Estrogen Research Articles

Impact of vaginal submucosal platelet-rich plasma combined with non-cross-linked hyaluronic acid injections on dyspareunia and sexual satisfaction in a Hodgkin lymphoma cancer survivor: a case report

Vaginal atrophy is a commonly encountered problem among young cancer survivors. Patients suffer from vaginal dryness, irritation, and dyspareunia secondary to oestrogen deficiency. Oestrogenbased hormone replacement therapy is effective, but unfortunately health concerns or contraindications in cancer survivors frequently limit its use. A 35-year-old female patient with dyspareunia that markedly affected her sexual relationship was referred to the gynaecology clinic. Treatment using topical oestrogen cream and sexual counselling were not successful. We treated her using two submucosal injections of PRP-non-cross-linked hyaluronic acid injections into the vestibule and lower third of the anterior vaginal wall mucosa, spaced a month apart. The patient reported marked reduction of dyspareunia and demonstrated an improvement of FSFI total score 1 month after the second injection. Both the patient and her husband showed an improvement of the index of sexual satisfaction score one month after the second injection compared to their pretreatment scores. Examination of the vaginal mucosa showed improvement of thickness and integrity of the mucosa and increased lubrication. PRP-non-cross-linked hyaluronic acid submucosal injections can be effective for cancer therapy-related vaginal atrophy, coitus-related pain, and sexual satisfaction.

Androgen Receptor Expression in ER and PR Negative Breast Cancer—A Study from a Tertiary Hospital in Northern India

Objectives Breast cancer is the leading cause of cancer-related deaths in women. Estrogen (ER) and progesterone receptor (PR) status and Her2 overexpression are major determinants in therapeutic decision making. Triple-negative breast cancers (TNBCs) have limited treatment options. Androgen receptor (AR) expression opens up therapeutic avenues for these patients. The aim of this article was to study the immunohistochemical expression of ARs in ER and PR Negative breast carcinomas and to correlate AR expression with various clinical, histopathological, and other immunohistochemical parameters.Materials and Methods It is a cross-sectional study including 105 ER and PR Negative cases of breast carcinoma. Clinical parameters, histopathology, and immunohistochemical expression of AR, Her2, and Ki67 were analyzed in all cases.Results AR expression was observed in 63.8% of ER and PR Negative breast cancers. In this group, AR expression was strongly associated with Her2 co-expression (89.2%) as compared to TNBCs (45.8%); p-value = 0.0002. Significant correlation was also observed between AR expression and tumor necrosis (p-value = 0.034) and postmenopausal status (p = 0.007).Conclusion Our study shows that significant proportion of ER and PR Negative breast carcinomas (ER- PR- Her2+ and TNBCs) show AR expression. We strongly recommend routine evaluation of all hormone receptor-negative breast carcinomas for AR status by immunohistochemistry.

In vitro bioassays to monitor complex chemical mixtures at a carbon-based indirect potable reuse plant

Potable water reuse technologies are used to treat wastewater to drinking water quality to help sustain a community's water resources. California has long led the adoption of potable water reuse technologies in the United States and more states are exploring these technologies as water resources decline. Reuse technologies also need to achieve adequate reductions in microbial and chemical contaminant risks to meet public health goals and secure public acceptance. In vitro bioassays are a useful tool for screening if reuse treatment processes adequately reduce toxicity associated with a range of chemical classes that are contaminants of concern. In this study, we used an aryl hydrocarbon receptor (AhR) and an estrogen receptor luciferase bioassay to detect the presence of dioxin-like and estrogenic compounds across a 3800 m3/d carbon-based indirect potable reuse plant that uses carbon-based treatment (SWIFT-RC). Our results demonstrate significant removal of dioxin-like compounds across the SWIFT-RC treatment train. Estrogenicity declined across the treatment train for some months but was extremely variable and low with many samples falling below the method quantification level; consequently, we were not able to reliably determine estrogenicity trends for SWIFT-RC. Comparing the bioanalytical equivalent concentrations detected in the SWIFT-RC water with established monitoring trigger levels from the state of California suggests that SWIFT-RC produced water that met the bioassay guidelines. The log total organic carbon concentration and AhR assay equivalent concentrations are weakly correlated when data across all SWIFT-RC processes are included. Overall, this research demonstrates the performance of in vitro bioassays at a demonstration-scale carbon-based IPR system and highlights both the potential utility and challenges associated with these methods for assessing system performance.

