Female Hormone 17β-estradiol Research Articles

Receptor mediated biological activities of phytoestrogens

Phytoestrogens are plant-derived compounds that have chemical structures and functions similar to estrogen. Phytoestrogens act as ligand-inducible transcription factors involved in cellular growth by binding to estrogen receptors (ERs), specifically ER alpha (ERα) and beta (ERβ). Through this mechanism, phytoestrogens have a physiological function similar to that of the female hormone 17β-estradiol (E2), which can be useful in treating osteoporosis, cardiovascular disease, and cancer. Furthermore, phytoestrogens have been found to elicit various cellular responses depending on their affinity for ERs; in particular, they show a greater affinity with for ERβ. This study aimed to comprehensively analyze the mode of action of eight phytoestrogens, namely kaempferol, coumestrol, glycitein, apigenin, daidzein, genistein, equol, and resveratrol, by evaluating their estrogenic activity as ER ligands. Based on the bioluminescence resonance energy transfer (BRET)-based ER dimerization and transactivation assay results, all the phytoestrogens tested were identified as estrogen agonists by mediating ERα and ERβ dimerization. The specific binding and functions of ERα and ERβ were distinguished by differentiating between their dimerization activity. In addition, this study contributes to advancing our understanding of the overall mechanism of action involving both ERs.

Sex discrimination of cultured greater amberjack Seriola dumerili using steroid hormones

The aquaculture of greater amberjack Seriola dumerili is of considerable research interest worldwide. The larviculture methods employed to culture this species, however, are still under development, and the majority of farms still rely on wild-caught juveniles. One of the problems associated with the hatchery production of this species is the optimal selection of broodstock to ensure a stable supply of high-quality eggs. Specifically, no reliable low-stress sex-discrimination technique is currently available for selecting broodstock of this species. This study investigated the efficacy of a hormone-based sex-discrimination method in full-cycle cultured S. dumerili, ranging in age from 412 to 1150 days after hatching (DAH). Plasma concentrations of the female hormone 17β-estradiol (E2) and the male hormone 11-ketotestosterone (11-KT) were measured in both spawning and non-spawning seasons, and the optimal threshold levels for sex discrimination were estimated using a receiver operating characteristic curve. Sex discrimination using E2 produced several false positives in younger fish, and had an overall accuracy of 78.7%. However, sex discrimination using 11-KT had an accuracy of 96.7%, even in 412 DAH fish. This study demonstrated that sex discrimination using 11-KT is a reliable method for optimizing the sex ratio of S. dumerili broodstock, even before the broodstock mature.

Female Hormone 17β-Estradiol Downregulated MMP-2 Expression and Upregulated A1PI Expression in Human Corneal Stromal Cells.

Collagens are essential for cornea functions. In non-ocular tissues, it has been demonstrated that sex hormones modulate the collagen remodeling. In this study, we investigated whether the primary female hormone 17β-estradiol plays a role in the expressions of matrix metalloproteinases and proteinase inhibitors in cultured human corneal stromal cells. We found that 17β-estradiol treatment significantly reduced the matrix metalloproteinase-2 mRNA in human corneal stromal cells as well as the matrix metalloproteinase-2 proteins, while the matrix metalloproteinase-9 mRNA level was not significantly altered. 17β-estradiol also upregulated the expression of proteinase inhibitor, alpha1-proteinase inhibitor. The expression of transcription factor specificity protein 1 was reduced by 17β-estradiol. Furthermore, 17β-estradiol did not change the viability and apoptosis of the corneal stromal cells. The downregulation of matrix metalloproteinase-2 and upregulation of alpha1-proteinase inhibitor by 17β-estradiol possibly serve as protective factor for the normal tomography in antagonizing the extracellular matrix degeneration in many cornea diseases.

Renal Protective Effects of 17β-Estradiol on Mice with Acute Aristolochic Acid Nephropathy.

Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by a Chinese herb containing aristolochic acid. Excessive death of renal tubular epithelial cells (RTECs) characterized the acute phase of AAN. Therapies for acute AAN were limited, such as steroids and angiotensin-receptor blockers (ARBs)/angiotensin-converting enzyme inhibitors (ACEIs). It was interesting that, in acute AAN, female patients showed relative slower progression to renal failure than males. In a previous study, female hormone 17β-estradiol (E2) was found to attenuate renal ischemia-reperfusion injury. Thus, the aim of this study was to investigate the potential protective role of E2 in acute AAN. Compared with male C57BL/6 mice of acute AAN, lower serum creatinine (SCr) and less renal injury, together with RTEC apoptosis in females, were found. Treatment with E2 in male AAN mice reduced SCr levels and attenuated renal tubular injury and RTEC apoptosis. In the mice kidney tissue and human renal proximal tubule cells (HK-2 cells), E2 both attenuated AA-induced cell apoptosis and downregulated the expression of phosphor-p53 (Ser15), p53, and cleaved-caspase-3. This study highlights that E2 exhibited protective effects on the renal injury of acute AAN in male mice by reducing RTEC apoptosis, which might be related to inhibiting the p53 signaling pathway.

