Case-control Study Of Postmenopausal Women Research Articles

Plasma Estradiol and Testosterone Levels and Ischemic Stroke in Postmenopausal Women.

Background and Purpose- Although exogenous hormone therapy (HT) use has been associated with increased risk of ischemic stroke in postmenopausal women, it remains unknown whether sex hormone levels contribute to ischemic stroke risk. We aimed to estimate associations between plasma sex hormone levels and ischemic stroke risk, by HT status, in a nested case-control study of postmenopausal women from the NHS (Nurses' Health Study). Methods- Women with confirmed incident ischemic stroke (n=419) were matched with controls (n=419) by age, HT use, and other factors. Plasma estradiol and testosterone levels were measured using liquid chromatography tandem mass spectrometry; SHBG (sex hormone-binding globulin) was assayed by electrochemiluminescence immunoassay. Associations of total and free estradiol and testosterone, the estradiol/testosterone ratio, and SHBG with ischemic stroke were estimated using conditional logistic regressions stratified by HT status with adjustment for matching and cardiovascular risk factors. Results- Current HT users had different hormone profiles from never/past users. No clear linear trends were observed between estradiol (total or free) levels or the estradiol/testosterone ratio and ischemic stroke risk among either current users (Ptrend>0.1) or never/past users (Ptrend>0.6). For both current and never/past users, the associations between some of the sex hormones and ischemic stroke differed by body mass index categories (Pinteraction≤0.04). For women with a body mass index <25 kg/m2, a higher estradiol/testosterone ratio was associated with significantly elevated ischemic stroke risk among current users (Ptrend=0.01), and higher levels of total and free estradiol were significantly associated with higher ischemic stroke risk among never/past users (Ptrend≤0.04). Testosterone and SHBG were not associated with ischemic stroke in either current or never/past users. Conclusions- Our findings do not support a role of sex hormone levels in mediating ischemic stroke risk among postmenopausal women. Replications in additional larger studies are required.

Biomarker panel for early detection of endometrial cancer in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial

Endometrial cancer is the most common gynecological cancer in the United States. However, no early detection test exists for asymptomatic women at average risk for endometrial cancer. We sought to identify early detection biomarkers for endometrial cancer using prediagnostic serum. We performed a nested case-control study of postmenopausal women in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial (n= 78,216), including 112 incident endometrial cancer cases and 112 controls. Prediagnostic serum was immunodepleted of high-abundance proteins and digested with sequencing grade porcine trypsin via pressure cycling technology. Quantitative proteomics and phosphoproteomics was performed using high-resolution liquid chromatography-tandem mass spectrometry and highly multiplexed isobaric mass tag combined with basic reversed-phase liquid chromatography. A set of proteins able to predict cancer status was identified with an integrated score assessed by receiver-operator curve analysis. Mean time from blood draw to endometrial cancer diagnosis was 3.5 years (SD, 1.9 years). There were 47 differentially abundant proteins between cases and controls (P < .05). Protein alterations with high predictive potential were selected by regression analysis and compiled into an aggregate score to determine the ability to predict endometrial cancer. An integrated risk score of 6 proteins was directly related to disease incidence in cases with blood draw ≤2 years, >2 years to ≤5 years or >5 years prior to cancer diagnosis. The integrated score distinguished cases from controls with an area under the curve of 0.80 (95% confidence interval, 0.72-0.88). An integrated score of 6 proteins using prediagnostic serum from the Prostate, Lung, Colorectal, and Ovarian cancer screening trial distinguishes postmenopausal endometrial cancer cases from controls. Validation is needed to evaluate whether this test can improve prediction or detection of endometrial cancer among postmenopausal women.

Postmenopausal Androgen Metabolism and Endometrial Cancer Risk in the Women’s Health Initiative Observational Study

