Selective Estrogen Modulators Research Articles

Revolutionizing anticancer drug delivery: Exploring the potential of tamoxifen-loaded nanoformulations

Tamoxifen (TAM), as a hydrophobic drug, is a selective estrogen modulator (SERM) applied to hormone therapy for breast cancer (BC). Although it is effective and affordable in BC therapy, there are some important challenges in the use of TAM. The major one is the side effects related to conventional doses, and decreasing the dose of TAM is the main solution. By using novel TAM-containing nanoformulations instead of chemotherapy, toxic effects will be greatly decreased. Nanocarriers are able to carry small amounts of TAM to tumors during a long time and limit their dose-dependent toxicity. Many attempts have been made to prepare TAM-loaded nanoformulations from different nanomaterials like liposomes, polymeric NPs, micelles, solid lipid nanoparticles, protein-based NPs, dendrimers, and other types of nanoparticles. Another important problem of TAM nanocarriers is the compatibility of nanoformulations with biological environments. Hence, understanding how different cell types respond to exposure to nanomaterials to assess the risks and advantages of nanomaterials is important. With increasing knowledge in this field, the development of improved formulations to remove the potential toxicity risk of nanomaterials on healthy cells will be available. The poisonous nature of nanoscale compoundscan beameliorated by modifying the surface like PEGylation (PEG). Small amounts of TAM can also be employed in directing the delivery ofnanoformulations containing different cargoes into cancer cells like ER + BC cells as a guiding vector. Stimulus-responsive drug delivery systems design is an emerging field in nanocarriers. In these systems, some features of the drugs can be modullatedin response to external and intrinsic physiochemical factors, like release profiles in a sustained manner and targeted permeation. Novel drug delivery systems could be synthesized by incorporating TAM into these carriers which have great therapeutic potential.

Risk of perioperative hormonal breast cancer therapy for microvascular flap complications in breast reconstruction

Hormone therapy with selective estrogen modulators (tamoxifen) and aromatase inhibitors is commonly used in the treatment of breast cancer. While the increased risk for thromboembolic events has been known since their early application, the potential risk in microsurgical breast reconstruction is still debated. This study aimed to evaluate the risk for microvascular flap complications in patients with perioperative hormone therapy. All patients who underwent microsurgical breast reconstruction with a deep inferior epigastric perforator (DIEP) or transverse myocutaneous gracilis flap at our institution between March 2010 and November 2020 were retrospectively identified in our records. Patients were grouped according to the type and use of perioperative hormone therapy. Flap-related thromboembolic events, flap loss, and revision procedures were compared and analyzed between groups. Risk factors associated with postoperative microsurgical complications were determined. A total of 560 patients (656 flaps) were included in our analysis. One hundred ninety-eight patients (224 flaps) received perioperative hormone therapy (35.4%) and 50 (8.9%) postoperative microsurgical events occurred. Tamoxifen and aromatase inhibitors were not associated with postoperative microsurgical events (p=0.254), full flap loss (p= 0.702), or partial flap loss (p= 0.916). Patients receiving DIEP flaps had a higher risk for postoperative microsurgical complications (OR 2.36, p=0.004) and partial flap loss (OR 14.66, p< 0.001). A BMI >30 was associated with an increased risk for partial flap loss (OR 4.2; p< 0.001) CONCLUSION: This article presents one of the largest single-center datasets for the risks of hormone therapy in microsurgical breast reconstruction. Our results show that perioperative hormone therapy does not increase the risk for microsurgical complications. The findings of our study do challenge the common practice of discontinued hormone therapy before microsurgical breast reconstruction.

