MiRNAs related in signaling pathways of women's reproductive diseases: an overview.

BACKGROUND: One of the main health issues that can affect women's health is reproductive diseases, such as polycystic ovary syndrome (PCOS), endometriosis (EMs), uterine leiomyomas (ULs), and ovarian cancer (OC). Although these diseases are very common, we do not have a complete understanding of their underlying cellular and molecular mechanisms. It is important to mention that the majority of patients are diagnosed with these diseases at later stages because of the absence of early diagnostic techniques and dependable molecular indicators. Hence, it is crucial to discover novel and non-invasive biomarkers that have prognostic, diagnostic and therapeutic capabilities. MiRNAs, also known as microRNAs, are small non-coding RNAs that play a crucial role in regulating gene expression at the post-transcriptional level. They are short in length, typically consisting of around 22 nucleotides, and are highly conserved across species. Numerous studies have shown that miRNAs are expressed differently in various diseases and can act as either oncogenes or tumor suppressors. METHODS: The author conducted a comprehensive review of all the pertinent papers available in web of science, PubMed, Google Scholar, and Scopus databases. RESULTS: We achieved three goals: providing readers with better information, enhancing search results, and making peer review easier. CONCLUSIONS: This review focuses on the investigation of miRNAs and their involvement in various reproductive disorders in women, including their molecular targets. Additionally, it explores the role of miRNAs in the development and progression of these disorders.

Spontaneous regression of a giant uterine leiomyoma after delivery: a case report and literature review.

BACKGROUND: Uterine leiomyomas are hormone-dependent benign tumors and often begin to shrink after menopause due to the reduction in ovarian steroids. The influence of pregnancy on uterine leiomyomas size remains unclear. Here, we present a case of spontaneous regression of a giant uterine leiomyoma after delivery. CASE PRESENTATION: A 40-year-old woman presented with multiple uterine leiomyomas, one of which is a giant uterine leiomyomas (approximately 8 cm in diameter) that gradually shrinked after delivery. At over two months postpartum, the large myometrial leiomyoma had transformed into a submucosal leiomyoma, and over 3 years postpartum, both the submucosal leiomyoma and multiple intramural leiomyomas completely regressed. CONCLUSION: Spontaneous regression of a giant uterine leiomyom is rare after delivery. Considering uterine leiomyoma regression until over 3 year postpartum,we need to observe the regression of uterine fibroid for a longer time postpartum in the absence of fibroid related complications. In addition, it will provide new insights for treatment options of uterine leiomyomas in the future.

Periostin's role in uterine leiomyoma development: a mini-review on the potential periostin poses as a pharmacological intervention for uterine leiomyoma.

Uterine leiomyomas, also known as fibroids or myomas, occur in an estimated 70-80% of reproductive aged women. Many experience debilitating symptoms including pelvic pain, abnormal uterine bleeding (AUB), dyspareunia, dysmenorrhea, and infertility. Current treatment options are limited in preserving fertility, with many opting for sterilizing hysterectomy as a form of treatment. Currently, surgical interventions include hysterectomy, myomectomy, and uterine artery embolization in addition to endometrial ablation to control AUB. Non-surgical hormonal interventions, including GnRH agonists, are connotated with negative side effects and are unacceptable for women desiring fertility. Periostin, a regulatory extra cellular matrix (ECM) protein, has been found to be expressed in various gynecological diseases including leiomyomas. We previously determined that periostin over-expression in immortalized myometrial cells led to the development of a leiomyoma-like cellular phenotype. Periostin is induced by TGF-ß, signals through the PI3K/AKT pathway, induces collagen production, and mediates wound repair and fibrosis, all of which are implicated in leiomyoma pathology. Periostin has been linked to other gynecological diseases including ovarian cancer and endometriosis and is being investigated as pharmacological target for treating ovarian cancer, post-surgical scarring, and numerous other fibrotic conditions. In this review, we provide discussion linking pathological inflammation and wound repair, with a TGF-ß-periostin-collagen signaling in the pathogenesis of leiomyomas, and ultimately the potential of periostin as a druggable target to treat leiomyomas.

Insulin-Like Growth Factor-1 Promotes Human Uterine Leiomyoma Cell Proliferation via PI3K/AKT/mTOR Pathway.

