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LE Magazine August 2008


Vitamin D receptor gene polymorphisms and haplotypes and postmenopausal breast cancer risk.

INTRODUCTION: Vitamin D receptor (VDR) genotypes may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D, but epidemiological studies have been inconsistent. Effect modification by serum 25-hydroxyvitamin D (25 [OH]D), the biomarker for vitamin D status in humans, has rarely been examined. METHODS: We assessed the effects of two frequently analyzed polymorphisms (FokI and TaqI) and two potentially functional variants (VDR-5132 and Cdx2) in the VDR gene, which thus far have not been analyzed with respect to breast cancer risk, on postmenopausal breast cancer risk in a population-based, case-control study including 1,408 patients (cases) and 2,612 control individuals (controls) matched for year of birth. Odds ratios (ORs) for breast cancer adjusted for potential confounders were calculated for genotypes and estimated haplotypes. RESULTS: No differences in serum 25(OD)D concentrations by VDR genotype were observed. None of the analyzed polymorphisms was associated with overall risk for postmenopausal breast cancer. However, the TaqI polymorphism was associated with a significantly increased risk for oestrogen receptor positive tumours (OR = 1.18, 95% confidence interval [CI] = 1.00 to 1.38, comparing t allele carriers with noncarriers) but not for oestrogen receptor negative tumours (OR = 0.88, 95% CI = 0.69 to 1.13; P for interaction = 0.04). Haplotype analysis revealed the haplotype FtCA (FokI F, TaqI t, VDR-5132 C, Cdx2 A), which contains the TaqI t allele, to be associated with a significantly greater breast cancer risk as compared with the most frequent haplotype FTCG (OR = 1.43, 95% CI = 1.00 to 2.05). No significant interaction between VDR genotypes or haplotypes and 25(OH)D was observed. CONCLUSION: Our results support potential effects of VDR polymorphisms on postmenopausal breast cancer risk and possible differential effects of receptor status of the tumour. However, further studies focusing on the influence of polymorphisms and haplotypes on VDR functionality, activity and concentration are needed.

Breast Cancer Res. 2008;10(2):R31

Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial.

BACKGROUND: Numerous observational studies have found supplemental calcium and vitamin D to be associated with reduced risk of common cancers. However, interventional studies to test this effect are lacking. OBJECTIVE: The purpose of this analysis was to determine the efficacy of calcium alone and calcium plus vitamin D in reducing incident cancer risk of all types. DESIGN: This was a 4-y, population-based, double-blind, randomized placebo-controlled trial. The primary outcome was fracture incidence, and the principal secondary outcome was cancer incidence. The subjects were 1,179 community-dwelling women randomly selected from the population of healthy postmenopausal women aged >55 y in a 9-county rural area of Nebraska centered at latitude 41.4 degrees N. Subjects were randomly assigned to receive 1,400-1,500 mg supplemental calcium/d alone (Ca-only), supplemental calcium plus 1,100 IU vitamin D3/d (Ca + D), or placebo. RESULTS: When analyzed by intention to treat, cancer incidence was lower in the Ca + D women than in the placebo control subjects (P < 0.03). With the use of logistic regression, the unadjusted relative risks (RR) of incident cancer in the Ca + D and Ca-only groups were 0.402 (P = 0.01) and 0.532 (P = 0.06), respectively. When analysis was confined to cancers diagnosed after the first 12 mo, RR for the Ca + D group fell to 0.232 (CI: 0.09, 0.60; P < 0.005) but did not change significantly for the Ca-only group. In multiple logistic regression models, both treatment and serum 25-hydroxyvitamin D concentrations were significant, independent predictors of cancer risk. CONCLUSIONS: Improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women. This trial was registered at as NCT00352170.

Am J Clin Nutr. 2007 Jun;85(6):1586-91

Glycemic load, glycemic index, and the risk of breast cancer among Mexican women.

OBJECTIVE: The amount and composition of dietary carbohydrates is a major determinant of postprandial blood glucose and insulin, and risk of breast cancer has been positively associated with plasma levels of insulin and insulin-like growth factor 1. We sought to evaluate dietary glycemic load (GL) and overall glycemic index (GI) in relation to breast cancer risk in Mexican women. METHODS: We examined dietary GL and overall GI and breast cancer risk among 475 women with histologically-confirmed breast cancer and a random sample of 1,391 women from Mexico City households. Diet was assessed using a food frequency questionnaire adapted to the Mexican population. RESULTS: The multivariate adjusted or for all women comparing the highest quartile of dietary GL with the lowest quartile was 1.62 (95% CI 1.13-2.32; p-test for trend = 0.02) with a significant trend. In postmenopausal women, the multivariate adjusted or comparing the extreme quartiles was 2.18 (95% CI 1.34-3.55; p-test for trend=0.005). Overall GI was not significantly associated with risk of breast cancer. CONCLUSION: High intake of rapidly absorbed carbohydrate appears to play an important role in the risk of breast cancer in Mexican women.

