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Estetrol (E4) is a weak estrogen that recently has been approved for contraception. We evaluated the effect of E4 on the growth of endometriotic-like lesions and the expression of TNF-\u03b1, estrogen receptors (ERs), and progesterone receptors (PRs) in an in vivo murine model. Endometriosis was induced surgically in female C57BL\/6 mice. E4 was delivered via Alzet pump (3 mg\/kg\/day) from the 15th postoperative day for 4 weeks. E4 significantly reduced the volume (p &lt; 0.001) and weight (p &lt; 0.05) of ectopic lesions. Histologically, E4 did not affect cell proliferation (PCNA immunohistochemistry) but it did increase cell apoptosis (TUNEL assay) (p &lt; 0.05). Furthermore, it modulated oxidative stress (SOD, CAT, and GPX activity, p &lt; 0.05) and increased lipid peroxidation (TBARS\/MDA, p &lt; 0.01). Molecular analysis showed mRNA (RT-qPCR) and protein (ELISA) expression of TNF-\u03b1 decreased (p &lt; 0.05) and mRNA expression of Esr2 reduced (p &lt; 0.05), in contrast with the increased expression of Esr1 (p &lt; 0.01) and Pgr (p &lt; 0.05). The present study demonstrates for the first time that E4 limited the development and progression of endometriosis in vivo.<\/jats:p>","DOI":"10.3390\/biom14050580","type":"journal-article","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T03:35:55Z","timestamp":1715744155000},"page":"580","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Estetrol Inhibits Endometriosis Development in an In Vivo Murine Model"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2488-0978","authenticated-orcid":false,"given":"Ana Sofia","family":"Zabala","sequence":"first","affiliation":[{"name":"Laboratorio de Biolog\u00eda de la Reproducci\u00f3n (LABIR), Facultad de Qu\u00edmica, Bioqu\u00edmica y Farmacia, Universidad Nacional de San Luis, Instituto Multidisciplinario de Investigaciones Biol\u00f3gicas de San Luis (IMIBIO-SL-CONICET), San Luis D5700HHW, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3434-2178","authenticated-orcid":false,"given":"Roc\u00edo Ayelem","family":"Conforti","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda de la Reproducci\u00f3n (LABIR), Facultad de Qu\u00edmica, Bioqu\u00edmica y Farmacia, Universidad Nacional de San Luis, Instituto Multidisciplinario de Investigaciones Biol\u00f3gicas de San Luis (IMIBIO-SL-CONICET), San Luis D5700HHW, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2556-1205","authenticated-orcid":false,"given":"Mar\u00eda Bel\u00e9n","family":"Delsouc","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda de la Reproducci\u00f3n (LABIR), Facultad de Qu\u00edmica, Bioqu\u00edmica y Farmacia, Universidad Nacional de San Luis, Instituto Multidisciplinario de Investigaciones Biol\u00f3gicas de San Luis (IMIBIO-SL-CONICET), San Luis D5700HHW, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2039-0731","authenticated-orcid":false,"given":"Ver\u00f3nica","family":"Filippa","sequence":"additional","affiliation":[{"name":"Histolog\u00eda, Facultad de Qu\u00edmica, Bioqu\u00edmica y Farmacia, Universidad Nacional de San Luis, San Luis D5700HHW, Argentina"},{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), San Luis D5700HHW, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8648-3845","authenticated-orcid":false,"given":"Maria Magdalena","family":"Montt-Guevara","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0512-4435","authenticated-orcid":false,"given":"Andrea","family":"Giannini","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2971-0079","authenticated-orcid":false,"given":"Tommaso","family":"Simoncini","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7031-0643","authenticated-orcid":false,"given":"Sandra Silvina","family":"Vallcaneras","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda de la Reproducci\u00f3n (LABIR), Facultad de Qu\u00edmica, Bioqu\u00edmica y Farmacia, Universidad Nacional de San Luis, Instituto Multidisciplinario de Investigaciones Biol\u00f3gicas de San Luis (IMIBIO-SL-CONICET), San Luis D5700HHW, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4334-5845","authenticated-orcid":false,"given":"Marilina","family":"Casais","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda de la Reproducci\u00f3n (LABIR), Facultad de Qu\u00edmica, Bioqu\u00edmica y Farmacia, Universidad Nacional de San Luis, Instituto Multidisciplinario de Investigaciones Biol\u00f3gicas de San Luis (IMIBIO-SL-CONICET), San Luis D5700HHW, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Smolarz, B., Szy\u0142\u0142o, K., and Romanowicz, H. 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