Postmenopausal Subjects Research Articles

Abstract P4-01-12: Optical imaging of breast density correlates with magnetic resonance imaging in patients undergoing neoadjuvant chemotherapy

Abstract Background: In addition to being a strong risk factor for breast cancer, data from recent studies suggests that breast density changes correlate with response to preventative or adjuvant tamoxifen treatment for breast cancer. Breast density may be a surrogate biomarker for survival and indication of the need for additional treatments such as radiotherapy. However, quantitative methods to assess breast density in the clinic are limited. In this study, we assess how Diffuse Optical Spectroscopic Imaging (DOSI) may be used to evaluate and understand changes in breast density in patients undergoing neoadjuvant chemotherapy. Methods: DOSI was used to measure hemodynamic and metabolic information from the contralateral normal breast of 28 breast cancer patients undergoing neoadjuvant chemotherapy. DOSI uses near-infrared light to determine absolute tissue molar concentrations of oxyhemoglobin (ctO2Hb), deoxyhemoglobin (ctHHb), water, and lipid content without requirement of an exogenous contrast agent. DOSI measurements were compared to 3.0T MRI measured fibroglandular density before and during therapy. Results: Water (r = 0.843; P<0.001), ctHHb (r = 0.785; P = 0.003), and lipid (r = -0.707; P = 0.010) concentration measured with DOSI correlated strongly with MRI-measured density before therapy. During neoadjuvant treatment measured at ∼90 days after treatment commenced, significant reductions were observed in ctO2Hb for pre- (-20.0%; 95% confidence interval (CI), -32.7 to -7.4) and postmenopausal subjects (-20.1%; 95% CI, -31.4 to -8.8), and water concentration for premenopausal subjects (- 1.9%; 95% CI, -17.1 to -6.7) compared to baseline. Lipid content increased slightly in premenopausal subjects (3.8%; 95% CI, 1.1 to 6.5) and water increased slightly in postmenopausal subjects (4.4%; 95% CI, 0.1 to 8.6). Percentage change in water at the end of therapy compared with baseline correlated strongly with percentage change in MRI-measured density (r = 0.864; P = 0.012). Discussion: For this patient cohort, non-invasive optical measurement may provide an assessment of breast density and yield additional information that complements MRI and mammography techniques. We demonstrate a strong baseline correlation between water and ctHHb with breast density, reflecting the increased water content and rate of metabolism in fibroglandular breast tissue. Significant changes in optical markers for vascular density and supply (ctO2Hb and water) are observed during treatment. A significant decrease in ctO2Hb is observed in both menopausal groups. The steady reduction of ctO2Hb without a corresponding decrease in ctHHb suggests that chemotherapy agents act directly on the normal breast tissue, perhaps by causing a reduction of perfusion. The greater reduction in breast-tissue water in premenopausal subjects suggests that chemo-reduced ovarian hormone levels may exert a role in reducing breast-tissue density. Although from a limited patient dataset, these results suggest that DOSI may provide new functional indices of breast density based on hemoglobin and water that could be used at the bedside to assess response to therapy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-12.

Assessment of circulatory endothelin-1 level among pre- and post-menopausal rural women in Bangladesh: Result from a population-based study

Aims: Prevalence of non-communicable diseases is a challenging problem among menopausal women especially in a least developing country like Bangladesh. Recently, plasma levels of endothelin-1 or related molecules are reported to be associated with metabolic syndrome and its components. So we determined the circulatory level of endothelin-1 in Bangladeshi rural pre- and post-menopausal women and its association with various cardiometabolic risk factors. Main methods: This study is based on a community based cross-sectional survey among 1678 rural women over the age of 15. We measured plasma level of endothelin-1 by ELISAand used multipleregressions to estimate the association between circulatory endothelin-1 level and cardio-metabolic risk factors. Key findings: Endothelin-1 levels were significantly higher in post-menopausal subjects than in pre-menopausal (post-menopausal vs. pre-menopausal: 3.13 ± 0.09 vs. 2.29 ± 0.05pg/ml, p=0.001). Mean values of age, systolic blood pressure, diastolic blood pressure, plasma triglyceride level, fasting plasma glucose level, and HDL cholesterol were significantly higher in post-menopause compared to pre-menopausal group (P<0.05). In both univariate and multiple regression analysis, we found that ET-1 had significant positive association withage only. Metabolic syndrome was present in 25.6% respondents and it was more prevalent among post-menopausal (39.3%) as compared to pre-menopausal (16.8%) women. Prevalence of hypertension was also greater in post-menopausal women than in pre-menopausal women (30.7% vs. 9.8%). Significance: The higher level of circulatory endothelun-1 level may be associated with various medical problems and events/syndromes of post-menopausal women in rural Bangladesh. Proper intervention strategies should be warranted among these high-risk subjects.

