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PURPOSE: The incidence of endometrial cancer (EC) has been increasing faster among Black women than among other racial/ethnic groups in the United States. Although the mortality rate is nearly twice as high among Black than White women, there is a paucity of literature on risk factors for EC among Black women, particularly regarding menopausal hormone use and severe obesity. METHODS: We pooled questionnaire data on 811 EC cases and 3,124 controls from eight studies with data on self-identified Black women (4 case-control and 4 cohort studies). We analyzed cohort studies as nested case-control studies with up to 4 controls selected per case. We used logistic regression to estimate multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We observed a positive association between BMI and EC incidence (P(trend)

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.

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. Outdoor light at night (LAN) can result in circadian disruption and hormone dysregulation and is a suspected risk factor for some cancers. Our study is the first to evaluate the association between LAN and risk of endometrial cancer, a malignancy with known relationship to circulating estrogen levels. METHODS. We linked enrollment addresses (1996) for 97,677 postmenopausal women in the prospective NIH-AARP cohort to satellite imagery of nighttime radiance to estimate LAN exposure. Multivariable Cox models estimated hazard ratios (HR) and 95% confidence intervals (95%CI) for LAN quintiles and incident endometrial cancer overall (1,669 cases) and endometrioid adenocarcinomas (991 cases) through follow-up (2011). We tested for interaction with established endometrial cancer risk factors. RESULTS. We observed no association for endometrial cancer overall (HR(Q1vsQ5)=0.92; 95%CI=0.78–1.08; ptrend=0.67) or endometrioid adenocarcinoma (HR(Q1vsQ5)=1.01; 95%CI=0.82–1.24; ptrend=0.36). Although body mass index and menopause hormone therapy were both associated with risk, there was no evidence of interaction with LAN (pinteractions=0.52 and 0.50, respectively). CONCLUSION. Our study did not find an association between outdoor LAN and endometrial cancer risk, but was limited by inability to account for individual-level exposure determinants. Future studies should consider approaches to improve characterization of personal exposures to light.

Funder: Funding details are provided in the Supplementary Material, Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, ���select and shrink for summary statistics��� (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28���1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08���1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30���1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

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: 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.

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.

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.

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: 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.

The association of progesterone/progesterone metabolites with elevated mammographic breast density (MBD) and delayed age-related terminal duct lobular unit (TDLU) involution, strong breast cancer risk factors, has received limited attention. Using a reliable liquid chromatography-tandem mass-spectrometry assay, we quantified serum progesterone/progesterone metabolites and explored cross-sectional relationships with MBD and TDLU involution among women, ages 40–65, undergoing diagnostic breast biopsy. Quantitative MBD measures were estimated in pre-biopsy digital mammograms. TDLU involution was quantified in diagnostic biopsies. Adjusted partial correlations and trends across MBD/TDLU categories were calculated. Pregnenolone was positively associated with percent MBD-area (MBD-A, rho: 0.30; p-trend = 0.01) among premenopausal luteal phase women. Progesterone tended to be positively associated with percent MBD-A among luteal phase (rho: 0.26; p-trend = 0.07) and postmenopausal (rho: 0.17; p-trend = 0.04) women. Consistent with experimental data, implicating an elevated 5α-pregnanes/3α-dihydroprogesterone (5αP/3αHP) metabolite ratio in breast cancer, higher 5αP/3αHP was associated with elevated percent MBD-A among luteal phase (rho: 0.29; p-trend = 0.08), but not postmenopausal women. This exploratory analysis provided some evidence that endogenous progesterone and progesterone metabolites might be correlated with MBD, a strong breast cancer risk factor, in both pre- and postmenopausal women undergoing breast biopsy. Additional studies are needed to understand the role of progesterone/progesterone metabolites in breast tissue composition and breast cancer risk.

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 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.

