Effect Of Exogenous Estrogen Research Articles

FRI451 Effect Of Estrogen Replacement On Various Metabolic Parameters In Turner’s Syndrome

Abstract Disclosure: I. Mishra: None. S. Jena: None. A.K. Baliarsinha: None. Turner’s Syndrome is a rare genetic disorder caused by complete or partial X chromosome monosomy in a phenotypic female, and is associated with increased morbidity and mortality for cardiovascular diseases, impaired glucose tolerance, liver dysfunction and dyslipidemia. Estrogen therapy was initially focused on pubertal induction and preservation of bone health. Recent longitudinal studies have shown the beneficial effect of estrogen therapy on various metabolic parameters, liver dysfunction and insulin resistance in these patients.To study the effect of estrogen therapy on various metabolic parameters, a cohort of 24 adolescent girls with Turner’s Syndrome planned for hormonal replacement therapy were recruited. Baseline data of detailed history, clinical examination, biochemical evaluation including glycemic status, lipid profile, liver function test and fibroscan were collected. At 6 month follow-up of estrogen replacement, repeat biochemical evaluation and fibroscan were done.The data obtained was entered into Microsoft Excel Worksheet and analysed using Statistical Package for Social Sciences (SPSS, IBM Corp. Released 2020. IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY: IBM Corp.). The normal distribution of data was confirmed with Shapiro-Wilk's test and appropriate parametric tests were employed. Mean and standard deviation were computed for all continuous variables. At baseline visit and 6 month follow up, statistically significant improvement, was found in fasting plasma glucose, post-prandial plasma glucose, fasting insulin, HOMA-IR, VLDL and total bilirubin with estrogen therapy. Maximum reduction (p <0.001) was seen in LDL, AST, ALT and fibroscan values .No improvement was seen in triglyceride, HDL, direct bilirubin and ALP levels. Estrogen has been shown to improve insulin sensitivity and suppress gluconeogenesis by transcription factor Foxo1(1). Hepatoprotective role of estrogen has been explained by anti-inflammatory effects and protection from oxidative stress, mainly mediated via β estrogen receptor(2). Beneficial effects of estrogen on lipid profile have been verified in several studies. We conclude that the benefits of estrogen therapy in Turner’s Syndrome are much beyond the limit of puberty induction and bone health and pleiotropic actions of estrogen still need to be elucidated with further studies. Reference: (1) Yan et al; Estrogen Improves Insulin Sensitivity and Suppresses Gluconeogenesis via the Transcription Factor Foxo1. Diabetes 1 February 2019; 68 (2): 291–304. (2) Koulouri O et al. Liver dysfunction in Turner's syndrome: prevalence, natural history and effect of exogenous oestrogen. ClinEndocrinol (Oxf). 2008 Aug;69(2):306-10. Presentation: Friday, June 16, 2023

SAT647 Quantifying The Effects Of Gender-Affirming Hormone Therapy On Bone Density Of Transgender Patients: Emerging Results Of A Single-center Study

