Does local vaginal estrogen after tension-free transobturator vaginal tape reduce overactive bladder symptoms in postmenopausal women? A prospective randomized, controlled study

Objective:We aimed to evaluate the efficacy of topical estrogen after transvaginal tension-free vaginal tape-obturator(TVT-O)in the treatment of de novo overactive bladder symptoms that appear after surgery.Methods:This is a prospective randomized controlled study performed in the Urology and Gynecology Departments,Kasr Al Ainy Hospital,Cairo University,Cairo,Egypt.Two hundred and ten postmenopausal females presenting during the period between January 2017 and November 2020 with stress urinary incontinence were included in the study.Patients were divided into two groups,105 patients in Group A(treatment group)and 105 patients in Group B(control group).Patients in Group A underwent transvaginal TVT-O followed by local vaginal estrogen treatment for 6 months,while patients in Group B underwent transvaginal TVT-O only.The study included any postmenopausal female with urodynamic stress urinary incontinence.All patients had to fulfill a 3-day bladder diary,overactive bladder symptoms score,urine analysis,urodynamic study,and post-voiding residual urine measurement by abdominal ultrasound preoperatively and at 3-month and 6-month follow-ups.Results:At 6-month follow-up,daytime frequency was reduced to 8%in Group A(increased to 21%in Group B)with a statistically significant difference between both groups(p=0.009).At 6-month follow-up,nocturia was 8%in Group A(11%in Group B)with no statistically significant difference between both groups(p=0.469).There was a statistically significant difference between both groups as regards to urinary urgency at 6-month follow-up(p=0.024).There was a statistically significant difference in postoperative wound healing events as regards to cure,hyperemia,gapping,and wound infection 1 week after intervention between both groups(p=0.008).No local or systemic side-effects were reported from local estrogen use.Conclusion:Local vaginal estrogen treatment given to postmenopausal patients after midurethral sling procedures can reduce the symptoms of daytime frequency and urinary urgency.Long-term follow-up is needed.

Estrogen restores disordered lipid metabolism in visceral fat of prediabetic mice

BACKGROUND Visceral obesity is increasingly prevalent among adolescents and young adults and is commonly recognized as a risk factor for type 2 diabetes.Estrogen[17β-estradiol(E2)]is known to offer protection against obesity via diverse me-chanisms,while its specific effects on visceral adipose tissue(VAT)remain to be fully elucidated.AIM To investigate the impact of E2 on the gene expression profile within VAT of a mouse model of prediabetes.METHODS Metabolic parameters were collected,encompassing body weight,weights of visceral and subcutaneous adipose tissues(VAT and SAT),random blood glucose levels,glucose tolerance,insulin tolerance,and overall body composition.The gene expression profiles of VAT were quantified utilizing the Whole Mouse Genome Oligo Microarray and subsequently analyzed through Agilent Feature Extraction software.Functional and pathway analyses were conducted employing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses,respectively.RESULTS Feeding a high-fat diet(HFD)moderately increased the weights of both VAT and SAT,but this increase was mitigated by the protective effect of endogenous E2.Conversely,ovariectomy(OVX)led to a significant increase in VAT weight and the VAT/SAT weight ratio,and this increase was also reversed with E2 treatment.Notably,OVX diminished the expression of genes involved in lipid metabolism compared to HFD feeding alone,signaling a widespread reduction in lipid metabolic activity,which was completely counteracted by E2 adminis-tration.This study provides a comprehensive insight into E2's local and direct protective effects against visceral adiposity in VAT at the gene level.CONCLUSION In conclusion,the present study demonstrated that the HFD-induced over-nutritional challenge disrupted the gene expression profile of visceral fat,leading to a universally decreased lipid metabolic status in E2 deficient mice.E2 treatment effectively reversed this condition,shedding light on the mechanistic role and therapeutic potential of E2 in combating visceral obesity.

