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Since the beginning of the COVID-19 pandemic, it has been evident that women and young people were less susceptible to severe infections compared to males. In a previous study, we observed a reduced prevalence of SARS-CoV-2 infections in hormonal-driven breast cancer patients undergoing SERM (selective estrogen receptor modulator) therapy with respect to other treatments inhibiting estrogen synthesis. In addition to being used in anticancer therapy, SERMs are also prescribed for postmenopausal osteoporosis prevention and treatment. Therefore, in this study, a retrospective analysis of the clinical outcomes of SARS-CoV-2 infections in a population of women over 50 years who were treated for the management of menopausal symptoms was performed. SARS-CoV-2 infections, hospitalizations, and death rates were evaluated in women residing in the Italian north-eastern Veneto Region who were undergoing treatment with Estrogen Modulators (EMs); Estrogen or Progestin, and their combination (EPs); Bisphosphonates (BIs); or cholecalciferol (vitamin D3) ± calcium supplementation (CC). The final cohort study included 124,393 women, of whom 6412 were found to be SARS-CoV-2 infected (CoV2+ve). The results indicated that only women treated with vitamin D3 alone or in combination with calcium showed a significant reduction in their SARS-CoV-2 infection risk by 26% (OR 0.74; 95%CI 0.60–0.91). On the other hand, an increased risk of hospitalization (OR 2.69; 95%CI 1.77–4.07) was shown for the same treatments. The results highlighted in this work contribute to shedding some light on the widely debated role of vitamin D in the prevention of SARS-CoV-2 infections and the disease's treatment. [ABSTRACT FROM AUTHOR]

Women go through several predictable conditions and symptoms during menopause that are caused by age, changes in sex hormone levels, and other factors. Conventional menopause hormone therapy has raised serious concerns about the increased risks of cancers, blood clots, depression, etc. Selective estrogen receptor modulators (SERMs) that can be both agonists and antagonists of estrogen receptors in a tissue‐specific manner are being developed to reduce the health concerns associated with menopause hormone therapy. Here, we have searched the Chinese national traditional Chinese medicine (TCM) patent database to identify potential SERM‐like compounds with reduced health risks. TCM has been widely used for treating complex symptoms associated with menopause syndrome and thus can be a particularly rich source for pharmaceutical alternatives with SERM properties. After extensive literature review and molecular simulation, we conclude that protopanaxatriol, paeoniflorin, astragalin, catalpol, and hyperoside among others may be particularly promising as SERM‐like compounds in treating the menopausal syndrome. Compounds in TCM hold promise in yielding comparable outcomes to hormone therapy but with reduced associated risks, thus presenting promising avenues for their clinical applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Estrogen Receptor α (ERα) is a key target for hormonal treatment of breast cancer. However, treatment with antihormonal therapies such as tamoxifen will eventually fail, presumably through hormone-independent signaling through estrogen receptors. It has been shown that a component of this resistance to hormonal therapy may be through expression of an alternative form of estrogen receptor, ERα36. Here, we show that targeting the enzyme CK2, either with the clinical stage CK2 inhibitor CX-4945, or by disrupting expression of its regulatory β subunit, can result in decreased expression of both the canonical form of ERα protein as well as the ERα36 isoform in tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. Our studies provide a rationale for the clinical investigation of CX-4945 in the treatment of ERα-expressing breast cancers. Aberrant estrogen receptor (ERα) signaling mediates detrimental effects of tamoxifen including drug resistance and endometrial hyperplasia. ERα36, an alternative isoform of ERα, contributes to these effects. We have demonstrated that CK2 modulates ERα expression and function in breast cancer (BCa). Here, we assess if CX-4945 (CX), a clinical stage CK2 inhibitor, can disrupt ERα66 and ERα36 signaling in BCa. Using live cell imaging, we assessed the antiproliferative effects of CX in tamoxifen-sensitive and tamoxifen-resistant BCa cells in monolayer and/or spheroid cultures. CX-induced alterations in ERα66 and ERα36 mRNA and protein expression were assessed by RT-PCR and immunoblot. Co-immunoprecipitation was performed to determine the differential interaction of ERα isoforms with HSP90 and CK2 upon CX exposure. CX caused concentration-dependent decreases in proliferation in tamoxifen-sensitive MCF-7 and tamoxifen-resistant MCF-7 Tam1 cells and significantly repressed spheroid growth in 3D models. Additionally, CX caused dramatic decreases in endogenous or exogenously expressed ERα66 and ERα36 protein. Silencing of CK2β, the regulatory subunit of CK2, resulted in destabilization and decreased proliferation, similar to CX. Co-immunoprecipitation demonstrated that ERα66/36 show CK2 dependance for interaction with molecular chaperone HSP90. Our findings show that CK2 functions regulate the protein stability of ERα66 and ERα36 through a mechanism that is dependent on CK2β subunit and HSP90 chaperone function. CX may be a component of a novel therapeutic strategy that targets both tamoxifen-sensitive and tamoxifen-resistant BCa, providing an additional tool to treat ERα-positive BCa. [ABSTRACT FROM AUTHOR]

Background: Estrogen receptor (ER)‐positive (ER+) breast cancer accounts for approximately 75% of all breast cancers. Tamoxifen, a selective estrogen receptor modulator, is the standard adjuvant treatment. Although better tolerated than aromatase inhibitors, tamoxifen increases the risk of venous thromboembolism (VTE) 1.4‐fold. Aim: To assess the hemostatic imbalance induced by tamoxifen in adjuvant treatment of ER+ breast cancer. Method: Twenty‐five patients in remission from ER+ breast cancer under tamoxifen were included. One hundred and thirty one age‐ and BMI‐matched healthy controls were included to establish reference ranges of thrombin generation assay (TGA) parameters. TGA was performed in the absence and presence of exogenous activated protein C (APC) to calculate the normalized APC sensitivity ratio (nAPCsr), a marker of APC resistance. Results: All TG parameters except the endogenous thrombin potential (ETP) (−APC) were significantly impacted by tamoxifen (p < 0.001). In absence of APC, regardless of TGA parameters, at least 50% of results were outside the reference ranges except for ETP, which was above the upper reference limit in only two individuals. The most impacted parameter was the Peak Height with 52% (−APC) and 80% (+APC) of results above the upper reference range limit, respectively. The nAPCsr was significantly higher in tamoxifen users (mean ± standard deviation = 3.18 ± 0.91) compared to the control group (2.19 ± 0.92, p < 0.0001). Conclusion: This observational study showed that patients in remission from ER+ breast cancer taking tamoxifen had altered thrombin generation, as well as an acquired APC resistance. Moreover, this is the first study using the validated ETP‐based APC resistance assay in tamoxifen‐treated patients. [ABSTRACT FROM AUTHOR]