After menopause, several androgens continue to be produced primarily by the adrenal glands; these can be converted into estrogens via aromatization or into androgen metabolites. It is unclear if androgens are associated with endometrial cancer risk independently of their being precursors to estrogens or if alternative metabolic pathways influence risk. We measured prediagnostic serum concentrations of 12 androgens and their metabolites using highly sensitive liquid chromatography-tandem mass spectrometry assays in a nested case-control study of postmenopausal women from the Women's Health Initiative Observational Study (313 endometrial cancer case subjects, 354 matched control subjects). Estrogens were previously assayed. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for endometrial cancer with adjustment for confounders. Compared to the lowest concentrations, the highest levels of adrenal androgens were associated with increased endometrial cancer risk: dehydroepiandrosterone (5th vs 1st quintile: OR = 1.85, 95% CI = 1.06 to 3.25), androstenedione (OR = 2.36, 95% CI = 1.34 to 4.16), and testosterone (OR = 1.91, 95% CI = 1.12 to 3.24). Downstream androgen metabolites were not associated with endometrial cancer. Although increased risks for the parent androgens were still suggested after adjustment for unconjugated estradiol, the associations attenuated, and with the exception of androstenedione, were no longer statistically significant. We also evaluated ratios of estrogens relative to their androgenic precursors; both higher unconjugated estrone:androstenedione and higher unconjugated estradiol:testosterone were associated with increased endometrial cancer risk. We identified increased risks for endometrial cancer with the highest levels of adrenal androgens and high levels of estrogens relative to these androgens. As adrenal androgens can be aromatized to estrogens, this suggests androgens likely influence endometrial carcinogenesis via estrogen metabolism.

Serum IGFBP-2 and Risk of Atypical Hyperplasia of the Breast.

Atypical hyperplasia of the breast (AH) is associated with increased risk of subsequent invasive breast cancer, yet little is known about the etiology of AH. Insulin-like growth factor binding protein 2 (IGFBP-2) may contribute to the development of AH due to its proliferative effects on mammary tissue. We conducted a nested case-control study of postmenopausal women enrolled in Women's Health Initiative-Clinical Trial. Cases were 275 women who developed incident AH during follow-up, individually (1 : 1) matched to controls. Levels of IGFBP-2 were determined from fasting serum collected at baseline. Multivariable conditional logistic regression models were used to estimate odds ratios for the association of IGFBP-2 with risk of AH. Serum IGFBP-2 was associated with a nonsignificant decrease in risk for AH, when comparing the highest quartile to lowest quartile (OR = 0.65; 95% CI = 0.32–1.31). This decrease in risk was most evident when analyses were restricted to nondiabetic, nonusers of hormone therapy (OR = 0.33, 95% CI = 0.13–0.86, p trend = 0.06) and nondiabetic women who were overweight or obese (OR = 0.43, 95% CI = 0.18–1.03, p trend = 0.05). Results from this study provide some support for an inverse association between serum IGFBP2 levels and risk of AH, particularly in nondiabetic women who are overweight or obese. Further studies are required to confirm these results.

Circulating Adipokine Levels and Endometrial Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Background: Circulating adipokine levels may be associated with endometrial cancer risk, yet few studies have evaluated these markers prospectively. Methods: We conducted a nested case-control study of postmenopausal women in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n=78,216), including 167 incident endometrial cancer cases and 327 controls that were matched on age, study center, race, study year of diagnosis, year of blood draw, time of day of blood draw and menopausal hormone therapy (MHT) use. Adipokine and estradiol levels were categorized into tertiles (T). Odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of adiponectin, leptin and visfatin with endometrial cancer risk were estimated by conditional logistic regression, adjusting for known endometrial cancer risk factors, including body mass index (BMI) and circulating estradiol levels. Results: Adiponectin levels were inversely associated with risk of endometrial cancer [OR T3vsT1=0.48 (95%CI: 0.29-0.80); p-trend<0.01], whereas elevated leptin levels showed a positive association [2.77 (1.60-4.79); p-trend<0.01]. These results remained significant after adjustment for estradiol, but not after further adjustment for BMI. When analyses were restricted to non-MHT users, associations of adiponectin and leptin were stronger and remained significant after adjustment for estradiol and BMI [0.27 (0.09-0.80); p-trend=0.01 and 4.29 (1.07-17.15); p-trend=0.02, respectively]. Non-significant positive associations were observed for visfatin. Conclusion: Adipokines may influence endometrial cancer risk through pathways other than estrogen-mediated cell growth in postmenopausal women not currently on MHT. Impact: Understanding how adipokines influence endometrial cancer risk may help to elucidate biological mechanisms important for the observed obesity-endometrial cancer association.

