Review Article | Published:

Estrogens and prostate cancer

Prostate Cancer and Prostatic Diseases (2018) | Download Citation



Hormonal influences such as androgens and estrogens are known contributors in the development and progression of prostate cancer (CaP). While much of the research to the hormonal nature of CaP has focused on androgens, estrogens also have critical roles in CaP development, physiology as well as a potential therapeutic intervention.


In this review, we provide a critical literature review of the current basic science and clinical evidence for the interaction between estrogens and CaP.


Estrogenic influences in CaP include synthetic, endogenous, fungi and plant-derived compounds, and represent a family of sex hormones, which cross hydrophobic cell membranes and bind to membrane-associated receptors and estrogen receptors that localize to the nucleus triggering changes in gene expression in various organ systems.


Estrogens represent a under-recognized contributor in CaP development and progression. Further research in this topic may provide opportunities for identification of environmental influencers as well as providing novel therapeutic targets in the treatment of CaP.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2016;66:7–30.

  2. 2.

    Huggins CH. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293–7.

  3. 3.

    Pagliarulo V, et al. Contemporary role of androgen deprivation therapy for prostate cancer. Eur Urol. 2012;61:11–25.

  4. 4.

    Lorand T, Vigh E, Garai J. Hormonal action of plant derived and anthropogenic non-steroidal estrogenic compounds: phytoestrogens and xenoestrogens. Curr Med Chem. 2010;17:3542–74.

  5. 5.

    Lee HR, Kim TH, Choi KC. Functions and physiological roles of two types of estrogen receptors, ERalpha and ERbeta, identified by estrogen receptor knockout mouse. Lab Anim Res. 2012;28:71–6.

  6. 6.

    Yeh CR, Da J, Song W, Fazili A, Yeh S. Estrogen receptors in prostate development and cancer. Am J Clin Exp Urol. 2014;2:161–8.

  7. 7.

    Rago V, Romeo F, Giordano F, Ferraro A, Carpino A. Identification of the G protein-coupled estrogen receptor (GPER) in human prostate: expression site of the estrogen receptor in the benign and neoplastic gland. Andrology. 2016;4:121–7.

  8. 8.

    Heldring N, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 2007;87:905–31.

  9. 9.

    Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest. 2006;116:561–70.

  10. 10.

    Mauvais-Jarvis F, Clegg DJ, Hevener AL. The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev. 2013;34:309–38.

  11. 11.

    Driscoll SG, Taylor SH. Effects of prenatal maternal estrogen on the male urogenital system. Obstet Gynecol. 1980;56:537–42.

  12. 12.

    Ho SM, Tang WY, Belmonte de Frausto J, Prins GS. Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res. 2006;66:5624–32.

  13. 13.

    Wibowo E, Schellhammer P, Wassersug RJ. Role of estrogen in normal male function: clinical implications for patients with prostate cancer on androgen deprivation therapy. J Urol. 2011;185:17–23.

  14. 14.

    Cooke BM. Steroid-dependent plasticity in the medial amygdala. Neuroscience. 2006;138:997–1005.

  15. 15.

    Hofman MA, Swaab DF. The sexually dimorphic nucleus of the preoptic area in the human brain: a comparative morphometric study. J Anat. 1989;164:55–72.

  16. 16.

    Nelles JL, Hu WY, Prins GS. Estrogen action and prostate cancer. Expert Rev Endocrinol Metab. 2011;6:437–51.

  17. 17.

    Hu WY, et al. Estrogen-initiated transformation of prostate epithelium derived from normal human prostate stem-progenitor cells. Endocrinology. 2011;152:2150–63.

  18. 18.

    Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P. Loss of ERbeta expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer. 2004;11:537–51.

  19. 19.

    Levakov AF, et al. The expression and localization of estrogen receptor beta in hyperplastic and neoplastic prostate lesions. Vojnosanit Pregl. 2015;72:906–13.

