Anterior Gradient Protein 3 and S100 Calcium-Binding Protein P Levels in Different Endometrial Epithelial Compartments May Play an Important Role in Recurrent Pregnancy Failure

Tempest, Nicola; Batchelor, Elizabeth; Hill, Christopher J.; Al-Lamee, Hannan; Drury, Josephine A.; Drakeley, Andrew J.; Hapangama, Dharani

doi:10.3390/ijms22083835

Cited by 7 publications

(11 citation statements)

References 25 publications

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“…The human endometrium contains multiple cell types, each undergo dramatic transformation throughout the menstrual cycle. Our findings highlight the important requirement to explore the specific areas of the human endometrium according to cellular subtypes, as this may provide clinically useful insights when investigating pathologies such as RRF (Wang et al, 2020;Tempest et al, 2021). Understanding the aetiology for different clinical subtypes of RRF will enable us to undertake future functional studies and discover novel therapeutic targets.…”

Section: Discussionmentioning

confidence: 87%

“…RIF is most commonly accepted as the unsuccessful transfer of three or more good quality embryos following in vitro fertilisation (IVF) and affects approximately 10% of women undergoing IVF treatment ( Margalioth et al 2006 , Tempest et al 2021 ). Inadequate endometrial receptivity is said to be responsible for two-thirds of RIF ( Simon & Laufer 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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Altered endometrial oestrogen-responsiveness and recurrent reproductive failure

Al-Lamee

Ellison

Drury

et al. 2022

Reproduction and Fertility

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Recurrent reproductive failure (RRF) encompasses recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL). These highly prevalent, distressing conditions have many unanswered questions regarding aetiology and management. Oestrogen-receptor beta (ERβ) is the predominant oestrogen-receptor expressed in vascular endothelium of endometrium during the window of implantation (WOI). Establishment of normal endometrial receptivity is integrally associated with progesterone receptor (PR). Therefore, we aimed to investigate whether women with RRF have clinical, type-specific endometrial aberrations in ERβ, PR and Ki-67 expression during the WOI. Thirty eight endometrial biopsies were collected; 29 RRF (10 RIF, 9 recurrent loss of early pregnancy (RLEP), 10 recurrent fetal loss (RFL)) and 9 fertile controls (FC). Within RIF, RLEP and RFL groups, the perivascular compartment showed significantly lower levels of ERβ versus FC (p = 0.02, p = 0.03 and p = 0.01). Vascular endothelium also displayed significantly lower levels of ERβ within RIF and RFL cohorts versus FC (p = 0.03 and p = 0.003). The expression of Ki-67 was significantly lower within vascular endothelium of all RRF; RIF (p = 0.02), RLEP (p = 0.02), and RFL (p < 0.01). PR was significantly reduced (p < 0.001) in the perivascular area of women with RIF. These findings provide novel insights into biological correlates of clinical subtypes of RRF. Endometrium of women with RRF display significantly altered levels of ERβ, PR and Ki-67 during the WOI, furthering our understanding of the defective endometrial phenotype of women suffering from RRF, with possible impaired glandular function, angiogenesis and decidualisation.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Altered endometrial oestrogen-responsiveness and recurrent reproductive failure

Al-Lamee

Ellison

Drury

et al. 2022

Reproduction and Fertility

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“…Recurrent pregnancy loss (RPL) ( Eshre Special Interest Group et al , 2018 ) is one of the major challenges for clinicians; ∼50% of cases remain unexplained in aetiology, and the management options are limited and poorly understood ( RCOG, 2011 ; El Hachem et al , 2017 ). Many studies have now suggested an association between unexplained RPL and a defective endometrium ( Quenby et al , 2007 ; Hapangama et al , 2008a ; Lucas et al , 2016 ; Ticconi et al , 2019 ; Dimitriadis et al , 2020 ; Tempest et al , 2021 ). Additionally, inadequate endometrial receptivity may be responsible for two-thirds of recurrent implantation failure (RIF), in which there is failure to implant after multiple transfers of good quality embryos using ART ( Hapangama et al , 2008a ; Simon and Laufer, 2012 ; Bashiri et al , 2018 ; Tempest et al , 2021 ).…”

Section: Implications For Endometrial Pathologiesmentioning

confidence: 99%

“…Many studies have now suggested an association between unexplained RPL and a defective endometrium ( Quenby et al , 2007 ; Hapangama et al , 2008a ; Lucas et al , 2016 ; Ticconi et al , 2019 ; Dimitriadis et al , 2020 ; Tempest et al , 2021 ). Additionally, inadequate endometrial receptivity may be responsible for two-thirds of recurrent implantation failure (RIF), in which there is failure to implant after multiple transfers of good quality embryos using ART ( Hapangama et al , 2008a ; Simon and Laufer, 2012 ; Bashiri et al , 2018 ; Tempest et al , 2021 ). These devastating conditions are important reproductive health issues with many unanswered questions, leading to significant emotional and psychological impact for patients and their partners ( De Klerk et al , 2007 ; Koert et al , 2019 ; Voss et al , 2020 ).…”

