Novel Medicine for Endometriosis and Its Therapeutic Effect in a Mouse Model

Abstract

Current therapeutic medicines for endometriosis cannot be administered during assisted reproductive technology (ART) because they have bad effects during pregnancy. In this study, we created an animal model of endometriosis and evaluated the therapeutic effect of progestin (Dienogest), dopamine agonist (Cabergoline), and their combination (Dienogest + Cabergoline). We established a mouse model mimicking human endometriosis. The mice with endometriosis were then treated with a single drug (Dienogest or Cabergoline) or both drugs (Dienogest + Cabergoline) for 14 days. An immunohistological study was then performed to analyze inflammatory lesions in the recipient mice. Real-time polymerase chain reaction (RT-PCR) and Western blotting were also performed to determine the levels of genes and proteins in inflammatory lesions to assess the recovery of endometriosis. Histologic staining showed that all medication groups showed a clear decrease in the inflammatory phenotype in the uterus, peritoneum, and intestine. Gene and protein expression analysis showed a therapeutic effect in all medication groups. In conclusion, Cabergoline had a therapeutic effect similar to that of Dienogest and could be used as an alternative to Dienogest during ART for patients with infertility; compared to the individual drugs, the combination treatment has a synergistic effect on endometriosis.

Endometriosis related sex steroid hormones, hypothalamic pituitary gonadal axis hormones and related animal modeling: A comprehensive review of published articles and endometriosis induction methods from 2010 to 2021 with scoring based approach

“…Utilizing novel animal models to assess endometriosis pathophysiology is not something new (86, 116). There has been extensive research using proposed animal models to assess etiology (117), diagnosis (118), resemblance (119), genetics (120), biomarkers (121) and therapeutics (122) for endometriosis disease. Sometimes these studies have reported promising results to encounter endometriosis as a multifactorial gynecological disease (123).…”

Endometriosis in the Mouse: Challenges and Progress Toward a ‘Best Fit’ Murine Model

“…For intraperitoneal injection models using decidualized endometrium, decidualization is often induced by injecting oil (Greaves et al, 2014;Forster et al, 2019;Horne et al, 2019;Kim et al, 2020) into, or by scratching (Ferrero et al, 2017), the uterine horn and harvesting the decidualized tissue with forceps. A variety of hormonal paradigms in ovariectomized or intact female mice are described to induce endometrial decidualization prior to harvest (Greaves et al, 2014;Ferrero et al, 2017;Forster et al, 2019;Horne et al, 2019;Kim et al, 2020). The uterine horn is opened longitudinally and the decidualized endometrium is dissected or scraped from the underlying myometrium (Kim et al, 2020).…”

“…A variety of hormonal paradigms in ovariectomized or intact female mice are described to induce endometrial decidualization prior to harvest (Greaves et al, 2014;Ferrero et al, 2017;Forster et al, 2019;Horne et al, 2019;Kim et al, 2020). The uterine horn is opened longitudinally and the decidualized endometrium is dissected or scraped from the underlying myometrium (Kim et al, 2020). Additionally, decidualization can be induced by scratching the antimesometrial lumen with a 27-G needle inside the uterine horn (Ferrero et al, 2017).…”

“…Harvested tissue is suspended in 200 -500 µl of solution before injection into the peritoneal cavity. Solutions vary between studies, and include saline (Pittaluga et al, 2010;Uegaki et al, 2015;Ruiz et al, 2016;Dodds et al, 2017;Sanchez et al, 2017;Yan et al, 2019;Kim et al, 2020), Hank's Balanced Salt Solution (HBSS) (Fattori et al, 2020), phosphate-buffered saline (PBS) (Bacci et al, 2009;Chen et al, 2009;Altan et al, 2010;Jensen et al, 2010;Wieser et al, 2012;Tomio et al, 2013;Greaves et al, 2014;Heard et al, 2016;Yuan et al, 2018;Horne et al, 2019;Woo et al, 2020), and warmed Dulbecco's Modified Eagle Medium (DMEM) (Nowak et al, 2008). The solutions chosen mimic the salinity and pH of the peritoneal cavity and maintain viability of the uterine tissue.…”

“…Minced tissue is taken from the uterine horns of a donor mouse, stripped of fat, muscle, and myometrium, and fragmented into smaller pieces usually less than 1.5 mm (Dabrosin et al, 2002;Burns et al, 2012;Jones et al, 2018). For decidualized tissue injections, decidualization is induced in ovariectomized females following the protocols discussed above in the intraperitoneal method section (Kim et al, 2020). In all studies, the uterine material is suspended in a solution that mimics the salinity and pH of the peritoneal cavity to maintain viability of the uterine tissue before injection into the peritoneal cavity; however, the suspension solution and volume (200 -500 µl) varies among studies [e.g., saline (Alali et al, 2020), PBS (Burns et al, 2012;Jones et al, 2018), Hank's buffered saline [HBS] (Li et al, 2016), and Basal Medium Eagle [BME] (Kim et al, 2014)].…”