A Systematic Review of Epigenetics of Endometriosis.

Objective: To assess the current literature evaluating the epigenetics of endometriosis in humans. Evidence Review: A systematic review was conducted in accordance with the PRISMA guidelines within PubMed, EBSCOhost, Cochrane Library, Embase, Scopus, and Web of Science Core Collection. A comprehensive search strategy was developed by a data informationist. Observational and interventional studies assessing epigenetics in humans published in English up to January 15th, 2023, were included. Two reviewers independently screened studies evaluating the role of epigenetics in endometriosis. The risk of bias was assessed using Cochrane RoB 2.0 tool and the Newcastle-Ottawa scale. Extracted data were analyzed descriptively. Results: We identified 18.639 studies, of which 57 were included, comprising 1.623 patients with endometriosis and 1.243 controls. Among the 57 studies included, 50 (88%) were case-control studies, and 7 (12%) were cross-sectional. Fifty-nine percent of the studies were Asian, 25% were from America, 14% were European, and 2% were from Africa. Acetylation and methylation were the two main key histone modifications that were centered in this review. Accordingly, we classified the studies as those focusing on genome-wide methylation and those on histone acetylation. Several studies identified an association between endometriosis and hypermethylated genes, including the PGR-B, SF-1, and RASSF1A. The genes HOXA10, COX-2, IL-12B, and GATA6 were found to be hypomethylated in endometriotic tissue by several studies. In regards to histone modification, multiple studies reported that the acetylation levels of histones H3 and H4 affect multiple genes associated with endometriosis. In addition, HDAC2 was found to be elevated in endometriosis patients in two studies. Conclusion: Several studies reported a significant difference between specific genes' methylation levels in endometrial biopsies and normal tissue, which suggests that DNA methylation may play an important role in the modulation of the genotype in endometriotic tissue. Acetylation and methylation are the two key histone modifications leading to differential gene expression in endometriotic tissues. The alterations in gene expression reported by the 57 studies can have direct implications on cell cycle growth, cell cycle arrest, and apoptosis and, therefore, might play a key role in the pathogenesis of endometriosis. This review offers insight that histone modifications need further research to evaluate their role as potential biomarkers and treatment targets for endometriosis. Although several key similarities were reported, there were some disagreements among the results, which might be attributable to the heterogeneity between studies. Further research with a more robust standardization is needed to validate the epigenetic changes in endometriosis.

A Systematic Review of the Psychosocial Impact of Endometriosis before and after Treatment.

While endometriosis is a common gynecologic disease associated with infertility, the psychosocial impact of endometriosis has not been evaluated against various quality of life (QoL) instruments and compared with other chronic illnesses. We rigorously analyzed the psychosocial burden of endometriosis in adult women and compared standardized and validated QoL scores of women with and without endometriosis, before and following treatment, and against other chronic illnesses. We searched PubMed, PsychINFO Embase, and Cochrane Reviews and ClinicalTrials.gov from January 1990 to December 2022 for publications using a detailed list of search terms related to QoL, endometriosis, and questionnaires. Only English-language publications that evaluated the association between Endometriosis and QoL using standardized and validated questionnaires measured at baseline and following treatment were considered. Four reviewers first performed a title and abstract screening followed by full text-review to finalize included articles. QoL scores of women with endometriosis were measured at baseline and analyzed against women without endometriosis and women with endometriosis who had undergone treatment. Additionally, baseline endometriosis scores were assessed against the published QoL scores of populations with other chronic conditions. Assessment of risk of bias was performed in accordance with Cochrane and Newcastle-Ottawa Scale guidelines. A total of 30 articles were included in this review: 4 randomized trials and 26 observational studies. The diagnosis and experience of women with symptomatic endometriosis had an equal or worse QoL score than that of other chronic conditions including heart disease, diabetes, and breast cancer when compared using the 36-Item Short Form Survey and World Health Organization Quality of Life questionnaires. Evidence showed association between low QoL and infertility, sexual dysfunction, mental health struggles, physical pain, poor sleep and fatigue. QoL scores were lower at baseline compared to following treatment in the majority of these domains. Endometriosis is associated with significant psychosocial burden and impaired QoL scores across baseline measurements in comparison to controls and other chronic illnesses. Medical and surgical interventions significantly decreased experienced burdens and improved QoL of women with endometriosis.