Comprehensive Analysis of Estrogen Receptor 1 Dysregulation in Liver Hepatocellular Carcinoma: Implications for Prognosis and Therapeutic Targeting - A Secondary Publication

The study investigates the expression pattern and regulatory mechanisms of estrogen receptor 1 (ESR1) in liver hepatocellular carcinoma (LIHC) through comprehensive bioinformatics analysis. Utilizing UALCAN and GEPIA2 databases, significant down-regulation of ESR1 expression is observed in LIHC samples compared to normal controls, indicating its potential role in tumor progression. Further analysis reveals consistent down-regulation across different clinical variables including patient age, gender, race, and various stages of LIHC, affirming the regulatory role of ESR1 in tumor development and progression. Additionally, promoter methylation analysis demonstrates hypermethylation of ESR1 in LIHC samples, negatively correlating with its expression. This association persists across different clinical parameters, emphasizing the inverse relationship between ESR1 methylation and expression levels. Survival analysis indicates that up- regulation of ESR1 is associated with better overall survival, suggesting its potential as a prognostic biomarker in LIHC. Furthermore, genetic mutation analysis using cBioPortal reveals a spectrum of alterations in ESR1, including amplification, missense mutation, deep deletion, splice mutation, and truncating mutation, highlighting the genetic complexity of ESR1 in LIHC. These findings collectively contribute to a deeper understanding of ESR1 dysregulation in LIHC and its clinical implications as a potential therapeutic target and prognostic marker.

Effect of estrogen pretreatment in GnRH antagonist protocol-Meta-analysis

Objective:To evaluate the effect of estrogen pre-treatment in patients with different ovarian response in antagonist protocol.Methods:Randomized controlled trials(RCTs)and retrospective studies about the effect of estrogen pre-treatment in antagonist prorocol were searched in PubMed,Web of Science,China National Knowledge Infrastructure,Wanfang Database.R software was used for meta-analysis.Results:Seven RCTs and two retrospective studies were included.In order to explore the source of heterogeneity,subgroup analysis was used,which was mainly conducted according to the ovarian response of the included population,which were divided into low responders,non-low responders and mixed responders.In the study about gonadotropin hormone(Gn)days,patients were divided into wash-out subgroup and non-wash-out subgroup according to drug use-pattern.Meta-results showed that the number of Gn days increased significantly in the non-wash-out subgroup(WMD=1.07,95%CI[0.83;1.31],I2=66%).The number of Gn days in the wash-out subgroup were not affected(WMD=-0.12,95%CI[-0.45;0.21],I2=0%).In the low-response subgroup,the number of oocytes retrieved(WMD=0.46,95%CI[-0.23;1.16],I2=81%),the fresh cycle clinical pregnancy rate(RR=0.77,95%CI[0.55;1.06],I2=73%)and the cycle cancellation rate(RR=0.80,95%CI[0.40;1.61],I2=83%)were not significantly changed with estrogen pre-treatment.In the non-low-response subgroup,the number of oocytes obtained(WMD=0.21,95%CI[-0.69;1.11],I2=2%),fresh cycle clinical pregnancy rate(RR=0.94,95%CI[0.77;1.14],I2=41%),live birth rate(RR=0.82,95%CI[0.62;1.08],I2=0%)and cycle cancellation rate(RR=0.89,95%CI[0.54;1.47],I2=2%)were not significantly changed with estrogen pre-treatment.Conclusions:Estrogen pre-treatment(with non-wash-out period)in antagonist protocol increases Gn days,dose not improve IVF outcomes in non-low responders and low responders.

Changes of Estrogen in Serum and Estrogen Receptor β in the Relevant Brain Regions Following Mating Behavior of the Male Mandarin Vole Microtus mandarinus

In order to investigate the estrogen and estrogen receptor β changes after mating behavior of male mandarin vole （Microtus mandarinus）, the radioimmunoassay （RIA） and immunohistochemistry methods were used to investigate changes of the serum estrogen （E） concentrations, estrogen immunoreactive neurons （E-IRs） and estrogen receptor β immunoreactive neurons （ERβ-IRs） in the relevant brain regions following mating behavior. Fifteen sexually matured male voles were randomly divided into three groups and treated differently： （1） control group： voles were exposed to clean hard-wood shavings （n=5）, （2） exposure group： voles were exposed to the soiled bedding for more than 24h on which estrous females had been placed （n=5）, and （3） mating group： voles were placed with an estrous female for more than 24h （n=5）. The results showed circulating serum E concentrations were significantly higher in the mating group than in the exposure group and the control group, and there were no significant difference between the exposure group and the control group. E-IRs and ERβ-IRs were detected in the following brain regions related to mating behavior： the arcuate nucleus （ARC）, bed nucleus of the stria terminalis （BST）, lateral septal nucleus （LS）, medial amygdaloid nucleus （ME）, medial preoptic area （MPO） and ventromedial hypothalamic nucleus （VMH）. The results showed that there were significantly more E-IRs in the six brain regions in the mating group than in the control group and the exposure group, and there were no significant difference between the exposure group and the control group except for LS. There was no significant difference in ERβ-IRs in the six brain regions among the three groups, and there were some lighter -stained ERβ-IRs in these brain regions. The results suggested that estrogen affect mating activity of male mandarin voles, but ERβ might not play an important role in mating behavior of male mandarin voles. Instead, it might be through other receptors.