Section: Implications For Endometrial Pathologiesmentioning

confidence: 99%

Novel microarchitecture of human endometrial glands: implications in endometrial regeneration and pathologies

Tempest

Hill

Maclean

et al. 2021

Human Reproduction Update

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BACKGROUND Human endometrium remains a poorly understood tissue of the female reproductive tract. The superficial endometrial functionalis, the site of embryo implantation, is repeatedly shed with menstruation, and the stem cell-rich deeper basalis is postulated to be responsible for the regeneration of the functionalis. Two recent manuscripts have demonstrated the 3D architecture of endometrial glands. These manuscripts have challenged and replaced the prevailing concept that these glands end in blind pouches in the basalis layer that contain stem cells in crypts, as in the intestinal mucosa, providing a new paradigm for endometrial glandular anatomy. This necessitates re-evaluation of the available evidence on human endometrial regeneration in both health and disease in the context of this previously unknown endometrial glandular arrangement. OBJECTIVE AND RATIONALE The aim of this review is to determine if the recently discovered glandular arrangement provides plausible explanations for previously unanswered questions related to human endometrial biology. Specifically, it will focus on re-appraising the theories related to endometrial regeneration, location of stem/progenitor cells and endometrial pathologies in the context of this recently unravelled endometrial glandular organization. SEARCH METHODS An extensive literature search was conducted from inception to April 2021 using multiple databases, including PubMed/Web of Science/EMBASE/Scopus, to select studies using keywords applied to endometrial glandular anatomy and regeneration, and the references included in selected publications were also screened. All relevant publications were included. OUTCOMES The human endometrial glands have a unique and complex architecture; branched basalis glands proceed in a horizontal course adjacent to the myometrium, as opposed to the non-branching, vertically coiled functionalis glands, which run parallel to each other as is observed in intestinal crypts. This complex network of mycelium-like, interconnected basalis glands is demonstrated to contain endometrial epithelial stem cells giving rise to single, non-branching functionalis glands. Several previous studies that have tried to confirm the existence of epithelial stem cells have used methodologies that prevent sampling of the stem cell-rich basalis. More recent findings have provided insight into the efficient regeneration of the human endometrium, which is preferentially evolved in humans and menstruating upper-order primates. WIDER IMPLICATIONS The unique physiological organization of the human endometrial glandular element, its relevance to stem cell activity and scarless endometrial regeneration will inform reproductive biologists and clinicians to direct their future research to determine disease-specific alterations in glandular anatomy in a variety of endometrial pathological conditions.

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“…Recurrent reproductive failure (RRF) encompasses two separate but related conditions, recurrent implantation failure (RIF), and recurrent pregnancy loss (RPL) [ 3 , 5 , 6 , 7 ]. RIF affects around 10% of women undergoing embryo transfers (ETs) during in vitro fertilisation (IVF) treatment [ 8 ], and the generally accepted definition is three or more failed ET attempts [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Endometrial Stem/Progenitor Cells in Recurrent Reproductive Failure

Al-Lamee

Hill

Turner

et al. 2022

JPM

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Recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL), collectively referred to as recurrent reproductive failure (RRF), are both challenging conditions with many unanswered questions relating to causes and management options. Both conditions are proposed to be related to an aberrant endometrial microenvironment, with different proposed aetiologies related to a restrictive or permissive endometrium for an invading embryo. The impressive regenerative capacity of the human endometrium has been well-established and has led to the isolation and characterisation of several subtypes of endometrial stem/progenitor cells (eSPCs). eSPCs are known to be involved in the pathogenesis of endometrium-related disorders (such as endometriosis) and have been proposed to be implicated in the pathogenesis of RRF. This review appraises the current knowledge of eSPCs, and their involvement in RRF, highlighting the considerable unknown aspects in this field, and providing avenues for future research to facilitate much-needed advances in the diagnosis and management of millions of women suffering with RRF.

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Anterior Gradient Protein 3 and S100 Calcium-Binding Protein P Levels in Different Endometrial Epithelial Compartments May Play an Important Role in Recurrent Pregnancy Failure

Cited by 7 publications

References 25 publications

Altered endometrial oestrogen-responsiveness and recurrent reproductive failure

Altered endometrial oestrogen-responsiveness and recurrent reproductive failure

Novel microarchitecture of human endometrial glands: implications in endometrial regeneration and pathologies

The Role of Endometrial Stem/Progenitor Cells in Recurrent Reproductive Failure

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