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.
Subject(s)
Disease Models, Animal , Endometriosis , Estetrol , Mice, Inbred C57BL , Tumor Necrosis Factor-alpha , Animals , Endometriosis/metabolism , Endometriosis/pathology , Endometriosis/drug therapy , Female , Mice , Estetrol/pharmacology , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/genetics , Receptors, Progesterone/metabolism , Receptors, Progesterone/genetics , Oxidative Stress/drug effects , Apoptosis/drug effects , Cell Proliferation/drug effects , Lipid Peroxidation/drug effects , Estrogen Receptor alpha/metabolism , Estrogen Receptor alpha/genetics , Receptors, Estrogen/metabolism , Receptors, Estrogen/geneticsABSTRACT
Estetrol es un esferoide estrogénico sintetizado exclusivamente por el hígado fetal, que traspasa a la circulación materna por la placenta. Descrito por primera vez por Diczfalusy en 1965. Desde esa fecha se han realizado diversas investigaciones preclínicas. En los últimos años, el interés por el estetrol ha aumentado, dado el logro de su síntesis en el laboratorio y la demostración de su buena biodisponibilidad y larga vida media al administrarlo por vía oral a mujeres. Se presenta una revisión de su síntesis, metabolismo y de la información científica existente de sus diferentes efectos en los tejidos estrógeno sensibles en distintos modelos animales.
Estetrol is an estrogenic steroid synthesized exclusively by the fetal liver. It crosses over from the placenta to the maternal circulation. It was first described in 1965 by Diczfalusy and from this date onwards, several preclinical investigations have been carried out. In recent years, the interest for estetrol has been growing due to its laboratory synthesis and the demonstration of its good bioavailability together with its long half life, when administered orally to women. A review of its synthesis, metabolism and existing scientific information on its different effects on estrogen sensitive tissues, in a variety of animal models, is here presented.