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Objective: To determine if ovarian responsiveness to gonadotropin stimulation differs by race/ethnicity and whether this predicts live birth rates (LBRs) in non-White patients undergoing in vitro fertilization (IVF)., Design: Retrospective cohort study., Setting: Academic infertility center., Patient(s): White, Asian, Black, and Hispanic patients undergoing ovarian stimulation for IVF., Intervention(s): Self-reported race and ethnicity., Main Outcome Measure(s): The primary outcome was ovarian sensitivity index (OSI), defined as (the number of oocytes retrieved ÷ total gonadotropin dose) × 1,000 as a measure of ovarian responsiveness, adjusting for age, body mass index, infertility diagnosis, and cycle number. Secondary outcomes included live birth and clinical pregnancy after first retrievals, adjusting for age, infertility diagnosis, and history of fibroids, as well as miscarriage rate per clinical pregnancy, adjusting for age, body mass index, infertility diagnosis, duration of infertility, history of fibroids, and use of preimplantation genetic testing for aneuploidy., Result(s): The primary analysis of OSI included 3,360 (70.2%) retrievals from White patients, 704 (14.7%) retrievals from Asian patients, 553 (11.6%) retrievals from Black patients, and 168 (3.5%) retrievals from Hispanic patients. Black and Hispanic patients had higher OSIs than White patients after accounting for those with multiple retrievals and adjusting for confounders (6.08 in Black and 6.27 in Hispanic, compared with 5.25 in White). There was no difference in OSI between Asian and White patients. The pregnancy outcomes analyses included 2,299 retrievals. Despite greater ovarian responsiveness, Black and Hispanic patients had lower LBRs compared with White patients, although these differences were not statistically significant after adjusting for confounders (adjusted odds ratio, 0.83; 95% confidence interval [CI], 0.63-1.09, for Black; adjusted odds ratio, 0.93; 95% CI, 0.61-1.43, for Hispanic). Ovarian sensitivity index was modestly predictive of live birth in White and Asian patients but not in Black (area under the curve, 0.51; 95% CI, 0.38-0.64) and Hispanic (area under the curve, 0.50; 95% CI, 0.37-0.63) patients., Conclusion(s): Black and Hispanic patients have higher ovarian responsiveness to stimulation during IVF but do not experience a consequent increase in LBR. Factors beyond differences in responsiveness to ovarian stimulation need to be explored to address the racial/ethnic disparity established in prior literature., Competing Interests: Declaration of interests I.T.L has nothing to disclose. D.S.B. has nothing to disclose. N.K. has nothing to disclose. S.S. reports funding from National Institutes of Health and AbbVie and consulting fees for participation on Ferring Oocyte Cryopreservation Advisory Board and is Co-Chair of the Society for Assisted Reproductive Technology Committee, outside the submitted work. M.M. has nothing to disclose., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Leiomyomas (LMs) are the most frequent uterine benign tumors, representing the leading cause of hysterectomy indications worldwide. They are highly associated with women's reproductive complications, and endocrine disruptors may influence their etiology. In this sense, air pollution represents a relevant hormonal disruptor that acts on key signaling pathways, resulting in tumor development and infertility. Our goal was to evaluate submucosal LM samples from patients living in the metropolitan and Sao Paulo city regions, focusing on genes involved in tumor development and infertility features. Twenty-four patients were selected based on their region of residence and clinical information availability. Several genes were differentially expressed between women living in metropolitan areas and Sao Paulo city. Significant associations were observed between BCL-2 , DVL1 , FGFR3 , and WNT5b downregulation and contraceptive use in the samples from women living in Sao Paulo city. ESR1 and HHAT downregulation was associated with ethnicity. WNT5b and GREM were associated with LM treatment and related pathologies, respectively. In the samples from women living in other cities of the metropolitan region, abortion occurrence was associated with BMP4 upregulation. Although further studies may be necessary, our results showed that air pollution exposure influences the expression of genes related to LM development and female reproductive features.

Objective: To investigate the outcome of total laparoscopic hysterectomy (TLH) and postoperative pain characteristics and compare the pain severity after TLH for adenomyosis or uterine fibroids., Methods: This prospective observational study collected 101 patients received TLH for adenomyosis (AD group) including 41 patients were injected goserelin (3.6 mg) 28 days before TLH, while other adenomyosis patients received TLH without preoperative treatment, and 113 patients received TLH for uterine fibroids (UF group). Pain scores were evaluated at different time sites from operation day to postoperative 72 h using the numeric rating scale. Clinical data were collected from clinical record., Results: Operative time and anaesthetic time were longer in the AD group than those in the UF group (66.88 ± 8.65 vs. 64.46 ± 7.21, p  = 0.04; 83.95 ± 10.05 vs. 79.77 ± 6.88, p  < 0.01), severe endometriosis was quite more common in AD group (23.76% vs. 2.65%, p  < 0.01). Postoperative usage of Flurbiprofen in AD group were more than that of UF group (15.48 ± 38.00 vs. 4.79 ± 18.16, p  = 0.02). Total pains and abdominal visceral pains of AD group were more severe compared with UF group in motion and rest pattern at several time sites, while incision pain and shoulder pain were similar. The total postoperative pains after goserelin preoperative treatment in AD group were less than that without goserelin preoperative treatment ( p  < 0.05). The levels of serum NPY, PGE2 and NGF after laparoscopic hysterectomy of adenomyosis reduced with GnRH agonist pretreatment., Conclusions: Acute postoperative pain for adenomyosis and uterine fibroids showed considerably different severity, postoperative total pain and abdominal visceral pains of TLH for adenomyosis were more severe compared with uterine fibroids. While patients received goserelin before laparoscopic hysterectomy of adenomyosis suffered from less severity of postoperative total pain than that without goserelin preoperative treatment.

According to recent studies and observations in clinical practice, uterine fibroids increase the risk of preterm birth. There are several theories on the pathogenesis of preterm birth in the presence of fibroids. One theory proclaims that fibroid necrosis leads to preterm birth, though pathophysiological mechanisms have not been described. Necrotic tissue secretes specific cytokines and proteins and we suggest these to be comparable to the inflammatory response leading to spontaneous preterm birth. We hypothesize that fibroid necrosis could induce preterm parturition through a similar inflammatory response. This new hypothesis generates novel perspectives for future research and the development of preventative strategies for preterm birth. Moreover, we emphasize the importance of the recognition of fibroids and especially fibroid necrosis by clinicians during pregnancy.

Uterine fibroids are benign monoclonal neoplasms of the myometrium, representing the most common tumors in women worldwide. To date, no long-term or noninvasive treatment option exists for hormone-dependent uterine fibroids, due to the limited knowledge about the molecular mechanisms underlying the initiation and development of uterine fibroids. This paper comprehensively summarizes the recent research advances on uterine fibroids, focusing on risk factors, development origin, pathogenetic mechanisms, and treatment options. Additionally, we describe the current treatment interventions for uterine fibroids. Finally, future perspectives on uterine fibroids studies are summarized. Deeper mechanistic insights into tumor etiology and the complexity of uterine fibroids can contribute to the progress of newer targeted therapies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders., Methods and Findings: Logistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios [ORs] = 1.02-1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06-2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR [95% CI] per 1-kg increase in predicted VAT mass = 1.32 [1.06-1.64], P = 0.0130), PCOS (OR [95% CI] = 1.15 [1.08-1.23], P = 3.24 × 10-05), and pre-eclampsia (OR [95% CI] = 3.08 [1.98-4.79], P = 6.65 × 10-07). Increased waist circumference posed a higher genetic risk (ORs = 1.16-1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06-1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy., Conclusions: We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: C.M.B. reports grants from Bayer AG, AbbVie Inc, Volition Rx, MDNA Life Sciences, Roche Diagnostics Inc., and consultancy for Myovant. He is a member of the independent data monitoring board at ObsEva; I.G. reports grants from Bayer AG; K.T.Z. reports grants from Bayer AG, AbbVie Inc, Volition Rx, MDNA Life Sciences, Roche Diagnostics Inc, and non-financial scientific collaboration with Population Diagnostics Ltd, outside the submitted work; M.V.H. has consulted for Boehringer Ingelheim, and in adherence to the University of Oxford’s Clinical Trial Service Unit & Epidemiological Studies Unit (CSTU) staff policy, did not accept personal honoraria or other payments from pharmaceutical companies; C.M.L. reports grants from Bayer AG and Novo Nordisk and has a partner who works at Vertex; no other relationships or activities that could appear to have influenced the submitted work. All disclosed competing interests are outside the submitted work.

