Materiały źródłowe

• #1 Adenomyosis: Mechanisms and Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7932680/

  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.

• #2 Thieme E-Journals – Seminars in Reproductive Medicine / Abstract

  https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0040-1716687

  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.

• #3 Uterine adenomyosis – UpToDate

  https://www.uptodate.com/contents/uterine-adenomyosis

  Uterine adenomyosis is a disorder in which endometrial glands and stroma are present within the myometrium (uterine musculature), resulting in hypertrophy of the surrounding myometrium. […] Historically the diagnosis of adenomyosis was made retrospectively and based solely on histologic assessment of hysterectomy specimens. However, the diagnosis is now made by imaging-based criteria using transvaginal ultrasonography (TVUS) and/or magnetic resonance imaging (MRI) which has resulted in a greater understanding of the disease, its prevalence, effect on younger patients and patients with reproductive dysfunction, and treatment options.

• #4

  https://link.springer.com/article/10.1007/s13669-022-00326-7

  In order to explain the migration of endometrial cells and development of adenomyotic lesions within the myometrium, at least three theories are currently debated: a invasion from inside, b metaplasia of displaced embryonic pluripotent Mullerian remnants or adult stem cells, or c invasion from outside. […] In order to invade the myometrium, endometrial cells undergo a series of pathogenic processes which involve endocrine (gonadal sex steroid hormones), immune (inflammation), vascular (neoangiogenesis), and neuronal (neurogenesis) mechanisms. […] Several mechanisms are involved in the pathogenesis of adenomyosis: impaired gonadal sex steroids hormones receptors function, altered cell proliferation and differentiation, inflammatory reaction, processes of neuroangiogenesis and fibrosis. […] Adenomyosis is promoted by an imbalance between estrogens and progesterone signaling in women during reproductive life.

• #5 Adenomyosis: Mechanisms and Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7932680/

  The invagination theory of adenomyosis development has been proposed to result from altered endometrial basalis cells or cell groups invading into the myometrium, crossing an injured or abnormal junctional zone, and subsequently establishing ectopic adenomyotic lesions and inducing hypotrophy and dysfunction of myocytes in the IM and OM. In support of this hypothesis are the clinical observations that adenomyosis risk increases with repeated sharp endometrial curettage, cesarean delivery, and prior uterine surgery wherein the EMI is breached. Studies demonstrating enhanced endometrial cell migration, proliferation, epithelial-to-mesenchymal transition (EMT), and resistance to apoptosis and dysregulation of extracellular matrix function in eutopic endometrium of women with adenomyosis compared with controls support mechanistic underpinnings of the invagination theory and are presented later.

• #6 Pathogenesis of Human Adenomyosis: Current Understanding and Its Association with Infertility

  https://www.mdpi.com/2077-0383/11/14/4057

  The aim of this review article was to summarize our current understanding on the etiologies and pathogenesis of human adenomyosis and to clarify the relative association between adenomyosis and infertility. The exact pathogenesis of adenomyosis is still elusive. Among different reported concepts, direction invagination of gland cells from the basalis endometrium deep into myometrium is the most widely accepted opinion on the development of adenomyosis. […] Several theories supporting the pathogenesis of adenomyosis have been advocated since the etiology of this condition has remained unclear for more than a half-century. Among them, the two most common and widely accepted theories that have been postulated are invagination of the basalis endometrium into the myometrium and de novo origin from the metaplasia of embryonic Mϋllerian remnants or of endometrial stem/progenitor cells with the myometrium. A panel of mechanisms has been reported, indicating tissue damage or injury at the endometrial-myometrial interface (EMI), leading to inflammation, local estrogen production and development of adenomyosis.

• #7 Exploring the Endocrine Mechanisms in Adenomyosis: From Pathogenesis to Therapies

  https://www.mdpi.com/2673-396X/5/1/4

  Even though theories have emerged to clarify the mechanisms driving ADM development, none of them have been accepted yet. The three theories proposed are (a) the invagination of basalis endometrial cells in the myometrium caused by the activation of tissue injury and repair (TIAR) mechanism, (b) metaplasia from Mullerian rests, and (c) retrograde menstruation of adult stem cells. […] The prevailing hypothesis suggests that the endometrial myometrial junction zone (JZ), susceptible to steroid hormonal influences, undergoes trauma from myometrial contractions. […] This biomechanical stress leads to the localized release of additional estrogen. […] Evidence shows that, due to the injury at the JZ, inflammatory cascade reactions will lead to the elevation of interleukin 1B (IL-1B). […] This local elevation in IL-1B subsequently triggers the production of prostaglandin E2 (PGE2) by cyclooxygenase-2 (COX-2).