Relationship between autonomic nervous system activity and bone mineral density in non-medicated perimenopausal women

The autonomic nervous system (ANS) has attracted attention as a regulator of bone remodeling and the effects of beta-blockers on the prevention of osteoporosis have been studied. However, results are as yet inconclusive and the physiological role of the ANS in bone metabolism has not been clarified. Thus, we investigated the relationship between bone mineral density (BMD) and ANS activity in non-medicated perimenopausal women. ANS activity was evaluated by power spectral analysis of heart rate variability, and overall ANS activity and the balance between sympathetic and parasympathetic nervous activities (SNS and PNS) were quantified. Pre- and postmenopausal subjects were divided into higher or lower overall ANS activity groups, and were also divided into SNS- and PNS-dominant groups. BMD (percentage of young adult mean) was significantly higher in the higher overall ANS group than in the lower group (112.2 ± 16.2 % vs 99.7 ± 14.8 %, p < 0.05) of premenopausal subjects, but not in postmenopausal subjects (91.5 ± 15.9 % vs 91.0 ± 14.9 %). BMD was significantly higher in the SNS-dominant group than in the PNS-dominant group (94.1 ± 16.3 % vs 88.4 ± 18.8 %, p < 0.05) of postmenopausal subjects, but not in the premenopausal subjects (103.5 ± 18.4 % vs. 107.2 ± 14.6 %). Our study revealed that ANS influences bone metabolism under physiological conditions. Thus, it appears to be worthwhile to introduce ANS activity evaluation into the management of bone health in perimenopausal women.

Polymorphisms in Base Excision Repair Genes Are Associated With Endometrial Cancer Risk Among Postmenopausal Japanese Women

Polymorphisms in base excision repair (BER) genes are associated with risk for several types of cancers but have not been studied with respect to endometrial cancer among Japanese women. Therefore, we conducted a case-control study to explore the association between polymorphisms in BER genes and the risk for endometrial cancer. This study included a total of 91 postmenopausal subjects with endometrial cancer and 261 controls without cancer who visited the Aichi Cancer Center between 2001 and 2005. We focused on single nucleotide polymorphisms within coding regions of 5 BER genes (OGG1, MUTYH, XRCC1, APEX1, and PARP1). To assess lifestyle in the etiology of endometrial cancer, we used a self-administered questionnaire. Associations were evaluated using multivariate unconditional logistic regression models. We also assessed whether there were intergenic associations or an interaction with obesity. We observed a significant association between endometrial cancer risk and XRCC1 rs1799782 (C > T, Arg194Trp) and XRCC1 rs25487 (G > A, Arg399Gln). We uncovered a significant association between obesity (body mass index, ≥ 25) and rs25487. The XRCC1 polymorphisms were in complete linkage disequilibrium, and the XRCC1 haplotype TG associated significantly with endometrial cancer risk. The interaction between the CA haplotype and body mass index was marginally significant, whereas interaction between haplotype in XRCC1 and rs1136410 (PARP1) was not significant. We found a significant association between endometrial cancer risk and XRCC1 polymorphisms and haplotype TG in postmenopausal Japanese women.

Soy and Calcium Supplementation Reduces Postmenopausal Problems

This was a purposive randomized intervention trial which assessed the occurrence of postmenopausal symptoms/ problems and effectiveness of soy protein isolate and calcium supplementation on overcoming these symptoms in 100 postmenopausal subjects. Questionnaire cum interview schedule was used to collect required information and intervention trials were carried out for a period of 100 days each. Large number of subjects reported a variety of problems associated with menopause. Somatic complaints were reported by 49.43% to 70.78% of the women and were significantly (p<0.05) more prevalent than psychological complaints (17.97% to 98.87%) and urogenital problems. Majority of the subjects (83.14%) had moderate degree of problems. Soy protein isolate intervention was effective in reducing most of the somatic problems in 8.00% to 58.82% of the subjects. Maximum improvement was reported on flushes, heart problems and sleep disturbances. Calcium supplementation was effective in reducing mainly joint pain in the subjects (57.89%). Thus, dietary interventions in the form of soy protein isolate and calcium help in decreasing postmenopausal problems.

