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Background: This AMEERA-2 study evaluated the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy with dose escalation in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer., Methods: In this open-label, nonrandomized, phase I study, patients received amcenestrant 400 mg once daily (QD) (n = 7) and 300 mg twice daily (BID) (n = 3). The incidence of dose-limiting toxicities (DLT), recommended dose, maximum tolerated dose (MTD), pharmacokinetics, efficacy, and safety were assessed., Results: No DLTs were observed and MTD was not reached in the 400 mg QD group. One DLT (grade 3 maculopapular rash) was reported in a patient treated with 300 mg BID. After repeated oral administration of either dosing regimen, steady state reached before day 8, without accumulation. Four out of 5 response-evaluable patients from 400 mg QD group achieved clinical benefit and showed tumor shrinkage. No clinical benefit was reported in the 300 mg BID group. Overall, most patients (8/10) experienced a treatment-related adverse event (TRAE), with skin and subcutaneous tissue disorders most commonly reported (4/10 patients). No ≥ grade 3 TRAE in 400 mg QD group and 1 grade 3 TRAE in 300 mg BID group were reported., Conclusions: Amcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer., Trial Registration: Clinical trial registration NCT03816839., (© 2023. The Author(s).)

Despite the well documented increased risk of osteopenia in patients with breast cancer during chemotherapy and endocrine therapy, spontaneous cerebrospinal fluid rhinorrhea (CSFR) is still rare. The authors present a case of spontaneous CSFR that occurred during chemotherapy and endocrine therapy for breast cancer. The patient underwent a repair using myofascia and adipose tissue and was started on mannitol. There was no recurrence at 1-year follow-up. Therefore, clinicians should pay attention to the possibility of CSFR in patients with breast cancer, to avoid misdiagnosis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

The aim of the study was to compare 3 blood sampling methods, including capillary blood sampling, for determining Tamoxifen (TAM), Z-endoxifen (END), and 4-hydroxytamoxifen (4HT) concentrations. High performance liquid chromatography-mass spectrometry was used to quantify concentrations of TAM, END, and 4HT in plasma, venous blood, and capillary blood samples of 16 participants on TAM therapy for breast cancer. The rhelise kit was used for capillary sampling. Calibration curves using 13 C-labeled analogs of TAM, END, and 4HT as internal standards were used for quantifications. A capillary sampling kit was used successfully for all participants. Mean TAM concentrations did not differ significantly in the 3 types of samples. Mean END and 4HT concentrations did differ significantly between capillary and venous blood samples, possibly related to photodegradation in the internal standards prior to use or degradation products with chromatographic retention times similar to the metabolites. TAM, END, and 4HT concentrations were relatively stable when stored for 14 days at 8 °C and 20 °C. Therapeutic drug monitoring of TAM using an innovative kit and capillary blood sampling is feasible. Preliminary data from this study will aid in developing a multicenter, randomized clinical trial of personalized TAM dose monitoring and adjustments, with the goal of enhancing the quality-of-life and outcomes of patients with breast cancer.Clinical Trial Identification: EudraCT No 2017-000641-44., (© 2022. The Author(s).)

Breast Cancer (BC) is a leading cause of death in women, currently affecting 13% of female population worldwide. First-line clinical treatments against Estrogen Receptor positive (ER+) BC rely on suppressing estrogen production, by inhibiting the aromatase (AR) enzyme, or on blocking estrogen-dependent pro-oncogenic signaling, by targeting Estrogen Receptor (ER) α with selective Modulators/Degraders (SERMs/SERDs). The development of dual acting molecules targeting AR and ERα represents a tantalizing alternative strategy to fight ER + BC, reducing the incidence of adverse effects and resistance onset that limit the effectiveness of these gold-standard therapies. Here, in silico design, synthesis, biological evaluation and an atomic-level characterization of the binding and inhibition mechanism of twelve structurally related drug-candidates enable the discovery of multiple compounds active on both AR and ERα in the sub-μM range. The best drug-candidate 3a displayed a balanced low-nanomolar IC 50 towards the two targets, SERM activity and moderate selectivity towards a BC cell line. Moreover, most of the studied compounds reduced ERα levels, suggesting a potential SERD activity. This study dissects the key structural traits needed to obtain optimal dual acting drug-candidates, showing that multitarget compounds may be a viable therapeutic option to counteract ER + BC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Tamoxifen is an estrogen receptor (ER) antagonist that is most commonly used for the treatment of ER-positive breast cancer. However, tamoxifen resistance remains a major cause of cancer recurrence and progression. Here, we aimed to identify hub genes implicated in the progression and prognosis of ER-positive breast cancer following tamoxifen treatment. Microarray data (GSE9893) for 155 tamoxifen-treated primary ER-positive breast cancer samples were obtained from the Gene Expression Omnibus database. In total, 1706 differentially expressed genes (DEGs), including 859 up-regulated and 847 down-regulated genes, were identified between relapse and relapse-free samples. Weighted correlation network analysis clustered genes into 13 modules, among which the tan and blue modules were the most significantly related to prognosis. From these two modules, we further identified and validated two prognosis-related hub genes (G-rich RNA sequence binding factor 1 (GRSF1) and microtubule-associated protein τ (MAPT)) via survival analysis based on several publicly available datasets. High expression of GRSF1 predicted poor prognosis, whereas MAPT indicated favorable outcomes in ER-positive breast cancer. Using breast cancer cell lines and tissue samples, we confirmed that GRSF1 was significantly up-regulated and MAPT was down-regulated in the tamoxifen-resistant group compared with the tamoxifen-sensitive group. The prognostic value of GRSF1 and MAPT was also verified in 48 tamoxifen-treated ER-positive breast cancer patients in our hospital. Gene set enrichment analysis (GSEA) suggested that GRSF1 was potentially involved in RNA degradation and cell cycle pathways, while MAPT was strongly linked to immune-related signaling pathways. Taken together, our findings established novel prognostic biomarkers to predict tamoxifen sensitivity, which may facilitate individualized management of breast cancer., (© 2021 The Author(s).)

Apigenin, a flavonoid, is reported to act as an estrogen receptor (ER) agonist and inhibit aromatase enzyme. However, amentoflavone, a biflavonoid bearing two apigenin molecules, has not been evaluated for its endocrine modulatory effects. Besides, it is highly consumed by young people to build muscles, enhance mood and lose weight. In the present study, apigenin was used as a reference molecule and ER mediated as well as ER-independent estrogenic/antiestrogenic activity of amentoflavone was investigated. Antitumor activity of amentoflavone was also investigated in both ER positive (MCF-7 BUS) and triple-negative (MDA-MB-231) breast cancer cells and its cytotoxicity was evaluated in human breast epithelial cells (MCF-10A). Our data confirmed ER agonist, aromatase inhibitory and cytotoxic effects of apigenin in breast cancer cells, where no ER mediated estrogenic effect and physiologically irrelevant, slight, aromatase inhibition was found for amentoflavone. Although selective cytotoxicity of amentoflavone was found in MCF-7 BUS cells, it does not seem to be an alternative to the present cytotoxic drugs. Therefore, neither an adverse effect, mediated by an estrogenic/antiestrogenic effect of amentoflavone nor a therapeutical benefit would be expected from amentoflavone. Further studies could be performed to investigate its in vivo effects.

