Physiological Levels Of Estrogen Research Articles

Physiological estrogen levels are dispensable for the sex difference in immune responses during allergen-induced airway inflammation

Women show an increased prevalence of adult-onset asthma compared to men and previous studies have shown that testosterone inhibits while estrogen worsens allergen-induced airway inflammation. However, detailed knowledge about the aggravating effects of estrogen on immune responses remain unclear. Defining the effects of physiological levels of estrogen on immune responses in asthma would aid in the development of improved treatment strategies.In this study, the importance of estrogen for the sex difference in asthma was determined using a murine model of house dust mite (HDM)-induced airway inflammation on intact female and male mice, as well as on ovariectomized (OVX) female mice treated with a physiological dose of 17β-estradiol (E2). Innate and adaptive immune responses were defined in bronchoalveolar lavage fluid, mediastinal lymph node (mLN) and lung tissue.The results reveal increased numbers of lung eosinophils, macrophages, and dendritic cells in female but not in male mice after HDM challenge. Females also exhibit higher numbers of Th17 cells in both mLN and lung in response to HDM. However, treatment of OVX mice with physiological levels of E2 does not influence any of the analyzed cell populations.Together, this study confirms the previously reported sex difference in allergen-induced airway inflammation and show that female mice mount stronger innate and adaptive immune responses to HDM challenge, but these effects are not mediated by physiological levels of E2.

Aromatase-Inhibitor-Induced Musculoskeletal Inflammation Is Observed Independent of Oophorectomy in a Novel Mouse Model.

Aromatase Inhibitors (AIs) block estrogen production and improve survival in patients with hormone-receptor-positive breast cancer. However, half of patients develop aromatase-inhibitor-induced arthralgia (AIIA), which is characterized by inflammation of the joints and the surrounding musculoskeletal tissue. To create a platform for future interventional strategies, our objective was to characterize a novel animal model of AIIA. Female BALB/C-Tg(NFκB-RE-luc)-Xen mice, which have a firefly luciferase NFκB reporter gene, were oophorectomized and treated with an AI (letrozole). Bioluminescent imaging showed significantly enhanced NFκB activation with AI treatment in the hind limbs. Moreover, an analysis of the knee joints and legs via MRI showed enhanced signal detection in the joint space and the surrounding tissue. Surprisingly, the responses observed with AI treatment were independent of oophorectomy, indicating that inflammation is not mediated by physiological estrogen levels. Histopathological and pro-inflammatory cytokine analyses further demonstrated the same trend, as tenosynovitis and musculoskeletal infiltrates were detected in all mice receiving AI, and serum cytokines were significantly upregulated. Human PBMCs treated with letrozole/estrogen combinations did not demonstrate an AI-specific gene expression pattern, suggesting AIIA-mediated pathogenesis through other cell types. Collectively, these data identify an AI-induced stimulation of disease pathology and suggest that AIIA pathogenesis may not be mediated by estrogen deficiency, as previously hypothesized.

Annexin A2 acts as an adherent molecule under the regulation of steroids during embryo implantation.

We previously showed that annexin A2 (Axna2) was transiently expressed at the embryo-uterine luminal epithelium interface during the window of implantation and was involved in mouse embryo implantation. At the same time, Axna2 was reported to be upregulated in human receptive endometrium, which was critical for embryo attachment as an intracellular molecule. Here, we identified Axna2 as a membrane-bound molecule on human endometrial epithelial cells and trophoblast cells, and the outer surface membrane-bound Axna2 was involved in human embryo attachment. In addition, physiological levels of estrogen and progesterone increased the expression of overall Axna2 as well as that in the extracellular surface membrane protein fraction in human endometrial cells. Furthermore, p11 (or S100A10, a member of the S100 EF-hand family protein, molecular weight 11 kDa) was involved in the translocation of Axna2 to the outer surface membrane of endometrial epithelial cells without affecting its overall expression. Finally, the surface relocation of Axna2 was also dependent on cell-cell contact and calcium binding. A better understanding of the function and regulation of Axna2 in human endometrium may help us to identify a potential therapeutic target for subfertile and infertile patients.