Soy and Calcium Supplementation Reduces Postmenopausal Problems

This was a purposive randomized intervention trial which assessed the occurrence of postmenopausal symptoms/ problems and effectiveness of soy protein isolate and calcium supplementation on overcoming these symptoms in 100 postmenopausal subjects. Questionnaire cum interview schedule was used to collect required information and intervention trials were carried out for a period of 100 days each. Large number of subjects reported a variety of problems associated with menopause. Somatic complaints were reported by 49.43% to 70.78% of the women and were significantly (p<0.05) more prevalent than psychological complaints (17.97% to 98.87%) and urogenital problems. Majority of the subjects (83.14%) had moderate degree of problems. Soy protein isolate intervention was effective in reducing most of the somatic problems in 8.00% to 58.82% of the subjects. Maximum improvement was reported on flushes, heart problems and sleep disturbances. Calcium supplementation was effective in reducing mainly joint pain in the subjects (57.89%). Thus, dietary interventions in the form of soy protein isolate and calcium help in decreasing postmenopausal problems.

Genistein in the Metabolic Syndrome: Results of a Randomized Clinical Trial

This study was performed to evaluate the effects of genistein on metabolic and cardiovascular risk factors in Caucasian postmenopausal subjects with metabolic syndrome (MetS). Our objective was to assess the effects of genistein on surrogate endpoints associated with diabetes and cardiovascular disease. This was a randomized, double-blind, placebo-controlled trial at 3 university medical centers in Italy. Patients included 120 postmenopausal women with MetS according to modified Third Report of the National Cholesterol Education Program (NCEP), Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) criteria. After a 4-week stabilization period, postmenopausal women with MetS were randomly assigned to receive placebo (n = 60) or 54 mg genistein daily (n = 60) for 1 year. The primary outcome was homeostasis model assessment for insulin resistance (HOMA-IR) at 1 year. Secondary outcomes were fasting glucose, fasting insulin, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, visfatin, adiponectin, and homocysteine levels. Data on adverse events were also recorded. At 1 year in genistein recipients, fasting glucose, fasting insulin, and HOMA-IR (mean from 4.5 to 2.7; P < .001) decreased and were unchanged in placebo recipients. Genistein statistically increased HDL-C (mean from 46.4 to 56.8 mg/dL) and adiponectin and decreased total cholesterol, LDL-C (mean from 108.8 to 78.7 mg/dL), triglycerides, visfatin, and homocysteine (mean from 14.3 to 11.7 μmol/L) blood levels. Systolic and diastolic blood pressure was also reduced in genistein recipients. Genistein recipients neither experienced more side adverse effects than placebo nor discontinued the study. One year of treatment with genistein improves surrogate endpoints associated with risk for diabetes and cardiovascular disease in postmenopausal women with MetS.

Interaction of Metabolic Syndrome with Asthma in Postmenopausal Women: Role of Adipokines

The increasing prevalence of both asthma and obesity are major health problems. Recent studies established a possible link between obesity and asthma; however, the underlying mechanism is not clear. The aim of the study was to analyze the prevalence of metabolic syndrome in postmenopausal subjects with asthma and search the interactions between adipokines, metabolic syndrome, and asthma. A total of 45 female patients (57.5 ± 13.9 years) with asthma and 30 healthy subjects (59.6 ± 12.8 years) in postmenopausal status were enrolled in this study. For the diagnosis of metabolic syndrome, modified World Health Organization diagnostic criteria were used. Blood levels of glucose, lipid profile, HbA1c, insulin, CRP, leptin, adiponectin, tumor necrosis factor-alpha, interleukin (IL)-6, IL-8 and plasminogen activator inhibitor-1 (PAI-1) were measured. The mean body mass index was 29.6 ± 5.4 for asthma patients and 28.2 ± 5.3 for the control group. The incidence of metabolic syndrome was found as 26 % for both groups. Insulin resistance as calculated by homeostasis model assessment (HOMA-IR) and fasting insulin levels were significantly higher in asthma patients (p < 0.001 for both parameters). Leptin levels were significantly higher (p = 0.001) and adiponectin levels were lower (p = 0.029) in asthma patients compared to controls. We concluded that although incidence of obesity and metabolic syndrome was not higher in postmenopausal asthma patients than controls, there was an impairment of glucose metabolism and altered adipokine levels in asthma patients.