Mechanical forces in a constrained cellular environment were recently established as a facilitator of chromosomal damage. Whether this could contribute to tumorigenesis is not known. Uterine leiomyomas are common neoplasms that display relatively few chromosomal aberrations. We hypothesized that if mechanical forces contribute to chromosomal damage, signs of this could be seen in uterine leiomyomas from parous women. We examined the karyotypes of 1946 tumors, and found a striking overrepresentation of chromosomal damage associated with parity. We then subjected myometrial cells to physiological forces similar to those encountered during pregnancy, and found this to cause DNA breaks and a DNA repair response. While mechanical forces acting in constrained cellular environments may thus contribute to neoplastic degeneration, and genesis of uterine leiomyoma, further studies are needed to prove possible causality of the observed association. No evidence for progression to malignancy was found., (© 2021. The Author(s).)

Uterine leiomyoma (LM) is the most common tumor in women. Via its receptor (PGR) expressed in differentiated LM cells, progesterone stimulates paracrine signaling that induces proliferation of PGR-deficient LM stem cells (LSCs). Antiprogestins shrink LM but tumors regrow after treatment cessation possibly due to persisting LSCs. Using sorted primary LM cell populations, we found that the PGR gene locus and its target cistrome are hypermethylated in LSCs, inhibiting the expression of genes critical for progesterone-induced LSC differentiation. PGR knockdown shifted the transcriptome of total LM cells toward LSCs and increased global DNA methylation by regulating TET methylcytosine dioxygenases. DNA methylation inhibitor 5'-Aza activated PGR signaling, stimulated LSC differentiation, and synergized with antiprogestin to reduce tumor size in vivo. Taken together, targeting the feedback loop between DNA methylation and progesterone signaling may accelerate the depletion of LSCs through rapid differentiation and sensitize LM to antiprogestin therapy, thus preventing tumor regrowth., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Uterine leiomyomas represent the most common benign gynecologic tumor. These hormone-dependent smooth-muscle formations occur with an estimated prevalence of ~70% among women of reproductive age and cause symptoms including pain, abnormal uterine bleeding, infertility, and recurrent abortion. Despite the prevalence and public health impact of uterine leiomyomas, available treatments remain limited. Among the potential causes of leiomyomas, early hormonal exposure during periods of development may result in developmental reprogramming via epigenetic changes that persist in adulthood, leading to disease onset or progression. Recent developments in unbiased high-throughput sequencing technology enable powerful approaches to detect driver mutations, yielding new insights into the genomic instability of leiomyomas. Current data also suggest that each leiomyoma originates from the clonal expansion of a single transformed somatic stem cell of the myometrium. In this review, we propose an integrated cellular and molecular view of the origins of leiomyomas, as well as paradigm-shifting studies that will lead to better understanding and the future development of non-surgical treatments for these highly frequent tumors.

Study Question: To what extent are ambient concentrations of particulate matter <2.5 microns (PM2.5), nitrogen dioxide (NO2) and ozone (O3) associated with risk of self-reported physician-diagnosed uterine leiomyomata (UL)?, Summary Answer: In this large prospective cohort study of Black women, ambient concentrations of O3, but not PM2.5 or NO2, were associated with increased risk of UL., What Is Known Already: UL are benign tumors of the myometrium that are the leading cause of gynecologic inpatient care among reproductive-aged women. Black women are clinically diagnosed at two to three times the rate of white women and tend to exhibit earlier onset and more severe disease. Two epidemiologic studies have found positive associations between air pollution exposure and UL risk, but neither included large numbers of Black women., Study Design, Size, Duration: We conducted a prospective cohort study of 21 998 premenopausal Black women residing in 56 US metropolitan areas from 1997 to 2011., Participants/material, Setting, Methods: Women reported incident UL diagnosis and method of confirmation (i.e. ultrasound, surgery) on biennial follow-up questionnaires. We modeled annual residential concentrations of PM2.5, NO2 and O3 throughout the study period. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for a one-interquartile range (IQR) increase in air pollutant concentrations, adjusting for confounders and co-pollutants., Main Results and the Role of Chance: During 196 685 person-years of follow-up, 6238 participants (28.4%) reported physician-diagnosed UL confirmed by ultrasound or surgery. Although concentrations of PM2.5 and NO2 were not appreciably associated with UL (HRs for a one-IQR increase: 1.01 (95% CI: 0.93, 1.10) and 1.05 (95% CI: 0.95, 1.16), respectively), O3 concentrations were associated with increased UL risk (HR for a one-IQR increase: 1.19, 95% CI: 1.07, 1.32). The association was stronger among women age <35 years (HR: 1.26, 95% CI: 0.98, 1.62) and parous women (HR: 1.28, 95% CI: 1.11, 1.48)., Limitations, Reasons for Caution: Our measurement of air pollution is subject to misclassification, as monitoring data are not equally spatially distributed and we did not account for time-activity patterns. Our outcome measure was based on self-report of a physician diagnosis, likely resulting in under-ascertainment of UL. Although we controlled for several individual- and neighborhood-level confounding variables, residual confounding remains a possibility., Wider Implications of the Findings: Inequitable burden of air pollution exposure has important implications for racial health disparities, and may be related to disparities in UL. Our results emphasize the need for additional research focused on environmental causes of UL., Study Funding/competing Interest(s): This research was funded by the National Cancer Institute (U01-CAA164974) and the National Institute of Environmental Health Sciences (R01-ES019573). L.A.W. is a fibroid consultant for AbbVie, Inc. and accepts in-kind donations from Swiss Precision Diagnostics, Sandstone Diagnostics, FertilityFriend.com and Kindara.com for primary data collection in Pregnancy Study Online (PRESTO). M.J. declares consultancy fees from the Health Effects Institute (as a member of the review committee). The remaining authors declare they have no actual or potential competing financial interests., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To investigate the relationship between vitamin D deficiency and the risk of asymptomatic uterine fibroids (UFs)., Design: Cross-sectional study., Setting: University hospital., Patient(s): The present analysis recruited 133 asymptomatic patients with UFs and 80 normal control subjects from October 2017 to June 2020. Age matching created 61 pairs., Intervention(s): Medical history, transvaginal or transabdominal genital ultrasound scan, blood sampling, and measurement of vitamin D concentrations., Main Outcome Measure(s): Evaluation of the impact of vitamin D level on the risk of newly diagnosed asymptomatic UFs in premenopausal Han Chinese women., Result(s): Vitamin D levels of UF-positive patients were lower than those of healthy control subjects in unmatched samples (12.1 ng/mL vs. 16.8 ng/mL) and in matched samples (11.4 vs. 17.5 ng/mL). Younger patients (≤40 years) had a lower vitamin D level than older subjects in healthy control group (15.1 ng/mL vs. 19.0 ng/mL). We did not observe any age-vitamin D interactive effect in unmatched samples. Multivariate logistic regression revealed that asymptomatic patients presented a lower level of vitamin D than did normal groups in both unmatched and matched sample. In addition, the optimal threshold vitamin D level for having asymptomatic UFs was 14.34 ng/mL., Conclusion(s): Vitamin D deficiency may be associated with increased risk of asymptomatic UFs in premenopausal Han Chinese women., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Uterine myomas or fibroids are the most common benign female tumors of the reproductive organs, associated with significant morbidity and quality of life impairment. Several epidemiological risk factors for their occurrence have been identified so far, including nutrition and dietary habits. In this investigation, authors reviewed, as a narrative review, the data about diet and uterine myoma development in order to homogenize the current data. A PubMed search was conducted for the years 1990-2020, using a combination of keywords of interest for the selected topic. The authors searched the databases, selecting the randomized clinical studies, the observational studies, and the basic (experimental), clinical, and epidemiological researches. Once they collected the articles, they analyzed them according to the number of citations of each article, starting from the most cited to the least cited articles. Subsequently, authors collected the data of each article and inserted them in the various research paragraphs, summarizing the data collected. In this way, they crossed the available data regarding the association between nutrition habits and dietary components and myoma onset and growth. Many nutrients and dietary habits are associated with myoma development risk. These factors include low intakes of fruit, vegetables, and vitamin D, as well as pollutants in food. Despite the available data on the influence of some foods on the development of fibroids, further research is mandatory to understand all the nutrition risk factors which contribute to myoma growth and how exactly these risk factors influence myoma pathogenesis.

