OBJECTIVE: To determine if engineered HMGA2 overexpressing uterine primary myometrial cells recapitulate the transcriptional and epigenomic features of HMGA2-subtype leiomyomas.
METHODS: Isolated primary, \"normal\" myometrial cells from 3 patients were engineered to overexpress HMGA2 to determine how HMGA2 establishes transcriptomic and epigenomic features of HMGA2-overexpressing leiomyoma.
METHODS: Academic research laboratory PATIENTS: Primary myometrial cells were isolated from normal myometrium obtained from three patients undergoing hysterectomy.
METHODS: Not applicable MAIN OUTCOME MEASURES: Determined genome-wide transcriptomic and epigenomic features of engineered HMGA2-overexpressing uterine primary myometrial cells.
RESULTS: Engineered HMGA2-V5-overexpressing primary myometrial cells approximated the HMGA2 expression level observed in HMGA2-overexpression subtype leiomyoma. HMGA2-V5 expression resulted in differential expression of 1612 genes (FDR < 0.05) which were found to be enriched in pathways associated with leiomyoma formation, including extracellular matrix organization. Comparative gene expression analysis between HMGA2-V5 engineered primary cells and HMGA2-overexpression subtype leiomyoma revealed significant overlap of differentially expressed genes. Mechanistically, HMGA2-V5 overexpression resulted in 41,323 regions with differential H3K27ac deposition (FDR < 0.05) and 205,605 regions of altered chromatin accessibility (FDR < 0.05). Transcription factor binding site analysis implicated the AP-1 family of transcription factors.
UNASSIGNED: • What clinical problem is addressed by these studies? About 10-15% of the uterine leiomyoma cases exhibit increased expression of HMGA2; our study addresses the primary role of HMGA2 overexpression in the pathogenesis of leiomyoma. • What are the key findings? Ectopic expression of HMGA2 in primary myometrial cells transforms transcriptional and epigenomic machinery in these cells which to some extent resemble features of leiomyoma. • How do these findings apply to human fertility or the reproductive process? Our study provides a comprehensive analysis into the changes occurring in epigenome of myometrial cells when HMGA2 is overexpressed. Because epigenome can be targeted with drugs, therefore understanding alterations in epigenome provides new avenues for treating leiomyoma which affects reproductive age women.

Uterine fibroids and endometriosis may be associated with an increased risk of ovarian cancer. Less is known about the role of hysterectomy in these associations. We estimated the independent and joint associations of hysterectomy, fibroids, and endometriosis with ovarian cancer incidence in the prospective Sister Study cohort (2003-2009). We used time-varying Cox proportional hazards models to estimate covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). By the end of follow-up, 34% of 40,928 eligible participants had fibroids, 13% had endometriosis, and 7% had both. A total of 274 women developed ovarian cancer during follow-up (median=12.3 years). In mutually adjusted models, fibroids (HR=1.65, 95% CI: 1.28, 2.12) and possibly endometriosis (HR=1.16, 95% CI: 0.82, 1.63), were positively associated with ovarian cancer. Hysterectomies (20% of participants) were also positively associated with ovarian cancer (HR=1.29, 95% CI: 0.95, 1.74). There was some evidence that hysterectomies may mitigate ovarian cancer risk among women with fibroids (HR=0.83, 95% CI: 0.56, 1.24), but not among women with endometriosis (HR=1.20, 95% CI: 0.65, 2.22). Identifying these joint associations adds to our understanding of ovarian cancer etiology and may help inform decisions about how women with fibroids, endometriosis, and hysterectomies are treated and surveilled for ovarian cancer.

