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.

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.

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.

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.

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.

Association of Surgical Start Time with Outcomes of Benign Hysterectomy.

STUDY OBJECTIVE: To evaluate whether surgical start time is associated with clinical and financial outcomes of hysterectomies performed for benign indications. DESIGN: Retrospective cohort study. SETTING: University 5-hospital healthcare system. PATIENTS: Women who underwent benign hysterectomy between 2014 and 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed demographic, operative, and financial data to evaluate the relationships between surgical start time and perioperative outcomes including operating room time, estimated blood loss, length of stay, same-day discharge, and adverse perioperative events. Additionally, we evaluated the impact of surgical start time on total hysterectomy charges. Descriptive statistics and multivariate logistic and linear regressions were performed adjusting for confounders. Our study identified 2894 women who underwent benign hysterectomy, with 1910 hysterectomies starting prior to 12 pm (am group) and 984 hysterectomies starting after 12 pm (pm group). A pm start time was associated with higher estimated blood loss (Median 100, interquartile range 50, 200 in the am group vs Median 125, interquartile range 75, 250), increased length of stay, and decreased likelihood of same-day discharge. No significant differences were noted in the rates of adverse perioperative events between the 2 groups. Surprisingly, an afternoon start time was associated with decreased total hospital charges (median am $14 055.30 versus median pm $11 724.80). These cost differences persisted after multivariate linear regression, and when stratified by hysterectomy surgical approach, remained significant in the open and laparoscopic cohorts. CONCLUSION: Afternoon hysterectomy start time is associated with increased blood loss and length of stay with decreased rates of same-day discharge; however, there was no associated increase in perioperative adverse events or mortality. Awareness regarding surgical start time and outcomes can guide surgical scheduling and optimize same-day discharge.

Cardiometabolic profile of women with uterine leiomyoma: a cross-sectional study.

BACKGROUND: Emerging evidence suggests that cardiometabolic risk factors contribute to uterine leiomyoma development, but cardiometabolic profiles of women with the tumor remain poorly defined. This study aimed to determine the association of cardiometabolic comorbidities and cardiometabolic medication use with a leiomyoma diagnosis. METHODS: In this cross-sectional study, aggregate-level data from 2013-2020 were collected using the SlicerDicer feature of Epic (Epic, Verona, WI, USA) electronic medical record system. Women ≥18 years with at least one visit or hospital encounter at the Johns Hopkins Health System (N.=679,981) were assigned as cases or controls according to leiomyoma status. Individual prevalence of each prespecified cardiometabolic comorbidity and relevant prescription medications was obtained. Prevalence Odds Ratios were used to assess the association of cardiometabolic comorbidities and medication use with uterine leiomyoma. RESULTS: Women with uterine leiomyoma (N.=27,703) were more likely to be obese (2.56; 95% CI: 2.49-2.63), have metabolic syndrome (1.82; 95% CI: 1.51-2.19), essential hypertension (1.45; 95% CI: 1.42-1.49), diabetes mellitus (1.29; 95% CI: 1.24-1.33) and hyperlipidemia (1.23; 95% CI: 1.19-1.26). These associations were stronger among younger women and persisted after excluding those with a hysterectomy. Notably, statins were the only medications associated with a lower leiomyoma risk (0.81; 95% CI: 0.79-0.84). CONCLUSIONS: Uterine leiomyoma is associated with a spectrum of cardiometabolic comorbidities and use of associated medications, constituting an unfavorable cardiometabolic profile in women with the tumor. If definitively correlated, prevention and early management of cardiometabolic risk factors may decrease uterine leiomyoma incidence, and screening women with uterine leiomyoma for cardiometabolic comorbidities may aid in cardiovascular disease prevention.

Adipocyte coculture induces a pro-inflammatory, fibrotic, angiogenic, and proliferative microenvironment in uterine leiomyoma cells.