A systematic review of association between use of hair products and benign and malignant gynecological conditions.

Hair products often contain chemicals like para-phenylenediamine (PPD) and endocrine-disrupting chemicals (EDCs); giving rise to concerns about the possible adverse effects such as hormonal disturbances and carcinogenicity. The objective of this systematic review was to evaluate the association between the use of different hair products and benign and malignant gynecological conditions. Studies were identified from three databases including PubMed, Embase, and Scopus, and evaluated in accordance with PRISMA guidelines. The risk of bias was assessed using the Newcastle-Ottawa Scale. A total of 17 English-language studies met the inclusion criteria. Associations of hair relaxer or hair dye use with breast and ovarian cancer were observed in at least one well-designed study, but these findings were not consistent across studies. Further sub-analysis showed 1.08 times (95 % CI: 1.01-1.15) increased risk of breast cancer in females with permanent hair dye use. Chang et al. reported strong association between uterine cancer risk and hair relaxer use (HR 1.8, 95 % CI: 1.12-2.88), with no observed association with hair dye use. Studies conducted by Wise et al. and James-Todd et al. for benign gynecological conditions; including uterine leiomyoma (IRR 1.17, 95 % CI: 1.06-1.30), early onset of menarche (RR 1.4, 95 % CI: 1.1-1.9), and decreased fecundability (FR 0.89, 95 % CI: 0.81-0.98) revealed positive associations with hair relaxer use, but these findings were based on small sample sizes. In summary, the available evidence regarding personal use of hair products and gynecological conditions is insufficient to determine whether a positive association exists.

The impact of fibroid treatments on quality of life and mental health: a systematic review.

Fibroids significantly impact the quality of life (QOL) and mental health of affected women. However, there are limited comparative data on QOL measures after medical, surgical, and radiologic interventions in women with fibroids. This study aimed to assess the current literature evaluating the impact of fibroids on QOL measures using several validated questionnaires for radiologic, medical, or surgical interventions or a combination of interventions before and after treatment. PubMed, PsycINFO, ClinicalTrials.gov, Embase, and Cochrane Library were searched from January 1990 to October 2023 to evaluate the available evidence, and the risk of bias was assessed using Cochrane RoB 2.0 or the Newcastle-Ottawa Scale. The review criteria included randomized controlled trials (RCTs) and observational cohort studies that included premenopausal women with symptomatic uterine fibroids, confirmed by imaging, who underwent an intervention to target fibroid disease. Only reports using validated questionnaires with a numerical baseline (pretreatment) and posttreatment scores were included. The exclusion criteria included perimenopausal or postmenopausal patients, conditions in addition to uterine fibroids that share similar symptoms, or studies that did not focus on QOL assessment. Abstracts were screened, and full texts were reviewed to determine whether studies met the inclusion criteria. A total of 67 studies were included after final review: 18 RCTs and 49 observational studies. All interventions were associated with a significant improvement in uterine fibroid-specific QOL measures, mental health metrics, and a reduction in symptom severity scores after treatment. These data reveal a substantial impact of uterine fibroids on the QOL and mental health of women with fibroids and indicate the metrics that can be used to compare the effectiveness of fibroid treatment options.

Fibroids and unexplained infertility treatment with epigallocatechin gallate: a natural compound in green tea (FRIEND) - protocol for a randomised placebo-controlled US multicentre clinical trial of EGCG to improve fertility in women with uterine fibroids.

