Dataset Information

The Pathogenesis of Endometriosis: Molecular and Cell Biology Insights.

ABSTRACT: The etiopathogenesis of endometriosis is a multifactorial process resulting in a heterogeneous disease. Considering that endometriosis etiology and pathogenesis are still far from being fully elucidated, the current review aims to offer a comprehensive summary of the available evidence. We performed a narrative review synthesizing the findings of the English literature retrieved from computerized databases from inception to June 2019, using the Medical Subject Headings (MeSH) unique ID term "Endometriosis" (ID:D004715) with "Etiology" (ID:Q000209), "Immunology" (ID:Q000276), "Genetics" (ID:D005823) and "Epigenesis, Genetic" (ID:D044127). Endometriosis may origin from Müllerian or non-Müllerian stem cells including those from the endometrial basal layer, Müllerian remnants, bone marrow, or the peritoneum. The innate ability of endometrial stem cells to regenerate cyclically seems to play a key role, as well as the dysregulated hormonal pathways. The presence of such cells in the peritoneal cavity and what leads to the development of endometriosis is a complex process with a large number of interconnected factors, potentially both inherited and acquired. Genetic predisposition is complex and related to the combined action of several genes with limited influence. The epigenetic mechanisms control many of the processes involved in the immunologic, immunohistochemical, histological, and biological aberrations that characterize the eutopic and ectopic endometrium in affected patients. However, what triggers such alterations is not clear and may be both genetically and epigenetically inherited, or it may be acquired by the particular combination of several elements such as the persistent peritoneal menstrual reflux as well as exogenous factors. The heterogeneity of endometriosis and the different contexts in which it develops suggest that a single etiopathogenetic model is not sufficient to explain its complex pathobiology.

SUBMITTER: Lagana AS

PROVIDER: S-EPMC6888544 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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The Pathogenesis of Endometriosis: Molecular and Cell Biology Insights.

Laganà Antonio Simone AS Garzon Simone S Götte Martin M Viganò Paola P Franchi Massimo M Ghezzi Fabio F Martin Dan C DC

International journal of molecular sciences 20191110 22

The etiopathogenesis of endometriosis is a multifactorial process resulting in a heterogeneous disease. Considering that endometriosis etiology and pathogenesis are still far from being fully elucidated, the current review aims to offer a comprehensive summary of the available evidence. We performed a narrative review synthesizing the findings of the English literature retrieved from computerized databases from inception to June 2019, using the Medical Subject Headings (MeSH) unique ID term "End ...[more]

PMID: 31717614

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Project description:Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo- or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosis-associated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinum-resistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future.

Project description:We provide the first analysis and synthesis of the evolutionary and mechanistic bases for risk of endometriosis in humans, structured around Niko Tinbergen's four questions about phenotypes: phylogenetic history, development, mechanism and adaptive significance. Endometriosis, which is characterized by the proliferation of endometrial tissue outside of the uterus, has its phylogenetic roots in the evolution of three causally linked traits: (1) highly invasive placentation, (2) spontaneous rather than implantation-driven endometrial decidualization and (3) frequent extensive estrogen-driven endometrial proliferation and inflammation, followed by heavy menstrual bleeding. Endometriosis is potentiated by these traits and appears to be driven, proximately, by relatively low levels of prenatal and postnatal testosterone. Testosterone affects the developing hypothalamic-pituitary-ovarian (HPO) axis, and at low levels, it can result in an altered trajectory of reproductive and physiological phenotypes that in extreme cases can mediate the symptoms of endometriosis. Polycystic ovary syndrome, by contrast, is known from previous work to be caused primarily by high prenatal and postnatal testosterone, and it demonstrates a set of phenotypes opposite to those found in endometriosis. The hypothesis that endometriosis risk is driven by low prenatal testosterone, and involves extreme expression of some reproductive phenotypes, is supported by a suite of evidence from genetics, development, endocrinology, morphology and life history. The hypothesis also provides insights into why these two diametric, fitness-reducing disorders are maintained at such high frequencies in human populations. Finally, the hypotheses described and evaluated here lead to numerous testable predictions and have direct implications for the treatment and study of endometriosis. Lay summary: Endometriosis is caused by endometrial tissue outside of the uterus. We explain why and how humans are vulnerable to this disease, and new perspectives on understanding and treating it. Endometriosis shows evidence of being caused in part by relatively low testosterone during fetal development, that 'programs' female reproductive development. By contrast, polycystic ovary syndrome is associated with relatively high testosterone in prenatal development. These two disorders can thus be seen as 'opposite' to one another in their major causes and correlates. Important new insights regarding diagnosis, study and treatment of endometriosis follow from these considerations.

Dataset Information

The Pathogenesis of Endometriosis: Molecular and Cell Biology Insights.

Publications

The Pathogenesis of Endometriosis: Molecular and Cell Biology Insights.

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