• #8 Pathogenesis of Human Adenomyosis: Current Understanding and Its Association with Infertility

  https://www.mdpi.com/2077-0383/11/14/4057

  The exact etiology of adenomyosis is currently unclear. Several theories for its development have been proposed, including direct invasion of basalis endometrial cells deep into the myometrium as a result of activation of tissue injury and repair (TIAR) mechanism, metaplasia of displaced embryonic pluripotent Mϋllerian remnants, and differentiation of embryonic stem/progenitor cells. […] Local estrogen production in the eutopic and ectopic endometrium of patients with adenomyosis may play a central role in the etiology of adenomyosis. A state of hyperestrogenism, resulting from increased local aromatization and decreased local estrogen metabolism in the eutopic and ectopic endometria of patients with adenomyosis, has been reported. […] A line of evidence demonstrated that the healing process after cyclic tissue injury at EMI can be mediated by the occurrence of tissue hypoxia. Repetitive tissue injury causes disruption of local vasculature and extravasation of blood, leading to platelet aggregation and the formation of clots.

• #9 Pathology and Pathogenesis of Adenomyosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7987203/

  Adenomyosis represents a unique pathophysiological condition in which normal-appearing endometrial mucosa resides within myometrium and is thus protected from menstrual shedding. […] The pathogenesis of adenomyosis, especially the steps through which normal-appearing endometrial tissue is displaced to myometrium, and the mechanisms by which adenomyotic foci cause symptoms, remain largely unclear. Current evidence from histopathological observations and recent molecular genetic studies indicates that adenomyosis is derived from invagination from the basal layer of endometrium into adjacent myometrium, a modern view resonant with what Cullen proposed almost one century ago. […] This architecture of adenomyosis resembles that in the basal layer of endometrium. […] If this is the case, it would be different from that seen in carcinoma. If this were a bone fide invasion, both glandular epithelium and stroma would have to acquire a constellation of complex molecular and cellular changes including expression of proteases that degrade the extracellular matrix, enhanced motility, and the ability to comigrate and dissect into remarkably cohesive smooth muscle layers.

• #10 Pathology and Pathogenesis of Adenomyosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7987203/

  The aforementioned evidence supports that invagination of the endometrial basalis into the myometrium is the favored model for the genesis of adenomyosis, as both epithelial and stromal progenitor cells residing in basalis are responsible not only for regenerating the entire functional layer after menstruation but can also promote adenomyosis development in the opposite direction.

• #11 Pathology and Pathogenesis of Adenomyosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7987203/

  Moreover, adenomyosis does not exhibit a classical stromal reaction (desmoplasia), which is one of the hallmarks of tumor invasion under microscopic examination. Rather, we propose that the genesis of adenomyosis derives from an embryonic or an early postnatal invagination of the basal endometrium followed by extension deep into myometrium, likely associated with a physiological or pathological defect of the endometrialmyometrial junction. […] Despite the histopathological evidence, the tissue origin of adenomyosis from eutopic endometrium has only recently received molecular validation; the identification of somatic mutations using next-generation sequencing has provided unequivocal evidence that adenomyosis develops from eutopic endometrium. […] The study also showed that KRAS mutations were often shared by cooccurring adenomyosis and endometriotic lesions.

• #12 Adenomyosis – Wikipedia

  https://en.wikipedia.org/wiki/Adenomyosis

  Adenomyosis is a medical condition characterized by the growth of cells that proliferate on the inside of the uterus (endometrium) atypically located among the cells of the uterine wall (myometrium), as a result, thickening of the uterus occurs. […] The pathogenesis of adenomyosis still remains unclear, but the functioning of the inner myometrium, also called the junction zone (JZ), is believed to play a major role in the development of adenomyosis. […] The tissue injury and repair (TIAR) theory is now widely accepted and suggests that uterine hyperperistalsis (i.e., increased peristalsis), during early periods of reproductive life will induce micro-injury at the endometrial-myometrial interface (EMI) region. […] Misplaced endometrial tissue proliferation in the myometrium causes symptoms through different mechanisms.

