Cells & development · 2026
Estetrol potentiates progesterone-driven growth restraint while blunting pro-angiogenic activation in murine endometriosis lesions.
СтатьяНазвание и аннотация: Перевод в очереди
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Maldonado Gabriel, Espinoza Cristian, Arias Anna, Muñoz Anaís, Cabrera Germán, Johnson María Cecilia, Espinoza Juan Pablo, Gutiérrez Ignacio, González Pamela, Owen Gareth, Orellana-Walden Renán, Moreno Ricardo D
Аннотация
BACKGROUND: Endometriosis is sustained by ectopic endometrial implants that remain proliferative and vascularized, making endocrine modulation a cornerstone of therapy. Estetrol (E4) an endogenous estrogen produced during pregnancy, with selective tissue activity, may modulate progesterone (P4) outputs in ectopic tissue and potentially shift lesion biology toward growth restraint without reinforcing vascular support.
OBJECTIVE: To test whether E4 modifies P4 effects on lesion proliferation, apoptosis-related signaling, and angiogenic/endothelial activation in vivo.
METHODS: Hormonally intact female mice bearing allografted endometriotic lesions received vehicle, E4 (3 mg/day), P4 (4.25 mg/day), or E4 + P4 once daily for 14 days. Lesions and eutopic endometrium were assessed by immunohistochemistry (Ki-67, cleaved caspase-3, BAX, VEGF, PECAM-1/CD31, Cyclin D1) with epithelial/stromal quantification, and endothelial angiogenic behavior was evaluated using a tube-formation assay.
RESULTS: Lesions exhibited higher proliferative activity than eutopic endometrium. P4 reduced lesion proliferation, and the E4 + P4 combination produced the strongest growth restraint. Apoptosis-related markers increased under endocrine treatments, with the combined regimen showing robust activation. Notably, P4 enhanced angiogenesis-related readouts (VEGF and PECAM/CD31), whereas E4 + P4 prevented these increases and reduced endothelial tube formation, consistent with attenuated endothelial activation under the combined regimen.
CONCLUSIONS: The E4-P4 combination supports a "balanced" endocrine profile-robust growth restraint without concurrent endothelial activation-thereby decoupling proliferation restraint from angiogenic activation.
OBJECTIVE: To test whether E4 modifies P4 effects on lesion proliferation, apoptosis-related signaling, and angiogenic/endothelial activation in vivo.
METHODS: Hormonally intact female mice bearing allografted endometriotic lesions received vehicle, E4 (3 mg/day), P4 (4.25 mg/day), or E4 + P4 once daily for 14 days. Lesions and eutopic endometrium were assessed by immunohistochemistry (Ki-67, cleaved caspase-3, BAX, VEGF, PECAM-1/CD31, Cyclin D1) with epithelial/stromal quantification, and endothelial angiogenic behavior was evaluated using a tube-formation assay.
RESULTS: Lesions exhibited higher proliferative activity than eutopic endometrium. P4 reduced lesion proliferation, and the E4 + P4 combination produced the strongest growth restraint. Apoptosis-related markers increased under endocrine treatments, with the combined regimen showing robust activation. Notably, P4 enhanced angiogenesis-related readouts (VEGF and PECAM/CD31), whereas E4 + P4 prevented these increases and reduced endothelial tube formation, consistent with attenuated endothelial activation under the combined regimen.
CONCLUSIONS: The E4-P4 combination supports a "balanced" endocrine profile-robust growth restraint without concurrent endothelial activation-thereby decoupling proliferation restraint from angiogenic activation.