UroToday - Previous animal studies suggested a role for estrogens in the pathogenesis of benign prostatic hyperplasia (BPH) 1,2. Estrogens interact with two forms of estrogen receptor (ER), ERα and ERβ. We recently reported the differential expression of the two ER subtypes in stromal and epithelial cells derived from human BPH tissues 3. We also observed that aromatase enzyme activity converting androgen to estrogen was present in prostate stromal but not epithelial cells in culture 3. A direct stimulatory effect of estradiol on stromal cells was detected but there was no parallel effect on epithelial cell proliferation in vitro 3. Given the above findings, we hypothesized that prostate cells not only respond to estrogen stimulation via the expression of ERs but are also capable of modulating such effects by active metabolism of estrogens. To date, little is known about the conversion of estrogens to their metabolites in human prostate cells.

To establish if prostate cells can metabolize the natural estrogens, estradiol (E2) and estrone (E1), stromal and epithelial cells in primary culture derived from BPH tissues were incubated with 10 nmol/L radiolabeled E2 or E1 for 1-24 hours. Steroids in culture media were then extracted by ethyl acetate followed by analysis using high-performance liquid chromatography.

Both cell types converted E2 to the weaker estrogen E1 up to 24 hours of incubation but the metabolism was not reversible in these cells. Conversion rate of E2 to E1 during the first 4 hours of incubation was linear for both stromal (6.1 ± 0.7 pmol/mg protein/h; mean ± s.e.m. of 3 patients) and epithelial cells (11.9 ± 0.7 pmol/mg protein/h). Rate of E2 to E1 conversion in stromal cells was approximately 50% less than that measured in epithelial cells. After extraction of steroids from the culture media, no radioactivity remained in the aqueous phase, indicating that neither cell types conjugated E2 or E1 to water-soluble metabolites in vitro.

To date, at least ten different mammalian 17β-hydroxysteroid dehydrogenase (17βHSD types 1 to 10) have been identified, eight of which are known to have estrogen-metabolizing activities 4-6. 17βHSD subtypes exhibit different substrate specificities; 17βHSD types 1 and 7 have strong reductase activity converting E1 to E2, whereas types 2, 4, 6, 8, 9 and 10 show variable degrees of dehydrogenase activity, capable of converting E2 to E1 4-6. Though expression of mRNA or protein of different 17βHSDs has been previously described in human prostate tissues 7-10 and mRNA expression of 17βHSD types 2, 3 and 4 was reported in human prostate cells in primary culture 8,11, to our knowledge, this is the first report on the metabolism of E2 by oxidative 17βHSD activity in prostate stromal and epithelial cells in primary culture. Both prostate cell types exhibited 17βHSD oxidative activity converting E2 to E1 but no reductase activity in the opposite direction was detected.

The rates of metabolism of E2 to E1 in the present study are comparable to those of the oxidation of testosterone to androstenedione previously described in human prostate stromal cells in primary culture (3.1 pmol/mg protein/h) 12, possibly by the action of 17βHSD type 2. However, it should be borne in mind that the net 17βHSD activity measured in cell culture at any point in time is the product of the cumulative activities of the various steroid metabolic enzymes present in the cell at that time. Therefore, the lack of conversion of E1 to E2 does not reflect the absence of enzymes capable of catalyzing E1 to E2 but may be due to the prevailing enzymatic conditions favoring a relatively high activity of 17βHSD enzymes converting E2 to E1 at the expense of the reductive 17βHSD activity; this results in a net E2 oxidation in these cells. Whether this pattern is also reflected in the in vivo system still remains to be established.

Taken together, the above observations and our recent report lend support to the hypothesis that both androgen conversion to estrogen and estrogen metabolism in prostate cells can regulate a local estrogenic environment within the prostate.

References

1. Walsh PC and Wilson JD: The induction of prostatic hypertrophy in the dog with androstanediol. J Clin Invest. 57: 1093-7, 1976.
2. DeKlerk DP, Coffey DS, Ewing LL, McDermott IR, Reiner WG, Robinson CH, Scott WW, Strandberg JD, Talalay P, Walsh PC et al.: Comparison of spontaneous and experimentally induced canine prostatic hyperplasia. J Clin Invest. 64: 842-9, 1979.
3. Ho CK, Nanda J, Chapman KE and Habib FK: Oestrogen and benign prostatic hyperplasia: effects on stromal cell proliferation and local formation from androgen. J Endocrinol. 197: 483-91, 2008.
4. Peltoketo H, Luu-The V, Simard J and Adamski J: 17beta-hydroxysteroid dehydrogenase (HSD)/17-ketosteroid reductase (KSR) family; nomenclature and main characteristics of the 17HSD/KSR enzymes. J Mol Endocrinol. 23: 1-11, 1999.
5. Napoli JL: 17beta-Hydroxysteroid dehydrogenase type 9 and other short-chain dehydrogenases/reductases that catalyze retinoid, 17beta- and 3alpha-hydroxysteroid metabolism. Mol Cell Endocrinol. 171: 103-9, 2001.
6. Yang SY, He XY and Schulz H: Multiple functions of type 10 17beta-hydroxysteroid dehydrogenase. Trends Endocrinol Metab. 16: 167-75, 2005.
7. Elo JP, Akinola LA, Poutanen M, Vihko P, Kyllonen AP, Lukkarinen O and Vihko R: Characterization of 17beta-hydroxysteroid dehydrogenase isoenzyme expression in benign and malignant human prostate. Int J Cancer. 66: 37-41, 1996.
8. Delos S, Carsol JL, Fina F, Raynaud JP and Martin PM: 5alpha-reductase and 17beta-hydroxysteroid dehydrogenase expression in epithelial cells from hyperplastic and malignant human prostate. Int J Cancer. 75: 840-6, 1998.
9. Krazeisen A, Breitling R, Imai K, Fritz S, Moller G and Adamski J: Determination of cDNA, gene structure and chromosomal localization of the novel human 17beta-hydroxysteroid dehydrogenase type 7(1). FEBS Lett. 460: 373-9, 1999.
10. He XY, Merz G, Yang YZ, Pullakart R, Mehta P, Schulz H and Yang SY: Function of human brain short chain L-3-hydroxyacyl coenzyme A dehydrogenase in androgen metabolism. Biochim Biophys Acta. 1484: 267-77, 2000.
11. Delos S, Carsol JL, Ghazarossian E, Raynaud JP and Martin PM: Testosterone metabolism in primary cultures of human prostate epithelial cells and fibroblasts. J Steroid Biochem Mol Biol. 55: 375-83, 1995.
12. Tsugaya M, Habib FK, Chisholm GD, Ross M, Tozawa K, Hayashi Y, Kohri K and Tanaka S: Testosterone metabolism in primary cultures of epithelial cells and stroma from benign prostatic hyperplasia. Urol Res. 24: 265-71, 1996.

Clement KM Ho, Jyoti Nanda, Karen E Chapman, and Fouad K Habib, as part of Beyond the Abstract on UroToday.

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