INTRODUCTION: Uterine fibroids affect 30%-77% of reproductive-age women and are a significant cause of infertility. Surgical myomectomies can restore fertility, but they often have limited and temporary benefits, with postoperative complications such as adhesions negatively impacting fertility. Existing medical therapies, such as oral contraceptives, gonadotropin hormone-releasing hormone (GnRH) analogues and GnRH antagonists, can manage fibroid symptoms but are not fertility friendly. This study addresses the pressing need for non-hormonal, non-surgical treatment options for women with fibroids desiring pregnancy. Previous preclinical and clinical studies have shown that epigallocatechin gallate (EGCG) effectively reduces uterine fibroid size. We hypothesise that EGCG from green tea extract will shrink fibroids, enhance endometrial quality and increase pregnancy likelihood. To investigate this hypothesis, we initiated a National Institute of Child Health and Human Development Confirm-funded trial to assess EGCG's efficacy in treating women with fibroids and unexplained infertility. METHODS AND ANALYSIS: This multicentre, prospective, interventional, randomised, double-blinded clinical trial aims to enrol 200 participants with fibroids and unexplained infertility undergoing intrauterine insemination (IUI). Participants will be randomly assigned in a 3:1 ratio to two groups: green tea extract (1650 mg daily) or a matched placebo, combined with clomiphene citrate-induced ovarian stimulation and timed IUI for up to four cycles. EGCG constitutes approximately 45% of the green tea extract. The primary outcome is the cumulative live birth rate, with secondary outcomes including conception rate, time to conception, miscarriage rate, change in fibroid volume and symptom severity scores and health-related quality of life questionnaire scores. ETHICS AND DISSEMINATION: The FRIEND trial received approval from the Food and Drug adminstration (FDA) (investigational new drug number 150951), the central Institutional Review Board (IRB) at Johns Hopkins University and FRIEND-collaborative site local IRBs. The data will be disseminated at major conferences, published in peer-reviewed journals and support a large-scale clinical trial. TRIAL REGISTRATION NUMBER: NCT05364008.

Biomarkers Assessing the Role of Cumulus Cells on IVF Outcomes: A Systematic Review.

PURPOSE: Although significant improvements in assisted reproductive technology (ART) outcomes have been accomplished, a critical question remains: which embryo is most likely to result in a pregnancy? Embryo selection is currently based on morphological and genetic criteria; however, these criteria do not fully predict good-quality embryos and additional objective criteria are needed. The cumulus cells are critical for oocyte and embryo development. This systematic review assessed biomarkers in cumulus-oocyte complexes and their association with successful IVF outcomes. METHODS: A comprehensive search was conducted using PubMed, Embase, Scopus, and Web of Science from inception until November 2022. Only English-language publications were included. Inclusion criteria consisted of papers that evaluated genetic biomarkers associated with the cumulus cells (CCs) in humans and the following three outcomes of interest: oocyte quality, embryo quality, and clinical outcomes, including fertilization, implantation, pregnancy, and live birth rates. RESULTS: The search revealed 446 studies of which 42 met eligibility criteria. Nineteen studies correlated genetic and biochemical biomarkers in CCs with oocyte quality. A positive correlation was reported between oocyte quality and increased mRNA expression in CCs of genes encoding for calcium homeostasis (CAMK1D), glucose metabolism (PFKP), extracellular matrix (HAS2, VCAN), TGF-ß family (GDF9, BMP15), and prostaglandin synthesis (PTGS2). Nineteen studies correlated genetic and biochemical biomarkers in CCs with embryo quality. A positive correlation was reported between embryo quality and increased mRNA expression in CCs of genes encoding for extracellular matrix (HAS2), prostaglandin synthesis (PTGS2), steroidogenesis (GREM1), and decreased expression of gene encoding for hormone receptor (AMHR2). Twenty-two studies assessed genetic and biochemical biomarkers in CCs with clinical outcomes. Increased expression of genes encoding for extracellular matrix (VCAN), and TGF-ß family (GDF9, BMP15) were positively correlated with pregnancy rate. CONCLUSION: Genetic biomarkers from cumulus cells were associated with oocyte quality (CAMK1D, PFKP, HAS2, VCAN, GDF-9, BMP-15, PTGS2), embryo quality (GREM1, PTGS2, HAS2), and pregnancy rate (GDF9, BMP15, VCAN). These results might help guide future studies directed at tests of cumulus cells to devise objective criteria to predict IVF outcomes.

A Systematic Review of Autoimmune Oophoritis Therapies.