(112) Treatment Options for Female Sexual Dysfunction in Patients with Epilepsy: A Systematic Review

Abstract Introduction Epilepsy is one of the most common neurologic conditions worldwide, affecting approximately 5 million people globally every year. Many with this diagnosis rely on lifelong medications for seizure prophylaxis, which involve complex mechanisms of action with various hormones. The myriad of therapeutic side effects and the debilitating nature of this disease process make sexual dysfunction a common occurrence, with low libido, arousal, and orgasm being the primary complaints for 30-67% of female patients with epilepsy. Prioritizing quality of life from a biopsychosocial perspective is imperative – the need for investigating diverse treatment options for sexual dysfunction in these female patients becomes increasingly evident. Objective This study aims to discuss the available treatment options for sexual dysfunction in females with diagnosed epilepsy. Methods A systematic review in the PubMed database that spanned between January 2015 and November 2022 was executed. Six authors independently and thoroughly screened titles, abstracts, and full-text articles. They assessed the relevant medical literature that acknowledged the presence of female sexual dysfunction and explicitly stated treatment options for patients who have epilepsy. MeSH advanced key terms used to refine the search include: [“epilepsy”], [“female sexual dysfunction”], AND [“treatment”]. Results The published articles (n = 26) that fit the inclusion criteria were reviewed. The pathophysiology behind sexual dysfunction in patients with epilepsy is multifactorial. Seizure activity preferentially occurring in the temporal and frontal lobes alters several fundamental functions of the brain and nervous system, including the HPA axis and the release of gonadal hormones. Furthermore, anti-epileptic drugs target complex substrates that influence the limbic system, hypothalamus, pituitary, endocrine glands, as well as steroid and protein synthesis and metabolism in the liver and adipose tissue. Specifically, drugs documented to correlate with sexual dysfunction negatively are valproate, topiramate, and gabapentin. Agents such as lamotrigine, oxcarbazepine, and levetiracetam are reported to result in fewer sexual side effects and may even have a protective role against sexual dysfunction. Non-pharmacological approaches such as treating underlying comorbidities, addressing psychosocial variables, and mindfulness-based cognitive therapy have also proven significantly beneficial in treating and preventing adverse sexual outcomes. Conclusions Sexual dysfunction, secondary to epilepsy-induced seizures or anti-epileptic drug management, is not adequately explored and treated. The body of literature supports treating sexual dysfunction in females with epilepsy from a multidimensional standpoint; however, there remains a lack of thorough discussion on treatment options tailored to female pelvic anatomy. Going forward, continued research on how the pathologic consequences of epilepsy affect sexual function, unrelated to the use of anti-epileptic drugs, could enhance the prevention and comprehensive management of female sexual dysfunction in this population. Additionally, evaluating the effectiveness of topical estrogens, 5-HT1a agonists/5HT2a antagonist like Flibanserin, and melanocortin receptor agonists like Bremelanotide in female patients with epilepsy and other neurologic disorders may aid in the understanding of this relationship and spark further discussion. Sexual dysfunction and related symptoms have a devastating impact, indicating the need for this research, standardized guidelines, and a wide array of biopsychosocial treatment options. Disclosure No

Discordant and Converting Receptor Expressions in Brain Metastases from Breast Cancer: MRI-Based Non-Invasive Receptor Status Tracking.

Discordance and conversion of receptor expressions in metastatic lesions and primary tumors is often observed in patients with brain metastases from breast cancer. Therefore, personalized therapy requires continuous monitoring of receptor expressions and dynamic adaptation of applied targeted treatment options. Radiological in vivo techniques may allow receptor status tracking at high frequencies at low risk and cost. The present study aims to investigate the potential of receptor status prediction through machine-learning-based analysis of radiomic MR image features. The analysis is based on 412 brain metastases samples from 106 patients acquired between 09/2007 and 09/2021. Inclusion criteria were as follows: diagnosed cerebral metastases from breast cancer; histopathology reports on progesterone (PR), estrogen (ER), and human epidermal growth factor 2 (HER2) receptor status; and availability of MR imaging data. In total, 3367 quantitative features of T1 contrast-enhanced, T1 non-enhanced, and FLAIR images and corresponding patient age were evaluated utilizing random forest algorithms. Feature importance was assessed using Gini impurity measures. Predictive performance was tested using 10 permuted 5-fold cross-validation sets employing the 30 most important features of each training set. Receiver operating characteristic areas under the curves of the validation sets were 0.82 (95% confidence interval [0.78; 0.85]) for ER+, 0.73 [0.69; 0.77] for PR+, and 0.74 [0.70; 0.78] for HER2+. Observations indicate that MR image features employed in a machine learning classifier could provide high discriminatory accuracy in predicting the receptor status of brain metastases from breast cancer.

