Cholesterol and Immune Microenvironment: Path Towards Tumorigenesis.

PURPOSE OF REVIEW: Since obesity is a major risk factor for many different types of cancer, examining one of the most closely associated comorbidities, such as hypercholesterolemia, is crucial to understanding how obesity causes cancer. Hypercholesterolemia is usually associated with many cardiovascular complications such as hypertension, angina, and atherosclerosis. In addition, cholesterol may be a major factor in increasing cancer risk. Cancer patients who received statins, an anti-hypercholesteremic medicine, demonstrated improved prognosis possibly through its effect on tumor proliferation, apoptosis, and oxidative stress. Cholesterol could also aid in tumor progression through reprogramming tumor immunological architecture and mediators. This review focuses on the immunomodulatory role of cholesterol on cellular and molecular levels, which may explain its oncogenic driving activity. We look at how cholesterol modulates tumor immune cells like dendritic cells, T cells, Tregs, and neutrophils. Further, this study sheds light on the modification of the expression pattern of the common cancer-related immune mediators in the tumor immune microenvironment, such as programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), transforming growth factor-beta (TGF-ß), interleukin 12 (IL-12), IL-23, and forkhead box protein P3 (FOXP3). RECENT FINDINGS: We highlight relevant literature demonstrating cholesterol's immunosuppressive role, leading to a worse cancer prognosis. This review invites further research regarding the pathobiological role of cholesterol in many obesity-related cancers such as uterine fibroids, post-menopausal breast, colorectal, endometrial, kidney, esophageal, pancreatic, liver, and gallbladder cancers. This review suggests that targeting cholesterol synthesis may be a fruitful approach to cancer targeting, in addition to traditional chemotherapeutics.

Feasibility and Perioperative Outcomes of Minimally Invasive Higher Order Myomectomy.

STUDY OBJECTIVE: To investigate perioperative outcomes of minimally invasive higher order myomectomy as defined by removal of 10 or more fibroids. DESIGN: A retrospective cohort study between January 2018 and December 2022. SETTING: A tertiary academic medical center. PATIENTS: Women who underwent minimally invasive myomectomy via laparoscopic or robotic approach. INTERVENTIONS: Surgical intervention in the form of minimally invasive myomectomy. MEASUREMENTS AND MAIN RESULTS: 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). CONCLUSION: 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.

The Role of Nanomedicine in Benign Gynecologic Disorders.

Nanomedicine has revolutionized drug delivery in the last two decades. Nanoparticles appear to be a promising drug delivery platform in the treatment of various gynecological disorders including uterine leiomyoma, endometriosis, polycystic ovarian syndrome (PCOS), and menopause. Nanoparticles are tiny (mean size < 1000 nm), biodegradable, biocompatible, non-toxic, safe, and relatively inexpensive materials commonly used in imaging and the drug delivery of various therapeutics, such as chemotherapeutics, small molecule inhibitors, immune mediators, protein peptides and non-coding RNA. We performed a literature review of published studies to examine the role of nanoparticles in treating uterine leiomyoma, endometriosis, PCOS, and menopause. In uterine leiomyoma, nanoparticles containing 2-methoxyestradiole and simvastatin, promising uterine fibroid treatments, have been effective in significantly inhibiting tumor growth compared to controls in in vivo mouse models with patient-derived leiomyoma xenografts. Nanoparticles have also shown efficacy in delivering magnetic hyperthermia to ablate endometriotic tissue. Moreover, nanoparticles can be used to deliver hormones and have shown efficacy as a mechanism for transdermal hormone replacement therapy in individuals with menopause. In this review, we aim to summarize research findings and report the efficacy of nanoparticles and nanotherapeutics in the treatment of various benign gynecologic conditions.

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.

Senescence-associated secretory phenotype (SASP) and uterine fibroids: Association with PD-L1 activation and collagen deposition.

