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Functional Investigation on Aromatase in Endometrial Hyperplasia in Polycystic Ovary Syndrome Cases

  • Zhao, Pan-Lin ;
  • Zhang, Qiu-Fang ;
  • Yan, Li-Ying ;
  • Huang, Shuo ;
  • Chen, Yuan ;
  • Qiao, Jie
  • Published : 2014.11.06

Abstract

Objective: To explore the possible significance of aromatase P450 in endometrial hyperplasia with a background of polycystic ovary syndrome (PCOS). Methods: Immunohistochemistry was used to determine the expression of aromatase P450 in endometrium of PCOS patients. Semiquantitative analysis of aromatase P450 expression of mRNA and protein level wasalso carried out by real-time quantitative RT-PCR method. After endometrial cells were stimulated by testosterone and letrozole in vitro, the estradiol ($E_2$) level was determined, and the expression of cell aromatase P450 mRNA was assessed. Results: The aromatase P450 mRNA level was increased in endometria of PCOS patients. When endometrial cells were cultured with $10^{-6}M$ testosterone, the $E_2$ level in the culture medium increased. An inhibitory effect on $E_2$ generation and expression of aromatase P450 mRNA was observed when the endometrial cells were treated with $10^{-5}M$ letrozole. Conclusions: There is an increased expression of aromatase P450 in PCOS patient endometrium. Androgen stimulation could enhance the synthesis of aromatase P450 mRNA and the production of $E_2$ in endometrial cells in vitro while letrozole could do the reverse.

Keywords

Polycystic ovary syndrome;endometrial hyperplasia;aromatase P450;letrozole;testosterone

