Postmenopausal Controls Research Articles

Dietary patterns and breast cancer risk in Asian American women

Background: The role of diet as a cause of breast cancer in Asian Americans has not been adequately studied.Objective: We investigated the association between dietary patterns and breast cancer risk in Asian Americans.Design: This population-based case-control study in Los Angeles County compared dietary patterns between 1248 Asian American women with incident breast cancer and 1148 age-, ethnicity-, and neighborhood-matched controls. The relation between dietary patterns and serum concentrations of estrogens, androgens, and sex hormone–binding globulin (SHBG) was investigated in 2172 postmenopausal control women.Results: We used a scoring method proposed by Trichopoulou et al (1) and found that adherence to a Mediterranean diet was inversely associated with risk; the odds ratio (OR) was 0.65 (95% CI: 0.44, 0.95) in women with the highest scores (=8; most adherent) compared with those with the lowest scores (0–3; P for trend = 0.009), after adjustment for key covariates. We also used factor analysis and identified 3 dietary patterns (Western-meat/starch, ethnic-meat/starch, and vegetables/soy). In a combined index of the 3 patterns, women who were high consumers of Western and ethnic meat/starch and low consumers of the vegetables/soy diets showed the highest risk (OR: 2.19; 95% CI: 1.40, 3.42; P for trend = 0.0005). SHBG concentrations were 23% lower in women with a high intake of the meat/starch pattern and a low intake of the vegetables/soy pattern than in those with a low intake of the meat/starch pattern and a high intake of the vegetables/soy pattern (P for trend = 0.069).Conclusion: Our results suggest that a diet characterized by a low intake of meat/starches and a high intake of legumes is associated with a reduced risk of breast cancer in Asian Americans.

Hormone replacement therapy in women with systemic lupus erythematosus and risk of cardiovascular disease

We sought to determine the impact of hormone replacement therapy (HRT) on the occurrence of coronary artery disease (CAD) in women with systemic lupus erythematosus (SLE). Women in the University of Toronto lupus database who had taken HRT with no history of CAD were compared with all post-menopausal female patients with no history of HRT or CAD. Chi-squared and t-tests were used to compare the risk factors of CAD and Kaplan-Meier curve, log rank test and proportional hazard model with time-dependent covariates were used to compare the time from entry into the clinic to occurrence of CAD. A total of 114 HRT-user patients with no history of CAD were compared with 227 post-menopausal non-HRT user SLE controls. The groups were similar with respect to lupus anticoagulant, antiphospholipid antibody, cumulative steroid dose and classic cardiac risk factors. A similar percentage of patients developed CAD in the control (13.7%) and HRT (11.4%) groups. There was no difference in the time to development of CAD. In the multivariate analysis, HRT was not a risk factor for CAD. Only age (P = 0.0001, HR = 1.11, 95% CI = 1.05, 1.17) and SLEDAI-2K (P = 0.0001, HR = 1.10, 95% CI = 1.05, 1.16) were significantly associated with the risk of CAD. In this small group of patients with SLE, HRT alone did not appear to predispose to CAD.

Serum total oxidative and antioxidative status in patients with postmenopausal osteoporosis in Gaziantep, Turkey

Objectives Osteoporosis is a musculoskeletal disorder characterized by low bone mass and deterioration of microarchitecture of the bone tissue, which leads to bone fragility with a resulting increase in fracture risk. Oxidative stress damages main structures of human organism such as protein, lipid, carbohydrates and DNA. In this study, we explored to determine the relationship between serum total oxidative/antioxidative capacity in postmenopausal women and healthy controls and the relationship between oxidative stress with bone mineral density and its role in the etiopathogenesis of osteoporosis. Design & Methods 56 postmenopausal osteoporotic and 55 healthy for a total of 111 women were included in this study. The mean age of patients and control groups were 59.79 ± 8.95 and 55.53 ± 8.32 respectively. Patients, who smoke cigarettes, had systemic metabolic diseases and used drugs were excluded from the study. Results There was no statistical difference in the oxidative capacity between two groups, but the total antioxidative capacity was lower in the disease group than in the healthy control group ( p Conclusion The total antioxidative capacity is affected in postmenopausal women, so increasing the antioxidants in diets of these women may be useful for the treatment.

