Obstetrics and Gynaecology - Research Publications
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ItemNo Preview AvailableA molecular staging model for accurately dating the endometrial biopsy(NATURE PORTFOLIO, 2023-10-06)Natural variability in menstrual cycle length, coupled with rapid changes in endometrial gene expression, makes it difficult to accurately define and compare different stages of the endometrial cycle. Here we develop and validate a method for precisely determining endometrial cycle stage based on global gene expression. Our 'molecular staging model' reveals significant and remarkably synchronised daily changes in expression for over 3400 endometrial genes throughout the cycle, with the most dramatic changes occurring during the secretory phase. Our study significantly extends existing data on the endometrial transcriptome, and for the first time enables identification of differentially expressed endometrial genes with increasing age and different ethnicities. It also allows reinterpretation of all endometrial RNA-seq and array data that has been published to date. Our molecular staging model will significantly advance understanding of endometrial-related disorders that affect nearly all women at some stage of their lives, such as heavy menstrual bleeding, endometriosis, adenomyosis, and recurrent implantation failure.
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ItemNo Preview AvailableThe genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions(NATURE PORTFOLIO, 2023-03)Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.
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ItemGene expression of the endocannabinoid system in endometrium through menstrual cycle(NATURE PORTFOLIO, 2022-06-07)Endocannabinoids mediate cellular functions and their activity is controlled by a complex system of enzymes, membrane receptors and transport molecules. Endocannabinoids are present in endometrium, a cyclical regenerative tissue requiring tightly regulated cellular mechanisms for maturation. The objective of this study was to investigate the gene expression of key elements involved in the endocannabinoid system across the menstrual cycle. RNA was isolated from endometrial tissue and genome-wide gene expression datasets were generated using RNA-sequencing. An a priori set of 70 genes associated with endocannabinoid system were selected from published literature. Gene expression across the menstrual cycle was analyzed using a moderated t test, corrected for multiple testing with Bonferroni's method. A total of 40 of the 70 genes were present in > 90% of the samples, and significant differential gene expression identified for 29 genes. We identified 4 distinct regulation patterns for synthesizing enzymes, as well as a distinct regulation pattern for degradations and transporting enzymes. This study charts the expression of endometrial endocannabinoid system genes across the menstrual cycle. Altered expression of genes that control endocannabinoid may allow fine control over endocannabinoid concentrations and their influence on cellular function, maturation and differentiation as the endometrium matures through the menstrual cycle.
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ItemDilated Thin-Walled Blood and Lymphatic Vessels in Human Endometrium: A Potential Role for VEGF-D in Progestin-Induced Break-Through Bleeding (vol 7, e30916, 2012)(PUBLIC LIBRARY SCIENCE, 2021-10-26)[This corrects the article DOI: 10.1371/journal.pone.0030916.].
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ItemPeripheral, Central, and Cross Sensitization in Endometriosis-Associated Pain and Comorbid Pain Syndromes.(Frontiers Media S.A., 2021)Endometriosis-associated pain and the mechanisms responsible for its initiation and persistence are complex and difficult to treat. Endometriosis-associated pain is experienced as dysmenorrhea, cyclical pain related to organ function including dysuria, dyschezia and dyspareunia, and persistent pelvic pain. Pain symptomatology correlates poorly with the extent of macroscopic disease. In addition to the local effects of disease, endometriosis-associated pain develops as a product of peripheral sensitization, central sensitization and cross sensitization. Endometriosis-associated pain is further contributed to by comorbid pain conditions, such as bladder pain syndrome, irritable bowel syndrome, abdomino-pelvic myalgia and vulvodynia. This article will review endometriosis-associated pain, its mechanisms, and its comorbid pain syndromes with a view to aiding the clinician in navigating the literature and terminology of pain and pain syndromes. Limitations of our current understanding of endometriosis-associated pain will be acknowledged. Where possible, commonalities in pain mechanisms between endometriosis-associated pain and comorbid pain syndromes will be highlighted.
