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

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-alpha (TNF-alpha) or interleukin-1 beta (IL-1 beta) 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-alpha and IL-1 beta 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. (C) 2014 by American Society for Reproductive Medicine.