Case-control study of endogenous sex steroid hormones and risk of endometrial cancer.

BACKGROUND: Epidemiologic evidence regarding the role of endogenous sex hormones in endometrial cancer etiology remains inconsistent. The objective of this study was to investigate if circulating levels of endogenous estrone, estradiol, sex hormone binding globulin (SHBG), testosterone, and androstenedione are associated with endometrial cancer risk. METHODS: We conducted a population-based case-control study of 522 incident endometrial cancer cases and 976 population controls, in Alberta, Canada from 2002 to 2006. Study participants completed in-person interviews and provided fasting blood samples. Sex hormone levels were determined by enzyme-linked immunosorbent assays. RESULTS: Higher levels of androstenedione were associated with increased endometrial cancer risk (OR 1.44, 95% CI 1.04-2.02). Endometrial cancer risk in pre- and peri-menopausal women was reduced for the highest versus lowest quartiles of estrone (OR 0.44, 95% CI 0.22-0.88) and estradiol (OR 0.30, 95% CI 0.14-0.65), but in post-menopausal women, the endometrial cancer risk was increased for the highest versus lowest quartile of androstenedione (OR 1.82, 95% CI 1.25-2.65). In addition, endometrial cancer risk in normal/underweight women was decreased for the highest versus lowest quartile of serum SHBG (OR 0.39, 95% CI 0.19-0.84). CONCLUSIONS: Overall, positive associations were found for androstenedione concentrations, while sub-group analyses revealed = inverse associations with estrogens and SHBG. Results of this study provide empirical evidence for the role of circulating sex hormones in endometrial cancer etiology and highlight the importance of modifiable factors that contribute to changes in sex hormone concentration levels.

Are physical activity levels linked to nutrient adequacy? Implications for cancer risk.

Cancer prevention guidelines recommend a healthy body mass index, physical activity, and nutrient intake from food rather than supplements. Sedentary individuals may restrict energy intake to prevent weight gain and in so doing may compromise nutritional intake. We conducted a cross-sectional analysis to determine if adequacy of micronutrients is linked to physical activity levels (PALs) in healthy-weight adults. Tomorrow Project participants in Alberta, Canada (n = 5333), completed past-year diet and physical activity questionnaires. The percent meeting Dietary Reference Intakes (DRIs) was reported across low and high PAL groups, and the relation between PAL and percent achieved DRI was determined using multiple linear regression analyses. Overall, <50% of healthy-weight participants met DRIs for folate, calcium, and vitamin D. Percent achieved DRI increased linearly with increasing PAL in both genders (P < 0.01). A hypothetical increase in PAL from 1.4 to 1.9 was associated with a DRI that was 8%-13% higher for folate and vitamin C (men) and 5%-15% higher for calcium and iron (women). Healthy-weight adults at higher PALs appear more likely to meet DRIs for potential cancer-preventing nutrients. The benefits of higher PALs may extend beyond the usual benefits attributed to physical activity to include having a more favorable impact on nutrient adequacy.

Anthropometric measures and the risk of endometrial cancer, overall and by tumor microsatellite status and histological subtype.

Obesity is an established risk factor for endometrial cancer, but this association is not well understood for subtypes of endometrial cancer. We evaluated the association of recent and adult-life obesity with subtypes of endometrial cancer based on microsatellite status (microsatellite-stable (MSS) vs. microsatellite-instable (MSI)) and histology (type I vs. type II). Analyses were based on a population-based case-control study (524 cases and 1,032 controls) conducted in Alberta, Canada (2002-2006) and included the following groupings of subtypes: MSS = 337 and MSI = 130; type I = 458 and type II = 66. Logistic and polytomous logistic regression were used to estimate odds ratios and 95% confidence intervals for overall endometrial cancer and subtypes of endometrial cancer, respectively. The risks of all subtypes of endometrial cancer, except type II, increased with an increase in all of the anthropometric characteristics examined. The risks for MSI tumors were suggestively stronger than those for MSS tumors; the risk with high (≥30) body mass index (weight (kg)/height (m)(2)) was significantly stronger for MSI tumors (odds ratio = 4.96, 95% confidence interval: 2.76, 8.91) than for MSS tumors (odds ratio = 2.33, 95% confidence interval: 1.66, 3.28) (P-heterogeneity = 0.02). Obesity is associated with most subtypes of endometrial cancer, and further studies are warranted to elucidate the biological mechanisms underlying the stronger risk for the MSI subtype with a high body mass index.

