Estetrol potentiates progesterone-driven growth restraint while blunting pro-angiogenic activation in murine endometriosis lesions

Maldonado G, Gabriel Maldonado, Espinoza C, Cristian Espinoza, Arias A, Anna Arias, Muñoz A, Anaïs Munoz, Anaís Muñoz, Cabrera G, Germán Cabrera, Marı́a Cecilia Johnson, Johnson MC, María Cecilia Johnson, Espinoza JP, Juan Pablo Espinoza, Ignacio Gutiérrez, Gutiérrez I, Pamela González, González P, Owen G, Gareth Owen, Orellana-Walden R, Renán Orellana, Renán Orellana-Walden, Moreno RD, Ricardo D Moreno
Cells & development · 2026 · vol. 187 , pp. 204096 · doi:10.1016/j.cdev.2026.204096 · PMID:42398859 · W7167280905
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Estetrol combined with progesterone strongly restrains endometriosis lesion growth and apoptosis while preventing the pro-angiogenic effects of progesterone alone.

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Abstract

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.

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chemicals 5
estetrol progesterone estetrol estrogen progesterone
organisms 1
mus sp.

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