Increased long-term recreational physical activity is associated with older age at natural menopause among heavy smokers: the California Teachers Study.

OBJECTIVE: Although physical activity modulates the hypothalamic-pituitary-ovarian axis, the few studies that have investigated whether physical activity is associated with age at natural menopause have yielded mixed results. We set out to determine whether physical activity is associated with the timing of natural menopause in a large cohort of California women overall and by smoking history. METHODS: We investigated the association between long-term physical activity (h/wk/y) and age at natural menopause among 97,945 women in the California Teachers Study. Multivariable Cox proportional hazards regression methods were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). The impact of cigarette smoking (never smoker, former light smoker, former heavy smoker, current light smoker, and current heavy smoker) as an effect modifier was evaluated. RESULTS: In a multivariable model adjusted for body mass index at age 18 years, age at menarche, race/ethnicity, and age at first full-term pregnancy, increased physical activity was statistically significantly associated with older age at natural menopause (P(trend) = 0.005). Higher body mass index at age 18 years (P(trend) = 0.0003) and older age at menarche (P(trend) = 0.0003) were also associated with older age at natural menopause. Hispanic ethnicity (vs non-Hispanic whites; HR, 1.17; 95% CI, 1.09-1.26), current smokers (vs never smokers; HR, 1.68; 95% CI, 1.60-1.75 for current light smokers; HR, 1.38; 95% CI, 1.33-1.44 for current heavy smokers), and older age at first full-term pregnancy (HR(≥29, 2+ full-term pregnancies) vs HR(<29, 2+ full-term pregnancies), 1.10; 95% CI, 1.06-1.14) were associated with earlier age at natural menopause. Upon stratification by smoking history, increased physical activity was statistically significantly associated with older age at natural menopause among heavy smokers only (HR(highest quartile) vs HR(lowest quartile), 0.88; 95% CI, 0.81-0.97; P(trend) = 0.02 for former heavy smokers; HR(highest quartile) vs HR(lowest quartile), 0.89; 95% CI, 0.80-0.99; P(trend) = 0.04 for current heavy smokers). CONCLUSIONS: Age at natural menopause is a complex trait; the determinants of age at natural menopause, including physical activity, may differ by smoking status.

Duration of lactation, maternal metabolic profile, and body composition in the Norwegian EBBA I-study.

OBJECTIVE: There is conflicting evidence as to whether duration of lactation may decrease the risk of subsequent development of an unfavorable maternal metabolic profile, including overweight and obesity. We hypothesized that duration of lactation is associated with a more favorable metabolic profile and healthier anthropometric measurements. SUBJECTS AND METHODS: Ninety-eight parous women were studied from the Norwegian EBBAI-study (Energy Balance and Breast cancer Aspects-study), a cross-sectional study of healthy premenopausal women 25-35 years old. Historical lactation data were collected, anthropometric measurements were taken, fasting blood samples (for serum glucose, triglycerides, total cholesterol, and high-density lipoprotein cholesterol) were drawn, and women were asked to fill in a precoded food diary. RESULTS: Mean time since last birth was 4.7 years, mean number of children was 1.9, mean total duration of lactation was 19 months, and average length of lactation per child was 10.3 months. Women who on average lactated for less than 10 months per child had higher mean levels of fasting serum glucose (5.2 mmol/L vs. 5.0 mmol/L, p=0.04), serum triglyceride (0.91 mmol/L vs. 0.66 mmol/L, p=0.001), and serum cholesterol (4.78 mmol/L vs. 4.32 mmol/L, p=0.004) and a higher waist-to-hip ratio (0.81 vs. 0.77, p=0.001) than women who lactated for 10 months or more per child. The inverse association between average length of lactation per child and waist-to-hip ratio persisted after adjustment for potential confounders. CONCLUSIONS: These results support the hypothesis that duration of lactation may be associated with a healthier metabolic profile and healthier anthropometric measurements, especially lipid levels and waist-to-hip ratio, even years after weaning.

Physical activity and lung cancer prevention.

