GPER activation attenuates cardiac dysfunction by upregulating the SIRT1/3-AMPK-UCP2 pathway in postmenopausal diabetic rats.

Postmenopausal diabetic women are at higher risk to develop cardiovascular diseases (CVD) compared with nondiabetic women. Alterations in cardiac cellular metabolism caused by changes in sirtuins are one of the main causes of CVD in postmenopausal diabetic women. Several studies have demonstrated the beneficial actions of the G protein-coupled estrogen receptor (GPER) in postmenopausal diabetic CVD. However, the molecular mechanisms by which GPER has a cardioprotective effect are still not well understood. In this study, we used an ovariectomized (OVX) type-two diabetic (T2D) rat model induced by high-fat diet/streptozotocin to investigate the effect of G-1 (GPER-agonist) on sirtuins, and their downstream pathways involved in regulation of cardiac metabolism and function. Animals were divided into five groups: Sham-Control, T2D, OVX+T2D, OVX+T2D+Vehicle, and OVX+T2D+G-1. G-1 was administrated for six weeks. At the end, hemodynamic factors were measured, and protein levels of sirtuins, AMP-activated protein kinase (AMPK), and uncoupling protein 2 (UCP2) were determined by Western blot analysis. In addition, cardiac levels of oxidative stress biomarkers were measured. The findings showed that T2D led to left ventricular dysfunction and signs of oxidative stress in the myocardium, which were accompanied by decreased protein levels of Sirt1/2/3/6, p-AMPK, and UCP2 in the heart. Moreover, the induction of the menopausal state exacerbated these changes. In contrast, treatment with G-1 ameliorated the hemodynamic changes associated with ovariectomy by increasing Sirt1/3, p-AMPK, UCP2, and improving oxidative status. The results provide evidence of the cardioprotective effects of GPER operating through Sirt1/3, p-AMPK, and UCP2, thereby improving cardiac function. Our results suggest that increasing Sirt1/3 levels may offer new therapeutic approaches for postmenopausal diabetic CVD.

Daily blueberry consumption for 12 weeks improves endothelial function in postmenopausal women with above-normal blood pressure through reductions in oxidative stress: a randomized controlled trial.

Estrogen-deficient postmenopausal women have oxidative stress-mediated suppression of endothelial function that is exacerbated by high blood pressure. Previous research suggests blueberries may improve endothelial function through reductions in oxidative stress, while also exerting other cardiovascular benefits. The objective of this study was to examine the efficacy of blueberries to improve endothelial function and blood pressure in postmenopausal women with above-normal blood pressure, and to identify potential mechanisms for improvements in endothelial function. A randomized, double-blind, placebo-controlled, parallel-arm clinical trial was performed, where postmenopausal women aged 45-65 years with elevated blood pressure or stage 1-hypertension (total n = 43, endothelial function n = 32) consumed 22 g day-1 of freeze-dried highbush blueberry powder or placebo powder for 12 weeks. Endothelial function was assessed at baseline and 12 weeks through ultrasound measurement of brachial artery flow-mediated dilation (FMD) normalized to shear rate area under the curve (FMD/SRAUC) before and after intravenous infusion of a supraphysiologic dose of ascorbic acid to evaluate whether FMD improvements were mediated by reduced oxidative stress. Hemodynamics, arterial stiffness, cardiometabolic blood biomarkers, and plasma (poly)phenol metabolites were assessed at baseline and 4, 8, and 12 weeks, and venous endothelial cell protein expression was assessed at baseline and 12 weeks. Absolute FMD/SRAUC was 96% higher following blueberry consumption compared to baseline (p < 0.05) but unchanged in the placebo group (p > 0.05), and changes from baseline to 12 weeks were greater in the blueberry group than placebo (+1.09 × 10-4 ± 4.12 × 10-5vs. +3.82 × 10-6 ± 1.59 × 10-5, p < 0.03, respectively). The FMD/SRAUC response to ascorbic acid infusion was lower (p < 0.05) at 12 weeks compared to baseline in the blueberry group with no change in the placebo group (p > 0.05). The sum of plasma (poly)phenol metabolites increased at 4, 8, and 12 weeks in the blueberry group compared to baseline, and were higher than the placebo group (all p < 0.05). Increases in several plasma flavonoid and microbial metabolites were also noted. No major differences were found for blood pressure, arterial stiffness, blood biomarkers, or endothelial cell protein expression following blueberry consumption. These findings suggest daily consumption of freeze-dried blueberry powder for 12 weeks improves endothelial function through reduced oxidative stress in postmenopausal women with above-normal blood pressure. The clinical trial registry number is NCT03370991 (https://clinicaltrials.gov).