Abstract Disclosure: C.M. Godar: None. S.C. De La Torre: None. O. Bonsu: None. M.K. Shakir: None. T.D. Hoang: None. Introduction: The care of transgender patients with gender-affirming hormone therapy (GAHT) is becoming increasingly common throughout the United States. Estrogen-based hormone therapy has well-known anabolic effects on bone density in post-menopausal women. Few studies have evaluated the long-term effect of exogenous estrogen or testosterone on bone density of transgender patients. Current guidelines do not suggest a recommended age of DXA screening onset or screening interval for transgender patients on GAHT, or whether to use birth gender vs. affirmed gender standards. In this single-center study, we aim to better characterize bone mineral density (BMD) patterns of transgender patients on GAHT over a 1-year period. Methods: 17 transgender patients underwent DXA scan at baseline, 6 months, and 1 year after starting GAHT. 11 transgender females on estradiol and 6 transgender males on testosterone were included. BMD, T-score, and Z-score data for lumbar spine, total hip, femoral neck, and forearm were measured. 2 patients did not receive 6-month scan, but all patients received baseline and 1-year scans. Mean BMD was calculated at all time points. Data were compared to known T-score and Z-score cutoffs for low BMD (T-score: ≥-1 normal, -1.1 to -2.4 osteopenia, ≤-2.5 osteoporosis; Z-score ≤-2 low BMD for age). Results: Mean BMD change for transgender males at 1 year was +1.8% at lumbar spine, -0.7% at femoral neck, +1.4% at total hip, and -13.3% at forearm. Mean BMD change for transgender females was +4.5% at lumbar spine, +2.8% at femoral neck, -6.9% at total hip, and +1.5% at forearm. Using male T-score standards, 1 transgender male who was osteoporotic at baseline was osteopenic at one year. Using female Z-score standards, 1 transgender female with low BMD for age achieved normal BMD at one year. Male Z-score and female T-score trends did not change any individual’s BMD categorization. Conclusion: These results suggest a trend of modest BMD improvement at lumbar spine after patients begin GAHT regardless of gender, with a pattern of worsening total hip BMD in transgender females and worsening forearm BMD in transgender males. These results are limited by a small study population that is growing as data collection continues. Further statistical analyses are needed to determine significance of our findings. Bone density increases may be attributed to hormone therapy, though it is hypothesized that correction of gender dysphoria and greater physical well-being play a role as well. For these variable BMD changes, we suggest that universal DXA screening guidelines could be considered for transgender patients after 1 year of GAHT, though a decision to treat based on abnormal results remains controversial. Studies of longer duration are needed to make conclusions on long-term bone density effects of GAHT. Presentation: Saturday, June 17, 2023

The effects of exogenous estrogen in women with SAR-CoV-2 infection: a systematic review and meta-analysis

Does exogenous estrogen use affect COVID-19-related mortality in women? Menopausal hormone therapy (MHT) was associated with a lower likelihood of all-cause fatality related to COVID-19in postmenopausal women (odds ratio (OR) 0.28, 95% CI 0.18, 0.44; 4 studies, 21 517 women) but the combined oral contraceptive pill in premenopausal women did not have a significant effect (OR 1.00, 95% CI 0.42-2.41; 2 studies, 5099 women). Men are much more likely to die from COVID-19 than women. In this systematic meta-analysis, a literature search was conducted using the following search terms related toCOVID-19 and estrogen, sex hormones, hormonal replacement, menopause, or contraception. The PubMed, Scopus, Cochrane Library, and EMBASE databases were searched to identify relevant studies published between December 2019 and December 2021. We also searched MedRxiv as a preprint database and reviewed the reference lists of all included studies and clinical trial registries for ongoing clinical studies until December 2021. All comparative studies that compared the rates mortality and morbidity (hospitalization, intensive care unit (ICU) admission, and ventilation support) due to COVID-19 in women using exogenous estrogen to a control group of women (nonusers) were included. A review of the studies for inclusion, extraction of data, and assessment of the risk of bias was performed independently by two reviewers. The ROBINS-I tool and the RoB 2 tool were used for bias assessment of the included studies. Pooled odds ratios (ORs) with 95% CIs were calculated using Review Manager V5.4.1. The I2 statistic was used to quantify heterogeneity. The quality of the evidence was assessed using GRADE criteria. After searching the databases, we identified a total of 5310 studies. After removing duplicate records, ineligible studies, and ongoing studies, a total of four cohort studies and one randomized controlled trial comprising 177 809 participants were included in this review. There was a moderate certainty of evidence that MHT was associated with a lower likelihood of all-cause fatality related to COVID-19 (OR 0.28, 95% CI 0.18, 0.44; I2 = 0%; 4 studies, 21 517 women). The review indicated a low certainty of evidence for other outcomes. The mortality rate of premenopausal women in the combined oral contraceptive pill group did not differ significantly from the control group (OR 1.00, 95% CI 0.42-2.41; 2 studies, 5099 women). MHT marginally increased the rate of hospitalization and ICU admission (OR 1.37, 95% CI 1.18-1.61; 3 studies, 151 485 women), but there was no significant difference in the need for respiratory support between MHT users and nonusers (OR 0.91, 95% CI 0.52-1.59; 3 studies, 151 485 women). Overall, the tendency and magnitude of the effects of MHT in postmenopausal women with COVID-19 were consistent across the included studies. The certainty of the evidence for other outcomes of this review may be limited, as all included studies were cohort studies. In addition, the dosages and durations of exogenous estrogen used by postmenopausal women varied from study to study, and combined progestogen administration may have had some effect on the outcomes. The findings of this study can aid in counseling postmenopausal women taking MHT when they are diagnosed with COVID, as they have a lower chance of death than those not taking MHT. Khon Kaen University provided financial support for this review and had no involvement at any stage of the study. The authors have no conflicts of interest to declare. PROSPERO, CRD42021271882.

