Excess Estrogen Research Articles

Tumor board presentation of a woman with metastatic, hormone receptor‐positive, mismatch repair‐deficient endometrial cancer

Tumor board presentation of a woman with metastatic, hormone receptor‐positive, mismatch repair‐deficient endometrial cancer

Morphological alteration of the pancreatic islet in ovariectomized rats fed a high-fat high-fructose diet.

Diabetes and its complications are major causes of mortality worldwide. Type 2 diabetes coexists with insulin resistance and β-cell dysfunction, which are aggravated by overconsumption and estrogen-deprived conditions. However, the morphology of pancreatic islets in a combined condition of excessive caloric intake and estrogen deficiency has never been described. Herein, we examined morphological changes in the pancreatic islets of ovariectomized (OVX) rats fed a high-fat high-fructose diet (HFFD) for 12weeks. The histological changes in the size and number of pancreatic islets were assessed by hematoxylin-eosin and immunohistochemical staining. Enlarged pancreatic islets with fat deposition in OVX rats were accompanied by whole-body insulin resistance and hyperglycemia. The addition of a HFFD to OVX rats (OVX + HFFD) further aggravated insulin resistance, with a substantial increase in the density of enlarged pancreatic islets and fat accumulation. The augmented number of enlarged islets was correlated with elevated plasma glucose and insulin levels. Intriguingly, unlike the HFFD and OVX alone, the OVX + HFFD markedly expanded the area of insulin-producing β-cells and glucagon-producing α-cells. Importantly, enlarged islets, pancreatic fat deposits, and diabetic states developing in OVX + HFFD conditions were resolved by estrogen replacement. Collectively, the morphological characteristics of pancreatic islets were influenced in an insulin-resistant state caused by estrogen deficiency and HFFD consumption and were distinct from each factor alone. A combination of estrogen deficiency with HFFD consumption worsened the integrity of pancreatic islets, ultimately resulting in disease progression. These findings expand our understanding of the causal relationship between pancreatic morphology and diabetes development and suggest therapeutic strategies.

Tumor of the Granulosa of the Ovary About a Case

Ovarian granulosa tumors are very rare; they belong to the group of sex cord and stromal tumors. Their slow evolution in the adult forms which are more frequent (95%) and less aggressive than the much rarer juvenile forms. The exact etiology of these tumors is unknown, but higher than normal estrogen levels are frequently found in women with ovarian granulosa cell tumors. A woman's menstrual status with excess estrogen is related to the presence of certain symptoms such as: early puberty in young women, increase in the size of the abdomen, menstrual cycle disorders in pre menopause or bleeding abnormal uteri in postmenopausal women. The most frequent ultrasound aspect is the solid-cystic aspect and pathological examination remains the diagnostic key. The treatment is essentially surgical, but sometimes associated with complementary therapies such as: chemotherapy, radiotherapy, hormone therapy. Recurrences occur late, hence the importance of post-therapeutic follow-up. Some aggressive forms relapse and progress more rapidly, which justifies rigorous therapeutic monitoring. The prognostic factors for recurrence identified in the literature are the FIGO stage, the presence of residual tumor and the tumor size. We report a case of observation and we draw attention to the epidemiological, clinical particularities, as well as the various prognostic factors in order to carry out a better therapeutic management.

Endometriosis in Postmenopausal Women

There is functional endometrial tissue anywhere other than the uterine cavity and uterine mucosa with a penchant for infiltration and invasion. It is labeled as endometriosis. It is a chronic inflammatory condition. It can occur anywhere, but the most common site is the ovary. It is also labeled as endometrioma or Chocolate cyst. Other common sites for endometriosis are the pouch of Douglas (POD), posterior leaf of the broad ligament, uterosacral ligament, fallopian tube. Barin is the least common site for Endometriosis. Endometriosis is never seen in the spleen. This condition, which impacts 10–15 percent of women of childbearing age, is characterized by pelvic pain and infertility. Dysmenorrhoea, adnexal mass, and infertility are the classical triad of clinical features. This classical triad is mainly seen in the women of childbearing age but can also be seen in the women after menopause. Endometriosis is an estrogen-dependent condition that tends to go away on its own or after surgery. It tends to regress after menopause because it is an estrogen-dependent condition. Endometriosis is associated with cellular and humoral immunity also. Impaired immune function may contribute to the development of endometriosis. Despite this, up to 2.2 percent of women after menopause are affected. Endometriosis in postmenopausal women is seen mainly after elevated systemic estrogen concentrations or excess exogenous estrogen intake. In most women, symptomatic endometriosis after menopause begins more than ten years after menopause in the absence of elevated systemic estrogen concentrations or exogenous estrogen intake. This is necessary to understand the pathophysiology and management of endometriosis after menopause.