The effect of estrogen-mediated ubiquitin on cardiovascular diseases:a bioinformatics analysis

Objective:Using data mining tools,study the potential pathways of estrogen’s cardiovascular effects.Methods:The GeneExpression Omnibus database was used to download the relevant high-throughput microarray dataset GSE72180,which was then analyzed for differential genes using the GEO2R online analysis tool,gene function and pathway enrichment analysis using DAVID 6.8,protein interaction network analysis using the STRING database,and core network extraction using the MCODE algorithm.Results:A total of 131 differential genes were identified and enriched for gene function and signaling pathway analysis,which indicated that these genes were related with focal adhesion and the HIF-1 signaling pathway.MCODE algorithm analysis extracted 1 core sub-network of these genes to be related to ubiquitin protein transferase activity,protein polyubiquitination,protein ubiquitination involved in ubiquitin-dependent proteolytic metabolic processes,ligase activity,and clustering on ubiquitin-mediated protein hydrolysis signaling pathway.Conclusion:By using data mining tools,it is possible to identify how estrogen may influence the cardiovascular system by controlling the ubiquitination process.This information may be used as a reference for etiology and preventive studies of cardiovascular illnesses.

Protective estrogen-like properties and mechanism of quercetin in rat cerebral cortex neurons

OBJECTIVE To investigate the effect of quercetin on primary cultured newborn rat cortex neuron cell which is estrogen depletion,and discuss the possible mechanism,to provide new ideas and strategies for developing a drug of neurodegenerative disease.METHODS Rat cortex neurons were isolated from one day old Sprague Dawley rats and treated with estrogen,quercetin and estrogen receptor antagonists(ICI182,780).Cell viability was determined by MTT assay,neurite outgrowth was measured by fluorescent microsope and estrogen receptors were determine by Western blot.RESULTS Quercetin functions like estrogen to increase cortex neuronal cell viability,the Que(50,100μmol·L^(-1))group compared with the control group could significantly improve the activity of the cortical neurons(P<0.05).It can also increase neurite out growth,the Que(50,100μmol·L^(-1))group significantly promoted the formation of synapse,most of the neurons were full,and the synapses of neurons became thick,growth,and connect to a dense neural network.And in the Western blot experiments,Que(50,100μmol·L^(-1))group could obviously increase the expression of estrogen receptor alpha protein,in addition,the neural protective effect of quercetin can be inhibited by ICI182,780.CONCLUSION Quercetin like estrogen can protected cortex neuronal and the effect of quercetin on cortex neuronal cells was mediated by estrogen receptor alpha.

Expression of estrogen receptor (ER) -α and -βtranscripts in the neonatal and adult rat cerebral cortex, cerebellum, and olfactory bulb

In the present study expression of estrogen receptor subtype -alpha (ERalpha) and -beta (ERbeta) in the cerebral cortex, cerebellum, and olfactory bulb was investigated and compared between neonatal (1 to approximately 3-days-old) and adult (250 to approximately 350 g) rats, using reverse transcription-polymerase chain reaction (RT-PCR). No ERalpha transcripts were detectable in the adult cerebellum and olfactory bulb, whereas very weak expression of ERalpha was present in the adult cerebral cortex. No significant difference in ERbeta transcripts was detectable between the neonatal and adult rats. While transcripts for both ER subtypes were co-expressed in these brain areas of neonatal rats, although ERalpha expression was significantly weaker than ERbeta. Even in the cerebral cortex known to contain both ER subtypes in adult rats, ERalpha transcripts in neonatal rats were much higher than in adult. These observations provide evidence for the existence of different expression patterns of ERalpha/ERbeta transcripts in these three brain areas between the neonatal and adult rats, suggesting that each ER subtype may play a distinct role in the regulation of differentiation, development, and functions of the brain by estrogen.

