title: Dienogest inhibits nerve growth factor expression induced by tumor necrosis factor-α or interleukin-1β.
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.
  
  
  METHODS
  Prospective basic research study using immortalized hEEC lines.
  
  
  METHODS
  Development Research, Mochida Pharmaceutical Co., Ltd., Japan.
  
  
  METHODS
  None.
  
  
  METHODS
  Not applicable.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Development Research, Mochida Pharmaceutical Co., Ltd., Gotemba, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Mita
authors.affiliation: Development Research, Mochida Pharmaceutical Co., Ltd., Gotemba, Japan. Electronic address: shimizuy@mochida.co.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Development Research, Mochida Pharmaceutical Co., Ltd., Gotemba, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Sato
authors.affiliation: Development Research, Mochida Pharmaceutical Co., Ltd., Gotemba, Japan.
authors.forename: Tatsuto
authors.initials: T
authors.lastname: Notsu
authors.affiliation: Development Research, Mochida Pharmaceutical Co., Ltd., Gotemba, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Imada
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kyo
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology*; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D016716:PC12 Cells; D011446:Prospective Studies; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D006727:Hormone Antagonists; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; C023635:dienogest; D009277:Nandrolone; D020932:Nerve Growth Factor
keywords: Dienogest; P receptor; endometrial epithelial cells; nerve growth factor