Impact of body mass index on estradiol depletion by aromatase inhibitors in postmenopausal women with early breast cancer.
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ABSTRACT:
SUBMITTER: Pfeiler G
PROVIDER: S-EPMC3777005 | biostudies-other | 2013 Sep
REPOSITORIES: biostudies-other
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Project description:Mitochondrial and oxidative stress have been related to obesity and breast cancer, and this cancer is more frequent and more aggressive in postmenopausal women with obesity. To investigate if Mexican-Mestizo postmenopausal women with breast cancer and obesity presented different somatic mutations in the mitochondrial DNA (mtDNA) when compared to women with normal body mass index.
2019-03-31 | GSE125801 | GEO
Project description:BackgroundThere is widespread concern about the use of body mass index (BMI) to define obesity status in postmenopausal women because it may not accurately represent an individual's true obesity status. The objective of the present study is to examine and adjust for exposure misclassification bias from using an indirect measure of obesity (BMI) compared with a direct measure of obesity (percent body fat).MethodsWe used data from postmenopausal non-Hispanic black and non-Hispanic white women in the Women's Health Initiative (n=126,459). Within the Women's Health Initiative, a sample of 11,018 women were invited to participate in a sub-study involving dual-energy x-ray absorptiometry scans. We examined indices of validity comparing BMI-defined obesity (≥30 kg/m), with obesity defined by percent body fat. We then used probabilistic bias analysis models stratified by age and race to explore the effect of exposure misclassification on the obesity-mortality relationship.ResultsValidation analyses highlight that using a BMI cutpoint of 30 kg/m to define obesity in postmenopausal women is associated with poor validity. There were notable differences in sensitivity by age and race. Results from the stratified bias analysis demonstrated that failing to adjust for exposure misclassification bias results in attenuated estimates of the obesity-mortality relationship. For example, in non-Hispanic white women 50-59 years of age, the conventional risk difference was 0.017 (95% confidence interval = 0.01, 0.023) and the bias-adjusted risk difference was 0.035 (95% simulation interval = 0.028, 0.043).ConclusionsThese results demonstrate the importance of using quantitative bias analysis techniques to account for nondifferential exposure misclassification of BMI-defined obesity. See video abstract at, http://links.lww.com/EDE/B385.
| S-EPMC6481627 | biostudies-literature
Project description:AIMS:Central adiposity is associated with increased cardiovascular disease (CVD) risk, even among people with normal body mass index (BMI). We tested the hypothesis that regional body fat deposits (trunk or leg fat) are associated with altered risk of CVD among postmenopausal women with normal BMI. METHODS AND RESULTS:We included 2683 postmenopausal women with normal BMI (18.5 to <25?kg/m2) who participated in the Women's Health Initiative and had no known CVD at baseline. Body composition was determined by dual energy X-ray absorptiometry. Incident CVD events including coronary heart disease and stroke were ascertained through February 2017. During a median 17.9?years of follow-up, 291 incident CVD cases occurred. After adjustment for demographic, lifestyle, and clinical risk factors, neither whole-body fat mass nor fat percentage was associated with CVD risk. Higher percent trunk fat was associated with increased risk of CVD [highest vs. lowest quartile hazard ratio (HR) = 1.91, 95% confidence interval (CI) 1.33-2.74; P-trend <0.001], whereas higher percent leg fat was associated with decreased risk of CVD (highest vs. lowest quartile HR = 0.62, 95% CI 0.43-0.89; P-trend = 0.008). The association for trunk fat was attenuated yet remained significant after further adjustment for waist circumference or waist-to-hip ratio. Higher percent trunk fat combined with lower percent leg fat was associated with particularly high risk of CVD (HR comparing extreme groups = 3.33, 95% CI 1.46-7.62). CONCLUSION:Among postmenopausal women with normal BMI, both elevated trunk fat and reduced leg fat are associated with increased risk of CVD.