Background/Objectives: Our objective was to evaluate changes in the management of symptomatic fibroids after establishing a multidisciplinary fibroid center with minimally invasive gynecologic surgery (MIGS) and interventional radiology (IR). Methods: A retrospective cohort study was conducted at the fibroid center created in September 2020. Patients were offered same-day consults with both MIGS and IR providers. Data were collected for patients with initial consultations from January to June 2019 (pre-fibroid center) and from January to June 2021 (post-fibroid center). Results: Among 615 patients meeting inclusion criteria, 273 had consultations pre-center and 342 post-center. More patients seen post-center had previously attempted medical management (30.1% vs. 20.2%), with a significant proportion having no prior medical or surgical treatment (53.2% vs. 61.5%). Post-center, there were more MIGS consultations (65.5% vs. 53.1%) and a decrease in general gynecology (GYN) consultations (19.0% vs. 25.6%). More patients sought additional opinions post-center (83.6% vs. 67.0%), particularly with MIGS (58.8% vs. 37.0%). General GYNs referred to MIGS (79.3% vs. 73.1%) and IR specialists (16.0% vs. 13.0%) more often in 2021. In 2021, use of MRI increased (66.5% vs. 52.4%), and more patients underwent uterine artery embolization (UAE) within 1 year of consultation compared to the pre-center period (13.8% vs. 6.9%). Conclusions: Patients with symptomatic fibroids often seek the expertise of specialists to explore treatment options. A multidisciplinary fibroid center that integrates efforts of MIGS and IR enables thorough counseling and a rise in the utilization of minimally invasive procedures, including UAE.

BACKGROUND: Chronic pelvic pain (CPP) is a multifactorial syndrome that can substantially affect a patient\'s quality of life. Endometriosis is one cause of CPP, and alterations of the immune and microbiome profiles have been observed in patients with endometriosis. The objective of this pilot study was to investigate differences in the vaginal and gastrointestinal microbiomes and cervicovaginal immune microenvironment in patients with CPP and endometriosis diagnosis compared to those with CPP without endometriosis and no CPP.
METHODS: Vaginal swabs, rectal swabs, and cervicovaginal lavages (CVL) were collected among individuals undergoing gynecologic laparoscopy. Participants were grouped based on patients seeking care for chronic pain and/or pathology results: CPP and endometriosis (CPP-Endo) (n = 35), CPP without endometriosis (n = 23), or patients without CPP or endometriosis (controls) (n = 15). Sensitivity analyses were performed on CPP with endometriosis location, stage, and co-occurring gynecologic conditions (abnormal uterine bleeding, fibroids). 16S rRNA sequencing was performed to profile the microbiome, and a panel of soluble immune mediators was quantified using a multiplex assay. Statistical analysis was conducted with SAS, R, MicrobiomeAnalyst, MetaboAnalyst, and QIIME 2.
RESULTS: Significant differences were observed between participants with CPP alone, CPP-Endo, and surgical controls for body mass index, ethnicity, diagnosis of ovarian cysts, and diagnosis of fibroids. In rectal microbiome analysis, both CPP alone and CPP-Endo exhibited lower alpha diversity than controls, and both CPP groups revealed enrichment of irritable bowel syndrome-associated bacteria. CPP-Endo exhibited an increased abundance of vaginal Streptococcus anginosus and rectal Ruminococcus. Patients with CPP and endometrioma (s) demonstrated increased vaginal Streptococcus, Lactobacillus, and Prevotella compared to other endometriosis sites. Further, abnormal uterine bleeding was associated with an increased abundance of bacterial vaginosis-associated bacteria. Immunoproteomic profiles were distinctly clustered by CPP alone and CPP-Endo compared to controls. CPP-Endo was enriched in TNF⍺, MDC, and IL-1⍺.
CONCLUSIONS: Vaginal and rectal microbiomes were observed to differ between patients with CPP alone and CPP with endometriosis, which may be useful in personalized treatment for individuals with CPP and endometriosis from those with other causes of CPP. Further investigation is warranted in patients with additional co-occurring conditions, such as AUB/fibroids, which add additional complexity to these conditions and reveal the enrichment of distinct pathogenic bacteria in both mucosal sites. This study provides foundational microbiome-immunoproteomic knowledge related to chronic pelvic pain, endometriosis, and co-occurring gynecologic conditions that can help improve the treatment of patients seeking care for pain.