Estrogen,male dominance and esophageal adenocarcinoma:Is there a link?

Esophageal adenocarcinoma is a cancer with poor prognosis, and its incidence has risen sharply over recent decades. Obesity is a major risk factor for developing this cancer and there is a clear male gender bias in the incidence that cannot be fully explained by known risk factors. It is possible that a difference in the expression of estrogen, or its signaling axes, may contribute to this gender bias. We undertook a com- prehensive literature search and analyzed the available data regarding estrogen and estrogen receptor expres- sion, and the possible sex-specific links with esopha- geal adenocarcinoma development. Potentially relevant associations between visceral vs subcutaneous fat deposition and estrogen expression, and the effect of crosstalk between estrogen and leptin signaling were identified. We also found limited studies suggesting a role for estrogen receptor 13 expression in esophageal adenocarcinoma development. The current literature supports speculation on an etiological role for estrogen in the male gender bias in esophageal adenocarcino- ma, but further studies are required.

New insights into estrogenic regulation of O^6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells： Co-degradation of ER-α and MGMT proteins by fulvestrant or O^6-benzylguanine indicates fresh avenues for therapy

Endocrine therapy using estrogen receptor-u （ER-α） antagonists for attenuating horm2one-driven cell proliferation is a major treatment modality for breast cancers. To exploit any DNA repair deficiencies associated with endocrine therapy, we investigated the functional and physical interactions of ER-α with O^6-methylguanine DNA methyltransferase （MGMT）, a unique DNA repair protein that confers tumor resistance to various anticancer alkylating agents. The ER-α -positive breast cancer cell lines （MCF-7, T47D） and ER- negative cell lines （MDAMB- 468, MDAMB-231）, and established inhibitors of ER-α and MGMT, namely, ICI-182,780 （Faslodex） and O^6- benzylguanine, respectively, were used to study MGMT- ER interactions. The MGMT gene promoter was found to harbor one full and two half estrogen-responsive elements （EREs） and two antioxidant-responsive elements （AREs）. MGMT expression was upregulated by estrogen, downregulated by tamoxifen in Western blot and promoter-linked reporter assays. Similarly, both transient and stable transfections of Nrf-2 （nuclear factor-erythroid 2-related factor-2） increased the levels of MGMT protein and activity 3 to 4-fold reflecting novel regulatory nodes for this dragresistance determinant. Of the different ER-α antagonists tested, the pure anti-estrogen fulvestrant was most potent in inhibiting the MGMT activity in a dose, time and ER-α dependent manner, similar to O^6-benzylguanine. Interestingly, fulvestrant exposure led to a degradation of both ER-α and MGMT proteins and O^6-benzylguanine also induced a specific loss of ER-a and MGMT proteins in MCF-7 and T47D breast cancer cells with similar kinetics. Immunoprecipitation revealed a specific association of ER-a and MGMT proteins in breast cancer cells. Furthermore, silencing of MGMT gene expression triggered a decrease in the levels of both MGMT and ER-a proteins. The involvement of proteasome in the drug-induced degradation of both proteins was also demonstrated. Fulvestrant enhanced the cytotoxicity of MGMT-targeted alkylating agents, namely, temozolomide and BCNU by 3 to 4-fold in ER-α positive cells, but not in ER-negative cells. We conclude that MGMT and ER-α proteins exist as a complex and are co-targeted for ubiquitin-conjugation and subsequent proteasomal degradation. The findings offer a clear rationale for combining alkylating agents with endocrine therapy.

phytoestrogens/insoluble fibers and colonic estrogen receptor β: randomized, double-blind, placebo-controlled study