Autoimmune primary ovarian insufficiency (POI) is a devastating disease with limited clinical guidance. The objective of this systematic review was to identify treatments for autoimmune POI and analyze their efficacy. A comprehensive search of CINAHL, Cochrane, Embase, PubMed, Scopus, and Web of Science was performed from inception to April 2022. English language publications that evaluated women with autoimmune POI after a documented intervention were included. Animal models of autoimmune POI were also included. Risk of bias was assessed with the SYRCLE's risk of bias tool for animal studies or the NIH Quality Assessment Tool for Case Series as appropriate. Twenty-eight studies were included in this review, with 11 RCTs, 15 case reports, and 2 case series. Seventeen studies were in humans, and 11 were in animal models. No completed RCTs, cohort studies, or case-control studies were identified in humans. In observational human studies, corticosteroids were effective in select patients. In many case reports, adequate treatment of comorbid autoimmune conditions resulted in return of menses, hormonal normalization, or spontaneous pregnancy. In terms of assisted reproductive technologies, there was case report evidence for both in vitro fertilization (IVF) and in vitro maturation (IVM) in women wishing to conceive with their own oocytes. Ovulation induction, IVF, and IVM resulted in a total of 15 pregnancies and 14 live births. In animal models, there was additional evidence for stem cell therapies and treatments used in traditional Chinese medicine, although this research may not be generalizable to humans. Furthermore, litter size was not evaluated in any of the animal studies. Additional research is needed to establish the efficacy of current treatments for autoimmune POI with a controlled experimental design and larger sample size. Additionally, there is a critical need to develop novel therapies for this condition, as understanding of its pathophysiology and  available tools to modulate the immune response have progressed.

The Mediator Complex Subunit 12 (MED-12) Gene and Uterine Fibroids: a Systematic Review.

Uterine leiomyomas are the most common tumor of reproductive-age women worldwide. Although benign, uterine fibroids cause significant morbidity and adversely impact the quality of life for affected women. Somatic mutations in the exon 2 of the mediator complex subunit 12 (MED-12) gene represent the most common single gene mutation associated with uterine leiomyomas. The objective of this review was to evaluate the current role of MED-12 mutation in the pathophysiology of uterine fibroids, to assess the prevalence of MED-12 mutation among different populations, and to identify the most common subtypes of MED-12 mutations found in uterine fibroids. A comprehensive search was conducted using Pubmed, Embase, Scopus, and the Web of Science. English-language publications that evaluated MED-12 mutation and uterine fibroids in humans, whether experimental or clinical, were considered. We identified 380 studies, of which 23 were included, comprising 1353 patients and 1872 fibroid tumors. Of the total number of tumors analyzed, 1045 (55.8%) harbored a MED-12 mutation. Among the 23 studies included, the frequency of MED-12 mutation varied from 31.1 to 80% in fibroid samples. The most common type of MED-12 mutation was a heterozygous missense mutation affecting codon 44 of exon 2, specifically the nucleotide 131. Studies reported that MED-12 mutation acts by increasing levels of AKT and disrupting the cyclin C-CDK8/19 kinase activity. The overall average prevalence of MED-12 mutation in uterine fibroids was found to be 55.8% across the global population, though the frequency varied greatly among different countries.

Beta blockers reduce uterine fibroid incidence in hypertensive women.

OBJECTIVE: Is prior beta blocker (BB) use associated with reduced odds of the clinical incidence of leiomyomas? WHAT IS KNOWN ALREADY: In-vitro and in-vivo evidence has supported the role of beta receptor blockade in reducing leiomyoma cell proliferation and growth. However, no population-based study to date has investigated this potential association. STUDY DESIGN, SIZE, DURATION: A nested case-control study was conducted in a population of women aged 18-65 with arterial hypertension (n = 699,966). Cases (n = 18,918) with a leiomyoma diagnosis were matched to controls (n = 681,048) with no such diagnosis at a 1:36 ratio by age and region of origin within the United States. PARTICIPANTS/MATERIALS, SETTING, METHODS: This population was assembled from the Truven Health MarketScan® Research Database, which includes health insurance claims from January 1st, 2012 to December 31st, 2017. Prior use of BB wasdetermined fromoutpatient drug claims and leiomyoma development was indicated by a first-time diagnosis code. We conducted a conditional logistic regression to determine the odds of uterine fibroid development in women with prior use of BB compared to women with no such history. We then conducted subset analyses, stratifying the women by age group and by type of BB. RESULTS: Women on a BB experienced 15% reduced odds of developing clinically recognized leiomyoma compared to non-users (OR 0.85, 95% CI 0.76-0.94). This association was significant for the 30-39 age group (OR 0.61, 95% CI 0.40-0.93) but no other age group. Of the BBs, propranolol (OR 0.58, 95% CI 0.36-95) demonstrated a significant association with reduced leiomyoma incidence and metoprolol (OR 0.82, 95% CI 0.70-0.97) was associated with lower uterine fibroid incidence after adjustment for comorbidities. CONCLUSIONS: Hypertensive women with prior BB use experienced reduced odds of developing clinically recognized leiomyoma compared to non-users. A key predisposing risk factor for uterine leiomyoma is elevated blood pressure. Thus, the results of this analysis may have clinical relevance to women with hypertension, as the use of this drug may introduce a dual benefit of managing hypertension as well as curbing an increased risk of leiomyomas.