Tamoxifen Like Estradiol Attenuates Systemic Inflammation in Young and Aged Female Mice Fed with High-Fat Diet

Background: Consumption of a high-fat diet (HFD) is associated with an increased incidence of inflammatory diseases and metabolic disorders. Also, these disorders will increase in women with aging and menopause, which is probably due to the reduced role of estradiol (E2). Selective estrogen modulators including tamoxifen (TAM), which acts through estrogen receptors, have important metabolic effects. This study aimed to determine whether TAM and E2 have protective effects on inflammation caused by HFD in young and aged mice. Methods: Four-month-old (Sham and ovariectomized [OVX]) and 20-month-old female C57BL/6J mice were used in this study. After feeding them with HFD for 12 weeks, they were divided into nine groups consisting of Sham+Oil, Sham+TAM, Sham+E2, OVX+Oil, OVX+TAM, OVX+E2, Aged+Oil, Aged+TAM, and Aged+E2. TAM and E2 were injected subcutaneously every four days for four weeks. At the end of the experiments, the mice’s blood was sampled. The serum cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) were also determined using ELISA kits. Results: The results revealed that HFD increased inflammation by reducing IL-10 and increasing TNF-a/IL-10 and IL-6/IL-10 ratio in young and aged mice, and TAM and E2 therapy resulted in a significant decrease in TNF-α and IL-6, and an increase in IL-10 in young and aged mice. Conclusion: In conclusion, the results of this study indicated that TAM, in addition to being used as an anticancer drug, can reduce HFD-induced inflammation in both young and aged mice. Therefore, probably it is a good candidate to substitute E2.

Abstract GS5-07: Estradiol represses anti-tumoral immune response to promote progression of triple-negative breast cancer brain metastases

Abstract Background: Younger women with breast cancer have increased risk of development of brain metastases irrespective of the tumor subtype. We have shown that pre-menopausal levels of 17-β-Estradiol (E2) contributes to the promotion of brain metastases by influencing the tumor microenvironment. E2 promotes brain metastasis (BM) of estrogen receptor negative (ER¯) BC cells by inducing neuroinflammatory ER+ astrocytes in the brain niche to secrete pro-metastatic factors critical for early brain colonization. Ovarieoctomy (OVX) in combination with the aromatase inhibitor (Letrozole) prevented brain colonization of triple negative (TNBC) (ER-PR-HER2-) human xenografts (MDA231BR/NSG) and murine models (E0711/C57Bl6, 4T1/BALBc) through paracrine activation of EGFR and TRKB, pathways involved in increased invasion and early tumor initiation. Yet, the extent to which E2-depletion therapies can decrease progression of established BM in combination with current standard of care for brain metastasis remains unknown. Goal: Current standard of care (SOC) for patients with TNBC brain metastasis includes irradiation (SRS, whole brain) and immunotherapy (PD-1/PDL-1 inhibitors). The goal of this study was to assess how E2-depletion therapies affects brain immune function in the context of SOC for brain metastatic progression of TNBC. Results: To assess whether E2-depletion could decrease BM progression in a model that mimics standard of care for BM, TNBC E0771-GFP-luc cells were injected intracardially in syngeneic ovariectomized (OVX)-female C57Bl6 mice supplemented with pre-menopausal levels of E2. Seven days after injection (when cancer cells have colonized), mice received a single 15Gy dose brain irradiation and were randomized to continue receiving E2, E2 withdrawal (E2WD) or E2WD plus the aromatase-inhibitor letrozole (E2WD+LET). Brain metastatic burden significantly decreased in E2WD and E2WD+Letrozole treated mice as compared to E2-treated mice. Injection of E0711 cells in immunocompromised NSG mice or in the absence of brain irradiation abolished this effect, suggesting that E2-depletion therapies decrease BM progression through boosting radiation-induced anti-tumor immunity. Accordingly, there were no differences in BM progression in E2, E2WD or E2WD+let treated mice in a xenograft model (F2-7 TNBC cells) in NSG mice, even in the presence of brain irradiation. Immune-profiling of brains from OVX+E2, OVX and OVX+Let C57BL6 mice carrying BMs showed dynamic changes in immune populations at early and late stages of brain metastatic colonization. At early stages post brain colonization (3 days post ic injection) E2-treated mice showed a decreased fraction of CD11b+CD45Int CD206+ microglia/CNS macrophages as compared to OVX+LET-treated mice, without significant changes in the fraction of infiltrated lymphocytes, suggesting E2 represses early immunosurveillance through repression of microglia/CNS macrophage activation. At later stages of brain colonization (7 days post ic injection), E2-treated mice showed an increased fraction of proinflammatory microglia and decreased fraction of T and B cells as compared to OVX or OVX+let treated mice. While E2-depletion increased the recruitment of T cells to the brain niche, the fraction of CD279 (PD1+) brain T cells was similar among groups. Ongoing studies assess the efficacy of E2-depletion therapies in combination with brain radiation and PD-1 inhibitors to decrease metastatic burden and improve survival in preclinical models. Conclusion: Our results support the hypothesis that estradiol promotes brain metastatic progression by stimulating an immunosuppressive brain microenvironment. As such, FDA-approved E2-depletion therapies (aromatase inhibitors and selective-estrogen modulators) could be used in combination with brain irradiation and PD-1 inhibitors to promote a more effective anti-tumoral immune response. Citation Format: Diana Cittelly, Maria J. Contreras-Zarate, Karen ALvarez-Eraso, Vesna Tesic, Nicole Tsuji, Leanna Chafee, Sana Karam, D. Ryan Ormond, Peter Kabos. Estradiol represses anti-tumoral immune response to promote progression of triple-negative breast cancer brain metastases [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-07.

