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Proc Natl Acad Sci U S A. Jun 7, 1994; 91(12): 5402–5405.

Estradiol causes the rapid accumulation of cAMP in human prostate.


Androgens are widely acknowledged to be central to the pathogenesis of benign prostatic hypertrophy (BPH). However, BPH increases in prevalence as men age, at precisely the stage of life when plasma androgens are decreasing. The decrease in total plasma androgens is amplified by an age-related increase in plasma sex hormone-binding globulin (SHBG) that results in a relatively greater decrease in free androgens than in total androgens. In addition, estrogens have long been suspected to be important in BPH, but a direct effect on the human prostate has never been demonstrated. We present data that are consistent with a role for estradiol, and for a decrease in androgens and an increase in SHBG, in the pathogenesis of BPH. We show that estradiol, but not dihydrotestosterone, acts in concert with SHBG to produce an 8-fold increase in intracellular cAMP in human BPH tissue. This increase is not blocked by an antiestrogen and is not provoked by an estrogen (diethylstilbestrol) that does not bind to SHBG, thus excluding the classic estrogen receptor as being operative in these events. Conversely, dihydrotestosterone, which blocks the binding of estradiol to SHBG, completely negates the effect of estradiol. Finally, we demonstrate that the SHBG-steroid-responsive second-messenger system is primarily localized to the prostatic stromal cells and not to the prostatic epithelial cells. Thus, we have shown a cell-specific, powerful, nontranscriptional effect of estradiol on the human prostate.

