Background.Prenatal and postnatal stimulations have been revealed to have long-term effects on rat offspring various reproductive and behavioral reactions.The current study was designed to assay the impact of prenatal and postnatal exposure to different colors on variations of serum estrogen levels in female adult offspring. Four groups of pregnant female Wistar rats (seven rats in each) were enrolled in this study. The pregnant rats were placed in color chambers including green, blue, black and white (control). After delivery, female offspring’s were kept in color chambers until age 8-9 weeks, and then estrogen concentration in serum of female adult offspring’s were measured using the ELISA Kit. Our study result revealed that serum estrogen level increased in female adult offspringwho were prenatally and postnatally exposed to white and black colors compared to female adult offspring’s who were exposed to green and blue colors. Exposure to blue color significantly decreased serum estrogen level in female adult offspring. These findings demonstrated serious changes of estrogen in female offspring due to prenatal and postnatal exposure to different colors which can be translated as estrogen variables. We can document that prenatal and postnatal stimulation can lead to estrogen alterations in female offspring and such changes can be made by colors.
This is to certify that the dissertation titled “Transvaginal ultrasound measurement of endometrial thickness as a biomarker of estrogen level in postmenopausal women” is a bonafide work done by Dr.S.Anitha, Government R.S.R.M. lying in Hospital, Stanley Medical College to the Faculty of Obstetrics and Gynaecology, The Tamilnadu Dr. M.G.R. Medical university, Chennai in partial fulfillment of the requirement for the award of M.D. Degree (Obstetrics and Gynaecology) is a bonafide research work carried out by her under our direct supervision and guidance.
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The present study may be limited by its case-control study design, which is subject to recall and selection biases. Dietary assessment based on individual interview may introduce measurement errors and attenuate the association between variables. Although this study included both pre- and postmenopausal women, the total number of subjects was insufficient to allow us to conduct further sub-analyses to investigate the association between the breast cancer risk factors in pre- and postmenopausal women. Finally, the association between breast cancer and other variables such as; generalized obesity, central obesity, estrogen level and fat mass may be subjected to some possible confounders for which the smaller number of cancer cases wouldn’t allow for adjustment.
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Our results show that at the age of two months, there was a highly significant decrease in the height of epithelial cell layer of the uterus and in estrogen level (P < 0.01) in both G2 and G3. The decrease of estrogen level might be the cause for the change in the morphology of epithelial cell layer ,  and changed the type of luminal and glandular epithelia and the morphology of epithelial cells. 
pared with the age-matched males. Similarly, untreated post-menopausal women seem to have a lower intervertebral disc height in com- parison with the estrogen replacement treat- ment females. Taken together, it seems the estrogen level is closely associated with the degeneration of the intervertebral disc [1, 19]. The intervertebral disc is a non-vascular struc- ture consists of cartilage endplate, nucleus pulposus, and annulus fibrosis. The nutrients of the IVD are mainly supplied from two sources. First, the peripheral micro-circulatory system, which only provides the nutrients for the periph- ery of the IVD. Second, the marrow contact channel of the CEP, which is the most important mechanism that provided most nutrients for the avascular tissues inside the IVD, roles by diffusion and liquid flow to exchange wastes and nutrients [7, 20, 21]. Previous studies dem- onstrated that loss of the chondrogenic pheno- type of the CEP is an important part of the degeneration of IVD, as the number and volume of capillaries or medullary sinuses decreases, which affects the nutrient supply and finally accelerates disc degeneration . As a result, the degeneration of the cartilaginous endplate plays an important role in the degeneration pro- cess of IVD. The present study successfully demonstrates that decreased estrogen level may accelerate the degeneration of the carti- lage endplate by increasing calcification, which may be an important part of the degeneration of IVD.