Uterine fibroids (or uterine leiomyoma, UFs) are one of the most prevalent benign uterine tumors with high proliferation and collagen synthesis capabilities. UFs are a significant worldwide health issue for women, affecting their physical and financial well-being. Risk factors for UFs include age, racial disparities, obesity, uterine infections, hormonal variation, and lifestyle (i.e., diet, exercise, stress, and smoking). Senescence and its associated secretory phenotypes (SASPs) are among the most salient changes accompanying the aging process. As a result, SASPs are suggested to be one of the major contributors to developing UFs. Interleukin 6 (IL-6), IL-8, IL-1, chemokine ligand 20 (CCL-20), and transforming growth factor-beta (TGF-ß) are the most prominent SASPs associated with aging. In addition, different processes contribute to UFs such as collagen deposition and the changes in the immune microenvironment. Programmed death ligand 1 is a major player in the tumor immune microenvironment, which helps tumor cells evade immune attacks. This review focuses on the correlation of SASPs on two axes of tumor progression: immune suppression and collagen deposition. This review opens the door towards more investigations regarding changes in the UF immune microenvironment and age-UFs correlation and thus, a novel targeting approach for UF treatment.

Uterine Fibroids and Hypertensive Disorders in Pregnancy: A Systematic Review and Meta-Analysis.

Capsule: In this study the presence of uterine fibroids was significantly associated with an increased risk of development of hypertensive disorders of pregnancy even when accounting for age and BMI in meta-regression. This finding has potential implications for risk stratification and monitoring for hypertension during pregnancy in this population. Objective: To examine the association between uterine fibroids and the development of hypertensive disorders in pregnancy. Data sources: Cochrane, Embase, PubMed, MEDLINE, Scopus, and Web of Science databases were searched from inception through April 2023. Study Selection and Synthesis: Cohort, case-control, or case series studies including uterine fibroid status and hypertensive disorders of pregnancy status were included. The comparison group was pregnant women without uterine fibroids. Inverse-variance weighted random effects models were used to pool RR and OR estimates separately. Age and BMI were explored as potential sources of heterogeneity using inverse-variance weighted meta-regression. Main Outcomes: Hypertensive disorders of pregnancy (HDP) defined as gestational hypertension, pre-eclampsia, eclampsia, superimposed preeclampsia, or hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Results: A total of 17 studies were included (Total N=1,374,395 participants, N=64,968 with uterine fibroids). Thirteen studies were retrospective cohorts and four were case-control studies. Women with uterine fibroids had a significantly higher risk of hypertensive disorders in pregnancy compared to women without uterine fibroids with RR 1.74 (95% CI 1.33-2.27, p<0.01), and OR 2.87 (95% CI 1.38-5.97, p<0.01), in cohort studies and case-control studies, respectively. In meta-regression analyses, age did not significantly change the positive association between uterine fibroids and hypertensive disorders in pregnancy. Conclusion: Uterine fibroids were associated with an increased risk of hypertensive disorders of pregnancy when all available literature was synthesized, including when shared risk factors are examined in meta-regression analyses. Relevance: If confirmed in future studies, investigations into the mechanisms of this association are needed as this finding potentially has implications for risk stratification and monitoring for hypertensive disorders of pregnancy in this population. Trial Registration: PROSPERO, ID # 331528.

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

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 (I2 > 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.

Immunosuppressive tumor microenvironment and uterine fibroids: Role in collagen synthesis.

Uterine fibroids (UF), also called uterine leiomyoma, is one of the most prevalent uterine tumors. UF represents a serious women's health global problem with a significant physical, emotional, and socioeconomic impact. Risk factors for UF include racial disparities, age, race, hormonal factors, obesity, and lifestyle (diet, physical activity, and stress. There are several biological contributors to UF pathogenesis such as cellular proliferation, angiogenesis, and extracellular matrix (ECM) accumulation. This review addresses tumor immune microenvironment as a novel mediator of ECM deposition. Polarization of immune microenvironment towards the immunosuppressive phenotype has been associated with ECM deposition. Immunosuppressive cells include M2 macrophage, myeloid-derived suppressor cells (MDSCs), and Th17 cells, and their secretomes include interleukin 4 (IL-4), IL-10, IL-13, IL-17, IL-22, arginase 1, and transforming growth factor-beta (TGF-ß1). The change in the immune microenvironment not only increase tumor growth but also aids in collagen synthesis and ECM disposition, which is one of the main hallmarks of UF pathogenesis. This review invites further investigations on the change in the UF immune microenvironment as well as a novel targeting approach instead of the traditional UF hormonal and supportive treatment.

Uterine Collagen Cross-Linking: Biology, Role in Disorders, and Therapeutic Implications.