Potential utility of high preoperative levels of serum type I collagen markers in postmenopausal women with primary hyperparathyroidism with respect to their short-term variations after parathyroidectomy

We evaluated short-term changes in serum amino-terminal procollagen propeptide (P1NP) and cross-linked C-terminal telopeptide (betaCTX) of type I collagen after parathyroidectomy (PTX) in 41 postmenopausal women with primary hyperparathyroidism (PHPT). Serum levels of 25-hydroxyvitamin D, intact PTH, calcium, phosphate, albumin, creatinine, P1NP, and betaCTX were measured before and 2 days after PTX. Their P1NP and betaCTX levels were compared with those measured in 41 normally menstruating and 30 postmenopausal controls. Fifteen of these 41 women had both pre-surgery P1NP and betaCTX concentrations above the upper limit noted in our postmenopausal controls [high turnover (HT) subgroup], while betaCTX levels were solely above the upper limit lastly mentioned in 11 women [high bone resorption (HBR) subgroup]. In addition, these two markers were within the postmenopausal control range in 12 of them [normal turnover (NT) subgroup]. A more significant decrease in postoperative betaCTX levels was observed in the 15 HT compared with the 12 NT PHPT women. The significant postoperative increase in P1NP levels observed in the 15 HT as well as in the 11 HBR was no longer significant in the 12 NT women. In conclusion, higher pre-surgery P1NP and betaCTX levels in post-menopausal PHPT women are associated with a preferential activation of bone formation over bone resorption after PTX.

Two-year Longitudinal Changes in Forearm Cortical Bone Geometry in Postmenopausal Women with Mild Primary Hyperparathyroidism without Parathyroidectomy

Several studies suggest that mild PTH excess does not have any deteriorative effects on bone mineral density (BMD) in several-year-longitudinal studies of patients with mild primary hyperparathyroidism (pHPT) without parathyroidectomy (PTX). However, it remains unknown about the change in bone geometry in pHPT patients without PTX. We examined the longitudinal effects of mild PTH excess on cortical bone geometry in postmenopausal patients with mild pHPT without PTX by using peripheral quantitative computed tomography (pQCT), and we compared them with normal and hypoparathyroidism women. Nine postmenopausal female patients who were diagnosed as pHPT, six postmenopausal female patients with hypoparathyroidism (3 idiopathic and 3 postoperative), and thirty postmenopausal control subjects participated in this study. Radial volumetric (v) BMD and several bone geometry parameters were measured by pQCT at basal line and after 2 years. Cortical vBMD was significantly lower in pHPT group. Moreover, total area and periosteal circumferences were significantly higher in pHPT group. Total and cortical vBMD were significantly decreased after 2 years in control group. However, they were stable in pHPT group after 2-year follow-up. As for bone geometry, cortical thickness and area were also stable in pHPT group during 2-year follow-up, although they were significantly reduced in control group and hypoparathyroidism group. In conclusion, the present longitudinal study revealed that there were no significant changes in radial vBMD and cortical bone geometry in postmenopausal women with mild pHPT, whereas age-related thinning of cortical bone as well as decrease of vBMD were observed in the control and patients with hypoparathyroidism.

Long-term consequences of polycystic ovary syndrome on cardiovascular risk

Most available data suggest that the prevalence of cardiovascular diseases in women with polycystic ovary syndrome (PCOS) is smaller than expected based on risk calculations during fertile years; therefore, more studies are needed on long-term cardiovascular consequences. Evidence is accumulating that postmenopausal women with PCOS have an increased risk of cerebrovascular events and cardiovascular morbidity. These events are partially related to persisting hyperandrogenism but are mostly correlated with excessive body weight (mainly visceral obesity); this suggests that our best long-term strategy is to ensure that women with PCOS are informed about their high risk for metabolic and cardiovascular diseases.