The Selective Estrogen Receptor Modulator, Raloxifene, Is Protective Against Renal Ischemia-reperfusion Injury.

There is increasing evidence that estrogen is responsible for improved outcomes in female kidney transplant recipients. Although the exact mechanism is not yet known, estrogen appears to exert its protective effects by ameliorating ischemia-reperfusion injury (IRI). In this study, we have examined whether the beneficial effects of exogenous estrogen in renal IRI are replicated by therapy with any one of several selective estrogen receptor modulators. C57BL/6 adult mice underwent standardized warm renal ischemia for 28 min after being injected with the selective estrogen receptor modulators, raloxifene, lasofoxifene, tamoxifen, bazedoxifene, or control vehicle (dimethyl sulfoxide), at 16 and 1 h before IRI. Plasma concentrations of blood urea nitrogen and creatinine were assessed 24, 48, 72, and 96 h post-IRI. Tissue was collected 30 d postischemia for fibrosis analysis using Sirius Red staining. Raloxifene treatment in female mice resulted in significantly lower blood urea nitrogen and creatinine after IRI and significantly lower fibrosis 30 d following IRI. Raloxifene is protective against both acute kidney injury and fibrosis resulting from renal IRI in a mouse model.

In vitro fertilization and hypertriglyceridemic pancreatitis: Case report

Few cases of hypertriglyceridemic pancreatitis have been reported in women during a vitro fertilization treatment (IVF) cycle. Here, we describe a 41-year-old woman with primary infertility and a history of acute pancreatitis (of unknown etiology) who was started on high dose ethinyl estradiol to prepare for transfer of cryopreserved embryos. She subsequently presented with nausea, vomiting, and abdominal pain to an emergency room and was found to have hypertriglyceridemic pancreatitis. Her hospitalization involved a prolonged intensive care unit stay in which she underwent three sessions of plasmapheresis. Eventually, with discontinuation of ethinyl estrogen, aggressive intravenous fluid hydration, plasmapheresis, a low-fat diet, and gemfibrozil, she had resolution of severe hypertriglyceridemia and all symptoms related to acute pancreatitis. Our case highlights the possibility that ethinyl estradiol, a commonly used form of estrogen for endometrial preparation during IVF cycles, may cause severe hypertriglyceridemia and acute pancreatitis in certain predisposed individuals. Only seven cases of hypertriglyceridemic pancreatitis during in vitro fertilization have been previously reported, and only one of these prior cases experienced pancreatitis during transfer of cryopreserved embryos like our patient. Our case, along with the few prior reported cases, demonstrate hypertriglyceridemic pancreatitis can occur during IVF. Further work is needed to understand the effects of exogenous estrogen on lipids for women undergoing IVF.

