Effect of taurine supplementation on plasma homocysteine levels of the middle-aged Korean women.

January 30th, 2011

Adv Exp Med Biol. 2009;643:415-22.

Ahn CS.

Department of Food and Nutrition, Ansan College, Ansan, Korea. csan@ansan.ac.kr

Abstract

The purpose of this study was to evaluate the effect of taurine supplementation on plasma homocysteine (Hcy) levels, an independent risk factor of cardiovascular disease. The subjects consisted of 22 healthy middle-aged women (33 to 54 years). Serum lipids, plasma taurine and plasma Hcy levels were measured before and after supplying 3 g taurine per day for 4 weeks. The concentration of plasma taurine was significantly increased from 63.7 +/- 14.2 micromol/L to 73.8 +/- 16.6 micromol/L after taurine supplementation (p < 0.001). On the other hand, the concentration of plasma Hcy was significantly decreased from 8.5 +/- 1.2 micromol/L to 7.6 +/- 1.1 micromol/L after taurine supplementation (p < 0.05). The effect of taurine on the levels of plasma Hcy was assessed by regression analysis (R2 = 0.304). After taurine supplementation, plasma taurine and Hcy concentration exhibited a significant negative correlation (p < 0.05). In conclusion, taurine is an effective nutrient that antagonizes Hcy levels. Therefore, this study suggests that sufficient taurine intake might be an effective way of preventing cardiovascular diseases, such as atherosclerosis.

Posted in Cardiovascular | No Comments »

Use of Supplements of Multivitamins, Vitamin C, and Vitamin E in Relation to Mortality

January 30th, 2011
  1. Gaia Pocobelli,
  2. Ulrike Peters,
  3. Alan R. Kristal and
  4. Emily White
  1. Correspondence to Gaia Pocobelli, Fred Hutchinson Cancer Research Center, M3-B232, 1100 Fairview Avenue North, Seattle, WA 98109-1024 (e-mail: gpocobel@u.washington.edu).

?

Abstract

In this cohort study, the authors evaluated how supplemental use of multivitamins, vitamin C, and vitamin E over a 10-year period was related to 5-year total mortality, cancer mortality, and cardiovascular disease (CVD) mortality. Participants (n =?77,719) were Washington State residents aged 50–76 years who completed a mailed self-administered questionnaire in 2000–2002. Adjusted hazard ratios and 95% confidence intervals were computed using Cox regression. Multivitamin use was not related to total mortality. However, vitamin C and vitamin E use were associated with small decreases in risk. In cause-specific analyses, use of multivitamins and use of vitamin E were associated with decreased risks of CVD mortality. The hazard ratio comparing persons who had a 10-year average frequency of multivitamin use of 6–7 days per week with nonusers was 0.84 (95% confidence interval: 0.70, 0.99); and the hazard ratio comparing persons who had a 10-year average daily dose of vitamin E greater than 215 mg with nonusers was 0.72 (95% confidence interval: 0.59, 0.88). In contrast, vitamin C use was not associated with CVD mortality. Multivitamin and vitamin E use were not associated with cancer mortality. Some of the associations we observed were small and may have been due to unmeasured healthy behaviors that were more common in supplement users.

Posted in Antioxidants, Cardiovascular | No Comments »

Low serum carotenoids are associated with a decline in walking speed in older women

January 30th, 2011
Volume 13, Number 3, 170-175, DOI: 10.1007/s12603-009-0053-6

N. Alipanah, R. Varadhan, K. Sun, L. Ferrucci, L. P. Fried and Richard D. Semba

Background and Objectives

Walking speed is an important measure of physical performance that is predictive of disability and mortality. The relationship of dietary factors to changes in physical performance has not been well characterized in older adults. The aim was to determine whether total serum carotenoid concentrations, a marker for fruit and vegetable intake, and serum selenium are related to changes in walking speed in older women.

Subjects and Methods

The relationship between total serum carotenoids and selenium measured at baseline, 12, and 24 months follow-up and walking speed assessed at baseline and every six months for 36 months was examined in 687 moderately to severely disabled women, 65 years or older, living in the community.

Results

Mean total serum carotenoids were associated with mean walking speed over three years of follow-up (P = 0.0003) and rate of change of walking speed (P = 0.007) in multivariate linear regression models adjusting for age, body mass index, and chronic diseases. Mean serum selenium was associated with mean walking speed over three years of follow-up (P = 0.0003) but not with the rate of change of walking speed (P = 0.26).

Conclusions

These findings suggest that a higher fruit and vegetable intake, as indicated by higher total serum carotenoid concentrations, may be protective against a decline in walking speed in older women.

Posted in Antioxidants, Arthritis/Gout, Pain | No Comments »

Dietary fish and meat intake and dementia in Latin America, China, and India: a 10/66 Dementia Research Group population-based study

January 30th, 2011
  1. Emiliano Albanese,
  2. Alan D Dangour,
  3. Ricardo Uauy,
  4. Daisy Acosta,
  5. Mariella Guerra,
  6. Sara S Gallardo Guerra,
  7. Yueqin Huang,
  8. KS Jacob,
  9. Juan Llibre de Rodriguez,
  10. Lisseth Hernandex Noriega,
  11. Aquiles Salas,
  12. Ana Luisa Sosa,
  13. Renata M Sousa,
  14. Joseph Williams,
  15. Cleusa P Ferri, and
  16. Martin J Prince

+ Author Affiliations


  1. 1From King’s College London, Section of Epidemiology, Health Services and Population Research Department, De Crespigny Park, London, United Kingdom (EA, CF, RS, and MJP); the Nutrition and Public Health Intervention Research Unit, London School of Hygiene & Tropical Medicine, London, United Kingdom (ADD); the Public Health Nutrition Division, Instituto Nutricion y Tecnologia de Alimentos, Universidad de Chile, Santiago, Chile (RU); Universidad Nacional Pedro Henriquez Ureña, Internal Medicine Department, Geriatric Section, Santo Domingo, Dominican Republic (DA); the Psychogeriatric Unit, National Institute of Mental Health “Honorio Delgado Hideyo Noguchi,” Lima, Perú (MG and SSGG); Peking University, Institute of Mental Health, Beijing, China (YH); Christian Medical College, Vellore, India (KSJ); the Facultad de Medicina Finley-Albarran, Medical University of Havana, Havana, Cuba (JLdR); the Community Mental Health Centre, Mariano, Cuba (LHN); the Medicine Department, Caracas University Hospital, Faculty of Medicine, Universidad Central de Venezuela, Caracas, Venezuela (AS); the Cognition and Behavior Unit, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico (ALS); and the Department of Community Health, Voluntary Health Services, Chennai, India (JW).

  • ?2 The 10/66 Dementia Research Group was supported by the Wellcome Trust Health Consequences of Population Change Programme (GR066133 for Cuba and Brazil and GR08002 for Peru, Mexico, Argentina, Cuba, Dominican Republic, and China), the World Health Organization (India, Dominican Republic, and China), the US Alzheimer’s Association (IIRG-04-1286 for Peru, Mexico, and Argentina), and Fondo Nacional de Ciencia y Tecnologia and Universidad Central de Venezuela (Venezuela). The 10/66 Dementia Research Group works closely with Alzheimer’s Disease International (ADI), the nonprofit federation of 77 Alzheimer associations worldwide; ADI provided support for networking and infrastructure and partially funds EA’s research and dissemination activities. The study design, data collection and analysis, and interpretation of findings were independent of all sponsors.

  • ?3 Address reprint requests and correspondence to E Albanese King’s College London, Health Service & Population Research Department, De Crespigny Park, SE5 8AF London, United Kingdom. E-mail: emiliano.albanese@iop.kcl.ac.uk.

Abstract

Background: Evidence of an association between fish and meat consumption and risk of dementia is inconsistent and nonexistent in populations in developing countries.

Objective: The objective was to investigate associations between fish and meat consumption with dementia in low- and middle-income countries.

Design: One-phase cross-sectional surveys were conducted in all residents aged ?65 y in 11 catchment areas in China, India, Cuba, the Dominican Republic, Venezuela, Mexico, and Peru. A total of 14,960 residents were assessed by using the 10/66 standardized protocol, which includes face-to-face interviews for dietary habits and a cross-culturally validated dementia diagnosis.

Results: Dietary intakes and the prevalence of dementia varied between sites. We combined site-specific Poisson regression prevalence ratios (PRs) for the association between fish and meat consumption and dementia in 2 fixed-effect model meta-analyses adjusted for sociodemographic and health characteristics and fish and meat consumption as appropriate. We found a dose-dependent inverse association between fish consumption and dementia (PR: 0.81; 95% CI: 0.72, 0.91) that was consistent across all sites except India and a less-consistent, dose-dependent, direct association between meat consumption and prevalence of dementia (PR: 1.19; 95% CI: 1.07, 1.31).

