Protective Effect Of Estrogen Research Articles

Gonadal hormone contributions to individual differences in eating disorder risk.

Females experience eating disorders at substantially higher rates than males. Although sociocultural factors have traditionally been thought to underlie this sex disparity, accumulating evidence implicates differential exposure to gonadal hormones early in life. Gonadal hormones also impact within-sex variability in disordered eating, helping to explain why not all women develop an eating disorder, and some men do. We review recent findings regarding these gonadal hormone effects and their implications for the etiology of eating disorders. Males are exposed to significantly higher testosterone levels than females perinatally, and this exposure appears to protect against later binge eating in males relative to females. Within-sex, higher estradiol levels among females and higher testosterone levels among males appear to be protective. Progesterone exhibits minimal direct phenotypic effects on disordered eating but appears to counteract the protective effects of estrogen in adult females. Importantly, gonadal hormone effects may be moderated by psychosocial factors. Evidence suggests that gonadal hormones play a critical role in the etiology of disordered eating. Overall, higher testosterone and estrogen appear to be protective across development. Additional research is needed to identify mechanisms underlying these effects and further explore interactions between hormonal and psychosocial risk.

The protective effects of estrogen of chronic intermittent hypoxia induced endothelial dysfunction

The protective effects of estrogen of chronic intermittent hypoxia induced endothelial dysfunction

Association of Fat Body Mass With Vertebral Fractures in Postmenopausal Women With Early Breast Cancer Undergoing Adjuvant Aromatase Inhibitor Therapy

Aromatase inhibitors induce a profound depletion in serum estrogen levels. Postmenopausal obese women receiving aromatase inhibitor therapy may be at increased risk of bone fractures owing to the detrimental association of adiposity with bone quality and the loss of the protective effect of estrogens on bone mineral density. To determine whether fat body mass (FBM), as measured by dual-energy x-ray absorptiometry, is associated with vertebral fracture prevalence in postmenopausal women undergoing adjuvant aromatase inhibitor therapy for breast cancer. In this single-center, cross-sectional study, 556 postmenopausal women with early-stage breast cancer were consecutively enrolled from October 15, 2013, to June 30, 2018, and stratified according to whether they were aromatase inhibitor-naive or aromatase inhibitor-treated for at least 2 years. The database was locked on December 31, 2018, and data analysis was completed on February 28, 2019. Eligible patients in both groups had normal renal function, no metabolic diseases, and no previous or current treatment with antiosteoporotic drugs or glucocorticoids. Previous chemotherapy, but not tamoxifen, was permitted. Data were gathered once, at baseline. Vertebral fracture prevalence associated with FBM in aromatase inhibitor-naive and aromatase inhibitor-treated patients. Of the 556 women enrolled, the mean age was 63.0 years (95% CI, 62.2-63.8 years). The 195 aromatase inhibitor-treated patients were older than the 361 aromatase inhibitor-naive patients (mean age, 66.1 vs 61.3 years; P < .001), had a higher body mass index (mean, 26.4 vs 25.3; P = .009), were less likely to engage in physical activity (65.3% vs 73.7%; P = .03), and were less likely to consume alcoholic beverages (68.4% vs 80.9%; P = .001). Among the aromatase inhibitor-naive patients, the vertebral fracture prevalence was higher in the subgroup with FBM below the median value than in those with high FBM, but the difference was not statistically significant (19.2% vs 13.3%; P = .13). Conversely, the proportion of vertebral fractures in the aromatase inhibitor-treated group was 20.0% in patients with low FBM vs 33.3% in patients with high FBM (P = .04). An opposite trend in the association of FBM with vertebral fracture prevalence according to aromatase inhibitor group was shown by multivariable analysis in the propensity score-matched sample: odds ratio, 0.38 (95% CI, 0.12-1.19) and 1.94 (95% CI, 0.67-5.64) in the aromatase inhibitor-naive and aromatase inhibitor-treated groups, respectively (odds ratio for the interaction, 5.77 [95% CI, 1.08-30.81]; P for interaction term = .03). Fat body mass may be associated with fragility-related fractures in patients with breast cancer who undergo aromatase inhibitor therapy. If these data are confirmed, obesity could be included in the algorithm for assessing fracture risk and selecting patients to receive bone resorption inhibitors.