Since lung cancer is among the cancers with the highest incidence and has the highest mortality rate of cancer worldwide, the means of reducing its impact are urgently needed. Emerging evidence shows that physical activity plays an etiological role in lung cancer risk reduction. The majority of studies support the fact that total and recreational physical activity reduces lung cancer risk by 20-30% for women and 20-50% for men, and there is evidence of a dose-response effect. The biological mechanisms operating between physical activity and lung cancer are likely complex and influenced by many factors including inherited or acquired susceptibility genes, gender, smoking, and other environmental factors. Several plausible biological factors and mechanisms have been hypothesized linking physical activity to reduced lung cancer risk including: improved pulmonary function, reduced concentrations of carcinogenic agents in the lungs, enhanced immune function, reduced inflammation, enhanced DNA repair capacity, changes in growth factor levels and possible gene-physical activity interactions. Future research should target the possible subgroup effects and the biologic mechanisms that may be involved.

Does a variation in self-reported physical activity reflect variation in objectively measured physical activity, resting heart rate, and physical fitness? Results from the Tromso study.

AIMS: To study the association between self-reported physical activity (PA) and objectively measured PA, resting heart rate, and physical fitness. METHODS: During 2007-08, 5017 men and 5607 women aged 30-69 years attended the sixth survey of the Tromsø study. Self-reported PA during leisure-time and work were assessed and resting heart rate was measured. In a sub-study, the activity study, PA (Actigraph LLC) and physical fitness (VO2(max)) were objectively measured among 313 healthy men and women aged 40-44 years. RESULTS: Self-reported leisure PA was significantly correlated with VO2(max) (ml/kg/min) (women 0.40, p < 0.001, men 0.44 p < 0.001) and moderate-to-vigorous PA (>2000 counts/min) (women 0.28, p < 0.01, men 0.25, p < 0.01). The intra-class correlation coefficient between self-reported leisure PA and overall PA (counts/min) measured by accelerometer was 0.62 (95% CI 0.51, 0.71) for women and 0.59 (95% CI 0.47, 0.69) for men, and for VO2(max) the intra-class correlation coefficient was 0.86 (95% CI 0.81, 0.90) for both sexes. Among all participants, an inverse dose-response relationship was observed between self-reported leisure PA and resting heart rate for both men and women (p < 0.0001). More women than men met the international recommendations of 10,000 step counts/day (27% vs. 22%) and the recommendation of at least 30 minutes/day of moderate-to-vigorous intensities (30% vs. 22 %). CONCLUSIONS: The Tromsø physical activity questionnaire has acceptable validity and provides valid estimates of high-intensity leisure activity. However, these results underscore the need for collecting objectively PA measurements in large epidemiological studies.

Metabolic profile, physical activity, and mortality in breast cancer patients.

Metabolic components [body mass index (BMI), blood pressure, serum lipids] and physical activity may affect biological mechanisms of importance for breast cancer prognosis. A population-based survival study among 1,364 breast cancer cases within the Norwegian Counties Study during 1974-2005 was conducted. Pre-diagnostic measurements of BMI, blood pressure, serum lipids, and self-reported physical activity were assessed. Multivariable Cox proportional hazard models were used in analyses (SAS version 9.11). Among these breast cancer cases (age at diagnosis 27-79 years), 429 women died (8.2 mean follow-up years). Those with a BMI >or= 30 kg/m(2) had a 1.47 higher risk of dying during follow-up than women with a BMI of 18.5-25 kg/m(2) [hazard ratio (HR) = 1.47, 95% CI 1.08-1.99]. Women with BMI < 25 kg/m(2) and age of diagnosis >or=55 years had a 66% reduction in overall mortality if they regularly exercised before diagnosis compared with sedentary women (HR = 0.34, 95% CI 0.16-0.71). Women in the highest tertile of total cholesterol had a 29% increase in mortality compared to women in the lowest tertile (HR = 1.29, 95% CI 1.01-1.64). Additionally, women in the highest tertile of blood pressure had a 41% increase in mortality compared to women in the lowest tertile of blood pressure (HR = 1.41, 95% CI 1.09-1.83). Our study supports a relationship between mortality not only in relation to BMI, but also blood pressure, lipids, and physical activity among breast cancer patients. These factors may all be important targets for invention among breast cancer patients.

Adult height, insulin, and 17beta-estradiol in young women.