Estrogen therapy affects right hemisphere functioning in postmenopausal women

It has been suggested that hormone therapy (HT) in postmenopausal women differentially affects verbal and visuo-spatial abilities which mainly rely on left hemisphere (LH) and right hemisphere (RH) functioning, respectively. Thus, it seems likely that HT-related effects on cognition are driven by associated hormonal changes and their impact on functional brain organization, and functional cerebral asymmetries (FCAs) in particular. The present study investigated HT-related effects on FCAs in sixty-seven postmenopausal women who received hormone therapy either with estrogen (E) alone ( n = 14), an E-gestagen combination ( n = 22) or without HT (control group, n = 31). Saliva levels of free E and progesterone (P) were analyzed using chemiluminescence assays. FCAs were measured with the visual half-field (VHF) technique using a word matching and a figural comparison task. In agreement with previous results, a postmenopausal control group showed a left hemisphere (LH) advantage in the verbal task and a right hemisphere (RH) advantage in visuo-spatial processing. In contrast, both HT groups revealed significantly reduced FCAs in the figural comparison task as a result of an E-related decrease in RH performance. The findings suggest that E-therapy in postmenopausal women can affect visuo-spatial abilities by modulating the functional brain organization and RH functioning in particular.

TLR3 and TLR4 expression in healthy and diseased human endometrium

BackgroundToll-like receptors (TLRs) play an essential role in the innate immune system by initiating and directing immune response to pathogens. TLRs are expressed in the human endometrium and their regulation might be crucial for the pathogenesis of endometrial diseases.MethodsTLR3 and TLR4 expression was investigated during the menstrual cycle and in postmenopausal endometrium considering peritoneal endometriosis, hyperplasia, and endometrial adenocarcinoma specimens (grade 1 to 3). The expression studies applied quantitative RT-PCR and immunolabelling of both proteins.ResultsTLR3 and TLR4 proteins were mostly localised to the glandular and luminal epithelium. In addition, TLR4 was present on endometrial dendritic cells, monocytes and macrophages. TLR3 and TLR4 mRNA levels did not show significant changes during the menstrual cycle. In patients with peritoneal endometriosis, TLR3 and TLR4 mRNA expression decreased significantly in proliferative diseased endometrium compared to controls. Interestingly, ectopic endometriotic lesions showed a significant increase of TLR3 und TLR4 mRNA expression compared to corresponding eutopic tissues, indicating a local gain of TLR expression. Endometrial hyperplasia and adenocarcinoma revealed significantly reduced receptor levels when compared with postmenopausal controls. The lowest TLR expression levels were determined in poor differentiated carcinoma (grade 3).ConclusionOur data suggest an involvement of TLR3 and TLR4 in endometrial diseases as demonstrated by altered expression levels in endometriosis and endometrial cancer.

Association between low lean body mass and osteoporotic fractures after menopause

This study evaluated dual-energy x-ray absorptiometry-assessed whole-body bone-muscle relationship (bone mineral content/lean mass [BMC/LM]) as an indicator of its nonmechanical perturbations (ie, systemic) in pre- and postmenopausal women. A total of 3,205 women were studied, either healthy (no fracture [No Fx] groups, 1,035 premenopausal, 1,556 postmenopausal) or with recent fractures (Fx groups, 139 premenopausal, 475 postmenopausal) located at osteoporotic sites (hip, spine, long-bone metaphyses; Type II Fx, n = 386) or at other skeletal sites (Type I Fx, n = 228) to evaluate the impact of decreased muscle mass on fracture incidence before and after menopause. SD-scored graphs of BMC/LM proportionality were obtained from the No Fx groups as normal references. Based on the reference BMC versus LM curves obtained from their respective No Fx pre- and postmenopausal controls, BMC-LM SD scores were calculated for all women with fractures. BMC-LM SD scores in all premenopausal women with fractures and in Type I Fx postmenopausal women were similar to the reference. In contrast, SD scores in Type II Fx postmenopausal women were lower than the reference, especially in those with hip fractures. Except for Type II Fx postmenopausal women, all groups showed linear and similar BMC versus LM curves. Type II Fx postmenopausal women showed nonlinear relationships, with progressively decreasing BMC and BMC-LM SD scores as their LM decreased. Results suggest that both LM and BMC-LM SD scores can help to differentiate between systemic and mechanical (disuse-related) osteopenia/osteoporosis after menopause. Low LM values or BMC-LM SD scores seem to constitute additional fracture risk factors beyond those usually detected in premenopausal women or in women with other types of fractures. This application of dual-energy x-ray absorptiometry technology may lead to more effective diagnosis and treatment at low cost.