OBJECTIVE: Obesity and its consequences are among the biggest challenges facing the healthcare system. Uterine leiomyomas are the most common gynecologic tumors. The risk of leiomyoma increases with obesity, but the underlying mechanisms of this association remain unclear. The aim of the present study to determine the cellular and molecular mechanisms by which adipocyte contributes to both leiomyoma tumor initiation and promotion. METHODS: Primary myometrium and leiomyoma cells were isolated from patients who underwent a hysterectomy or myomectomy. Pro-inflammatory, fibrotic, and angiogenic factors were measured using a multiplex cytokine array in human primary and immortalized myometrial and leiomyoma cells cocultured with human adipocyte (SW872) cells, or in animal ELT3 leiomyoma cells cocultured with 3 T3-L1 adipocytes. The free fatty acids (FFAs) and fatty acid-binding protein 4 (FABP4) levels were measured using immunofluorescence assays. Other protein abundances were determined using western blots. The expression levels of TNF-α, MCP-1, phospho-NF-κB, TGFß3 and VEGF-A in lean and obese in different leiomyoma patients were determined by immunofluorescence staining. RESULTS: Adipocytes promote inflammation, fibrosis, and angiogenesis in uterine leiomyoma cells by upregulating associated factors, such as IL-1ß, TNF-α, MCP-1, GM-CSF, TGF-ßs, PLGF, VEGF, HB-EGF, G-CSF and FGF2. Coculture led to the transfer of FFAs and FABP4 from adipocytes to leiomyoma cells, suggesting that adipocytes may modulate metabolic activity in these tumor cells. Increased levels of FFA and FABP4 expressions were detected in obese leiomyoma tissue compared to lean. The adipocyte-leiomyoma cell interaction increased the phospho-NF-κB level, which plays a key role in inflammation, restructuring metabolic pathways, and angiogenesis. Obese leiomyoma patients expressed a higher amount of TNF-α, MCP-1, phospho-NF-κB, TGFß3 and VEGF-A than lean leiomyoma patients, consistent with in vitro findings. Furthermore, we found that adipocyte secretory factors enhance leiomyoma cell proliferation by increasing PCNA abundance. Finally, the inhibition of the inflammatory factors TNF-α, MCP-1, and NF-κB abrogated the adipocyte coculture-induced proliferation of leiomyoma cells. CONCLUSIONS: Adipocytes release inflammatory, fibrotic, and angiogenic factors, along with FFAs, which contribute to a tumor-friendly microenvironment that may promote leiomyoma growth and can represent a new target for leiomyoma prevention and treatment.

The influence of COVID-19 infection-associated immune response on the female reproductive system†.

Coronavirus disease 2019 (COVID-19) is a multi-system disease that has led to a pandemic with unprecedented ramifications. The pandemic has challenged scientists for the past 2 years and brought back previously abandoned research topics. COVID-19 infection causes a myriad of symptoms ranging from mild flu-like symptoms to severe illness requiring hospitalization. Case reports showed multiple systemic effects of COVID-19 infection, including acute respiratory distress syndrome, fibrosis, colitis, thyroiditis, demyelinating syndromes, and mania, indicating that COVID-19 can affect most human body systems. Unsurprisingly, a major concern for women all over the globe is whether a COVID-19 infection has any long-term effects on their menstrual cycle, fertility, or pregnancy. Published data have suggested an effect on the reproductive health, and we hypothesize that the reported reproductive adverse effects are due to the robust immune reaction against COVID-19 and the associated cytokine storm. While the COVID-19 receptor (angiotensin converting enzyme, ACE2) is expressed in the ovaries, uterus, vagina, and placenta, we hypothesize that it plays a less important role in the adverse effects on the reproductive system. Cytokines and glucocorticoids act on the hypothalamo-pituitary gonadal axis, arachidonic acid pathways, and the uterus, which leads to menstrual disturbances and pregnancy-related adverse events such as preterm labor and miscarriages. This hypothesis is further supported by the apparent lack of long-term effects on the reproductive health in females, indicating that when the cytokine storm and its effects are dampened, the reproductive health of women is no longer affected.

Perioperative opioid dispensing and persistent use after benign hysterectomy: a systematic review and meta-analysis.