Background: Adjuvant endocrine therapy (AET) improves long-term survival of breast cancer patients, yet many women are nonadherent or discontinue this treatment. In this study we aimed to describe AET adherence trajectories over 5 years after treatment initiation and to identify factors associated with these trajectories, in a nationwide French cohort of breast cancer survivors., Patients and Methods: Every woman diagnosed with a first nonmetastatic breast cancer in 2011 in France who initiated AET in the 12 months after surgery was included from the French cancer cohort. We identified all reimbursements for AET from national health administrative data sets and modeled AET adherence trajectories over 5 years, using group-based trajectory modeling on the basis of the monthly proportion of days covered by AET. Associated factors were identified using multinomial logistic regressions., Results: We included 33,260 women. A 6-trajectory model was selected: 1, immediate discontinuation (6.6%); 2, continuous suboptimal adherence (4.3%); 3, progressive nonadherence then discontinuation (6.3%); 4, early nonadherence then discontinuation (5.7%); 5, continuous optimal adherence (68.8%); and 6, late nonadherence then discontinuation (8.3%). The main factors associated with nonadherence trajectories were extreme age (younger than 50 and older than 70 years) and switching AET., Conclusion: Approximately 70% of women had optimal adherence over all 5 years. The original nationwide approach enabled us to identify the "continuous suboptimal adherence trajectory" never previously described., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Neoadjuvant endocrine therapy (NAET) is used in the management of oestrogen receptor (ER)-positive breast cancer. The optimal method for histological assessment of response and the effect of NAET on the tumour morphology, grade and molecular profile remain unclear. The aim of this study is to investigate the NAET effect on tumour type, grade and molecular profile by analysing a well-characterised cohort of breast cancer samples in a single large UK tertiary referral centre, and to provide guidance on the pathological assessment of those lesions to inform adjuvant management and prognosis., Methods and Results: A single large-institution cohort of 132 patients who received NAET over a 13-year period was identified. Comprehensive clinical, histopathological and follow-up data were collected. A detailed histological review of a subset with residual post-treatment carcinoma was undertaken. Two carcinomas (both of the lobular type) achieved complete pathological response. Central scarring was seen in 49.3% of tumours post-treatment. Significant changes in tumour type (41.6%), tumour grade (downgrading in one-third of tumours), and progesterone receptor (PR) expression (22.3%), with a switch to PR-negative status in 17.6% of cases, were observed. The last of these was associated with an absence of tumour-infiltrating lymphocytes (P = 0.005). Ten per cent of cases showed a change in HER2 expression (P = 0.002). The median patient survival was 60 months, and downgrading of tumours was associated with better overall survival (P = 0.05)., Conclusions: We propose a histological method for assessment of residual carcinoma following NAET, and recommend repeat ER/PR/HER2 testing to inform management and prognosis., (© 2021 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Background: The root of Rehmannia glutinosa (R. glutinosa) is commonly used in various traditional Chinese herbal formulae to ameliorate nephropathy; however, little is known about its active component(s) and mechanisms., Aim: In the present study, we examined the protective effect and potential mechanism of rehmapicrogenin, a monomeric compound extracted from R. glutinosa, against Adriamycin (ADR)-induced nephropathy (AN) in vivo and in vitro., Methods: In this study, an ADR-induced kidney injury model was employed to investigate the nephroprotective effects of rehmapicrogenin in mice. In vivo, ELISA kits, flow cytometry, haematoxylin-eosin staining, immunofluorescence techniques, and western blotting were used to evaluate the effect of rehmapicrogenin on kidney injury in mice. In vitro, the effects of rehmapicrogenin on NRK-52E cellular damage induced by ADR were determined using the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The mechanism was investigated using ELISA kits, flow cytometry and In-Cell Western™ blotting., Results: In vivo, rehmapicrogenin treatment significantly attenuated the pathological changes in the kidney induced by ADR; rescued weight, serum creatinine (Scr), blood urea nitrogen (BUN) and urine albumin (U-ALB) levels; reduced reactive oxygen species (ROS) accumulation; and decreased oxidative stress, the apoptosis rate, and cell survival in ADR-treated mice. Importantly, both in vivo and in vitro experimental results demonstrated that rehmapicrogenin regulates the Nrf2/ARE signalling pathway, the most important pathway for oxidative stress. Rehmapicrogenin attenuated ADR-induced kidney damage by reducing oxidative stress through the oestrogen receptor pathway. Moreover, after treatment with ICI 182780 (the oestrogen receptor-nonspecific antagonist Faslodex), the improvement induced by rehmapicrogenin was significantly reversed., Conclusions: In conclusion, rehmapicrogenin attenuates kidney damage by reducing inflammatory factor release through the oestrogen signalling pathway., (Copyright © 2021. Published by Elsevier Masson SAS.)

Aromatase and steroidal sulfatase (STS) are steroidogenic enzyme that increases the concentration of estrogens in circulation, a primary factor leading to breast cancer. At molecular level, 87% of STS is expressed and an inhibitor targeting STS could decrease the level of estrogens. In an attempt to identify the chemical structural requirement targeting placental STS inhibition, 26 compounds with pIC 50 ranging from 4.61 to 9.46 were subjected to computational studies including Quantitative Structural-Activity Relationship (QSAR), MolecularDocking followed by Density Functional Theory (DFT) studies. A robust and predictable model were developed with good R 2 (0.834) and cross-validated correlation coefficient value Q 2 LOO (0.786) explaining the relationship quantitatively. The regression graphs suggests that the STS inhibition was greatly dependent on the electro topological state of an atom, sum of the atom type E-state (SdssC), maximum E-states for strong hydrogen bond acceptors (maxHBa) and basic group count descriptor (BCUTp-1h). Furthermore, docking results showed favorable interactions of sulfamate analogs with catalytically important amino acid residues such as LEU74, VAL101, and VAL486. The interactions of the best active compound 3j when compared with standard Irosustat show similar binding energies. DFT studies further confirm the presence of HOMO orbital centered on chromenone ring further highlighting its importance for receptor ligand hydrophobic interaction. The study reveals that substitution of thio in chromenone nucleus and introduction of adamantyl substitution at second position are favorable in inhibiting the enzyme STS.

There is robust evidence that the appropriate treatment of dyslipidaemia substantially reduces cardiovascular disease-related morbidity and mortality. Raloxifene is a selective oestrogen receptor modulator that also interferes with the lipid metabolism and may be of aid in the management of lipid abnormalities in females. Therefore, we conducted a systematic review and meta-analysis of the available randomized clinical trials (RCTs) exploring the effect of raloxifene on the lipid profile in women. The Scopus, Web of Science, PubMed/Medline and EMBASE databases were systematically and independently searched by two assessors from inception until 20 November 2020 without time and language restrictions. The overall findings were generated from 30 eligible RCTs. As compared to controls, raloxifene resulted in a significant elevation of the high-density lipoprotein-cholesterol (HDL-C) (WMD: 2.41 mg/dL, 95% CI: 0.84-3.97, P = 0.003) and a significant reduction of the total cholesterol (TC) (WMD:-14.84 mg/dL, 95% CI: -20.37 to -9.317, P = 0.000) and of the low-density lipoprotein-cholesterol (LDL-C) (WMD: -17 mg/dL, 95% CI: -25.77, -8.22, P = 0.000). In the stratified analysis, a significant decrease of serum triglycerides (TG) (WMD: -22.06 mg/dL) was achieved in the RCTs with a duration of ≤ 26 weeks (WMD -8.70 mg/dL) and with baseline TG concentrations of ≥ 130 mg/dL (WMD: -23.02 mg/dL). In conclusion, raloxifene treatment can increase HDL-C and lower LDL-C and TC. In terms of TG, a significant decrease can be observed if the administration of raloxifene lasts ≤ 26 weeks and if the baseline TG concentrations are ≥ 130 mg/dL., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To evaluate outcomes including libido, semen parameters, testosterone, estradiol (E2), follicle stimulating hormone (FSH), and luteinizing hormone when converting men with low libido on Clomiphene Citrate (CC) to Natesto., Methods: A retrospective chart review was performed. Baseline hormones prior to treatment, and again on CC and Natesto, as well as semen parameters on CC and on Natesto were assessed., Results: In 41 men, there was no difference in serum testosterone levels on CC vs Natesto, however; there was a significantly higher E2 on CC than on Natesto. Although FSH levels were significantly lower on Natesto than at baseline, the mean FSH level on Natesto remained in the normal reference range. There was no difference in luteinizing hormone levels at baseline vs on Natesto. There was not a significant difference in semen parameter values when men were on CC vs when they were on Natesto for 3 months. At 3 months after changing to Natesto, 38 of 41 (92.7%) men reported significantly improved libido on Natesto when compared to CC., Conclusion: Men on CC and Natesto reach eugonadal testosterone levels, however; on CC the E2 level nearly doubled from baseline, and converting men from CC to Natesto returned E2 to nearly baseline levels. There was not a detrimental effect on semen parameters, and there was subjective reporting of improved libido after converting from CC to Natesto in this cohort, but further long-term studies are needed prior to Natesto being established as a definitive treatment for hypogonadism for men desiring to maintain fertility., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Translational Relevance: No prophylactic treatments for COVID-19 have been clearly proven and found. In this pandemic context, cancer patients constitute a particularly fragile population that would benefit the best from such treatments, a present unmet need. TMPRSS2 is essential for COVID-19 replication cycle and it is under androgen control. Estrogen and androgen receptor dependent cues converge on TMPRSS2 regulation through different mechanisms of action that can be blocked by the use of hormonal therapies. We believe that there is enough body of evidence to foresee a prophylactic use of hormonal therapies against COVID-19 and this hypothesis can be easily tested on cohorts of breast and prostate cancer patients who follow those regimens. In case of pandemic, if the protective effect of hormonal therapies will be proven on cancer patients, the use of specific hormonal therapies could be extended to other oncological groups and to healthy individuals to decrease the overall risk of infection by SARS-CoV-2., Given the COVID-19 coronavirus emergency, a special focus is needed on the impact of this rapidly spreading viral infection on cancer patients. Androgen receptor (AR) signaling in the transmembrane protease serine 2 (TMPRSS2) regulation is emerging as an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility. In our study, we analyzed AR and TMPRSS2 expression in 17,352 normal and 9,556 cancer tissues from public repositories and stratified data according to sex and age. The emerging picture is that some patient groups may be particularly susceptible to SARS-CoV-2 infection and may benefit from antiandrogen- or tamoxifen-based therapies. These findings are relevant to choose proper treatments in order to protect cancer patients from concomitant SARS-CoV-2 contagion and related symptoms and put forward the idea that hormonal therapies could be used as prophylactic agents against COVID-19.

