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ObjectivesBoth aerobic moderate to vigorous physical activity (MVPA) and muscle-strengthening exercise (MSE) are recommended, but the mortality benefits of weightlifting, a specific type of MSE, are limited.MethodsIn the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, we used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% CIs for the associations between weightlifting and mortality, adjusting for demographics, lifestyle and behavioural risk factors. The sample included 99 713 adults who completed the follow-up questionnaire that assessed weightlifting who were subsequently followed up through 2016 to determine mortality (median 9, IQR 7.6–10.6 years).ResultsMean age at the follow-up questionnaire was 71.3 (IQR 66–76) years, 52.6% female, with mean body mass index of 27.8 (SD 4.9) kg/m2. Weightlifting was associated with a 9% lower risk of all-cause mortality (HR=0.91 (95% CI 0.88 to 0.94)) and CVD mortality (0.91 (95% CI 0.86 to 0.97)) after adjusting for MVPA. Joint models revealed that adults who met aerobic MVPA recommendations but did not weightlift had a 32% lower all-cause mortality risk (HR=0.68 (95% CI 0.65 to 0.70)), while those who also reported weightlifting 1–2 times/week had a 41% lower risk (HR=0.59 (95% CI 0.54 to 0.64)), both compared with adults reporting no aerobic MVPA or weightlifting. Without adjustment for MVPA, weightlifting was associated with lower cancer mortality (HR=0.85 (95% CI 0.80 to 0.91)).ConclusionWeightlifting and MVPA were associated with a lower risk of all-cause and CVD mortality, but not cancer mortality. Adults who met recommended amounts of both types of exercise appeared to gain additional benefit.

Background: The degree to which uterine cancer metastatic to the ovary is misdiagnosed as synchronous stage I uterine and ovarian cancers is unclear. We sought to determine whether patients with synchronous cancers had mortality patterns similar to either stage IIIA uterine, stage I uterine, or stage I ovarian cancers alone. Methods: The Surveillance, Epidemiology, and End Results database was used to compare mortality of patients with synchronous stage I uterine and stage I ovarian cancers versus those with stage IIIA uterine, stage I uterine, or stage I ovarian cancers alone. We calculated age-adjusted mortality hazard ratios (HR) and 95% confidence intervals (CI) accounting for calendar year and grade, adjuvant treatment, grade 1 endometrioid cancers, grade 3 endometrioid cancers, and stage IA cancers. Results: Among the 9,321 patients, we observed lower age-adjusted mortality in patients with stage I synchronous cancers (n = 937) compared to those with stage IIIA uterine (n = 531; HR, 0.45 95% CI, 0.35–0.58), stage I uterine (n = 6,919; HR, 0.74; 95% CI, 0.60–0.91), and stage I ovarian cancers (n = 934; HR, 0.52; 95% CI, 0.41–0.67). Results were similar after taking into account diagnosis year and grade, and limiting to those receiving adjuvant therapy, grade 1 or grade 3 endometrioid cancers, or stage IA cancers. Conclusions: We observed lower mortality for synchronous stage I uterine and ovarian cancers, which was not explained by younger age, earlier stage, lower grade, histology type, or adjuvant therapy. Impact: The possible misdiagnosis associated with clinicopathologic of synchronous uterine and ovarian cancers does not appear to worsen survival on a population level.

Background: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects. Methods: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data. Results: There was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03–1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11–1.54). Conclusions: A higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival. Impact: Given that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.

BACKGROUND: Limited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial cancer risk; particularly among certain subgroups characterized by body mass and tumor pathology.MATERIALS AND METHODS: Data from 12 prospective cohort studies participating in the Epidemiology of Endometrial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid intakes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study-specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk.RESULTS: Women with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01-1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99-1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were associated with 12-19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not differ by cancer grade.CONCLUSION: Higher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly overweight/obese women.

Recently, ovarian cancer research has evolved considerably because of the emerging recognition that rather than a single disease, ovarian carcinomas comprise several different histotypes that vary by etiologic origin, risk factors, molecular profiles, therapeutic approaches and clinical outcome. Despite significant progress in our understanding of the etiologic heterogeneity of ovarian cancer, as well as important clinical advances, it remains the eighth most frequently diagnosed cancer in women worldwide and the most fatal gynecologic cancer. The International Agency for Research on Cancer and the United States National Cancer Institute jointly convened an expert panel on ovarian carcinoma to develop consensus research priorities based on evolving scientific discoveries. Expertise ranged from etiology, prevention, early detection, pathology, model systems, molecular characterization and treatment/clinical management. This report summarizes the current state of knowledge and highlights expert consensus on future directions to continue advancing etiologic, epidemiologic and prognostic research on ovarian carcinoma.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further similar to 15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.

PURPOSE Frequent aspirin use has been associated with reduced ovarian cancer risk, but no study has comprehensively assessed for effect modification. We leveraged harmonized, individual-level data from 17 studies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across subgroups of women with other ovarian cancer risk factors. METHODS Nine cohort studies from the Ovarian Cancer Cohort Consortium (n = 2,600 cases) and eight case-control studies from the Ovarian Cancer Association Consortium (n = 5,726 cases) were included. We used Cox regression and logistic regression to assess study-specific associations between frequent aspirin use (≥ 6 days/week) and ovarian cancer risk and combined study-specific estimates using random-effects meta-analysis. We conducted analyses within subgroups defined by individual ovarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of risk factors (0, 1, and ≥ 2). RESULTS Overall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20), with no significant heterogeneity by study design ( P = .48) or histotype ( P = .60). Although no association was observed among women with endometriosis, consistent risk reductions were observed among all other subgroups defined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, all P-heterogeneity > .05), including women with ≥ 2 risk factors (relative risk, 0.81; 95% CI, 0.73 to 0.90). CONCLUSION This study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent aspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer risk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of principle that chemoprevention programs with frequent aspirin use could target higher-risk subgroups.

Disinfection byproducts (DBPs) andWe investigated the relationship of these exposures with endometrial cancer risk in a large prospective cohort.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 (Higher average concentrations of DBPs (95th percentile: TTHMWe 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.

Though studies have observed inverse associations between use of analgesics (aspirin, NSAIDs, and acetaminophen) and the risk of several cancers, the potential biological mechanisms underlying these associations are unclear. We investigated the relationship between analgesic use and serum concentrations of estrogens, androgens, and their metabolites among postmenopausal women to provide insights on whether analgesic use might influence endogenous hormone levels, which could in turn influence hormone-related cancer risk. The study included 1,860 postmenopausal women from two case–control studies nested within the Women's Health Initiative Observational Study. Analgesic use was reported at study baseline. Fifteen estrogens and estrogen metabolites and 12 androgens and androgen metabolites were quantified in baseline serum by LC/MS-MS. Linear regression with inverse probability weighting, stratified by menopausal hormone therapy (MHT) use, was used to estimate adjusted geometric mean concentrations of each hormone by analgesic use. Among women not currently using MHT (n = 951), low-dose aspirin ( Prevention relevance: This study explores a potential pathway by which analgesic medications such as aspirin may prevent hormone-related cancers. The findings support a positive association between low-dose aspirin use and endogenous estrogens, indicating that further elucidation of the interplay between low-dose aspirin, estrogen concentrations, and cancer risk is needed.

Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271

PURPOSE: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival. METHODS: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery. RESULTS: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend

PURPOSE: Disentangling the effects of endogenous estrogens and inflammation on obesity-related diseases requires a clearer understanding of how the two biological mechanisms relate to each other. METHODS: We studied 155 healthy postmenopausal women not taking menopausal hormone therapy enrolled in the Prostate Lung Colorectal and Ovarian (PLCO) screening cancer trial. From a baseline blood draw, we measured endogenous estradiol and 69 inflammation biomarkers: cytokines, chemokines, adipokines, angiogenic factors, growth factors, acute phase proteins, and soluble receptors. We evaluated the estradiol–inflammation relationship by assessing associations across different models (linear, ordinal logistic, and binary logistic) using a variety of estradiol classifications. We additionally investigated the estradiol–inflammation relationship stratified by baseline obesity status (BMI < 30 stratum and BMI > 30 stratum). RESULTS: Associations of estradiol with 7 inflammation biomarkers met p < 0.05 statistical significance in linear and ordinal models: C-reactive protein (CRP), adiponectin, chemokine (C-X-C motif) ligand-6, thymus activation-regulated chemokine, eosinophil chemotactic protein, plasminogen activator inhibitor-1, and serum amyloid A. The positive association between estradiol and CRP was robust to model changes. Each standard deviation increase in endogenous estradiol doubled a woman’s odds of having CRP levels higher than the study median (odds ratio 2.29; 95% confidence interval 1.28, 4.09). Estradiol was consistently inversely associated with adiponectin. Other estradiol–inflammation biomarker associations were not robust to model changes. CONCLUSIONS: Endogenous estradiol appears to be associated with CRP and adiponectin; the evidence is limited for other inflammation biomarkers.

Objective: To evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis. Design: Pooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium. Setting: Population-based. Patient(s): We included 8,500 women with ovarian cancer, 13,592 control women. Intervention(s): Ten well-established ovarian cancer risk factors. Main Outcome Measure(s): Risk of ovarian cancer for women with and without endometriosis. Result(s): Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25–2 was associated with increased ovarian cancer risk among women with endometriosis (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.00–1.60), but not associated with the risk among women without endometriosis (OR = 0.97; 95% CI, 0.91–1.05) when compared with BMI 18.5–2; an increased risk was observed for a BMI ≥30 kg/m2, although there was little difference comparing women with endometriosis (OR = 1.21; 95% CI, 0.94–1.57) to women without (OR = 1.13; 95% CI, 1.04–1.22) (P-interaction = .51). Genital talcum powder use and long-term menopausal estrogen-only therapy use showed increased ovarian cancer risk, but risk appeared greater for those with endometriosis vs. those without (genital talcum powder: OR = 1.38; 95% CI, 1.04–1.84 vs. OR = 1.12; 95% CI, 1.01–1.25, respectively; ≥10 years of estrogen-only therapy: OR = 1.88; 95% CI, 1.09–3.24 vs. OR = 1.42; 95% CI, 1.14–1.76, respectively); neither of these interactions were statistically significant (P-interaction = .65 and P-interaction = .96, respectively). Conclusion(s): The associations between ovarian cancer and most risk factors were similar among women with and without endometriosis. However, there was some suggestion of differences by endometriosis status for BMI, menopausal hormone therapy use, and genital talcum powder use, highlighting the complexity of ovarian cancer etiology.

PURPOSE To determine whether recommended amounts of leisure-time physical activity (ie, 7.5-15 metabolic equivalent task [MET] hours/week) are associated with lower cancer risk, describe the shape of the dose-response relationship, and explore associations with moderate- and vigorous-intensity physical activity. METHODS Data from 9 prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence were pooled. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% CIs of the relationships between physical activity with incidence of 15 types of cancer. Dose-response relationships were modeled with restricted cubic spline functions that compared 7.5, 15.0, 22.5, and 30.0 MET hours/week to no leisure-time physical activity, and statistically significant associations were determined using tests for trend ( P < .05) and 95% CIs (< 1.0). RESULTS A total of 755,459 participants (median age, 62 years [range, 32-91 years]; 53% female) were followed for 10.1 years, and 50,620 incident cancers accrued. Engagement in recommended amounts of activity (7.5-15 MET hours/week) was associated with a statistically significant lower risk of 7 of the 15 cancer types studied, including colon (8%-14% lower risk in men), breast (6%-10% lower risk), endometrial (10%-18% lower risk), kidney (11%-17% lower risk), myeloma (14%-19% lower risk), liver (18%-27% lower risk), and non-Hodgkin lymphoma (11%-18% lower risk in women). The dose response was linear in shape for half of the associations and nonlinear for the others. Results for moderate- and vigorous-intensity leisure-time physical activity were mixed. Adjustment for body mass index eliminated the association with endometrial cancer but had limited effect on other cancer types. CONCLUSION Health care providers, fitness professionals, and public health practitioners should encourage adults to adopt and maintain physical activity at recommended levels to lower risks of multiple cancers.

Background: Prolonged sitting and physical inactivity are associated with higher circulating levels of estrogens. It is unknown whether these risk factors are associated with circulating androgens/androgen metabolites, another set of hormones implicated in the etiology of cancers in postmenopausal women. Methods: We conducted a cross-sectional analysis of 1,782 postmenopausal women in the Women's Health Initiative Observational Study. Serum concentrations of 12 androgens/androgen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Physical activity and sitting time were self-reported at baseline. We performed linear regression to estimate geometric means (GM) of androgen/androgen metabolite concentrations (pmol/L) according to physical activity and sitting time, adjusting for potential confounders and stratified by menopausal hormone therapy (MHT) use. Results: Physical activity (≥15 vs. 0 MET-h/wk) was inversely associated with estrogen-to-androgen ratios among never/former MHT users (adj-GM = 37.5 vs. 49.6 unconjugated estrone:androstenedione; 20.2 vs. 30.3 unconjugated estradiol:testosterone; all Ptrend ≤ 0.03) but was not associated among current MHT users. Prolonged sitting (≥10 vs. ≤5 h/d) was positively associated with these ratios among both never/former (adj-GM = 44.2 vs. 38.3, Ptrend = 0.10; adj-GM = 23.4 vs. 20.2, Ptrend = 0.17; respectively) and current MHT users (adj-GM = 197 vs. 147; 105 vs. 75.5; respectively; all Ptrend ≤0.02), but the associations were statistically significant among current MHT users only. The associations persisted after adjustment for BMI. After adjustment for adrenal androgens, physical activity and sitting were not associated with androgen metabolites. Conclusions: Physical activity and sitting were associated with serum estrogen-to-androgen ratios but not androgen metabolites. Impact: This study contributes to our understanding of the link between physical activity, sitting, and cancer risk in postmenopausal women.

