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Gonadotrophin-releasing hormone (GnRH) antagonists have been demonstrated to reduce endometriosis-associated pain. Because of the hypo-oestrogenic state they induce, however, higher dosages of GnRH antagonists are not recommended for used long term. This unwanted effect may be eliminated by so-called add-back therapy (ABT). This review was conducted to assess the safety and efficacy of GnRH antagonists, with or without add-back hormonal replacement therapy. Out of the 345 studies selected through the initial search, seven randomized controlled trials were included, comparing different oral GnRH antagonists at varying dosages, from a minimum of 50 mg to a maximum of 200 mg once or twice daily. Women treated with the lowest dose of GnRH antagonists had significantly greater mean pain score reductions from baseline throughout treatment compared with those treated with placebo (odds ratio [OR] -13.12, 95% CI -17.35 to -8.89 and OR -3.08, 95% CI -4.39 to -1.76 for dysmenorrhoea and non-menstrual pelvic pain, respectively). Compatible with the dose-response effect, a positive correlation was found between response rates and adverse event rates. While GnRH antagonists offer an advantage in terms of pain reduction for endometriosis, the more recent literature suggests using GnRH antagonists with ABT, which, while mitigating the hypo-oestrogenic effects of GnRH antagonists, maintain their efficacy, while allowing their long-term use.
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Gender-based violence (GBV) and, more specifically, violence against women (VAW) are commonly considered a consequence of a patriarchal structure-a social system granting the senior male absolute authority over the family and the community as a whole. Anthropologists have documented that human male dominance is rooted in evolution, with male violent behavior observed among the great apes. Given that evolution is a continuous process, human progress over millennia has modified pre-existing behavior, demonstrating that humans can move beyond ancestral ways of life over time. Precisely because of the imperative to change and improve, at the global international level as well as in individual countries, strong movements are in action to eliminate GBV/VAW. FIGO has been and continues to be at the forefront of the battle for equality, with initiatives that cover many aspects of this, including the imperative to involve men, who-in the majority of cases-are the perpetrators. Since men are often the root of the problem, they must also be at the forefront of the battle to eradicate it. GBV/VAW comprises many facets, including selective female abortion, infanticide, femicide, honor killing, female genital mutilation, and child marriage. These deeply rooted forms of violence continue to perpetuate gender inequalities, remain major obstacles to health and societal progress, and violate the most basic human rights.
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BACKGROUND: Thomas Cullen described bleeding abnormalities and dysmenorrhea as the "expected" presentations of adenomyomas. Adenomyosis is included within the FIGO classification of structural causes of abnormal uterine bleeding (AUB). Nevertheless, this long-standing association has been questioned by some authors who reported a high incidence of adenomyosis in uteri removed for indications other than AUB or dysmenorrhea. Here, we examine evidence for the link between adenomyosis and AUB. METHODS: A comprehensive Medline literature review of all publications to October 2023. RESULTS: Sixty-three articles were identified and included in the review. Despite a large body of studies, the available literature does not provide conclusive evidence of a link between adenomyosis and AUB. This is because of unsuitable study design, or poor characterization of the study population or of the inclusion or exclusion criteria. Additional challenges arise because of the lack of agreed criteria for diagnosing adenomyosis and the often absence of detailed assessment of menstrual blood loss. Adenomyosis often coexists with other conditions that have also been linked to similar symptoms, and many cases of adenomyosis are asymptomatic. CONCLUSION: Most of the existing literature and studies that addressed treatment outcome of adenomyosis started from the premise that a link between the condition and AUB had been proven. Yet, published information shows that aspects such a relationship is still uncertain. Further research is needed to address the relation between AUB and adenomyosis burden (or subtypes), distribution, and concomitant pathology.
