Diffuse Adenomyosis Research Articles

Scribble downregulation in adenomyosis compromises endometrial stromal decidualization by decreasing FOXO1 expression.

Does Scribble (SCRIB) contribute to aberrant decidualization of endometrial stromal cells (ESC) in adenomyosis? SCRIB knockdown impairs decidualization of ESC by decreasing Fork-head box O1A (FOXO1) expression through the protein kinase B (AKT) and atypical protein kinase C (aPKC) activated pathways. Stromal SCRIB is required for primary decidual zone formation and pregnancy success in mice. In our previous studies, decidualization was dampened in ESC isolated from adenomyosis patients, yet the underlying molecular mechanisms remain elusive. Eutopic endometrium tissue samples from diffuse adenomyosis and non-adenomyosis patients in proliferative, early-secretory and mid-secretory phase (n = 10 per phase for each group) were explored. In parallel, in vitro decidualization studies were carried out in ESC isolated from non-adenomyosis women (n = 8). The endometrial SCRIB expression was analyzed using immunohistochemistry staining and western blot. Quantitative RT-PCR (qRT-PCR), western blot and immunofluorescence staining were used to explore the expression of SCRIB in ESC during in vitro decidualization. siRNA-mediated SCRIB knockdown followed by decidual markers expression analysis, flow cytometry for cell cycle analysis and phalloidin staining for morphological analysis were performed to examine the function of SCRIB in ESC decidualization. RNA-sequencing was performed to examine the SCRIB-mediated transcriptional changes in decidualized ESC (DSC). Rescue experiments using an AKT inhibitor MK2206 and aPKC inhibitor NSC37044 were used to investigate the signaling pathways through which could mediate SCRIB-regulated FOXO1 protein expression and ESC decidualization. We found that the expression of SCRIB in the mid-secretory phase eutopic endometrial stroma of adenomyosis patients was significantly lower than that of non-adenomyosis. SCRIB knockdown reduced the expression of decidual markers, abrogated the epithelioid-like morphological changes, inhibited the mesenchymal-to-epithelial transitions process and promoted the cell cycle progression of ESC during in vitro decidualization. SCRIB knockdown-induced decidualization defects were attributed to a decrease in expression of transcription factor FOXO1, known to regulate decidualization. Furthermore, we found that SCRIB knockdown induced the aberrant activation of AKT and aPKC, which led to FOXO1 phosphorylation and degradation. Rescue assay confirmed that restoring the expression of FOXO1 effectively reversed the decidualization defects and cell cycle progression caused by SCRIB knockdown. N/A. In this study, it was demonstrated that SCRIB knockdown mediated the activation of AKT and aPKC, contributing to FOXO1 degradation and aberrant decidualization, however, the molecular link between AKT and aPKC signaling was not determined, and still requires further exploration. Our findings support the hypothesis that adenomyosis interferes with embryo implantation due to insufficient endometrial receptivity. Abnormal decidualization of the endometrial stroma may clarify the possible association between adenomyosis and infertility. Our findings may be clinically useful for counseling and treatment of infertile adenomyosis patients. This study was supported by the National Natural Science Foundation of China (82001523 and 82171639). The authors have no conflicts of interest to disclose. N/A.

Clinical-anamnestic features and life quality of patients with nodular and diffuse adenomyosis

Introduction.Adenomyosis remains one of the significant challenges in modern gynecology and affects a large number of women of reproductive age. The clinical presentation of adenomyosis is variable, with severity of symptoms depending on the form of the disease. In case of the occurrence of severe pelvic pain, dysmenorrhea and dyspareunia, the disease disrupts social functions and leads to a decrease in the patient’s quality of life.Aim.To study clinical and anamnestic features and patient’s quality of life with diffuse and nodular forms of adenomyosis.Materials and methods.The study included 126 patients with various forms of adenomyosis (45 patients with nodular adenomyosis (NAM), 81 with stage III – IV DAM). The control group included 20 patients with tubo-peritoneal factor of infertility, without adenomyosis based on the ultrasound and hysteroscopy findings. All patients underwent a comprehensive examination, including general clinical, instrumental and laboratory tests. The study included a comparative analysis of the obtained data and determination of the clinical and anamnestic characteristics of the patients with stage III – IV DAM as compared with the patients with NAM. We also studied the quality of life of patients with NAM and DAM on the basis of a specialized questionnaire on the study of the quality of life of patients with endometriosis – Endometriosis Health Profile, ENR-5+6. Statistical analysis and data processing were conducted using Microsoft Excel (version 16), Statistica 10.0, StatPlus 7.3, GraphPad Prism 9 software. Data processing was performed in accordance with the guidelines for medical and biological research.Results and discussion.As compared with patients with nodular adenomyosis, the patients with stage III-IV diffuse adenomyosis are characterized by an older age (42.1 (4.6) and 34.6 (6.2) years, respectively; p <0.001), have a high prevalence of somatic (96 and 77%, respectively; p < 0.05) and gynecological pathology (79 and 51%, respectively; p < 0.001) in past medical history, a higher frequency of intrauterine manipulations (hysteroscopy, separate diagnostic curettage) (73 and 42%, respectively; p < 0.001) and medical abortions (52 and 28%, respectively, p < 0.001). Complaints of heavy menstruation, bloody vaginal discharge between periods, and intestinal symptoms had a special place among the complaints of such patients. Moderate to severe anemia, as a consequence of heavy menstrual bleeding, was also a frequent concomitant pathology.Conclusions.Stage III-IV DAM is characterized by a more severe course and marked symptoms as compared with NAM, and significantly affects the patient’s quality of life.