Administration of selective estrogen receptor modulators (SERMs) and anti-estrogens has been shown to reduce the size of pituitary tumors. However, previous studies were performed on animal pituitary tumors or tissue cultures. We administered oral tamoxifen to a postoperative patient with a nonfunctioning pituitary neuroendocrine tumor (NF-PitNET) to investigate its potential effect on tumor volume. This case report presents the case of a 47-year-old female patient with a null cell adenoma who had undergone surgical resection as primary treatment and was left with a residual tumor that grew significantly. She was treated with tamoxifen 20–40 mg daily for one year. She was followed up to assess tamoxifen adherence, tolerability, and adverse events. The resected pituitary tumor was stained with estrogen receptor alpha (ERα) and beta (ERβ), proliferation markers (ki-67 and p53), and H&E staining for mitotic count. MRI of the pituitary gland was performed before starting treatment, after 6 months, and after 1 year of tamoxifen therapy. Her resected tumor showed high-intensity ERβ staining in the absence of ERα expression. She was able to tolerate oral tamoxifen therapy without side effects. Tamoxifen therapy resulted in a remarkable reduction in residual tumor volume of up to 87 % in this patient. Tamoxifen has a potential therapeutic effect in treating patients with residual NF-PitNET tumors that have regrown after primary resection. This finding may provide an alternative treatment modality for recurrent NF-PitNET. ERβ expression may predict response to tamoxifen in this subset of patients.

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Purpose of review. The purpose of this paper is to review the current concepts regarding a new-old pharmacological class, SARM (Selective Androgen Receptor Modulator). Especially how SARM can be beneficial in treatment of orthopedic disease. Materials and methods. Androgens (testosterone and dihydrotestosterone (DHT)) are the male sex hormones required for development of the male reproductive system and secondary sexual characteristics. SARMs due to ability to bind androgen receptor are excellent in treatment of various diseases. Discussion. Based on the published literature, a review has been carried out on SARM and its fields of application in the treatment of muscle wasting pathologies. Starting from the history of the SARMs, its role in prevention of muscle wasting, anabolic effects and side effects were addressed. Conclusions. Nonsteroidal SARMs are unique in their ability to bind the androgen receptor with high affinity and exhibit tissue selective activity. SARMs can be used to treat muscle wasting conditions, osteoporosis, frailty syndrome without unwanted side effects associated with androgens. [ABSTRACT FROM AUTHOR]

Since the beginning of the COVID-19 pandemic, it has been evident that women and young people were less susceptible to severe infections compared to males. In a previous study, we observed a reduced prevalence of SARS-CoV-2 infections in hormonal-driven breast cancer patients undergoing SERM (selective estrogen receptor modulator) therapy with respect to other treatments inhibiting estrogen synthesis. In addition to being used in anticancer therapy, SERMs are also prescribed for postmenopausal osteoporosis prevention and treatment. Therefore, in this study, a retrospective analysis of the clinical outcomes of SARS-CoV-2 infections in a population of women over 50 years who were treated for the management of menopausal symptoms was performed. SARS-CoV-2 infections, hospitalizations, and death rates were evaluated in women residing in the Italian north-eastern Veneto Region who were undergoing treatment with Estrogen Modulators (EMs); Estrogen or Progestin, and their combination (EPs); Bisphosphonates (BIs); or cholecalciferol (vitamin D3) ± calcium supplementation (CC). The final cohort study included 124,393 women, of whom 6412 were found to be SARS-CoV-2 infected (CoV2+ve). The results indicated that only women treated with vitamin D3 alone or in combination with calcium showed a significant reduction in their SARS-CoV-2 infection risk by 26% (OR 0.74; 95%CI 0.60–0.91). On the other hand, an increased risk of hospitalization (OR 2.69; 95%CI 1.77–4.07) was shown for the same treatments. The results highlighted in this work contribute to shedding some light on the widely debated role of vitamin D in the prevention of SARS-CoV-2 infections and the disease’s treatment.

Breast cancer, a complex and varied disease, has four distinct subtypes based on estrogen receptor and human epidermal growth factor receptor 2 (HER2) levels, among which a significant subtype known as HR+/HER2-breast cancer that has spurred numerous research. The prevalence of breast cancer and breast cancer-related death are the most serious threats to women's health worldwide. Current progress in treatment strategies for HR+/HER2-breast cancer encompasses targeted therapy, endocrine therapy, genomic immunotherapy, and supplementing traditional methods like surgical resection and radiotherapy. This review article summarizes the current epidemiology of HR+/HER2-breast cancer, introduces the classification of HR+/HER2-breast cancer and the commonly used treatment methods. The mechanisms of action of various drugs, including targeted therapy drugs and endocrine hormone therapy drugs, and their potential synergistic effects are deeply discussed. In addition, clinical trials of these drugs that have been completed or are still in progress are included. [ABSTRACT FROM AUTHOR]

Background and hypothesis Several studies suggest that raloxifene, a selective estrogen receptor modulator, improves symptoms and cognition in post-menopausal women with Schizophrenia-Spectrum Disorders (SSD). We aimed to assess the effects of adjunctive raloxifene in women and men with SSD. Study design This parallel, randomized, double-blind, placebo-controlled trial included adult SSD patients across the Netherlands and Belgium. Participants were stratified by age, sex, and global functioning and randomly assigned 1:1 to 12-week add-on raloxifene or placebo. Primary outcomes were symptom severity at 6, 12, and 38 weeks and cognition at 12 and 38 weeks, as measured with the Positive and Negative Syndrome Scale and the Brief Assessment of Cognition in Schizophrenia, respectively. Intention-to-treat analyses were performed using linear mixed-effect models. Study results We assessed 261 patients for eligibility, of which 102 (28% female) were assigned to raloxifene (n  = 52) or placebo (n  = 48). Although we found no main effect of raloxifene, secondary sex-specific analysis showed that in women, raloxifene had beneficial effects on negative symptoms at week 6 (LSM −2.92; adjusted P  = 0.020) and week 12 (LSM −3.12; adjusted P  = 0.030), and on working memory at week 38 (LSM 0.73; adjusted P  = 0.040), while having negative effects on working memory at week 38 in men (LSM −0.53; adjusted P  = 0.026). The number of adverse events was similar between groups. Conclusions Our results do not support the use of raloxifene in patients with SSD in general, but suggest female-specific beneficial effects of raloxifene on negative symptoms and working memory. Our findings encourage further research on sex-specific pharmacotherapeutic treatment. [ABSTRACT FROM AUTHOR]