Effects of Benzophenone-3 and Propylparaben on Estrogen Receptor-Dependent R-Loops and DNA Damage in Breast Epithelial Cells and Mice.

Background:Endocrine-disrupting chemicals have been shown to have broad effects on development, but their mutagenic actions that can lead to cancer have been less clearly demonstrated. Physiological levels of estrogen have been shown to stimulate DNA damage in breast epithelial cells through mechanisms mediated by estrogen-receptor alpha (). Benzophenone-3 (BP-3) and propylparaben (PP) are xenoestrogens found in the urine of of U.S. population.Objectives:We investigated the effect of BP-3 and PP on estrogen receptor–dependent transactivation and DNA damage at concentrations relevant to exposures in humans.Methods:In human breast epithelial cells, DNA damage following treatment with (), BP-3, and PP was determined by immunostaining with antibodies against and 53BP1. Estrogenic responses were determined using luciferase reporter assays and gene expression. Formation of R-loops was determined with DNA: RNA hybrid–specific S9.6 antibody. Short-term exposure to the chemicals was also studied in ovariectomized mice. Immunostaining of mouse mammary epithelium was performed to quantify R-loops and DNA damage in vivo.Results:Concentrations of and BP-3 or PP increased DNA damage similar to that of treatment in a manner. However, BP-3 and PP had limited transactivation of target genes at and concentrations. BP-3 and PP exposure caused R-loop formation in a normal human breast epithelial cell line when was introduced. R-loops and DNA damage were also detected in mammary epithelial cells of mice treated with BP-3 and PP.Conclusions:Acute exposure to xenoestrogens (PP and BP-3) in mice induce DNA damage mediated by formation of R-loops at concentrations 10-fold lower than those required for transactivation. Exposure to these xenoestrogens may cause deleterious estrogenic responses, such as DNA damage, in susceptible individuals. https://doi.org/10.1289/EHP5221

Generation of Multicellular Human Primary Endometrial Organoids.

The human endometrium is one of the most hormonally responsive tissues in the body and is essential for the establishment of pregnancy. This tissue can also become diseased and cause morbidity and even death. Model systems to study human endometrial biology have been limited to in vitro culture systems of single cell types. In addition, the epithelial cells, one of the major cell types of the endometrium, do not propagate well or retain their physiological traits in culture, and thus our understanding of endometrial biology remains limited. We have generated, for the first time, endometrial organoids that consist of both epithelial and stromal cells of the human endometrium. These organoids do not require any exogenous scaffold materials and specifically organize so that epithelial cells encompass the spheroid-like structure and become polarized with stromal cells in the center that produce and secrete collagen. Estrogen, progesterone and androgen receptors are expressed in the epithelial and stromal cells and treatment with physiological levels of estrogen and testosterone promote the organization of the organoids. This new model system can be used to study normal endometrial biology and disease in ways that were not possible before.

GW29-e1619 GPR30 mediated cardioprotection of estrogen against stress through rapid signaling pathway

Estrogen receptors (ERs) and β-adrenergic receptors (β-ARs) play important roles in the cardiovascular system. Physiological level of estrogen (E2) can improve the cardiac function during the extreme stress. The lately discovered estrogen receptor GPR30 executes rapid effects of E2. On this basis

Abstract B05: Recurrence and hormone therapy resistance of cervical cancer in a transgenic mouse model