(460) A Case Series on Vulvovaginal Obliteration

Abstract Introduction Between Dec. 2018 & June 2020, 5 cases of Vulvovaginal Obliteration, also known as Labial Adhesion were diagnosed, evaluated and treated. All of the presenting cases had a history which shared certain features, including more than 2 decades without sexual activity, no history of masturbation, no use of hormone replacement therapy and chronic urinary tract symptoms. The most severe case had the longest period without vaginal penetration (>30years). In 3 of the 5 cases the patients didn't have a partner, while the other 2 patients were not sexually active with their partner in any way. Objective To add new cases to the literature about this rarely described disorder. To show this condition is one of the most extreme consequences of Genitourinary Syndrome of Menopause. To demonstrate the importance of vaginal penetration and hormone replacement therapy (HRT) to prevent postmenopausal labial adhesion. Methods This is a case series reviewing the effective management of labial adhesion in post-menopausal women. Results In 2 of the cases the patients main complaint was their inability to urinate due to obstruction of the urethral outlet by the fused labia. This obstruction caused urocolpos, extremely distended urinary bladder, megaloureters, & bilateral hydronephrosis. Leakage of urine also occurred at the posterior fourchette. All of these urinary symptoms disappeared after an urgent introital incision was performed in the OR. In both cases the exclusive use of local estrogens postoperatively failed to prevent recurrent closure. Only the combined use of local estrogens and the regular use of dilators (3-4 times/day/2 weeks, then 1-2 times /day/2 weeks, then PRN) prevented recurrence. In 3 of the 5 cases, regular use of the dilators caused them to reach orgasm for the first time in their lives. The ages of these women were between 76 & 92 years old. The last 2, and more mild cases had 50% labial fusion, without urinary retention. The use of progressively increasing sizes of dilators and estrogen cream resolved the problem without surgical interventions. Conclusions Labial adhesion is one of the worst consequences of GSM, due to progression towards urinary retention. It is caused by insufficient maintenance of sexual activity after menopause, combined with lack of prevention with HRT, and is successfully managed with surgery, dilators and topical estrogens. Disclosure No

(015) Vulvar Lichen Sclerosus is Associated with New Diagnoses of Mood Disorders

Abstract Introduction Vulvar lichen sclerosus (VLS) often presents with chronic pruritus. While VLS is associated with feelings of isolation, risk of mood disorders among females with VLS has yet to be quantified on a large scale. Objective Our objective was to assess the association of VLS with development of depressive episode, anxiety disorder, major depressive disorder (MDD), and prescription of antidepressants and benzodiazepines, and to evaluate the impact of VLS treatment. Methods A US claims database network (TriNetX Diamond Network) was queried from 2009 to 2022. Cohorts included women aged ≥18 with lichen sclerosus (LS) (ICD-10: L90.0) without prior diagnosis of MDD (F33), depressive episode (F32), or anxiety disorder (F40-F48) or previously prescribed antidepressants (VA: CN600) or benzodiazepines (CN302). We compared a control cohort of women with LS sparing the vulva with women with LS affecting the vulva (N90.4). We conducted a sub-analysis by age (18-40, 41-55, and >55 years). We compared women aged ≥18 with VLS who received treatment (topical steroids (DE200), vaginal estrogen (GU500), prednisone (8640), hydroxyzine (5553), amitriptyline (704), gabapentin (25480), or tacrolimus (42316)) with women aged ≥18 with VLS who did not receive treatment within 6 months of VLS diagnosis. Finally, we compared women receiving only topical VLS treatment (topical steroids, vaginal estrogen, and tacrolimus) with those receiving no treatment. Outcomes of interest were depressive episodes, anxiety disorder, MDD or prescription of antidepressants or benzodiazepines within 6 months of VLS diagnosis. Propensity score matching was performed for age, ethnicity, race, type 1 diabetes (E10), vitiligo (L80), autoimmune thyroiditis (E06.3), alopecia areata (L63), pernicious anemia (D51.0), overweight and obesity (E66), type 2 diabetes (E11), hyperlipidemia (E78), essential hypertension (I10), and alcohol abuse (F10.10). Results 124,237 patients had LS sparing the vulva and 16,676 had VLS. VLS was associated with increased risk of depressive episode (risk ratio (RR) [95% Confidence Interval] 1.62 [1.32-1.99]), anxiety disorder (RR 1.82 [1.50-2.22]), and MDD (RR 2.61 [1.69-4.03]) (Table 1) compared to LS sparing the vulva. Women with VLS were also more likely to receive antidepressants (RR 1.91 [1.60-2.29]) and benzodiazepines (RR 1.70 [1.44-2.01]). Among menopausal women, VLS was associated with increased risk of anxiety disorder (RR 2.00 [1.10-3.63]) (Table 2). Among postmenopausal women, VLS was associated with increased risk of depressive episode (RR 1.73 [1.38-2.17]), MDD (RR 2.60 [1.64-4.12]), anxiety disorder (RR 1.58 [1.29-1.94]), antidepressants (RR 1.55 [1.30-1.86]), and benzodiazepines (RR 1.48 [1.24-1.76]). Among women with VLS, VLS treatment was associated with decreased risk of depressive episode (RR 0.68 [0.47-0.98]) and increased risk of antidepressants (RR 2.00 [1.54-2.59]) and benzodiazepines (RR 1.70 [1.31-2.20]) compared to women without VLS treatment (Table 3). Stratifying by treatment type, women treated solely with topicals had numerically, but not significantly, lower risk of developing depressive episode (RR 0.73 [0.48-1.11]) compared to women without VLS treatment. Conclusions We demonstrate that women with VLS, compared to those with LS sparing the vulva, have an increased risk of antidepressant and benzodiazepine prescriptions and development of depressive episode, anxiety disorder, or MDD. Patients with VLS should be screened for these conditions, and VLS treatment should be considered. Disclosure No