Recent advances in the molecular mechanism of sex disparity in hepatocellular carcinoma (Review)

Hepatocellular carcinoma (HCC) is more frequently observed and aggressive in men compared with women. Increasing evidence demonstrates that the sex disparity appears to be mediated by the stimulatory effects of androgens and the protective effects of estrogen in the development and progression of HCC. In the past few decades, studies on the sex difference of HCC mainly focused on the effect of sex hormones on the transactivation of hepatitis B virus X protein and the release of inflammatory cytokines, and these studies have further intensified in recent years. Sex hormones are also involved in genetic alterations and DNA damage repair in hepatocytes through binding to their specific cellular receptors and affecting the corresponding signaling pathways. Furthermore, the theory of sex chromosomes participating in HCC has been considered. The present review discussed the recent advances in the molecular mechanisms of sex disparity in HCC, with the aim of improving the understanding of the underlying critical factors and exploring more effective methods for the prevention and treatment of HCC.

Differentially Expressed Genes Associated with the Estrogen Receptor Pathway in Cerebral Aneurysms

The pathophysiology of cerebral aneurysm formation remains to be elucidated. Estrogen is thought to be protective against the development of aneurysms. The aim of this study is to identify differentially expressed genes in the estrogen receptor pathway that may be linked to the development of cerebral aneurysms. Data from 6 Gene Expression Omnibus (GEO) databases with gene expression profiles of cerebral aneurysm tissue were analyzed (GSE6551, GSE15629, GSE26969, GSE46337, GSE54083, and GSE75436). Ninety-four genes associated with the estrogen receptor pathway were identified from the Kyoto Encyclopedia of Genes and Genomes pathway database. A meta-analysis using a random-effects model was used to evaluate the association of the estrogen receptor pathway genes with aneurysm formation. Four genes related to the estrogen receptor pathway were significantly associated with intracranial aneurysms, 2 of which were downregulated (PIK3R1: fold change [FC]= 0.41, false discovery rate [FDR]= 6.1× 10-5, ADCY9: FC= 0.55, FDR= 2.3× 10-4) and 2 of which were upregulated (HBEGF: FC= 1.46, FDR= 4.9× 10-4; ADCY7: FC= 2.11, FDR= 6.0× 10-3). Furthermore, subgroup analysis of 2 GEO databases with information provided about sex demonstrated PIK3R1 to be significant independently in both men (FC= 0.46, FDR= 6.3× 10-5) and women (FC= 0.46, FDR= 2.3× 10-4), whereas JUN, ADCY5, and MMP9 were significant in women only. The analysis of 6 GEO databases revealed 4 differentially expressed genes (PIK3R1, HBEGF, ADCY7, and ADCY9) in cerebral aneurysm tissue that are associated with the estrogen receptor pathway. Further analysis of estrogen-associated differentially expressed genes may provide information about the protective effects of estrogen on cerebral aneurysm development.

Relationship Between Endothelial Function and the Eliciting Shear Stress Stimulus in Women: Changes Across the Lifespan Differ to Men.