Gender dimorphism in body composition abnormalities in acromegaly: males are more affected than females

Acromegaly changes body composition (BC), but long-term gender differences have not been reported. To evaluate BC in active and controlled acromegalic patients. Clinical and biochemical variables and BC (by dual-energy X-ray absorptiometry) were evaluated in 60 acromegalic patients (19 active, 41 controlled) and 105 controls, matched for age and gender. Acromegalic males (n=24) had more total mass (89+/-13 vs 76.5+/-15.3 kg, P<0.001), lean body mass (LBM; 64.6+/-8.7 vs 56.4+/-5.8 kg, P<0.001), and bone mineral content (BMC; 2.9+/-0.5 vs 2.6+/-0.3 kg, P<0.05) than controls (n=33). Controlled male patients (n=14) had more total mass (89+/-14.7 vs 76.5+/-15.3 kg, P<0.05) and a trend to have more LBM (61.8+/-9.4 vs 56.4+/-5.8 kg, P=0.065) than controls. Only in active disease was a decrease in fat mass (FM) observed, compared with controlled patients and controls (males: 19.5+/-5.3 vs 27+/-6.2 and 25.9+/-4%, P<0.001; females: 30.3+/-6.7 vs 37.1+/-5.8 and 36.5+/-6.6%, P<0.01). In females, no further differences were observed. No differences in BMC were found between eugonadal and hypogonadal acromegalic patients, but in hypogonadal females, acromegaly appeared to prevent the BMC loss seen in hypogonadal postmenopausal controls. GH and IGF1 levels were negatively correlated with FM (males, P<0.05; females, P<0.001), but in the regression analysis GH was a predictor of FM only in women. Control of acromegaly reverts decreased FM in both genders; only in males more total mass and a trend for more LBM persist. The anabolic effect of GH on bone reverted in cured males, but persisted in females and appeared to override the bone loss of menopause.

Local topological analysis of densitometer-generated scan images of the proximal femur for differentiation between patients with hip fracture and age-matched controls

We evaluate densitometer-generated scan images of the proximal femur with respect to topological properties of bone mineral distribution patterns in selected regions of interest. In a population of 100 post-menopausal women, the method has a highly discriminative potential with a performance superior to standard densitometry. Results vary with anatomical location within the proximal femur. The objectives of the study were to evaluate densitometer-generated scan images of the proximal femur with respect to topological properties of bone mineral distribution patterns in selected regions of interest, to test the ability for differentiation between post-menopausal women hip fracture and controls, and to compare results with standard bone densitometry. We used dual-energy X-ray absorptiometry (DXA) to measure the femoral bone mineral density (BMD) of 100 post-menopausal women (73.4 +/- 12.2), 50 of whom had a recent hip fracture. Local bone mineral distribution in the scanner-generated images was analyzed in the standard DXA-regions of interest (ROIs; femoral neck, the shaft, the trochanteric area; and the total hip) using an optimized, local topological parameter MF2D. Performance of topological analysis and BMD was tested by receiver-operator characteristic and discriminant analysis. Area under the curve (AUC) for correct differentiation between patients with and without fractures by BMD in the different ROIs ranged from 0.64 to 0.71; AUC of regional density-pattern analysis varied between 0.79 and 0.84. Using multivariate statistical models, between 71% and 84% of patients were correctly identified as fracture/non-fracture cases by regional topological analysis, whereas BMD reached levels from 58% to 68%. Our analysis indicates that identification of patients with hip fracture by regional evaluation of density patterns varies with anatomical location within the proximal femur. In our study population, performance of the novel parameter was superior to densitometry.

Association of genetic polymorphisms in CYP19A1 and blood levels of sex hormones among postmenopausal Chinese women

