Endometrial Cancer in a Transgender Man with Prolonged Exogenous Testosterone Use.

BACKGROUND: Hormone therapy (HT) in transgender males requires monitoring. For amenorrheic transmasculine individuals on HT, episodes of abnormal vaginal bleeding should be assessed promptly. CASE: A 33-year-old transgender man on exogenous testosterone therapy for medical gender transition was found to have stage IV endometrioid endometrial adenocarcinoma. Surgical resection was performed for symptom control, and the patient was treated with palliative chemotherapy. The tumor was androgen receptor-negative, and, after a multidisciplinary discussion of the risks and benefits of continuing exogenous testosterone, testosterone therapy was restarted postoperatively. CONCLUSION: Long-term androgen use may have unknown implications for the development of malignancy, and treating reproductive organ cancer in transgender males may be complicated by the desire to continue androgen therapy.

Exposure to select PFAS and PFAS mixtures alters response to platinum-based chemotherapy in endometrial cancer cell lines.

BACKGROUND: Exposure to per- and poly-fluoroalkyl substances (PFAS) has been associated with significant alterations in female reproductive health. These include changes in menstrual cyclicity, timing of menarche and menopause, and fertility outcomes, as well as increased risk of endometriosis, all of which may contribute to an increased risk of endometrial cancer. The effect of PFAS on endometrial cancer cells, specifically altered treatment response and biology, however, remains poorly studied. Like other gynecologic malignancies, a key contributor to lethality in endometrial cancer is resistance to chemotherapeutics, specifically to platinum-based agents that are used as the standard of care for patients with advanced-stage and/or recurrent disease. OBJECTIVES: To explore the effect of environmental exposures, specifically PFAS, on platinum-based chemotherapy response and mitochondrial function in endometrial cancer. METHODS: HEC-1 and Ishikawa endometrial cancer cells were exposed to sub-cytotoxic nanomolar and micromolar concentrations of PFAS/PFAS mixtures and were treated with platinum-based chemotherapy. Survival fraction was measured 48-h post-chemotherapy treatment. Mitochondrial membrane potential was evaluated in both cell lines following exposure to PFAS ± chemotherapy treatment. RESULTS: HEC-1 and Ishikawa cells displayed differing outcomes after PFAS exposure and chemotherapy treatment. Cells exposed to PFAS appeared to be less sensitive to carboplatin, with instances of increased survival fraction, indicative of platinum resistance, observed in HEC-1 cells. In Ishikawa cells treated with cisplatin, PFAS mixture exposure significantly decreased survival fraction. In both cell lines, increases in mitochondrial membrane potential were observed post-PFAS exposure ± chemotherapy treatment. DISCUSSION: Exposure of endometrial cancer cell lines to PFAS/PFAS mixtures had varying effects on response to platinum-based chemotherapies. Increased survival fraction post-PFAS + carboplatin treatment suggests platinum resistance, while decreased survival fraction post-PFAS mixture + cisplatin exposure suggests enhanced therapeutic efficacy. Regardless of chemotherapy sensitivity status, mitochondrial membrane potential findings suggest that PFAS exposure may affect endometrial cancer cell mitochondrial functioning and should be explored further.

Occupational exposure to pesticides and endometrial cancer in the Screenwide case-control study.

BACKGROUND: Endometrial cancer is the most common gynaecological tumour in developed countries and disease burden is expected to increase over the years. Identifying modifiable risk factors may help developing strategies to reduce the expected increasing incidence of these neoplasms. OBJECTIVE: This study evaluates the association between occupational exposure to pesticides and endometrial cancer using data from a recent case-control study in Spain. METHODS: The analyses included data from 174 consecutive incident endometrial cancer cases and 216 hospital controls frequency-matched by age. Data were collected through structured epidemiological questionnaires and exposure to pesticides was assessed using a Spanish job-exposure matrix (MatEmESp). RESULTS: Overall, 12% of controls and 18% of cases were occupationally exposed to pesticides. We observed a positive association between occupational exposure to pesticides and endometrial cancer (OR = 2.08; 95% CI = 1.13-3.88 compared to non-exposed). In general, exposures that occurred farther in the past were significantly associated with endometrial cancer. Exposure to insecticides, fungicides and herbicides were positively associated with endometrial cancer (OR = 2.08; 95% CI = 1.13-3.88, OR = 4.40; 95% CI = 1.65-13.33, and OR = 5.25; 95% CI = 1.84-17.67, respectively). The agricultural, poultry and livestock activities scenario was associated with endometrial cancer (OR = 4.16; 95% CI = 1.59-12.32), while the cleaning exposure scenario was not (OR = 1.22; 95% CI = 0.55-2.67). CONCLUSIONS: Assessment of occupational exposure to pesticides assessed using a Spanish job-exposure matrix revealed a positive association with endometrial cancer. The elucidation of the role of pesticide compounds on endometrial cancer should shed a light on the aetiology of this tumour.

