Non-persistent endocrine disrupting chemical mixtures and uterine leiomyomata in the study of environment, lifestyle and fibroids (SELF).

BACKGROUND: Results of studies investigating associations between individual endocrine-disrupting chemicals (EDCs) and incidence of uterine leiomyomata (UL), a hormone-dependent gynecological condition, have been inconsistent. However, few studies have evaluated simultaneous exposure to a mixture of EDCs with UL incidence. METHODS: We conducted a case-cohort analysis (n = 708) of data from the Study of the Environment, Lifestyle and Fibroids (SELF), a prospective cohort study. Participants were aged 23-35 years at enrollment, had an intact uterus, and identified as Black or African American. We measured biomarker concentrations of 21 non-persistent EDCs, including phthalates, phenols, parabens, and triclocarban, in urine collected at baseline, 20-month, and 40-month clinic visits. We ascertained UL incidence and characteristics using ultrasounds at baseline and approximately every 20 months through 60 months. We used probit Bayesian Kernel Machine Regression (BKMR-P) to evaluate joint associations between EDC mixtures with cumulative UL incidence. We estimated the mean difference in the probit of UL incidence over the study period, adjusting for baseline age, education, years since last birth, parity, smoking status and body mass index. We converted probit estimates to odds ratios for ease of interpretation. RESULTS: We observed that urinary concentrations of the overall EDC mixture were inversely associated with UL incidence in the overall mixtures model, with the strongest inverse associations at the 70th percentile of all biomarkers compared with their 50th percentile (odds ratio = 0.59; 95% confidence interval: 0.36, 0.96). Strongest contributors to the joint association for the mixture were bisphenol S (BPS), ethyl paraben (EPB), bisphenol F (BPF) and mono (2-ethyl-5-carboxypentyl) phthalate (MECPP), which each demonstrated inverse associations except for MECPP. There was suggestive evidence of an interaction between MECPP and EPB. CONCLUSION: In this prospective ultrasound study, we observed evidence of an inverse association between the overall mixture of urinary biomarker concentrations of non-persistent EDCs with UL incidence.

Hair relaxer use and risk of uterine cancer in the Black Women's Health Study.

BACKGROUND: Chemical hair relaxers, use of which is highly prevalent among Black women in the US, have been inconsistently linked to risk of estrogen-dependent cancers, such as breast cancer, and other reproductive health conditions. Whether hair relaxer use increases risk of uterine cancer is unknown. METHODS: In the Black Women's Health Study, 44,798 women with an intact uterus who self-identified as Black were followed from 1997, when chemical hair relaxer use was queried, until 2019. Over follow-up, 347 incident uterine cancers were diagnosed. We used multivariable Cox proportional hazards regression models, adjusted for age and other potential confounders, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of hair relaxer use with risk of uterine cancer. RESULTS: Compared to women who never used hair relaxers or used them infrequently (<4 years and ≤1-2 times/year), the HR for uterine cancer associated with heavy use (≥15 years and at least 5 times/year) was 1.18 (95% CI: 0.81, 1.71). However, among postmenopausal women, compared to never/light use, the HR for moderate use was 1.60 (95% CI: 1.01, 2.53), the HR for heavy use was 1.64 (1.01, 2.64), and the HR for ≥20 years of use regardless of frequency was 1.71 (1.08, 2.72). Results among premenopausal women were null. CONCLUSIONS: In this large cohort of Black women, long-term use of chemical hair relaxers was associated with increased risk of uterine cancer among postmenopausal women, but not among premenopausal women. These findings suggest that hair relaxer use may be a potentially modifiable risk factor for uterine cancer.