Pollution Characteristics and Risk Assessment of Typical Endocrine Disrupting Chemicals in Drains Flowing into the Yellow River of Ningxia

Solid-phase extraction and ultra-high performance liquid chromatography-mass spectrometry were used to detect and analyze the contamination of nine typical endocrine disrupting chemicals (EDCs) in drains flowing into the Yellow River of Ningxia. Sources of these EDCs were analyzed, and their risks were assessed. The results showed that EDCs were detected in drains at all 33 sampling sites, with total concentrations （ΣEDCs） of 82.28-1730.09 ng·L-1. Among phenolic compounds, bisphenol A (BPA) and nonylphenol (NP) were two that were more commonly detected EDCs, with the detection rates above 90%; estrone (E1) and estriol (E3) were more commonly detected estrogenic compounds, both with detection rates of 79%. On a spatial scale, the average concentrations of ΣEDCs in the drains in Shizuishan and Yinchuan were much higher than those in Wuzhong and Zhongwei. Concentrations of ΣEDCs at the sampling sites before flowing into Yellow River ranged from 82.28 to 979.82 ng·L-1. The source analysis showed that industrial wastewater and domestic sewage were two primary sources for BPA, whereas industrial wastewater was the primary source for OP. The primary sources of E1 and E3 were livestock and poultry breeding wastewater and domestic sewage, respectively. Risk assessment results showed that EDCs in drains flowing into the Yellow River posed low or moderate ecological risk but high risk for estrogenic activity at all sampling sites.

Serum metabolomic profiling reveals potential biomarkers in systemic sclerosis

BackgroundSystemic sclerosis (SSc) is a chronic and systemic autoimmune disease marked by the skin and visceral fibrosis. Metabolic alterations have been found in SSc patients; however, serum metabolomic profiling has not been thoroughly conducted. Our study aimed to identify alterations in the metabolic profile in both SSc patients before and during treatment, as well as in mouse models of fibrosis. Furthermore, the associations between metabolites and clinical parameters and disease progression were explored. MethodsHigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS)/MS was performed in the serum of 326 human samples and 33 mouse samples. Human samples were collected from 142 healthy controls (HC), 127 newly diagnosed SSc patients without treatment (SSc baseline), and 57 treated SSc patients (SSc treatment). Mouse serum samples were collected from 11 control mice (NaCl), 11 mice with bleomycin (BLM)-induced fibrosis and 11 mice with hypochlorous acid (HOCl)-induced fibrosis. Both univariate analysis and multivariate analysis (orthogonal partial least-squares discriminate analysis (OPLS-DA)) were conducted to unravel differently expressed metabolites. KEGG pathway enrichment analysis was performed to characterize the dysregulated metabolic pathways in SSc. Associations between metabolites and clinical parameters of SSc patients were identified by Pearson's or Spearman's correlation analysis. Machine learning (ML) algorithms were applied to identify the important metabolites that have the potential to predict the progression of skin fibrosis. ResultsThe newly diagnosed SSc patients without treatment showed a unique serum metabolic profile compared to HC. Treatment partially corrected the metabolic changes in SSc. Some metabolites (phloretin 2’-O-glucuronide, retinoyl b-glucuronide, all-trans-retinoic acid, and betaine) and metabolic pathways (starch and sucrose metabolism, proline metabolism, androgen and estrogen metabolism, and tryptophan metabolism) were dysregulated in new-onset SSc, but restored upon treatment. Some metabolic changes were associated with treatment response in SSc patients. Metabolic changes observed in SSc patients were mimicked in murine models of SSc, indicating that they may reflect general metabolic changes associated with fibrotic tissue remodeling. Several metabolic changes were associated with SSc clinical parameters. The levels of allysine and all-trans-retinoic acid were negatively correlated, while D-glucuronic acid and hexanoyl carnitine were positively correlated with modified Rodnan skin score (mRSS). In addition, a panel of metabolites including proline betaine, phloretin 2’-O-glucuronide, gamma-linolenic acid and L-cystathionine were associated with the presence of interstitial lung disease (ILD) in SSc. Specific metabolites identified by ML algorithms, such as medicagenic acid 3-O-b-D-glucuronide, 4’-O-methyl-(−)-epicatechin-3’-O-beta-glucuronide, valproic acid glucuronide, have the potential to predict the progression of skin fibrosis. ConclusionsSerum of SSc patients demonstrates profound metabolic changes. Treatment partially restored the metabolic changes in SSc. Moreover, certain metabolic changes were associated with clinical manifestations such as skin fibrosis and ILD, and could predict the progression of skin fibrosis.