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Adenomiose , Hemorragia Uterina , Humanos , Adenomiose/complicações , Adenomiose/patologia , Adenomiose/diagnóstico , Feminino , Hemorragia Uterina/etiologia , Hemorragia Uterina/diagnóstico , Dismenorreia/etiologia , Dismenorreia/diagnósticoRESUMO
BACKGROUND: There has been considerable progress in our understanding of endometriosis, but its pathophysiology remains uncertain. Uncovering the underlying mechanism of the rare instances of endometriosis reported in early postmenarcheal years and in girls before menarche can have wide implications. METHODS: We conducted a literature review of all relevant articles on Medline. RESULTS: In the review, we explore the pathogenetic theories of premenarcheal endometriosis, the role of retrograde menstruation in the adult and its potential role in early-onset disease, as well as the factors that argue against the existence of a link between early-onset endometriosis (EOE) and neonatal uterine bleeding (NUB). CONCLUSIONS: As with endometriosis in adult women, the pathogenesis of early-onset disease remains unclear. A link between NUB and EOE is plausible, but there are considerable challenges to collating supporting evidence. The state of our understanding of early uterine development and of the pathophysiology of NUB leaves many unknowns that need exploration. These include proof of the existence of viable endometrial cells or endometrial mesenchymal stem cells in NUB, their passage to the pelvic cavity, their possible response to steroids, and whether they can reside within the pelvic cavity and remain dormant till menarche.
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Endometriose , Hemorragia Uterina , Humanos , Feminino , Endometriose/complicações , Endometriose/patologia , Hemorragia Uterina/etiologia , Recém-Nascido , Útero/patologia , Endométrio/patologia , Endométrio/metabolismo , Idade de InícioRESUMO
Today, there is strong and diversified evidence that in humans at least 50% of early embryos do not proceed beyond the pre-implantation period. This evidence comes from clinical investigations, demography, epidemiology, embryology, immunology, and molecular biology. The purpose of this article is to highlight the steps leading to the establishment of pregnancy and placenta formation. These early events document the existence of a clear distinction between embryonic losses during the first two weeks after conception and those occurring during the subsequent months. This review attempts to highlight the nature of the maternal-embryonic dialogue and the major mechanisms active during the pre-implantation period aimed at "selecting" embryos with the ability to proceed to the formation of the placenta and therefore to the completion of pregnancy. This intense molecular cross-talk between the early embryo and the endometrium starts even before the blastocyst reaches the uterine cavity, substantially initiating and conditioning the process of implantation and the formation of the placenta. Today, several factors involved in this dialogue have been identified, although the best-known and overall, the most important, still remains Chorionic Gonadotrophin, indispensable during the first 8 to 10 weeks after fertilization. In addition, there are other substances acting during the first days following fertilization, the Early Pregnancy Factor, believed to be involved in the suppression of the maternal response, thereby allowing the continued viability of the early embryo. The Pre-Implantation Factor, secreted between 2 and 4 days after fertilization. This linear peptide molecule exhibits a self-protective and antitoxic action, is present in maternal blood as early as 7 days after conception, and is absent in the presence of non-viable embryos. The Embryo-Derived Platelet-activating Factor, produced and released by embryos of all mammalian species studied seems to have a role in the ligand-mediated trophic support of the early embryo. The implantation process is also guided by signals from cells in the decidualized endometrium. Various types of cells are involved, among them epithelial, stromal, and trophoblastic, producing a number of cellular molecules, such as cytokines, chemokines, growth factors, and adhesion molecules. Immune cells are also involved, mainly uterine natural killer cells, macrophages, and T cells. In conclusion, events taking place during the first two weeks after fertilization determine whether pregnancy can proceed and therefore whether placenta's formation can proceed. These events represent the scientific basis for a clear distinction between the first two weeks following fertilization and the rest of gestation. For this reason, we propose that a new nomenclature be adopted specifically separating the two periods. In other words, the period from fertilization and birth should be named "gestation", whereas that from the completion of the process of implantation leading to the formation of the placenta, and birth should be named "pregnancy".