Background: Endometriosis is a common gynaecological condition affecting 10% to 15% of reproductive-age women and may cause dyspareunia, dysmenorrhoea, and infertility. One treatment strategy is combining surgery and medical therapy to reduce the recurrence of endometriosis. Though the combination of surgery and medical therapy appears to be beneficial, there is a lack of clarity about the appropriate timing of when medical therapy should be used in relation with surgery, that is, before, after, or both before and after surgery, to maximize treatment response., Objectives: To determine the effectiveness of medical therapies for hormonal suppression before, after, or both before and after surgery for endometriosis for improving painful symptoms, reducing disease recurrence, and increasing pregnancy rates., Search Methods: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in November 2019 together with reference checking and contact with study authors and experts in the field to identify additional studies., Selection Criteria: We included randomized controlled trials (RCTs) which compared medical therapies for hormonal suppression before, after, or before and after, therapeutic surgery for endometriosis., Data Collection and Analysis: Two review authors independently extracted data and assessed risk of bias. Where possible, we combined data using risk ratio (RR), standardized mean difference or mean difference (MD) and 95% confidence intervals (CI). Primary outcomes were: painful symptoms of endometriosis as measured by a visual analogue scale (VAS) of pain, other validated scales or dichotomous outcomes; and recurrence of disease as evidenced by EEC (Endoscopic Endometriosis Classification), rAFS (revised American Fertility Society), or rASRM (revised American Society for Reproductive Medicine) scores at second-look laparoscopy., Main Results: We included 26 trials with 3457 women with endometriosis. We used the term "surgery alone" to refer to placebo or no medical therapy. Presurgical medical therapy compared with placebo or no medical therapy Compared to surgery alone, we are uncertain if presurgical medical hormonal suppression reduces pain recurrence at 12 months or less (dichotomous) (RR 1.10, 95% CI 0.72 to 1.66; 1 RCT, n = 262; very low-quality evidence) or whether it reduces disease recurrence at 12 months - total (AFS score) (MD -9.6, 95% CI -11.42 to -7.78; 1 RCT, n = 80; very low-quality evidence). We are uncertain if presurgical medical hormonal suppression decreases disease recurrence at 12 months or less (EEC stage) compared to surgery alone (RR 0.88, 95% CI 0.78 to 1.00; 1 RCT, n = 262; very low-quality evidence). We are uncertain if presurgical medical hormonal suppression improves pregnancy rates compared to surgery alone (RR 1.16, 95% CI 0.99 to 1.36; 1 RCT, n = 262; very low-quality evidence). No trials reported pelvic pain at 12 months or less (continuous) or disease recurrence at 12 months or less. Postsurgical medical therapy compared with placebo or no medical therapy We are uncertain about the improvement observed in pelvic pain at 12 months or less (continuous) between postsurgical medical hormonal suppression and surgery alone (MD -0.48, 95% CI -0.64 to -0.31; 4 RCTs, n = 419; I 2 = 94%; very low-quality evidence). We are uncertain if there is a difference in pain recurrence at 12 months or less (dichotomous) between postsurgical medical hormonal suppression and surgery alone (RR 0.85, 95% CI 0.65 to 1.12; 5 RCTs, n = 634; I 2 = 20%; low-quality evidence). We are uncertain if postsurgical medical hormonal suppression improves disease recurrence at 12 months - total (AFS score) compared to surgery alone (MD -2.29, 95% CI -4.01 to -0.57; 1 RCT, n = 51; very low-quality evidence). Disease recurrence at 12 months or less may be reduced with postsurgical medical hormonal suppression compared to surgery alone (RR 0.30, 95% CI 0.17 to 0.54; 4 RCTs, n = 433; I 2 = 58%; low-quality evidence). We are uncertain about the reduction observed in disease recurrence at 12 months or less (EEC stage) between postsurgical medical hormonal suppression and surgery alone (RR 0.80, 95% CI 0.70 to 0.91; 1 RCT, n = 285; very low-quality evidence). Pregnancy rate is probably increased with postsurgical medical hormonal suppression compared to surgery alone (RR 1.22, 95% CI 1.06 to 1.39; 11 RCTs, n = 932; I 2 = 24%; moderate-quality evidence). Pre- and postsurgical medical therapy compared with surgery alone or surgery and placebo There were no trials identified in the search for this comparison. Presurgical medical therapy compared with postsurgical medical therapy We are uncertain about the difference in pain recurrence at 12 months or less (dichotomous) between postsurgical and presurgical medical hormonal suppression therapy (RR 1.40, 95% CI 0.95 to 2.07; 2 RCTs, n = 326; I 2 = 2%; low-quality evidence). We are uncertain about the difference in disease recurrence at 12 months or less (EEC stage) between postsurgical and presurgical medical hormonal suppression therapy (RR 1.10, 95% CI 0.95 to 1.28; 1 RCT, n = 273; very low-quality evidence). We are uncertain about the difference in pregnancy rate between postsurgical and presurgical medical hormonal suppression therapy (RR 1.05, 95% CI 0.91 to 1.21; 1 RCT, n = 273; very low-quality evidence). No trials reported pelvic pain at 12 months or less (continuous), disease recurrence at 12 months - total (AFS score) or disease recurrence at 12 months or less (dichotomous). Postsurgical medical therapy compared with pre- and postsurgical medical therapy There were no trials identified in the search for this comparison. Serious adverse effects for medical therapies reviewed There was insufficient evidence to reach a conclusion regarding serious adverse effects, as no studies reported data suitable for analysis., Authors' Conclusions: Our results indicate that the data about the efficacy of medical therapy for endometriosis are inconclusive, related to the timing of hormonal suppression therapy relative to surgery for endometriosis. In our various comparisons of the timing of hormonal suppression therapy, women who receive postsurgical medical therapy compared with no medical therapy or placebo may experience benefit in terms of disease recurrence and pregnancy. There is insufficient evidence regarding hormonal suppression therapy at other time points in relation to surgery for women with endometriosis., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Glioblastoma (GBM) is the most common primary malignant brain tumor, and it has a uniformly poor prognosis. Hypoxia is a feature of the GBM microenvironment, and previous work has shown that cancer cells residing in hypoxic regions resist treatment. Hypoxia can trigger the formation of stress granules (SGs), sites of mRNA triage that promote cell survival. A screen of 1120 FDA-approved drugs identified 129 candidates that delayed the dissolution of hypoxia-induced SGs following a return to normoxia. Amongst these candidates, the selective estrogen receptor modulator (SERM) raloxifene delayed SG dissolution in a dose-dependent manner. SG dissolution typically occurs by 15 min post-hypoxia, however pre-treatment of immortalized U251 and U3024 primary GBM cells with raloxifene prevented SG dissolution for up to 2 h. During this raloxifene-induced delay in SG dissolution, translational silencing was sustained, eIF2α remained phosphorylated and mTOR remained inactive. Despite its well-described role as a SERM, raloxifene-mediated delay in SG dissolution was unaffected by co-administration of β-estradiol, nor did β-estradiol alone have any effect on SGs. Importantly, the combination of raloxifene and hypoxia resulted in increased numbers of late apoptotic/necrotic cells. Raloxifene and hypoxia also demonstrated a block in late autophagy similar to the known autophagy inhibitor chloroquine (CQ). Genetic disruption of the SG-nucleating proteins G3BP1 and G3BP2 revealed that G3BP1 is required to sustain the raloxifene-mediated delay in SG dissolution. Together, these findings indicate that modulating the stress response can be used to exploit the hypoxic niche of GBM tumors, causing cell death by disrupting pro-survival stress responses and control of protein synthesis.