BACKGROUND: Adult height and insulin are thought to modify the development of breast cancer. However, little is known about the association between height and 17beta-estradiol, a key factor in breast carcinogenesis, and whether insulin modifies such an association. METHODS: Among 204 healthy women, ages 25 to 35 years, who participated in the Energy Balance and Breast Cancer Aspect I study, adult height (in centimeters) and fasting serum concentrations of insulin (pmol/L) were measured. 17beta-Estradiol concentrations were measured in daily saliva samples throughout an entire menstrual cycle through RIA. Age and multivariate linear regression models were used to study the association between adult height and 17beta-estradiol levels throughout an entire menstrual cycle and whether serum levels of fasting insulin may modify such an association. RESULTS: The women had a mean age of 30.7 years, adult height of 166.9 cm, and serum insulin of 85.7 pmol/L. For each increase of one SD in insulin levels in the upper tertile of adult height, the adjusted level of 17beta-estradiol increased by 3.1 pmol/L (95% confidence interval, 1.1-5.2), equivalent to a 17.3% higher mean average concentration of 17beta-estradiol. Women with an adult height > or =170 cm (upper tertile) and insulin levels >101 pmol/L (upper quartile) experienced, on average, 41% higher 17beta-estradiol levels throughout the entire menstrual cycle compared with women with the same adult height and insulin levels <101 pmol/L. CONCLUSION: Our findings support that premenopausal levels of 17beta-estradiol vary in response to adult height and insulin levels, of possible importance for breast cancer risk.

Influence of birth weight and adult body composition on 17beta-estradiol levels in young women.

BACKGROUND: Estrogens induce cellular proliferation and are associated with an increased risk of breast cancer. Birth weight and adult body weight have independently been associated with both estrogen levels and breast cancer risk. Thus, we hypothesize that low birth weight, in combination with adult overweight, may influence premenopausal 17beta-estradiol over an entire menstrual cycle of possible importance for breast cancer. METHODS: Among 204 healthy women, aged 25-35 years, who participated in the Norwegian EBBA-I Study, birth weight and age at menarche were assessed. Levels of 17beta-estradiol were measured in daily saliva samples over one menstrual cycle using radioimmunoassay (RIA). Measurements of body composition; waist circumference (cm), body mass index (BMI, kg/m(2)), and total fat percentage (DEXA, %) were assessed. Fasting blood samples were drawn, and serum concentrations of lipids and hormones were determined. RESULTS: The participating women had mean birth weight of 3,389 g and age at menarche 13.1 years. Women within the highest tertile of birth weight had the lowest 17beta-estradiol throughout the menstrual cycle (p = 0.03), and they tended to have a later age at menarche (p = 0.06). When we looked into birth weight in combination with adult-attained weight, we found that women with lower birth weights, combined with excess weight during adulthood, had higher levels of free 17beta-estradiol over an entire menstrual cycle compared with women with high birth weights and adult overweight. Women with birth weights <3,530 g, who later developed excess body weight (waist >or= 84 cm), showed 33% higher 17beta-estradiol concentrations over a menstrual cycle compared with women with higher birth weights (>or=3,530 g) and adult excess body weight (p = 0.03). The association was even more pronounced in women with birth weights <3,220 g, early age at menarche (<12 years), and adult overweight. CONCLUSION: Our findings support variation of premenopausal levels of 17beta-estradiol in response to birth weight and energy status in adult life, suggesting that women with low birth weight in combination with adult overweight are put at risk for higher estradiol levels throughout menstrual cycles, which is of possible importance for breast cancer risk.

Physical activity, heart rate, metabolic profile, and estradiol in premenopausal women.