Breast cancer risk prediction and individualised screening based on common genetic variation and breast density measurement

IntroductionOver the last decade several breast cancer risk alleles have been identified which has led to an increased interest in individualised risk prediction for clinical purposes.MethodsWe investigate the performance of an up-to-date 18 breast cancer risk single-nucleotide polymorphisms (SNPs), together with mammographic percentage density (PD), body mass index (BMI) and clinical risk factors in predicting absolute risk of breast cancer, empirically, in a well characterised Swedish case-control study of postmenopausal women. We examined the efficiency of various prediction models at a population level for individualised screening by extending a recently proposed analytical approach for estimating number of cases captured.ResultsThe performance of a risk prediction model based on an initial set of seven breast cancer risk SNPs is improved by additionally including eleven more recently established breast cancer risk SNPs (P = 4.69 × 10-4). Adding mammographic PD, BMI and all 18 SNPs to a Swedish Gail model improved the discriminatory accuracy (the AUC statistic) from 55% to 62%. The net reclassification improvement was used to assess improvement in classification of women into low, intermediate, and high categories of 5-year risk (P = 8.93 × 10-9). For scenarios we considered, we estimated that an individualised screening strategy based on risk models incorporating clinical risk factors, mammographic density and SNPs, captures 10% more cases than a screening strategy using the same resources, based on age alone. Estimates of numbers of cases captured by screening stratified by age provide insight into how individualised screening programs might appear in practice.ConclusionsTaken together, genetic risk factors and mammographic density offer moderate improvements to clinical risk factor models for predicting breast cancer.

Estrogen metabolism genotypes, use of long-term hormone replacement therapy and risk of postmenopausal breast cancer

Association between long-term hormone replacement therapy (HRT) use and increased risk of breast cancer is still under debate. Functionally relevant genetic variants within the estrogen metabolic pathway may alter exposure to exogenous sex hormones and affect the risk of postmenopausal breast cancer. We investigated the associations of common polymorphisms in 4 genes encoding key proteins of the estrogen metabolic pathway, duration of HRT use and their interactions with breast cancer risk. We studied 530 breast cancer cases and 270 controls of the same age and ethnicity participating in a case-control study of postmenopausal women. Duration of HRT use was ascertained through a postal questionnaire. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695) and MnSOD (rs4880) polymorphisms by PCR-based RFLP and TaqMan® allelic discrimination method. Adjusted odds ratios and 95% confidence intervals were calculated using logistic regression analysis. HRT use was significantly associated with decreased breast cancer risk (p<0.001). None of the polymorphisms studied was associated with breast cancer risk. A significant interaction was observed between MnSOD 47T>C and HRT use (pinteraction=0.036); the risk of breast cancer associated with long-term vs. short-term HRT use was decreased in women homozygous for the wild-type allele and increased in women with at least one variant allele of the MnSOD 47T>C polymorphism. Our results suggest that MnSOD 47T>C polymorphism in interaction with long-term HRT use may modify the risk of breast cancer.

Combined effect of CYP1B1, COMT, GSTP1, and MnSOD genotypes and risk of postmenopausal breast cancer

ObjectiveEstrogen plays a key role in breast cancer development and functionally relevant genetic variants within the estrogen metabolic pathway are prime candidates for a possible association with breast cancer risk. We investigated the independent and the combined effects of commonly occurring polymorphisms in four genes encoding key proteins of estrogen metabolic pathway on their potential contribution to breast cancer risk.MethodsWe studied 530 breast cancer cases and 270 controls of the same age and ethnicity participating in a case-control study of postmenopausal women. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695), and MnSOD (rs4880) polymorphisms by polymerase chain reaction based restriction fragment length polymorphism and TaqMan allelic discrimination method. Adjusted ORs and 95% CIs were calculated using logistic regression.ResultsNone of the 4 genetic variants examined contributed to breast cancer risk individually. When the combined effects of the risk genotypes were investigated, significant associations were observed among women with two high-risk genotypes in CYP1B1 and COMT (OR, 2.0; 95% CI, 1.1 to 3.5) and two high-risk genotypes in COMT and MnSOD (OR, 2.0; 95% CI, 1.0 to 3.8), compared to those with low-risk genotypes.ConclusionOur results suggest that individual susceptibility to breast cancer incidence may be increased by combined effects of the high-risk genotypes in CYP1B1, COMT, and MnSOD estrogen metabolic genes.