Latin America and the Caribbean Code Against Cancer 1st Edition: Medical interventions including hormone replacement therapy and cancer screening.

Prostate, breast, colorectal, cervical, and lung cancers are the leading cause of cancer in Latin America and the Caribbean (LAC) accounting for nearly 50% of cancer cases and cancer deaths in the region. Following the IARC Code Against Cancer methodology, a group of Latin American experts evaluated the evidence on several medical interventions to reduce cancer incidence and mortality considering the cancer burden in the region. A recommendation to limit the use of HRT was issued based on the risk associated to develop breast, endometrial, and ovarian cancer and on growing concerns related to the over-the-counter and without prescription sales, which in turn bias estimations on current use in LAC. In alignment with WHO breast and cervical cancer initiatives, biennial screening by clinical breast examination (performed by trained health professionals) from the age of 40 years and biennial screening by mammography from the age of 50 years to 74, as well as cervical screening by HPV testing (either self-sampling or provider-sampling) every 5-10 years for women aged 30-64 years, were recommended. The steadily increasing rates of colorectal cancer in LAC also led to recommend colorectal screening by occult blood testing every two years or by endoscopic examination of the colorectum every 10 years for both men and women aged 50-74 years. After evaluating the evidence, the experts decided not to issue recommendations for prostate and lung cancer screening; while there was insufficient evidence on prostate cancer mortality reduction by prostate-specific antigen (PSA) testing, there was evidence of mortality reduction by low-dose computed tomography (LDCT) targeting high-risk individuals (mainly heavy and/or long-term smokers) but not individuals with average risk to whom recommendations of this Code are directed. Finally, the group of experts adapted the gathered evidence to develop a competency-based online microlearning program for building cancer prevention capacity of primary care health professionals.

Comparative safety of conjugated estrogens/bazedoxifene versus estrogen/progestin combination hormone therapy among women in the United States: a multidatabase cohort study.

OBJECTIVE: To assess the risk of select safety outcomes including endometrial cancer, endometrial hyperplasia, and breast cancer among women using conjugated estrogens/bazedoxifene (CE/BZA) as compared with estrogen/progestin combination hormone therapy (EP). METHODS: We conducted a new-user cohort study in five US healthcare claims databases representing more than 92 million women. We included CE/BZA or EP new users from May 1, 2014, to August 30, 2019. EP users were propensity score (PS) matched to users of CE/BZA. Incidence of endometrial cancer, endometrial hyperplasia, breast cancer, and eight additional cancer and cardiovascular outcomes were ascertained using claims-based algorithms. Rate ratios (RR) and differences pooled across databases were estimated using random-effects models. RESULTS: The study population included 10,596 CE/BZA and 33,818 PS-matched EP new users. Rates of endometrial cancer and endometrial hyperplasia were slightly higher among CE/BZA users (1.6 and 0.4 additional cases per 10,000 person-years), although precision was limited because of small numbers of cases (endometrial cancer: RR, 1.50 [95% confidence interval {CI}, 0.79-2.88]; endometrial hyperplasia: RR, 1.69 [95% CI, 0.51-5.61]). Breast cancer incidence was lower in CE/BZA users (9.1 fewer cases per 10,000 person-years; RR, 0.79; 95% CI, 0.58-1.05). Rates of other outcomes were slightly higher among CE/BZA users, but with confidence intervals compatible with a wider range of possible associations. CONCLUSIONS: CE/BZA users might experience slightly higher rates of endometrial cancer and endometrial hyperplasia, and a lower rate of breast cancer, than EP users in the first years of use.

Depot medroxyprogesterone acetate and endometrial cancer: A multicenter case-control study.

