Estrogen Receptors: Therapeutic Perspectives for the Treatment of Cardiac Dysfunction after Myocardial Infarction.

Estrogen receptors (ER) mediate functions beyond their endocrine roles, as modulation of cardiovascular, renal, and immune systems through anti-inflammatory and anti-apoptotic effects, preventing necrosis of cardiomyocytes and endothelial cells, and attenuating cardiac hypertrophy. Estradiol (E2) prevents cardiac dysfunction, increases nitric oxide synthesis, and reduces the proliferation of vascular cells, yielding protective effects, regardless of gender. Such actions are mediated by ER (ER-alpha (ERα), ER-beta (ERß), or G protein-coupled ER (GPER)) through genomic or non-genomic pathways, which regulate cardiovascular function and prevent tissue remodeling. Despite the extensive knowledge on the cardioprotective effects of estrogen, clinical studies conducted on myocardial infarction (MI) and cardiovascular diseases still include favorable and unfavorable profiles. The purpose of this review is to provide up-to-date information regarding molecular, preclinical, and clinical aspects of cardiovascular E2 effects and ER modulation as a potential therapeutic target for the treatment of MI-induced cardiac dysfunction.

Nuclear role for human Argonaute-1 as an estrogen-dependent transcription coactivator.

In mammals, argonaute (AGO) proteins have been characterized for their roles in small RNA-mediated posttranscriptional and also in transcriptional gene silencing. Here, we report a different role for AGO1 in estradiol-triggered transcriptional activation in human cells. We show that in MCF-7 mammary gland cells, AGO1 associates with transcriptional enhancers of estrogen receptor α (ERα) and that this association is up-regulated by treating the cells with estrogen (E2), displaying a positive correlation with the activation of these enhancers. Moreover, we show that AGO1 interacts with ERα and that this interaction is also increased by E2 treatment, but occurs in the absence of RNA. We show that AGO1 acts positively as a coactivator in estradiol-triggered transcription regulation by promoting ERα binding to its enhancers. Consistently, AGO1 depletion decreases long-range contacts between ERα enhancers and their target promoters. Our results point to a role of AGO1 in transcriptional regulation in human cells that is independent from small RNA binding.

Metastatic genes targeted by an antioxidant in an established radiation- and estrogen-breast cancer model.

Breast cancer remains the second most common disease worldwide. Radiotherapy, alone or in combination with chemotherapy, is widely used after surgery as a treatment for cancer with proven therapeutic efficacy manifested by reduced incidence of loco-regional and distant recurrences. However, clinical evidence indicates that relapses occurring after radiotherapy are associated with increased metastatic potential and poor prognosis in the breast. Among the anticarcinogenic and antiproliferative agents, curcumin is a well-known major dietary natural yellow pigment derived from the rhizome of the herb Curcuma longa (Zingiberaceae). The aim of the present study was to analyze the differential expression of metastatic genes in radiation- and estrogen-induced breast cancer cell model and the effect of curcumin on such metastatic genes in breast carcinogenesis. Expression levels of TGF-α and TGFß1 genes were upregulated in MCF-10F and downregulated in Tumor2 cell lines treated with curcumin. Expression levels of other genes such as caspase 9 and collagen 4 A2 were upregulated in both MCF-10F and Tumor2-treated cell lines. Integrin α5 and cathepsin B and D decreased its expression in Tumor2, whereas E-Cadherin, c-myc and CD44 expressions were only increased in MCF-10F. It can be concluded that metastatic genes can be affected by curcumin in cancer progression and such substance can be used in breast cancer patients with advanced disease without side-effects commonly observed with therapeutic drugs.

Plasticity in Uterine Innervation: State of the Art.