Gut Microbiota and Acylcarnitine Metabolites Connect the Beneficial Association between Estrogen and Lipid Metabolism Disorders in Ovariectomized Mice.

Decreased estrogen level is one of the main causes of lipid metabolism disorders and coronary heart disease in women after menopause. Exogenous estradiol benzoate is effective to some extent in alleviating lipid metabolism disorders caused by estrogen deficiency. However, the role of gut microbes in the regulation process is not yet appreciated. The objective of this study was to investigate the effects of estradiol benzoate supplementation on lipid metabolism, gut microbiota, and metabolites in ovariectomized (OVX) mice and to reveal the importance of gut microbes and metabolites in the regulation of lipid metabolism disorders. This study found that high doses of estradiol benzoate supplementation effectively attenuated fat accumulation in OVX mice. There was a significant increase in the expression of genes enriched in hepatic cholesterol metabolism and a concomitant decrease in the expression of genes enriched in unsaturated fatty acid metabolism pathways. Further screening of the gut for characteristic metabolites associated with improved lipid metabolism revealed that estradiol benzoate supplementation influenced major subsets of acylcarnitine metabolites. Ovariectomy significantly increased the abundance of characteristic microbes that are significantly negatively associated with acylcarnitine synthesis, such as Lactobacillus and Eubacterium ruminantium group bacteria, while estradiol benzoate supplementation significantly increased the abundance of characteristic microbes that are significantly positively associated with acylcarnitine synthesis, such as Ileibacterium and Bifidobacterium spp. The use of pseudosterile mice with gut microbial deficiency greatly facilitated the synthesis of acylcarnitine due to estradiol benzoate supplementation and also alleviated lipid metabolism disorders to a greater extent in OVX mice. IMPORTANCE Our findings establish a role for gut microbes in the progression of estrogen deficiency-induced lipid metabolism disorders and reveal key target bacteria that may have the potential to regulate acylcarnitine synthesis. These findings suggest a possible route for the use of microbes or acylcarnitine to regulate disorders of lipid metabolism induced by estrogen deficiency.

71P MicroRNA (miRNA) a putative biomarker to better define the molecular apocrine breast cancer (MABC) subtype

Breast cancer (BC), is a heterogeneous disease, divided into molecular subtypes based on gene expression and clinical outcomes. MABC is a poorly diagnosed subtype, characterized by estrogen (ER), progesterone receptor (PR) negativity, and HER-2-amplification in most cases; yet it overexpresses androgen receptor (AR) and activates its pathway. Its improper diagnosis demands the adoption of complementary tools to refine classification; miRNA, key players in regulating cell behavior, AR, and tumorigenic processes of BC hold promise in defining and studying the behavior of MABC. 539 breast cancer microarray data were downloaded from The Cancer Genome Atlas (TCGA-BRCA). Cases with available miRNA data were retained and classified using citbcmst R package (PMID: 30289602). Differential expression analysis identified deregulated miRNAs using DEseq2. A validation set of 131 ER-neg samples was constituted and MABC tumors were characterized apart of triple-negative (TN)BC by the previously described molecular signature (AR, FOXA1 and AR-related genes, PMID: 23663520) on fresh tissue sections. Using miRCURY LNATM miRNA PCR assay, miRNA profiling was done for a panel of 6 differentially expressed miRNAs. Finally, expression of in silico predicted target genes of these miRNAs was assessed by RT-qPCR in MABC and TNBC cell lines after transfection with miRNA mimics. TCGA data analysis indicated MABC as a separate entity based on gene signature. MiRNA-seq data analysis depicted a set of 6 significantly deregulated miRNA with absolute value of log2 fold change> 1 and P-adjusted value <0.05 between MABC and TNBC. We validated on 78 MABC (27 HER2-/ 51 HER2+), and 53 TN samples, by miRNA profiling, significant upregulation of miR-2115-3p and miR-187-3p in MABC compared to TNBC. Preliminary data, showed that the overexpression of these miRNAs significantly downregulates in silico predicted target genes (FGF2, HMGCS1, and ADAM12) implicated in carcinogenesis differently in each of the models used. MABC has a unique signature of miRNA compared to TNBC. The identified miRNAs regulate a set of genes implicated in tumorigenic processes and can potentially serve as biomarkers to effectively diagnose, prognose and treat MABC

Deletion of myostatin alters obesity-induced estrogen metabolism in skeletal muscle

