The challenge of measuring circulating estradiol at low concentrations

Demand for measuring estradiol at low concentrations is increasing, and the widely used 'direct' radioimmunoassays that do not require a preliminary organic purification step may be inadequate in patient care because of their limited accuracy. In observational epidemiology, however, the main concern is to obtain a correct ranking of individuals' hormone concentration relative to the true level (as determined through a 'gold standard'). Despite differences in the absolute scale of measured and true concentrations, correct ranking will permit calculation of unbiased estimates of hormone–disease associations. In prospective studies, the major concerns are the limited volume of often irreplaceable specimens and the need to perform a large number of assays within a reasonable period of time. Organic purification is often not feasible because of sample volume requirements and logistic difficulties, and so the development of accurate, rapid and inexpensive methods to measure sex steroids at low concentrations would represent a valuable new research tool for both clinicians and epidemiologists

Deficits in plasma oestradiol measurement in studies and management of breast cancer

The determination of plasma oestradiol has numerous applications in epidemiology, reproductive medicine and breast cancer management. Commercially available analytical methods, which measure the hormone levels without prior purification, have been successfully developed for measuring oestradiol in premenopausal women. The application of these methodologies to the quantification of the very low levels of oestradiol in postmenopausal women is more problematic in terms of accuracy and interpretation. The importance of using appropriate methodology is discussed and illustrated with data demonstrating the disparity in the results obtained when low levels of oestradiol were quantified using direct and indirect methods

Weight loss decreases follicle stimulating hormone in overweight postmenopausal women

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109940/1/oby20917.pd

Carbohydrates, glycemic index, glycemic load, sugars and breast cancer risk: a systematic review and dose-response meta-analysis of prospective studies

Context: The investigation of dose–response associations between carbohydrate intake, glycemic index, glycemic load, and risk of breast cancer stratified by menopausal status, hormone receptor status, and body mass index (BMI) remains inconclusive. Objective: A systematic review and dose–response meta-analyses was conducted to investigate these associations. Data Sources: As part of the World Cancer Research Fund/American Institute for Cancer Research Continuous Update Project, PubMed was searched up to May 2015 for relevant studies on these associations. Study Selection: Prospective studies reporting associations between carbohydrate intake, glycemic index, or glycemic load and breast cancer risk were included. Data Extraction: Two investigators independently extracted data from included studies. Results: Random-effects models were used to summarize relative risks (RRs) and 95%CIs. Heterogeneity between subgroups, including menopausal status, hormone receptor status, and BMI was explored using meta-regression. Nineteen publications were included. The summary RRs (95%CIs) for breast cancer were 1.04 (1.00–1.07) per 10 units/d for glycemic index, 1.01 (0.98–1.04) per 50 units/d for glycemic load, and 1.00 (0.96–1.05) per 50 g/d for carbohydrate intake. For glycemic index, the association appeared slightly stronger among postmenopausal women (summary RR per 10 units/d, 1.06; 95%CI, 1.02–1.10) than among premenopausal women, though the difference was not statistically significant (Pheterogeneity = 0.15). Glycemic load and carbohydrate intake were positively associated with breast cancer among postmenopausal women with estrogen-negative tumors (summary RR for glycemic load, 1.28; 95%CI, 1.08–1.52; and summary RR for carbohydrates, 1.13; 95%CI, 1.02–1.25). No differences in BMI were detected. Conclusions: Menopausal and hormone receptor status, but not BMI, might be potential influencing factors for the associations between carbohydrate intake, glycemic index, glycemic load, and breast cancer

Premenopausal endogenous oestrogen levels and breast cancer risk: a meta-analysis.

BACKGROUND: Many of the established risk factors for breast cancer implicate circulating hormone levels in the aetiology of the disease. Increased levels of postmenopausal endogenous oestradiol (E2) have been found to increase the risk of breast cancer, but no such association has been confirmed in premenopausal women. We carried out a meta-analysis to summarise the available evidence in women before the menopause. METHODS: We identified seven prospective studies of premenopausal endogenous E2 and breast cancer risk, including 693 breast cancer cases. From each study we extracted odds ratios of breast cancer between quantiles of endogenous E2, or for unit or s.d. increases in (log transformed) E2, or (where odds ratios were unavailable) summary statistics for the distributions of E2 in breast cancer cases and unaffected controls. Estimates for a doubling of endogenous E2 were obtained from these extracted estimates, and random-effect meta-analysis was used to obtain a pooled estimate across the studies. RESULTS: Overall, we found weak evidence of a positive association between circulating E2 levels and the risk of breast cancer, with a doubling of E2 associated with an odds ratio of 1.10 (95% CI: 0.96, 1.27). CONCLUSION: Our findings are consistent with the hypothesis of a positive association between premenopausal endogenous E2 and breast cancer risk