Background The incidence of testicular cancer in the United States (US) has substantially increased in recent decades. The majority of testicular cancers are germ cell tumors (TGCT), which are the most commonly occurring malignancies among men aged 15–44 years in the US. To date, few studies have focused on testicular cancer among men aged ≥ 50 years. Thus, we sought to examine detailed descriptive features, including incidence rates and age patterns, of tumors that arise in the testes among men aged ≥ 50 years. Methods Data from forty-one US cancer registries were included for the years 1999–2014. Incidence rates per 100,000 person-years and their 95% confidence intervals (CI) were calculated by race/ethnicity, histology, and age at diagnosis. Estimates of annual percent change (APC) were also calculated. Results Age-specific incidence rates of spermatocytic tumors, sex cord stromal tumors and lymphomas rose with age, while age-specific incidence rates of seminomas and nonseminomas declined. Between 1999 and 2014, the incidence of nonseminoma (APC = 3.26, 95% CI: 2.27–4.25) increased more than any other tumor type. The incidence of seminoma (APC: 1.15, 95% CI: 0.59–1.71) also increased, while rates of testicular lymphoma (APC: −0.66, 95% CI: −1.16 to −0.16), spermatocytic tumors (APC: 0.42, 95% CI: −1.42 to 2.29), and sex cord stromal tumors (APC: 0.60, 95% CI: −3.21 to 4.55) remained relatively unchanged. Conclusion Given the distinct time-trends and age-specific patterns of testicular cancer in men aged ≥50 years, additional investigation of risk factors for these tumors is warranted.

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.

Preliminary evidence suggests that sex steroid hormones, such as Danazol (a synthetic sex steroid hormone) may be involved in enhancing telomerase activity. Elucidating underlying mechanisms of telomerase activity may further therapeutic options for individuals with telomeropathies and potentially avert certain age-related conditions. Therefore, we conducted a cross-sectional study to investigate the relationship between circulating sex steroid hormones and SHBG with leukocyte telomere length among 499 males in NHANES (1999–2002 surveys). Sample-weighted linear regression analyses were conducted to assess age-adjusted and multivariable-adjusted estimates of associations. Estimates were rescaled to represent telomere length change in base pairs per half the value of the interquartile range of the independent variable. Estradiol and free estradiol were significantly inversely associated with leukocyte telomere length (β(continuous per ½ IQR) = −61, p=0.04; free estradiol β(continuous per ½ IQR) = −67, p=0.03). Testosterone, free testosterone, androstanediol glucuronide, and SHBG were not associated with leukocyte telomere length. The inverse association seen in the present study indicates that a Danazol-induced hypoestrogenic state could partly underlie the previously observed association between Danazol therapy and increased leukocyte telomere length.

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

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.

Marijuana has been reported to have several effects on the male reproductive system. Marijuana has previously been linked to reduced adult testosterone, however, a study in Denmark reported increased testosterone concentrations among marijuana users. This study was performed to estimate the effect of marijuana use on testosterone in U.S. males. Data on serum testosterone, marijuana use, and covariates for 1577 men from the 2011-2012 U.S. National Health and Nutrition Examination Survey (NHANES) were analyzed. Information on marijuana use was collected by a self-administered computer-assisted questionnaire. Serum testosterone was determined using isotope dilution liquid chromatography tandem mass spectrometry. The effects of marijuana use on serum testosterone concentrations were examined by frequency, duration, and recency of use. Adjusted means and 95% confidence intervals (CI) of serum testosterone across levels of marijuana use were estimated using multiple linear regression weighted by the survey weights. The majority (66.2%) of the weighted study population reported ever using marijuana with 26.6% reporting current marijuana use. There was no difference in serum testosterone between ever users (adjusted mean = 3.69 ng/mL, 95% CI: 3.46, 3.93) and never users (adjusted mean = 3.70 ng/mL, 95% CI: 3.45, 3.98) upon multivariable analysis. However, serum testosterone was inversely associated with time since last regular use of marijuana (p-value for trend = 0.02). When restricted to men aged 18-29 years, this relationship strengthened (p-value for trend0.01), and serum testosterone was also inversely associated with time since last use (p-value for trend0.01), indicating that recency of use, and not duration or frequency, had the strongest relationship with testosterone levels. Serum testosterone concentrations were higher in men with more recent marijuana use. Studies are needed to determine the extent to which circulating testosterone concentrations mediate the relationship of marijuana use with male reproductive outcomes.

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.

Over the past decade, a number of consortia have formed to further investigate genetic associations, pathogenesis, and epidemiologic risk and prognostic factors for ovarian cancer. Here, we review the benefits that ovarian cancer consortia provide as well as challenges that have arisen. Methods for managing key challenges are also discussed. We review the structural organization and some of the milestone epidemiologic publications of five consortia dedicated to the study of ovarian cancer, including the Ovarian Cancer Association Consortium (OCAC), the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Ovarian Cancer Cohort Consortium (OC3), the Collaborative Group on Epidemiological Studies of Ovarian Cancer (The Oxford Collaborative Group), and the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium. As ovarian cancer is a rare and heterogeneous disease, consortia have made important contributions in the study of risk factors by improving statistical power beyond what any single study, or even a few studies, would provide. Thus, a major accomplishment of consortial research is enhanced characterization of histotype-specific risk factor associations. In addition, consortia have facilitated impressive synergy between researchers across many institutions, spawning new collaborative research. Importantly, through these efforts, many challenges have been met, including difficulties with data harmonization and analysis, laying a road map for future collaborations. While ovarian cancer consortia have made valuable contributions to the ovarian cancer epidemiological literature over the past decade, additional efforts comprising of new, well-designed case–control studies are needed to further elucidate novel, histotype-specific risk, and prognostic factors which are not consistently available in existing studies.

