Association between anxiety and frailty in postmenopausal women.

OBJECTIVE: To explore the association between anxiety and frailty in community-dwelling postmenopausal women. METHODS: This was a cross-sectional study in which 390 postmenopausal women (aged 60-83 years) who were attending a comprehensive care program were surveyed between January 2018 and February 2020. Each participant was administered a validated Spanish version of the Hospital Anxiety and Depression Scale (HADS) to assess their anxiety status. Those scoring 8 or higher on the anxiety subscale of the HADS were indicative of anxiety. The assessment of frailty utilized the Fried's phenotype, with a diagnosis of frailty established if the participant met at least three out of the five criteria. Factors associated with frailty were analyzed using multivariate logistic regression. RESULTS: The mean age of participants was 70.08 years, with an average of 12.58 ± 3.19 years since menopause. Frailty was diagnosed in 43.85% of the total series, while anxiety was present in 41.08%, rising to 69.59% in participants with frailty. Neither body mass index, years since menopause, educational level, economic status, nor smoking habit demonstrated significant associations with frailty. Upon multivariate analysis, anxiety (OR 8.56), multimorbidity (OR 2.18), and age (OR 2.73) emerged as independently associated with frailty (p < .001, p = .005, and p < .001, respectively). CONCLUSIONS: Among postmenopausal women with frailty, anxiety was detected in over two thirds of cases and was independently associated with frailty. This underscores the relevance of implementing anxiety screening in comprehensive care programs for postmenopausal women, with the goal of improving frailty through anxiety diagnosis and treatment.

Mediterranean diet for cancer prevention and survivorship.

Cancer is one of the main noncommunicable diseases in terms of health impact. Factors such as a progressively aging population point to future increases in the incidence of cancer on a global level. The elevated number of affected individuals, together with continuous improvements in cancer prevention and therapy, is creating a growing population of cancer survivors, with often inadequately met needs. Lifestyle is a key modulator of cancer risk and of associated morbidity and mortality, and is included in all approaches to the long-term management of cancer. Diet is a principal component of lifestyle, and most of the available evidence is centered on the Mediterranean diet. Our objective was to provide a narrative review of the evidence on the effect of the Mediterranean diet on cancer risk and health threats related to cancer survivorship. For this purpose, we searched the PubMed database for articles published between January 1, 2000, and June 12, 2023. Current data show that the Mediterranean diet is inversely associated with risk, or is risk neutral, for most types of cancer. Tumors of the digestive system have received preferential interest, but studies have also been published on tumors in other organs. The evidence, however, is meager due to the observational nature of most studies, although it is reassuring that benefit is reproduced in studies performed in different populations and environments. Evidence related to cancer survivors is limited by the paucity of studies, yet several findings regarding survival, recurrence, and short- and long-term morbidity suggest a potential role for the Mediterranean diet that warrants further research.

Variants translating reduced expression of the beta estrogen receptor gene were associated with increased carotid intima media thickness: A cross-sectional study in late postmenopausal women.

ABSTRACT: There is debate on the role of estrogens in modulating the risk for atherosclerosis in women. Our purpose was to investigate whether the size of the estrogenic impact was independently associated with variation of carotid intima-media thickness (IMT) in healthy late postmenopausal women. The levels of circulating estrogens have been used in previous studies but the influence of SNPs of the estrogen receptors (ER) α and ß have not been investigated.We performed a crossed-sectional study of 91 women in a university hospital. We used a double approach in which, in addition to the measurement of estradiol levels by ultrasensitive methods, genetic variants (SNPs) associated with differing expression of the ER α and ß genes were assessed. Multivariable analysis was used to examine the association of candidate factors with the value of IMT and plaque detection at both the carotid wall and the sinus.A genotype combination translating reduced gene expression of the ERß was directly associated with IMT at both the carotid wall (P = .001) and the sinus (P = .002). Other predictors of IMT were the levels of glucose, positively associated with IMT at both the carotid wall (P < .001) and the sinus (P = .001), age positively associated with IMT at the sinus (P = .003), and levels of vitamin D, positively associated with IMT at the carotid wall (P = .04).Poorer estrogenic impact, as concordant with a SNP variant imposing reduced expression of the ERß, was directly associated with IMT at both the carotid wall and the sinus. Glucose level, vitamin D only for the carotid wall, and age only for the sinus, also emerged as independent factors in the IMT variance.