The gallstone disease is a condition which is caused by several factors or different causing factors. There are several different factors are involved to cause gallstones, the main factor for the formation of gallstone is gender; the females are more susceptible to get gallstones compared to males. The valid reason is to get gallstone in female is due to estrogen, the estrogen level increases the cholesterol secretion and leads to cholesterol supersaturation, further causes the formation of crystals, stones. The other different causing factors are genetic factors, age, and race. The formation of gallstones not only occurs by age, genes & race but also they are associated with other addition factors; like being overweight, glucose intolerance, insulin resistance, drinking alcohol, diabetes mellitus, lack of fiber intake, high consumption of cholesterol and fat diet, sudden loss of weight, due to intake of drugs, during pregnancy time 31 . As above
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There is also evidence that ER- cancers can emerge over time after exposure to tamoxifen. ER+ primary tumors may recur as ER- metastases in up to 20% of cases [8-10]. A recent meta- analysis of patients with ER+ or progesterone receptor posi- tive (PR+) primary tumors showed 22% (range 0.17 to 0.3) of ER+ and 20% (range 0.2 to 0.33) of PR+ tumors recurred with hormone receptor negative disease . Interestingly, prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers under the age of 40 years causes a 60% reduction in the risk of developing breast cancer. This is remarkable because 80% of BRCA1 tumors are ER-. These observations support the possibility that hormonal manipulations are effec- tive in preventing the emergence of both ER+ and ER- tumors [7,12]. King et al. , in their subset analysis of cases from the BCPT, suggest that tamoxifen is effective in preventing breast cancer in women with BRCA2 mutations, but not BRCA1 mutations. Because the majority of BRCA1 tumors are ER-, these data question our assumption that tamoxifen does not prevent the outgrowth of ER- cancers. The number of mutation carriers in the BCPT study was small enough, how- ever, that it is difficult to draw conclusions about these data in regards to our hypothesis; only 19 women were known to be BRCA1 or BRCA2 mutation carriers in the BCPT (8 BRCA1 and 11 BRCA2). However, we do know that ovarian suppres- sion (a different form of estrogen suppression) does reduce the incidence of breast cancers in BRCA1 carriers. Further- more, new data from Dr Narod's consortium suggest that tamoxifen does indeed prevent the development of breast can- cers in BRCA1 carriers whose tumors are primarily negative (manuscript submitted; J. McClenann, personal communication).
The classical estrogen receptor ER a mediates many of the known cardiovascular effects of estrogen and is expressed in male and female vascular cells. Estrogen-independent acti- vation of ER a is known to occur in cells from reproductive tissues, but has not been investigated previously in vascular cells. In this study, transient transfection assays in human saphenous vein smooth muscle cells (HSVSMC) and pulmo- nary vein endothelial cells (PVEC) demonstrated ER a - dependent activation of estrogen response element-based, and vascular endothelial growth factor–based reporter plas- mids by both estrogen-deficient FBS (ED-FBS) and EGF. In nonvascular cells, ER a -mediated gene expression can be activated via mitogen-activated protein (MAP) kinase– induced phosphorylation of serine 118 of ER a . However, in vascular cells, we found that pharmacologic inhibition of MAP kinase did not alter EGF-mediated ER a activation. In addition, a mutant ER containing an alanine-for-serine substitution at position 118 was activated to the same de- gree as the wild-type receptor by ED-FBS and EGF in both HSVSMC and PVEC. Furthermore, constitutively active MAP kinase kinase (MAPKK) activated ER a in Cos 1 cells as expected, but MAPKK inhibited ER activation in PVEC. We conclude that growth factors also stimulate ER a -medi- ated gene expression in vascular cells, but find that this oc- curs via a MAP kinase–independent pathway distinct from that reported previously in nonvascular cells. ( J. Clin. In- vest. 1998. 101:2851–2861.) Key words: steroid hormone re- ceptors • gene transcription • crosstalk • vascular smooth muscle cells • vascular endothelial cells
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Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the estrogen receptor (ER), now referred to as selective estrogen receptor modulators (SERMs), can demonstrate remarkable differences in activity in the various estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for understanding these tissue-selective actions. As discussed in this thematic review, the development of optimal SERMs should now be viewed in the context of two estrogen receptor subtypes, ER α and ER β , that have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites. Cellular, biochemical, and structural approaches have also shown that the nature of the ligand affects the conformation assumed by the ER–ligand complex, thereby regulating its state of phosphorylation and the recruitment of different coregulator proteins. Growth factors and protein kinases that control the phosphorylation state of the complex also regulate the bioactivity of the ER. These interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as medical therapeutic agents.