• #13 Exploring the Endocrine Mechanisms in Adenomyosis: From Pathogenesis to Therapies

  https://www.mdpi.com/2673-396X/5/1/4

  Hyperestrogenism from aberrant levels of ER-b is hypothesized to initiate the growth of adenomyotic lesions. […] The tissue repair mechanisms also involve macrophages, platelets, and their secreted cytokines, leading to chronic inflammation at the JZ and facilitating endometrial attachment, as well as infiltration. […] The EMID theory claims that adenomyotic lesions arise de novo, autonomously from metaplasia of misplaced embryonic pluripotent Müllerian remnants in the myometrium. […] The last theory, the retrograde hypothesis, is based on the transformation of multipotent adult stem cells in the myometrium. […] The local increase in estrogen concentration with normal peripheral E2 levels may cause hyperperistalsis of the uterus. […] The higher risk of developing ADM is associated with hypersensitivity to estrogen via specific polymorphism and relatively increased expression of ERα.

• #14 Adenomyosis: Mechanisms and Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7932680/

  A less rigid extracellular cell matrix (ECM) may facilitate endometrial cell migration and invasion into the myometrium and development of adenomyosis. Lysyl oxidase (LOX) is a copper-dependent amine oxidase that plays a critical role in the biogenesis of connective tissue matrices by cross-linking the ECM proteins collagen and elastin. LOX gene expression is highly downregulated in eutopic endometrium of women with versus without adenomyosis, consistent with a less rigid ECM. Moreover, matrix metalloproteinases (MMPs) MMP2, MMP3, and MMP9 are upregulated in eutopic endometrium from women with adenomyosis, compared with controls. Transcriptome sequencing of eutopic endometrium of women with adenomyosis also revealed dysfunction in connective tissues. Thus, the dysregulation of ECM function in the eutopic endometrium induced by MMPs, LOX, and junctional proteins may promote invagination of endometrium into myometrium, resulting in adenomyosis.

• #15

  http://waocp.com/journal/index.php/apjcb/article/view/1086

  Pseudo-invasive, vasculocentric adenomyosis is a rare benign lesion of the uterus, characterized by the aberrant, pathological presence of variable sized, non-neoplastic endometrial glands and surrounded by endometrial stroma deep within the myometrial blood vessels. […] Pseudo-invasive, vasculocentric adenomyosis is a rare benign condition of the uterus, characterized by the pathological presence of variable sized, non-neoplastic endometrial glands surrounded by endometrial stroma deep within the myometrial blood vessels. […] Adenomyosis is described as a distinct entity in the PALM-COEIN FIGO classification. […] Disturbances in these contractions leads to repeated trauma to the junctional zone, resulting in invasion of myometrium by the basal layer of the endometrium through this altered hormone responsive zone.

• #16

  https://link.springer.com/article/10.1007/s13669-022-00326-7

  The imbalance between estrogens and progesterone signaling is also caused by a decrease of progesterone activity, as suggested by the evidence that stromal cells of the functionalis and basalis endometrium of women with adenomyosis display a reduced immunoreactivity for isoform B of P receptor (PR-B), causing a loss of P effects. […] The development of adenomyosis is related to the endometrial cells invasiveness of myometrium, and the epithelial-to-mesenchymal transition (EMT) is the one of the most accepted mechanism to support the changes undergoing ectopic endometrial cells. […] Nowadays, adenomyosis is considered as a chronic inflammatory disease characterized by abundant inflammatory mediators both into adenomyotic lesions and in the peritoneal fluid. […] An increased expression of COX2 and PGs is observed in the presence of corticotropin releasing hormone (CRH) and urocortin (UCN), two potent inflammatory peptides, whose mRNA expression is increased in patients with adenomyosis.

• #17 Pathogenesis of Human Adenomyosis: Current Understanding and Its Association with Infertility

  https://www.mdpi.com/2077-0383/11/14/4057

  The cascade of EMT is composed of three components: (i) disruption of cell-cell adhesion of epithelial origin, (ii) cell migration/invasion, and (iii) transition of epithelial cell phenotype into fibroblast-like phenotype. […] In addition to the widely accepted invagination theory, adenomyotic lesions may originate de novo from metaplasia of displaced embryonic pluripotent Mϋllerian remnants. […] We cannot rule out the possibility of other de novo development of adenomyosis in addition to invagination theory. Transfer of endometrial stem/progenitor cells to the uterine wall during menstruation and their differentiation into endometrial gland and stromal cells could be another attractive hypothesis. […] A line of evidence indicated that adenomyosis, like endometriosis, may be considered as an epigenetic disease because epigenetic alterations have been detected in adenomyosis.