Bazedoxifene increases the proliferation of human arterial endothelial cells but does not affect the expression of cyclins A, B, and D1 and of p27Kip1.

OBJECTIVE: Endothelial dysfunction and denudation are considered a first step in atherosclerosis. Endothelial proliferation is key for cellular repair. The effect of bazedoxifene on the vascular endothelium has not been explored. We investigated the effect of bazedoxifene on endothelial cell proliferation. METHODS: Primary cultures from human umbilical artery endothelial cells were used in dose-response experiments (0.1, 1.0, and 10.0 EC50 dose) with bazedoxifene, estradiol, raloxifene and a combination of bazedoxifene and estradiol. Proliferation was assessed with the XTT colorimetric cell-proliferation assay. The possible participation of cyclins A, B, D1 and p27Kip1 was analyzed by the measurement of their expression at both the protein and the gene levels. RESULTS: A significant increase of similar size for cell proliferation was obtained with bazedoxifene, estradiol and raloxifene, but no significant change was observed for the association of bazedoxifene and estradiol. The impact was detected at the first 0.1 EC50 dose and was not dose-dependent. Estradiol achieved a significant increase in the protein expression of cyclin A and p27Kip1, but no change was detected for the other compounds at either the gene or protein level. CONCLUSION: Bazedoxifene demonstrated a proliferative effect of similar size to estradiol in cultured human umbilical artery endothelial cells. The molecular mechanisms need further investigation.

Comparative transcriptome analysis identifies CARM1 and DNMT3A as genes associated with osteoporosis.

To identify new candidate genes in osteoporosis, mainly involved in epigenetic mechanisms, we compared whole gene-expression in osteoblasts (OBs) obtained from women undergoing hip replacement surgery due to fragility fracture and severe osteoarthritis. Then, we analyzed the association of several SNPs with BMD in 1028 women. Microarray analysis yielded 2542 differentially expressed transcripts belonging to 1798 annotated genes, of which 45.6% (819) were overexpressed, and 54.4% (979) underexpressed (fold-change between - 7.45 and 4.0). Among the most represented pathways indicated by transcriptome analysis were chondrocyte development, positive regulation of bone mineralization, BMP signaling pathway, skeletal system development and Wnt signaling pathway. In the translational stage we genotyped 4 SNPs in DOT1L, HEY2, CARM1 and DNMT3A genes. Raw data analyzed against inheritance patterns showed a statistically significant association between a SNP of DNMT3A and femoral neck-(FN) sBMD and primarily a SNP of CARM1 was correlated with both FN and lumbar spine-(LS) sBMD. Most of these associations remained statistically significant after adjusting for confounders. In analysis with anthropometric and clinical variables, the SNP of CARM1 unexpectedly revealed a close association with BMI (p = 0.000082), insulin (p = 0.000085), and HOMA-IR (p = 0.000078). In conclusion, SNPs of the DNMT3A and CARM1 genes are associated with BMD, in the latter case probably owing to a strong correlation with obesity and fasting insulin levels.

Diet to Reduce the Metabolic Syndrome Associated with Menopause. The Logic for Olive Oil.

The rates of metabolic syndrome are increasing in parallel with the increasing prevalence of obesity, primarily due to its concomitant insulin resistance. This is particularly concerning for women, as the years around menopause are accompanied by an increase in visceral obesity, a strong determinant of insulin resistance. A fall in estrogens and increase in the androgen/estrogen ratio is attributed a determining role in this process, which has been confirmed in other physiological models, such as polycystic ovary syndrome. A healthy lifestyle, with special emphasis on nutrition, has been recommended as a first-line strategy in consensuses and guidelines. A consistent body of evidence has accumulated suggesting that the Mediterranean diet, with olive oil as a vital component, has both health benefits and acceptable adherence. Herein, we provide an updated overview of current knowledge on the benefits of olive oil most relevant to menopause-associated metabolic syndrome, including an analysis of the components with the greatest health impact, their effect on basic mechanisms of disease, and the state of the art regarding their action on the main features of metabolic syndrome.