Occurrence of chronic endometritis in different types of human adenomyosis.

PurposeHuman adenomyosis has an adverse effect on female fertility. Exact mechanistic basis is still unclear. We investigated the occurrence of chronic endometritis (CE) in different types of human adenomyosis.MethodsThis is a prospective non‐randomized observational study enrolling patients with focal (n = 30), diffuse (n = 26), intrinsic (n = 23), and extrinsic (n = 10) adenomyosis. Endometrial biopsy samples were collected from hysterectomy specimens. Immunohistochemical analysis was performed using antibody against CD68 (Mφ marker) with biopsy samples of intrinsic/extrinsic adenomyosis and CD138 (Syndecan‐1), a marker of plasma cells, in all biopsy samples.ResultsIn GnRHa‐untreated groups, a higher trend in the occurrence of CE, as characterized by infiltration of ≥1 plasma cells in endometrial stroma, was found in women with focal (58.8%, p = 0.0849) and diffuse adenomyosis (60.0%, p = 0.0841) comparing to control women (10.0%). In women with focal adenomyosis, ipsilateral side showed a significantly higher occurrence of CE (58.8%) than on the contralateral side (11.7%) (p = 0.043). Tissue infiltration of macrophages in endometria was significantly higher in intrinsic than in extrinsic adenomyosis (p = 0.03) without showing any significant difference in the occurrence of CE between these two variants of adenomyosis.ConclusionA variable occurrence of CE in different types of adenomyosis may be involved in adverse reproductive outcome.

SINGLE CELL ANALYSIS REVEALS HETEROGENEITY IN THE DISEASE RELEVANT CELL TYPES OF ADENOMYOSIS

To identify cellular composition and gene expression profiles of the cell types in adenomyotic tissue, eutopic endometrium, and normal myometrium of the women with diffuse adenomyosis. Adenomyotic tissue (n=3), eutopic endometrium (n=3), and myometrium (n=3) were obtained from premenopausal women who underwent hysterectomy for diffuse adenomyosis and confirmed by frozen section histologic evaluation. Following digestion, the stromal and smooth muscle cells were collected, and the epithelial cell pellets were further digested. After checking the viability, which was at least 75%, samples subjected the 10x Genomics® Single Cell Protocol. Processed data from the Cell Ranger pipeline was analyzed using the R package Seurat (v3.2). Uniform Manifold Approximation and Projection was generated to visualize cell clusters. The Wilcoxon rank sum test was used to compare the gene expression profile for each cluster which were annotated by marker genes. We identified ciliated and unciliated epithelial cells, fibroblast-like cells, smooth muscle cells (SMC), endothelial cells, pericytes, vascular SMCs, progenitor cells, T cells, NK cells, B cells, MQ, and monocytes, neurons and myeloid progenitors in the adenomyotic uterus. Notably, comparative transcriptome analysis of epithelial cells in eutopic endometrium and adenomyotic tissue revealed a small subset of differentially expressed genes, indicating the stability of the transcriptional program of these cells. On the other hand, we identified a high degree of heterogeneity among the fibroblast populations. Intriguingly, fibroblast-like cells in adenomyotic vs eutopic endometrial tissue showed higher expression of progesterone-responsive genes. In contrast, eutopic endometrial epithelial cells displayed higher expression of progesterone-responsive genes. Pseudo-time analysis in eutopic endometrium have demonstrated evidence of both epithelial-mesenchymal and mesenchymal-epithelial transition originating from a progenitor cell population and pericytes, respectively. Our analyses revealed 15 distinct cell populations in adenomyotic tissue. Fibroblast-like cells constituted the majority of all cell types which showed a high degree of heterogeneity, which may be due to different transcriptional states linked to the intense inflammatory processes in adenomyosis. Our results suggest that progesterone response may vary between cell types in adenomyotic tissue. The lack of a substantial difference between epithelial cells in adenomyosis and adjacent endometrium supports the postulated mechanism whereby invagination of eutopic endometrial tissue is responsible for adenomyosis.