Sensitivity of transvaginal ultrasound screening for endometrial cancer in postmenopausal women: a case-control study within the UKCTOCS cohort

The increase in the worldwide incidence of endometrial cancer relates to rising obesity, falling fertility, and the ageing of the population. Transvaginal ultrasound (TVS) is a possible screening test, but there have been no large-scale studies. We report the performance of TVS screening in a large cohort. We did a nested case-control study of postmenopausal women who underwent TVS in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) following recruitment between April 17, 2001, and Sept 29, 2005. Endometrial thickness and endometrial abnormalities were recorded, and follow-up, through national registries and a postal questionnaire, documented the diagnosis of endometrial cancer. Our primary outcome measure was endometrial cancer and atypical endometrial hyperplasia (AEH). Performance characteristics of endometrial thickness and abnormalities for detection of endometrial cancer within 1 year of TVS were calculated. Epidemiological variables were used to develop a logistic regression model and assess a screening strategy for women at higher risk. Our study is registered with ClinicalTrials.gov, number NCT00058032, and with the International Standard Randomised Controlled Trial register, number ISRCTN22488978. 48,230 women underwent TVS in the UKCTOCS prevalence screen. 9078 women were ineligible because they had undergone a hysterectomy and 2271 because their endometrial thickness had not been recorded; however, 157 of these women had an endometrial abnormality on TVS and were included in the analysis. Median follow-up was 5·11 years (IQR 4·05-5·95). 136 women with endometrial cancer or AEH within 1 year of TVS were included in our primary analysis. The optimum endometrial thickness cutoff for endometrial cancer or AEH was 5·15 mm, with sensitivity of 80·5% (95% CI 72·7-86·8) and specificity of 86·2% (85·8-86·6). Sensitivity and specificity at a 5 mm or greater cutoff were 80·5% (72·7-86·8) and 85·7% (85·4-86·2); for women with a 5 mm or greater cutoff plus endometrial abnormalities, the sensitivity and specificity were 85·3% (78·2-90·8) and 80·4% (80·0-80·8), respectively. For a cutoff of 10 mm or greater, sensitivity and specificity were 54·1% (45·3-62·8) and 97·2% (97·0-97·4). When our analysis was restricted to the 96 women with endometrial cancer or AEH who reported no symptoms of postmenopausal bleeding at the UKCTOCS scan before diagnosis and had an endometrial thickness measurement available, a cutoff of 5 mm achieved a sensitivity of 77·1% (67·8-84·3) and specificity of 85·8% (85·7-85·9). The logistic regression model identified 25% of the population as at high risk and 39·5% of endometrial cancer or AEH cases were identified within this high risk group. In this high-risk population, a cutoff at 6·75 mm achieved sensitivity of 84·3% (71·4-93·0) and specificity of 89·9% (89·3-90·5). Our findings show that TVS screening for endometrial cancer has good sensitivity in postmenopausal women. The burden of diagnostic procedures and false-positive results can be reduced by limiting screening to a higher-risk group. The role of population screening for endometrial cancer remains uncertain, but our findings are of immediate value in the management of increased endometrial thickness in postmenopausal women undergoing pelvic scans for reasons other than vaginal bleeding.

Lack of association between methylenetetrahydrofolate reductase genetic polymorphisms and postmenopausal breast cancer risk

Published data on the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and breast cancer risk are inconclusive. We investigated the independent and the combined effects of two commonly occurring polymorphisms, MTHFR 677C>T (rs1801133) and MTHFR 1298A>C (rs1801131), as well as their interaction with the use of hormone replacement therapy (HRT), to determine their potential contribution to breast cancer risk. We studied 530 breast cancer cases and 270 controls of the same age and ethnicity participating in a case-control study of postmenopausal women. The duration of HRT use was ascertained through a postal questionnaire. Genotyping was conducted by TaqMan® allelic discrimination. Adjusted odds ratios and 95% confidence intervals were calculated using logistic regression. No significant association was observed between either the individual or the combined MTHFR genotypes and the risk of postmenopausal breast cancer. Additionally, no effects resulting from the interaction between MTHFR genotypes and HRT use were detected. Therefore, our data do not support the hypothesis that genetic variation in the MTHFR gene is implicated in the aetiology of postmenopausal breast cancer.