Uterine leiomyomata (UL) are associated with severe reproductive morbidity and are the primary indication for hysterectomy in the United States. A recent prospective cohort study of Black women reported positive associations between intakes of marine-sourced ω-3 fatty acids and UL risk. We examined whether intakes of dietary fat were associated with UL incidence in a 5-year prospective study of premenopausal Black women living in Detroit who underwent serial ultrasound. At baseline (2010-2012) and 20, 40, and 60 months of follow-up, participants underwent transvaginal ultrasound. Among 1,171 UL-free women at baseline, incident UL were detected in 277 women. Cox regression was used to estimate hazard ratios and 95% confidence intervals for the association of dietary fat and UL incidence. Intakes of total fat and saturated, monounsaturated, polyunsaturated, and trans-fat were not appreciably associated with UL incidence. Intake of the marine ω-3 polyunsaturated fatty acid, docosahexaenoic acid, was associated with 49% higher UL incidence (quartile 4 vs. 1: hazard ratio = 1.49, 95% confidence interval: 1.04, 2.14; P for trend = 0.01). Intakes of total marine ω-3 polyunsaturated fatty acids were similarly associated with elevated UL incidence (hazard ratio = 1.35, 95% confidence interval: 0.94, 1.93; P for trend = 0.03). It remains unclear whether the fatty acids or persistent environmental pollutants drive the association., (© Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Although uterine leiomyomas are the most common benign uterine tumors in women, there is no effective therapy that can also preserve the uterus and maintain fertility. The work aimed to work was to discover a potential natural agent that has pharmacological activities on uterine leiomyomas with fewer adverse effects. We chose Rhus verniciflua Stokes (RVS) as a candidate after primary cytotoxicity testing, and analyzed the RVS components that showed pharmacological activity. Leiomyoma cells and myometrium cells were cultured from uterine tissues obtained from patients, and were treated with RVS at varying concentrations. RVS was cytotoxic in both leiomyoma and myometrium cells; however, the effects were more prominent in the leiomyoma cells. Among the bioactive components of RVS, fisetin showed significant pharmacological effects on leiomyoma cells. Fisetin showed excellent leiomyoma cell cytotoxicity and induced apoptotic cell death with cell cycle arrest. The apoptotic cell death appeared to involve not one specific pathway but multichannel pathways (intrinsic, extrinsic, MARK, and p53-mediated pathways), and autophagy. The multichannel apoptosis pathways were activated with a low concentration of fisetin (20 ) and were more vigorously activated at high concentrations (>IC 50 ). This is the first demonstration to show the pharmacological activities of fisetin on leiomyoma cells. These findings suggest that fisetin may be used for the prevention and treatment of uterine leiomyomas. Since fisetin can be obtained from plants, it may be a safe and effective alternative treatment for uterine leiomyomas.

Uterine fibroids (UFs) are the most common benign tumors of the female genital tract. Their prevalence usually is estimated at 30-40%, but may reach up to 70-80% in predisposed groups of women. UFs may cause various clinical issues which might constitute the major reason of the overall deterioration of the quality of life. The mechanisms leading to UFs formation and growth still remain poorly understood. The transformation of smooth muscle cells of the uterus into abnormal, immortal cells, capable of clonal division, is thought to be a starting point of all pathways leading to UF formation. Micro-ribonucleic acids (miRNAs) are non-coding single-stranded RNAs about 22 nucleotides in length, that regulate gene expression. One of recent advances in this field is the comprehension of the role of miRNAs in tumorigenesis. Alterations in the levels of miRNAs are related to the formation and growth of several tumors which show a distinct miRNA signature. The aim of this review is to summarize the current data about the role of miRNAs in the pathophysiology of UFs. We also discuss future directions in the miRNA research area with an emphasis on novel diagnostic opportunities or patient-tailored therapies. In our opinion data concerning the regulation of miRNA and its gene targets in the UFs are still insufficient in comparison with gynecological malignancies. The potential translational use of miRNA and derived technologies in the clinical care is at the early phase and needs far more evidence. However, it is one of the main areas of interest for the future as the use of miRNAs in the diagnostics and treatment of UFs is a new and exciting opportunity.

Background: Uterine fibroids (UFs) are the most common benign tumors of the uterus with an unknown etiology, affecting many women of reproductive age. We aimed to evaluate the association between UFs and anthropometric features, subcutaneous and preperitoneal fat thickness and lipid profile., Methods: This is a case-control study conducted on 212 women who were available in the Al-Zahra specialized referral hospital from March 2018 to March 2019. Study variables including weight, height, waist and hip circumference were measured for all individuals. For patients with UFs, the size, number and location of fibroids were recorded. Also, subcutaneous and preperitoneal fat thicknesses were measured. Finally, the data were analyzed using the SPSS software ver.16.0., Results: The most common complaint was abnormal uterine bleeding (AUB) in both groups. Most of the patients had a body mass index (BMI) of 25-30. There were significant differences between the two groups in terms of age (P = 0.0001) and waist circumference (P = 0.011). Cholesterol levels were much higher in the case group. Only age and low-density lipoprotein-cholesterol (LDL-C) levels in the case group were positively related to developing UFs, such that with advancing aging and increasing levels of LDL-C, the likelihood of experiencing UFs rose by 10% and 1.1%, respectively. Also, there were no significant differences between the two groups regarding in either preperitoneal fat thickness (PFT) or subcutaneous fat thickness (SFT)., Conclusion: Our findings suggest that with aging and higher levels of LDL-C, the likelihood of developing UFs rises., (© 2019 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Objective: Uterine leiomyoma (UL) can be considered as the most common benign gynecological tumors of the smooth muscle cells in the myometrium. They are likely to be associated with infertility and recurrent abortion as well as obstructed labor and post-partum hemorrhage. Moreover, altered vascular-related genes can be linked to developing leiomyoma. Polymorphisms of the angiotensin-converting enzyme (ACE) gene are associated with some vascular diseases. The present study was carried out to investigate the association of ACE I/D and AGTR1 A1166C gene polymorphisms and the risk of uterine leiomyoma in a sample of Iranian population. Methods: The study was carried out on a total of 413 women divided into 202 patients with diagnosed uterine leiomyomas and a control group of 211. Genotyping was performed using the PCR or PCR-RFLP methods. Results: The ID and DD genotypes of ACE I/D polymorphism were associated with 2 and 2.9 fold higher risk of UL compared to II genotype (OR, 2 [95% CI, 1.3 to 3.2]; P = 0.004 and OR, 2.9 [95% CI, 1.6 to 5]; P = 0.0002). The frequencies of ACE D alleles were 53.7% in women with UL and 40.3% in controls, which were observed to be statistically different (P < 0.0001). The alleles and genotypes of AGTR1 A1166C polymorphism were not different between UL and control women (P=0.9). Conclusion: The ACE ID and DD genotypes were associated with a higher risk of UL. No relationship was found between AGTR1 A1166C polymorphism and UL.