A plain language summary of the safety of relugolix combination therapy and improvement in symptoms in women with uterine fibroids from the LIBERTY 1 and LIBERTY 2 studies.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of research studies (known as clinical trials) called LIBERTY 1 and LIBERTY 2. The LIBERTY 1 and LIBERTY 2 studies looked at how well a medication called relugolix combination therapy worked to reduce heavy bleeding at the time of menstruation compared with placebo. The studies also looked at what side effects were reported in women with uterine fibroids and heavy menstrual bleeding. WHAT WERE THE RESULTS?: Researchers looked at 388 adult women in the LIBERTY 1 study and 382 adult women in the LIBERTY 2 study. All women had heavy menstrual bleeding with uterine fibroids before the start of the LIBERTY 1 and LIBERTY 2 studies. The women were given one of three treatments during the studies: relugolix combination therapy or placebo for 24 weeks, or delayed relugolix combination therapy (relugolix alone for the first 12 weeks, then relugolix combination therapy for the last 12 weeks of the studies). More women taking relugolix combination therapy in the LIBERTY 1 study (73%) and LIBERTY 2 study (71%) had menstrual blood loss of less than one-third of a cup (80 mL) and had reduction of at least 50% less blood loss during their last menstrual period after 24 weeks of taking the medicine compared with placebo (LIBERTY 1: 19% and LIBERTY 2: 15%). The women taking relugolix combination therapy also had less pain than those taking placebo. Side effects were similar across treatment groups. Headaches and hot flushes were the most common side effects. WHAT DO THE RESULTS MEAN?: More women with uterine fibroids taking relugolix combination therapy for 24 weeks were likely to have fewer uterine fibroid symptoms than women receiving placebo. Clinical Trial Registration: NCT03049735 (LIBERTY 1); NCT03103087 (LIBERTY 2).

Hormone replacement therapy and cancer risks in perimenopausal women: A retrospective cohort study using a Japanese claims database.

AIM: Hormone replacement therapy (HRT) relieves menopausal syndromes but concerns regarding certain cancer risks remain. This study aimed to investigate cancer risks in perimenopausal women using HRT. METHODS: Using a health care database in Japan, we compared breast cancer and other cancer risks in perimenopausal women who started HRT between January 2011 and October 2021 at age 45-54 years with that of women who did not use HRT. Women in the control group were selected by 1:4 exact matching on birth year, and followed from the same index time as their counterparts. RESULTS: Data from 12 207 women in the exposure group and 48 828 age-matched women in the control group were analyzed. The median HRT duration was 16.1 (interquartile range, 9.9-28.0) months. Breast cancer risk was lower in the HRT group (adjusted hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.54-0.82). When stratified by age, breast cancer risk was lower in the HRT group who started HRT at age 45-49 years (adjusted HR, 0.54; 95% CI, 0.40-0.72). Estrogen-major HRT accounted for approximately one-third of HRT and uterine corpus cancer risk was increased in estrogen-major HRT (adjusted HR, 2.44; 95% CI, 1.56-3.81). CONCLUSIONS: Breast cancer risk in women starting HRT between 45 and 49 years is lower than that in the average population; this finding might be susceptible to unmeasured factors such as early menopause among HRT recipients. Unopposed estrogen therapy accounts for considerable proportion of HRT in Japan and it increases uterine corpus cancer.

Efficacy and safety of trabectedin for the treatment of advanced uterine or ovarian carcinosarcoma: Results of a phase II multicenter clinical trial (MITO-26).

OBJECTIVE: This open-label phase II clinical trial evaluated the antitumor activity and safety of trabectedin in patients with advanced ovarian (OC) or uterine carcinosarcomas (UC). METHODS: Eligible patients were adults (≥18 years) with histologically proven recurrent OC/UC not amenable to surgery or radiotherapy who received up to two prior chemotherapy lines. Trabectedin 1.3 mg/m2 was administered as a 3-h infusion every three weeks. The primary endpoint was objective response rate (ORR) as per RECIST v.1.1. If at least 8 of 43 patients (18.6%) achieve an objective response, trabectedin would be declared worthy for further investigations. RESULTS: Forty-five patients with either OC (n = 32) or UC (n = 13) from seven MITO centers across Italy were enrolled. The ORR was 11.9% (90% CI: 6-23) and included two patients with a complete response and three with a partial response. Eight patients (19.0%) had disease stabilization for a disease control rate of 31.0% (90% CI: 20-44). Median progression-free survival was 2.01 months (95% CI: 1.78-2.30) and median overall survival was 4.64 months (95% CI: 3.19-8.29). Neutrophil count decreases (n = 8, 18.2%) and transaminase increases (n = 6, 13.6%) were the most common grade 3-5 adverse events related with trabectedin. Two patients died due to trabectedin-related grade 5 hematological toxicity. CONCLUSION: Although trabectedin did not meet the prespecified activity criteria, it confers modest but clinically meaningful benefit to patients with advanced OC/UC as being as effective as any other available treatment for this indication. The toxicity profile appears in line with that previously reported for the drug.