Objective: Obesity alters sex hormone balance in males, resulting in low testosterone and altered metabolism of estrogen, independent risk factors for cardiometabolic dysfunction. The basis of these alterations and how they are impacted by factors that improve cardiometabolic outcomes in obesity are unknown. Methods: Control and obese mice ( db/db) with or without deletion of myostatin to induce hypermuscularity were used. Mice were analyzed for plasma sex hormones via mass-spectrometry with or without 10mg/kg/day fadrazole to inhibit aromatase. Quantitative PCR was used to measure aromatase along with cytochrome P450 enzymes involved in estrogen metabolism in the liver, skeletal muscle, and visceral adipose tissue. HEK293a cells were treated with myostatin in vitro and enzyme levels assessed. Results: Obesity decreased plasma testosterone 30% and increased estrogen 20% with no change in gonadal weight. Deletion of myostatin increased muscle mass &gt;30% and resulted in a reduction in estrogen levels without a parallel increase in androgens in obese mice. Inhibition of aromatase restores estrogen levels indicating the excess estrogen in obesity is derived from testosterone conversion. Since estrogen was lowered without increasing testosterone and estrogen metabolism must be increased. Aromatase was increased in obesity but unaffected by changes in muscle mass. CYP1B1, an enzyme that converts estradiol to hydroxy estrogens, showed 2.5 fold expression in obese skeletal muscle, which is improved in the absence of myostatin, with no change in other P450s involved in estrogen metabolism. Moreover, changes in P450 enzymes in liver or fat were either absent or changed directionally opposite to observed hormone changes. In HEK cells, treatment with myostatin recapitulated changes in CYP1B1 expression seen in vitro, suggesting a direct link between the myokine and sex hormone metabolism by skeletal muscle. Conclusion: In summary, obesity causes a shift in sex hormone levels to estrogen production, which is improved by myostatin deletion, without restoration of androgens. A potential mechanism responsible could be altered estrogen catabolism, leading to decreased estrogen levels without the restoration of androgen levels. Together, these data suggest CYP1B1 drives the conversion of estrogen to hydroxestrogens, which are known pro-oxidant and pro-lipidemic influences that may contribute to cardiometabolic disease. Whether targeting CYP1B1 improves cardiometabolic function in obesity remains to be determined. D.W. Stepp and D.J. Fulton are supported by NIH 1R01HL147159 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Breast cancer and the molecular mechanism of estrogen signaling

Cancer is a complex pathology that occurs due to the uncontrolled proliferation and growth of cells in any organ or tissue of the body. Breast cancer is the most frequently diagnosed cancer among women worldwide and is the second leading cause of cancer-related deaths. Breast cancer is a pathology that exhibits heterogeneity in which genetic and environmental risk factors play a role. Although many treatment approaches have been developed for breast cancer today, the frequency of the number of patients diagnosed with breast cancer and lost their lives due to this reason is increasing in the world. The most significant limitation to the success of the treatment approaches developing drug resistance in breast cancer cells, and the disease relapses after a certain period and exhibits a more aggressive profile. Therefore, understanding the molecular biology of breast cancer is essential for developing potent therapeutic approaches. It is known that the development of breast cancer is related to changes in direct and indirect signaling mechanisms mediated by estrogen and estrogen receptor. These signaling mechanisms exhibit highly complex interaction patterns. This review summarizes the pathology of breast cancer, estrogenic compounds, estrogen receptors, genomic and non-genomic molecular signaling mechanisms mediated by estrogen and estrogen receptor.

CmPn/CmP Signaling Networks in the Maintenance of the Blood Vessel Barrier.

Cerebral cavernous malformations (CCMs) arise when capillaries within the brain enlarge abnormally, causing the blood-brain barrier (BBB) to break down. The BBB serves as a sophisticated interface that controls molecular interactions between the bloodstream and the central nervous system. The neurovascular unit (NVU) is a complex structure made up of neurons, astrocytes, endothelial cells (ECs), pericytes, microglia, and basement membranes, which work together to maintain blood-brain barrier (BBB) permeability. Within the NVU, tight junctions (TJs) and adherens junctions (AJs) between endothelial cells play a critical role in regulating the permeability of the BBB. Disruptions to these junctions can compromise the BBB, potentially leading to a hemorrhagic stroke. Understanding the molecular signaling cascades that regulate BBB permeability through EC junctions is, therefore, essential. New research has demonstrated that steroids, including estrogens (ESTs), glucocorticoids (GCs), and metabolites/derivatives of progesterone (PRGs), have multifaceted effects on blood-brain barrier (BBB) permeability by regulating the expression of tight junctions (TJs) and adherens junctions (AJs). They also have anti-inflammatory effects on blood vessels. PRGs, in particular, have been found to play a significant role in maintaining BBB integrity. PRGs act through a combination of its classic and non-classic PRG receptors (nPR/mPR), which are part of a signaling network known as the CCM signaling complex (CSC). This network couples both nPR and mPR in the CmPn/CmP pathway in endothelial cells (ECs).