BackgroundPremenopausal women have a lower incidence of cardiovascular disease, which may partly be due to a protective effect of estrogen on endothelial function. Animal studies suggest that estrogen may also improve the relationship between shear rate (SR) and endothelial function. We aimed to explore the relationship between endothelial function (ie, flow‐mediated dilation [FMD]) and SR (ie, SR area under the curve [SRAUC]) in women versus men, and between pre‐ versus postmenopausal women.Methods and ResultsBrachial artery FMD and SRAUC were measured in accordance with expert‐consensus guidelines in 932 healthy participants who were stratified into young adults (18‐40 years, 389 men, 144 women) and older adults (>40 years, 260 men, 139 women). Second, we compared premenopausal (n=173) and postmenopausal women (n=110). There was evidence of a weak correlation between SRAUC and FMD in all groups but older men, although there was variation in strength of outcomes. Further exploration using interaction terms (age‐sex×SRAUC) in linear regression revealed differential relationships with FMD (young women versus young men [β=−5.8−4, P=0.017] and older women [β=−5.9−4, P=0.049]). The correlation between SRAUC and FMD in premenopausal women (r 2=0.097) was not statistically different from that in postmenopausal women (r 2=0.025; Fisher P=0.30). Subgroup analysis using stringent inclusion criteria for health markers (n=505) confirmed a stronger FMD‐SRAUC correlation in young women compared with young men and older women.ConclusionsEvidence for a stronger relationship between endothelial function and the eliciting SR stimulus is present in young women compared with men. Estrogen may contribute to this finding, but larger healthy cohorts are required for conclusive outcomes.

Activation of G protein-coupled estrogen receptor protects intestine from ischemia/reperfusion injury in mice by protecting the crypt cell proliferation.

The intestinal ischemia/reperfusion (I/R) injury is a common clinical event related with high mortality in patients undergoing surgery or trauma. Estrogen exerts salutary effect on intestinal I/R injury, but the receptor type is not totally understood. We aimed to identify whether the G protein-coupled estrogen receptor (GPER) could protect the intestine against I/R injury and explored the mechanism. Adult male C57BL/6 mice were subjected to intestinal I/R injury by clamping (45 min) of the superior mesenteric artery followed by 4 h of intestinal reperfusion. Our results revealed that the selective GPER blocker abolished the protective effect of estrogen on intestinal I/R injury. Selective GPER agonist G-1 significantly alleviated I/R-induced intestinal mucosal damage, neutrophil infiltration, up-regulation of TNF-α and cyclooxygenase-2 (Cox-2) expression, and restored impaired intestinal barrier function. G-1 could ameliorate the impaired crypt cell proliferation ability induced by I/R and restore the decrease in villus height and crypt depth. The up-regulation of inducible nitric oxide synthase (iNOS) expression after I/R treatment was attenuated by G-1 administration. Moreover, selective iNOS inhibitor had a similar effect with G-1 on promoting the proliferation of crypt cells in the intestinal I/R model. Both GPER and iNOS were expressed in leucine-rich repeat containing G-protein coupled receptor 5 (Lgr5) positive stem cells in crypt. Together, these findings demonstrate that GPER activation can prompt epithelial cell repair following intestinal injury, which occurred at least in part by inhibiting the iNOS expression in intestinal stem cells (ISCs). GPER may be a novel therapeutic target for intestinal I/R injury.

Estrogen ameliorates allergic airway inflammation by regulating activation of NLRP3 in mice.

Background: Estrogen has been suggested to play a protective role against airway inflammations, such as asthma. In these processes, the inflammasome nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3) partly accounts for the activation of pro-inflammatory factors. The aim of the present study was to investigate whether NLRP3 was involved in the protective effect of estrogen against allergic airway inflammation. Methods: An ovariectomy was performed on female C57BL/6 mice; some were sham-operated (sham). We then sensitized and challenged them with ovalbumin (OVA) to establish an airway inflammation model. Meanwhile, some mice were treated with 17β-estradiol (E2) for 28 days. Results: The expression of NLRP3 inflammasome and its downstream products, caspase-1 and the pro-inflammatory cytokine interleukin (IL)-1β (IL-1β), increased concomitantly with OVA-challenged airway inflammation and decreased with the expression of estrogen receptor β (ERβ). In addition, treating ovariectomized (OVX) mice with E2 dramatically ameliorated airway inflammation via such mechanisms as leukocyte recruitment, mucus production, and secretion of pro-inflammatory cytokines other than IL-18 in bronchoalveolar lavage (BAL) fluid (BALF). Furthermore, E2 suppressed both the mRNA expression and protein expression of NLRP3, caspase-1, and IL-1β. In summary, our study showed that NLRP3 inflammasome activation and pro-inflammatory cytokine production markedly increased in OVA-induced airway inflammation, and E2 effectively abrogated such inflammation by regulating the activation of NLRP3.