Protection of mice against carbon tetrachloride-induced acute liver injury by endogenous and exogenous estrogens

Gender is a crucial factor determining susceptibility to drug-induced liver injury (DILI) in humans and experimental animals. However, no general concept of sex differences in DILI has been established, as metabolic events specific to one DILI model are difficult to apply to other DILI models. Herein, we examined sex differences in carbon tetrachloride (CCl4)-induced hepatotoxicity, a widely employed DILI model. Male and female CD-1 mice were intraperitoneally administered CCl4. Additionally, some male mice were administered genistein or another isoflavone to evaluate the effects of exogenous estrogens. Dose-dependent alanine aminotransferase leakage was observed at a CCl4 range of 0.5–10 mmol/kg, with male-dominant sex differences mainly observed at lower doses. No sex differences in hepatic glutathione levels or thiobarbituric acid-reactive substance formation were detected. CCl4 induced hepatic inflammatory genes, interleukin (IL)-6 and tumor necrosis factor (TNF)-α, predominantly in female mice, which might be involved in DILI resistance, observed in female mice. Treatment of male mice with phytoestrogens, especially genistein, attenuated CCl4-induced hepatotoxicity. Moreover, genistein inhibited IL-6 and TNF-α expression, suggesting possible hepatoprotection via immunosuppression. In conclusion, female mice are resistant to CCl4-induced hepatotoxicity, and male mice were afforded protection by genistein, probably via mechanisms based on anti-estrogenic, antioxidant and/or anti-inflammatory effects.

Effects of menopausal hormone therapy on erythrocyte n–3 and n–6 PUFA concentrations in the Women’s Health Initiative randomized trial

The factors other than dietary intake that determine tissue concentrations of EPA and DHA remain obscure. Prior studies suggested that, in women, endogenous estrogen may accelerate synthesis of DHA from ɑ-linolenic acid (ALA), but the effects of exogenous estrogen on RBC n-3 (ɷ-3) PUFA concentrations are unknown. We tested the hypothesis that menopausal hormone therapy (HT) would increase RBC n-3 PUFA concentrations. Postmenopausal women (ages 50-79 y) were assigned to HT or placebo in the Women's Health Initiative (WHI) randomized trial. The present analyses included a subset of 1170 women (ages 65-79 y) who had RBC PUFA concentrations measured at baseline and at 1 y as participants in the WHI Memory Study. HT included conjugated equine estrogens (E) alone for women without a uterus (n=560) and E plus medroxyprogesterone acetate (P) for those with an intact uterus (n=610). RBC n-3 and n-6 (ɷ-6) PUFAs were quantified. Effects of E alone and E+P on PUFA profiles were similar and were thus combined in the analyses. Relative to the changes in the placebo group after 1 y of HT, docosapentaenoic acid (DPA; n-3) concentrations decreased by 10% (95% CI: 7.3%, 12.5%), whereas DHA increased by 11% (95% CI: 7.4%, 13.9%) in the HT group. Like DHA, DPA n-6 increased by 13% from baseline (95% CI: 10.0%, 20.3%), whereas linoleic acid decreased by 2.0% (95% CI: 1.0%, 4.1%; P values at least <0.01 for all). EPA and arachidonic acid concentrations were unchanged. HT increased RBC concentrations of the terminal n-3 and n-6 PUFAs (DHA and DPA n-6). These findings are consistent with an estrogen-induced increase in DHA and DPA n-6 synthesis, which is consistent with an upregulation of fatty acid elongases and/or desaturases in the PUFA synthetic pathway. The clinical implications of these changes require further study. The Women's Health Initiative Memory Study is registered at clinicaltrials.gov as NCT00685009. Note that the data presented here were not planned as part of the original trial, and therefore are to be considered exploratory.

Estrogen Aggravates Tumor Growth in a Diffuse Gastric Cancer Xenograft Model.