The present research aimed to evaluate the expression of insulin-like growth factor-1 (IGF-1) in uterine leiomyoma, and explore its relationship with the occurrence and development of uterine leiomyoma and potential signal pathways. qRT-PCR and enzyme-linked immunosorbent assay were used for estimating the levels of IGF-1 in human uterine leiomyoma compared to myometrium. The expression of cell proliferation and PI3K/AKT/mTOR signaling pathway-related proteins in uterine leiomyoma cells was evaluated by western blot. Cell viability analysis was performed by CCK-8 assay. Lentivirus infection was used for IGF-1 overexpression and knockdown in uterine leiomyoma cells. The IGF-1 expression level was elevated in human uterine leiomyomas compared to myometrium. IGF-1 promoted the cell viability of human uterine leiomyoma cells. Overexpression of IGF-1 induced the expression of pro-proliferation markers including c-Myc, PCNA, and cyclin D1 in uterine leiomyoma cells. IGF-1 elevated the phosphorylation levels of PI3K, AKT, and mTOR, thus modifying PI3K/AKT/mTOR signaling in uterine leiomyoma cells. IGF-1 promotes proliferation of human uterine leiomyoma cells via PI3K/AKT/mTOR pathway.

Halofuginone inhibits cell proliferation and AKT/mTORC1 signaling in uterine leiomyoma cells.

The present study aimed to explore the effects of antifibrotic agent halofuginone on uterine leiomyomas (ULs) cells. The survival of the uterine smooth muscle (UtSMC) cells and UL ELT3 cells were measured. Flow cytometry was used to assess the cell cycle distribution and apoptosis. Effects of halofuginone on the state of AKT/mTOR pathway were evaluated. Xenograft animal model was applied to explore the effects of halofuginone in vivo. Halofuginone inhibited the proliferation of ELT3 cells dose-dependently without obvious influence on UtSMC cells. Halofuginone suppressed cell cycle progression and promoted apoptosis of ELT3 cells dose-dependently. Also, p-AKT/AKT and p-p70S6/p70S6 were significantly lowered after treatment with 20 nM halofuginone. Additionally, halofuginone reduced ELT3 tumor growth in xenograft tumor animal model. The present study illustrates that halofuginone inhibits cell proliferation of ULs with low side effects on normal smooth muscle cells, and AKT/mTOR signaling pathway was inactivated meanwhile.

Single-cell sequencing reveals novel cellular heterogeneity in uterine leiomyomas.

STUDY QUESTION: What are the cellular composition and single-cell transcriptomic differences between myometrium and leiomyomas as defined by single-cell RNA sequencing? SUMMARY ANSWER: We discovered cellular heterogeneity in smooth muscle cells (SMCs), fibroblast and endothelial cell populations in both myometrium and leiomyoma tissues. WHAT IS KNOWN ALREADY: Previous studies have shown the presence of SMCs, fibroblasts, endothelial cells and immune cells in myometrium and leiomyomas. However, there is no information on the cellular heterogeneity in these tissues and the transcriptomic differences at the single-cell level between these tissues. STUDY DESIGN, SIZE, DURATION: We collected five leiomyoma and five myometrium samples from a total of eight patients undergoing hysterectomy. We then performed single-cell RNA sequencing to generate a cell atlas for both tissues. We utilized our single-cell sequencing data to define cell types, compare cell types by tissue type (leiomyoma versus myometrium) and determine the transcriptional changes at a single-cell resolution between leiomyomas and myometrium. Additionally, we performed MED12-variant analysis at the single-cell level to determine the genotype heterogeneity within leiomyomas. PARTICIPANTS/MATERIALS, SETTING, METHODS: We collected five MED12-variant positive leiomyomas and five myometrium samples from a total of eight patients. We then performed single-cell RNA sequencing on freshly isolated single-cell preparations. Histopathological assessment confirmed the identity of the samples. Sanger sequencing was performed to confirm the presence of the MED12 variant in leiomyomas. MAIN RESULTS AND ROLE OF CHANCE: Our data revealed previously unknown heterogeneity in the SMC, fibroblast cell and endothelial cell populations of myometrium and leiomyomas. We discovered the presence of two different lymphatic endothelial cell populations specific to uterine leiomyomas. We showed that both myometrium and MED12-variant leiomyomas are relatively similar in cellular composition but differ in cellular transcriptomic profiles. We found that fibroblasts influence the leiomyoma microenvironment through their interactions with endothelial cells, immune cells and SMCs. Variant analysis at the single-cell level revealed the presence of both MED12 variants as well as the wild-type MED12 allele in SMCs of leiomyomatous tissue. These results indicate genotype heterogeneity of cellular composition within leiomyomas. LARGE SCALE DATA: The datasets are available in the NCBI Gene Expression Omnibus (GEO) using GSE162122. LIMITATIONS, REASONS FOR CAUTION: Our study focused on MED12-variant positive leiomyomas for single-cell RNA sequencing analyses. Leiomyomas carrying other genetic rearrangements may differ in their cellular composition and transcriptomic profiles. WIDER IMPLICATIONS FOR THE FINDINGS: Our study provides a cellular atlas for myometrium and MED12-variant positive leiomyomas as defined by single-cell RNA sequencing. Our analysis provides significant insight into the differences between myometrium and leiomyomas at the single-cell level and reveals hitherto unknown genetic heterogeneity in multiple cell types within human leiomyomas. Our results will be important for future studies into the origin and growth of human leiomyomas. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by funding from the National Institute of Child Health and Human Development (HD098580 and HD088629). The authors declare no competing interests.