Collagen is an essential constituent of the uterine extracellular matrix that provides biomechanical strength, resilience, structural integrity, and the tensile properties necessary for the normal functioning of the uterus. Cross-linking is a fundamental step in collagen biosynthesis and is critical for its normal biophysical properties. This step occurs enzymatically via lysyl oxidase (LOX) or non-enzymatically with the production of advanced glycation end-products (AGEs). Cross-links found in uterine tissue include the reducible dehydro-dihydroxylysinonorleucine (deH-DHLNL), dehydro-hydroxylysinonorleucine (deH-HLNL), and histidinohydroxymerodesmosine (HHMD); and the non-reducible pyridinoline (PYD), deoxy-pyridinoline (DPD); and a trace of pentosidine (PEN). Collagen cross-links are instrumental for uterine tissue integrity and the continuation of a healthy pregnancy. Decreased cervical cross-link density is observed in preterm birth, whereas increased tissue stiffness caused by increased cross-link density is a pathogenic feature of uterine fibroids. AGEs disrupt embryo development, decidualization, implantation, and trophoblast invasion. Uterine collagen cross-linking regulators include steroid hormones, such as progesterone and estrogen, prostaglandins, proteoglycans, metalloproteinases, lysyl oxidases, nitric oxide, nicotine, and vitamin D. Thus, uterine collagen cross-linking presents an opportunity to design therapeutic targets and warrants further investigation in common uterine disorders, such as uterine fibroids, cervical insufficiency, preterm birth, dystocia, endometriosis, and adenomyosis.

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

OBJECTIVES: To assess the effect of simvastatin on uterine leiomyoma growth and extracellular matrix (ECM) deposition. DESIGN: Laboratory analysis of human leiomyoma cell culture, xenograft in a mouse model, and patient tissue from a clinical trial. SETTING: Academic research center. PATIENT(S): Tissue culture from human leiomyoma tissue and surgical leiomyoma tissue sections from a placebo-controlled randomized clinical trial. INTERVENTION(S): Simvastatin treatment. MAIN OUTCOME MEASURE(S): Serum concentrations, xenograft volumes, and protein expression. RESULTS: 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. CONCLUSIONS: 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.

Cardiovascular collapse during laparoscopy: a brief overview.

This review article considers the physiology, differential diagnosis and immediate management of vasovagal response, vascular injury and carbon dioxide embolism caused during the creation of the laparoscopic pneumoperitoneum. These pathologies account for over half of all laparoscopic complications and therefore, by taking a systematic approach to these possibly life-threatening events, laparoscopy can become even safer.

Obesity Contributes to Transformation of Myometrial Stem-Cell Niche to Leiomyoma via Inducing Oxidative Stress, DNA Damage, Proliferation, and Extracellular Matrix Deposition.

Leiomyomas (fibroids) are monoclonal tumors in which myometrial stem cells (MSCs) turn tumorigenic after mutation, abnormal methylation, or aberrant signaling. Several factors contribute to metabolic dysfunction in obesity, including abnormal cellular proliferation, oxidative stress, and DNA damage. The present study aims to determine how adipocytes and adipocyte-secreted factors affect changes in MSCs in a manner that promotes the growth of uterine leiomyomas. Myometrial stem cells were isolated from the uteri of patients by fluorescence-activated cell sorting (FACS) using CD44/Stro1 antibodies. Enzyme-linked immunosorbent assay (ELISA), Western blot, and immunocytochemistry assays were performed on human adipocytes (SW872) co-cultured with MSCs and treated with leptin or adiponectin to examine the effects of proliferation, extracellular matrix (ECM) deposition, oxidative damage, and DNA damage. Co-culture with SW872 increased MSC proliferation compared to MSC culture alone, according to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) results. The expressions of PCNA and COL1A increased significantly with SW872 co-culture. In addition, the expression of these markers was increased after leptin treatment and decreased after adiponectin treatment in MSCs. The Wnt/ß-catenin and TGF-ß/SMAD signaling pathways promote proliferation and ECM deposition in uterine leiomyomas. The expression of Wnt4, ß-catenin, TGFß3, and pSMAD2/3 of MSCs was increased when co-cultured with adipocytes. We found that the co-culture of MSCs with adipocytes resulted in increased NOX4 expression, reactive oxygen species production, and γ-H2AX expression. Leptin acts by binding to its receptor (LEP-R), leading to signal transduction, resulting in the transcription of genes involved in cellular proliferation, angiogenesis, and glycolysis. In MSCs, co-culture with adipocytes increased the expression of LEP-R, pSTAT3/STAT3, and pERK1/2/ERK/12. Based on the above results, we suggest that obesity may mediate MSC initiation of tumorigenesis, resulting in leiomyomas.