Gastric cancer has the fifth-highest incidence rate and is the third leading cause of cancer-related deaths worldwide. The incidence of gastric cancer is higher in men than in women, but for the diffuse types of gastric cancer, the trend is opposite. Estrogen is considered the prime culprit behind these differences. Nevertheless, the action of estrogen in gastric cancers remains unclear. In this study, we investigated the effect of estrogen on diffuse-type gastric cancer. Human female diffuse gastric cancer SNU-16 cells were transplanted into male and female mice to analyze the effect of endogenous estrogen on tumor growth. Furthermore, the effect of exogenous estrogen was evaluated in ovariectomized mice. Expressed genes were compared between female and male xenograft models using RNA sequencing analysis. Furthermore, human gene expression omnibus databases were utilized to examine the effect of our target genes on overall survival. SNU-16-derived tumor growth was faster in female mice than in male mice. In total RNA sequencing, interferon gamma receptor 2 (IFNGR2), IQ motif containing E (IQCE), transient receptor potential cation channel subfamily M member 4 (TRPM4), and structure-specific endonuclease subunit SLX4 (SLX4) were found. These genes could be associated with the tumor growth in female diffuse-type gastric cancer which was affected by endogenous estrogen. In an ovariectomized gastric cancer xenograft model, exogenous estrogen promoted tumor growth. Especially, our results indicated that estrogen induced G protein-coupled estrogen receptor expression in these mice. These results suggest that estrogen aggravates tumor progression in female diffuse gastric cancer.

Alterations in the estrogen receptor profile of cardiovascular tissues during aging.

Estrogen exerts protective effects on the cardiovascular system via three known estrogen receptors: alpha (ERα), beta (ERß), and the G protein-coupled estrogen receptor (GPER). Our laboratory has previously showed the importance of GPER in the beneficial cardiovascular effects of estrogen. Since clinical studies indicate that the protective effects of exogenous estrogen on cardiovascular function are attenuated or reversed 10 years post-menopause, the hypothesis was that GPER expression may be reduced during aging. Vascular reactivity and GPER protein expression were assessed in female mice of varying ages. Physiological parameters, blood pressure, and estrogen receptor transcripts via droplet digital PCR (ddPCR) were assessed in the heart, kidney, and aorta of adult, middle-aged, and aged male and female C57BL/6 mice. Vasodilation to estrogen (E2) and the GPER agonist G-1 were reduced in aging female mice and were accompanied by downregulation of GPER protein. However, ERα and GPER were the predominant receptors in all tissues, whereas ERß was detectable only in the kidney. Female sex was associated with higher mRNA for both ERα and GPER in both the aorta and the heart. Aging impacted receptor transcript in a tissue-dependent manner. ERα transcript decreased in the heart with aging, while GPER expression increased in the heart. These data indicate that aging impacts estrogen receptor expression in the cardiovascular system in a tissue- and sex-specific manner. Understanding the impact of aging on estrogen receptor expression is critical for developing selective hormone therapies that protect from cardiovascular damage.

Factors associated with endometrial cancer and hyperplasia among middle-aged and older Hispanics

ObjectiveWhile disparities in endometrial hyperplasia and endometrial cancer are well documented in Blacks and Whites, limited information exists for Hispanics. The objective is to describe the patient characteristics associated with endometrial hyperplasia symptoms, endometrial hyperplasia with atypia and endometrial cancer, and assess factors contributing to racial/ethnic differences in disease outcomes. MethodsThis single-center, retrospective study included women aged ≥50 years with ≥ two encounters for endometrial hyperplasia symptoms, endometrial hyperplasia with atypia and endometrial cancer between 2012 and 2016. Multivariate logistic regression models evaluated the predictors of endometrial cancer and hyperplasia. ResultsWe included 19,865 women (4749 endometrial hyperplasia symptoms, 71 endometrial hyperplasias with atypia, 201 endometrial cancers) with mean age of 60.45 years (SD 9.94). The odds of endometrial hyperplasia symptoms were higher in non-Hispanic Blacks (Odds Ratio [OR] 1.56, 95% Confidence Interval [CI] 1.20–1.72), Hispanics (OR 1.35, 95% CI 1.22–1.49), family history of female cancer (OR 1.25, 95% CI 1.12–1.39), hypertension (OR 1.24, 95% CI 1.14–1.35), and birth control use (OR 1.29, 95% CI 1.15–1.43). Odds of endometrial cancer and atypical hyperplasia increased for ages 60–64 (OR 7.95, 95% CI 3.26–19.37; OR 3.66, 95% 1.01–13.22) and being obese (OR 1.61, 95% CI 1.08–2.41; OR: 6.60, 95% CI 2.32–18.83). Odds of endometrial cancer increased with diabetes (OR 1.68, 95% CI 1.22–2.32). Conclusion(s)Patients with obesity and diabetes had increased odds of endometrial cancer and hyperplasia with atypia. Further study is needed to understand the exogenous estrogen effect contributing to the increased incidence among Hispanics.