Comparison of two multimarker serum tests for the prediction of ovarian cancer in women with a pelvic mass.

5555 Background: Distinguishing between benign and malignant disease in women with a pelvic mass is difficult. OVA1 and ROMA are two multi-marker serum tests that are FDA-cleared to assess risk of malignancy in individuals with a pelvic mass. This study compared the accuracy of these tests for the prediction of ovarian cancer (OCa) in women with a pelvic mass. Methods: OVA1 and ROMA risk scores were determined in a subset of 146 serum samples obtained prospectively from pelvic mass patients. Patients were categorized by an initial cancer risk assessment (ICRA) performed by a physician and true cancer status determined surgically. 31 patients with malignancy (6 with a benign ICRA) and 115 patients with benign disease (25 with a malignant ICRA) were evaluated. Quest Diagnostics performed the OVA1 tests (CA-125, prealbumin, apolipoprotein A-1, β2-microglobulin, transferrin) and calculated and interpreted the risk score. ROMA tests (CA-125 and HE-4) were determined by automated immunoassay using an Abbott Architect analyzer. ROMA risk scores were calculated using published formulas and interpreted against cutpoints previously established for automated CA-125 and HE-4 performed by manual ELISA. Results: There were 70 pre- and 76 post-menopausal subjects. Of the 31 with malignancy, 26 had OCa (54% &gt;stage II), 5 with an ICRA of benign. ROC curve analysis of the entire cohort produced an AUC of 0.88 (95% CI 0.80-0.95) and 0.93 (95% CI 0.87-0.99) for OVA1 and ROMA, respectively. OVA1 had a sensitivity of 0.97 and a specificity of 0.55. ROMA had a sensitivity of 0.84 and a specificity of 0.83. The sensitivity of OVA1 for OCa in the ICRA benign cohort (N = 5) was 0.80 and for ROMA was 0.40. The respective specificity for benign disease in this cohort (N=90) was 0.64 and 0.90. The sensitivity of ROMA for OCa increased to 0.60 with a slight decrease in specificity (0.87) when a cutpoint determined by ROC curve analysis was used. Conclusions: Overall, OVA1 and ROMA have similar performance characteristics. In women with an ICRA of benign, OVA1 was more sensitive among those who had OCa but ROMA was more specific among those who did not. The use of a ROMA cutpoint specific for the combination of automated CA-125 and HE-4 tests improved sensitivity.

Pharmacokinetics of omeprazole and its metabolites in premenopausal and postmenopausal females

The pharmacokinetic (PK) of omeprazole (OMP), 5-hydroxy-omeprazole (5-OH-OMP) and omeprazole sulphone (OMP-SUL), was investigated in healthy premenopausal and postmenopausal females. A single oral dose, open-label, non-controlled, pharmacokinetic study was conducted in healthy premenopausal (n = 16) and postmenopausal (n = 8) females. The samples were analyzed using reversed phase high performance liquid chromatography (HPLC), different pharmacokinetics (PK) parameters were determined and compared statistically to evaluate the difference between two groups. The activities of CYP2C19 and CYP3A4 were determined as AUCOMP/AUCOH-OMP and AUCOMP /AUCOMP-SUL, respectively. The significant differences (P < 0.05) between Cmax, tmax, [AUC]to, [AUC]ooo, t1/2 and metabolic ratios (MR) of OMP, 5-OH-OMP and OMP-SUL were observed between premenopausal and postmenopausal females. The present studies showed the higher AUC and longer t1/2 in postmenopausal subjects. The increase in MR for 5–OH-OMP and also OMP-SUL determined as AUCOH-OMP/AUCOMP and AUCOMP-SUL/AUCOMP, respectively, was also observed in postmenopausal females compared with the premenopausal females. Key words: Omeprazole, pharmacokinetics, menopause.

