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1.
Effect of estrogen-active compounds on the expression of RACK1 and immunological implications.
Buoso, E, Masi, M, Galbiati, V, Maddalon, A, Iulini, M, Kenda, M, Sollner Dolenc, M, Marinovich, M, Racchi, M, Corsini, E
Archives of toxicology. 2020;(6):2081-2095
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Abstract
We previously demonstrated the existence of a balance among steroid hormones, i.e. glucocorticoids and androgens, in RACK1 (receptor for activated C kinase 1) expression and innate immunity activation, which may offer the opportunity to use RACK1 expression as marker to evaluate immunotoxicity of hormone-active substances. Because of the existence of close interconnections between the different steroid hormone receptors with overlapping ligand specificities and signaling pathways, in this study, we wanted to investigate a possible effect of estrogenic active compounds, namely 17β-estradiol, diethylstilbestrol, and zearalenone, on RACK-1 expression and innate immune responses using THP-1 cells as experimental model. All compounds increased RACK1 transcriptional activity as evaluated by reporter luciferase activity, mRNA expression as assessed by real time-PCR and protein expression by western blot analysis, which paralleled an increase in LPS-induced IL-8, TNF-α production, and CD86 expression, which we previously demonstrated to be dependent on RACK1/PKCβ activation. As the induction of RACK1 expression can be blocked by the antagonist G15, induced by the agonist G1 and by the non-cell permeable 17β-estradiol conjugated with BSA, a role of GPER (previously named GPR30) activation in estrogen-induced RACK1 expression could be demonstrated. In addition, a role of androgen receptor (AR) in RACK1 transcription was also demonstrated by the ability of flutamide, a nonsteroidal antiandrogen, to completely prevent diethylstilbestrol-induced RACK1 transcriptional activity and protein expression. Altogether, our data suggest that RACK1 may represent an interesting target of steroid-active compounds, and its evaluation may offer the opportunity to screen the immunotoxic potential of hormone-active substances.
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Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids.
Schlaff, WD, Ackerman, RT, Al-Hendy, A, Archer, DF, Barnhart, KT, Bradley, LD, Carr, BR, Feinberg, EC, Hurtado, SM, Kim, J, et al
The New England journal of medicine. 2020;(4):328-340
Abstract
BACKGROUND Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding. METHODS We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal "add-back" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation. RESULTS A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy. CONCLUSIONS Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.).
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Herbal supplements interactions with oral oestrogen-based contraceptive metabolism and transport.
Hlengwa, N, Muller, CJF, Basson, AK, Bowles, S, Louw, J, Awortwe, C
Phytotherapy research : PTR. 2020;(7):1519-1529
Abstract
The increased use of herbal supplements as complementary or alternative medicines has become a clinical conundrum due to the potential for herb-drug interactions. This is exacerbated by an increased supply of new herbal supplements in the market claiming various health advantages. These herbal supplements are available as over-the-counter self-medications. Herbal supplements are generally perceived as efficacious without side effects commonly associated with conventional drugs. However, despite regulations, claims related to their therapeutic effects are mostly unsupported by scientific evidence. These products often lack suitable product quality controls, labelled inadequately and with batch to batch variations, potentially compromising the safety of the consumer. Amongst health practitioners, the greatest concern is related to the lack of chemical characterization of the active compounds of the herbal supplements. The interaction between these different active components and their concomitant effects on other conventional drugs is generally not known. This review will focus on herbal supplements with the potential to effect pharmacokinetic and pharmacodynamic properties of oestrogen-based oral contraceptives. The use of herbal supplements for weight management, depression, and immune boosting benefits were selected as likely herbal supplements to be used concomitantly by women on oral contraceptives.
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Association between FTO gene polymorphisms and breast cancer: the role of estrogen.