A Systematic Review of the Psychosocial Impact of Polycystic Ovarian Syndrome Before and After Treatment.

While polycystic ovarian syndrome (PCOS) is one of the most common hormonal endocrine disorders among women of reproductive age, the psychosocial impact of PCOS has not been evaluated across different quality of life (QoL) indicators. We rigorously analyzed available evidence pertaining to the psychosocial burden of PCOS in women of reproductive age and compared validated QoL scores of women with and without PCOS before and after treatment. We searched and considered publications from PubMed, PsychINFO, Embase, and Cochrane Library that evaluated the association between diagnosed PCOS and QoL by standardized and validated questionnaires at baseline and after treatment. Reviewers assessed the risk of bias using established Cochrane and Newcastle-Ottawa Scale guidelines. A total of 33 studies were included in the review: 14 randomized controlled trials and 19 observational studies. The 36-Item Short Form Survey and World Health Organization Quality of Life - BREF questionnaire both revealed that the diagnosis and life experience of PCOS had a disability score that was similar to or surpassed that of heart disease, diabetes mellitus, or breast cancer. QoL scores, associated with mental health issues, infertility, sexual dysfunction, obesity, menstrual disorder, and hirsutism, were lower at the baseline than after treatment in the majority of instruments measuring these variables in women with PCOS. PCOS is associated with significant psychosocial stress and reduced QoL across baseline measures and in comparison, to other diseases. Evidence suggests that treatment with therapy, medications, and lifestyle management decreased psychosocial burdens and alleviated QoL experienced by women with PCOS.

Green Tea and Benign Gynecologic Disorders: A New Trick for An Old Beverage?

Green tea is harvested from the tea plant Camellia sinensis and is one of the most widely consumed beverages worldwide. It is richer in antioxidants than other forms of tea and has a uniquely high content of polyphenolic compounds known as catechins. Epigallocatechin-3-gallate (EGCG), the major green tea catechin, has been studied for its potential therapeutic role in many disease contexts, including pathologies of the female reproductive system. As both a prooxidant and antioxidant, EGCG can modulate many cellular pathways important to disease pathogenesis and thus has clinical benefits. This review provides a synopsis of the current knowledge on the beneficial effects of green tea in benign gynecological disorders. Green tea alleviates symptom severity in uterine fibroids and improves endometriosis through anti-fibrotic, anti-angiogenic, and pro-apoptotic mechanisms. Additionally, it can reduce uterine contractility and improve the generalized hyperalgesia associated with dysmenorrhea and adenomyosis. Although its role in infertility is controversial, EGCG can be used as a symptomatic treatment for menopause, where it decreases weight gain and osteoporosis, as well as for polycystic ovary syndrome (PCOS).

Assessing the Hepatic Safety of Epigallocatechin Gallate (EGCG) in Reproductive-Aged Women.