Nowadays, selective estrogen receptor modulators (SERMs) and downregulators (SERDs) are used as the first‐line medical treatment for estrogen receptor positive (ER+) tumors. Herein we report synthesis, ER‐α binding activity, and cytotoxicity of LSZ102 selenium analogues 11 and 28. TR‐FRET competitive ER‐α binding experiments and cytotoxicity assays have shown that the selenium analogues exhibit closely related activity to LSZ102. Furthermore, the prepared selenium analogues are not toxic in rat cardiomyoblasts (H9C2), indicating that substituted benzo[b]selenophene is a prospective scaffold for the development of ER‐α modulators and downregulators for the treatment of ER+ cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial cancer is the most common gynecologic cancer in the developed world and in the recurrent setting has a dismal prognosis. As the endometrium is a hormonally active tissue, hormonal therapy has long been an integral treatment modality. There are many options for hormonal therapy including progesterones, agents that target the estrogen pathway, and combinations with targeted therapies, which are described in detail in this review. High disease control rate, long duration of response, and easy tolerability make hormonal therapy an excellent option for patients with low-grade hormone receptor-positive disease who would like to avoid or cannot tolerate cytotoxic chemotherapy or other targeted therapies. Hormonal therapy has long been a treatment modality for recurrent endometrial cancer. It is appealing for patients with low-grade, slow-growing tumors or in patients for which other treatment types may be too toxic. Hormonal therapy is well tolerated and has response rates ranging from 9 to 33%. Hormonal treatment options take advantage of the estrogen-dependent molecular pathways in endometrial cancers. Current options for hormonal therapies include progesterone therapy (medroxyprogesterone acetate and megestrol acetate) as a single agent or in combination and agents that target the estrogen pathway. Aromatase inhibitors have had modest single-agent activity, but synergistic effects have been found when used in combination with targeted therapy including mTOR inhibitors and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Molecular profiling of endometrial cancers has begun to help individualize treatments. This review will report on existing data and ongoing trials investigating novel hormonal therapy agents. [ABSTRACT FROM AUTHOR]

Due to the complexity of estrogen signaling mediated by estrogen receptors (ERs) in a variety of biological environments, there is great interest in the identification and optimization of selective estrogen receptor ligands. Prodrugs that can be activated in specific environments allow for tissue selectivity. Therefore, there have been recent advances in the development of prodrugs for ERs that can be released through enzymatic reactions, chemical reactions (eg, oxidation by reactive oxygen species or reduction by ascorbic acid), or light-mediated processes. In addition, researchers have linked ER ligands to additional drugs for selective cellular targeting. In this review, we highlight the compounds that have been generated and their potential uses in disease states such as breast cancer, inflammation, and menopause. [ABSTRACT FROM AUTHOR]

Conjugated estrogens (CE) delay the onset of type 2 diabetes (T2D) in postmenopausal women, but the mechanism is unclear. In T2D, the endoplasmic reticulum (ER) fails to promote proinsulin folding and, in failing to do so, promotes ER stress and β cell dysfunction. We show that CE prevent insulin-deficient diabetes in male and in female Akita mice using a model of misfolded proinsulin. CE stabilize the ER-associated protein degradation (ERAD) system and promote misfolded proinsulin proteasomal degradation. This involves activation of nuclear and membrane estrogen receptor-α (ERα), promoting transcriptional repression and proteasomal degradation of the ubiquitin-conjugating enzyme and ERAD degrader, UBC6e. The selective ERα modulator bazedoxifene mimics CE protection of β cells in females but not in males.

Introduction: This systematic review analyzes the state-of-art repurposing of the drug tamoxifen (TAM) in the treatment of Duchenne Muscular Dystrophy (DMD), including its mechanism of action, toxicological findings, and past and ongoing clinical trials. A parallel aim of this work was to explore whether evidence exists to support further funding of investigation on TAM treatment for DMD patients with a pivotal trial in young patients. Bringing evidence and answering the scientificquestion ofwhether this treatment could improve the quality-of-life ofDMD patients is needed to establish guidelines and accelerate access to promising therapies for DMD patients. Methods: The search was conducted in January 2022 utilizing PubMed. AllMeSH terms for "Duchenne Muscular Dystrophy" and "tamoxifen" were used. The inclusion and exclusion criteria were defined according to the PICOS framework. Results: The included publications all explored the use of TAM with promising outcomes in muscular strength recovery and a decrease in pathology biomarkers. Two reviews recognize TAM as a potential treatment for DMD patients and state that drug repurposing plays a crucial role in the quest for a drug candidate to treat this rare disease. Conclusion: According to available data, TAM shows promise as a treatment for DMD, both pharmacologically and clinically. However, published data to date are insufficient to definitively conclude the beneficial effect of TAM on quality-of-life and ultimately survival, particularly in the youngest patients diagnosed with DMD. [ABSTRACT FROM AUTHOR]

Introduction: Hormone-mediated therapies are on the rise and are key therapies in the treatment of some of the most common cancer entities. Proarrhythmic effects have been described in patients treated with SERMs while little to none is known about the electrophysiological effects of the potentially less arrhythmogenic selective estrogen receptor degraders. Methods: Twenty hearts of female New Zealand White rabbits were excised and retrogradely perfused employing a Langendorff setup. An electrophysiology study was performed to obtain CL-dependent action potential duration at 90% of repolarization (APD90), QT interval, effective refractory period (ERP), and post-repolarization refractoriness (PRR = ERP-APD90). After generating baseline data, the hearts were assigned to two groups and perfused with (n = 10) increasing doses of fulvestrant (1 µM and 5 µM; n = 10) or tamoxifen (2.5 µM and 7.5 µM; n = 10), and the protocol was repeated again. Results: Fulvestrant led to a decrease in APD90 and QT interval and an increased PRR. The inducibility of ventricular tachycardia (VT) episodes was unaltered. Tamoxifen showed similar effects, resulting in a shortened APD90 and QT interval and no increased VT incidence in the setting of a prolonged PRR. Conclusion: The present study shows no acute proarrhythmic effect of tamoxifen and fulvestrant in an established whole heart model when employing clinically relevant concentrations. [ABSTRACT FROM AUTHOR]

