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Seminars in Reproductive Medicine May 2020Adenomyosis is a common disorder of the uterus, and is associated with an enlarged uterus, heavy menstrual bleeding (HMB), pelvic pain, and infertility. It is... (Review)
Review
Adenomyosis is a common disorder of the uterus, and is associated with an enlarged uterus, heavy menstrual bleeding (HMB), pelvic pain, and infertility. It is characterized by endometrial epithelial cells and stromal fibroblasts abnormally found in the myometrium where they elicit hyperplasia and hypertrophy of surrounding smooth muscle cells. While both the mechanistic processes and the pathogenesis of adenomyosis are uncertain, several theories have been put forward addressing how this disease develops. These include intrinsic or induced (1) microtrauma of the endometrial-myometrial interface; (2) enhanced invasion of endometrium into myometrium; (3) metaplasia of stem cells in myometrium; (4) infiltration of endometrial cells in retrograde menstrual effluent into the uterine wall from the serosal side; (5) induction of adenomyotic lesions by aberrant local steroid and pituitary hormones; and (6) abnormal uterine development in response to genetic and epigenetic modifications. Dysmenorrhea, HMB, and infertility are likely results of inflammation, neurogenesis, angiogenesis, and contractile abnormalities in the endometrial and myometrial components. Elucidating mechanisms underlying the pathogenesis of adenomyosis raise possibilities to develop targeted therapies to ameliorate symptoms beyond the current agents that are largely ineffective. Herein, we address these possible etiologies and data that support underlying mechanisms.
Topics: Adenomyosis; Animals; Cell Movement; Dysmenorrhea; Endometrium; Female; Humans; Infertility, Female; Menorrhagia; Myometrium
PubMed: 33032339
DOI: 10.1055/s-0040-1716687 -
Endocrine Reviews Jul 2022Uterine fibroids are benign monoclonal neoplasms of the myometrium, representing the most common tumors in women worldwide. To date, no long-term or noninvasive... (Review)
Review
Uterine fibroids are benign monoclonal neoplasms of the myometrium, representing the most common tumors in women worldwide. To date, no long-term or noninvasive treatment option exists for hormone-dependent uterine fibroids, due to the limited knowledge about the molecular mechanisms underlying the initiation and development of uterine fibroids. This paper comprehensively summarizes the recent research advances on uterine fibroids, focusing on risk factors, development origin, pathogenetic mechanisms, and treatment options. Additionally, we describe the current treatment interventions for uterine fibroids. Finally, future perspectives on uterine fibroids studies are summarized. Deeper mechanistic insights into tumor etiology and the complexity of uterine fibroids can contribute to the progress of newer targeted therapies.
Topics: Female; Humans; Leiomyoma; Myometrium; Risk Factors; Uterine Neoplasms
PubMed: 34741454
DOI: 10.1210/endrev/bnab039 -
Nature Apr 2023The relationship between the human placenta-the extraembryonic organ made by the fetus, and the decidua-the mucosal layer of the uterus, is essential to nurture and...
The relationship between the human placenta-the extraembryonic organ made by the fetus, and the decidua-the mucosal layer of the uterus, is essential to nurture and protect the fetus during pregnancy. Extravillous trophoblast cells (EVTs) derived from placental villi infiltrate the decidua, transforming the maternal arteries into high-conductance vessels. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia. Here we have generated a spatially resolved multiomics single-cell atlas of the entire human maternal-fetal interface including the myometrium, which enables us to resolve the full trajectory of trophoblast differentiation. We have used this cellular map to infer the possible transcription factors mediating EVT invasion and show that they are preserved in in vitro models of EVT differentiation from primary trophoblast organoids and trophoblast stem cells. We define the transcriptomes of the final cell states of trophoblast invasion: placental bed giant cells (fused multinucleated EVTs) and endovascular EVTs (which form plugs inside the maternal arteries). We predict the cell-cell communication events contributing to trophoblast invasion and placental bed giant cell formation, and model the dual role of interstitial EVTs and endovascular EVTs in mediating arterial transformation during early pregnancy. Together, our data provide a comprehensive analysis of postimplantation trophoblast differentiation that can be used to inform the design of experimental models of the human placenta in early pregnancy.