Background: Postmenopausal pregnenolone and/or progesterone levels in relation to endometrial and ovarian cancer risks have been infrequently evaluated. To address this, we utilized a sensitive and reliable assay to quantify prediagnostic levels of seven markers related to endogenous hormone metabolism. Methods: Hormones were quantified in baseline serum collected from postmenopausal women in a cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT). Women using exogenous hormones at baseline (1992–1993) were excluded. Incident endometrial (n = 65) and ovarian (n = 67) cancers were diagnosed during 12 follow-up years and compared with a subcohort of 345 women (no hysterectomy) and 413 women (no oophorectomy), respectively. Cox models with robust variance were used to estimate cancer risk. Results: Circulating progesterone levels were not associated with endometrial [tertile (T)3 vs. T1 HR (95% confidence interval): 1.87 (0.85–4.11); Ptrend = 0.17] or ovarian cancer risk [1.16 (0.58–2.33); 0.73]. Increasing levels of the progesterone-to-estradiol ratio were inversely associated with endometrial cancer risk [T3 vs. T1: 0.29 (0.09–0.95); 0.03]. Increasing levels of 17-hydroxypregnenolone were inversely associated with endometrial cancer risk [0.40 (0.18–0.91); 0.03] and positively associated with ovarian cancer risk [3.11 (1.39–6.93); 0.01]. Conclusions: Using sensitive and reliable assays, this study provides novel data that endogenous progesterone levels are not strongly associated with incident endometrial or ovarian cancer risks. 17-hydroxypregnenolone was positively associated with ovarian cancer and inversely associated with endometrial cancer. Impact: While our results require replication in large studies, they provide further support of the hormonal etiology of endometrial and ovarian cancers.

BACKGROUND The overall incidence of gastric cancer in women is half that in men for most global populations. Sex hormone pathways may be involved in carcinogenesis and estrogens have been postulated to protect women against gastric cancer. AIM To evaluate associations of gastric cancer with estrogen metabolites in postmenopausal women. METHODS AND RESULTS We performed an analysis of 233 gastric cancer cases and 281 age-matched controls from three prospective cohorts and two case-control studies of early-stage gastric cancer, mainly conducted in high-risk Asian populations. Fifteen estrogen-parent (estrone and estradiol) and -metabolite analytes (2-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestrone-3-methyl ether, 4-hydroxyestrone; 4-methoxyestrone, 4-methoxyestradiol, 2-methoxyestrone, 2-methoxyestradiol, estriol, 16α-hydroxyestrone, 16-ketoestradiol, 16-epiestriol, and 17-epiestriol) were measured in spot urines using liquid chromatography-tandem mass spectrometry. Odds ratios for association with each marker were estimated by logistic regression. Heterogeneity was assessed by Cochran's Q test. Study-specific odds ratios were pooled by fixed-effects meta-analysis. Urinary levels of estrogen-related molecules were not associated with gastric cancer (adjusted odds ratios ranged from 0.87 to 1.27; p-values >.05), with low between-study heterogeneity (p-values >.1) for all but two metabolites (2-hydroxyestrone-3-methyl ether and 2-methoxyestradiol). CONCLUSION To date, this is the first comprehensive assessment of endogenous estrogens with gastric cancer risk in women. Estrogens do not appear to have an etiologic role in gastric cancer risk among postmenopausal women. Given the complex network of sex steroid hormones and their extreme variation over the lifespan, further evaluation of this hypothesis is warranted.

Menstrual pain has been associated with increased ovarian cancer risk, presumably through increased inflammation, which is known to play a critical role in ovarian carcinogenesis. Analgesic medications are frequently used to treat menstrual pain, some of which lower ovarian cancer risk. In this study, we examined the association between analgesic use for menstrual pain during the premenopausal period and ovarian cancer risk among women with history of menstrual pain. We used data from the New England Case-Control Study, including 1,187 epithelial ovarian cancer cases and 1,225 population-based controls enrolled between 1998 and 2008 with detailed information on analgesic use for their menstrual pain. We used unconditional logistic regression to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between analgesic use (i.e., aspirin, ibuprofen, acetaminophen) for menstrual pain and ovarian cancer risk. We further conducted a stratified analysis by intensity of menstrual pain (mild/moderate, severe). Among women with menstrual pain during their 20s and 30s, ever use of analgesics for menstrual pain was not significantly associated with ovarian cancer risk. However, among women with severe menstrual pain, ever use of aspirin or acetaminophen for menstrual pain was inversely associated with risk (OR, 0.41; 95% CI, 0.18–0.94 and OR, 0.43; 95% CI, 0.21–0.88 compared with never users, respectively). No significant association was observed between analgesic use and ovarian cancer risk among women with mild/moderate menstrual pain (Pinteraction ≤ 0.03). Our results suggest that use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer. Prevention Relevance: This study investigates whether analgesic use specifically for menstrual pain during the premenopausal period influences ovarian cancer risk. Our results suggest use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer among women with severe menstrual pain.

Background Physical activity is associated with lower risk for endometrial cancer, but the extent to which the association is mediated by body mass index (BMI) in midlife is unclear. This study describes the physical activity–endometrial cancer association and whether BMI mediates this relationship. Methods Participants were 67 705 women in the National Institutes of Health-AARP Diet and Health Study (50-71 years) who recalled their physical activity patterns starting at age 15-18 years. We identified 5 long-term physical activity patterns between adolescence and cohort entry (ie, inactive, maintained low, maintained high, increasers, decreasers). We used Cox regression to assess the relationship between these patterns and midlife BMI and endometrial cancer, adjusting for covariates. Mediation analysis was used to estimate the proportion of the physical activity–endometrial cancer association that was mediated by midlife BMI. Results During an average 12.4 years of follow-up 1468 endometrial cancers occurred. Compared with long-term inactive women, women who maintained high or increased activity levels had a 19% to 26% lower risk for endometrial cancer (maintained high activity: hazard ratio = 0.81, 95% confidence interval [CI] = 0.67 to 0.98; increasers: hazard ratio = 0.74, 95% CI = 0.61 to 0.91). They also had a 50% to 77% lower risk for obesity in midlife (eg, maintained high activity: odds ratio for a BMI of 30-39.9 kg/m2 = 0.50, 95% CI = 0.46 to 0.55; and maintained high activity, odds ratio for a BMI of ≥40 kg/m2 = 0.32, 95% CI = 0.26 to 0.39). BMI was a statistically significant mediator accounting for 55.5% to 62.7% of the physical activity–endometrial cancer associations observed. Conclusions Both maintaining physical activity throughout adulthood and adopting activity later in adulthood can play a role in preventing obesity and lowering the risk for endometrial cancer.

Objective To clarify associations between metabolic syndrome, its components, and ovarian cancer risk. Methods Using a case-control study within the U.S.-based Surveillance, Epidemiology and End Results (SEER)–Medicare linked database, we examined metabolic syndrome, its components (obesity, impaired fasting glucose, hypertension, HDL cholesterol, triglycerides), and ovarian/fallopian tube cancer risk. Cases (n = 16,850) were diagnosed with cancer between age 68–89 from 1994 through 2013. Controls (n = 281,878) were Medicare enrollees without these cancers living in registry areas. We estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) with logistic regression. Results Women with metabolic syndrome had reduced ovarian cancer risk compared to women not meeting the diagnostic criteria (OR 0.86, CI 0.82–0.89). Having one or two syndrome components was associated with increased risk, but having ≥3 was not, when compared to women without any components. Impaired fasting glucose, which was highly prevalent among those with metabolic syndrome, was associated with reduced risk (OR 0.90, CI 0.87–0.93). Hypertension and high triglycerides, the most prevalent components among women without metabolic syndrome, were associated with increased risks (OR 1.08, CI 1.04–1.12; OR 1.05, CI 1.01–1.08, respectively). Conclusions Specific metabolic syndrome components may have modest associations with ovarian cancer. These associations varied in direction and the prevalence of the components influenced the overall association between metabolic syndrome and ovarian cancer. Evaluating metabolic syndrome as a composite exposure could be misleading in ovarian cancer research, but further study of the syndrome components is warranted.