AIM:To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-β and biological parameters in sporadic colonic adenomas. METHODS:A randomized, double-blind placebo-controlled trial was performed. Patients scheduled to undergo surveillance colonoscopy for previous sporadic colonic adenomas were identified, and 60 eligible patients were randomized to placebo or active dietary intervention (ADI) twice a day, for 60 d before surveillance colonoscopy. ADI was a mixture of 175 mg milk thistle extract, 20 mg secoisolariciresinol and 750 mg oat fiber extract. ER-β and ER-α expression, apoptosis and proliferation (Ki-67 LI) were assessed in colon samples. RESULTS:No adverse event related to ADI was recorded. ADI administration showed a significant increases in ER-β protein (0.822 ± 0.08 vs 0.768 ± 0.10, P = 0.04) and a general trend to an increase in ER-β LI (39.222 ± 2.69vs 37.708 ± 5.31,P = 0.06), ER-β/ER-α LI ratio (6.564 ± 10.04 vs 2.437 ± 1.53, P = 0.06), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (35.592 ± 14.97 vs 31.541 ± 11.54, P = 0.07) and Ki-67 (53.923 ± 20.91 vs 44.833 ± 10.38, P = 0.07) approximating statistical significance. A significant increase of ER-β protein (0.805 ± 0.13 vs 0.773 ± 0.13,P = 0.04), mRNA (2.278 ± 1.19vs 1.105 ± 1.07, P < 0.02) and LI (47.533 ± 15.47 vs 34.875 ± 16.67,P < 0.05) and a decrease of ER-α protein (0.423 ± 0.06vs 0.532 ± 0.11,P < 0.02) as well as a trend to increase of ER-β/ER-α protein in ADI vs placebo group were observed in patients without polyps (1.734 ± 0.20 vs 1.571 ± 0.42, P = 0.07). CONCLUSION:The role of ER-β on the control of apoptosis, and its amenability to dietary intervention, are supported in our study.

The Relationship of the Expression of Estrogen Receptor in Cartilage Cell and Osteoarthritis Induced by Bilateral Ovariectomy in Guinea Pig

To investigate the estrogen receptor（ER） expression in cartilage cell in the development of oste0arthritis induced by bilateral ovariectomy in guinea pig and to find their relationship. 30 two-month-old female guinea pigs were randomly divided into two groups （n=15 each） ： sham operation （control）group and ovariectomized group （OVX）; Scanning electorne microscope （SEM） and transmission electron microscope （TEM） were obtained to analysis the cartilage degeneration of the hind limb knee joint after 6 and 12 weeks of ovariectomy. Dextran-Coated-Charcoal （DCC） was taken to quantitively detect the expression of ER. The serum levels of estrogen and gestone were detected by immune contest assay. The results showed that ER do exist in the cartilages of the guinea pigs, with higher expression in the control group than in OVX group at the same time point （P〈0. 05）. It was increased also at 12 th week after operation than that of preoperation. The blood serum levels of estrogen and gestone showed a similar tendency to the expression of ER. Joint cartilage degeneration detected by SEM and TEM could be found at 6 th week, but severe degenerative lesions at 12 th week in the OVX group compared with the control group （P〈0.01）. The data suggested that bilateral ovariectomy in guinea pig lead to severe os.teoarthritis which mighgt be related to the lower serum level of estrogen and the downregulation of the expression of ER in the cartilage also.

Combined treatment with valproic acid and estrogen has neuroprotective effects in ovariectomized mice with Alzheimer’s disease

Postmenopausal women with Alzheimer’s disease exhibit dramatically reduced sensitivity to estrogen replacement therapy,which is though to be related to an estrogen receptor(ER)α/ERβratio imbalance arising from a significantly decreased level of ERs of the brain.The aim of our study was to investigate whether valproic acid(VPA)can enhance the beneficial effects of estrogen on cognitive function through restoration of ERαand ERβexpression in the brain.We removed the ovaries of female APP/PS1 mice to simulate the low estrogen levels present in postmenopausal women and then administered VPA(30 mg/kg,intraperitoneal injection,once daily),17β-estradiol(E2)(2.4μg,intraperitoneal injection,once daily),liquiritigenin(LG)(50μg/kg,intragastric infusion,once daily),VPA+E2,or VPA+LG for 4 successive weeks.Compared with treatment with a single drug,treatment with VPA+E2 or VPA+LG significantly increased the level of glycogen synthase kinase 3β,increased the expression of estrogen receptorα,reduced the expression of small ubiquitin-like modifiers,and increased the level of estrogen receptorβ.This resulted in enhanced sensitivity to estrogen therapy,reduced amyloidβaggregation,reduced abnormal phosphorylation of the tau protein,reduced neuronal loss,increased dendritic spine and postsynaptic density,and significantly alleviated memory loss and learning impairment in Alzheimer’s disease.This study was approved by the Chongqing Medical University Animal Protection and Ethics Committee,China on March 6,2013.