Molecular docking analysis of phytochemicals with estrogen receptor alpha.

Breast cancer (BC) is linked to estrogen receptor alpha (ER-α) positive. Tamoxifen and other estrogen selective modulators have proven to be beneficial in slowing the progression of ER-α BC. However, tamoxifen resistance emerges as a result of long-term treatment and cancer development. Therefore, it is of interest to document data on the molecular docking analysis of phytochemicals targeting with Estrogen Receptor-alpha. The screening of the phytochemicals from the ZINC database (a total of 87133 compounds) against ER-α protein was completed. We show that ZINC69481841 and ZINC95486083bind strongly to ER- with binding energies of 10.47 and 11.88 Kcal/mol, respectively, which were significantly greater than the control compound (-8.32Kcal/mol). ZINC69481841 and ZINC95486083 were found to bind with the key residues (Leu387, Arg394, Glu353, and Thr347) of ER-α protein. Data shows that the lead compounds (ZINC69481841 and ZINC95486083) have an acceptable range of ADMET and drug-likeness properties for further consideration in drug discovery.

Computational modeling, ligand-based drug design, drug-likeness and ADMET properties studies of series of chromen-2-ones analogues as anti-cancer agents

BackgroundIn spite of the significant escalation in the depth of our conception and regulation of breast cancer over the past decades, the malady is still a serious community health challenge globally and poses a substantial tasks. Selective estrogen modulators (SERMs) such as Tamoxifen are approved for the therapy of this illness but developed drug resistance and unwanted side effects such as endometrial cancer caused by the long-term Tamoxifen chemotherapy limit their therapeutic applicability. Hence, developing new ER+ drugs with better therapeutic effect is strongly needed. In an attempt to overcome this challenge, this research is aimed at designing novel chromen-2-one analogues with better inhibition capacity against MCF-7 breast cancer cell line via structural modification of the reference compound and predict their activities using a developed QSAR model.ResultsFour models were developed, and the first was selected for the design as it has the highest statistical parameters such as: coefficient of determination (R2 = 0.950), cross-validation coefficient (Qcv2 = 0.912), adjusted R2 (Radj2 = 0.935), and external validation R2 (Rpred2 = 0.7485). Twelve (12) new novel chromen-2-one analogs were designed through structural modification of the reference compound. Their activities was predicted using the selected model, and their pIC50 was found to be better than that of the reference compound and standard drug (Tamoxifen) used in the research. Results of pharmacokinetic study of the designed compounds revealed that they possess drug-likeness properties as none of them violated the Lipinski’s rule of five while ADMET studies confirmed designed compounds 6, 8, 11 and 12 as orally safe and non-toxic. Furthermore, molecular docking analysis was performed between these orally safe designed compounds and the active site of the ER+ receptor and the result showed that they have higher binding affinities than the reference compound and the standard drug used for this research.ConclusionHence, designed compounds 6, 8, 11 and 12 can be used as novel ER+ breast cancer drug candidates after performing in vivo and in vitro studies.