17β-estradiol and methylation of migraine-related genes

Migraine is much more common in women than in men, especially during the reproductive part of their lives. Fluctuations in the female hormone 17β-estradiol throughout the menstrual cycle are thought to be an important factor in causing migraine attacks in women. Although it has been shown that 17β-estradiol can change vascular sensitivity to CGRP, it is still unknown how 17β-estradiol causes these effects. GWAS studies have identified genes that may be relevant for migraine, but an influence of environmental factors is likely. Interestingly, the prophylactic effectivity of valproate, a DNA methylation inhibitor, may point to the involvement of epigenetic mechanisms in migraine. 17β-estradiol is known to be involved in epigenetic mechanisms and recently it was shown that CGRP can be regulated via epigenetic mechanisms. Therefore, the aim of this study was to investigate the role of 17β-estradiol in the methylation of migraine-related genes. Female SD rats were ovariectomized (ovx) and treated with 17β-estradiol or placebo pellets. DNA was isolated from blood, aorta, dura mater, trigeminal caudal nucleus and trigeminal ganglion. PCR was performed for 10 migraine- and female hormone-related genes (MTHFR, eNOS, ESR1, GPER, CGRP, USF1, USF2, RAMP1, CRCP and CRLR) and DNA methylation was assessed through bisulfite treatment and sequenom mass spectrometry. No difference in DNA methylation was seen between control animals, ovx placebo-treated or ovx 17β-estradiol-treated animals for the MTHFR, GPER, eNOS, CGRP, USF1 and USF2 genes. Tissue-specific differences in methylation were seen for the ESR1, CRCP, eNOS and CRLR genes. Remarkably, our results point to an increase in methylation of the CRCP gene in the trigeminal caudal nucleus in the 17β-estradiol-treated animals. These esults indicate a possible epigenetic regulatory mechanism for one part of the CGRP receptor in the trigeminal caudal nucleus.

Estrogen Sulfotransferase: Intracrinology Meets Metabolic Diseases

Over the past two decades, the female hormone 17β-estradiol (estrogen) has emerged as an important contributor to energy homeostasis in both males and females. Early clinical evidence involved the observation that men lacking estrogen synthesis secondary to mutations in aromatase—the enzyme that converts androgen to estrogen—or men harboring estrogen resistance secondary to mutation of the estrogen receptor (ER)α, develop visceral obesity, insulin resistance, and/or glucose intolerance (1,2). As an experimental confirmation, it was observed that elimination of the aromatase or ERα genes in male and female mice produced the same metabolic syndrome as in humans (3,4). Thus, it is reasonable to assume that although men have lower circulating estrogen concentrations than premenopausal women, aromatization of circulating androgen to estrogen in target metabolic tissues equilibrates cellular estrogen concentrations, and ER activation is critical in both sexes in promoting fuel homeostasis (5). This is consistent with the paradigm that estrogen functions as a circulating hormone in premenopausal women. Conversely, in men and in postmenopausal women—in whom estrogen concentrations are low—estradiol does not function as a hormone; instead, it is synthesized in extragonadal sites such as breast, brain, bone, and fat where it acts locally as a paracrine or intracrine factor (6). Thus, in men and in postmenopausal women, the driver of estrogen action is not circulating estrogens; rather, it depends on estrogen biosynthesis from a circulating source of androgenic precursors such as testosterone. A logical consequence …

Selective estrogen receptor modulation in pancreatic β-cells and the prevention of type 2 diabetes

We recently showed that the female hormone 17β-estradiol (E2) protects against β-cell failure in rodent models of type 2 diabetes (T2D) by suppressing islet fatty acids and glycerolipids synthesis, thus preventing lipotoxic β-cell failure. E2 anti-lipogenic actions were recapitulated by pharmacological activation of the estrogen receptor (ER)α, ERβ and the G-protein coupled ER (GPER) in cultured rodent and human β-cells. In vivo, in mouse islets, ERα activation inhibited β-cell lipogenesis by suppressing fatty acid synthase expression (and activity) via an extranuclear, estrogen response element (ERE)-independent pathway requiring the signal transducer and activator of transcription 3. Here, we show that in INS-1 insulin-secreting cells, the selective ER modulator (SERM), Raloxifene, behaves both as ER antagonist with regard to nuclear ERE-dependent actions and as an ER agonist with regard to suppressing triglyceride accumulation. This additional finding opens the perspective that SERMs harboring ER agonistic activity in β-cells could have application in postmenopausal prevention of T2D. Additional studies using novel generation SERMs are needed to address this issue.