  20. 20.

    Mishra S., et al. Estrogen and estrogen receptor alpha promotes malignancy and osteoblastic tumorigenesis in prostate cancer. Oncotarget. 2016;6:44388–402.

  21. 21.

    Attia DM, Ederveen AG. Opposing roles of ERalpha and ERbeta in the genesis and progression of adenocarcinoma in the rat ventral prostate. Prostate. 2012;72:1013–22.

  22. 22.

    Pupo M, Maggiolini M, Musti AM. GPER mediates non-genomic effects of estrogen. Methods Mol Biol. 2016;1366:471–88.

  23. 23.

    Prins GS, Birch L, Tang WY, Ho SM. Developmental estrogen exposures predispose to prostate carcinogenesis with aging. Reprod Toxicol. 2007;23:374–82.

  24. 24.

    Prins GS, Tang WY, Belmonte J, Ho SM. Perinatal exposure to oestradiol and bisphenol A alters the prostate epigenome and increases susceptibility to carcinogenesis. Basic Clin Pharmacol Toxicol. 2008;102:134–8.

  25. 25.

    Bosland MC. The role of estrogens in prostate carcinogenesis: a rationale for chemoprevention. Rev Urol. 2005;7(Suppl 3):S4–S10.

  26. 26.

    Bosland MC. A perspective on the role of estrogen in hormone-induced prostate carcinogenesis. Cancer Lett. 2013;334:28–33.

  27. 27.

    Prins GS, Ho SM. Early-life estrogens and prostate cancer in an animal model. J Dev Orig Health Dis. 2010;1:365–70.

  28. 28.

    Huang L, Pu Y, Hepps D, Danielpour D, Prins GS. Posterior Hox gene expression and differential androgen regulation in the developing and adult rat prostate lobes. Endocrinology. 2007;148:1235–45.

  29. 29.

    Huang L, Pu Y, Alam S, Birch L, Prins GS. The role of Fgf10 signaling in branching morphogenesis and gene expression of the rat prostate gland: lobe-specific suppression by neonatal estrogens. Dev Biol. 2005;278:396–414.

  30. 30.

    Garnick MB. Hormonal therapy in the management of prostate cancer: from Huggins to the present. Urology. 1997;49:5–15.

  31. 31.

    Melnick S, Cole P, Anderson D, Herbst A. Rates and risks of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix. An update. N Engl J Med. 1987;316:514–6.

  32. 32.

    Gill WB, et al. Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities. J Urol. 1979;122:36–9.

  33. 33.

    Arai Y, Chen CY, Nishizuka Y. Cancer development in male reproductive tract in rats given diethylstilbestrol at neonatal age. Gan . 1978;69:861–2.

  34. 34.

    Ramos JG, et al. Prenatal exposure to low doses of bisphenol A alters the periductal stroma and glandular cell function in the rat ventral prostate. Biol Reprod. 2001;65:1271–7.

  35. 35.

    Prins GS, et al. Prostate cancer risk and DNA methylation signatures in aging rats following developmental BPA exposure: a dose-response analysis. Environ Health Perspect. 2017;125:077007.

  36. 36.

    Tarapore P, et al. Exposure to bisphenol A correlates with early-onset prostate cancer and promotes centrosome amplification and anchorage-independent growth in vitro. PLoS ONE. 2014;9:e90332.

  37. 37.

    Prins GS, et al. Bisphenol A promotes human prostate stem-progenitor cell self-renewal and increases in vivo carcinogenesis in human prostate epithelium. Endocrinology. 2014;155:805–17.

  38. 38.

    Ho SM, Lee MT, Lam HM, Leung YK. Estrogens and prostate cancer: etiology, mediators, prevention, and management. Endocrinol Metab Clin North Am. 2011;40:591–614.