Inhibition of GP130/STAT3 and EMT by combined bazedoxifene and paclitaxel treatment in ovarian cancer.

The interleukin 6 (IL-6)/glycoprotein 130 (GP130)/signal transducer and activator of transcription 3 (STAT3) signalling pathway, with GP130 as an intermediate membrane receptor, is involved in the survival, metastasis, and resistance of ovarian cancer. Bazedoxifene, an FDA-approved drug, is an inhibitor of GP130 and a selective estrogen modulator (SERM). We studied the mechanism of the combination therapy of bazedoxifene and paclitaxel in inhibiting the IL-6-mediated GP130/STAT3 signaling pathway in ovarian cancer. Surface plasmon resonance (SPR) was used to assess the binding of bazedoxifene to GP130. Migration, invasion, and apoptosis of ovarian cancer cells were assessed using bazedoxifene and paclitaxel. In addition, we determined the effects of bazedoxifene and paclitaxel alone or in combination on the GP130/STAT3 pathway and epithelial-mesenchymal transition (EMT). The results revealed that the combination of bazedoxifene and paclitaxel suppressed cell viability, migration, and invasion in the ovarian cancer cells. In addition, the combination treatment increased apoptosis. Furthermore, bazedoxifene combined with paclitaxel inhibited the growth of ovarian cancer cells in a xenograft tumour model. This combination reduced STAT3 phosphorylation and suppressed gene expression and EMT. In conclusion, inhibition of GP130/STAT3 signalling and EMT via a combination of bazedoxifene and paclitaxel could be used as a therapeutic strategy by which to overcome ovarian cancer.

Bazedoxifene, a GP130 Inhibitor, Modulates EMT Signaling and Exhibits Antitumor Effects in HPV-Positive Cervical Cancer.

Persistent HPV (Human Papillomavirus) infection is the primary cause of cervical cancer. Despite the development of the HPV vaccine to prevent infections, cervical cancer is still a fatal malignant tumor and metastatic disease, and it is often difficult to treat, so a new treatment strategy is needed. The FDA-approved drug Bazedoxifene is a novel inhibitor of protein–protein interactions between IL-6 and GP130. Multiple ligand simultaneous docking and drug repositioning approaches have demonstrated that an IL-6/GP130 inhibitor can act as a selective estrogen modulator. However, the molecular basis for GP130 activation in cervical cancer remains unclear. In this study, we investigated the anticancer properties of Bazedoxifene in HPV-positive cervical cancer cells. In vitro and in vivo experiments showed that Bazedoxifene inhibited cell invasion, migration, colony formation, and tumor growth in cervical cancer cells. We also confirmed that Bazedoxifene inhibits the GP130/STAT3 pathway and suppresses the EMT (Epithelial-mesenchymal transition) sub-signal. Thus, these data not only suggest a molecular mechanism by which the GP130/STAT3 pathway may promote cancer, but also may provide a basis for cervical cancer replacement therapy.

Abstract 1976: Ras-Raf-MEK-ERK signaling pathway: a novel target of ERRα and tamoxifen in TNBC cells