Circulating estrogen levels have been related to the risk of several female cancers. Blood levels of estrogen are controlled by estrogen synthesis enzymes. Genetic variation of estrogen genes thus may influence circulating estrogen levels. We investigated the associations of genetic polymorphisms in CYP19A1, a critical gene involved in estrogen synthesis, with plasma levels of sex hormones among postmenopausal Chinese women. Included in this study were 345 postmenopausal community controls from a population-based case-control study conducted in Shanghai. Fasting blood samples from those women were measured for blood estradiol, estrone, estrone sulfate, and testosterone. A total of 19 genetic polymorphisms in CYP19A1 were genotyped using ABI7900 or PCR-restriction fragment length polymorphism methods. Differences in plasma levels of hormones by genotype were examined using variance analysis. The geometric means of plasma levels of estradiol, estrone, estrone sulfate, and testosterone were 10.1, 16.8, 969.0, and 202.9 pg/ml, respectively, for this study population. We found that plasma levels of estrone were associated with rs28566535 (P=0.0180), rs730154 (P=0.0141), and rs936306 (P=0.0274) in block 2. In the same block, the haplotype CGCTA was related to level of estrone (P=0.0064). Single nucleotide polymorphism rs1902584 in block 1 was associated with estradiol only in overweight postmenopausal women. No clear association with sex hormones was noted for the other genetic polymorphisms evaluated in the study. Single nucleotide polymorphisms in blocks 1 and 2 of the CYP19A1 gene are related to plasma levels of estrogen among postmenopausal Chinese women and may therefore play an important role in the etiology of hormone-related cancers.

The catechol- O-methyltransferase (COMT) gene polymorphism and prevalence of uterine fibroids

Objective To assess the possible association between the catechol- O-methyltransferase (COMT) polymorphism and uterine fibroids in Brazilian women. Design Case-control study. Setting Department of Gynecology; teaching hospital. Patient(s) One hundred twenty-four premenopausal women with fibroids, and 193 postmenopausal controls not presenting the disease. Intervention(s) The subjects were classified as white or non-white (black and mulatto), and COMT genotypes were determined. DNA was extracted from the uterus of cases and from peripheral blood of controls and submitted to polymerase chain reaction (PCR) and agarose gel electrophoresis. Main outcome measure(s) The presence of the COMT polymorphism was recorded for all patients, and the frequency and distribution among cases and controls were compared according to race. Binomial log regression models were used to estimate odds-ratios (OR) for uterine volumes of <290 cm 3 (small fibroids) vs. those >290 cm 3 (large fibroids). Potential confounding variables (age, race and parity) were added to the model. Results Genotypes positive for the COMT polymorphism (heterozygous or mutant homozygous) were found in 45% of white and 28.9% of non-white women ( p = .013) and the polymorphic allele frequencies in these groups were 27.2% and 16.3%, respectively ( p = .006). However, there were no clear differences between patients and controls within the white subgroup with regard to the presence of COMT polymorphism-containing genotypes (41.5% vs. 46.0%, respectively) ( p = .60), or for the polymorphic allele frequency (26.8% vs. 27.3%, respectively) ( p = .92). For non-white women, there were also no differences between cases and controls for the frequency of polymorphic genotypes (28.9% vs. 28.9%, respectively) ( p = .995), or for the polymorphic allele frequency (17.8 vs. 14.5, respectively) ( p = .565). Estimated OR for small or large fibroids in association with the polymorphic allele revealed a positive association between the allele with lower activity and large fibroids (vs. small) (OR = 3.3; 95% confidence interval [CI] = 1.31–8.46). The adjusted OR was 4.35 (95% confidence interval [CI] = 1.58–11.9). Conclusions The catechol- O-methyltransferase polymorphism is a risk factor for the development of large uterine fibroids in Brazilian women suffering from fibroids.

Detection of antibodies to ovarian antigens in women with premature ovarian failure.

Premature ovarian failure is a common condition of uncertain aetiology in most cases, although autoimmunity is thought to play a role in a proportion of cases. The frequency of ovarian antibodies, which may be markers for an autoimmune aetiology in this condition, remains unclear. To define this further, we have examined the sera of 45 women with premature ovarian failure (five with iatrogenic ovarian failure, nine with an associated autoimmune disease, and 27 with idiopathic ovarian failure), as well as four women with infertility due to Turner's syndrome and 41 pre- and post-menopausal controls. Using two human ovarian antigen preparations, 24% and 60% of the ovarian failure patients reacted in an ELISA (P < 0.05 and P < 0.001 compared with controls), but frequent cross-reactivity was found with fallopian tube antigens. The apparent aetiology of ovarian failure did not correlate with the presence of ovarian antibodies. Using bovine ovary as an antigen, there was a significant overall increase in binding by the ovarian failure patients, but this was almost identical to binding in an ELISA with bovine fallopian tube. In contrast to a previous report, there was no significant increase of binding to soluble or Triton-extracted membrane fractions of bovine corpora lutea containing the LH/hCG receptor by the patients with ovarian failure. These results suggest that ovarian antibodies are common in premature ovarian failure, but their specificity and pathogenic role are questionable.