Cancer Causes Control. 2005 Dec;16(10):1165-9

Consumption of dairy products and the risk of breast cancer: a review of the literature.

Differences in eating patterns and breast cancer rates across countries suggest that several dietary components, including dairy products, could affect breast cancer risk. However, dairy products are a diverse food group in terms of the factors that could potentially influence risk. Some dairy products, such as whole milk and many types of cheese, have a relatively high saturated fat content, which may increase risk. Moreover, milk products may contain contaminants such as pesticides, which have carcinogenic potential, and growth factors such as insulin-like growth factor I, which have been shown to promote breast cancer cell growth. In contrast, the calcium and vitamin D contents of dairy products have been hypothesized to reduce breast cancer risk. We reviewed the current epidemiologic literature on the relation between dairy product intakes and breast cancer risk, focusing primarily on the results of cohort and case-control studies. Most of the studies reviewed showed no consistent pattern of increased or decreased breast cancer risk with a high consumption of dairy products as a whole or when broken down into high-fat and low-fat dairy products, milk, cheese, or butter. Measurement error may have attenuated any modest association with dairy products. The available epidemiologic evidence does not support a strong association between the consumption of milk or other dairy products and breast cancer risk.

Am J Clin Nutr. 2004 Jul;80(1):5-14

Consumption of sweet foods and breast cancer risk in Italy.

BACKGROUND: The relation between the intake of sugar and sweets and the risk of breast cancer has been considered in ecological, prospective and case-control studies, but the results are unclear. We analyzed such a relation in a case-control study conducted between 1991 and 1994 in Italy. PATIENTS AND METHODS: Cases were 2,569 women with histologically confirmed incident breast cancer and controls were 2,588 women admitted to hospital for acute, non-neoplastic, non-hormone-related conditions. Information on diet was based on an interviewer-administered questionnaire tested for reproducibility and validity. The odds ratios (OR) and 95% confidence intervals (CI) were computed by multiple logistic regression equations. RESULTS: Compared with women with the lowest tertile of intake, women in the highest tertile of intake of desserts (including biscuits, brioches, cakes, puffs and ice-cream) and sugars (including sugar, honey, jam, marmalade and chocolate) had multivariate ORs of 1.19 (95% CI 1.02-1.39) and 1.19 (95% CI 1.02-1.38), respectively. The results were similar in strata of age, body mass index, total energy intake and other covariates. CONCLUSIONS: We found a direct association between breast cancer risk and consumption of sweet foods with high glycemic index and load, which increase insulin and insulin growth factors.

Ann Oncol. 2006 Feb;17(2):341-5

Serum enterolactone levels and the risk of breast cancer in women with palpable cysts.

Low levels of lignans, namely enterolactone, have been reported to be associated with an increased risk of breast cancer in the general female population. We assessed, retrospectively, the relationship between serum enterolactone concentrations and the occurrence of breast cancer in women with palpable cysts. The levels of enterolactone in cryopreserved serum aliquots, obtained from 383 women with palpable cysts at the time of their first cyst aspiration, were measured using a time-resolved fluoroimmunoassay (TR-FIA). After a median follow-up time of 6.5 years (range 0.5-12.75 years), 18 women were found to have developed an invasive breast cancer. Median values of serum enterolactone were significantly lower in women who subsequently developed breast cancer: 8.5 nM/l versus 16.0 nM/l: P=0.04. Odd Ratios (OR) for breast cancer were: 0.36 (P=0.03), 0.57 (P=0.3) and 0.38 (P=0.25) for 25th (8 nM/l), 50th (16 nM/l) and 75th (24 nM/l) percentile values, respectively. The receiver operating characteristic (ROC) analysis showed a satisfactory accuracy for enterolactone as a breast cancer risk indicator (area under the curve (AUC)=0.64: P=0.04). Logistic regression analysis confirmed that the enterolactone concentration had a strong protective effect on the breast cancer risk. These findings may have important clinical implications with regard to interventional diet-focused chemo-preventive trials.

Eur J Cancer. 2004 Jan;40(1):84-9

Dietary lignan intakes and risk of pre- and postmenopausal breast cancer.