Brenner tumors.

Brenner tumors are rare ovarian neoplasms composed of ovarian transition cells surrounded by dense fibrous tissue. Most of them are small tumors (<2 cm), detected incidentally in asymptomatic women. Its predominantly fibrous content results in relatively low signal on T2 weighted images, establishing differential diagnosis with ovarian fibroma and thecoma. Their imaging features are very similar, the differentiation is based on secondary characteristics, such as signs or symptoms of estrogen excess and the presence of a second ovarian neoplasm, which has been reported in up to 30% of patients with Brenner tumor. Although originally thought to be universally benign, there have been scattered reports in the past decades of borderline and malignant forms of Brenner tumors.

The Pathological Mechanisms of Estrogen-Induced Cholestasis: Current Perspectives.

Estrogens are steroid hormones with a wide range of biological activities. The excess of estrogens can lead to decreased bile flow, toxic bile acid (BA) accumulation, subsequently causing intrahepatic cholestasis. Estrogen-induced cholestasis (EIC) may have increased incidence during pregnancy, and within women taking oral contraception and postmenopausal hormone replacement therapy, and result in liver injury, preterm birth, meconium-stained amniotic fluid, and intrauterine fetal death in pregnant women. The main pathogenic mechanisms of EIC may include deregulation of BA synthetic or metabolic enzymes, and BA transporters. In addition, impaired cell membrane fluidity, inflammatory responses and change of hepatocyte tight junctions are also involved in the pathogenesis of EIC. In this article, we review the role of estrogens in intrahepatic cholestasis, and outlined the mechanisms of EIC, providing a greater understanding of this disease.

Optimal solution of the fractional order breast cancer competition model

In this article, a fractional order breast cancer competition model (F-BCCM) under the Caputo fractional derivative is analyzed. A new set of basis functions, namely the generalized shifted Legendre polynomials, is proposed to deal with the solutions of F-BCCM. The F-BCCM describes the dynamics involving a variety of cancer factors, such as the stem, tumor and healthy cells, as well as the effects of excess estrogen and the body’s natural immune response on the cell populations. After combining the operational matrices with the Lagrange multipliers technique we obtain an optimization method for solving the F-BCCM whose convergence is investigated. Several examples show that a few number of basis functions lead to the satisfactory results. In fact, numerical experiments not only confirm the accuracy but also the practicability and computational efficiency of the devised technique.

In utero Exposure to Excessive Estrogen Impairs Homologous Recombination and Oogenesis via Estrogen Receptor 2 in Mice.

The association between the accumulation of synthetic chemicals with estrogenic activity and risks to oogenesis has become a growing concern. This study indicates that in utero estrogen exposure can affect homologous recombination in early oogenesis and influence the reproductive potential and lifespan of female offspring. We conducted this study in developing mouse ovaries using two different models: oral doses administered to the mother, and fetal ovary cultures. Our analyses of meiotic fetal oocytes suggest that 17-β-estradiol induces gross aberrations in prophase I events, including delayed meiotic progression, increased unrepaired DNA damage, and altered homologous recombination levels. These effects were mainly mediated by estrogen receptor 2 (ESR2) activation. Mid-gestation exposure to estrogen also led to delayed primordial folliculogenesis after birth, impaired follicle development after prepuberty, and ultimately reduced the total litter size of the offspring. This raises the concern that maternal exposures to substances activating ESR2 may compromise the fertility of the exposed female fetus.

Estrogen Modulates Epithelial Breast Cancer Cell Mechanics and Cell-to-Cell Contacts.