• #18 The Molecular Basis of Adenomyosis Development

  https://www.e-jarb.org/journal/view.html?doi=10.12750/JET.2018.33.1.49

  Therefore, more precise studies evaluating the molecular mechanisms involved in adenomyosis are required to design suitable clinical trials and allow prevention, appropriate treatment, and prompt diagnosis. […] It has been suggested that genetic mutations in endometrial cells also induce adenomyosis. […] One study reported that mutations of estrogen receptor alpha (ER) gene (ESR1) were found in adenomyosis. […] Although the above study identified only a 5% prevalence of ESR1 mutations, this finding implies that the mutations may induce development of adenomyosis. […] Epithelial to mesenchymal transition (EMT) refers to the phenotypic transition of epithelial cells to mesenchymal cells, which ultimately results in the conversion of epithelial cells into cells with metastatic and invasive potential.

• #19 Endometriosis vs. adenomyosis : is there a common pathogenesis ? | EndoNews

  https://www.endonews.com/endometriosis-vs.-adenomyosis-is-there-a-common-pathogenesis-

  Both endometriosis and adenomyosis seem to undergo identical molecular events, like epithelial–mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, smooth muscle metaplasia, and fibrogenesis. […] The finding of common mutations in endometriosis and adenomyosis, especially of KRAS, lend support to the view of shared predisposition, but this is inadequate for any common causative factor. […] Important unresolved questions remain for the hypothesis of adenomyosis and endometriosis being a single disease with common pathophysiology, however, it seems clear that adenomyosis is not simply endometriosis of the uterus. […] The most significant pathogenetic common factor is the finding of common mutations, particularly of KRAS, in adenomyosis and endometriosis however, it is insufficient for a shared causation.

• #20 Epithelial-mesenchymal transition as a pathogenetic mechanism of development and progression of adenomyosis – Pechenikova – Journal of obstetrics and women’s diseases

  https://journals.eco-vector.com/jowd/article/view/108828/en_US

  In recent years, an important role in the pathogenesis of adenomyosis has been assigned to invasive properties of the cells of the basal layer of the endometrium, which provide them with the capacity to grow into the underlying layers of the myometrium. […] The displacement of elements of the eutopic endometrium into the thickness of the myometrium and further progression of adenomyosis is provided by two parallel pathogenetic mechanisms, namely, invasive growth due to matrix metalloproteinase type 9 activation and epithelial cell migration due to the epithelial-mesenchymal transition.

• #21 Adenomyosis: Mechanisms and Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7932680/

  That adenomyosis as an estrogen-dependent disease is based on multiple observations. For example, in a mouse model, prolonged treatment with estrogen results in inducing adenomyosis. In women, elevated E2 levels in menstrual blood of those with adenomyosis without concomitant elevations in peripheral blood, compared with controls, suggest that local rather than systemic hyperestrogenism contributes to the development of the disease. Moreover, aromatase cytochrome P450, a key enzyme in synthesis of E2, is expressed in eutopic endometrium of women with adenomyosis. And lower expression of 17-hydroxysteroid dehydrogenase type 2 (17-HSD2), which converts E2 to the less potent estrogen, E1, has been reported in the eutopic and ectopic endometrium of adenomyosis patients, compared with controls. Thus, increased biosynthesis and decreased conversion of E2 contribute to a local hyperestrogenic milieu, suggesting a key role for E2 in the development of disease.

• #22 Adenomyosis: Mechanisms and Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7932680/

  The bulk of evidence supports that adenomyosis is an estrogen-dependent gynecological disorder resulting from one of several mechanisms: invasion of the endometrial basalis into the myometrium induced by enhanced cell survival, EMT, and cell migration; continuous auto-microtrauma of the junctional zone; de novo metaplasia from adult stem cells and embryonic Mullerian remnants; and from outside to inside invasion. There are also genetic, epigenomic, environmental, and pituitary triggers of the disease. In addition to a central role for local hyperestrogenism, progesterone resistance, and inflammation in the pathogenesis of adenomyosis, these factors along with abnormal uterine contractility, neurogenesis, and neoangiogenesis are key pathogenic mediators of the pain, HMB, and infertility experienced by women with adenomyosis.