Conclusions: Our results extend findings on the associations of fish and meat consumption with dementia risk to populations in low- and middle-income countries and are consistent with mechanistic data on the neuroprotective actions of omega-3 (n–3) long-chain polyunsaturated fatty acids commonly found in fish. The inverse association between fish and prevalent dementia is unlikely to result from poorer dietary habits among demented individuals (reverse causality) because meat consumption was higher in those with a diagnosis of dementia.

  • Received February 3, 2009.
  • Accepted May 21, 2009.

Articles citing this article

  • Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial Am J Clin Nutr 2010 91: 6 1725-1732
  • Association of Marine Omega-3 Fatty Acid Levels With Telomeric Aging in Patients With Coronary Heart Disease JAMA 2010 303: 3 250-257

Posted in Brain Health | No Comments »

Vitamin D From Dietary Intake and Sunlight Exposure and the Risk of Hormone-Receptor-Defined Breast Cancer

January 30th, 2011

Am J Epidemiol. 2008 Oct 15;168(8):915-24. Epub 2008 Aug 27.

Click here to read

Evidence has emerged for a role of vitamin D in the development of breast cancer, and there is some suggestion that its antiproliferative effect is greater in hormone-receptor-positive cells. Few epidemiologic studies have considered the association between vitamin D and hormone-receptor-defined breast cancer, and the results are conflicting. Considering 759 cases and 1,135 controls from a case-control study (Ontario, Canada, 2003–2005), the authors examined the association between vitamin D intake at specific ages and combined estrogen-receptor- (ER) and progesterone-receptor- (PR) defined breast cancer. While increased intake of vitamin D (from the sun and diet) was most consistently associated with a significantly reduced risk of ER+/PR+ tumors (e.g., odds ratio = 0.76, 95% confidence interval: 0.59, 0.97 for use of cod liver oil during adolescence), comparable nonsignificant associations were found for receptor-negative (ER?/PR?) (odds ratio = 0.74, 95% confidence interval: 0.53, 1.04) and mixed (ER+/PR?) (odds ratio = 0.79, 95% confidence interval: 0.51, 1.22) tumors. This study suggests that vitamin D is associated with a reduced risk of breast cancer regardless of ER/PR status of the tumor. Future studies with a larger number of receptor-negative and mixed tumors are required.

Key words

Studies supporting a role of vitamin D in the prevention of several cancers, including breast cancer, have recently emerged (1–3). Vitamin D is primarily obtained through exposure of the skin surface to ultraviolet B radiation, but small amounts can be ingested through limited dietary sources (e.g., fortified milk, fatty fish) and supplements (4–6). The biologic mechanism by which vitamin D might prevent breast cancer has been summarized previously (5–11). The active form of vitamin D (1,25-dihydroxyvitamin D (1,25(OH)2D)) can inhibit cellular proliferation and induce differentiation and apoptosis in normal and cancerous breast cells (7–10). In carcinogen-exposed rats, 1,25(OH)2D or its analogues have been shown to reduce the incidence and size of tumors and delay mammary tumor development (11). 25(OH)D-1-? hydroxylase, the enzyme that converts 25-hydroxyvitamin D (25(OH)D) to its active form, and the vitamin D receptor, through which 1,25(OH)2D mediates its effects, are present in normal and cancerous breast epithelia (7–10).

Estrogen receptor (ER) and progesterone receptor (PR) are widely studied markers in breast tissue, and there is evidence that some breast cancer risk factors vary by hormone receptor status (reviewed by Althuis et al. (12)). An antiproliferative effect of 1,25(OH)2D in both ER+ and ER? cell lines has been demonstrated, although some studies suggest the effect is greater in ER+ cells (8, 9). To our knowledge, only 3 studies have examined the association between dietary vitamin D intake and hormone receptor status (13–15), and one considered blood levels of 1,25(OH)2D and hormone receptor status (16). Of these studies, 3 demonstrated a stronger inverse association with risk of receptor-positive tumors (ER+, PR+, ER+/PR+) (13, 14, 16), whereas another demonstrated stronger relative risks for women with a negative ER and PR status (15). Nonetheless, in some studies (13, 15, 16), receptor status was unavailable for a significant proportion of cases (30%–50%); in others, the total number of cases with a negative ER and PR status was very small (n < 100) (14), thereby limiting interpretation of the overall findings. Furthermore, these studies did not assess sun exposure history and hormone receptor status.

In a recently completed, population-based case-control study, we found a strong inverse association between several reported vitamin D exposures from the sun (e.g., odds ratio = 0.65, 95% confidence interval: 050, 0.85 for the highest quartile of outdoor activities vs. the lowest) and diet (e.g., odds ratio = 0.76, 95% confidence interval: 0.62, 0.92 for cod liver oil use) during adolescence and overall breast cancer risk (17). Some evidence was observed for exposures during early adulthood, with little evidence of a relation between perimenopausal exposures and breast cancer (17). To add to the limited literature regarding the relation between vitamin D and hormone-receptor-defined breast cancer, we examined whether the associations observed between reported vitamin D exposures from the sun and diet during these 3 time periods and subsequent breast cancer varied by joint ER and PR status. In contrast to previous studies, receptor status was available for approximately 80% of cases.

MATERIALS AND METHODS

Details of the study design and population have previously been described (17). This study was approved by the local institution’s research ethics board. We conducted a population-based-case-control study in the province of Ontario, Canada. Cases were identified through the Ontario Cancer Registry and were randomly sampled from women aged less than 70 years with incident, pathology confirmed, first primary invasive breast cancer diagnosed between July 1, 2003, and August 31, 2004. Of the 1,610 eligible cases identified, physician permission to contact 1,350 (84%) was obtained. Of the 1,350 women we attempted to contact, 972 (72%) completed a telephone interview.

For the majority of recruited cases (n = 665, 68%), ER and PR status (positive/negative) was available from pathology reports obtained from the Ontario Cancer Registry. However, for the remaining cases (n = 307, 32%), hormone receptor status was unavailable. For these cases, consent was obtained from 249 women (81%) authorizing release of pathology reports from the medical records departments of hospitals where surgery had been performed. Pathology reports were received for 224 (90%) of these women, 129 (58%) of which contained information on ER and PR status. Immunohistochemical assays were the predominant method used to determine hormone receptor status. In total, ER status was available for 784 cases (81%), PR status was available for 763 cases (78%), and joint ER and PR status (ER+/PR+, ER+/PR?, ER?/PR+, ER?/PR?) was available for 762 cases (78%). A status of “borderline” was considered unknown. Because the number of ER?/PR+ cases was small (n = 3), this category was omitted from the analysis, resulting in a total of 759 cases.

Population controls were women who reported no prior breast cancer and were living in the province of Ontario. Controls were identified through randomly selected residential telephone number lists and were frequency matched to cases by 5-year age group. Of the 1,974 telephone numbers for which an eligible control was identified, 1,376 (70%) potential controls agreed to participate; of these women, 1,135 (82%) completed the telephone interview.

During the interview, cases and controls were asked to recall their sun exposure history and their dietary and supplemental vitamin D intake with respect to 3 age groups: 10–19, 20–29, and 45–54 years (17). These age groups were chosen to capture exposures during breast development in adolescence and early adulthood and breast involution occurring around the time of menopause. Studies have shown that some risk factors (e.g., smoking, ionizing radiation, phytoestrogen intake) may have a greater influence on subsequent breast cancer risk when exposures occur during periods of rapid tissue growth and change (18–20).

Sun-exposure-related variables included number of days per week on which at least half an hour was spent outside (<7 vs. 7), total number of outdoor activity episodes of at least half an hour during the summer (quartiles based on the distribution among controls), ever having a job involving at least half an hour of outdoor work per day (yes/no), usually keeping arms and legs covered when outside in the summer (no, partial coverage, yes), skin usually burned or darkened in the summer (yes/no), usually used sunscreen in the summer (yes/no), ever took a trip to a summer climate in the winter (yes/no), and ever used a sunlamp or sun (tanning) bed (yes/no). In Canada, major food sources of vitamin D are limited, and dietary intake variables included number of glasses of milk per week (none, <5, 5–9, ?10), number of servings of salmon/tuna (canned or fresh) per week (none, <1, 1, >1), ever took cod liver oil at least once per week (yes/no), and use of vitamin supplements (none, supplements without vitamin D, vitamin D or multivitamins).

Unordered polytomous logistic regression was used to generate odds ratios and their 95% confidence intervals for variables related to vitamin D (from the sun and diet) for each joint hormone receptor subgroup (ER+/PR+, ER+/PR?, ER?/PR?). In this model, the dependent variable (receptor-status-defined breast cancer) was treated as a polytomous nominal variable, and the logit estimator always compared each joint-receptor-status-defined case with the common control group, enabling simultaneous estimation of subgroup-specific risk parameters. Significant differences in odds ratios among the 3 case subgroups for vitamin-D-related exposures were tested by using the Wald statistic P value, which is calculated based on differences in parameter estimates and their covariances from the polytomous logistic regression model (21).