Excessive estrogen exposure is connected with increased risk of breast cancer and has been shown to promote epithelial-mesenchymal-transition. Malignant cancer cells accumulate changes in cell mechanical and biochemical properties, often leading to cell softening. In this work we have employed atomic force microscopy to probe the influence of estrogen on the viscoelastic properties of MCF-7 breast cancer cells cultured either in normal or hormone free-medium. Estrogen led to a significant softening of the cells in all studied cases, while growing cells in hormone free medium led to an increase in the studied elastic and viscoelastic moduli. In addition, fluorescence microscopy shows that E-cadherin distribution is changed in cells when culturing them under estrogenic conditions. Furthermore, cell-cell contacts seemed to be weakened. These results were supported by AFM imaging showing changes in surfaces roughness, cell-cell contacts and cell height as result of estrogen treatment. This study therefore provides further evidence for the role of estrogen signaling in breast cancer.

Apigenin acts as a partial agonist action at estrogen receptors in vivo

The flavone apigenin is widely distributed in vegetables and fruits and has a variety of pharmacological effects. However, there is no definitive scientific evidence that apigenin could act as a phytoestrogen and exert exerting estrogenic or antiestrogenic efficacy in vivo. Therefore, this study was established an ovariectomy (OVX) and estrogenized mouse model to evaluate the effects of apigenin on reproductive target tissues. Our data demonstrated that apigenin could exert a double-directional adjusting estrogenic effect in vivo. Specifically, treatment with apigenin reversed the weight changes caused by abnormal estrogen levels and altered the status of vaginal epithelial cells via the estrogen receptors. In addition, we found that apigenin exhibited a significant estrogenic activity, as indicated by the reversal of uterine atrophy. Apigenin treatment could also regulate the target tissue coefficient changes and estrogen disorders caused by excessive estrogen. Importantly, the administration of apigenin could upregulated the estrogen receptor (ER) α and ER β expression as a partial agonist. Our results demonstrate that apigenin has a double directional adjusting function in different physiological environments.

Aromatase Inhibitors in Erectile Dysfunction

Hyperestrogenism may cause erectile dysfunction(ED) by impeding normal penile development,increasing venous vascular permeability and leakage(via VEGF) and by inhibiting testosterone(T)production. Estrogen excess can impair spermatogenesis and may increase the risk of estrogen-sensitive cancers(viz.breast cancer)[1,2]Weekly and biweekly letrozole(2.5 mg),an aromatase inhibitor,has been reported to normalize serum T in males with obesity related hypogonadism and poor sperm quality,respectively.[3,4]A 40-year old insulin requiring,normotensive,obese(BMI-26.9),diabetic(12 years duration) was evaluated for ED.T was 187 ng/dl and estradiol(E2) was 69 pg/ml(normal-11-44 pg/ml) with normal LH and prolactin levels. There was normalization of T(increased to 487 ng/dl) with 2.5 mg letrozole every 3 weeks. Another patient,55 year old male, insulin requiring,hypertensive,obese(BMI-28.8),diabetic(21 years duration) had normalization of T(401 ng/dl) with baseline low T(224.4 ng/dl) and normal E2(33 pg/ml) with T-E2 ratio of less than 10,with weekly 2.5 mg letrozole. There was one kg weight gain and 0.2 ng/ml increase in PSA in two years. These cases highlight the significance of estimating both T and E2 in the evaluation of ED. Moreover,it also highlights the efficacy and safety of weekly and even every 3-week 2.5 mg letrozole therapy.

FOXO1 Mitigation of FOXL2C143W/SMAD3 Transcriptomic Landscape in a Model of Granulosa Cell Tumor