Early studies often claimed that autonomic nerves were unimportant for uterine function, since denervation of the uterus had little effects on reproductive success. In 1979, Thorbert wrote, "It seems unlikely that Nature has equipped the uterus with a complex innervation merely as a structural ornament. Our ignorance in this area may be rather due to defects in methods of study". Investigations carried out over the last four decades proved that Thorbert's words were correct, because it is now clear that autonomic and sensory nerves regulate many critical uterine functions. However, the most remarkable aspect of uterine innervation is its capacity to change in response to physiological fluctuations in levels of sex hormones, as those accompanying pregnancy, the sex cycle and puberty. The present review provides an overview about how sex hormones influence uterine innervation. Data are presented about how this physiological plasticity is mimicked by exogenous administration of sex hormones, particularly estrogen. We will review recent developments illustrating the complex multifactorial mechanisms regulating uterine neural plasticity and the nature of molecular signals involved. Finally, we will go through recent findings pointing to the relevance of uterine innervation in gynecological diseases leading to pain and infertility.

Estrogen signaling in the proliferative endometrium: implications in endometriosis.

Even though the physiological role of estrogen in the female reproductive cycle and endometrial proliferative phase is well established, the signaling pathways by which estrogen exerts its action in the endometrial tissue are still little known. In this regard, advancements in cell culture techniques and maintenance of endometrial cells in cultures enabled the discovery of new signaling mechanisms activated by estrogen in the normal endometrium and in endometriosis. This review aims to present the recent findings in the genomic and non-genomic estrogen signaling pathways in the proliferative human endometrium specifically associated with the pathogenesis and development of endometriosis.

Estrogen signaling in the proliferative endometrium: implications in endometriosis / Sinalização pelo estrogênio no endométrio proliferativo: implicações na endometriose

SUMMARY Even though the physiological role of estrogen in the female reproductive cycle and endometrial proliferative phase is well established, the signaling pathways by which estrogen exerts its action in the endometrial tissue are still little known. In this regard, advancements in cell culture techniques and maintenance of endometrial cells in cultures enabled the discovery of new signaling mechanisms activated by estrogen in the normal endometrium and in endometriosis. This review aims to present the recent findings in the genomic and non-genomic estrogen signaling pathways in the proliferative human endometrium specifically associated with the pathogenesis and development of endometriosis.

RESUMO Embora esteja bem estabelecido o papel fisiológico do estrogênio no ciclo reprodutivo feminino e na fase proliferativa do endométrio, as vias de sinalização por meio das quais a ação do estrogênio é exercida no tecido endometrial são ainda pouco conhecidas. Nesse sentido, o avanço nas técnicas de cultura celular e a manutenção de células endometriais em cultivo possibilitaram a descoberta de novos mecanismos sinalizadores ativados pelo estrogênio no endométrio normal e na endometriose. Esta revisão tem o objetivo de apresentar as descobertas recentes envolvendo as vias de sinalização genômica e não genômica do estrogênio no endométrio proliferativo humano, especificamente associadas à patogênese e ao desenvolvimento da endometriose.

Genetic polymorphism in sex hormone metabolism and prostate cancer risk.

We compared single-nucleotide polymorphisms for point mutations in cytochrome P450 genes, including cytochrome P450c17α (CYP17), cytochrome P450 aromatase (CYP19), steroid-5-a-reductase (SRD5A2), and prostate-specific antigen (PSA) involved in androgen and estrogen production. Between January 2008 and January 2010, 90 patients were enrolled in the study. Of these patients, 28 were diagnosed with benign prostatic hyperplasia and 32 with prostate cancer, while 30 subjects were included as a control group. CYP19 1531 C>T, SRD5A2 gene V89L, CYP17 gene -34 T/C, PSA-158 (G/A) regions were evaluated for the association between polymorphisms and benign prostatic hyperplasia and prostate cancer in study population. Age, body mass index, peak urinary flow rate (Q max), voided urine volume, post-void residual urine volume, total PSA, free PSA, free/total PSA ratio, prostate weights measured by transrectal ultrasonography, erectile dysfunction score, and international prostate symptom score were compared between groups. No statistically significant difference in CYP19 1531 C>T, SRD5A2 V89L, and CYP17 -34T/C was observed in both groups when compared to the control group. The homozygote variant of PSA- 158 (G/A) was significantly lower for prostate cancer. Age, total PSA, free PSA, free/total PSA ratio, prostate weight, and Q max were evaluated using multi-variant analysis. Only Q max was significant for the homozygote variant. The probability of being homozygous was 5.8- fold higher in subjects with Q max >14 mL/s. In the Turkish population, the homozygote variant of PSA-158 (G/A) was significantly lower for prostate cancer.