All models included age (continuous), defined as age at diagnosis for cases and age at interview for controls, and all fully adjusted models included education (high school or less, some university or technical school, university graduate) and ethnicity (northern European, mixed or other European, non-European). We considered the following known breast cancer risk factors as potential confounders: age at menarche (?11, 12, 13, ?14 years), menopausal status (premenopausal, postmenopausal, unknown), menopausal status with age at menopause (premenopausal, unknown, and age at menopause in 4 categories), hormone therapy ever use (no/yes), age at first birth (<20, 20–24, 25–29, ?30 years; nulliparous), parity (none, 1, 2, ?3 births), ever breastfed (no/yes), first-degree family history of breast cancer (no/yes), body mass index (weight (kg)/height (m)2) 2 years prior to the reference date (?20.0, 20.1–24.9, 25.0–29.9, ?30), body mass index at age 18 years (?20.0, 20.1–24.9, ?25.0), and alcohol use (none, <7 drinks/week, ?7 drinks/week). In this study, age at menarche, age at first birth, ever breastfed, and first-degree family history were all significantly associated with risk of breast cancer and were therefore also included in the fully adjusted models.

Tests of linear trend were performed by using polytomous logistic regression. Stratified analyses according to menopausal status (premenopausal and postmenopausal) were also executed. Differences in vitamin-D-related exposures between women with known and unknown receptor status were examined by using a chi-square analysis. All analyses were conducted with SAS version 9.1 software (Stata Corporation, College Station, Texas). All tests were 2 sided, with P < 0.05 as the criterion for significance.

RESULTS

Table 1 describes cases and controls according to demographic and other characteristics. Among the 759 cases considered in the analysis, 450 (59%) were ER+/PR+, 110 (14%) were ER+/PR?, and 199 (26%) were ER?/PR?.

Table 1.

Characteristics of Breast Cancer Cases (Joint Receptor Status Known) and Population Controls, Ontario, Canada, 2003–2005

Cases with ER+/PR? tumors were slightly older and more likely to be postmenopausal, be nulliparous, and to have never breastfed. A higher proportion of women with ER+/PR? and ER?/PR? tumors were of non-European heritage. Women with ER+/PR+ tumors were slightly more likely to report a first-degree family history of breast cancer.

We observed few and inconsistent differences in risk estimates regarding vitamin-D-related exposure variables (from diet and the sun) between subsets of patients defined by joint ER and PR status (Tables 2 and 3). Between the ages of 10 and 19 years, ever having taken cod liver oil was associated with a significantly reduced risk of ER+/PR+ tumors, although the estimates in ER+/PR? and ER?/PR? subgroups were comparable. The negative association for increasing milk consumption in adolescence and early adulthood was significantly different between all 3 tumor subgroups (P = 0.002 and P = 0.03, respectively), with a stronger reduced risk for ER+/PR+ tumors (P for linear trend = 0.003 and P for linear trend = 0.03, respectively). However, significant trends were observed for ER?/PR? tumors for both age groups (P = 0.02 and P = 0.01, respectively). Between the ages of 20 and 29 years, increased milk consumption also showed similar inverse associations for ER+/PR? tumors, and the P for trend approached significance (P = 0.05). The odds ratios for general vitamin supplement use (vitamin D/multivitamins and other) between the ages of 10 and 19 and 20 and 29 years were significantly different between tumor subgroups (P = 0.002 and P = 0.006, respectively), being more significantly associated with a reduced risk of ER+/PR+ tumors.

Table 2.

Fully Adjusted Odds Ratios and 95% Confidence Intervals for an Association Between Dietary and Supplement Vitamin D Intake at Specific Ages and Breast Cancer According to Joint Estrogen and Progesterone Receptor Status, Ontario, Canada, 2003–2005

Table 3.

Fully Adjusted Odds Ratios and 95% Confidence Intervals for an Association Between Vitamin-D-Related Sun Exposure Variables at Specific Ages and Breast Cancer According to Joint Estrogen and Progesterone Receptor Status, Ontario, Canada, 2003–2005

Table 3 shows the association between sun exposure variables and breast cancer by joint ER and PR status of the tumor. Between the ages of 10 and 19 years, the inverse association with increasing frequency of outdoor activities was more pronounced among women with ER+/PR+ and ER+/PR? tumors, and the P for trend was significant for both subgroups (P = 0.007 and P = 0.04, respectively); however, a significant difference in odds ratios among the 3 tumor subtypes was not observed (P = 0.12). A similar pattern was observed for increasing frequency of outdoor activities between the ages of 20 and 29 years. The reduced risk of breast cancer for women who reported ever working outdoors between the ages of 10 and 19 years was different across tumor subtypes (P = 0.003), showing a stronger reduced risk associated with both ER+/PR? and ER?/PR? tumors.

Between the ages of 10 and 19 and 20 and 29 years, a significant positive association and a significant P for trend were observed between degree of limb coverage and ER+/PR+ breast cancers (P for trend = 0.001 for both). Weaker positive associations were observed for ER+/PR? and ER?/PR? tumors, although the difference in estimates among the 3 tumor subgroups approached significance (age 10–19 years, P = 0.06; age 20–29 years, P = 0.05). Women whose skin did not darken or burn in adolescence had a significantly increased risk of ER+/PR+ tumors, although the odds ratio was not significantly different from that for the other tumor subtypes (P = 0.13).

Examination of vitamin-D-related exposures (from the sun and diet) among women with and without information on ER and PR status revealed no significant differences (data not shown). We further observed no significant differences in the results between premenopausal and postmenopausal women or between women who used and did not use hormone therapy (ever vs. never users) (data not shown). Results for ER+/PR+ tumors were similar to those for ER+ and PR+ cases alone, and those for ER?/PR? tumors were similar to results for ER? and PR? cases alone (data not shown).

DISCUSSION

In this study, vitamin D from dietary intake and sun exposure during adolescence and early adulthood was most consistently associated with a reduced risk of ER+/PR+ tumors, possibly because this subgroup was the largest. However, some significant and nonsignificant inverse associations were also observed for receptor-negative (ER?/PR?) and/or mixed (ER+/PR?) tumors.

The epidemiologic evidence to date regarding vitamin D intake and hormone-receptor-defined breast cancer is limited and conflicting (13–16). In the Cancer Prevention Study II Nutrition Cohort, a stronger inverse relation was observed between increased dietary vitamin D intake (>300 IU/day vs. ?100 IU/day) and ER+ postmenopausal breast cancer; however, for total vitamin D (diet plus supplements), no association was found with increasing intake (13). Results were similar when combined ER/PR status was considered (i.e., ER+/PR+ was similar to ER+ alone, and ER?/PR? was similar to ER?). Conversely, in the Iowa Women’s Health Study, for postmenopausal women, a stronger, nonsignificant inverse association was observed for the highest versus lowest groups of total vitamin D intake (?800 IU/day vs. <400 IU/day) among women with ER?/PR? tumors (15). In the Women’s Health Study, higher intake of total vitamin D (in quintiles) was associated with a reduced risk of developing ER+ or PR+ tumors among premenopausal women only (14). Janowsky et al. (16) found that the risk associated with levels of 1,25(OH)2D in whole blood below the median value was higher for receptor-positive (ER and/or PR present) than receptor-negative (neither receptor present) breast cancers.

In contrast to previous studies, we considered vitamin D intake from specific dietary sources separately in our analysis. Milk contributes about 100 IU of vitamin D per glass (22), and milk drinking during adolescence and early adulthood did contribute more strongly to a reduced risk of ER+/PR+ tumors, although weaker inverse associations were observed for ER?/PR? tumors. Salmon and tuna provide approximately 360 IU per serving and 200 IU per serving (Office of Dietary Supplements, National Institutes of Health (http://ods.od.nih.gov/factsheets/vitamind.asp)), respectively; however, we did not observe an association with any tumor subgroup, likely because these fish were rarely eaten more than once a week. We only crudely assessed vitamin D supplement use and found that vitamin use in general during adolescence and early adulthood was associated with a reduced risk of ER+/PR+ tumors. Since we examined exposures earlier in life, we did, however, consider cod liver oil, a traditional source of vitamin D particularly for children, which provides about 400 IU per teaspoon (5 mL) (4). Although we observed a significantly reduced risk of ER+/PR+ tumors when cod liver oil was taken earlier in life, similar inverse associations were found for the other 2 tumor subgroups. Previous studies likely did not ask about cod liver oil because they focused on dietary intake later in life (i.e., age 45 years or older) (13–15). The original Nurses’ Health Study and Nurses’ Health Study II examined dietary intake of vitamin D during high school, but neither considered hormone receptor status of the tumor and did not consider cod liver oil (23, 24).

