Patterns of Ultraviolet Radiation Exposure and Skin Cancer Risk: the E3N-SunExp Study.

BACKGROUND: While ultraviolet (UV) radiation exposure is a recognized risk factor for skin cancer, associations are complex and few studies have allowed a direct comparison of exposure profiles associated with cutaneous melanoma, basal-cell carcinoma (BCC), and squamous-cell carcinoma (SCC) within a single population. METHODS: We examined associations between UV exposures and skin cancer risk in a nested case-control study within E3N, a prospective cohort of 98,995 French women born in 1925-1950. In 2008, a lifetime UV exposure questionnaire was sent to all reported skin cancer cases and three controls per case, which were matched on age, county of birth, and education. Analyses were performed using conditional logistic regression and included 366 melanoma cases, 1,027 BCC cases, 165 SCC cases, and 3,647 controls. RESULTS: A history of severe sunburns <25 years was associated with increased risks of all skin cancers (melanoma: OR 2.7; BCC: OR 1.7; SCC: OR 2.0 for ≥6 sunburns vs. none), while sunburns ≥25 years were associated with BCC and SCC only. While high-sun protection factor sunscreen use before age 25 was associated with lower BCC risk (Ptrend = 0.02), use since age 25 and reapplication of sunscreen were associated with higher risks of all three types of skin cancer. There were positive linear associations between total UV score and risks of BCC (Ptrend = 0.01) and SCC (Ptrend = 0.09), but not melanoma. While recreational UV score was strongly associated with BCC, total and residential UV scores were more strongly associated with SCC. CONCLUSIONS: Melanoma, BCC, and SCC are associated with different sun exposure profiles in women.

Egg and cholesterol intake and incident type 2 diabetes among French women.

Egg consumption is a major source of dietary cholesterol, a nutrient that may disrupt glucose metabolism. We prospectively evaluated the relation between egg consumption and cholesterol-intake and diabetes in 65 364 French disease-free women who responded to a validated diet history questionnaire in 1993. Egg consumption included hardboiled eggs and eggs consumed in an omelette or a mixed dish, and dietary cholesterol was estimated using a French nutrient database. Over 14 years of follow-up, 1803 incident diabetes cases were identified through self-reports, supplementary questionnaires and drug reimbursement information. Multivariable Cox regression models were adjusted for age, education, menopause, menopausal hormone therapy, hypertension and hypercholesterolaemia, BMI, physical activity, smoking, alcohol, fruit, vegetables, processed red meat, coffee and sugar and artificially sweetened beverages. No association was observed between egg consumption and risk of type 2 diabetes. When comparing women who consumed at least five eggs per week with non-consumers, the multivariable hazard ratio (HR) was found to be 1·00 (95 % CI 0·78, 1·29; across categories, P trend=0·11). Women in the highest quintile of dietary cholesterol had a 40 % higher rate of diabetes compared with those in the lowest quintile (HR 1·40; 95 % CI 1·19, 1·63; across quintiles, P trend<0·0001). A 100 mg increase of dietary cholesterol per 4184 kJ (or 1000 kcal) was associated with a 14 % increase in the risk of diabetes (HR 1·14; 95 % CI 1·02, 1·26). In this large prospective cohort, we observed an association between dietary cholesterol and type 2 diabetes, but no association with egg consumption. In the absence of a clear underlying mechanism and potential residual confounding, these results should be interpreted with caution.

Association between melanocytic nevi and risk of breast diseases: The French E3N prospective cohort.

BACKGROUND: While melanocytic nevi have been associated with genetic factors and childhood sun exposure, several observations also suggest a potential hormonal influence on nevi. To test the hypothesis that nevi are associated with breast tumor risk, we explored the relationships between number of nevi and benign and malignant breast disease risk. METHODS AND FINDINGS: We prospectively analyzed data from E3N, a cohort of French women aged 40-65 y at inclusion in 1990. Number of nevi was collected at inclusion. Hazard ratios (HRs) for breast cancer and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. Associations of number of nevi with personal history of benign breast disease (BBD) and family history of breast cancer were estimated using logistic regression. Over the period 15 June 1990-15 June 2008, 5,956 incident breast cancer cases (including 5,245 invasive tumors) were ascertained among 89,902 women. In models adjusted for age, education, and known breast cancer risk factors, women with "very many" nevi had a significantly higher breast cancer risk (HR = 1.13, 95% CI = 1.01-1.27 versus "none"; ptrend = 0.04), although significance was lost after adjustment for personal history of BBD or family history of breast cancer. The 10-y absolute risk of invasive breast cancer increased from 3,749 per 100,000 women without nevi to 4,124 (95% CI = 3,674-4,649) per 100,000 women with "very many" nevi. The association was restricted to premenopausal women (HR = 1.40, ptrend = 0.01), even after full adjustment (HR = 1.34, ptrend = 0.03; phomogeneity = 0.04), but did not differ according to breast cancer type or hormone receptor status. In addition, we observed significantly positive dose-response relationships between number of nevi and history of biopsy-confirmed BBD (n = 5,169; ptrend<0.0001) and family history of breast cancer in first-degree relatives (n = 7,472; ptrend = 0.0003). The main limitations of our study include self-report of number of nevi using a qualitative scale, and self-reported history of biopsied BBD. CONCLUSIONS: Our findings suggest associations between number of nevi and the risk of premenopausal breast cancer, BBD, and family history of breast cancer. More research is warranted to elucidate these relationships and to understand their underlying mechanisms.

