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Objective: Fibroids are hormonally dependent uterine tumors. The literature on adiposity and fibroid prevalence is inconsistent. Previous work usually combined all those with a body mass index (BMI) ≥30 kg/m2 into a single category and relied on clinically diagnosed fibroids, which misclassifies the many women with undiagnosed fibroids. We used a prospective cohort design with periodic ultrasound screening to investigate associations between repeated measures of BMI and fibroid incidence and growth assessed at each follow-up ultrasound., Methods: The Study of Environment, Lifestyle & Fibroids followed 1693 Black/African American women, ages 23 to 35 years from Detroit, Michigan, with ultrasound every 20 months for 5 years. Measured height and repeated weight measures were used to calculate BMI. Fibroid incidence was modeled using Cox models among those who were fibroid free at the enrollment ultrasound. Fibroid growth was estimated for individual fibroids matched across visits as the difference in log-volume between visits and was modeled using linear mixed models. All models used time-varying BMI and adjusted for time-varying covariates., Results: Compared with BMI <25 kg/m2, those with BMI 30 to <35 kg/m2 had increased fibroid incidence (adjusted hazard ratio, 1.37; 95% CI, 0.96-1.94), those with BMI ≥40 kg/m2 had reduced incidence (adjusted hazard ratio, 0.61; 95% CI, 0.41-0.90). Fibroid growth had mostly small magnitude associations with BMI., Conclusion: BMI has a nonlinear association with fibroid incidence, which could be driven by effects of BMI on inflammation and reproductive hormones. More detailed measures of visceral and subcutaneous adiposity and their effects on hormones, DNA damage, and cell death are needed., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)

Selective progesterone receptor modulators (SPRMs) are synthetic steroid compounds that interact with the progesterone receptor, inducing various agonist, antagonist or mixed responses. First identified with mifepristone, they are now represented by ulipristal acetate (UPA), used for emergency contraception and uterine fibroids. Despite a few rare cases of severe hepatic insufficiency, SPRMs offer advantages in the treatment of uterine fibroids, reducing their volume without the hypoestrogenic side-effects of GnRH agonists, thus preserving patients' bone capital and quality of life. Despite temporary suspension of UPA administrated on a daily basis, research is exploring the potential of SPRMs in the management of endometriosis, adenomyosis and breast cancer. Despite certain concerns, SPRMs offer promising prospects in gynecological pathologies, opening up new therapeutic avenues to improve women's health and quality of life. This article describes the case of a patient with peritoneal leiomyomatosis for whom UPA significantly alleviated symptoms, reduced disease progression and improved quality of life, even allowing a pregnancy.

Background: Many risk factors in uterine fibroid development have been identified, but women and their physicians are less aware of the influence of lifestyle on uterine fibroid development. The objective of this systematic review is to investigate and summarize modifiable prognostic factors associated with uterine fibroid development., Methods: Pubmed and Embase were searched for relevant articles according to PRISMA guidelines. References from included articles were screened and when relevant also included. Human in vivo studies on modifiable factors in fibroid development were included. Studies on non-modifiable factors and treatment, in vitro studies and animal studies were excluded. 607 articles were screened and 33 articles were included. Two independent investigators collected data from the report., Results: The strongest risk factor for fibroid development was a high BMI, while the strongest protective factors were a high fruit and vegetable intake and high vitamin D intake., Conclusion: More high-quality studies are necessary to better understand the impact of the abovementioned factors as well as the role they play in the growth of already existing fibroids.

Background: We aimed to evaluate changes in ovarian reserve and quality of life in women treated with ultrasound-guided high-intensity focused ultrasound (USgHIFU) for uterine fibroids., Methods: In this single-center prospective study, a total of 69 patients with uterine fibroids treated with USgHIFU from October 2018 to November 2021 were enrolled. Fibroid volume, anti-Müllerian hormone (AMH) levels, uterine fibroid symptom scores, and uterine fibroid symptoms and quality of life (UFS-QOL) questionnaire scores before and 1, 3, and 6 months after USgHIFU treatment were analyzed. Correlations between AMH levels and age, fibroid type, and fibroid location were assessed., Results: Data from 54 of the 69 patients included in the present study were analyzed. The UFS-QOL scores at baseline and at 1 month and 6 months after USgHIFU treatment were 70 (50.75-87.50), 57 (44.75-80.00), and 52 (40.75-69.00) points, respectively (p < 0.001). The rate of fibroid volume reduction increased significantly at the 3-month follow-up compared with the 1-month follow-up (p < 0.001), and no significant change was observed between the 3-month and 6-month follow-ups (p > 0.99). The median AMH levels before and at 1, 3 and 6 months after treatment were 1.22 (0.16-3.28) ng/ml, 1.12 (0.18-2.52) ng/ml, 1.15 (0.19-2.08) ng/ml and 1.18 (0.36-2.43) ng/ml, respectively (p = 0.2). Multivariate linear regression analyses revealed that age was independently associated with AMH levels., Conclusions: USgHIFU treatment for uterine fibroids can significantly improve quality of life with minimal adverse effects on ovarian function., (© 2024. The Author(s).)

Objective: Uterine fibroids increase the risk of preterm birth. The current study highlights uterine fibroid necrosis as a possible cause of (extreme) preterm birth., Study Design: Retrospective cohort study in one Dutch academic hospital. Cases were selected from the 526 participants of the MyoFert study (Netherlands Trial Register, NL7990), which included patients who presented between 2004 and 2018 and were between the age of 18 and 45 years at the time of diagnosis of uterine fibroids. Of these participants, 414 women became pregnant. A retrospective chart review of the first pregnancies was performed. The main outcomes were (imminent) preterm birth and signs of fibroid necrosis on ultrasound. In women with signs of fibroid necrosis, the following data were collected systematically: fibroid characteristics, clinical presentation, pregnancy outcome, and postpartum period., Results: In total, 66 women had a preterm birth (16 %, 66/414), of which 25 pregnancies ended between 16 and <24 weeks (38 %, 25/66) and 41 pregnancies ended between 24 and <37 weeks of gestation (62 %, 41/66). Of all women with preterm birth and available ultrasound images, 15 % (7/48) had fibroid necrosis at the time of labour. These seven patients, supplemented with three patients with fibroid necrosis during their first pregnancy and at least one episode of imminent preterm birth, are described in more detail. In these ten patients, the fibroids increased substantially in size during the first and second trimester, leading to severe abdominal pain in all patients and hospital admission in seven patients. Ultrasound examination of the fibroids showed heterogenic changes and focal transonic areas in the fibroid, which are characteristics that indicate fibroid necrosis. In four patients, myomectomy was performed and necrosis was confirmed histologically., Conclusion: Fibroid necrosis during pregnancy is likely associated with (imminent) preterm birth. Clinicians are advised to structurally evaluate the myometrium in pregnancy, specifically in women presenting with abdominal pain in the second trimester., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Uterine fibroids (UF) are the most frequent tumors in ladies and can pose an enormous threat to complications, such as miscarriage. The accuracy of prognosis may also be affected by way of doctor inexperience and fatigue, underscoring the want for automatic classification fashions that can analyze UF from a giant wide variety of images., Methods: A hybrid model has been proposed that combines the MobileNetV2 community and deep convolutional generative adversarial networks (DCGAN) into useful resources for medical practitioners in figuring out UF and evaluating its characteristics. Real-time automated classification of UF can aid in diagnosing the circumstance and minimizing subjective errors. The DCGAN science is utilized for superior statistics augmentation to create first-rate UF images, which are labeled into UF and non-uterine-fibroid (NUF) classes. The MobileNetV2 model then precisely classifies the photos based totally on this data., Results: The overall performance of the hybrid model contrasts with different models. The hybrid model achieves a real-time classification velocity of 40 frames per second (FPS), an accuracy of 97.45%, and an F1 rating of 0.9741., Conclusion: By using this deep learning hybrid approach, we address the shortcomings of the current classification methods of uterine fibroid., (© 2024 Wiley Periodicals LLC.)