Ovarian cancer is the eighth most common cancer in women worldwide and incidence rates vary markedly by world region. This study provides a comprehensive overview of ovarian cancer incidence trends globally, examining the influence of birth cohort and period of diagnosis on changing risk. We presented current patterns and trends of ovarian cancer incidence until 2012 using data from successive volumes of Cancer Incidence in Five Contents. The incidence of ovarian cancer is highest in northern and eastern European countries, and in northern America. Declining trends were observed in most countries with the exception of a few central and eastern Asian countries. Marked declines were seen in Europe and North America for women aged 50–74 where rates have declined up to 2.4% (95% CI: −3.9, ‒0.9) annually in Denmark over the last decade. Additionally, declines in the incidence rate ratio (IRR) were observed for generations born after the 1930s, with an additional strong period effect seen around 2000 in United States and Denmark. In contrast, IRRs increased among younger generations born after the 1950s in Japan and Belarus. Overall, the favourable trends in ovarian cancer incidence is likely due to the increase use of oral contraceptive pills, and changes in the prevalence of other reproductive risk and protective factors for ovarian cancer over the years studied. Changes in disease classifications and cancer registry practices may also partially contribute to the variation in ovarian cancer incidence rates. Thus, continuous cancer surveillance is essential to detect the shifting patterns of ovarian cancer.

Background Experimental studies suggest that shallow uterine cytotrophoblastic invasion in preeclampsia may be associated with alterations in estrogen metabolism. The objective of this study was to examine the association of parent estrogens and their metabolites between preeclamptics and normotensive controls at three time points during pregnancy. Methods Parent estrogens and their metabolites were measured in urine by high-performance liquid chromatography-tandem mass spectrometry in 66 singleton preeclampsia cases and 137 matched controls. Percent change in geometric means were estimated by general linear models adjusted for gestational age at sampling, maternal age, parity, race, body mass index, and use of assisted reproductive technologies. Results Urinary estradiol concentrations were approximately 50% higher in early pregnancy in preeclampsia cases than controls, but similar late in pregnancy. There was an approximate 20% reduction in total 2-pathway metabolites and 4-pathway metabolites in cases compared with controls in mid- and later pregnancy that was slightly attenuated with adjustment for BMI, and a reduction in 16-pathways in mid-pregnancy but not later. Conclusion(s) Our findings show that estradiol concentrations were elevated in preeclampsia versus controls in early pregnancy. In mid-pregnancy, all three estrogen metabolism (2-, 4-, and 16-) pathways showed some reduction in preeclampsia that appeared to continue for the 2- and 4-pathways in late pregnancy. We hypothesize that this may indicate that there is a generalized reduction in estrogen metabolism in preeclampsia rather than a deficit of specific enzymes, such as those involved in the 2-hydroxylation pathway.

Background: Evidence suggests that inflammation increases risk for ovarian cancer. Aspirin has been shown to decrease ovarian cancer risk, though the mechanism is unknown. Studies of inflammatory markers, lipid molecules such as arachidonic acid, linoleic acid, and alpha-linoleic acid metabolites, and development of ovarian cancer are essential to understand the potential mechanisms. Methods: We conducted a nested case–control study (157 cases/156 matched controls) within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Unconditional logistic regression was used to estimate the association between prediagnostic serum levels of 31 arachidonic acid/linoleic acid/alpha-linoleic acid metabolites and risk of ovarian cancer. Results: Five of the 31 arachidonic acid/linoleic acid/alpha-linoleic acid (free fatty acids) metabolites were positively associated with ovarian cancer risk: 8-HETE [tertile 3 vs. 1: OR 2.53 (95% confidence interval [CI] 1.18–5.39), Ptrend 0.02], 12,13-DHOME [2.49 (1.29–4.81), 0.01], 13-HODE [2.47 (1.32–4.60), 0.005], 9-HODE [1.97 (1.06–3.68), 0.03], 9,12,13-THOME [2.25 (1.20–4.21), 0.01]. In analyses by subtype, heterogeneity was suggested for 8-HETE [serous OR (95% CI): 2.53 (1.18–5.39) vs. nonserous OR (95% CI): 1.15 (0.56–2.36), Phet 0.1] and 12,13-EpOME [1.95 (0.90–4.22) vs. 0.82 (0.39–1.73), 0.05]. Conclusions: Women with increased levels of five fatty acid metabolites (8-HETE, 12,13-DHOME, 13-HODE, 9-HODE, and 9,12,13-THOME) were at increased risk of developing ovarian cancer in the ensuing decade. All five metabolites are derived from either arachidonic acid (8-HETE) or linoleic acid (12,13-DHOME, 13-HODE, 9-HODE, 9,12,13-THOME) via metabolism through the LOX/cytochrome P450 pathway. Impact: The identification of these risk-related fatty acid metabolites provides mechanistic insights into the etiology of ovarian cancer and indicates the direction for future research.

Background: Adult body size is related to ovarian cancer risks, but size in childhood may also influence risks. We investigated if childhood body mass index (kg/m2), height, and growth patterns were associated with ovarian cancer overall and by histologic subtypes, including effects of birthweight. Methods: A cohort of 155,958 girls from the Copenhagen School Health Records Register, born 1930 to 1989 with measured weights and heights from 7 to 13 years, were included. During follow-up, 1,041 ovarian cancers were recorded. Overweight was defined using International Obesity Task Force criteria. Cox regressions were performed. Results: Compared with non-overweight girls, at most ages girls with overweight had increased risks of ovarian cancer overall (HR range: 1.24–1.34), mucinous, endometrioid, and clear cell ovarian cancers, but not serous and other ovarian cancers. Childhood height had positive and significant associations with ovarian cancer overall (HR range: 1.07–1.10 per z-score) and the endometrioid subtype but not with the other subtypes. Adjusting for birthweight minimally altered the associations with childhood body size. In growth analyses, girls with overweight or who were tall at 7 and 13 years had increased risks of ovarian cancer overall compared with average-sized girls at both ages. Conclusions: Ovarian carcinogenesis is linked to childhood overweight, tallness, and growth, with variations across histological subtypes, suggesting that early life plays a role in the origins of this disease. Impact: These findings emphasize that healthy body size and growth during childhood are important as they may contribute to reducing ovarian cancer risks.

BACKGROUND: Studies disagree as to whether intakes of folate-mediated one-carbon metabolism nutrients are associated with endometrial cancer. METHODS: Using data from the large, prospective NIH-AARP Diet and Health Study, we used Cox proportional hazards models to evaluate endometrial cancer risk associated with calorie-adjusted dietary intake of several B vitamins and methionine. All models accounted for age, race, body mass index (BMI), smoking, oral-contraceptive use, menopausal hormone therapy use and caloric intake. We estimated associations by time from baseline (≤3 or >3 years) and stratified models by BMI (3 years from baseline. We observed risks for the highest intakes of B2 [Q5 vs Q1: HR 1.27 95% confidence interval (CI) 1.07–1.50], B12 (Q5 vs Q1: HR 1.38 CI 1.17–1.63) and methionine (Q5 vs Q1: HR 1.26 CI 1.07–1.48) among women who were overweight/obese, but not among normal/underweight women. CONCLUSIONS: Our findings indicate that one-carbon metabolism plays a role in endometrial carcinogenesis and exploration of this role in tissue and cellular biology studies is warranted.