• #23 Exploring the Endocrine Mechanisms in Adenomyosis: From Pathogenesis to Therapies

  https://www.mdpi.com/2673-396X/5/1/4

  Also proposed is the notion that progesterone resistance may contribute to the hormonal imbalance theory in ADM, as with endometriosis. […] In short, the highly localized concentrations of estrogen combined with altered expression of steroid receptors are central mechanisms leading to ADM. […] Genetic variants influence enzyme activity and increase the risk of estrogen dependency in ADM. […] Evidence also reports several types of epigenetic alterations in ADM. […] EDCs can be divided into persistent and non-persistent organic pollutants (POPs, nonPOPs), based on their lipid solubility. […] The significant clinical coexistence of both conditions within a patient strongly supports a high probability of a causal relationship between EDC exposure and the initiation of endometrium-related diseases.

• #24 BCL6 (B-cell lymphoma 6) expression in adenomyosis, leiomyomas and normal myometrium | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0317136

  Adenomyosis is a benign uterine disease characterized by the pathological presence of endometrial glands and stroma within the myometrium. […] It is thought to result from an invagination of the endometrium following the disruption of the junctional zone between the basal endometrium and the myometrium. […] Molecular validation by Inoue et al. confirmed that adenomyosis develops from eutopic endometrium through the identification of somatic mutations using next-generation sequencing. […] The KRAS gene provides instructions for the production of a protein called K-Ras, which is part of the RAS/MAPK signaling pathway involved in cell proliferation and differentiation. […] Mutations in KRAS stimulate pathways that increase cell survival and proliferation and are associated with progesterone resistance in adenomyosis and endometriosis.

• #25 LPS/TLR4-mediated stromal cells acquire an invasive phenotype and are implicated in the pathogenesis of adenomyosis | Scientific Reports

  https://www.nature.com/articles/srep21416

  The present study tested whether the LPS/TLR4 signal pathway in endometrial stromal cells is essential for the pathogenesis of adenomyosis. […] This study suggested that stromal cells were activated by the TLR4 signalling pathway, which processed the cellular inflammatory proliferation and invasive growth involved in the pathogenesis of adenomyosis. […] Emerging evidence suggests that this disease may be linked to the expression of inflammatory mediators and the induction of an immune response. […] Our findings proposed that adenomyosis may be associated with intrauterine infection. […] Our results showed that TLR4, MD2, MyD88 and NF-B significantly increased after LPS treatment. Our current findings indicated that TLR4-MyD88-NF-B had vital functions in the development of adenomyosis. […] This study clearly showed that VEGF, EGF, MMP2, TGF- and IL-6 were significantly higher in CESE, EuESC and EESC after LPS treatment. […] Our current findings may provide clues in targeting TLR4 in new therapeutic strategies for women with adenomyosis.

• #26

  https://link.springer.com/article/10.1007/s13669-022-00326-7

  Angiogenesis is a mechanism that involves the formation of new capillaries from pre-existing blood vessels and occurs physiologically in the proliferative phase of the menstrual cycle. […] An abnormal and intensified vascularization has been observed also in adenomyosis and, in this regard, estrogens promote cell mobilization and microvascular integration. […] Fibrosis is another mechanism involved in the pathogenesis of adenomyosis. […] The stiffness of the lesion appears to be related with the amount of fibrosis and with the intensity of painful symptoms in patients with adenomyosis. […] The understanding of the pathogenetic mechanisms of adenomyosis may open new perspectives in developing new tools for the diagnosis and treatment, toward a more and more personalized medicine.

• #27 Role of Vascular Endothelial Cell Growth Factor on Pathophysiology of Uterine Adenomyosis

  https://www.imrpress.com/journal/CEOG/49/6/10.31083/j.ceog4906133/htm

  Vascular endothelial growth factor (VEGF) may be associated with the progression of adenomyosis. […] Several previous reports have suggested that expansion of adenomyosis is related to increased vascular endothelial cell growth factor (VEGF) levels, regardless of whether they have a diffuse or focal pattern. […] It is known that VEGF has a crucial role in regulating tumor growth and that it facilitates metastasis by inducing neovascularization. […] VEGF contributes to the progression of uterine adenomyosis and may be more strongly activated in the stromal component of the myometrium than in the endometrial (eutopic or ectopic) component of the adenomyosis in the same uterus. […] This suggests that VEGF plays a significant role in the muscular component of the endometrium during the progression of adenomyosis.