Simple Summary: Estrogen receptor-positive (ER+) breast cancer is a notable cause of global death from breast cancer in premenopausal and postmenopausal women. Lethality is driven, amongst other things, by endocrine resistance, which is intrinsic or acquired in approximately 60% of patients after anti-estrogen therapy. Anti-estrogen therapy resistance, which has become a major clinical problem, results from high mutation rates of therapy targets, multiple subclonal diversity, dysregulation of downstream survival pathways, as well as alterations in the expression of non-coding RNAs (e.g., microRNA) that regulate the activity of signaling molecules. This review focuses on the current status of anti-estrogen therapy resistance and the key contributing mechanisms, as well as potential novel combination therapy strategies with anti-estrogen drugs to improve patient survival. Breast cancer (BC) is the most commonly diagnosed cancer in women, constituting one-third of all cancers in women, and it is the second leading cause of cancer-related deaths in the United States. Anti-estrogen therapies, such as selective estrogen receptor modulators, significantly improve survival in estrogen receptor-positive (ER+) BC patients, which represents about 70% of cases. However, about 60% of patients inevitably experience intrinsic or acquired resistance to anti-estrogen therapies, representing a major clinical problem that leads to relapse, metastasis, and patient deaths. The resistance mechanisms involve mutations of the direct targets of anti-estrogen therapies, compensatory survival pathways, as well as alterations in the expression of non-coding RNAs (e.g., microRNA) that regulate the activity of survival and signaling pathways. Although cyclin-dependent kinase 4/6 and phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors have significantly improved survival, the efficacy of these therapies alone and in combination with anti-estrogen therapy for advanced ER+ BC, are not curative in advanced and metastatic disease. Therefore, understanding the molecular mechanisms causing treatment resistance is critical for developing highly effective therapies and improving patient survival. This review focuses on the key mechanisms that contribute to anti-estrogen therapy resistance and potential new treatment strategies alone and in combination with anti-estrogen drugs to improve the survival of BC patients. [ABSTRACT FROM AUTHOR]

Endometriosis is a chronic, estrogen-dependent, inflammatory disease associated with pelvic pain, infertility, impaired sexual function, and psychological suffering. Therefore, tailored patient management appears of primary importance to address specific issues and identify the appropriate treatment for each woman. Over the years, abundant research has been carried out with the objective to find new therapeutic approaches for this multifaceted disease. This narrative review aims to present the latest advances in the pharmacological management of endometriosis. In particular, the potential role of GnRH antagonists, selective progesterone receptor modulators (SPRMs), and selective estrogen receptors modulators (SERMs) will be discussed. We performed a literature search in PubMed and Embase, and selected the best quality evidence, giving preference to the most recent and definitive original articles and reviews. Medical therapy represents the cornerstone of endometriosis management, although few advances have been made in the last decade. Most studies have focused on the evaluation of the efficacy and safety of GnRH antagonists (plus add-back therapy in cases of prolonged treatment), which should be used as second-line treatment options in selected cases (i.e. non-responders to first-line treatments). Further studies are needed to identify the ideal treatment for women with endometriosis. [ABSTRACT FROM AUTHOR]

Introduction: This systematic review analyzes the state-of-art repurposing of the drug tamoxifen (TAM) in the treatment of Duchenne Muscular Dystrophy (DMD), including its mechanism of action, toxicological findings, and past and ongoing clinical trials. A parallel aim of this work was to explore whether evidence exists to support further funding of investigation on TAM treatment for DMD patients with a pivotal trial in young patients. Bringing evidence and answering the scientific question of whether this treatment could improve the quality-of-life of DMD patients is needed to establish guidelines and accelerate access to promising therapies for DMD patients.Methods: The search was conducted in January 2022 utilizing PubMed. All MeSH terms for “Duchenne Muscular Dystrophy” and “tamoxifen” were used. The inclusion and exclusion criteria were defined according to the PICOS framework.Results: The included publications all explored the use of TAM with promising outcomes in muscular strength recovery and a decrease in pathology biomarkers. Two reviews recognize TAM as a potential treatment for DMD patients and state that drug repurposing plays a crucial role in the quest for a drug candidate to treat this rare disease.Conclusion: According to available data, TAM shows promise as a treatment for DMD, both pharmacologically and clinically. However, published data to date are insufficient to definitively conclude the beneficial effect of TAM on quality-of-life and ultimately survival, particularly in the youngest patients diagnosed with DMD.

Objective: To evaluate total testosterone (TT) kinetics and its predictors 6 months after the discontinuation of clomiphene citrate (CC) in patients with hypogonadism. Materials and methods: Consecutive patients with normal testicles and male hypogonadism defined by TT < 300 ng/dl in the presence of signs or symptoms according to the previous consensus were prospectively evaluated in a urologic outpatient clinic by TT levels at baseline (T0), after a daily dose of 50 mg CC for 40 days (T1), and after the washout period of 6 months of CC discontinuation (T2). Results: Among 75 patients, mean age 56.8 years, testosterone at T1 > 300 ng/dl was achieved by 69 (92%), 450–600 ng/dl by 32 (42.6%), and > 600 ng/dl by 27 (36.0%). 18 subjects (24%) maintained asymptomatic and TT levels over 300 ng/dl at T2. Age negatively related to testosterone response and T1 response > 810 ng/dl predicts a median gain of 166.5 ng/dl at 6 months of CC discontinuation. Conclusions: CC is a compelling option to treat male hypogonadism, although a chronic treatment is needed in most patients. About one in every four patients respond to a CC short trial to "reboot" the physiology. Further understanding of TT kinetics in these patients in the long term is warranted. [ABSTRACT FROM AUTHOR]