Association between equol producers and type 2 diabetes mellitus among Japanese older adults.

AIMS/INTRODUCTION: Equol, which is produced by enteric bacteria from soybean isoflavones, has a chemical structure similar to estrogen. Both in vivo and in vitro studies have shown the beneficial metabolic effects of equol. However, its effects on type 2 diabetes remain unclear. We investigated the association between the equol producers/non-producers and type 2 diabetes. MATERIALS AND METHODS: The participants included 147 patients with type diabetes mellitus aged 70-89 years, and 147 age- and sex-matched controls. To ascertain the equol producers or non-producers, we used the comparative logarithm between the urinary equol and daidzein concentrations (cut-off value -1.75). RESULTS: The urinary equol concentration was significantly lower in the diabetes group compared with the non-diabetes group (P = 0.01). A significant difference in the proportion of equol producers was observed among all participants (38.8% in the diabetes group and 53.1% in the non-diabetes group; P = 0.01). The proportion of equol producers among women was significantly lower in the diabetes group (31.4%) than in the non-diabetes group (52.8%; P < 0.01). Additionally, the frequency of dyslipidemia in female equol producers was significantly lower than that in female non-equol producers (P < 0.01). Among men, no such differences were observed. We found a significant positive correlation between the urinary equol and daidzein concentrations among equol producers (r = 0.55, P < 0.01). CONCLUSIONS: Our study findings showed that postmenopausal women had a low proportion of equol producers with diabetes and dyslipidemia.

Evaluation of the association between circulating IL-1ß and other inflammatory cytokines and incident atrial fibrillation in a cohort of postmenopausal women.

BACKGROUND: Inflammatory cytokines play a role in atrial fibrillation (AF). Interleukin (IL)-1ß, which is targeted in the treatment of ischemic heart disease, has not been well-studied in relation to AF. METHODS: Postmenopausal women from the Women's Health Initiative were included. Cox proportional hazards regression models were used to evaluate the association between log-transformed baseline cytokine levels and future AF incidence. Models were adjusted for body mass index, age, race, education, hypertension, diabetes, hyperlipidemia, current smoking, and history of coronary heart disease, congestive heart failure, or peripheral artery disease. RESULTS: Of 16,729 women, 3,943 developed AF over an average of 8.5 years. Racial and ethnic groups included White (77.4%), Black/African-American (16.1%), Asian (2.7%), American Indian/Alaska Native (1.0%), and Hispanic (5.5%). Baseline IL-1ß log continuous levels were not significantly associated with incident AF (HR 0.86 per 1 log [pg/mL] increase, P= .24), similar to those of other inflammatory cytokines, IL-7, IL-8, IL-10, IGF-1, and TNF-α. There were significant associations between C-reactive protein (CRP) and IL-6 with incident AF. CONCLUSIONS: In this large cohort of postmenopausal women, there was no significant association between IL-1ß and incident AF, although downstream effectors, CRP and IL-6, were associated with incident AF.

Influence of Nordic walking with poles with an integrated resistance shock absorber on carbohydrate and lipid metabolic indices and white blood cell subpopulations in postmenopausal women.