Aims: We have previously reported that Centchroman (CC), an oral contraceptive drug, inhibits breast cancer progression and metastasis. In this study, we investigated whether CC inhibits local invasion of tumor cells and/or their metastatic colonization with detailed underlying mechanisms., Main Methods: The effect of CC on the experimental metastasis and spontaneous metastasis was demonstrated by using tail-vein and orthotopic 4T1-syngeneic mouse tumor models, respectively. The anti-angiogenic potential of CC was evaluated using well established in vitro and in vivo models. The role of RAC1/PAK1/β-catenin signaling axis in the metastasis was investigated and validated using siRNA-mediated knockdown of PAK1 as well as by pharmacological PAK1-inhibitor., Key Findings: The oral administration of CC significantly suppressed the formation of metastatic lung nodules in the 4T1-syngeneic orthotopic as well as experimental metastatic models. More importantly, CC treatment suppressed the tube formation and migration capacities of human umbilical vein endothelial cells (HUVEC) and inhibited pre-existing vasculature as well as the formation of neovasculature. The suppression of migration and invasion capacities of metastatic breast cancer cells upon CC treatment was associated with the inhibition of small GTPases (Rac1 and Cdc42) concomitant with the downregulation of PAK1 and downstream β-catenin signaling. In addition, CC upregulated the expression of miR-145, which is known to target PAK1., Significance: This study warrants the repurposing of CC as a potential therapeutic agent against metastatic breast cancer., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Autoimmune progesterone dermatitis (APD) is a rare cutaneous disorder with cyclic skin eruptions during the luteal phase of the menstrual cycle. Patients can present with various clinical manifestations, including urticaria and angioedema, erythema multiforme, eczema, fixed drug eruption and centrifugal erythema annulare. In our case, however, the patient's skin lesions mimic necrotic migratory erythema (NME) which is most commonly associated with glucagonoma and rarely with liver disease, inflammatory bowel disease, malnutrition and other tumors. To our knowledge, this is the first case of NME-like APD and is successfully controlled by danazol. This also sheds lights on the etiologic diversity of NME., (© 2019 Japanese Dermatological Association.)

Background: The relationship between anti-estrogen drugs and macular telangiectasia type 2 (MacTel-2) remains unknown. Here we report a case with anti-estrogen maculopathy resembling MacTel-2 with improved visual function and macular morphology following cessation of anti-estrogen drugs., Case Presentation: A 53-year-old woman presented with a 5-month history of central vision loss and anorthopia in both eyes. She had received oral tamoxifen followed by toremifene for 69 months. Funduscopy, fluorescein angiography, and optical coherence tomography (OCT) revealed MacTel-2-like findings OU. Fundus autofluorescence (FAF) showed hyper-autofluorescence at the fovea OU. Visual acuity, macular morphology on OCT, and FAF findings gradually improved after cessation of anti-estrogen drugs., Conclusions: In the present case, visual acuity, macular morphology, and impairment of the retinal pigment epithelium (RPE) improved following cessation of anti-estrogen drugs, suggesting the relationship between retinal toxicity of anti-estrogen drugs and the development of MacTel-2-like findings. From these results and the previous observations, toxicity of both photoreceptor and RPE cells caused by anti-estrogen drugs may contribute to the development of anti-estrogen maculopathy similar to MacTel-2.

Accumulating evidence suggests that Specificity Protein 1 (SP1) and 4 (SP4) transcription factors are involved in the pathophysiology of schizophrenia. The therapeutic use of selective oestrogen modulators such as raloxifene added to antipsychotic drugs in the treatment of postmenopausal women with schizophrenia has been investigated in a few clinical trials, which reported an improvement in negative, positive, and general psychopathological symptoms. We aimed to investigate the possible association between peripheral SP protein levels and symptom improvement in postmenopausal women with schizophrenia treated with adjuvant raloxifene. In a subgroup of 14 postmenopausal women with schizophrenia from a 24-week, randomized, parallel, double-blind, placebo-controlled clinical trial (NCT015736370), we investigated changes in SP1 and SP4 protein levels in peripheral blood mononuclear cells. Participants were randomized to either 60 mg/day adjunctive raloxifene or placebo. Psychopathological symptoms were assessed at baseline and at week 24 with the Positive and Negative Syndrome Scale (PANSS). The expression of SP proteins was evaluated by immunoblot, and changes in PANSS scores and protein levels were compared at baseline and after 24 weeks of treatment. An improvement in symptoms was observed in the intervention group, but not in placebo group. Post-treatment protein levels of SP4, but not SP1, correlated with improvements in general and total PANSS subscales in the raloxifene intervention group. A reduction in SP4 levels was found after raloxifene treatment. These results suggest that SP4 may be involved in raloxifene symptom improvement in postmenopausal women and could be a potential candidate for future studies investigating blood-based biomarkers for raloxifene effectiveness.

Tamoxifen and raloxifene have been approved for the primary prevention of breast cancer in high-risk women, but are associated with an increased risk of serious side effects. Few studies have characterized risk-benefit profiles for chemoprevention among women who initiate tamoxifen or raloxifene outside of a clinical trial setting. Use of raloxifene and tamoxifen for chemoprevention was self-reported in 2014 to 2016 by participants in The Sister Study, a prospective cohort of women with a sister who had been diagnosed with breast cancer. After exclusions, 432 current raloxifene users and 96 current tamoxifen users were matched to 4,307 and 953 nonusers, respectively, on age and year of cohort enrollment. Conditional logistic regression was used to evaluate characteristics associated with chemoprevention use. Risk-benefit profiles were examined using published indices that assess the level of evidence (none, moderate, strong) that the benefits of chemoprevention outweigh the risk of serious side effects. Among current chemoprevention users, 44% of tamoxifen users and 5% of raloxifene users had no evidence of a net benefit. In analyses of factors associated with chemoprevention use, having strong evidence of benefit was a significant predictor of raloxifene use, but not of tamoxifen use. In our sample of women with a first-degree family history of breast cancer, raloxifene was more commonly used for breast cancer prevention than tamoxifen. Most raloxifene users, but <60% of tamoxifen users, were likely to benefit. Use of risk-benefit tables can help women and their healthcare providers make an informed decision about breast cancer chemoprevention., (©2019 American Association for Cancer Research.)

Breast cancers (BCs) with expression of estrogen receptor-alpha (ERα) occur in more than 70% of newly-diagnosed patients in the U.S. Endocrine therapy with antiestrogens or aromatase inhibitors is an important intervention for BCs that express ERα, and it remains one of the most effective targeted treatment strategies. However, a substantial proportion of patients with localized disease, and essentially all patients with metastatic BC, become resistant to current endocrine therapies. ERα is present in most resistant BCs, and in many of these its activity continues to regulate BC growth. Fulvestrant represents one class of ERα antagonists termed selective ER downregulators (SERDs). Treatment with fulvestrant causes ERα down-regulation, an event that helps overcome several resistance mechanisms. Unfortunately, full antitumor efficacy of fulvestrant is limited by its poor bioavailability in clinic. We have designed and tested a new generation of steroid-like SERDs. Using ERα-positive BC cells in vitro, we find that these compounds suppress ERα protein levels with efficacy similar to fulvestrant. Moreover, these new SERDs markedly inhibit ERα-positive BC cell transcription and proliferation in vitro even in the presence of estradiol-17β. In vivo, the SERD termed JD128 significantly inhibited tumor growth in MCF-7 xenograft models in a dose-dependent manner (P < 0.001). Further, our findings indicate that these SERDs also interact with ER-positive immune cells in the tumor microenvironment such as myeloid-derived suppressor cells (MDSC), tumor infiltrating lymphocytes and other selected immune cell subpopulations. SERD-induced inhibition of MDSCs and concurrent actions on CD8+ and CD4 + T-cells promotes interaction of immune checkpoint inhibitors with BC cells in preclinical models, thereby leading to enhanced tumor killing even among highly aggressive BCs such as triple-negative BC that lack ERα expression. Since monotherapy with immune checkpoint inhibitors has not been effective for most BCs, combination therapies with SERDs that enhance immune recognition may increase immunotherapy responses in BC and improve patient survival. Hence, ERα antagonists that also promote ER downregulation may potentially benefit patients who are unresponsive to current endocrine therapies., (Copyright © 2019. Published by Elsevier Ltd.)

Objective: Previous research has shown that up to 50% of breast cancer survivors prescribed tamoxifen do not take it as recommended, which is associated with increased risk of recurrence and mortality. Little research has attempted to identify modifiable psychosocial factors associated with tamoxifen nonadherence. This study aimed to examine how tamoxifen adherence rates change over a year and to identify modifiable predictors of nonadherence., Method: Three hundred and forty-five breast cancer survivors who were in their first year of tamoxifen prescription were sent questionnaires at 4 points over a 12-month period. Questionnaires assessed demographic and clinical factors, side effects, beliefs about the illness and medication, social support, distress and tamoxifen adherence. Adherence was assessed using the Medication Adherence Rating Scale. Latent Growth Modeling was used to identify predictors of tamoxifen nonadherence., Results: Reported rates of nonadherence increased over time (37-48%). Several demographic, clinical, and psychosocial variables were associated with nonadherence. Women who were nonadherent were more likely to be from a minority ethnic group, to have more negative medication beliefs and to have lower confidence in their ability to take tamoxifen., Conclusions: These demographic and clinical variables can be used to identify women at higher risk of nonadherence. The modifiable psychosocial variables can be used as the basis for psychological interventions to improve adherence in this population. Interventions should focus on both intentional and unintentional nonadherence. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Endometriosis is an estrogen-dependent chronic inflammatory disease associated with pelvic pain symptoms that are often severe, mainly dysmenorrhea, nonmenstrual pelvic pain and dyspareunia. This condition is also associated with peripheral and central sensitization. The current medical treatment options for endometriosis-associated pain are limited. Recently, the US FDA approved the novel, oral, nonpeptide gonadotropin-releasing hormone antagonist elagolix for the management of moderate to severe endometriosis-associated pain. Elagolix produces dose-dependent estrogen suppression, from partial suppression at lower doses to nearly full suppression at higher doses. This review article summarizes the current understanding of the pathophysiology of endometriosis, with a focus on the role of estrogen and the mechanisms of pain symptoms, and reviews the clinical development of elagolix in women with endometriosis-associated pain.