Uterine fibroids are the most common tumors in females affecting up to 70% of women world-wide, yet targeted therapeutic options are limited. Oxidative stress has recently surfaced as a key driver of fibroid pathogenesis and provides insights into hypoxia-induced cell transformation, extracellular matrix pathophysiology, hypoxic cell signaling cascades, and uterine biology. Hypoxia drives fibroid tumorigenesis through (1) promoting myometrial stem cell proliferation, (2) causing DNA damage propelling transformation of stem cells to tumor initiating cells, and (3) driving excess extracellular matrix (ECM) production. Common fibroid-associated DNA mutations include MED12 mutations, HMGA2 overexpression, and Fumarate hydratase loss of function. Evidence suggests an interaction between hypoxia signaling and these mutations. Fibroid development and growth are promoted by hypoxia-triggered cell signaling via various pathways including HIF-1, TGFβ, and Wnt/β-catenin. Fibroid-associated hypoxia persists due to antioxidant imbalance, ECM accumulation, and growth beyond adequate vascular supply. Current clinically available fibroid treatments do not take advantage of hypoxia-targeting therapies. Growing pre-clinical and clinical studies identify ROS inhibitors, anti-HIF-1 agents, Wnt/β-catenin inhibition, and TGFβ cascade inhibitors as agents that may reduce fibroid development and growth through targeting hypoxia.

Uterine fibroids represent the most prevalent genital tract tumours among women, with a disproportionately higher impact on ethnic minority groups, notably black women. These hormonally dependent monoclonal tumours, characterized by excessive extracellular matrix and influenced by genetic, epigenetic, and lifestyle factors, significantly affect women\'s quality of life and pose substantial economic burdens on healthcare systems. Recent advances in early detection and minimally invasive treatment options have shifted management paradigms towards personalized care, yet challenges in early diagnosis, education and access to treatment persist. This review synthesizes current knowledge on uterine fibroids, highlighting the impact of fibroids on women\'s health, risk factors, principles of screening, diagnostic tools, and treatment modalities. It emphasizes the importance of early screening and individualized management strategies in improving patient outcomes and reducing healthcare costs. The article also discusses the socio-economic and health disparities affecting the disease burden, underscoring the need for improved patient education, clinician training, and public health strategies to enhance fibroid management. This review proposes a pathway to not only ameliorate the quality of life for women with fibroids, but also to advance global women\'s health equity.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are endocrine-disrupting chemicals used in commercial and consumer products.
OBJECTIVE: We evaluated PFAS exposure in relation to incidence and growth of uterine leiomyomata (UL), hormone-dependent neoplasms that are associated with severe gynecologic morbidity.
METHODS: We studied 1158 participants in the Study of Environment, Lifestyle, and Fibroids, a Detroit-based prospective cohort study of Black females aged 23-35 years at enrollment (2010-2012). At enrollment and four subsequent visits during 10 years of follow-up, participants attended in-person clinic visits, completed questionnaires, provided non-fasting blood samples, and underwent ultrasound for UL detection. We quantified 7 PFAS in baseline plasma samples using mass spectrometry. We used Cox regression and probit Bayesian kernel machine regression to estimate individual and joint effects of PFAS on UL incidence. We fit linear mixed models to estimate effects of individual PFAS on UL growth. We stratified by parity, an important route of PFAS elimination and determinant of UL.
RESULTS: In individual PFAS analyses, we observed inverse associations for perfluorodecanoate (PFDA; ≥0.3 vs. <0.2 ng/ml: hazard ratio [HR] = 0.74; 95% confidence interval [CI]: 0.54-1.00) and perfluoroundecanoate (detected vs. non-detected: HR = 0.78; 95% CI: 0.61-1.01) and a weak positive association for perfluorohexane sulfonate (≥1 vs. <0.6 ng/ml: HR = 1.17; 95% CI: 0.85-1.61), while perfluorooctane sulfonate, perfluorooctanoate, perfluorononanoate (PFNA), and 2-N-methyl-perfluorooctane sulfonamido acetate (MeFOSAA) showed little association with UL incidence. The PFAS mixture was inversely associated with UL incidence, a finding driven by MeFOSAA and PFDA; however, PFNA was positively associated with UL incidence. The inverse association for PFDA and positive association for PFNA were stronger among nulliparous participants. Most PFAS showed slight inverse associations with UL growth.
UNASSIGNED: In this prospective ultrasound study of 1158 Black females aged 23-35 years at enrollment, we conducted a mixtures analysis to account for co-pollutant confounding and interaction. MeFOSAA and PFDA concentrations were inversely associated with UL incidence, while PFNA concentrations were positively associated with UL incidence. Concentrations of most PFAS were associated with decreased UL growth. This study contributes data to the sparse literature on PFAS exposure and UL development.