Abstract 5814: Association between ADH1B and ADH1C haplotype tag SNPs and breast cancer risk, and the interaction with alcohol drinking

Abstract Alcohol consumption has been found to be associated with breast cancer with some consistency. Alcohol dehydrogenase is rate limiting in alcohol metabolism. We investigated the association of haplotype tag SNPs in ADH1B and ADH1C with breast cancer risk and the interaction with alcohol drinking in a population-based case control study (the WEB Study) conducted in western New York between 1996 and 2001. Genomic DNA and SNP genotyping was performed by allelic discrimination real time PCR for 991 cases and 1698 controls. Haplotype tag SNPs were selected from the Caucasian HapMap data. Lifetime alcohol consumption was queried by interview. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Backwards selection was employed to obtain the most parsimonious model starting with the full model with interactions. Two tag SNPs, rs1042026 in ADH1B and rs1614972 in ADH1C, were associated with risk for postmenopausal women. The ADH1B SNP rs1042026 located in the 3’UTR is in LD with several functional SNPs from ADH6, ADH1A, ADH1B and ADH1C. This SNP was in Hardy Weinberg equilibrium in the postmenopausal control and not in postmenopausal cases, which strengthens the evidence of association. This SNP showed evidence of significant interaction with alcohol consumption. The OR for postmenopausal breast cancer in women with both CC genotype and who consume alcohol versus without the AA genotype and who abstain was 1.94, 95%CI 1.13-3.30. In addition, we found evidence of a trend for dose response depending on the amount of alcohol consumption when alcohol consumption was examined in three categories of abstainers, low and high consumption (p=0.08). The ADH1C SNP rs1614972 located in intron 8 is in LD with other six nonsynonymous exonic SNPs including the functional I350V (rs698). There was an interaction with alcohol consumption with the presence of the CC genotype and risk conferring a protective effect varying inversely proportional with the drinking level (p=0.0092). Moreover, the CC genotype decreased the odds of breast cancer in women who consume alcohol versus those that abstain regardless of the menopausal status (OR=0.56, 95%CI 0.35-0.90). In conclusion, haplotype tag SNPs in ADH1B and ADH1C were associated with breast cancer risk especially in postmenopausal women, and showed evidence of significant interaction with alcohol consumption. Supported by the following grants: DAMD-17-03-1-0446, DAMD-17-00-1-0417 and NCI-RO1CA92040 Marian C. was supported by an AVON-AACR International Scholar in Breast Cancer Research award

C-Reactive Protein Is Elevated 30 Years After Eclamptic Pregnancy

Women with a history of preeclampsia or eclampsia (seizure during preeclamptic pregnancy) are at increased risk for cardiovascular disease after pregnancy for reasons that remain unclear. Prospective studies during pregnancy suggest that inflammation, dyslipidemia, and insulin resistance are associated with increased risk of preeclampsia. Elevated serum C-reactive protein (CRP >3 mg/L) is an indicator of inflammation and cardiovascular risk. We hypothesized that Icelandic postmenopausal women with a history of eclampsia would manifest higher concentrations of serum CRP than Icelandic postmenopausal controls with a history of uncomplicated pregnancies. We also asked whether elevated CRP is associated with the dyslipidemia and insulin resistance previously identified in this cohort. CRP, measured by high-sensitivity enzyme-linked immunoassay, was higher in women with prior eclampsia (n=25) than controls (n=28) (median mg/L [interquartile range]: 9.0 [0.9 to 13.2] versus 2.0 [0.3 to 5.1]; P<0.03). This difference remained significant after adjustment for body mass index, smoking, hormone replacement, and current age. Women with prior eclampsia clustered into either high CRP (range 8.97 to 40.6 mg/L, n=13) or lower CRP (median 1.0, range 0.05 to 3.77, n=12) subsets. The prior eclampsia/high CRP subset displayed significantly elevated systolic blood pressures, lower high-density lipoprotein (HDL) cholesterol, higher apolipoprotein B, and higher fasting insulin and homeostasis model of insulin resistance (HOMA) values compared to controls, whereas the prior eclampsia/low CRP subset differed from controls only by marginally increased apolipoprotein B. The triad of inflammation, low HDL, and insulin resistance may elevate risk for both preeclampsia/eclampsia and cardiovascular disease in later life.