A study of correlation between body mass index and lipid profile in postmenopausal women

Background: Menopause is a physiological event in every woman’s life which is characterized by cessation of menses due to hormonal changes. Menopause occurs between the late 40s and early 50s. Postmenopausal women are particularly at risk of cardiovascular complications due to loss of protective effect of estrogen on cardiovascular system. During menopause, there is fall in estrogen and progesterone levels. After menopause, there is increase in fat storage with simultaneous lipid deposition in central part of body. The body mass index (BMI) has a major influence on blood pressure and lipid profile and as such is a good predictor of hypertension and hyperlipidemia. Menopause predisposes the woman to the risk of ischemic heart disease. Aims and Objectives: This study was carried out to correlate between BMI and blood triglyceride level and low-density lipoprotein (LDL) in postmenopausal women. These parameters were studied in 100 postmenopausal apparently healthy women. Materials and Methods: Our study was approved by the institutional ethics committee. The subjects were divided into two groups according to the duration of their menopause period 5 years. Parameters studied were BMI and triglycerides and LDL. Results: In our study in both groups, BMI values were raised but statistically not significant (P = 0.920), and in lipid profile, triglycerides (P = 0.059) and LDL cholesterol were raised and were statistically significant (P = 0.307). Conclusion: Since postmenopausal women lack cardioprotective action of estrogen, they are prone to cardiovascular diseases faulty habits of diet and lifestyle further increase the risk of cardiovascular disease. Awareness among perimenopausal women about menopause and cardiovascular health should be created and women are encouraged to adapt healthy life.

Visualizing peroxynitrite fluxes in myocardial cells using a new fluorescent probe reveals the protective effect of estrogen.

A tetraphenyl ethylene (TPE)-based fluorescent probe specific for ONOO- was developed to evaluate and verify the protective effect of estrogen on myocardial cells during OGD/R.

Estradiol ameliorates antioxidant axis SIRT1-FoxO3a-MnSOD/catalase in the heart of fructose-fed ovariectomized rats

Harmful effects of fructose-rich diet (FRD) were predominantly observed in males, suggesting protective effects of estrogens. Little is known about AMPK/sirtuin-1 (SIRT1)/forkhead box O3 (FoxO3a)/manganese superoxide dismutase (MnSOD)/catalase signaling in the heart in state of metabolic syndrome and oxidative stress induced by fructose over-consumption. We investigated the effect of 10% FRD on expression of AMPK-SIRT1-FoxO3a-MnSOD/catalase axis in myocardium and potentially beneficial effect of 17β-estradiol replacement. The expression of NADPH oxidase 4 (Nox4) and miRNA-155, unfavorable regulators of this axis, were also investigated. FRD significantly increased AMPK and decreased FoxO3a activity, decreased SIRT1, MnSOD and Nox4 protein expression while E2 reverted these changes, except for Nox4, and increased catalase protein level. E2 diminished Nox4 and MnSOD mRNA level in FRD ovariectomized rats. These results suggest independent response of AMPK and SIRT to FRD treatment. The proposed signaling in the heart should be further investigated in the prooxidative and antioxidative milieu.

Continuous access to snacks from weaning onwards in female rats causes weight gain, insulin insensitivity, and sustained leptin resistance in adulthood