Sun exposure is a major source of vitamin D, and a maximal dose (?20,000 IU) can be obtained from a slight reddening of the skin (1 minimal erythemal dose) in less than 0.5 hours for light-colored skin, although a longer time is required for darker skin (25). In contrast to most other studies, we asked about summer sun exposure behaviors since, at northern latitudes, vitamin D is produced at this time only (5, 6). Similar to our dietary findings, greater sun exposure earlier in life (i.e., outdoor activities/job, degree of limb coverage, whether skin burned/darkened) was more consistently associated with a reduced risk of ER+/PR+ tumors, but comparable significant and nonsignificant estimates were found for women with ER?/PR? and/or ER+/PR? tumors. Previous studies that did not consider sun exposure may have missed associations between vitamin D and hormone-receptor-defined subgroups.

Two possible reasons could explain the conflicting evidence reported in the present and earlier studies. The first is the possibility of inadequate statistical power due to the small number of cases within strata defined by hormone receptor status, especially among receptor-negative tumors, which constitute a minority of breast cancers diagnosed (20). Of all studies, those by McCullough et al. (13) and Robien et al. (15) included the largest number of receptor-negative cases (n = 227 and n = 274, respectively); however, in the first study, ER status was available for only 53% of the population, whereas, in the second study, joint receptor status was available for 68% of the population. In the Women’s Health Study, the number of cases with ER– and PR– tumors was even smaller, particularly among premenopausal women (n = 59 and n = 74, respectively), but the overall proportion of cases with known ER and PR status was high (95%) (14). The study by Janowsky et al. (16) had both a small proportion of cases whose receptor status was known (56%) and a very small number of receptor-negative cases (n = 21). In our study, receptor status was available for 80% of cases, and we had a slightly larger number of ER? and PR– cases (ER?, n = 206; PR?, n = 309; and ER?/PR?, n = 199) compared with some studies (14, 16).

Second, although an inverse relation between vitamin D and breast cancer is evident, vitamin D may not affect the risk of developing a specific type of hormonally defined breast cancer. Some data support the concept that the antiproliferative and antitumor effects of vitamin D and its analogues (e.g., EB1089) on estrogen-responsive breast cancer cells (ER+) are mediated via disruption of estrogen mitogenic and survival signals (8, 9). However, more recent studies of intracellular signaling in ER– breast cancer cell lines with a functional vitamin D receptor (e.g., SUM-159PT) have shown that vitamin D and its analogues can inhibit proliferation and induce growth arrest and apoptosis in these cells as well (26, 27). Hence, even though the estrogen signaling pathway is disrupted, sensitivity to the effects of vitamin D is maintained during the progression from an estrogen-dependent to an estrogen-independent state via the presence of the vitamin D receptor (26, 27).

This study has several strengths and limitations worth noting. Strengths include the consideration of potential markers of vitamin D synthesis from sun exposure as well as exposures earlier in life and risk of hormone-receptor-defined breast cancer. Joint ER and PR status was also available for 80% of cases, and we were able to examine associations among women with ER+/PR? tumors in addition to receptor-positive and -negative cases. However, the number of ER?/PR? and ER+/PR? tumors was still relatively small, although significant associations were observed in a few cases. Some findings may also be subject to chance because of the many analyses performed. Accuracy of recall, especially for early-life exposures, is a concern in any case-control study, although several studies have found evidence that sun exposure, both recent and in childhood and adolescence, could be recalled reasonably consistently (28). Recent studies, including our own, comparing responses to vitamin-D-related questions (from the sun and/or diet) to circulating levels of 25(OH)D showed significant associations between recent exposures and 25(OH)D levels (28, 29). Biased recall between cases and controls is also a concern, although differential recall between cases with differing hormone-defined breast cancer is unlikely. At the time our study was conducted, there was little media attention regarding a potential relation between vitamin D or sun exposure and breast cancer (17).

To conclude, we previously reported an inverse relation between increased vitamin D intake from the sun and diet, especially during adolescence and early adulthood, and overall breast cancer risk (17). In the present study, results suggest that vitamin D intake early in life influences breast cancer risk regardless of ER/PR receptor status. Although significant estimates were most consistently found for women with receptor-positive cancers (ER+/PR+), the largest subgroup, similar nonsignificant and significant associations were at times observed for receptor-negative and mixed tumors. Future studies should include a larger number of women with receptor-negative cancers.

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Posted in Cancer, Hormone Balance | No Comments »

Urinary 6-sulfatoxymelatonin levels and risk of breast cancer in postmenopausal women.

January 30th, 2011

J Natl Cancer Inst. 2008 Jun 18;100(12):898-905. Epub 2008 Jun 10.

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Schernhammer ES, Berrino F, Krogh V, Secreto G, Micheli A, Venturelli E, Sieri S, Sempos CT, Cavalleri A, Schünemann HJ, Strano S, Muti P.

Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Ave, Boston, MA 02115, USA. eva.schernhammer@channing.harvard.edu

Abstract

BACKGROUND: Low urinary melatonin levels have been associated with an increased risk of breast cancer in premenopausal women. However, the association between melatonin levels and breast cancer risk in postmenopausal women remains unclear.

METHODS: We investigated the association between melatonin levels and breast cancer risk in postmenopausal women in a prospective case-control study nested in the Hormones and Diet in the Etiology of Breast Cancer Risk cohort, which included 3966 eligible postmenopausal women. The concentration of melatonin’s major metabolite, 6-sulfatoxymelatonin, was measured in a baseline 12-hour overnight urine sample from 178 women who later developed incident breast cancer and from 710 matched control subjects. We used multivariable-adjusted conditional logistic regression models to investigate associations. Relative risks are reported as odds ratios (ORs). All statistical tests were two-sided.

RESULTS: Increased melatonin levels were associated with a statistically significantly lower risk of invasive breast cancer in postmenopausal women (for women in the highest quartile of total overnight 6-sulfatoxymelatonin output vs the lowest quartile, multivariable OR also adjusted for testosterone = 0.56, 95% confidence interval [CI] = 0.33 to 0.97; P(trend) = .02). This association was strongest among never and past smokers (OR = 0.38, 95% CI = 0.20 to 0.74; P(trend) = .001) and after excluding women who were diagnosed with invasive breast cancer within 4 years after urine collection (OR = 0.34, 95% CI = 0.15 to 0.75; P(trend) = .002). We did not observe substantial variation in relative risks by hormone receptor status of breast tumors. Among the 3966 women in the cohort, 40 of the 992 women in the highest quartile of 6-sulfatoxymelatonin developed breast cancer during follow-up, compared with 56 of the 992 women in the lowest quartile of 6-sulfatoxymelatonin.

CONCLUSION: Results from this prospective study provide evidence for a statistically significant inverse association between melatonin levels, as measured in overnight morning urine, and invasive breast cancer risk in postmenopausal women.

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A Prospective Study of Age-Specific Physical Activity and Premenopausal Breast Cancer

January 30th, 2011

J Natl Cancer Inst. 2008 May 21;100(10):728-37. Epub 2008 May 13.

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Maruti SS, Willett WC, Feskanich D, Rosner B, Colditz GA.

Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., M4-B402, Seattle, WA 98109-1024, USA. smaruti@fhcrc.org

Abstract

Background Physical activity has been consistently associated with lower risk of postmenopausal breast cancer, but its relationship with premenopausal breast cancer is unclear. We investigated whether physical activity is associated with reduced incidence of premenopausal breast cancer, and, if so, what age period and intensity of activity are critical.

Methods A total of 64?777 premenopausal women in the Nurses’ Health Study II reported, starting on the 1997 questionnaire, their leisure-time physical activity from age 12 to current age. Cox regression models were used to examine the relationship between physical activity, categorized by age period (adolescence, adulthood, and lifetime) and intensity (strenuous, moderate, walking, and total), and risk of invasive premenopausal breast cancer.

Results During 6 years of follow-up, 550 premenopausal women developed breast cancer. The strongest associations were for total leisure-time activity during participants’ lifetimes rather than for any one intensity or age period. Active women engaging in 39 or more metabolic equivalent hours per week (MET-h/wk) of total activity on average during their lifetime had a 23% lower risk of premenopausal breast cancer (relative risk = 0.77; 95% confidence interval = 0.64 to 0.93) than women reporting less activity. This level of total activity is equivalent to 3.25 h/wk of running or 13 h/wk of walking. The age-adjusted incidence rates of breast cancer for the highest (?54 MET-h/wk) and lowest (<21 MET-h/wk) total lifetime physical activity categories were 136 and 194 per 100?000 person-years, respectively. High levels of physical activity during ages 12–22 years contributed most strongly to the association.