Background: Regular and individualised physical activities have been shown to prevent adverse changes associated with the aging process. The main purpose of this study was to evaluate changes in carbohydrate and lipid metabolism and white blood cell (WBC) subpopulations in postmenopausal women participating in Nordic walking (NW) training and to compare the use of poles with an integrated resistance shock absorber (RSA) with the use of classic poles. Materials & Methods: A total of 23 postmenopausal women participated in a 8-week programme of systematic physical activity between February and April. Before and after the training programme, somatic features and serum concentrations of 25-hydroxyvitamin D, glucose, and insulin, were assessed, as well as lipid profile and WBC count and its specific subpopulations. Results: Analysis of differences in somatic features and biochemical indices before and after training in the group of women who used RSA poles showed significant decreases in fat mass content (p < 0.05), insulin (p < 0.05), homeostatic model assessment of insulin resistance (p < 0.05), triglycerides (p < 0.05), total cholesterol (p < 0.05) and monocytes (p ≤ 0.01). In the group of women who used classic poles (NW), there was a significant decrease in WBC (p ≤ 0.01), lymphocytes (p < 0.05), monocytes (p ≤ 0.01) and granulocytes (p < 0.05). Conclusion: Increasing the training load through the use of RSA poles resulted in greater changes in carbohydrate and lipid metabolic indices compared to the use of classic NW poles. In turn, the more significant effect on WBC and its specific subpopulations count in the NW, compared to the RSA training programme, may indicate that specificity of training load is an important factor in modifying the immune system response.

Change in metabolic parameters and reproductive hormones from baseline to 6-month hormone therapy.

ABSTRACT: Adequate evidence showed hormone therapy (HT) reduces the risk of new-onset diabetes in midlife women by decreasing fasting glucose and insulin. However, the improvement of these diabetic biomarkers varied with each individual in clinical observations. The objective of our study was to investigate potential baseline factors associated with the change of fasting glucose and insulin during HT.A retrospective cohort study was performed among 263 midlife participants aged 40 to 60 years with menopausal symptoms who have received 6-month individualized HT. Demographic information and laboratory indicators including reproductive hormone, lipid profiles, diabetic indicators were collected and measured at baseline and were followed-up. A series of statistical analyses were performed to confirm the effectiveness of HT and compare the baseline factors between participants with different glycemic or insulinemic response. Multivariable linear regression model with stepwise variable selection was further used to identify the associated factor with the change of fasting glucose and insulin.Of all participants, fasting glucose (P = .001) and fasting insulin (P < .001) were significantly decreased after individualized HT. Significant differences in baseline reproductive hormones were observed in participants with different glycemic response to HT (P < .001 for both follicle stimulating hormone [FSH] and estradiol). Stepwise linear regression model showed that in addition to baseline fasting glucose levels, baseline FSH was also independently associated with the change of fasting glucose (ß = -0.145, P = .019 for baseline FSH) but not fasting insulin. Greater reduction in fasting glucose in women with higher FSH levels was observed even though they have already been in better metabolic conditions (P = .037).Midlife women with higher baseline FSH levels have greater reduction in fasting glucose but not fasting insulin. FSH could be an independent predictor of glycemic response to HT in peri- and postmenopausal women.

Relationship between Menopause and Complications of Hyperthyroidism in Female Patients in Iraq.

Hyperthyroidism is a health problem characterized by an overactive thyroid gland, resulting in extra triiodothyronine (T3) and thyroxine (T4) production, as well as a decrease in thyroid-stimulating hormone (TSH). The oxidative stress indicators in hyperthyroid patients and the relationship with impaired metabolism of lipid are still controversial, especially in menopausal women suffering from a lack of ovulation hormones. In this study, blood samples were withdrawn from 120 subjects, including healthy premenopausal (n=30) and postmenopausal women (n=30) as control groups (G1 and G2), as well as 30 hyperthyroid women in each group of premenopausal and postmenopausal patient groups (G3 and G4). The levels of T3, T4, and TSH, blood pressure, and lipid profiles, such as triglyceride, total cholesterol (TC), high-density lipoprotein, and low-density lipoprotein, superoxide dismutase (SOD) activity, malondialdehyde (MDA), and advanced oxidation protein products (AOPP) in the two healthy control groups and patient groups with hyperthyroidism were measured. In addition, serum progesterone levels were measured by the Bio-Merieux kit France, according to the manufacturer's instructions. The results revealed a significant decrease in SOD activity in the postmenopausal group, as compared to that in premenopausal women and control groups. Hyperthyroidism groups demonstrated a significant increase in MDA and AOPP levels, compared to control groups. Patient groups reported a decreased level of progesterone, in comparison with control groups. Moreover, there was a significant increase in T3 and T4 in patient groups (G3 and G4), compared to that in control groups (G1 and G2). There was a significant increase in systolic and diastolic blood pressure in menopausal hyperthyroidism (G4), compared to that in other groups. The TC decreased significantly in G3 and G4, compared to that in both control groups (P<0.05); nonetheless, there was no significant difference between patient groups (G3 and G4), as well as between control groups (G1 and G2). The study suggested that hyperthyroidism causes an increase in oxidative stress, which negatively affects the antioxidant system and drops levels of progesterone in both premenopausal and postmenopausal female patients. Therefore, low levels of progesterone are linked with hyperthyroidism, leading to aggravating symptoms of the disease.