| S-EPMC6933870 | biostudies-literature
Project description:PurposeHemodilution refers to reduced concentrations of analytes in the blood secondary to increased fluid volume. Given that obesity is associated with expanded vascular volume, hemodilution may result in a lower ratio of blood concentrations of analytes among heavier subjects. Assessing the relationship of hormone concentration to total mass varies by body mass index (BMI) is etiologically important because obesity is related to hormone metabolism and cancer risk.MethodsWe evaluated data for 194 postmenopausal controls in an endometrial cancer case-control study. Height, weight, and serum hormone concentrations were measured previously. We estimated serum hormone mass from concentration based on estimates of calculated plasma volume. We assessed the effect of BMI on relationships of sex steroid hormone concentration and mass using multivariate linear regression.ResultsHigher BMI was associated with increased estrone, estrone sulfate, estradiol, and albumin-bound estradiol concentrations and masses (p-trend ≤ 0.001). With increasing BMI, androstenedione concentration did not change significantly (p-trend = 0.548), but its mass increased (p-trend = 0.024).ConclusionsRelationships of sex steroid hormone concentration and mass were generally similar, except for androstenedione in which the relationship was only significant for mass. Future studies to assess both sex steroid hormone concentration and mass may have value in etiological research.
| S-EPMC3090465 | biostudies-literature
Project description:BackgroundNeck circumference, a proxy for upper-body subcutaneous fat, is a unique and pathogenic fat depot that confers additional metabolic risk. The purpose of present study was to determine whether neck circumference associates with nonalcoholic fatty liver disease (NAFLD) in postmenopausal women with normal body mass index.MethodsA cross-sectional survey (n = 2492) and a 3.1-year follow-up investigation (n = 1354) were conducted among Chinese postmenopausal women with normal BMI (18.5 to < 25 kg/m2). Neck circumference was measured horizontally at the lower margin of the laryngeal prominence.ResultsIn the cross-sectional analysis, large neck circumference was associated with the presence of NAFLD (odds ratio 2.28; 95% CI 1.74-2.98; highest tertile versus lowest tertile) after adjustment for confounding factors. Among 1354 subjects without the NAFLD at baseline, 429 (31.7%) incident NAFLD cases occurred at 3.1 years. Neck circumference was positively associated with triglycerides, homeostasis model assessment of insulin resistance, C-reactive protein, and negatively associated with high-density lipoprotein cholesterol and adiponectin. Individuals with large baseline neck circumference had a significantly higher risk of NAFLD than those with small neck circumference. The multivariable adjusted hazard ratio was 1.42 (95% CI 1.15-1.97; p for trend = 0.004) for the highest versus the lowest tertile of neck circumference, and was 1.22 (95% CI 1.10-1.41; p = 0.006) per 1-standard deviation increment in neck circumference.ConclusionsAmong postmenopausal women with normal BMI, relatively large neck circumference levels are associated with an increased risk of NAFLD.
| S-EPMC7967966 | biostudies-literature
Project description:ImportanceAromatase inhibitors induce a profound depletion in serum estrogen levels. Postmenopausal obese women receiving aromatase inhibitor therapy may be at increased risk of bone fractures owing to the detrimental association of adiposity with bone quality and the loss of the protective effect of estrogens on bone mineral density.ObjectiveTo determine whether fat body mass (FBM), as measured by dual-energy x-ray absorptiometry, is associated with vertebral fracture prevalence in postmenopausal women undergoing adjuvant aromatase inhibitor therapy for breast cancer.Design, setting, and participantsIn this single-center, cross-sectional study, 556 postmenopausal women with early-stage breast cancer were consecutively enrolled from October 15, 2013, to June 30, 2018, and stratified according to whether they were aromatase inhibitor-naive or aromatase inhibitor-treated for at least 2 years. The database was locked on December 31, 2018, and data analysis was completed on February 28, 2019. Eligible patients in both groups had normal renal function, no metabolic diseases, and no previous or current treatment with antiosteoporotic drugs or glucocorticoids. Previous chemotherapy, but not tamoxifen, was permitted. Data were gathered once, at baseline.Main outcomes and measuresVertebral fracture prevalence associated with FBM in aromatase inhibitor-naive and aromatase inhibitor-treated patients.ResultsOf the 556 women enrolled, the mean age was 63.0 years (95% CI, 62.2-63.8 years). The 195 aromatase inhibitor-treated patients were older than the 361 aromatase inhibitor-naive patients (mean age, 66.1 vs 61.3 years; P < .001), had a higher body mass index (mean, 26.4 vs 25.3; P = .009), were less likely to engage in physical activity (65.3% vs 73.7%; P = .03), and were less likely to consume alcoholic beverages (68.4% vs 80.9%; P = .001). Among the aromatase inhibitor-naive patients, the vertebral fracture prevalence was higher in the subgroup with FBM below the median value than in those with high FBM, but the difference was not statistically significant (19.2% vs 13.3%; P = .13). Conversely, the proportion of vertebral fractures in the aromatase inhibitor-treated group was 20.0% in patients with low FBM vs 33.3% in patients with high FBM (P = .04). An opposite trend in the association of FBM with vertebral fracture prevalence according to aromatase inhibitor group was shown by multivariable analysis in the propensity score-matched sample: odds ratio, 0.38 (95% CI, 0.12-1.19) and 1.94 (95% CI, 0.67-5.64) in the aromatase inhibitor-naive and aromatase inhibitor-treated groups, respectively (odds ratio for the interaction, 5.77 [95% CI, 1.08-30.81]; P for interaction term = .03).Conclusions and relevanceFat body mass may be associated with fragility-related fractures in patients with breast cancer who undergo aromatase inhibitor therapy. If these data are confirmed, obesity could be included in the algorithm for assessing fracture risk and selecting patients to receive bone resorption inhibitors.
