Endometriosis and Uterine Fibroids (Leiomyomata): Comorbidity, Risks and Implications

Uimari, Outi; Nazri, H M; Tapmeier, Thomas T.

doi:10.3389/frph.2021.750018

Cited by 18 publications

(10 citation statements)

References 66 publications

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“…Two endometriosis patients in the study family had been diagnosed with uterine leiomyoma (UL), and UL was suspected in one additional individual. Endometriosis and UL are both common, and their comorbidity has been shown in observational studies [ 50 ]. There is also genetic evidence linking these conditions.…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing reveals candidate high-risk susceptibility genes for endometriosis

Nousiainen,

Kuismin,

Reinikka

et al. 2023

Hum Genomics

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Background Endometriosis is a common, chronic disease among fertile-aged women. Disease course may be highly invasive, requiring extensive surgery. The etiology of endometriosis remains elusive, though a high level of heritability is well established. Several low-penetrance predisposing loci have been identified, but high-risk susceptibility remains undetermined. Endometriosis is known to increase the risk of epithelial ovarian cancers, especially of endometrioid and clear cell types. Here, we have analyzed a Finnish family where four women have been diagnosed with surgically verified, severely symptomatic endometriosis and two of the patients also with high-grade serous carcinoma. Results Whole-exome sequencing revealed three rare candidate predisposing variants segregating with endometriosis. The variants were c.1238C>T, p.(Pro413Leu) in FGFR4, c.5065C>T, p.(Arg1689Trp) in NALCN, and c.2086G>A, p.(Val696Met) in NAV2. The only variant predicted deleterious by in silico tools was the one in FGFR4. Further screening of the variants in 92 Finnish endometriosis and in 19 endometriosis–ovarian cancer patients did not reveal additional carriers. Histopathology, positive p53 immunostaining, and genetic analysis supported the high-grade serous subtype of the two tumors in the family. Conclusions Here, we provide FGFR4, NALCN, and NAV2 as novel high-risk candidate genes for familial endometriosis. Our results also support the association of endometriosis with high-grade serous carcinoma. Further studies are required to validate the findings and to reveal the exact pathogenesis mechanisms of endometriosis. Elucidating the genetic background of endometriosis defines the etiology of the disease and provides opportunities for expedited diagnostics and personalized treatments.

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Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing reveals candidate high-risk susceptibility genes for endometriosis

Nousiainen,

Kuismin,

Reinikka

et al. 2023

Hum Genomics

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“…While HMB was historically given as a blood loss of more than 80 mL per day ( 2 )—a definition not considered useful any longer given the large variation in women's physique and the fact that most women who seek treatment for HMB do not actually meet this criterion ( 3 )—HMB is now defined as “excessive menstrual blood loss which interferes with a woman's physical, social, emotional and/or material quality of life” ( 1 ). It can occur on its own or in combination with other symptoms such as acute and chronic pelvic pain, or infertility ( 4 ). The severity can be estimated by self-reporting in questionnaires ( 5 ).…”

Section: Heavy Menstrual Bleeding and Uterine Fibroidsmentioning

confidence: 99%

“…Despite the name, fibroids largely comprise of myocytes rather than fibroblasts and are characterized by the excessive deposition of extracellular matrix substances, mainly collagen, within the tumor ( 7 ). The bulk growth of this extremely dense tissue leads an enlarged and deformed uterus and to some of the key symptoms associated with uterine fibroids in addition to HMB such as pressure symptoms, abdominal pain, and infertility ( 4 , 6 ). In the United States, fibroids are cited to be the cause for over 50% of hysterectomies ( 8 ), and direct costs for their treatment is estimated between 4 and 9 billion USD ( 9 ).…”

Section: Heavy Menstrual Bleeding and Uterine Fibroidsmentioning

confidence: 99%

“…With a comprehensive treatment plan lacking ( 6 ), current treatment of uterine fibroids largely provides symptomatic control. Treatment options are dictated by patient compliance, age, fertility preservation, and other common (co)morbidities such as endometriosis, adenomyosis, endometrial polyps, and endometrial hyperplasia that cause overlapping symptoms [pain and abnormal uterine bleeding ( 4 )]. Follow-up evaluations of the tumor growth rate are recommended for asymptomatic fibroids by most evidence-based guidelines ( 18 ).…”

Section: Clinical Considerations and Treatment Optionsmentioning

confidence: 99%

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Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding

Uimari

Subramaniam

Vollenhoven

et al. 2022

Front. Reprod. Health

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Uterine Fibroids, or leiomyomata, affect millions of women world-wide, with a high incidence of 75% within women of reproductive age. In ~30% of patients, uterine fibroids cause menorrhagia, or heavy menstrual bleeding, and more than half of the patients experience symptoms such as heavy menstrual bleeding, pelvic pain, or infertility. Treatment is symptomatic with limited options including hysterectomy as the most radical solution. The genetic foundations of uterine fibroid growth have been traced to somatic driver mutations (MED12, HMGA2, FH−/−, and COL4A5-A6). These also lead to downstream expression of angiogenic factors including IGF-1 and IGF-2, as opposed to the VEGF-driven mechanism found in the angiogenesis of hypoxic tumors. The resulting vasculature supplying the fibroid with nutrients and oxygen is highly irregular. Of particular interest is the formation of a pseudocapsule around intramural fibroids, a unique structure within tumor angiogenesis. These aberrations in vascular architecture and network could explain the heavy menstrual bleeding observed. However, other theories have been proposed such as venous trunks, or venous lakes caused by the blocking of normal blood flow by uterine fibroids, or the increased local action of vasoactive growth factors. Here, we review and discuss the evidence for the various hypotheses proposed.

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“…Women with endometriosis often experience severe menstrual and non-menstrual pain involving the lower abdomen, pelvis or lumbosacral region, deep dyspareunia, dyschezia, and dysuria ( Uimari et al , 2021 ) and infertility in 30–50% of cases ( Prescott et al , 2016 ). Patients with endometriosis suffer from chronic fatigue ( Ramin-Wright et al , 2018 ) and are at a higher risk of psychiatric disturbances (56.4%) than those without endometriosis (43.6%) ( Pope et al , 2015 ).…”

Section: Introductionmentioning

confidence: 99%

The role of small extracellular vesicle-miRNAs in endometriosis

Nazri,

Greaves,

Quenby

et al. 2023

Human Reproduction

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Endometriosis is defined by the presence of extrauterine endometrial-like tissue, which can cause pain and infertility in 10% of reproductive-age women. To date, the pathogenesis is poorly understood resulting in significant diagnostic delays and poor therapeutic outcomes in many women. Small extracellular vesicles (sEVs) (<200 nm) are cell-derived vesicles containing molecules that can influence gene expression and behaviour in target cells. One such cargo are microRNAs (miRNAs), which are short, non-coding RNAs mostly 19–25 nucleotides in length that regulate post-transcriptional gene expression. This mini-review focuses on the role of sEV-miRNAs, which are conceivably better biomarkers for endometriosis than free miRNAs, which reflect the true pathophysiological state in the body, as sEV-encapsulated miRNAs are protected from degradation compared to free miRNA and provide direct cell-to-cell communication via sEV surface proteins. sEV-miRNAs have been implicated in the immunomodulation of macrophages, the proliferation, migration and invasion of endometrial cells, and angiogenesis, all hallmarks of endometriosis. The diagnostic potential of sEV-miRNA was investigated in one study that reported the sensitivity and specificity of two sEV-miRNAs (hsa-miR-22-3p and hsa-miR-320a-3p) in distinguishing endometriosis from non-endometriosis cases. Only three studies have explored the therapeutic potential of sEV-miRNAs in vivo in mice—two looked into the role of sEV-hsa-miR-214-3p in decreasing fibrosis, and one investigated sEV-hsa-miR-30c-5p in suppressing the invasive and migratory potential of endometriotic lesions. While early results are encouraging, studies need to further address the potential influence of factors such as the menstrual cycle as well as the location and extent of endometriotic lesions on miRNA expression in sEVs. Given these findings, and extrapolating from other conditions such as cancer, diabetes, and pre-eclampsia, sEV-miRNAs could present an attractive and urgently needed future diagnostic and therapeutic target for millions of women suffering from endometriosis. However, research in this area is hampered by lack of adherence to the International Society for Extracellular Vesicles 2018 guideline in separating and characterising sEVs, as well as the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project protocols.

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Endometriosis and Uterine Fibroids (Leiomyomata): Comorbidity, Risks and Implications

Cited by 18 publications

References 66 publications

Whole-exome sequencing reveals candidate high-risk susceptibility genes for endometriosis

Whole-exome sequencing reveals candidate high-risk susceptibility genes for endometriosis

Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding

The role of small extracellular vesicle-miRNAs in endometriosis

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