Molecular Mechanisms of Treatment Resistance in Endometriosis: The Role of Progesterone–Hox Gene Interactions

Hakan Cakmak, Hakan Çakmak, Hugh S Taylor
Seminars in reproductive medicine · 2010 · vol. 28(01) , pp. 069–074 · doi:10.1055/s-0029-1242996 · PMID:20104430 · PMC3107856 · W2081047129
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⚙ AI-generated summary by claude@2026-06, 2026-06-10 ⓘ

Progesterone resistance in endometriosis, potentially mediated by HOXA10 hypermethylation, leads to dysregulated HOX gene expression and downstream defects in endometrial receptivity.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 ⓘ

This paper reviews and synthesizes evidence that progesterone-driven HOX gene expression (HOXA10 and HOXA11) in human endometrium fails to reach maximal levels in women with endometriosis. It argues that altered progesterone receptor expression or progesterone signaling leads to attenuated progesterone target gene expression, with downstream reductions in HOX-regulated mediators of endometrial receptivity (including pinopodes, αvβ3 integrin, and IGFBP-1). A major limitation highlighted by the paper is that much of the mechanistic linkage is based on prior demonstrations and correlational findings, including HOXA10 hypermethylation as an epigenetic mechanism for progesterone resistance, rather than entirely new experimental data in this review format. Relevance to endometriosis: it is specifically focused on endometriosis-related progesterone resistance via progesterone–HOX gene interactions, including cited findings that HOXA10 expression and receptivity determinants are dysregulated in endometriosis.

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Abstract

HOX genes, encoding homeodomain transcription factors, are dynamically expressed in endometrium, where they are necessary for endometrial growth, differentiation, and implantation. In human endometrium, the expression of HOXA10 and HOXA11 is driven by sex steroids, with peak expression occurring at time of implantation in response to rising progesterone levels. However, the maximal HOXA10 and HOXA11 expression fails to occur in women with endometriosis. In endometriosis, altered progesterone receptor expression or diminished activity may lead to attenuated or dysregulated progesterone response and decreased expression of progesterone-responsive genes including HOX genes in the eutopic endometrium. In turn, other mediators of endometrial receptivity that are regulated by HOX genes, such as pinopodes, alphavbeta3 integrin, and IGFBP-1, are downregulated in endometriosis. HOXA10 hypermethylation has recently been demonstrated to silence HOXA10 gene expression and account for decreased HOXA10 in the endometrium of women with endometriosis. Silencing of progesterone target genes by methylation is an epigenetic mechanism that mediates progesterone resistance. The relatively permanent nature of methylation may explain the widespread failure of treatments for endometriosis-related infertility.

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Condition tags

endometriosisinfertility

MeSH descriptors

Endometriosis Genes, Homeobox Gene Silencing Progesterone Animals DNA Methylation Endometriosis Endometriosis Endometriosis Endometrium Endometrium Female Humans Infertility, Female Infertility, Female Infertility, Female Insulin-Like Growth Factor Binding Protein 1 Insulin-Like Growth Factor Binding Protein 1 Mice Progesterone

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