Inhibitory effects of estetrol on the invasion and migration of immortalized human endometrial stromal cells

Akihiko Wakatsuki, Yinzhi Lin, Shiori Kojima, Hiroshi Matsushita, Kosei Takeuchi, Kazuo Umezawa
In: Endocrine Journal · 2023 · vol. 71(2) , pp. 199–206 · doi:10.1507/endocrj.ej23-0397 · W4390285591
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⚙ AI-generated summary by claude@2026-06, 2026-06-13 ⓘ

Estetrol inhibited E2-induced invasion and migration of human endometrial stromal cells by downregulating WASF-1 expression, suggesting a potential therapeutic role in endometriosis.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-13 · read from full text ⓘ

The study examined how the natural estrogen estetrol (E4) and 17β-estradiol (E2) affect invasion and migration in immortalized human endometrial stromal cells (HESCs), using Matrigel invasion assays and wound-healing/cell-tracking migration analyses, with WASF-1 expression measured by real-time PCR. E4 significantly inhibited E2-induced invasion and migration, with E2 upregulating WASF-1 and E4 downregulating it, while WASF-1 knockdown via siRNA reduced migration. The paper’s main limitation is that experiments were performed in immortalized cell models, so findings reflect cellular behavior rather than lesion biology in vivo. This paper is centrally about endometriosis — it tests whether estetrol can oppose E2-driven invasion/migration of endometrial stromal cells via WASF-1, a mechanism proposed to reduce endometriotic lesion progression.

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Abstract

Endometriosis, a common gynecological disorder characterized by the growth of endometrial gland and stroma outside the uterus, causes several symptoms such as dysmenorrhea, hypermenorrhea, and chronic abdominal pain. 17β estradiol (E2) stimulates the growth of endometriotic lesions. Although estetrol (E4), produced by human fetal liver, is also a natural estrogen, it may have the opposite effects on endometriotic cells. We investigated different effects of E4 and E2 on the invasion and migration of immortalized human endometrial stromal cells (HESCs) and evaluated whether E4 affects the expression of Wiskott-Aldrich syndrome protein (WASP) family member 1 (WASF-1). We measured the invasion of HESCs by a Matrigel chamber assay. Cell migration was measured by wound healing assay and cell tracking analysis. The expression of WASF-1 was confirmed by independent real-time PCR analysis. Transfection of cells with siRNAs was carried out to knock down the expression of WASF-1 in HESCs. E4 significantly inhibited E2-induced invasion and migration of HESCs. WASF-1 was found to be a potential mediator based on metastasis PCR array. WASF-1 was upregulated by E2 and downregulated by E4. Knockdown of WASF-1 inhibited migration. Our results suggest that E4 may inhibit E2-induced growth of endometriotic lesions. Downregulation of WASF-1 is involved in the inhibitory effects of E4 on migration. The use of E4 combined with progestins as combined oral contraceptives may cause endometriotic lesions to regress in women with endometriosis.
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NOTE Inhibitory effects of estetrol on the invasion and migration of immortalized human endometrial stromal cells 2024 Volume 71 Issue 2 Pages 199-206 Details Abstract Endometriosis, a common gynecological disorder characterized by the growth of endometrial gland and stroma outside the uterus, causes several symptoms such as dysmenorrhea, hypermenorrhea, and chronic abdominal pain. 17β estradiol (E2) stimulates the growth of endometriotic lesions. Although estetrol (E4), produced by human fetal liver, is also a natural estrogen, it may have the opposite effects on endometriotic cells. We investigated different effects of E4 and E2 on the invasion and migration of immortalized human endometrial stromal cells (HESCs) and evaluated whether E4 affects the expression of Wiskott-Aldrich syndrome protein (WASP) family member 1 (WASF-1). We measured the invasion of HESCs by a Matrigel chamber assay. Cell migration was measured by wound healing assay and cell tracking analysis. The expression of WASF-1 was confirmed by independent real-time PCR analysis. Transfection of cells with siRNAs was carried out to knock down the expression of WASF-1 in HESCs. E4 significantly inhibited E2-induced invasion and migration of HESCs. WASF-1 was found to be a potential mediator based on metastasis PCR array. WASF-1 was upregulated by E2 and downregulated by E4. Knockdown of WASF-1 inhibited migration. Our results suggest that E4 may inhibit E2-induced growth of endometriotic lesions. Downregulation of WASF-1 is involved in the inhibitory effects of E4 on migration. The use of E4 combined with progestins as combined oral contraceptives may cause endometriotic lesions to regress in women with endometriosis. © The Japan Endocrine Society This article is licensed under a Creative Commons [Attribution-NonCommercial-NoDerivatives 4.0 International] license. https://creativecommons.org/licenses/by-nc-nd/4.0/deed.en Favorites & Alerts Recently viewed articles Predecessor

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