Histological and Biochemical Study on the Estrogen Role in Indomethacin-induced Gastric Ulcer of Menopausal Rats

Background: Estrogen is a principal female sex hormone that originally characterized by its importance in sexual growth and reproduction. Nevertheless, emergent evidence proposes clinical relationship between estrogen/ estrogen receptors and gastric diseases. This association is definitely under several investigated topics.Aim: The current study designed to explore exogenous estrogen effect on indomethacin-induced gastric ulcers in postmenopausal female rats.Matrial and methods: Twenty-four female rats (200 ± 20 gram BW) were allocated randomly into four groups; control, ulcer-induced, ranitidine-treated and (ranitidine&estradiol velerate) combined-treated group. Animal in all group except control subjected to ovariectomy to assimilate menopausal condition. At end of the experiment, the stomach fundus examined macroscopically to assess the ulcer severity and ulcer score in different groups. Histopatholgical and biochemical evaluation also were performed and all results were statistically analyzed.Results: Indomethacin-induced gastric ulcer in ovariectomized rats showed destroyed fundic mucosa and mucus layer, increase oxidative stress markers, inflammatory mediators and myeloperoxidase. Treatment with ranitidine attenuated the histological and biochemical changes but within limits. Better improvement was accomplished when ranitidine combined with estrogen.Conclusion: The postmenopausal women should be supplemented with estrogen not only to control menopausal symptoms but also to protect and maintain gastric mucosal integrity.

Effect of exogenous estrogens and progestogens on the course of migraine during reproductive age: a consensus statement by the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESCRH)

We systematically reviewed data about the effect of exogenous estrogens and progestogens on the course of migraine during reproductive age. Thereafter a consensus procedure among international experts was undertaken to develop statements to support clinical decision making, in terms of possible effects on migraine course of exogenous estrogens and progestogens and on possible treatment of headache associated with the use or with the withdrawal of hormones. Overall, quality of current evidence is low. Recommendations are provided for all the compounds with available evidence including the conventional 21/7 combined hormonal contraception, the desogestrel only oral pill, combined oral contraceptives with shortened pill-free interval, combined oral contraceptives with estradiol supplementation during the pill-free interval, extended regimen of combined hormonal contraceptive with pill or patch, combined hormonal contraceptive vaginal ring, transdermal estradiol supplementation with gel, transdermal estradiol supplementation with patch, subcutaneous estrogen implant with cyclical oral progestogen. As the quality of available data is poor, further research is needed on this topic to improve the knowledge about the use of estrogens and progestogens in women with migraine. There is a need for better management of headaches related to the use of hormones or their withdrawal.

Effect of exogenous estrogen on the ovarian development and gene expression in the female swimming crab Portunus trituberculatus (Miers, 1876) (Decapoda: Brachyura: Portunidae)

Effect of exogenous estrogen on the ovarian development and gene expression in the female swimming crab Portunus trituberculatus (Miers, 1876) (Decapoda: Brachyura: Portunidae)

Menopause and menopausal hormone therapy in women: cardiovascular benefits and risks

The last decade has brought many challenges and uncertainties regarding the use of menopausal hormone therapy in women. Two early key studies, the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative (WHI) failed to prove beneficial effects of exogenous estrogen, and estrogen combined with progestin, in cardiovascular prevention. More recent studies, however, introduced the concept of a possible “window-of-opportunity” for hormonal therapy, in which menopausal hormone therapy is used early after the onset of menopause, and may lead to more favorable, cardio-protective outcomes. Despite the increasing wealth of clinical data, menopausal hormone therapy is not currently recommended for primary or secondary prevention of coronary heart disease in women. Further research is needed to understand the risk-benefit balance of menopausal hormone therapy.