Abstract TNBC, or triple-negative breast cancer, is an aggressive type of breast cancer that is associated with a worse prognosis, higher rates of metastases, and a poorer outcome. Historically, TNBC has been proven challenging to treat, due to disease heterogeneity and the fact that the breast cancer tests negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) protein, and thus does not respond to traditional therapies. As such, treatment options for TNBC patients are extremely limited and there is a tremendous need to identify molecular targets and biomarkers that can offer novel targeted approaches. Additionally, due to disease heterogeneity in TNBC, it is important to subclassify TNBC based on prognostic markers and create tailored targeted therapies. ERRα, an orphan nuclear receptor, is an example of a prognostic marker that is correlated with a more aggressive disease progression and a worse outcome. However, ERRα is also a predictive marker for patient response to tamoxifen treatment of ER-negative and TNBC patients, indicating that there may be an alternative use for the selective estrogen modulator (SERM) tamoxifen in the context of TNBC. This led us to investigate whether there is a common pathway that is regulated by both ERRα and tamoxifen that would explain tamoxifen response in the context of TNBC cells. We performed a phosphoproteomic analysis of MDA-MB-231 cells, treated with either tamoxifen or XCT-790, an inverse agonist of ERRα, to identify common downstream targets of both ERRα and tamoxifen. Our findings indicate that the Ras-Raf-MEK-ERK signaling pathway is a common target of both XCT-790 and tamoxifen. This provides a novel treatment strategy that should be investigated for the treatment of TNBC patients, opens the door for investigation of novel targeted therapies, and highlights the need for the use of prognostic markers to identify sub-populations that benefit from individualized treatment strategies. Citation Format: David Musheyev, Adi Ronen, Miriam T. Lattin, Anya Alayev. Ras-Raf-MEK-ERK signaling pathway: a novel target of ERRα and tamoxifen in TNBC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1976.

Progesterone Modulator May Offer PMDD Relief

Progesterone Modulator May Offer PMDD Relief

Atypical vessels in hysteroscopy: Usefulness in prediction of malignant diseases in patients treated with tamoxifen.

Tamoxifen (TAM) is widely used in adjuvant endocrine therapy for invasive breast cancer as a selective estrogen modulator, but this treatment has a risk of developing endometrial malignancy. However, hysteroscopic findings during or after TAM treatment are unclear. The aim of this study is to examine the association between hysteroscopic patterns and malignant histological findings during or after treatment with TAM. The subjects were patients who received TAM after surgery for breast cancer and underwent hysteroscopy at our institution from January 2016 to December 2019. Clinicopathological factors and hysteroscopic findings were collected from medical records and investigated retrospectively. Histologically, atypical endometrial hyperplasia, endometrial cancer, and carcinosarcoma were classified as malignant diseases. A total of 26 patients were eligible for the study. Hysteroscopic findings included an irregular surface of the endometrium (n = 3, 11.5%), atypical vessels (n = 10, 38.5%), papillary structure (n = 3, 11.5%), and polypoid structure (n = 18, 69.2%). Histological examination revealed malignancy in six patients (23.0%). The percentage of atypical vessels in patients with malignancies was significantly higher than that in patients with a normal endometrium or benign lesion (100% vs. 20%, p = 0.0009). The sensitivity and specificity of atypical vessels in hysteroscopy for diagnosis of malignant diseases were 100% and 80%, respectively. Hysteroscopic findings of atypical vessels may be useful for prediction of malignant diseases in patients treated with TAM.

Correlation between bone mineral density and endometrial thickness over time in women with breast cancer history.