MTHFR C677T and postmenopausal breast cancer risk by intakes of one-carbon metabolism nutrients: a nested case-control study

IntroductionThe C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene has been hypothesized to increase breast cancer risk. However, results have been inconsistent, and few studies have reported the association by menopausal status or by intakes of nutrients participating in one-carbon metabolism. Our aims were to investigate whether MTHFR C677T was associated with postmenopausal breast cancer risk and whether this relation was modified by intakes of folate, methionine, vitamins B2, B6, and B12, and alcohol.MethodsWe studied 318 incident breast cancer cases and 647 age- and race-matched controls participating in a nested case-control study of postmenopausal women within the VITamins And Lifestyle (VITAL) cohort. Genotyping was conducted for MTHFR C677T and dietary and supplemental intakes were ascertained from a validated questionnaire. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression.ResultsWe observed a 62% increased risk of breast cancer among postmenopausal women with the TT genotype (OR = 1.62; 95% CI: 1.05 to 2.48). Women with a higher number of variant T alleles had higher risk of breast cancer (P for trend = 0.04). Evidence of effect-modification by intakes of some B vitamins was observed. The most pronounced MTHFR-breast cancer risks were observed among women with the lowest intakes of dietary folate (P for interaction = 0.02) and total (diet plus supplemental) vitamin B6 (P for interaction = 0.01), with no significant increased risks among women with higher intakes.ConclusionsThis study provides support that the MTHFR 677TT genotype is associated with a moderate increase in risk of postmenopausal breast cancer and that this risk may be attenuated with high intakes of some one-carbon associated nutrients.

Oxidative stress-related genotypes, fruit and vegetable consumption and breast cancer risk

Dietary antioxidants may interact with endogenous sources of pro- and antioxidants to impact breast cancer risk. A nested case-control study of postmenopausal women (505 cases and 502 controls) from the Cancer Prevention Study-II Nutrition Cohort was conducted to examine the interaction between oxidative stress-related genes and level of vegetable and fruit intake on breast cancer risk. Genetic variations in catalase (CAT) (C-262T), myeloperoxidase (MPO) (G-463A), endothelial nitric oxide synthase (NOS3) (G894T) and heme oxygenase-1 (HO-1) [(GT)(n) dinucleotide length polymorphism] were not associated with breast cancer risk. Women carrying the low-risk CAT CC [odds ratio (OR) = 0.75, 95% confidence interval (CI) 0.50-1.11], NOS3 TT (OR = 0.54, 95% CI = 0.26-1.12, P-trend = 0.10) or HO-1 S allele and MM genotype (OR = 0.56, 95% CI = 0.37-0.55), however, were found to be at non-significantly reduced breast cancer risk among those with high vegetable and fruit intake (> or = median; P-interactions = 0.04 for CAT, P = 0.005 for NOS3 and P = 0.07 for HO-1). Furthermore, those with > or = 4 putative low-risk alleles in total had significantly reduced risk (OR = 0.53, 95% CI = 0.32-0.88, P-interaction = 0.006) compared with those with < or = 2 low-risk alleles. In contrast, among women with low vegetable and fruit intake (< median), the low-risk CAT CC (OR = 1.33, 95% CI = 0.89-1.99), NOS3 TT (OR = 2.93, 95% CI = 1.38-6.22) and MPO AA (OR = 2.09, 95% CI = 0.73-5.95) genotypes appeared to be associated with raised breast cancer risk, with significantly increased risks observed in those with > or = 4 low-risk alleles compared with participants with < or = 2 low-risk alleles (OR = 1.77, 95% CI = 1.05-2.99, P-interaction = 0.006). Our results support the hypothesis that there are joint effects of endogenous and exogenous antioxidants.

Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study

Recent evidence has linked long-term bisphosphonate use with insufficiency fractures of the femur in postmenopausal women. In this case-control study, we have identified a significant association between a unique fracture of the femoral shaft, a transverse fracture in an area of thickened cortices, and long-term bisphosphonate use. Further studies are warranted. Although clinical trials confirm the anti-fracture efficacy of bisphosphonates over 3-5 years, the long-term effects of bisphosphonate use on bone metabolism are unknown. Femoral insufficiency fractures in patients on prolonged treatment have been reported. We performed a retrospective case-control study of postmenopausal women who presented with low-energy femoral fractures from 2000 to 2007. Forty-one subtrochanteric and femoral shaft fracture cases were identified and matched by age, race, and body mass index to one intertrochanteric and femoral neck fracture each. Bisphosphonate use was observed in 15 of the 41 subtrochanteric/shaft cases, compared to nine of the 82 intertrochanteric/femoral neck controls (Mantel-Haenszel odds ratio (OR), 4.44 [95% confidence interval (CI) 1.77-11.35]; P = 0.002). A common X-ray pattern was identified in ten of the 15 subtrochanteric/shaft cases on a bisphosphonate. This X-ray pattern was highly associated with bisphosphonate use (OR, 15.33 [95% CI 3.06-76.90]; P < 0.001). Duration of bisphosphonate use was longer in subtrochanteric/shaft cases compared to both hip fracture controls groups (P = 0.001). We found a significantly greater proportion of patients with subtrochanteric/shaft fractures to be on long-term bisphosphonates than intertrochanteric/femoral neck fractures. Bisphosphonate use was highly associated with a unique X-ray pattern. Further studies are warranted.