Minimally invasive myomectomy: practice trends and differences between Black and non-Black women within a large integrated healthcare system.

BACKGROUND: Although multiple professional organizations encourage minimally invasive surgical approaches whenever feasible, nationally, fewer than half of myomectomies are performed via minimally invasive routes. Black women are less likely than their non-Black counterparts to have minimally invasive surgery. OBJECTIVE: This study aimed to assess the trends in surgical approach among women who underwent minimally invasive myomectomies for uterine leiomyomas within a large integrated healthcare system as initiatives were implemented to encourage minimally invasive surgery, particularly evaluating differences in the proportion of minimally invasive surgery performed in Black vs non-Black women. STUDY DESIGN: We conducted a retrospective cohort study of women, aged ≥18 years, who underwent a myomectomy for a uterine leiomyoma within Kaiser Permanente Northern California between 2009 and 2019. Generalized estimating equations and Cochran-Armitage testing were used to assess myomectomy incidence and linear trend in the proportions of myomectomy by surgical route-abdominal myomectomy and minimally invasive myomectomy. Multivariable logistic regression analyses were used to assess the associations between surgical route and (1) race and ethnicity and (2) complications, controlling for patient demographic, clinical, and surgical characteristics. RESULTS: A total of 4033 adult women underwent a myomectomy during the study period. Myomectomy incidence doubled from 0.12 (95% confidence interval, 0.12-0.13) per 1000 women in 2009 to 0.25 (95% confidence interval, 0.24-0.25) per 1000 women in 2019 (P<.001). During the 11-year study period, the proportion of minimally invasive myomectomy increased from 6.0% to 89.5% (a 15-fold increase). The proportion of minimally invasive myomectomy in Black women remained lower than in non-Black women (54.5% vs 64.7%; P<.001). Black women undergoing myomectomy were younger (36.4±5.6 vs 37.4±5.8 years; P<.001), had a higher mean fibroid weight (436.0±505.0 vs 324.7±346.1 g; P<.001), and had a higher mean body mass index (30.8±7.3 vs 26.6±5.9 kg/m2; P<.001) than their non-Black counterparts. In addition to patient race, surgery performed between 2016 and 2019 compared with surgery performed between 2009 and 2012 and higher surgeon volume compared with low surgeon volume were associated with an increased proportion of minimally invasive myomectomy (adjusted relative risks, 12.58 [95% confidence interval, 9.96-15.90] and 6.63 [95% confidence interval, 5.35-8.21], respectively). Black race and fibroid weight of >500 g each independently conferred lower rates of minimally invasive myomectomy. In addition, there was an interaction between race and fibroid weight such that Black women with a fibroid weight of ≤500 g or >500 g were both less likely to have minimally invasive myomectomy than non-Black women with a fibroid weight of ≤500 g (adjusted relative risks, 0.74 [95% confidence interval, 0.58-0.95] and 0.26 [95% confidence interval, 0.18-0.36], respectively). Operative, perioperative, and medical complications were low during the 11-year study period. In regression analyses, after controlling for race, age, fibroid weight, parity, low-income residence, body mass index, surgeon volume, and year of myomectomy, the risk of complications was not markedly different comparing abdominal myomectomy with minimally invasive myomectomy. Similar results were found comparing laparoscopic minimally invasive myomectomy with robotic-assisted minimally invasive myomectomy except for women who underwent laparoscopic minimally invasive myomectomy had a lower risk of experiencing any medical complications than those who underwent robotic-assisted minimally invasive myomectomy (adjusted relative risk, 0.27; 95% confidence interval, 0.09-0.83; P=.02). CONCLUSION: Within an integrated healthcare delivery system, although initiatives to encourage minimally invasive surgery were associated with a marked increase in the proportion of minimally invasive myomectomy, Black women continued to be less likely to undergo minimally invasive myomectomy than their non-Black counterparts. Race and fibroid weight alone did not explain the disparities in minimally invasive myomectomy.

