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      Uterine leiomyoma is associated with the risk of developing endometriosis: A nationwide cohort study involving 156,195 women

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          Abstract

          Objective

          Evidence for an association between uterine leiomyoma and increased risk of endometriosis is limited by small sample sizes and short follow-up periods. We assessed this association in a large nationwide sample with 14 years of data.

          Design

          Data were sourced from Taiwan’s Longitudinal Health Insurance Database 2000 (LHID2000).

          Materials and methods

          We identified 31,239 women aged ≥20 years diagnosed with uterine leiomyoma (International Classification of Disease, Ninth Revision, Clinical Modification [ICD-9-CM] code 218) between Jan 1, 2000 and Dec 31, 2012, who were matched with 124,956 controls (1:4) by 5-year age groups and year of diagnosis. Follow-up was from the date of LHID2000 entry to the first occurrence of endometriosis, loss to follow-up, insurance termination, or until December 31, 2013, whichever was earlier.

          Results

          In Cox regression analysis, the adjusted hazard ratio (aHR) for endometriosis in women with uterine leiomyoma was 6.44 (95% CI, 6.18, 6.72) compared with controls. The risk of endometriosis was significantly increased in women with uterine leiomyoma and comorbidities of tube-ovarian infection (aHR 2.86; 95% CI, 1.28, 6.36), endometritis (1.14; 1.06, 1.24), infertility (1.26; 1.16, 1.37), or allergic diseases (1.11; 1.05, 1.17). Having both uterine leiomyoma and endometritis significantly increased the risk of endometriosis (aHR 6.73; 95% CI, 6.07, 7.45) versus having only uterine leiomyoma (6.61; 6.33, 6.91) or endometritis (1.49; 1.31, 1.69). Similarly, having both uterine leiomyoma and infertility significantly increased the risk of endometriosis (aHR 6.95; 95% CI, 6.21, 7.78) versus having only uterine leiomyoma (6.66; 6.38, 6.96) or infertility (1.78; 1.57, 2.02).

          Conclusions

          A diagnosis of uterine leiomyoma appears to increase the risk of endometriosis. Patients presenting with uterine fibroids should be encouraged to give informed consent for possible simultaneous surgical treatment of endometriosis.

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          Most cited references34

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          Endometriosis.

          Endometriosis is an oestrogen-dependent disorder that can result in substantial morbidity, including pelvic pain, multiple operations, and infertility. New findings on the genetics, the possible roles of the environment and the immune system, and intrinsic abnormalities in the endometrium of affected women and secreted products of endometriotic lesions have given insight into the pathogenesis of this disorder and serve as the background for new treatments for disease-associated pain and infertility. Affected women are at higher risk than the general female population of developing ovarian cancer, and they also may be at increased risk of breast and other cancers as well as autoimmune and atopic disorders. Clinicians should assess and follow up affected women for these and other associated disorders. There will probably be a new repertoire of approaches for treatment and perhaps cure of this enigmatic disorder in the near future.
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            Uterine fibroids.

            E Stewart (2001)
            Uterine leiomyomas (fibroids or myomas), benign tumours of the human uterus, are the single most common indication for hysterectomy. They are clinically apparent in up to 25% of women and cause significant morbidity, including prolonged or heavy menstrual bleeding, pelvic pressure or pain, and, in rare cases, reproductive dysfunction. Thus, both the economic cost and the effect on quality of life are substantial. Surgery has been the mainstay of fibroid treatment, and various minimally invasive procedures have been developed in addition to hysterectomy and abdominal myomectomy. Formation of new leiomyomas after these conservative therapies remains a substantial problem. Although medications that manipulate concentrations of steroid hormones are effective, side-effects limit long-term use. A better approach may be manipulation of the steroid-hormone environment with specific hormone antagonists. There has been little evidence-based evaluation of therapy. New research into the basic biology of these neoplasms may add new treatment options for the future as the role of growth factors and genetic mutations in these tumours are better understood.
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              Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis.

              The identification of molecular differences in the endometrium of women with endometriosis is an important step toward understanding the pathogenesis of this condition and toward developing novel strategies for the treatment of associated infertility and pain. In this study, we conducted global gene expression analysis of endometrium from women with and without moderate/severe stage endometriosis and compared the gene expression signatures across various phases of the menstrual cycle. The transcriptome analysis revealed molecular dysregulation of the proliferative-to-secretory transition in endometrium of women with endometriosis. Paralleled gene expression analysis of endometrial specimens obtained during the early secretory phase demonstrated a signature of enhanced cellular survival and persistent expression of genes involved in DNA synthesis and cellular mitosis in the setting of endometriosis. Comparative gene expression analysis of progesterone-regulated genes in secretory phase endometrium confirmed the observation of attenuated progesterone response. Additionally, interesting candidate susceptibility genes were identified that may be associated with this disorder, including FOXO1A, MIG6, and CYP26A1. Collectively these findings provide a framework for further investigations on causality and mechanisms underlying attenuated progesterone response in endometrium of women with endometriosis.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Writing – original draft
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Writing – original draft
                Role: Data curationRole: Supervision
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                26 August 2021
                2021
                : 16
                : 8
                : e0256772
                Affiliations
                [1 ] Department of Obstetrics and Gynecology, Women and Children’s Health, Royal North Shore Hospital, Sydney, NSW, Australia
                [2 ] Department of Obstetrics and Gynecology, Bankstown-Lidcombe Hospital, Sydney, NSW, Australia
                [3 ] Department of Obstetrics and Gynaecology, Ryde Hospital, Sydney, NSW, Australia
                [4 ] Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan
                [5 ] Department of Public Health, China Medical University, Taichung, Taiwan
                [6 ] Centre for Advanced Reproductive Endosurgery, Sydney, NSW, Australia
                [7 ] School of Chinese Medicine, China Medical University, Taichung, Taiwan
                University of Insubria, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                ‡ These authors are co-first authors on this work.

                Author information
                https://orcid.org/0000-0002-0002-3208
                Article
                PONE-D-21-09322
                10.1371/journal.pone.0256772
                8389431
                34437644
                a2746fb5-6ee3-41ea-8358-8b9cfb3de29c
                © 2021 Lin et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 March 2021
                : 15 August 2021
                Page count
                Figures: 2, Tables: 4, Pages: 13
                Funding
                The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Epidemiology
                Medical Risk Factors
                Cancer Risk Factors
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                Clinical Medicine
                Clinical Immunology
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                Biology and Life Sciences
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