OBJECTIVE: To assess the associations between depot medroxyprogesterone acetate (DMPA) and endometrial cancer. METHODS: This multicenter case-control study was conducted among tertiary hospitals in Thailand. Patients were women with endometrial cancer. Controls were women admitted for other conditions, matched for age within 5 years of the patients' age. The controls had to have no abnormal vaginal bleeding, history of hysterectomy, or cancers of the other organs. A standardized questionnaire was used to gather information. Conditional logistic regression was applied to calculate adjusted odds ratio (aORs) and 95% confidence intervals (CIs). RESULTS: During 2015 to 2021, 378 patients and 1134 controls were included. Ever use of DMPA was associated with a 70% decreased overall risk of endometrial cancer (aOR, 0.30 [95% CI, 0.21-0.42]). Endometrial cancer risk declined by 3% (aOR, 0.97 [95% CI, 0.96-0.98]) for every 3 months of DMPA use. The magnitude of the decline in endometrial cancer risk did not vary appreciably by cancer subtypes (aOR, 0.26 [95% CI, 0.17-0.41] and 0.38 [95% CI, 0.22-0.65] for low-grade and high-grade tumors, respectively). CONCLUSIONS: Depot medroxyprogesterone acetate use was inversely associated with endometrial cancer risk in a duration-dependent manner. This association was independent of cancer subtype.

Tamoxifen use and risk of endometrial cancer in breast cancer patients: A systematic review and dose-response meta-analysis.

BACKGROUND: Worse prognosis of endometrial cancers (EC) in tamoxifen-treated women compared to non-tamoxifen-treated women been proposed. The relationship between tamoxifen treatment of breast cancer (BC) and the risk of EC is controversial and there is no agreement between publication results on this issue (the answer to all comments provided in the page 2 of manuscript). The aim of this study is investigation the association between tamoxifen treatment and the risk of EC in patients with BC. METHODS AND RESULTS: We conducted a comprehensive search with related keywords in MEDLINE/PubMed, SCOPUS, and Web of Science databases until April 16, 2022. Random-effects model (DerSimonian and Laird) was used to pool risk ratios (RRs) with 95% confidence intervals (CIs) of EC. Dose, cumulative dose, and duration-response analysis were performed in linear and non-linear states. Twenty-six studies reported a relation between tamoxifen treatment and risk of EC in patients with BC. Results showed a direct relationship between tamoxifen use and EC (RR: 2.03, 95% CI: 1.68-2.45; I2:76%). By increase the age of participants, the risk of EC was decrease (coef = -.0206), although this was not statistically significant (p = .37). Linear dose-response model indicated a direct significant association between dose and duration use of tamoxifen and EC (dose: exe(b) = 1.019, p = .001; duration: exe(b) = 1.014, p = .001). Non-linear dose-response analysis confirmed linear analysis. CONCLUSION: This study highlights that tamoxifen use is a significant risk factor related to the incidence of EC in patients with BC.

Risk factors for the development of endometrial lesions in breast cancer patients using tamoxyphen: a retrospective cohort study.

INTRODUCTION: breast cancer is the cancer with the highest incidence in women in Brazil, representing 29.7% of all cancers. More than two thirds of women with breast cancer show expression for hormone receptors, and in these cases, hormone therapy with tamoxifen is indicated, which may represent a risk factor for the development of endometrial cancer (four-fold greater relative risk). OBJECTIVE: this study aimed to evaluate the association of tamoxifen and the development of endometrial disturbances and to assess possible other associated risk factors. PATIENTS AND METHOD: a total of 364 breast cancer patients were evaluated, 286 who used tamoxifen and 78 who did not use this hormone therapy. Results: patients who used tamoxifen had a mean follow-up time of 51.42 months similar to those without hormone therapy (p=0.081). A total of 21 (7.3%) women who used tamofixen and no cases among women without hormone therapy presented endometrial changes during follow-up (p=0.01). Despite information regarding obesity was available for only 270 women, obesity was also significantly associated with the development of endometrial changes (p=0.008). CONCLUSION: furthermore, the association between tamofixen and endometrial changes remained significant (p=0.039) after adjusting for obesity.

Expression and Release of Tumor Cell Tissue Factor Triggers Recurrent Thromboembolism in a Patient with Endometrial Cancer.