Abstract Persistent HPV infection and other cofactors are required for the progression of cervical cancer. Oral contraceptive use or multiple parities increases risk for cervical cancer in HPV-positive women. These risk factors have hormonal balance skewed toward estrogen (i.e., an increase in estrogen levels is much greater than an increase in progesterone levels). It is consistent that transgenic mice expressing HPV16 E6 and E7 (K14E6/K14E7) develop cervical cancer only when treated with physiological levels of estrogen. Using this validated mouse model, we demonstrated that estrogen receptor alpha (ERα) antagonists (e.g., raloxifene) or a progesterone receptor (PR) agonist [e.g. medroxyprogesterone acetate (MPA)] is efficient in treating cervical cancer. Cervical cancer recurs after raloxifene therapy, and recurring disease remains sensitive to raloxifene. The present study investigates whether cervical cancer recurs after stopping MPA treatment. Consistent with our prior results, K14E6/K14E7 mice (7 of 7) developed cervical cancer after 6-month estrogen treatment (initial cancer), which regressed in 14 of 14 mice upon 2-month MPA treatment (i.e., complete response). When the mice were re-treated for 2 months with estrogen after MPA therapy, cervical cancer was observed in 6 of 6 mice (100%). As a control, a group of mice were left untreated for first 6 months, and then treated with MPA for 2 months followed by 2-month estrogen treatment. We defined cervical disease in this group as newly arising disease. Cancer incidence in this group (25%; 4 of 16 mice) was significantly lower. These results indicate that cervical cancer recurs if MPA treatment is discontinued. Interestingly, recurrence was also observed in 8 of 8 mice without readministration of estrogen, indicating that recurring cancers are independent of exogenous estrogen (we do not know whether they depend on endogenous estrogen). Strikingly, when mice bearing recurring cancers were re-treated with MPA, cancer incidence (100%, 5 of 5 mice) and cancer multiplicity remained similar to a control group, and moderate reduction in cancer size was observed. These results indicate that recurring cervical cancers acquired resistance to PR agonist therapy. This resistance was not due to loss of PR because PR status in recurring cancers was similar to that in initial cancers. Further study is warranted to determine a mechanism of therapy resistance in this mouse model, which is anticipated to facilitate development of a more efficient therapy for the disease. Citation Format: Fabiola Mehta, Sang-Hyuk Chung. Recurrence and hormone therapy resistance of cervical cancer in a transgenic mouse model. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B05.

High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT2-Receptor Dependent Mechanism.

Physiological levels of estrogen appear to enhance angiotensin type 2 receptor- (AT2R-) mediated vasodilatation. However, the effects of supraphysiological levels of estrogen, analogous to those achieved with high-dose estrogen replacement therapy in postmenopausal women, remain unknown. Therefore, we pretreated ovariectomized rats with a relatively high dose of estrogen (0.5 mg/kg/week) for two weeks. Subsequently, renal hemodynamic responses to intravenous angiotensin II (Ang II, 30–300 ng/kg/min) were tested under anesthesia, while renal perfusion pressure was held constant. The role of AT2R was examined by pretreating groups of rats with PD123319 or its vehicle. Renal blood flow (RBF) decreased in a dose-related manner in response to Ang II. Responses to Ang II were enhanced by pretreatment with estradiol. For example, at 300 ng kg−1 min−1, Ang II reduced RBF by 45.7 ± 1.9% in estradiol-treated rats but only by 27.3 ± 5.1% in vehicle-treated rats. Pretreatment with PD123319 blunted the response of RBF to Ang II in estradiol-treated rats, so that reductions in RBF were similar to those in rats not treated with estradiol. We conclude that supraphysiological levels of estrogen promote AT2R-mediated renal vasoconstriction. This mechanism could potentially contribute to the increased risk of cardiovascular disease associated with hormone replacement therapy using high-dose estrogen.

Estrogen as Jekyll and Hyde: regulation of cell death

Sustained estrogenic exposure increases the risk and/or the progression of various cancers, including those of the breast, endometrium and ovary. Unexpectedly, physiological level of estrogen together with a novel IKKα inhibitor BAY11-7082 could effectively induce cell apoptosis in ER-positive breast cancer cells, suggesting combining estrogen with IKKα inhibition may be beneficial for breast cancer patients. This opinion article touches upon the dual role estrogen played in inducing cancer cell death and asks whether use of estrogen in combination with IKKα-targeted therapy would be possible reconsider the newly identified crosstalk between ER and NFκB pathway which can be utilized to switch the effects of estrogen on cell death.