Effects of total bilirubin on the prevalence of osteoporosis in postmenopausal women without potential liver disease

It is still uncertain whether total bilirubin per se is a risk factor for osteoporosis in postmenopausal women and no study has so far examined this important issue. This study was designed to assess the sheer effects of total bilirubin on the prevalence of osteoporosis in postmenopausal women without potential liver disease. In the present study, postmenopausal female subjects without potential liver disease (n=918) who underwent measurement of bone mineral density were enrolled. Correlation and logistic regression analysis were used to assess the relationship between total bilirubin and other variables. As a result, subjects with osteoporosis had a significantly lower total bilirubin level (P=0.005). A 0.1mg/dl increase in total bilirubin was associated with reduced odds ratio of the risk by 38% for osteoporosis [OR 0.62 (95% CI 0.52-0.88), P=0.012] after adjustment for several variables. Total bilirubin was independently associated with BMD [coefficient=0.41, 95% CI (0.35-0.47), P<0.001 for lumbar spine and coefficient=0.44, 95% CI (0.36-0.48), P<0.001 for femur neck]. A positive correlation could be observed with significant difference between total bilirubin and z-score (r=0.33, P<0.001 for lumbar spine and r=0.37, P<0.001 for femur neck) and total bilirubin was positively correlated with serum calcium (r=0.13, P<0.001) as well. Therefore, this study demonstrates an independent inverse association between total bilirubin and the prevalence of osteoporosis in postmenopausal women without potential liver disease. Total bilirubin would be useful as a provisional new risk factor of osteoporosis in such a population.

Variations in the PDCD6 Gene Are Associated with Increased Uterine Leiomyoma Risk in the Chinese

Programmed cell death 6 (PDCD6) participates in T cell receptor, Fas, and glucocorticoid-induced programmed cell death. To test the relationship between PDCD6 polymorphisms and uterine leiomyomas (UL) risk, we investigated the association of two SNPs (rs4957014 and rs3756712) in PDCD6 with UL risk in a case-control study of 295 unrelated premenopausal UL patients and 436 healthy postmenopausal control subjects in a population of China. Genotypes of the two SNPs were determined with the use of PCR-restriction fragment length polymorphism assay. Significantly increased UL risks were found to be associated with the T allele of rs4957014 and the T allele of rs3756712 (p=0.016, odds ratio [OR]=1.325, 95% confidence intervals [CI]=1.053-1.668 for rs4957014; p<0.0001, OR=1.898, 95% CI=1.457-2.474 for rs3756712, respectively). Increased UL risks were associated with them in different genetic models. The present study provided evidence that rs4957014 and rs3756712 are associated with UL risk, the results indicated that genetic polymorphisms in PDCD6 may contribute to the development of UL.

The Sublingual Glycocalyx : A Novel Noninvasive Predictor of Coronary Artery Disease in Females

The glycocalyx (GC) provides in healthy blood vessels limited access to flowing red blood cells (RBC). Recent studies have suggested that RBCs penetrate deeper into a damaged GC, which has been associated with microcirculatory dysfunction that accompanies coronary artery disease (CAD). We hypothesize that the presence of CAD could be predicted by measuring the dimension of the RBC perfused boundary region (PBR), the space between median RBC column width and the outer edge of RBC permeable vascular lumen. In healthy vessels PBR is relatively small due to limited penetration of RBC into the GC and it is hypothesized that PBR will increase when GC is damaged. We used sidestream dark field imaging of the sublingual microvasculature in post‐menopausal female subjects with angiographic CAD (N=10) and healthy controls (N=15). From these images, PBR was determined in over 3000 vascular segments (diameter 5–30 μm) per subject. The mean PBR increased from 2.08 ± 0.07 μm to 2.34 ± 0.08 μm (P&lt;0.05) comparing controls with CAD patients, respectively. These data demonstrate that CAD patients have a significant increase in the RBC accessible component of the sublingual microvascular GC compared to control subjects. A wider permeable portion of the GC indicates a change in GC structure which may be associated with a reduced vascular protective function of the GC. Supported by AHA 12POST9400001 and NIH K08 1 K08 HL086730–01