Xenoestrogens challenge 17β-estradiol protective effects in colon cancer

Several epidemiological,cellular,and molecular studies demonstrate the role of environmental chemicals with endocrine disrupting activities,typical of Westernized societies,in the pathogenesis of numerous diseases including cancer.Nonetheless this information,the design and execution of studies on endocrine disruptors are not yet cognizant that the specific actions of individual hormones often change with development and ageing,they may be different in males and females and may be mediated by different receptors isoforms expressed in different tissues or at different life stages.These statements are particularly true when assessing the hazard of endocrine disruptors against 17β-estradiol(E2)actions in that this hormone is crucial determinant of sexrelated differences in anatomical,physiological,and behavioral traits which characterize male and female physiology.Moreover,E2 is also involved in carcinogenesis.The oncogenic effects of E2 have been investigated extensively in breast and ovarian cancers where hormone-receptor modulators are now an integral part of targeted treatment.Little is known about the E2preventive signalling in colorectal cancer,although this disease is more common in men than women,the difference being more striking amongst pre-menopausal women and age-matched men.This review aims to dissect the role and action mechanisms of E2 in colorectal cancer evaluating the ability of estrogen disruptors(i.e.,xenoestrogens)in impair these E2 actions.Data discussed here lead to define the possible role of xenoestrogens in the impairment and/or activation of E2signals important for colorectal cancer prevention.

Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis

AIM To investigate gender-specific liver estrogen receptor(ER) expression in normal subjects and patients with hepatitis C virus(HCV)-related cirrhosis and hepatocellular carcinoma(HCC).METHODS Liver tissues from normal donors and patients diagnosed with HCV-related cirrhosis and HCV-related HCC were obtained from the NIH Liver Tissue and Cell Distribution System. The expression of ER subtypes, ERα and ERβ, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ERα and ERβ was further determined in nuclear and cytoplasmic tissue lysates along with the expression ofinflammatory [activated NF-κB and IκB-kinase(IKK)] and oncogenic(cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ERα and ERβ was correlated with the expression of activated NF-κB, activated IKK and cyclin D1 by Spearman's correlation. RESULTS Both ER subtypes were expressed in normal livers but male livers showed significantly higher expression of ERα than females(P < 0.05). We observed significantly higher m RNA expression of ERα in HCV-related HCC liver tissues as compared to normals(P < 0.05) and ERβ in livers of HCV-related cirrhosis and HCV-related HCC subjects(P < 0.05). At the protein level, there was a significantly higher expression of nuclear ERα in livers of HCV-related HCC patients and nuclear ERβ in HCV-related cirrhosis patients as compared to normals(P < 0.05). Furthermore, we observed a significantly higher expression of phosphorylated NF-κB and cyclin D1 in diseased livers(P < 0.05). There was a positive correlation between the expression of nuclear ER subtypes and nuclear cyclin D1 and a negative correlation between cytoplasmic ER subtypes and cytoplasmic phosphorylated IKK in HCV-related HCC livers. These findings suggest that dysregulated expression of ER subtypes following chronic HCVinfection may contribute to the progression of HCVrelated cirrhosis to HCV-related HCC.CONCLUSION Gender differences were observed in ERα expression in normal livers. Alterations in ER subtype expression observed in diseased livers may influence genderrelated disparity in HCV-related pathogenesis.

Effects of estrogen receptor modulators on cytoskeletal proteins in the central nervous system

Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1（MAP1）, MAP2, neurofilament 38（NF38） by different mechanisms of action and at different levels： neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects.

Estrogen receptor beta treats Alzheimer's disease

In vitro studies have shown that estrogen receptor β can attenuate the cytotoxic effect of amyloid protein on PC12 cells through the Akt pathway without estrogen stimulation. In this study, we aimed to observe the effect of estrogen receptor β in Alzheimer＇s disease rat models established by intraventricular injection of amyloid β protein. Estrogen receptor β lentiviral particles delivered via intraventricular injection increased Akt content in the hippocampus, decreased interleukin-1β mRNA tumor necrosis factor a mRNA and amyloid β protein levels in the hippocampus, and improved the learning and memory capacities in AIzheimer＇s disease rats. Estrogen receptor β short hairpin RNA lentiviral particles delivered via intraventricular injection had none of the above impacts on AIzheimer＇s disease rats. These experimental findings indicate that estrogen receptor β, independent from estrogen, can reduce inflammatory reactions and amyloid β deposition in the hJppocampus of AIzheimer＇s disease rats, and improve learning and memory capacities. This effect may be mediated through activation of the Akt pathway.