Minireview: Estrogenic Protection of β-Cell Failure in Metabolic Diseases

The prevalence of diabetes is lower in premenopausal women, especially diabetic syndromes with insulin deficiency, suggesting that the female hormone 17beta-estradiol protects pancreatic beta-cell function. In classical rodent models of beta-cell failure, 17beta-estradiol at physiological concentrations protects pancreatic beta-cells against lipotoxicity, oxidative stress, and apoptosis. In this review, we integrate evidence showing that estrogens and their receptors have direct effects on islet biology. The estrogen receptor (ER)-alpha, ER beta, and the G-protein coupled ER are present in beta-cells and enhance islet survival. They also improve islet lipid homeostasis and insulin biosynthesis. We also discuss evidence that ERs modulate insulin sensitivity and energy homeostasis, which indirectly alter beta-cell biology in diabetic and obese conditions.

17β-Estradiol treatment following permanent focal ischemia does not influence recovery of sensorimotor function

The development of therapy to aid poststroke recovery is essential. The female hormone 17beta-estradiol has been shown to promote synaptogenesis; the purpose of this study was to attempt to harness these mechanisms to promote repair and recovery in the peri-infarct zone. Rats were ovariectomized, tested for sensorimotor function, and the middle cerebral artery permanently occluded (MCAO). Infarct volumes were calculated using MRI, and damage was equivalent in all animals prior to implantation of either 17beta-estradiol or placebo pellets. Animals were tested for functional recovery for 28 days and tissue processed for synaptic marker syntaxin immunohistochemistry. The stroke induced a significant behavioral deficit, which persisted out to 28 days, and was not significantly different between 17beta-estradiol and placebo treatment groups. There was no difference in syntaxin immunostaining between groups in either the peri-infarct cortex or in the dendritic CA1 reference region. In conclusion, 17beta-estradiol treatment, delivered poststroke, did not influence recovery of function or synaptogenesis.

Modulation of peroxisome proliferator-activated receptors (PPARs) by PPARα- and PPARγ-specific ligands and by 17β-estradiol in isolated zebrafish hepatocytes

Peroxisome proliferation is a phenomenon occurring when responsive animals are exposed to certain compounds so-called peroxisome proliferators and is regulated through a nuclear receptor named peroxisome proliferator-activated receptor (PPAR). PPAR family members exhibit a strong binding affinity for both saturated and unsaturated fatty acids. Activators of PPARα include a variety of endogenously present fatty acids, leukotrienes and hydroxyeicosatetraenoic acids (HETEs) and clinically used drugs, such as fibrates. PPARβ activators include fatty acids, prostaglandin A 2 (PGA 2) and prostacyclin (PGI 2). PPARγ is the most selective receptor and, among others, 15-deoxy-Δ 12,14 prostaglandin J 2 (PGJ 2) has been described to be a PPARγ-specific ligand. The aim of the present study was to determine if known PPARα and PPARγ ligands were able to alter the expression of these subtypes in an in vitro model of zebrafish primary hepatocyte culture. With this purpose, a PPARα specific ligand (8S-HETE), a PPARγ specific ligand (PGJ 2) and a peroxisome proliferator of the fibrate class (clofibrate) were selected. In addition, the female hormone 17β-estradiol was also used as it is known to interact with PPARs. After cell exposure for 24 h, cells were immunohistochemically stained for both PPARs and immunolabeling was quantified as percentage of positive nuclei and cells. Levels of expression of PPARs were also measured by image analysis as grey level per cell. Expression was induced for both PPARα and PPARγ by clofibrate (at 0.5 mM for PPARα and at 1 and 2 mM for PPARγ), by HETE (1 μM), and by PGJ 2 (0.3 and 1 μM for PPARα and 0.3 μM for PPARγ). Expression of PPARγ was also induced at 10 μM by 17β-estradiol. The percentage of PPARα positive nuclei increased significantly at 1 μM HETE and the percentage of PPARγ positive cells decreased at 10 μM 17β-estradiol. As a conclusion, clofibrate, HETE and PGJ 2 are able to induce expression of both PPARα and PPARγ in zebrafish primary hepatocyte cultures. Further studies are needed to identify how the expression of different PPAR subtypes is regulated and to elucidate the implication of PPAR subtypes in zebrafish cell functions.