Estetrol Inhibits Endometriosis Development in an In Vivo Murine Model

Author:

Zabala Ana Sofia1ORCID,Conforti Rocío Ayelem1ORCID,Delsouc María Belén1ORCID,Filippa Verónica23ORCID,Montt-Guevara Maria Magdalena4ORCID,Giannini Andrea4ORCID,Simoncini Tommaso4ORCID,Vallcaneras Sandra Silvina1ORCID,Casais Marilina1ORCID

Affiliation:

1. Laboratorio de Biología de la Reproducción (LABIR), Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Instituto Multidisciplinario de Investigaciones Biológicas de San Luis (IMIBIO-SL-CONICET), San Luis D5700HHW, Argentina

2. Histología, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis D5700HHW, Argentina

3. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Luis D5700HHW, Argentina

4. Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy

Abstract

Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus, and it is associated with alterations in the expression of hormone receptors and inflammation. 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-α, 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 < 0.001) and weight (p < 0.05) of ectopic lesions. Histologically, E4 did not affect cell proliferation (PCNA immunohistochemistry) but it did increase cell apoptosis (TUNEL assay) (p < 0.05). Furthermore, it modulated oxidative stress (SOD, CAT, and GPX activity, p < 0.05) and increased lipid peroxidation (TBARS/MDA, p < 0.01). Molecular analysis showed mRNA (RT-qPCR) and protein (ELISA) expression of TNF-α decreased (p < 0.05) and mRNA expression of Esr2 reduced (p < 0.05), in contrast with the increased expression of Esr1 (p < 0.01) and Pgr (p < 0.05). The present study demonstrates for the first time that E4 limited the development and progression of endometriosis in vivo.

Funder

National University of San Luis

Consejo Nacional de Investigaciones Científicas y Técnicas

Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación

Publisher

MDPI AG

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