 

  67. Habib, F. K. et al. The localisation and expression of 5 alpha-reductase types I and II mRNAs in human hyperplastic prostate and in prostate primary cultures. J. Endocrinol. 156, 509–517 (1998).

    CAS  Article  PubMed  Google Scholar 

  68. Pelletier, G., Luu-The, V., Huang, X. F., Lapointe, H. & Labrie, F. Localization by in situ hybridization of steroid 5alpha-reductase isozyme gene expression in the human prostate and preputial skin. J. Urol. 160, 577–582 (1998).

    CAS  Article  PubMed  Google Scholar 

  69. Iehlé, C. et al. Differences in steroid 5alpha-reductase iso-enzymes expression between normal and pathological human prostate tissue. J. Steroid Biochem. Mol. Biol. 68, 189–195 (1999).

    Article  PubMed  Google Scholar 

  70. Shirakawa, T. et al. Messenger RNA levels and enzyme activities of 5 alpha-reductase types 1 and 2 in human benign prostatic hyperplasia (BPH) tissue. Prostate 58, 33–40 (2004).

    CAS  Article  PubMed  Google Scholar 

  71. Bonkhoff, H., Stein, U., Aumüller, G. & Remberger, K. Differential expression of 5 alpha-reductase isoenzymes in the human prostate and prostatic carcinomas. Prostate 29, 261–267 (1996).

    CAS  Article  PubMed  Google Scholar 

  72. Eicheler, W. et al. Immunocytochemical localization of human 5 alpha-reductase 2 with polyclonal antibodies in androgen target and non-target human tissues. J. Histochem. Cytochem. 42, 667–675 (1994).

    CAS  Article  PubMed  Google Scholar 

  73. Silver, R. I. et al. Cell type specific expression of steroid 5 alpha-reductase 2. J. Urol. 152, 438–442 (1994).

    CAS  Article  PubMed  Google Scholar 

  74. Levine, A. C. et al. Immunohistochemical localization of steroid 5 alpha-reductase 2 in the human male fetal reproductive tract and adult prostate. J. Clin. Endocrinol. Metab. 81, 384–389 (1996).

    CAS  PubMed  Google Scholar 

  75. Berman, D. M. & Russell, D. W. Cell-type-specific expression of rat steroid 5 alpha-reductase isozymes. Proc. Natl Acad. Sci. USA 90, 9359–9363 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. Span, P. N., Benraad Th. J., Sweep, C. G. & Smals, A. G. Kinetic analysis of steroid 5alpha-reductase activity at neutral pH in benign prostatic hyperplastic tissue: evidence for type I isozyme activity in the human prostate. J. Steroid Biochem. Mol. Biol. 57, 103–108 (1996).

    CAS  Article  PubMed  Google Scholar 

  77. Bartsch, G., Rittmaster, R. S. & Klocker, H. Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia. World J. Urol. 19, 413–425 (2002).

    CAS  Article  PubMed  Google Scholar 

  78. Isaacs, J. T., Brendler, C. B. & Walsh, P. C. Changes in the metabolism of dihydrotestosterone in the hyperplastic human prostate. J. Clin. Endocrinol. Metab. 56, 139–146 (1983).

    CAS  Article  PubMed  Google Scholar 

  79. Bartsch, W., Klein, H., Schiemann, U., Bauer, H. W. & Voigt, K. D. Enzymes of androgen formation and degradation in the human prostate. Ann. NY Acad. Sci. 595, 53–66 (1990).

    CAS  Article  PubMed  Google Scholar 

  80. Berthaut, I., Portois, M. C., Cussenot, O. & Mowszowicz, I. Human prostatic cells in culture: different testosterone metabolic profile in epithelial cells and fibroblasts from normal or hyperplastic prostates. J. Steroid Biochem. Mol. Biol. 58, 235–242 (1996).

    CAS  Article  PubMed  Google Scholar 

  81. Kaufman, K. D. in Testosterone: Action, Deficiency, Substitution (eds Nieschlag, E. & Behre, H. M.) 571–596 (Cambridge University Press, Cambridge, 2004).

    Book  Google Scholar 

  82. Rittmaster, R. S. 5Alpha-reductase inhibitors in benign prostatic hyperplasia and prostate cancer risk reduction. Best Pract. Res. Clin. Endocrinol. Metab. 22, 389–402 (2008).