Ultrasound Findings of Adenomyosis in Adolescents: Type and Grade of the Disease

To evaluate the ultrasound features, types, and degrees of adenomyosis among adolescents and to correlate these findings with clinical symptoms DESIGN: A retrospective observational study. Gynecological ultrasound units from January 2014 to June 2020. A total of 43 adolescents (aged 12-20 years) who were diagnosed as having adenomyosis at a pelvic ultrasound examination. Ultrasound features and location and type of adenomyosis within the uterus were evaluated on stored 2-dimensional images and videos and 3-dimensional volumes. Adenomyosis was classified as mild, moderate, and severe according to the extension of the disease in the uterus as described in our previous published classification. Adenomyotic features recorded among our population were myometrial hyperechoic areas, uterine wall asymmetry, intramyometrial cystic areas, and some types of junctional zone alterations. The posterior uterine wall (58%) and the outer myometrial layer (93%) were mostly affected. In 44% of adolescents (19/43) with adenomyosis, at least 1 location of pelvic endometriosis was documented. Dysmenorrhea was the most commonly reported symptoms (88%), and it was associated with adenomyosis of the outer myometrium, myometrial hyperechoic areas, uterine wall asymmetry, and intramyometrial cystic areas. Adolescents with dyspareunia showed diffuse adenomyosis (9/9 patients) including both the inner and outer myometrium (7/9 patients) and in the posterior wall (7/9 patients). Heavy menstrual bleeding was associated with diffuse adenomyosis (18/23 patients) mostly of the outer myometrium (22/23 patients). Scoring system showed predominantly mild disease and no severe adenomyosis was found. Adolescents with diffuse adenomyosis were significantly older and showed a high percentage of heavy menstrual bleeding compared with those with the focal disease of the inner myometrium. This study shows that adenomyosis is not only a pathology of adult life, but it involves young patients mostly in a mild-to-moderate form and is associated with typical painful symptoms. In adolescents, the diagnosis of adenomyosis is feasible through a noninvasive way with ultrasound and a proper management can be set.

A case of adenomyosis with leiomyoma that was effectively treated with relugolix and kamishoyosan add-on therapy

BackgroundRecently, relugolix, an oral gonadotropin-releasing hormone receptor antagonist, has been considered an effective therapy for leiomyoma based on a phase 3 study in Japanese women. Leiomyoma combined with severe adenomyosis occasionally occurs in perimenopausal women; however, little information on the effectiveness of relugolix against severe adenomyosis exists.Case presentationA 49-year-old woman was referred to our hospital with acute lower abdominal pain and abnormal uterine bleeding. Magnetic resonance imaging revealed multiple leiomyomas with diffuse adenomyosis. Left hydrosalpinx was also observed. The patient refused surgical treatment and preferred oral relugolix. Since she experienced a hot flush and headache induced by relugolix, a traditional Japanese Kampo, kamishoyosan, was added to improve the side effects of relugolix. The patient was asymptomatic at the time of this report and experienced a significant shrinkage in uterine volume. Ultimately, she avoided hysterectomy as desired.ConclusionsTo our knowledge, this is the first report of co-occurring adenomyosis and leiomyoma, which was effectively treated with relugolix. Although the management of adverse side effects, including hot flush and headache by relugolix, has recently attracted attention and controversy, relugolix add-on therapy with kamishoyosan may help treat menopausal symptoms.

Influence of nodular and severe forms of diffuse adenomyosis on reproductive function: a review of reproductive outcomes of surgical interventions and IVF

This review includes an analysis of clinical studies evaluating the effect of adenomyosis on reproductive function, as well as a review of studies on the relationship between surgical treat-ment options for adenomyosis and reproductive outcomes. Different studies of women populations after in vitro fertilization and/or intracytoplasmic sperm injection (IVF/ICSI) and after surgical treatment of deep adenomyosis have shown that adenomyosis in both cases has a negative effect on the reproductive outcome, although there are significant differences in these populations. In the literature, there are relatively few data on the degree of influence of the depth of the lesion on the realization of the reproductive function, however, a significant correlation was revealed between them. The positive effect of treatment with gonadotropin-releasing hormone agonists, followed by surgical treatment of adenomyosis, has also been described in several literary sources, but there have been no controlled studies on this topic. Many studies do not meet the validity criteria due to the lack of clear criteria for inclusion and exclusion from the study. The choice of the optimal treatment options for adenomyosis based on the actual data is difficult due to the lack of reliable evidence of the relationship between fertility and the degree of adenomyosis. However, it is known that adenomyosis can reduce the likelihood of successful implantation so ramatically that surgical or other treatment options are reasonably recom-mended. At the same time, it is necessary to assess the possible positive effect of the treatment options available in the doctor’s arsenal. Thus, timely referral to specialized treatment of ade-nomyosis may be crucial for the successful implementation of reproductive function in patients with suspicion or with an established diagnosis of adenomyosis in combination with recurrent miscarriage, who refuse to use assisted reproductive technologies, medical institutions. This review will analyze the relationship between infertility and adenomyosis, as well as review studies of reproductive outcomes in different options for surgical treatment of adenomyosis in infertile patients.

O-146 Assessment of focal and diffuse adenomyosis lesions before and after pregnancy on magnetic resonance imaging : a cohort of 139 patients