Despite the major negative impact uterine fibroids (UFs) have on female reproductive health, little is known about early events that initiate development of these tumors. Somatic fibroid-causing mutations in mediator complex subunit 12 (MED12), the most frequent genetic alterations in UFs (up to 85% of tumors), are implicated in transforming normal myometrial stem cells (MSCs) into tumor-forming cells, though the underlying mechanism(s) leading to these mutations remains unknown. It is well accepted that defective DNA repair increases the risk of acquiring tumor-driving mutations, though defects in DNA repair have not been explored in UF tumorigenesis. In the Eker rat UF model, a germline mutation in the Tsc2 tumor suppressor gene predisposes to UFs, which arise due to "second hits" in the normal allele of this gene. Risk for developing these tumors is significantly increased by early-life exposure to endocrine-disrupting chemicals (EDCs), suggesting increased UF penetrance is modulated by early drivers for these tumors. We analyzed DNA repair capacity using analyses of related gene and protein expression and DNA repair function in MSCs from adult rats exposed during uterine development to the model EDC diethylstilbestrol. Adult MSCs isolated from developmentally exposed rats demonstrated decreased DNA end-joining ability, higher levels of DNA damage, and impaired ability to repair DNA double-strand breaks relative to MSCs from age-matched, vehicle-exposed rats. These data suggest that early-life developmental EDC exposure alters these MSCs' ability to repair and reverse DNA damage, providing a driver for acquisition of mutations that may promote the development of these tumors in adult life.

This study aims to retrospectively analyze the potential risk factors for uterine leiomyoma and prospectively examine whether these risk factors can increase the incidence of uterine leiomyoma.Women who attended our outpatient department from January 1, 2010 to December 31, 2010 were enrolled. General demographical characteristics, personal information, and living habits were collected. Univariate and multivariate logistic regression analyses were used to identify the potential risk factors. Follow-up was regularly conducted to complete the prospective analysis.A total of 1273 women were enrolled including 213 uterine leiomyomas (case group) and 1060 nonuterine leiomyoma women (control group). No statistical differences were found on the age, marital status, number and complication of pregnancy, frequent physical exercise, frequent alcohol consumption, and family history of uterine diseases between two groups (all P > .05). Mean body mass index (P = .043), high school education (P = .041), frequent smoking (P = .030), frequent caffeine consumption (P = .019), frequent milk or soybean consumption (P = .025), and frequent oral contraceptive use (P = .034) were statistically correlated with the onset of uterine leiomyoma. Multivariate analysis verified that frequent milk or soybean consumption (7.349 [5.081-9.454]; P = .039] and frequent oral contraceptive use (8.103 [4.486-12.583]; P = .018] were the independent risk factors for uterine leiomyoma.Frequent milk or soybean consumption and frequent oral contraceptive use are associated with a high risk of uterine leiomyoma, and proper education on the prevention of uterine leiomyoma is highly recommended in clinical practice.

Uterine fibroids remain a burning issue for modern gynecology and cause suffering to women, significantly worsening their quality of life. This article includes the latest information about etiology, risk factors, pathobiochemical, genetic and immunological features of pathogenesis, clinical findings, early detection of fibroids and sarcoma differential diagnostic criteria by ultrasonography and MRI. Foreign publications form the basis of the given article, as well as domestic ones.

Uterine fibroids, or leiomyoma, are the most common benign tumors in women of reproductive age. In this work, the effect of silencing the mediator complex subunit 12 (Med12) gene in human uterine fibroid cells was evaluated. The role of Med12 in the modulation of Wnt/β-catenin and cell proliferation-associated signaling was evaluated in human uterine fibroid cells. Med12 was silenced in the immortalized human uterine fibroid cell line (HuLM) using a lentivirus-based Med12 gene-specific RNA interference strategy. HuLM cells were infected with lentiviruses carrying Med12-specific short hairpin RNA (shRNA) sequences or a nonfunctional shRNA scrambled control with green fluorescence protein. Stable cells that expressed low levels of Med12 protein were characterized. Wnt/β-catenin signaling, sex steroid receptor signaling, cell cycle-associated, and fibrosis-associated proteins were measured. Med12 knockdown cells showed significantly (P < 0.05) reduced levels of Wnt4 and β-catenin proteins as well as cell proliferation, as compared with scrambled control cells. Med12 knockdown cells also showed reduced levels of cell cycle-associated cyclin D1, Cdk1, and Cdk2 proteins as well as reduced activation of p-extracellular signal-regulated kinase, p-protein kinase B, and transforming growth factor (TGF)-β signaling pathways as compared with scrambled control cells. Moreover, TGF-β-regulated fibrosis-related proteins such as fibronectin, collagen type 1, and plasminogen activator inhibitor-1 were significantly (P < 0.05) reduced in Med12 knockdown cells as compared with scrambled control cells. Together, these results suggest that Med12 plays a key role in the regulation of HuLM cell proliferation through the modulation of Wnt/β-catenin, cell cycle-associated, and fibrosis-associated protein expression., (Copyright © 2017 by the Endocrine Society.)