Lignans are plant compounds metabolized in the mammalian gut to produce the phytoestrogens enterolactone and enterodiol. Because estrogens have been linked to breast cancer etiology, lignans could affect breast cancer risk through modulation of endogenous estrogen metabolism or competitive inhibition with estrogen receptors. We examined breast cancer risk and dietary lignan intake in a population-based case-control study of 1,122 women with primary, incident, histologically confirmed breast cancer and 2,036 controls frequency matched to cases on age and county of residence as part of the Western New York Exposures and Breast Cancer (WEB) Study. Diet was assessed with a self-administered 104-item food frequency questionnaire and other relevant data were collected by detailed in-person interviews. Lignans were expressed as the sum of the dietary precursors secoisolariciresinol and matairesinol. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression, adjusting for age, total energy and other breast cancer risk factors. Premenopausal women in the highest quartile of dietary lignan intake had reduced breast cancer risk (OR = 0.66; 95% CI = 0.44-0.98). No association was observed between lignan intakes and postmenopausal breast cancer. Our results suggest that dietary lignans may be important in the etiology of breast cancer, particularly among premenopausal women.

Int J Cancer. 2004 Sep 1;111(3):440-3

Pilot study: effect of 3,3’-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer.

Dietary indoles, present in Brassica plants such as cabbage, broccoli, and Brussels sprouts, have been shown to provide potential protection against hormone-dependent cancers. 3,3’-Diindolylmethane (DIM) is under study as one of the main protective indole metabolites. Postmenopausal women aged 50-70 yr from Marin County, California, with a history of early-stage breast cancer, were screened for interest and eligibility in this pilot study on the effect of absorbable DIM (BioResponse-DIM) supplements on urinary hormone metabolites. The treatment group received daily DIM (108 mg DIM/day) supplements for 30 days, and the control group received a placebo capsule daily for 30 days. Urinary metabolite analysis included 2-hydroxyestrone (2-OHE1), 16-alpha hydroxyestrone (16alpha-OHE1), DIM, estrone (El), estradiol(E2), estriol (E3), 6beta-hydroxycortisol (6beta-OHC), and cortisol in the first morning urine sample before intervention and 31 days after intervention. Nineteen women completed the study,for a total of 10 in the treatment group and 9 in the placebo group. DIM-treated subjects, relative to placebo, showed a significant increase in levels of2-OHE1 (P=0. 020), DIM (P =0. 045), and cortisol (P = 0.039), and a nonsignificant increase of 47% in the 2-OHE1/16alpha-OHE1 ratio from 1.46 to 2.14 (P=0.059). In this pilot study, DIM increased the 2-hydroxylation of estrogen urinary metabolites.

Nutr Cancer. 2004;50(2):161-7

A phase I study of indole-3-carbinol in women: tolerability and effects.

We completed a phase I trial of indole-3-carbinol (I3C) in 17 women (1 postmenopausal and 16 premenopausal) from a high-risk breast cancer cohort. After a 4-week placebo run-in period, subjects ingested 400 mg I3C daily for 4 weeks followed by a 4-week period of 800 mg I3C daily. These chronic doses were tolerated well by all subjects. Hormonal variables were measured near the end of the placebo and dosing periods, including determination of the urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio. Measurements were made during the follicular phase for premenopausal women. Serum estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone binding globulin showed no significant changes in response to I3C. Caffeine was used to probe for cytochrome P450 1A2 (CYP1A2), N-acetyltransferase-2 (NAT-2), and xanthine oxidase. Comparing the results from the placebo and the 800 mg daily dose period, CYP1A2 was elevated by I3C in 94% of the subjects, with a mean increase of 4.1-fold. In subjects with high NAT-2 activities, these were decreased to 11% by I3C administration but not altered if NAT-2 activity was initially low. Xanthine oxidase was not affected. Lymphocyte glutathione S-transferase activity was increased by 69% in response to I3C. The apparent induction of CYP1A2 was mirrored by a 66% increase in the urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio in response to I3C. The maximal increase was observed with the 400 mg daily dose of I3C, with no further increase found at 800 mg daily. If the ratio of hydroxylated estrone metabolites is a biomarker for chemoprevention, as suggested, then 400 mg I3C daily will elicit a maximal protective effect.

Cancer Epidemiol Biomarkers Prev. 2005 Aug;14(8):1953-60

Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer.