Polymorphisms in genes involved in sex hormone metabolism, estrogen plus progestin hormone therapy use, and risk of postmenopausal breast cancer.

Hormone therapy, estrogen plus progestin (E+P) particularly, is associated with increased risk of breast cancer. Functionally relevant polymorphisms in genes involved in sex hormone metabolism may alter exposure to exogenous sex hormones and affect risk of postmenopausal breast cancer. We evaluated associations of common polymorphisms in genes involved in estrogen and/or progesterone metabolism, E+P use, and their interactions with breast cancer risk in a case-control study of postmenopausal women (324 cases; 651 controls) nested within the VITAL cohort. None of the polymorphisms studied was, by itself, statistically significantly associated with breast cancer risk. E+P use was significantly associated with increased breast cancer risk (> or =10 years versus never; odds ratio, 1.9; 95% confidence interval, 1.3-2.8; P(trend) = 0.0002). Statistically significant interactions between CYP1A1 Ile(462)Val (P(interaction) = 0.04), CYP1A1 MspI (P(interaction) = 0.003), CYP1B1 Val(432)Leu (P(interaction) = 0.007), CYP1B1 Asn(453)Ser (P(interaction) = 0.04) and PGR Val(660)Leu (P(interaction) = 0.01), and E+P use were observed. The increased risk of breast cancer associated with E+P use was greater among women with at least one rare allele of the CYP1A1 Ile(462)Val, CYP1A1 MspI, CYP1B1 Asn(453)Ser, and PGR Val(660)Leu polymorphisms than among women homozygous for the common allele of these polymorphisms. Risk of breast cancer increased little with increasing years of E+P use among women with at least one CYP1B1 Val(432) allele; a large increase in risk was seen among women homozygous for CYP1B1 Leu(432). Our results support the hypothesis that specific polymorphisms in genes involved in sex hormone metabolism may modify the effect of E+P use on breast cancer risk.

Genetic Variability in Iron-Related Oxidative Stress Pathways (Nrf2, NQ01, NOS3, andHO-1), Iron Intake, and Risk of Postmenopausal Breast Cancer

Oxidative stress resulting from excess reactive oxygen species and/or deficiencies in antioxidant capabilities may play a role in breast cancer etiology. In a nested case-control study of postmenopausal women (505 cases and 502 controls) from the American Cancer Society Prevention II Nutrition Cohort, we examined relationships between breast cancer risk and genetic polymorphisms of enzymes involved in the generation and removal of iron-mediated reactive oxygen species. Using unconditional logistic regression, genetic variations in Nrf2 (11108C>T), NQO1 (609C>T), NOS3 (894G>T), and HO-1 [(GT)(n) dinucleotide length polymorphism] were not associated with breast cancer risk in a multivariate model. A significant dose trend (P trend = 0.04), however, was observed for total number of putative "at-risk" alleles (Nrf T, NQO1 T, NOS T, and HO-1 LL and LM genotypes), with those carrying three or more at-risk alleles having an odds ratio (OR) of 1.56 [95% confidence interval (95% CI), 0.97-2.51] compared with those having none. When examined in relation to iron, carriage of three or more high-risk alleles in the highest tertile of iron intake (OR, 2.27; 95% CI, 0.97-5.29; P trend = 0.02; P interaction = 0.30) or among users of supplemental iron (OR, 2.39; 95% CI, 1.09-5.26; P trend = 0.02; P interaction = 0.11) resulted in a greater than 2-fold increased risk compared with women with no high-risk alleles. Increased risk was also observed among supplement users with the HO-1 LL or LM genotypes (OR, 1.56; 95% CI, 1.01-2.41; P interaction = 0.32) compared with S allele carriers and MM genotypes combined. These results indicate that women with genotypes resulting in potentially higher levels of iron-generated oxidative stress may be at increased risk of breast cancer and that this association may be most relevant among women with high iron intake.