Transitional cell metaplasia of the uterine cervix: A histopathological and immunohistochemical analysis suggesting a possible role of androgenic conversion during urothelial-like differentiation in peri/postmenopausal women.

Transitional cell metaplasia (TCM) of the uterine cervix and vagina is typically seen in patients with adrenogenital syndrome with high serum androgen levels and in those under androgen treatment as well as in some peri/postmenopausal women. Considering that TCM occurs in patients with increased serum androgen levels, a microenvironment with altered sex hormones might be involved in the urothelial-like differentiation observed in TCM. To investigate a histogenetic role of androgen in TCM development, we compared the distribution patterns and intensity of androgen receptor (AR), estrogen receptor (ER), GATA3 (a transcription factor involved in androgen regulation), Ki-67, and AKR1C3 (an enzyme involved in androgen biosynthesis) expression in normal exocervical mucosa in young women (n = 25), senile atrophy (n = 23), and TCM (n = 29). In TCM, AR, ER, AKR1C3, and GATA3, expression was stronger and significantly increased upward into the intermediate and superficial layers compared with the senile atrophic mucosa and normal mucosa in young women. The epithelial layer in TCM is thicker than that in senile atrophic mucosa, although both conditions may occur in the same age group. Proliferation in TCM was significantly lower than that in young women but slightly higher than that in senile atrophy. Considering the conversion activity of AKR1C3, thicker epithelial layers in TCM compared with those in senile atrophy might be due to increased conversion of androstenedione to testosterone via increased AKR1C3 activity, increased conversion of testosterone to 17ß-estradiol by aromatization, and AR activation.

Recreational Physical Activity, Sitting, and Androgen Metabolism among Postmenopausal Women in the Women's Health Initiative Observational Study.

BACKGROUND: Prolonged sitting and physical inactivity are associated with higher circulating levels of estrogens. It is unknown whether these risk factors are associated with circulating androgens/androgen metabolites, another set of hormones implicated in the etiology of cancers in postmenopausal women. METHODS: We conducted a cross-sectional analysis of 1,782 postmenopausal women in the Women's Health Initiative Observational Study. Serum concentrations of 12 androgens/androgen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Physical activity and sitting time were self-reported at baseline. We performed linear regression to estimate geometric means (GM) of androgen/androgen metabolite concentrations (pmol/L) according to physical activity and sitting time, adjusting for potential confounders and stratified by menopausal hormone therapy (MHT) use. RESULTS: Physical activity (≥15 vs. 0 MET-h/wk) was inversely associated with estrogen-to-androgen ratios among never/former MHT users (adj-GM = 37.5 vs. 49.6 unconjugated estrone:androstenedione; 20.2 vs. 30.3 unconjugated estradiol:testosterone; all P trend ≤ 0.03) but was not associated among current MHT users. Prolonged sitting (≥10 vs. ≤5 h/d) was positively associated with these ratios among both never/former (adj-GM = 44.2 vs. 38.3, P trend = 0.10; adj-GM = 23.4 vs. 20.2, P trend = 0.17; respectively) and current MHT users (adj-GM = 197 vs. 147; 105 vs. 75.5; respectively; all P trend ≤0.02), but the associations were statistically significant among current MHT users only. The associations persisted after adjustment for BMI. After adjustment for adrenal androgens, physical activity and sitting were not associated with androgen metabolites. CONCLUSIONS: Physical activity and sitting were associated with serum estrogen-to-androgen ratios but not androgen metabolites. IMPACT: This study contributes to our understanding of the link between physical activity, sitting, and cancer risk in postmenopausal women.