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  • Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol. 1984 Sep;132(3):474–479. [PubMed]
  • Henderson D, Habenicht UF, Nishino Y, el Etreby MF. Estrogens and benign prostatic hyperplasia: the basis for aromatase inhibitor therapy. Steroids. 1987 Jul-Sep;50(1-3):219–233. [PubMed]
  • Schweikert HU, Tunn UW, Habenicht UF, Arnold J, Senge T, Schulze H, Schröder FH, Blom JH, Ennemoser O, Horniger W, et al. Effects of estrogen deprivation on human benign prostatic hyperplasia. J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):573–576. [PubMed]
  • Coffey DS, Walsh PC. Clinical and experimental studies of benign prostatic hyperplasia. Urol Clin North Am. 1990 Aug;17(3):461–475. [PubMed]
  • Davidson JM, Chen JJ, Crapo L, Gray GD, Greenleaf WJ, Catania JA. Hormonal changes and sexual function in aging men. J Clin Endocrinol Metab. 1983 Jul;57(1):71–77. [PubMed]
  • Tenover JS, Matsumoto AM, Plymate SR, Bremner WJ. The effects of aging in normal men on bioavailable testosterone and luteinizing hormone secretion: response to clomiphene citrate. J Clin Endocrinol Metab. 1987 Dec;65(6):1118–1126. [PubMed]
  • Rosner W. Plasma steroid-binding proteins. Endocrinol Metab Clin North Am. 1991 Dec;20(4):697–720. [PubMed]
  • Hryb DJ, Khan MS, Rosner W. Testosterone-estradiol-binding globulin binds to human prostatic cell membranes. Biochem Biophys Res Commun. 1985 Apr 16;128(1):432–440. [PubMed]
  • Hryb DJ, Khan MS, Romas NA, Rosner W. Solubilization and partial characterization of the sex hormone-binding globulin receptor from human prostate. J Biol Chem. 1989 Apr 5;264(10):5378–5383. [PubMed]
  • Rosner W, Smith RN. Isolation and characterization of the testosterone-estradiol-binding globulin from human plasma. Use of a novel affinity column. Biochemistry. 1975 Nov 4;14(22):4813–4820. [PubMed]
  • Khan MS, Ehrlich P, Birken S, Rosner W. Size isomers of testosterone-estradiol-binding globulin exist in the plasma of individual men and women. Steroids. 1985 May;45(5):463–472. [PubMed]
  • Nakhla AM, Khan MS, Rosner W. Biologically active steroids activate receptor-bound human sex hormone-binding globulin to cause LNCaP cells to accumulate adenosine 3',5'-monophosphate. J Clin Endocrinol Metab. 1990 Aug;71(2):398–404. [PubMed]
  • Ofner P, Douglas WH, Spilman SD, Vena RL, Krinsky-Feibush P, LeQuesne PW. Hydroxylation of [3H]5 alpha-androstane-3 beta,17 beta-diol by whole tissue, epithelial cells and fibroblasts from the same hyperplastic human prostate. J Steroid Biochem. 1985 Mar;22(3):391–397. [PubMed]
  • Pugeat MM, Dunn JF, Nisula BC. Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 1981 Jul;53(1):69–75. [PubMed]
  • Hryb DJ, Khan MS, Romas NA, Rosner W. The control of the interaction of sex hormone-binding globulin with its receptor by steroid hormones. J Biol Chem. 1990 Apr 15;265(11):6048–6054. [PubMed]
  • Rosner W, Hryb DJ, Khan MS, Nakhla AM, Romas NA. Sex hormone-binding globulin. Binding to cell membranes and generation of a second messenger. J Androl. 1992 Mar-Apr;13(2):101–106. [PubMed]
  • Evans RM. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889–895. [PubMed]
  • Cooke RR, McIntosh JE, McIntosh RP. Circadian variation in serum free and non-SHBG-bound testosterone in normal men: measurements, and simulation using a mass action model. Clin Endocrinol (Oxf) 1993 Aug;39(2):163–171. [PubMed]
  • Partin AW, Oesterling JE, Epstein JI, Horton R, Walsh PC. Influence of age and endocrine factors on the volume of benign prostatic hyperplasia. J Urol. 1991 Feb;145(2):405–409. [PubMed]
  • Krieg M, Nass R, Tunn S. Effect of aging on endogenous level of 5 alpha-dihydrotestosterone, testosterone, estradiol, and estrone in epithelium and stroma of normal and hyperplastic human prostate. J Clin Endocrinol Metab. 1993 Aug;77(2):375–381. [PubMed]
  • Stone NN, Fair WR, Fishman J. Estrogen formation in human prostatic tissue from patients with and without benign prostatic hyperplasia. Prostate. 1986;9(4):311–318. [PubMed]
  • Moudgil VK. Phosphorylation of steroid hormone receptors. Biochim Biophys Acta. 1990 Dec 10;1055(3):243–258. [PubMed]
  • Ortí E, Bodwell JE, Munck A. Phosphorylation of steroid hormone receptors. Endocr Rev. 1992 Feb;13(1):105–128. [PubMed]
  • Katsaros D, Ally S, Cho-Chung YS. Site-selective cyclic AMP analogues are antagonistic to estrogen stimulation of growth and proto-oncogene expression in human breast-cancer cells. Int J Cancer. 1988 Jun 15;41(6):863–867. [PubMed]
  • Jung-Testas I, Schumacher M, Bugnard H, Baulieu EE. Stimulation of rat Schwann cell proliferation by estradiol: synergism between the estrogen and cAMP. Brain Res Dev Brain Res. 1993 Apr 16;72(2):282–290. [PubMed]
  • Ree AH, Frøysa A, Eskild W, Jahnsen T, Hansson V. Biphasic regulation of the messenger ribonucleic acid coding for the estrogen receptor by cyclic adenosine 3':5'-monophosphate in tumor Leydig cells. Cancer Res. 1990 Mar 1;50(5):1528–1531. [PubMed]
  • Cunha GR, Donjacour AA, Cooke PS, Mee S, Bigsby RM, Higgins SJ, Sugimura Y. The endocrinology and developmental biology of the prostate. Endocr Rev. 1987 Aug;8(3):338–362. [PubMed]

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