Alterations of Cortical and Trabecular Architecture Are Associated With Fractures in Postmenopausal Women, Partially Independent of Decreased BMD Measured by DXA: The OFELY Study

We assessed the role of low aBMD and impaired architecture-assessed by an HR-pQCT system-in a case-control study of postmenopausal women with fractures. Vertebral and nonvertebral fractures are associated with low volumetric BMD and architectural alterations of trabecular and cortical bone, independent of aBMD assessed by DXA. Alterations of bone architecture and low BMD both contribute to skeletal fragility, but the contribution of cortical and trabecular architecture, independently of areal BMD (aBMD), to the risk of fracture in postmenopausal women has not been thoroughly evaluated. We assessed the role of impaired architecture and low BMD in postmenopausal women with fractures. A matched case-control study in women from the OFELY cohort was performed after 13 years of follow-up. One hundred one women (mean, 73.7+/-8 years) who sustained a fragility fracture during the follow-up of the study were age-matched with one control who never had a fracture. Density and architecture at the distal radius and tibia were measured with high-resolution pQCT (HR-pQCT) using an XTreme CT (Scanco Medical AG, Bassersdorf, Switzerland). aBMD at the total hip and ultradistal radius was measured by DXA. There were 80 peripheral fractures in 72 women, 44 vertebral fractures in 34 women, and both types of fractures in 5 women over the 14 years of follow-up. At the distal radius, women with fractures had lower volumetric total (D tot) and trabecular (D trab) BMDs, BV/TV, cortical thickness (Cort Th), trabecular number (TbN), and trabecular thickness (TbTh) and higher trabecular separation (TbSp) and distribution of trabecular separation (TbSpSd) than controls without fractures. In a logistic model, each SD decrease of volumetric total and trabecular densities was associated with a significantly increased risk of fracture at both sites (ORs ranged from 2.00 to 2.47). After adjusting for aBMD measured by DXA at the ultradistal radius, differences between cases and controls remained significant for D trab, and there was a similar trend for TbN, TbSp, and TbSpSd, with adjusted ORs ranging from 1.32 to 1.50. At the distal tibia, before and after adjusting for total hip aBMD, differences between cases and controls remained significant for D tot, D trab, Cort Th, and TbTh, with adjusted ORs ranging from 1.80 to 2.09. In postmenopausal women, vertebral and nonvertebral fractures are associated with low volumetric BMD and architectural alterations of trabecular and cortical bone that can be assessed noninvasively and that are partially independent of aBMD assessed by DXA.

Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk

Oral oestrogen-replacement therapy (ERT) activates blood coagulation and increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal ERT has little effect on haemostasis, but data assessing its effect on thrombotic process are scarce. We aimed to examine the effect of the route of oestrogen administration on VTE risk. We did a multicentre hospital-based case-control study of postmenopausal women in France. During 1999-2002, we recruited 155 consecutive cases with a first documented episode of idiopathic VTE (92 with pulmonary embolisms and 63 with deep venous thrombosis), and 381 controls matched for centre, age, and time of recruitment. Overall, 32 (21%) cases and 27 (7%) controls were current users of oral ERT, whereas 30 (19%) cases and 93 (24%) controls were current users of transdermal ERT. After adjustment for potential confounding variables, the odds ratio for VTE in current users of oral and transdermal ERT compared with non-users was 3.5 (95% CI 1.8-6.8) and 0.9 (0.5-1.6), respectively. Estimated risk for VTE in current users of oral ERT compared with transdermal ERT users was 4.0 (1.9-8.3). Oral but not transdermal ERT is associated with risk of VTE in postmenopausal women. These data suggest that transdermal ERT might be safer than oral ERT with respect to thrombotic risk.

Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women's Health Initiative observational study.