Use of Straighteners and Other Hair Products and Incident Uterine Cancer.

BACKGROUND: Hair products may contain hazardous chemicals with endocrine-disrupting and carcinogenic properties. Previous studies have found hair product use to be associated with a higher risk of hormone-sensitive cancers including breast and ovarian cancer; however, to our knowledge, no previous study has investigated the relationship with uterine cancer. METHODS: We examined associations between hair product use and incident uterine cancer among 33 947 Sister Study participants aged 35-74 years who had a uterus at enrollment (2003-2009). In baseline questionnaires, participants in this large, racially and ethnically diverse prospective cohort self-reported their use of hair products in the prior 12 months, including hair dyes; straighteners, relaxers, or pressing products; and permanents or body waves. We estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) to quantify associations between hair product use and uterine cancer using Cox proportional hazard models. All statistical tests were 2-sided. RESULTS: Over an average of 10.9 years of follow-up, 378 uterine cancer cases were identified. Ever vs never use of straightening products in the previous 12 months was associated with higher incident uterine cancer rates (HR = 1.80, 95% CI = 1.12 to 2.88). The association was stronger when comparing frequent use (>4 times in the past 12 months) vs never use (HR = 2.55, 95% CI = 1.46 to 4.45; Ptrend = .002). Use of other hair products, including dyes and permanents or body waves, was not associated with incident uterine cancer. CONCLUSION: These findings are the first epidemiologic evidence of association between use of straightening products and uterine cancer. More research is warranted to replicate our findings in other settings and to identify specific chemicals driving this observed association.

Effects of bisphenol A on uterine leiomyoma: In vitro and in vivo evaluation with mechanistic insights related to XBP1.

The incidence rate of human uterine leiomyomas is over 70% in the women of childbearing age, which has caused serious health and financial burden. Our previous study confirmed that Bisphenol A (BPA)，representative environmental estrogen, promoted the proliferation of human uterine leiomyomas and up-regulated the expression of cell proliferation-related genes. In this study, by combining ChIP-seq and RNA-seq, it was shown that after BPA intervention, H3K27ac modification levels and gene expression levels were altered in uterine leiomyomas cells. Moreover experimental verification found that BPA can regulate ITGA2 through the transcription factor XBP1, activate the downstream PI3K/AKT signaling pathway, eventually promote the proliferation of uterine leiomyomas. The present study provides new insights into the pathogenesis associated with exposure to BPA and other endocrine disruptors with similar effects by defining XBP1 as an important regulator, and which may act as an intervention and treatment target for uterine leiomyomas.

Short-term tetrabromobisphenol A exposure promotes fibrosis of human uterine fibroid cells in a 3D culture system through TGF-beta signaling.

Tetrabromobisphenol A (TBBPA), a derivative of BPA, is a ubiquitous environmental contaminant with weak estrogenic properties. In women, uterine fibroids are highly prevalent estrogen-responsive tumors often with excessive accumulation of extracellular matrix (ECM) and may be the target of environmental estrogens. We have found that BPA has profibrotic effects in vitro, in addition to previous reports of the in vivo fibrotic effects of BPA in mouse uterus. However, the role of TBBPA in fibrosis is unclear. To investigate the effects of TBBPA on uterine fibrosis, we developed a 3D human uterine leiomyoma (ht-UtLM) spheroid culture model. Cell proliferation was evaluated in 3D ht-UtLM spheroids following TBBPA (10-6 -200 µM) administration at 48 h. Fibrosis was assessed using a Masson's Trichrome stain and light microscopy at 7 days of TBBPA (10-3  µM) treatment. Differential expression of ECM and fibrosis genes were determined using RT² Profiler™ PCR arrays. Network and pathway analyses were conducted using Ingenuity Pathway Analysis. The activation of pathway proteins was analyzed by a transforming growth factor-beta (TGFB) protein array. We found that TBBPA increased cell proliferation and promoted fibrosis in 3D ht-UtLM spheroids with increased deposition of collagens. TBBPA upregulated the expression of profibrotic genes and corresponding proteins associated with the TGFB pathway. TBBPA activated TGFB signaling through phosphorylation of TGFBR1 and downstream effectors-small mothers against decapentaplegic -2 and -3 proteins (SMAD2 and SMAD3). The 3D ht-UtLM spheroid model is an effective system for studying environmental agents on human uterine fibrosis. TBBPA can promote fibrosis in uterine fibroid through TGFB/SMAD signaling.

