Antiproliferative and apoptotic effects of norethisterone on endometriotic stromal cells in vitro

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• 作者：Toshiyuki Minami^a ; ^{t.minami@po.nippon-shinyaku.co.jp} ; Keiji Kosugi^a ; Izumi Suganuma^b ; Kaoruko Yamanaka^b ; Izumi Kusuki^b ; Tatsuya Oyama^a ; Jo Kitawaki^b
• 关键词：Norethisterone ; Progesterone ; Endometriotic stromal cells ; Proliferation ; Apoptosis
• 刊名：European Journal of Obstetrics and Gynecology and Reproductive Biology
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：166
• 期：1
• 页码：76-80
• 全文大小：496 K

文摘

Objectives

Low-dose estrogen-progestin (LEP) agents are often used for relieving endometriosis-associated chronic pelvic pain, but a direct effect of LEP on endometriotic lesions remains to be demonstrated. The objective of this study is to investigate the antiproliferative and apoptotic effects of the synthetic progestin norethisterone (NET) against human endometriotic stromal cells (ESCs).

Study design

Ovarian endometrioma specimens were obtained at laparoscopy from 19 patients with endometriosis, and ESCs were isolated. The antiproliferative effect of compounds against cultured ESCs was evaluated by measuring the inhibition of [³H]thymidine incorporation. The ability of compounds to induce apoptosis in the cultured cells was evaluated by the measurement of caspase 3/7 activity and by nuclear staining. The cytotoxicity of compounds was evaluated by measuring the leakage of lactate dehydrogenase (LDH) into the supernatant of the cell culture.

Results

NET and progesterone (P4) at concentrations of greater than 10 nM significantly inhibited [³H]thymidine incorporation in a dose-dependent manner. Co-treatment with 17¦Â-estradiol at 0.1 ng/mL did not affect the inhibition of [³H]thymidine incorporation by NET. At concentrations greater than 100 nM, NET significantly increased caspase 3/7 activity and the numbers of apoptotic cells, whereas P4 did not. Treatment of ESCs for 24 h with NET or P4 at concentrations of up to 1000 nM did not cause LDH leakage.

Conclusions

NET inhibits the proliferation of ESCs and induces their apoptosis. These results suggest a possible direct effect of NET on endometriotic lesions in patients with endometriosis.