Conclusions Leisure-time physical activity was associated with a reduced risk for premenopausal breast cancer in this cohort. Premenopausal women regularly engaging in high amounts of physical activity during both adolescence and adulthood may derive the most benefit.

CONTEXT AND CAVEATS

Prior knowledge

Physical activity is associated with reduced risk of breast cancer among postmenopausal women.

Study design

Cohort study of premenopausal nurses who were surveyed about the type and duration of leisure-time physical activity they engaged in during their lifetime and were monitored for breast cancer for 6 years.

Contributions

Average lifetime physical activity equivalent to 3.25 h/wk of running or 13 hours per week of walking was associated with a reduced risk for breast cancer compared with less activity (136 vs 196 breast cancers per 100?000 person-years). High amounts of physical activity during ages 12–22 were the most important.

Implications

In this cohort, women who regularly engaged in high amounts of physical activity during adolescence and early adulthood had a lower risk of premenopausal breast cancer than women who engaged in less activity.

Limitations

The results are likely to be generalizable only to premenopausal white women. Nearly 90% of the women in the cohort also regularly engaged in regular occupational physical activity (walking). Other lifestyle behaviors may also be important. In addition, the physical activity data were based on recall.

A quarter of all breast cancer diagnoses occur among premenopausal women (1), but few modifiable risk factors have been identified. Breast cancers among young women are more likely to have a higher grade, increased proliferation rate, and higher vascular invasion and may be more difficult to treat than breast cancers among older women (2,3). Moreover, risk factors such as body mass index (BMI) (4,5), oral contraceptive use (6), and reproductive characteristics (7) vary by menopausal status, suggesting different etiologies for pre- and postmenopausal breast cancers. An expert panel of the World Cancer Research Fund/American Institute for Cancer Research (8) and a recent systematic review (9) suggested that physical activity is associated with lower postmenopausal breast cancer incidence but that the relationship for premenopausal breast cancer is uncertain. Further unresolved questions include the role of physical activity at different age periods and intensity of activity on premenopausal breast cancer risk.

Physical activity has been hypothesized to reduce breast cancer risk through several mechanisms, including lowering the production or bioavailability of endogenous hormones such as estrogen, insulin, and insulin-like growth factor (IGF), which can act as mitogens (10,11). Estrogen stimulates the growth and division of epithelial breast cells, which can potentially increase cancer risk by allowing for the propagation of genetic errors. Insulin and IGF may raise cancer risk by increasing cellular proliferation and survival (12). Moreover, it has been hypothesized that the mechanism by which physical activity acts varies over time. Exposures during adolescence may be particularly relevant for breast cancer development because this period is characterized by increases in sex hormone levels and rapid proliferation of incompletely differentiated breast tissue. Among girls, strenuous activity is associated with later menarche and delayed establishment of regular menstrual cycles (13–16). Among adult women, exercise is related to decreased sex hormone levels, increased frequency of anovulation, and increased incidence of amenorrhea (17–19). Physical activity during both adolescence and adulthood may confer the greatest benefit for breast cancer risk by lowering lifetime levels of hormone risk factors (20). However, only three prospective studies (21–23), including one with only 12 breast cancer patients, have examined physical activity before adulthood, and none have examined lifetime activity in detail.

In this study, we investigated whether physical activity is associated with reduced incidence of premenopausal breast cancer, and if so, what age period and intensity of exercise are most critical. In two earlier prospective investigations, we did not detect an association between premenopausal breast cancer and leisure-time physical activity during adolescence (22) or adulthood (24). Here, we used a more detailed measure of adolescent physical activity and investigated the role of lifetime (ages 12 years to current) physical activity. Based on proposed biologic mechanisms and some observational findings, we hypothesized that physical activity is associated with reduced risk of premenopausal breast cancer.

Subjects and Methods

Study Population

The Nurses’ Health Study II (NHSII) is an ongoing cohort study that began in 1989, when 116?608 female registered nurses (aged 25–42 years) completed a self-administered questionnaire about risk factors for cancer. Biennially, participants are sent a follow-up questionnaire to update information on lifestyle factors and to report newly diagnosed conditions; response rates are approximately 90%. Reports of death are confirmed by searches of the National Death Index (25,26).

For this analysis, we followed women for 6 years, starting in 1997, when participants, who were then 33–51 years of age, reported their adolescent and adult physical activity. Women were excluded if they died before 1997, had a report of cancer (except for nonmelanoma skin cancer) before 1997, were diagnosed with breast cancer that was not invasive, did not report their physical activity during their youth, or were postmenopausal. After these exclusions, 64?777 eligible premenopausal women remained. This study was approved by the Human Subjects Committee at Brigham and Women’s Hospital in Boston, Massachusetts. Written informed consent was assumed upon completion and return of the questionnaire.

Assessment of Physical Activity

In 1997, participants were asked about their walking or leisure-time activity (ie, outside of work) during five age periods: grades 7–8 (ages 12–13), grades 9–12 (ages 14–17), ages 18–22, ages 23–29, and ages 30–34. For each period, participants reported the average hours per week they engaged in each of three activity categories, with examples given for each: strenuous (eg, running, aerobics, swimming laps), moderate (eg, hiking, walking for exercise, casual cycling, and yard work), and walking to and from school or work. In 1997 and again in 2001, participants reported the average hours per week spent on the following walking or leisure-time activities in the previous year: jogging, running, bicycling (including stationary machine), racquet sports, swimming laps, walking or hiking outdoors, calisthenics or aerobics, and other aerobic activities.

Occupational activity was assessed in 1997, when participants were asked to best describe their work activity during ages 23–29 and 30–34; answer choices were: not employed, mostly sitting, mostly standing, mostly walking with little lifting, mostly walking with much lifting, and heavy manual labor. Similar questions have been used in other studies (27,28). In this investigation, we chose, a priori, to primarily examine activity outside of work because there was little variation in participants’ reported occupational levels (86% reported mostly walking with little or some amount of lifting).

All these physical activity questions are available online (29). When we evaluated the leisure-time physical activity measures, they had good reproducibility and validity. Recalled activity during the first three life periods had high 4-year reproducibility in a subgroup of 160 NHSII participants (average correlation r = 0.76 for strenuous, r = 0.70 for strenuous plus moderate, and r = 0.64 for total activity) (30). As for validity, our measure of physical activity in the previous year performed well when compared with previous week activity recalls (r = 0.79, 95% confidence interval [CI] = 0.64 to 0.88) and separately, with four 7-day activity diaries (r = 0.62, 95% CI = 0.44 to 0.75) in a subsample of NHSII participants (31). Moreover, in a validation study among 238 men, higher past year vigorous activity, as self-reported on a similar activity assessment, was associated with lower resting pulse (r = >0.45) (32). Furthermore, among 50 women aged 20–59, the physical activity score, as determined on a similar questionnaire, was correlated with maximal oxygen consumption (a measure of physical fitness) (r = 0.54) (33).

Estimation of Physical Activity by Intensity and Age

To classify intensity of leisure-time activity, each past year activity was assigned a metabolic equivalent (MET) value (31) based on the categorizations by Ainsworth et al. (34). The MET value is the ratio of the metabolic rate of an activity divided by the resting metabolic rate and generally describes the effort required for that activity (34). For example, running (12 METs) requires 12 times the energy as sitting quietly. We defined jogging, running, bicycling (including stationary machine), racquet sports, and swimming laps as strenuous (?7.0 METs). Calisthenics or aerobics and other aerobic activity were moderate (4.0–6.0 METs); walking was categorized separately, with METs assigned according to pace (average = 3 METs). The intensity categories were based on Centers for Disease Control and Prevention designations (35) and are consistent with a recent 2007 consensus (36).

In these analyses, strenuous, moderate, and walking activities were expressed in hours per week and calculated by summing the hours per week of each activity. Total activity, expressed in MET hours per week (MET-h/wk), was computed by multiplying the hours per week of strenuous, moderate, and walking activities with their corresponding MET value and summing the values. To estimate activity levels for the five life periods, we assigned strenuous, moderate, and walking categories MET values of 7.0, 4.5, and 3.0, respectively.

To obtain mean leisure-time activity (for strenuous, moderate, walking, and total) during different age periods, we averaged activity levels for specific ages and across a woman’s lifetime. We used linear interpolation to calculate yearly adult activity between the last life period report for ages 30–34 and the past year assessments. For example, in the case of a woman who was 45 in 1997, linear interpolation was used to estimate her activity for each age between 34 and 45, assuming that activity changed at the same rate. Mean lifetime physical activity was calculated by averaging activity from age 12 to the participant’s current age. For example, if the sum of a 45-year-old woman’s total activity from ages 12 to 45 (as weekly averages for each year) was 1320 MET-h/wk, her lifetime average would be 38.8 MET-h/wk (1320 MET/34). We similarly computed mean activity levels of women at ages 12–22 (referred to as “youth” for simplicity), 23–34, and 35 and older.