A large part of the daily intake of children in the U.S. consists of snacks, with the average child consuming three snacks per day. Despite this, little research has been conducted to determine the metabolic and behavioral effects of snacking. Using a developing female rat model, our studies aimed to determine the effects of snacking during development before the protective effects of estrogen on weight gain would be relevant. Additionally, to determine if snack composition is important, we created one healthy and one unhealthy snacking group provided with chow and three snacks each in addition to a chow-only group. We found that both snacking groups experienced increased weight gain, elevated abdominal fat pad mass, prolonged leptin resistance into adulthood, and insulin insensitivity that was not observed in their non-snacking counterparts. These physiological differences were measured despite both snacking groups having a similar caloric intake as the chow-only group throughout the study. In addition to physiological changes, both snacking groups showed a preference for snacks over chow and ate more often during the inactive light phase than typical for rats, with the unhealthy snacking group presenting this behavioral change earlier than the healthy snacking group. Our results suggest that constant access to palatable snacks, which is often the case for children in western countries, alters feeding behaviors in relation to food choice and time of day when eating occurs. Snacking during development seemed to promote signs of metabolic syndrome in adulthood even when excess caloric intake was not observed. Our work further suggests that development is a vulnerable time for palatable snack presentation when prepubertal females lack the protective effects of estrogen and exhibit reduced leptin feedback on food intake. Thus snacking from weaning onward could be a contributor to the current childhood obesity crisis.

Ameliorative effect of low-dose spironolactone on obesity and insulin resistance is through replenishment of estrogen in ovariectomized rats.

Women have a lower incidence of cardiovascular diseases (CVD) than men at a similar age but the reverse is the case after menopause, indicating a possible protective effect of estrogen on cardiometabolic function. Although various hormonal therapies have been formulated to combat the CVD risks in postmenopausal state, the beneficial effects have not been consistent. Obesity with insulin resistance (IR) is closely linked to CVD risks while ovariectomized rodents have been shown to mimic a state of obesity and IR. We therefore hypothesized that low-dose spironolactone would ameliorate obesity and IR in estrogen-deprived rats by replenishing estrogen and suppressing elevated glycogen synthase kinase-3 (GSK-3). Ten-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM), spironolactone (SPL; 0.25 mg/kg), and ovariectomized (OVX) rats treated with or without spironolactone daily for 8 weeks. Results showed that estrogen deprivation through ovariectomy caused increased body mass gain and visceral adiposity that are accompanied by increased HOMA-IR, HOMA-β, 1-hour postload glucose, glucose intolerance, platelet/lymphocyte ratio, plasma insulin, atherogenic dyslipidemia, uric acid, GSK-3, corticosterone, and aldosterone and depressed 17β-estradiol. However, treatment of OVX rats with spironolactone ameliorated all these effects. Taken together, the results demonstrate that treatment with low-dose spironolactone improves obesity and IR, which appears to involve replenishment of estrogen and suppression of GSK-3 along with circulating mineralocorticoid and glucocorticoid. The findings imply a positive cardiometabolic effect of low-dose spironolactone usage in estrogen-deprived conditions.

Effects of Estrogen and Estrogen Receptors on Transcriptomes of HepG2 Cells: A Preliminary Study Using RNA Sequencing.

Men have a much higher incidence of hepatocellular carcinoma (HCC), the predominant form of liver cancer, than women, suggesting that estrogens play a protective role in liver cancer development and progression. To begin to understand the potential mechanisms of estrogens' inhibitory effects on HCC development, RNA sequencing was used to generate comprehensive global transcriptome profiles of the human HCC-derived HepG2 cell line following treatment of vehicle (control), estradiol (E2), estrogen receptor alpha- (ERα-) specific agonist 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), or ERβ-specific agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) using a small set of cells. Gene ontology (GO) analysis identified increased expression of genes involved in the biological process (BP) of response to different stimuli and metabolic processes by E2 and ER agonists, which enhanced molecular function (MF) in various enzyme activities and chemical bindings. Kyoto Encyclopedia of Genes and Genomes (KEGG) functional pathway analysis indicated enhanced pathways associated with carbohydrate metabolism, complement and coagulation cascades, and HIF-1 signaling pathway by E2 and ER agonists. GO analysis also identified decreased expression of genes by E2, PPT, and DPN involved in BP related to the cell cycle and cell division, which reduced MF in activity of multiple enzymes and microtubule activity. KEGG analysis indicated that E2, PPT, and DPN suppressed pathways associated with the cell cycle; E2 and PPT suppressed pathways associated with chemical carcinogenesis and drug metabolism, and DPN suppressed DNA replication, recombination, and repair. Collectively, these differentially expressed genes across HepG2 cell transcriptome involving cellular and metabolic processes by E2 and ER agonists provided mechanistic insight into protective effects of estrogens in HCC development.