Association of a single nucleotide polymorphism of RANK gene with blood pressure in Spanish women.

In addition to governing key functions in bone metabolism and the immune system, the RANK/RANKL/OPG system plays a role in the vascular system, particularly in vascular calcification and atherosclerosis.Given that these 2 phenotypes are considered a major cause of high blood pressure (BP), in this study we analyzed the association of SNPs in RANK and OPG genes with blood pressure. An observational study was conducted of 2 SNPs in the RANK gene (rs884205 and rs78326403) and 1 in the OPG gene (rs4876869) with systolic (SBP) and diastolic blood pressure (DBP) in a cohort of 695 women.Data analysis revealed a statistically significant association between the SNP rs884205 and BP pressure (SBP and DBP). Analyzing this relationship by the dominant inheritance model for this SNP (allele risk: A), women of the AA/AC genotype showed higher BP than women of the CC genotype, both for SBP (P = .001) and for DBP (P = .003), and these associations both surpassed the Bonferroni threshold for multiple comparisons. Multivariate regression analysis including known predictors of BP as independent variables was performed to evaluate the strength of this association, which in the case of the SNP rs884205 of the RANK gene remained statistically significant after adjustment for both SBP (P = .0006) and DBP (P = .005), demonstrating the key role of this SNP in BP.We report a robust association between the SNP rs884205 in RANK gene and BP in women, and this SNP is validated as a candidate in cardiovascular risk studies.

Mediterranean diet and health: A systematic review of epidemiological studies and intervention trials.

Diet is a crucial variable for a healthy life. A rapidly growing number of studies in recent years support the hypothesis that the Mediterranean diet (MedDiet) has a beneficial effect on certain body systems, but the highly varied objectives and quality of these publications warrants an updated assessment. In the present review we performed a comprehensive evaluation of current evidence on the impact of the MedDiet on human health, assessing its effect on the incidence or progression of the main non-communicable diseases and their intermediate outcomes and risk factors. We scrutinised the clinical evidence from observational studies and randomised controlled trials. Cardiovascular disease was the condition with most information. The MedDiet showed a general preventive effect, which was reproduced to varying degrees for certain intermediate cardiovascular outcomes such as blood pressure, lipids, obesity, metabolic syndrome and diabetes. Benefits were also found for several types of cancer, brain function (including cognition, mood and to a lesser extent Parkinson's disease) and mortality. The quality of the published evidence was, however, generally moderate or low. In conclusion, the MedDiet shows a favourable impact on health. General adoption of a MedDiet is concordant with current policies promoting healthy and sustainable nutrition worldwide. Nonetheless, more high-quality research is needed to improve the consistency of the findings.

Vitamin D levels in Mediterranean breast cancer patients compared with those in healthy women.

OBJECTIVES: To evaluate the vitamin D status of postmenopausal women with early estrogen-receptor-positive breast cancer and to compare it with that of healthy postmenopausal women from the same Mediterranean region. STUDY DESIGN AND OUTCOME MEASURES: Data from 691 breast cancer (BC) patients in the B-ABLE cohort were analyzed after recent cancer intervention (recent-BC) or after a minimum of two years since this intervention (long-term-BC). Patients were also stratified by previous chemotherapy exposure (ChT+ and ChT-). Plasma levels of 25-hydroxyvitamin D [25(OH)D] (25(OH)D) were compared with data from 294 healthy women (non-BC) by linear regression to estimate ß-coefficients using non-BC participants as the reference group. Age, body mass index and season of blood extraction were selected as potential confounders. RESULTS: Of the recent-BC patients, 23.7% had 25(OH)D deficiency, compared with 17.7% of the long-term-BC group, and just 1.4% of the non-BC participants. Most of the women were located in the insufficient 25(OH)D category regardless of study group. BC patients had significantly lower 25(OH)D levels than non-BC participants (adjusted ß-coefficients: -4.84 [95%CI -6.56 to -3.12] in recent-BC, and -2.05 [95%CI -4.96 to -0.14] in long-term-BC). Among BC patients, the lowest 25(OH)D levels were found in the recent-BC (ChT+) group (p < 0.001). No differences were found between the long-term-BC (ChT-), long-term-BC (ChT+) and recent-BC (ChT-) groups. Among the BC ChT+ patients, the recent-BC group had significantly lower 25(OH)D levels than the long-term-BC group (p < 0.001). CONCLUSION: Severely reduced 25(OH)D levels were detected in patients with breast cancer, particularly after recent chemotherapy. These 25(OH)D levels had partially recovered over the long term, but still remained much lower than in the healthy population.