Objective: To evaluate the influence of 25-hydroxyvitamin D and transforming growth factor β3 (TGF-β3) serum concentrations, weight, and family history on the risk of developing uterine fibroids., Design: Retrospective cohort study., Setting: University hospital., Patient(s): A total of 188 women, including patients admitted for uterine fibroid surgery (n = 105) as the study group and healthy women of similar age (n = 83) as controls., Intervention(s): Medical history and completion of specially designed questionnaire, transvaginal or transabdominal genital ultrasound scan, blood sampling, and measurement of vitamin D and TGF-β3 serum concentrations., Main Outcome Measure(s): Evaluation of the impact of family history, vitamin D, and TGF-β3 serum concentrations on the risk of developing uterine fibroids., Result(s): Mean 25-hydroxyvitamin D serum concentrations were 21.9 ± 8.9 ng/mL and 26.7 ± 11.9 ng/mL in patients with uterine fibroids and controls, respectively. The difference was statistically significant. The TGF-β3 serum concentrations in the fibroid-positive group ranged from 1.20 to 436.15 pg/mL (half the patients had concentrations >16.25 pg/mL). Concentrations in the control group ranged from 0.96 to 49.08 pg/mL (half the women had concentrations of >11.80 pg/mL). The differences were statistically significant. Higher body mass index (BMI) and positive family history were also found to be among the risk factors for uterine fibroids., Conclusion(s): Our study confirmed higher BMI, positive family history, and lower vitamin D and higher TGF-β3 serum concentrations as risk factors for uterine fibroids., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate the effect of vitamin D supplementation in women with hypovitaminosis D and "small burden" uterine fibroids.This study focused on 208 women diagnosed with uterine fibroids and concomitant hypovitaminosis D, from January to December 2014. One hundred eight women of the initial study population were diagnosed with "small burden" uterine fibroids. Among them, those who underwent a proper vitamin D supplementation constituted the "study group" (n = 53), while women who spontaneously refused the therapy or did not perform it properly, constituted the "control group" (n = 55). The characteristics of uterine fibroids, the fibroid-related symptoms, and the vitamin D serum levels were evaluated 12 months after the initial diagnosis.In women with uterine fibroids, a negative correlation emerged between the baseline 25-hydroxy-cholecalciferol (25-OH-D3) concentration and both the volume of the largest fibroid (r = -0.18, P = 0.01) and the total volume of fibroids (r = -0.19, P = 0.01). No correlation was found between the baseline 25-OH-D3 levels and the number of fibroids per patient (r = -0.10, P = 0.16). In women of the "study group," a significant increase in the 25-OH-D3 serum level was observed after 12 months of supplementation, and a lower rate of surgical or medical treatment due to the "progression to extensive disease" was reported (13.2% vs 30.9%, P = 0.05).Supplementation therapy with 25-OH-D3 restores normal vitamin D serum levels in women with "small burden" fibroids. In these women, vitamin D supplementation seems to reduce the progression to an extensive disease, and thus the need of conventional surgical or medical therapy., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Background: Iatrogenic parasitic myomas (PMs), caused by intra-corporeal power morcellation during laparoscopy is gradually increasing. However, the pathogenesis and medical treatment of PMs remain largely unelucidated., Methods: Laparoscopically-induced PM xenografted mouse model was conducted by xenografting human uterine myoma fragments into the abdominal cavity of SCID mice and hormonal manipulation was performed using this mouse model to demonstrate the role of oestrogen in the development of implanted PMs. Immunohistochemistry of oestrogen receptor α (ERα), progesterone receptor (PR), vimentin, vascular endothelial growth factor (VEGF), microvessel density (MVD) and Ki-67 index was performed and compared., Results: In the patient with PMs, ERα, PR, angiogenesis and proliferative property expression were upregulated in PM lesions compared to uterine myomas. In the laparoscopically-induced PM mouse model, implanted myomas had more steroid receptor expressions, angiogenesis and proliferative property compared with pre-xenografted or non-implanted myoma. Depletion of oestrogen in the ovariectomized (OVX) mice decreased laparoscopically-induced PM implantations. In comparison, the implantations of PMs were increased with additional E2 supplement. Hormonal manipulation in the PM mouse model, including AI, GnRHa and SERM groups, were compared and AI significantly decreased the implantations, steroid receptor, angiogenesis, cell density, and proliferative index of PMs compared with control group. Furthermore, GnRHa significantly decreased VEGF and MVD expressions compared with control group., Conclusions: These data highlight the crucial role of oestrogen in the development of laparoscopically-induced PMs and suggest that hormone manipulation may be a potential therapeutic agent., Trial Registration: This protocol was approved by the Human and Animal Institutional Review Board of Taipei Veterans General Hospital ( VGHIRB No 2014-10-002C on Nov. 17 th , 2014; IACUC 2014-119 on Aug. 22 nd , 2014).

Angiogenesis is a process of development of new vessels from the preexisting vascular network of a host. This is process which is seen in many physiological situations but it accompanies also a development of different lesions, i.e. neoplasms. Uterine fibroids are one of the most frequent lesions which affect human internal female genital tracts. Authors briefly review most important pro-angiogenic factors, based on their own observation as well as reviewing current literature. They pay much attention to vascular density which is significantly changed in the uterine tumors.

Uterine fibroids or uterine leiomyomas are the most common benign tumors of the uterus among women of fertile age, while the etiology is still incompletely elucidated. The occurrence and development of the fibromatosis may be related to certain risk factors and genic mechanisms, although the exact causes are not yet fully known. The development of uterine fibroids is correlated not only with the metabolism and with the level of female sexual hormones, estrogen, and progesterone, but also with the number of these hormone receptors expressed on the surface of the myometrium. Proliferative effects of estrogen and progesterone may be exercised through proinflammatory factors (TNF alpha), growth factors (IGF1, IGF2, TGFbeta3 and betaFGF) or inhibitors of apoptosis (p53 suppression). A number of predisposing factors such as ethnicity - black skin, early menarche, nulliparity, caffeine and alcohol, chronic inflammation, obesity, were also identified. Approximately 40% of the uterine fibroids are caused by the same cytogenetic alterations found in the other tumor types such as kidney, lung, or leiomyosarcoma. As part of a system dysfunction, uterine fibromatosis was connected to other disorders such as AHT (arterial hypertension), endometrium adenocarcinoma, adenomyosis, endometriosis, diabetes mellitus, breast tumors, seemingly with a common causality. The action and effect of some hormonal imbalances over the various organs depend on the histological and local expression particularities of the various receptors, being the cause for many disorders, among which the uterine fibromatosis, coexisting or accompanying the later. This article examines and summarizes the latest data refreshed literature etiopathogenesis offering indicators of uterine fibroids.

Background: Reproductive disorders and infertility are associated with the risk of obstetric complications and have a negative impact on pregnancy outcome. Affected patients often require assisted reproductive technologies (ART) to conceive, and advanced maternal age is a further confounding factor. The challenge is to dissect causation, correlation and confounders in determining how infertility and reproductive disorders individually or together predispose women to poor pregnancy outcomes., Methods: The published literature, to June 2015, was searched using PubMed, summarizing all evidences concerning the perinatal outcome of women with infertility and reproductive disorders and the potential mechanisms that may influence poor pregnancy outcome., Results: Reproductive disorders (endometriosis, adenomyosis, polycystic ovary syndrome and uterine fibroids) and unexplained infertility share inflammatory pathways, hormonal aberrations, decidual senescence and vascular abnormalities that may impair pregnancy success through common mechanisms. Either in combination or alone, these disorders results in an increased risk of preterm birth, fetal growth restriction, placental pathologies and hypertensive disorders. Systemic hormonal aberrations, and inflammatory and metabolic factors acting on endometrium, myometrium, cervix and placenta are all associated with an aberrant milieu during implantation and pregnancy, thus contributing to the genesis of obstetric complications. Some of these features have been also described in placentas from ART., Conclusions: Reproductive disorders are common in women of childbearing age and rarely occur in isolation. Inflammatory, endocrine and metabolic mechanisms associated with these disorders are responsible for an increased incidence of obstetric complications. These patients should be recognized as 'high risk' for poor pregnancy outcomes and monitored with specialized follow-up. There is a real need for development of evidence-based recommendations about clinical management and specific obstetric care pathways for the introduction of prompt preventative care measures., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics.

The cellular, genetic, and hormonal understanding of uterine fibroids is rapidly growing, but the therapeutic options remain similar. Are we really advancing the field?, (Copyright © 2014. Published by Elsevier Inc.)

We have previously reported that leiomyoma expressed lower levels of miR-200c and elevated IL8 as compared to paired myometrium. Here we addressed the regulatory functions of miR-200c on the expression of inflammatory mediators and cellular viability using leiomyomas and paired myometrium and their isolated primary smooth muscle cells. Our results indicated that gain-of function or knockdown of miR-200c in leiomyoma smooth muscle cells (LSMC) regulated IL8 mRNA and protein expression through direct targeting of IKBKB and alteration of NF-kB activity. Additionally, leiomyoma expressed higher levels of phosphorylated IKBKB with no significant difference in the level of IKBKB mRNA and protein as compared to matched myometrium. Gain-of function of miR-200c in LSMC resulted in decreased IkBα phosphorylation and p65 nuclear translocation, which led to decreased p65 transcriptional activity of IL8 promoter, and increased caspase 3/7 activity which was not reversible following IL8 restoration. Collectively, our results suggest that NF-κB signaling pathway is a target of miR-200c regulatory function, and low level of miR-200c expression in leiomyoma by transcriptional regulation of inflammatory mediators such as IL8, in part account for development of leiomyomas.