G-protein-coupled estrogen receptor as a new therapeutic target for treating coronary artery disease

Coronary heart disease(CHD) continues to be the greatest mortality risk factor in the developed world. Estrogens are recognized to have great therapeutic potential to treat CHD and other cardiovascular diseases; however,a significant array of potentially debilitating side effects continues to limit their use. Moreover,recent clinical trials have indicated that long-term postmenopausal estrogen therapy may actually be detrimental to cardiovascular health. An exciting new development is the finding that the more recently discovered G-protein-coupled estrogen receptor(GPER) is expressed in coronary arteries-both in coronary endothelium and in smooth muscle within the vascular wall. Accumulating evidence indicates that GPER activation dilates coronary arteries and can also inhibit the prolif-eration and migration of coronary smooth muscle cells. Thus,selective GPER activation has the potential to increase coronary blood flow and possibly limit the debilitating consequences of coronary atherosclerotic disease. This review will highlight what is currently known regarding the impact of GPER activation on coronary arteries and the potential signaling mechanisms stimulated by GPER agonists in these vessels. A thorough understanding of GPER function in coronary arteries may promote the development of new therapies that would help alleviate CHD,while limiting the potentially dangerous side effects of estrogen therapy.

Ulcerative colitis: From inflammation to cancer. Do estrogen receptors have a role?

Ulcerative colitis(UC) is a condition at increased risk for colorectal carcinoma(CRC) development. Nowadays, screening and follow-up programs are routinely performed worldwide to promote the early detection of CRCs in subjects with well known risk factors(extent, duration and severity of the disorder). The diffusion of these procedures is presumably the main reason for the marked reduction of cancer incidence and mortality in the course of UC. In addition, chemoprevention has been widely investigated and developed in many medical fields, and aspirin has shown a preventive effect against CRC, while mesalazine has been strongly invoked as a potential chemopreventive agent in UC. However, available studies show some limitations due to the obvious ethical implications of drug withdrawal in UC in order to design a control group. The estrogenreceptors(ER) alpha/beta balance seems to have a relevant influence on colorectal carcinogenesis and ER beta appears to parallel apoptosis, and hence an anticarcinogenic effect. Phytoestrogens are compounds acting as ER beta agonists and have shown a promising chemopreventive effect on sporadic as well as genetically inherited CRC. There is evidence suggesting a role for ERs in UC-related carcinogenesis. In this perspective, since these substances can be considered as dietary supplements and are completely free from side effects, phytoestrogens could be an interesting option for CRC prevention, even when the disease is a consequence of long-term chronic inflammation, as in the course of UC. Further studies of their effects are warranted in both the basic research and clinical fields.

Effect of Compound Recipe Gengniankang (更年康) on Senile Sexual Hormone and Expression of Estrogen Receptor in Bone of Climacteric Female Rats

Objective： To compare the therapeutic effect of Compound Recipe Gengniankang （更年康, GNK） with that of hormone replacement treatment （HRT） on climacteric female rats with osteoporosis, and to investigate the roles of estrogen and estrogen receptors in the mechanism of osteoporosis. Methods： Climacteric female rats with osteoporosis were chosen and divided into three groups （GNK group, HRT group and control group）. Apoptosis of ovarian granulose cells was measured by terminal-deoxynucleotidyl transferae mediated nick end labeling （TUNEL） assay. Serum level of estrdiol （E2）, follicle stimulating hormone （FSH）, luteinizing hormone （LH） were determined by the method of radioimmunoassay （RIA）. Reverse transcriptase polymerase chain reaction （RT-PCT） technology was used to evaluate the expression of estrogen receptor （ER） in bone. Bone mineral density （BMD） was measured by double energy X-ray absorption （DEXA）. Results： In the climacteric rats, BMD, serum E2, ER mRNA expression in bone decreased remarkably, and serum FSH, LH and apoptosis of ovarian granulose cells increased obviously. After treating with GNK, all the indexes were reversed except serum E2. The increase of E2 was not significant. Conclusion： GNK is effective on climacteric osteoporosis female rats. Its role is performed not by increasing serum E2 but by enhancing ER in the bone and inhibiting apoptosis of ovarian granulose cells. GNK can deter further exhaustion of ovarian function.