ABSTRACT Despite a remarkable improvement in health care and continued drug discovery efforts, malaria control efforts are continuously challenged by the emergence of drug-resistant parasite strains. Given a long and risky development path of new drugs, repurposing existing drugs for the treatment of malaria is an attractive and shorter path. Tamoxifen, a selective estrogen receptor modulator (SERM) for the treatment and prevention of estrogen receptor-positive breast cancer, possesses antibacterial, antifungal, and antiparasitic activities. Hence, we assessed tamoxifen, raloxifene, and bazedoxifene, which represent the first-, second-, and third-generation SERMs, respectively, for antimalarial activity. Raloxifene and bazedoxifene inhibited the erythrocytic development of Plasmodium falciparum with submicromolar 50% inhibitory concentration (IC50) values. Among the three, bazedoxifene was the most potent and also decreased P. berghei infection in female mice but not in male mice. However, bazedoxifene similarly inhibited P. falciparum growth in erythrocytes of male and female origin, which highlights the importance of sex-specific host physiology in drug efficacy. Bazedoxifene was most potent on early ring-stage parasites, and about 35% of the treated parasites did not contain hemozoin in the food vacuole. Bazedoxifene-treated parasites had almost 34% less hemozoin content than the control parasites. However, both control and bazedoxifene-treated parasites had similar hemoglobin levels, suggesting that bazedoxifene inhibits hemozoin formation and that toxicity due to accumulation of free heme could be a mechanism of its antimalarial activity. Because bazedoxifene is in clinical use and bazedoxifene-chloroquine combination shows an additive antiparasitic effect, bazedoxifene could be an adjunctive partner of currently used antimalarial regimens. IMPORTANCE The emergence and spread of drug-resistant strains of the human malaria parasite Plasmodium falciparum has necessitated new drugs. Selective estrogen receptor modulators are in clinical use for the prevention and treatment of breast cancer and postmenopausal osteoporosis. We demonstrate that bazedoxifene, a third-generation selective estrogen receptor modulator, has potent inhibitory activity against both susceptible and drug-resistant strains of Plasmodium falciparum. It also blocked the development of Plasmodium berghei in mice. The inhibitory effect was strongest on the ring stage and resulted in the inhibition of hemozoin formation, which could be the major mechanism of bazedoxifene action. Hemozoin is a nontoxic polymer of heme, which is a by-product of hemoglobin degradation by the malaria parasite during its development within the erythrocyte. Because bazedoxifene is already in clinical use for the treatment of postmenopausal osteoporosis, our findings support repurposing of bazedoxifene as an antimalarial.

Estrogen deprivation is one of the major factors responsible for many age-related processes including poor wound healing in postmenopausal women. However, the reported side-effects of estrogen replacement therapy (ERT) have precluded broad clinical administration. Therefore, selective estrogen receptor modulators (SERMs) have been developed to overcome the detrimental side effects of ERT on breast and/or uterine tissues. The use of natural products isolated from plants (e.g., soy) may represent a promising source of biologically active compounds (e.g., genistein) as efficient alternatives to conventional treatment. Genistein as natural SERM has the unique ability to selectively act as agonist or antagonist in a tissue-specific manner, i.e., it improves skin repair and simultaneously exerts anti-cancer and chemopreventive properties. Hence, we present here a wound healing phases-based review of the most studied naturally occurring SERM.

Bilateral Fibrocystic Breast is the most common form of benign breast disease and besides tender breasts is clinically associated with a relative risk for the subsequent development of cancer. We present a successful reversal of macrocytic anemia using iron bisglycinate, B-vitamins, and protein powder alongside symptomatic regression of bilateral fibrocystic breast with correction of concomitant mastodynia and dysmenorrhea using therapeutic iodine paired with estrogen metabolite support with GLA, DIM, I3C, and estrogen excretion with Calcium D-Glucarate. [ABSTRACT FROM AUTHOR]

Osteoporosis (OP) is closely related to aging, with higher prevalence in the elderly than in the young and middle-aged, which seriously endangers the health of the elderly. Gonadal steroid hormones play an important role in the male bone metabolism. Estrogen and androgen can promote bone formation and reduce bone loss, while progesterone may play a negative role in the maintenance of male bone mass. The deficiency of estrogen and androgen in the elderly men leads to the decrease of bone mineral density and increases their OP incidence rate. Gonadal steroid hormones and their receptor modulators provide new ideas for the treatment of OP. Estrogen is commonly used for the treatment of postmenopausal osteoporosis (PMOP), while not recommended for male OP. Androgen replacement therapy can increase bone mineral density in elderly men. However, there are doubts about prostate and cardiovascular safety, so routine use is not recommended. Selective estrogen receptor modulator (SERM) can increase the serum testosterone level, increase bone mineral density of lumbar spine and hip joint, and reduce the risk of fracture. But it has also not been officially approved for the treatment of male OP, and its efficacy and safety need to be verified by more clinical trials. Researches on the application of selective androgen receptor modulator (SARM) in OP are still at the initial stage. At present, SARM has only been proved to increase the bone strength of male mice in animal models. This paper reviews and summarizes the role of gonadal steroid hormones in the pathogenesis and treatment of OP in elderly men, aiming to provide some references for the clinical work of doctors. [ABSTRACT FROM AUTHOR]

Estrogen receptor (ER) is the major driver of most metastatic breast cancers (mBCs). Endocrine therapy (ET) is the most effective treatment for ER + mBC, but its effectiveness is limited by high rates of de novo and acquired resistance. A growing understanding of the biological characteristics and complexity of the ER pathway and the mechanisms of ET resistance has led to the development of a new generation of targeted therapies. One such mechanism is the cell cycle signaling pathways, which lead to the development of cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) that have, in turn, transformed the management of such tumors. Another important mechanism is the alteration of the phosphatidylinositol 3′-kinase/AKT/mammalian target of rapamycin pathway. Drugs targeting each component of these pathways are currently used in clinical practice, and several more are in development. As a result, a myriad of new targeted therapies are consistently being added to the clinical oncologist armamentarium. Navigating the evolving and highly complex treatment landscape of HR + /HER2− mBC remains both an art and a challenge. In this review, we discuss the biological features of HR + /HER2− mBC and the different mechanisms of resistance to ET. We also discuss the management of mBC as the disease changes from endocrine-sensitive to endocrine-resistant. [ABSTRACT FROM AUTHOR]

