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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ItemObstetric Outcome After Surgical Treatment of Endometriosis: A Review of the Literature(FRONTIERS MEDIA SA, 2021-12-24)A diagnosis of endometriosis is associated with increased risks of adverse pregnancy outcomes including placenta praevia and preterm birth. Some studies have also suggested associations with gestational hypertension, foetal growth restriction, gestational diabetes, perinatal death, and obstetric haemorrhage. This review aims to assess the impact of pre-pregnancy surgical treatment of endometriosis on future obstetric outcomes. A search of the Medline, Embase and PubMed electronic databases was performed to identify studies reporting pre-pregnancy surgery for endometriosis and subsequent pregnancy outcome compared to controls with unresected endometriosis. Three studies met the inclusion criteria. The studies were heterogenous in design, definition of study groups and outcome measures. All three studies were judged at critical risk of bias. Pre-pregnancy excision of endometriosis was associated with an increased risk of caesarean section in one of two studies, OR 1.72 (95% CI 1.59-1.86) and OR 1.79 (95% CI 0.69-4.64). Placenta praevia rates were also increased in one of two studies OR 2.83 (95% CI 0.56-12.31) and OR 2.04 (95% CI 1.66-2.52). One study found increased risks of preterm birth, small for gestational age, gestational hypertension, and antepartum and postpartum haemorrhage (all p < 0.05) with pre-pregnancy excision of endometriosis. There is insufficient evidence examining the role of pre-pregnancy endometriosis surgery in ameliorating adverse pregnancy outcomes, and thus reliable conclusions cannot be drawn. Prospectively designed studies are needed to assess the relationship between surgical treatments for endometriosis and obstetric outcome and examine potential confounders such as comorbid adenomyosis and infertility.
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ItemA multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes(CELL PRESS, 2022-03-15)Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Using data from large endometriosis and EOC genome-wide association meta-analyses, we estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and EOC histotypes, and identify shared susceptibility loci. We estimate a significant genetic correlation (rg) between endometriosis and clear cell (rg = 0.71), endometrioid (rg = 0.48), and high-grade serous (rg = 0.19) ovarian cancer, associations supported by Mendelian randomization analyses. Bivariate meta-analysis identified 28 loci associated with both endometriosis and EOC, including 19 with evidence for a shared underlying association signal. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlights several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases.
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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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ItemPrevalence and incidence of endometriosis in Australian women: a data linkage cohort study(WILEY, 2021-03)OBJECTIVE: To estimate the prevalence and incidence of endometriosis among Australian women. DESIGN: Population-based cohort study linked to administrative health records. SETTING: Secondary analysis of seven surveys collected between 2000 and 2018 from a population-based cohort study. POPULATION: A total of 13 508 Australian women, born 1973-78, from a prospective cohort study of 14 247 women conducted between 1996 and 2018. METHODS: During 2000 and 2018, self-reported longitudinal survey data were linked to three administrative health databases to separately identify women with clinically confirmed or suspected endometriosis across the multiple data sources. MAIN OUTCOME MEASURES: Prevalence and incidence of clinically confirmed endometriosis in the cohort were first estimated using national hospital data. Data were then combined with other administrative health databases and the survey data to capture all clinically confirmed and suspected diagnoses of endometriosis. RESULTS: The cumulative prevalence of clinically confirmed endometriosis was 6.0% (95% CI 5.8-6.2%) by age 40-44 years. The cumulative prevalence increased to 11.4% (95% CI 11.1-11.7%) when adding diagnoses of clinically suspected endometriosis. Age-specific incidence estimates peaked to 6 per 1000 person-years at age 30-34 years. CONCLUSIONS: Among 13 508 Australian women followed for 20 years, one in nine women had clinically confirmed or suspected endometriosis by the age of 44, with most diagnosed during their early thirties. Endometriosis is a significant public health issue requiring increased surveillance, clinical awareness and management. Efforts to expand knowledge on the aetiology of the disease and optimal methods for disease management are crucial to women's health. TWEETABLE ABSTRACT: In a national study of 13 508 Australian women, one in nine women were diagnosed with endometriosis by age 44.
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ItemPrognostic gene expression signature for high-grade serous ovarian cancer(ELSEVIER, 2020-09)BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
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ItemReduced live birth rates in frozen versus fresh single cleavage embryo transfer cycles: A cross -sectional study(SHAHID SADOUGHI UNIV MEDICAL SCIENCES, 2020-07)BACKGROUND: Studies have suggested that embryo-endometrial developmental asynchrony caused by slow-growing embryos can be corrected by freezing the embryo and transferring it back in a subsequent cycle. Therefore, we hypothesized that live birth rates (LBR) would be higher in frozen embryo transfer (FET) compared with fresh embryo transfers. OBJECTIVE: To compare LBR between fresh and FET cycles. MATERIALS AND METHODS: A cross-sectional analysis of 10,744 single autologous embryo transfer cycles that used a single cleavage stage embryo was performed. Multivariate analysis was performed to compare LBR between FET and fresh cycles, after correcting for various confounding factors. Sub-analysis was also performed in cycles using slow embryos. RESULTS: Both LBR (19.13% vs 14.13%) and clinical pregnancy (22.48% vs 16.25%) rates (CPR) were higher in the fresh cycle group (p < 0.00). Multivariate analysis for confounding factors also confirmed that women receiving a frozen-thawed embryo had a significantly lower LBR rate compared to those receiving a fresh embryo (OR 0.76, 95% CI 0.68-0.86, p < 0.00). In the sub-analysis of 1,154 cycles using slow embryos, there was no statistical difference in LBR (6.40% vs 6.26%, p = 0.92) or CPR (8.10% vs 7.22%, p = 0.58) between the two groups. CONCLUSION: This study shows a lower LBR in FET cycles when compared to fresh cycles. Our results suggest that any potential gains in LBR due to improved embryo-endometrial synchrony following FET are lost, presumably due to freeze-thaw process-related embryo damage.