The role of CD40 and CD40L in bone mineral density and in osteoporosis risk: A genetic and functional study.

Compelling data are revealing that the CD40/CD40L system is involved in bone metabolism. Furthermore, we have previously demonstrated that polymorphisms in both genes are associated with bone phenotypes. The aim of this study is to further characterize this association and to identify the causal functional mechanism. We conducted an association study of BMD with 15 SNPs in CD40/CD40L genes in a population of 779 women. In addition, we assessed the functionality of this association through the study of the allele-dependent expression of CD40 and CD40L in peripheral blood leukocytes (PBLs) and in human osteoblasts (OBs) obtained from bone explants by qPCR and by sequencing. When an allelic imbalance (AI) was detected, studies on allele-dependent in vitro transcription rate and on CpG methylation in the gene promoter were also performed. Our results confirm the genetic association between SNP rs116535 (T>C) of CD40L gene with LS-BMD. Regarding CD40 gene, two SNPs showed nominal P-values<0.05 for FN- and LS-BMD (Z-scores), although the association was not significant after correcting for multiple testing. Homozygous TT women for SNP rs1883832 (C>T) of CD40 gene showed a trend to have lower levels of OPG (Q-value=0.059), especially when women of BMD-quartile ends were selected (P<0.05). Regarding functionality, we detected an AI for rs1883832 with the C allele the most expressed in OBs and in PBLs. Since the rs116535 of CD40L gene did not show AI, it was not further analyzed. Finally, we described a differential methylation of CpGs in the CD40 promoter among women of high in comparison to low BMD. Our results suggest that the CD40/CD40L system plays a role in regulating BMD. Effectively, our data suggest that a decreased production of OPG could be the cause of the lower BMD observed in TT women for rs1883832 of the CD40 gene and that the degree of methylation of CpGs in the CD40 promoter could contribute to the acquisition of BMD. One possibility that deserves further study is whether the degree of methylation of the CD40 gene affects the level of CD40 expression and, consequently, the level of OPG.

Bone metabolic changes during pregnancy: a period of vulnerability to osteoporosis and fracture.

Changes in bone density and bone markers suggest that pregnancy is associated with deterioration of bone mass in the mother. The metabolism of calcium resets to allow for the needs imposed by the building of the fetal skeleton. The fetus contributes to the process through the output of regulators from the placenta. Understanding of the whole process is limited, but some changes are unambiguous. There is an increase in the circulating levels of vitamin D, but its functional impact is unclear. Fetal parathyroid hormone (PTH) and PTH-related peptide (PTHrp) play an indirect role through support of a calcium gradient that creates hypercalcemia in the fetus. Placental GH, which increases up to the end of pregnancy, may exert some anabolic effects, either directly or through the regulation of the IGF1 production. Other key regulators of bone metabolism, such as estrogens or prolactin, are elevated during pregnancy, but their role is uncertain. An increase in the ratio of receptor activator of nuclear factor kappa B ligand (RANKL) to osteoprotegerin (OPG) acts as an additional pro-resorbing factor in bone. The increase in bone resorption may lead to osteoporosis and fragility fracture, which have been diagnosed, although rarely. However, the condition is transitory as long-term studies do not link the number of pregnancies with osteoporosis. Prevention is limited by the lack of identifiable risk factors. When fractures are diagnosed, rest, analgesics, or, when indicated, orthopedic intervention have demonstrated efficacy. Systemic treatment with anti-osteoporotic drugs is effective, but the potential harm to the fetus imposes caution in their use.

