Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why

Bruce A Lessey, Lessey BA, J Julie Kim, Julie Kim
Fertility and sterility · 2017 · vol. 108(1) , pp. 19–27 · doi:10.1016/j.fertnstert.2017.05.031 · PMID:28602477 · PMC5629018 · W2624413373
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⚙ AI-generated summary by claude@2026-06+body, 2026-06-13 ⓘ

Endometriosis causes infertility by inducing chronic inflammation, progesterone resistance, and altered endometrial receptivity, affecting implantation and pregnancy rates.

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

The paper investigates how endometriosis alters eutopic endometrium biology and reduces embryo implantation by shifting normal progesterone-driven receptivity toward a chronic inflammatory, estrogen-dominant state. Using evidence from clinical studies (e.g., increased infertility and lower IVF implantation/pregnancy outcomes), animal models, and prior endometrial biomarker work (including decreased integrins such as αvβ3 and reduced L-selectin ligands, as well as dysregulated ESR1, LIF, and HOXA10), the authors argue that inflammatory signaling pathways and progesterone resistance contribute to defective implantation. They discuss mechanisms involving progesterone withdrawal-like inflammatory responses, NF-κB/Rel-A effects on progesterone receptor activity, reduced anti-inflammatory regulators (e.g., ARID1A, PIAS3), and IL-17– and IL-6–driven STAT3 activation that stabilizes HIF1A and promotes downstream pro-implantation disruptions. A major caveat is that the review-like synthesis draws together multiple types of evidence rather than presenting new experimental data within the manuscript. This paper is centrally about endometriosis — it focuses on how endometriosis affects eutopic endometrial receptivity through inflammation, progesterone resistance, and altered implantation biomarkers.

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Abstract

The endometrium maintains complex controls on proliferation and apoptosis as part of repetitive menstrual cycles that prepare the endometrium for the window of implantation and pregnancy. The reliance on inflammatory mechanisms for both implantation and menstruation creates the opportunity in the setting of endometriosis for establishment of chronic inflammation that is disruptive to endometrial receptivity, causing both infertility and abnormal bleeding. Clinically, there can be little doubt that the endometrium of women with endometriosis is less receptive to embryo implantation, and strong evidence exists to suggest that endometrial changes are associated with decreased cycle fecundity as a result of this disease. Here we provide unifying concepts regarding those changes and how they are coordinated to promote progesterone resistance and estrogen dominance through aberrant cell signaling pathways and reduced expression of key homeostatic proteins in eutopic endometrium of women with endometriosis.
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Intro

The endometrium maintains complex autocrine, paracrine and endocrine signaling involving sex steroids, cytokines and chemokines and intracellular signaling, culminating in receptivity to embryo implantation ( 1 ). In lieu of a successful pregnancy, the endometrium undergoes complex inflammatory changes that, in a non-scarring fashion, sloughs the lining so that it can be replaced following menstruation ( 2 ). While acute inflammation is required for both implantation and menstruation ( 3 ), chronic inflammation is disruptive and a major cause of infertility and menstrual bleeding disorders ( 4 - 6 ). Endometriosis affects millions of women, and a major cause of infertility and pelvic pain ( 7 ). Women with endometriosis are twice as likely to have infertility ( 8 , 9 ) and pregnancy loss ( 10 , 11 ). Changes in endometrial receptivity due to endometriosis has been well studied and several key studies support our argument that endometriosis affects the endometrium and reduces fertility. How these changes affect fertility is equally important, as a thorough understanding of the physiological mechanism will provide opportunities for both diagnosis and therapy for this common condition.

Summary

While clinical studies support the concept of endometrial receptivity defects endometriosis, these observations need to be based on a physiological mechanism. In this review, we hope that the reader can better understand how those changes noted in the eutopic endometrium of women with infertility and endometriosis biologically impact endometrial receptivity. In vitro Fertilization (IVF) is taking on a larger role for the treatment of infertile couples and is a platform on which endometrial receptivity defects are increasingly being tested ( 141 ). Many of the defective pathways described here contribute to infertility and have therapeutic and diagnostic implications. Increasingly, it appears that endometriosis has a negative impact on IVF outcomes, and treatment strategies are evolving to address such defects. Endometrial receptivity defects should remain a relevant and vital part of the workup of couples with infertility.

Conclusions

Strong evidence supports the concept that endometrial defects exist in women with endometriosis. The inflammatory nature of this disease, accompanied by excess estrogen action that leads to a constellation of changes in the eutopic endometrium that interferes with normal embryo implantation. Signaling pathways associated with proliferation and cell survival are activated in endometriosis, while anti-proliferative progesterone pathways are being turned off. Progesterone resistance results in inadequate antagonism of estrogen action, increased inflammation, inadequate differentiation of the stroma and remodeling of the endometrium, all of which can lead to an non-receptive endometrium for embryo implantation. Inflammation appears to be central to these defects. For these reasons, it seems clear that the eutopic endometrium is a primary barrier to implantation in women with active endometriosis.