Background: It is well established that tumors are dependent on angiogenesis for their growth and survival. Although uterine fibroids are known to be benign tumors with reduced vascularization, recent work demonstrates that the vasculature of fibroids is grossly and microscopically abnormal. Accumulating evidence suggests that angiogenic growth factor dysregulation may be implicated in these vascular and other features of fibroid pathophysiology., Methods: Literature searches were performed in PubMed and Google Scholar for articles with content related to angiogenic growth factors and myometrium/leiomyoma. The findings are hereby reviewed and discussed., Results: Multiple growth factors involved in angiogenesis are differentially expressed in leiomyoma compared with myometrium. These include epidermal growth factor (EGF), heparin-binding-EGF, vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor-β and adrenomedullin. An important paradox is that although leiomyoma tissues are hypoxic, leiomyoma feature down-regulation of key molecular regulators of the hypoxia response. Furthermore, the hypoxic milieu of leiomyoma may contribute to fibroid development and growth. Notably, common treatments for fibroids such as GnRH agonists and uterine artery embolization (UAE) are shown to work at least partly via anti-angiogenic mechanisms., Conclusions: Angiogenic growth factors play an important role in mechanisms of fibroid pathophysiology, including abnormal vasculature and fibroid growth and survival. Moreover, the fibroid's abnormal vasculature together with its aberrant hypoxic and angiogenic response may make it especially vulnerable to disruption of its vascular supply, a feature which could be exploited for treatment. Further experimental studies are required in order to gain a better understanding of the growth factors that are involved in normal and pathological myometrial angiogenesis, and to assess the potential of anti-angiogenic treatment strategies for uterine fibroids.

The aim of the study was to present clinical issues concerning uterine artery embolization (UAE) in women with uterine fibromas. In order to ensure high clinical efficiency of UAE and prevent subsequent complications, it is necessary to carefully select patients eligible for the procedure. Patients with intramural fibromas, who do not plan to conceive, are the best candidates for the procedure. Fibroma necrosis, with following infection, and premature ovarian failure remain to be the most common complications after UAE. UAE may cause amenorrhea and increase FSH levels, what is typical for menopause. Thus, it may be responsible for problems with conception as well as optimal development of a pregnancy. It may also cause premature, iatrogenic menopause. This complication significantly more frequently occurs in women over the age of 45 as compared to younger patients. UAE is considered as an alternative therapeutic procedure, available to women who do not desire the surgery or wish to preserve the uterus. Patients subject to this procedure should be informed about the possible side effects.

Uterine fibroid (UFs) affect 77 % of women by menopause and account for $9.4 billion in healthcare costs each year. Although UFs are heritable, genetic risk is poorly understood. The first genome-wide association study (GWAS) of UFs was recently performed in a Japanese population, with reported genome-wide significance for single nucleotide polymorphisms (SNPs) across three chromosomal regions. We tested these SNPs for association with UFs in US cohorts. Women were enrolled in the Right from the Start (RFTS) cohort and the BioVU DNA repository. UF status in both cohorts was determined by pelvic imaging. We tested 65 candidate and haplotype-tagging SNPs for association with UFs presence using logistic regression in RFTS and the top three GWAS-associated SNPs in BioVU. We also combined association results from both cohorts using meta-analysis. 1,086 European American (EA) cases and 1,549 controls were examined. Two SNP associations replicated [blocked early in transport 1 homolog (BET1L) rs2280543, RFTS-BioVU meta-odds ratio (OR) = 0.67 95 % confidence interval (CI) 0.38-0.96, Q = 0.70, I = 0, p = 6.9 × 10⁻³; trinucleotide repeat containing 6B (TNRC6B) rs12484776, RFTS-BioVU meta-OR = 1.21, 95 % CI 1.07-1.35, Q = 0.24, I = 28.37, p = 8.7 × 10⁻³). Meta-analyses combining evidence from RFTS, BioVU, and prior GWAS showed little heterogeneity in effect sizes across studies, with meta-p values between 7.45 × 10⁻⁸ and 3.89 × 10⁻⁹, which were stronger than prior GWAS and supported associations observed for all previously identified loci. These data suggest common variants increase risk for UF in both EA and Japanese populations. However, further research is needed to assess the role of these genes across other racial groups.

Context: Recent in vitro and in vivo experimental evidence supports a role of vitamin D insufficiency as an important factor in the development of uterine leiomyomas. However, epidemiological data supporting this possibility are scanty., Objective: Our objective was to investigate vitamin D status in women with and without uterine leiomyomas., Design: This was a case-control study of women referring to 2 infertility units in Italy. Women were eligible as cases if they were diagnosed with at least 1 uterine leiomyoma with a mean diameter ≥10 mm at transvaginal ultrasound. Each of them was matched to the 2 subsequent women of the same age (±1 year) whose uterus resulted unremarkable at ultrasound. Selected women provided a blood sample for the quantitative detection of 25-hydroxyvitamin D₃ levels., Main Outcome Measure: We measured serum concentration of 25-hydroxyvitamin D₃., Results: A total of 128 women with leiomyomas and 256 controls were selected. The mean ± SD serum concentration of 25-hydroxyvitamin D3 was significantly lower in affected women compared with controls (18.0 ± 7.7 vs 20.8 ± 11.1 ng/mL respectively, P = .010). The number (proportion) of women with 25-hydroxyvitamin D3 deficiency (ie, <10 ng/mL) in cases and controls was 19 (15%) and 19 (7%), respectively (P = .022). The adjusted odds ratio for the presence of leiomyomas in women with serum levels of 25-hydroxyvitamin D₃ deficiency was 2.4 (95% confidence interval = 1.2-4.9) (P = .016)., Conclusions: Vitamin D is an emerging regulator of uterine leiomyoma development. Cohort and interventional studies are pressingly needed to confirm a causal relationship and to investigate the potential therapeutic benefits of vitamin D supplementation.