Towards an integrated model for breast cancer etiology: The lifelong interplay of genes, lifestyle, and hormones

While the association of a number of risk factors, such as family history and reproductive patterns, with breast cancer has been well established for many years, work in the past 10–15 years also has added substantially to our understanding of disease etiology. Contributions of particular note include the delineation of the role of endogenous and exogenous estrogens to breast cancer risk, and the discovery and quantification of risk associated with several gene mutations (e.g. BRCA1). Although it is difficult to integrate all epidemiologic data into a single biologic model, it is clear that several important components or pathways exist. Early life events probably determine both the number of susceptible breast cells at risk and whether mutations occur in these cells. High endogenous estrogens are well established as an important cause of breast cancer, and many known risk factors appear to operate through this pathway. Estrogens (and probably other growth factors) appear to accelerate the development of breast cancer at many points along the progression from early mutation to tumor metastasis, and appear to be influential at many points in a woman's life. These data now provide a basis for a number of strategies that can reduce risk of breast cancer, although some strategies represent complex decision-making. Together, the modification of nutritional and lifestyle risk factors and the judicious use of chemopreventive agents could have a major impact on breast cancer incidence. Further research is needed in many areas, but a few specific arenas are given particular mention

Risk factors for breast cancer in postmenopausal Caucasian and Chinese-Canadian women

Abstract Introduction Striking differences exist between countries in the incidence of breast cancer. The causes of these differences are unknown, but because incidence rates change in migrants, they are thought to be due to lifestyle rather than genetic differences. The goal of this cross-sectional study was to examine breast cancer risk factors in populations with different risks for breast cancer. Methods We compared breast cancer risk factors among three groups of postmenopausal Canadian women at substantially different risk of developing breast cancer - Caucasians (N = 413), Chinese women born in the West or who migrated to the West before age 21 (N = 216), and recent Chinese migrants (N = 421). Information on risk factors and dietary acculturation were collected by telephone interviews using questionnaires, and anthropometric measurements were taken at a home visit. Results Compared to Caucasians, recent Chinese migrants weighed on average 14 kg less, were 6 cm shorter, had menarche a year later, were more often parous, less often had a family history of breast cancer or a benign breast biopsy, a higher Chinese dietary score, and a lower Western dietary score. For most of these variables, Western born Chinese and early Chinese migrants had values intermediate between those of Caucasians and recent Chinese migrants. We estimated five-year absolute risks for breast cancer using the Gail Model and found that risk estimates in Caucasians would be reduced by only 11% if they had the risk factor profile of recent Chinese migrants for the risk factors in the Gail Model. Conclusions Our results suggest that in addition to the risk factors in the Gail Model, there likely are other factors that also contribute to the large difference in breast cancer risk between Canada and China

Breast density and polymorphisms in genes coding for CYP1A2 and COMT: the Multiethnic Cohort

BACKGROUND: Mammographic density is a strong predictor of breast cancer risk and is increased by hormone replacement therapy (HRT). Some associations with genetic polymorphisms in enzymes involved in estrogen metabolism have been described. This cross-sectional analysis examined the relation between mammographic density and the CYP1A2*1F and COMT Val(58 )Met polymorphisms among 332 breast cancer cases and 254 controls in the Hawaii component of the Multiethnic Cohort. METHODS: Mammographic density, before diagnosis in cases, was quantified by using a validated computer-assisted method. Blood samples were genotyped by standard PCR/RFLP methods. Adjusted mean percent density was calculated by genotype using mixed models with the unstructured covariance option. RESULTS: A positive association between the C allele in the CYP1A2*1F gene and percent density, but not the dense area, was suggested (p = 0.11). The relation was limited to controls (p = 0.045), postmenopausal women not using HRT (p = 0.08), and normal weight subjects (p = 0.046). We did not observe any relation between the COMT Val(58 )Met polymorphism and breast density. CONCLUSION: The lack of an association between the CYP1A2 genotype and the size of the dense areas suggests an effect on the non-dense, i.e., fatty breast tissue. The discrepancies among studies may be due to differential susceptibility; changes in enzyme activity as a result of the CYP1A2*1F polymorphism may influence breast tissue differently depending on hormonal status. Larger studies with the ability to look at interactions would be useful to elucidate the influence of genetic variation in CYP1A2 and COMT on the risk of developing breast cancer