Research Question: What is the expression pattern of Raf kinase inhibitory protein (RKIP) in different subtypes of leiomyoma (usual type, cellular, apoplectic or haemorrhagic leiomyoma, leiomyoma with bizarre nuclei and lipoleiomyoma) and leiomyosarcoma specimens, and what is its biological role in leiomyosarcoma cells?, Design: Leiomyoma and leiomyosarcoma specimens underwent immunohistochemistry staining. Leiomyosarcoma SK-LMS-1 cell line was RKIP knocked down and RKIP overexpressed, and cell viability, wound healing migration and clonogenicity assays were carried out., Results: A higher immunohistochemical expression of RKIP was observed in bizarre leiomyomas, than in usual-type leiomyomas. Decreased expression was also found in cellular leiomyoma, with generally absent staining in leiomyosarcomas. Upon RKIP expression manipulation in SK-LMS-1 cell line, no major differences were observed in cell viability and migration capacity over time. RKIP knockout, however, resulted in a significant increase in the cell's ability to form colonies (P = 0.011)., Conclusion: RKIP distinct expression pattern among leiomyoma histotype and leiomyosarcoma, and its effect on leiomyosarcoma cells on colony formation, encourages further studies of RKIP in uterine smooth muscle disorders., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Uterine leiomyomas (ULs) are non-cancerous tumors composed of smooth muscle cells that develop within the myometrium and represent the most prevalent pathological condition affecting the female genital tract. Despite the volume of available research, many aspects of ULs remain unresolved, making it a "paradoxical disease" where the increase in available scientific literature has not been matched by an increase in solid evidence for clinical management. Fertility stands at the top of the list of clinical issues where the role of ULs is still unclear. The leiomyoma subclassification system, released by the International Federaion of Gynecology and Obstetrics (FIGO) in 2008, introduced a new and more effective way of categorizing uterine fibroids. The aim was to go beyond the traditional classification "subserosal, intramural and submucosal", facilitating a detailed examination of individual ULs impact on the female reproductive system. The "type 3 UL" is a special type of myoma, characterized by its complete myometrial development while encroaching the endometrium. It is a unique "hybrid" between a submucous and an intramural UL, that may exert a detrimental "double hit" mechanism, which is of particular interest in patients wishing pregnancy. To date, no robust evidence is available regarding the management of type 3 ULs. The aim of this narrative review is to provide a comprehensive overview of the physiopathological mechanisms that type 3 UL may exert on fertility, and to present new perspectives that may help us to better understand both the need for and the methods of treating this unique type of fibroid., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Introduction: Black and underinsured women in the United States are more likely than their counterparts to develop uterine fibroids (UFs) and experience more severe symptoms. Uterine artery embolization (UAE), a uterine-sparing therapeutic procedure, is less invasive than the common alternative, open hysterectomy. To determine whether demographic disparities persist in UF treatment utilization, we reviewed patient characteristics associated with UAE versus hysterectomy for UF among studies of US clinical practices., Methods: A systematic literature review was conducted via PubMed, Embase, and CINAHL (PROSPERO CRD42023455051), yielding 1,350 articles (January 1, 1995, to July 15, 2023) that outlined demographic characteristics of UAE compared with hysterectomy. Two readers screened for inclusion criteria, yielding 13 full-text US-based comparative studies specifying at least one common demographic characteristic. Random effects meta-analysis was performed on the data (STATA v18.0). Egger's regression test was used to quantify publication bias., Results: Nine (138,960 patients), four (183,643 patients), and seven (312,270 patients) studies were analyzed for race, insurance status, and age as predictors of treatment modality, respectively. Black race (odds ratio = 3.35, P < .01) and young age (P < .05) were associated with UAE, whereas private insurance (relative to Medicare and/or Medicaid) was not (odds ratio = 1.06, P = .52). Between-study heterogeneity (I 2 > 50%) was detected in all three meta-analyses. Small-study bias was detected for age but not race or insurance., Conclusions and Implications: Knowledge of demographic characteristics of patients with UFs receiving UAE versus hysterectomy is sparse (n = 13 studies). Among these studies, which seem to be racially well distributed, Black and younger women are more likely to receive UAE than their counterparts., (Copyright © 2024 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Uterine fibroid is the most common non-cancerous tumor with no satisfactory options for long-term pharmacological treatment. Fibroblast activation protein-α (FAP) is one of the critical enzymes that enhances the fibrosis in uterine fibroids. Through STITCH database mining, we found that dipeptidyl peptidase-4 inhibitors (DPP4i) have the potential to inhibit the activity of FAP. Both DPP4 and FAP belong to the dipeptidyl peptidase family and share a similar catalytic domain. Hence, ligands which have a binding affinity with DPP4 could also bind with FAP. Among the DPP4i, linagliptin exhibited the highest binding affinity (Dock score = -8.562 kcal/mol) with FAP. Our study uncovered that the differences in the S 2 extensive-subsite residues between DPP4 and FAP could serve as a basis for designing selective inhibitors specifically targeting FAP. Furthermore, in a dynamic environment, linagliptin was able to destabilize the dimerization interface of FAP, resulting in potential inhibition of its biological activity. True to the in-silico results, linagliptin reduced the fibrotic process in estrogen and progesterone-induced fibrosis in rat uterus. Furthermore, linagliptin reduced the gene expression of transforming growth factor-β (TGF-β), a critical factor in collagen secretion and fibrotic process. Masson trichrome staining confirmed that the anti-fibrotic effects of linagliptin were due to its ability to reduce collagen deposition in rat uterus. Altogether, our research proposes that linagliptin has the potential to be repurposed for the treatment of uterine fibroids., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: This study examined the levels of VitD, VitD binding protein (DBP), and free VitD in leiomyomas patients and their association with the quantity, dimensions, and site of fibroid growths. Additionally, we evaluated the potentiality of employing these factors as a biomarker tool for the diagnosis and assessment of uterine fibroid progression., Methods: This study involved the participation of 55 women with leiomyomas and 50 healthy women. We utilized commercial ELISA kits to measure the levels of total VitD and DBP in their serum. Additionally, we calculated the levels of free VitD and the ratio of VitD to DBP. Moreover, we determined the number, size, and location of the leiomyomas in the patients., Results: There were no significant differences in the levels of total VitD between the groups. However, patients had significantly lower levels of free VitD and higher levels of DBP compared to the control group. The size of the largest leiomyomas showed a negative relationship with free VitD and a positive relationship with DBP. Receiver operating characteristic analyses, showed that the cut-off value for free VitD was 4.47 pg/mL, with a sensitivity of 75.6% and a specificity of 74.4%. The cut-off value for DBP was 256.2 μg/mL, with a sensitivity of 86% and a specificity of 70.3%., Conclusions: Free VitD and DBP potentially contribute to the development of leiomyomas and are linked to the size of these tumors. The measurement of serum levels of these factors could serve as additional biomarkers for the diagnosis of leiomyomas., (© 2024 Japan Society of Obstetrics and Gynecology.)

Purpose: A prospective investigation to assess the impact of 3 months of treatment with epigallocatechin gallate (EGCG), vitamin D and D-chiro-inositol (DCI) in the treatment of uterine fibroids (UF) with laparoscopic myomectomy as evidenced by surgical outcomes and effect on liver function., Methods: Non-pregnant or lactating women aged between 30 and 40 years were scheduled for laparoscopic myomectomy to treat symptoms or looking to conceive. After enrollment, patients were assigned to either (1) intervention group, assuming a total of 300 mg EGCG, 50 μg vitamin D, and 50 mg DCI divided in 2 pills per day for 3 months, or (2) control group, including untreated women scheduled to undergo laparoscopic myomectomy after 3 months., Results: 91 patients completed the study. The comparison of the surgical outcomes between the intervention (n = 44) and the control (n = 47) groups revealed that the treatment significantly reduces the duration of surgery (41.93 ± 7.56 min vs 56.32 ± 10.63 min, p < 0.001). Moreover, the treatment also reduced blood loss during surgery (149.09 ± 25.40 mL vs 168.41 ± 21.34 mL, p < 0.001), resulting in treated patients having higher Hb levels at discharge 11.27 ± 0.82 mL vs 10.56 ± 0.82 mL, p < 0.01). The surgery induced an increase in AST and in total bilirubin regardless of the assigned group, and the treatment induced no change in liver function., Conclusions: Our data suggest that EGCG plus vitamin D, and DCI could represent a safe option for women with UF scheduled for laparoscopic myomectomy, improving surgical outcomes without affecting liver functionality., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To quantify the reintervention rate and analyze the risk factors for reintervention after high-intensity focused ultrasound (HIFU) ablation of uterine fibroids., Methods: Eighteen studies were selected from the seven databases. A meta-analysis was applied to synthesize the reintervention rates for fibroids across various follow-up durations. Subgroup-analysis was conducted based on the year of surgery, sample size, guide methods, and non-perfusion volume ratio (NPVR). Signal intensity of T2-weighted imaging (T2WI) was independently evaluated for reintervention risk., Results: The study enrolled 5216 patients with fibroids treated with HIFU. There were 3247, 1239, 1762, and 2535 women reaching reintervention rates of 1% (95% confidence interval (CI): 1-1), 7% (95% CI: 4-11), 19% (95% CI: 11-27), and 29% (95% CI: 14-44) at 12, 24, 36, and 60-month after HIFU. The reintervention rates of patients treated with US-guided HIFU (USgHIFU) were significantly lower than those of patients treated with MR-guided focused ultrasound surgery (MRgFUS). When the NPVR of fibroids was over 50%, the reintervention rates at 12, 36 and 60-month after HIFU were 1% (95% CI: 0.3-2), 5% (95% CI: 3-8), and 15% (95% CI: 9-20). The reintervention risk for hyper-intensity fibroids on T2WI was 3.45 times higher (95% CI: 2.7-4.39) for hypo-/iso-intensity fibroids., Conclusion: This meta-analysis showed that the overall reintervention rates after HIFU were acceptable and provided consultative suggestions regarding treatment alternatives for patients with fibroids. Subgroup-analysis revealed that USgHIFU, NPVR ≥ 50%, and hypo-/iso-intensity of fibroids on T2WI were significant factors in reducing reintervention., Systematic Review Registration: PROSPERO, CRD42023456094.