Abstract Study question How to assess the different adenomyosis phenotype before and after pregnancy on magnetic resonance imaging according to stringent validated criteria ? Summary answer Diffuse adenomyosis increases significantly after pregnancy while the rate of focal adenomyosis and the mean volume of focal adenomyosis lesions decrease significantly after pregnancy. What is known already Adenomyosis and endometriosis are benign hormone-dependent disorders associated with pelvic pain, dysmenorrhea and/or infertility. The natural course of adenomyosis and endometriosis is still unclear, particularly during pregnancy. Pregnancy is considered to have a positive impact on endometriosis. Several studies regarding the impact of adenomyosis on pregnancy are available. Adenomyosis can cause fertility disorders, miscarriage, preterm birth. However, available data evaluating the effect of pregnancy on adenomyosis are lacking. Study design, size, duration Between January 1st 2010 and September 30th 2020, 139 patients were followed in our referral care center (Gynecology department of Port-Royal Hospital, Paris) for symptomatic adenomyosis and or endometriosis. For each of them, a magnetic resonance imaging were performed before and after pregnancy. The data based on magnetic resonance imaging, pre- and post-pregnancy, were analyzed in a single retrospective study. Participants/materials, setting, methods Patients had to be over 18 years old, to be pregnant and to be followed for symptomatic adenomyosis or endometriosis without any previous surgery. Each pelvic magnetic resonance imaging were performed by a single experienced radiologist. The protocol was identical on a 1.5 T magnetic resonance imaging machine based on validated criteria. The rate of diffuse and focal adenomyosis, the volume of focal adenomyosis lesions and the thickness of maximal junctional zone were reported. Main results and the role of chance The mean age of patients was 34.6 ± 3.4 years old, 83 (59.7%) of patients underwent assisted reproductive technology to be pregnant. The mean time interval between the MRI and the delivery was 55.2 months and the mean time interval between the delivery and the MRI was 32.2 months. Before pregnancy, there was 96 (69.1%) patients with adenomyosis, all phenotype combined versus 111 (79.9%) after pregnancy (p = 0.04) on magnetic resonance imaging. The rate of diffuse adenomyosis increased significantly on magnetic resonance imaging after pregnancy compared to before pregnancy (n = 22 (15.8%) vs n = 41 (29.5%), p = 0.01). The thickness of junctional zone maximal was significantly higher after pregnancy (8.0 mm ± 5.1 vs 12.0 mm ± 4.8, p < 0.01). The rate of focal adenomyosis (n = 55 (39.6) vs n = 34 (24.5), p = 0.01) as well as the volume of focal adenomyosis lesions (6.7 mm3 2.5± vs 6.4 mm3 ± 2.3, p < 0.01) decreased significantly after pregnancy on magnetic resonance imaging. Limitations, reasons for caution This single-center study was conducted in a referral center whom patients presented more severe forms of adenomyosis, which could have affected the external validity of this study. The mean time interval between delivery and MRI was 32.2 month which implies a short follow up period to observe long term outcomes. Wider implications of the findings The hypothesis that a specific hormonal environment during pregnancy may imply a positively impact of the evolution of focal adenomyosis is raised by this study. The evolution of focal adenomyosis after pregnancy is similar to the evolution of endometriosis lesions volume that support shared etiopathogenic mechanisms between the two entities. Trial registration number ‘not applicable’

P–348 Laparoscopic radiofrequency thermal ablation for diffuse adenomyosis: symptomatology after a long-term follow-up

Abstract Study question Is conservative laparoscopic treatment with RFA (radiofrequency thermal ablation) related to a good outcome on a long-term follow-up? Summary answer RFA for diffuse adenomyosis was related to a good outcome on a long-term follow-up in terms of pain and ultrasonographic reduction. What is known already Uterine adenomyosis may cause symptoms refractory to medical treatment. New, uterine-sparing treatments have been introduced for patients who desire avoiding hysterectomy. Among surgical techniques used for this purpose, radiofrequency thermal ablation (RFA) has been introduced, first for the treatment of uterine fibroids and then for focal adenomyosis. Diffuse adenomyosis is characterized by an extensive involvement of uterus, as on ultrasound less than 25% of the lesion is surrounded by healthy myometrium. It often leads to enhanced uterine volume, which presents soft consistence and globular aspect. Conservative treatment of diffuse adenomyosis is a real challenge. Study design, size, duration All consecutive patients who underwent RFA for diffuse adenomyosis in our institution between July 2011 and August 2017. Patients with focal adenomyosis were not included in the study. The treatment was reserved to selected patients who wanted to conserve the uterus and presented symptoms such as pain or abnormal uterine bleeding refractory to medical treatment. In all cases the treatment was performed by laparoscopy, which allowed for complete removal of extrauterine endometriosis, if associated. Participants/materials, setting, methods Nineteen patients (aged 33–49, mean 40) underwent radiofrequency thermal ablation for diffuse adenomyosis, and all of them completed the follow-up. Setting: referral center for endometriosis (Department of Obstetrics and Gynecology, Gynecologic Oncology and Minimally-Invasive Pelvic Surgery, International School of Surgical Anatomy, Negrar). Follow-up consisted on ambulatory clinical evaluation with pelvic ultrasound and assessment of pain using the visual analog scale (VAS) ranging from 0 to 10 points for all pain components. Main results and the role of chance: Endometriosis was associated in12 cases, (63%) and in all cases was removed completely during surgery. The mean follow-up was 64 months (range 29–105). Abnormal uterine bleeding was present in 11 (60%) patients before the treatment and only in four of them (21%) during the follow-up. Preoperative and postoperative mean VAS score for dysmenorrea, dyspareunia, dyschezia and chronic pelvic pain was 6.95 vs 3.7, 4.1 vs 1.4, 3.7 vs 0.9 and 3.9 vs 1.5 respectively (p < 0.05 for all pain components). The reduction of adenomyosis on ultrasound was observed in 75% of cases. After surgery, two of four patients who desired pregnancy conceived, one of them delivered at term by caesarian section and one had an extrauterine pregnancy. Hysterectomy was performed in two cases during follow-up, at 35 and at 84 months after RFA. Limitations, reasons for caution The present study reports outcome in a limited population as the treatment was reserved to selected cases. The results, particularly regarding fertility and pregnancy outcome should be taken with caution because of small numbers. In our opinion for the moment the treatment should be performed in selected cases. Wider implications of the findings: The present treatment could be performed to avoid hysterectomy, as it was necessary only in two cases in our study. No cases of hysterectomy were reported within the first two years from surgery, so we can consider that RFA allows at least a temporary benefit on symptoms. Trial registration number Not applicable