PURPOSE: The comparability between serum, plasma, and urinary measurements of estrogen metabolites via liquid chromatography-tandem mass spectrometry (LC-MS/MS) has not been largely explored, and it is unclear if urinary LC-MS/MS measurements are suitable surrogates of circulating levels. METHODS: Serum, plasma (EDTA and heparin), and urinary estrogen/estrogen metabolite levels were measured via LC-MS/MS in paired samples from 64 healthy volunteers (18 men, 20 premenopausal women, 26 postmenopausal women). Geometric means and Spearman correlation coefficients were used to compare individual and combined pathway levels of estrogens/estrogen metabolites across biologic matrices by sex/menopausal status. RESULTS: Measured concentrations of estrogens/estrogen metabolites across blood matrices were almost identical (percent differences

Background: The association between circulating cholesterol and triglyceride levels and ovarian cancer risk remains unclear. Methods: We prospectively evaluated the association between cholesterol [total, low-density lipoprotein (LDL-C), and high-density lipoprotein (HDL-C)] and triglycerides and ovarian cancer incidence in a case–control study nested in the Nurses' Health Study (NHS) and NHSII cohorts and a longitudinal analysis in the UK Biobank. Results: A total of 290 epithelial ovarian cancer cases in the NHS/NHSII and 551 cases in UK Biobank were diagnosed after blood collection. We observed a reduced ovarian cancer risk comparing the top to bottom quartile of total cholesterol [meta-analysis relative risk (95% confidence interval): 0.81 (0.65–1.01), Ptrend 0.06], with no heterogeneity across studies (Pheterogeneity = 0.74). Overall, no clear patterns were observed for HDL-C, LDL-C, or triglycerides and ovarian cancer risk. Comparing triglyceride levels at clinically relevant cut-off points (>200 vs. ≤200 mg/dL) for cases diagnosed more than 2 years after blood draw saw a positive relationship with risk [1.57 (1.03–2.42); Pheterogeneity = 0.003]. Results were similar by serous/non-serous histotype, menopausal status/hormone use, and body mass index. Conclusions: Data from two large cohorts in the United States and United Kingdom suggest that total cholesterol levels may be inversely associated with ovarian cancer risk, while triglycerides may be positively associated with risk when assessed at least 2 years before diagnosis, albeit both associations were modest. Impact: This analysis of two large prospective studies suggests that circulating lipid levels are not strongly associated with ovarian cancer risk. The positive triglyceride–ovarian cancer association warrants further evaluation.

When powder is applied to the genital area, it has the potential to reach internal reproductive organs and promote carcinogenesis by irritating and inflaming exposed tissues. Although many studies have considered the association between genital powder use and ovarian cancer risk, the relationship between genital powder use and uterine cancer is less well-studied. We pooled data from four large, prospective cohorts (the Nurses' Health Study, the Nurses' Health Study II, the Sister Study and the Women's Health Initiative - Observational Study). We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for prespecified confounders. In total, 209 185 women were included, with 37% reporting ever genital powder use. Over a mean 14.5 years of follow-up, 3272 invasive uterine cancers were diagnosed. There was no overall association between ever genital powder use and uterine cancer (HR = 1.01, 95% CI: 0.94-1.09), with little difference observed for frequent (≥1 times/week) vs never use (HR = 1.05, 95% CI: 0.95-1.16; P-for-trend = .46). Long-term use (>20 years; HR = 1.12, 95% CI: 0.96-1.31; P-for-trend = 0.14) was associated with a small, but not statistically significant, increase in risk, compared to never use. There were not clear differences by uterine cancer histologic subtypes or across strata of relevant covariates, including race/ethnicity, follow-up time, menopausal status and body mass index. The results of this large, pooled analysis do not support a relationship between the use of genital powder and uterine cancer, although the positive associations observed for long-term use may merit further consideration.

Background: The role of progestogens in colorectal cancer development is poorly characterized. To address this, our group developed a highly sensitive assay to measure concentrations of seven markers of endogenous progestogen metabolism among postmenopausal women. Methods: The markers were measured in baseline serum collected from postmenopausal women in a case-cohort study within the breast and bone follow-up to the fracture intervention trial (B∼FIT). We followed women not using exogenous hormones at baseline (1992–1993) for up to 12 years: 187 women with incident colorectal cancer diagnosed during follow-up and a subcohort of 495 women selected on strata of age and clinical center. We used adjusted Cox regression models with robust variance to estimate risk for colorectal cancer [hazard ratios (HR), 95% confidence intervals (CI)]. Results: High concentrations of pregnenolone and progesterone were not associated with colorectal cancer [quintile(Q)5 versus Q1: pregnenolone HR, 0.71, 95% CI, 0.40–1.25; progesterone HR, 1.25; 95% CI, 0.71–2.22]. A trend of increasing risk was suggested, but statistically imprecise across quintiles of 17-hydroxypregnenolone (Q2 to Q5 HRs, 0.75–1.44; Ptrend, 0.06). Conclusions: We used sensitive and reliable assays to measure multiple circulating markers of progestogen metabolism. Progestogens were generally unassociated with colorectal cancer risk in postmenopausal women. Impact: Our findings are consistent with most prior research on circulating endogenous sex hormones, which taken together suggest that sex hormones may not be major drivers of colorectal carcinogenesis in postmenopausal women.

Background: Epithelial ovarian, fallopian tube, and primary peritoneal cancers have shared developmental pathways. Few studies have prospectively examined heterogeneity in risk factor associations across these three anatomic sites. Methods: We identified 3,738 ovarian, 337 peritoneal, and 176 fallopian tube incident cancer cases in 891,731 women from 15 prospective cohorts in the Ovarian Cancer Cohort Consortium. Associations between 18 putative risk factors and risk of ovarian, peritoneal, and fallopian tube cancer, overall and for serous and high-grade serous tumors, were evaluated using competing risks Cox proportional hazards regression. Heterogeneity was assessed by likelihood ratio tests. Results: Most associations did not vary by tumor site (Phet ≥ 0.05). Associations between first pregnancy (Phet = 0.04), tubal ligation (Phet = 0.01), and early-adult (age 18–21 years) body mass index (BMI; Phet = 0.02) and risk differed between ovarian and peritoneal cancers. The association between early-adult BMI and risk further differed between peritoneal and fallopian tube cancer (Phet = 0.03). First pregnancy and tubal ligation were inversely associated with ovarian, but not peritoneal, cancer. Higher early-adult BMI was associated with higher risk of peritoneal, but not ovarian or fallopian tube, cancer. Patterns were generally similar when restricted to serous and high-grade serous cases. Conclusions: Ovarian, fallopian tube, and primary peritoneal cancers appear to have both shared and distinct etiologic pathways, although most risk factors appear to have similar associations by anatomic site. Impact: Further studies on the mechanisms underlying the differences in risk profiles may provide insights regarding the developmental origins of tumors arising in the peritoneal cavity and inform prevention efforts.