The symptomatic burden of uterine fibroids has been demonstrated to disproportionately affect Black and Hispanic women. The primary aim of this study was to evaluate if racial disparities seen in disease severity in regards to bleeding symptoms and surgical management also applied to presurgical medical management. A retrospective chart review evaluated women aged 18-50 with the diagnosis of fibroids who underwent a myomectomy or hysterectomy between 2012 and 2021. Black and Hispanic women were more likely to have preoperative hemoglobin values under 10 mg/dL (p < 0.001) and had higher rates of preoperative blood transfusions than White women (p = 0.001). Black women utilized the highest number of medications before excisional procedures, followed by Hispanic women. Asian women reported the lowest average (p = 0.037). There was no preferential use of GnRH analogues, intrauterine devices, or oral hormonal therapies between races. Minor procedures were infrequently utilized without statistically significant variations among races. This study confirms previous evidence that Black and Hispanic women are more severely affected by uterine fibroids. This severity is mirrored in increased utilization of medications, but patients continue to be under optimized prior to surgery. Further research should identify factors preventing these groups from achieving better symptom control preoperatively.

Objective: To assess the appropriateness of hysterectomies performed at a large tertiary health system using the 1997 RAND appropriateness classification system and an updated algorithm. Design: We abstracted structured and unstructured data from electronic medical records on patient demographics, primary indication(s) for hysterectomy, diagnosis codes associated with the hysterectomy, previous treatments, and laboratory results. Subjects: Patients aged 18-44 years. Exposure: Receipt of hysterectomy for benign and nonobstetric conditions from October 2014 to December 2017. Main Outcome Measures: Using these data, we provided a RAND-based (dichotomous: inappropriate/appropriate) and Wright-based (3-level: inappropriate/ambiguous/appropriate) appropriateness rating and characterized missing information patterns associated with inappropriate ratings. Results: We analyzed 1,829 hysterectomies across 30 nonmutually exclusive primary indications for surgery. Nearly a third (32.8%) of surgeries had only one primary indication for surgery. Using the RAND-based classifier, 31.3% of hysterectomies were rated as appropriate and 68.7% as inappropriate. Using the Wright-based algorithm, 58.1% of hysterectomies were rated as appropriate, 15.7% as ambiguous, and 26.2% as inappropriate. Missing information on diagnostic procedures was the most common characteristic related to both RAND-based (46.1%) and Wright-based (51.2%) inappropriate ratings. Conclusions: The 1997 RAND classification lacked guidance for several contemporary indications, including gender-affirming care. RAND also has an outdated requirement for diagnostic surgeries such as laparoscopies, which have decreased in practice as diagnostic imaging has improved. Sensitivity analyses suggest that inappropriate surgeries cannot all be attributed to bias from missing electronic medical record data. Accurately documenting care delivery for benign gynecological conditions is key to ensuring quality and equity in gynecological care.

UNASSIGNED: Bicornuate uterus is a rare type of congenital mullerian anomaly, presenting as a diagnostic challenge. Metroplasty either via an open approach or laparoscopically can be performed to definitively diagnose and treat the defect.
METHODS: A 26-year-old female, with no known comorbids and past surgical history of endometriotic cyst excision presented with acute symptoms of left lower abdominal pain, burning micturition, and relative constipation. After clinical and radiologic investigations, the diagnosis of bicornuate was suspected. An elective exploratory laparotomy was then performed due to limited resources and skilled surgical techniques. Intra-operatively it was found that she had a bicornuate uterus with a single cervix and vagina, with the left cornuate being non-communicating with fluid suggesting hematometra. Dense adhesions were reported with drainage of 150-200 ml of free fluid upon opening the rectus sheath. Postoperatively she remained vitally stable and was discharged home.
UNASSIGNED: We report a rare case of a bicornuate uterus with double horns along with submucosal fibroids, rectus sheath hematoma, and left sided hydronephrosis. Diagnosis of bicornuate uterus is associated with diagnostic uncertainty mainly due to its rarity and nonspecific presentation.
CONCLUSIONS: Although bicornuate is rare, it may result in complications if not attended to timely. Early diagnosis and management are necessary to minimize associated morbidity and mortality that can occur as a consequence of associated unattended pressure symptoms.