Isotretinoin and risk of inflammatory bowel disease: a French nationwide study.

OBJECTIVES: Isotretinoin, a drug widely prescribed for severe acne, has been suspected to increase the risk of ulcerative colitis (UC), but data are conflicting. To further examine the association between isotretinoin use and risk for UC and Crohn's disease (CD), we conducted a large nationwide case-control study in France. METHODS: We used information from the National Health Insurance system for all French people covered by the general scheme between 1 January 2008 and 31 December 2010, totaling over 50 million individuals (i.e., 76% of the whole French population). All incident claims for UC and CD and all medical drug reimbursements were automatically recorded in the database. For each case, four controls were matched on age, gender, year of enrollment, and follow-up duration. The association between isotretinoin use and UC or CD claim was estimated by conditional logistic regression. RESULTS: We included 7,593 cases of inflammatory bowel disease (IBD; 3,187 UC, 4,397 CD, and 9 indeterminate colitis) and 30,372 controls; among them, 26 cases (0.3%) (15 UC (0.5%) and 11 CD (0.3%)) and 140 controls (0.4%) were exposed to isotretinoin. Isotretinoin exposure was not associated with an increased risk for UC (odds ratio (OR)=1.36 (95% confidence intervals (CI): 0.76, 2.45)) but was associated with a decreased risk for CD (OR=0.45 (95% CI: 0.24, 0.85)), P value for homogeneity between UC and CD=0.001. Results were similar in analyses restricted to individuals below the age of 40 years, to cases with colonoscopy or intestinal surgery, or when adjusting for other acne treatments. CONCLUSIONS: In this population-based case-control study, isotretinoin use was not associated with increased UC risk but was associated with a decreased CD risk. This study provides reassuring data for people using isotretinoin.

Body mass index, diabetes, and mortality in French women: explaining away a "paradox".

BACKGROUND: Obesity is associated with increased mortality in the general population but, paradoxically, with decreased mortality in persons with diabetes. METHODS: Among 88,373 French women participating in the E3N-EPIC study who were free of diabetes in 1990, we estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) of mortality for body mass index (BMI) levels by diabetes status. RESULTS: During an average 16.7 years of follow-up, 2421 cases of diabetes were identified and 3750 deaths occurred. For overweight/obese versus normal-weight women, the HR of mortality was 1.42 (95% CI = 1.32-1.53) in women without diabetes and 0.69 (0.40-1.18) in women with incident diabetes. As BMI increased, mortality among women without diabetes increased and that among women with diabetes decreased. CONCLUSIONS: We found the obesity "paradox" among women with and without incident diabetes in the same population. Selection bias may be a simple explanation for this "paradox."

Childhood and adolescent exposures and the risk of endometriosis.

BACKGROUND: Because endometriosis is diagnosed predominantly in young women, exposures occurring during childhood or adolescence may have a major impact on the disease. However, potential risk factors during this time period have received little attention. Our objective was to investigate relationships between childhood and adolescent exposures and the risk of endometriosis. METHODS: E3N is a prospective cohort of 98,995 French women aged 40-65 at enrollment in 1990. Follow-up questionnaires were sent every 2-3 years. Using a nested case-control design, we computed odds ratios (ORs) and 95% confidence intervals using unconditional logistic regression models. RESULTS: A total of 2684 endometriosis cases were reported as surgically ascertained among the 75,918 included women. There were inverse relationships of endometriosis risk with menarcheal age (test for trend, P < 0.0001) and with menstrual cycle length before 17 years of age (test for trend, P = 0.06), whereas menstrual cycle regularity before 17 years of age was not associated with risk. There were modest associations of endometriosis risk with exposure to pet animals (OR = 1.12 [95% confidence interval =1.02-1.22]) or living in a farm for 3 or more consecutive months during childhood (1.12 [1.02-1.24]), although with no link to any specific type of farm animal. In addition, there were positive linear associations between endometriosis risk and level of indoor exposure to passive smoking during childhood (up to 1.34 [1.09-1.64] with several hours exposure a day), experiencing food deprivation during World War II (1.34 [0.94-1.91]), and walking activity at 8-15 years of age (1.17 [1.05-1.31] for 5+ hours a week). CONCLUSIONS: This large study suggests that some exposures during childhood or adolescence may influence the risk of endometriosis. Further research is needed to confirm and better understand these relationships.