Methadone maintenance treatment (MMT) remains the cornerstone for the management of opiate abuse. However, MMT can be associated with complex factors, including complications during the tolerance phase, the inability of some patients to maintain treatment effects during the tapering or abstinence phases, and the development of methadone dependence. Previous studies have revealed a sex disparity in MMT efficacy, showing that women undergoing MMT experiencing an increase in psychological symptoms compared with men and suggesting a link between disparate responses and the effects of estrogen signaling on methadone metabolism. More specifically, estradiol levels are positively associated with MMT dosing, and the expression of a single-nucleotide polymorphism (SNP) associated with estrogen receptor (ER) regulation is also associated with MMT dosing. In addition to performing mechanistic dissections of estrogen signaling in the presence of methadone, past studies have also proposed the targeting of estrogen signaling during MMT. The present report provides an overview of the relevant literature regarding sex effects, including differences in sex hormones and their potential impacts on MMT regimens. Moreover, this article provides a pharmacological perspective on the targeting of estrogen signals through the use of selective ER modulators (SERMs) during MMT. Preliminary preclinical experiments were also performed to evaluate the potential effects of targeting estrogen signaling with tamoxifen on methadone metabolism.

Efforts to improve estrogen receptor-a (ER)-targeted therapies in breast cancer have relied upon a single mechanism, with ligands having a single side chain on the ligand core that extends outward to determine antagonism of breast cancer growth. Here, we describe inhibitors with two ER-targeting moieties, one of which uses an alternate structural mechanism to generate full antagonism, freeing the side chain to independently determine other critical properties of the ligands. By combining two molecular targeting approaches into a single ER ligand, we have generated antiestrogens that function through new mechanisms and structural paradigms to achieve antagonism. These dual-mechanism ER inhibitors (DMERIs) cause alternate, noncanonical structural perturbations of the receptor ligand-binding domain (LBD) to antagonize proliferation in ERpositive breast cancer cells and in allele-specific resistance models. Our structural analyses with DMERIs highlight marked differences from current standard-of-care, single-mechanism antiestrogens. These findings uncover an enhanced flexibility of the ER LBD through which it can access nonconsensus conformational modes in response to DMERI binding, broadly and effectively suppressing ER activity. [ABSTRACT FROM AUTHOR]

In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to the backbone of therapy, estrogen deprivation by aromatase inhibition. How these mutations affect tumor sensitivity to established and novel therapies are active areas of research. These therapies include estrogen receptor-targeting agents, such as selective estrogen receptor modulators, covalent antagonists, and degraders (including tamoxifen, fulvestrant, and novel agents), and combination therapies, such as endocrine therapy plus CDK4/6, PI3K, or mTORC1 inhibition. In this review, we summarize existing knowledge surrounding the mechanisms of action of ESR1 mutations and roles in resistance to aromatase inhibition. We then analyze the recent literature on how ESR1 mutations affect outcomes in estrogen receptor-targeting and combination therapies. For estrogen receptor-targeting therapies such as tamoxifen and fulvestrant, ESR1 mutations cause relative resistance in vitro but do not clearly lead to resistance in patients, making novel agents in this category promising. Regarding combination therapies, ESR1 mutations nullify any aromatase inhibitor component of the combination. Thus, combinations using endocrine alternatives to aromatase inhibition, or combinations where the non-endocrine component is efficacious as monotherapy, are still effective against ESR1 mutations. These results emphasize the importance of investigating combinatorial resistance, challenging as these efforts are. We also discuss future directions and open questions, such as studying the differences among distinct ESR1 mutations, asking how to adjust clinical decisions based on molecular surveillance testing, and developing novel therapies that are effective against ESR1 mutations. [ABSTRACT FROM AUTHOR]

Methadone maintenance treatment (MMT) remains the cornerstone for the management of opiate abuse. However, MMT can be associated with complex factors, including complications during the tolerance phase, the inability of some patients to maintain treatment effects during the tapering or abstinence phases, and the development of methadone dependence. Previous studies have revealed a sex disparity in MMT efficacy, showing that women undergoing MMT experiencing an increase in psychological symptoms compared with men and suggesting a link between disparate responses and the effects of estrogen signaling on methadone metabolism. More specifically, estradiol levels are positively associated with MMT dosing, and the expression of a single-nucleotide polymorphism (SNP) associated with estrogen receptor (ER) regulation is also associated with MMT dosing. In addition to performing mechanistic dissections of estrogen signaling in the presence of methadone, past studies have also proposed the targeting of estrogen signaling during MMT. The present report provides an overview of the relevant literature regarding sex effects, including differences in sex hormones and their potential impacts on MMT regimens. Moreover, this article provides a pharmacological perspective on the targeting of estrogen signals through the use of selective ER modulators (SERMs) during MMT. Preliminary preclinical experiments were also performed to evaluate the potential effects of targeting estrogen signaling with tamoxifen on methadone metabolism. [ABSTRACT FROM AUTHOR]

Objective: Breast cancer treatments bring adverse consequences that interfere with everyday functioning. Importantly, some of these treatments are associated with cognitive and language changes. Tamoxifen is a selective estrogen receptor modulator and is a common endocrine therapy treatment for breast cancer. The current review examines the specific domains of cognition and language affected by the use of tamoxifen in women with breast cancer.Methods: We conducted a systematic search that examined cognitive and/or language functions in chemotherapy-naïve women with breast cancer taking tamoxifen. PubMed, Cochrane CENTRAL, CINAHL Complete, PsycINFO, Scopus, EMBASE, and the Grey Literature Report (greylit.org) were searched. Covidence Systematic Review software (covidence.org) was used to manage the screening process of study titles and abstracts as well as full texts. A total of 17 studies were included in the review.Results: A range of cognitive and language domains were reported. These were grouped into seven broad domains: attention, memory, speed, executive functioning, verbal abilities, visual abilities, and language abilities. Results showed that there is compelling evidence that specific domains of memory and speed are negatively affected by the use of tamoxifen. In addition, there was a pattern of change in domains of executive functions and verbal abilities.Conclusions: Tamoxifen affects specific cognitive and language domains. Language domains beyond semantics have not been studied and thus conclusions related to these domains, and language in general, could not be made. Studies exploring the effects of tamoxifen on the different domains of language are recommended. [ABSTRACT FROM AUTHOR]