Objective: To summarize the information regarding pathogenetic factors of leiomyoma formation and growth, and to make a simple integrated pathogenetic view of this tumor for further thinking to establish new therapeutic options., Design: PubMed and Google Scholar searches were conducted to identify the relevant studies on pathogenesis of uterine leiomyoma, which are hereby reviewed and discussed., Setting: Academic medical center., Patient(s): Not applicable., Intervention(s): Not applicable., Main Outcome Measure(s): Not applicable., Result(s): To date, the pathogenesis of uterine leiomyomas is not well understood. However, genetic alterations (especially MED12 and HMGA2) and involvement of epigenetic mechanisms (DNA methylation, histone modifications, and microRNA) in leiomyoma provide the clue of initiator of this tumor. Estrogens and P are considered as promoters of leiomyoma growth, and growth factors, cytokines, and chemokines are thought to be as potential effectors of estrogens and P. Extracellular matrix components are a major structural part of leiomyoma tissue that are abnormally orientated and can modify mechanical stress on cells, which leads to activation of internal mechanical signaling and may contribute to leiomyoma growth., Conclusion(s): Besides many genetics and epigenetic factors, the important link among the sex steroids, growth factors, cytokines, chemokines, and extracellular matrix and their involvement in cell proliferation, fibrotic processes, apoptosis, and angiogenesis are implicating a complex network in leiomyoma formation and growth. Those findings could provide information to establish future therapeutic options for the management of this tumor., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Progesterone receptor (PR) mediates the actions of the ovarian steroid progesterone, which together with estradiol regulates gonadotropin secretion, prepares the endometrium for implantation, maintains pregnancy, and differentiates breast tissue. Separation of estrogen and progesterone actions in hormone-responsive tissues remains a challenge. Pathologies of the uterus and breast, including endometrial cancer, endometriosis, uterine fibroids, and breast cancer, are highly associated with estrogen, considered to be the mitogenic factor. Emerging evidence supports distinct roles of progesterone and its influence on the pathogenesis of these diseases. Progesterone antagonizes estrogen-driven growth in the endometrium, and insufficient progesterone action strikingly increases the risk of endometrial cancer. In endometriosis, eutopic and ectopic tissues do not respond sufficiently to progesterone and are considered to be progesterone-resistant, which contributes to proliferation and survival. In uterine fibroids, progesterone promotes growth by increasing proliferation, cellular hypertrophy, and deposition of extracellular matrix. In normal mammary tissue and breast cancer, progesterone is pro-proliferative and carcinogenic. A key difference between these tissues that could explain the diverse effects of progesterone is the paracrine interactions of PR-expressing stroma and epithelium. Normal endometrium is a mucosa containing large quantities of distinct stromal cells with abundant PR, which influences epithelial cell proliferation and differentiation and protects against carcinogenic transformation. In contrast, the primary target cells of progesterone in the breast and fibroids are the mammary epithelial cells and the leiomyoma cells, which lack specifically organized stromal components with significant PR expression. This review provides a unifying perspective for the diverse effects of progesterone across human tissues and diseases.

Objective: To determine whether programmed cell death 4 (PDCD-4) is altered in autologous leiomyoma and myometrial tissues and what microRNA-21's (miR-21) role is in PDCD-4 expression, apoptosis, and translation., Design: Laboratory research., Setting: Academic medical center., Patient(s): Myometrial and leiomyoma tissues from patients with symptomatic leiomyomata., Intervention(s): Tissue analysis and miR-21 knockdown in cultured immortalized myometrial (UtM) and leiomyoma (UtLM) cells., Main Outcome Measure(s): MiR-21 and PDCD-4 mRNA and protein expression., Result(s): Leiomyoma tissues robustly expressed the full-length 51 kd isoform of PDCD-4, but normal myometrial tissue had negligible expression. Consistent with autologous tissues, UtLM cells expressed elevated miR-21 and a similar pattern of PDCD-4 compared with UtM cells. Knockdown of miR-21 increased PDCD-4 levels in UtM cells and UtLM cells, indicating that it can regulate PDCD-4 expression. Loss of miR-21 also increased cleavage of caspase-3 (apoptosis marker) and increased phosphorylation of elongation factor-2 (marker of reduced translation) in both cell lines., Conclusion(s): Elevated leiomyoma miR-21 levels are predicted to decrease PDCD-4 levels, thus leiomyomas differ from other tumors where loss of PDCD-4 is associated with tumor progression. Our studies indicate regulation of PDCD-4 expression is not a primary miR-21 function in leiomyomas, but instead miR-21 is able to impact cellular apoptosis and translation, through unknown targets, in a manner consistent with its involvement in the pathophysiology of uterine fibroids., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Uterine leiomyomas are common, benign, reproductive tract tumors affecting a majority of reproductive aged women. They are associated with gynecologic morbidity and detrimentally affect reproductive potential. The etiology of leiomyomas is poorly understood and their diagnosis prior to treatment with Assisted Reproductive Technologies (ART) represents a management dilemma. The purpose of this paper is to review known genetic and molecular contributions to the etiologies of leiomyomas, describe their impact on ART outcomes and reproductive potential, and review alternative therapies and future directions in management., Methods: A critical review of the literature pertaining to genetic component of uterine leiomyomas, their impact on ART and pregnancy and leiomyoma therapeutics was performed., Results: Uterine leiomyomas are characterized by complex molecular mechanisms. Their location and size determines their potential detriment to ART and reproductive function and novel therapeutic modalities are being developed., Conclusion: The high prevalence of uterine leiomyomas and their potential detrimental influence on ART and reproductive function warrants continued well-designed studies to ascertain their etiology, optimal treatment and novel less morbid therapies.

Recent gynaecological studies show that childbirth, constipation, trauma and surgery cause injuries to autonomic nerves at different anatomical sites in the female pelvis resulting in endometriosis, adenomyosis and fibroids. Re-growth of abnormal nerves causes allodynic symptoms ('light touch causing pain or discomfort') some years later including vulvodynia, dyspareunia, dysmenorrhea, irritative bladder and bowel symptoms. Further consequences of autonomic denervation include tissue hypoplasia and hyperplasia, visceral dysfunction, susceptibility to infection, alcohol, tobacco and drugs, as well as pain with sensitization of the central nervous system. The 'autonomic denervation' view extrapolates these observations from the female pelvis to the varied anatomy of branches of the cardiac and coeliac plexi to provide primary mechanisms for many forms of Western disease. This account sets out the autonomic denervation view, identifies features of autonomic denervation in extrapelvic organs, and, contrasts it with prior accounts of chronic Western diseases including those of DP Burkitt, PRJ Burch and DP Barker.

Background: Growth factors are proteins secreted by a number of cell types that are capable of modulating cellular growth, proliferation and cellular differentiation. It is well accepted that uterine cellular events such as proliferation and differentiation are regulated by sex steroids and their actions in target tissues are mediated by local production of growth factors acting through paracrine and/or autocrine mechanisms. Myometrial mass is ultimately modified in pregnancy as well as in tumour conditions such as leiomyoma and leiomyosarcoma. Leiomyomas, also known as fibroids, are benign tumours of the uterus, considered to be one of the most frequent causes of infertility in reproductive years in women., Methods: For this review, we searched the database MEDLINE and Google Scholar for articles with content related to growth factors acting on myometrium; the findings are hereby reviewed and discussed., Results: Different growth factors such as epidermal growth factor (EGF), transforming growth factor-α (TGF-α), heparin-binding EGF (HB-EGF), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF) and TGF-β perform actions in myometrium and in leiomyomas. In addition to these growth factors, activin and myostatin have been recently identified in myometrium and leiomyoma., Conclusions: Growth factors play an important role in the mechanisms involved in myometrial patho-physiology.

Objective: To evaluate whether menstrual and reproductive characteristics may influence development of uterine leiomyomata since sex steroid hormones have been hypothesized to play a role in their development., Design: A prospective cohort study (Nurses' Health Study II)., Setting: Participants were identified from 14 states and followed for 14 years., Patient(s): A cohort of 116,609 female registered nurses ages 25-42 at baseline., Intervention(s): We obtained data on uterine leiomyomata incidence and exposures through biennial questionnaires. We calculated hazard ratios and 95% confidence intervals adjusted for known and suspected risk factors., Main Outcome Measure(s): Uterine leiomyomata confirmed by ultrasound or hysterectomy., Result(s): During 1,163,439 person-years of follow-up, 9,847 self-reported cases of hysterectomy- or ultrasound-confirmed uterine leiomyomata were reported. We observed a lower incidence of uterine leiomyomata with later age at menarche, longer menstrual cycles, parity, later age at first and last birth, shorter time since last birth, and breastfeeding., Conclusion(s): Hormonal and anatomical changes associated with menstruation and pregnancy may influence uterine leiomyomata incidence., (Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Total abdominal hysterectomy is a commonly performed gyneacological procedure. Although it is safe, it can still be associated with development of complication. The aim of this study was to determine morbidity associated with total abdominal hysterectomy in our environment., Method: All cases of total abdominal hysterectomy done over a five-year period (January 2003-December 2006) at the University of Maiduguri Teaching Hospital (UMTH) were reviewed. Information was obtained from the patients' case notes, gynaecology ward, and theatre records. The complications of the procedure were determined. Multiple logistic regression was used to find the factors that were independently associated with development of complications., Results: During the study there were 101 cases of total abdominal hysterectomy out of 729 gynaecological operations, a rate of 13.8%. In majority of the cases 56 (68.3%) the indication of the hysterectomy was uterine fibroid (symptomatic). Overall 37 (45.1%) experience some form of complication out of which 26 (70.3%) was febrile morbidity Finding enlarged uterus intraoperatively {OR (95% CI) = 14.5 (1.84-114.6), p = 0.011}, blood transfusion {OR (95% CI) = 31.1(1.35-718.8), p = 0.032}and postoperative PCV < 30% {OR (95%CI) = 9.63 (1.14-81.3) p = 0.037} were found to be significantly associated with development of complication. conclusions: Total abdominal hysterectomy was associated with development of complications and enlarged uterus, increasing parity independent risk factors for development of the complication.