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Implantação do Embrião , Placenta , Animais , Humanos , Gravidez , Feminino , Placenta/fisiologia , Implantação do Embrião/fisiologia , Endométrio , Útero , Embrião de Mamíferos/fisiologia , MamíferosRESUMO
BACKGROUND: The occurrence of vaginal bleeding in early neonatal life has been observed for centuries and was considered a consequence of the sudden drop in circulating hormones following birth. As such, neonatal uterine bleeding was dismissed as having no clinical significance. Interest in the phenomenon was renewed when a new theory suggested a link between neonatal uterine bleeding (NUB) and accelerated endometrial maturation. This theory was based on the observation of a higher incidence of NUB in babies born post-term or after pregnancies complicated by intrauterine growth restriction, preeclampsia, or blood group incompatibility. OBJECTIVE: The objective of this study was to review of available evidence on the pathogenesis of NUB. METHOD: Review of available literature using Medline search (August 2022, no limit on start date or language) to identify articles that may link NUB with features of the uterus and/or endometrium. OUTCOME: The fetal endometrial responses differ from that of the adult. In the fetus, the endometrium features progestogenic response only in a minority of cases. The endometrium in most newborn girls does not exhibit secretory or decidual changes which indicate lack of progesterone response. Most newborn girls do not have visible bleeding. Animal studies linked exogenous progestogen exposure during the period of organogenesis to poor endometrial gland development, progesterone resistance, and to alterations of reproductive performance. Although the fetal endometrium may not exhibit a full proliferative response, it is clearly sensitive to circulating estrogens. Molecular mechanisms involved in NUB may include "ontogenetic progesterone resistance." CONCLUSION AND OUTLOOK: Endometrial development and its response to withdrawal of hormones at birth varies and may be affected by intrauterine stressors and gestational age. Factors that affect endometrial development during fetal life and in preterm neonates can have implications on future reproductive performance.
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As understanding their pathogenesis remains elusive, both endometriosis and adenomyosis are often referred to as "enigmatic diseases". The uncertainty and heightened interest are reflected in the range of expressed views and opinions. There is a sense of urgency because of the entailed patient suffering. The plethora of opinions calls for a critical analysis of proposed theories, both old and new. A series of papers published since 2009 proposed that both endometriosis and adenomyosis originate from the same aberrations occurring within the uterus. This came to be recognized as the tissue injury and repair theory, and the newly coined term "archimetrosis" posits that the two diseases share the same origin. While the theory opens an interesting channel for exploration, its claim as a unifying theory necessitates a critical appraisal. We, thus, undertook this review of the theory and analyzed its underpinnings based on a comprehensive review of the literature. Our appraisal indicates that the theory is open to a range of criticisms. Chief among these is the need for confirmatory evidence of features of abnormal uterine contractility and the lack of data addressing the question of causality. In addition, the theory has, as yet, no supporting epidemiological evidence, which is a major weakness. The theory suffers as it is not open to the test of falsifiability, and it lacks the ability to make useful predictions. It has not addressed the questions, such as why only a small percentage of women develop adenomyosis or endometriosis, given the ubiquity of uterine peristalsis. On the other hand, the triggers and prevention of hyper- or dys-peristalsis become critical to a theory of causation. We conclude that additional supportive evidence is required for the theory to be accepted.
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Adenomiose , Endometriose , Feminino , Humanos , Adenomiose/patologia , Endometriose/etiologia , Endometriose/patologia , ÚteroRESUMO
Practically unknown outside of China, the "endometrial determinism" theory was proposed to account for the apparent gap between the relatively low prevalence of endometriosis and nearly universal retrograde menstruation. Attracting uncritical advocacy, the theory culminates in a recent consensus by elite Chinese gynecologists in favor of "root treatment", intended to nip endometriosis in the bud. Correcting endometrial "defects" can gain further momentum by the presence of cancer-driver mutations such as KRAS mutations in the endometrium of women with endometriosis and the recent introduction of therapeutics aiming to rectify the effect of these mutations for cancer treatment. We provide a critical appraisal of evidence for endometrial aberrations in endometriosis and relevant experimental evidence. All available evidence of endometrial "defect" is invariably post hoc and may well be secondary to induced endometriosis. We propose that the theory of "endometrial determinism" needs to demonstrate a clear causal and a phylogenetic relationship between endometrial aberrations and endometriosis. We argue that while it is highly likely that endometriosis is a consequence of retrograde menstruation, the case that molecular aberrations as a sole or a necessary determinant remains to be proven. "Root treatment" is a worthy ambition but as of now it is close to a fanciful Utopia.