Combined Exposure to Multiple Endocrine Disruptors and Uterine Leiomyomata and Endometriosis in US Women.

Background: Uterine leiomyomata (UL) and endometriosis (EM) are common gynecological diseases damaging the reproductive health of fertile women. Among all the potential factors, environmental endocrine-disrupting chemicals are insufficiently addressed considering the multiple pollutants and mixture exposure. Methods: Women aged 20 to 54 years old in the National Health and Nutrition Examination Survey (NHANES) 2001-2006, having a complete measurement of ten commonly exposed endocrine-disrupting chemicals (including urinary phthalate metabolites, equol, and whole blood heavy metals) and answered questions about UL and EM were included (N=1204). Multivariable logistic regression model, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models were implemented to analyze the combined effect of chemicals on the overall association with UL and EM. Results: In single chemical analysis, equol (OR: 1.90, 95% CI: 1.11, 3.27) and mercury (Hg) (OR: 1.91, 95% CI: 1.14, 3.25) were found positively associated with UL in tertile 3 vs. tertile 1. In WQS regression and BKMR models, the significant positive association between WQS index and UL (OR: 2.54, 95% CI: 1.52, 4.29) was identified and the positive relationship between equol and Hg exposure and UL were further verified. Besides, the mixture evaluation models (WQS and BKMR) also found MEHP negatively associated with UL. Although none of the single chemicals in tertile 3 were significantly associated with EM, the WQS index had a marginally positive association with EM (OR: 2.01, 95% CI: 0.98, 4.15), and a significant positive association was identified in subanalysis with participants restricted to premenopausal women (OR: 2.18, 95% CI: 1.03, 4.70). MIBP and MBzP weighted high in model of EM and MEHP weighted the lowest. Conclusion: Comparing results from these three statistical models, the associations between equol, Hg, and MEHP exposure with UL as well as the associations of MIBP, MBzP, and MEHP exposure with EM warrant further research.

The role of endocrine-disrupting chemicals in uterine fibroid pathogenesis.

PURPOSE OF REVIEW: Uterine leiomyoma (fibroids) is a gynecologic disorder impacting the majority of women in the United States. When symptomatic, these noncancerous tumors can cause severe morbidity including pelvic pain, menorrhagia, and infertility. Endocrine-disrupting chemicals (EDCs) may represent a modifiable risk factor. The aim of this review is to summarize recent human and experimental evidence on EDCs exposures and fibroids. RECENT FINDINGS: Multiple EDCs are associated with fibroid outcomes and/or processes including phthalates, parabens, environmental phenols, alternate plasticizers, Diethylstilbestrol, organophosphate esters, and tributyltin. Epidemiologic studies suggest exposure to certain EDCs, such as di-(2-ethylhxyl)-phthalate (DEHP), are associated with increased fibroid risk and severity. Both human and experimental studies indicate that epigenetic processes may play an important role in linking EDCs to fibroid pathogenesis. In-vitro and in-vivo studies show that DEHP, bisphenol A, and diethylstilbestrol can impact biological pathways critical to fibroid pathogenesis. SUMMARY: While research on EDCs and fibroids is still evolving, recent evidence suggests EDC exposures may contribute to fibroid risk and progression. Further research is needed to examine the impacts of EDC mixtures and to identify critical biological pathways and windows of exposure. These results could open the door to new prevention strategies for fibroids.