Topics: Female; Humans; Pregnancy; Cell Movement; Multiomics; Placenta; Pregnancy Trimester, First; Trophoblasts; Decidua; Maternal-Fetal Relations; Single-Cell Analysis; Myometrium; Cell Differentiation; Organoids; Stem Cells; Transcriptome; Transcription Factors; Cell Communication
PubMed: 36991123
DOI: 10.1038/s41586-023-05869-0 -
Ultrasound in Obstetrics & Gynecology :... Jul 2022To evaluate whether the Morphological Uterus Sonographic Assessment (MUSA) features of adenomyosis need to be better defined and, if deemed necessary, to reach consensus...
OBJECTIVES
To evaluate whether the Morphological Uterus Sonographic Assessment (MUSA) features of adenomyosis need to be better defined and, if deemed necessary, to reach consensus on the updated definitions.
METHODS
A modified Delphi procedure was performed among European gynecologists with expertise in ultrasound diagnosis of adenomyosis. To identify MUSA features that might need revision, 15 two-dimensional (2D) video recordings (four recordings also included three-dimensional (3D) still images) of transvaginal ultrasound (TVS) examinations of the uterus were presented in the first Delphi round (online questionnaire). Experts were asked to confirm or refute the presence of each of the nine MUSA features of adenomyosis (described in the original MUSA consensus statement) in each of the 15 videoclips and to provide comments. In the second Delphi round (online questionnaire), the results of the first round and suggestions for revision of MUSA features were shared with the experts before they were asked to assess a new set of 2D and 3D still images of TVS examinations and to provide feedback on the proposed revisions. A third Delphi round (virtual group meeting) was conducted to discuss and reach final consensus on revised definitions of MUSA features. Consensus was predefined as at least 66.7% agreement between experts.
RESULTS
Of 18 invited experts, 16 agreed to participate in the Delphi procedure. Eleven experts completed and four experts partly finished the first round. The experts identified a need for more detailed definitions of some MUSA features. They recommended use of 3D ultrasound to optimize visualization of the junctional zone. Fifteen experts participated in the second round and reached consensus on the presence or absence of ultrasound features of adenomyosis in most of the still images. Consensus was reached for all revised definitions except those for subendometrial lines and buds and interrupted junctional zone. Thirteen experts joined the online meeting, in which they discussed and agreed on final revisions of the MUSA definitions. There was consensus on the need to distinguish between direct features of adenomyosis, i.e. features indicating presence of ectopic endometrial tissue in the myometrium, and indirect features, i.e. features reflecting changes in the myometrium secondary to presence of endometrial tissue in the myometrium. Myometrial cysts, hyperechogenic islands and echogenic subendometrial lines and buds were classified unanimously as direct features of adenomyosis. Globular uterus, asymmetrical myometrial thickening, fan-shaped shadowing, translesional vascularity, irregular junctional zone and interrupted junctional zone were classified as indirect features of adenomyosis.
CONCLUSION
Consensus between gynecologists with expertise in ultrasound diagnosis of adenomyosis was achieved regarding revised definitions of the MUSA features of adenomyosis and on the classification of MUSA features as direct or indirect signs of adenomyosis. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Adenomyosis; Delphi Technique; Female; Humans; Musa; Myometrium; Pregnancy; Ultrasonography; Uterus
PubMed: 34587658
DOI: 10.1002/uog.24786 -
Human Reproduction (Oxford, England) Sep 2022What are the cellular composition and single-cell transcriptomic differences between myometrium and leiomyomas as defined by single-cell RNA sequencing?
STUDY QUESTION
What are the cellular composition and single-cell transcriptomic differences between myometrium and leiomyomas as defined by single-cell RNA sequencing?
SUMMARY ANSWER
We discovered cellular heterogeneity in smooth muscle cells (SMCs), fibroblast and endothelial cell populations in both myometrium and leiomyoma tissues.
WHAT IS KNOWN ALREADY
Previous studies have shown the presence of SMCs, fibroblasts, endothelial cells and immune cells in myometrium and leiomyomas. However, there is no information on the cellular heterogeneity in these tissues and the transcriptomic differences at the single-cell level between these tissues.
STUDY DESIGN, SIZE, DURATION
We collected five leiomyoma and five myometrium samples from a total of eight patients undergoing hysterectomy. We then performed single-cell RNA sequencing to generate a cell atlas for both tissues. We utilized our single-cell sequencing data to define cell types, compare cell types by tissue type (leiomyoma versus myometrium) and determine the transcriptional changes at a single-cell resolution between leiomyomas and myometrium. Additionally, we performed MED12-variant analysis at the single-cell level to determine the genotype heterogeneity within leiomyomas.