Low doses of 17α-ethinyl estradiol alter the maternal brain and induce stereotypies in CD-1 mice exposed during pregnancy and lactation

Maternal care is critical for the survival, development and long-term success of offspring. Despite our current understanding of the role of endogenous estrogen in both maternal behavior and the maternal brain, the potential effects of exogenous estrogens on these endpoints remain poorly understood. Here, pregnant CD-1 mice were exposed to low doses of 17α-ethinyl estradiol (EE2), commonly used as a positive control in studies of other xenoestrogens, from day 9 of pregnancy until weaning. Using traditional maternal behavior assays, we document no significant changes in maternal behavior throughout the lactational period. However, EE2 induced increases in repetitive tail retrieval, which may indicate a stereotypy or obsessive compulsive (OCD)-like behavior. We also observed a significant reduction in tyrosine hydroxylase (TH) immunoreactivity in the ventral tegmental area (VTA), a region important for maternal motivation. These results suggest that pregnant adult females are not immune to the effects of this compound.

Estrogen protects both sexes against EAE by promoting common regulatory cell subtypes independent of endogenous estrogen.

Autoimmune diseases including multiple sclerosis predominantly affect females. Although high levels of sex hormones, particularly estrogen (E2), can reduce proinflammatory immune responses, it remains unclear if a lack of endogenous sex hormones might affect treatment with exogenous sex hormones. Pretreatment with E2 almost completely prevents intact female and male mice from developing clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) by promoting various regulatory immune cell phenotypes. To evaluate the effects of exogenous estrogen in the absence of endogenous sex hormones, the current study compared EAE severity and the emergence of different immunoregulatory cell populations after E2 pretreatment of ovariectomized (OVX) female versus male mice. We found that E2 equally protected both OVX females and males from EAE over a 21day observation period concomitant with reduced total cell numbers in spleen and spinal cord (males only), but enhanced percentages of CD19+CD5+CD1dhi, CD19+CD138+CD44hi and CD19+Tim-1+ Breg cells, CD8+CD122+ Treg cells and CD11b+CD 206+ARG-1+ anti-inflammatory M2-like monocytes/macrophages in both groups. In contrast, E2 decreased the percentage of CD4+CD25+FoxP3+ Treg cells in OVX females but increased these Treg cells in males and intact female mice. These data suggest that with the exception of CD4+CD25+FoxP3+ Treg cells, E2 protection against EAE promotes highly overlapping immunoregulatory subsets in OVX females and males.

Effects of low dose of bisphenol A on the proliferation and mechanism of primary cultured prostate epithelial cells in rodents.

Bisphenol A (BPA) is a well-known endocrine disruptor compound (EDC) that aggravates testosterone-induced benign prostate hyperplasia by increasing the relative weight of the ventral and dorsolateral prostate in rats. This phenomenon is primarily attributed to the exogenous estrogen effect of BPA. However, the direct effect of BPA on prostate cells has not been characterized. The present study investigated the proliferative effect and possible mechanisms of action of BPA on the prostatic epithelium of rats. The ventral prostate epithelial cells were cultured in vitro and the proliferation effects of BPA on cells were studied. The cells were identified as prostatic epithelial cells, and cell viability, cell apoptosis and the expressions of androgen receptors (AR) and estrogen receptors (ER), were detected. It was observed that 0.01–1 nM BPA promoted cell growth, with 1 nM BPA inducing the greatest increase in the rate of cell growth. However, BPA-treated cells exhibited no marked morphological changes compared with the control group. The cell apoptosis rate in each BPA-treated group was lower compared with the control group. The expression levels of ERα and ERβ increased, but the expression of AR decreased. The present study demonstrated that environmental exposure to BPA directly promoted the proliferation of prostate cells in rats through increasing the expression of estrogen receptors, reducing the expression of androgen receptors of the cells and decreasing apoptosis-induced cell death.

Estrogen therapy increases BDNF expression and improves post-stroke depression in ovariectomy-treated rats.

