The human endometrium is a highly regenerative organ undergoing over 400 cycles of shedding and regeneration over a woman’s lifetime. Menstrual shedding and the subsequent repair of the functional layer of the endometrium is a process unique to humans and higher-order primates. This massive regenerative capacity is thought to have a stem cell basis, with human endometrial stromal stem cells having already been extensively studied. Studies on endometrial epithelial stem cells are sparse, and the current belief is that the endometrial epithelial stem cells reside in the terminal ends of the basalis glands at the endometrial/myometrial interface. Since almost all endometrial pathologies are thought to originate from aberrations in stem cells that regularly regenerate the functionalis layer, expansion of our current understanding of stem cells is necessary in order for curative treatment strategies to be developed. This review critically appraises the postulated markers in order to identify endometrial stem cells. It also examines the current evidence supporting the existence of epithelial stem cells in the human endometrium that are likely to be involved both in glandular regeneration and in the pathogenesis of endometrial proliferative diseases such as endometriosis and endometrial cancer.

Regular menstrual shedding and repair of the endometrial functionalis is unique to humans and higher‐order primates. The current consensus postulates endometrial glands to have a single‐tubular architecture, where multi‐potential stem cells reside in the blind‐ending glandular‐bases. Utilising fixed samples from patients, we have studied the three‐dimensional (3D) micro‐architecture of the human endometrium. We demonstrate that some non‐branching, single, vertical functionalis glands originate from a complex horizontally interconnecting network of basalis glands. The existence of a multipotent endometrial epithelial stem cell capable of regenerating the entire complement of glandular lineages was demonstrated by in vivo lineage tracing, using naturally occurring somatic mitochondrial DNA mutations as clonal markers. Vertical tracking of mutated clones showed that at least one stem‐cell population resides in the basalis glands. These novel findings provide insight into the efficient and scar‐less regenerative potential of the human endometrium. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Endometriosis is a common, oestrogen driven chronic condition, where endometrium-like epithelial and stromal cells exist in ectopic sites. At present, no curative treatments are available and the existing evidence for disease progression is conflicting. The pathogenesis is still unknown and evidently complex, as mechanisms of initiation may depend on the anatomical distribution of endometriotic lesions. However, amongst the numerous theories and plethora of mechanisms, contributions of the fallopian tubes (FT) to endometriosis are rarely discussed. The FT are implicated in all endometriosis associated symptomatology and clinical consequences; they may contribute to the origin of endometriotic tissue, determine the sites for ectopic lesion establishment and act as conduits for the spread of proinflammatory media. Here, we examine the available evidence for the contribution of the human FT to the origin, pathogenesis and symptoms/clinical consequences of endometriosis. We also examine the broader topic linking endometriosis and the FT epithelium to the genesis of ovarian epithelial cancers. Further studies elucidating the distinct functional and phenotypical characteristics of FT mucosa may allow the development of novel treatment strategies for endometriosis that are potentially curative.

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.

Recurrent implantation failure (RIF) is a devastating condition that leaves many undergoing fertility treatment childless. The human endometrium is receptive to a blastocyst for a brief period, the window of implantation. Critical knowledge underpinning biological processes leading to RIF, essential for effective treatment, is lacking. We employed spatial transcriptomics to define region- and cell-type-specific differences in endometrial gene expression in luteinizing hormone timed biopsies between women with RIF (n = 8) and fertile controls (FC) (n = 8). Differentially expressed genes (DEGs) were identified when comparing endometrial regions between FC and RIF (685 luminal epithelium, 293 glandular epithelium, 419 subluminal stroma, 264 functionalis stroma, 1,125 subluminal stromal CD45 ⁺ leukocytes, and 1,049 functionalis stromal CD56 ⁺ leukocytes). Only 57 DEGs were common to all subregions and cell types, which highlights that multiple DEGs are lost when the endometrium is examined as a single entity. When RIF-specific DEGs were leveraged against knowledge from mouse genetic models, genes associated with aberrant embryo implantation phenotypes were observed, mostly in immune cell populations. Dysregulated pathways in specific endometrial regions included the “WNT signaling pathway,” altered in the functionalis and subluminal stroma. “Response to estradiol” and “ovulation cycle” pathways were dysregulated in the subluminal stroma. In silico drug screening identified potential compounds that can reverse the RIF gene expression profile (e.g., raloxifene, bisoprolol). Our findings, in a well-characterized cohort, highly endorse consideration of each endometrial region and cell type as separate entities. Ignoring individual regions and composite cell populations will overlook important aberrations, forego potential treatment targets, and lead to research waste pursuing clinically irrelevant treatment options.

Background An increased body mass index (BMI) can lead to subfertility; however, current literature fails to exclude the effect of other confounding medical conditions, raising questions regarding the direct link between increased BMI and fertility outcomes. Objectives To conduct a systematic review and meta-analysis to elucidate the effects of increased BMI on fertility outcomes in females with no other comorbidities. Search strategy A comprehensive search was conducted using EMBASE, MEDLINE and the Cochrane library from January 2000 until July 2023. Data collection and analysis Two authors independently conducted data extraction and assessed study quality. Odds ratio (OR) (dichotomous data), standardised mean difference (SMD) (continuous data) and 95% CIs were calculated. Main results Nine eligible studies were identified: one natural conception and eight assisted reproductive technology (ART). Aggregated data revealed women with BMI ≥25 were less likely to attain clinical pregnancy (OR 0.76, 95% CIs 0.62 to 0.93, p=0.007), with BMI ≥30 associated with a further decreased likelihood of clinical pregnancy (OR 0.61, 95% CIs 0.39 to 0.98, p=0.04). Women with raised BMI required longer duration of stimulation (SMD=0.08, 95% CIs 0.00 to 0.16, p=0.04) and obtained reduced oocytes (SMD=−0.11, 95% CIs −0.18 to −0.04, p=0.002). Conclusions These data demonstrate an adverse impact of being overweight/obese on ART outcomes in women with no other diagnosed medical comorbidities and highlight the distinct lack of data concerning the effects of isolated obesity on natural conception. Infertility represents an enormous burden for couples and society; it is essential to identify and tackle modifiable risk factors to improve chances of conception. PROSPERO registration number CRD42022293631.