Single dose pharmacokinetics and bioequivalence of conjugated estrogens (0.625 mg × 2) tablets in healthy post-menopausal female subjects in fasting and fed studies

AbstractConjugated estrogens are sulfate esters of naturally occurring estrogens. The pharmacokinetics of various estrogen formulations is complex and varying due to its endogenous availability. The present studies were designed to evaluate pharmacokinetic parameters and bioequivalence between two formulations of conjugated estrogens (0.625 mg tablets). Both the studies were designed as two-treatment, four-period, replicate cross-over single dose studies in 60 healthy post-menopausal female subjects under fasting and fed conditions, respectively. Since estrone is present endogenously, for baseline correction three pre-dose samples were obtained for total and unconjugated estrone. Plasma samples were analyzed by validated LC-MS/MS method and pharmacokinetic parameters were estimated for total and unconjugated forms of both estrone and equilin. The least square mean ratios and its 90% confidence interval for primary pharmacokinetic parameters Cmax, AUC0–t and AUC0–inf were found to be within bioequivalence ...

Sclerostin and DKK1 in Primary Hyperparathyroidism

Bone formation is influenced by the Wnt pathway through effects on osteoblast functionality, and these actions are opposed by two antagonists: sclerostin and Dickkopf-1 (DKK1). Decreased levels of serum sclerostin were found after treatment with the PTH analogue teriparatide and in patients with primary hyperparathyroidism (PHPT), while treatment with teriparatide of postmenopausal osteoporosis is associated with increases in serum DKK1. We studied mineral metabolism and Wnt pathway in 21 postmenopausal women affected by PHPT and in 42 age-matched healthy women. Mean serum calcium and PTH were significantly higher and serum phosphates significantly lower in the PHPT group compared with the control group. Serum 25-OH-vitamin D (25OHD) was lower in PHPT patients and 1,25 dihydroxy-vitamin D [1,25(OH)2D] was significantly higher. Patients with PHPT had significantly higher levels of bone alkaline phosphatase (BAP) and of serum C-terminal telopeptides of type I collagene (sCTX). Serum sclerostin in PHPT was significantly lower (-26 %) and serum DKK1 significantly higher (+57 %) than in healthy control subjects. Serum PTH was positively correlated with 1,25OH2D (p < 0.001), BAP (p = 0.036), sCTX (p = 0.003), and DKK1 (p = 0.007) and negatively with 25OHD (p = 0.002) and sclerostin (p = 0.02). In PHPT patients, serum sclerostin was negatively correlated with BAP (p = 0.038) and sCTX (p = 0.07). Patients with PHPT have significantly lower sclerostin and higher DKK1 levels compared with healthy postmenopausal control subjects. Further studies are warranted in order to verify whether the balance between these two opposite effects on Wnt function might help explain the variable bone involvement among patients with PHPT.

Relationship between Serum Uric Acid Level and Nonalcoholic Fatty Liver Disease in Pre- and Postmenopausal Women

Background/Aims: Nonalcoholic fatty liver disease (NAFLD) is an emerging health problem worldwide. No study specifically examining the relationship between serum uric acid level (UA) and NAFLD in females according to menopausal status has been reported. We conducted this study in order to assess the association of UA with NAFLD in pre- and postmenopausal women. Methods: A total of 487 female subjects (221 premenopausal and 266 postmenopausal) with a normal UA, who underwent a health check-up, were enrolled in this study. NAFLD was defined as a hepatic steatosis observed on liver ultrasonography in the absence of a secondary cause. Results: Among postmenopausal women, a higher UA was observed in subjects with NAFLD than in those without (3.95± 0.10 vs. 4.38 ± 0.80 mg/dl, p = 0.001). Results of multiple correlation analysis revealed a significant association between UA and NAFLD in postmenopausal subjects after adjusting for confounding variables including age, body mass index and the presence of metabolic syndrome (β coefficient 1.149, 95% confidence interval 1.055–1.910, p = 0.021). However, no association in premenopausal women was observed. Conclusions: UA within the normal range showed an association with NAFLD, not in premenopausal women, but in postmenopausal women. Postmenopausal women with increased levels of serum uric acid were more likely to have NAFLD than those without increased levels.