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SERMs selectively act on ERs in target tissues and the adverse events of SERMs are significantly reduced com- pared with estrogen . Almost all SERMs have anti- estrogenic action in the breast and do not increase the risk of breast cancer. Moreover, some SERMs such as tamoxifen, toremifene, and raloxifene can be used for the treatment or prevention of estrogen-sensitive breast cancer . SERMs have relatively varied effects on the uterus. Furthermore, very few SERMs, such as tamoxi- fen, stimulate endometrial proliferation with the in- creased risk of endometrial cancer. In fact, the majority of SERMs have neutral or anti-estrogenic effects on the endometrium and do not increase the risk of endomet- rial cancer . In addition, most SERMs do not in- crease the risk of cardiovascular events . Although some SERMs are reported to slightly increase the inci- dence of hot flashes or vulvar vaginal atrophy, the symp- toms are mild and do not affect the clinical application of SERMs. Currently, the primary limit of clinical appli- cation of most SERMs is the increased risk of venous thrombosis embolism .
Resorption and formation activities in bone remodeling process have been shown to involve several genetic factors. Administration of serum receptor activator of nuclear factor kappa- B ligand (RANKL) to mice have been shown to promote activation and growth of osteoclast cells leading to increased resorption and development of osteoporosis by binding to RANK receptors located on osteoclast precursors and promoting its differentiation and activation into mature osteoclast cells that control bone resorption (Lacey et al., 19 98 ; Teiteilbau m, 2 00 0 ). Anoth er factor, Osteoprotegerin (OPG) produced by osteoblast cells along with RANKL was also reported to regulate bone resorption. OPG acts as antiresorptive decoy receptor that binds to RANKL thereby preventing it from binding to main RANK receptors. As a result, it inhibits osteoclast differentiation and its resorptive activities. The process of osteoclastogenesis also requires another factor expressed by osteoblasts called macrophage-colony stimulating factor ( MCSF ). This factor binds to the MCSF receptors in the osteoclast cells and stimulates osteoclastogenesis through an unclear mechanism. Numerous factors such as bone morphogenetic protein-2 ( BMP-2 ) are known to affect osteoblast differentiation and activity (Riley et al., 1996). Estrogen used for protection of bone density have exhibited regulation of expressions of genes of these factors (Bord et al., 2003).
controversial [29-32]. In our study, expression of ERs decreased in the hypothalamus of ovariectomized rats and increased upon treatment with TG-decoction. Simi- lar results have been recently reported by Wu et al.  who have found that total flavonoids of Epimedium sagittatum reversed the markedly reduced ERa expres- sion in the hypothalamus of ovariectomized rats. The impact of ovariectomy and estrogen treatment on the expression of ER a and b varies in different parts of the rat brain [34,35]. Also, within the hypothalamus, ER expression may differ in various subregions during aging [20,21]. Further studies are necessary to find out how the expression of ERs in various subregions of the hypothalamus is influenced by the TG-decoction.