Estrogen as Jekyll and Hyde: regulation of cell death

Sustained estrogenic exposure increases the risk and/or the progression of various cancers, including those of the breast, endometrium and ovary. Unexpectedly, physiological level of estrogen together with a novel IKKα inhibitor BAY11-7082 could effectively induce cell apoptosis in ER-positive breast cancer cells, suggesting combining estrogen with IKKα inhibition may be beneficial for breast cancer patients. This opinion article touches upon the dual role estrogen played in inducing cancer cell death and asks whether use of estrogen in combination with IKKα-targeted therapy would be possible reconsider the newly identified crosstalk between ER and NFκB pathway which can be utilized to switch the effects of estrogen on cell death.

Estrogen as Jekyll and Hyde: regulation of cell death.

Estrogen has profound effects on growth, differentiation and function in male and female reproductive systems, and it is important for bone density, brain function and cholesterol mobilization. Despite beneficial estrogen functions, sustained estrogenic exposure increases the risk and/or the progression of various cancers, including those of the breast, endometrium and ovary. This opinion article touches upon the dual role estrogen played in cancer and asks whether the use of estrogen in combination with other targeted therapy would be possible, considering the newly identified crosstalk pathway which can switch the effects of estrogen.

Premenstrual Dysphoric Disorder and the Brain

Premenstrual Dysphoric Disorder and the Brain

Sex differences in the antidepressant-like effects of ketamine

Current medications for major depression suffer from numerous limitations. Once the right drug for treatment has been determined, it still takes several weeks for it to take effect and improve mood. This time lag is a serious concern for the healthcare community when dealing with patients with suicidal thoughts. However, recent clinical studies have shown that a single low-dose injection of ketamine, an N-methyl d-aspartate receptor (NMDAR) antagonist, has rapid antidepressant effects that are observed within hours and are long lasting. Although major depression affects twice as many women as men, all studies examining the rapid antidepressant effects of ketamine have focused on male subjects. Thus, we have investigated the behavioral and molecular effects of ketamine in both male and female rats and demonstrated greater sensitivity in female rats at a low dose of ketamine, a dose does not have antidepressant-like effects in male rats. The antidepressant-like effects of this low dose of ketamine were completely abolished when female rats were ovariectomized (OVX), and restored when physiological levels of estrogen and progesterone were supplemented, suggesting a critical role for gonadal hormones in enhancing the antidepressant-like effects of ketamine in female rats. In preclinical studies, the mammalian target of rapamycin (mTOR) in the medial prefrontal cortex and the eukaryotic elongation factor (eEF2) in the hippocampus have been proposed as critical mediators of ketamine's rapid antidepressant actions. In our hands, the increased sensitivity of female rats to a low dose of ketamine was not mediated through phosphorylation of mTOR or eEF2.

Low Estrogen Exposure and/or Defective Estrogen Signaling Induces Disturbances in Glucose Uptake and Energy Expenditure

Correlations between estrogen signaling and human morbidity seems to be very unclear and difficult topic. Nowadays, the opinions of scientists have been partially changed regarding “estrogen induced diseases”, but the overwhelming literary data are still contradictory. Physiological estrogen levels in healthy premenopausal women supply protection against insulin resistance, hypertension, cardiovascular diseases and malignancies as compared with men of the same age. However, after menopause a decreased ovarian estrogen synthesis will rapidly deteriorate the glucose sensitivity and increases the prevalence of life threatening diseases. New findings on the functions of tissular estrogen receptors (ERs) indicate that estradiol plays important role in the maintenance of glucose homeostasis and energy expenditure. Diverse disorders associated with insulin resistance are usually well treatable by estradiol substitution both in pre- and postmenopausal women as well as in animal experiments. ERs seem to have balanced interplay in the maintenance of adaptation to the momentarily changing intra and extracellular stimuli. This equilibrium may be shattered in case of a defective estrogen supply or by the derangement of ER signaling pathways. Understanding the crosstalk and interplay between ERs illuminates the fact that there is no good or bad ER isoform, but they construe a complex system so as to achieve an ideal internal milieu. Considering the regulatory effects of ERs on food intake, insulin secretion, glucose uptake and metabolic processes, estrogen administration may be a therapeutic avenue to repair insulin sensitivity in patients with dysmetabolism and diabetes mellitus.