Objective: Three-dimensional surface rendering of 2-D ultrasound images of the uterus in mapping uterine fibroids is a fast-evolving imaging technique that holds great potential for gynecology. The purpose of this study was to assess the accuracy of 3-D surface rendering of 2-D ultrasound images of the uterus using a new Fibroid Mapping Reviewer Application (FMRA) software for mapping uterine fibroids as compared with the pathological evaluation of uterine fibroids in pre-menopausal women undergoing hysterectomy., Methods: We enrolled women aged 35-55 y scheduled for hysterectomy for symptomatic fibroids at a tertiary care hospital from 2019 to 2021. Per pre-set guidelines, we recorded 2-D images and videos of the uterus with fibroids during the transvaginal ultrasound. The recordings were transferred through USB, loaded in the FMRA software and post-processed to generate a 3-D rendered uterus model. An experienced pathologist assessed and documented the gross examination details per a set protocol. We compared the pre-specified dimensions related to the size (L1, L2) and location (X, Y) of fibroids between the 3-D model and the pathologist's assessment of the hysterectomy specimen., Results: A total of 25 fibroids in 25 women, the single largest per woman, were considered for analysis. The two methods had good correlation with respect to size (for L1, R² = 0.9723, and for L2, R² = 0.9784) and location (for X, R² = 0.9618, and for Y, R² = 0.9753). Inter-observer analysis revealed that measurements from two sonologists were reproducible (Cronbach's α = 0.9 for the L1, L2 and L3 dimensions of fibroids from the 3-D model)., Conclusion: The FMRA is a novel tool for mapping fibroids. With its proven accuracy, it will be helpful in planning surgeries and during guided procedures for managing uterine fibroids., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the factors which may cause thermal injury of abdominal skin in patients with uterine fibroids (UFs) who underwent ultrasound-guided focused ultrasound ablation surgery (FUAS)., Method: A total of 123 patients were enrolled in the injury group. In contrast, 246 patients without thermal injury were assigned to the non-injury group. The relationship between patient and treatment parameters and injury were explored using univariate analysis and multiple logistic regression analyses. In addition, the factors influencing the degree of thermal injury were analyzed using Kruskal-Wallis H., Results: (1) Abdominal scars ( p  = .007, OR = 2.187, 95% CI: 1.242-3.849), abdominal wall thickness ( p  < .001, OR = 1.042, 95% CI: 1.019-1.067), fundus fibroids ( p  = .038, OR = 1.790, 95% CI: 1.033-3.100), UFs with hyperintense/mixed T2-weighted imaging (T2WI) signals ( p  = .022, OR = 1.843, 95% CI: 1.091-3.115), average sonication power (AP) ( p  = .025, OR = 1.021, 95% CI: 1.003-1.039), and treatment time (TT) ( p  < .001, OR = 1.017, 95% CI: 1.011-1.023) were independent risk factors for thermal injury, while treatment volume (TV) ( p  = .002, OR = 0.775, 95% CI: 0.661-0.909) was a protective factor for injury. (2) Four groups were subdivided according to the degree of thermal injury(Group A: without skin injury. Group B: with changed T2WI signal in the abdominal wall, Group C: mild skin injury, Group D: severe skin injury), comparison of each with every other showed that the abdominal wall in Groups A and D was thinner than Groups B and C, with statistically significant differences (P AB <0.05, P AC <0.01, P DC <0.05, P DB <0.05); Group A was slightly thicker than D, however, without statistical difference. The ratio of sonication time (ST) to TV in Group A was the lowest of all (P AB , P AC , P AD all < 0.05). And as the level of thermal injury rose, the ratio gradually increased, however, without statistical difference., Conclusions: Based on our limited results, the following conclusion was made. (1) Abdominal scars, abdominal wall thickness, fundus fibroids, UFs with T2WI hyperintense/mixed signals, AP and TT were independent risk factor. (2) Neither too thick nor too thin abdominal walls would be recommended, as both might increase the risk of skin injury. (3) Noticeably, the risk of skin injury might increase considerably when the ST was longer and the sonication area was more fixed.

A 59-year-old female was referred to our hospital for pancreatic tumor. She had undergone resection of uterine fibroids 27 years ago, and leiomyoma in the left thigh 8 years ago. Tumor markers were normal. A well-defined hypoechoic tumor measuring 26 mm × 22 mm was detected at the pancreatic tail using ultrasound. Inside the tumor, a small cystic structure was observed. High-sensitivity Doppler imaging revealed faint signals indicating blood flow from the periphery to the interior. Contrast-enhanced ultrasonography in the arterial phase revealed slow, heterogenous enhancement from the periphery to the center of the mass that occurred later than that in the pancreatic parenchyma. The tumor then exhibited homogeneous enhancement except for the periphery, with subsequent washout. Endoscopic ultrasound-fine-needle aspiration was performed. Histopathological examination diagnosed a leiomyoma. The left thigh tumor resected 8 years ago had been diagnosed as benign metastatic leiomyoma (BML). We considered that the current pancreatic tumor was also BML clinically. We report this case because pancreatic metastasis from uterine fibroids is extremely rare. Uterine fibroids are benign tumors, but there are rare cases of metastasis to various organs, which should be considered when performing ultrasound., (© 2023. Japanese Society of Gastroenterology.)

Uterine fibroid is a common gynecological disorder that affects women of reproductive age and has emerged as a major public health concern. The symptoms have a negative influence on both their physical health and quality of life. The cost of treatment has a significant impact on the disease's burden. Even though its origin is uncertain, estrogen is thought to be a key player in fibroid pathophysiology. Many theories, including those based on genetic and environmental factors, explain what causes hyper-estrogenic condition in fibroid patients. One such possibility that is currently being explored is the hypothesis that an altered gut microbiome can contribute to the development of diseases characterized by estrogen dominance. Gut dysbiosis is often a "hot area" in the health sciences. According to a recent study, uterine fibroid patients have altered gut microbiome. A variety of risk factors influence both fibroid development and gut homeostasis. Diet, lifestyle, physical activity, and environmental contaminants have an impact on estrogen and the gut flora. A better understanding of uterine fibroids' pathophysiology is required to develop effective preventative and treatment options. A few ways by which the gut microbiota contributes to UF include estrogen, impaired immune function, inflammation, and altered gut metabolites. Therefore, in the future, while treating fibroid patients, various strategies to deal with changes in the gut flora may be advantageous. For developing suggestions for clinical diagnosis and therapy, we reviewed the literature on the relationship between uterine fibroids and the gut microbiota., (© 2023. The Author(s).)

Uterine fibroids (UFs) are common tumors in women of reproductive age. It is imperative to comprehend UFs' associated risk factors to facilitate early detection and prevention. Simple relying on surgical/pharmacological treatment of advanced disease is not only highly expensive, but it also deprives patients of good quality of life (QOL). Unfortunately, even if the disease is discovered early, no medical intervention is traditionally initiated until the disease burden becomes high, and only then is surgical intervention performed. Furthermore, after myomectomy, the recurrence rate of UFs is extremely high with the need for additional surgeries and other interventions. This confused approach is invasive and extremely costly with an overall negative impact on women's health. Secondary prevention is the management of early disease to slow down its progression or even halt it completely. The current approach of watchful observation for early disease is considered a major missed opportunity in the literature. The aim of this article is to present an approach named the ESCAPE (Evidence-Based Approach for Secondary Prevention) of UF management. It comprises simple, inexpensive, and safe steps that can arrest the development of UFs, promote overall reproductive health, decrease the number of unnecessary surgeries, and save billions of health care systems' dollars worldwide.