Aim: The aim of the study is to analyse whether letrozole (L) and zoledronic acid plus L (ZL) are more effective than tamoxifen (T) as adjuvant endocrine treatment of premenopausal patients with breast cancer with hormone receptor-positive (HR+) tumours., Patients and Methods: In a phase 3 trial, 1065 premenopausal patients with HR + early breast cancer received triptorelin to suppress ovarian function and were randomly assigned (1:1:1) to adjuvant T, L or ZL for 5 years. Cancer recurrence, second breast or non-breast cancer and death were considered events for the intention-to-treat disease-free survival (DFS) analysis., Results: With a 64-month median follow-up and 134 reported events, the disease-free rate at 5 years was 85.4%, 93.2% and 93.3% with T, L and ZL, respectively (overall P = 0.008). The hazard ratio for a DFS event was 0.52 (95% confidence interval [CI], 0.34 to 0.80; P = 0.003) with ZL vs T, 0.72 (95% CI, 0.48 to 1.07; P = 0.06) with L vs T and 0.70 (95% CI, 0.44 to 1.12; P = 0.22) with ZL vs L. With 36 deaths, there was no significant difference in overall survival (P = 0.14). Treatment was stopped for toxicity or refusal in 7.3%, 7.3% and 16.6% patients, and in the safety population, grade 3-4 side-effects were reported in 4.2%, 6.9% and 9.1% patients treated with T, L or ZL, respectively., Conclusion: HOBOE study shows that in premenopausal patients with early breast cancer undergoing ovarian function suppression with triptorelin, ZL significantly improves DFS, while worsening compliance and toxicity, as compared with T. (NCT00412022)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Breast cancer, a most common malignancy in women, was known to be associated with steroid hormone estrogen. The discovery of estrogen receptor (ER) gave us not only a powerful predictive and prognostic marker, but also an efficient target for the treatment of hormone-dependent breast cancer with various estrogen ligands. ER consists of two subtypes i.e. ERα and ERβ, that are mostly G-protein-coupled receptors and activated by estrogen, specially 17β-estradiol. The activation is followed by translocation into the nucleus and binding with DNA to modulate activities of different genes. ERs can manage synthesis of RNA through genomic actions without directly binding to DNA. Receptors are tethered by protein-protein interactions to a transcription factor complex to communicate with DNA. Estrogens also exhibit nongenomic actions, a characteristic feature of steroid hormones, which are so rapid to be considered by the activation of RNA and translation. These are habitually related to stimulation of different protein kinase cascades. Majority of post-menopausal breast cancer is estrogen dependent, mostly potent biological estrogen (E2) for continuous growth and proliferation. Estrogen helps in regulating the differentiation and proliferation of normal breast epithelial cells. In this review we have investigated the important role of ER in development and progression of breast cancer, which is complicated by receptor's interaction with co-regulatory proteins, cross-talk with other signal transduction pathways and development of treatment strategies viz. selective estrogen receptor modulators (SERMs), selective estrogen receptor down regulators (SERDs), aromatase and sulphatase inhibitors., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Estrogen receptor (ER) is a nuclear hormone receptor and plays an important role in mediating the cellular effects of estrogen. ER can be classified into two receptors: estrogen receptor alpha (ERα) and beta (ERβ), and the former is expressed in 50~80% of breast tumors and has been extensively investigated in breast cancer for decades. Excessive exposure to estrogen can obviously stimulate the growth of breast cancers primarily mediated by ERα, and thus anti-estrogen therapies by small molecules are of concern to clinicians and pharmaceutical industry in the treatment of ERα-positive breast cancers. Although a series of estrogen receptor modulators have been developed, these drugs can lead to resistance and side effects. Therefore, the development of small molecule inhibitors with high target specificity has been intensified. In this pursuit, an integrated computer-aided virtual screening technique, including molecular docking and pharmacophore model screening, was used to screen traditional Chinese medicine (TCM) databases. The compounds with high docking scores and fit values were subjected to ADME (adsorption, distribution, metabolism, excretion) and toxicity prediction, and ten hits were identified as potential inhibitors targeting ERα. Molecular docking was used to investigate the binding modes between ERα and three most potent hits, and molecular dynamic simulations were chosen to explore the stability of these complexes. The rank of the predicted binding free energies evaluated by MM/GBSA is consistent with the docking score. These novel scaffolds discovered in the present study can be used as critical starting point in the drug discovery process for treating ERα-positive breast cancer. Graphical abstract .

Objective: To evaluate whether receipt of 17α-hydroxyprogesterone caproate within seven days of delivery is associated with increased risk of postpartum hemorrhage., Study Design: This was a retrospective cohort study of women who were receiving 17α-hydroxyprogesterone caproate for preterm birth prevention and delivered between 2010 and 2014. Women were dichotomized by whether a dose of 17α-hydroxyprogesterone caproate was administered within seven days of delivery. Demographic and clinical characteristics were examined, including obstetric history and details of 17α-hydroxyprogesterone caproate receipt. Bivariable analyses were used to compare the frequency of postpartum hemorrhage in women stratified by 17α-hydroxyprogesterone caproate receipt within seven days of delivery. Multivariable analysis was used to adjust for potential confounders., Results: Of 221 women who met inclusion criteria, 93 (42%) received 17α-hydroxyprogesterone caproate within seven days of delivery and 18 (7.8%) experienced a postpartum hemorrhage. No differences were observed in the frequency of postpartum hemorrhage between women who did and did not deliver within seven days of 17α-hydroxyprogesterone caproate injection (9.7% vs 7.0%, p=0.478). These findings persisted after adjusting for potential confounders (aOR for PPH 2.9, 95% CI, 0.5-15.8)., Conclusion: Recent receipt of 17α-hydroxyprogesterone caproate for prevention of recurrent preterm birth is not associated with risk of postpartum hemorrhage., Competing Interests: Disclosures: The authors report no conflict of interest.

Background: Based on estrogen active substances, many women consume soy foods in the belief that it could prevent breast cancer (BC). Women with different molecular subtypes would be likely to have diverse reactions to soy foods, especially those with the estrogen-receptor-positive (ER + ) subtype. The aim of the current study is to identify the differentially expressed genes (DEGs) on soy foods in premenopausal patients with Lumina A subtype of BC (LABC) after soy food treatment, and to further investigate the critical molecule change., Materials and Methods: GSE58792 retrieved from Gene Expression Omnibus was analyzed to obtain DEGs using GEO2R. Gene Ontology and pathway enrichment analysis were performed using FunRich and GeneMINIA. Overall survival of critical genes was performed by the Kaplan-Meier plotter online tool., Results: A total of 108 DEGs were obtained from the dataset, among which 35 were up-regulated and 73 down-regulated. Soy foods significantly reduced the expression of TFF3, TFF1, GATA3, and ESR1, which were related to the activity of the ER-related pathway and the sensitivity of tamoxifen. Furthermore, the lower expressions of TOX3, FSIP1, ESR1, and CLGN were related to prolonged survival time of patients with BC. The most significant signaling pathways were epithelial-to-mesenchymal transition in up-regulated DEGs, mesenchymal-to-epithelial transition, and mammary gland alveolus development in down-regulated DEGs, which were all related to the development and prognosis of BC., Conclusions: Soy foods could dramatically alter the ER-related gene profile in LABC. Particularly, down-regulated DEGs of TFF3, TFF1, GATA3, and ESR1 might weaken the sensitivity of tamoxifen and increase the efficacy of neoadjuvant chemotherapy in premenopausal patients with LABC., (Copyright © 2018. Published by Elsevier Inc.)