Endometriosis

Endometriosis has been described as a progesterone resistant disease due to the blunted or inadequate response to progesterone of both the eutopic and ectopic endometrial cells and tissue ( 101 - 103 ). This is demonstrated by low expression of PR ( 104 ), blunted expression of progesterone target genes ( 105 - 107 ), and an inadequate decidualization response ( 103 , 105 , 107 ). Progesterone resistance associated with endometriosis contributes to increased cell proliferation and survival ( 54 ) and elevated estrogen receptors ( 55 ). As progesterone plays a role in decreasing inflammation in the endometrium, the insensitivity to progesterone signaling results in a pro-inflammatory condition ( 108 , 109 ). The consequences of this is far-reaching affecting estrogen driven mechanisms and differentiating capacity of the tissue. A role for eutopic endometrium in endometriosis-related infertility has also been focused on the defects in decidualization, a change in endometrial morphology that is essential for pregnancy success ( 110 - 112 ). There are multiple pathways by which decidualization defects might arise, and many have been identified as aberrant in endometriosis and defects in decidual responses have been widely reported ( 103 , 113 , 114 ). The decidua is an important component of the maternal/embryo interface that provides nutrients to the embryo, protects the developing embryo from stress pathways and immune rejection, and regulates the invasion of the trophoblast. Thus, aberrant decidualization would lead to unfavorable effects on embryo implantation and pregnancy. Although progesterone is a key hormone involved in initiating and prolonging the decidualization process signaling pathways have been demonstrated to amplify this response, including the PKA pathway ( 115 - 119 ), while the AKT and MAPK pathways have been demonstrated to blunt decidualization. Impaired decidualization has been reported in both eutopic and ectopic tissues in endometriosis ( 103 , 110 , 120 ). Human endometrial stromal cells suppress AKT during decidualization ( 121 ) and increased activation of PI3K/AKT impedes decidualization ( 103 ). FOX01, required for decidualization, is inactivated by AKT pathway ( 122 ) while inhibition of PI3K and AKT increases nuclear FOXO1 and IGFBP1 expression in response to progestin and dibutyryl cAMP treatment ( 103 ). PI3K/AKT also activates estrogen receptor alpha (ESR1), increasing its activation ( 123 ). In addition, in keeping with clinical observations of decreased estrogen receptor beta (ESR2)( 124 ) AKT has also been shown to down-regulate ESR2( 124 ), with the net effect of enhancing estrogen action. The AKT pathway may also impact progesterone action; AKT can downregulate PR protein expression of PR in breast cancer and endometrial cancer cells, and in stromal cells derived from endometriosis ( 125 - 127 ). AKT has been shown to attenuate PR action in endometrial cancer cells by affecting recruitment of coregulators to PR on chromatin ( 128 ). AKT inhibitors increased cellular PR and decreased cell survival and increased apoptosis in endometriosis ( 127 ). NOTCH1 is another gene that is critical for decidualization of both mouse and human uterine stromal cells ( 129 ). Decreased Notch signaling is associated with endometriosis and contributes to impaired decidualization through the down-regulation of FOXO1 ( 129 ). Interestingly, NOTCH1 may be a target of SIRT1 ( 130 ). Studies have demonstrated that the MAPK pathway is also overactive in the eutopic endometrium from women with endometriosis ( 131 ). Microarray analysis in eutopic endometrium from endometriosis patients identified members of the MAPK and PI3K signaling pathways to be significantly regulated ( 132 , 133 ). These genes included RON, SOS, 14-3-3 protein eta, and uPAR in epithelial cells and KSR and PI3K p85 regulatory subunit alpha in stromal cells. A recent GWAS analysis of Stage A endometriosis revealed a total of 14 pathways were enriched, including the Grb2-Sos, Wnt signaling p130Cas, and extracellular signal-regulated kinase (ERK)1/ERK2/MAPK pathways ( 134 ). Wu et al, ( 135 ) conducted a comprehensive profiling of gene expression differences between the ectopic and eutopic endometrium taken from women with endometriosis adjusted for menstrual phase and the location of the lesions. Regulators of the MAPK signaling pathway including DUSP5, AKT1, HSPB2, PDGFB, PDGFRA, PLA2G5, MAPK6, MAPK7, RAC1, RAF1, RPS6KA3, TGFB3, MKNK1 were altered. Global analysis of genes performed by Burney et al ( 136 ) of eutopic endometrium of women with endometriosis, identified genes associated with inactivation of MAPK signaling cascades such as ERBB receptor feedback inhibitor 1 (ERRFI1, also known as MIG-6), and regulators of G protein signaling 1 (RGS1), which is an activator of GTPases that rapidly turns off G-protein coupled receptor signaling pathways, were decreased in endometriosis. Velarde et al ( 131 ) showed that increased ERK1/2 activity in the eutopic endometrial stromal cells from women with endometriosis inhibited cAMP-mediated down-regulation of cyclin D1. FOXO1 an important mediator of decidualization of endometrial stromal cells can be phosphorylated and its function modified by ERK and p38 ( 137 ) as well as other kinases such as DYRK1a ( 138 ), CK1 ( 139 ), and SGK ( 140 ).

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Condition tags

endometriosis

MeSH descriptors

Embryo Implantation Embryo Transfer Endometriosis Endometrium Fertilization in Vitro Infertility, Female Infertility, Female Animals Embryo Implantation Embryo Transfer Endometriosis Endometrium Endometrium Evidence-Based Medicine Female Fertilization in Vitro Humans Infertility, Female Menstrual Cycle Menstrual Cycle

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