Objective: To identify variables predictive of durable clinical success after MRI-guided focused ultrasound (MRgFUS) treatment of uterine fibroids., Materials and Methods: In this prospective, multicenter trial, 99 women with symptomatic uterine fibroids were treated using MRgFUS. Pelvic MRI was obtained at baseline and treatment day. The Uterine Fibroid Symptom-Quality of Life questionnaire was used to calculate a symptom severity score (SSS) at baseline and 6, 12, 24, and 36 months following treatment. Clinical, imaging, and treatment variables were correlated with symptom reduction sustained through the 12- and 24-month time points using univariable and multivariable logistic regression analyses. A novel parameter, the ratio of non-perfused volume to total fibroid load (NPV/TFL), was developed to determine association with durable outcomes., Results: Post-treatment, mean symptom severity decreased at the 6-, 12-, 24-, and 36-month follow-ups (p < 0.001, all time points). In univariable analysis, three variables predicted treatment success (defined by ≥ 30-point improvement in SSS) sustained at both the 12-month and 24-month time points: increasing ratio of NPV/TFL (p = 0.002), decreasing total fibroid load (p = 0.04), and the absence of T2-weighted Funaki type 2 fibroids (p = 0.02). In multivariable analysis, the NPV/TFL was the sole predictor of durable clinical success (p = 0.01). Patients with ratios below 30% had less improvement in SSS and lacked durable clinical response compared with those between 30-79 (p = 0.03) and ≥ 80% (p = 0.01)., Conclusion: Increased non-perfused volume relative to total fibroid volume was significantly associated with durable reduction of symptoms of abnormal uterine bleeding and bulk bother., Clinical Relevance Statement: Patient selection for sustained clinical benefit should emphasize those with likelihood of achieving high ablation ratios, as determined by imaging (e.g., device access, Funaki type) and by considering the total fibroid load, not just the primary symptomatic fibroid., Trial Registration: Clinical trial ID: NCT01285960., Key Points: • Patient selection/treatment approach associated with durable symptom relief in MRI-guided focused ultrasound ablation of uterine fibroids remains unclear. • The ablation ratio, non-perfused volume/total fibroid volume, was positively associated with sustained symptom relief in both bleeding and bulk bother at 1- and 2-year follow-ups. • Selecting patients with imaging features that favor a high ratio of ablation to total fibroid load (including non-targeted fibroids) is the main factor in predicting durability of symptom relief after uterine fibroid treatment., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Objective: To determine whether cyclic strain affects fibroid cell cytoskeletal organization, proliferation, and collagen synthesis differently than myometrial cells., Design: A basic science study using primary cultures of patient-matched myometrial and fibroid cells., Setting: Academic laboratory., Patient(s): Premenopausal women undergoing myomectomy or hysterectomy for the treatment of symptomatic uterine fibroids., Intervention(s): Application of uniaxial strain patterns mimicking periovulation, menses, or dysmenorrhea using the Flexcell tension system or static control. Secondarily, inhibition of G protein-coupled estrogen receptor-1 and phosphatidylinositol 3-kinase., Main Outcome Measure(s): Cell alignment, cell number, and collagen content., Result(s): Menses-strained cells demonstrated the most variation in cell alignment, cell proliferation, and procollagen content between myometrial and fibroid cells. Procollagen content decreased in myometrial cells with increasing strain amplitude and decreasing frequency. G protein-coupled estrogen receptor-1 inhibition decreases cellular alignment in the presence of strain., Conclusion(s): Mechanotransduction affecting cytoskeletal arrangement through the G protein-coupled estrogen receptor-1-phosphatidylinositol 3-kinase pathway is altered in fibroid cells. These results highlight the importance of incorporating mechanical stimulation into the in vitro study of fibroid pathology., Competing Interests: Declaration of interests R.W. has nothing to disclose. A.M.Z. has nothing to disclose. C.N. has nothing to disclose. M.M. has nothing to disclose. E.G.H. has nothing to disclose. S.C.S. has nothing to disclose., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Uterine fibroids, the most common benign tumors of the myometrium in women, are characterized by abnormal extracellular matrix deposition and uterine smooth muscle cell neoplasia, with high recurrence rates. Here, we investigated the potential of the marine natural product manzamine A (Manz A), which has potent anti-cancer effects, as a treatment for uterine fibroids. Manz A inhibited leiomyoma cell proliferation in vitro and in vivo by arresting cell cycle progression and inducing caspase-mediated apoptosis. We performed target prediction analysis and identified sterol o-acyltransferases (SOATs) as potential targets of Manz A. Cholesterol esterification and lipid droplet formation were reduced by Manz A, in line with reduced SOAT expression. As a downstream target of SOAT, Manz A also prevented extracellular matrix deposition by inhibiting the β-catenin/fibronectin/metalloproteinases axis and enhanced autophagy turnover. Excessive free fatty acid accumulation by SOAT inhibition led to reactive oxygen species to impair mitochondrial oxidative phosphorylation and trigger endoplasmic reticulum stress via PERK/eIF2α/CHOP signaling. The inhibitory effect of ManzA on cell proliferation was partially restored by PERK knockdown and eliminated by tauroursodeoxycholic acid, suggesting oxidative stress plays a critical role in the mechanism of action of Manz A. These findings suggest that targeting SOATs by Manz A may be a promising therapeutic approach for uterine fibroids., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Long non-coding RNAs (lncRNAs) play crucial regulatory roles in various cellular processes, including gene expression, chromatin remodeling, and protein localization. Dysregulation of lncRNAs has been linked to several diseases, making it essential to understand their functions in disease mechanisms and therapeutic strategies. However, traditional experimental methods for studying lncRNA function are time-consuming, expensive, and offer limited insights. In recent years, computational methods have emerged as valuable tools for predicting lncRNA functions and their associations with diseases. However, many existing methods focus on constructing separate networks for lncRNA and disease similarity, resulting in information loss and insufficient processing capacity for isolated nodes. To address this, we developed 'RGLD' by combining Random Walk with restarting (RWR), Graph Neural Network (GNN), and Graph Attention Networks (GAT) to predict lncRNA-disease associations in a heterogeneous network. RGLD achieved an impressive AUC of 0.88, outperforming other methods. It can also predict novel associations between lncRNAs and diseases. RGLD identified HOTAIR, MEG3, and PVT1 as lncRNAs associated with uterine fibroids. Biological experiments directly or indirectly verified the involvement of these three lncRNAs in uterine fibroids, validating the accuracy of RGLD's predictions. Furthermore, we extensively discussed the functions of the target genes regulated by these lncRNAs in uterine fibroids, providing evidence for their role in the development and progression of the disease., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Abstract: Uterine fibroids (UFs) are benign tumors arising from the uterus, characterized by accumulation of abundant extracellular matrix (ECM) and sex steroid-dependent growth. Women with symptomatic UFs have reduced quality of life and decreased labor productivity. Among the driver gene mutations identified in UFs, mutations in MED12, a component of the cyclin-dependent kinase (CDK) Mediator module, are the most common and observed in 50-80% of UFs. They are gain-of-function mutations and are more frequently observed in Black women and commonly observed even in small UFs. MED12 mutation-positive UFs (MED12-UFs) often develop multiple rather than solitary and have distinct gene expression profiles, DNA methylomes, transcriptomes, and proteomes. Gene expressions related to ECM organization and collagen-rich ECM components are upregulated, and impaired Mediator kinase activity and dysregulation of Wnt/β-catenin signaling are identified in MED12-UFs. Clinically, the UF shrinking effect of gonadotropin-releasing hormone agonists and ulipristal acetate is dependent on the MED12 mutation status. Understanding of characteristics of MED12-UFs and functions of MED12 mutations for UF tumorigenesis may elucidate the pathophysiology of UFs, leading to the development of new therapeutic options in women with symptomatic UFs.

Introduction: Uterine fibroids are the most common noncancerous tumors in women of childbearing age. This review was developed to evaluate the current role of gonadotropin-releasing hormone (GnRH) agonists and antagonists in the therapy of symptomatic uterine fibroids., Areas Covered: There is a great need for alternative methods for surgical treatment of uterine fibroids. Hormonal therapy remains the first-line treatment option for most patients. GnRH analogs (agonists and antagonists) modulate the pulsatile release of GnRH. This review summarizes the available literature concerning pharmacologic principles underlying the mechanism of action of GnRH and its analogs, as well as individual therapeutic applications to which these drugs have been applied., Expert Opinion: In many cases, it is possible to try to treat uterine fibroids pharmacologically. Both groups of GnRH analogs are used in therapy, agonists instead as a preparation for surgery, and antagonists as a drug for long-term use. It is essential to develop this path further and look for at least long-term-release systems or new methods of administering these drugs. It is also important from the patient's perspective to search for possible drugs that may have an additive effect of decreasing side effects when combined with GnRH analogs.

Malignant transformation in leiomyoma is rare, with a few documented cases of sarcomatous transformation in leiomyomas. However, carcinosarcomatous transformation in leiomyomas is extremely infrequent. A 45-year-old female presented with a mass sensation per abdomen for the last five months. An abdominal ultrasound revealed multiple uterine fibroids. Contrast-enhanced magnetic resonance imaging revealed a large multiloculated abdominopelvic mass arising from the fundus of the uterus, along with multiple smaller subserosal fibroids. A total abdominal hysterectomy with bilateral salpingectomy was performed. Grossly, the uterus was bosselated with multiple subserosal fibroids. The larger degenerated fibroid showed a smooth outer surface; however, the cut surface was predominantly cystic and filled with necrotic material. Microscopically and immunohistochemically, the larger mass showed a high-grade biphasic tumor comprising carcinomatous and sarcomatous components with the peripheral solid areas showing compressed smooth muscle bundles representing the residual leiomyomatous areas. A final diagnosis of carcinosarcomatous transformation in leiomyoma was rendered. The index report highlights the significance of systematic gross and microscopic examination of all the uterine masses in patients with multiple leiomyomata.