The prevalence of obesity is enhanced in menopausal women 8 and the regulation of their adipose metabolism is quite complex. It is modulated by leptin, visfatin, adipo- nectin, estrogen, and ERs. Adipokines, such as leptin and visfatin, exhibit positive correlations with obesity, while adiponectin is protective, showing a negative correlation with obesity. 9–11 Thus, the mechanisms of obesity are complicated and affected by the interactions between estrogen, ERs, and adipokines. In a study from 2014, Grantham found that men in developing countries are exposed to environmental estrogen-like substances that reduce the risk of obesity. 7 The results of an animal study also suggest that estrogen signaling may decrease the effects of obesity on obesity-related diseases in men. 12 These ﬁ ndings provide evidence that estrogen is protective against obesity. 13 ERs, including ER α and ER β , play a crucial role in the effects of estrogen. Liu 2010 demon- strated that ERs modulate insulin sensitivity and energy homeostasis closely associated with obesity. 13 Both ER α and ER β are expressed in subcutaneous and visceral adi- pose tissues. Park 2011 found that the knockout of ER α in mice leads to central obesity, while nonclassical ER α signaling may reduce the risks associated with obesity. 14 Lizcano 2014 believed that ER α plays a more important role in fat distribution and adipocyte activity. 2 A subse- quent report suggested that selective activation of ER α may be a novel therapeutic target for promoting the bei- ging of white adipose tissues. 15 In this respect, ER α is protective against obesity. 16 The roles of ER β , however, are poorly understood. Evidence suggests that ER β plays an important role in metabolism. 17 Recently, Gonzalez- Granillo et al reported that ER β is protective in ovariecto- mized female mice. 18 Other studies show that the index of ER α /ER β ratios is more sensitive and it has been used in several studies. Our previous ﬁ ndings demonstrate that enhancement of the hippocampal ER α /ER β ratio is neuro- protective against perimenopausal anxiety and depression
Since BRCA1 negatively regulates SLUG, a factor that is essential to maintain the pluripotency of mammary epithelial stem/progenitor cells, it is rea- sonable to suspect that the function of BRCA1 is to pave the way for differentiation by repressing stem cell related transcriptional factors . But in BRCA1 mutation circumstances, the overlapped effects of estrogen and BRCA1 mutation may significantly promote the cell proliferation and the expression of the factors, such as SLUG and SOX9 that promote de-differentiation . A recent study suggested that intestinal epithelial cells can de-differentiate upon NF- κ B activation, which results in oncogenic trans- formation . The mediator of NF- κ B activation is Wnt signaling. Thus, cell proliferation and cell de-differentiation may be the prerequisite to turn on the neoplastic transformation in mammary epithelial cells with BRCA1 mutation as well. This idea is ap- pealing because this will explain the increased breast cancer risk in BRCA1 deficient patients when being over-exposed to estrogen. Moreover, absence of BRCA1 reduces the ability of cells to deal with the oxidative stress partially raised by E-ER. Therefore, the cells that experience the de-differentiation may have much higher opportunity to be exposed to oxi- dative damages that accelerate the tumorigenesis (Fig. 2).
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have liked to determine the statistical significance of the differ- ences in association between genotype and tumor character- istics in ER-negative cancers versus ER-positive cancers. Unfortunately, the small sample size, particularly for the ER- negative samples, did not allow us to have power for this anal- ysis. Thus, although this observation was interesting, it needs to be interpreted with caution since the number of subjects for whom the ER status was known was small (Table 1). These observations might, however, generate interesting hypotheses for future testing in larger studies. Also, because of the restricted sample size we did not have enough statistical power to include all polymorphic estrogen metabolizing enzymes, such as cytochrome P450 isoforms, catechol-O- methyltransferase and glutathione S-transferase isoforms, in this analysis. Larger cohorts need to be analyzed to answer the question of interaction of all these genes and their combined effect on tumor phenotypes.