Two kinds of microglia are known, classical M1 and alternative M2 phenotypes. Amyloid β (Aβ), a critical cause of Alzheimer's disease (AD), promotes M1 microglial polarization, leading to neuroinflammation and neuronal death. M2 microglia play important roles in anti-inflammatory effects, Aβ clearance, and memory recovery in AD. Therefore, increasing of M2 microglia is expected to recover from AD. We previously found that naringenin, a blood-brain barrier penetrating compound, decreased Aβ deposits and recovers memory function in transgenic AD model mice. Naringenin reportedly showed anti-inflammatory properties. Here, we aim to investigate potential effects of naringenin on microglial polarization and to reveal the underlying mechanisms of Aβ reduction. Primary cultured cortical microglia were treated with Aβ 1-42 , following administration of naringenin. Naringenin remarkably promoted M2 microglia polarization and inhibited Aβ 1-42 -induced M1 microglia activation. Because microglia reportedly played a critical role in cerebral Aβ clearance through Aβ degradation enzymes after phagocytosis, we investigated the expression of Aβ degradation enzymes, such as neprilysin and insulin degradation enzyme. After naringenin treatment, these Aβ degradation enzymes were downregulated in M1 microglia and upregulated in M2 microglia. Taken together, our results showed that naringenin increased Aβ degradation enzymes in M2 microglia, probably leading to Aβ plaque reduction., (© 2019 John Wiley & Sons, Ltd.)

Purpose: Approximately 70-80% of breast cancers are hormone receptor-positive (HR+). OET, including tamoxifen and aromatase inhibitors, is considered standard adjuvant therapy for HR+ breast cancer. Despite demonstrated benefits, nearly half of patients are non-adherent and over two-thirds discontinue therapy before the recommended 5 years. Our objective was to identify and summarize literature-reported barriers associated with non-adherence/non-persistence to OET among breast cancer survivors., Methods: A PUBMED literature search was conducted using the following terms: 'breast cancer,' 'oral endocrine therapy' or 'Tamoxifen' or 'Aromatase Inhibitors,' 'adherence,' or 'barriers.' The search was restricted to past six years. The abstracts of each result were reviewed and categorized as either patient-reported or physician-reported. All patient- and physician-reported factors that affected adherence and persistence were listed and grouped together into the three main categories: Socio-demographic and medical parameters, general psychosocial parameters, and psychosocial parameters related to OET., Results: A total of 320 articles were identified, of which 19 met inclusion criteria. Adverse drug reactions were the most commonly reported barrier but were generally underreported among physicians. Among patient-reported barriers, common social-demographic and medical parameters were age, comorbidity, and financial status. General psychosocial variables were lack of patient-provider communication, depressive symptoms, and lack of perceived self-efficacy. Treatment toxicity was the most commonly reported psychosocial parameter related to OET., Conclusion: The determinants of non-adherence and non-persistence are multi-dimensional and influenced by several factors. The three categories of adherence barriers should be evaluated and considered when designing future interventions to enhance OET adherence for a tailored approach.

Objectives: We carried out a systematic review of the literature to evaluate the effect of centchroman on mastalgia as well as any side effects., Methods: The databases of the Cochrane Library, Medline (PubMed), Embase, ProQuest and ClinicalTrials.gov were systematically searched. The quality of randomised controlled clinical trials (RCTs) was assessed using the Cochrane Collaboration's tool for assessing risk of bias in randomised clinical trials. The quality of non-randomised clinical trials was assessed using the Cochrane risk of bias assessment tool for non-randomised studies of interventions (ROBINS-I). Owing to different outcomes reporting, a meta-analysis of the results was not possible., Results: Thirteen papers were included in the study. Of these, 12 showed a significant effect of centchroman in reducing breast pain at 3 months. One study that compared the effect of centchroman with that of tamoxifen reported a significant reduction in breast pain in both groups at 3 months; the difference between the two groups was not significant. Six studies showed the effectiveness of centchroman at 6 months. None of the papers reported any serious side effects of centchroman., Conclusions: Since a meta-analysis could not be conducted and the quality of the papers was low, there was insufficient evidence to evaluate the effect of centchroman on mastalgia. It is therefore recommended to conduct well-designed RCTs to compare the effect of centchroman on mastalgia with that of a placebo or other medication.

Endoplasmic reticulum (ER) stress and oxidative stress contribute greatly to myocardial ischemia-reperfusion (MI/R) injury. Naringenin, a flavonoid derived from the citrus genus, exerts cardioprotective effects. However, the effects of naringenin on ER stress as well as oxidative stress under MI/R condition and the detailed mechanisms remain poorly defined. This study investigated the protective effect of naringenin on MI/R-injured heart with a focus on cyclic guanosine monophosphate- (cGMP-) dependent protein kinase (PKG) signaling. Sprague-Dawley rats were treated with naringenin (50 mg/kg/d) and subjected to MI/R surgery with or without KT5823 (2 mg/kg, a selective inhibitor of PKG) cotreatment. Cellular experiment was conducted on H9c2 cardiomyoblasts subjected to simulated ischemia-reperfusion treatment. Before the treatment, the cells were incubated with naringenin (80  μ mol/L). PKGI α siRNA was employed to inhibit PKG signaling. Our in vivo and in vitro data showed that naringenin effectively improved heart function while it attenuated myocardial apoptosis and infarction. Furthermore, pretreatment with naringenin suppressed MI/R-induced oxidative stress as well as ER stress as evidenced by decreased superoxide generation, myocardial MDA level, gp91 phox expression, and phosphorylation of PERK, IRE1 α , and EIF2 α as well as reduced ATF6 and CHOP. Importantly, naringenin significantly activated myocardial cGMP-PKGI α signaling while inhibition of PKG signaling with KT5823 (in vivo) or siRNA (in vitro) not only abolished these actions but also blunted naringenin's inhibitory effects against oxidative stress and ER stress. In summary, our study demonstrates that naringenin treatment protects against MI/R injury by reducing oxidative stress and ER stress via cGMP-PKGI α signaling. Its cardioprotective effect deserves further clinical study.

Background: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare, potentially life-threatening disorder characterized by recurrent edematous attacks. The edema formation is the consequence of interaction of bradykinin and various vasoactive peptides with endothelium. Besides these agents, danazol, a modified testosterone derivative used in these patients to prevent edematous attacks, can also affect the function of the endothelium, because it shifts the blood lipid profile to a pro-atherogenic phenotype., Objective: To assess the endothelial function in C1-INH-HAE patients and in healthy matched controls., Methods: To evaluate the endothelial function, we used the flow-mediated dilation method measured in the region of the brachial artery in 33 C1-INH-HAE patients and in 30 healthy matched controls. Laboratory measurements of standard biochemical parameters were performed on computerized laboratory analyzers., Results: No difference was found in endothelial function (reactive hyperemia, RH) between patients (median, 9.0; 25%-75% percentile, 6.3-12.9) and controls (median, 7.37; 25%-75% percentile, 4.52-9.93). Although we found elevated cardiovascular risk (high body mass index and low-density lipoprotein/high-density lipoprotein ratio) in danazol-treated C1-INH-HAE patients, RH values did not differ between danazol-treated and nontreated patients. Furthermore, risk factors correlated with the endothelial function only in healthy controls and patients not treated with danazol., Conclusion: In summary, our results did not indicate any signs of endothelial dysfunction in C1-INH-HAE patients. Moreover, the normal endothelial function in danazol-treated patients with pro-atherogenic lipid profile suggests that elevated bradykinin level or other factor(s) involved in the pathogenesis of edematous attacks may have a protective role against endothelial dysfunction and atherosclerosis., (Copyright © 2018. Published by Elsevier Inc.)

In postmenopausal women, the risk of diabetic cardiovascular disease drastically increases compared with that of premenopausal women. In the present study we surveyed the effects of Tamoxifen (TAM) and 17-β-estradiol (E2) on diabetic cardiovascular dysfunction. Female wistar rats were divided into six groups: sham-control, Diabetes, Ovariectomized (OVX) + Diabetes, OVX + Diabetes + Vehicle, OVX + Diabetes + E2, OVX + Diabetes + TAM. Type 2 diabetes was induced by High Fat Diet and low doses of STZ. E2 and TAM were administrated every four days for four weeks. Results show that, TAM or E2 reduces cardiac weight, atherogenic and cardiac risk indices. Mean arterial blood pressure (MABP) increased in diabetes group, while TAM and E2 prevented MABP increment. Also, fasting blood glucose was decreased by TAM and E2. Significant decrement in the level of IL-10 was observed in diabetes group and this effect was abolished by TAM and E2. Also, treatment with TAM and E2 resulted in improved inflammatory balance in favor of anti-inflammation. Although diabetes resulted in, increment of TC and LDL, TAM and E2 reduced lipids profile. Furthermore, treatment with TAM prevented the reduction of estrogen receptors (ERs) α and β protein levels, but its effect on the ERβ protein level was higher. Our results indicated that TAM protects against diabetic cardiovascular dysfunction and is a good candidate for E2 substitution., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: Older Breast Cancer (BC) survivors are an increased risk of osteoporosis due to natural aging and long-term cancer treatment-related toxicity. It is well known that anti-estrogen therapy (AET), especially aromatase inhibitors (AI), is associated with rapid bone loss and thus increases the risk of osteoporosis. This study characterizes patterns and predictors of receiving guideline-recommended bone densitometry (BD) screening at AET initiation., Methods: A retrospective cohort study (1998-2012) of all women ≥65 years of age initiating AET was designed using claims data from Quebec's universal health care. Associations with BD screening were estimated using a generalized estimating equations regression model, adjusting for clustering of patients within physicians., Results: Among 16,480 women initiating AET, 36.1% received a baseline BD. Among AI users, the rate was 58.4%. In the multivariate analysis, age, lower socioeconomic status, tamoxifen use, lack of periodic health exam and having a general practitioner as the AET prescriber were associated with lower odds of BD screening. In terms of quality of care-related variables, lack of guideline-appropriate radiotherapy (OR: 0.69 (95% CI, 0.57-0.83), or chemotherapy consideration (0.82 (95% CI, 0.71-0.94)) and non-adherence to AET (0.76 (95% CI, 0.68-0.84)) were associated with lower odds of receiving BD screening. Women diagnosed with BC after 2003 had significantly better odds of being screened., Conclusion: Despite an increase in rates since 2003, BD screening remains suboptimal, especially for women at higher risk of osteoporosis. Coordination of health care and service-delivery monitoring can potentially optimize long-term management of treatment-related toxicity in older BC survivors., (Copyright © 2018. Published by Elsevier Inc.)