Menopausal hormone therapy and risk of cholecystectomy: a prospective study based on the French E3N cohort.

BACKGROUND: Studies in the United States and the United Kingdom have reported an increased risk of cholecystectomy among women exposed to menopausal hormone therapy, but with substantial heterogeneity between types of hormone treatments. We evaluated the risk of cholecystectomy associated with different regimens of menopausal hormone therapy in a large prospective cohort study. METHODS: Between 1992 and 2008, 70 928 menopausal women from the French E3N study cohort were sent questionnaires assessing their use of menopausal hormone therapy, medical history and lifestyle characteristics. The primary outcome was cholecystectomy. We analyzed the risk of cholecystectomy associated with use of menopausal hormone therapy using Cox proportional models, with age as time-scale. RESULTS: During follow-up, 45 984 (64.8%) of the participants were exposed to menopausal hormone therapy, and 2819 cholecystectomies were recorded. The use of menopausal hormone therapy was associated with an increased risk of cholecystectomy (adjusted hazard ratio [HR] 1.10, 95% confidence interval [CI] 1.01-1.20) compared with women who were not exposed to menopausal hormone therapy. The association was restricted to unopposed oral estrogen therapy (adjusted HR 1.38, 95% CI 1.14-1.67). Over 5 years, about 1 cholecystectomy in excess would be expected in every 150 women using oral estrogen therapy without progestogens, compared with women not exposed to menopausal hormone therapy. INTERPRETATION: The risk of cholecystectomy was increased among women exposed to oral estrogen menopausal hormone therapy, especially oral regimens without a progestagen. Complicated gallstone disease should be added to the list of potential adverse events to be considered when balancing the benefits and risks associated with menopausal hormone therapy.

Cutaneous melanoma and endogenous hormonal factors: a large French prospective study.

To assess the role of endogenous hormonal factors on melanoma, the authors conducted a prospective analysis of 91,972 French women, aged 40-65 years at inclusion into the Etude Epidémiologique auprès de femmes de l'Education Nationale (E3N) cohort. Between 1990 and 2005, 460 melanoma cases were ascertained. Relative risks and 95% confidence intervals were computed by using Cox proportional hazards regression models. Risks of melanoma were reduced in women with ≥ 15 years at menarche (relative risk (RR) = 0.67, 95% confidence interval (CI): 0.46, 0.97, compared with 13-14 years), irregular menstrual cycles (RR = 0.52, 95% CI: 0.31, 0.89, compared with regular cycles of 25-31 days), <48 years at natural menopause (RR = 0.70, 95% CI: 0.48, 1.02, compared with 48-51 years), and shorter ovulatory life (RR = 0.51, 95% CI: 0.28, 0.91, for <33 years compared with ≥ 39 years). Modest inverse associations were observed with parity, as well as number of pregnancies and miscarriages. There was no evidence of an association between melanoma risk and age at first birth or pregnancy, age at last birth, time since last birth, breastfeeding duration, age at menstruation regularity, or menopausal status. Results did not significantly differ according to ambient ultraviolet radiation dose and melanoma site or subtype. These findings from a large prospective cohort may suggest a reduced melanoma risk associated with decreased exposure to ovarian hormones.

Processed and unprocessed red meat consumption and hypertension in women.

BACKGROUND: High processed red meat consumption is associated with increased risk of cardiovascular disease. The high sodium content of processed red meat could increase blood pressure and explain the association with cardiovascular disease. OBJECTIVE: We evaluated the relation between the consumption of unprocessed and processed red meat and incident hypertension. DESIGN: In a prospective cohort of 44,616 disease-free French women who responded to a validated dietary questionnaire, we observed 10,256 incident cases of hypertension between 1993 and 2008. Cases were identified through self-reports of diagnosed or treated hypertension. Multivariate Cox regression models were adjusted for age, education, smoking, physical activity, body mass index, menopause, menopausal hormone therapy, and alcohol, bread, coffee, and fruit and vegetable consumption. RESULTS: Women who consumed ≥5 servings of processed red meat/wk (50 g = 1 serving) had a 17% higher rate of hypertension than that of women who consumed <1 serving/wk (HR: 1.17; 95% CI: 1.09, 1.26; P-trend = 0.0002). No association was observed between unprocessed red meat consumption and hypertension. When women who consumed ≥5 servings of unprocessed red meat/wk (100 g = 1 serving) were compared with women who consumed <1 serving unprocessed red meat/wk, the multivariate HR was 0.99 (95% CI: 0.91, 1.08; P-trend = 0.63). CONCLUSIONS: In this large prospective cohort of French women, we observed an association between the consumption of processed red meat and hypertension. We observed no association for unprocessed red meat consumption and hypertension.