Risk of premature ovarian failure is associated to the PvuII polymorphism at estrogen receptor gene ESR1.

PURPOSE: Estrogen plays an important role in the human reproductive system and it action is mediated mainly by two specific receptors: α (ERα) and ß (ERß). There were described polymorphic variants in ESR1 and ESR2 genes and studies showed controversial results regarding their association with premature ovarian failure. We aimed to determine the prevalence of ESR1 and ESR2 polymorphisms in Brazilian patients and controls. After associate the polymorphisms with premature ovarian failure (POF). METHODS: Genetic association study was performed with 70 women with POF and 73 normally menopaused controls. Detection of ESR1 (PvuII/and XbaI) and ESR2 (AluI and RsaI) gene polymorphisms were performed using TaqMan PCR. The single-nucleotide polymorphism (SNPs) and haplotype effects were analyzed by multivariate logistic regression and haplotype analysis and a p-value < 0.05 was considered significant. RESULTS: Individual SNP analysis revealed that PvuII polymorphism was statistically associated with POF (p = 0.034) under a recessive model. Regarding XbaI, AluI and RsaI SNPs, no statistical difference was observed between POF group and controls (p = 0.575, p = 0.258 and p = 0.483, respectively). Combined genotypes of ESR1 and ESR2 polymorphisms did not identify a risk haplotype associated with POF. CONCLUSION: In Brazilian population evaluated results have demonstrated that the genetic variation in ESR1 gene (PvuII polymorphism) is associated to POF risk.

Variability in estrogen-metabolizing genes and their association with genomic instability in untreated breast cancer patients and healthy women.

In the present study, we investigated the relationship between polymorphisms in the estrogen-metabolizing genes CYP17, CYP1B1, CYP1A1, and COMT and genomic instability in the peripheral blood lymphocytes of 62 BC patients and 62 controls considering that increased or prolonged exposure to estrogen can damage the DNA molecule and increase the genomic instability process in breast tissue. Our data demonstrated increased genomic instability in BC patients and that individuals with higher frequencies of MN exhibited higher risk to BC when belonging Val/Met genotype of the COMT gene. We also observed that CYP17 and CYP1A1 polymorphisms can modify the risk to BC depending on the menopause status. We can conclude that the genetic background in estrogen metabolism pathway can modulate chromosome damage in healthy controls and patients and thereby influence the risk to BC. These findings suggest the importance to ally biomarkers of susceptibility and effects to estimate risk groups.

[Body mass regulation by estrogen and physical activity]. / Regulação da massa corpórea pelo estrogênio e pela atividade física.

Female steroid hormones deficiency leads to a significant increase in body mass, but the possible central and peripheral mechanisms involved in increased food ingestion and fat accumulation in this situation are still unknown. In animal models, the specific lack of estrogen or its action produce progressive body mass gain, clearly demonstrating the possible role of this hormone in overweight after menopause. Obesity and overweight correspond to a relevant human health problem that can lead to premature death. Therefore unraveling the mechanisms underlying body mass gain is of great relevance, as well as the development of strategies to prevent its establishment. Energy balance regulation is associated with the control of body mass, and physical exercise is an important modulator of this homeostatic parameter. However, the influence of physical exercise in mass gain development during estrogen deficiency is controversial and depends on the exercise protocol used. In this study, we intend to review the data on the effects of estrogen deficiency on body mass gain in humans and animal models.

Glucose transporters in sex steroid hormone related cancer.