Postmenopausal hormone replacement therapy (HRT) has been shown to elevate C-reactive protein (CRP) levels. Several inflammatory biomarkers, including CRP, are associated with increased cardiovascular risk. However, whether the effect of HRT on CRP represents a clinical hazard is unknown. To assess the association between baseline levels of CRP and interleukin 6 (IL-6) and incident coronary heart disease (CHD) and to examine the relationship between baseline use of HRT, CRP, and IL-6 levels as they relate to subsequent vascular risk. Prospective, nested case-control study of postmenopausal women, forming part of the Women's Health Initiative, a large, nationwide, observational study. Among 75 343 women with no history of cardiovascular disease or cancer, 304 women who developed incident CHD were defined as cases and matched by age, smoking status, ethnicity, and follow-up time with 304 study participants who remained event free during a median observation period of 2.9 years. Incidence of first myocardial infarction or death from CHD. Median baseline levels of CRP (0.33 vs 0.25 mg/dL; interquartile range [IQR], 0.14-0.71 vs 0.10-0.47; P<.001) and IL-6 (1.81 vs 1.47 pg/mL; IQR, 1.30-2.75 vs 1.05-2.15; P<.001) were significantly higher among cases compared with controls. In matched analyses, the odds ratio (OR) for incident CHD in the highest vs lowest quartile was 2.3 for CRP (95% confidence interval [CI], 1.4-3.7; P for trend =.002) and 3.3 for IL-6 (95% CI, 2.0-5.5; P for trend <.001). After additional adjustment for lipid and nonlipid risk factors, both inflammatory markers were significantly associated with a 2-fold increase in odds for CHD events. As anticipated, current use of HRT was associated with significantly elevated median CRP levels. However, there was no association between HRT and IL-6. In analyses comparing individuals with comparable baseline levels of either CRP or IL-6, those taking or not taking HRT had similar CHD ORs. In analyses stratified by HRT, we observed a positively graded relationship between plasma CRP levels and the OR for CHD among both users and nonusers of HRT across the full spectrum of baseline CRP. These prospective findings indicate that CRP and IL-6 independently predict vascular events among apparently healthy postmenopausal women and that HRT increases CRP. However, use or nonuse of HRT had less importance as a predictor of cardiovascular risk than did baseline levels of either CRP or IL-6.

Odds ratios for hip- and lower forearm fracture using peripheral bone densitometry; a case-control study of postmenopausal women

Odds ratios for hip- and lower forearm fracture using peripheral bone densitometry; a case-control study of postmenopausal women

Fatty Acid Composition of the Subcutaneous Adipose Tissue and Risk of Proliferative Benign Breast Disease and Breast Cancer

Studies in animals and geographic correlations across populations suggest that fatty acid intake may have a positive relationship with breast cancer risk, but analytic epidemiologic studies of fat intake have been less supportive. Adipose tissue analysis provides a more objective assessment of intakes of fatty acids that are not endogenously synthesized than do the questionnaire survey methods used in many epidemiologic studies. This case-control study of postmenopausal women was designed to examine the relationship between fatty acid composition of subcutaneous adipose tissue and risk of breast cancer and proliferative benign breast disease. In addition, we examined specific hypotheses that breast cancer risk is negatively associated with long-chain N-3 fatty acid intake, positively associated with trans fatty acid intake, and positively associated with increased intake of polyunsaturated fat together with low intake of antioxidants. Aspirates of subcutaneous fat from the buttocks were obtained from 380 women with newly diagnosed stage I or II breast cancer and 176 with proliferative benign breast disease. A total of 397 women who were evaluated for breast abnormalities at the same institutions but did not require breast biopsy or whose biopsy revealed nonproliferative benign breast disease served as the control group. We examined associations between saturated, monounsaturated, polyunsaturated, trans, or long-chain N-3 fatty acids and breast cancer, atypical hyperplasia, or proliferative benign breast disease without atypia. We observed no consistent patterns of association between breast cancer risk and any of the categories of fatty acids or the individual constituent fatty acids in the adipose tissue. Saturated fatty acids were inversely associated with risk of proliferative benign breast disease without atypia but not with atypical hyperplasia or breast cancer. This association was not observed, however, when total fat intake was taken into account. Women with high levels of polyunsaturated fatty acids in adipose tissue and low serum or dietary levels of antioxidants were not observed to be at higher risk of breast cancer. Using an objective measure of intake, we observed no major associations between polyunsaturated fatty acids, including long-chain N-3 fatty acids and trans fatty acids, and risk of breast cancer or proliferative benign breast disease. These data do not support the hypothesis that intake of specific fatty acids, particularly polyunsaturated and trans fatty acids, is an important risk factor for malignant or benign breast disease.