Although cancer-associated thrombosis (CAT) is a frequent complication in patients with malignancies, its treatment remains a challenge in daily practice. Here, we report the clinical course of a 51-year-old woman presenting with a highly thrombogenic paraneoplastic coagulopathy. Despite therapeutic anticoagulation with various agents, including rivaroxaban, fondaparinux, and low-molecular-weight heparin, the patient suffered from recurrent venous and arterial thromboembolism. Locally advanced endometrial cancer was identified. Tumor cells showed strong expression of tissue factor (TF), and significant concentrations of TF-bearing microvesicles were detected in patient plasma. Coagulopathy was controlled only by continuous intravenous anticoagulation with the direct thrombin inhibitor, argatroban. Multimodal antineoplastic treatment, including neoadjuvant chemotherapy followed by surgery and postoperative radiotherapy, resulted in clinical cancer remission, which was paralleled by normalization of tumor markers, CA125 and CA19-9, D-dimer levels, and TF-bearing microvesicles. In summary, continuous anticoagulation with argatroban and multimodal anticancer treatment may be necessary to control TF-driven coagulation activation with recurrent CAT in endometrial cancer.

Metformin in Combination with Progesterone Improves the Pregnancy Rate for Patients with Early Endometrial Cancer.

Objective. To study the therapeutic effects of metformin in combination with medroxyprogesterone in the early endometrial cancer patients with fertility requirements. A total of 120 patients with early endometrial cancer admitted to and treated in our hospital were enrolled and evenly assigned into two groups according to different therapeutic regimens, namely, metformin group (metformin combined with medroxyprogesterone acetate) and control group (medroxyprogesterone acetate alone). The objective response rate (ORR) and disease control rate (DCR) were 71.7% (43/60) and 90.0% (54/60) in the metformin group and 53.3% (32/60) and 78.3% (47/60) in the control group, respectively. Adverse reactions such as gastrointestinal reaction, headache, and insomnia were mainly observed in patients. The body mass index (BMI) declined from (34.43 ± 4.34) kg/m2 to (24.77 ± 2.39) kg/m2 in the metformin group and from (33.37 ± 4.49) kg/m2 to (31.28 ± 3.55) kg/m2 in the control group after treatment. After treatment, serum levels of vascular endothelial growth factor (VEGF), angiotensin-2 (Ang-2), carbohydrate antigen 125 (CA125), and CA19-9 in the metformin group were significantly lower than those in the control group (P = 0.005, P < 0.001, P = 0.002, and P < 0.001). During follow-up, the pregnancy rate was 81.7% (49/60) in the metformin group and 61.7% (37/60) in the control group, and the former was prominently higher than the latter (P = 0.025). Metformin in combination with progesterone is effective in treating early endometrial cancer patients with fertility requirements, which significantly reduced the BMI of patients and increased the pregnancy rate after treatment.

Drinking Water Disinfection Byproducts, Ingested Nitrate, and Risk of Endometrial Cancer in Postmenopausal Women.

BACKGROUND: Disinfection byproducts (DBPs) and N-nitroso compounds (NOC), formed endogenously after nitrate ingestion, are suspected endometrial carcinogens, but epidemiological studies are limited. OBJECTIVES: We investigated the relationship of these exposures with endometrial cancer risk in a large prospective cohort. METHODS: Among postmenopausal women in the Iowa Women's Health Study cohort, we evaluated two major classes of DBPs, total trihalomethanes (TTHM) and five haloacetic acids (HAA5), and nitrate-nitrogen (NO3-N) in public water supplies (PWS) in relation to incident primary endometrial cancer (1986-2014). For women using their PWS >10y at enrollment (n=10,501; cases=261), we computed historical averages of annual concentrations; exposures were categorized into quantiles and when possible ≥95th percentile. We also computed years of PWS use above one-half the U.S. maximum contaminant level (>½ MCL; 40µg/L TTHM; 30µg/L HAA5; 5mg/L NO3-N). Dietary nitrate/nitrite intakes were estimated from a food frequency questionnaire. We estimated hazard ratios (HR) and 95% confidence intervals (CI) via Cox models adjusted for age, endometrial cancer risk factors [e.g., body mass index, hormone replacement therapy (HRT)], and mutually adjusted for DBPs or NO3-N. We evaluated associations for low-grade (cases=99) vs. high-grade (cases=114) type I tumors. We assessed interactions between exposures and endometrial cancer risk factors and dietary factors influencing NOC formation. RESULTS: Higher average concentrations of DBPs (95th percentile: TTHM ≥93µg/L, HAA5 ≥49µg/L) were associated with endometrial cancer risk (TTHM: HR95vsQ1=2.19, 95% CI: 1.41, 3.40; HAA5: HR95vsQ1=1.84, 95% CI: 1.19, 2.83; ptrend<0.01). Associations were similarly observed for women greater than median years of PWS use with levels >½ MCL, in comparison with zero years (TTHM: HR36+vs0y=1.61, 95% CI: 1.18, 2.21; HAA5: HR38+vs0y=1.85, 95% CI: 1.31, 2.62). Associations with DBPs appeared stronger for low-grade tumors (TTHM: HRQ4vsQ1=2.12, 95% CI: 1.17, 3.83; p-trend=0.008) than for high-grade tumors (TTHM: HRQ4vsQ1=1.40, 95% CI: 0.80, 2.44; p-trend=0.339), but differences were not statistically significant (p-heterogeneity=0.43). Associations with TTHM were stronger among ever HRT users than non-HRT users (p-interaction<0.01). We observed no associations with NO3-N in drinking water or diet. DISCUSSION: We report novel associations between the highest DBP levels and endometrial cancer for our Iowa cohort that warrant future evaluation. https://doi.org/10.1289/EHP10207.