A similar abstract of the interim analysis was previously published in Fertility and Sterility. EPIGALLOCATECHIN GALLATE (EGCG) FOR TREATMENT OF UNEXPLAINED INFERTILITY ASSOCIATED WITH UTERINE FIBROIDS (PRE-FRIEND TRIAL): EARLY SAFETY ASSESSMENT. Uterine fibroids are the most common cause of unexplained infertility in reproductive-aged women. Epigallocatechin gallate (EGCG), a green tea catechin, has demonstrated its ability to shrink uterine fibroids in prior preclinical and clinical studies. Hence, we developed an NICHD Confirm-funded trial to evaluate the use of EGCG for treating women with fibroids and unexplained infertility (FRIEND trial). Prior to embarking on that trial, we here conducted the pre-FRIEND study (NCT04177693) to evaluate the safety of EGCG in premenopausal women. Specifically, our aim was to assess any adverse effects of EGCG alone or in combination with an ovarian stimulator on serum liver function tests (LFTs) and folate level. In this randomized, open-label prospective cohort, participants were recruited from the FRIEND-collaborative clinical sites: Johns Hopkins University, University of Chicago, University of Illinois at Chicago, and Yale University. Thirty-nine women, ages ≥18 to ≤40 years, with/without uterine fibroids, were enrolled and randomized to one of three treatment arms: 800 mg of EGCG daily alone, 800 mg of EGCG daily with clomiphene citrate 100 mg for 5 days, or 800 mg of EGCG daily with Letrozole 5 mg for 5 days. No subject demonstrated signs of drug induced liver injury and no subject showed serum folate level outside the normal range. Hence, our data suggests that a daily dose of 800 mg of EGCG alone or in combination with clomiphene citrate or letrozole (for 5 days) is well-tolerated and is not associated with liver toxicity or folate deficiency in reproductive-aged women.

Utilization and cost of cell salvage in minimally invasive myomectomy.

OBJECTIVE: To assess the utilization and cost of intraoperative cell salvage (ICS) in minimally invasive myomectomy. STUDY DESIGN: Retrospective cohort study of patients who underwent minimally invasive myomectomy at a quaternary care academic hospital. Patients were classified into: ICS setup vs no ICS setup, ICS setup with reinfusion vs ICS setup without reinfusion. RESULTS: Of 382 patients who underwent minimally invasive myomectomy, 67 (17.5 %) had ICS setup, 30 (44.8 %) of those patients reinfused. Median volume of reinfusion per patient was 300 mL (range 125-1000 mL). Patients who ultimately underwent ICS reinfusion, compared to those with ICS setup only, had significantly larger mean maximum fibroid size (9.8 cm vs 8.0 cm, p = 0.02), higher median total specimen weight (367 vs 304 g, p = 0.03), higher median estimated blood loss (575 vs 300 mL, p < 0.0001), longer mean operative time (261 vs 215 min, p = 0.04). No perioperative complications were associated with ICS. Higher costs are associated with universal use or complete lack of ICS; lowest cost is associated with ICS setup only for those ultimately reinfused. CONCLUSION: ICS might reduce requirements for allogeneic blood transfusions in patients undergoing minimally invasive myomectomy, and may contribute to cost savings. Uterine and maximum fibroid sizes are possible preoperative indicators for patients who require cell salvage reinfusion.

A Systematic Review of Minimally Invasive Approaches to Uterine Fibroid Treatment for Improving Quality of Life and Fibroid-Associated Symptoms.

Improvement in symptom severity and quality of life (QoL) are critical concerns for women with fibroids as they evaluate treatment options. This systematic review analyzed available evidence regarding minimally invasive approaches to fibroid treatment and compared validated QoL and fibroid-associated symptom scores before and after treatment. A comprehensive search was conducted using PubMed, Embase, Cochrane Library, and Scopus from January 1990 to July 2020. English-language publications were included if they evaluated associations between minimally invasive approaches to fibroid treatment and QoL or fibroid-associated symptoms, and they used validated questionnaires before and after treatment. QoL or fibroid-associated symptom scores were compared and summarized for each minimally invasive approach. Thirty-seven studies were ultimately included in this review: 26 evaluating individual approaches and 11 which were comparative studies of minimally invasive approaches and surgical interventions. Radiofrequency ablation (RFA) and ultrasound-guided sclerotherapy (USGS) significantly improved overall QoL. Uterine artery embolization (UAE) and ultrasound-guided high-intensity frequency ultrasound (US-HIFU) improved overall QoL to a similar extent as surgical interventions. Twenty-eight studies assessed fibroid-associated symptoms with the Uterine Fibroid Symptoms Quality of Life Questionnaire (UFS-QoL). UAE, magnetic resonance imaging-guided high-intensity frequency ultrasound (MR-HIFU), US-HIFU, RFA, and percutaneous microwave ablation (PMWA) significantly decreased Symptom Severity Score by a range of 21 to 39 points (out of 100) at 6 months. Minimally invasive approaches to treat fibroids were effective alternatives to surgical interventions for improving quality of life, fibroid-associated symptoms, and pain. Outcomes among minimally invasive approaches were similar, presenting patients with numerous options for fibroid treatment.