Functional Characterization of FH Mutation c.557G>A Underlies Uterine Leiomyomas.

The FH gene encodes the fumarate hydratase of the Krebs cycle and functions as a homotetramer to catalyze the hydration of fumarate to malate. Mutations in FH result in uterine leiomyomas, a rare autosomal dominant inherited metabolic disease. However, how FH mutations result in this disease is poorly understood. Here, the FH mutation c.557G>A (p.S186N) was identified in a family with uterine leiomyomas phenotype. A series of studies were performed to confirm the pathogenicity of this mutation. Results showed that the FH mutant exhibited significantly lower fumarase enzyme activity and increased the fumarates level compared with the wildtype, which might be due to the impaired homotetramer formation in the native gel electrophoresis. Interestingly, the immunofluorescence study revealed that the overexpressed FH mutant exhibited puncta structures compared with the evenly expressed FH wildtype in cytoplasm suggesting that the altered amino acid might result in dysfunctional proteins which were accumulated to reduce its cytotoxicity. Importantly, the cells overexpressing the FH mutant exhibited higher proliferation and extracellular acidification rate value (ECAR) which might be caused by the upregulated HIF-1α indicating the tumor phenotype. Notably, phospho-mTOR was significantly increased and autophagy was inhibited in the FH mutant overexpression cells compared with the wildtype. Our work provides new insight into the FH mutation c.557G>A (p.S186N) underlies uterine leiomyomas and important information for accurate genetic counseling and clinical diagnosis of the disease.

Transradial versus transfemoral arterial access in the uterine artery embolization of fibroids.

Purpose: Transradial arterial access has become more popular in body interventional procedures but has not been ubiquitously adapted. This retrospective study assesses the efficacy of this approach in uterine artery embolization. Aim of the study was to compare transradial to transfemoral arterial access in patients undergoing uterine artery embolization for the treatment of fibroids. Material and methods: A total of 172 patients underwent uterine artery embolization procedures at our institute from October 2014 to June 2020. Of these, 76 patients had their operations performed via transfemoral access while 96 underwent transradial access. The peak radiation dose, fluoroscopy time, procedure time, total contrast volume, and equipment cost for each procedure were all reviewed to evaluate for statistical differences between the 2 groups. Results: All cases were technically successful without major complications. The average peak skin dose was 2281 mGy,with no statistical difference between the transradial or transfemoral cohorts. Average fluoroscopy time was 25 minutes, also with no statistical difference between the subsets. Mean procedure time was 100 min, and mean contrast volume usage was 138 mL with no statistical differences. Similarly, the average equipment cost was $2204, with no significant differences found between transradial and transfemoral access. Conclusions: With respect to many pertinent radiation parameters, transradial access was evaluated as being an equally efficacious alternative to transfemoral access in uterine artery embolization procedures. The results of this study suggest that transradial access should be considered more often, whenever viable, as an option in the uterine artery embolization treatment of fibroids.

Association of Single Nucleotide Polymorphism LEP-R c.668A>G (p.Gln223Arg, rs1137101) of leptin receptor gene with endometrial cancer.