Background: Adult granulosa cell tumor (aGCT) is a rare type of stromal cell malignant cancer of the ovary. Postmenopausal genital bleeding is the main aGCT clinical sign which is attributed to estrogen excess driven by CYP19 upregulation. Typically, aGCTs that are diagnosed at an initial stage can be treated with surgery. However, recurrences are mostly fatal1. Current studies are focused on finding new molecular markers and targets that aim to treat the aGCTs recurrence. Between 95-97% of aGCTs harbor a somatic mutation in the FOXL2 gene, Cys134Trp (c.402C<G)2. A TGF-β pathway protein, SMAD3, was identified as an essential partner in FOXL2C134W transcriptional activity driving CYP19 upregulation3. Recently, the antitumoral FOXO1 gene has been recognized as a potential target for suppressing the FOXL2C134W pathogenic action4. Aim: The objective of this study was to examine whether FOXO1 upregulation affects the FOXL2C143W/SMAD3 transcriptomic landscape. Methods: RNA-seq analysis was performed comparing the effect of FOXL2WT/SMAD3 and FOXL2C143W/SMAD3 overexpression in presence of FOXO1 by transfection of an established human GC line (HGrC1). RNA-seq libraries were prepared using the illumina TrueSeq and sequenced using an illumina HiSeq Platform4000. To quantify transcript abundance for each sample we used salmon (1.1.0) with default parameters, using indexes from hg38. Data was subsequently imported in R using the tximport package and processed with the DESeq2 package. Results: RNA-seq data show that FOXL2C143W/SMAD3 significantly drives 717 genes compared with the WT and enabled us to identify targets (TGFB2, SMARCA4, HSPG2, MKI67, NFKBIA) and neoplastic pathways directly associated with the mutant. To provide evidence that the differences in gene expression were attributed to a direct consequence of FOXL2 binding, we annotated gene promoters with previously published FOXL2 ChIP-seq analysis. The majority (73-40%) of the differential expressed genes (DEGs) between FOXL2C134W and FOXL2WT had a FOXL2 binding site at their promoters, which was a significantly higher proportion than in non-DEGs (Fisher’s exact test, murine: p= 7.9x10-157; human, p= 9.9x10-39). Surprisingly, the number of DEGs between FOXL2C134W + FOXO1 and FOXL2WT was much lower (230) with respect to the number of DEGs between FOXL2C134W and FOXL2WT (717, of which 130 in common; linear regression slope ß = 0 .58), suggesting that the effect of FOXL2C134W compared with FOXL2WT is moderated by the addition of FOXO1. Conclusions: Our transcriptomic study provides the first evidence that FOXO1 can efficiently mitigate 40% of the altered genome-wide effect specifically related to FOXL2C134W in a model of human aGCT.1 Farkkila, A. et al. Ann Med (2017). 2 Jamieson, S. & Fuller, P. J. Endocr Rev (2012). 3 Belli, M. et al. Endocrinology (2018). 4 Belli, M et al. J Endocr Soc (2019).

Gynaecomastia: when and why to refer to specialist care.

Gynaecomastia is the commonest male breast complaint. Most cases are benign but the condition may signify a serious underlying illness. The challenge in primary care is to identify which patients with gynaecomastia are at greatest risk of pathological aetiology, so that they may be offered prompt specialty-appropriate referral and treatment. This article offers guidance on the assessment and management of patients with gynaecomastia, including when and why to refer to secondary care. Gynaecomastia refers to the enlargement of male glandular breast tissue. The condition develops because of an imbalance in the male oestrogen:testosterone ratio from a relative oestrogen excess or testosterone deficiency. Pseudo-gynaecomastia is caused by an excess of adipose tissue and does not warrant investigation or treatment. Gynaecomastia is frequently observed in general practice. Prevalence is between 35%–65% in males aged 50–69 years in the UK.1 Patients typically describe a soft swelling in one or usually both breasts. Tenderness, social embarrassment, or worry about cancer are typical reasons for presentation to primary care. Other men are asymptomatic and gynaecomastia may be noted incidentally on physical examination of the chest. Physiological gynaecomastia is common in newborns, adolescence, and senility. Most do not require investigation or referral. Neonatal gynaecomastia arises from the placental transfer of oestrogen. Over half of all adolescent boys will experience transient gynaecomastia during puberty due to a lag in testosterone secretion, with median age of onset at 14 years.2 Physiological gynaecomastia is common among males aged >50 years as testosterone levels fall with increasing age. Adult gynaecomastia is most commonly idiopathic (Figure 1). Male …

TOX3 Promotes Ovarian Estrogen Synthesis: An RNA-Sequencing and Network Study.