  39. 39.

    de Jong FH, et al. Peripheral hormone levels in controls and patients with prostatic cancer or benign prostatic hyperplasia: results from the Dutch-Japanese case-control study. Cancer Res. 1991;51:3445–50.

  40. 40.

    Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA. 2014;311:806–14.

  41. 41.

    Cohen PG. Obesity in men: the hypogonadal-estrogen receptor relationship and its effect on glucose homeostasis. Med Hypotheses. 2008;70:358–60.

  42. 42.

    Schneider G, Kirschner MA, Berkowitz R, Ertel NH. Increased estrogen production in obese men. J Clin Endocrinol Metab. 1979;48:633–8.

  43. 43.

    Leitner L., et al. Osteopontin promotes aromatase expression and estradiol production in human adipocytes. Breast Cancer Res Treat. 2015;154:63–9.

  44. 44.

    Williams G. Aromatase up-regulation, insulin and raised intracellular oestrogens in men, induce adiposity, metabolic syndrome and prostate disease, via aberrant ER-alpha and GPER signalling. Mol Cell Endocrinol. 2012;351:269–78.

  45. 45.

    Prins GS. Endocrine disruptors and prostate cancer risk. Endocr Relat Cancer. 2008;15:649–56.

  46. 46.

    Keum N., et al. Adult weight gain and adiposity-related cancers: a dose-response meta-analysis of prospective observational studies. J Natl Cancer Inst. 2015;107:1–14.

  47. 47.

    Di Zazzo E, Galasso G, Giovannelli P, Di Donato M, Castoria G. Estrogens and their receptors in prostate cancer: therapeutic implications. Front Oncol. 2018;8:2.

  48. 48.

    Goris Gbenou MC, Peltier A, Schulman CC, Velthoven RV. Increased body mass index as a risk factor in localized prostate cancer treated by radical prostatectomy. Urol Oncol. 2016;34:254.e1–6.

  49. 49.

    Gross M, et al. Expression of androgen and estrogen related proteins in normal weight and obese prostate cancer patients. Prostate. 2009;69:520–7.

  50. 50.

    Laukkanen JA, et al. Metabolic syndrome and the risk of prostate cancer in Finnish men: a population-based study. Cancer Epidemiol Biomark Prev. 2004;13:1646–50.

  51. 51.

    Hammarsten J, Hogstedt B. Clinical haemodynamic, anthropometric, metabolic and insulin profile of men with high-stage and high-grade clinical prostate cancer. Blood Press. 2004;13:47–55.

  52. 52.

    Dimitropoulou P, et al. Association of obesity with prostate cancer: a case-control study within the population-based PSA testing phase of the ProtecT study. Br J Cancer. 2011;104:875–81.

  53. 53.

    Rundle A, Richards C, Neugut AI. Body composition, abdominal fat distribution, and prostate-specific antigen test results. Cancer Epidemiol Biomark Prev. 2009;18:331–6.

  54. 54.

    Freedland SJ, Platz EA. Obesity and prostate cancer: making sense out of apparently conflicting data. Epidemiol Rev. 2007;29:88–97.

  55. 55.

    Rhee H, Vela I, Chung E. Metabolic syndrome and prostate cancer: a review of complex interplay amongst various endocrine factors in the pathophysiology and progression of prostate cancer. Horm Cancer. 2016;7:75–83.

  56. 56.

    Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 2002;168:9–12.

  57. 57.

    Sciarra A, et al. Oral ethinylestradiol in castration-resistant prostate cancer: a 10-year experience. Int J Urol. 2015;22:98–103.

  58. 58.

    Mohler JL, et al. Prostate cancer, version 2.2014. J Natl Compr Cancer Netw. 2014;12:686–718.

  59. 59.

    Heidenreich A, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467–79.

  60. 60.

    Hedlund PO, et al. Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5. Scand J Urol Nephrol. 2008;42:220–9.

  61. 61.

    Langley RE, et al. Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09). Lancet Oncol. 2013;14:306–16.

