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.

The human uterus consists of the inner endometrium, the myometrium, and the outer serosa. Knowledge of the function of the uterus in health and disease is relevant to reproduction, fertility, embryology, gynaecology, endocrinology, and oncology. Research performed on uterine biopsies is essential to further the current understanding of human uterine biology. This brief review explores the value of the uterine biopsy in gynaecological and human fertility research and explores the common problems encountered when analysing data generated from different types of uterine biopsies, with the aim of improving the quality, reproducibility, and clinical translatability of future research.

Early diagnosis of the rare and life-threatening uterine leiomyosarcoma (LMS) is essential for prompt treatment, to improve survival. Preoperative distinction of LMS from benign leiomyoma remains a challenge, and thus LMS is often diagnosed post-operatively. This retrospective observational study evaluated the predictive diagnostic utility of 32 preoperative variables in 190 women who underwent a hysterectomy, with a postoperative diagnosis of leiomyoma (n = 159) or LMS (n = 31), at the Liverpool Women’s National Health Service (NHS) Foundation Trust, between 2010 and 2019. A total of 7 preoperative variables were associated with increased odds of LMS, including postmenopausal status (p < 0.001, OR 3.08), symptoms of pressure (p = 0.002, OR 2.7), postmenopausal bleeding (p = 0.001, OR 5.01), neutrophil count ≥7.5 × 10⁹/L (p < 0.001, OR 5.72), haemoglobin level <118 g/L (p = 0.037, OR 2.22), endometrial biopsy results of cellular atypia or neoplasia (p = 0.001, OR 9.6), and a mass size of ≥10 cm on radiological imaging (p < 0.0001, OR 8.52). This study has identified readily available and easily identifiable preoperative clinical variables that can be implemented into clinical practice to discern those with high risk of LMS, for further specialist investigations in women presenting with symptoms of leiomyoma.

STUDY QUESTION: What is the hormone receptor profile of adenomyosis lesions in comparison to correctly located endometrium? SUMMARY ANSWER: Adenomyosis lesions exhibit increased oestrogen receptor (ER) expression compared to the eutopic endometrium; there are conflicting results regarding progesterone receptor (PR) expression and a lack of studies on androgen receptor (AR) expression. WHAT IS KNOWN ALREADY: Adenomyosis lesions express hormone receptors indicating an influence from ovarian steroid hormones. However, hormone treatments are often ineffective in controlling adenomyosis symptoms, which suggests alternate hormonal responses and, potentially, a distinct hormone receptor expression profile within adenomyosis lesions compared to the eutopic endometrium. STUDY DESIGN, SIZE, DURATION: This systematic review with a thematic analysis retrieved studies from the PubMed, Ovid Medline, Embase, Scopus, and Cochrane Library databases, and searches were conducted from inception through to May 2024. Human studies were included and identified using a combination of exploded MeSH terms (‘adenomyosis’) and free-text search terms (‘oestrogen receptor’, ‘progesterone receptor’, ‘androgen receptor’, ‘hormone receptor’). PARTICIPANTS/MATERIALS, SETTING, METHODS: This review was reported in accordance with the PRISMA guidelines. All studies reporting original data concerning hormone receptors in adenomyosis lesions compared to eutopic endometrium in adenomyosis were included. Studies that did not report original data or provide a review of the field were excluded. Bias analysis was completed for each study using the Newcastle–Ottawa scoring system. MAIN RESULTS AND THE ROLE OF CHANCE: There were 1905 studies identified, which were screened to include 12 studies that met the eligibility criteria, including 11 proteomic studies and one transcriptional study, with a total of 555 individual participants. ER expression was consistently increased in adenomyosis lesions compared to the eutopic endometrium, specifically in the secretory phase. When endometrial subregion was considered, this difference was specific to the endometrial functionalis only. When different isoforms were considered, this increase in ER expression was specific to ERα rather than ERβ. There were conflicting results on PR expression, with most studies showing no significant difference or reduced levels in adenomyosis lesions compared to the eutopic endometrium. There is a paucity of data on AR expression in adenomyosis lesions, with only one study of small sample size included. LIMITATIONS, REASONS FOR CAUTION: A high risk of bias arose from studies grouping endometrial samples across different menstrual cycle phases for analysis. The coexistence of gynecological conditions like endometriosis may also confound the hormone receptor profile of the eutopic endometrium. Most studies employing immunostaining did not comment on region-specific differences in the endometrium. Given the well-documented cyclical variations in hormone receptor expression within the endometrium, the need for more attention to region-specific differences represents a notable limitation in the current body of literature. WIDER IMPLICATIONS OF THE FINDINGS: The systematic review highlights oestrogen dominance through elevated ERα levels in adenomyosis lesions, which agrees with the literature suggesting local hyper-oestrogenism in adenomyosis lesions. Heterogeneity in menstrual cycle timing and lack of endometrial region specificity prevent conclusions on progesterone resistance within adenomyosis lesions in this study. Future investigations should minimize the bias through well-defined cohorts, leading to robust exploration of hormone receptor profiles in adenomyosis lesions to identify therapeutic targets and deepen our understanding of adenomyosis pathogenesis. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Wellbeing of Women Research Project grants RG1073 and RG2137 (D.K.H.), a Wellbeing of Women Entry-Level Scholarship ELS706 and a Medical Research Council grant MR/V007238/1 (A.M. and D.K.H.), as well as the University of Liverpool (L.T.). There are no conflicts of interest. HROPEN-24-0294.R2: The review protocol was published in the PROSPERO Register of Systematic Reviews on 27 September 2023, registration number CRD4202346.