BackgroundWomen who undergo chronic exposure to excessive estrogen are at a high risk of developing breast cancer. TOX3 has been reported to be highly expressed in breast tumors and is closely related to estrogen receptors. However, the effect of TOX3 on estrogen synthesis remains poorly understood.MethodsUsing lentiviruses as a vector, we stably overexpressed TOX3 in the ovarian granulosa cell line KGN, the cells where estradiol is primarily produced, to investigate its role in estrogen production as well as cell viability and apoptosis. RNA-Sequencing was applied to uncover the global gene expression upon TOX3 overexpression.ResultsWe observed an increased level of cell viability and a reduced cell apoptosis rate after TOX3 overexpression, and the level of estradiol in the cell culture supernatant also increased significantly. Gene set enrichment analysis of the transcriptome showed that the ovarian steroidogenesis pathway was significantly enriched. Similarly, pathway mapping using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses also showed that TOX3 overexpression affects the ovarian steroidogenesis pathway. Further experiments showed that upregulated FSHR, CYP19A1, and BMP6 accounted for the enhanced estrogen synthesis.ConclusionOur study demonstrated that TOX3 quantitatively and qualitatively stimulates estrogen synthesis by enhancing estrogen signaling pathway–related gene expression in ovarian granulosa cells. These findings suggest that TOX3 may play a vital role in the pathogenesis of breast cancer.

Abstract PO007: Evaluation of crosstalk between estrogen and Wnt signaling in endometrial cancer

Abstract Estrogen signaling through estrogen receptor alpha (ER) is considered to be a driving oncogenic signal in type 1 endometrial cancer. However, excess estrogen exposure isn’t sufficient to initiate tumorigenesis in mouse models, suggesting additional genomic or epigenomic changes are required for tumor formation. Activating mutations in beta-catenin, a downstream regulator of Wnt signaling, are prevalent in type I endometrial tumors, with almost 40% of cases harboring these mutations. The combination of excess estrogen and Wnt signals appears to drive endometrial cancer formation and growth, but the mechanisms underlying interplay between these pathways is not well understood. Based on previous studies and our preliminary data, we are currently exploring the hypothesis that beta-catenin acts as a cofactor for ER, representing a convergence of these two oncogenic pathways. Using Ishikawa cells, a type 1 endometrial cancer cell line expressing wildtype beta-catenin, we are measuring differences in gene expression and chromatin between cells that have been induced with 17-beta-estradiol (E2), Wnt3a, or the combination. Our findings suggest that a combination induction affects where ER and beta-catenin bind the genome. In the presence of E2 and Wnt3a, ER’s genomic occupancy expanded and revealed Wnt dependent ER sites separate from canonical ER and Wnt binding sites. Analysis of acetylation of lysine 27 on histone H3 (H3K27ac) using ChIP-seq support this pattern, where acetylation is enriched in the combination treatment over an E2 or Wnt3a induction alone. Additionally, we observed unique gene expression patterns with a simultaneous E2 and Wnt3a induction. We are in the process of creating an isogenic Ishikawa cell line that harbors an activating beta-catenin mutation to determine molecular differences between Wnt ligand activation and constitutively active beta-catenin and discover how these forms of Wnt activation relate to estrogen signaling. Overall, we hope our studies deepen our understanding of estrogen driven transcriptional regulation and shed light on the functional consequences of beta-catenin activating mutations in endometrial cancer. Citation Format: Krystle Osby, Adriana C. Rodriguez, Jay Gertz. Evaluation of crosstalk between estrogen and Wnt signaling in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO007.

Investigating new positive, bounded, and convergent numerical solution for the nonlinear time‐dependent breast cancer dynamic competition model

Breast cancer is a big health problem in females all over the world. It is termed as the deadliest disease in women, and the reasons of its occurrence in a human body are still unknown. In this paper, an analysis of dynamic nonlinear time‐dependent breast cancer competition model is carried out, and its numerical solution is investigated using the reliable FVIM scheme. The convergence of the solution is shown, and the results are further discussed using figures. The variation of cancer stem cell, tumor cell, healthy cell, immune cell population, and excess estrogen in females with time is also depicted through figures. The effects of parameters on the cell population is also shown with time. The results clearly indicate that FVIM is very systematic, efficient, and easy to use in finding a solution to this nonlinear fractional model.

Therapeutic effect of metformin in the treatment of endometrial cancer.