Laparoscopic administration of bupivacaine at the uterosacral ligaments during benign laparoscopic and robotic hysterectomy: a randomized controlled trial.

BACKGROUND: Postoperative pain continues to be an undermanaged part of the surgical experience. Multimodal analgesia has been adopted in response to the opioid epidemic, but opioid prescribing practices remain high after minimally invasive hysterectomy. Novel adjuvant opioid-sparing analgesia to optimize acute postoperative pain control is crucial in preventing chronic pain and minimizing opioid usage. OBJECTIVE: This study aimed to determine the effect of direct laparoscopic uterosacral bupivacaine administration on opioid usage and postoperative pain in patients undergoing benign minimally invasive (laparoscopic and robotic) hysterectomy. STUDY DESIGN: This was a single-blinded, triple-arm, randomized controlled trial at an academic medical center between March 15, 2021, and April 8, 2022. The inclusion criteria were patients aged >18 years undergoing benign laparoscopic or robotic hysterectomy. The exclusion criteria were non-English-speaking patients, patients with an allergy to bupivacaine or actively using opioid medications, patients undergoing transversus abdominis plane block, and patients undergoing supracervical hysterectomy or combination cases with other surgical services. Patients were randomized in a 1:1:1 fashion to the following uterosacral administration before colpotomy: no administration, 20 mL of normal saline, or 20 mL of 0.25% bupivacaine. All patients received incisional infiltration with 10 mL of 0.25% bupivacaine. The primary outcome was 24-hour oral morphine equivalent usage (postoperative day 0 and postoperative day 1). The secondary outcomes were total oral morphine equivalent usage in 7 days, last day of oral morphine equivalent usage, numeric pain scores from the universal pain assessment tool, and return of bowel function. Patients reported postoperative pain scores, total opioid consumption, and return of bowel function via Qualtrics surveys. Patient and surgical characteristics and primary and secondary outcomes were compared using chi-square analysis and 1-way analysis of variance. Multiple linear regression was used to identify predictors of opioid use in the first 24 hours after surgery and total opioid use in the 7 days after surgery. RESULTS: Of 518 hysterectomies screened, 410 (79%) were eligible, 215 (52%) agreed to participate, and 180 were ultimately included in the final analysis after accounting for dropout. Most hysterectomies (70%) were performed laparoscopically, and the remainder were performed robotically. Most hysterectomies (94%) were outpatient. Patients randomized to bupivacaine had higher rates of former and current tobacco use, and patients randomized to the no-administration group had higher rates of previous surgery. There was no difference in first 24-hour oral morphine equivalent use among the groups (P=.10). Moreover, there was no difference in numeric pain scores (although a trend toward significance in discharge pain scores in the bupivacaine group), total 7-day oral morphine equivalent use, day of last opioid use, or return of bowel function among the groups (P>.05 for all). The predictors of increased 24-hour opioid usage among all patients included only increased postanesthesia care unit oral morphine equivalent usage. The predictors of 7-day opioid usage among all patients included concurrent tobacco use and mood disorder, history of previous laparoscopy, estimated blood loss of >200 mL, and increased oral morphine equivalent usage in the postanesthesia care unit. CONCLUSION: Laparoscopic uterosacral administration of bupivacaine at the time of minimally invasive hysterectomy did not result in decreased opioid usage or change in numeric pain scores.

PEGylated Polymeric Nanoparticles Loaded with 2-Methoxyestradiol for the Treatment of Uterine Leiomyoma in a Patient-Derived Xenograft Mouse Model.

Leiomyomas, the most common benign neoplasms of the female reproductive tract, currently have limited medical treatment options. Drugs targeting estrogen/progesterone signaling are used, but side effects and limited efficacy in many cases are major limitation of their clinical use. Previous studies from our laboratory and others demonstrated that 2-methoxyestradiol (2-ME) is promising treatment for uterine fibroids. However, its poor bioavailability and rapid degradation hinder its development for clinical use. The objective of this study is to evaluate the in vivo effect of biodegradable and biocompatible 2-ME-loaded polymeric nanoparticles in a patient-derived leiomyoma xenograft mouse model. PEGylated poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles loaded with 2-ME were prepared by nanoprecipitation. Female 6-week age immunodeficient NOG (NOD/Shi-scid/IL-2Rγnull) mice were used. Estrogen-progesterone pellets were implanted subcutaneously. Five days later, patient-derived human fibroid tumors were xenografted bilaterally subcutaneously. Engrafted mice were treated with 2-ME-loaded or blank (control) PEGylated nanoparticles. Nanoparticles were injected intraperitoneally and after 28 days of treatment, tumor volume was measured by caliper following hair removal, and tumors were removed and weighed. Up to 99.1% encapsulation efficiency was achieved, and the in vitro release profile showed minimal burst release, thus confirming the high encapsulation efficiency. In vivo administration of the 2-ME-loaded nanoparticles led to 51% growth inhibition of xenografted tumors compared to controls (P < 0.01). Thus, 2-ME-loaded nanoparticles may represent a novel approach for the treatment of uterine fibroids.