Quantitative determination of progesterones and corticosteroids in human urine using gas chromatography/mass spectrometry: application to pelvic organ prolapse patients

A quantitative analytical method using gas chromatography/mass spectrometry (GC/MS) to determine urinary concentrations of eight progesterones and corticosteroids has been developed. After enzymatic hydrolysis with beta-glucouronidase/arylsulfatase, urine samples were extracted by simple one-step solid-phase extraction. Obtained extracts were derivatized with a mixture of N-methyl-N-(trimethylsilyl)trifluoroacetamide/ammonium iodide/dithiothreitol and determined by GC/MS in selected ion monitoring mode to increase the sensitivity. d(4)-Cortisol and d(9)-progesterone were used as internal standards for two different steroid groups. The linear correlation coefficient was in the range of 0.9913 to 0.9998 and recoveries were over 80% for all compounds. Precision and accuracy were in the range of 0.9-18.1 and 84.1-118.7%, respectively. The limit of quantitation (LOQ) was 10 ng/mL for 11-deoxycorticosterone and 21-deoxycortisol and 5 ng/mL for all other analytes. The developed method was successfully applied on pelvic organ prolapsed patients (n = 10, age: 67.9 +/- 4.9) and post-menopausal (n = 10, age: 63.6 +/- 5.5) control women. Urinary levels of most progesterones and corticosteroids except 11-deoxycorticosterone decreased but only that of 17 alpha-hydroxyprogesterone significantly decreased in patients compared with the control groups. Thus, it is concluded that progesterones could be a factor in the pathogenesis of pelvic organ prolapse, and, among them, 17 alpha-hydroxyprogesterone could be a biomarker for pelvic organ prolapse.

A comprehensive analysis of common genetic variation in prolactin (PRL) and PRL receptor (PRLR) genes in relation to plasma prolactin levels and breast cancer risk: the Multiethnic Cohort

BackgroundStudies in animals and humans clearly indicate a role for prolactin (PRL) in breast epithelial proliferation, differentiation, and tumorigenesis. Prospective epidemiological studies have also shown that women with higher circulating PRL levels have an increase in risk of breast cancer, suggesting that variability in PRL may also be important in determining a woman's risk.MethodsWe evaluated genetic variation in the PRL and PRL receptor (PRLR) genes as predictors of plasma PRL levels and breast cancer risk among African-American, Native Hawaiian, Japanese-American, Latina, and White women in the Multiethnic Cohort Study (MEC). We selected single nucleotide polymorphisms (SNPs) from both the public (dbSNP) and private (Celera) databases to construct high density SNP maps that included up to 20 kilobases (kb) upstream of the transcription initiation site and 10 kb downstream of the last exon of each gene, for a total coverage of 59 kb in PRL and 210 kb in PRLR. We genotyped 80 SNPs in PRL and 173 SNPs in PRLR in a multiethnic panel of 349 unaffected subjects to characterize linkage disequilibrium (LD) and haplotype patterns. We sequenced the coding regions of PRL and PRLR in 95 advanced breast cancer cases (19 of each racial/ethnic group) to uncover putative functional variation. A total of 33 and 60 haplotype "tag" SNPs (tagSNPs) that allowed for high predictability (Rh2 ≥ 0.70) of the common haplotypes in PRL and PRLR, respectively, were then genotyped in a multiethnic breast cancer case-control study of 1,615 invasive breast cancer cases and 1,962 controls in the MEC. We also assessed the association of common genetic variation with circulating PRL levels in 362 postmenopausal controls without a history of hormone therapy use at blood draw. Because of the large number of comparisons being performed we used a relatively stringent type I error criteria (p < 0.0005) for evaluating the significance of any single association to correct for performing approximately 100 independent tests, close to the number of tagSNPs genotyped for both genes.ResultsWe observed no significant associations between PRL and PRLR haplotypes or individual SNPs in relation to breast cancer risk. A nominally significant association was noted between prolactin levels and a tagSNP (tagSNP 44, rs2244502) in intron 1 of PRL. This SNP showed approximately a 50% increase in levels between minor allele homozygotes vs. major allele homozygotes. However, this association was not significant (p = 0.002) using our type I error criteria to correct for multiple testing, nor was this SNP associated with breast cancer risk (p = 0.58).ConclusionIn this comprehensive analysis covering 59 kb of the PRL locus and 210 kb of the PRLR locus, we found no significant association between common variation in these candidate genes and breast cancer risk or plasma PRL levels. The LD characterization of PRL and PRLR in this multiethnic population provide a framework for studying these genes in relation to other disease outcomes that have been associated with PRL, as well as for larger studies of plasma PRL levels.