P–287 Uterine adenomyosis does not affect perinatal outcomes in ART treatments

Abstract Study question Is adenomyosis associated with worse clinical and perinatal outcomes in ovum donation cycles? Summary answer Adenomyosis was associated with reduced live birth rate per embryo transfer but not with increased risk of miscarriage or worse perinatal outcomes than controls. What is known already The effect of adenomyosis on IVF/ICSI outcomes are controversial as studies addressing this issue are limited in number and heterogeneous. Conclusions withdrawn from previous works differ regarding the prospective or retrospective design of the study. Two different metanalysis conducted showed that adenomyosis reduced implantation and clinical pregnancy rate and increased miscarriage risk. However, current data regarding perinatal outcomes of assisted reproduction techniques cycles in patients diagnosed with uterine adenomyosis is scarce. Study design, size, duration A retrospective cohort study in which 3307 patients undergoing ovum donation cycles were included. Patients who underwent single embryo transfer (SET) between years 2018 and 2019 were included and divided into two groups: adenomyosis (n = 179) and controls (n = 3218). Participants/materials, setting, methods Inclusion criteria consisted of patients in an oocyte donation program who had fresh SET on day 5 blastocyst stage development. Patients diagnosed with miomas and/or severe endometriosis and those who had undergone previous uterine surgical interventions were excluded from the study. Cases consisted of patients with a history of either focal or diffuse adenomyosis diagnosed via transvaginal ultrasonography (TVUS). Main results and the role of chance Clinical pregnancy rate per embryo transfer was 82/179 (45.8%) in those women diagnosed with adenomyosis versus 1869/3218 (59.8%) in control group (OR = 0.57 95% CI. 0.41–0.78, p < 0.001). Miscarriage rate was similar in the two study groups and differences found were not statistically significant, being 15/82 (18.3%) for adenomyosis and 309/1869 (16.5%) for control group. A lower live birth rate per embryo transfer was observed in women diagnosed with adenomyosis versus control, being 68/179 (38%) and 1560/3128 (49.9%) respectively (OR = 0.615 95% CI 0.44–0.85, p = 0.002). There were no statistically significant differences between childbirth delivery methods (vaginal versus caesarean section). Furthermore, means of gestational age at the time of delivery, newborn size and weight and incidences of low birth weight, preterm birth and admission in neonate intensive care unit (NICU) did not differ between the two groups. In addition, IVF and perinatal outcomes were similar in patients with diffuse adenomyosis compared to focal adenomyosis. Limitations, reasons for caution This is an observational study and thus possible confounders cannot be completely excluded. Diagnostic of adenomyosis is complex and, despite imaging via TVUS is both sensitive and specific, different criteria may be combined in order to fully assess the diagnostic. Wider implications of the findings: Published literature has described how adenomyosis negatively impacts clinical outcomes in ART cycles; however, data regarding perinatal results is scarce. This study is of interest as it provides a first insight for clinicians showing that adenomyosis affects clinical but not perinatal outcomes in ovum donation cycle. Trial registration number Not applicable

Ultra-Long GnRH Agonist Protocol During IVF/ICSI Improves Pregnancy Outcomes in Women With Adenomyosis: A Retrospective Cohort Study.

ObjectiveThis study aimed to compare the ultra-long gonadotropin-releasing hormone agonist (GnRH-a) protocol and the long GnRH-a protocol during in vitro fertilization (IVF) or intracytoplasmic sperm (ICSI) treatment on fertility outcomes in women with adenomyosis.Materials and MethodsThis study was a retrospective cohort study. From January 2011 to May 2018, a total of 371 fresh IVF/ICSI cycles were included. Among the cycles included, 237 cycles of 212 women underwent the ultra-long GnRH-a protocol, while 134 cycles of 116 women underwent the long GnRH-a protocol. The rates of implantation, clinical pregnancy per embryo transfer, live birth, and early miscarriage were estimated between the compared protocols.ResultsIn the study, the early miscarriage rate in women undergoing the ultra-long GnRH-a protocol was significantly lower than those undergoing the long GnRH-a protocol (12.0% versus 26.5%, p = 0.045), whereas the differences in the rates of biochemical pregnancy, implantation, clinical pregnancy, and live birth in women between the two groups showed no statistical significance. The pregnancy outcomes were also sub-analyzed according to the adenomyotic region (diffuse and focal). As for diffuse adenomyosis, the rates of clinical pregnancy and live birth in women undergoing the ultra-long GnRH-a protocol were significantly higher than those undergoing the long GnRH-a protocol (55.3% versus 37.9%, p = 0.025; 43.4% versus 25.9%, p = 0.019, respectively). However, pregnancy outcomes showed no difference between the two protocols in women with focal adenomyosis.ConclusionsThe ultra-long GnRH-a protocol during IVF/ICSI improves pregnancy outcomes in women with adenomyosis, especially in women with diffuse adenomyosis when compared with the long GnRH-a protocol.