Uterine Transcriptome: Understanding Physiology and Disease Processes.

In recent years, transcriptomics has enabled us to gain a deeper understanding of fundamental reproductive physiology, including the menstrual cycle, through a more precise molecular analysis. The endometrial mRNA transcript levels fluctuate during the normal menstrual cycle, indicating changes in the relative recruitment and abundance of inflammatory cells, as well as changes in the receptivity and remodeling of the endometrium. In addition to providing a more comprehensive understanding of the molecular underpinnings of pathological gynecological conditions such as endometriosis, leiomyomas, and adenomyosis through RNA sequencing, this has allowed researchers to create transcriptome profiles during both normal menstrual cycles and pathological gynecological conditions. Such insights could potentially lead to more targeted and personalized therapies for benign gynecological conditions. Here, we provide an overview of recent advances in transcriptome analysis of normal and pathological endometrium.

Oxidative Stress and Antioxidants in Uterine Fibroids: Pathophysiology and Clinical Implications.

In the last few decades, our understanding of the complex pathobiology of uterine fibroid development has grown. While previously believed to be a purely neoplastic entity, we now understand that uterine fibroids possess different and equally important aspects of their genesis. An increasing body of evidence suggests that oxidative stress, the imbalance between pro- and antioxidants, is an important factor in fibroid development. Oxidative stress is controlled by multiple, interconnecting cascades, including angiogenesis, hypoxia, and dietary factors. Oxidative stress in turn influences fibroid development through genetic, epigenetic, and profibrotic mechanisms. This unique aspect of fibroid pathobiology has introduced several clinical implications, both diagnostic and therapeutic, that can aid us in managing these debilitating tumors by using biomarkers as well as dietary and pharmaceutical antioxidants for diagnosis and treatment. This review strives to summarize and add to the current evidence revealing the relationship between oxidative stress and uterine fibroids by elucidating the proposed mechanisms and clinical implications.

Relationship Among Surgical Fibroid Removal, Blood Pressure, and Biomarkers of Renin-Angiotensin-Aldosterone System Activation.

Fibroids are common benign neoplasms in women and have recently been associated with cardiometabolic risk factors including hypertension. The objective of this study is to determine whether fibroid removal is associated with lower blood pressure (BP). We performed a single-center IRB-approved retrospective chart review of patients undergoing hysterectomy/myomectomy for fibroids and other benign gynecological surgical procedures from January 2016 to December 2019, and a prospective cohort study of patients undergoing hysterectomy/myomectomy for fibroids from August 2021 to April 2022. We measured demographic factors, preoperative/postoperative BP on day of surgery and at postoperative visit. In our prospective cohort, to evaluate for alterations in the renin-angiotensin-aldosterone system (RAAS) induced by fibroid removal, we measured serum angiotensin-II (Ang-II) and angiotensin converting enzyme (ACE) levels pre- and post-operatively. In our retrospective study (n = 294; mean age 41.9 ± 10.6, 43.5% Black, 50% with fibroids), we found that compared to patients without fibroids, patients with fibroids had significantly elevated systolic BP (SBP) (pre-op: p = 0.0005; post-op: p = 0.02), although this did not hold after adjusting for covariates. Fibroid removal was associated with a marginally albeit not statistically significant decrease in SBP (p = 0.062). In our prospective study (n = 11), there was a significant decrease in SBP following fibroid removal, but no change in diastolic BP (p = 0.019, p = 0.18, respectively). Serum levels of Ang-II and ACE were not significantly altered following surgical fibroid removal (p = 0.72, p = 0.81, respectively). Altogether, these findings suggest that fibroids are not independently associated with BP or RAAS activation, but do suggest that fibroid removal may be associated with a small drop in SBP.