PURPOSE: Since the 1960s, increasing oral contraceptive (OC) use has mirrored decreasing ovarian cancer incidence. The impact of intrauterine devices (IUDs) on cancer risk is less well established. With improved access and increased options, we must consider how changing usage can affect cancer risks. METHODS: Nationally representative data from the National Health and Nutrition Examination Survey (NHANES, 1999–2016) and the National Survey for Family Growth (NSFG, 2006–2017) were used to evaluate contraceptive use over time in premenopausal women (NHANES N=13,179; NSFG N=26,262). Trends were assessed overall and by race, age, pregnancy history, education, and body mass index. RESULTS: The average annual absolute increase in self-reported IUD use was 0.81% (NSFG), while OC use decreased 0.49% in NSFG and 0.47% in NHANES. This represents a significant decrease in OC use in NSFG [annual percent change (APC) −2.2% (95%CI −3.4, −1.0%), P

Objective Identifying potentially modifiable risk factors for ovarian cancer is essential for prevention because this cancer is predominantly detected at a late stage. Here, we estimated the relations of general adiposity and measures reflecting body fat distribution to the risk of epithelial ovarian cancer. Methods We ascertained 683 ovarian epithelial cancers (343 high-grade serous, 141 non-high grade serous) among 145,575 women, aged 50–72 years (median follow-up 12.6 years), from the National Institutes of Health—American Association of Retired Persons (NIH-AARP) Diet and Health Study. Using Cox models, we estimated confounder-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for associations of overall ovarian cancer, high-grade serous and non-high-grade serous carcinoma with body mass index, waist circumference, hip circumference, waist–hip ratio, waist–height ratio, body adiposity index, body shape index, and abdominal volume index. Results Anthropometric measures were unrelated to overall ovarian cancer, high-grade serous cancer, and non-high-grade serous cancer. For example, the HR for overall ovarian cancer per standard deviation increment of body mass index at baseline was 0.98 (95% CI 0.88–1.10). Similar associations were observed with measurements of body fat distribution. Conclusion These results do not indicate that adult adiposity is associated with ovarian cancer risk in post-menopausal women.

OBJECTIVE: Frequent use of aspirin has been associated with reduced ovarian cancer risk in observational studies, but it is unclear if only daily, low-dose aspirin confers a protective benefit. We examined associations between patterns of aspirin use and ovarian cancer risk among postmenopausal women in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. METHODS: Participants were enrolled in PLCO between 1993-2001 and followed for cancer outcomes through 2014. Detailed data on aspirin use (e.g., dose, frequency and duration) were ascertained via the supplemental questionnaire (SQX) administered in 2006-2007. We used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between aspirin use (defined as use ≥once/week) and incident ovarian cancer. We conducted analyses among all women in the study sample and stratified by age at the time of the SQX. RESULTS: There were 41,633 women included in this analysis, of whom 223 developed incident ovarian cancer. Overall, aspirin use was not significantly associated with ovarian cancer risk (HR: 0.93, 95% CI: 0.72-1.21). Among women

PURPOSE: Daily aspirin use has been shown to reduce risk of colorectal, and possibly other, cancers, but it is unknown if these benefits are consistent across subgroups of people with differing cancer risk factors. We investigated whether age, body mass index (BMI), smoking status, physical inactivity, and family history of cancer modify the effect of daily aspirin use on colorectal, ovarian, breast, endometrial and aggressive prostate cancer risk. METHODS: We pooled 423,495 individuals from two prospective, U.S.-based studies: the NIH-AARP Diet and Health Study (1995–2011) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (1993–2009). Using Cox proportional hazards regression, we examined associations between daily aspirin use (≥5 days/week) and risk of colorectal, ovarian, breast, endometrial, and aggressive prostate cancer, overall and across strata of risk factors. RESULTS: Daily aspirin use was associated with a 15% reduction in colorectal cancer risk (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.80–0.89). Risk reductions were generally consistent across strata of risk factors but attenuated with increasing BMI (p-interaction=0.16). For ovarian cancer, there was no significant association overall (HR: 0.93, 95% CI: 0.80–1.08) but reduced risk among obese women (HR: 0.73, 95% CI: 0.52–0.98, p-interaction=0.12). Weak or null associations were observed for breast, endometrial, and aggressive prostate cancer, with no strong effect modification observed. CONCLUSIONS: Daily aspirin use appears to reduce colorectal cancer risk regardless of other risk factors, though the potential modifying effect of BMI warrants further investigation and may need to be considered in risk-benefit calculations for aspirin use.

Background: Body size in adult life is likely associated with risks of endometriosis and adenomyosis, yet little is known about associations with body size earlier in life. Aim: To examine whether birth weight, childhood body mass index (BMI) and height are associated with risks of endometriosis and adenomyosis. Subjects and methods: From the Copenhagen School Health Records Register, 171,447 girls born 1930–1996, with measured weights and heights at ages 7–13 were included. Outcomes were obtained from health registers. Cox regressions were performed to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results: During follow-up, 2149 endometriosis cases and 1410 adenomyosis cases were diagnosed. Childhood BMI was inversely associated with endometriosis (HR = 0.92 [95% CI: 0.88–0.96] per z-score at age 7). In contrast, childhood height was positively associated with endometriosis (HR = 1.09 [95% CI: 1.05–1.14] per z-score at age 7). Associations with childhood body size did not differ by endometriosis location. Childhood BMI and height had limited associations with adenomyosis. Birth weight was not associated with endometriosis or adenomyosis. Conclusion: Lean and tall girls are more often diagnosed with endometriosis, but not adenomyosis. These findings suggest that indicators of endometriosis risk are already apparent at early ages.

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile ( Significance: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.

Timing of breast development (or thelarche) and its endogenous and exogenous determinants may underlie global variation in breast cancer incidence. The study objectives were to characterize endogenous estrogen levels and bisphenol A (BPA) exposure using a migrant study of adolescent girls and test whether concentrations explained differences in thelarche by birthplace and growth environment. Estrogen metabolites (EM) and BPA-glucuronide (BPA-G) were quantified in urine spot samples using liquid chromatography tandem mass spectrometry (LC-MS/MS) from a cross-sectional study of Bangladeshi, first- and second-generation Bangladeshi migrants to the UK, and white British girls aged 5&ndash, 16 years (n = 348). Thelarche status at the time of interview was self-reported and defined equivalent to Tanner Stage &ge, 2. We compared geometric means (and 95% confidence interval (CIs)) of EM and BPA-G using linear regression and assessed whether EM and BPA-G explained any of the association between exposure to the UK and the age at thelarche using hazard ratios and 95% confidence intervals. Average EM decreased with exposure to the UK, whereas BPA-G increased and was significantly higher among white British (0.007 ng/mL, 95% CI: 0.0024&ndash, 0.0217) and second-generation British-Bangladeshi girls (0.009 ng/mL, 95% CI: 0.0040&ndash, 0.0187) compared to Bangladeshi girls (0.002 ng/mL, 95% CI: 0.0018&ndash, 0.0034). Two of four EM ratios (16-pathway/parent and parent/all pathways) were significantly associated with thelarche. The relationship between exposure to the UK and thelarche did not change appreciably after adding EM and BPA-G to the models. While BPA-G is often considered a ubiquitous exposure, our findings suggest it can vary based on birthplace and growth environment, with increasing levels for girls who were born in or moved to the UK. Our study did not provide statistically significant evidence that BPA-G or EM concentrations explained earlier thelarche among girls who were born or raised in the UK.