Unveiling the vulnerabilities of synthetic lethality in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most invasive molecular subtype of breast cancer (BC), accounting for about nearly 15% of all BC cases reported annually. The absence of the three major BC hormone receptors, Estrogen (ER), Progesterone (PR), and Human Epidermal Growth Factor 2 (HER2) receptor, accounts for the characteristic "Triple negative" phraseology. The absence of these marked receptors makes this cancer insensitive to classical endocrine therapeutic approaches. Hence, the available treatment options remain solemnly limited to only conventional realms of chemotherapy and radiation therapy. Moreover, these therapeutic regimes are often accompanied by numerous treatment side-effects that account for early distant metastasis, relapse, and shorter overall survival in TNBC patients. The rigorous ongoing research in the field of clinical oncology has identified certain gene-based selective tumor-targeting susceptibilities, which are known to account for the molecular fallacies and mutation-based genetic alterations that develop the progression of TNBC. One such promising approach is synthetic lethality, which identifies novel drug targets of cancer, from undruggable oncogenes or tumor-suppressor genes, which cannot be otherwise clasped by the conventional approaches of mutational analysis. Herein, a holistic scientific review is presented, to undermine the mechanisms of synthetic lethal (SL) interactions in TNBC, the epigenetic crosstalks encountered, the role of Poly (ADP-ribose) polymerase inhibitors (PARPi) in inducing SL interactions, and the limitations faced by the lethal interactors. Thus,the future predicament of synthetic lethal interactions in the advancement of modern translational TNBC research is assessed with specific emphasis on patient-specific personalized medicine.

A novel UPLC-ESI-MS assay for fifteen portal estrogens and metabolites detection and application in hepatic fibrosis

Estrogens and their metabolites (EMs) are involved in chronic liver disease and gut microbiota regulates estrogen metabolism, whereas the role of enterogenous EMs in liver disease is still elusive. Because of the extremely low level of EMs in portal serum and the EMs contain multiple pairs of isomers, an accurate determination of portal serum EMs is urgently needed. This study established a quantitative detection method for portal serum EMs and applied to non-alcoholic fatty liver disease (NAFLD) related hepatic fibrosis mice model. The serum was derived with a novel derivatization reagent 4-acetyl aminobenzene sulfonyl chloride, and a UPLC-ESI-MS system was used for quantification of 15 EMs in 120 min. Compared with normal group, the concentrations of E1, E2 in model group were significantly decreased by 4–8 times, all the C2 and C4 substitution products (2-OHE1, 2-OHE2, 2-MeOE1, 4-OHE1, 4-MeOE1, 4-OHE2, 4-MeOE2, 2-MeOE2) were significantly decreased by 2–22 times. However, the C16 and C17 substitution products (E3, 16-epiE3, 17-epiE3, 16-ketoE2) levels were increased by 3–5 times (P < 0.01). This study elucidated the changes of enterogenous EMs which entered the liver via portal vein in NAFLD - related hepatic fibrosis and provided methodological platform for other related studies on estrogen metabolism.

Incidence Rate and Clinical Characteristics of Triple Negative Breast Cancer Patients in Hasan Sadikin Hospital, for the Last Five Years

Breast cancer is the most common cancer in Indonesia and ranks as the first cause of cancer death. Data from the Global Cancer Observatory (GLOBOCAN) 2020 shows that as many as 16.6% of the total 396,914 new cases of cancer in Indonesia are breast cancer with a mortality rate of more than 22 million. This study took all data on breast cancer patients at Hasan Sadikin Hospital (RSHS) from 2015-2019. Where from all this data, then the inclusion criteria are patients who have TNBC from immunohistochemistry analysis. From all existing samples, the patient's age is then recorded and then grouped. This age mapping is to find out what age group TNBC occurs the most. Of the 4050 breast cancer patients who went to RSHS in 2015-2019, 628 patients showed supportive immunohistochemistry results towards a triple negative diagnosis. From all these data, it was then found that the age group that was most diagnosed with TNBC in RSHS was 41-50 years old, which was 237 people or about 37%. From all existing data, a recidivist incidence rate of 11 cases or around 1.7% was obtained. TNBC is a malignant and aggressive type of breast cancer because the immunohistochemistry (IHC) presentation does not have three receptors that can be found in other types of breast cancer, namely estrogen (ER), progesterone (PR), and a protein known as human epidermal growth factor (HER2). This research has limitations, namely that the data available is very minimal so that it is considered less representative. Research on a larger scale and longer time is needed to provide a more real and representative picture.

XPERT® breast cancer STRAT4 as an alternative method of identifying breast cancer phenotype in Cape Verde (preliminary results).