The Utility and Impact of the Painful Periods Screening Tool (PPST) to Improve Healthcare Delivery for People with Symptoms of Pelvic Pain.

The objective of this study was to evaluate the utility and impact of the Painful Periods Screening Tool (PPST) to improve healthcare delivery for people with symptoms of pelvic pain. The design of this study was a survey study. After IRB approval, patients aged 18-55 years with self-reported pelvic, abdominal, or lower back pain before, during, or after menstrual periods were invited to participate in the study from September 2020 to June 2021. Participants filled out the PPST questionnaire on the day of their Johns Hopkins clinic visit and the follow-up questionnaire 1-14 days after the clinic visit. Demographics and duration of pain were assessed, and participants who completed the PPST questionnaire were sent a follow-up questionnaire to assess utility and impact of PPST. Of the 1352 patients who met study eligibility, 1000 participants responded to both questionnaires. Most subjects (82.9%; 95% CI: 80.4-85.2%) reported having severe pelvic/abdominal or lower back pain during menses. Nine hundred fifteen participants (91.5%; 95% CI: 89.6-93.2%) reported that if given regularly, the PPST would help women discuss their pain symptoms with their healthcare provider. Six hundred seventy-eight participants (67.8%; 95% CI: 64.8-70.7%) reported that the PPST helped them initiate a conversation about their symptoms. Seven hundred seven participants (70.7%; 95% CI: 67.8-73.5%) were more comfortable discussing symptoms of pelvic pain with their provider after filling out the PPST. These findings support the utility of PPST as an endometriosis screening tool and suggest that this tool facilitated communication between patients and providers about pain symptoms.

A Systematic Review of Vitamin D and Fibroids: Pathophysiology, Prevention, and Treatment.

Uterine fibroids are the most common tumor of reproductive-age women worldwide and cause significant morbidity in affected women. Vitamin D has emerged as a potential therapy for uterine fibroids based on experimental and epidemiologic evidence. The objective of this systematic review was to evaluate the role of vitamin D in the pathophysiology of uterine fibroids and its efficacy for prevention and treatment of fibroids. A comprehensive search was conducted of Cochrane Library, Embase, PubMed, Scopus, and Web of Science from inception to March 2022. English-language publications that evaluated vitamin D and uterine fibroids in humans, whether experimental or clinical, were considered. The search yielded 960 publications, and 89 publications met inclusion criteria: 23 preclinical studies, 25 clinical studies, and 41 review articles. Preclinical studies indicated that the vitamin D receptor was decreased in fibroid cells. Vitamin D treatment of fibroid cells decreased proliferation, extracellular matrix protein expression, and Wnt/ß-catenin signaling. Fourteen clinical studies (n = 3535 participants) assessed serum vitamin D level in women with ultrasound-proven fibroids, and all found an inverse correlation between serum vitamin D level and presence of fibroids. Five clinical studies (n = 472 patients) evaluated treatment of fibroids with vitamin D. Four of five studies showed vitamin D significantly inhibited fibroid growth. One pilot study (n = 109 patients) of vitamin D for secondary prevention of fibroids demonstrated smaller recurrent fibroids in the treated group. These studies provide evidence for vitamin D as a therapy for uterine fibroids and underscore the need for well-designed, randomized, placebo-controlled clinical trials.

Association between embryo morphological quality and birth weight for singletons conceived via autologous fresh embryo transfer: an analysis using Society for Assisted Reproductive Technology Clinical Outcomes Reporting System.