Endocrine Disruptors and Endometrial Cancer: Molecular Mechanisms of Action and Clinical Implications, a Systematic Review.

It has been widely demonstrated that endocrine disruptors play a central role in various physiopathological processes of human health. In the literature, various carcinogenic processes have been associated with endocrine disruptors. A review of the molecular mechanisms underlying the interaction between endocrine disruptors and the endometrial cancer has been poorly developed. A systematic review was performed using PubMed®/MEDLINE. A total of 25 in vivo and in vitro works were selected. Numerous endocrine disruptors were analyzed. The most relevant results showed how Bisphenol A (BPA) interacts with the carcinogenesis process on several levels. It has been demonstrated how BPA can interact with hormonal receptors and with different transcription proliferative and antiproliferative factors. Furthermore, the effect of Polycyclic aromatic hydrocarbons on Aryl hydrocarbon receptors was investigated, and the role of flame retardants in promoting proliferation and metastasis was confirmed. The results obtained demonstrate how the mechanisms of action of endocrine disruptors are manifold in the pathophysiology of endometrial cancer, acting on different levels of the cancerogenesis process.

Dostarlimab for the treatment of advanced endometrial cancer.

INTRODUCTION: Between 20% and 30% of the endometrial cancers (EC) are associated with a deficiency of a mismatch repair (MMRd) protein or high microsatellite instability (MSI-H), characteristics that render the tumor more sensitive to immune checkpoint inhibitors. There is no standard treatment for advanced EC after progression to a platinum-containing regimen. AREAS COVERED: The phase I GARNET clinical trial assessed the safety, tolerability, and antitumor activity of anti-PD1 dostarlimab in patients with advanced solid tumors. The A1 cohort of this trial enrolled patients with MMRd or MSI-H recurrent or advanced EC who had previously received a platinum-containing regimen. The results of this cohort showed significant clinical activity, durable responses, and a favorable safety profile, without reducing quality of life. Based on these data, dostarlimab achieved accelerated approval. EXPERT OPINION: Although a randomized study has not yet been conducted, dostarlimab monotherapy should be the treatment of choice for patients with advanced MMRd EC in progression after a platinum-containing regimen. Selecting patients with EC for immune checkpoint inhibitors using the MMRd predictive biomarker could facilitate more efficient and sustainable health systems and avoid the use of more toxic combinations, leading to personalized medicine.

Preliminary evaluation on the beneficial effects of pioglitazone in the treatment of endometrial cancer.

Endometrial cancer (EMC) is one of the complicated gynecological cancers, affecting more than three million women worldwide. Anticancer strategies such as chemotherapy, radiation, and surgery are found to be ineffective and are associated with patient incompliances. The aim of the present study is to repurpose non-oncological drug, i.e., Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, in the treatment of endometrial cancer. The study groups consist of 50 female Swiss albino mice, out of which 40 had endometrial cancer induced with N-ethyl-N-nitrosourea (ENU) and estradiol hexadrobenzoate (EHB). The other groups received saline, EHB, paclitaxel, and different test doses of pioglitazones. Different preliminary parameters such as weekly body weight, mean survival time, percentage increase in life span, and uterine tissue weight were analyzed along with histopathological analysis. We observed a significant change in weekly body weight, improvement in percentage life span, and partial restoration of uterine tissue weight to normal compared to a standard drug, paclitaxel. In the present preliminary evaluation, we have identified that pioglitazone exhibited a significant dose-dependent anticancer activity against ENU- and EHB-induced endometrial cancer, compared to the standard paclitaxel.