    CAS  Article  PubMed  Google Scholar 

  83. Harris, G. et al. Identification and selective inhibition of an isozyme of steroid 5 alpha-reductase in human scalp. Proc. Natl Acad. Sci. USA 89, 10787–10791 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. Edwards, J. E. & Moore, R. A. Finasteride in the treatment of clinical benign prostatic hyperplasia: a systematic review of randomised trials. BMC Urol. 2, 14 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Roehrborn, C. G., Boyle, P., Nickel, J. C., Hoefner, K. & Andriole, G. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 60, 434–441 (2002).

    Article  PubMed  Google Scholar 

  86. Clark, R. V. et al. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. J. Clin. Endocrinol. Metab. 89, 2179–2184 (2004).

    CAS  Article  PubMed  Google Scholar 

  87. Fagelman, E. & Lowe, F. C. Herbal medications in the treatment of benign prostatic hyperplasia (BPH). Urol. Clin. North Am. 29, 23–29, vii (2002).

    Article  PubMed  Google Scholar 

  88. Madersbacher, S., Ponholzer, A., Berger, I. & Marszalek, M. Medical management of BPH: role of plant extracts. EAU-EBU Update Series 5, 197–205 (2007).

    Article  Google Scholar 

  89. Carraro, J. C. et al. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. Prostate 29, 231–240; discussion 241–242 (1996).

    Article  PubMed  Google Scholar 

  90. Wilt, T. J. et al. Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA 280, 1604–1609 (1998).

    CAS  Article  PubMed  Google Scholar 

  91. Iehlé, C. et al. Human prostatic steroid 5 alpha-reductase isoforms—a comparative study of selective inhibitors. J. Steroid Biochem. Mol. Biol. 54, 273–279 (1995).

    Article  PubMed  Google Scholar 

  92. Bayne, C. W., Donnelly, F., Ross, M. & Habib, F. K. Serenoa repens (Permixon): a 5alpha-reductase types I and II inhibitor-new evidence in a coculture model of BPH. Prostate 40, 232–241 (1999).

    CAS  Article  PubMed  Google Scholar 

  93. Carilla, E., Briley, M., Fauran, F., Sultan, C. & Duvilliers, C. Binding of Permixon, a new treatment for prostatic benign hyperplasia, to the cytosolic androgen receptor in the rat prostate. J. Steroid Biochem. 20, 521–523 (1984).

    CAS  Article  PubMed  Google Scholar 

  94. Di Silverio, F. et al. Evidence that Serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy patients. Eur. Urol. 21, 309–314 (1992).

    CAS  Article  PubMed  Google Scholar 

  95. Walsh, P. C. & Wilson, J. D. The induction of prostatic hypertrophy in the dog with androstanediol. J. Clin. Invest. 57, 1093–1097 (1976).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. DeKlerk, D. P. et al. Comparison of spontaneous and experimentally induced canine prostatic hyperplasia. J. Clin. Invest. 64, 842–849 (1979).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. Gray, A., Feldman, H. A., McKinlay, J. B. & Longcope, C. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J. Clin. Endocrinol. Metab. 73, 1016–1025 (1991).

    CAS  Article  PubMed  Google Scholar 

  98. Ferrini, R. L. & Barrett-Connor, E. Sex hormones and age: a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. Am. J. Epidemiol. 147, 750–754 (1998).

    CAS  Article  PubMed  Google Scholar 

  99. Harman, S. M., Metter, E. J., Tobin, J. D., Pearson, J. & Blackman, M. R. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J. Clin. Endocrinol. Metab. 86, 724–731 (2001).

    CAS  Article  PubMed  Google Scholar 

  100. Vermeulen, A., Kaufman, J. M., Goemaere, S. & van Pottelberg, I. Estradiol in elderly men. Aging Male 5, 98–102 (2002).

    CAS  Article  PubMed  Google Scholar 

  101. Hammarsten, J. et al. Insulin and free oestradiol are independent risk factors for benign prostatic hyperplasia. Prostate Cancer Prostatic Dis. 12, 160–165 (2009).

    CAS  Article  PubMed  Google Scholar 

  102. Voigt, K. D. & Bartsch, W. Intratissular androgens in benign prostatic hyperplasia and prostatic cancer. J. Steroid Biochem. 25, 749–757 (1986).

    CAS  Article  PubMed  Google Scholar 

  103. Hill, M. et al. The identification and simultaneous quantification of 7-hydroxylated metabolites of pregnenolone, dehydroepiandrosterone, 3beta, 17beta-androstenediol, and testosterone in human serum using gas chromatography-mass spectrometry. J. Steroid Biochem. Mol. Biol. 96, 187–200 (2005).