Forskolin promotes vasculogenic mimicry and invasion via Notch­1­activated epithelial­to­mesenchymal transition in syncytiolization of trophoblast cells in choriocarcinoma.

Choriocarcinoma (CC) is characterized by earlier blood metastasis compared with other female genital tumors and a high incidence of massive hemorrhage. Vasculogenic mimicry (VM) is highly associated with metastasis, and syncytiotrophoblast is involved in the formation of VM in CC. Forskolin is a typical activator of the cAMP pathway, which is involved in the syncytiolization of trophoblastic cells. In the present study, to determine the effects and mechanism of forskolin on cell invasion and VM during syncytiolization in vitro and in vivo, JEG­3 and JAR cell lines were treated with 100 µM forskolin for 48 h, and wound healing and invasion assays were used to verify cell migratory and invasive capacities. A 3D culture and tube formation assays were established to detect VM. Variation of morphology and markers of the epithelial­to­mesenchymal transition (EMT) were assessed, and the role of the Notch signaling pathway was investigated in CC cells treated with forskolin. The results of the present study demonstrated that 100 µM forskolin induced syncytiolization of trophoblastic cells and enhanced the migratory and invasive abilities of JEG­3 and JAR cell lines. In addition, the capacity of VM was significantly increased, whereas tube formation ability was decreased by forskolin in vitro and in vivo compared with the respective control groups. The cellular morphology exhibited EMT during the syncytiolization process, which was further supported by the changes in EMT marker expression, including downregulation of E­cadherin and cytokeratin and upregulation of N­cadherin, vimentin and zinc finger E­box­binding homeobox 1. The Notch­1 signaling pathway was activated to induce EMT in forskolin­induced VM process in CC cells, and VM and EMT could be reversed by using the γ­secretase inhibitor DAPT to block the Notch­1 pathway. Overall, the results of the present study demonstrated that forskolin enhanced the capacity of VM formation and metastasis through Notch­1­activated EMT in the syncytiolization of trophoblastic cells.

Risk Factors Associated with Endometrial Pathology in Premenopausal Breast Cancer Patients Treated with Tamoxifen.

PURPOSE: To evaluate factors associated with endometrial pathology during tamoxifen use in premenopausal breast cancer (BC) patients. MATERIALS AND METHODS: We reviewed the medical records of premenopausal BC patients treated with tamoxifen who underwent endometrial biopsy with or without hysteroscopy. Clinical characteristics were compared between women with endometrial pathology (endometrial hyperplasia or cancer) and those with normal histology or endometrial polyps. RESULTS: Among 284 endometrial biopsies, endometrial hyperplasia was diagnosed in 7 patients (2.5%), endometrial cancer was diagnosed in 5 patients (1.8%), normal histology was noted in 146 patients (51.4%), and endometrial polyp was present in 114 patients (40.1%). When comparing women with endometrial cancer (n=5) to women with normal histology, abnormal uterine bleeding was more common (p=0.007), and endometrial thickness was greater (p=0.007) in women with endometrial cancer. Chemotherapy for BC was also more common in patients with endometrial cancer (p=0.037). When comparing women with endometrial polyps and those with endometrial hyperplasia or cancer, the presence of abnormal uterine bleeding was more common in patients with endometrial hyperplasia or cancer (p<0.001); however, tamoxifen duration and endometrial thickness did not differ significantly between the two groups. CONCLUSION: In premenopausal BC patients treated with tamoxifen, abnormal uterine bleeding, increased endometrial thickness, and chemotherapy for BC were associated with the occurrence of endometrial cancer. These findings may provide useful information for gynecologic surveillance and counseling during tamoxifen treatment in premenopausal BC patients.

A nongenomic mechanism for "metalloestrogenic" effects of cadmium in human uterine leiomyoma cells through G protein-coupled estrogen receptor.