Fibrous components of extracellular matrix and smooth muscle of the vaginal wall in young and postmenopausal women: Stereological analysis.

The anterior vaginal wall is subject to many diseases, such as pelvic organ prolapse. The pathophysiology of this illness is multifactorial, and as such, structural components of the vagina are involved. Furthermore, it is more prevalent in older women. There is a lack of data in the literature regarding the extracellular matrix components of the vaginal wall and its changes with aging. The work presented herein aims to perform a stereological study of the extracellular matrix in young and old women. It was observed a decrease of the volumetric density of smooth muscle (45.5 ± 3.2 % and 32.8 ± 5.8 % for the G1 and G2 samples, respectively) and an increase of collagen and elastic fibers with age (35.9 ± 2.1 % and 54.1 ± 5.9 % for the G1 and G2, respectively) in the mucosa of the vaginal wall. These results could help to better understand the pathophysiology of pelvic organ prolapse concerning the aging process.

Associations of Age at Menopause With Postmenopausal Bone Mineral Density and Fracture Risk in Women.

CONTEXT: Menopause before age 45 is a risk factor for fractures, but menopause occurs at age ≥45 in ~90% of women. OBJECTIVE: To determine, in women with menopause at age ≥45, whether (1) years since the final menstrual period (FMP) is more strongly associated with postmenopausal bone mineral density (BMD) than chronological age and (2) lower age at FMP is related to more fractures. DESIGN AND SETTING: The Study of Women's Health Across the Nation, a longitudinal cohort study of the menopause transition (MT). PARTICIPANTS: A diverse cohort of ambulatory women (pre- or early perimenopausal at baseline, with 15 near-annual follow-up assessments). MAIN OUTCOME MEASURES: Postmenopausal lumbar spine (LS) or femoral neck (FN) BMD (n = 1038) and time to fracture (n = 1554). RESULTS: Adjusted for age, body mass index (BMI), cigarette use, alcohol intake, baseline LS or FN BMD, baseline MT stage, and study site using multivariable linear regression, each additional year after the FMP was associated with 0.006 g/cm2 (P < 0.0001) and 0.004 g/cm2 (P < 0.0001) lower postmenopausal LS and FN BMD, respectively. Age was not related to FN BMD independent of years since FMP. In Cox proportional hazards regression, accounting for race/ethnicity, BMI, cigarette use, alcohol intake, prior fracture, diabetes status, exposure to bone-modifying medications/supplements, and study site, the hazard for incident fracture was 5% greater for each 1-year decrement in age at FMP (P = 0.02). CONCLUSIONS: Years since the FMP is more strongly associated with postmenopausal BMD than chronological age, and earlier menopause is associated with more fractures.

Association Between Metabolic Syndrome and Immunohistochemical Profile at Breast Cancer Diagnosis in Postmenopausal Women.