The aim of the study was to develop and characterise raloxifene (RL-HCL)-loaded soy lecithin-chitosan (CS) nanoparticles (NPs) for the treatment of a commom bone disease osteoporosis. Raloxifene HCl is a poorly water soluble drug with poor bioavailability. Enhancement of the oral bioavailability of this drug was also the aim of our study. Biodegradable natural polymer chitosan and an anionic lipid soy lecithin were used to prepare raloxifene HCl-loaded hybrid nanoparticles for the efficient delivery of lipophilic drug raloxifene - HCl. The hybrid NPs were prepared by modified ionic interaction method and evaluated for particle size, zeta potential (ZP), entrapment efficiency and release kinetics study. The results indicated the NPs with the value of ZP to be +22.3 mV, particle sizes were in the range of 140-380 nm and the entrapment efficiency was 70.39%. The optimised formulation was prepared with CS: Soy lecithin ratio of 1:4 w/w and a stirring speed of 1500 rpm. The release study of drug for 45 h with 88.58% cumulative drug release and the optimised formulation showed the promising results of Ral-loaded SL-CS NPs. [ABSTRACT FROM AUTHOR]

Estrogen receptor (ER) is a major transcriptional regulator that plays an important role in the treatment of breast cancer. Herein, we rationally designed and synthesized a novel small-molecule near-infrared (NIR) fluorescent probe, 2-(4-(2-(2,5-bis(2-fluoro-4-hydroxyphenyl)thiophen-3-yl)vinyl)− 3-cyano-5,5-dimethylfuran-2(5 H)ylidene)malononitrile (TCFT) , which could enable prolonged live-cell imaging by three-dimensional (3D) confocal microscopy. Moreover, this bifunctional probe also exhibited photostability, selective estrogen receptor modulator activity, and potent antiproliferative activity for targeted breast cancer therapy, which would be a prominent NIR fluorescent probe for breast cancer study. [Display omitted] • A novel photostable NIR fluorescent probe TCFT was developed for estrogen receptor. • TCFT was successfully applied in prolong live-cell imaging of estrogen receptor by 3D confocal microscopy. • TCFT exhibited selective estrogen receptor modulator activity and potent antiproliferative activity for breast cancer therapy. • TCFT possessed the potential as a theranostic probe for estrogen receptor (+) breast cancer study. [ABSTRACT FROM AUTHOR]

Purpose: Currently, the exact role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we showed that expression of phosphorylated ERβ correlates with a poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Here, we hypothesized that raloxifene, a FDA-approved selective ER modulator (SERM), may suppress PDAC tumor growth by interfering with ERβ signaling. To test this hypothesis, we studied the impact of raloxifene on interleukin-6/glycoprotein-130/signal transducer and activator of transcription-3 (IL-6/gp130/STAT3) signaling. Methods: Human PDAC cell lines were exposed to raloxifene after which growth inhibition was assessed using a BrdU assay. ER knockdown was performed using siRNAs specific for ERα and ERβ. The effects of raloxifene on IL-6 expression and STAT3 phosphorylation in PDAC cells were assessed by ELISA and Western blotting, respectively. In addition, raloxifene was administered to an orthotopic PDAC tumor xenograft mouse model, after which tumor growth was monitored and immunohistochemistry was performed. Results: Raloxifene inhibited the in vitro growth of PDAC cells, and this effect was reversed by siRNA-mediated knockdown of ERβ, but not of ERα, indicating ER isotype-specific signaling. We also found that treatment with raloxifene inhibited the release of IL-6 and suppressed the phosphorylation of STAT3Y705 in PDAC cells. In vivo, we found that orthotopic PDAC tumor growth, lymph node and liver metastases as well as Ki-67 expression were reduced in mice treated with raloxifene. Conclusions: Inhibition of ERβ and the IL-6/gp130/STAT3 signaling pathway by raloxifene leads to potent reduction of PDAC growth in vitro and in vivo. Our results suggest that ERβ signaling and IL-6/gp130 interaction may serve as promising drug targets for pancreatic cancer and that raloxifene may serve as an attractive therapeutic option for PDAC patients expressing the ERβ isotype. [ABSTRACT FROM AUTHOR]

The actions of selective estrogen receptor modulators are tissue dependent. The primary objective of the current study was to determine the tis sue selective effects of bazedoxifene (BZA) on the musculoskeletal system of ovariectomized (OVX) female mice, focusing on the strengths of muscle-bone pairs in the lower hindlimb. Treatment with BZA after ovariectomy (OVX+BZA) did not prevent body or fat mass gains (P < 0.05). In vivo plantarflexor muscle isometric torque was not affected by treatment with BZA (P = 0.522). Soleus muscle peak isometric, concentric and eccentric tetanic force production were greater in OVX+BZA mice compared to OVX+E2 mice (P ≤ 0.048) with no effect on maximal isometric specific force (P = 0.228). Tibia from OVX+BZA mice had greater cortical crosssectional area and moment of inertia than OVX mice treated with placebo (P < 0.001), but there was no impact of BZA treatment on cortical bone mineral density, cortical thickness, tibial bone ultimate load or stiffness (P ≥ 0.086). Overall, these results indicate that BZA may be an estrogen receptor agonist in skeletal muscle, as it has previously been shown in bone, providing minor benefits to the musculoskeletal system. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused corona virus disease 2019 (COVID-19) pandemic and led to mass casualty. Even though much effort has been put into development of vaccine and treatment methods to combat COVID-19, no safe and efficient cure has been discovered. Drug repurposing or drug repositioning which is a process of investigating pre-existing drug candidates for novel applications outside their original medical indication can speed up the drug development process. Raloxifene is a selective estrogen receptor modulator (SERM) that has been approved by FDA in 1997 for treatment and prevention of postmenopausal osteoporosis and cancer. Recently, raloxifene demonstrates efficacy in treating viral infections by Ebola, influenza A, and hepatitis C viruses and shows potential for drug repurposing for the treatment of SARS-CoV-2 infection. This review will provide an overview of raloxifene's mechanism of action as a SERM and present proposed mechanisms of action in treatment of viral infections. [ABSTRACT FROM AUTHOR]