As the efficacy of chemotherapy and adjuvant endocrine therapy for breast cancer increase, the quality-of-life to cancer survivors could be more important issue in strategies of breast cancer treatment. Bone health has become more compelling in care of breast cancer survivor than ever before. This retrospective study was aimed to evaluate factors relating to the change in BMD and to ascertain the correlation between changes in BMD and EMT of women with breast cancer in follow-up. Records of 164 women who underwent surgery for breast cancer were reviewed in this study. The basal characteristics included parity, menopausal state, medication with vitamin D, bisphosphonate, selective estrogen modulator (SERM), aromatase inhibitor (AI), gonadotrophin releasing hormone agonist (GnRHa), chemotherapy, radiotherapy, cancer type including positivity of estrogen receptor, progesterone receptor and HER2, combined the other gynecologic disease or the other origin cancer. At initial and follow-up visit, all subjective were checked with BMD, endometrial thickness (EMT). The mean age was 52.1 ± 8.5 years old and overall interval between initial and follow-up visits were 17.6 ± 7.5 month in this study. The BMDs of L1-4 (1.040 ± 0.166 g/cm2 vs 1.070 ± 0.181 g/cm2, p < 0.001), femur neck (0.850 ± 0.121 g/cm2 vs 0.870 ± 0.136 g/cm2, p < 0.001), and femur total (0.902 ± 0.132 g/cm2 vs 0.915 ± 0.138 g/cm2, p < 0.001) at follow-up visit were significantly lower than those at initial visit. The change in BMDs of L1-4 (ΔBMDL1-4, r = 0.353, p < 0.001, and r = 0.228, p = 0.003), femur neck (ΔBMDNeck, r = 0.198, p = 0.011, and r = 0.282, p < 0.001), femur total (ΔBMDTotal, r = 0.294, p < 0.001, and r = 0.327, p < 0.001) had positive correlation with age and the change in EMT (ΔEMT). After age correction, ΔEMT had positive correlation with ΔBMDNeck (r = 0.245, p = 0.002) and ΔBMDTotal (r = 0.273, p < 0.001). ΔBMDL1-4 and ΔBMDNeck differed according to menopausal state (p < 0.001 and p = 0.035), bisphosphonate (p < 0.001 and p < 0.001), and GnRHa (p < 0.001 and p < 0.001). In follow-up of women with history of breast cancer, ΔEMT could be an alternative screening marker for BMD decrease.

Adjunctive Raloxifene and Isradipine Improve Cognitive Functioning in Patients With Schizophrenia: A Pilot Study.

Cognitive impairment is the most important feature of schizophrenia leading to severe functional disability. To identify pathways that improve pathophysiological neurocognition in schizophrenia is a current challenge for the development of goal-directed clinical interventions. In the present study, we investigated the effects of raloxifene (a selective estrogen modulator) and isradipine (a voltage-gated L-type calcium channel blocker) on cognitive deficits in patients with schizophrenia. We designed a double-blind, randomized, parallel, placebo-controlled trial. We randomized 60 patients with schizophrenia into 3 groups including isradipine 5 mg, raloxifine 60 mg, and placebo for 6 consequent weeks, all in the same shape capsules, 2 times a day, along with treatment as usual. The initial and final results of blood tests, electrocardiograms, and cognitive tests in specific domains, such as attention, processing speed, executive function, and verbal memory were evaluated. Our findings revealed a remarkable association between adjunctive raloxifene treatment and the alleviation of verbal memory deficits. Isradipine treatment significantly improved the verbal memory and attention dysfunction in some variables of the Stroop test, compared with the placebo. However, no effect was observed in processing speed and executive function deficits. To the best of our knowledge, this study provides the first evidence that isradipine is a novel therapy option improving verbal memory and attention, both related to its activity in the hippocampus and the cerebellum. Further investigations are necessary to elucidate the mechanisms of action for both drugs in schizophrenia.

Novel Tamoxifen Nanoformulations for Improving Breast Cancer Treatment: Old Wine in New Bottles

Breast cancer (BC) is one of the leading causes of death from cancer in women; second only to lung cancer. Tamoxifen (TAM) is a hydrophobic anticancer agent and a selective estrogen modulator (SERM), approved by the FDA for hormone therapy of BC. Despite having striking efficacy in BC therapy, concerns regarding the dose-dependent carcinogenicity of TAM still persist, restricting its therapeutic applications. Nanotechnology has emerged as one of the most important strategies to solve the issue of TAM toxicity, owing to the ability of nano-enabled-formulations to deliver smaller concentrations of TAM to cancer cells, over a longer period of time. Various TAM-containing-nanosystems have been successfully fabricated to selectively deliver TAM to specific molecular targets found on tumour membranes, reducing unwanted toxic effects. This review begins with an outline of breast cancer, the current treatment options and a history of how TAM has been used as a combatant of BC. A detailed discussion of various nanoformulation strategies used to deliver lower doses of TAM selectively to breast tumours will then follow. Finally, a commentary on future perspectives of TAM being employed as a targeting vector, to guide the delivery of other therapeutic and diagnostic agents selectively to breast tumours will be presented.