Purpose: Uterine fibroid is the most common benign tumor in female reproductive organs. In order to guide the treatment, it is crucial to detect the location, shape, and size of the tumor. This study proposed a deep learning approach based on attention mechanisms to segment uterine fibroids automatically on preoperative Magnetic Resonance (MR) images., Methods: The proposed method is based on U-Net architecture and integrates two attention mechanisms: channel attention of squeeze-and-excitation (SE) blocks with residual connections, spatial attention of pyramid pooling module (PPM). We did the ablation study to verify the performance of these two attention mechanisms module and compared DARU-Net with other deep learning methods. All experiments were performed on a clinical dataset consisting of 150 cases collected from our hospital. Among them, 120 cases were used as the training set, and 30 cases are used as the test set. After preprocessing and data augmentation, we trained the network and tested it on the test dataset. We evaluated segmentation performance through the Dice similarity coefficient (DSC), precision, recall, and Jaccard index (JI)., Results: The average DSC, precision, recall, and JI of DARU-Net reached 0.8066 ± 0.0956, 0.8233 ± 0.1255, 0.7913 ± 0.1304, and 0.6743 ± 0.1317. Compared with U-Net and other deep learning methods, DARU-Net was more accurate and stable., Conclusion: This work proposed an optimized U-Net with channel and spatial attention mechanisms to segment uterine fibroids on preoperative MR images. Results showed that DARU-Net was able to accurately segment uterine fibroids from MR images., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

For a long time, the uterus had been considered a sterile organ, meaning that under physiological conditions the uterus would not be colonized by bacteria. Based on available data, it may be concluded that the gut and uterine microbiome are related, and that the role of this microbiome is greater than expected. Despite being the most common pelvic neoplasms in women of reproductive age, uterine fibroids (UFs) are still poorly understood tumors whose etiology has not been fully determined. This systematic review presents the relationship between intestinal and uterine dysbiosis and uterine fibroids. A systematic review of three medical databases was carried out: the MEDLINE/PubMed, Scopus and Cochrane. In this study, 195 titles and abstracts were reviewed, including only original articles and clinical trials of uterine microbiome criteria. Finally, 16 studies were included to the analysis. In recent years, researchers dealing with reproduction in a broad sense have focused on the microbiome in various locations to study its role in the pathogenesis and, consequently, the prevention and treatment of diseases of the genital organ. Conventional microbial detection methods are not suitable for identifying bacteria, which are difficult to culture. Next-generation sequencing (NGS) provides an easier and faster and more informative analysis of bacterial populations. It seems that gut microbiota dysbiosis has the potential to be a risk factor for uterine fibroids or affect the disease process. Some changes were shown in many types of bacteria, such as Firmicutes, Proteobacteria, Actinobacteria and Verrucomicrobia detected in fecal samples in patients with uterine fibroids. In view of the few results on the link between the microbiome and uterine fibroids, further intensive studies in humans and animal models are necessary, including the possible use of different microbiome modulations in the prevention or treatment of uterine fibroids., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Korczynska, Zeber-Lubecka, Zgliczynska, Zarychta, Zareba, Wojtyla, Dabrowska and Ciebiera.)

Background: Uterine fibroids are the most common benign neoplasm of the uterus and a major source of morbidity for women. We report an overview of trends in uterine fibroids of incidence rate, prevalence rate, years lived with disability (YLDs) rate in 204 countries and territories over the past 30 years and associations with age, period, and birth cohort., Methods: The incident case, incidence rate, age-standardized rate (ASR) for incidence, prevalent case, prevalence rate, ASR for prevalence, number of YLDs, YLD rate, and ASR for YLDs were derived from the Global Burden of Disease 2019 (GBD 2019) study. We utilized an age-period-cohort (APC) model to estimate overall annual percentage changes in the rate of incidence, prevalence, and YLDs (net drifts), annual percentage changes from 10 to 14 years to 65-69 years (local drifts), period and cohort relative risks (period/cohort effects) between 1990 and 2019., Results: Globally, the incident cases, prevalent cases, and the number of YLDs of uterine fibroids increased from 1990 to 2019 with the growth of 67.07%, 78.82% and 77.34%, respectively. High Socio-demographic Index (SDI) and high-middle SDI quintiles with decreasing trends (net drift < 0.0%), and increasing trends (net drift > 0.0%) were observed in middle SDI, low-middle SDI, and low SDI quintiles in annual percentage change of incidence rate, prevalence rate and YLDs rate over the past 30 years. There were 186 countries and territories that showed an increasing trend in incidence rate, 183 showed an increasing trend in prevalence rate and 174 showed an increasing trend in YLDs rate. Moreover, the effects of age on uterine fibroids increased with age and peaked at 35-44 years and then declined with advancing age. Both the period and cohort effects on uterine fibroids showed increasing trend in middle SDI, low-middle SDI and low SDI quintiles in recent 15 years and birth cohort later than 1965., Conclusions: The global burden of uterine fibroids is becoming more serious in middle SDI, low-middle SDI and low SDI quintiles. Raising awareness of uterine fibroids, increasing medical investment and improving levels of medical care are necessary to reduce future burden., (© 2023. The Author(s).)

Objective: To examine the association between keloids, hypertrophic scars, and uterine fibroid incidence as well as growth. Both keloids and fibroids are fibroproliferative conditions that have been reported to be more prevalent among Blacks than Whites, and they share similar fibrotic tissue structures, including extracellular matrix composition, gene expression, and protein profiles. We hypothesized that women with a history of keloids would have greater uterine fibroid development., Design: A prospective community cohort study (enrollment 2010-2012) with 4 study visits over 5 years to conduct standardized ultrasounds to detect and measure fibroids ≥0.5 cm in diameter, assess the history of keloid and hypertrophic scars, and update covariates., Setting: Detroit, Michigan area., Patients: A total of 1,610 self-identified Black and/or African American women aged 23-35 years at enrollment without a previous clinical diagnosis of fibroids., Exposure(s): Keloids (raised scars that grow beyond the margins of the original injury) and hypertrophic scars (raised scars that stay within the bounds of the original injury). Because of the difficulties in distinguishing keloids and hypertrophic scars, we separately examined the history of keloids and the history of either keloids or hypertrophic scars (any abnormal scarring) and their associations with fibroid incidence and growth., Main Outcome Measure(s): Fibroid incidence (new fibroid after a fibroid-free ultrasound at enrollment) was assessed using Cox proportional-hazards regression. Fibroid growth was assessed using linear mixed models. The estimates for the change in log volume per 18 months were converted to the estimated percentage difference in volume for scarring vs. no-scarring. Both incidence and growth models were adjusted for time-varying demographic, reproductive, and anthropometric factors., Result(s): Of the 1,230 fibroid-free participants, 199 (16%) reported ever having keloids, 578 (47%) reported keloids or hypertrophic scars, and 293 (24%) developed incident fibroids. Neither keloids (adjusted hazard ratio = 1.04; 95% confidence interval: 0.77, 1.40) nor any abnormal scarring (adjusted hazard ratio = 1.10; 95% confidence interval: 0.88, 1.38) were associated with fibroid incidence. Fibroid growth differed little by scarring status., Conclusion(s): Despite molecular similarities, self-reported keloid and hypertrophic scars did not show an association with fibroid development. Future research may benefit from the examination of dermatologist-confirmed keloids or hypertrophic scars; however, our data suggest little shared susceptibility for these 2 types of fibrotic conditions., (Copyright © 2023 American Society for Reproductive Medicine. All rights reserved.)

Uterine fibroid or leiomyoma is the most common benign uterus tumor. The tumor is primarily composed of smooth muscle (fibroid) cells, myofibroblast, and a significant amount of extracellular matrix components. It mainly affects women of reproductive age. They are uncommon before menarche and usually disappear after menopause. The fibroids have excessive extracellular matrix components secreted by activated fibroblast cells (myofibroblast). Myofibroblast has the characteristics of fibroblast and smooth muscle cells. These cells possess contractile capability due to the expression of contractile proteins which are normally found only in muscle tissues. The rigid nature of the tumor is responsible for many side effects associated with uterine fibroids. The current drug treatment strategies are primarily hormone-driven and not anti-fibrotic. This paper emphasizes the fibrotic background of uterine fibroids and the mechanisms behind the deposition of excessive extracellular matrix components. The transforming growth factor-β, hippo, and focal adhesion kinase-mediated signaling pathways activate the fibroblast cells and deposit excessive extracellular matrix materials. We also exemplify how dipeptidyl peptidase-4 and fibroblast activation protein inhibitors could be beneficial in reducing the fibrotic process in leiomyoma. Dipeptidyl peptidase-4 and fibroblast activation protein inhibitors prevent the fibrotic process in organs such as the kidneys, lungs, liver, and heart. These inhibitors are proven to inhibit the signaling pathways mentioned above at various stages of their activation. Based on literature evidence, we constructed a narrative review on the mechanisms that support the beneficial effects of dipeptidyl peptidase-4 and fibroblast activation protein inhibitors for treating uterine fibroids., (© 2022. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Aim: Laparoscopic power morcellator (LPM) can be used for tissue retrieval through laparoscopic port site, but the dissemination of uterine and/or myoma tissues is a serious complication. To study the use of LPM for uterine fibroid treatment in Japan, we aimed to perform two national cross-sectional surveys comprising multiple questionnaires., Methods: The first survey (2011-2013) was conducted in November 2014, and 203 medical institutions responded. The second survey (2017-2019) was conducted in December 2020, and 302 medical institutions were investigated., Results: Overall, 72 104 and 120 425 surgeries and 0.04% and 0.05% cases of postoperative malignancy diagnosis were reported in the first and second surveys, respectively. Magnetic resonance imaging was performed in >90% of the cases in the first and second surveys as preoperative examinations. The frequency of LPM at hysterectomy was 8.9% and 4.6% and the frequency of LPM at laparoscopic myomectomy was 80.4% and 54.8% in the first and second surveys, respectively; both the parameters decreased in the second survey., Conclusions: It is impossible to completely exclude malignant diseases even if extensive preoperative diagnosis has been done before surgery. Therefore, the use of LPM in patients requires careful attention and informed consent in Japan., (© 2022 Japan Society of Obstetrics and Gynecology.)