Gene expression profile induced by ovariectomy in bone marrow of mice: a functional approach to identify new candidate genes associated to osteoporosis risk in women.

Osteoporosis is a multifactorial skeletal pathology with a main genetic component. To date, however, the majority of genes associated with this pathology remain unknown since genes cataloged to date only explain a part of the heritability of bone phenotypes. In the present study, we have used a genome-wide gene expression approach by means of microarrays to identify new candidate genes involved in the physiopathology of osteoporosis, using as a model the ovariectomized (OVX) mice by comparing global bone marrow gene expression of the OVX mice with those of SHAM operated mice. One hundred and eighty transcripts were found to be differentially expressed between groups. The analysis showed 23 significant regulatory networks, of which the top five canonical pathways included B-cell development, primary immunodeficiency signaling, PI3K signaling in B-cells, phospholipase C signaling, and FcgRIIB signaling in B-cells. Twelve differentially expressed genes were validated by MALDI-TOF mass spectrometry with good reproducibility. Finally, the association to bone phenotypes of SNPs in genes whose expression was increased (IL7R and CD79A) or decreased (GPX3 and IRAK3) by OVX in mice was analyzed in a cohort of 706 postmenopausal women. We detected an association of a SNP in a gene involved in the detoxification of free radicals like glutathione peroxidase 3 (GPX3) with femoral neck BMD (rs8177447, P=0.043) and two SNPs in the Ig-alpha protein of the B-cell antigen component gene (CD79A) with lumbar spine BMD (rs3810153 and rs1428922, P=0.016 and P=0.001, respectively). These results reinforce the role of antioxidant pathways and of B-cells in bone metabolism. Furthermore, it shows that a genome-wide gene expression approach in animal models is a useful method for detecting genes associated to BMD and osteoporosis risk in humans.

Transient regional osteoporosis.

Transient regional osteoporosis (TRO) is a disease that predisposes to fragility fracture in weight bearing joints of mid-life women and men. Pregnant women may also suffer the process, usually at the hip. The prevalence of TRO is lower than the systemic form, associated with postmenopause and advanced age, but may be falsely diminished by under-diagnosis. The disease may be uni- or bilateral, and may migrate to distinct joints. One main feature of TRO is spontaneous recovery. Pain and progressive limitation in the functionality of the affected joint(s) are key symptoms. In the case of the form associated with pregnancy, difficulties in diagnosis derive from the relatively young age at presentation and from the clinical overlapping with the frequent aches during gestation. Densitometric osteoporosis in the affected region is not always present, but bone marrow edema, with or without joint effusion, is detected by magnetic resonance. There are not treatment guidelines, but the association of antiresorptives to symptomatic treatment seems to be beneficial. Surgery or other orthopedic interventions can be required for specific indications, like hip fracture, intra-medullary decompression, or other.

Surgical planning after sleep versus awake techniques in patients with obstructive sleep apnea.

OBJECTIVE/HYPOTHESIS: This study examined correlations between surgical recommendations based on either drug-induced sleep endoscopy (DISE) or common awake examination methods in patients with obstructive sleep apnea syndrome (OSAS). STUDY DESIGN: Prospective, blinded, clinical trial at a university hospital. METHODS: An otorhinolaryngologist designed surgical plans for patients with OSAS after clinical examination, lateral cephalometry, the Müller maneuver, and Friedman staging. A second otorhinolaryngologist blinded to the previous plans made surgical recommendations after DISE. A third person tested agreement between the two sets of plans using Cohen's kappa statistic and the chi-squared test. RESULTS: One hundred and sixty-two patients (15 females, 147 males) completed the protocol. Good correlation was observed between DISE and Friedman staging regarding recommendations for isolated oropharyngeal or multilevel surgery (kappa = 0.61). Correlations between DISE and clinical examination, lateral cephalometry, and the Müller maneuver regarding surgical procedures on specific structures contributing to upper airway obstruction ranged from fair for velum/tonsil surgery (k = 0.41-0.60) to poor (k = 0.01-0.20) for tongue-base, lateral pharyngeal wall, and epiglottal surgery. The most informative value was DISE versus clinical evaluation, lateral cephalometry, and the Müller maneuver, which changed surgical recommendations concerning the structures contributing to hypopharyngeal or laryngeal obstruction in > 40% of patients. CONCLUSIONS: Our results indicate that DISE provides more information about the anatomical locations and pattern of obstruction, particularly regarding the specific structures contributing to hypopharyngeal and laryngeal obstruction. DISE changes surgical decision making compared to awake evaluation methods.