Case-control study of lifetime alcohol consumption and endometrial cancer risk.

PURPOSE: Alcohol consumption is hypothesized to increase the risk of endometrial cancer by increasing circulating estrogen levels. This study sought to investigate the association between lifetime alcohol consumption and endometrial cancer risk. METHODS: We recruited 514 incident endometrial cancer cases and 962 frequency age-matched controls in this population-based case-control study in Alberta, Canada, from 2002 to 2006. Participants completed in-person interviews querying lifetime alcohol consumption and other relevant health and lifestyle factors. Participants reported the usual number of drinks of beer, wine, and liquor consumed; this information was compiled for each drinking pattern reported over the lifetime to estimate average lifetime exposure to alcohol. RESULTS: Lifetime average alcohol consumption was relatively low (median intake: 3.9 g/day for cases, 4.9 g/day for controls). Compared with lifetime abstainers, women consuming >2.68 and ≤8.04 g/day alcohol and >8.04 g/day alcohol on average over the lifetime showed 38 and 35 % lower risks of endometrial cancer, respectively (p trend = 0.023). In addition, average lifetime consumption of all types of alcohol was associated with decreased risks. There was no evidence for effect modification by body mass index, physical activity, menopausal status, and hormone replacement therapy use combined and effects did not differ by type of endometrial cancer (type I or II). CONCLUSION: This study provides epidemiologic evidence for an inverse association between relatively modest lifetime average alcohol consumption (approximately 1/4 to 1/2 drink/day) and endometrial cancer risk. The direction of this relation is consistent with previous studies that examined similar levels of alcohol intake.

Glycemic load and endometrial cancer risk in a case-control study of Canadian women.

INTRODUCTION: The evidence for a role of dietary carbohydrate intake with endometrial cancer risk is conflicting. We therefore evaluated the association between glycemic load (GL) and endometrial cancer in a population-based-case control study using a comprehensive quantitative food frequency questionnaire for the estimation of GL. METHODS: Diet in the year before the reference date was assessed with the self-administered Canadian Diet History Questionnaire in 511 cases and 980 controls in Alberta, Canada between 2002 and 2006. Multivariable logistic regression was used to examine the association between GL and endometrial cancer risk, with non-linearity evaluated by the examination of cubic splines. RESULTS: The risk for endometrial cancer did not change based on GL (for the highest versus lowest quartile, adjusted odds ratio=0.87, 95% confidence interval=0.52-1.46), even after the removal of participants previously diagnosed with diabetes ((diabetics n cases=63, n controls=55 excluded) adjusted odds ratio=0.77, 95% confidence interval=0.44-1.36). We observed no evidence of effect modification by Body Mass Index (BMI)(p-interaction term=0.22). CONCLUSIONS: Intake of foods eliciting a glycemic response was not associated with endometrial cancer risk in this population of Canadian women.

Hormonal and reproductive risk factors for sporadic microsatellite stable and unstable endometrial tumors.

Hormonal and reproductive factors modulate bioavailable estrogen to influence endometrial cancer risk. Estrogen affects the microsatellite status of tumors, but the relation between these estrogen-related factors and microsatellite instability (MSI) status of endometrial tumors is not known. We evaluated associations between hormonal and reproductive factors and risks of microsatellite stable (MSS) and MSI endometrial cancer among postmenopausal women (MSS cases = 258, MSI cases = 103, and controls = 742) in a population-based case-control study in Alberta, Canada (2002-2006). Polytomous logistic regression was used to estimate ORs and 95% confidence intervals (95% CI). We observed a significant trend in risk reduction for MSI (Ptrend = 0.005) but not MSS (Ptrend = 0.23) cancer with oral contraceptive use; with 5-year use or more, the risk reduction was stronger for MSI (OR = 0.42; 95% CI, 0.23-0.77) than for MSS cancer (OR = 0.80; 95% CI, 0.54-1.17; Pheterogeneity = 0.05). For more recent use (<30 years), the risk reduction was stronger for MSI (OR = 0.36; 95% CI, 0.19-0.69) than for MSS cancer (OR = 0.77; 95% CI, 0.51-1.15; Pheterogeneity = 0.032). No differential risk associations were observed for menopausal hormone use, parity and age at menarche, menopause or first pregnancy. We found limited evidence for statistical heterogeneity of associations of endometrial cancer risk with hormonal and reproductive factors by MSI status, except with oral contraceptive use. This finding suggests a potential role for the MMR system in the reduction of endometrial cancer risk associated with oral contraceptive use, although the exact mechanism is unclear. This study shows for the first time that oral contraceptive use is associated with a reduced risk for MSI but not for MSS endometrial cancer.