Background: Gonadotropin-releasing hormone agonists are used to treat premenopausal uterine leiomyomas; however, leiomyoma volume reduction is not always achieved. The reduction rate after this treatment varies for each leiomyoma, even in the same patient. Therefore, an effective method for predicting uterine leiomyoma volume reduction is required to reduce the adverse hypoestrogenic effects and drug-related economic burden related to gonadotropin-releasing hormone agonists., Objective: This study aimed to determine the predictive use of MED12 mutations for evaluating the effect of gonadotropin-releasing hormone agonist treatment concerning reducing uterine leiomyoma volume and to predict the MED12 mutation status based on the findings of magnetic resonance imaging performed before treatment., Study Design: MED12 exon 2 mutation and erythropoietin expression in uterine leiomyomas were evaluated concerning volume reduction, as measured using magnetic resonance imaging. We developed a system for classifying leiomyomas according to T2-weighted magnetic resonance imaging signals to noninvasively predict the presence or absence of MED12 mutations in leiomyomas. Leiomyoma samples (>5 cm) were obtained from 168 patients during surgery (hysterectomy or myomectomy) between 2005 and 2021 at Yokohama City University Hospital. To analyze the rate of leiomyoma volume reduction, 41 patients had been preoperatively administered the gonadotropin-releasing hormone agonist (leuprorelin acetate 3.75 mg, monthly subcutaneous injection) for 3 months; magnetic resonance imaging was performed before and after treatment without contrast material., Results: Patients with MED12 exon 2 mutations had smaller volume reduction after treatment with the gonadotropin-releasing hormone agonist (P<.001, Mann-Whitney U test) and displayed lower signal intensity on T2-weighted images than those with leiomyomas expressing wild-type MED12 exon 2. The newly proposed magnetic resonance imaging-based classification system showed that MED12 exon 2 mutations were more frequent in the low-signal group than in the high-signal group, with nearly equal proportions of mutated and wild-type MED12 exon 2 leiomyomas noted in the intermediate group. The low-signal group had significantly lower erythropoietin expression levels than the high-signal group (P<.001, Kruskal-Wallis test with the Dunn posthoc analysis)., Conclusion: MED12 mutation status can be a candidate marker for predicting the effect of gonadotropin-releasing hormone agonists on uterine leiomyoma reduction. Magnetic resonance imaging findings can be used to determine MED12 mutation status as a noninvasive strategy to select patients who will most likely benefit from gonadotropin-releasing hormone agonist treatment., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To determine treatment options (myomectomy vs. uterine artery embolization (UAE)) for women wishing to avoid hysterectomy., Methods: A multicenter randomized controlled trial was conducted on 254 women and data were collected on fibroid-specific quality of life (UFS-QOL), loss of menstrual blood, and pregnancy., Results: At 4 years, the mean difference in the UFS-QOL was 5.0 points (95% confidence interval (CI) -1.4 to 11.5; P = 0.13) in favor of myomectomy. This was not statistically significant as it was at 2 years. There were no differences in bleeding scores, rates of amenorrhea, or heavy bleeding. Of those who were still menstruating, the majority reported regular or fairly regular periods: 36 of 48 (75%) in the UAE group and 30 of 39 (77%) in the myomectomy group. Twelve women after UAE and six women after myomectomy became pregnant (4 years) with seven and five live births, respectively (hazard ratio 0.48, 95% CI 0.18-1.28). There was no difference between the levels of hormones associated with the uterine reserve in each group., Conclusion: Leiomyoma are common in reproductive-aged women, causing heavy menses and subfertility. Among women with uterine fibroids, myomectomy resulted in better fibroid-related quality of life at 4 years, compared with UAE but the treatments decreased menstrual bleeding equally. There was also no significant difference in the impact of treatment on ovarian reserve., (© 2022 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Objectives: Our study aims at the comprehensive analysis of adverse events (AEs) in patients with symptomatic uterine fibroids (UFs) who underwent magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) in the last 6 years in one of the major Polish centers performing this type of therapy., Methods: The presented retrospective case-control study was conducted in the Department of Obstetrics and Gynecology, Pro-Familia Hospital, Rzeszów in cooperation with the Second Department of Obstetrics and Gynecology, Center of Postgraduate Medical Education, Warsaw. The study enrolled 372 women with symptomatic UFs who underwent MR-HIFU and reported AEs during or after the procedure. The occurrence of particular AEs was analyzed. Statistical comparison of two cohorts (patients with and without AEs) was conducted based on epidemiological factors, UF characteristics, fat layer thickness, the presence of abdominal scars and technical parameters of the procedure., Results: The overall mean occurrence rate of AEs was 8.9% ( n  = 33). No major AEs were reported. The only statistically significant risk factor of AEs was the treatment of type II UFs according to Funaki (OR 2.12, CI 95%, p  = 0.043). Other investigated factors did not have a statistically significant influence on AE occurrence. Abdominal pain was the most common AE., Conclusion: Our data showed that MR-HIFU seemed to be a safe procedure. The AE rate after the treatment is relatively low. According to the obtained data it seems that the occurrence of AEs does not depend on the technical parameters of the procedure and the volume, position and location of UFs. Further prospective, randomized studies and with long follow-up are necessary to confirm the final conclusions.

Objectives: The aim of this review was to analyze and summarize the most common adverse events (AEs) and complications after magnetic resonance-guided focused ultrasound (MRgFUS) therapy in uterine fibroids (UFs) and to establish the risk factors of their occurrence., Methods: We searched for original research studies evaluating MRgFUS therapy in UFs with outcomes containing AEs and/or complications in different databases (PubMed/MEDLINE, SCOPUS, COCHRANE) until March 2022. Reviews, editorials, opinions or letters, case studies, conference papers and abstracts were excluded from the analysis. The systematic literature search identified 446 articles, 43 of which were analyzed., Results: According to available evidence, the overall incidence of serious complications in MRgFUS therapy is relatively low. No AEs/complications were reported in 11 out of 43 analyzed studies. The mean occurrence of all AEs in the analyzed material was 24.67%. The most commonly described AEs included pain, skin burns, urinary tract infections and sciatic neuropraxia. Major AEs, such as skin ulcerations or deep vein thrombosis, occurred in 0.41% of cases in the analyzed material., Conclusion: MRgFUS seems to be safe in UF therapy. The occurrence of AEs, especially major ones, is relatively low in comparison with other methods. The new devices and more experience of their users seem to reduce AE rate. The lack of unification in AE reporting and missing data are the main issues in this area. More prospective, randomized studies with unified reporting and long follow-up are needed to determine the safety in a long-term perspective.

Objective: To predict the risk of postoperative reintervention for uterine fibroids using clinical-imaging features and T2WI radiomics before high-intensity focused ultrasound (HIFU) ablation., Methods: Among patients with uterine fibroids treated with HIFU from 2019 to 2021, 180 were selected per the inclusion and exclusion criteria (42 reintervention and 138 non-reintervention). All patients were randomly assigned to either the training ( n  = 125) or validation ( n  = 55) cohorts. Multivariate analysis was used to determine independent clinical-imaging features of reintervention risk. The Relief and LASSO algorithm were used to select optimal radiomics features. Random forest was used to construct the clinical-imaging model based on independent clinical-imaging features, the radiomics model based on optimal radiomics features, and the combined model incorporating the above features. An independent test cohort of 45 patients with uterine fibroids tested these models. The integrated discrimination index (IDI) was used to compare the discrimination performance of these models., Results: Age ( p  < .001), fibroid volume ( p  = .001) and fibroid enhancement degree ( p  = .001) were identified as independent clinical-imaging features. The combined model had AUCs of 0.821 (95% CI: 0.712-0.931) and 0.818 (95% CI: 0.694-0.943) in the validation and independent test cohorts, respectively. The predictive performance of the combined model was 27.8% (independent test cohort, p  < .001) and 29.5% (independent test cohort, p  = .001) better than the clinical-imaging and radiomics models, respectively., Conclusion: The combined model can effectively predict the risk of postoperative reintervention for uterine fibroids before HIFU ablation. It is expected to help clinicians to develop accurate, personalized treatment and management plans. Future studies will need to be prospectively validated.