A12457 The Characteristic of central blood pressure and arterial stiffness in hypertensive female with different menopause period

Objectives: The aim of this study is to make sure the characteristic of central blood pressure and arterial stiffness in female hypertension with different menopause period. Methods: One hundred and eighteen subjects of essential hypertension were selected from Lanzhou University Second Hospital during November 2014 to November 2015. All female patients divided into two groups by the duration of menopause,one was short-term group (duration of menopause ≤5 Years).And at same time,the male patients whose age similar to female were selected as the short duration controls group.Another female hypertensive patients was long-term menopausegroup (duration of menopause 5 > years),equally,the male patients of similar age were also selected as the long-term control subjects.Sex hormone of female,SBP,DBP,PP were measured. cSBP,cDBP,CPP,AP,AIx,AIx75HR,carotid-femoral pulse wave velocity (cf-PWV) were detected. Results: In short-term control group,SBP,DBP,HR,cSBP,cf-PWV were higher than short-term menopause group,but the parameters of PP,AP,CPP,AIx and AIx75HR were higher in short-term group.The difference of SBP,DBP,cDBP,AIx75HR between tow groups a were significant (P < 0.05)).However,in long-term menopause group,the parameter of SBP,DBP,PP,HR,cSBP,CPP,AP,AIx,AIx75HR and cf-PWV were higher than those of in long-term control group,and the differences of SBP,PP,cDBP, CPP,AP,AIx75HR were significant (P < 0.05).For the short-tern groups,the estrogen of estradial (eE2) and progesterone (PGRE) were higher than long-term groups,and the difference of eE2 is significant (P < 0.05). Conclusion: For the short-term menopause females the protective effect of estrogen were existed,this effect is not only protect the peripheral brachial blood pressure but also the central blood pressure.But the effect of estrogen on arterial stiffness were not clearly.

A different effect of obesity on ECG in premenopausal and postmenopausal women

Both obesity and menopause are significant cardiovascular risk factors. In postmenopausal women the protective effect of estrogens is reduced and menopause is frequently associated with occurrence of other significant cardiovascular factors including obesity. This study was focused on evaluating the effect of obesity on the QRS complex in pre- and postmenopausal women.We present results of analysis of 199 electrocardiograms of pre- and postmenopausal women analyzed in relation to the body mass index within normal limits (BMI 20 to 24.9 kg/m2) and obesity (BMI > 30 kg/m2), respectively.Obesity in premenopausal women and menopause significantly affected both the electrical axis (EA) and maximum QRS spatial vector magnitude (QRSmax). The highest QRSmax and electrical axis values were observed in premenopausal lean women, and they were significantly higher as than in the premenopausal obese women, postmenopausal lean and obese women (QRSmax: 1.66 ± 0.4 mV, 1.17 ± 0.35 mV, 1.4 ± 0.46 mV, and 1.35 ± 0.39 mV, resp.). (EA: 56.4 ± 18.0°, 38.22 ± 18.38°, 45.82 ± 18.63°, and 36.75 ± 17.51°). The differences between obese premenopausal women, lean and obese postmenopausal women were not statistically significant. These differences were reflected in 12-lead ECG amplitude. The presence of additional cardiovascular risk factors did not affect the ECG parameters.Obesity significantly affected QRS complex in premenopausal women. This effect was comparable with the effect of menopause. Because all QRS complex changes were within normal limits, these results suggest that ECG evaluation in women should go beyond traditional diagnostic categories and consider the relationship between ECG changes and two cardiovascular risk factors – obesity and menopause.

The relationship between sex hormones, the vaginal microbiome and immunity in HIV-1 susceptibility in women.