The present study investigated the effect of exogenous estrogen on post-stroke depression. Rats were exposed to chronic mild stress following middle cerebral artery occlusion. The occurrence of post-stroke depression was evaluated according to the changes in preference for sucrose and performance in a forced swimming test. Estrogen therapy significantly improved these neurological symptoms, indicating that estrogen is effective in treating post-stroke depression. Increased brain-derived neurotrophic factor (BDNF) expression was reported in the hippocampus of rats that had been treated with estrogen for two weeks, suggesting that BDNF expression may be an important contributor to the improvement of post-stroke depression that is observed following estrogen therapy.

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen.

Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple biologic processes, including hepatic lipid metabolism. Estrogen exerts actions affecting energy homeostasis, including a liver fat-lowering effect. Increasing evidence indicates the crosstalk between these two molecules. The aim of this study was to evaluate whether Nrf2 modulates estrogen signaling in hepatic lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) was induced in wild-type and Nrf2-null mice fed a high-fat diet and the liver fat-lowering effect of exogenous estrogen was subsequently assessed. We found that exogenous estrogen eliminated 49% and 90% of hepatic triglycerides in wild-type and Nrf2-null mice with NAFLD, respectively. This observation demonstrates that Nrf2 signaling is antagonistic to estrogen signaling in hepatic fat metabolism; thus, Nrf2 absence results in striking amplification of the liver fat-lowering effect of estrogen. In addition, we found the association of trefoil factor 3 and fatty acid binding protein 5 with the liver fat-lowering effect of estrogen. In summary, we identified Nrf2 as a novel and potent inhibitor of estrogen signaling in hepatic lipid metabolism. Our finding may provide a potential strategy to treat NAFLD by dually targeting Nrf2 and estrogen signaling.

Effects of estrogen on cerebrovascular function: age-dependent shifts from beneficial to detrimental in small cerebral arteries of the rat.

In the present study, interactions of age and estrogen in the modulation of cerebrovascular function were examined in small arteries <150 μM. The hypothesis tested was that age enhances deleterious effects of exogenous estrogen by augmenting constrictor prostanoid (CP)-potentiated reactivity of the female (F) cerebrovasculature. F Sprague-Dawley rats approximating key stages of "hormonal aging" in humans were studied: perimenopausal (mature multi-gravid, MA, cyclic, 5-6 mo of age) and postmenopausal (reproductively senescent, RS, acyclic 10-12 mo of age). Rats underwent bilateral ovariectomy and were given estrogen replacement therapy (E) or placebo (O) for 14-21 days. Vasopressin reactivity (VP, 10(-12)-10(-7) M) was measured in pressurized middle cerebral artery segments, alone or in the presence of COX-1- (SC560, 1 μM) or COX-2- (NS398, 10 μM) selective inhibitors. VP-stimulated release of prostacyclin (PGI2) and thromboxane (TXA2) were assessed by radioimmunoassay of 6-keto-PGF1α and TXB2 (stable metabolites). VP-induced vasoconstriction was attenuated in ovariectomized + estrogen-replaced, multigravid adult rats (5-6 mo; MAE) but potentiated in older ovariectomized + estrogen-replaced, reproductively senescent rats (12-14 mo; RSE). SC560 and NS398 reduced reactivity similarly in ovariectomized multigravid adult rats (5-6 mo; MAO) and ovariectomized reproductively senescent rat (12-14 mo; RSO). In MAE, reactivity to VP was reduced to a greater extent by SC560 than by NS398; however, in RSE, this effect was reversed. VP-stimulated PGI2 was increased by estrogen, yet reduced by age. VP-stimulated TXA2 was increased by estrogen and age in RSE but did not differ in MAO and RSO. Taken together, these data reveal that the vascular effects of estrogen are distinctly age-dependent in F rats. In younger MA, beneficial and protective effects of estrogen are evident (decreased vasoconstriction, increased dilator prostanoid function). Conversely, in older RS, detrimental effects of estrogen begin to be manifested (enhanced vasoconstriction and CP function). These findings may lead to age-specific estrogen replacement therapies that maximize beneficial and minimize detrimental effects of this hormone on small cerebral arteries that regulate blood flow.