Cadmium (Cd) is a ubiquitous environmental metal that is reported to be a "metalloestrogen." Uterine leiomyomas (fibroids) are estrogen-responsive gynecologic neoplasms that can be the target of xenoestrogens. Previous epidemiology studies have suggested Cd may be associated with fibroids. We have shown that Cd can stimulate proliferation of human uterine leiomyoma (ht-UtLM) cells, but not through classical estrogen receptor (ER) binding. Whether nongenomic ER pathways are involved in Cd-induced proliferation is unknown. In the present study, by evaluating G protein-coupled estrogen receptor (GPER), ERα36, and phospho-epidermal growth factor receptor (EGFR) expression in human tissues, we found that GPER, ERα36 and phospho-EGFR were all highly expressed in fibroids compared to patient-matched myometrial tissues. In ht-UtLM cells, cell proliferation was increased by low doses of Cd (0.1 µM and 10 µM), and this effect could be inhibited by GPER-specific antagonist (G15) pretreatment, or silencing (si) GPER, but not by siERα36. Cd-activated MAPK was dependent on GPER/EGFR transactivation, through significantly increased phospho-Src, matrix metalloproteinase-2 (MMP2) and MMP9, and heparin-binding EGF-like growth factor (HB-EGF) expression/activation. Also, phospho-Src could interact directly to phosphorylate EGFR. Overall, Cd-induced proliferation of human fibroid cells was through a nongenomic GPER/p-src/EGFR/MAPK signaling pathway that did not directly involve ERα36. This suggests that Cd may be a risk factor for uterine fibroids through cross talk between hormone and growth factor receptor pathways.

Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) Hull Extract and Active Compounds Inhibit Proliferation of Primary Human Leiomyoma Cells and Protect against Sexual Hormone-Induced Mice Smooth Muscle Hyperproliferation.

Uterine leiomyomas, also known as fibroids, are benign neoplasms of the uterus and have a high incidence rate in women of reproductive age. Hysterectomy or myomectomy is the initial treatment, but fibroids will recur if the patient is still exposed to similar risk factors. Therefore, developing new therapeutic strategies are urgently necessary. In this study, the anti-proliferation effects of each fraction of adlay seeds were evaluated in uterine leiomyomas, and we identified the potential phytochemical compounds. We found that the ethyl acetate fraction of adlay hull (AHE-ea) appeared to be highly efficient in the anti-proliferation of rat uterine leiomyoma ELT3 cells and primary human uterine leiomyoma (hUL) cells. The proliferation of primary human normal uterine smooth muscle (UtSMC) and normal uterine myometrial (hUM) cells were also suppressed by AHE-ea. Two phytosterols, stigmasterol and ß-sitosterol, were identified from AHE-ea fraction. Mice treated with AHE-ea and stigmasterol alone demonstrated reduced diethylstilbestrol/medroxyprogesterone 17-acetate (DES/MPA)-induced uterine myometrial hyperplasia, which is the critical step for the development of leiomyoma. Taken together, our results suggest that the AHE-ea fraction could be considered as a natural plant-based medicine in the prevention or treatment of uterine leiomyoma growth.

Tamoxifen related Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT): A case report and literature review of this possible association.

It is well known that a large number of patients treated with Tamoxifen develops endometrial pathologies ranging from benign endometrial polyps and hyperplasia to adenocarcinomas, carcinosarcomas and adenosarcomas. UTROSCT (Uterine Tumor Resembling Ovarian Sex Cord Tumor) is defined as a mesenchymal tumors of the uterine corpus that morphologically resembles ovarian sex cord tumors, without recognizable endometrial stroma. To date only 4 cases have been reported in patients treated with tamoxifen. In this article, we describe an additional case occurring in a 62-years-old patient undergoing 3 years of Tamoxifen therapy for bilateral breast carcinoma. The present work represents a further evidence of the possible association between Tamoxifen therapy and UTROSCT. A comprehensive literature review on this topic is also provided.

Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study.