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ItemVascular endothelial growth factor-D over-expressing tumor cells induce differential effects on uterine vasculature in a mouse model of endometrial cancer(BIOMED CENTRAL LTD, 2010-07-08)BACKGROUND: It has been hypothesised that increased VEGF-D expression may be an independent prognostic factor for endometrial cancer progression and lymph node metastasis; however, the mechanism by which VEGF-D may promote disease progression in women with endometrial cancer has not been investigated. Our aim was to describe the distribution of lymphatic vessels in mouse uterus and to examine the effect of VEGF-D over-expression on these vessels in a model of endometrial cancer. We hypothesised that VEGF-D over-expression would stimulate growth of new lymphatic vessels into the endometrium, thereby contributing to cancer progression. METHODS: We initially described the distribution of lymphatic vessels (Lyve-1, podoplanin, VEGFR-3) and VEGF-D expression in the mouse uterus during the estrous cycle, early pregnancy and in response to estradiol-17beta and progesterone using immunohistochemistry. We also examined the effects of VEGF-D over-expression on uterine vasculature by inoculating uterine horns in NOD SCID mice with control or VEGF-D-expressing 293EBNA tumor cells. RESULTS: Lymphatic vessels positive for the lymphatic endothelial cell markers Lyve-1, podoplanin and VEGFR-3 profiles were largely restricted to the connective tissue between the myometrial circular and longitudinal muscle layers; very few lymphatic vessel profiles were observed in the endometrium. VEGF-D immunostaining was present in all uterine compartments (epithelium, stroma, myometrium), although expression was generally low. VEGF-D immunoexpression was slightly but significantly higher in estrus relative to diestrus; and in estradiol-17beta treated mice relative to vehicle or progesterone treated mice. The presence of VEGF-D over-expressing tumor cells did not induce endometrial lymphangiogenesis, although changes were observed in existing vessel profiles. For myometrial lymphatic and endometrial blood vessels, the percentage of profiles containing proliferating endothelial cells, and the cross sectional area of vessel profiles were significantly increased in response to VEGF-D in comparison to control tumor cells. In contrast, no significant changes were noted in myometrial blood vessels. In addition, examples of invading cells or tumor emboli were observed in mice receiving VEGF-D expressing 293EBNA cells. CONCLUSIONS: These results illustrate that VEGF-D over-expression has differential effects on the uterine vasculature. These effects may facilitate VEGF-D's ability to promote endometrial cancer metastasis and disease progression.
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ItemCharacterization of Diffuse Intrinsic Pontine Glioma Radiosensitivity using Synchrotron Microbeam Radiotherapy and Conventional Radiation Therapy In Vitro(RADIATION RESEARCH SOC, 2018-02)Synchrotron microbeam radiation therapy is a promising preclinical radiotherapy modality that has been proposed as an alternative to conventional radiation therapy for diseases such as diffuse intrinsic pontine glioma (DIPG), a devastating pediatric tumor of the brainstem. The primary goal of this study was to characterize and compare the radiosensitivity of two DIPG cell lines (SF7761 and JHH-DIPG-1) to microbeam and conventional radiation. We hypothesized that these DIPG cell lines would exhibit differential responses to each radiation modality. Single cell suspensions were exposed to microbeam (112, 250, 560, 1,180 Gy peak dose) or conventional (2, 4, 6 and 8 Gy) radiation to produce clonogenic cell-survival curves. Apoptosis induction and the cell cycle were also analyzed five days postirradiation using flow cytometry. JHH-DIPG-1 cells displayed greater radioresistance than SF7761 to both microbeam and conventional radiation, with higher colony formation and increased accumulation of G2/M-phase cells. Apoptosis was significantly increased in SF7761 cells compared to JHH-DIPG-1 after microbeam irradiation, demonstrating cell-line specific differential radiosensitivity to microbeam radiation. Additionally, biologically equivalent doses to microbeam and conventional radiation were calculated based on clonogenic survival, furthering our understanding of the response of cancer cells to these two radiotherapy modalities.