Purpose: Magnetic resonance - high-intensity focused ultrasound (MR-HIFU) is a noninvasive treatment option for symptomatic uterine leiomyomas. Currently, pretreatment MRI is used to assess tissue characteristics and predict the most likely therapeutic response for individual patients. However, these predictions still entail significant uncertainties. The impact of tissue properties on therapeutic outcomes remains poorly understood and detailed knowledge of the histological effects of ultrasound ablation is lacking. Investigating these aspects could aid in optimizing patient selection, enhancing treatment effects and improving treatment outcomes., Methods and Materials: We present seven patients who underwent MR-HIFU treatment for leiomyoma followed by second-line surgical treatment. Tissue samples obtained during the surgery were stained with hematoxylin and eosin, Masson's trichrome and Herovici to evaluate general morphology, fibrosis and collagen deposition of leiomyomas. Immunohistochemical CD31, Ki-67 and MMP-2 stainings were performed to study vascularization, proliferation and matrix metalloproteinase-2 protein expression in leiomyomas, respectively., Results: The clinical characteristics and radiological findings of the leiomyomas prior to treatment as well as qualitative histological findings after the treatment are presented and discussed in the context of current literature. A tentative model for volume reduction is presented., Conclusion: These findings provide insights into potential factors contributing to suboptimal therapeutic outcomes and the variability in histological changes following treatment.

Purpose: To determine efficacy and safety of contrast-enhanced ultrasonography (CEUS) in high-intensity focused ultrasound (HIFU) ablation of uterine fibroids (UFs)., Methods: We retrospectively reviewed women undergoing HIFU ablation for UFs between June 2018 and January 2020. Before and after HIFU, patients underwent CEUS and magnetic resonance imaging (MRI) examinations. The relationship between CEUS features and ablation rate was analyzed. The time-intensity curves on CEUS were measured before and after HIFU ablation, and compared with those obtained using MRI. Adverse reactions were recorded., Results: A total of 64 patients were included. The immediate HIFU ablation rate significantly differed between low-, iso-, and high-enhancement UFs (87.2% ± 1.6%, 83.3% ± 2.1%, and 72.9% ± 3.1%, respectively; p < 0.05). On CEUS, the peak time of the time-intensity curve was significantly longer after treatment than before treatment (32.2 ± 9.7 and 26.7 ± 9.4 s, respectively; p < 0.05). Peak intensity was significantly lower after treatment than before treatment (13.7 ± 7.5 and 30.9 ± 11.2 dB, respectively; p < 0.05). All measurements were comparable between CEUS and MRI. The most common peri- and post-procedure adverse reaction was pain, which was temporary., Conclusion: CEUS could dynamically and safely evaluate the immediate effects of the HIFU ablation of UFs., (© 2022 Wiley Periodicals LLC.)

Uterine leiomyomas, or fibroids, are very common smooth muscle tumors that arise from the myometrium. They can be divided into distinct molecular subtypes. We have previously shown that 3'RNA-sequencing is highly effective in classifying archival formalin-fixed paraffin-embedded (FFPE) leiomyomas according to the underlying mutation. In this study, we performed 3'RNA-sequencing with 111 FFPE leiomyomas previously classified as negative for driver alterations in mediator complex subunit 12 (MED12), high mobility group AT-hook 2 (HMGA2), and fumarate hydratase (FH) by Sanger sequencing and immunohistochemistry. This revealed 43 tumors that displayed expression features typically seen in HMGA2-positive tumors, including overexpression of PLAG1. We explored 12 such leiomyomas by whole-genome sequencing to identify their underlying genomic drivers and to evaluate the feasibility of detecting chromosomal driver alterations from FFPE material. Four tumors with significant HMGA2 overexpression at the protein-level served as controls. We identified chromosomal rearrangements targeting either HMGA2, HMGA1, or PLAG1 in all 16 tumors, demonstrating that it is possible to detect chromosomal driver alterations in archival leiomyoma specimens as old as 18 years. Furthermore, two tumors displayed biallelic loss of DEPDC5 and one tumor harbored a COL4A5-COL4A6 deletion. These observations suggest that instead of only HMGA2-positive leiomyomas, a distinct leiomyoma subtype is characterized by rearrangements targeting either HMGA2, HMGA1, or PLAG1. The results indicate that the frequency of HMGA2-positive leiomyomas may be higher than estimated in previous studies where immunohistochemistry has been used. This study also demonstrates the feasibility of detecting chromosomal driver alterations from archival FFPE material., (© 2022 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Background: Uterine fibroid embolisation (UFE) is an established treatment method for symptomatic uterine myomas. This study evaluates the efficacy of UFE using objective magnetic resonance imaging (MRI) data for size and perfusion analysis as well as patient questionnaires assessing fibroid-related symptoms., Method: Patients underwent MR-Angiography before UFE and 4 days, 6 and 12 months after the procedure. The images were evaluated using dedicated software. Patient questionnaires were completed before UFE and at 12 months follow-up, focussing on the embolization procedure and symptoms associated with uterine fibroids. Statistical analysis of the questionnaires was performed using paired sample t-test and Wilcoxon signed rank test, while Kruskal-Wallis test and Friedman test were applied for MRI-analysis., Results: Eleven women were included. There was a significant reduction in fibroid-related symptoms. The volume reduction after 12 months was significant in both, uterus and myomas, after an initial increase in uterine volume at the first post-interventional MRI. The perfusion analysis showed that blood flow to the fibroids could be significantly reduced up to 12 months after UFE while uterine tissue was not affected., Conclusion: This study shows that uterine fibroid embolisation induces a significant long-term decrease in myoma size and perfusion while healthy uterine tissue remains unaffected. Fibroid-related symptoms are reduced for the sake of improved quality of life., (© 2022. The Author(s).)

Myometrium cells are an important reproductive niche in which cyclic mechanical forces of a pico-newton range are produced continuously at millisecond and second intervals. Overproduction and/or underproduction of micro-forces, due to point or epigenetic mutation, aberrant methylation, and abnormal response to hypoxia, may lead to the transformation of fibroid stem cells into fibroid-initiating stem cells. Fibroids are tumors with a high modulus of stiffness disturbing the critical homeostasis of the myometrium and they may cause unfavorable and strong mechanical forces. Micro-mechanical forces and soluble-chemical signals play a critical role in transcriptional and translational processes' maintenance, by regulating communication between the cell nucleus and its organelles. Signals coming from the external environment can stimulate cells in the format of both soluble biochemical signals and mechanical ones. The shape of the cell and the plasma membrane have a significant character in sensing electro-chemical signals, through specialized receptors and generating responses, accordingly. In order for mechanical signals to be perceived by the cell, they must be converted into biological stimuli, through a process called mechanotransduction. Transmission of fibroid-derived mechanical signals to the endometrium and their effects on receptivity modulators are mediated through a pathway known as solid-state signaling. It is not sufficiently clear which type of receptors and mechanical signals impair endometrial receptivity. However, it is known that biomechanical signals reaching the endometrium affect epithelial sodium channels, lysophosphatidic acid receptors or Rho GTPases, leading to conformational changes in endometrial proteins. Translational changes in receptivity modulators may disrupt the selectivity and receptivity functions of the endometrium, resulting in failed implantation or early pregnancy loss. By hypermethylation of the receptivity genes, micro-forces can also negatively affect decidualization and implantation. The purpose of this narrative review is to summarize the state of the art of the biomechanical forces which can determine fibroid stem cell transformation and, thus, affect the receptivity status of the endometrium with regard to fertilization and pregnancy.

Research Question: What is the effect of myomectomy in women with uterine fibroids on time to live birth and other reproductive outcomes?, Design: This was a monocentric retrospective cohort study of 311 women with fibroids, of whom 165 eventually received myomectomy and 146 remained on expectant management. To assess the primary outcome time to live birth, a Cox proportional hazards model with a time-varying covariate for myomectomy was used. In the sensitivity analyses, this was combined with an approach to account for confounders via a cloning/censoring/weighting that aimed to emulate a randomized controlled trial., Results: Notable differences in baseline characteristics between the myomectomy and expectant management group were fibroid size (fibroid >7 cm: myomectomy 48%; expectant management 15%) and whether the patient had fibroid-related complaints (myomectomy 85%, expectant management 67%). The adjusted hazard ratio for the effect of myomectomy compared with expectant management on live birth was 1.26 (95% CI 0.87-1.81). Sensitivity analyses yielded similar results, but secondary outcomes showed that women remaining on expectant management had more often received assisted reproductive technology (63%) compared with those who eventually received myomectomy (38%)., Conclusions: The study did not find a significant difference in time to live birth after myomectomy compared with expectant management in women with fibroids and a wish to conceive, despite more, larger and more symptomatic fibroids in the myomectomy group. The results after myomectomy encourage the execution of a randomized controlled trial in women with large (symptomatic) fibroids not or minimally distorting the intrauterine cavity, and infertility or a desire to conceive., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Acute abdomen comprises several emergencies. Hemoperitoneum associated with uterine fibroids, which can present as acute abdominal pain, is rare and difficult to diagnose. Especially, spontaneous hemorrhage from the rupture of the superficial vessels overlying a uterine fibroid is extremely rare, and its diagnosis and management have not been established., Case Presentation: We report a case of a 55-year-old woman who presented at our hospital with acute abdomen. After performing a computed tomography scan, we conducted a laparoscopic examination and diagnosed hemoperitoneum of ambiguous origin. We treated the patient surgically, performing a laparoscopic myomectomy to remove the origin of the hemorrhage. The patient recovered well., Conclusions: We report a case of hemoperitoneum of ambiguous origin that was diagnosed laparoscopically and treated by laparoscopic myomectomy to remove the origin of the hemorrhage. Surgeons should rapidly diagnose and manage acute abdominal pain in women with a history of uterine fibroids to prevent severe morbidity or even mortality. Therefore, laparoscopic surgery is recommended in patients with stable hemodynamics., (© 2022. The Author(s).)