Gholamalizadeh, M, Jarrahi, AM, Akbari, ME, Bourbour, F, Mokhtari, Z, Salahshoornezhad, S, Doaei, S
Expert review of endocrinology & metabolism. 2020;(2):115-121
Abstract
Introduction: The fat mass and obesity-associated (FTO) gene may be associated with breast cancer risk. This study aimed to systematically investigate the association between FTO gene polymorphisms and breast cancer and the possible role of estrogen in this association.Areas covered: We performed an extensive search of electronic databases such as PubMed, Science Direct, Scopus, and Cochran for published original studies on the association of FTO gene polymorphisms with breast cancer risk. Keywords such as breast cancer and/or FTO gene and/or polymorphism were used in order to identify the related articles. We excluded studies unrelated to the FTO genotype and the outcome of breast cancer.Expert opinion: FTO gene may have a significant association with the risk of breast cancer. The association between FTO gene polymorphisms and breast cancer was influenced by the status of estrogen receptors. Estrogen may promote breast cancer cell proliferation through up-regulation of FTO gene expression and activation of the PI3 K/Akt signaling pathway in estrogen receptor positive patients. Further studies are warranted to identify the underlying mechanisms and signaling pathways involved in the interactions between FTO gene, estrogen, and the risk of breast cancer.
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5.
Sex Differences in Adipose Tissue Function.
Gavin, KM, Bessesen, DH
Endocrinology and metabolism clinics of North America. 2020;(2):215-228
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Abstract
Regional adipose tissue distribution differs between men and women. Differences in the accumulation of adipose tissue as well as the regulation of secretion of a number of products from adipose tissue are under the control of sex steroids, which act through a wide variety of mechanisms, both direct and indirect, to tailor metabolism to the unique needs of each sex. A fuller understanding of sex-based differences in adipose tissue function may help with tailored strategies for disease prevention and treatment and provide insights into fundamental differences in the processes that regulate nutrient homeostasis and body weight.
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Characterization of Hormone-Dependent Pathways in Six Human Prostate-Cancer Cell Lines: A Gene-Expression Study.
Franko, A, Berti, L, Guirguis, A, Hennenlotter, J, Wagner, R, Scharpf, MO, de Angelis, MH, Wißmiller, K, Lickert, H, Stenzl, A, et al
Genes. 2020;(10)
Abstract
Prostate cancer (PCa), the most incident cancer in men, is tightly regulated by endocrine signals. A number of different PCa cell lines are commonly used for in vitro experiments, but these are of diverse origin, and have very different cell-proliferation rates and hormone-response capacities. By analyzing the gene-expression pattern of main hormone pathways, we systematically compared six PCa cell lines and parental primary cells. We compared these cell lines (i) with each other and (ii) with PCa tissue samples from 11 patients. We found major differences in the gene-expression levels of androgen, insulin, estrogen, and oxysterol signaling between PCa tissue and cell lines, and between different cell lines. Our systematic characterization gives researchers a solid basis to choose the appropriate PCa cell model for the hormone pathway of interest.
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The Case for an Estrogen-iron Axis in Health and Disease.
Hamad, M, Bajbouj, K, Taneera, J
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2020;(4):270-277
Abstract
Clinical and experimental evidence suggest that estrogen manipulates intracellular iron metabolism and that elevated levels of estrogen associate with increased systemic iron availability. This has been attributed to the ability of estrogen to suppress hepcidin synthesis, maintain ferroportin integrity and enhance iron release from iron-absorbing duodenal enterocytes and iron-storing macrophages and hepatocytes. These observations speak of a potential "estrogen-iron" axis that manipulates iron metabolism in response to hematologic (erythropoiesis) and non-hematologic (uterine growth, pregnancy, lactation) needs for iron. Such an axis could contribute to minimizing iron deficiency in premenopausal women and iron overload in postmenopausal women. It could also exacerbate iron overload and related clinical consequences including cancer, osteoporosis, cardiovascular complications and neurodegenerative symptoms, especially in postmenopausal women on hormonal replacement therapy. Understanding the role of estrogen in iron metabolism may shed some light on the pleotropic, but often paradoxical, roles of estrogen in human health and disease.