Cancer cells, as with most mammalian cells, depend on a continuous supply of glucose; not only as a precursor of glycoproteins, triglycerides and glycogen, but also as an important source of energy. This review concentrates on GLUT transporter expression in both normal and cancerous classical sex-steroid hormone tissues (i.e. breast, uterus, ovary, testis and prostate, among others). Given the importance of estrogen, progesterone and androgens in carcinogenesis, as well as in survival and propagation of these cancers, this review also highlights the current literature on hormone regulation of glucose transporters and on the role of hypoxia in their expression. Given the recent explosion of information on the newer GLUT6-12 family members, a brief overview on their function and general expression has been included. Finally, an insight into the use of glucose transporters as markers of cancer progression and clinical outcome is also discussed.

Regulação da massa corpórea pelo estrogênio e pela atividade física: [revisão] / Body mass regulation by estrogen and physical activity: [review]

A deficiência de esteroides gonadais femininos acelera o ganho de massa corpórea, mas os possíveis mecanismos centrais e periféricos envolvidos no aumento da ingestão alimentar e no ganho de massa adiposa que ocorrem nessa condição são pouco conhecidos. Em modelos animais, tanto a falta quanto os defeitos na ação do estrogênio causam aumento da massa corpórea, demonstrando claramente um possível papel desse esteroide no sobrepeso pós-menopausa. Sabe-se que a obesidade e o sobrepeso estão associados a diversas comorbidades que podem levar à morte prematura. Portanto, desvendar os mecanismos relacionados ao ganho de massa corpórea é de grande relevância, assim como desenvolver estratégias que possam prevenir o seu estabelecimento. A regulação do balanço energético está associada ao controle da massa corpórea, sendo o exercício físico um importante modulador desse parâmetro homeostático. Porém, a influência do exercício físico sobre o ganho de massa corpórea durante a deficiência de estrogênio é controversa e depende do protocolo de exercício utilizado. Neste estudo, pretendemos revisar os achados que relacionam a deficiência de estrogênio ao ganho de massa corpórea em animais e seres humanos.

Female steroid hormones deficiency leads to a significant increase in body mass, but the possible central and peripheral mechanisms involved in increased food ingestion and fat accumulation in this situation are still unknown. In animal models, the specific lack of estrogen or its action produce progressive body mass gain, clearly demonstrating the possible role of this hormone in overweight after menopause. Obesity and overweight correspond to a relevant human health problem that can lead to premature death. Therefore unraveling the mechanisms underlying body mass gain is of great relevance, as well as the development of strategies to prevent its establishment. Energy balance regulation is associated with the control of body mass, and physical exercise is an important modulator of this homeostatic parameter. However, the influence of physical exercise in mass gain development during estrogen deficiency is controversial and depends on the exercise protocol used. In this study, we intend to review the data on the effects of estrogen deficiency on body mass gain in humans and animal models.

Advancement of reproductive senescence and changes in the early expression of estrogen, progesterone and micro-opioid receptors induced by neonatal hypoxia in the female rat.

Perinatal hypoxia is a frequent birth complication, and although its early consequences on brain development have been well studied, few studies address any long-term effects. Postnatal insults producing small disturbances in endocrine function can have marked and long-lasting effects. In the present work we studied the effects of two types of perinatal brain injury: global hypoxia (H, 6.5% O2 for 50 min) and hypoxia plus ischemia (HI, ligature of the right carotid artery) on female rat reproductive performance and expression of mediobasal hypothalamus-preoptic area (MBH-PO) estrogen, progesterone and micro-opioid receptors at different times after injury, measuring the mRNA (by semiquantitative RT-PCR) and protein (by Western blot). H or HI advanced approximately 3 months after the appearance of blunted preovulatory LH surges and cyclic irregularities (prolonged estrus) characteristic of the early stages of reproductive senescence. 48 h after H or HI we observed decreases in ERbeta, microOR and PR (only in the H group) mRNAs and in total ER and microOR proteins, followed by increased PR levels (mRNA and protein) 7 days post-injury and by increased microOR protein and ERbeta mRNA in the H group and ERalpha, ERbeta and microOR mRNAs and ER protein in the HI group 30 days post-injury. Thus, an episode of hypoxia suffered during early postnatal life induces premature reproductive senescence on the female rats, accompanied by early changes in some MBH-PO hormone receptors (microOR, ER and PR), whose expression is intimately involved in the regulation of gonadotropin secretion and female sexual cyclicity.