    CAS  Article  PubMed  Google Scholar 

  104. Levine, A. C., Ren, M., Huber, G. K. & Kirschenbaum, A. The effect of androgen, estrogen, and growth factors on the proliferation of cultured fibroblasts derived from human fetal and adult prostates. Endocrinology 130, 2413–2419 (1992).

    CAS  PubMed  Google Scholar 

  105. Collins, A. T., Zhiming, B., Gilmore, K. & Neal, D. E. Androgen and oestrogen responsiveness of stromal cells derived from the human hyperplastic prostate: oestrogen regulation of the androgen receptor. J. Endocrinol. 143, 269–277 (1994).

    CAS  Article  PubMed  Google Scholar 

  106. King, K. J., Nicholson, H. D. & Assinder, S. J. Effect of increasing ratio of estrogen: androgen on proliferation of normal human prostate stromal and epithelial cells, and the malignant cell line LNCaP. Prostate 66, 105–114 (2006).

    CAS  Article  PubMed  Google Scholar 

  107. Ho, C. K., Nanda, J., Chapman, K. E. & Habib, F. K. Oestrogen and benign prostatic hyperplasia: effects on stromal cell proliferation and local formation from androgen. J. Endocrinol. 197, 483–491 (2008).

    CAS  Article  PubMed  Google Scholar 

  108. Zhang, Z. et al. The proliferative effect of estradiol on human prostate stromal cells is mediated through activation of ERK. Prostate 68, 508–516 (2008).

    CAS  Article  PubMed  Google Scholar 

  109. Park, I. I. et al. 17Beta-estradiol at low concentrations acts through distinct pathways in normal versus benign prostatic hyperplasia-derived prostate stromal cells. Endocrinology 150, 4594–4605 (2009).

    CAS  Article  PubMed  Google Scholar 

  110. Daehlin, L., Bergh, A. & Damber, J. E. Direct effects of oestradiol on growth and morphology of the Dunning R3327H prostatic carcinoma. Urol. Res. 15, 169–172 (1987).

    CAS  Article  PubMed  Google Scholar 

  111. Ehara, H. et al. Expression of estrogen receptor in diseased human prostate assessed by non-radioactive in situ hybridization and immunohistochemistry. Prostate 27, 304–313 (1995).

    CAS  Article  PubMed  Google Scholar 

  112. Bonkhoff, H., Fixemer, T., Hunsicker, I. & Remberger, K. Estrogen receptor expression in prostate cancer and premalignant prostatic lesions. Am. J. Pathol. 155, 641–647 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. Royuela, M. et al. Estrogen receptors alpha and beta in the normal, hyperplastic and carcinomatous human prostate. J. Endocrinol. 168, 447–454 (2001).

    CAS  Article  PubMed  Google Scholar 

  114. Pasquali, D. et al. Estrogen receptor beta expression in human prostate tissue. Mol. Cell. Endocrinol. 178, 47–50 (2001).

    CAS  Article  PubMed  Google Scholar 

  115. Tsurusaki, T. et al. Zone-dependent expression of estrogen receptors alpha and beta in human benign prostatic hyperplasia. J. Clin. Endocrinol. Metab. 88, 1333–1340 (2003).

    CAS  Article  PubMed  Google Scholar 

  116. Alonso-Magdalena, P. et al. A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia. Proc. Natl Acad. Sci. USA 106, 2859–2863 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. Lau, K. M., LaSpina, M., Long, J. & Ho, S. M. Expression of estrogen receptor (ER)-alpha and ER-beta in normal and malignant prostatic epithelial cells: regulation by methylation and involvement in growth regulation. Cancer Res. 60, 3175–3182 (2000).

    CAS  PubMed  Google Scholar 

  118. Ye, Q., Chung, L. W., Cinar, B., Li, S. & Zhau, H. E. Identification and characterization of estrogen receptor variants in prostate cancer cell lines. J. Steroid Biochem. Mol. Biol. 75, 21–31 (2000).

    CAS  Article  PubMed  Google Scholar 

  119. Ogawa, S. et al. Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor of estrogen action in human. Nucleic Acids Res. 26, 3505–3512 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. Moore, J. T. et al. Cloning and characterization of human estrogen receptor beta isoforms. Biochem. Biophys. Res. Commun. 247, 75–78 (1998).

    CAS  Article  PubMed  Google Scholar 

  121. Inoue, S. et al. An estrogen receptor beta isoform that lacks exon 5 has dominant negative activity on both ERalpha and ERbeta. Biochem. Biophys. Res. Commun. 279, 814–819 (2000).