Replication study of three functional polymorphisms associated with bone mineral density in a cohort of Spanish women.

Gene candidate and genome-wide association studies have revealed tens of loci of susceptibility for osteoporosis. Some limitations such as sample size, use of confounding variables, and control for multiple testing and for population stratification, however, represent common problems in these studies that make replication in independent cohorts desirable and even necessary. The main objective of the present study is to replicate previous data on three functional polymorphisms in a cohort of Spanish women. To that end, we performed an association study of three functional polymorphisms previously associated with bone phenotypes in the LRP5, TNFRSF11B, and FGFBP1 genes with low bone mineral density (BMD) in a cohort of 721 Spanish women, most of them postmenopausal. We detected a strong significant association, even when correcting for multiple comparisons, for polymorphism rs312009 in the LRP5 gene with low BMD at the lumbar-spine site. These were women with the CC genotype, which showed the worst bone parameters. Moreover, these women had a higher risk of osteoporosis (adjusted odds ratio 2.82, P = 0.001) than women with the TT/TC genotype. This association seems to be caused because the rs312009 single nucleotide polymorphism (SNP) is located at a binding site for the transcription factor RUNX2 at the 5' region of the LRP5 gene, and the T allele seems to be a better transcriber than the C allele. Regarding the other two SNPs, only the rs4876869 SNP in the TNFRSF11B gene showed a suggestive trend for both skeletal sites. These results underscore the significance of the LRP5 gene in bone metabolism and emphasize the significance of the replication of previous results in independent cohorts.

Associations between aromatase CYP19 rs10046 polymorphism and breast cancer risk: from a case-control to a meta-analysis of 20,098 subjects.

Lifetime exposure to estrogen is a factor that plays an important role in the pathogenesis and progression of breast cancer. Genetic variants in genes of the biosynthesis and metabolism of estrogen have been associated with breast cancer risk. Among them, the CYP19 gene encodes for aromatase, the enzyme that catalyzes the conversion of androgens to estrogens. The rs10046 polymorphism on the CYP19 gene has been related to levels of circulating estradiol and to the estradiol/testosterone ratio. To date, epidemiological studies of rs10046 have been performed in different populations with contradictory results. In the present study, we have conducted a case-control analysis (522 cases and 1221 controls) in a Spanish population. Furthermore, we have performed a meta-analysis including 20,098 subjects (7,998 cases and 12,100 controls) to summarize the data available for rs10046 and breast cancer risk. An odds ratio (OR) with a 95% confidence interval (CI) was applied to assess the association. The results of our case-control study show an association between the carriers of at least one C allele (dominant model) and breast cancer risk (OR = 1.29, 95% CI 1.01-1.66, p-value = 0.038). The meta-analysis shows no significant association with breast cancer risk in any of the genetic models tested. The analysis by ethnic subgroups also failed to produce associations. The evaluation of heterogeneity, influence analysis, and publication bias confirms the reliability of the analysis. We can conclude that the rs10046 polymorphism on CYP19 by itself does not constitute breast cancer risk. We cannot, however, reject the possibility that it could contribute (interact), together with other genetic variants, to modify the circulating levels of estradiol.

Effects of administration of hormone therapy or raloxifene on the immune system and on biochemical markers of bone remodeling.