OBJECTIVE: To perform an expedited assessment of cancer risk associated with exposure to N-nitrosodimethylamine (NDMA) through contaminated valsartan products. DESIGN: Nationwide cohort study. SETTING: Danish health registries on individual level prescription drug use, cancer occurrence, and hospital diagnoses. PARTICIPANTS: 5150 Danish patients with no history of cancer, aged 40 years or older, and using valsartan at 1 January 2012 or initiating use between 1 January 2012 and 30 June 2017. Participants were followed from one year after cohort entry (lag time period) until experiencing a cancer outcome, death, migration, or end of study period (30 June 2018). Each participant's exposure to NDMA (ever exposure and predefined categories of cumulative valsartan exposure) was mapped out as a time varying variable while also applying a one year lag. MAIN OUTCOME MEASURES: Association between NDMA exposure and a primary composite endpoint comprising all cancers except non-melanoma skin cancer, estimated using Cox regression. In supplementary analyses, the risk of individual cancers was determined. RESULTS: The final cohort comprised 5150 people followed for a median of 4.6 years. In total, 3625 cohort participants contributed 7344 person years classified as unexposed to NDMA, and 3450 participants contributed 11 920 person years classified as ever exposed to NDMA. With 104 cancer outcomes among NDMA unexposed participants and 198 among exposed participants, the adjusted hazard ratio for overall cancer was 1.09 (95% confidence interval 0.85 to 1.41), with no evidence of a dose-response relation (P=0.70). For single cancer outcomes, increases in risk were observed for colorectal cancer (hazard ratio 1.46, 95% confidence interval 0.79 to 2.73) and for uterine cancer (1.81, 0.55 to 5.90), although with wide confidence intervals that included the null. CONCLUSIONS: The results do not imply a markedly increased short term overall risk of cancer in users of valsartan contaminated with NDMA. However, uncertainty persists about single cancer outcomes, and studies with longer follow-up are needed to assess long term cancer risk.

Establishment of a rat model for uterine leiomyomas based on Western and traditional Chinese medicine theories.

Uterine leiomyomas (ULs) are benign monoclonal tumors that arise from the underlying myometrial tissue in the uterus. Effective therapies are still lacking because of poor understanding of the pathophysiology and epidemiology. Hence, it is urgent to establish efficient animal models to screen novel anti-UL therapies. In this study, for the first time, traditional Chinese medicine and Western medicine were combined to establish an animal model of ULs in rats. In order to evaluate the function and value of the novel model, it was compared with other models. The long-term and short-term rat models for ULs were established using progesterone and diethylstilbestrol. Rats in Qi stagnation and blood stasis group were injected with epinephrine hydrochloride and received chronic unpredictable stress for two weeks. Rats in combining disease with syndrome group (CDWSG) received not only epinephrine hydrochloride injection and chronic unpredictable stress but also progesterone and diethylstilbestrol treatment. We analyzed differences in organ coefficient, uterus size, uterine pathology, concentrations of progesterone, estradiol, progesterone receptor, estrogen receptor, expression of desmin, α-smooth muscle actin, and vimentin among the five groups. The animal model of ULs was successfully constructed by loading the rats with estrogen and progesterone. The rat model of CDWSG was more stable than other groups and the method was the most efficient.

Uterine adenocarcinoma in the rat induced by afidopyropen. An analysis of the lesion's induction, progression and its relevance to humans.

Afidopyropen is a novel insecticide that acts as a TRPV channel modulator in chordotonal organs of target insects. In two carcinogenicity studies with Fischer rats, an increased incidence of uterine adenocarcinomas was observed at 1000 and 3000 ppm. This finding prompted an investigation of the mechanism of the tumor formation as well as the relevance of this mechanism to humans. The mechanistic work took parallel paths: one path investigated the pharmacokinetic properties of the test substance at the doses where the tumors were found; while the second path examined the key mechanistic events that culminated in uterine adenocarcinomas. The results of the investigation indicated that the tumors only occurred at doses where excretion of test substance was saturated - indicating that homeostatic biological and/or physiological processes were overwhelmed. At the doses where these processes were overwhelmed, the test substance acted through a mechanism of dopamine agonism, triggering a cascade key events that resulted in uterine adenocarcinomas. An analysis of these mechanisms observed in rat showed that they are both quantitatively (pharmacokinetic mechanism) and qualitatively (dopamine agonism mechanism) not relevant to humans. Therefore the uterine adenocarcinomas observed in the rat associated with high doses of Afidopyropen are not expected to pose a carcinogenic risk to humans.