    CAS  Article  PubMed  Google Scholar 

  122. McPherson, S. J. et al. Estrogen receptor-beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFalpha mediated. Proc. Natl Acad. Sci. USA 107, 3123–3128 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. Osborne, C. K., Zhao, H. & Fuqua, S. A. Selective estrogen receptor modulators: structure, function, and clinical use. J. Clin. Oncol. 18, 3172–3186 (2000).

    CAS  Article  PubMed  Google Scholar 

  124. Nomura, H. et al. Effect of selective estrogen receptor modulators on cell proliferation and estrogen receptor activities in normal human prostate stromal and epithelial cells. Prostate Cancer Prostatic Dis. 12, 375–381 (2009).

    CAS  Article  PubMed  Google Scholar 

  125. Glienke, W. et al. Induction of apoptosis in human prostate stromal cells by 4-hydroxytamoxifen: an alternative therapy for benign prostate hyperplasia. World J. Urol. 22, 452–456 (2004).

    CAS  Article  PubMed  Google Scholar 

  126. Brolin, J., Skoog, L. & Ekman, P. Immunohistochemistry and biochemistry in detection of androgen, progesterone, and estrogen receptors in benign and malignant human prostatic tissue. Prostate 20, 281–295 (1992).

    CAS  Article  PubMed  Google Scholar 

  127. Hiramatsu, M., Maehara, I., Orikasa, S. & Sasano, H. Immunolocalization of oestrogen and progesterone receptors in prostatic hyperplasia and carcinoma. Histopathology 28, 163–168 (1996).

    CAS  Article  PubMed  Google Scholar 

  128. Suzuki, K. et al. Gene expression profiles in human BPH: utilization of laser-capture microdissection and quantitative real-time PCR. Anticancer Res. 21, 3861–3864 (2001).

    CAS  PubMed  Google Scholar 

  129. Williams, G. R. & Franklyn, J. A. Physiology of the steroid-thyroid hormone nuclear receptor superfamily. Baillieres Clin. Endocrinol. Metab. 8, 241–266 (1994).

    CAS  Article  PubMed  Google Scholar 

  130. Mobbs, B. G., Johnson, I. E., DeSombre, E. R., Toth, J. & Hughes, A. Regulation of estrogen and progestin receptor concentrations in an experimental rat prostatic carcinoma by estrogen, antiestrogen, and progesterone. Cancer Res. 47, 2645–2651 (1987).

    CAS  PubMed  Google Scholar 

  131. Sebastian, S. & Bulun, S. E. A highly complex organization of the regulatory region of the human CYP19 (aromatase) gene revealed by the Human Genome Project. J. Clin. Endocrinol. Metab. 86, 4600–4602 (2001).

    CAS  Article  PubMed  Google Scholar 

  132. Harada, N., Utsumi, T. & Takagi, Y. Tissue-specific expression of the human aromatase cytochrome P-450 gene by alternative use of multiple exons 1 and promoters, and switching of tissue-specific exons 1 in carcinogenesis. Proc. Natl Acad. Sci. USA 90, 11312–11316 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. Simpson, E. R. et al. Aromatase expression in health and disease. Recent Prog. Horm. Res. 52, 185–213 (1997).

    CAS  PubMed  Google Scholar 

  134. Harada, N. Aromatase and intracrinology of estrogen in hormone-dependent tumors. Oncology 57 (Suppl. 2), 7–16 (1999).

    CAS  Article  PubMed  Google Scholar 

  135. Hiramatsu, M. et al. Aromatase in hyperplasia and carcinoma of the human prostate. Prostate 31, 118–124 (1997).

    CAS  Article  PubMed  Google Scholar 

  136. Simpson, E. R. et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr. Rev. 15, 342–355 (1994).

    CAS  PubMed  Google Scholar 

  137. Sasano, H. & Harada, N. Intratumoral aromatase in human breast, endometrial, and ovarian malignancies. Endocr. Rev. 19, 593–607 (1998).

    CAS  PubMed  Google Scholar 

  138. Tsugaya, M. et al. Aromatase mRNA levels in benign prostatic hyperplasia and prostate cancer. Int. J. Urol. 3, 292–296 (1996).

    CAS  Article  PubMed  Google Scholar 

  139. Matzkin, H. & Soloway, M. S. Immunohistochemical evidence of the existence and localization of aromatase in human prostatic tissues. Prostate 21, 309–314 (1992).

    CAS  Article  PubMed  Google Scholar 

  140. Takase, Y. et al. Expression of enzymes involved in estrogen metabolism in human prostate. J. Histochem. Cytochem. 54, 911–921 (2006).