Background: Several trials evaluated the role of ovarian function suppression for the adjuvant treatment of premenopausal patients with hormone receptor-positive early breast cancer. Based on the results of the SOFT and TEXT trials, international guidelines recommend the addition of ovarian function suppression to standard adjuvant endocrine therapy for patients at higher risk of relapse., Methods: The ERA project (Evaluation of Risk factors in the Adjuvant treatment of breast cancer in premenopausal patients) was devised with the objective of obtaining a consensus on the identification of risk factors and the use of ovarian function suppression in the adjuvant treatment of these women. To this aim, a panel of 31 Italian oncologists with expertise in breast cancer participated in a Delphi consensus study in June 2017., Results: A total of 29 statements related to prognostic factors, therapeutic strategies and ovarian function suppression were defined and voted to gain final consensus. For each topic we report data supporting the acquired consensus and the relevant issues discussed., Conclusions: The SOFT and TEXT trials have changed the standard adjuvant treatment of premenopausal patients with hormone receptor-positive early breast cancer, but the available treatment options require a careful risk assessment and toxicities evaluation to ensure the greatest clinical benefit for each patient.

Objective: The objective of this study was to investigate the relationship between preterm birth in a prior pregnancy and preterm birth in a twin pregnancy., Study Design: We performed a secondary analysis of a randomized controlled trial evaluating 17-α-hydroxyprogesterone caproate in twins. Women were classified as nulliparous, multiparous with a prior term birth, or multiparous with a prior preterm birth. We used logistic regression to examine the odds of spontaneous preterm birth of twins before 35 weeks according to past obstetric history., Results: Of the 653 women analyzed, 294 were nulliparas, 310 had a prior term birth, and 49 had a prior preterm birth. Prior preterm birth increased the likelihood of spontaneous delivery before 35 weeks (adjusted odds ratio [aOR]: 2.44, 95% confidence interval [CI]: 1.28-4.66), whereas prior term delivery decreased these odds (aOR: 0.55, 95% CI: 0.38-0.78) in the current twin pregnancy compared with the nulliparous reference group. This translated into a lower odds of composite neonatal morbidity (aOR: 0.38, 95% CI: 0.27-0.53) for women with a prior term delivery., Conclusion: For women carrying twins, a history of preterm birth increases the odds of spontaneous preterm birth, whereas a prior term birth decreases odds of spontaneous preterm birth and neonatal morbidity for the current twin pregnancy. These results offer risk stratification and reassurance for clinicians., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

This systematic review aimed to compare the clinical efficacy of tamoxifen with that of clomiphene citrate (CC) in anovulatory patients. The PubMed, EMBASE, and CNKI databases were searched up to October 2016 for literature comparing tamoxifen with CC in anovulatory women. The pooled risk ratios (RR) or standardized mean differences (SMD) with 95% confidence intervals (CIs) were subjected to statistical analysis. Twelve studies involving 1302 patients with 2030 ovulation-induction cycles were summarized. There were no statistically significant differences for the ovulation and pregnancy rates in the tamoxifen comparing to the CC group in the pooled analysis. However, in the subgroup of case-control studies, tamoxifen was identified to be associated with higher ovulation (RR = 1.28, 95% CI: 1.07, 1.54, I 2 = 0.0%) and pregnancy rates (RR = 1.82, 95% CI: 1.09, 3.06, I 2 = 0.0%) than CC. However, no differences were detected in the subgroup of RCTs, even after sensitivity analyses. In addition, no significant differences were found in endometrial thickness and miscarriage rate. Our study showed that there might be some distinctions in the efficacy of TMX and CC for ovulation and pregnancy rates. However, the exact efficacy was needed to be confirmed further., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Problem: It is not known whether 17-alpha-hydroxyprogesterone caproate (17OHP-C) is effective for preventing preterm delivery with an episode of preterm labor (PTL) with or without intra-amniotic inflammation/infection., Methods of Study: This was a retrospective cohort study. One hundred and seven PTL patients were selected and divided into a 17OHP-C group (use of 17OHP-C: n = 53) and a no-treatment group (no use of 17OHP-C: n = 54). Moreover, the patients were divided into three subgroups (subgroup A: without intra-amniotic inflammation, B: with mild intra-amniotic inflammation, and C: with severe intra-amniotic inflammation) according to their level of amniotic interleukin (IL)-8, and perinatal prognosis was analyzed., Results: Interval from admission to delivery (days) in the 17OHP-C group (76 [13-126], n = 34) was significantly longer than that in the no-treatment group (50 [8-104], n = 33; P = .012) in subgroup B. In cases without intra-amniotic microbes in subgroup B, a significant prolongation of gestational days was associated with the 17OHP-C group (79 [13-126], n = 25) compared with the no-treatment group (50 [8-104], n = 29; P = .029). However, there were no significant differences in subgroups A or C., Conclusion: 17OHP-C could prolong gestational period in limited PTL cases with sterile mild intra-amniotic inflammation., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The activity of palbociclib as a single agent in advanced breast cancer has not been extensively studied, with the only available clinical data limited to heavily pretreated patients. Preclinical data suggests palbociclib may partially reverse endocrine resistance, though this hypothesis has not been evaluated in previous clinical studies. This phase II, open-label, multicenter study examined the activity of palbociclib monotherapy, as well as palbociclib given in combination with the same endocrine therapy (ET) that was received prior to disease progression, in postmenopausal women with moderately pretreated, estrogen receptor-positive, HER2 negative advanced breast cancer., Patients and Methods: Eligible women with advanced disease which had progressed on one or two prior ETs were randomized 1 : 1 to receive either palbociclib alone, or palbociclib in combination with the ET as previously received. Primary end point was clinical benefit rate (CBR); secondary end points included progression-free survival (PFS)., Results: Between October 2012 and July 2016, a total of 115 patients were randomized. The CBR was 54% [95% confidence interval (CI): 41.5-63.7] for combination therapy, and 60% (95% CI: 47.8-72.9) for monotherapy. Median PFS was 10.8 months (95% CI: 5.6-12.7) for combination therapy, and 6.5 months (95% CI: 5.4-8.5) for monotherapy [hazard ratio (HR) 0.69; 95% CI: 0.4-1.1, exploratory P-value = 0.12]. Exploratory analyses revealed the PFS advantage for combination therapy was seen in the subgroup of patients who received prior ET for >6 months (HR 0.53; 95% CI: 0.3-0.9, exploratory P-value = 0.02), but not in those who received prior ET for ≤6 months., Conclusion: Palbociclib has clinical activity as a single agent in women with moderately pretreated, oestrogen receptor-positive, HER2-negative advanced breast cancer. Palbociclib may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET., Clinical Trial Information: NCT02549430.

Variants of the CYP2D6 gene may lead to a poor prognosis of tamoxifen (TAM)-treated patients. Our study validated the association between the CYP2D6 genotype and outcomes of patients receiving TAM in adjuvant endocrine therapy. A total of 778 breast cancer patients who received adjuvant TAM (n = 325) or aromatase inhibitors (AIs) (n = 453) at the National Cancer Center were analyzed. Nine single nucleotide polymorphisms (SNPs) in the CYP2D6 gene were selected from online databases. The associations of each SNP genotype with disease-free survival (DFS) and clinicopathological characteristics were analyzed. A total of 167 (21.5%) patients carried the CYP2D6*10 (c.100C>T) T/T genotype. Among the 325 patients who received TAM, the 5-year DFS rate was considerably lower in CYP2D6*10 T/T genotype patients than C/C or C/T patients (54.9% vs. 70.9%, p = 0.007). The T/T genotype for CYP2D6*10 was a significant prognostic marker for DFS in multivariate analysis (hazard ratio = 1.87; p = 0.006). The CYP2D6*10 genotype in women who received AIs was not significantly associated with DFS (p = 0.332). Other SNPs were not related to the survival of patients who received TAM. Our finding showed patients with CYP2D6*10 T/T received less benefit from TAM adjuvant treatment. This conclusion may optimize the individualized treatments for this subgroup of patients., (© 2018 UICC.)