Estrogens and male reproduction: a new concept.

The mammalian testis serves two main functions: production of spermatozoa and synthesis of steroids; among them estrogens are the end products obtained from the irreversible transformation of androgens by a microsomal enzymatic complex named aromatase. The aromatase is encoded by a single gene (cyp19) in humans which contains 18 exons, 9 of them being translated. In rats, the aromatase activity is mainly located in Sertoli cells of immature rats and then in Leydig cells of adult rats. We have demonstrated that germ cells represent an important source of estrogens: the amount of P450arom transcript is 3-fold higher in pachytene spermatocytes compared to gonocytes or round spermatids; conversely, aromatase activity is more intense in haploid cells. Male germ cells of mice, bank voles, bears, and monkeys express aromatase. In humans, we have shown the presence of a biologically active aromatase and of estrogen receptors (alpha and ss) in ejaculated spermatozoa and in immature germ cells in addition to Leydig cells. Moreover, we have demonstrated that the amount of P450arom transcripts is 30% lower in immotile than in motile spermatozoa. Alterations of spermatogenesis in terms of number and motility of spermatozoa have been described in men genetically deficient in aromatase. These last observations, together with our data showing a significant decrease of aromatase in immotile spermatozoa, suggest that aromatase could be involved in the acquisition of sperm motility. Thus, taking into account the widespread localization of aromatase and estrogen receptors in testicular cells, it is obvious that, besides gonadotrophins and androgens, estrogens produced locally should be considered to be physiologically relevant hormones involved in the regulation of spermatogenesis and spermiogenesis.

Estrogens and male reproduction: a new concept

The mammalian testis serves two main functions: production of spermatozoa and synthesis of steroids; among them estrogens are the end products obtained from the irreversible transformation of androgens by a microsomal enzymatic complex named aromatase. The aromatase is encoded by a single gene (cyp19) in humans which contains 18 exons, 9 of them being translated. In rats, the aromatase activity is mainly located in Sertoli cells of immature rats and then in Leydig cells of adult rats. We have demonstrated that germ cells represent an important source of estrogens: the amount of P450arom transcript is 3-fold higher in pachytene spermatocytes compared to gonocytes or round spermatids; conversely, aromatase activity is more intense in haploid cells. Male germ cells of mice, bank voles, bears, and monkeys express aromatase. In humans, we have shown the presence of a biologically active aromatase and of estrogen receptors (alpha and ß) in ejaculated spermatozoa and in immature germ cells in addition to Leydig cells. Moreover, we have demonstrated that the amount of P450arom transcripts is 30 percent lower in immotile than in motile spermatozoa. Alterations of spermatogenesis in terms of number and motility of spermatozoa have been described in men genetically deficient in aromatase. These last observations, together with our data showing a significant decrease of aromatase in immotile spermatozoa, suggest that aromatase could be involved in the acquisition of sperm motility. Thus, taking into account the widespread localization of aromatase and estrogen receptors in testicular cells, it is obvious that, besides gonadotrophins and androgens, estrogens produced locally should be considered to be physiologically relevant hormones involved in the regulation of spermatogenesis and spermiogenesis.

Organizational and activational effects of estrogenic endocrine disrupting chemicals.

Endocrine disruption is a hypothesis of common mode of action that may define a set of structurally varied chemicals, both natural and synthetic. Their common mode of action may suggest that they produce or contribute to similar toxic effects, although this has been difficult to demonstrate. Insights from developmental biology suggest that development of hormone sensitive systems, such as the brain and the genitourinary tract, may be particularly sensitive to EDCs. Because these systems are both organized and later activated by hormones, the brain and vagina may be valuable model systems to study the toxicity of EDCs in females and to elucidate mechanisms whereby early exposures appear to affect long term function.