Sex steroids, growth factors and mammographic density: a cross-sectional study of UK postmenopausal Caucasian and Afro-Caribbean women

INTRODUCTION: Sex steroids, insulin-like growth factors (IGFs) and prolactin are breast cancer risk factors but whether their effects are mediated through mammographic density, one of the strongest risk factors for breast cancer, is unknown. If such a hormonal basis of mammographic density exists, hormones may underlie ethnic differences in both mammographic density and breast cancer incidence rates. METHODS: In a cross-sectional study of 270 postmenopausal Caucasian and Afro-Caribbean women attending a population-based breast screening service in London, UK, we investigated whether plasma biomarkers (oestradiol, oestrone, sex hormone binding globulin (SHBG), testosterone, prolactin, leptin, IGF-I, IGF-II and IGF binding protein 3 (IGFBP3)) were related to and explained ethnic differences in mammographic percent density, dense area and nondense area, measured in Cumulus using the threshold method. RESULTS: Mean levels of oestrogens, leptin and IGF-I:IGFBP3 were higher whereas SHBG and IGF-II:IGFBP3 were lower in Afro-Caribbean women compared with Caucasian women after adjustment for higher mean body mass index (BMI) in the former group (by 3.2 kg/m(2) (95% confidence interval (CI): 1.8, 4.5)). Age-adjusted percent density was lower in Afro-Caribbean compared with Caucasian women by 5.4% (absolute difference), but was attenuated to 2.5% (95% CI: -0.2, 5.1) upon BMI adjustment. Despite ethnic differences in biomarkers and in percent density, strong ethnic-age-adjusted inverse associations of oestradiol, leptin and testosterone with percent density were completely attenuated upon adjustment for BMI. There were no associations of IGF-I, IGF-II or IGFBP3 with percent density or dense area. We found weak evidence that a twofold increase in prolactin and oestrone levels were associated, respectively, with an increase (by 1.7% (95% CI: -0.3, 3.7)) and a decrease (by 2.0% (95% CI: 0, 4.1)) in density after adjustment for BMI. CONCLUSIONS: These findings suggest that sex hormone and IGF levels are not associated with BMI-adjusted percent mammographic density in cross-sectional analyses of postmenopausal women and thus do not explain ethnic differences in density. Mammographic density may still, however, be influenced by much higher premenopausal hormone levels

Mammographic density and epithelial histopathologic markers

<p>Abstract</p> <p>Background</p> <p>We explored the association of mammographic density, a breast cancer risk factor, with hormonal and proliferation markers in benign tissue from tumor blocks of pre-and postmenopausal breast cancer cases.</p> <p>Methods</p> <p>Breast cancer cases were recruited from a case-control study on breast density. Mammographic density was assessed on digitized prediagnostic mammograms using a computer-assisted method. For 279 participants of the original study, we obtained tumor blocks and prepared tissue microarrays (TMA), but benign tissue cores were only available for 159 women. The TMAs were immunostained for estrogen receptor alpha (ERα) and beta (ERβ), progesterone receptor (PR), HER2/neu, Ki-67, and Proliferating Cell Nuclear Antigen (PCNA). We applied general linear models to compute breast density according to marker expression.</p> <p>Results</p> <p>A substantial proportion of the samples were in the low or no staining categories. None of the results was statistically significant, but women with PR and ERβ staining had 3.4% and 2.4% higher percent density. The respective values for Caucasians were 5.7% and 11.6% but less in Japanese women (3.5% and -1.1%). Percent density was 3.4% higher in women with any Ki-67 staining and 2.2% in those with positive PCNA staining.</p> <p>Conclusion</p> <p>This study detected little evidence for an association between mammographic density and expression of steroid receptors and proliferation markers in breast tissue, but it illustrated the problems of locating tumor blocks and benign breast tissue samples for epidemiologic research. Given the suggestive findings, future studies examining estrogen effects in tissue, cell proliferation, and density in the breast may be informative.</p