Growing epidemiologic evidence supports chronic inflammation as a mechanism of ovarian carcinogenesis. An association between a circulating marker of inflammation, C-reactive protein (CRP), and ovarian cancer risk has been consistently observed, yet, potential heterogeneity of this association by tumor and patient characteristics has not been adequately explored. In this study, we pooled data from case–control studies nested within six cohorts in the Ovarian Cancer Cohort Consortium (OC3) to examine the association between CRP and epithelial ovarian cancer risk overall, by histologic subtype and by participant characteristics. CRP concentrations were measured from prediagnosis serum or plasma in 1,091 cases and 1,951 controls. Multivariable conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI). When CRP was evaluated using tertiles, no associations with ovarian cancer risk were observed. A 67% increased ovarian cancer risk was found for women with CRP concentrations >10 mg/L compared with 10 mg/L was positively associated with risk of mucinous (OR = 9.67; 95% CI = 1.10–84.80) and endometrioid carcinoma (OR = 3.41; 95% CI = 1.07–10.92), and suggestively positive, although not statistically significant, for serous (OR = 1.43; 95% CI = 0.82–2.49) and clear cell carcinoma (OR = 2.05; 95% CI = 0.36–11.57; Pheterogeneity = 0.20). Heterogeneity was observed with oral contraceptive use (Pinteraction = 0.03), where the increased risk was present only among ever users (OR = 3.24; 95% CI = 1.62–6.47). This study adds to the existing evidence that CRP plays a role in ovarian carcinogenesis and suggests that inflammation may be particularly implicated in the etiology of endometrioid and mucinous carcinoma. Significance: C-reactive protein is involved in ovarian carcinogenesis, and chronic inflammation may be particularly implicated in the etiology of mucinous and endometrioid carcinomas.

Many pregnancy‐related factors are associated with reduced endometrial cancer risk. However, it remains unclear whether pregnancy‐related complications (e.g., hypertensive conditions) are associated with risk and whether these associations vary by endometrial cancer subtype. Thus, we evaluated the risk of endometrial cancer, overall and by subtype, in relation to pregnancy‐related factors, pregnancy complications and birth characteristics. Utilizing population‐based register data from four Nordic countries, we conducted a nested case–control analysis of endometrial cancer risk. We included 10,924 endometrial cancer cases and up to 10 matched controls per case. Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models. We further evaluated associations by individual histology (i.e., endometrioid, serous, etc.) or, for rare exposures (e.g., pregnancy complications), by dualistic type (Type I [n = 10,343] and Type II [n = 581]). Preexisting and pregnancy‐related hypertensive conditions were associated with increased endometrial cancer risk (OR [95% CI]: preexisting hypertension 1.88 [1.39–2.55]; gestational hypertension 1.47 [1.33–1.63]; preeclampsia 1.43 [1.30–1.58]), with consistent associations across dualistic type. Increasing number of pregnancies (≥4 vs. 1 birth: 0.64 [0.59–0.69]) and shorter time since last birth (

PURPOSE: Menopausal hormone therapy (MHT) use induces alterations in circulating estrogens/estrogen metabolites, which may contribute to the altered risk of reproductive tract cancers among current users. Thus, the current study assessed associations between circulating estrogens/estrogen metabolites and ovarian and endometrial cancer risk among MHT users. METHODS: We conducted a nested case-control study among postmenopausal women using MHT at baseline in the Women’s Health Initiative Observational Study (179 ovarian cancers, 396 controls; 230 endometrial cancers, 253 controls). Multivariable logistic regression was utilized to estimate odds ratios and 95% confidence intervals overall and by subtype. RESULTS: Estrogen/estrogen metabolite levels were not associated with overall or serous ovarian cancer risk, examined separately. However, unconjugated estradiol was positively associated with non-serous ovarian cancer risk [quintile 5 vs. quintile 1: 3.01 (1.17–7.73); p-trend=0.03; p-het