Worse Renal Disease in Postmenopausal F2[Dahl S x R]-Intercross Rats: Detection of Novel QTLs Affecting Hypertensive Kidney Disease

The prevalence of hypertension increases after menopause with 75% of postmenopausal women developing hypertension in the United States, along with hypertensive end organ diseases. While human and animal model studies have indicated a protective role for estrogen against cardiovascular disease and glomerulosclerosis, clinical studies of hormone replacement therapy in postmenopausal women have shown polar results with some improvement in hypertension but worsening of hypertensive kidney disease, or no effect at all. These observations suggest that the pathogenesis of postmenopausal hypertension and its target organ complications is more complex than projected, and that loss of endogenous estrogens induces epigenetic changes that alter genetic susceptibility to end-organ complications per se resulting in pathogenetic mechanisms beyond correction by hormone replacement. We studied postmenopausal-induced changes in renal disease and performed a total genome scan for quantitative trait loci (QTLs) affecting kidney disease in postmenopausal 16m-old F2[Dahl S x R]-intercross female rats. We used glomerular injury score (GIS) as quantitative trait. We compared QTLs amongst premenopausal, ovariectomized and postmenopausal F2[Dahl S x R]-intercross rats using identical phenotype characterization. Postmenopausal F2[Dahl S x R]-intercross rats exhibited increased hypertensive glomerulosclerosis (P<0.01) and equivalent levels of kidney disease when compared to premenopausal and ovariectomized F2[Dahl S x R]-intercross rats respectively. We detected three significant to highly significant GIS-QTLs (GIS-pm1 on chromosome 4, LOD 3.54; GIS-pm2 on chromosome 3, LOD 2.72; GIS-pm3 on chromosome 5, LOD 2.37) and two suggestive GIS-QTLs (GIS-pm4 on chromosome 2, LOD 1.70; GIS-pm5 on chromosome 7, LOD 1.28), all of which were unique to this postmenopausal population. Detection of increased renal disease phenotype in postmenopausal and ovariectomized subjects suggests a protective role of ovarian hormones. Furthermore, the detection of distinct GIS-QTLs in postmenopausal intercross female rats suggests that distinct genetic mechanisms underlie hypertensive glomerulosclerosis in premenopausal and postmenopausal states.

Optical imaging correlates with magnetic resonance imaging breast density and revealscomposition changes during neoadjuvant chemotherapy

IntroductionIn addition to being a risk factor for breast cancer, breast density has been hypothesized to be a surrogate biomarker for predicting response to endocrine-based chemotherapies. The purpose of this study was to evaluate whether a noninvasive bedside scanner based on diffuse optical spectroscopic imaging (DOSI) provides quantitative metrics to measure and track changes in breast tissue composition and density. To access a broad range of densities in a limited patient population, we performed optical measurements on the contralateral normal breast of patients before and during neoadjuvant chemotherapy (NAC). In this work, DOSI parameters, including tissue hemoglobin, water, and lipid concentrations, were obtained and correlated with magnetic resonance imaging (MRI)-measured fibroglandular tissue density. We evaluated how DOSI could be used to assess breast density while gaining new insight into the impact of chemotherapy on breast tissue.MethodsThis was a retrospective study of 28 volunteers undergoing NAC treatment for breast cancer. Both 3.0-T MRI and broadband DOSI (650 to 1,000 nm) were obtained from the contralateral normal breast before and during NAC. Longitudinal DOSI measurements were used to calculate breast tissue concentrations of oxygenated and deoxygenated hemoglobin, water, and lipid. These values were compared with MRI-measured fibroglandular density before and during therapy.ResultsWater (r = 0.843; P < 0.001), deoxyhemoglobin (r = 0.785; P = 0.003), and lipid (r = -0.707; P = 0.010) concentration measured with DOSI correlated strongly with MRI-measured density before therapy. Mean DOSI parameters differed significantly between pre- and postmenopausal subjects at baseline (water, P < 0.001; deoxyhemoglobin, P = 0.024; lipid, P = 0.006). During NAC treatment measured at about 90 days, significant reductions were observed in oxyhemoglobin for pre- (-20.0%; 95% confidence interval (CI), -32.7 to -7.4) and postmenopausal subjects (-20.1%; 95% CI, -31.4 to -8.8), and water concentration for premenopausal subjects (-11.9%; 95% CI, -17.1 to -6.7) compared with baseline. Lipid increased slightly in premenopausal subjects (3.8%; 95% CI, 1.1 to 6.5), and water increased slightly in postmenopausal subjects (4.4%; 95% CI, 0.1 to 8.6). Percentage change in water at the end of therapy compared with baseline correlated strongly with percentage change in MRI-measured density (r = 0.864; P = 0.012).ConclusionsDOSI functional measurements correlate with MRI fibroglandular density, both before therapy and during NAC. Although from a limited patient dataset, these results suggest that DOSI may provide new functional indices of density based on hemoglobin and water that could be used at the bedside to assess response to therapy and evaluate disease risk.