Role of proteoglycans in the organization of periurethral connective tissue in women with stress urinary incontinence

Objectives Connective tissue consists of fibroblasts and extracellular matrix (ECM) with collagen and elastic fibers, glycoproteins and proteoglycans (PGs) and it is considered an important factor of the supportive structures of the genitourinary region. Since PGs are essential for the organization of the collagen fibrils in the ECM, we investigated the presence of two PGs, fibromodulin and lumican, and of collagen type I in the periurethral connective tissue from women with stress urinary incontinence (SUI), compared to asymptomatic controls. Methods Thirty-two patients participated in the study and they were divided into four groups: premenopausal incontinents, premenopausal controls, postmenopausal incontinents and postmenopausal controls. All patients underwent gynaecologic surgical procedures and punch biopsies from the periurethral tissue were obtained. Immunohistochemistry for collagen type I, fibromodulin and lumican was performed on the histological slides. Results In premenopausal incontinents the immunoreactivity for collagen type I was weaker with an irregular distribution compared to premenopausal controls; while for fibromodulin, the staining was stronger in premenopausal incontinents than in premenopausal controls. Between the two postmenopausal groups there was not a significant difference in the intensity of collagen type I and fibromodulin staining that instead were less strong than in premenopausal groups. Lumican staining had the same distribution in the four groups. Conclusions Our results suggest an altered remodelling of connective tissue in the periurethral region of premenopausal patients with SUI, with a significant decrease of collagen content and an irregular organization and distribution of the collagen fibrils, compared to premenopausal controls. In the SUI patients this abnormal ECM remodelling, mainly related to the observed change in PGs expression, might affect significantly the tensile strength of the connective tissue and consequently the support that is provided by the urogenital suspensory apparatus to urethra and bladder base. Moreover, the significant decrease in collagen type I content in postmenopausal patients respect to premenopausal patients, suggests that age and hormonal factors could contribute to the pathological modifications of the supportive genitourinary connective tissues in the SUI patients.

The breast of parous women without cancer has a different genomic profile compared to those with cancer

Our studies are aimed at determining whether pregnancy induces a specific genomic signature in the postmenopausal breast that is responsible for the protective effect elicited by this physiological process. For this purpose we designed a study to compare the gene expression profiles in normal breast tissue from parous postmenopausal women with (case) and without (control) breast cancer. We have used breast samples from 18 parous controls and 41 parous cases. The epithelium and the interlobular stroma were dissected using laser capture microdissection and the RNA of each compartment and each sample was isolated, amplified using PCR methodology, and hybridized to cDNA glass-microarrays containing 40,000 genes, placing the human reference RNA in the green channel (Cy3) and the breast tissue samples in the red channel (Cy5). The normalization and statistical analysis of the expression data were carried out by using the LIMMA software package for the R programming environment which provides functions to summarize the results using the linear model perform hypothesis tests and adjust the p-values for multiple testing. We were able to identify 126 genes that were upregulated and 103 that were downregulated in the parous control group. There were only 56 genes differentially expressed in the interlobular stroma in the parous control group in relation to the other group of women under study. The gene categories that were overrepresented in the breast epithelium of the parous control breast are related to apoptosis, DNA repair, response to exogenous agents and transcription regulation. In the present study we demonstrate that full-term pregnancy imprints a specific genomic signature in the breast epithelium of postmenopausal parous control women that is significantly different from women who have developed cancer. This genomic signature induced by pregnancy could help to predict in which women parity is protective.