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Endometriose , Feminino , Humanos , Filogenia , Utopias , Endométrio , Distúrbios Menstruais/complicaçõesRESUMO
OBJECTIVE: Many women experience negative feelings during menstrual bleeding. Aim of the study was to evaluate the attitudes of Italian women towards menstrual bleeding, their desire to reduce its frequency and knowledge of the existence of methods capable of achieving such an objective. METHODS: An internet-based anonymous questionnaire has been sent to women willing to fill it in through different social media (Instagram, WhatsApp, Facebook, Twitter). The survey evaluated, objective parameters such as number of pads, use of painkillers, duration of period and pain intensity. Judgement towards period and knowledge about methods to reduce frequency and amount of menstrual flow were analysed. RESULT: 1072 Women aged 18 - 40 years, answered the survey. The level of education of responders was high, with 61.7% having a university degree. 27.5% of respondents viewed positively the occurrence of a menstrual period. Ideal frequency of menstrual cycles was considered 3 months and the perfect duration was considered to be 3 days. Half of the respondents ignored the existence of methods to suppress menstruation or reduce its frequency. 52% of participants stated that they would not use a contraceptive method because they considered it not 'natural'. CONCLUSIONS: In our sample, in spite of the discomfort reported by half of the women interviewed, menstruation was considered positively by one fourth as because confirm their fertility. The majority of women did consider bleeding every month a healthy, but they preferred a three-monthly frequency. Knowledge of contraceptive methods capable of reducing the frequency of menstrual bleeding was scarce.
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Atitude , Menstruação , Feminino , Humanos , Menstruação/psicologia , Itália , Inquéritos e Questionários , Adolescente , Adulto Jovem , AdultoRESUMO
Religions continue to be a strong moral, even political, force in the world. They are often seen to be in conflict with women's health; we argue that this should not continue to be the case. The conflict can be traced back to when religions had their birth and early development in patriarchal communities in which women were marginalized to the edges of society. In addition, religious leadership has traditionally been dominated by men and exclusive of women. The recent introduction of new scientific technologies, which has empowered women to regulate and control their fertility, challenged traditional norms and raised a religious-inspired moral panic. However, a recent initiative has been gaining momentum. An enlightened religious leadership and a new generation of feminist religious activists are calling for a review of the original texts and a reinterpretation in a sociocultural context that is different from when they were first revealed. Obstetrician-gynecologists, while having to practice in a socioreligious context and continuing to face challenges in providing health care in religiously diverse societies, have a social responsibility to stand by women and to uphold that religions do not and should not stand in the way of advancing their health and rights.
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Ginecologista , Direitos da Mulher , Feminino , Humanos , Masculino , Obstetra , Religião , Saúde da MulherRESUMO
In recent literature reviews, we concluded that the possibility that endometrial molecular aberrations are the sole or a necessary determinant of endometriosis and the Tissue Injury and Repair (TIAR) theory are yet to be convincingly proven. Here, we critically examine the theory that adenomyosis and endometriosis represent different phenotypes of a single disease. A common etiopathology for adenomyosis and endometriosis has been suggested because both conditions entail the presence of endometrial tissue at locations other than the lining of the uterus. There are wide differences in reported disease incidence and prevalence and, consequently, in estimates of the coexistence of both conditions. There are some similarities but also differences in their clinical features and predisposing factors. Each condition has a range of subtypes. These differences alone pose the question of whether subtypes of endometriosis and adenomyosis have different etiopathologies, and, in turn, this raises the question of whether they all share a common etiology. It is debatable whether the recognized differences between the eutopic endometrium in adenomyosis and endometriosis compared to those in unaffected women are the cause or the effect of the disease. The finding of common mutations, particularly of KRAS, lend support to the notion of shared predisposing factors, but this alone is insufficient evidence of causation.
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Adenomiose , Endometriose , Feminino , Humanos , Adenomiose/genética , Endometriose/genética , Endométrio , Útero , FenótipoRESUMO
Today, a diverse range of contraceptive techniques is available to women; this, coupled with continued positive trends in female children and adults' educational attainment, will hasten declines in fertility and continue to slow population growth [...].