Anthropometric features and cutaneous melanoma risk: a prospective cohort study in French women.

BACKGROUND: Epidemiological studies on anthropometric features and cutaneous melanoma risk in women yielded inconsistent results, with few analyses involving prospective cohort data. Our objective was to explore several anthropometric characteristics in relation to the risk of melanoma in women. METHODS: We prospectively analysed data from E3N, a French cohort involving 98,995 women born in 1925-1950. Participants completed self-administered questionnaires sent biennially over 1990-2008. Relative risks (RRs) and 95% confidence intervals (CIs) were computed using Cox proportional hazards regression models, adjusted for age, number of naevi, freckling, skin and hair colour, skin sensitivity to sun exposure, residential sun exposure, and physical activity. RESULTS: Height was positively associated with melanoma in age-adjusted models only (RR=1.27, 95% CI=1.05-1.55 for ≥ 164 cm vs. <160 cm; P for trend=0.02). After full adjustment, there was a significantly positive relationship between sitting-to-standing height ratio and melanoma risk (RR=1.40, 95% CI=1.06-1.86 for ≥ 0.533 vs. <0.518; P for trend=0.02). A large body shape at menarche was inversely associated with the risk of melanoma (RR=0.78, 95% CI=0.62-0.98; compared with lean). However, weight, body mass index, body surface area, waist or hip circumference, sitting height or leg length were not significantly associated with risk. CONCLUSION: These results suggest that height, sitting-to-standing height ratio and body shape at menarche may be associated with melanoma risk. Further research is required to confirm these relationships and better understand the underlying mechanisms.

Latitude and ultraviolet radiation dose in the birthplace in relation to menarcheal age in a large cohort of French women.

BACKGROUND: Age at menarche is an important determinant of hormonal-related neoplasia and other chronic diseases. Spatial and temporal variations in age at menarche have been observed in industrialised countries and several environmental factors were reported to have an influence. METHOD: We examined geographical variations in self-reported age at menarche and explored the effects of both latitude and ultraviolet radiation (UVR) dose on the onset of menarche in 88,278 women from the French E3N cohort (aged 40-65 years at inclusion). RESULTS: The mean age at menarche was 12.8 years. After adjustment for potential confounders (birth cohort, prematurity, birth weight and length, father's income index, body silhouette in childhood, food deprivation during World War II, population of birthplace, number of siblings, breastfeeding exposure and indoor exposure to passive smoking during childhood), latitude and UVR dose (annual or spring/summer) in county of birth were significantly associated with age at menarche (P(trend) < 0.0001). Women born at lower latitudes or in regions with higher annual or spring/summer UVR dose had a 3- to 4-month earlier menarche than women born at higher latitudes or in regions with lower UVR. On a continuous scale, a 1° increment in latitude resulted in a 0.04-year older age at menarche [95% confidence interval (CI): 0.03, 0.05], whereas a 1-kJ/m(2) increment in annual UVR dose resulted in a 0.42-year younger age at menarche (95% CI: -0.55, -0.29). CONCLUSION: These data further suggest that light exposure in childhood may influence sexual maturation in women.

Determinants of age at menarche and time to menstrual cycle regularity in the French E3N cohort.

PURPOSE: Early menarche has been associated with a greater risk of several major chronic diseases. Although largely genetically determined, age at menarche also has been related to environmental and lifestyle factors. METHODS: Using linear regression models, we explored simultaneously several pre- and postnatal factors as potential determinants of age at menarche and time to menstrual cycle regularity in 96,493 women participating, since 1990, in the French E3N prospective cohort. RESULTS: Younger age at recruitment, greater father's income index, urban birth place, greater birth length, and larger body silhouette during childhood were associated with an earlier age at menarche (from -1.3 to -4.6 months, P(trend) < .0001) whereas greater family size, food deprivation during childhood, and greater birth weight resulted in a delayed menarche (from +1.5 months to +5.3 months, P(trend) < .0001). Father's income index, urban birth place, and prematurity predicted a shorter time to menstrual cycle regularity (from -1.1 to -1.9 months, P(trend) < .04), whereas birth cohort, larger body silhouette at menarche, and childhood exposure to passive smoking were associated with a longer time to menstrual cycle regularity (from +1.1 months to +8.6 months, P(trend) < .006). CONCLUSIONS: Age at menarche and menstrual cycle regularity are significantly influenced by several individual, environmental and lifestyle factors.