The present review aims at reviewing the role of metformin in the treatment of endometrial cancer (EC). According to the literature, excessive estrogen levels and insulin resistance are established risk factors of EC. As a traditional insulin sensitizer and newly discovered anticancer agent, metformin directly and indirectly inhibits the development of EC. The direct mechanisms of metformin include inhibition of the LKB1-AMP-activated protein kinase-mTOR, PI3K-Akt and insulin-like growth factor 1-related signaling pathways, which reduces the proliferation and promotes the apoptosis of EC cells. In the indirect mechanism, metformin increases the insulin sensitivity of body tissues and decreases circulating insulin levels. Decreased levels of insulin increase the blood levels of sex hormone binding globulin, which leads to reductions in circulating estrogen and androgens. The aforementioned findings suggest that metformin serves an important role in the treatment of EC. Increased understanding of the mechanism of metformin in EC may provide novel insights into the treatment of this malignancy.

Apigenin Attenuates the Allergic Reactions by Competitively Binding to ER With Estradiol

Apigenin (API) is a natural phytoestrogen with properties including anti-inflammatory and other abilities. This study aims to 1) systematically validate that excessive estrogen exacerbates allergic reactions; 2) explore the anti-allergic effects and mechanisms of API. We conduct a survey of college students, indicating that of the 505 effective results, 70 individuals were self-reported allergic and 74.1% of them were women, which proved the gender difference in allergic reactions. BALB/c mice are grouped into the negative control group (N-Ctrl), the OVA-sensitized group (P-Ctrl), the estrogenized OVA-sensitized group (E2), and three treatment groups administrating different dose of API (E2 + API/L/M/H). In vivo data indicated that API treatment significantly inhibited the enhancement of estradiol on clinical symptoms. Moreover, we found that high doses of API inhibited Th2 type humoral response and mast cell degranulation levels in vivo and in vitro. Additionally, medium, and high doses of API significantly reduced the potentiation of estradiol on ER expression, attenuated the transmission of estrogen/ER signaling, thereby inhibiting the phosphorylation of ERK1/2 and JNK1/2/3 in the MAPK. Besides, we found that API competitively bound to ER with estradiol, and showed a weak selectivity to ERβ. Overall, we identified API can be beneficial in allergic disease.

Need of the hour: to raise awareness on vicious fragrances and synthetic musks

Synthetic fragrance compounds have become a ubiquitous part of household cleaning products and personal care agents. To improve aesthetics, fragrances are added, but the current research has unveiled detrimental effects of these odorous compounds. The exposure to the synthetic fragrances and musks, which are produced in quantities of thousands of tons per year, has been shown to elicit several pathologies. The fragrance compounds are regarded as toxins by the human immune system, and to eliminate them, cytochrome enzymes, especially aromatases, are overexpressed. These enzymes also convert androgens into estrogens, but excess estrogen production affects the endocrine system in both males and females. Although the estrogenic properties of cosmetics are increasingly being proven, the link between fragrance compounds and a wide variety of modern lifestyle diseases is not known to the majority of the public. It is increasingly being evident that all diseases have common roots, i.e., inflammation. The unprecedented prevalence of diabetes, obesity, cancer, and depression, among others pathologies, is tied to the limitless usage of fragrance compounds. Therefore, it is important to further investigate the dangers associated with fragrance compounds, to inform the regulatory bodies to allow them to better control manufacturers, and to alert consumers. This article is directed for facilitation of that objective.

Androgenic Granulosa Cell Tumor in an Adolescent Girl

Virilizing tumors may arise from adrenals or ovary. Androgen secreting ovarian tumors constitute less than 0.2% of cases of hyperandrogenism and less than 1% of all ovarian tumors. Hyperandrogenism is seen with Leydig cell tumors, Sertoli cell tumors, steroid cell tumors not otherwise specified and ovarian thecomas. Adult granulosa cell tumors (GCTs) are the most common type of ovarian sex cord tumors. These tumors usually produce estrogens and hence cause symptoms and signs of estrogen excess. GCTs mostly present in perimenopausal and postmenopausal women with complaints of abnormal uterine bleeding. Androgen secreting GCT is a rare clinical entity. Here we are reporting one such case in an adolescent girl with features of hyperandrogenism and ovarian mass.