Uterine fibroids (UFs) are the most common benign tumors of female genital diseases, unlike uterine leiomyosarcoma (LMS), a rare and aggressive uterine cancer. This narrative review aims to discuss the biology and diagnosis of LMS and, at the same time, their differential diagnosis, in order to distinguish the biological and molecular origins. The authors performed a Medline and PubMed search for the years 1990-2022 using a combination of keywords on the topics to highlight the many genes and proteins involved in the pathogenesis of LMS. The mutation of these genes, in addition to the altered expression and functions of their enzymes, are potentially biomarkers of uterine LMS. Thus, the use of this molecular and protein information could favor differential diagnosis and personalized therapy based on the molecular characteristics of LMS tissue, leading to timely diagnoses and potential better outcomes for patients.

Uterine fibroids (leiomyomas), the most common benign tumors in women of reproductive age, are a frequent cause of abnormal vaginal bleeding and other reproductive complaints among women. This study investigates the feasibility of using histotripsy, a non-invasive, non-thermal focused ultrasound ablation method, to ablate uterine fibroids. Human fibroid samples (n = 16) were harvested after hysterectomy or myomectomy procedures at Carilion Memorial Hospital. Histotripsy was applied to ex vivo fibroids in two sets of experiments using a 700-kHz clinical transducer to apply multicycle histotripsy pulses and a prototype 500-kHz transducer to apply single-cycle histotripsy pulses. Ultrasound imaging was used for real-time treatment monitoring, and post-treatment ablation was quantified histologically using hematoxylin and eosin and Masson trichrome stains. Results revealed that multicycle histotripsy generated diffuse cavitation in targeted fibroids, with minimal cellular ablative changes after treatment with 2000 pulses/point. Single-cycle pulsing generated well-confined bubble clouds with evidence of early coagulative necrosis on histological assessment in samples treated with 2000 pulses/point, near-complete ablation in samples treated with 4000 pulses/point and complete tissue destruction in samples treated with 10,000 pulses/point. This study illustrates that histotripsy is capable of fibroid ablation under certain pulsing parameters and warrants further investigation as an improved non-invasive ablation method for the treatment of leiomyomas., Competing Interests: Conflict of interest disclosure E.V. has financial ties and research collaborations with HistoSonics, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

According to recent studies and observations in clinical practice, uterine fibroids increase the risk of preterm birth. There are several theories on the pathogenesis of preterm birth in the presence of fibroids. One theory proclaims that fibroid necrosis leads to preterm birth, though pathophysiological mechanisms have not been described. Necrotic tissue secretes specific cytokines and proteins and we suggest these to be comparable to the inflammatory response leading to spontaneous preterm birth. We hypothesize that fibroid necrosis could induce preterm parturition through a similar inflammatory response. This new hypothesis generates novel perspectives for future research and the development of preventative strategies for preterm birth. Moreover, we emphasize the importance of the recognition of fibroids and especially fibroid necrosis by clinicians during pregnancy.

Introduction: Uterine fibroids are the most common benign gynecological tumors affecting women of reproductive ages. Although surgery is the definitive treatment choice, several medical approaches have been investigated to control their symptoms. The main issue of currently employed drugs for uterine fibroids is the long-term safety and tolerability profile. Today, new emerging options represent hopeful alternatives that could potentially overcome these limitations., Areas Covered: This manuscript aims to give an updated overview of the pharmacodynamic and pharmacokinetic properties of current and new investigational medical drugs for the treatment of symptomatic uterine fibroids. The bibliographic research was conducted by searching alone or combined keywords on the following electronic databases: Medline, PubMed, Embase, Science Citation Index via Web of Science., Expert Opinion: The most recent therapeutic strategies for uterine fibroids are represented by gonadotropin-releasing hormone antagonists (GnRH-ants; elagolix and relugolix) and selective progesterone receptor modulators (SPRM; ulipristal acetate). After early promising results, studies on innovative drugs, such as linzagolix (GnRH-ant) and vilaprisan (SPRM) are demanding. In the near future, a deeper knowledge of biological mechanisms at the basis of the genesis and growth of uterine fibroids could pave the way for the development of innovative targeted therapies.

The FK506-binding protein 51 (FKBP51) binds progesterone receptor (PR), glucocorticoid receptor (GR), and androgen receptor (AR) to coregulate their transcriptional activity. We evaluated FKBP51 expression and function in human leiomyoma vs. myometrial tissues and primary cultures to discover FKBP51 role(s) in the pathogenesis of leiomyomas. Quantification of in situ FKBP51 mRNA and protein levels inpaired myometrial vs. leiomyoma tissues from proliferative and secretory phases were analyzed by qPCR (n = 14), immunoblotting (n = 20), and immunohistochemistry (n = 12). Control (scramble) vs. FKBP5 siRNA-transfected leiomyoma cell cultures were assessed for proliferation, apoptosis, and mRNA levels of genes involved in cell survival and extracellular matrix (ECM) formation. Significantly higher FKBP5 mRNA levels were detected in leiomyoma vs. paired myometrium (P < 0.001). Immunoblot (P = 0.001) and immunostaining (P ≤ 0.001) confirmed increased FKBP51 levels in leiomyoma vs. paired myometrium. Compared to control siRNA transfection, FKBP5-silenced leiomyoma cell cultures displayed significantly decreased cell survival factors and reduced proliferation (P < 0.05). Moreover, qPCR analysis revealed significantly lower mRNA levels of ECM, TIPM1, and TIPM3 proteins in FKBP5-silenced leiomyoma cell cultures (P < 0.05). Increased FKBP51 expression in leiomyoma likely involves dysregulation of steroid signaling by blocking GR and PR action and promoting proliferation and ECM production. Evaluating the effect of FKBP51 inhibition in preclinical studies will clarify its significance as a potential therapeutic approach against leiomyoma., (© 2022. Society for Reproductive Investigation.)

Objective: To evaluate the effect of different levels of physician experience on the high-intensity focused ultrasound (HIFU) ablation of uterine fibroids and to provide a reference for the use of non-perfused volume ratio (NPVR) standards during training., Methods: This prospective multicentre study enrolled patients with uterine fibroids. The effect of the physician's level of experience on the outcomes under different NPVR standards and the learning curve of six centres without HIFU experience were analysed. The impact of patient demographic and clinical characteristics were also evaluated., Results: A total of 1352 patients from 20 centres were included in the study. The median NPVRs were 92.00%, 88.10% and 92.86% in the no experience group, inexperienced group and experienced group, respectively. Posterior wall fibroids, lateral wall fibroids and fundus fibroids were inversely correlated with NPVR, while experienced physicians were positively correlated with NPVR. With NPVR ≥ 70% and NPVR ≥ 80% standards, physicians in the no experience group completed the learning curve on the 11th and 16th procedure, respectively. Physicians under a standard of an NPVR ≥ 90% did not complete the learning curve., Conclusions: NPVR ≥ 80% is a standard that is worth using for HIFU treatment of uterine fibroids.

Objective: Uterine fibroids are often associated with lower urinary tract symptoms (LUTS), the exact prevalence of which has been underexplored. Our main objective was to evaluate the effect of surgical treatment of fibroids on LUTS. Our secondary objectives were to assess the prevalence of LUTS in women undergoing fibroid surgery and to analyze the relationship between the characteristics of fibroids and the severity of symptoms., Methods: This was a prospective study of women conducted between 2019 and 2021. The main endpoint was the change in the total UDI-6, IIQ7, ICIQ-SF and CONTILIFE scores preoperatively and 6 weeks postoperatively., Results: Of the 55 included women, 63.6% had frequency and 60% had urgency. Six weeks postoperatively, urinary symptoms had significantly improved for all scores. The presence of an anterior fibroid was significantly associated with higher urinary symptom scores for the UDI-6 (p = 0.007) and ICIQ-SF scores (p = 0.04). The size of the uterus or dominant fibroid was not significantly associated with the severity of urinary symptoms., Conclusion: Fibroids are often associated with symptoms of overactive bladder. An anterior location of the fibroid appears to be associated with greater severity scores. Surgical treatment appears to reduce urinary symptoms 6 weeks postoperatively., Competing Interests: Disclosure of interest None., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)