Influence of estrogen on pulmonary arterial hypertension: role of oxidative stress

Pulmonary arterial hypertension (PAH) is a disease that increases the pulmonary vascular resistance, causing hypertrophy and subsequent right heart failure. Oxidative stress is involved in the pathogenesis of PAH, and estrogen is considered an antioxidant. Thus, the aim of this study was to test the hypothesis that estrogen could attenuate PAH by modulating oxidative stress. Female Wistar rats were ovariectomized or suffered the surgery simulation (sham). After 7 days, subcutaneous pellets with 17β-estradiol or sunflower oil were implanted. At this time, PAH was induced by means of a single dose of monocrotaline (MCT) (60 mg·kg(-1) i.p.). The experimental groups were as follows: (1) sham, (2) sham + MCT, (3) ovariectomy (O), (4) ovariectomy + MCT (OM), (5) ovariectomy + estrogen replacement + MCT (ORM). Hemodynamic measurements were performed 21 days after MCT or saline. Nonovariectomized animals were assessed in the stage of diestrus. Afterwards, the rats were killed to collect the heart, the lung and the liver to evaluate morphometry. Samples of the right ventricle were used to analyse the reduced glutathione : oxidized glutathione ratio. Lung congestion in the OM group, which was decreased in the ORM group, was observed. Right ventricle end-diastolic pressure was increased in the OM and the ORM groups. The glutathione ratio decreased in the groups O, OM and ORM. The data suggest that estrogen can exert great influence on the cellular redox balance. The maintenance of physiological estrogen levels may help to avoid the appearance of pulmonary oedema, characteristic of this model of PAH, and right ventricular failure.

Discrepancy in improvement of hearing loss between left and right ears after postmenopausal hormone therapy

Physiological levels of estrogen would seem to have a possible protective effect on hearing function and estrogen replacement therapy may delay hearing loss in menopausal women. Treatment of healthy menopausal women with Tibolone for 6 months resulted in improvement in audiometry results at low frequencies which was more prominent on the right side. The reason of better improvement on the right side is not known. There might be some other factors modifying the condition or effect of the drug such as laterality. There might be hearing lateralization in menopausal women. Especially significant improvement on right ear might be explained by differences in distribution of estrogen receptor (ER) in the ear, in another words lateralization of ER concentration. ER-α and -β might be more dense in the right ear, so give better response to estrogen treatment. Another reason might be difference in bone mineral density of sides of body which is lower on the right side. Similarly lower bone mineral density right ear bones would cause better response to estrogen therapy and better improvement in audiometry results on that side.

Neuroprotective efficacy of estrogen in experimental spinal cord injury in rats

Spinal cord injury (SCI) leads to neurological deficits and motor dysfunction. Methylprednisolone, the only drug used for treating SCI, renders limited neuroprotection and remains controversial. Estrogen is one of the most potent multiactive neuroprotective agents and it is currently under investigation in our laboratory for its efficacy in SCI. The present review briefly summarizes our earlier findings on the therapeutic potential of pharmacological/supraphysiological levels of estrogen in SCI and outlines our ongoing research, highlighting the efficacy of physiological levels of estrogen against neuronal injury, axonal degeneration, and gliosis and also the molecular mechanisms of such neuroprotection in experimental SCI. Furthermore, our ongoing studies designed to explore the different translational potential of estrogen therapy suggest that this multiactive steroid may act as an adjunct therapy to promote angiogenesis, thus enhancing the functional recovery following chronic SCI. Taken together, these studies confirm that estrogen is a potential therapeutic agent for treating SCI.