PURPOSE: The link between lipid-stabilizing medications and epithelial ovarian carcinogenesis is incompletely understood. Statins may reduce ovarian cancer risk, but results are inconclusive. METHODS: We conducted a systematic review and meta-analysis of studies reporting associations between statin use and ovarian cancer risk in PubMed. Summary risk ratios (RRs) and confidence intervals (CIs) were calculated. Subgroup analyses by cancer histotype, statin class (lipo- or hydrophilic) and duration of statin use were conducted. Use of individual statins in populations was assessed to determine population-specific differences in statin types. RESULTS: Nine studies with 435,237 total women were included (1 Randomized controlled trial (RCT); 4 prospective; 4; case-control). Statin use was associated with a reduced risk of ovarian cancer (RR 0.87, 95% CI: 0.74–1.03) and risk was significantly reduced in populations with low pravastatin use (RR 0.83, 95% CI: 0.70–0.99). Risk estimates varied by statin class (3 studies; lipophilic: RR 0.88, 95% CI: 0.69–1.12; hydrophilic: RR 1.06, 95% CI: 0.72–1.57) and cancer histotype (3 studies; serous: RR 0.95, 95% CI: 0.69–1.30; clear cell: RR 1.17, 95% CI: 0.74–1.86). Long-term use was associated with a reduced risk of ovarian cancer (RR 0.77, 95% CI: 0.54–1.10) that further reduced when pravastatin use was low (RR 0.68, 95% CI: 0.46–1.01). Between-study heterogeneity was high overall and in subgroups (I(2) > 60%). CONCLUSION: Statins may be associated with a reduced risk of ovarian cancer, but the effect likely differs by individual statin, duration of use and cancer histotype. Additional well-powered studies are needed to elucidate important subgroup effects.

Background - Regular use of aspirin has been associated with a reduced risk of cancer at several sites but the data for endometrial cancer are conflicting. Evidence regarding use of other analgesics is limited. Patients and methods - We pooled individual-level data from seven cohort and five case–control studies participating in the Epidemiology of Endometrial Cancer Consortium including 7120 women with endometrial cancer and 16 069 controls. For overall analyses, study-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression and combined using random-effects meta-analysis; for stratified analyses, we used mixed-effects logistic regression with study as a random effect. Results - At least weekly use of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an approximately 15% reduced risk of endometrial cancer among both overweight and obese women (OR = 0.86 [95% CI 0.76–0.98] and 0.86 [95% CI 0.76–0.97], respectively, for aspirin; 0.87 [95% CI 0.76–1.00] and 0.84 [0.74–0.96], respectively, for non-aspirin NSAIDs). There was no association among women of normal weight (body mass index 2, Pheterogeneity = 0.04 for aspirin, Pheterogeneity = 0.003 for NSAIDs). Among overweight and obese women, the inverse association with aspirin was stronger for use 2–6 times/week (OR = 0.81, 95% CI 0.68–0.96) than for daily use (0.91, 0.80–1.03), possibly because a high proportion of daily users use low-dose formulations. There was no clear association with use of acetaminophen. Conclusion - Our pooled analysis provides further evidence that use of standard-dose aspirin or other NSAIDs may reduce risk of endometrial cancer among overweight and obese women.

Background Non-epithelial ovarian cancers are divided into sex cord-stromal tumours (SCSTs) and germ cell tumours (GCTs). Whereas parity and other pregnancy-related factors are protective for epithelial ovarian cancer, their associations with SCSTs and GCTs remains unclear. Methods Using data from the medical birth registries from Denmark, Finland, Norway and Sweden, we compared all parous women with a diagnosis of SCSTs (n = 420) or GCTs (n = 345) 1970–2013 with up to 10 parous controls (SCSTs n = 4041; GCTs n = 2942) matched on the cases’ birth year and country. We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) of associations between pregnancy-related factors and SCSTs and GCTs. Results The risk of SCSTs, but not GCTs, decreased with higher age at last birth [≥40 versus Conclusions We found a decreased risk of SCSTs with higher age at last birth and shorter time since last birth. The risk of SCSTs (but not GCTs) may be influenced by the woman’s reproductive history.

Epithelial ovarian cancer is a fatal disease of largely unknown etiology. Higher parity is associated with reduced risk of ovarian cancer. However, among parous women, the impact of pregnancy-related factors on risk is not well understood. This population-based case–control study included all parous women with epithelial ovarian cancer in Denmark, Finland, Norway and Sweden during 1967–2013 (n = 10,957) and up to 10 matched controls (n = 107,864). We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for pregnancy-related factors and ovarian cancer risk by histological subtype. Preterm delivery was associated with an increased risk [pregnancy length (last pregnancy) ≤30 vs. 39–41 weeks, OR 1.33 (95% CI 1.06–1.67), adjusted for number of births]; the OR increased as pregnancy length decreased (p for trend < 0.001). Older age at first and last birth was associated with a decreased risk [first birth: 30–39 vs. heterogeneity < 0.001]. No associations were observed for multiple pregnancies, preeclampsia or offspring size. In conclusion, in addition to high parity, full-term pregnancies and pregnancies at older ages were associated with decreased risk of ovarian cancer. Our findings favor the cell clearance hypothesis, i.e. a recent pregnancy provides protection by clearing of precancerous cells from the epithelium of the ovary/fallopian tubes, mediated by placental or ovarian hormones.

Background The etiology of testicular germ cell tumors (TGCT) is poorly understood, however, exposure to endocrine disrupting chemicals (EDCs) may be related to increased risk. Personal care products, some of which contain EDCs, are widely used on a daily basis and are known to cross the placenta, be present in breastmilk, and are capable of inducing reproductive tract abnormalities. To determine the association between personal care product use during pregnancy and breastfeeding and TGCT risk, an analysis among mothers of TGCT cases and controls was conducted. Methods The US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) study enrolled TGCT cases and controls and their mothers between 2002 and 2005. The current analysis examined personal care product use during pregnancy among 527 mothers of TGCT cases and 562 mothers of controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for identified covariates. Results Maternal use of face lotion more than one time per week was associated with a significantly increased risk of TGCT (OR: 1.42, 95% CI: 1.08–1.86, p-trend: 0.01). None of the other products examined (perfume, hairspray, nail polish, hair dye, permanent wave, body lotion, deodorant, sunscreen) were associated with TGCT risk. Conclusions Frequent exposure to face lotion during pregnancy and while breastfeeding may be associated with increased TGCT risk. Further investigation into the endocrine disrupting effects of personal care products is warranted.