ABSTRACTThe role of sex hormones in regulating immune responses in the female genital tract has been recognized for decades. More recently, it has become increasingly clear that sex hormones regulate susceptibility to sexually transmitted infections through direct and indirect mechanisms involving inflammation and immune responses. The reproductive cycle can influence simian/human immunodeficiency virus (SHIV) infections in primates and HIV-1 infection in ex vivo cervical tissues from women. Exogenous hormones, such as those found in hormonal contraceptives, have come under intense scrutiny because of the increased susceptibility to sexually transmitted infections seen in women using medroxyprogesterone acetate, a synthetic progestin-based contraceptive. Recent meta-analyses concluded that medroxyprogesterone acetate enhanced HIV-1 susceptibility in women by 40%. In contrast, estradiol-containing hormonal contraceptives were not associated with increased susceptibility and some studies reported a protective effect of estrogen on HIV/SIV infection, although the underlying mechanisms remain incompletely understood. Recent studies describe a key role for the vaginal microbiota in determining susceptibility to sexually transmitted infections, including HIV-1. While Lactobacillus spp.-dominated vaginal microbiota is associated with decreased susceptibility, complex microbiota, such as those seen in bacterial vaginosis, correlates with increased susceptibility to HIV-1. Interestingly, sex hormones are inherently linked to microbiota regulation in the vaginal tract. Estrogen has been postulated to play a key role in establishing a Lactobacillus-dominated microenvironment, whereas medroxyprogesterone acetate is linked to hypo-estrogenic effects. The aim of this Review is to contribute to a better understanding of the sex-hormone–microbiome–immunity axis, which can provide key information on the determinants of HIV-1 susceptibility in the female genital tract and, consequently, inform HIV-1 prevention strategies.

The protective effects of estrogen on hepatic ischemia-reperfusion injury in rats by downregulating the Ang II/AT1R pathway

BackgroundHepatic ischemia/reperfusion (I/R) injury continued to be a significant clinical problem. The aim of this study was to examine whether the protective effects of 17-estradiol (E2) on hepatic ischemia/reperfusion (I/R) injury was associated with the downregulation of the angiotensin II (Ang II)/AT1R pathway. MethodsForty male Sprague Dawley rats were randomized into five groups: Sham operation, ischemia/reperfusion (I/R), I/R + E2, I/R + E2+estrogen receptor antagonist ICI 182,780 (ICI), and I/R + E2+ Ang II subtype I receptor (AT1R) antagonist losartan (LOS) groups. A model of total hepatic I/R was established by portal pedicle clamping for 60 min followed by reperfusion. At onset of ischemia, rats were treated with vehicle, E2, or LOS. ICI was given 30 min before E2 administration. At 24 h after reperfusion, blood samples and liver tissues were collected and subjected to histological examination, biochemical assays, and Western blot assays. ResultsCompared with I/R group, the degree of hepatocyte damage, serum ALT and TNF-α levels, hepatic MDA level and MPO activity were decreased in I/R + E2 group (all p < 0.05). Moreover, the serum and liver Ang II levels and hepatic AT1R protein level in I/R + E2 group were also significantly reduced compared with I/R group (all p < 0.05). However, the protective effect of E2 could be abolished by ICI administration. In contrast, administration of LOS conferred similar, but not as effective as E2, protective effects on hepatic I/R injury, without affecting Ang II and AT1R levels. ConclusionsThe salutary effects of E2 on hepatic I/R injury are mediated in part by downregulating the Ang II/AT1R pathway.

Abstract 1807: Inter-individual variation in response to estrogen in the mammary gland