PARTICIPANTS/MATERIALS, SETTING, METHODS
We collected five MED12-variant positive leiomyomas and five myometrium samples from a total of eight patients. We then performed single-cell RNA sequencing on freshly isolated single-cell preparations. Histopathological assessment confirmed the identity of the samples. Sanger sequencing was performed to confirm the presence of the MED12 variant in leiomyomas.
MAIN RESULTS AND ROLE OF CHANCE
Our data revealed previously unknown heterogeneity in the SMC, fibroblast cell and endothelial cell populations of myometrium and leiomyomas. We discovered the presence of two different lymphatic endothelial cell populations specific to uterine leiomyomas. We showed that both myometrium and MED12-variant leiomyomas are relatively similar in cellular composition but differ in cellular transcriptomic profiles. We found that fibroblasts influence the leiomyoma microenvironment through their interactions with endothelial cells, immune cells and SMCs. Variant analysis at the single-cell level revealed the presence of both MED12 variants as well as the wild-type MED12 allele in SMCs of leiomyomatous tissue. These results indicate genotype heterogeneity of cellular composition within leiomyomas.
LARGE SCALE DATA
The datasets are available in the NCBI Gene Expression Omnibus (GEO) using GSE162122.
LIMITATIONS, REASONS FOR CAUTION
Our study focused on MED12-variant positive leiomyomas for single-cell RNA sequencing analyses. Leiomyomas carrying other genetic rearrangements may differ in their cellular composition and transcriptomic profiles.
WIDER IMPLICATIONS FOR THE FINDINGS
Our study provides a cellular atlas for myometrium and MED12-variant positive leiomyomas as defined by single-cell RNA sequencing. Our analysis provides significant insight into the differences between myometrium and leiomyomas at the single-cell level and reveals hitherto unknown genetic heterogeneity in multiple cell types within human leiomyomas. Our results will be important for future studies into the origin and growth of human leiomyomas.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by funding from the National Institute of Child Health and Human Development (HD098580 and HD088629). The authors declare no competing interests.
Topics: Endothelial Cells; Female; Humans; Leiomyoma; Mutation; Myometrium; Single-Cell Analysis; Tumor Microenvironment; Uterine Neoplasms
PubMed: 36001050
DOI: 10.1093/humrep/deac183 -
American Journal of Obstetrics and... Sep 2022Placenta accreta has been described as a spectrum of abnormal attachment of villous tissue to the uterine wall, ranging from superficial attachment to the inner... (Review)
Review
Placenta accreta has been described as a spectrum of abnormal attachment of villous tissue to the uterine wall, ranging from superficial attachment to the inner myometrium without interposing decidua to transmural invasion through the entire uterine wall and beyond. These descriptions have prevailed for more than 50 years and form the basis for the diagnosis and grading of accreta placentation. Accreta placentation is essentially the consequence of uterine remodeling after surgery, primarily after cesarean delivery. Large cesarean scar defects in the lower uterine segment are associated with failure of normal decidualization and loss of the subdecidual myometrium. These changes allow the placental anchoring villi to implant, and extravillous trophoblast cells to migrate, close to the serosal surface of the uterus. These microscopic features are central to the misconception that the accreta placental villous tissue is excessively invasive and have led to much confusion and heterogeneity in clinical data. Progressive recruitment of large arteries in the uterine wall, that is, helicine, arcuate, and/or radial arteries, results in high-velocity maternal blood entering the intervillous space from the first trimester of pregnancy and subsequent formation of placental lacunae. Recently, guided sampling of accreta areas at delivery has enabled accurate correlation of prenatal imaging data with intraoperative features and histopathologic findings. In more than 70% of samples, there were thick fibrinoid depositions between the tip of most anchoring villi and the underlying uterine wall and around all deeply implanted villi. The distortion of the uteroplacental interface by these dense depositions and the loss of the normal plane of separation are the main factors leading to abnormal placental attachment. These data challenged the classical concept that placenta accreta is simply owing to villous tissue sitting atop the superficial myometrium without interposed decidua. Moreover, there is no evidence in accreta placentation that the extravillous trophoblast is abnormally invasive or that villous tissue can cross the uterine serosa into the pelvis. It is the size of the scar defect, the amount of placental tissue developing inside the scar, and the residual myometrial thickness in the scar area that determine the distance between the placental basal plate and the uterine serosa and thus the risk of accreta placentation.