Aging and estrogen: Modulation of inflammatory responses after injury

Aged subjects have a poor prognosis after traumatic injury and, regardless of the type of injury, they have slower recoveries and suffer more complications than their younger counterparts. The age-dependent responses may be influenced by the hyper-inflammatory state observed in the aged prior to injury, including elevated levels of interleukin-6 (IL-6). Physiological levels of estrogen are beneficial to the immune system, due, in part, to the hormone’s ability to attenuate aberrant production of pro-inflammatory cytokines. Using two independent injury models, we have found increased mortality and elevated serum levels of IL-6 in aged mice, when compared to young animals ( p < 0.05). In parallel studies, groups of aged mice given estrogen (17β-estradiol) prior to scald burn, had significantly improved survival ( p < 0.05) and lowered serum IL-6 ( p < 0.05). Multiple cellular mechanisms may be involved in mediating the beneficial effects of estrogen on inflammatory and immune responses in aged individuals who sustain an injury. These mechanisms are discussed herein.

Estrogen induces death of tamoxifen-resistant MCF-7 cells: Contrasting effect of the estrogen receptor downregulator fulvestrant

A common problem in breast cancer therapy is resistance to the antiestrogen tamoxifen. However, tamoxifen-resistant breast tumors can still respond to other hormonal therapies. In animal models of tamoxifen-resistant breast cancer cells, physiological levels of estrogen can induce tumor regression. Recently, the estrogen receptor downregulator fulvestrant was shown to promote tumor growth of tamoxifen-resistant cells when added in combination with physiological levels of estrogen. Here, we show, using a cell culture model, that continuous exposure of tamoxifen-resistant cells to physiological levels of estrogen leads to cell death. Addition of the estrogen receptor downregulator fulvestrant prevents estrogen-induced death in a dose-dependent manner. Our data indicate that endogenous levels of estrogen affect the response of tamoxifen-resistant cells to fulvestrant. These results suggest that failure of fulvestrant to inhibit tumor growth in some tamoxifen-resistant patients may be due to endogenous estrogen levels. Moreover, these studies support short-term treatment with estrogen as a second-line hormonal therapy for tamoxifen-resistant breast cancer.

Potential of Aromatase Inhibitors for Ovulation and Superovulation Induction in Infertile Women

For almost half a century, the first-line treatment for ovulation induction in cases of anovulation, unexplained infertility, or mild male factor has been clomifene (clomiphene citrate). Clomifene is an effective and safely used oral agent, but is known to have relatively common antiestrogenic endometrial and cervical mucous adverse effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancies with clomifene compared with natural cycles. These drawbacks are mainly a result of the extended antiestrogenic effect of clomifene as a result of its accumulation in the body (clomifene isomers have a half-life of several days up to few weeks). Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of clomifene. Over the last few years several published studies, both controlled and noncontrolled, compared clomifene and treatment with aromatase inhibitors (AIs), either alone or in combination with gonadotropins, for ovulation induction or augmentation. These studies found AIs as effective as clomifene in inducing ovulation, with the major advantage of absence of any antiestrogenic adverse effects. Several other major advantages of AIs include the lower serum estrogen production per developing follicle resulting in more physiological estrogen levels around the time of ovulation and good pregnancy rates with a lower incidence of multiple pregnancy than with clomifene. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of gonadotropins required for optimal follicle recruitment and improve the response to gonadotropin stimulation in poor responders. Such preliminary evidence suggests that AIs may replace clomifene in the future because of similar efficacy with a reduced adverse-effect profile. However, we believe that definitive studies in the form of randomised controlled trials comparing clomifene with AIs are needed.