Abstract Background: Previous research has highlighted the paradoxical nature of estrogen in both contributing to and reducing the risk of breast cancer. Exposure to xenoestrogens may affect this delicate balance between the protective effects of estrogen and its contribution to breast cancer risk. The effects of xenoestrogens may differ among individual women, as genetic diversity has been shown to impact responses to chemicals and breast cancer susceptibility. We hypothesize that there are subsets of individuals uniquely sensitive to estrogen and xenoestrogens. Methods: In order to identify high and low estrogen response groups, we utilized primary human breast tissues and primary human breast epithelial cells. Explant cultures of primary human breast tissues maintain the normal tissue architecture, while primary human breast epithelial cells are more efficiently used for mechanistic studies. Primary breast tissues were treated with 17β-estradiol (E2), an estrogen receptor alpha (ERα) specific agonist PPT, and an estrogen receptor beta (ERβ) specific agonist ERB041 in order to examine estrogen responsiveness. TUNEL assays were used to examine apoptotic responses. Because expression of estrogen receptor in primary human breast epithelial cells is lost in culture, we treat with TGFβ receptor inhibitors RepSox and SB431542 to restore estrogen receptor expression. We also take conditionally immortalized human breast epithelial cell (ciHMEC) lines and TERT immortalized normal breast epithelial cell lines and transfect in ESR1 to examine responses to E2 and xenoestrogens BP3 and PP. Results: Our results show that, based on quantitative PCR analysis of estrogen receptor target genes, individuals vary in response to estrogen receptor agonist treatment. Our results from treatment of primary breast epithelial cells with TGFβ inhibitors show an increase in the levels of ESR1 expression by 2-3 fold compared to control. We are testing whether this is sufficient to restore estrogen-induced responses. Current results from the ciHMEC and normal TERT immortalized breast epithelial cell lines also illustrate the differences in response among individuals. Some individuals have estrogenic responses at physiological doses of BP3 and PP which are similar to responses seen from treating with pregnancy levels of E2. Conclusions: These models demonstrate the variation in estrogenic responses between individual patient samples. Estrogenic compounds PPT, ERB041, PP, and BP3 can induce similar responses to those of E2 in certain individuals, as reflected in target gene expression and transactivation data. Responses to E2 and xenoestrogens vary among TERT immortalized lines and ciHMEC lines, just as responses to E2 and other estrogen receptor agonists varied among individual explant patient samples. The ciHMEC lines can be used to define the mechanistic differences in estrogen sensitivity among women. Citation Format: Karen A. Dunphy, Amye L. Black, Sallie S. Schneider, D Joseph Jerry. Inter-individual variation in response to estrogen in the mammary gland [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1807.

The protective effect of estrogen on cisplatin‐induced cytotoxicity of HK‐2 cells

Introduction and hypothesisCisplatin is a widely used chemotherapeutic agent and has significant renal toxicity. Estrogen is a major sex hormone in females, and previous studies have shown that estrogen has many physiological protective effects. HK‐2 cell line is an immortalized proximal tubule epithelial cell line from healthy men. In this study, we investigated the protective roles of estrogen on cisplatin‐induced nephrotoxicity by the in vitro HK‐2 cell model.MethodsHK‐2 Cells were pretreated with 17β‐estradiol (0~20 nM), estrogen receptor agonists, and estrogen receptor antagonists for 24 hours respectively. All groups of cells were followed treated with cisplatin (0–15 mg/ml) for 24 hours. The cell survival rate, proliferation, morphology were analyzed by ELISA. The apoptosis/necrosis were analyzed by Annexin‐V/PI staining using flow cytometry. Estrogen receptors and apoptosis related proteins expressions were confirmed by Western blotting.ResultsAll three types of estrogen receptors could be expressed by the HK‐2 cells. In cisplatin‐induced nephrotoxicity cell model, 17β‐estradiol pretreatment have higher cell survival rate than vehicle when dose larger than 10 nM. The Annexin‐V positive apoptotic cells and caspase‐3 expressions in 17β‐estradiol pretreated group is significant lower than vehicle control. The three types of estrogen agonists exert the protective effects in cisplatin‐induced cytotoxicity, and acted on the G protein‐coupled estrogen receptor (GPER) is the most effective. In addition, blocked GPER also significantly accentuated cytotoxicity of cisplatin treated HK‐2 cells.ConclusionsOur data suggested that estrogen pretreatment could protect HK‐2 cells from cisplatin induced cytotoxicity, and this protective effect occurs mainly through the GPER pathway. It may offer a novel therapeutic strategy for cisplatin‐induced nephrotoxicity. Further investigation into the molecular mechanisms and clinical applications are needed.Support or Funding InformationKMU‐TP105E37This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.