  62. 62.

    Mikkola A, Aro J, Rannikko S, Oksanen H, Ruutu M. Finnprostate g. Cardiovascular complications in patients with advanced prostatic cancer treated by means of orchiectomy or polyestradiol phosphate. Scand J Urol Nephrol. 2005;39:294–300.

  63. 63.

    Ockrim JL, et al. Transdermal estradiol improves bone density when used as single agent therapy for prostate cancer. J Urol. 2004;172:2203–7.

  64. 64.

    Norman G, et al. Parenteral oestrogen in the treatment of prostate cancer: a systematic review. Br J Cancer. 2008;98:697–707.

  65. 65.

    Turo R, et al. Diethylstilboestrol for the treatment of prostate cancer: past, present and future. Scand J Urol. 2014;48:4–14.

  66. 66.

    Geier R, Adler S, Rashid G, Klein A. The synthetic estrogen diethylstilbestrol (DES) inhibits the telomerase activity and gene expression of prostate cancer cells. Prostate. 2010;70:1307–12.

  67. 67.

    Koong LY, Watson CS. Direct estradiol and diethylstilbestrol actions on early- versus late-stage prostate cancer cells. Prostate. 2014;74:1589–603.

  68. 68.

    Montgomery B, et al. Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer. Bmc Cancer. 2010;10:244.

  69. 69.

    Izumi K, et al. Ethinylestradiol improves prostate-specific antigen levels in pretreated castration-resistant prostate cancer patients. Anticancer Res. 2010;30:5201–5.

  70. 70.

    Clemons J, Glode LM, Gao D, Flaig TW. Low-dose diethylstilbestrol for the treatment of advanced prostate cancer. Urol Oncol. 2013;31:198–204.

  71. 71.

    Serrate C, et al. Diethylstilbestrol (DES) retains activity and is a reasonable option in patients previously treated with docetaxel for castration-resistant prostate cancer. Ann Oncol. 2009;20:965.

  72. 72.

    Wilkins A, et al. Diethylstilbestrol in castration-resistant prostate cancer. BJU Int. 2012;110:E727–735.

  73. 73.

    von Schoultz B, et al. Estrogen therapy and liver function—metabolic effects of oral and parenteral administration. Prostate. 1989;14:389–95.

  74. 74.

    Shamash J, et al. A multi-centre randomised phase III trial of dexamethasone vs dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred diethylstilbestrol. Br J Cancer. 2011;104:620–8.

  75. 75.

    Ockrim J, Lalani el N, Abel P. Therapy insight: parenteral estrogen treatment for prostate cancer—a new dawn for an old therapy. Nat Clin Pract Oncol. 2006;3:552–63.

  76. 76.

    Ricke WA, et al. Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling. FASEB J. 2008;22:1512–20.

  77. 77.

    Price D, et al. Toremifene for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia: results of a double-blind, placebo controlled, phase IIB clinical trial. J Urol. 2006;176:965–70.

  78. 78.

    Taneja SS, et al. Prostate cancer diagnosis among men with isolated high-grade intraepithelial neoplasia enrolled onto a 3-year prospective phase III clinical trial of oral toremifene. J Clin Oncol. 2013;31:523–9.

  79. 79.

    Kim IY, et al. Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis in androgen-independent human prostate cancer cell lines. Cancer Res. 2002;62:5365–9.

  80. 80.

    Shazer RL, et al. Raloxifene, an oestrogen-receptor-beta-targeted therapy, inhibits androgen-independent prostate cancer growth: results from preclinical studies and a pilot phase II clinical trial. BJU Int. 2006;97:691–7.

  81. 81.

    Fujimura T, et al. Toremifene, a selective estrogen receptor modulator, significantly improved biochemical recurrence in bone metastatic prostate cancer: a randomized controlled phase II a trial. BMC Cancer. 2015;15:836.

  82. 82.