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INTRODUCTION: We undertook a literature review of the use of levonorgestrel-releasing intrauterine devices when utilized for heavy menstrual bleeding and/or dysmenorrhea. METHODS: A narrative review of articles in the Scopus and Medline databases was conducted. RESULTS: A number of options exist for the management of both abnormal uterine bleeding (AUB) and dysmenorrhea, and evidence is accumulating that the insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) represents a useful option for their long-term treatment. The idea of using a progestogen released in utero was initially conceived to achieve long-term contraception, but it was quickly found that these systems could be utilized for a number of therapeutic applications. The first device to be made commercially available, Progestasert, was withdrawn from the market because, in the event of contraceptive failure, it caused a disproportionate percentage of extrauterine pregnancies. On the other hand, the LNG-IUS continues to be successfully utilized in its various variants, releasing 20, 13, or 8 µg/day. These devices have a respective duration of action of 7 (possibly 8), 5, and 3 years, and there exist versions of frameless systems affixed to the myometrium of the uterine fundus. In the present review, following a brief description of the major causes of AUB and dysmenorrhea, the molecular bases for the use of the LNG-IUS are summarized. This is followed by a compendium of its use in AUB and dysmenorrhea, concluding that the insertion of the system improves the quality of life, reduces menstrual blood loss better than other medical therapies, and decreases the extent of dysmenorrhea and pelvic pain. In addition, there is no evidence of a significant difference in these outcomes when the use of the LNG-IUS was compared with improvements offered by endometrial ablation or hysterectomy. Possibly, the most important mechanism of action of the system consists of its ability to induce amenorrhea, which effectively eliminates heavy bleeding and dysmenorrhea. However, no method is ideal for every woman, and, in the case of the LNG-IUS, younger age and severe dysmenorrhea seem to be associated with a higher risk of discontinuation. CONCLUSION: The higher-dose LNG-IUS is a useful tool for HMB and dysmenorrhea in women of all ages. The low cost and ease of use make the LNG-IUS an attractive option, especially when contraception is also desired.
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Introduction: Transvaginal sonography is the first-line imaging technique to diagnose endometriosis, but magnetic resonance imaging is more accurate in staging the extent of lesions, especially for deep pelvic endometriosis. The revised American Society for Reproductive Medicine and Enzian classifications are commonly used to stage the extent of endometriosis. However, a review underlined their weaknesses in terms of complexity, lack of clinical reproducibility and low correlation with surgical complications and fertility outcomes. Thus, to this day, in clinical practice, there is a lack of consensual, standardized or common nomenclature to stage the extent of endometriosis, posing a worldwide challenge. Objectives: The aims of our study were to: (i) develop a new classification (entitled Endo-Stage MRI) based on patterns of endometriosis as observed with magnetic resonance imaging; (ii) compare results with those of the rASRM classification; (iii) estimate the Endo-Stage MRI accuracy to predict the rate of surgical complications; and (iv) propose an Endo-Stage MRI system of triage (low, intermediate, high) that correlates with the risk of surgical complications. The goal is to improve the effectiveness of care pathways and allow for the planning of a multidisciplinary approach when necessary. Patients and methods: A single-center observational study using available clinical and imaging data. According to anatomical locations and the extent of endometriotic lesions, a standardized classification comprising six stages of severity (0-5) was designed. Results: A total of 751 patients with pelvic endometriosis underwent surgery from January 2013 to December 2018 in a tertiary care university hospital. Their Endo-Stage MRI classification was correlated with: (i) the rate of overall complications (grade I-IV Clavien-Dindo classification, (ii) the rate of major complications (grades III-IV) and (iii) the rate of voiding dysfunction requiring self-catheterization lasting more than one month. According to the Endo-Stage MRI classification, stages 0, 1, 2, 3, 4 and 5 were observed in 26 (3%), 156 (21%), 40 (5%), 22 (3%), 290 (39%) and 217 (29%) patients, respectively. Using the proposed Endo-Stage MRI system as triage, low (stages 0-2), intermediate (stages 3-4) and high-risk (stage 5), complications were observed in 29 (13%), 109 (34.9%) and 103 (47.4%) patients, respectively. In multivariate analysis, the Endo-Stage MRI system of triage was strongly predictive of surgical complications and achieved higher accuracy than the revised American Society for Reproductive Medicine classification (AUC: 0.78 (95% CI, 0.76-0.80) vs. 0.61 (95% CI, 0.58-0.64)). Conclusion: Our study proposes a new imaging classification of endometriosis coined Endo-Stage MRI classification. The results suggest that when applied to a clinical situation, it may improve care pathways by providing crucial information for identifying intermediate and/or high-risk stages of endometriosis with increased rates of surgical complications. To make this classification applicable, a multicentric validation study is necessary to assess the relevancy and clinical value of the current anatomical MRI classification.