BACKGROUND: The aim of this study was to analyze the frequencies of genotypes and alleles of Single Nucleotide Polymorphism (SNP) LEP-R c.668A>G (p.Gln223Arg, rs1137101) of leptin receptor gene and to assess the influence this DNA marker has on endometrial cancer (EC) with respect to total body fat content. METHODS: The study comprised 120 patients treated for endometrial cancer and 90 controls treated for uterine fibroids. In total, 210 patients were included in this research. DNA was isolated from archival post-operative specimens. Polymerase Chain Reaction - Restriction Fragment Length Polymorphism was employed to analyze the SNP. RESULTS: In this paper we have demonstrated that heterozygous genotype AG of SNP LEP-R c.668A>G (p.Gln223Arg, rs1137101) is statistically less frequent in women with endometrial cancer (EC) than in controls: 33 versus 57%, respectively. Similarly, this heterozygous genotype is statistically significantly less frequent in obese (BMI > 30) women with EC than in lean controls (BMI < 25): 30 versus 63%, respectively. CONCLUSIONS: AG polymorphic variant of SNP LEP-R c.668A>G (p.Gln223Arg, rs1137101) in LEP-R may be considered a protective factor in the development of endometrial cancer.

An HMGA2-p62-ERα axis regulates uterine leiomyomas proliferation.

Uterine leiomyomas (ULM) are a major public health issue contributing to high morbidity and poor pregnancy outcomes. However, its molecular pathogenesis is poorly understood. HMGA2-ULM is the second major subtype of human ULM and associates with large sizes, fast-growth, and high percentages of estrogen receptor α (ERα). As altered ERα expression plays a distinct role in ULM growth, here, we investigate a regulatory mechanism driving ULM growth via HMGA2 and ERα. We reveal a positive correlation of HMGA2 with ERα protein and demonstrate that HMGA2 promotes ULM cells proliferation via ERα. In addition, autophagy pathway and p62/SQSTM1 (a selective autophagy receptor) are found to participate in the regulation of HMGA2 and ERα. Moreover, HMGA2 suppresses the transcription of p62 by binding to its promoter, meanwhile, p62 interacts with ERα, and inhibition of p62 increases ERα expression and enhances cell viability in ULM, suggesting a novel mechanism of the HMGA2-p62-ERα axis in ULM proliferation. Notably, rapamycin, a familiar autophagy agonist, reduces ERα levels and the proliferation ability of ULM cells. This study demonstrates a causal role of the HMGA2-p62-ERα axis in preventing autophagy and increasing ERα expression in HMGA2-ULM. Therefore, blocking HMGA2-p62-ERα axis and targeting autophagy pathway establish a roadmap toward HMGA2-ULM medical treatment.

Nonenhanced MRI-based radiomics model for preoperative prediction of nonperfused volume ratio for high-intensity focused ultrasound ablation of uterine leiomyomas.

OBJECTIVES: To develop and assess nonenhanced MRI-based radiomics model for the preoperative prediction of nonperfused volume (NPV) ratio of uterine leiomyomas after high-intensity focused ultrasound (HIFU) treatment. METHODS: Two hundred and five patients with uterine leiomyomas treated by HIFU were enrolled and allocated to training (N =164) and testing cohorts (N = 41). Pyradiomics was used to extract radiomics features from T2-weighted images and apparent diffusion coefficient (ADC) map generated from diffusion-weighted imaging (DWI). The clinico-radiological model, radiomics model, and radiomics-clinical model which combined the selected radiomics features and clinical parameters were used to predict technical outcomes determined by NPV ratios where three classification groups were created (NPV ratio ≤ 50%, 50-80% or ≥ 80%). The receiver operating characteristic (ROC) curve, area under the curve (AUC), and calibration and decision curve analyses were performed to illustrate the prediction performance and clinical usefulness of model in the training and testing cohorts. RESULTS: The multi-parametric MRI-based radiomics model outperformed T2-weighted imaging (T2WI)-based radiomics model, which achieved an average AUC of 0.769 (95% confidence interval [CI], 0.701-0.842), and showed satisfactory prediction performance for NPV ratio classification. The radiomics-clinical model demonstrated best prediction performance for HIFU treatment outcome, with an average AUC of 0.802 (95% CI, 0.796-0.850) and an accuracy of 0.762 (95% CI, 0.698-0.815) in the testing cohort, compared to the clinico-radiological and radiomics models. The decision curve also indicated favorable clinical usefulness of the radiomics-clinical model. CONCLUSIONS: Nonenhanced MRI-based radiomics has potential in the preoperative prediction of NPV ratio for HIFU ablation of uterine leiomyomas.

Ulipristal acetate before in vitro fertilization: efficacy in infertile women with submucous fibroids.

BACKGROUND: The presence of submucous fibroids strongly impacts on IVF results, therefore, these patients should be considered for surgical or medical treatment. The aim of this study was to assess the role of Ulipristal acetate (UPA), a selective progesterone receptor modulator, in restoring uterine cavity deformation due to submucous fibroids, in infertile patients attempting an IVF treatment. The secondary study outcome was to evaluate the impact of preconception UPA treatment on rate of biochemical pregnancy, ongoing pregnancy, and live birth compared to a control group without fibroids. METHODS: Infertile patients with submucosal fibroid (Type 1 and Type 2 according to FIGO classification) were enrolled in the study as fibroids group and received 1 to 3 treatment cycles of UPA, according to their response, as reflected by fibroid volume reduction and restoration of normal uterine cavity. Patients in control group were randomly selected from a general IVF cohort by a ratio of 2:1 with fibroids group, matched by age, BMI, type and cause of infertility and antral follicle count. The impact of UPA on fibroids volume reduction was evaluated. IVF outcome was compared between groups. RESULTS: Twenty-six patients underwent UPA treatment revealed a mean volume reduction of their fibroids of 41%. A total of 15 (57.6%) biochemical pregnancy were obtained, resulting in 13 (50%) ongoing pregnancy and 9 (34.6%) healthy babies were already delivered. Similar results were obtained in control group. CONCLUSION: Restoration of normal uterine cavity by UPA treatment prior to IVF treatment avoids surgery and establishes a pregnancy rate comparable to a control group without fibroids.

Hereditary Leiomyomatosis and Renal Cell Cancer.

Hereditary leiomyomatosis and renal cell cancer is a genodermatosis with an autosomal dominant inheritance pattern. It is a tumour predisposition syndrome characterized by cutaneous and uterine leiomyomas, and increased susceptibility to develop renal cell carcinoma. There are 200-300 families with hereditary leiomyomatosis and renal cell carcinoma reported worldwide, but the syndrome is believed to be underdiagnosed. Cutaneous leiomyomas are small smooth muscle tumours that tend to grow over time. Larger lesions, in particular, can cause pain or itching. Uterine leiomyomas have a high penetrance in women with hereditary leiomyomatosis and renal cell cancer. They frequently cause symptoms, and surgical intervention is often necessary. Hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinomas have a high potential to metastasize. Patients are diagnosed by genetic testing if a pathogenic mutation is demonstrated in the gene encoding fumarate hydratase. Immunohistochemistry may be a useful diagnostic approach in patients without a detectable pathogenic mutation. Diagnosed patients should be monitored for renal tumours in a lifelong surveillance programme.

Intra-abdominal haemorrhage from uterine fibroids: a systematic review of the literature.

BACKGROUND: Uterine leiomyomas are common benign tumours found in women of reproductive age that are rarely associated with intra-abdominal haemorrhage. The aetiology behind this relationship is poorly understood and the aforementioned association poorly recognized from a patient's clinical presentation. Available information in the literature is limited to case reports. The aim of this systematic review is to document and highlight the occurrence of intra-abdominal haemorrhage from uterine fibroids, and determine associated morbidity and mortality. METHODS: A systematic review of Medline, EMBASE, Web of Science, Scopus, and The Cochrane Library - CENTRAL was performed from the databases inception through to December 2018 for case report and series of patients who experienced intra-abdominal haemorrhage from uterine fibroids. Findings were presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. RESULTS: We identified 115 publications reporting on 125 original case reports. The documented intra-abdominal haemorrhage were commonly due to the rupture of superficial blood vessels over the surface of a fibroid, followed by rupture and avulsion of the fibroid involved. A clinical picture of sudden and profound hypovolemic shock with severe abdominal pain was often the presenting complaint, with a correct pre-operative diagnosis only made in 7 cases on computed tomography imaging. Hysterectomy and myomectomy were the most common surgery performed. Mortality was reported in 4 cases which were directly related to complications of uterine fibroids. CONCLUSION: Intra-abdominal haemorrhage secondary to uterine fibroids remained a rare phenomenon which is poorly recognized among clinicians. While this association is not representative of the population of interest, it highlights the pathophysiological spectrum of uterine fibroids and its relevance to emergency physicians, surgeons and gynaecologists during clinical practice.

A nongenomic mechanism for "metalloestrogenic" effects of cadmium in human uterine leiomyoma cells through G protein-coupled estrogen receptor.

Cadmium (Cd) is a ubiquitous environmental metal that is reported to be a "metalloestrogen." Uterine leiomyomas (fibroids) are estrogen-responsive gynecologic neoplasms that can be the target of xenoestrogens. Previous epidemiology studies have suggested Cd may be associated with fibroids. We have shown that Cd can stimulate proliferation of human uterine leiomyoma (ht-UtLM) cells, but not through classical estrogen receptor (ER) binding. Whether nongenomic ER pathways are involved in Cd-induced proliferation is unknown. In the present study, by evaluating G protein-coupled estrogen receptor (GPER), ERα36, and phospho-epidermal growth factor receptor (EGFR) expression in human tissues, we found that GPER, ERα36 and phospho-EGFR were all highly expressed in fibroids compared to patient-matched myometrial tissues. In ht-UtLM cells, cell proliferation was increased by low doses of Cd (0.1 µM and 10 µM), and this effect could be inhibited by GPER-specific antagonist (G15) pretreatment, or silencing (si) GPER, but not by siERα36. Cd-activated MAPK was dependent on GPER/EGFR transactivation, through significantly increased phospho-Src, matrix metalloproteinase-2 (MMP2) and MMP9, and heparin-binding EGF-like growth factor (HB-EGF) expression/activation. Also, phospho-Src could interact directly to phosphorylate EGFR. Overall, Cd-induced proliferation of human fibroid cells was through a nongenomic GPER/p-src/EGFR/MAPK signaling pathway that did not directly involve ERα36. This suggests that Cd may be a risk factor for uterine fibroids through cross talk between hormone and growth factor receptor pathways.

Understanding Obesity as a Risk Factor for Uterine Tumors Using Drosophila.

Multiple large-scale epidemiological studies have identified obesity as an important risk factor for a variety of human cancers, particularly cancers of the uterus, gallbladder, kidney, liver, colon, and ovary, but there is much uncertainty regarding how obesity increases the cancer risks. Given that obesity has been consistently identified as a major risk factor for uterine tumors, the most common malignancies of the female reproductive system, we use uterine tumors as a pathological context to survey the relevant literature and propose a novel hypothesis: chronic downregulation of the cyclin-dependent kinase 8 (CDK8) module, composed of CDK8 (or its paralog CDK19), Cyclin C, MED12 (or MED12L), and MED13 (or MED13L), by elevated insulin or insulin-like growth factor signaling in obese women may increase the chances to dysregulate the activities of transcription factors regulated by the CDK8 module, thereby increasing the risk of uterine tumors. Although we focus on endometrial cancer and uterine leiomyomas (or fibroids), two major forms of uterine tumors, our model may offer additional insights into how obesity increases the risk of other types of cancers and diseases. To illustrate the power of model organisms for studying human diseases, here we place more emphasis on the findings obtained from Drosophila melanogaster.

SATB2 and NGR1: potential upstream regulatory factors in uterine leiomyomas.

PURPOSE: We attempted to identify the genes involved in the pathogenesis of uterine leiomyomas, under a hypothesis that the aberrant expression of upstream regulatory genes caused by aberrant DNA methylation is involved in the onset and development of uterine leiomyomas. METHODS: To find such genes, we compared genome-wide mRNA expression and DNA methylation in uterine leiomyomas and adjacent normal myometrium. Analysis of the data by Ingenuity Pathway Analysis software identified SATB2 which is known to be an epigenetic regulator, and NRG1 as candidate upstream regulatory genes. To infer the functions of these genes, human uterine smooth muscle cell lines overexpressing SATB2 or NRG1 genes were established (SATB2 or NRG1 lines), and their transcriptomes and pathways were analyzed. RESULTS: SATB2 and NRG1 were confirmed to be hypermethylated and upregulated in most uterine leiomyoma specimens (nine to 11 of the 11 cases). Among the established cell lines, morphological changes from spindle-like forms to fibroblast-like forms with elongated protrusions were observed in only the SATB2 line. Pathway analysis revealed that WNT/ß-catenin and TGF-ß signaling pathways which are related to the pathogenesis of uterine leiomyomas were activated in both SATB2 and NRG1 lines. In addition, signaling of growth factors including VEGF, PDGF, and IGF1, and retinoic acid signaling were activated in the SATB2 and NRG1 lines, respectively. CONCLUSIONS: These results indicate that SATB2 and NRG1 overexpression induced many of the signaling pathways that are considered to be involved in the pathogenesis of uterine leiomyomas, suggesting that these genes have roles as upstream regulatory factors.

Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) Hull Extract and Active Compounds Inhibit Proliferation of Primary Human Leiomyoma Cells and Protect against Sexual Hormone-Induced Mice Smooth Muscle Hyperproliferation.

Uterine leiomyomas, also known as fibroids, are benign neoplasms of the uterus and have a high incidence rate in women of reproductive age. Hysterectomy or myomectomy is the initial treatment, but fibroids will recur if the patient is still exposed to similar risk factors. Therefore, developing new therapeutic strategies are urgently necessary. In this study, the anti-proliferation effects of each fraction of adlay seeds were evaluated in uterine leiomyomas, and we identified the potential phytochemical compounds. We found that the ethyl acetate fraction of adlay hull (AHE-ea) appeared to be highly efficient in the anti-proliferation of rat uterine leiomyoma ELT3 cells and primary human uterine leiomyoma (hUL) cells. The proliferation of primary human normal uterine smooth muscle (UtSMC) and normal uterine myometrial (hUM) cells were also suppressed by AHE-ea. Two phytosterols, stigmasterol and ß-sitosterol, were identified from AHE-ea fraction. Mice treated with AHE-ea and stigmasterol alone demonstrated reduced diethylstilbestrol/medroxyprogesterone 17-acetate (DES/MPA)-induced uterine myometrial hyperplasia, which is the critical step for the development of leiomyoma. Taken together, our results suggest that the AHE-ea fraction could be considered as a natural plant-based medicine in the prevention or treatment of uterine leiomyoma growth.

Laparoscopic and Robotic-Assisted Hysterectomy for Uterine Leiomyomas: A Comparison of Complications and Costs.

OBJECTIVE: Robotic surgery is increasingly being used for treatment of malignant and benign gynaecologic diseases. The purpose of our study is to compare patient perioperative complications and costs of laparoscopic versus robotic-assisted hysterectomy for uterine leiomyomas. METHODS: A retrospective cohort study using the Nationwide Inpatient Sample database from the United States was conducted, comparing patients who underwent robotic-assisted hysterectomy and laparoscopic hysterectomy (total laparoscopic hysterectomy and laparoscopic-assisted vaginal hysterectomy) for uterine fibroids between 2008 and 2012. Baseline characteristics were compared between the two groups, and logistic regression was used to compare postoperative outcomes between laparoscopic and robotic approaches. Direct costs were compared between the two groups using linear regression models. RESULTS: Over a five-year period, the total number of hysterectomies performed increased. Patients undergoing robotic hysterectomy were older and had more comorbidities. In adjusted analyses, women who underwent robotic surgery were more likely to have respiratory failure (0.71% vs. 0.39%; P < 0.0108), postoperative fever (1.05% vs. 0.67%, P < 0.0002), and ileus (1.76% vs. 1.3%; P < 0.0060), and less likely to require transfusions (3.4% vs. 3.96%; P < 0.0037). Robotic surgery was consistently more expensive, with a median cost of $33 928.00 compared with $23 753.00 for laparoscopic hysterectomy. CONCLUSION: While there are only slight differences in postoperative complications between laparoscopic-assisted hysterectomy and robotic-assisted hysterectomy, robotic-assisted hysterectomy is associated with considerably greater direct costs. Unless specific indications for robotic-assisted hysterectomy exist, laparoscopic-assisted hysterectomy should be the preferred approach for minimally invasive surgical treatment of leiomyomas.