• #28 Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations | Nature Communications

  https://www.nature.com/articles/s41467-019-13708-y

  Uterine adenomyosis is a benign disorder that often co-occurs with endometriosis and/or leiomyoma, and impairs quality of life. The genomic features of adenomyosis are unknown. Here we apply next-generation sequencing to adenomyosis (70 individuals and 192 multi-regional samples), as well as co-occurring leiomyoma and endometriosis, and find recurring KRAS mutations in 26/70 (37.1%) of adenomyosis cases. Multi-regional sequencing reveals oligoclonality in adenomyosis, with some mutations also detected in normal endometrium and/or co-occurring endometriosis. KRAS mutations are more frequent in cases of adenomyosis with co-occurring endometriosis, low progesterone receptor (PR) expression, or progestin (dienogest; DNG) pretreatment. DNG’s anti-proliferative effect is diminished via epigenetic silencing of PR in immortalized cells with mutant KRAS. Our genomic analyses suggest that adenomyotic lesions frequently contain KRAS mutations that may reduce DNG efficacy, and that adenomyosis and endometriosis may share molecular etiology, explaining their co-occurrence. These findings could lead to genetically guided therapy and/or relapse risk assessment after uterine-sparing surgery.

• #29 The Molecular Basis of Adenomyosis Development

  https://www.e-jarb.org/journal/view.html?doi=10.12750/JET.2018.33.1.49

  Epigenetic changes in DNA expression have been studied in the development of adenomyosis. […] Therefore, these results suggest that abnormal epigenetic modifications may be critical factors in adenomyosis development. Evaluation of these epigenetic changes may be helpful in defining treatment, prevention, and diagnosis of adenomyosis. […] Understanding the underlying molecular mechanisms is crucial for the development of clinical trials and for the treatment, prevention, and diagnosis of gynecological diseases involving adenomyosis.

• #30 The Molecular Basis of Adenomyosis Development

  https://www.e-jarb.org/journal/view.html?doi=10.12750/JET.2018.33.1.49

  Determining the relationship between EMT control mechanisms and various signaling systems will help in better understanding of adenomyosis development. […] Several reports have described Wnt/-catenin signaling to play an important role in EMT progression. […] These results suggest that a dominant stabilized -catenin expression may play an important role in the pathogenesis of adenomyosis. […] Notch signaling also contributes to adenomyosis development by EMT progression. […] These data indicated that the Notch signaling pathway may contribute to the development and pathogenesis of adenomyosis. […] Another important pathway that causes adenomyosis development is the transforming growth factor beta (TGF-) signaling pathway. […] These results suggest that the TGF- signaling pathway may be an important target in the study of adenomyosis development.

• #31 The role of WNT and HOXA signaling cascades in the pathogenesis of adenomyosis – Malysheva – Journal of obstetrics and women’s diseases

  https://journals.eco-vector.com/jowd/article/view/121803

  Adenomyosis is a common gynecological disease with unknown pathogenesis. The HOXA10, HOXA11 and WNT4 genes may play an important role in the pathogenesis of adenomyosis both at the stage of embryonic development and in the postnatal period. […] The aberrant expression of the WNT4, HOXA10 and HOXA11 genes in the endometrium of patients with adenomyosis indicates a significant role of these genes in the development of the disease and infertility associated with adenomyosis. […] In the proliferative phase endometrial samples of patients with adenomyosis, a significant increase in the WNT4 (of almost two times), HOXA10 and HOXA11 (of one and a half to two times) gene expression levels was shown compared to the control group.

• #32 Recurrence rates and associated risk factors after conservative surgery for adenomyosis: a retrospective study | BMC Women’s Health | Full Text

  https://bmcwomenshealth.biomedcentral.com/articles/10.1186/s12905-024-03457-6

  Adenomyosis continues to have a relatively high long-term recurrence rate after conservative surgery. […] Patients with adenomyosis involving the posterior wall of the uterus, those with two or more adenomyotic lesions, and those with concomitant endometriosis are at high risk for recurrence after conservative surgery. […] Postoperative progestogen or GnRHa therapy may reduce the risk of recurrence of adenomyosis. […] Cox proportional risk analysis identified adenomyosis involving the posterior uterine wall (hazard ratio [HR] 6.505, P=0.018), two or more adenomyotic lesions (HR 6.310, P=0.030), laparotomy (HR 2.490, P=0.029), and concomitant endometriosis (HR 2.313, P=0.036) to be risk factors for recurrence after conservative surgery. […] The susceptibility of adenomyotic lesions located in the posterior wall to recurrence after surgery may be related to involvement of the bowel, more severe deep infiltrative lesions in the posterior region, and more rapid onset of symptomatic recurrence.

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