Oral contraceptive use by formulation and endometrial cancer risk among women born in 1947-1964: The Nurses' Health Study II, a prospective cohort study.

Oral contraceptives (OCs) have been associated with long-term lower endometrial cancer risk; relatively little is known about associations with more recent OC formulations and associations with longer-term risk. A total of 107,069 women from the Nurses' Health Study II recalled OC use from age 13 to baseline (1989); biennial questionnaires updated data on OC use until 2009. OCs were classified by estrogen and progestin type, dose, and potency based on reported brand. 864 incident endometrial cancer cases were identified through 2017. Multivariable Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals [95% CI] for the association of OC use with endometrial cancer risk. OC use was associated with lower endometrial cancer risk (ever use, HR 0.77 [95% CI 0.65-0.91]; >10 years of use, 0.43 [0.32-0.58] vs. never OC use). Inverse associations for duration were evident regardless of time since last use. Longer durations (> 5 years) of ethinyl estradiol (0.52 [0.41-0.67]) and second-generation progestins (0.43 [0.30-0.61]), both versus never use, were more strongly associated with lower risk than mestranol (0.66 [0.50-0.88], p-het = 0.01) and first-generation progestins (0.62 [0.49-0.78], p-het = 0.03). Inverse associations were generally observed for cross-classified cumulative average estrogen and progestin dose and potency (< vs. ≥ median; ever use vs. never OC use), with the exception of high estrogen and low progestin dose. OCs were associated with lower endometrial cancer risk, independent of time since last use. Use of ethinyl estradiol and second-generation progestins were more strongly inversely associated with risk compared with older formulations.

Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen.

BACKGROUND: Adjuvant tamoxifen reduces the risk of breast cancer recurrence in women with oestrogen receptor-positive breast cancer. Tamoxifen also increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer. The levonorgestrel-releasing intrauterine system (LNG-IUS) causes profound endometrial suppression. This systematic review considered the evidence that the LNG-IUS prevents the development of endometrial pathology in women taking tamoxifen as adjuvant endocrine therapy for breast cancer. OBJECTIVES: To determine the effectiveness and safety of the levonorgestrel intrauterine system (LNG-IUS) in pre- and postmenopausal women taking adjuvant tamoxifen following breast cancer for the outcomes of endometrial and uterine pathology including abnormal vaginal bleeding or spotting, and secondary breast cancer events. SEARCH METHODS: We searched the following databases on 29 June 2020; The Cochrane Gynaecology and Fertility Group specialised register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO and Cumulative Index to Nursing and Allied Health Literature. We searched the Cochrane Breast Cancer Group specialised register on 4 March 2020. We also searched two trials registers, checked references for relevant trials and contacted study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of women with breast cancer on adjuvant tamoxifen that compared the effectiveness of the LNG-IUS with endometrial surveillance versus endometrial surveillance alone on the incidence of endometrial pathology. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary outcome measure was endometrial pathology (including polyps, endometrial hyperplasia, or endometrial cancer), diagnosed at hysteroscopy or endometrial biopsy. Secondary outcome measures included fibroids, abnormal vaginal bleeding or spotting, breast cancer recurrence, and breast cancer-related deaths. We rated the overall certainty of evidence using GRADE methods. MAIN RESULTS: We included four RCTs (543 women analysed) in this review. We judged the certainty of the evidence to be moderate for all of the outcomes, due to imprecision (i.e. limited sample sizes and low event rates). In the included studies, the active treatment arm was the 20 µg/day LNG-IUS plus endometrial surveillance; the control arm was endometrial surveillance alone. In tamoxifen users, the LNG-IUS probably reduces the incidence of endometrial polyps compared to the control group over both a 12-month period (Peto odds ratio (OR) 0.22, 95% confidence interval (CI) 0.08 to 0.64, I² = 0%; 2 RCTs, n = 212; moderate-certainty evidence) and over a long-term follow-up period (24 to 60 months) (Peto OR 0.22, 95% CI 0.13 to 0.39; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). For long-term follow-up, this suggests that if the incidence of endometrial polyps following endometrial surveillance alone is assumed to be 23.5%, the incidence following LNG-IUS with endometrial surveillance would be between 3.8% and 10.7%.  The LNG-IUS probably slightly reduces the incidence of endometrial hyperplasia compared with controls over a long-term follow-up period (24 to 60 months) (Peto OR 0.13, 95% CI 0.03 to 0.67; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). This suggests that if the chance of endometrial hyperplasia following endometrial surveillance alone is assumed to be 2.8%, the chance following LNG-IUS with endometrial surveillance would be between 0.1% and 1.9%. However, it should be noted that there were only six cases of endometrial hyperplasia. There was insufficient evidence to reach a conclusion regarding the incidence of endometrial cancer in tamoxifen users, as no studies reported cases of endometrial cancer. At 12 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting compared to the control group (Peto OR 7.26, 95% CI 3.37 to 15.66; I² = 0%; 3 RCTs, n = 376; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 1.7%, the chance following LNG-IUS with endometrial surveillance would be between 5.6% and 21.5%. By 24 months of follow-up, abnormal vaginal bleeding or spotting occurs less frequently than at 12 months of follow-up, but is still more common in the LNG-IUS group than the control group (Peto OR 2.72, 95% CI 1.04 to 7.10; I² = 0%; 2 RCTs, n = 233; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 4.2%, the chance following LNG-IUS with endometrial surveillance would be between 4.4% and 23.9%. By 60 months of follow-up, there were no cases of abnormal vaginal bleeding or spotting in either group. The numbers of events for the following outcomes were low: fibroids (n = 13), breast cancer recurrence (n = 18), and breast cancer-related deaths (n = 16). As a result, there is probably little or no difference in these outcomes between the LNG-IUS treatment group and the control group.  AUTHORS' CONCLUSIONS: The LNG-IUS probably slightly reduces the incidence of benign endometrial polyps and endometrial hyperplasia in women with breast cancer taking tamoxifen. At 12 and 24 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. Data were lacking on whether the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available RCTs that the LNG-IUS affects the risk of breast cancer recurrence or breast cancer-related deaths. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and to determine whether the LNG-IUS might have an impact on the risk of secondary breast cancer events.