BACKGROUND: The aim of this study was to evaluate the association between metabolic syndrome (MetS) and the immunohistochemical profile of breast cancer (BC) in postmenopausal women. METHODS: This cross-sectional cohort study included 189 women, aged 45 to 75years and amenorrhea >12 months, with newly diagnosed BC and no previous cancer treatment. Clinical, anthropometric and biochemical data were collected, as well as data on BC hormone status (estrogen receptor, ER; progesterone receptor, PR; human epidermal growth factor receptor-2, HER-2), and epithelial proliferative activity (Ki-67). Tumors were divided into 5 subtypes:luminal A, luminal B HER-2 negative, luminal B HER-2 positive, non-luminal HER-2, and triple negative. Women with three or more of the following criteria were diagnosed with MetS: waist circumference ≥88cm; triglycerides ≥150mg/dL; HDL-cholesterol <50mg/dL; blood pressure ≥130/85mmHg; glucose ≥100mg/dL. RESULTS: Sixty-three (33.3%) of the 189 patients had MetS at the time of diagnosis. Women with MetS had a higher frequency of tumors ≤ 2cm than women without MetS (49.2% vs. 31.8%) (P = .038). There were no differences in histological grade, staging, or axillary lymph node metastasis (P > .05). The proportion of PR-positive (P = .006), HER-2-negative (P = .034), and luminal B HER-2-negative (P = .038) tumors was higher among patients with MetS compared to women without MetS (79.4% vs. 61.8%, 89.9% vs. 78.6% and 44.5% vs. 27.8%, respectively). Multivariate analysis adjusted for age, time since menopause and BMI showed a higher risk for luminal B HER-2-negative tumors among women with MetS (OR 2.00, 95% CI 1.03-3.89), obese patients (OR 2.03, 95% CI 1.06-3.90), and women with abdominal obesity (OR 1.96, 95% CI 1.01-4.03). CONCLUSION: In postmenopausal women with newly diagnosed BC, the presence of MetS was associated with smaller tumor size, PR-positive and HER-2-negative status, and the luminal B tumor subtype.

Early decrease in lean mass and bone mass in postmenopausal women: a cross-sectional study.

OBJECTIVE: The effect of menopause transition in body composition was evaluated in a cross-sectional study. METHOD: The study was carried out in an outpatient clinic of Brazil enrolling premenopausal (n = 64) and postmenopausal (n = 42) women aged between 44 and 52 years, with weight stability (±2 kg) for at least 6 months before evaluation. Participants answered a sociodemographic semi-structured questionnaire, the Menopause Rating Scale, the International Physical Activity Questionnaire, 24-h dietary recall and a visual analogue scale of appetite. Blood biochemical, anthropometry and densitometry measurements were used for body composition estimation. RESULTS: Most participants were overweight (31.4%) or obese (45.7%) and categorized as 'high active' in physical activity (65.7%). Lean mass and bone mass decreased in the first few years of menopause. A metabolic turn to an increase of lipids was observed, represented by greater total cholesterol and high-density lipoprotein cholesterol levels. Menopause transition did not alter body fat distribution. Total body fat, android fat and gynoid fat were positively related to smoking habit, and android fat was also positively related to waist circumference. CONCLUSION: Taken together, early postmenopause can be considered a time window of opportunity for preventing ailments such as atherogenic profile, obesity, increased cardiovascular risk and osteoporosis.

The Effect of a 6-Month Exercise Intervention Trial on Allostatic Load in Black Women at Increased Risk for Breast Cancer: the FIERCE Study.

BACKGROUND: Allostatic load comprises cardiovascular, metabolic, and inflammatory markers, which is characterized by abdominal obesity, high blood glucose levels, impaired glucose tolerance, dyslipidemia, and hypertension and associated with an increased risk in breast cancer. METHODS: The study was a 6-month, 3-arm randomized controlled trial of two moderate-intensity exercise interventions (compared with a control group) among obese, physically inactive, postmenopausal Black women aged 45 to 65 years, who were at increased risk for breast cancer based on the CARE model. Two hundred thirteen participants were randomly assigned to (1) supervised, facility-based aerobic exercise intervention (n = 73), (2) home-based exercise intervention (n = 69), or (3) a wait-listed control group (n = 71). The intervention effects of exercise on allostatic load were examined with intent-to-treat analyses using generalized linear models. RESULTS: It was revealed that statistically significant decreases in allostatic load over the 6-month period for both exercise intervention groups (i.e., home-based and supervised arms) compared to the controls were observed among the total population, pc-h = 0.023 and pc-s = 0.035, as well as among women with a family history of breast cancer, pc-h = 0.006 and pc-s = 0.012. CONCLUSIONS: Short-term aerobic activity improved allostatic load scores in metabolically unhealthy postmenopausal Black women at increased risk for cancer. TRIAL REGISTRATION: Clinical trial registration number NCT02103140.