OBJECTIVE: This meta-analysis was conducted to (1) assess the quantity and dose of perioperatively dispensed opioids for benign hysterectomy by procedure route and (2) identify the predictors of persistent opioid use after the procedure. DATA SOURCES: PubMed, Web of Science, and Embase were systematically searched from study inception to 25 March 2022. STUDY ELIGIBILITY CRITERIA: Studies reporting data on opioid dispensing among patients undergoing benign hysterectomy were considered eligible. The primary outcome was the dosage of opioids dispensed perioperatively (from 30 preoperative days to 21 postoperative days). The secondary outcome was the predictors of persistent opioid use after benign hysterectomy (from 3 months to 3 years postoperatively). Total opioid dispensing was measured in morphine milligram equivalents units. METHODS: The random-effects model was used to pool the mean differences or odds ratios and the corresponding 95% confidence intervals. RESULTS: A total of 8 studies presenting data on 377,569 women undergoing benign hysterectomy were included. Of these women, 83% (95% confidence interval, 81-84) were dispensed opioids during the perioperative period. The average amount of perioperatively dispensed opioids was 143.5 morphine milligram equivalents (95% confidence interval, 40-247). Women undergoing vaginal hysterectomy were dispensed a significantly lower amount of opioids than those undergoing laparoscopic or abdominal hysterectomies. The overall rate of persistent opioid use after benign hysterectomy was 5% (95% confidence interval, 2-8). Younger patient age (odds ratio, 1.38; 95% confidence interval, 1.17-1.63), smoking history (odds ratio, 1.87; 95% confidence interval, 1.67-2.10), alcohol use (odds ratio, 3.16; 95% confidence interval, 2.34-4.27), back pain (odds ratio, 1.50; 95% confidence interval, 1.10-2.05), and fibromyalgia (odds ratio, 1.60; 95% confidence interval, 1.39-1.83) were significantly associated with a higher risk of persistent opioid use after benign hysterectomy. However, there was no significant effect of hysterectomy route and operative complexity on persistent opioid use postoperatively. CONCLUSION: Perioperative opioid dispensing was significantly dependent on the route of hysterectomy, with the lowest dispensed morphine milligram equivalents of opioids for vaginal hysterectomy and the highest for abdominal hysterectomy. Nevertheless, hysterectomy route did not significantly predict persistent opioid use postoperatively, whereas younger age, smoking, alcohol use, back pain, and fibromyalgia were significantly associated with persistent opioid use.

Cost drivers for benign hysterectomy within a health care system: Influence of patient, perioperative, and hospital factors.

OBJECTIVE: To identify patient, perioperative, and hospital factors that drive total hospital charges for benign hysterectomy. METHODS: The authors conducted a retrospective cohort study between July 2014 and February 2019 at five academic and community hospitals within an integrated healthcare system in the state of Maryland with a Global Budget Revenue methodology for hospital charges. Predictor variables included patient, perioperative and hospital characteristics. One-way analysis of variance was used to compare charges among approaches. A multiple linear regression model was built to account for the interaction between covariates. RESULTS: A total of 2592 patients underwent hysterectomy via laparoscopic (61%), abdominal (16%), robotic (14%), or vaginal (9%) approaches. Before adjusting for covariates, laparoscopic and vaginal approaches had similar charges ($11 637 and $12 229, respectively), while robotic and open approaches had higher charges ($17 535 and $19 099, respectively). After adjusting, charges for open, laparoscopic, and robotic approaches were higher than the vaginal approach ($692, $712, and $1279, respectively). Each operating room minute resulted in an increased cost of $46. Length of stay >23 h was associated with an increase of $865. Year, uterine size, body mass index, additional procedures, and transfusion influenced charges. CONCLUSION: Perioperative and hospital characteristics significantly influence hospital charges for benign hysterectomy, more so than nonmodifiable patient characteristics. This provides opportunities to reduce healthcare expenditures, such as improving operating room efficiency and reducing length of stay.

Menstruation in the USA.

Purpose of review: Menstruation touches all spheres of human society, including psychology, education, business, policy, race, and religion. This narrative review aims to describe the relationship menstruation holds with these spaces. Recent findings: First, menstruation plays many roles in psychology - premenstrual syndrome affects psychological wellbeing and in turn, psychological stress impacts menstruation. Functional hypothalamic amenorrhea can result when stress hormones inhibit the Hypothalamus-Pituitary-Ovarian axis. Furthermore, menstruation has many implications for all aged individuals, especially adolescents and those who are menopausal. These implications underscore the importance of proper education surrounding menstruation, which can be achieved via social media, school systems, family, and clinicians. However, menstrual health education is highly variable depending on the state and family that someone is raised in. Additionally, menstruation can pose a financial burden as menstrual products can be expensive and access to these products is limited for those who are homeless, incarcerated, and low-income. Recent public policy measures in various states have aimed to achieve "menstrual equity," by requiring public schools to supply free menstrual products in bathrooms. Furthermore, racial disparities exist with menstrual disorders. Uterine fibroids occur more frequently in Black menstruators compared to White menstruators, and Black women experience worse outcomes overall with fibroids and endometriosis management. Finally, analysis of religion and its relationship to menstruation underscores the immense stigma and "impurity" associated with menstruation. Summary: Overall, this review highlights the universality of menstruation in society. As a "fifth vital sign", there is significant room for improvement in terms of education, research, and cultural acceptance of menstruation. Future research should explore interventions to reduce these gaps.