OBJECTIVE: To determine if morphologically suboptimal embryo quality is associated with adverse perinatal outcomes. DESIGN: A retrospective cohort. SETTING: SART CORS database. PATIENT(S): Singletons conceived from autologous in vitro fertilization fresh cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Birth weight (gram), birth weight z-score, low birth weight (LBW), small for gestational age (SGA), and large for gestational age (LGA). RESULT(S): Among 5,869 in vitro fertilization fresh cycles, 71.1% transferred morphologically good embryos, and 27.0% and 1.9% transferred fair and poor embryo(s), respectively. Compared with singletons conceived from good embryos, singletons from poor embryos had a higher birth weight (3,415.8 ± 562.0 vs. 3,202.7 ± 639.9). Proportions of LBW, SGA, and LGA were comparable across embryo quality groups. Multivariate regression analysis comparing perinatal outcomes from fair vs. good embryos showed no association for birth weight (0.69-gram difference; 95% CI, -24.30-25.68), birth weight z-score (Coefficient, 0.00; 95% CI, -0.07-0.08), LBW (adjusted odds ratio [aOR], 0.84; 95% CI, 0.63-1.11), SGA (aOR, 0.93; 95% CI, 0.78-1.11), and LGA (aOR, 1.07; 95% CI, 0.86-1.33). Stratified analysis, considering cleaved and blastocyst embryo transfers separately, confirmed these findings. Sensitivity analysis revealed increased odds of LGA (aOR, 1.53; 95% CI, 1.04-2.24) with fair-quality embryos only among single embryo transfer cycles. CONCLUSION(S): Once a singleton live birth from fresh embryo transfer is achieved, fair morphological embryo quality is not associated with a reduction in birth weight or increased risks of LBW, SGA, and LGA.

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.

A Systematic Review of Minimally Invasive Treatments for Uterine Fibroid-Related Bleeding.

Newer minimally invasive techniques provide treatment options for symptomatic uterine fibroids while allowing uterus preservation. The objective of this review was to analyze the efficacy of uterine-preserving, minimally invasive treatment modalities in reducing fibroid-related bleeding. A comprehensive search was conducted of PubMed, Embase, PsycINFO, ClinicalTrials.gov, Scopus, and Cochrane Library databases from inception to July 2020. English-language publications that evaluated premenopausal women with fibroid-related bleeding symptoms before and after treatment were considered. Randomized controlled trials were assessed for bias with the established Cochrane Risk of Bias Tool 2.0 and observational studies were assessed for quality under the New Castle-Ottawa Scale guidelines. Eighty-four studies were included in the review, including 10 randomized controlled trials and 74 observational studies. Six studies on myomectomy demonstrated overall bleeding symptom improvement in up to 95.9% of patients, though there was no significant difference between mode of myomectomy. Forty-one studies on uterine artery embolization reported significant reduction of fibroid-related bleeding, with symptomatic improvement in 79 to 98.5% of patients. Three studies suggested that embolization may be superior to myomectomy in reducing fibroid-related bleeding. Six studies reported that laparoscopic uterine artery occlusion combined with myomectomy led to greater reduction of bleeding than myomectomy alone. Fifteen studies demonstrated significantly reduced bleeding severity after radiofrequency ablation (RFA). Additional research is needed to establish the superiority of these modalities over one another. Long-term evidence is limited in current literature for magnetic resonance-guided focused ultrasound surgery, cryomyolysis, microwave ablation, and laser ablation.

Cost-effectiveness of preimplantation genetic testing for aneuploidy for fresh donor oocyte cycles.

OBJECTIVE: To determine whether in vitro fertilization (IVF) with preimplantation genetic testing for aneuploidy (PGT-A) is cost effective to achieve a live birth compared with IVF alone in fresh donor oocyte cycles. DESIGN: Theoretical cost-effectiveness study. SETTING: Not applicable. PATIENTS: None. INTERVENTIONS: Comparison between the cost of IVF with PGT-A vs. IVF alone to achieve a live birth. The model analyzed a hypothetical single fresh oocyte donor IVF cycle with PGT-A vs. IVF alone and followed the progression of a single embryo through the different decision nodes. Cost estimates assigned to each clinical event were based on data obtained from the literature and institutional costs. MAIN OUTCOME MEASURES: Cost per live birth. RESULTS: In the base-case analysis, IVF with PGT-A was not cost effective in fresh donor oocyte cycles when compared with IVF alone to achieve a live birth. The cycles using PGT-A cost an additional $6,018.66. The incremental cost-effectiveness ratio was found to be $119,606.59 per additional live birth achieved with IVF with PGT-A. Monte Carlo simulations demonstrated that IVF with PGT-A was not cost effective in nearly all iterations. CONCLUSIONS: PGT-A in fresh donor oocyte IVF cycles is not cost effective compared with IVF alone over a wide range of probabilities and costs.