For occupational activity, we assigned MET values based on the occupational activity categorizations of Ainsworth et al. (37): mostly sitting (1.5 METs), mostly standing (3.0 METs), mostly walking with little lifting (3.8 METs), mostly walking with much lifting (4.5 METs), and heavy manual labor (7.0 METs). We estimated work activity in MET-h/wk by multiplying 40 h/wk (the average work week in the United States) by the activity’s corresponding MET value. Thus, if a respondent chose mostly sitting during ages 23–29, her estimated work activity would be 60 MET-h/wk (1.5 METs × 40 h/wk). Occupational activity during ages 23–34 was obtained by calculating a weighted average of activity levels from ages 23–29 and 30–34 with the weights being the number of years in each period. Leisure plus occupational activity, in MET-h/wk, was the average of the two values. Individuals who reported not being employed were excluded from the occupation-related analyses.

Assessment of Incident Breast Cancer

Self-reported diagnoses of breast cancer on biennial NHSII questionnaires were confirmed by study physicians who, blinded to patient exposure status, reviewed participants’ medical records and pathology reports. Details about the diagnosis, including hormone receptor status, were also recorded. We identified 739 premenopausal women with a breast cancer diagnosis between 1997 and 2003 who had physical activity data. We excluded all in situ cancers (n = 159) and 30 unconfirmed breast cancer diagnoses, leaving 550 women with diagnoses of invasive premenopausal breast cancer during follow-up. There were too few invasive postmenopausal breast cancers (n = 129) during the follow-up period to analyze separately.

Covariates

Age at menarche, height, childhood body shape, and menstrual length and pattern during ages 18–22 years were reported on the 1989 questionnaire. Birthweight was reported in 1991, and alcohol and fat intakes were obtained on the 1995 questionnaire. Information on other risk factors used in this investigation, including parity, age at first birth (afb), history of benign breast disease, oral contraceptive use, menopausal status, use of multivitamins, smoking, and body weight, were reported on the 1997 questionnaire and updated every 2 years on subsequent questionnaires. Television watching was reported in 1997. Information about family history of breast cancer in mother and/or sister was obtained in 1989 and 1997, and data on socioeconomic status were collected in 1999 and 2001.

Statistical Analysis

Each participant contributed person-time from the return date of her questionnaire in 1997 until menopause, a diagnosis of breast cancer or other cancer (except nonmelanoma skin cancer), death, or the end of follow-up on June 1, 2003, whichever came first, giving 335?681 person-years of follow-up. Person-time was assigned to the appropriate level of physical activity and covariate categories at the beginning of each 2-year questionnaire cycle.

Spearman rank correlation coefficients between physical activity categories and their associated 95% confidence intervals were based on the arcsine transformation approach (38). For breast cancer risk, Cox proportional hazards models were used to estimate the age-adjusted and multivariable-adjusted relative risks (RRs) and their 95% confidence intervals. Age in months was the time scale. Physical activity exposures were divided into approximate quintiles and grouped into categories divisible by 3, the MET of average-paced walking. Relative risks represented the ratio of breast cancer incidence rates comparing each upper category of physical activity with the lowest group, adjusting for risk factors.

In multivariable analyses, we adjusted for several established risk factors for breast cancer: age (months), average childhood body shape [collapsed pictogram scale from 1 to ?5, (39)], duration and recency of oral contraceptive use (never, past <4 y, past ? 4 y, current < 4 y, and current ? 4 y), history of benign breast disease (yes, no), mother or sister with breast cancer (yes, no), parity and age at first birth (nulliparous; parity 1–2, afb < 25; parity 1–2, afb 25–29; parity 1–2, afb ? 30; parity ? 3, afb < 25; parity ? 3, afb 25–29; parity ? 3, afb ? 30), current alcohol consumption (none, >0.0–1.4 g/d, 1.5–4.9 g/d, 5.0–9.9 g/d, ? 10 g/d), and height (inches). Adjustment for other possible confounders (smoking, smoking cessation, animal fat intake, birthweight, television watching, multivitamin use, and socioeconomic status) did not change the relative risk estimates and were omitted from our final model. We did not include BMI or age at menarche as core covariates because we considered them as intermediates in the causal pathway between physical activity and breast cancer. However, these and other hypothesized intermediates were evaluated in additional models to examine potential mechanisms for the activity–breast cancer associations (discussed in “Results”). Tests for linear trend were performed by modeling the exposure as a continuous variable (there were no outliers). We examined effect modification by factors (BMI, oral contraceptive use, parity) that had biologic plausibility and for which we had sufficient numbers to conduct stratified analyses; tests of interaction were based on a Wald test of the interaction term. We observed no violation of proportional hazards by age. In ad hoc analyses to further investigate which age periods were critical for the association with breast cancer risk, we examined whether adolescent and adult activity were statistically significantly different from each other by entering both in the same regression model as continuous terms and evaluating whether the difference between their betas was statistically significant. For this, we used the test statistic (beta1 > beta2)/standard error (beta1 > beta2) and a standard normal table to evaluate the P value. All P values were two-sided. A P value less than .05 was considered statistically significant for all analyses. These analyses were performed using SAS version 9.0 (SAS Institute Inc, Cary, NC).

Results

We first examined the pattern of total levels of leisure-time physical activity over time when participants were between the ages 12 and 55 (eldest in 2001). Women’s average total activity levels declined appreciably with age (Figure 1). At young ages, women engaged in mostly strenuous or moderate activities; for adults, walking was most common.

Figure 1

Mean (diamonds) total leisure-time activity (MET h/wk) of women ages 12–55 (eldest in 2001). There are steps in the figure because activity data before age 35 were obtained for specific life periods.

Several established or possible risk factors for breast cancer were associated with leisure-time physical activity at the start of follow-up in 1997 (Table 1). After adjusting for age, physically active women were more likely to currently use oral contraceptives, to be nulliparous, to be taller, to consume greater than 10 grams of alcohol (about one glass of wine) per day, to take multivitamins, and to be current smokers. They had lower BMI (childhood, at age 18, and current) and animal fat intakes. More active women also were less likely to have an early age at menarche (<12 years) and long (>40 days) menstrual cycles than less active women. The magnitudes of these associations were modest.

Table 1

Characteristics of 64?777 women in 1997 according to categories of average lifetime total activity, Nurses’ Health Study II*

We investigated the role of intensity of leisure-time physical activity by conducting separate analyses of average lifetime strenuous, moderate, walking, and total activities (Table 2). The strongest association was for total activity. Risk of breast cancer was lower for women reporting 54 or greater MET-h/wk of total activity than for those reporting less than 21 MET-h/wk (RR = 0.77, 95% CI = 0.59 to 1.01; Ptrend = .04). The age-adjusted incidence rates of breast cancer for these highest (?54 MET-h/wk) and lowest (<21 MET-h/wk) total activity categories were 136 and 194 per 100?000 person-years, respectively. Because the results (Table 2) suggested a threshold effect, we compared women with 39 or greater MET-h/wk of total activity (equivalent to 3.25 h/wk of running) vs those with less than 39 MET-h/wk. We found a similar association (RR = 0.77, 95% CI = 0.64 to 0.93), suggesting a threshold effect. Results for strenuous, moderate, and walking activities were not statistically significant and were further attenuated when we mutually adjusted for each activity, suggesting that the association was not dependent on a single intensity but rather on total activity. The moderate correlations between the different intensities limited the ability to identify one as most important.

Table 2

RR of premenopausal breast cancer by intensity of lifetime physical activity, Nurses’ Health Study II, 1997–2003*

To evaluate the role of leisure-time physical activity during specific ages of life, we examined total activity during three different life periods (Table 3). Activity during ages 12–22 had the strongest association. Higher total activity during that period was statistically significantly associated with a 25% lower breast cancer risk (for ?72 vs <21 MET-h/wk, RR = 0.75, 95% CI = 0.57 to 0.99; Ptrend = .05). The relative risks were attenuated after mutually adjusting for activity at age 23 years or older (data not shown; between 12–22 and ?23 age periods, r = 0.55, 95% CI = 0.56 to 0.57). The associations with activity during ages 12–17 years were similarly inverse (for ?78 vs <21 MET-h/wk, RR = 0.76, 95% CI = 0.58 to 0.99; Ptrend = .09; data not shown). We observed a suggestion of lower breast cancer risk with higher total activity during ages 23–34 (Ptrend = .06), but no association with reduced risk was apparent after age 35.

Table 3

RR of premenopausal breast cancer by age periods of total physical activity, Nurses’ Health Study II, 1997–2003*

Because activity declined with age, we modeled activity during the three age periods as continuous terms and calculated the relative risks for the same 21 MET-h/wk increment of total activity to be able to make direct comparisons between relative risks. The estimates for the different age periods were similar (>4% to >6%, Table 3) and not independently statistically significant. A 21 MET-h/wk increase of lifetime activity was statistically significantly associated with a 9% reduction in risk.