Low Testosterone in Adolescents & Young Adults.

Male hypogonadism, the clinical syndrome with variable symptoms associated with gonadal dysfunction, can affect men of all ages. In older males, physiologic changes of the aging testis, account for the majority of decreased testosterone levels in this population. For younger males and adolescents, the etiology of hypogonadism is commonly due to congenital or acquired conditions that disrupt the testis production of testosterone or signaling from the hypothalamic-pituitary-gonadal axis. Diagnosis of hypogonadism in younger males can be a challenge, as symptoms such as decreased libido or erectile dysfunction, common in the older men, are not usually present, and young men instead commonly complain of low energy. While an underlying congenital cause should always be considered in young men with hypogonadism, acquired conditions such as obesity, diabetes, anabolic steroid or illicit drug use have all been associated with low testosterone levels. Outside of modifying identifiable risk factors for hypogonadism, pharmacologic testosterone therapy can also lead to therapeutic dilemmas in young men who desire paternity. Topical or injectable administration of testosterone, through negative feedback on the hypothalamus and pituitary, can decrease spermatogenesis, posing an infertility risk. Other agents that can replace testosterone or increase the body's natural production of testosterone without decreasing spermatogenesis are preferred, such as intranasal testosterone, selective estrogen modulators, aromatase inhibitors or human-chorionic gonadotrophin, often used in combination. Clinicians must maintain a high level of suspicion to properly diagnose young men with hypogonadism and tailor treatment based on both the underlying etiology and fertility goals.

A systematic review and meta-analysis of clinical trials implementing aromatase inhibitors to treat male infertility.

Aromatase activity has commonly been associated with male infertility characterized by testicular dysfunction with low serum testosterone and/or testosterone to estradiol ratio. In this subset of patients, and particularly in those with hypogonadism, elevated levels of circulating estradiol may establish a negative feedback on the hypothalamic–pituitary–testicular axis by suppressing follicle-stimulating hormone (FSH) and luteinizing hormone (LH) production and impaired spermatogenesis. Hormonal manipulation via different agents such as selective estrogen modulators or aromatase inhibitors to increase endogenous testosterone production and improve spermatogenesis in the setting of infertility is an off-label option for treatment. We carried out a systematic review and meta-analysis of the literature of the past 30 years in order to evaluate the benefits of the use of aromatase inhibitors in the medical management of infertile/hypoandrogenic males. Overall, eight original articles were included and critically evaluated. Either steroidal (Testolactone) or nonsteroidal (Anastrozole and Letrozole) aromatase inhibitors were found to statistically improve all the evaluated hormonal and seminal outcomes with a safe tolerability profile. While the evidence is promising, future prospective randomized placebo-controlled multicenter trials are necessary to better define the efficacy of these medications.

Targeted Therapies: Treatment Options for Patients With Metastatic Breast Cancer

Standard therapies for treating hormone-sensitive metastatic breast cancer (BC) include the blockage of estrogen pathways by using selective estrogen modulator receptors or selective estrogen receptor downregulators and by using aromatase inhibitors to block estrogen production. The addition of nonhormonal targeted therapies, including therapies based on alternative molecular pathways, continues to expand rapidly for advanced or metastatic BC. This article reviews targeted therapy treatment options for patients with metastatic BC, including strategies for administration, side effects, and nursing considerations.

Bazedoxifene Ameliorates Homocysteine-Induced Apoptosis via NADPH Oxidase-Interleukin 1β and 6 Pathway in Osteocyte-like Cells.

