{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:35:55Z","timestamp":1790174155672,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T00:00:00Z","timestamp":1688083200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003710","name":"Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI)","doi-asserted-by":"publisher","award":["HI21C1770000021"],"award-info":[{"award-number":["HI21C1770000021"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI)","doi-asserted-by":"publisher","award":["6-2020-0083"],"award-info":[{"award-number":["6-2020-0083"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002573","name":"Yonsei University, College of Medicine, Seoul, Republic of Korea","doi-asserted-by":"publisher","award":["HI21C1770000021"],"award-info":[{"award-number":["HI21C1770000021"]}],"id":[{"id":"10.13039\/501100002573","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002573","name":"Yonsei University, College of Medicine, Seoul, Republic of Korea","doi-asserted-by":"publisher","award":["6-2020-0083"],"award-info":[{"award-number":["6-2020-0083"]}],"id":[{"id":"10.13039\/501100002573","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Objectives: Formononetin is one of the phytoestrogens that functions like a selective estrogen receptor modulator (SERM). In this study, we evaluated the effects of formononetin on endometriosis progression in vitro and in vivo. Materials and methods: After pathological confirmation, 10 eutopic and ectopic endometria were collected from patients with endometriosis. Ten eutopic endometria samples were collected from patients who did not have endometriosis. To determine the cytotoxic dose and therapeutic dose of formononetin, the concentration of 70% of the cells that survived after formononetin administration was estimated using a Cell counting kit-8 (CCK 8) assay. Western blot analysis was used to determine the relative expression levels of BAX, p53, pAKT, ERK, pERK, p27, and pSTAT3 in the eutopic endometria without endometriosis, eutopic endometria with endometriosis, and ectopic endometria with endometriosis as the formononetin concentration was increased. We confirmed the effect of formononetin on apoptosis and migration in endometriosis using fluorescence-activated cell sorting (FACS) and wound healing assays, respectively. A mouse model of endometriosis was prepared using a non-surgical method, as previously described. The mice were intraperitoneally administered formononetin for four weeks after dividing them into control, low-dose formononetin (40 mg\/kg\/day) treatment, and high-dose (80 mg\/kg\/day) formononetin treatment groups. All the mice were euthanized after formononetin treatment. Endometriotic lesions were retrieved and confirmed using hematoxylin and eosin (H&amp;E) staining. Immunohistochemical (IHC) staining of p27 was performed. Results: We set the maximum concentration of formononetin administration to 80 \u03bcM through the CCK8 assay. Based on formononetin concentration, the expression levels of BAX, p53, pAKT, ERK, pERK, p27, and pSTAT3 proteins were measured using Western blot analysis (N = 4 per group). The expression level of pERK, p27, and pSTAT3 in eutopic endometrium with endometriosis tended to decrease with increasing formononetin concentration, and a significant decrease was noted at 80 \u03bcM. The expression of p27 in ectopic endometrium with endometriosis was also significantly decreased at 80 \u03bcM of formononetin. FACS analysis revealed that formononetin did not significantly affect apoptosis. In the wound healing assay, formononetin treatment revealed a more significant decrease in the proliferation of the eutopic endometrium in patients with endometriosis than in the eutopic endometrium without endometriosis. Relative expression of sex hormone receptors decreased with increasing formononetin doses. Although no significant differences were observed in the ER, PR-A, ER\u03b2\/ER\u03b1, and PR-B\/PR-A, significant down-regulation of PR-B expression was noted after formononetin treatment at 80 \u03bcM. In the in vivo study, endometriotic lesions in the formononetin-treated group significantly decreased compared to those in the control group. The relative expression of p27 using IHC was highest in the control group and lowest in the high-dose formononetin treatment group. Conclusions: Formononetin treatment was shown to inhibit the proliferation of eutopic and ectopic endometria in patients with endometriosis through the regulation of p27, pSTAT3, and PR-B. In an endometriosis mouse model, formononetin treatment significantly reduced the number of endometriotic lesions with decreased p27 expression. The results of this study suggest that formononetin may be used as a non-hormonal treatment option for endometriosis.<\/jats:p>","DOI":"10.3390\/nu15133001","type":"journal-article","created":{"date-parts":[[2023,7,3]],"date-time":"2023-07-03T00:42:46Z","timestamp":1688344966000},"page":"3001","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Formononetin Inhibits Progression of Endometriosis via Regulation of p27, pSTAT3, and Progesterone Receptor: In Vitro and In Vivo Studies"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3999-5300","authenticated-orcid":false,"given":"Yunjeong","family":"Park","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Guro Hospital, Korea University College of Medicine, Seoul 08308, Republic of Korea"},{"name":"Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Pil","family":"Choo","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gee Soo","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06229, Republic of Korea"},{"name":"Department of Medical Device Engineering and Management, Yonsei University College of Medicine, Seoul 06229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sehee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06229, Republic of Korea"},{"name":"Department of Medical Device Engineering and Management, Yonsei University College of Medicine, Seoul 06229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Jung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06229, Republic of Korea"},{"name":"Institute of Women\u2019s Life Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wooseok","family":"Im","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06229, Republic of Korea"},{"name":"Institute of Women\u2019s Life Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyemin","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inha","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4223-1395","authenticated-orcid":false,"given":"Jae Hoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06229, Republic of Korea"},{"name":"Institute of Women\u2019s Life Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2718-6645","authenticated-orcid":false,"given":"Sihyun","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06229, Republic of Korea"},{"name":"Institute of Women\u2019s Life Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1157-4822","authenticated-orcid":false,"given":"Young Sik","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Institute of Women\u2019s Life Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,30]]},"reference":[{"key":"ref_1","first-page":"93","article-title":"Metastatic or Embolic Endometriosis, due to the Menstrual Dissemination of Endometrial Tissue into the Venous Circulation","volume":"3","author":"Sampson","year":"1927","journal-title":"Am. 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