Objective: To elucidate the clinical profile of adenomyosis by comparison with uterine leiomyomas., Design: Retrospective case-control study., Setting: Academic medical center., Patient(s): The study comprised 76 women undergoing hysterectomy with adenomyosis and 152 women with uterine leiomyomas but no adenomyosis., Intervention(s): Retrospective medical record review of hospital and ambulatory records., Main Outcome Measure(s): Comparison of women undergoing hysterectomy with a sole pathologic finding of adenomyosis and women with leiomyomas alone., Result(s): Adenomyosis was independently associated with younger age (41.1 years vs. 44.3 years), history of depression (57.1% vs. 24.7%), dysmenorrhea (65.7% vs. 42.3%), and pelvic pain (52.9% vs. 21.1%) in a multivariable unconditional logistic regression analysis compared with women with leiomyomas, where women from both groups had gynecologic symptoms. Furthermore, in a second multivariate model where all subjects had uteri weighing>150 g, women with adenomyosis were more likely to have a history of depression (52.6% vs. 22.2%) and endometriosis (26.3% vs. 2.8%) compared with women with leiomyomas., Conclusion(s): Women undergoing hysterectomy with a histologic diagnosis of adenomyosis have a distinct symptomatology and medical history compared with women with leiomyomas. Better understanding of this disease is required to improve diagnosis and management., (Copyright (c) 2010. Published by Elsevier Inc.)

Objectives: To investigate the roles of insulin-like growth factor II (IGF2), myeloperoxidase (MPO), E-cadherin (CDH1), urokinase and xeroderma pigmentosum group A and D (XPA, XPD) polymorphisms upon leiomyoma susceptibility., Study Design: Women were divided into: group 1, leiomyoma (n=158); group 2, non-leiomyoma (n=156). Polymorphisms (IGF2 exon 9*A/G, MPO-463*A/G, CDH1-Pml I, urokinase-ApaL, XPA*A-23G, XPD*Lys751Gln) were amplified by polymerase chain reaction and detected by electrophoresis after restriction enzyme digestion. Genotype and allelic frequencies were compared between both groups., Results: Associations between leiomyoma with IGF2 and CDH1 polymorphism exist. Proportions of IGF2 exon 9*AA/AG/GG in and CDH1* CC/CT/TT in the groups were: group 1, 38/39.2/22.8% and 27.8/66.5/5.7%; group 2, 22.4/53.9/23.7% and 21.2/64.1/14.7. MPO, urokinase, XPA and XPD in both groups were non-significantly different. Proportions of MPO*AA/AG/GG, urokinase*CC/CT/TT, XPA*AA/AG/GG and XPD*AA/AC/CC were: group 1: 1.9/23.4/74.7%, 0.6/7/92.4%, 20.9/55.1/24%, 85.4/14.6/0%; group 2: 3.8/24.4/71.8%, 1.3/4.5/94.2%, 22.4/53.9/23.7%, 84.6/15.4/0%., Conclusion: IGF2*A allele and CDH1*C allele were correlated with leiomyoma susceptibility, which may be associated with leiomyoma development. MPO, urokinase, XPA and XPD polymorphisms are not related to leiomyoma susceptibilities.

Background: Phthalates are known to have estrogenic effects in cell models and experimental animals. However, the evidence regarding the effects of phthalates on human reproduction is still limited. We conducted a case-control study to determine whether estrogen-dependent diseases are associated with phthalate exposure and how the glutathione S-transferase M1 (GSTM1; a major detoxification enzyme) genotype modulates the risk., Methods: We recruited subjects who underwent laparotomy and had pathologic confirmation of endometriosis (EN) (n = 28), adenomyosis (AD) (n = 16) and leiomyoma (LEI) (n = 36) from the Department of Obstetrics and Gynecology at a medical center in Taiwan between 2005 and 2007. Controls (n = 29) were patients without any of the three aforementioned gynecologic conditions. Urine samples were collected before surgery and analyzed for seven phthalate metabolites using liquid chromatography-tandem mass spectrometry. Peripheral lymphocytes were used for GSTM1 genotype determination., Results: Patients with LEIs had significantly higher levels of total urinary mono-ethylhexyl phthalate (SigmaMEHP; 52.1 versus 18.9 microg/g creatinine, P < 0.05) than the controls, whereas patients with EN had an increased level of urinary mono-n-butyl phthalate (94.1 versus 58.0 microg/g creatinine, P < 0.05). Subjects with GSTM1 null genotype had significantly increased odds for AD relative to those with GSTM1 wild genotype [odds ratio (OR) = 5.30; 95% CI, 1.22-23.1], even after adjustment for age and phthalate exposure. Subjects who carried the GSTM1 null genotype and had a high urinary level of SigmaMEHP showed a significantly increased risk for AD (OR = 10.4; 95% CI, 1.26-85.0) and LEIs (OR = 5.93; 95% CI, 1.10-31.9) after adjustment for age, compared with those with GSTM1 wild-type and low urinary level of SigmaMEHP., Conclusions: These results suggest that both GSTM1 null and phthalate exposure are associated with AD and LEI. Larger studies are warranted to investigate potential interaction between GSTM1 null and phthalate exposure in the etiology of estrogen-dependent gynecologic conditions.

Background: Early-life exposures to hormonally active compounds and other factors may affect later response to estrogen or progesterone and hence may influence development of uterine leiomyomata (fibroids)., Objectives: We evaluated associations of in utero and early-life exposures, including soy formula, with self-report of physician-diagnosed fibroids by 35 years of age., Methods: Our study included 19,972 non-Hispanic white women who were 35-59 years of age when they enrolled in the Sister Study in 20032007. We estimated risk ratios (RRs) and 95% confidence intervals (CIs) using log-binomial regression models for fibroid associations with adjustment for participant's age and education, maternal age at participant's birth, birth order, and childhood family income., Results: Greater risk of early fibroid diagnosis was associated with soy formula during infancy (RR = 1.25; 95% CI, 0.971.61), maternal prepregnancy diabetes (RR = 2.05; 95% CI, 1.163.63), low childhood socioeconomic status (RR = 1.28; 95% CI, 1.011.63), and gestational age at birth (RR = 1.64; 95% CI, 1.272.13, for being born at least 1 month early). In utero diethylstilbestrol (DES) exposure was also associated with early fibroid diagnosis (RR = 1.42; 95% CI, 1.131.80), but this association was driven by women reporting probable rather than definite exposure., Conclusions: There are plausible biological pathways by which these early-life factors could promote fibroid pathogenesis. This is the first epidemiologic study to evaluate such exposures, with the exception of in utero DES, in relation to fibroid risk, and replication of findings in other populations is needed.