We next categorized activity for 12–22 years (youth) and for 23 years and older (adulthood) into tertiles and cross-classified them to examine whether a specific pattern of activity was related to breast cancer risk (Table 4). The relative risk for the high during youth and low during adulthood (high–low) activity pattern (RR = 0.63, 95% CI = 0.35 to 1.11) was similar to that of the high–high activity pattern (RR = 0.70, 95% CI = 0.53 to 0.93), suggesting that high levels of leisure-time physical activity during ages 12–22 were important, no matter the activity level during later years. However, most women were either inactive (low–low) or active (high–high) during both youth and adulthood, limiting our ability to examine specific age periods. Moreover, the associations with risk for activity during youth and adulthood were not statistically significantly different from each other when we entered each type of activity in the same regression model as continuous terms and evaluated the statistical significance of the difference between their betas.

Table 4

RR of premenopausal breast cancer by patterns of total physical activity during youth (12–22 years) and adulthood (?23 years), Nurses’ Health Study II, 1997–2003*

Because error in self-reporting can bias results, we corrected for measurement error by regression calibration (40,41) using past year adult activity from an earlier validation study (31). With the correction, we observed a 39% lower breast cancer risk for total lifetime physical activity comparing the most with the least active women, suggesting that our original estimate of a 23% lower risk was an underestimate of reduced risk.

We also evaluated the relationship between total lifetime physical activity and breast cancer risk by hormone receptor status. We observed a non–statistically significant inverse association for both estrogen receptor (ER)–positive (RR = 0.76, 95% CI = 0.54 to 1.06; Ptrend = .15, for 363 patients) and ER-negative (RR = 0.89, 95% CI = 0.48 to 1.63; Ptrend = .21, for 103 patients) breast cancers for the highest vs lowest categories of activity. Moreover, there were similar, non–statistically significant inverse associations for breast cancers with concordant ER and progesterone receptor (PR) status (comparing the most vs least active women: for ER+/PR+, RR = 0.80, 95% CI = 0.56 to 1.15, and for ER–/PR–, RR = 0.86, 95% CI = 0.46 to 1.61). There were too few patients to examine discordant receptor status (eg, ER–/PR+ or ER+/PR–).

Physical activity has been hypothesized to influence breast cancer risk by changing menstrual characteristics or BMI. Thus, we assessed the association between total lifetime activity and breast cancer risk after adjusting for age at menarche, regularity and length of menstrual cycle during youth and adulthood, and BMI (at age 18, current, and cumulatively updated). Relative risks were not appreciably different.

Lastly, we examined whether the relationship between total lifetime activity and breast cancer risk varied according to BMI, parity, or oral contraceptive use (Table 5, stratified analyses). Among women with a BMI of less than 25.0 kg/m2 in 1997, the most active women had a 32% lower risk compared with the least active women (RR = 0.68, 95% CI = 0.48 to 0.98; Ptrend = .02). However, among overweight women (BMI ? 25 kg/m2), activity was not statistically significantly associated with breast cancer risk (RR = 0.85, 95% CI = 0.56 to 1.30; Ptrend = .60). In addition, we observed a statistically significant inverse activity–breast cancer risk association among parous women (most vs least active; RR = 0.72, 95% CI = 0.53 to 0.98; Ptrend = .02) but not among nulliparous women (RR = 1.08; Ptrend = .68). However, formal tests for interaction with current BMI (P = .10) and parity (P = .45) were not statistically significant. Moreover, there were no substantial differences by subgroups of BMI at age 18 (<20.5 kg/m2, ?20.5 kg/m2, approximate median) or by oral contraceptive use (never, past, present use) in stratified analyses.

Table 5

RRs of breast cancer by total lifetime activity, stratified by adult body mass index and parity, Nurses’ Health Study II, 1997–2003*

There was little variation in work-related activity, with 86% of participants reporting mostly walking. The association of occupational activity during ages 23–34 years with breast cancer risk was non–statistically significantly inverse (for >171 vs <114 MET-h/wk, RR = 0.83, 95% CI = 0.63 to 1.09; Ptrend = .42). The relative risk for leisure plus occupational activity during ages 23–34 years was 0.80 (for ?216 vs <147 MET-h/wk, 95% CI = 0.61 to 1.04, Ptrend = .07). The correlation between occupational and total leisure-time activity during ages 23–34 years was low (r = 0.10, 95% CI = 0.10 to 0.11).

Discussion

In this large prospective study, total activity was most strongly associated with lower risk of premenopausal breast cancer. Women who had engaged in at least 39 MET-h/wk of total activity on average from ages 12 years onward had a 23% lower risk of premenopausal breast cancer than the least active women. This activity level translates to about 3.25 h/wk of running or 13 h/wk of walking. High quantities of total activity during youth (12–22 years) appeared to contribute most to this benefit.

Epidemiological results for the association of physical activity with premenopausal breast cancer risk have been inconsistent (8,9). Direct comparisons between investigations are particularly challenging due to the diversity in physical activity assessments, types of activity (eg, leisure time, occupational, household, total), units of activity, and the various study populations examined (42). For adolescent or lifetime leisure-time activity, there have been at least three prospective studies (21–23) and 15 case–control studies (20,43–56) examining premenopausal breast cancer risk. Wyshak and Frisch (21) observed a very strong association between physical activity and reduced risk for breast cancer (RR = 0.16, 95% CI = 0.04 to 0.64) in a prospective analysis comparing US college athletes vs nonathletes, but results were unstable, based on 12 patients. In a Swedish cohort, Margolis et al. (23) did not detect a relationship for physical activity at age 14 or for consistently high activity levels at ages 14 and 30 and enrollment and premenopausal breast cancer risk. In an earlier NHSII analysis, we did not detect statistically significant associations between strenuous activity during high school or ages 18–22 and risk of premenopausal breast cancer (22); however, the two-question activity measure used for the analysis was probably not sufficiently detailed. Among case–control studies reporting on premenopausal breast cancer, six observed statistically significant associations (20,43–48), ranging from moderate to strong decreased relative risks, and one (49) reported borderline, non–statistically significant inverse associations. Our study is consistent with these findings. Other case–control studies (50–56) have not found statistically significant associations.

For adult leisure-time activity, previously conducted cohort studies (23,24,27,57–63) have not observed statistically significant associations with premenopausal breast cancer risk, consistent with the current study and an earlier NHSII analysis (24). This finding may be due, in part, to declining levels of physical activity after age 35; for example, few participants in our study reported very vigorous activities such as running. Few studies have examined associations between occupational physical activity and breast cancer risk. Among four cohort studies, two observed statistically significantly decreased risks (27,64) with occupational activity whereas two reported no statistically significant associations (63,65). Among six case–control studies (47,49,52,66–68), no statistically significant associations with occupational activity were reported. Studies have varied in the quality and completeness of their assessments of physical activity, and in some investigations sample sizes have been small.

Our study adds to the current literature by being, to our knowledge, the first prospective study to collect data for a broad range of etiologically relevant ages (in this study, from ages 12 to a maximum of 55) and to prospectively examine the role of activity throughout life. Further strengths of this investigation include its relatively large number of premenopausal invasive breast cancers and the medical confirmation of cancer diagnoses. In addition, the age- and multivariable-adjusted relative risks were similar, suggesting no major sources of confounding.

This study also has some limitations. First, we relied on self-reported activity, which will inevitably be imperfect. In our previous investigations, these physical activity questions had good reproducibility (30) and validity as compared with 7-day activity diaries in a subgroup of NHSII participants (31). Moreover, self-reported physical activity using a similar questionnaire was well correlated with lowered resting pulse in men (32) and maximal oxygen consumption in women (33). Second, adult activity between questionnaire cycles was linearly interpolated. Although errors due to reporting and estimation of activity levels are inevitable, when we corrected for such errors in the analysis, we observed a stronger risk reduction (39%), indicating that our original estimate may have underestimated the association. Third, physical activity was correlated across different ages and intensities, as has been seen in other studies (69,70); this limited the ability to statistically identify one age period and intensity with the strongest association.

Our results are applicable to premenopausal white women. Although participants were registered nurses at the initiation of the study, previous exposure–disease relationships in this cohort, including those for breast cancer, have been confirmed in other populations, suggesting that our findings are generalizable on a population level. Although this study focused primarily on leisure-time activity, we did not observe much variation in physical activity at work (most reported walking) or a statistically significant association between occupational physical activity and breast cancer risk. Despite homogeneity in occupation levels, there was sufficient variation in leisure-time activity to examine associations with breast cancer risk.