Determinants and Assessment of Menstrual Blood Flow.

Purpose of review: a)The modifiable and non-modifiable determinants and the currently available methods of assessment of menstrual blood flow will be discussed, with the goal of helping healthcare providers, researchers, and those interested in public health. Recent findings: b)Several factors can impact menstruation. The determinants include modifiable factors such as smoking, nutrition, exercise, stress, weight fluctuation, and benign gynecologic diseases, and non-modifiable factors such as age, race, and the individual's genes. The intertwined dynamic among these determinants needs more critical attention. Currently, the methods for the assessment of menstruation all have advantages and disadvantages, often with a tradeoff between practicality and accuracy. Summary: c)Considered by many as the fifth vital, menstruation provides a window to an individual's general health. The discussion of its determinants and assessment can be more appropriate for individual contexts, especially from a public health perspective as it can improve the reproductive health of the population.

Strategies for Cost Optimization in Minimally Invasive Gynecologic Surgery.

Background: Cost and quality are important, complex, and intertwined surgical outcomes. Evidence suggests that major cost drivers include operating room time, length of stay, re-admission, surgical complications, and quality of pre-operative and operative care in general. Our practices shape both costs and quality of gynecologic surgery. Various factors are explored in this review article to present and identify ways to implement cost-effective change that also improve quality of patient care. Database: We searched MEDLINE and PubMed databases for relevant articles. Discussion: Clinical preferences and decisions, surgeon experience, trainee education, and defensive medicine can influence cost. In addition, an incongruent physician-administration relationship may impact decisions across the healthcare system. The accelerating adoption of minimally invasive surgery, particularly the robotic approach, presents both an opportunity and a challenge. An example of practices that improve outcomes, patient satisfaction, and cut cost is pre-operative optimization, enhanced recovery after surgery, and the growing adoption of outpatient hysterectomy. The identification of cost-drivers and finding strategies to improve them would simultaneously improve quality and patient outcomes while reducing costs in minimally invasive gynecologic surgery.

Simvastatin reduces plasma membrane caveolae and caveolin-1 in uterine leiomyomas.

AIMS: Uterine leiomyomas, or fibroids, are estrogen dependent benign tumor in women, however, they have limited treatment options. Simvastatin, a drug commonly used to treat high cholesterol. Recently we demonstrated that simvastatin alters estrogen signaling by reducing the expression and trafficking of the estrogen receptor-α (ER-α) in human uterine leiomyoma cells. Caveolae are invaginations of the plasma membrane where ER-α is known to localize and directly interacts with the caveolar protein caveolin-1 (CAV1). This study examines the effects of simvastatin on plasma membrane caveolae and the expression and palmitoylation of CAV1 in human leiomyomas which may influence ER-α signaling. MAIN METHODS: We performed in vitro experiments using primary and immortalized human uterine leiomyoma cells. The caveolae were quantified using transmission electron microscopy. Additionally, we examined the impact of simvastatin treatment (40 mg orally per day for 12 weeks) on human leiomyoma tissue obtained from a randomized controlled trial. The CAV1 protein and mRNA levels were determined using quantitative real-time polymerase chain reactions, western blotting, and immunofluorescence analyses. KEY FINDINGS: Simvastatin decreased the number of caveolae in primary leiomyoma cells and reduced CAV1 abundance in whole cells and remarkably the plasma protein fraction. It also decreased CAV1 palmitoylation, a post-translational modification associated with CAV1 activation. The effects of simvastatin on CAV1 were recapitulated in human leiomyoma tissue samples. SIGNIFICANCE: Our results identify caveolae and CAV1 as novel targets of simvastatin which may contribute to the recently described effects of simvastatin on ER-α signaling and plasma membrane trafficking.