PURPOSE: To study whether physical inactive women with a tendency to develop metabolic syndrome have high levels of 17beta-estradiol (E2) of importance for breast cancer risk. METHODS: Two hundred and four healthy women of reproductive age were assessed for self-reported leisure-time physical activity (LPA), resting heart rate (HR), blood pressure (BP), anthropometry, and serum glucose, lipids, and insulin [Norwegian Energy Balance and Breast Cancer Aspect (EBBA) study]. E2 was measured in daily saliva samples throughout an entire menstrual cycle. A clustered metabolic risk score [z metabolic syndrome (zMS); total cholesterol-high-density lipoprotein-cholesterol (HDL-C) ratio, insulin resistance, total fat tissue, BP, and triglycerides] was defined. Linear regression and linear mixed models were used, and confounding factors were tested. RESULTS: Physically active women had lower fat percentage (Ptrend = 0.003) and HRs (Ptrend = 0.003) than sedentary women. We estimated an increase in E2 of 1.27 pmol.L [95% confidence interval (CI), 0.06-2.47] for each 11.7 beats.min (1 SD) increase in HR, and this corresponds to the 7% change in mean concentration of E2 for the total group. Associations with E2 were also found for fat tissue, total cholesterol-HDL-C ratio, insulin resistance, and triglycerides. A dose-response relationship was observed among the three levels of LPA and HR and zMS (Ptrend = 0.03 for LPA; Ptrend = 0.004 for HR). Women in the highest tertile of the clustered metabolic risk score had average salivary E2profiles that were markedly higher, throughout the cycle, than those of the other groups, with a cycle peak-day difference in E2 of 22-28%. CONCLUSION: LPA and HR were associated with metabolic risk score, and this score was associated with daily level of E2, pointing to important biologic mechanisms operating between a sedentary lifestyle and an increased breast cancer risk.

Low high-density lipoprotein cholesterol may signal breast cancer risk: recent findings and new hypotheses.

Increasing bodyweight among women worldwide seems to be associated with a proportional rise in the number of women developing breast cancer. It is of utmost importance to obtain reliable biomarkers that may help clinicians to identify susceptible individuals among the growing population of women with excess adiposity. Our recent studies, reviewed within this article, support that adiposity-related metabolic disorders may represent high-risk phenotypes; specifically, we conclude that a low level of high-density lipoprotein cholesterol may be a reliable marker for breast cancer risk among overweight women. We tested our hypothesis among a large number of overweight women in the Norwegian Three County Cohort and the Norwegian cross-sectional study, the Energy Balance and Breast cancer Aspects (EBBA-I) study. Future studies should explore how genetic, environmental and behavioral factors may increase the susceptibility of overweight women to breast cancer, and how we can successfully establish targeted preventive strategies.

Metabolic and hormonal profiles: HDL cholesterol as a plausible biomarker of breast cancer risk. The Norwegian EBBA Study.

Low serum high-density lipoprotein cholesterol (HDL-C) is an important component of the metabolic syndrome and has recently been related to increased breast cancer risk in overweight and obese women. We therefore questioned whether serum HDL-C might be a biologically sound marker of breast cancer risk. We obtained cross-sectional data among 206 healthy women ages 25 to 35 years who participated in the Norwegian EBBA study. We included salivary ovarian steroid concentrations assessed by daily samples throughout one entire menstrual cycle, metabolic profile with measures of adiposity [body mass index (BMI) and truncal fat percentage], serum concentrations of lipids and hormones (insulin, leptin, testosterone, dehydroepiandrostendione sulfate, insulin-like growth factor-I, and its principal binding protein), and mammographic parenchymal pattern. We examined how components of the metabolic syndrome, including low serum HDL-C, were related to levels of hormones, and free estradiol concentration in particular, and studied predictors of mammographic parenchymal patterns in regression models. In women with BMI > or = 23.6 kg/m(2) (median), overall average salivary estradiol concentration dropped by 2.4 pmol/L (0.7 pg/mL; 13.2% change in mean for the total population) by each 0.33 mmol/L (12.8 mg/dl; 1SD) increase in serum HDL-C (P = 0.03; P(interaction) = 0.03). A subgroup of women characterized by both relatively high BMI (> or =23.6 kg/m(2)) and high serum LDL-C/HDL-C ratio (> or = 2.08; 75 percentile) had substantially higher levels of salivary estradiol by cycle day than other women (P = 0.001). BMI was the strongest predictor of overall average estradiol with a direct relationship (P< 0.001). Serum HDL-C was inversely related to serum leptin, insulin, and dehydroepiandrostendione sulfate (P < 0.001, P < 0.01, and P < 0.05, respectively). There was a direct relationship between breast density and healthy metabolic profiles (low BMI, high serum HDL-C; P < 0.001) and salivary progesterone concentrations (P < 0.05). Our findings support the hypothesis that low serum HDL-C might reflect an unfavorable hormonal profile with, in particular, increased levels of estrogens and gives further clues to biomarkers of breast cancer risk especially in overweight and obese women.