Exposure to endocrine disruptor alkylphenols and the occurrence of endometrial cancer.

Exposure to environmental chemicals with oestrogenic effects has been associated with the development of endometrial cancer (EMCa). EMCa has become the most commonly diagnosed cancer of the female genital tract. To further understand the potential association between exposure to environmental endocrine disruptors and the occurrence of EMCa, we performed a case-control study between 2011 and 2014. We aimed to detect and compare concentrations of a known hormone disruptor, alkylphenol, between women diagnosed with either EMCa or uterine leiomyoma, and those who did not have either of these. Subjects were women diagnosed with either EMCa or uterine leiomyoma (LM) and healthy controls. A structured questionnaire was administered to collect information on lifestyle and health status. Gas chromatography/mass spectrometry was used to measure urinary NP and OP concentrations in participants. Multiple regression analysis was used to examine the association between exposure and outcomes. Overall, 397 women were recruited, including 49 with EMCa, 247 with LM, and 101 controls. Among them, 73.6% showed detectable levels of NP and 61.0% showed detectable levels of OP. The EMCa group had a significantly higher NP concentration than the control group. Higher OP concentrations were also found in participants with EMCa than those with LM and controls. In addition, women in the upper tertile of the NP group had a significantly increased risk of EMCa occurrence (odds ratio [95% confidence interval] = 4.47 [1.69-11.84] for EMCa vs. control). The same was found in the group of women with more than the median level of OP (odds ratio [95% confidence interval] = 4.32 [2.01-9.30] for EMCa vs. LM). Stratification of pre- and post-menopausal groups resulted in a similar association. The results show that NP/OP exposure is associated with EMCa. Further investigations and exposure minimisation are suggested.

Contemporary hormonal contraception and risk of endometrial cancer in women younger than age 50: A retrospective cohort study of Danish women.