Role of caveolin-eNOS platform and mitochondrial ATP-sensitive potassium channel in abrogated cardioprotective effect of ischemic preconditioning in postmenopausal women

Abstract Caveolin, the protein of the caveolar membrane, interacts and binds with endothelial nitric oxide synthase (eNOS), forming a caveolin-eNOS complex leading to suppression of the eNOS activity. Caveolin, therefore, maintains eNOS in the inactivated state leading to reduced nitric oxide (NO) production. Ischemic preconditioning disrupts the caveolin-eNOS complex leading to activation of the eNOS and thus results in cardioprotection. During ischemic preconditioning, NO produces cardioprotection by the opening of the KATP channel, and the caveolin forms a suitable signalling platform facilitating the interaction of NO with the KATP channel. Estrogen deficiency has been reported to upregulate caveolin-1 expression. The article aims to review the various mechanisms that placed the women at the risk of coronary artery diseases after postmenopausal estrogen deficiency and their role in the cardioprotective effect of ischemic preconditioning.

Timing of Meals and Exercise Affects Hormonal Control of Glucoregulation, Insulin Resistance, Substrate Metabolism, and Gastrointestinal Hormones, but Has Little Effect on Appetite in Postmenopausal Women.

The current prevalence of obesity in the US is strongly associated with excessive food intake and insufficient physical activity. This study examined whether changing the timing of exercise before or after two daily meals could alter human appetite for food. Fifty-four healthy postmenopausal women were matched by body weight and assigned to two groups: (1) two bouts of 2-h moderate-intensity exercise ending one hour before each weight-maintenance meal (XM, n = 23), (2) two-hour moderate-intensity exercise starting 1 h after each weight-maintenance meal (MX, n = 23), and one sedentary control (SED) arm (n = 8). Measurements included appetite ratings, circulating glucose, free fatty acids (FFAs), a ketone body D-ß-hydroxybutyrate (BHB), glucoregulatory hormones insulin and glucagon, and gastrointestinal hormones associated with food digestion and absorption and implicated in appetite sensations. XM group increased concentrations of FFAs and BHB during exercise and increased insulin and homeostatic assessment of insulin resistance (HOMA-IR) during postprandial periods. MX group reduced postprandial insulin and HOMA-IR by about 50% without a major change in plasma glucose. There was brief suppression of hunger and an increase in satiation in both exercise groups near the end of the first postprandial period. The time course of hunger was unrelated to the perturbations in fuel metabolism, depletion of liver glycogen, and not correlated with concentration changes in hunger-stimulating hormone ghrelin during XM exercise before meals. Similarly, there was no correlation between the time course of fullness during exercise after meals with the postprandial secretion of gastrointestinal hormones including cholecystokinin (CCK) that has been linked to satiation. Hunger and satiation appear to depend on oral intake and gastrointestinal processing of nutrients and are not affected by metabolic and hormonal consequences of the timing of exercise with respect to meals. Moderate-intensity exercise performed shortly after meals induces a rapid and highly effective lowering of insulin resistance.

Serum levels of proinflammatory cytokines and selected bioelements in perimenopausal women with regard to body mass index.

During the menopause, decreased estrogen levels may be accompanied by increased levels of inflammatory mediators. Many studies also show significant relationships between the levels of bioelements and proinflammatory cytokines. The aim of this study was to assess the levels of proinflammatory cytokines, C-reactive protein (CRP), and selected bioelements in perimenopausal women with regard to BMI. METHODS: The study of 217 perimenopausal women involved the completion of questionnaires concerning sociodemographic and medical data, anthropometric measurements, and blood collection. RESULTS: In all studied women, the levels of IL-1ß significantly positively correlated with Ca, Mg, and Sr; IFNγ significantly negatively correlated with Sr, and IL-6 with Mg. In women with a normal BMI, the levels of IL-1ß significantly positively correlated with Ca and Sr, and CRP positively correlated with Zn. In overweight women, the levels of IL-1ß positively correlated with Ca, IL-6 with Na, and IFNγ negatively correlated with Sr. In obese women, the levels of CRP positively correlated with Zn, TNFα with Mg, IFNγ with Cu and P. The levels of IL-6 negatively correlated with Ca and Mg. CONCLUSIONS: BMI may be one of the factors that affect the relationship between serum bioelement levels and the levels of proinflammatory cytokines and CRP in women, especially during the menopausal period.