Physical activity has been hypothesized to lower breast cancer incidence through several hormone-related mechanisms (71). Estrogen is strongly implicated in breast cancer etiology (72,73). Physical activity can delay menarche or change menstrual cycle characteristics (71,74) and thus alter women’s lifetime exposure to the mitogenic effects of sex hormones (16). We observed modest changes in menstrual characteristics with increasing activity levels. Furthermore, among NHSII women, physical activity during adulthood has been inversely associated with plasma concentrations of luteal phase estrodiol, free estradiol, and estrogen (75). Second, physical activity is known to lower insulin concentrations (76). Insulin can increase hepatic production of IGF (12,77) and may raise levels of bioactive IGF and estrogen by lowering hepatic secretion of their respective binding proteins. IGF has been associated with increased premenopausal breast cancer risk (78), but results are conflicting (79,80). We observed suggestive inverse associations for both ER+ and ER> breast cancers, as had a previous study (81), suggesting that both ovarian and nonovarian hormonal mechanisms could be involved.

Although most studies suggest that physical activity during adulthood is associated with at least a 20% reduced risk of postmenopausal breast cancer (9,82), this and other investigations indicate that women need to regularly engage in physical activity starting at a young age to achieve a comparable benefit for premenopausal breast cancer. Unresolved questions for future investigations include whether higher physical activity during adolescence is associated with reduced risk of postmenopausal breast cancer, the role of physical activity at earlier ages such as during childhood, the role of occupational activity, and the mechanisms underlying a potential association with breast cancer risk. Only a handful of case–control studies have reported results in African American (46,48) and Hispanic (48,83) populations, and it is unclear whether the physical activity–breast cancer association differs by ethnicity.

In conclusion, these results suggest that consistent physical activity during a woman’s lifetime is associated with decreased breast cancer risk. Unlike many risk factors for breast cancer, physical activity is an exposure that can be modified. This association, if found to be causal, has public health implications for prevention. Moreover, physical activity at any age promotes health in many ways (84,85), and even walking has several well-documented benefits (86). Although the underlying mechanisms require further study, this research supports the benefits of regular exercise during all ages among women.

Funding

National Cancer Institute, National Institutes of Health (CA50385, and R25 CA98566 and R25 CA94880 to S.S.M.); American Cancer Society (Clinical Research Professorship to G.A.C.).

Footnotes

  • The funding agency did not have a role in the design, conduct, analysis, decision to report, or writing of the study.

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25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study.

January 30th, 2011

Edward Giovannucci, MD, ScD; Yan Liu, MS; Bruce W. Hollis, MD, PhD; Eric B. Rimm, ScD

Arch Intern Med. 2008;168(11):1174-1180.

ABSTRACT

Background Vitamin D deficiency may be involved in the development of atherosclerosis and coronary heart disease in humans.

Methods We assessed prospectively whether plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with risk of coronary heart disease. A nested case-control study was conducted in 18 225 men in the Health Professionals Follow-up Study; the men were aged 40 to 75 years and were free of diagnosed cardiovascular disease at blood collection. The blood samples were returned between April 1, 1993, and November 30, 1999; 99% were received between April 1, 1993, and November 30, 1995. During 10 years of follow-up, 454 men developed nonfatal myocardial infarction or fatal coronary heart disease. Using risk set sampling, controls (n = 900) were selected in a 2:1 ratio and matched for age, date of blood collection, and smoking status.

Results After adjustment for matched variables, men deficient in 25(OH)D (?15 ng/mL [to convert to nanomoles per liter, multiply by 2.496]) were at increased risk for MI compared with those considered to be sufficient in 25(OH)D (?30 ng/mL) (relative risk [RR], 2.42; 95% confidence interval [CI], 1.53-3.84; P < .001 for trend). After additional adjustment for family history of myocardial infarction, body mass index, alcohol consumption, physical activity, history of diabetes mellitus and hypertension, ethnicity, region, marine {omega}-3 intake, low- and high-density lipoprotein cholesterol levels, and triglyceride levels, this relationship remained significant (RR, 2.09; 95% CI, 1.24-3.54; P = .02 for trend). Even men with intermediate 25(OH)D levels were at elevated risk relative to those with sufficient 25(OH)D levels (22.6-29.9 ng/mL: RR, 1.60 [95% CI, 1.10-2.32]; and 15.0-22.5 ng/mL: RR, 1.43 [95% CI, 0.96-2.13], respectively).

Conclusion Low levels of 25(OH)D are associated with higher risk of myocardial infarction in a graded manner, even after controlling for factors known to be associated with coronary artery disease.

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Associations between vitamin D status and pain in older adults: the Invecchiare in Chianti study.

January 30th, 2011

J Am Geriatr Soc. 2008 May;56(5):785-91. Epub 2008 Mar 5.Click here to read

Hicks GE, Shardell M, Miller RR, Bandinelli S, Guralnik J, Cherubini A, Lauretani F, Ferrucci L.

Department of Physical Therapy, University of Delaware, Newark, Delaware 19716, USA. ghicks@udel.edu

Abstract

OBJECTIVES: To examine cross-sectional associations between vitamin D status and musculoskeletal pain and whether they differ by sex.

DESIGN: Population-based study of persons living in the Chianti geographic area (Tuscany, Italy).

SETTING: Community.

PARTICIPANTS: Nine hundred fifty-eight persons (aged > or = 65) selected from city registries of Greve and Bagno a Ripoli.

MEASUREMENTS: Pain was categorized as mild or no pain in the lower extremities and back; moderate to severe back pain, no lower extremity pain; moderate to severe lower extremity pain, no back pain; and moderate to severe lower extremity and back pain (dual region). Vitamin D was measured according to radioimmunoassay, and deficiency was defined as 25-hydroxyvitamin D (25(OH)D) less than 25 nmol/L.

RESULTS: The mean age+/-standard deviation was 75.1+/-7.3 for women and 73.9+/-6.8 for men. Fifty-eight percent of women had at least moderate pain in some location, compared with 27% of men. After adjusting for potential confounders, vitamin D deficiency was not associated with lower extremity pain or dual-region pain, although it was associated with a significantly higher prevalence of at least moderate back pain without lower extremity pain in women (odds ratio=1.96, 95% confidence interval=1.01-3.59) but not in men.

CONCLUSION: Lower concentrations of 25(OH)D are associated with significant back pain in older women but not men. Because vitamin D deficiency and chronic pain are fairly prevalent in older adults, these findings suggest it may be worthwhile to query older adults about their pain and screen older women with significant back pain for vitamin D deficiency.

PMID: 18331295 [PubMed - indexed for MEDLINE]PMCID: PMC2645670Free PMC Article

Images from this publication.See all images (1) Free text

Figure 1
Cumulative self-reported pain burden of the sample according to sex and vitamin D status.
LE = lower extremity.
J Am Geriatr Soc. Author manuscript; available in PMC 2009 May 1.;56(5):785-791.


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Metabolic therapy for early treatment of age-related macular degeneration

January 30th, 2011

Orv Hetil. 2007 Dec 2;148(48):2259-68.

Fehér J, Kovács B, Kovács I, Schvöller M, Corrado Balacco G.

Currently, age-related macular degeneration is one of the most common eye diseases causing severe and permanent loss of vision. This disease is estimated to affect approximately 300–500 thousand Hungarians. While earlier no treatment was available, in the recent decade an antioxidant therapy became very popular using combinations of high dosage antioxidant vitamins C, E, beta caroten and zinc. Based on theoretical concepts and mostly in vitro experiences, this combination was thought to be effective through neutralizing reactive oxigen species. According to a large clinical trial (AREDS) it reduced progression of intermediate state disease to advanced state, but did not influence early disease. This original combination, due to potential severe side effects, is not on the market anymore. However, the efficacy of modified formulas has not been proved yet. Recently, the metabolic therapy, a combination of omega-3 fatty acids, coenzyme Q10 and acetyl-L-carnitine has been introduced for treating early age-related macular degeneration through improving mitochondrial dysfunction, specifically improving lipid metabolism and ATP production in the retinal pigment epithelium, improving photoreceptor turnover and reducing generation of reactive oxygen species. According to a pilot study and a randomized, placebo-controlled, double blind clinical trial, both central visual field and visual acuity slightly improved after 3–6 months of treatment and they remained unchanged by the end of the study. The difference was statistically significant as compared to the base line or to controls. These functional changes were accompanied by an improvement in fundus alterations: drusen covered area decreased significantly as compared to the base line or to control. Characteristically, all these changes were more marked in less affected eyes. A prospective case study on long-term treatment confirmed these observations. With an exception that after slight improvement, visual functions remained stable, drusen regression continued for years. Sometimes significant regression of drusen was found even in intermediate and advanced cases. All these findings strongly suggested that the metabolic therapy may be the first choice for treating age-related macular degeneration. Currently, this is the only combination of ingredients corresponding to the recommended daily allowance, and at the same time, which showed clinically proved efficacy.

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