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Purpose: To analyze the characteristics of the ovarian endometrioma (OE) across the life span of a woman. In the past, the OE has traditionally been viewed as a single, monolithic disease. Today, there are emerging data indicating that OE phenotypes differ according to the age of the woman. Method: A narrative review of original articles on OE indexed by PubMed. Results: When appearing in infancy and early adolescence, OE may be the consequence of endometrial cells retrogradely shed with neonatal uterine bleeding. The post-menarcheal variant, manifesting itself during full adolescence, is singularly frequent in the presence of vaginal or uterine outflow obstructive anomalies. The typical and most frequent adult phenotype is characterized by increasing fibrosis and a tendency to progress; its mere presence exerts a detrimental effect on the surrounding healthy ovarian tissue. In postmenopause, an old lesion may be reactivated in the presence of exogenous or endogenous estrogens, or even be produced ex novo; rarely, it can spread to a variety of organs and structures and even degenerate causing malignancies. Conclusions: Given the existence of these variants, it is important to agree on management guidelines that take into consideration these different phenotypes.
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BACKGROUND: Adenomyosis is a common gynecological disorder traditionally viewed as "elusive". Several excellent review papers have been published fairly recently on its pathogenesis, and several theories have been proposed. However, the falsifiability, explanatory power, and predictivity of these theories are often overlooked. Since adenomyosis can occur spontaneously in rodents and many other species, the animal models may help us unveil the pathogenesis of adenomyosis. This review critically tallies experimentally induced models published so far, with a particular focus on their relevance to epidemiological findings, their possible mechanisms of action, and their explanatory and predictive power. METHODS: PubMed was exhaustively searched using the phrase "adenomyosis and animal model", "adenomyosis and experimental model", "adenomyosis and mouse", and "adenomyosis and rat", and the resultant papers were retrieved, carefully read, and the resultant information distilled. All the retrieved papers were then reviewed in a narrative manner. RESULTS: Among all published animal models of adenomyosis, the mouse model of adenomyosis induced by endometrial-myometrial interface disruption (EMID) seems to satisfy the requirements of falsifiability and has the predictive capability and also Hill's causality criteria. Other theories only partially satisfy Hill's criteria of causality. In particular, animal models of adenomyosis induced by hyperestrogenism, hyperprolactinemia, or long-term exposure to progestogens without much epidemiological documentation and adenomyosis is usually not the exclusive uterine pathology consequent to those induction procedures. Regardless, uterine disruption appears to be a necessary but not sufficient condition for causing adenomyosis. CONCLUSIONS: EMID is, however, unlikely the sole cause for adenomyosis. Future studies, including animal studies, are warranted to understand how and why in utero and/or prenatal exposure to elevated levels of estrogen or estrogenic compounds increases the risk of developing adenomyosis in adulthood, to elucidate whether prolactin plays any role in its pathogenesis, and to identify sufficient condition(s) that cause adenomyosis.
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Adenomyosis is a complex and poorly understood gynecological disease. It used to be diagnosed exclusively by histology after hysterectomy; today its diagnosis is carried out increasingly by imaging techniques, including transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI). However, the lack of a consensus on a classification system hampers relating imaging findings with disease severity or with the histopathological features of the disease, making it difficult to properly inform patients and clinicians regarding prognosis and appropriate management, as well as to compare different studies. Capitalizing on our grasp of key features of lesional natural history, here we propose adding elastographic findings into a new imaging classification of adenomyosis, incorporating affected area, pattern, the stiffest value of adenomyotic lesions as well as the neighboring tissues, and other pathologies. We argue that the tissue stiffness as measured by elastography, which has a wider dynamic detection range, quantitates a fundamental biologic property that directs cell function and fate in tissues, and correlates with the extent of lesional fibrosis, a proxy for lesional "age" known to correlate with vascularity and hormonal receptor activity. With this new addition, we believe that the resulting classification system could better inform patients and clinicians regarding prognosis and the most appropriate treatment modality, thus filling a void.