Topics: Cicatrix; Female; Humans; Myometrium; Placenta; Placenta Accreta; Placentation; Pregnancy
PubMed: 35248577
DOI: 10.1016/j.ajog.2022.02.038 -
Archives of Gynecology and Obstetrics Jul 2023Adenomyosis is identified by the enlargement of the uterus secondary to such areas of the endometrium as the endometrial glands and stroma located deep in the... (Review)
Review
Adenomyosis is identified by the enlargement of the uterus secondary to such areas of the endometrium as the endometrial glands and stroma located deep in the myometrium, which causes its hyperplasia and hypertrophy. The most common signs of the development of adenomyosis in a patient are copious menstrual bleeding and dysmenorrhea. However, it should be borne in mind that in some patients, the disease may be asymptomatic. Despite the wide abundance of imaging and other diagnostic methods for diagnosing adenomyosis, there are currently no standard verified diagnostic criteria for pathologists. In addition, women with adenomyosis often have other concomitant gynaecological diseases, such as endometriosis or leiomyomas, which makes it difficult to diagnose and choose the optimal treatment for patients. Therefore, the purpose of this study was to highlight up-to-date and relevant information for the practitioner about the epidemiology, clinical manifestations, diagnostics and treatment options for adenomyosis. Sources from four databases (PubMed, Web of Science, Elsevier and Google Scholar) were used to search for data. As a result of a literature review, it was established that the "gold" standard for the diagnostics of adenomyosis is histological research methods, in particular, biopsy performed during hysteroscopy or laparoscopy, whereas imaging methods (transvaginal sonography, magnetic resonance imaging) are more often used for differential diagnostics of adenomyosis with other diseases. In addition, magnetic resonance imaging allows for a better differential diagnostics between adenomyosis and myomatosis and helps to recognise the disease at an early stage. Regarding treatment, there is currently no particular therapy and algorithms for the treatment of adenomyosis, which is primarily due to the lack of precise criteria for the diagnostics of the disease. However, the most effective therapeutic methods at the present stage are the use of aromatase inhibitors and gonadotropin-releasing hormone antagonists, whilst minimally invasive techniques, in particular, endometrial ablation and uterine artery embolisation, are becoming increasingly popular amongst surgical techniques.
Topics: Humans; Female; Adenomyosis; Uterus; Myometrium; Endometriosis; Endometrium
PubMed: 37060397
DOI: 10.1007/s00404-023-06982-1 -
Human Reproduction Update Apr 2020Adenomyosis is a benign uterine disorder where endometrial glands and stroma are pathologically demonstrated within the uterine myometrium. The pathogenesis involves sex... (Review)
Review
BACKGROUND
Adenomyosis is a benign uterine disorder where endometrial glands and stroma are pathologically demonstrated within the uterine myometrium. The pathogenesis involves sex steroid hormone abnormalities, inflammation, fibrosis and neuroangiogenesis, even though the proposed mechanisms are not fully understood. For many years, adenomyosis has been considered a histopathological diagnosis made after hysterectomy, classically performed in perimenopausal women with abnormal uterine bleeding (AUB) or pelvic pain. Until recently, adenomyosis was a clinically neglected condition. Nowadays, adenomyosis may also be diagnosed by non-invasive techniques, because of imaging advancements. Thus, a new epidemiological scenario has developed with an increasing number of women of reproductive age with ultrasound (US) or magnetic resonance imaging (MRI) diagnosis of adenomyosis. This condition is associated with a wide variety of symptoms (pelvic pain, AUB and/or infertility), but it is also recognised that some women are asymptomatic. Furthermore, adenomyosis often coexists with other gynecological comorbidities, such as endometriosis and uterine fibroids, and the diagnostic criteria are still not universally agreed. Therefore, the diagnostic process for adenomyosis is challenging.
OBJECTIVE AND RATIONALE
We present a comprehensive review on the diagnostic criteria of adenomyosis, including clinical signs and symptoms, ultrasound and MRI features and histopathological aspects of adenomyotic lesions. We also briefly summarise the relevant theories on adenomyosis pathogenesis, in order to provide the pathophysiological background to understand the different phenotypes and clinical presentation. The review highlights the controversies of multiple existing criteria, summarising all of the available evidences on adenomyosis diagnosis. The review aims also to underline the future perspective for diagnosis, stressing the importance of an integrated clinical and imaging approach, in order to identify this gynecological disease, so often underdiagnosed.
