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Mol. Hum. Reprod. Advance Access published online on June 5, 2009
Molecular Human Reproduction, doi:10.1093/molehr/gap042
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© The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dienogest, a synthetic progestin, inhibits the proliferation of immortalized human endometrial epithelial cells with suppression of cyclin D1 gene expression

Yutaka Shimizu1,4, Takashi Takeuchi1, Shizuka Mita1, Kiyoshi Mizuguchi1, Tohru Kiyono2, Masaki Inoue3 and Satoru Kyo3

1Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., Gotemba 412-8524, Japan 2Virology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan 3Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-1192, Japan

4 To whom correspondence should be addressed at: Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., 722 Jimba-aza-Uenohara, Gotemba, Shizuoka 412-8524, Japan. Tel: +81-550-89-7881; Fax: +81-550-8070, E-mail address: shimizuy{at}mochida.co.jp

Dienogest is a specific progesterone receptor agonist with potent oral endometrial activity and is used in the treatment of endometriosis. In this study, we examined the direct effects of dienogest on the proliferation of human endometrial epithelial cells using an immortalized cell line. 5-Bromo-2’-deoxyuridine incorporation into the cells was inhibited by dienogest and by progesterone (P4) in dose-dependent fashion at concentrations of 10–8 mol/l or higher. To identify the target genes of dienogest and P4, we screened the expression of 84 genes related to cell cycle regulation by real-time polymerase chain reaction after 6 h of treatment at a concentration of 10–7 mol/l. Results showed that only cyclin D1 expression was significantly down-regulated, while expression of the other genes did not significantly change after dienogest or P4 treatment compared with the control. In a time-course study during the first 24 h after drug treatment, dienogest and P4 each produced a lasting decrease in the expression of cyclin D1 mRNA, followed by a decrease in cyclin E1 mRNA but not an increase in the expression of cell cycle inhibitor genes (p21, p27, and p53). These findings suggest that dienogest directly inhibits the proliferation of human endometrial epithelial cells with suppression of cyclin D1 gene expression.

Key Words: cell proliferation/cyclin D1/dienogest/endometrial epithelial cells/progesterone

Submitted on July 7, 2008; resubmitted on May 28, 2009; accepted on June 2, 2009.


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