Dienogest inhibits nerve growth factor expression induced by tumor necrosis factor-α or interleukin-1β

Mita S, Shizuka Mita, Yutaka Shimizu, Shimizu Y, Sato A, Ayumi Sato, Tatsuto Notsu, Notsu T, Imada K, Kazunori Imada, Satoru Kyo, Kyo S
Fertility and sterility · 2013 · vol. 101(2) , pp. 595–601.e1 · doi:10.1016/j.fertnstert.2013.10.038 · PMID:24289989 · W1982272648
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This study investigated the effects of dienogest on nerve growth factor (NGF) expression induced by inflammatory cytokines, finding that dienogest inhibited TNF-α or IL-1β mediated NGF upregulation.

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Abstract

OBJECTIVE: Dienogest (DNG), a selective P receptor (PR) agonist, is used to treat endometriosis. To investigate whether DNG affects nerve growth factor (NGF) expression, we stimulated human endometrial epithelial cells (hEECs) with inflammatory cytokines. DESIGN: Prospective basic research study using immortalized hEEC lines. SETTING: Development Research, Mochida Pharmaceutical Co., Ltd., Japan. PATIENT(S): None. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): In immortalized hEECs, NGF production induced by tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β) was evaluated in the presence or absence of the synthetic progestin DNG or endogenous P. The NGF messenger RNA (mRNA) and protein were measured using real-time reverse transcriptase-polymerase chain reaction (PCR) and ELISA, respectively. The NGF bioactivity in the culture medium was measured by assaying neurite outgrowth of PC-12 cells. RESULT(S): Tumor necrosis factor-α and IL-1β induced NGF mRNA and protein and increased NGF bioactivity in the culture medium. These activities were inhibited by DNG in a hEEC line that stably expresses PR. In contrast, in an hEEC line that constitutively expresses faint levels of PR, no inhibitory effect of DNG on NGF mRNA was detected. The NGF mRNA was also inhibited in hEEC lines that express only PR-A or only PR-B. CONCLUSION(S): Nerve growth factor is one of the key mediators that generates the pain associated with endometriosis. Dienogest inhibits NGF expression through PR-A and PR-B in hEEC, which may contribute to the pharmacological mechanisms of how DNG relieves pain in endometriosis.

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MeSH descriptors

Hormone Antagonists Interleukin-1beta Nandrolone Nerve Growth Factor Nerve Growth Factor Tumor Necrosis Factor-alpha Up-Regulation Up-Regulation Up-Regulation Up-Regulation Animals Animals Cell Line, Transformed Cell Line, Transformed Female Female Hormone Antagonists Hormone Antagonists Humans Humans

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