Estetrol Inhibits Endometriosis Development in an In Vivo Murine Model

• Published in: Biomolecules (Basel, Switzerland) Switzerland), 2024-05, Vol.14 (5), p.580
• Main Authors: Zabala, Ana Sofia, Conforti, Rocío Ayelem, Delsouc, María Belén, Filippa, Verónica, Montt-Guevara, Maria Magdalena, Giannini, Andrea, Simoncini, Tommaso, Vallcaneras, Sandra Silvina, Casais, Marilina
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Birth control; Care and treatment; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Chronic illnesses; Contraception; Disease Models, Animal; Endometriosis; Endometriosis - drug therapy; Endometriosis - metabolism; Endometriosis - pathology; Enzyme-linked immunosorbent assay; Enzymes; estetrol; Estetrol - pharmacology; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Female; Gene expression; hormone receptors; Immunohistochemistry; Laboratory animals; Lipid peroxidation; Lipid Peroxidation - drug effects; Menstruation; Mice; Mice, Inbred C57BL; Ovulation; Oxidative stress; Oxidative Stress - drug effects; Polymerase chain reaction; Progesterone; Progesterone receptors; proliferation; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Receptors, Progesterone - genetics; Receptors, Progesterone - metabolism; Transplants & implants; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom14050580

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 ) is a weak estrogen that recently has been approved for contraception. We evaluated the effect of E 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 was delivered via Alzet pump (3 mg/kg/day) from the 15th postoperative day for 4 weeks. E significantly reduced the volume ( < 0.001) and weight ( < 0.05) of ectopic lesions. Histologically, E did not affect cell proliferation (PCNA immunohistochemistry) but it did increase cell apoptosis (TUNEL assay) ( < 0.05). Furthermore, it modulated oxidative stress (SOD, CAT, and GPX activity, < 0.05) and increased lipid peroxidation (TBARS/MDA, < 0.01). Molecular analysis showed mRNA (RT-qPCR) and protein (ELISA) expression of TNF-α decreased ( < 0.05) and mRNA expression of reduced ( < 0.05), in contrast with the increased expression of ( < 0.01) and ( < 0.05). The present study demonstrates for the first time that E limited the development and progression of endometriosis in vivo.