References

  1. Anthoni H, Sucheston LE, Lewis BA, et al (2012). The aromatase gene CYP19A1, several genetic and functional lines of evidence supporting a role in reading, speech and language. Behav Genet, 42, 509-27. https://doi.org/10.1007/s10519-012-9532-3
  2. Barker LC, Brand IR, Crawford SM (2009). Sustained effect of the aromatase inhibitors anastrozole and letrozole on endometrial thickness in patients with endometrial hyperplasia and endometrial carcinoma. Curr Med Res Opin, 25, 1105-9. https://doi.org/10.1185/03007990902860549
  3. Bulun SE, Economos K, Miller D, et al (1994). CYP19 (aromatase cytochrome P450) gene expression in human malignant endometrial tumors. J Clin Endocrinol Metab, 79, 1831-4.
  4. Bulun SE, Takayama K, Suzuki T, et al (2004). Organization of the human aromatase p450 (CYP19) gene. Semin Reprod Med, 22, 5-9. https://doi.org/10.1055/s-2004-823022
  5. Bulun SE, Simpson ER (2008). Aromatase expression in women's cancers. Adv Exp Med Biol, 630, 112-32. https://doi.org/10.1007/978-0-387-78818-0_8
  6. Ghosh D, Griswold J, Erman M, et al (2010). X-ray structure of human aromatase reveals an androgen-specific active site. J Steroid Biochem Mol Biol, 118, 197-202. https://doi.org/10.1016/j.jsbmb.2009.09.012
  7. Gao C, Wang Y, Tian W, et al (2014). The therapeutic significance of aromatase inhibitors in endometrial carcinoma. Gynecol Oncol, 134, 190-5. https://doi.org/10.1016/j.ygyno.2014.04.060
  8. Hosono S, Matsuo K, Ito H, et al (2011). Interaction between CYP19A1 polymorphisms and body mass index in the risk of endometrial cancer in postmenopausal Japanese women. Asian Pac J Cancer Prev, 12, 2747-52.
  9. Khan SI, Zhao J, Khan IA, et al (2011). Potential utility of natural products as regulators of breast cancer-associated aromatase promoters. Reprod Biol Endocrinol, 9, 91. https://doi.org/10.1186/1477-7827-9-91
  10. Kim SH, Park IH, Lee H, et al (2012). Efficacy of exemestane after nonsteroidal aromatase inhibitor use in metastatic breast cancer patients. Asian Pac J Cancer Prev, 13, 979-83. https://doi.org/10.7314/APJCP.2012.13.3.979
  11. Knapp P, Chabowski A, Blachnio-Zabielska A, et al (2013). Expression of estrogen receptors ($\alpha$, $\beta$), cyclooxygenase-2 and aromatase in normal endometrium and endometrioid cancer of uterus. Adv Med Sci, 58, 96-103. https://doi.org/10.2478/v10039-012-0055-1
  12. Maia Jr H, Haddad C, Casoy J (2012). Correlation between aromatase expression in the eutopic endometrium of symptomatic patients and the presence of endometriosis. Int J Womens Health, 4, 61.
  13. Liu L, Wang L, Zheng J, et al (2013). Leptin promotes human endometrial carcinoma cell proliferation by enhancing aromatase (P450arom) expression and estradiol formation. Eur J Obstet Gynecol Reprod Biol, 170, 198-201. https://doi.org/10.1016/j.ejogrb.2013.04.004
  14. Li F, Wong TY, Lin SM, et al (2014). Coadministrating luteolin minimizes the side effects of the aromatase inhibitor letrozole. J Pharmacol Exp Ther, 351, 270-7. https://doi.org/10.1124/jpet.114.216754
  15. Lin L, Yang J, Ding Y, et al (2014). Genetic polymorphisms of TCF7L2 lack influence on risk of the polycystic ovary syndrome - a systemic analysis. Asian Pac J Cancer Prev, 15, 3331-3. https://doi.org/10.7314/APJCP.2014.15.7.3331
  16. Park JC, Lim SY, Jang TK, et al (2011). Endometrial histology and predictable clinical factors for endometrial disease in women with polycystic ovary syndrome. Clin Exp Med, 38, 42-6.
  17. Peigne M, Dewailly D (2014). Long term complications of polycystic ovary syndrome (PCOS). Ann Endocrinol, 75, 194-9. https://doi.org/10.1016/j.ando.2014.07.111
  18. Sen K, Hackett JC (2012). Coupled electron transfer and proton hopping in the final step of CYP19-catalyzed androgen aromatization. Biochemistry, 51, 3039-49. https://doi.org/10.1021/bi300017p
  19. Tseng L, Mazella J, Mann WJ, et al (1982). Estrogen synthesis in normal and malignant human endometrium. J Clin Endocrinol Metab, 55, 1029-31. https://doi.org/10.1210/jcem-55-5-1029
  20. Thangavelu A, Hewitt MJ, Quinton ND, et al (2013). Neoadjuvant treatment of endometrial cancer using anastrozole, a randomised pilot study. Gynecol Oncol, 131, 613-8. https://doi.org/10.1016/j.ygyno.2013.09.023
  21. Tabatabaie A, Karimi Zarchi M, Dehghani-Tafti M, et al (2013). Comparing letrozole with medroxyprogesterone acetate (MPA) as hormonal therapy for simple endometrial hyperplasia without atypia in adult and middle-aged women. Eur J Gynaecol Oncol, 34, 552-5.
  22. Tokmak A, Kokanali MK, Guzel AI, et al (2013). Polycystic ovary syndrome and risk of endometrial cancer, a minireview. Asian Pac J Cancer Prev, 15, 7011-4.
  23. Topcul M, Topcul F, Cetin I et al (2013). Effects of femara and tamoxifen on proliferation of FM3A cells in culture. Asian Pac J Cancer Prev, 14, 2819-22. https://doi.org/10.7314/APJCP.2013.14.5.2819
  24. Watanabe K, Sasano H, Harada N, et al (1995). Aromatase in human endometrial carcinoma and hyperplasia. Immunohistochemical, in situ hybridization, and biochemical studies. Am J Pathol, 146, 491-500.
  25. Yoshimoto FK, Guengerich FP (2014). Mechanism of the third oxidative step in the conversion of androgens to estrogens by cytochrome P450 19a1 steroid aromatase. J Am Chem Soc, [Epub ahead of print].

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