Several neurodegenerative disorders are characterized by proteasome dysfunctions leading to protein aggregations and pathogenesis. Since we showed that estrogen receptor alpha (ERα) activates the proteasome, drugs able to stimulate ERα in the central nervous system (CNS) could hold potential for therapeutic intervention. However, the transcriptional effects of selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, can be tissue specific. A direct comparison of the effects of different SERMs on gene transcription in the CNS has never been performed. Here, we report an RNA-seq analysis of the spinal cord treated with estrogen, tamoxifen, or raloxifene. We find stark SERM and sex-specific differences in gene expression profiles in the spinal cord. Notably, raloxifene, but not estrogen or tamoxifen, modulates numerous deubiquitinating enzymes, proteasome subunits and assembly factors, and these effects translate into decreased protein aggregates. In the SOD1-G93A mouse model of amyotrophic lateral sclerosis, we found that even a low dose of raloxifene causes a significant decrease in mutant SOD1 aggregates in the spinal cord, accompanied by a delay in the decline of muscle strength in females, but not in males. These results strongly indicate SERM-selective as well as sex-specific effects, and emphasize the importance of sex as a biological variable to be considered for the careful selection of specific SERM for use in clinical trials for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Following the discovery and approval of the oral contraceptive, the pharmaceutical industry sought new opportunities for the regulation of reproduction. The discovery of the first non-steroidal anti-oestrogen MER25, with antifertility properties in laboratory animals, started a search for 'morning-after pills'. There were multiple options in the 1960s, however, one compound ICI 46,474 was investigated, but found to induce ovulation in subfertile women. A second option was to treat sta ge IV breast cancer. Although the patent for ICI 46,474 was awarded in the early 196 0s in the UK and around the world, a patent in the USA was denied on the basis that the claims for breast cancer treatment were not supported by evidence. A trial at the Christ ie Hospital and Holt Radium Institute in Manchester, published in 1971, showed activity compared with alternatives: high-dose oestrogen or androgen treatment, but the US Patent Office was unswayed until 1985! The future of tamoxifen to be, was in the balance in 1972 but the project went forward as an orphan drug looking for applications and a translational research strategy was needed. Today, tamoxifen is known as the first targeted therapy in cancer with successful applications to treat all stages of b reast cancer, male breast cancer, and the first medicine for the reduction of breast cance r incidence in high-risk pre- and post-menopausal women. This is the unlikely story of h ow an orphan medicine changed medical practice around the world, with millions of women's lives extended. [ABSTRACT FROM AUTHOR]

Estrogen receptor alpha (ERα) is a ligand‐dependent transcription regulator, containing two transactivation functional domains, AF‐1 and AF‐2. The selective estrogen receptor modulators (SERMs), including 4‐hydroxytamoxifen (4OHT), activate AF‐1 preferentially rather than AF‐2. However, it is unclear whether this specific function is related to the tissue‐selective functionality of SERMs. Moreover, there is no information determining AF‐1–dependent estrogenic‐genes existing in tissues. We sought to identify AF‐1–dependent estrogenic‐genes using the AF‐2 mutated knock‐in (KI) mouse model, AF2ERKI. AF2ER is an AF‐2 disrupted estradiol (E2)‐insensitive mutant ERα, but AF‐1–dependent transcription can be activated by the estrogen‐antagonists, fulvestrant (ICI) and 4OHT. Gene profiling and ChIP‐Seq analysis identified Klk1b21 as an ICI‐inducible gene in AF2ERKI uterus. The regulatory activity was analyzed further using a cell‐based reporter assay. The 5′‐flanking 0.4k bp region of Klk1b21 gene responded as an ERα AF‐1–dependent estrogen‐responsive promoter. The 150 bp minimum ERα binding element (EBE) consists of three direct repeats. These three half‐site sequences were essential for the ERα‐dependent transactivation and were differentially recognized by E2 and 4OHT for the gene activation. This response was impaired when the minimum EBE was fused with a thymidine‐kinase promoter but could be restored by fusion with the 100 bp minimum transcription initiation element (TIE) of Klk1b21, suggesting that the cooperative function of EBE and TIE is essential for mediating AF‐1–dependent transactivation. These findings provide the first in vivo evidence that endogenous ERα AF‐1 dominant estrogenic‐genes exist in estrogen‐responsive organs. Such findings will aid in understanding the mechanism of ERα‐dependent tissue‐selective activity of SERMs. [ABSTRACT FROM AUTHOR]

Raloxifene (RAL) is an FDA-approved drug used to treat osteoporosis in postmenopausal women. RAL suppresses bone loss primarily through its role as a selective estrogen receptor modulator (SERM). This hormonal estrogen therapy promotes unintended side effects, such as hot flashes and increased thrombosis risk, and prevents the drug from being used in some patient populations at-risk for fracture, including children with bone disorders. It has recently been demonstrated that RAL can have significant positive effects on overall bone mechanical properties by binding to collagen and increasing bone tissue hydration in a cell-independent manner. A Raloxifene-Analog (RAL-A) was synthesized by replacing the 6-hydroxyl substituent with 6-methoxy in effort to reduce the compound's binding affinity for estrogen receptors (ER) while maintaining its collagen-binding ability. It was hypothesized that RAL-A would improve the mechanical integrity of bone in a manner similar to RAL, but with reduced estrogen receptor binding. Molecular assessment showed that while RAL-A did reduce ER binding, downstream ER signaling was not completely abolished. In-vitro, RAL-A performed similarly to RAL and had an identical concentration threshold on osteocyte cell proliferation, differentiation, and function. To assess treatment effect in-vivo, wildtype (WT) and heterozygous (OIM+/−) female mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL or RAL-A from 8 weeks to 16 weeks of age. There was an untreated control group for each genotype as well. Bone microarchitecture was assessed using microCT, and mechanical behavior was assessed using 3-point bending. Results indicate that both compounds produced analogous gains in tibial trabecular and cortical microarchitecture. While WT mechanical properties were not drastically altered with either treatment, OIM+/− mechanical properties were significantly enhanced, most notably, in post-yield properties including bone toughness. This proof-of-concept study shows promising results and warrants the exploration of additional analog iterations to further reduce ER binding and improve fracture resistance.

The increased availability of communication technologies has caused people to use the Internet to form their opinion on products and services more often. Company's reputation remains an important resource that can provide a competitive advantage, but the current information environment specificity forces us to rethink the approaches to reputation management. Сurrent specificity has conditioned by the threats concerning spontaneous information spread in the Internet, as well as the need to develop the methods of exploiting new information dissemination channels. Under these circumstances, a new competitive struggle principle has formed: «If you win in the In-ternet, you win in real life». To win, one just needs to possess the necessary technologies and to re-act to information environment changes in time. The article considers the problems of the online reputation management and the given ways of their solution.