OBJECTIVE: Over the last few years, conclusive evidence of the involvement of the immune system in the regulation of bone metabolism has been identified. Consequently, one question that should be formulated concerns the possible effects of antiresorptive therapies on the immune system. Therefore, the purpose of the present work was to evaluate both the functionality of the immune system and bone turnover in women receiving antiresorptive therapies, such as hormone therapy (HT; n = 33) and raloxifene (RLX; n = 66), acting through estrogen receptors. METHODS: To that end, this study analyzed bone turnover markers in a population of postmenopausal women before and after beginning therapy and compared these with data of women not treated (NT; n = 102). In a subgroup of participants (NT = 33, RLX = 24, and HT = 26), we analyzed the effects of treatments on immune system parameters such as serum levels of interleukin (IL)-6, tumor necrosis factor α, and IL-1ß; lymphocyte subpopulations; cell proliferation by peripheral blood mononuclear cells (PBMCs); in vitro production of IL-1ß by PBMCs; and the expression of receptor activator of nuclear factor-κB ligand, transforming growth factor ß, and IL-4 genes by PBMCs. RESULTS: The results showed that bone resorption was inhibited strongly in women in the RLX and HT groups when compared with women in the NT group. Interestingly, the administration of RLX inhibited the production of the Wnt/ß-catenin signaling pathway inhibitor Dickkopf Homolog-1 (P < 0.05) and tended to increase the levels of the osteoclastogenesis inhibitor osteoprotegerin at month 6 (P = 0.059). With regard to the immune system, the different treatments did not markedly perturb the parameters analyzed, with the exception of the increase in serum IL-1ß detected in the HT group at month 6 (P < 0.05). CONCLUSIONS: The main conclusions of the present work were that HT or RLX do not disturb the immune system and that both treatments have a similar antiresorptive power.

Estradiol induces endothelial cell migration and proliferation through estrogen receptor-enhanced RhoA/ROCK pathway.

Migration and proliferation of endothelial cells are involved in re-endothelialization and angiogenesis, two important cardiovascular processes that are increased in response to estrogens. RhoA, a small GTPase which controls multiple cellular processes, is involved in the control of cell migration and proliferation. Our aim was to study the role of RhoA on estradiol-induced migration and proliferation and its dependence on estrogen receptors activity. Human umbilical vein endothelial cells were stimulated with estradiol, in the presence or absence of ICI 182780 (estrogen receptors antagonist) and Y-27632 (Rho kinase inhibitor). Estradiol increased Rho GEF-1 gene expression and RhoA (gene and protein expression and activity) in an estrogen receptor-dependent manner. Cell migration, stress fiber formation and cell proliferation were increased in response to estradiol and were also dependent on the estrogen receptors and RhoA activation. Estradiol decreased p27 levels, and significantly raised the expression of cyclins and CDK. These effects were counteracted by the use of either ICI 182780 or Y-27632. In conclusion, estradiol enhances the RhoA/ROCK pathway and increases cell cycle-related protein expression by acting through estrogen receptors. This results in an enhanced migration and proliferation of endothelial cells.

Isoflavones and cardiovascular disease.

The specific profile of estrogens on cardiovascular risk, with limiting action on atherogenesis but a less clear protection on cardiovascular episodes, might be improved by other agonists of the estrogen receptor, such as isoflavones. By using a systematic search based on the electronic Medline database plus a hand-search of reference lists of selected review papers, we reviewed the rapidly growing body of experimental and clinical data that, on average, follow a pattern of benefit rather similar to estrogens. Experimental models have used endothelial and vascular smooth muscle cells, isolated arteries, and live animals, including monkeys. The clinical evidence arises from studies on the lipid profile and lipid oxidation, insulin resistance, hemostasis, changes in the inflammatory factors, and indicators of endothelial function, including metabolites of nitric oxide and prostacyclin. There are not randomized trials investigating the action of isoflavones on the incidence of clinical episodes, but a few recent, well-designed studies have suggested the association of the ingestion of isoflavones with a reduction in the atherosclerotic burden, as indicated by the measurement of the intima-media thickness in carotid vessels.