Several lines of evidence suggest that vitamin D may reduce incidence of breast cancer, but few epidemiologic studies have addressed the relation of plasma vitamin D metabolites to the risk of this disease. We prospectively examined the relationship between plasma levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and risk of breast cancer in a case-control study nested within the Nurses’ Health Study cohort. Blood samples were collected from study participants in 1989-1990. Breast cancer cases developing between blood collection and June 1, 1996, were matched to cancer-free controls on the basis of age, menopausal status, and other factors. Stored plasma samples from 701 cases and 724 controls were available for metabolite analysis. Cases had a lower mean 25(OH)D level than controls (P=0.01), but mean 1,25(OH)2D levels were similar (P=0.49). High levels of both metabolites were associated with a nonsignificant lower risk of breast cancer. Women in the highest quintile of 25(OH)D had a relative risk of 0.73 (95% confidence interval=0.49-1.07; Ptrend=0.06) compared with those in the lowest quintile. For 1,25(OH)2D, the comparable relative risk was 0.76 (95% confidence interval=0.52-1.11; Ptrend=0.39). For both metabolites, the association was stronger in women ages 60 years and older, but results were not statistically significant. Our findings suggest that high levels of 25(OH)D, and perhaps 1,25(OH)2D, may be modestly associated with reduced risk of breast cancer.

Cancer Epidemiol Biomarkers Prev. 2005 Aug;14(8):1991-7

25(OH)D3 and 1,25(OH)2D3 serum concentration and breast tissue expression of 1alpha-hydroxylase, 24-hydroxylase and Vitamin D receptor in women with and without breast cancer.

1,25(OH)2D3 is an antiproliferative agent that may inhibit proliferation of breast cancer (BC) cells in vitro and BC development in animals. Epidemiological studies have shown a high incidence of BC in people less exposed to solar rays. To unravel the role of Vitamin D3 in BC patients, we have investigated serum levels of 25(OH)D3 and its active form 1,25(OH)2D3 as well as tissue expression of 1alpha-hydroxylase, 24-hydroxylase, and Vitamin D-receptor (VDR), determined by semiquantitative RT-PCR, in 88 Brazilian BC patients and 35 women without cancer (submitted to mammoplasties or resection of benign lesions). Median age of women with and without cancer was 51 and 46 years, respectively, and the majority of BC patients were classified as clinical stage II (67%). Although no differences in 25(OH)D3 serum concentration were found, 1,25(OH)2D3 (40+/-21 pg/ml) levels in BC patients were lower than in women without cancer (53+/-23). Our results indicate that 24-hydroxylase, VDR and 1alpha-hydroxylase mRNA tissue expression is similar in both groups and no correlation between 24-hydroxylase, 1alpha-hydroxylase, and VDR expression in breast tumors was found. A low 1,25(OH)2D3 serum concentration seems to be associated to breast cancer, however, the mechanism involved in this regulation is still unclear.

J Steroid Biochem Mol Biol. 2006 Aug;100(4-5):184-92

Prevention and anti-aging in endocrinology.

The aging process is associated with a characteristic decline in the levels of certain hormones. In both sexes, growth hormones, melatonin, dehydroepiandrosterone (DHEA) and its sulfate compound DHEAS reach their maximum levels in the third decade of life, and then decline progressively. In addition, a constant decrease in the production of biologically active free testosterone of approximately 1% per year is observed in men.The abrupt cessation of sex hormone production seen in women is not observed in men. Irrespective of the hormone being supplemented, it should always be remembered that not merely the hormone-producing organ, but also the target tissue has aged, and may thus manifest a different reaction to the substituted hormone than youthful tissue.

MMW Fortschr Med. 2007 Mar 1;149(9):33-5

Symptoms associated with menopausal transition and reproductive hormones in midlife women.

OBJECTIVE: To test the hypothesis that prevalence of women with menopausal symptoms of hot flushes; aches, joint pain, and stiffness; depressed mood; poor sleep; decreased libido; or vaginal dryness increases with progression through the menopausal transition. METHODS: Women in the Penn Ovarian Aging Study were assessed longitudinally for 9 years. Data were obtained from structured interviews, a validated symptom questionnaire, menstrual bleeding dates and early follicular hormone measures (estradiol [E2], follicle-stimulating hormone [FSH], and inhibin b). Menopausal stages were based on menstrual bleeding patterns. Other risk factors included age, race, history of depression, current smoking, body mass index, and perceived stress. Generalized linear regression models for repeated measures were used to estimate associations among the variables with each symptom. RESULTS: The prevalence of hot flushes; aches, joint pain, and stiffness; and depressed mood increased in the menopausal transition. Menopausal stage was associated with hot flushes (P<.001); aches joint pain, and stiffness (P<.001); and depressed mood (P=.002). Within-woman fluctuations of E2 were associated with hot flushes and aches. Poor sleep, decreased libido, and vaginal dryness were not associated with menopausal stages. There was 80% power to detect an absolute difference of 11% for libido and vaginal dryness and 17% for poor sleep in the prevalence of these symptoms in the late menopausal transition compared with premenopausal status. CONCLUSION: The study highlights the role of menopausal stages for some symptoms of midlife women and indicates that stages in the transition to menopause are associated with hot flushes; aches, joint pain, and stiffness; and depressed mood. Fluctuations of E2, decreased levels of inhibin b, and increased FSH levels were associated with these symptoms. LEVEL OF EVIDENCE: II.