Expression of Sex Hormone Receptor and Immune Response Genes in Peripheral Blood Mononuclear Cells During the Menstrual Cycle.

Sex hormones are known to interact with the immune system on multiple levels but information on the types of sex hormone receptors (SHR) and their expression levels in immune cells is scarce. Estrogen, testosterone and progesterone are all considered to interact with the immune system through their respective cell receptors (ERα and ERß including the splice variant ERß2, AR and PGR). In this study expression levels of SHR genes in peripheral blood mononuclear cells (PBMCs) and cell subsets (CD4+ and CD8+ T-cells, CD56+ NK-cells, CD14+ monocytes and CD19+ B-cells) were analyzed using standard manual qPCR or a qPCR array (TLDA). Nine healthy individuals including men (n = 2), premenopausal (Pre-MP, n = 5) and postmenopausal (post-MP, n = 2) women were sampled for PBMCs which were separated to cell subsets using FACS. Ten Pre-MP women were longitudinally sampled for total PBMCs at different phases of the menstrual cycle. We found that ERα was most abundant and, unexpectedly, that ERß2 was the dominant ERß variant in several FACS sorted cell subsets. In total PBMCs, SHR (ERα, ERß1, ERß2, and AR) expression did not fluctuate according to the phase of the menstrual cycle and PGR was not expressed. However, several immune response genes (GATA3, IFNG, IL1B, LTA, NFKB1, PDCD1, STAT3, STAT5A, TBX21, TGFB1, TNFA) were more expressed during the ovulatory and mid-luteal phases. Sex hormone levels did not correlate significantly with gene expression of SHR or immune response genes, but sex hormone-binding globulin (SHBG), a steroid hormone transporting protein, was positively correlated to expression of ERß1 gene. This study provides new insights in the distribution of ERs in immune cells. Furthermore, expression patterns of several immune response genes differ significantly between phases of the menstrual cycle, supporting a role for sex hormones in the immune response.

Is the beta estradiol receptor receiving enough attention for its metabolic importance in postmenopause?

The relationship between menopause and the development of metabolic diseases is well established. In postmenopause women, there is an expansion of visceral white adipose tissue (WATv), which highly contributes to the rise of circulating lipids. Meanwhile, muscle glucose uptake decreases and hepatic glucose production increases. Consequently, in the pancreas, lipotoxicity and glycotoxicity lead to deficient insulin production. These factors initiate an energy imbalance and enhance the probability of developing cardiovascular and metabolic diseases. Although the activation of estradiol receptors (ER) has been shown to be beneficial for the WAT stock pattern, leading to the insulin-sensitive phenotype, authors have described the risk of these receptors' activation, contributing to neoplasia development. The selective activation of beta-type ER (ERß) seems to be a promising strategy in the treatment of energy imbalance, acting on several tissues of metabolic importance and allowing an intervention with less risk for the development of estrogen-dependent neoplasia. However, the literature on the risks and benefits of selective ERß activation still needs to increase. In this review, several aspects related to ERß were considered, such as its physiological role in tissues of energy importance, beneficial effects, and risks of its stimulation during menopause. PubMed, SciELO, Cochrane, and Medline/Bireme databases were used in this study.

Estrogenic hormones receptors in Alzheimer's disease.

Estrogens are hormones that play a critical role during development and growth for the adequate functioning of the reproductive system of women, as well as for maintaining bones, metabolism, and cognition. During menopause, the levels of estrogens are decreased, altering their signaling mediated by their intracellular receptors such as estrogen receptor alpha and beta (ERα and ERß), and G protein-coupled estrogen receptor (GPER). In the brain, the reduction of molecular pathways mediated by estrogenic receptors seems to favor the progression of Alzheimer's disease (AD) in postmenopausal women. In this review, we investigate the participation of estrogen receptors in AD in women during aging.