Case-control study of inflammatory markers and the risk of endometrial cancer.

Chronic inflammation may be important in endometrial cancer etiology. Several established endometrial cancer risk factors, particularly obesity, are hypothesized to operate through this pathway by increasing proinflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and acute-phase protein C-reactive protein (CRP). This study sought to investigate the association between inflammatory markers and the risk of endometrial cancer (types I and II). We recruited 519 incident endometrial cancer cases and 964 frequency age-matched controls in this population-based case-control study in Alberta (Canada) from 2002 to 2006. Participants completed in-person interviews, were assessed for anthropometric measures, and provided 8-h fasting blood samples either preoperatively or postoperatively. Blood was analyzed for the concentrations of TNF-α, IL-6, and CRP by immunoassay. Endometrial cancer cases had consistently higher mean levels of TNF-α, IL-6, and CRP compared with controls in these predominantly postmenopausal women. After adjusting for age, all markers were associated with statistically significant increased risks for endometrial cancer; however, after multivariable adjustment, only the risk from CRP remained elevated (odds ratio=1.22, 95% confidence interval: 1.02-1.47). Similarly, upon stratification by cancer type, only CRP was associated positively with an increased risk for type I endometrial cancer (odds ratio=1.25, 95% confidence interval: 1.03-1.52). All markers were associated with an elevated risk for the more rare and aggressive type II cancers; however, these findings were statistically nonsignificant, likely because of the small number of cases in this group. In conclusion, we found epidemiologic evidence for an association between CRP and the risk of endometrial cancer, which was slightly stronger for type I cancer. No associations emerged for TNF-α and IL-6.

Case-control study of markers of insulin resistance and endometrial cancer risk.

Markers of insulin resistance such as the adiponectin:leptin ratio (A:L) and the homeostasis model assessment ratio (HOMA-IR) are associated with obesity and hyperinsulinemia, both established risk factors for endometrial cancer, and may therefore be informative regarding endometrial cancer risk. This study investigated the association between endometrial cancer risk and markers of insulin resistance, namely adiponectin, leptin, the A:L ratio, insulin, fasting glucose, and the HOMA-IR. We analyzed data from 541 incident endometrial cancer cases and 961 frequency age-matched controls in a population-based case-control study in Alberta, Canada from 2002 to 2006. Participants completed interview-administered questionnaires were assessed for anthropometric measures, and provided 8-h fasting blood samples either pre- or postoperatively. Blood was analyzed for concentrations of leptin, adiponectin, and insulin by immunoassay, and fasting plasma glucose levels were determined by fluorimetric quantitative determination. Compared with the lowest quartile, the highest quartile of insulin and HOMA-IR was associated with 64% (95% confidence intervals (CI): 1.12-2.40) and 72% (95% CI: 1.17-2.53) increased risks of endometrial cancer, respectively, and the highest quartile of adiponectin was associated with a 45% (95% CI: 0.37-0.80) decreased risk after multivariable adjustments. Null associations were observed between fasting glucose, leptin and A:L, and endometrial cancer risk. This population-based study provides evidence for a role of insulin resistance in endometrial cancer etiology and may provide one possible pathway whereby obesity increases the risk of this common cancer. Interventions aimed at decreasing both obesity and insulin resistance may decrease endometrial cancer risk.