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The expression of ERα and ERβ in MCF-7 cells was examined by Western blotting (Figure 5). Compounds 13e (series I) and 22 (series III) were chosen for further biochemical evaluation; compound 22 showed an interesting profile of activity due to its lack of antiproliferative effect whilst having an extremely selective effect on ERβ. Compound 13e has potent antiproliferative activity in MCF-7 cells and good potency against both ERα and ERβ (Table 2). The pure estrogen antagonist 5, a known SERD, downregulates the expression of ERα and was used as a positive control. Compound 5 causes rapid proteasomal degradation of ERvia ubiquitinylation, resulting in shutdown of the estrogen-signaling process and thus inducing proliferation arrest and apoptosis of estrogen-dependent breast cancer cells. 36 In contrast, SERMs such as 4-hydroxytamoxifen (2b, Figure 1) bind to ER as antagonists or partial
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Background: Colorectal cancer incidence was reduced among women assigned to active treatment in the Women’s Health Initiative (WHI) estrogen plus progestin randomized trial, but the interpretation was obscured by an associated later stage of diagnosis. In contrast the estrogen-alone trial showed no incidence reduction or differential stage at diagnosis. Here, data from the WHI observational study are considered, in conjunction with colorectal cancer mortality data from the hormone therapy trials, in an attempt to clarify postmenopausal hormone therapy effects.
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ACE: Angiotensin-converting enzyme; ADAM: Disintegrin-metalloproteinase; ALDH2: Aldehyde dehydrogenase 2; AngII: Angiotensin II; Ap1: Activator protein-1; ArKO: Aromatase knockout; AROM+: Mice in which aromatase was transgenically upregulated; CAD: Coronary artery disease; CEE: Conjugated equine estrogens; CSE: Cystathionine γ -lyase; CVD: Cardiovascular disease; E2: 17Beta-estradiol, estrogen; EC: Endothelial cells; ECM: Extracellular matrix; eNOS: Nitric oxide synthase 3; EPC: Endothelial progenitor cells; ER: Estrogen receptors; ERKO: Estrogen receptor α knockout; ER α : Estrogen receptor α ; ER β : Estrogen receptor β ; ET-1: Endothelin-1; FGF: Fibroblast growth factor; GPR30: G-protein-coupled estrogen receptor; HERS: Heart and Estrogen/ progestin Replacement Study; HF: Heart failure; HRT: Hormone replacement therapy; I/R: Ischemia/reperfusion; KEEPS: Kronos Early Estrogen Prevention Study; LAD: Left anterior descending; LV: left ventricular; MI: Myocardial infarction; miR-22: MicroRNA 22; MMP: matrix metalloproteinaises; MPA: Medroxyprogesterone acetate; mPTP: Mitochondrial permeability transition pore; NO: Nitric oxide; OVX: Ovariectomy; PH: Pulmonary hypertension; RAMP3: Receptor active modifying protein 3; ROS: Reactive oxygen species; RV: Right ventricular; SCA: Sudden cardiac arrest; SMC: Smooth muscle cells; SOD2: Superoxide dismutase 2; Sp1: Specificity protein-1; O 2 − : Superoxide; TBARS: Thiobarbituric acid reactive substances;
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Interestingly, the standard hormone replacement therapy (which includes estrogen and a progestin) can be postulated to have an effect on seizures in postmenopausal women with epilepsy that is more evident than that of oral contraceptives in cycling women with epilepsy, because reproductive hormone levels during menopause are low and unchanging. The brain hormonal milieu in which exogenous hormones are introduced is markedly different in menopause from that in menstruating women. 62
blots of MCF-7 cells incubated with the three 'anti-estrogens'. As a control, untreated cells exhibited complete prenylation of HDJ2 (P, lane 1), while treatment with R115,777 (1 nM) resulted in an accumulation of unprenylated HDJ2, seen as a more slowly migrating band (U, lane 2). Furthermore, addition of neither ICI182,780 (5 nM) nor Tam (5 µ M) affected the far- nesylation of HDJ2, either alone or in combination with R115,777, which inhibits farnesylation of HDJ2 (lanes 3 to 6), even though the HMG CoA reductase promoter has been shown to be estrogen regulated . The selective AEBS ligand PBPE (10 µ M), however, was able to regulate HDJ2 far- nesylation itself in the absence of R115,777 (lane 7) and further increased the effect of R115,777 (lane 8). Finally, estradiol did not have any effect, either alone or in association with R115,777, ICI182,780 or Tam (data not shown), or indeed in the presence of PBPE (lane 9).