SEARCH METHODS
PubMed and Google Scholar were searched for all original and review articles related to diagnosis of adenomyosis published in English until October 2018.
OUTCOMES
The challenge in diagnosing adenomyosis starts with the controversies in the available pathogenic theories. The difficulties in understanding the way the disease arises and progresses have an impact also on the specific diagnostic criteria to use for a correct identification. Currently, the diagnosis of adenomyosis may be performed by non-invasive methods and the clinical signs and symptoms, despite their heterogeneity and poor specificity, may guide the clinician for a suspicion of the disease. Imaging techniques, including 2D and 3D US as well as MRI, allow the proper identification of the different phenotypes of adenomyosis (diffuse and/or focal). From a histological point of view, if the diagnosis of diffuse adenomyosis is straightforward, in more limited disease, the diagnosis has poor inter-observer reproducibility, leading to extreme variations in the prevalence of disease. Therefore, an integrated non-invasive diagnostic approach, considering risk factors profile, clinical symptoms, clinical examination and imaging, is proposed to adequately identify and characterise adenomyosis.
WIDER IMPLICATIONS
The development of the diagnostic tools allows the physicians to make an accurate diagnosis of adenomyosis by means of non-invasive techniques, representing a major breakthrough, in the light of the clinical consequences of this disease. Furthermore, this technological improvement will open a new epidemiological scenario, identifying different groups of women, with a dissimilar clinical and/or imaging phenotypes of adenomyosis, and this should be object of future research.
Topics: Adenomyosis; Endometriosis; Endometrium; Female; Humans; Leiomyoma; Magnetic Resonance Imaging; Myometrium; Pelvic Pain; Prevalence; Reproducibility of Results; Sensitivity and Specificity; Ultrasonography; Uterine Diseases; Uterine Hemorrhage
PubMed: 32097456
DOI: 10.1093/humupd/dmz049 -
Journal of Clinical Ultrasound : JCU 2023Uterine Arteriovenous malformations (AVM) are vascular disorders characterized by complex high-flow tangles of abnormal vessels connecting arteries and veins with... (Review)
Review
Uterine Arteriovenous malformations (AVM) are vascular disorders characterized by complex high-flow tangles of abnormal vessels connecting arteries and veins with bypassing capillaries. Recently, the terminology applied to describe uterine AVMs has been modified. Most AVMs are acquired. The term enhanced myometrial vascularity (EMV) is used to describe any condition in which any uterine pathology may lead to increased myometrial vascularity regardless of the absence or presence of residual tissue of gestation.
Topics: Female; Humans; Arteriovenous Malformations; Myometrium; Uterus; Methotrexate; Vascular Diseases
PubMed: 37285167
DOI: 10.1002/jcu.23495 -
The Journal of Steroid Biochemistry and... Nov 2023During pregnancy, the primary function of the uterus is to be quiescent and not contract, which allows the growing fetus to develop and mature. A uterine muscle layer,... (Review)
Review
During pregnancy, the primary function of the uterus is to be quiescent and not contract, which allows the growing fetus to develop and mature. A uterine muscle layer, myometrium, is composed of smooth muscle cells (SMCs). Before the onset of labor contractions, the uterine SMCs experience a complex biochemical and molecular transformation involving the expression of contraction-associated proteins. Labor is initiated when genes in SMCs are activated in response to a combination of hormonal, inflammatory and mechanical signals. In this review, we provide an overview of molecular mechanisms regulating the process of parturition in humans, focusing on the hormonal control of the myometrium, particularly the steroid hormone progesterone. The primary reason for discussing the regulation of myometrial contractility by progesterone is the importance of the clinical problem of preterm birth. It is thought that the hormonal mechanisms regulating premature uterine contractions represent an untimely triggering of the normal events occurring during term parturition. Yet, our knowledge of the complex and redundant hormonal pathways controlling uterine contractile activity leading to delivery of the neonate remains incomplete. Finally, we introduce recent animal studies using a novel class of drugs, Selective Progesterone Receptor Modulators, targeting progesterone signaling to prevent premature myometrial contractions.
Topics: Infant, Newborn; Pregnancy; Animals; Female; Humans; Progesterone; Myometrium; Premature Birth; Parturition; Labor, Obstetric; Receptors, Progesterone
PubMed: 37683774
DOI: 10.1016/j.jsbmb.2023.106397