Background Studies of birth weight associations with ovarian and endometrial cancer risks are limited with inconsistent results, and none has evaluated associations by histologic subtype. We utilized prospectively collected birth weight information to investigate the association with risk of ovarian and endometrial cancers overall and by histologic subtype. Methods 162,559 girls, born from 1930 to 1989, from the Copenhagen School Health Records Register (CSHRR) were followed prospectively via linkage with the Danish health registers. Ovarian (n=666) and endometrial (n=694) cancers were identified from 1978 to 2014. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results Women with lower (2.0–3.25 vs. 3.26–3.75kg) and higher (3.75–5.5 vs. 3.26–3.75kg) birth weights had increased risks of ovarian cancer overall [HR (95% CI): 1.27 (1.06–1.52); 1.51 (1.21–1.87), respectively] and serous ovarian cancers [1.54 (1.19–1.98); 1.98 (1.47–2.67), respectively]. A decreased risk of Type II endometrial tumors was suggested per kilogram increase in birth weight [HR (95% CI): 0.63 (0.40–1.00)]. Conclusions Our results suggest that both lower and higher birth weights were associated with increased ovarian cancer risk and associations were particularly strong for serous ovarian cancer, the most common subtype. Birth weight was not associated with most types of endometrial cancer.

OBJECTIVE: Many high-grade serous carcinomas initiate in fallopian tubes as serous tubal intraepithelial carcinoma (STIC), a microscopic lesion identified with specimen processing according to the Sectioning and Extensive Examination of the Fimbria protocol (SEE-Fim). Given that the tubal origin of these cancers was recently recognized, we conducted a survey of pathology practices to assess processing protocols that are applied to gynecologic surgical pathology specimens in clinical contexts in which finding STIC might have different implications. METHODS: We distributed a survey electronically to the American Society for Clinical Pathology list-serve to determine practice patterns and compared results between practice types by chi-square (χ2) tests for categorical variables. Free text comments were qualitatively reviewed. RESULTS: Survey responses were received from 159 laboratories (72 academic, 87 non-academic), which reported diverse specimen volumes and percentage of gynecologic samples. Overall, 74.1% of laboratories reported performing SEE-Fim for risk-reducing surgical specimens (82.5% academic versus 65.7% non-academic, p

Although use of oral contraceptives (OCs) is common, their influence on carcinogenesis is not fully understood. We used Cox proportional hazards models to examine OC use (never/

Background: Alcohol consumption is associated with an increased risk of several cancers. Potential mechanisms include altered oestrogen metabolism. Parent oestrogens metabolise into alternate pathways of oestrogen metabolites that may have variable effects on cancer pathogenesis. We examined associations of alcohol consumption with circulating oestrogen/oestrogen metabolites in postmenopausal women in the Women’s Health Initiative (WHI)-Observational Study (OS). Methods: We conducted a cross-sectional analysis of prediagnosis ovarian/endometrial cancer case-control data within WHI-OS (N=1864). Alcohol consumption was measured by validated food frequency questionnaire. Fasting serum parent oestrogens/oestrogen metabolites were assayed using liquid chromatography tandem mass-spectrometry. Geometric mean analyte concentrations (GM, pmol l−1) were calculated by alcohol category using inverse-probability weighted linear regression, adjusting for venepuncture age/year, race, smoking, body mass index, years since menopause, oral contraceptive duration, caffeine intake, and physical activity. Results: There was evidence for a positive association between alcohol consumption and oestrone, oestradiol and 2-hydroxylation oestrogen metabolite concentrations among menopausal hormone therapy (MHT) users. We observed an association between liquor consumption and parent oestrogens among non-MHT users, who consumed larger doses of liquor than MHT users. Conclusions: Among postmenopausal women, the association between alcohol intake and parent oestrogen, but not oestrogen metabolite concentrations, may be influenced by MHT and type of alcohol.

Prolonged sitting and lower levels of physical activity have been associated with increased levels of parent oestrogens (oestrone and oestradiol), the key hormones in female cancers, in postmenopausal women. However, it is unknown whether sitting and physical activity are associated with circulating oestrogen metabolite levels.Among 1804 postmenopausal women enrolled in the Women's Health Initiative Observational Study, 15 serum oestrogens/oestrogen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Physical activity and sitting were self-reported via questionnaire. Using baseline, cross-sectional data, geometric means (GM) of oestrogens/oestrogen metabolites (pmol lLonger time spent sitting (⩾10 vs ⩽5h per day) was associated with higher levels of unconjugated oestrone, independent of moderate- to vigorous-intensity physical activity and body mass index, among both never/former (GM=70.6 vs 57.7) and current MHT users (GM=242 vs 179) (P-trend ⩽0.03). Among never/former MHT users, sitting (⩾10 vs ⩽5h per day) was positively associated with 2-methoxyestradiol (GM=16.4 vs 14.4) and 4-methoxyestradiol (GM=2.36 vs 1.98) (P-trend ⩽0.04), independent of parent oestrogens. Inverse associations between moderate- to vigorous-intensity physical activity (⩾15 vs 0 metabolic equivalent task-hours per week) and parent oestrogens were found as expected. After adjustment for parent oestrogens, physical activity was not associated with oestrogen metabolites.Our data suggest that prolonged sitting and lower moderate- to vigorous-intensity physical activity are associated with higher levels of postmenopausal oestrogens/oestrogen metabolites, the oestrogen metabolism patterns that have previously been associated with higher endometrial and breast cancer risk.

To clarify risk factors for rare vulvar neoplasms.Within the NIH-AARP Study, among 201,469 women interviewed in 1995-1996 and followed for a mean of 13.8years, there were 370 diagnoses of incident vulvar neoplasms, including 170 invasive and 198 vulvar intraepithelial neoplasms grade 3 (VIN3). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated via multivariate logistic regression for various demographic, reproductive and lifestyle factors, with separate consideration of relations according to invasiveness, histology and age at diagnosis.Consistent with descriptive data, we found non-white women at lower risks of vulvar neoplasia than white women (HR=0.59, 95% CI 0.36-0.95). Significant risk factors for VIN3 included being divorced/separated (HR vs. currently married=1.77, 95% CI 1.24-2.51), a current cigarette smoker (3.88, 95% CI 2.64-5.72), a user of oral contraceptives (1.46, 95% CI 1.06-2.01), or a current user of menopausal hormones (1.73, 95% CI 1.24-2.41). Significant risk factors for invasive cancers were being obese (HR for BMI ≥30 vs.25=1.62, 95% CI 1.10-2.40) or a current smoker (1.86, 95% CI 1.21-2.87). Cigarette smoking was a risk factor mainly for neoplasms shown in other investigations to be HPV-related, namely VIN3 and invasive squamous cell cancers (SCCs) occurring in the younger stratum of cases. In contrast, obesity was primarily associated with the development of invasive SCCs.Our results support that vulvar neoplasia is a heterogeneous disease. VIN3 demonstrated risk factors consistent with an HPV-related etiology, while invasive cancers were additionally affected by obesity, suggesting that further attention should focus on the role of chronic inflammatory conditions.

Previous studies on pelvic inflammatory disease (PID) and the risk of ovarian cancer have found inconsistent results. We performed an updated meta-analysis to summarize the evidence of this association.PubMed, Embase, and ISI web of science databases were searched through October 2016 for studies that investigated the PID and ovarian cancer association. Summary risk estimates were calculated using random-effects meta-analysis.Thirteen studies were eligible for analysis, which included six cohort studies and seven case-control studies. PID was associated with an increased risk of ovarian cancer overall [relative risk (RR) 1.24, 95% CI 1.06-1.44; IOur results suggested that PID might be a potential risk factor of ovarian cancer, with pronounced associations among Asian women. Large and well-designed studies with objective assessment methods, such as hospital records, are needed to confirm the findings of this meta-analysis.