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ItemLymphangiogensis of normal endometrium and endometrial adenocarcinoma(OXFORD UNIV PRESS, 2007-06)BACKGROUND: Information about lymphatics and lymphangiogenesis in the human endometrium is limited. We investigated the distribution of endometrial lymphatic vessels during the normal menstrual cycle and in association with endometrial adenocarcinoma and investigated the expression of lymphangiogenic growth factors, vascular endothelial growth factor (VEGF)-C, VEGF-D and VEGF receptor-3 (VEGF-R3). METHODS AND RESULTS: Full thickness uterine samples (n = 23 proliferative; n = 23 secretory) and endometrial adenocarcinoma samples (n = 7 grade I; n = 10 grade III) were collected for the study and analysed by immunohistochemistry and western blotting. Lymphatic vessels of the functionalis were significantly reduced compared with basalis (P = 0.001) across the menstrual cycle with lymphatics of the basalis sometimes intimately associated with spiral arterioles. Lymphatic vessels of endometrial adenocarcinomas were located intra-tumoural and peri-tumoural with significant increases in the peri-tumoural lymphatic vessels compared with normal basalis (P = 0.02). Interestingly, high-grade adenocarcinoma vessels containing tumour emboli demonstrated a mixed blood/lymphatic endothelial cell phenotype. VEGF-C and VEGF-D were immunolocalized in glandular epithelium and some stromal cells with the staining intensity of this localization increasing in endometrial adenocarcinoma. Protein analysis identified VEGF-C (58, 41, 31 and 21 kD) and VEGF-D (56, 41, 31 and 21 kD) and VEGF-R3 (148 and 65 kD) peptides in normal endometrium, with significant increases in several of these peptides for VEGF-C and VEGF-D and no changes in protein expression for VEGF-R3 in endometrial adenocarcinoma. CONCLUSION: Endometrial lymphatics are significantly reduced in the functionalis, and increases in endometrial adenocarcinoma peri-tumoural lymphatics are associated with increases in VEGF-C and VEGF-D peptides.
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ItemEndometrial lymphangiogensis(W B SAUNDERS CO LTD, 2008-03)This article briefly summarises some of the more important recent advances in understanding of lymphangiogenesis, and then reviews current knowledge of the lymphatics and lymphangiogenesis in the endometrium. The recent identification of vascular endothelial growth factor-C (VEGF-C) and VEGF-D, as well as specific lymphatic endothelial cell (LEC) markers such as vascular endothelial growth factor receptor-3 (VEGF-R3), lymphatic endothelial hyaluronan receptor-1 (LYVE-1), podoplanin, and prospero-related homeobox-1 (PROX1), has provided the tools to characterize and investigate lymphatic development and function in a wide range of tissues. There are conflicting reports on the distribution of endometrial lymphatics, with some studies reporting lymphatics in the functional zone of human endometrium, others only in the endometrial basalis, and some reporting none at all. Using immunohistochemical methods we have shown that lymphatic vessels of the functionalis were small and sparsely distributed whereas the basalis lymphatics are larger, more frequent and often closely associated with spiral arterioles. Based on comparisons of serial sections, the majority of lymphatic vessels are positive for CD31 but not FVIII or CD34. By comparing CD31 with D2-40 (labels lymphatic endothelial cells) vessel immunostaining, it was estimated that 13% of the vessel profiles in the functionalis, 43% in the basalis and 28% in the myometrium were lymphatics. The lymphangiogenic growth factor VEGF-C is immunolocalized most prominently in the glandular cells, vascular endothelium and some stromal cells in normal cycling endometrium. There is no difference in staining intensity observed between the basalis and functionalis. VEGF-D is immunolocalized throughout the endometrial and myometrial tissues, with no difference in intensity between endometrial glands and stroma or between the basalis and functionalis across the normal cycle. In conclusion, despite an apparently similar distribution of VEGF-C, VEGF-D and VEGF-R3 in endometrial functionalis and basalis, the lymphatic vascular density is 4-5 times higher in the basalis compared to the functionalis. There is also a close association between some lymphatics in the basalis and the spiral arterioles, thus identifying a potential mechanism for a vascular control feedback loop.
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ItemEndometrial Angiogenesis, Vascular Maturation, and Lymphangiogenesis(SAGE PUBLICATIONS INC, 2009-02)Angiogenesis, arteriogenesis or vessel maturation, and lymphangiogenesis comprise a continuum of vascular development, with overlap and interaction between the mechanisms by which they are controlled. These processes are of clinical interest because they play roles in endometrial repair, placental development, and in gynecological disorders including endometrial cancer, endometriosis and abnormal uterine bleeding. Using mouse models we have shown that estrogen can be either proangiogenic or antiangiogenic in endometrium. Progesterone alone is proangiogenic, although this can be moderated by pretreatment with estrogen. Arteriogenesis also increases in response to progesterone, and this effect is not inhibited by estrogen. Lymphatics account for 13% of all vessels in the human functionalis compared to 57% in the basalis. Many of the basalis lymphatic vessels are closely associated with spiral arterioles and this intimate connection may provide a mechanism for paracrine communication between the functionalis and the arteries supplying the endometrium.