Breast cancer (BC) is a public health problem in developing countries, including Cape Verde. Immunohistochemistry (IHC) is the gold standard technique used for BC phenotypic characterisation to support efficient therapeutic decisions. However, IHC is a demanding technique that requires knowledge, trained technicians, expensive antibodies and reagents, controls, and results validation. The low number of cases in Cape Verde increases the risk of expiring the validity of the antibodies, and manual procedures often jeopardise the quality of the results. Thus, IHC is limited in Cape Verde, and an alternative technically easy solution is needed. A point-of-care messenger RNA (mRNA) STRAT4 BC assay to assess estrogen (ER), progesterone (PR), hormone growth factor 2 receptor (HER2), and Ki67, using the GeneXpert platform, has been recently validated on tissues from internationally accredited laboratories, showing excellent concordance with IHC results.To assess whether this technology can be implemented in Cape Verde to guide BC treatment we decided to study the level of agreement between the findings yielded by BC STRAT4 and the results are the same cases obtained by IHC. Formalin-fixed and paraffin-embedded (FFPE) tissue samples from 29 Cabo Verdean BC patients diagnosed in Agostinho Neto University Hospital were analysed by applying IHC and BC STRAT4 assay. The time between sample collection and pre-analytic procedures is unknown. All the samples were pre-processed in Cabo Verde (fixed in formalin and embedded in paraffin). IHC studies were performed in referenced laboratories in Portugal. STRAT4 and IHC result concordance was assessed by calculating the percentage of results agreement and Cohen's Kappa (K) statistics. STRAT4 assay failed in 2 out of the 29 analysed samples. Of the 27 successfully analysed samples, STRAT4/IHC results for ER, PR, HER2, and Ki67 were concordant in 25, 24, 25, and 18 cases, respectively. Ki67 was indeterminate in three cases, and PR was indeterminate once.The percentage of agreement between STRAT4 and IHC results for ER, PR, HER2, and Ki67 was 92.59%, 92.31%, 92.59% and 81.82%, respectively. The Cohen's K statistic coefficients for each biomarker were 0.809, 0.845, 0.757 and 0.506, respectively. According to our preliminary results, a point-of-care mRNA STRAT4 BC assay may be an alternative in laboratories unable to provide quality and/or cost-efficient IHC services. However, more data and improvement on sample pre-analytic processes are required to implement this BC STRAT4 Assay in Cape Verde.

Emerging Non-Antibiotic Options Targeting Uropathogenic Mechanisms for Recurrent Uncomplicated Urinary Tract Infection.

Urinary tract infections (UTIs) are the most frequent bacterial infections in the clinical setting. Even without underlying anatomic or functional abnormalities, more than 40% of women experience at least one UTI in their lifetime, of which 30% develop recurrent UTIs (rUTIs) within 6 months. Conventional management with antibiotics for rUTIs may eventually lead to the development of multidrug-resistant uropathogens. Targeting of the pathogenicity of rUTIs, the evolution of uropathogenic Escherichia coli (UPEC), and inadequate host defenses by immune responses should be explored to provide non-antibiotic solutions for the management of rUTIs. The adaptive evolution of UPEC has been observed in several aspects, including colonization, attachment, invasion, and intracellular replication to invade the urothelium and survive intracellularly. Focusing on the antivirulence of UPEC and modulating the immunity of susceptible persons, researchers have provided potential alternative solutions in four categories: antiadhesive treatments (i.e., cranberries and D-mannose), immunomodulation therapies, vaccines, and prophylaxis with topical estrogen therapy and probiotics (e.g., Lactobacillus species). Combination therapies targeting multiple pathogenic mechanisms are expected to be a future trend in UTI management, although some of these treatment options have not been well established in terms of their long-term efficacy. Additional clinical trials are warranted to validate the therapeutic efficacy and durability of these techniques.

Impact of Pathologic Complete Response on the Prognosis of Triple-Negative Breast Cancer Patients: A Cohort Study.

Introduction Triple-negative breast cancer (TNBC) is a molecular subtype in which estrogen (ER)/progesterone receptor (PR) and human epidermal growth receptor 2 (HER2) expression does not occur.The objective of this study was to analyze the impact of pathologic complete response (pCR) after neoadjuvant chemotherapy on the prognosis of triple-negative breast cancer (TNBC) patients. Methods This cohort study was conducted in a private-sector oncology clinic located in the city of Teresina, Brazil. Medical charts of 532 breast cancer patients treatedfrom 2007 to 2020 were analyzed. Of these patients, 83 women with TNBC were selected (10 patients were excluded from the study). Univariate and multivariate analyses (Cox regression) were performed to evaluate the impact on patient survival, comparing patients with or without pCR. A significance level of 5% was set. Overall survival (OS) and disease-free survival (DFS) curves were constructed according to the Kaplan-Meier model. Results Angiolymphatic invasion and positive sentinel lymph node were associated with a lower OS and/or DFS in TNBC (p<0.05). The 10-year OS was 78% and 49%, and the 10-year DFS was 97% and 32% in patients with or without pCR, respectively. Conclusion pCR after neoadjuvant chemotherapy was associated with improvement in OS and DFS in TNBC patients.