Adipocyte and Adipokines Promote a Uterine Leiomyoma Friendly Microenvironment.

Uterine leiomyomas are the most common benign tumors of the female reproductive system. Obese individuals have a higher burden of uterine leiomyoma, yet the mechanism relating obesity and leiomyoma development remains unknown. In this study, we observe the effect of adipocyte coculture and leptin treatment on human myometrium and leiomyoma cells. We isolated primary leiomyoma and myometrium cells from hysterectomy or myomectomy patients. Protein expression levels of phosphorylated ERK1/2/total ERK1/2, phosphorylated STAT3/total STAT3, and phosphorylated AKT1/2/3/total AKT1/2/3 were quantified using immunoblotting in immortalized and primary leiomyoma and myometrial cells cocultured with human adipocytes and treated with leptin. An enzyme-linked immunosorbent assay (ELISA) was used to assess pro-inflammatory, fibrotic, and angiogenic factors in immortalized human myometrium and leiomyoma cells treated with leptin. The effects of STAT3, ERK, and AKT inhibitors were assessed in leiomyoma cell lines additionally cultured with adipocytes. Adipocyte coculture and leptin treatment increases the expression of JAK2/STAT3, MAPK/ERK, and PI3K/AKT signaling while inhibitors suppressed this effect. Leptin induces a tumor-friendly microenvironment through upregulation of pro-inflammatory (IFNγ, IL-8, IL-6, GM-CSF, MCP-1, and TNF-α), fibrotic (TGF-ß1, TGF-ß2, and TGF-ß3), and angiogenic (VEGF-A, HGF, and Follistatin) factors in human leiomyoma cells. Furthermore, adipocyte coculture and leptin treatment increases leiomyoma cells growth through activation of MAPK/ERK, JAK2/STAT3, and PI3k/AKT signaling pathways. Finally, STAT3, ERK, and AKT inhibitor treatment suppressed PCNA, TNF-α, TGF-ß3, and VEGF-A intracellular staining intensity in both adipocyte coculture and leptin treated leiomyoma cells. These findings suggest that, in obese women, adipocyte secreted hormone or adipocytes may contribute to leiomyoma development and growth by activating leptin receptor signaling pathways.

Satisfaction with opioid prescription and use after minor gynaecologic surgery: a pilot prospective study.

To describe predictors of patient satisfaction with pain control including opioid prescribing practices, patients undergoing minor gynaecologic and urogynaecologic surgeries were included in a prospective cohort study. Satisfaction with postoperative pain control by opioid prescription status was analysed using bivariate analysis and multivariable logistic regression, controlling for potential confounders. Among participants completing both postoperative surveys, 112/141 (79.4%) reported pain control satisfaction by day 1-2 and 118/137 (86.1%) by day 14. While we were underpowered to detect a true difference in satisfaction by opioid prescription, there were no differences in opioid prescription among patients satisfied with pain control [52% vs. 60% (p = .43) among satisfied patients at day 1-2 and 58.5% vs. 37% (p = .08) at day 14]. Significant predictors of pain control satisfaction were postoperative day (POD) 1-2 average pain at rest [aOR 0.72 (95% CI 0.52-0.99), p = .04], rating of shared decision-making [aOR 1.16 (95% CI 1.004-1.34), p = .04], amount of pain relief [aOR 1.28 (95% CI 1.07-1.54), p = .008) and POD 14 shared decision-making rating [aOR 1.45 (95% CI 1.19-1.77), p = .002].Impact StatementWhat is already known on this subject? There are little data published on opioid prescription rates after minor gynaecologic procedures and no formal evidence-based guidance for gynaecologic providers for opioid prescribing. Few publications describe rates of opioid prescription and use following minor gynaecologic procedures. In the setting of a dramatic escalation of opioid misuse in the United States over the last decade, we sought to describe our practice of opioid prescription following minor gynaecologic procedures and answer the question of whether patient satisfaction is affected by opioid prescription, fill and use.What do the results of this study add? Though underpowered to detect our primary outcome, our results suggest that patient satisfaction with pain control may primarily be significantly affected by the patient's subjective assessment of shared decision-making with the gynaecologist.What are the implications of these findings for clinical practice and/or further research? Ultimately, these preliminary findings suggest a larger cohort is needed to answer the question of whether pain control satisfaction is influenced by receipt/fill/use of opioids after minor gynaecologic surgery.