Laparoscopic Uterine Artery Occlusion Combined with Uterine-sparing Pelvic Plexus Block and Partial Adenomyomectomy for Adenomyosis: A Video Case Report

OBJECTIVE Adenomyosis usually causes dysmenorrhea and anemia. Clinically, it is difficult to be solved by medicine and traditional surgery, and hysterectomy is always performed for radical treatment. In this article, we introduce a new method which could control the dysmenorrhea and anemia through laparoscopic uterine artery occlusion (LUAO) combined with uterine-sparing pelvic plexus block, and partial adenomyomectomy for uterus perservation.

The peculiarities of the management of women with endometriosis during pregnancy

Endometriosis is a significant problem in modern medicine. The prevalence of endometriosis is 10%, it occurs in 38% of women with infertility. For a century, it was believed that pregnancy contributes to the reduction in volume and even the disappearance of foci of endometriosis. Also, the state of «pseudopregnancy» under the influence of combined oral contraceptives was once considered an effective treatment strategy. To date, it is known that decidualization of endometrioid heterotopias not only contributes to their increase in size, but can also provoke bleeding. These changes can mimic ovarian cancer on ultrasonography. Typical complications of endometriosis are enlargement, rupture, or abscess formation.It has been proven that women with endometriosis have an increased relative risk of developing: preeclampsia by 19%; fetal growth retardation by 12%; premature birth by 46%; placenta previa almost threefold; preterm placental abruption by 40%; caesarean section operations by 49%; stillbirth by 27%; postpartum hemorrhage by 5%; spontaneous intra-abdominal bleeding by 24.6 times – only two cases are known in women with endometriosis and no bleeding from the intact peritoneum is known; spontaneous bowel perforation (only 18 cases are known). It has been proven that in pregnant women with endometriosis, the invasion of the extravillous trophoblast into the spiral vessels of the uterus is impaired. However, there is evidence that the endometrioid phenotype is not associated with placental dysfunction and does not increase the risk of developing great obstetric syndromes.Since most of the complications of endometriosis during pregnancy cannot be predicted, any additional interventions are not of use. So, to date, there is no evidence of the need to introduce separate protocols for the management of women with endometriosis during pregnancy. However, there should be an individualization of the approach in each separate case. The given atypical clinical case in a woman with diffuse adenomyosis demonstrates the importance of the problem of predicting various complications of pregnancy and childbirth. Moreover, clinical cases contribute to the continuation of the study of this disease.

The Value of Adenomyosis Type in Clinical Assessment: A Single-center Experience of 755 Nodular and Diffuse Adenomyosis Cases.

To investigate the incidence of nodular and diffuse adenomyosis, concomitant pathologies and also to compare the demographic and clinic differences among patients with adenomyosis and their surgery indications. This retrospective study was conducted in Tepecik Research Hospital, Izmir, Turkey between 2014 and 2016. Patients were divided into two groups of nodular and diffuse adenomyosis. The following variables were evaluated for both groups: age, gravidity, parity, menopausal status, indication for hysterectomy, ultrasonographic parameters, gynecological symptoms (abnormal uterine bleeding [AUB], pelvic pain and pelvic pressure, postmenopausal vaginal bleeding), preoperative and postoperative histopathological assessment, and coexisting pathologies. Of the total 3457 cases of hysterectomies, 755 (95% CI: 20.4-23.1) were confirmed with adenomyosis. There were 217 (95% CI: 23.9-30.0) postmenopausal women. Adenomyosis was most commonly detected in patients in the age of 40 to 50 (57.6%). The most common symptoms were AUB (n: 336) (95% CI: 40.9-48.0), pelvic pain or pressure (n:139) (18.4%), and postmenopausal vaginal bleeding (n: 119) (95% CI: 13.1-18,4). Seventy-four (95% CI: 7.9-11.9) of the patients had nodular and 681(95% CI: 88.0-92.3) had diffuse adenomyosis. Demographic data, age, parity, gravidity, endometrial thickness, and menopausal status were similar between the groups. AUB was more frequently detected in nodular adenomyosis (56.8%). Myoma uteri was the main hysterectomy indication in both groups. In addition, treatment-resistant AUB for nodular adenomyosis and endometrial pathologies for diffuse adenomyosis were the most frequent indications for hysterectomy after myoma uteri. The most common form of adenomyosis was the diffuse form. Endometrial pathologies were more frequently associated with diffuse adenomyosis. Asymptomatic and incidental adenomyosis were more common with the diffuse form. AUB was more frequently detected with nodular adenomyosis.

Imaging for evaluation of endometriosis and adenomyosis.

Endometriosis and adenomyosis are two frequent diseases that impair women's quality of life by causing pain and infertility. Both endometriosis and adenomyosis are heterogeneous diseases that manifest as different forms. Adenomyosis may be described as diffuse adenomyosis, focal adenomyosis especially of the outer myometrium and cystic adenomyoma. Endometriosis has three phenotypes: superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA), and deep infiltrating endometriosis (DIE). These two diseases are closely linked, and it is now clear that adenomyosis can either arise on its own or coexist with endometriosis. There is a strong clinical relationship between endometriosis and adenomyosis according to their respective phenotypes. Various classifications are available to describe both diseases. Transvaginal ultrasonography (TVUS) and/or pelvic magnetic resonance imaging (MRI) are the first examination performed when endometriosis or adenomyosis are suspected. These two imaging techniques, used in a combination manner, allow accurate description of both endometriosis and adenomyosis, to assess the diagnosis and to improve clinical and surgical care. In this review, we described the different imaging aspects of endometriosis and adenomyosis to help the less experienced radiologist or gynecologist in the diagnosis and evaluation of those diseases.