Case-Control Study on the Fibroblast Growth Factor Receptor 2 Gene Polymorphisms Associated with Breast Cancer in Chinese Han Women

PurposeGenetic variation in fibroblast growth factor receptor 2 (FGFR2) is a newly described risk factor for breast cancer. This study aimed to evaluate the association of four single nucleotide polymorphisms (SNPs) in FGFR2 with breast cancer in Han Chinese women.MethodsTwo hundred three women with breast cancer and 200 breast cancer-free age-matched controls were selected. Four SNPs (rs2981579, rs1219648, rs2420946, and rs2981582) and their haplotypes were analyzed to test for their association with breast cancer susceptibility. The presence of the four FGFR2 SNPs was determined by polymerase chain reaction-restriction fragment length polymorphism analysis.ResultsA statistically significant difference was observed in the frequency of rs2981582 in the FGFR2 gene (p<0.05) between case and control groups. In subjects stratified by menopausal status, rs2981582 TT, rs2420946 AA, and rs1219648 CC were significantly associated with the risk of breast cancer in postmenopausal subjects, but no significant associations between these four SNPs and the risk of breast cancer were identified in premenopausal subjects. Further, there was no significant association between hormone receptor status (estrogen receptor and progesterone receptor) and breast cancer risk. Six common (> 3%) haplotypes were identified. Three of these haplotypes, CGTC (odds ratio [OR], 0.613; 95% confidence interval [CI], 0.457-0.82; p=0.001), TGTC (OR, 6.561; 95% CI, 2.064-20.854; p<0.001), and CATC (OR, 12.645; 95% CI, 1.742-91.799; p=0.001) were significantly associated with breast cancer risk.ConclusionOur findings indicated that the SNP rs2981582 and haplotypes CGTC, TGTC, and CATC in FGFR2 may be associated with an increased risk of breast cancer in Han Chinese women.

A comparative study of lipid profile and oestradiol in pre- and post-menopausal women.

To investigate the relationship between the menopausal status and related hormonal variation of oestradiol with plasma lipid concentrations. Fifty premenopausal women and fifty postmenopausal women subjects were selected. Data was collected through clinical evaluation from questionnaires and laboratory investigations. Plasma oestradiol and lipid profile determinations were done by using competitive binding immunoassay methods and enzymatic methods respectively. Student's T test and Pearson's test of correlation were used for the statistical analysis. P-values of < 0.05 were considered to be statistically significant. There was a significant increase in serum Total Cholesterol (TC), Triglycerides (TG), LDL-cholesterol and VLDL-cholesterol levels in post-menopausal women. HDL-cholesterol level was significantly decreased in post-menopausal women. The calculated atherogenic index (Total Cholesterol/HDL ratio) was significantly increased in post-menopausal women as compared to that in premenopausal women. Oestradiol concentration was significantly lower (p<0.001) in post-menopausal women. Oestrogen changes the vascular permeability by increasing nitrous oxide production. It maintains a healthy lipoprotein profile. It stabilizes the endothelial cells, enhances antioxidant effect and alters fibrinolysis protein. All these cardioprotective mechanisms are lost in menopause. Postmenopausal women develop an increased risk for cardiovascular disease. Menopause leads to changes in lipid profile by reducing HDL, and elevating Total Cholesterol (TC), triglycerides (TG), LDL-cholesterol and VLDL-cholesterol, thus increasing the risk for cardiovascular disease. These changes are caused by reduced oestrogen concentrations which are seen in menopause.