Molecular mechanisms of treatment resistance in endometriosis: The role of progesterone–hox gene interactions
Open accessAbstract
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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These endometrial cells exhibit hypermethylation of the PR-B promoter, inducing expression of the receptor protein and resulting in progesterone resistance.
“these endometrial cells also exhibit hypermethylation of the PR-B promoter, inducing expression of the receptor protein [38,39,40] and finally resulting in a state of progesterone resistance.”
From Endometriosis and Medical Therapy: From Progestogens to Progesterone Resistance to GnRH Antagonists: A Review (2021) · cites this paper as [40]
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- Authors
- Cakmak, H., & Taylor, H.
- Affiliations
- Yale University (US)
- ORCID
- Taylor, Hugh
- Venue
- Seminars in Reproductive Medicine
- Publisher
- Georg Thieme Verlag KG
- Published
- 2010-01
- Volume
- 28
- Issue
- 01
- Pages
- 069-074
- ISSN
- 1526-4564 (ISSN-L)
- 1526-8004
- PMC
- PMC3107856
- OpenAlex
- W2081047129
- Cited by
- 105
- References
- 66
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 10 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 10 · 2019: 1 · 2018: 9 · 2017: 4 · 2016: 6 · 2015: 7 · 2014: 5 · 2013: 4 · 2012: 16
- FWCI
- 10.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Seminars in Reproductive Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD052668, R01HD036887)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- endometriosis, treatment resistance, progesterone resistance, Hox genes, HOXA10, HOXA11, progesterone receptor, endometrial receptivity, epigenetic methylation, endometriosis-associated infertility, pinopodes, integrin αvβ3, IGFBP-1, sex steroid regulation
- MeSH terms
- Animals, Endometriosis, Endometrium, Female, Genes, Homeobox, Humans, Infertility, Female, Progesterone, Insulin-Like Growth Factor Binding Protein 1, DNA Methylation, Gene Silencing, Mice
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