PubMed · 14390884
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R TRAISSAC. 1955. [Ossific endocervicitis; complementary note and conclusion].. https://pubmed.ncbi.nlm.nih.gov/14390884/
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BACKGROUND: Endometriosis affects about 10% of women usually of reproductive age. It often has severe negative impacts on patients' quality of life, but the average time to a definitive diagnosis remains 7-9 years, and there are few effective therapeutic options. Relatively little is known about the genetic drivers of the disease even though its heritability is fairly high. A recent large genome wide association study (GWAS) meta-analysis identified 42 genomic loci associated with risk of endometriosis, but together these explain only 5% of disease variance. METHODS: We used the PrecisionLife® combinatorial analytics platform to identify multi-SNP disease signatures significantly associated with endometriosis in a white European UK Biobank (UKB) cohort. We assessed the reproducibility of these multi-SNP disease signatures as well as 35 of the 42 meta-GWAS SNPs in a multi-ancestry American endometriosis cohort from All of Us (AoU) after controlling for population structure. RESULTS: We identified 1,709 disease signatures, comprising 2,957 unique SNPs in combinations of 2-5 SNPs, that were associated with increased prevalence of endometriosis in UKB. Pathways enriched in the disease signatures included cell adhesion, proliferation and migration, cytoskeleton remodeling, angiogenesis as well as biological processes involved in fibrosis and neuropathic pain.We observed a significant enrichment of these signatures (58-88%, p<0.04) that are also positively associated with endometriosis in the AoU cohort, including one 2-SNP signature that is individually significant. Reproducibility rates were greatest for higher frequency signatures, ranging from 80-88% for signatures with greater than 9% frequency (p<0.01) in AoU. Encouragingly, the disease signatures also show high reproducibility rates in non-white European AoU sub-cohorts (66-76%, p<0.04 for signatures with greater than 4% frequency).A total of 195 unique SNPs mapping to 98 genes were identified in the high frequency reproducing signatures (>9%). Of these, 7 genes were previously identified in the endometriosis meta-GWAS study and 16 genes have a previous association with endometriosis. 75 novel genes were identified in this study.We characterized 9 novel genes that occur at the highest frequency in reproducing signatures and that do not contain any SNPs linked to known GWAS genes, providing new evidence for links between endometriosis and autophagy and macrophage biology. Reproducibility rates, ranging between 73% to 85%. are especially strong for the signatures that contain these 9 genes independently of any SNPs mapping to the meta-GWAS genes. CONCLUSION: Although using much smaller, less well-characterized datasets than the previous whole genome meta-GWAS study, combinatorial analysis has provided important new insights into the genetics and biology of endometriosis including reproducible biologically relevant genes that are overlooked by GWAS approaches.The 75 novel gene associations provide new insights and routes for study of the disease and potential new therapies. Several of the novel genes identified are credible targets for drug discovery, repurposing and/or repositioning. Using the disease signatures identified as genetic biomarkers in trials of candidates drugs targeting specific mechanisms will enable precision medicine-based approaches. We hope this will encourage new targeted therapy discovery efforts.
OBJECTIVE: To clarify the rate of major intra-operative and post-operative complications experienced during excisional surgery for endometriosis. DESIGN: Prospective multi-centre observational study set in two University teaching hospitals and three private hospitals in Sydney, Australia. All consecutive subjects undergoing laparoscopic excisional surgery for minimal to severe endometriosis were recruited (790 subjects). Complications were recorded intra-operatively or post-operatively on a secure computerised patient database. Major intra- and post-operative complications i.e. inadvertent visceral or vascular injury or other complications directly related to surgery that either significantly prolonged the operating time, delayed discharge or necessitated re-admission. RESULTS: Seven hundred and ninety subjects were recruited over a 3-year period. Seven major complications were experienced (8.8/1000); four bowel injuries, one cystotomy, one ureteric transection, and one major vascular injury. All visceral or vascular injuries were diagnosed prior to completion of the surgery. No significant longterm sequelae were experienced. CONCLUSION: The incidence of major complications in this study of 8.8/1000 compares favourably with other similar reports. In view of the potential symptom relief obtained, the authors continue to believe the benefits of such surgery significantly outweigh the risks of subsequent operative-related morbidity.
Suppression of sex steroid production based on desensitisation and down-regulation of pituitary gonadotropin-releasing hormone (GnRH)-receptors by agonistic GnRH-analogues resulting in the blockage of gonadotropin release from the anterior pituitary gland is a well-established approach in a variety of clinical conditions. Antagonistic analogues of GnRH exert their effect by competing with endogenous GnRH for pituitary binding sites. Because of the lack of any intrinsic activity of these compounds, the characteristic initial 'flare-up' effect of GnRH-agonist administration is absent. A more rapid suppression of gonadotropin release from the pituitary gland can be achieved, enabling shorter treatment regimes in ovarian hyperstimulation for assisted reproduction. As yet, GnRH-antagonists have attained market approval only for the indication of premature luteinizing hormone (LH) surge prevention in controlled ovarian hyperstimulation and palliative treatment of advanced prostatic cancer. However, GnRH-antagonists may be useful in a variety of other malignant and non-malignant indications where rapid sex steroid suppression is desired, such as uterine leiomyomas, endometriosis, gynaecological cancers or benign prostatic hyperplasia. In the context of infertility treatment, available data on the application of GnRH-antagonists in the treatment of endometriosis and uterine leiomyomas are reviewed.