    CAS  Article  PubMed  Google Scholar 

  141. Smith, T., Chisholm, G. D. & Habib, F. K. Failure of human benign prostatic hyperplasia to aromatise testosterone. J. Steroid Biochem. 17, 119–120 (1982).

    CAS  Article  PubMed  Google Scholar 

  142. Bartsch, W., Klein, H., Stürenburg, H. J. & Voigt, K. D. Metabolism of androgens in human benign prostatic hyperplasia: aromatase and its inhibition. J. Steroid Biochem. 27, 557–564 (1987).

    CAS  Article  PubMed  Google Scholar 

  143. Brodie, A. M., Son, C., King, D. A., Meyer, K. M. & Inkster, S. E. Lack of evidence for aromatase in human prostatic tissues: effects of 4-hydroxyandrostenedione and other inhibitors on androgen metabolism. Cancer Res. 49, 6551–6555 (1989).

    CAS  PubMed  Google Scholar 

  144. Schweikert, H. U. Conversion of androstenedione to estrone in human fibroblasts cultured from prostate, genital and nongenital skin. Horm. Metab. Res. 11, 635–640 (1979).

    CAS  Article  PubMed  Google Scholar 

  145. Stone, N. N., Fair, W. R. & Fishman, J. Estrogen formation in human prostatic tissue from patients with and without benign prostatic hyperplasia. Prostate 9, 311–318 (1986).

    CAS  Article  PubMed  Google Scholar 

  146. Kaburagi, Y. et al. The possibility of aromatization of androgen in human prostate. J. Steroid Biochem. 26, 739–742 (1987).

    CAS  Article  PubMed  Google Scholar 

  147. Wu, Q. et al. Benign prostatic hyperplasia (BPH) epithelial cell line BPH-1 induces aromatase expression in prostatic stromal cells via prostaglandin E2. J. Endocrinol. 195, 89–94 (2007).

    CAS  Article  PubMed  Google Scholar 

  148. Miao, L. et al. Estrogen receptor-related receptor alpha mediates up-regulation of aromatase expression by prostaglandin E2 in prostate stromal cells. Mol. Endocrinol. 24, 1175–1186 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. Radlmaier, A. et al. Estrogen reduction by aromatase inhibition for benign prostatic hyperplasia: results of a double-blind, placebo-controlled, randomized clinical trial using two doses of the aromatase-inhibitor atamestane. Atamestane Study Group. Prostate 29, 199–208 (1996).

    CAS  Article  PubMed  Google Scholar 

  150. Schweikert, H. U. et al. Effects of estrogen deprivation on human benign prostatic hyperplasia. J. Steroid Biochem. Mol. Biol. 44, 573–576 (1993).

    CAS  Article  PubMed  Google Scholar 

  151. Katzenellenbogen, B. S. et al. Estrogen receptors: selective ligands, partners, and distinctive pharmacology. Recent Prog. Horm. Res. 55, 163–193 (2000).

    CAS  PubMed  Google Scholar 

  152. Gregory, C. W., He, B. & Wilson, E. M. The putative androgen receptor-A form results from in vitro proteolysis. J. Mol. Endocrinol. 27, 309–319 (2001).

    CAS  Article  PubMed  Google Scholar 

  153. Kuiper, G. G. et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138, 863–870 (1997).

    CAS  Article  PubMed  Google Scholar 

  154. Kuiper, G. G. et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139, 4252–4263 (1998).

    CAS  Article  PubMed  Google Scholar 

  155. Fang, H. et al. Study of 202 natural, synthetic, and environmental chemicals for binding to the androgen receptor. Chem. Res. Toxicol. 16, 1338–1358 (2003).

    CAS  Article  PubMed  Google Scholar 

  156. Zhou, Z. X., Wong, C. I., Sar, M. & Wilson, E. M. The androgen receptor: an overview. Recent Prog. Horm. Res. 49, 249–274 (1994).

    CAS  PubMed  Google Scholar 

  157. Enmark, E. et al. Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. J. Clin. Endocrinol. Metab. 82, 4258–4265 (1997).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

C. K. M. Ho and F. K. Habib contributed equally to researching data, discussing content, writing and editing of the manuscript.

Corresponding author

Correspondence to Fouad K. Habib.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ho, C., Habib, F. Estrogen and androgen signaling in the pathogenesis of BPH. Nat Rev Urol 8, 29–41 (2011). https://doi.org/10.1038/nrurol.2010.207

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrurol.2010.207

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing