Mostafa A. Borahay

Genetic Mechanisms Driving Uterine Leiomyoma Pathobiology, Epidemiology, and Treatment

Uterine leiomyomas (ULs) are the most common benign tumor of the uterus. They can be associated with symptoms including abnormal uterine bleeding, pelvic pain, urinary frequency, and pregnancy complications. Despite the high prevalence of UL, its underlying pathophysiology mechanisms have historically been poorly understood. Several mechanisms of pathogenesis have been suggested, implicating various genes, growth factors, cytokines, chemokines, and microRNA aberrations. The purpose of this study is to summarize the current research on the relationship of genetics with UL. Specifically, we performed a literature review of published studies to identify how genetic aberrations drive pathophysiology, epidemiology, and therapeutic approaches of UL. With regards to pathophysiology, research has identified MED12 mutations, HMGA2 overexpression, fumarate hydratase deficiency, and cytogenetic abnormalities as contributors to the development of UL. Additionally, epigenetic modifications, such as histone acetylation and DNA methylation, have been identified as contributing to UL tumorigenesis. Specifically, UL stem cells have been found to contain a unique DNA methylation pattern compared to more differentiated UL cells, suggesting that DNA methylation has a role in tumorigenesis. On a population level, genome-wide association studies (GWASs) and epidemiologic analyses have identified 23 genetic loci associated with younger age at menarche and UL growth. Additionally, various GWASs have investigated genetic loci as potential drivers of racial disparities in UL incidence. For example, decreased expression of Cytohesin 4 in African Americans has been associated with increased UL risk. Recent studies have investigated various therapeutic options, including ten-eleven translocation proteins mediating DNA methylation, adenovirus vectors for drug delivery, and “suicide gene therapy” to induce apoptosis. Overall, improved understanding of the genetic and epigenetic drivers of UL on an individual and population level can propel the discovery of novel therapeutic options.

Synergistic inhibition of progesterone receptor‐A/B signalling by simvastatin and mifepristone in human uterine leiomyomas

Angiotensin II drives proliferation and extracellular matrix deposition in human uterine fibroid cells in vitro

To investigate the effect of angiotensin II (Ang II) on proliferation and extracellular matrix (ECM) deposition in human uterine leiomyoma cells and normal myometrial cells. Experimental in vitro study using immortalized human leiomyoma (HuLM) cells, immortalized human uterine smooth muscle (UTSM) cells, and patient-derived primary fibroid and myometrial cells. Women with uterine fibroids who underwent hysterectomy. Administration of physiological and supraphysiological levels of Ang II (to mimic essential hypertension) to cultured HuLM, UTSM, primary fibroid, and myometrial cells to assess effects on cellular proliferation and ECM deposition. We evaluated HuLM, UTSM, primary fibroid, and UTSM cells for the presence of the Ang II type 1 receptor. Angiotensin II-induced proliferation and ECM deposition was assessed through MTS assay, Western blot analysis, immunofluorescence, and real-time polymerase chain reaction. Immortalized and primary leiomyoma and myometrial cells expressed Ang II type 1 receptor. Leiomyoma cells responded to Ang II with increased cellular proliferation measured by MTS assay, proliferating cell nuclear antigen protein levels, and Ki67 staining. The Ang II treatment of fibroid cells showed increased expression of Collagen 1A1, the predominant fibroid and myometrial collagen. Integrin β1, an upstream regulator of fibrosis, also showed an increase in protein and messenger ribonucleic acid expression in fibroid cells treated with Ang II. No difference in proliferation or ECM production was observed in myometrial cell controls. Angiotensin II promoted growth and matrix accumulation in fibroid cells, highlighting a potential link between fibroids and cardiovascular disease.

Glycolytic Reprogramming in Uterine Fibroids: Genetic, Transcriptomic, Proteomic, and Metabolomic Insights

Uterine leiomyomas or fibroids are a common but pernicious benign tumor impacting between 70–80% of women of reproductive age. Despite their high prevalence, the etiology of uterine fibroids is not fully understood. This review aims to highlight the distinct metabolic features that uterine fibroids adopt to meet biosynthetic demands, support proliferation, extracellular matrix production, survival, and fibrosis. Specifically, we posit the role of glycolytic reprogramming—an adaptation in fibrosis across organs (lung, kidney, heart, and liver) as a major contributor to uterine fibroid development. Previous genetic, transcriptomic, proteomic, and metabolic studies have drawn strong links between metabolism and uterine fibroid biology and identified genotype-specific metabolic alterations such as fumarate hydratase (FH) deficiency and mediator of RNA polymerase II transcription (MED12) gene mutations. Studies in non-uterine models have linked glycolysis to ECM production and fibrosis through activation of transforming growth factor-beta (TGF-β) and the canonical Wnt pathway (Wnt/β-catenin) signaling, supporting them as potential key pathways in uterine fibroid pathogenesis via glycolytic reprogramming. Other metabolic regulators, such as hypoxia-inducible factor 1-alpha (HIF-1α), mammalian target of rapamycin (mTOR), and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), may also sustain the fibrotic phenotype through coupling signaling that drives ECM production to metabolic programming. Overall, the proposed metabolic perspective of uterine fibroid pathogenesis invites further exploration of mechanistic investigation in uterine-specific models and therapeutic targeting through larger cohort studies.

The fibroid crisis in Black women: more work to be done!

Feasibility and Perioperative Outcomes of Minimally Invasive Higher Order Myomectomy

To investigate perioperative outcomes of minimally invasive higher order myomectomy as defined by removal of 10 or more fibroids. A retrospective cohort study between January 2018 and December 2022. A tertiary academic medical center. Women who underwent minimally invasive myomectomy via laparoscopic or robotic approach. Surgical intervention in the form of minimally invasive myomectomy. A total of 735 women met inclusion criteria of whom 578 had fewer than 10 fibroids removed, and 157 patients had 10 or more removed (average number of fibroids removed 3.8 vs 14.7, p <.001; specimen's weight 317.4 g vs 371.0 g, p = .07). Body mass index was similar in both groups (p = .66) and patients with higher order myomectomy were more likely to have a history of myomectomy (12.0% vs 26.8%, p <.001). The average estimated blood loss (EBL) was 246 mL vs 470 mL in each group (p <.001). There were no significant differences in packed red blood cell transfusion (1.0% vs 0.6%, p = .65), conversion to laparotomy (0.5% vs 0.6%, p = .86), or complications including visceral injury, wound complication, venous thromboembolism, ileus, or readmission (5.9% vs 4.5%, p = .49). The hospital length of stay was similar in both groups (0.5 days vs 0.5 days, p = .63). On linear regression analysis, after adjusting for specimen's weight, operative time, and history of myomectomy, EBL remained significantly higher in patients with 10 or more fibroids removed (p = .02). EBL is increased in higher order myomectomy; however, blood transfusions, conversion to laparotomy, complication rates, and length of hospital stay did not differ compared with patients with fewer than 10 fibroids removed, highlighting the feasibility of minimally invasive higher order myomectomy.

Patient Characteristics Associated With Embolization Versus Hysterectomy for Uterine Fibroids: A Systematic Review and Meta-Analysis

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. 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. 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 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.

Simvastatin induces degradation of the extracellular matrix in human leiomyomata: novel in vitro, in vivo, and patient level evidence of matrix metalloproteinase involvement

To assess the effect of simvastatin on uterine leiomyoma growth and extracellular matrix (ECM) deposition. Laboratory analysis of human leiomyoma cell culture, xenograft in a mouse model, and patient tissue from a clinical trial. Academic research center. Tissue culture from human leiomyoma tissue and surgical leiomyoma tissue sections from a placebo-controlled randomized clinical trial. Simvastatin treatment. Serum concentrations, xenograft volumes, and protein expression. Mice xenografted with 3-dimensional human leiomyoma cultures were divided as follows: 7 untreated controls; 12 treated with activated simvastatin at 10 mg/kg body weight; and 15 at 20 mg/kg body weight. Simvastatin was detected in the serum of mice injected at the highest dose. Xenograft volumes were significantly smaller (mean 53% smaller at the highest concentration). There was dissolution of compact ECM, decreased ECM formation, and lower collagen protein expression in xenografts. Membrane type 1 matrix metalloproteinase was increased in vitro and in vivo. Matrix metalloproteinase 2 and low-density lipoprotein receptor-related protein 1 were increased in vitro. Simvastatin exhibited antitumoral activity with ECM degradation and decreased leiomyoma tumor volume in vivo. Activation of the matrix metalloproteinase 2, membrane type 1 matrix metalloproteinase, and low-density lipoprotein receptor-related protein 1 pathway may explain these findings.

Effects of Simvastatin on Uterine Leiomyoma Size

The study aims to study the effect of simvastatin on the size of uterine fibroids.