Relationship between magnetic resonance imaging-based classification of adenomyosis and disease severity.

The purpose of this study is to first investigate the correlation between image features and histological findings and the clinical severity of adenomyosis; second, search for imaging features to assess the type and locoregional extension of the disease; and finally, discuss the notation of image-based classification. This paper combines a review of the literature on adenomyosis with a series of cases who underwent surgery at Nara Medical University Hospital. Currently, there has been a lack of clear, clinically relevant, and internationally acceptable definition and histological classification due to its diverse phenotype. A number of researchers have attempted to standardize the magnetic resonance imaging (MRI) features of adenomyosis. Some researchers have begun studies that relate the subtype classification using MRI to disease severity. There is evidence suggesting that diffuse adenomyosis and intrinsic adenomyosis are correlated with menstrual bleeding, while extrinsic adenomyosis and coexistence of deep infiltrating endometriosis (DIE) are related to pelvic pain. MRI-based classifications that are simple for use in the clinical setting are beginning to be proposed. However, the reliability and validity of these classifications have not yet been verified. A simplified notation is required to discuss the association between the classification and severity of adenomyosis. We introduce case reports using the notation of four items necessary for classification of adenomyosis. There is an urgent need to determine the definitions of terms used in subtype classification and to create and validate a globally unified notation that can predict the severity of adenomyosis symptoms.

An axonemal alteration in apical endometria of human adenomyosis.

Is there any change in the distribution of microvilli and microtubules in the apical endometria of women with adenomyosis? We observed microvilli damage in the apical endometria and an axonemal alteration characterized by abnormal distribution of longitudinal bundles of microtubules within microvilli in women with adenomyosis. Human adenomyosis has a negative impact on female fertility. Abnormal utero-tubal sperm transport, tissue inflammation and toxic effect of chemical mediators have been proposed as contributing factors. Inflammation-induced damage of mucosal cilia in the Fallopian tube has been reported. However, information on inflammation-induced damage of microvilli on the apical endometrial cells and its core bundles of microtubules in adenomyosis remains unknown. This is a prospective cohort study with subjects undergoing laparoscopic surgery or hysterectomy for clinical indication and evaluations of endometrial biopsy samples in two academic university hospitals. During the period between March 2015 and December 2018, endometrial biopsy samples were prospectively collected from 15 control women and 45 women with adenomyosis for immunohistochemical analysis and a separate cohort of 10 control women with cervical intraepithelial neoplasia Grade 3 (CIN3) and 20 women with adenomyosis for analysis by immunohistochemistry and transmission electron microscopy (TEM). For immunohistochemical study, endometrial biopsy samples were prospectively collected from 15 control women with fibroids, 25 women with focal adenomyosis and 20 women with diffuse adenomyosis after surgery. The diagnosis of fibroid and adenomyosis was made clinically by transvaginal ultrasonography and magnetic resonance imaging and confirmed by histology. Immunohistochemical analysis was performed retrospectively using antibody against CD68 (marker of macrophages) in endometrial biopsy specimens of women with and without adenomyosis. TEM was performed with the apical endometria collected from a separate cohort of 10 control women with CIN3 and 20 women with focal and diffuse adenomyosis for the identification of any change in the distribution of microvilli and longitudinal bundles of microtubules within microvilli. Comparing to control endometria and contralateral side, tissue infiltration of macrophages (Mφ) in the endometria was significantly higher on the ipsilateral side of focal adenomyosis (P = 0.02 and P = 0.03, respectively) and anterior/posterior walls of diffuse adenomyosis (P = 0.01 for both). In a subgroup analysis of patients with focal adenomyosis with and without symptoms, the endometria of symptomatic women displayed a tendency of higher Mφ infiltration on the ipsilateral side than in asymptomatic women (P = 0.07). Comparing to contralateral side endometria of symptomatic women, Mφ infiltration was significantly higher in the endometria of symptomatic women collected from the ipsilateral side of focal adenomyosis (P = 0.03). We found a significantly less tissue infiltration of Mφ in the endometria of women with CIN3 than that in endometria of women with focal adenomyosis. TEM analysis showed that number of microvilli in the endometria was significantly decreased on the ipsilateral side (P = 0.003) comparing to that on the contralateral side of focal adenomyosis. The Chi-squared test indicated that cases with abnormal (disruption in the normal arrangement of 9 peripheral pairs + 1 central pair) microtubules (MT) were significantly higher in women with adenomyosis than in cases with normal patterns (P = 0.0016). While contralateral side displayed significantly less abnormal MT (P = 0.0002), ipsilateral side of focal adenomyosis showed significantly higher abnormal MT (P = 0.0164) comparing to normal patterns. Cases with symptomatic adenomyosis showed significantly higher abnormal MT than normal MT (P = 0.0004). An axonemal alteration characterized by abnormal structural distribution of microtubules within microvilli in the apical endometria in response to endometrial inflammation may be involved in adverse reproductive outcome in women with adenomyosis. The average age of women in this study was high that may be associated with overall decline in fertility regardless of the presence or absence of adenomyosis or endometriosis. We collected endometrial biopsy samples from two completely separate cohorts of women for analysis by immunohiostochemistry and TEM. We need future follow-up study with increased sample size and from the same patients to precisely clarify the mechanistic link between axonemal alteration and negative fertility outcome. Our current findings may have some biological implication to better understand the endometrial epithelial biology and pathology in women with adenomyosis and may open the avenue for future study in other reproductive diseases. The ultra-structural abnormalities of microvilli and microtubules in the apical endometria in response to tissue inflammatory reaction may clarify the possible association between negative fertility outcome and adenomyosis. Our findings may be clinically useful during counseling with symptomatic patients with adenomyosis desiring pregnancy. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Sports, Culture, Science and Technology of Japan. There is no conflict of interest related to this study. N/A.