OBJECTIVE: To examine the association between contemporary hormonal contraceptives and endometrial cancer risk in women younger than age 50. STUDY DESIGN: Cohort study of women living in Denmark aged 15-49 years through 1995-2014. National registries provided information about hormonal contraception use, incident endometrial cancer and confounders. Ever, current or recent, and former users of any hormonal contraception were compared with non-users, using Poisson regression to calculate incidence rate ratios (RR) with 95% confidence intervals. Duration, time since last use, tumor-specific and product-specific analyses, and population prevented fraction, were calculated. RESULTS: During 21.1 million person-years, 549 incident endometrial cancers occurred, with ever users of any hormonal contraception having a reduced premenopausal endometrial cancer risk compared with non-users; RR 0.60 (95% Confidence Interval 0.49 to 0.73). A lower risk of endometrial cancer was seen in all current or recent users of any hormonal contraception; 0.65 (0.52 to 0.83) and combined contraceptives; 0.57 (0.43 to 0.75), but not progestin-only contraceptives; levonorgestrel intrauterine system, LNG-IUS; 0.97 (0.66 to 1.42); other progestin-only contraceptives; 0.61 (0.27 to 1.37). Increased RRs were found for current use of any hormonal, combined contraceptives or LNG-IUS of ≤one year, probably because of protopathic bias. Longer durations of use were associated with significant reductions that became stronger with longer use. Former users of any hormonal contraception continued to benefit from a reduced risk of endometrial cancer >10 years after stopping. There was little evidence of differences in risk reduction by the type of progestin in combined oral contraceptives. Current or recent use of any hormonal contraception was associated with an approximate halving of risk of the most common tumor type I carcinoma, and an increased risk of the rarer sarcoma. Overall the estimated absolute reduced risk of endometrial cancer in ever users of hormonal contraceptives was 1.4 per 100,000 person-years, or approximately one less endometrial cancer for every 71,400 women of reproductive age who used hormonal contraception for one year. Use of hormonal contraception was estimated to prevent 25% of endometrial cancers in this population. CONCLUSIONS: Currently available combined hormonal contraceptives are still associated with enduring protection against endometrial cancer, particularly for type I carcinomas. IMPLICATIONS: We report substantive evidence of the association between different types of contemporary hormonal contraception and endometrial cancer risk in a national cohort of young Danish women. Currently available combined hormonal contraceptives are still associated with enduring protection against endometrial cancer, particularly for type I carcinomas.

Assessment of Tamoxifen-Related Endometrial Changes in Premenopausal Female Patients With Diffusion-Weighted Magnetic Resonance Imaging.

PURPOSE: To evaluate tamoxifen-related endometrial changes in premenopausal female patients with diffusion-weighted magnetic resonance imaging (DWI). METHODS: This prospective study was performed on 71 premenopausal female patients (mean age, 41 years) who were receiving tamoxifen therapy. All patients underwent magnetic resonance imaging with DWI of the pelvis and hysteroscopic-guided endometrial biopsy. The apparent diffusion coefficient (ADC) values of the endometrial plate were calculated and correlated with pathological results. RESULTS: The mean ADCs of tamoxifen-related benign endometrial lesions (1.35 ± 0.19 and 1.32 ± 0.13 × 10 mm/s) were significantly higher (P = 0.001) than those of normal endometrial plate (0.95 ± 0.11 and 0.93 ± 0.11 × 10 mm/s) by both reviewers, respectively. The cutoff ADC values used to differentiate tamoxifen-related benign endometrial lesions from normal endometrium were 1.07 and 1.02 × 10 mm/s with areas under the curve of 0.94 and 0.93 and accuracy of 94.4 and 95.8 by both reviewers, respectively. The mean ADC values of endometrial polyp (EP) (1.44 ± 0.19 and 1.42 ± 0.22 × 10 mm/s) were significantly higher (P = 0.001) than those of endometrial hyperplasia (EH) (1.25 ± 0.19 and 1.23 ± 0.19 × 10 mm/s) by both reviewers, respectively. The cutoff ADC values used to differentiate EP from EH were 1.38 × 10 and 1.36 × 10 mm/s with areas under the curve of 0.81 and 0.77 and accuracy of 80% and 70% by both reviewers, respectively. There was an insignificant difference in ADC value between typical and atypical EH. The ADC values of endometrial cancer (0.80 and 0.78 × 10 mm/s) were lower than those of tamoxifen-related benign endometrial lesions. The final diagnosis was normal endometrium (n = 36), benign endometrial lesions either EH (n = 17), or EP (n = 16), and endometrial cancer in only 2 patients. CONCLUSIONS: We concluded that DWI helps in detection and characterization of different tamoxifen-related endometrial changes in the premenopausal female patients.