Obstet Gynecol. 2007 Aug;110(2 Pt 1):230-40

The effects of oral and transdermal hormone replacement therapy on C-reactive protein levels and other inflammatory markers in women with high risk of thrombosis.

INTRODUCTION: In the estrogen in venous thromboembolism (EVTET) study of 140 women with a history of venous thromboembolism (VTE), oral hormone replacement therapy (HRT) was associated with strong activation of coagulation markers and increased risk of recurrent VTE. No such associations were observed in the estrogen women atherosclerosis (EWA) study of 118 women with established coronary artery disease who were given transdermal HRT. OBJECTIVES AND METHODS: The aim of the present study was to evaluate the effects of oral and transdermal HRT on levels of C-reactive protein (CRP), which was assayed with a highly sensitive method. We also evaluated the effects on other inflammatory markers and the influence of possible confounding factors. RESULTS: Oral HRT was associated with a significant increase in CRP after 3 months as compared with placebo (median 79% [95% confidence interval 36-119%] versus -4% [-13 to 10%], p = 0.001). These changes sustained after 12 months. Among those allocated HRT, the median increase in CRP was higher in women who subsequently developed recurrent thrombosis (median 328%, n = 5, versus 54%, n = 60). TNF-alpha levels decreased significantly by mean -10% [-15 to -5%] versus 3% [-4 to 10%], p=0.004. Soluble VCAM-1 decreased in the HRT group compared to the placebo group (mean -13% [-18 to -8%] versus 1%, [-3 to 5%], p < 0.001). There were no significant changes in levels of IL-6, TGF-beta or P-selectin. On transdermal HRT no significant changes in CRP were observed after 3 and 12 months of treatment. CONCLUSIONS: Our findings substantiate that oral HRT containing estradiol is associated with a marked and rapid increase in CRP, whereas transdermal treatment is not. However, this increase on oral treatment was associated with no increases of other inflammatory markers.

Maturitas. 2005 Oct 16;52(2):111-8

Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women.

OBJECTIVES: We investigated whether the route of estrogen replacement therapy (ET) is the major determinant of C-reactive protein (CRP) in postmenopausal women. BACKGROUND: Recent studies demonstrated that oral ET causes a sustained increase in CRP, implicating a proinflammatory effect. Because CRP is synthesized in the liver, we hypothesized that estrogen-induced CRP elevation is related to first-pass hepatic metabolism. METHODS: In 21 postmenopausal women, we conducted a randomized, crossover, placebo-controlled study to compare the effects of transdermal versus oral ET on CRP and inflammatory cytokines. We measured CRP, interleukin (IL)-1-beta, IL-6, and tumor necrosis factor-alpha before and after eight weeks of transdermal estradiol (E(2)) (100 microg/day), oral conjugated estrogen (CEE) (0.625 mg/day), or placebo. Insulin-like growth factor-1 (IGF-1), a hepatic-derived anabolic peptide, was also measured. RESULTS: Transdermal E(2) had no effect on CRP or IGF-1 levels. In contrast, eight weeks of oral conjugated estrogens caused a more than twofold increase in CRP and a significant reduction in IGF-1 (p < 0.01) in the same women. The magnitude of increase in CRP was inversely correlated to the decrease in IGF-1 (r = -0.49, p = 0.008). Neither transdermal E(2) nor oral CEE had any effects on the plasma concentrations of cytokines that promote CRP synthesis. CONCLUSIONS: In postmenopausal women, oral but not transdermal ET increased CRP by a first-pass hepatic effect. An increase in CRP levels is accompanied by a reduction in IGF-1, an anti-inflammatory growth factor. Because CRP is a powerful predictor of an adverse prognosis in otherwise healthy postmenopausal women, the route of administration may be an important consideration in minimizing the adverse effects of ET on cardiovascular outcomes.

J Am Coll Cardiol. 2003 Apr 16;41(8):1358-63

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