Adenomyosis is associated with specific proton nuclear magnetic resonance (1H-NMR) serum metabolic profiles

To determine whether the adenomyosis phenotype affects the proton nuclear magnetic resonance (1H-NMR)-based serum metabolic profile of patients. Cohort study. University hospital-based research center. Seventy-seven patients who underwent laparoscopy for a benign gynecologic condition. Pelvic magnetic resonance imaging and collection of a venous peripheral blood sample were performed during the preoperative workup. The women were allocated to the adenomyosis group (n = 32), or the control group (n = 45). The adenomyosis group was further subdivided into two groups: diffuse adenomyosis of the inner myometrium (n = 14) and focal adenomyosis of the outer myometrium (n = 18). Other adenomyosis phenotypes were excluded. Metabolomic profiling based on 1H-NMR spectroscopy in combination with statistical approaches. The serum metabolic profiles of the patients with adenomyosis indicated lower concentrations of 3-hydroxybutyrate, glutamate, and serine compared with controls. Conversely, the concentrations of proline, choline, citrate, 2-hydroxybutyrate, and creatinine were higher in the adenomyosis group. The focal adenomyosis of the outer myometrium and the diffuse adenomyosis phenotypes also each exhibited a specific metabolic profile. Serum metabolic changes were detected in women with features of adenomyosis compared with their disease-free counterparts, and a number of specific metabolic pathways appear to be engaged according to the adenomyosis phenotype. The metabolites with altered levels are particularly involved in immune activation as well as cell proliferation and cell migration. Nevertheless, this study did find evidence of a correlation between metabolite levels and symptoms thought to be related to adenomyosis. Further studies are required to determine the clinical significance of these differences in metabolic profiles.

Applicability of sonoelastography in leiomyoma and adenomyosis

Background. Uterine leiomyoma and endometriosis are common gynecological diseases of women in childbearing potential. This fact necessitates developing an optimal protocol for examination of patients in order to implement an individual approach to treatment. Diagnosis of mixed forms of pathological myometrium conditions causes some difficulties. Elastography technique makes it possible to assess the density of the myometrium, which may be essential for differentiating the diagnosis of leiomyoma and adenomyosis in mixed forms.
 Рurpose – to ascertain the potential of transvaginal ultrasound along with compression sonoelastography to determine the deformation coefficient in differential diagnosis of various pathological myometrium conditions.
 Materials and methods. The paper presents the analysis of elastographic findings of the uterus in 155 women obtained via compression sonoelastography performed by means of HITACHI AVIUS device. Patients were divided into 4 groups: control, women with uterine leiomyoma, uterine adenomyosis, with combined leiomyoma and adenomyosis. The transabdominal/ transvaginal ultrasound findings were confirmed by histopathological examination. The standard point scale was used to determine the deformation coefficient.
 Results. Elastographic characteristics were assessed in accordance with sonoelastography findings, i. e. deformation coefficients common in leiomyoma and adenomyosis. The maximum values of the deformation coefficient were obtained in leiomyoma (in an amount of 2 to 6.0 units). In case of diffuse or focal adenomyosis, the deformation coefficient was in an amount of 0.5 to 1.5 units indicating high myometrial elasticity vs the unchanged myometrium. For its part, in Group I (control), the deformation coefficient ranged from 1 to 1.7 units. High myometrial elasticity in adenomyosis vs the unchanged myometrium as well low elasticity or high density of the myometrium in leiomyoma were observed.
 Conclusions. The deformation coefficients in patients with leiomyoma and adenomyosis and unchanged myometrium were obtained via ultrasound with compression sonoelastography and they made it possible to determine the degree of elasticity of the myometrium and its changes in the relevant pathology. Elastography is capable of identifying clear distinctive features of leiomyoma and adenomyosis. The coincidence of the diagnosis of adenomyosis based on elastography and histology is significant, but not optimal. The unchanged myometrium has a certain elasticity, which can be equated to a numerical value, i. e. the deformation coefficient, and this param changes in case of leiomyoma or adenomyosis, which makes it possible to differentiate these pathological conditions of the myometrium.

Spontaneous pregnancy, macrosomia, and cephalopelvic disproportion in diffuse adenomyosis: a case report

Spontaneous pregnancy, macrosomia, and cephalopelvic disproportion in diffuse adenomyosis: a case report