Objective: We sought to evaluate nitric oxide pathway placental gene expression and the epigenome (CpG methylation) among women receiving 17-α hydroxyprogesterone caproate (17-OHPC) with and without recurrent preterm birth (PTB)., Study Design: This was a case-control study. We prospectively recruited women with ≥ 1 prior singleton spontaneous PTB <34 weeks receiving 17-OHPC. DNA and RNA were isolated from placentas. RNA abundance (gene expression) and the methylome were analyzed for 84 genes in nitric oxide pathways. Women with recurrent PTB <34 weeks (cases) were compared with those delivering at term (controls). Statistical analysis included multivariable models with Bonferroni's corrected p -values., Results: In this study, 17 women met inclusion criteria; 7 preterm cases (delivered at 22.6 ± 2.9 weeks) and 10 term controls (delivered at 38.5 ± 0.8 weeks). Groups had similar PTB history, race/ethnicity, and socioeconomic risk factors for PTB. Twenty-seven nitric oxide genes displayed differential expression ( p  < 0.05 and q  < 0.10) when comparing placentas from preterm cases and term controls; all were downregulated in preterm cases. Eight hundred sixty corresponding CpG sites were differentially methylated between the preterm cases and term controls (Bonferroni's p -value <0.05)., Conclusion: CpG methylation and gene expression patterns in nitric oxide pathway genes differ among placentas from recurrent PTB compared with term birth following 17-OHPC exposure., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.

Objective To evaluate the role of transvaginal ultrasound triage in women with a history of tamoxifen treatment who present with post-menopausal bleeding. Study design A retrospective review was undertaken of patients who presented with symptoms of post-menopausal bleeding and underwent ultrasound triage. Endometrial thickness and ultrasonographic features were then correlated with hysteroscopic and histopathological outcome data. The findings and outcomes for women with a history of tamoxifen use (tamoxifen group) were compared to those who had not taken tamoxifen (non-tamoxifen group). Results A total of 614 women with post-menopausal bleeding underwent transvaginal ultrasound triage, of whom 53 had a history of current or previous tamoxifen treatment. An endometrial thickness of ≥5 mm or the presence of other abnormal features was used to triage women to further investigation by hysteroscopy and biopsy. Endometrial thickness was significantly greater in the tamoxifen group (11 mm vs. 6 mm). Nearly all of the tamoxifen group were triaged to further investigation (98.1%), compared with significantly fewer in the non-tamoxifen group (68.3%) Overall, the incidence of endometrial pathology was also significantly higher in tamoxifen patients (43.4% vs. 31.7%). Conclusion For women presenting with post-menopausal bleeding, the use of transvaginal ultrasound as a triage tool is rarely helpful in evaluating women who have a history as tamoxifen use, as most will require further investigation with hysteroscopy and biopsy. A post-menopausal bleeding protocol that omits transvaginal ultrasound for women with a history of tamoxifen use may be an appropriate and effective pathway for managing these patients.

Tamoxifen has played a vital role in endocrine therapy for the treatment of estrogen receptor-positive breast cancer. We examined the effect of tamoxifen in patients with a thin endometrium in frozen-thawed embryo transfer (FET) cycles and compared the improvement in endometrial thickness (EMT) and pregnancy outcomes stratified by different etiologies of thin endometrium. A total of 226 women were recruited for a new tamoxifen protocol; all had an EMT of less than 7.5 mm in previous cycles, including natural cycle (NC), hormone replacement treatment (HRT), and ovulation induction (OI) cycles. Compared with previous cycles, tamoxifen cycles showed a significantly increased EMT (from 6.11 ± 0.98 mm to 7.87 ± 1.48 mm in the NC group, from 6.24 ± 1.01 mm to 8.22 ± 1.67 mm in the HRT group, and from 6.34 ± 1.03 mm to 8.05 ± 1.58 mm in the OI group; all P < .001). Patients were further divided into 3 groups based on the causes of their thin endometrium: (1) history of intrauterine adhesion (n = 34), (2) history of uterine curettage (n = 141), and (3) polycystic ovary syndrome (PCOS; n = 51). Patients with PCOS obtained the thickest EMT (9.31 ± 1.55 mm), the lowest cycle cancellation rate (11.76%), and the highest rate of clinical pregnancy (60%) and live birth (55.56%) per transfer ( P < .001). Multivariable regression analysis showed that EMT was related to live birth (odds ratio: 1.487; 95% confidence interval: 1.172-1.887). A tamoxifen protocol improves EMT in patients after NC, HRT, and OI cycles during FET. Patients with PCOS show the most benefit from tamoxifen and achieve better pregnancy outcomes.

Background: Obesity causes secondary hypogonadism (HG) in men. Standard testosterone (T) replacement therapy improves metabolic parameters but leads to infertility., Objective: To evaluate clomiphene citrate (CC) treatment of adult men with male obesity-associated secondary hypogonadism (MOSH)., Design: Single-center, randomized, double-blind, placebo-controlled trial., Participants: Seventy-eight men aged 36.5 ± 7.8 years with a body mass index (BMI) > 30 kg/m 2 , total testosterone (TT) ≤ 300 ng/dL, and symptoms in the ADAM questionnaire., Intervention: Random allocation to receive 50 mg CC or placebo (PLB) for 12 weeks., Outcomes: (1) Clinical features: ADAM and sexual behavior questionnaires; (2) hormonal profile: serum TT, free T, estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex hormone-binding globulin (SHBG); (3) body composition: BMI, waist circumference, and bioelectric impedance analysis; (4) metabolic profile: blood pressure, fasting blood glucose, HbA1c, insulin, HOMA-IR, and lipid profile; (5) endothelial function: flow-mediated dilation of the brachial artery, quantitative assessment of endothelial progenitor cells and serum sICAM-1, sVCAM-1, and selectin-sE levels; (6) safety aspects: hematocrit, serum prostate-specific antigen, International Prostate Symptom Score, and self-reported adverse effects., Results: There was an improvement in one sexual complaint (weaker erections; P < 0.001); increases (P < 0.001) in TT, free T, E2, LH, FSH, and SHBG; and improvements in lean mass (P < 0.001), fat-free mass (P = 0.004), and muscle mass (P < 0.001) in the CC group. CC reduced HDL (P < 0.001). No statistically significant differences were seen in endothelial function., Conclusions: CC appeared to effectively improve the hormonal profile and body composition. CC may be an alternative treatment for MOSH in adult men.

Background: Raloxifene and tamoxifen are Food and Drug Administration-approved for breast cancer risk reduction; in 2013, the US Preventive Services Task Force recommended these drugs for breast cancer risk reduction in high-risk women. Information on the use of raloxifene and tamoxifen for breast cancer risk reduction in the general population indicates that the risk is believed to be low; however, there is little literature., Objective: The purpose of this study was to assess the use of breast cancer risk reduction medications by breast cancer risk level in an older cohort of women., Study Design: Women who were enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were assessed for the use of raloxifene, tamoxifen, and other medications. The data sources for use of the drugs were a mailed medication use questionnaire in 2013 and linked Medicare Part D claims files from 2010-2014. Estimated breast cancer risk within 5 years was assessed with the use of the modified Gail model and self-reported breast cancer risk factors; comorbidities were assessed through a questionnaire., Results: A total of 22,235 women completed the medication use questionnaire; of these, 13,640 women (61%) had linked Part D data. In 2013, 45% of the women were 65-74 years old, and 55% of the women were 75-84 years old. From the medication use questionnaire, raloxifene use (past month) was 1.8%, 2.5%, and 4.0% for women with breast cancer risk within 5 years of <1.66%, 1.66-3.0%, and ≥3%, respectively (probability value trend, <.0001). From Part D, for any use during the period among women with coverage, raloxifene rates were 3.3%, 4.0%, and 6.6% for the 3 categories for breast cancer risk within 5 years (probability value trend, <.0001); use was 7.4% and 3.3% in women with and without osteoporosis, respectively. Raloxifene use significantly decreased from 2010-2014, and specifically from 2012-2014, both for all women and for women with breast cancer risk within 5 years of ≥3%. Tamoxifen use from Part D was 0.36%, 0.45%, and 0.85% for the 3 categories for breast cancer risk within 5 years (probability value trend, .009)., Conclusion: Raloxifene use was low overall but increased modestly with breast cancer risk, and usage decreased from 2010-2014. Tamoxifen use was very low., (Published by Elsevier Inc.)