Estetrol Inhibits Endometriosis Development in an In Vivo Murine Model
2024
Ana Sofia Zabala | Rocío Ayelem Conforti | María Belén Delsouc | Verónica Filippa | Maria Magdalena Montt-Guevara | Andrea Giannini | Tommaso Simoncini | Sandra Silvina Vallcaneras | Marilina Casais
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 (E<sub>4</sub>) is a weak estrogen that recently has been approved for contraception. We evaluated the effect of E<sub>4</sub> 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. E<sub>4</sub> was delivered via Alzet pump (3 mg/kg/day) from the 15th postoperative day for 4 weeks. E<sub>4</sub> significantly reduced the volume (<i>p</i> < 0.001) and weight (<i>p</i> < 0.05) of ectopic lesions. Histologically, E<sub>4</sub> did not affect cell proliferation (PCNA immunohistochemistry) but it did increase cell apoptosis (TUNEL assay) (<i>p</i> < 0.05). Furthermore, it modulated oxidative stress (SOD, CAT, and GPX activity, <i>p</i> < 0.05) and increased lipid peroxidation (TBARS/MDA, <i>p</i> < 0.01). Molecular analysis showed mRNA (RT-qPCR) and protein (ELISA) expression of TNF-α decreased (<i>p</i> < 0.05) and mRNA expression of <i>Esr2</i> reduced (<i>p</i> < 0.05), in contrast with the increased expression of <i>Esr1</i> (<i>p</i> < 0.01) and <i>Pgr</i> (<i>p</i> < 0.05). The present study demonstrates for the first time that E<sub>4</sub> limited the development and progression of endometriosis in vivo.
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