| S-EPMC6777242 | biostudies-literature
Project description:BackgroundA large trial of postmenopausal women with breast cancer reported an imbalance in colorectal cancer events with aromatase inhibitors (AIs), compared with tamoxifen in the adjuvant setting. This unexpected signal was observed within 3?years of randomization. To date, no observational studies have examined this important safety question in the natural setting of clinical practice. Thus, the objective of this study was to determine whether AIs, when compared with tamoxifen, are associated with increased risk of colorectal cancer in postmenopausal women with breast cancer.Patients and methodsUsing the UK Clinical Practice Research Datalink, we identified women, at least 55?years of age, with breast cancer newly treated with either AIs or tamoxifen between 1 January 1996 and 30 September 2015, with follow-up until 30 September 2016. High-dimensional propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of incident colorectal cancer associated with AIs when compared with tamoxifen overall, by cumulative duration of use, and time since initiation. All exposures were lagged by 1 year for latency considerations.ResultsA total of 9701 and 8893 patients initiated AIs and tamoxifen as first-line hormonal therapy (median follow-up of 2.4 and 2.9?years, respectively). Compared with tamoxifen, AIs were not associated with an increased risk of colorectal cancer (incidence rates of 150 per 100?000 person-years in both groups; adjusted HR: 0.90, 95% CI: 0.53-1.52). Similarly, there was no evidence of an association with cumulative duration of use (P-heterogeneity?=?0.54), and time since initiation (P-heterogeneity?=?0.66).ConclusionsIn this first population-based study, the use of AIs was not associated with an increased risk of colorectal cancer. These findings should provide reassurance to the concerned stakeholders.
| S-EPMC5889043 | biostudies-literature
Project description:Objective:Estradiol (E2) regulates adipose tissue resulting in increased fat mass (FM) with declining E2. However, increased visceral fat and hyperestrogenemia are features of obese individuals. It is possible that adipocytes in obese individuals are less sensitive to E2 resulting in higher FM. Our objective is to identify the range of serum E2 for which postmenopausal women have the lowest FM and best body composition. Methods:Cross-sectional data from 252 community-dwelling postmenopausal women, 42-90?years old. Subjects were stratified into categories of E2 (pg/ml): (1) ?10.5; (2) 10.6-13.9; (3) 14.0-17.4; and (4) ?17.5. Body composition by dual-energy X-ray absorptiometry. Serum E2 by radioimmunoassay. Between-group comparisons by analysis of covariance. Results:E2 linearly increased with increasing body weight and body mass index (r?=?0.15 and p?=?0.01 for both), but not with total FM (kg) or %?FM (r?=?0.07, p?=?0.34 and r?=?-0.04, p?=?0.56, respectively). However, total FM (kg) followed a U-shaped distribution and was significantly lower in group 3 (27.6?±?10.6), compared with groups 1: (34.6?±?12.5), 2: (34.0?±?12.4), and 4: (37.0?±?10.6), p?=?0.005. %?FM was also lowest in group 3. While fat-free mass (FFM, kg) increased with increasing E2 (p?<?0.001), % FFM was highest in group 3. Conclusion:In our population of postmenopausal women, FM followed a U-shaped distribution according to E2 levels. E2 between 14.0 and 17.4?pg/ml is associated with the best body composition, i.e., lowest total and %?FM and highest % FFM. Given the role of E2 in regulating body fat, high FM at the high end of the E2 spectrum may suggest reduced E2 sensitivity in adipocytes among obese postmenopausal women. Clinical Trials:ClinicalTrials.gov identifier: NCT00146107.