    Chadha MK, et al. Phase II study of fulvestrant (Faslodex) in castration resistant prostate cancer. Prostate. 2008;68:1461–6.

  83. 83.

    Zhou JR, et al. Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J Nutr. 1999;129:1628–35.

  84. 84.

    Jacobsen BK, Knutsen SF, Fraser GE. Does high soy milk intake reduce prostate cancer incidence? The Adventist Health Study (United States). Cancer Causes Control. 1998;9:553–7.

  85. 85.

    Ozasa K, et al. Serum phytoestrogens and prostate cancer risk in a nested case-control study among Japanese men. Cancer Sci. 2004;95:65–71.

  86. 86.

    Vardi A, et al. Soy phytoestrogens modify DNA methylation of GSTP1, RASSF1A, EPH2 and BRCA1 promoter in prostate cancer cells. Vivo. 2010;24:393–400.

  87. 87.

    Hedelin M, et al. Dietary phytoestrogen, serum enterolactone and risk of prostate cancer: the cancer prostate Sweden study (Sweden). Cancer Causes Control. 2006;17:169–80.

  88. 88.

    Dalais FS, et al. Effects of a diet rich in phytoestrogens on prostate-specific antigen and sex hormones in men diagnosed with prostate cancer. Urology. 2004;64:510–5.

  89. 89.

    Thelen P, Wuttke W, Seidlova-Wuttke D. Phytoestrogens selective for the estrogen receptor beta exert anti-androgenic effects in castration resistant prostate cancer. J Steroid Biochem Mol Biol. 2014;139:290–3.

  90. 90.

    Prins GS, Korach KS. The role of estrogens and estrogen receptors in normal prostate growth and disease. Steroids. 2008;73:233–44.

  91. 91.

    Pisolato R., et al Expression and regulation of the estrogen receptors in PC-3 human prostate cancer cells. Steroids. 2016;107:74–86.

  92. 92. U.S. National Library of Medicine. Accessed 14 May 2018.

  93. 93.

    Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA. 1996;93:5925–30.

  94. 94.

    Nakayama T, et al. Epigenetic regulation of androgen receptor gene expression in human prostate cancers. Lab Investig. 2000;80:1789–96.

  95. 95.

    Lin J, et al. Disulfiram is a DNA demethylating agent and inhibits prostate cancer cell growth. Prostate. 2011;71:333–43.

  96. 96.

    Sharma V, et al. Disulfiram and its novel derivative sensitize prostate cancer cells to the growth regulatory mechanisms of the cell by re-expressing the epigenetically repressed tumor suppressor-estrogen receptor beta. Mol Carcinog. 2015;55:1843–57.

  97. 97.

    Ittmann M, et al. Animal models of human prostate cancer: the consensus report of the New York meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee. Cancer Res. 2013;73:2718–36.

  98. 98.

    Hu WY, Shi GB, Hu DP, Nelles JL, Prins GS. Actions of estrogens and endocrine disrupting chemicals on human prostate stem/progenitor cells and prostate cancer risk. Mol Cell Endocrinol. 2012;354:63–73.

  99. 99.

    Hu WY, et al. Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution. Stem Cell Res. 2017;23:1–12.

Download references

Author information


  1. Department of Urology, University of Illinois at Chicago, Chicago, IL, USA

    • Ryan W. Dobbs
    • , Neha R. Malhotra
    • , David T. Greenwald
    • , Gail S. Prins
    •  & Michael R. Abern
  2. Department of Urology, Vanderbilt University, Nashville, TN, USA

    • Alice Y. Wang


  1. Search for Ryan W. Dobbs in:

  2. Search for Neha R. Malhotra in:

  3. Search for David T. Greenwald in:

  4. Search for Alice Y. Wang in:

  5. Search for Gail S. Prins in:

  6. Search for Michael R. Abern in:

Conflicts of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Michael R. Abern.

About this article

Publication history