Background: Laterality of epithelial ovarian tumors may reflect the underlying carcinogenic pathways and origins of tumor cells. Methods: We pooled data from 9 prospective studies participating in the Ovarian Cancer Cohort Consortium. Information on measures of tumor size or tumor dominance was extracted from surgical pathology reports or obtained through cancer registries. We defined dominant tumors as those restricted to one ovary or where the dimension of one ovary was at least twice as large as the other, and nondominant tumors as those with similar dimensions across the two ovaries or peritoneal tumors. Competing risks Cox models were used to examine whether associations with reproductive and hormonal risk factors differed by ovarian tumor dominance. Results: Of 1,058 ovarian cancer cases with tumor dominance information, 401 were left-dominant, 363 were right-dominant, and 294 were nondominant. Parity was more strongly inversely associated with risk of dominant than nondominant ovarian cancer (Pheterogeneity = 0.004). Ever use of oral contraceptives (OC) was associated with lower risk of dominant tumors, but was not associated with nondominant tumors (Pheterogeneity = 0.01). Higher body mass index was associated with higher risk of left-dominant tumors, but not significantly associated with risk of right-dominant or nondominant tumors (Pheterogeneity = 0.08). Conclusions: These data suggest that reproductive and hormonal risk factors appear to have a stronger impact on dominant tumors, which may have an ovarian or endometriosis origin. Impact: Examining the associations of ovarian cancer risk factors by tumor dominance may help elucidate the mechanisms through which these factors influence ovarian cancer risk.

Background: Reproductive factors, including parity, breastfeeding, and contraceptive use, affect lifetime ovulatory cycles and cumulative exposure to gonadotropins and are associated with ovarian cancer. To understand the role of ovulation-regulating hormones in the etiology of ovarian cancer, we prospectively analyzed the association of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B with ovarian cancer risk. Methods: Our study included 370 women from the Janus Serum Bank, including 54 type I and 82 type II invasive epithelial ovarian cancers, 49 borderline tumors, and 185 age-matched controls. We used conditional logistic regression to assess the relationship between hormones and risk of ovarian cancer overall and by subtype (types I and II). Results: Inhibin B was associated with increased risk of ovarian cancer overall [OR, 1.97; 95% confidence interval (CI), 1.14–3.39; Ptrend = 0.05] and with type I ovarian (OR, 3.10; 95% CI, 1.04–9.23; Ptrend = 0.06). FSH was not associated with ovarian cancer risk overall, but higher FSH was associated with type II ovarian cancers (OR, 2.78; 95% CI, 1.05–7.38). AMH was not associated with ovarian cancer risk. Conclusions: FSH and inhibin B may be associated with increased risk in different ovarian cancer subtypes, suggesting that gonadotropin exposure may influence risk of ovarian cancer differently across subtypes. Impact: Associations between prospectively collected AMH, FSH, and inhibin B levels with risk of ovarian cancer provide novel insight on the influence of premenopausal markers of ovarian reserve and gonadotropin signaling. Heterogeneity of inhibin B and FSH effects in different tumor types may be informative of tumor etiology.

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.

Background In 2016, the WHO introduced an updated classification for testicular tumors. The application of this updated classification to cancer registry data requires some recoding of tumors. Objectives The aim of this study was to provide up-to-date population-based incidence estimates of subtypes of testicular germ cell tumors (TGCT) according to the updated classification. Material and methods We reviewed 2251 pathology reports (42.9%) out of 5252 testicular tumors at the cancer registry of North Rhine-Westphalia for the years 2008-2013. We used population counts to estimate age-standardized incidence rates per million person-years (EUROSTAT revised European Standard Population). Results The application of the updated WHO classification resulted in a recoding of 8.9% of all testicular tumors. While the recodings have no influence on the incidence of seminomatous and non-seminomatous TGCTs that include mixed TGCTs, they influence the incidence of individual histological types of seminomatous and non-seminomatous TGCTs. Among the 4935 testicular germ cell tumors (TGCT), 23.7% were mixed TGCTs. Overall, 46.9% of all mixed TGCTs included seminoma and age-standardized incidence rates were highest for the combination seminoma plus embryonal carcinoma (5.9 per million person-years) and embryonal carcinoma plus teratoma (4.9 per million person-years). The median age at diagnosis was higher for mixed TGCTs including seminoma (31 years) than those that did not include seminoma (28 years). Discussion and conclusions Population-based incidence time trends for seminomatous and non-seminomatous TGCTs that include mixed TGCTs are not distorted by the introduction of the WHO update. Trend distortions can only be expected if time trends of individual histological subtypes of the seminomatous and non-seminomatous TGCTs are examined.

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in