| S-EPMC6036116 | biostudies-literature
Project description:Background:Elevated body mass index (BMI) is associated with increased risk of postmenopausal breast cancer. The underlying mechanisms, however, remain elusive. Methods:In a nested case-control study of 621 postmenopausal breast cancer case participants and 621 matched control participants, we measured 617 metabolites in prediagnostic serum. We calculated partial Pearson correlations between metabolites and BMI, and then evaluated BMI-associated metabolites (Bonferroni-corrected ? level for 617 statistical tests = P < 8.10?×?10-5) in relation to invasive breast cancer. Odds ratios (ORs) of breast cancer comparing the 90th vs 10th percentile (modeled on a continuous basis) were estimated using conditional logistic regression while controlling for breast cancer risk factors, including BMI. Metabolites with the lowest P values (false discovery rate < 0.2) were mutually adjusted for one another to determine those independently associated with breast cancer risk. Results:Of 67 BMI-associated metabolites, two were independently associated with invasive breast cancer risk: 16a-hydroxy-DHEA-3-sulfate (OR?=?1.65, 95% confidence interval [CI] = 1.22 to 2.22) and 3-methylglutarylcarnitine (OR?=?1.67, 95% CI?=?1.21 to 2.30). Four metabolites were independently associated with estrogen receptor-positive (ER+) breast cancer risk: 16a-hydroxy-DHEA-3-sulfate (OR?=?1.84, 95% CI?=?1.27 to 2.67), 3-methylglutarylcarnitine (OR?=?1.91, 95% CI?=?1.23 to 2.96), allo-isoleucine (OR?=?1.76, 95% CI?=?1.23 to 2.51), and 2-methylbutyrylcarnitine (OR?=?1.89, 95% CI?=?1.22 to 2.91). In a model without metabolites, each 5 kg/m2 increase in BMI was associated with a 14% higher risk of breast cancer (OR?=?1.14, 95% CI?=?1.01 to 1.28), but adding 16a-hydroxy-DHEA-3-sulfate and 3-methylglutarylcarnitine weakened this association (OR?=?1.06, 95% CI?=?0.93 to 1.20), with the logOR attenuating by 57.6% (95% CI?=?21.8% to 100.0+%). Conclusion:These four metabolites may signal metabolic pathways that contribute to breast carcinogenesis and that underlie the association of BMI with increased postmenopausal breast cancer risk. These findings warrant further replication efforts.
| S-EPMC6279273 | biostudies-literature
Project description:ContextAromatase deficiency causes obesity and insulin resistance in aromatase knockout mice and humans with rare mutations of the aromatase gene (CYP19). Aromatase inhibitors are a commonly prescribed therapy for postmenopausal breast cancer.ObjectiveWe hypothesized that aromatase inhibitors induce obesity and insulin resistance when used in treatment of breast cancer.DesignCase-control study.SettingUniversity teaching hospital.ParticipantsPatients with postmenopausal breast cancer (n = 20) treated with aromatase inhibitors and 20 age-matched control subjects.Main outcome measuresThe primary outcome measure was insulin sensitivity index - Matsuda, derived from a 75-g oral glucose tolerance test. Body composition was assessed by dual energy x-ray absorptiometry and biopsy specimens of subcutaneous adipose tissue obtained for assessment of mRNA transcript levels. Data are reported as mean ± SEM (patients receiving inhibitors vs control group, respectively).ResultsAromatase inhibitor therapy was associated with significantly lower insulin sensitivity (5.15 ± 0.45 vs 6.80 ± 0.64; P = 0.041), higher peak insulin concentration after oral glucose tolerance test (693.4 ± 78.6 vs 527.6 ± 85.5 pmol/L; P = 0.035), greater percentage of body fat (38.4% ± 1.0% vs 34.6% ± 1.3%; P = 0.026), and higher plasma leptin concentration (23.5 ± 2.8 vs 15.5 ± 2.3 ng/mL; P = 0.035).ConclusionWomen who received aromatase inhibitors for postmenopausal breast cancer had greater percentage body fat and insulin resistance compared with control subjects with no history of breast cancer.
| S-EPMC6642666 | biostudies-literature