Homocysteine (Hcy) increases oxidation and inflammation; however, the mechanism of Hcy-induced bone fragility remains unclear. Because selective estrogen modulators (SERMs) have an anti-oxidative effect, SERMs may rescue the Hcy-induced bone fragility. We aimed to examine whether oxidative stress and pro-inflammatory cytokines such as interleukin (IL)-1β and IL-6 are involved in the Hcy-induced apoptosis of osteocytes and whether bazedoxifene (BZA) inhibits the detrimental effects of Hcy. We used mouse osteocyte-like cell lines MLO-Y4-A2 and Ocy454. Apoptosis was examined by DNA fragmentation ELISA and TUNEL staining, and gene expression was evaluated by real-time PCR. Hcy 5mM significantly increased expressions of NADPH oxidase (Nox)1, Nox2, IL-1β, and IL-6 as well as apoptosis in MLO-Y4-A2 cells. Nox inhibitors, diphenyleneiodonium chloride and apocynin, significantly suppressed Hcy-induced IL-1β and IL-6 expressions. In contrast, an IL-1β receptor antagonist and an IL-6 receptor monoclonal antibody had no effects on Hcy-induced Nox1 and Nox2 expressions, but significantly rescued Hcy-induced apoptosis. BZA (1nM-1μM) and 17β estradiol 100nM significantly rescued Hcy-induced apoptosis, while an estrogen receptor blocker ICI 182,780 reversed the effects of BZA and 17β estradiol. BZA also rescued Hcy-induced apoptosis of Ocy454 cell, and ICI canceled the effect of BZD. Moreover, BZA significantly ameliorated Hcy-induced expressions of Nox1, Nox2, IL-1β, and IL-6, and ICI canceled the effects of BZA on their expressions. Hcy increases apoptosis through stimulating Nox 1 and Nox 2-IL-1β and IL-6 expressions in osteocyte-like cells. BZA inhibits the detrimental effects of Hcy on osteocytes via estrogen receptor.

Regulation of estrogen signaling and breast cancer proliferation by an ubiquitin ligase TRIM56

Breast cancer ranks no. 1 in women cancer worldwide, while 60–70% are estrogen receptor alpha positive. The estrogen selective modulators, such as tamoxifen, become the effective drugs for controlling ER alpha breast cancer progression. However, tamoxifen resistance will develop during long-time treatment and cancer progression. Thus, further understanding of ER alpha signaling becomes necessary for the improvement of breast cancer therapy. Here, we identify TRIM56 as a novel regulatory factor in ER alpha signaling. TRIM56 expression is positively correlated with ER alpha and PR in breast cancer samples and is related to poor prognosis in endocrine therapy patients. TRIM56 depletion significantly decreases ER alpha signaling activity and ER-alpha-positive breast cancer proliferation in vitro and in vivo. TRIM56 associates with AF1 domain of ER alpha via its WD40 domain in the cytoplasm. TRIM56 prolongs ER alpha protein stability, possibly through targeting ER alpha K63-linked ubiquitination. In conclusion, our study reveals an interesting posttranslational mechanism between TRIM56 and ER alpha in breast cancer progression. Targeting TRIM56 could be a promising approach for ER-alpha-positive breast cancer.

130 Toremifene Citrate Improves High-Density Lipoprotein Levels in Men on Testosterone Replacement Therapy

Decreases in high-density lipoprotein (HDL) levels have been observed in men on testosterone therapy (TTh). Niacin is commonly used as a therapy for low HDL, although its side effect (SE) profile often leads to frequent discontinuation. Toremifine citrate is an oral selective estrogen modulator (SERM) that is well tolerated and can improve lipid profiles by raising HDL levels in both breast and prostate cancer patients. Here we assess the role of toremifene in the management of HDL abnormalities in men on TRT. Determine the effect of torimifene citrate on the HDL levels of hypogonadal men on TTh compared to both niacin and control groups. Men on TTh with low HDL levels (<39 mg/dL) at a single andrology clinic treated between October 2015 and August 2017 treated with either toremifine (60 mg daily), niacin (titrated to 1,000 mg daily over 2 months) plus krill oil (1,000 mg daily) (NKO), or no treatment (patient refusal) were reviewed in a retrospective intent-to-treat analysis. Patient age, type of TTh, length of follow-up, and baseline and subsequent non-fasting lipid panels, total testosterone (TT) levels, and estrogen (E) levels were determined. Analysis of variance (ANOVA) was used to determine differences between groups.