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Elucidating Binding Sites and Affinities of ERα Agonists and Antagonists to Human Alpha-Fetoprotein by In Silico Modeling and Point Mutagenesis.
Moldogazieva, NT, Ostroverkhova, DS, Kuzmich, NN, Kadochnikov, VV, Terentiev, AA, Porozov, YB
International journal of molecular sciences. 2020;(3)
Abstract
Alpha-fetoprotein (AFP) is a major embryo- and tumor-associated protein capable of binding and transporting a variety of hydrophobic ligands, including estrogens. AFP has been shown to inhibit estrogen receptor (ER)-positive tumor growth, which can be attributed to its estrogen-binding ability. Despite AFP having long been investigated, its three-dimensional (3D) structure has not been experimentally resolved and molecular mechanisms underlying AFP-ligand interaction remains obscure. In our study, we constructed a homology-based 3D model of human AFP (HAFP) with the purpose of molecular docking of ERα ligands, three agonists (17β-estradiol, estrone and diethylstilbestrol), and three antagonists (tamoxifen, afimoxifene and endoxifen) into the obtained structure. Based on the ligand-docked scoring functions, we identified three putative estrogen- and antiestrogen-binding sites with different ligand binding affinities. Two high-affinity binding sites were located (i) in a tunnel formed within HAFP subdomains IB and IIA and (ii) on the opposite side of the molecule in a groove originating from a cavity formed between domains I and III, while (iii) the third low-affinity binding site was found at the bottom of the cavity. Here, 100 ns molecular dynamics (MD) simulation allowed us to study their geometries and showed that HAFP-estrogen interactions were caused by van der Waals forces, while both hydrophobic and electrostatic interactions were almost equally involved in HAFP-antiestrogen binding. Molecular mechanics/Generalized Born surface area (MM/GBSA) rescoring method exploited for estimation of binding free energies (ΔGbind) showed that antiestrogens have higher affinities to HAFP as compared to estrogens. We performed in silico point substitutions of amino acid residues to confirm their roles in HAFP-ligand interactions and showed that Thr132, Leu138, His170, Phe172, Ser217, Gln221, His266, His316, Lys453, and Asp478 residues, along with two disulfide bonds (Cys224-Cys270 and Cys269-Cys277), have key roles in both HAFP-estrogen and HAFP-antiestrogen binding. Data obtained in our study contribute to understanding mechanisms underlying protein-ligand interactions and anticancer therapy strategies based on ERα-binding ligands.
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Decreased bone mineral density and reproductive axis dysfunction: more than oestrogen.
DeLoughery, EP, Dow, ML
The Netherlands journal of medicine. 2020;(2):50-54
Abstract
Decreased bone mineral density (BMD) in oestrogendeficient states has long been thought to be a direct outcome of the reduction in oestrogen. In physiologic and many pathologic hypo-oestrogenic states, oestrogen supplementation improves BMD. However, the relationship between oestrogen replacement and BMD is less clear in the case of reproductive axis dysfunction secondary to decreased caloric intake or increased energy expenditure, such as in female athletes or anorexia nervosa. This decrease in oestrogen is associated with decreased BMD, but oestrogen replacement in these states fails to conclusively improve BMD. This suggests that the decrease in BMD in these states is not driven solely by low oestrogen. Cortisol and other markers of inflammation may play a role in BMD reduction but further research is needed. What is clear is that increased caloric consumption and restoration of menses and the reproductive axis are essential to improving BMD, while pharmacologic therapy, including oestrogen replacement through hormone therapy or contraceptives, does not provide conclusive benefit.
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The Use of Transdermal Estrogen in Castrate-resistant, Steroid-refractory Prostate Cancer.
Smith, K, Galazi, M, Openshaw, MR, Wilson, P, Sarker, SJ, O'Brien, N, Alifrangis, C, Stebbing, J, Shamash, J
Clinical genitourinary cancer. 2020;(3):e217-e223
Abstract
BACKGROUND Androgen-deprivation therapy is the mainstay of treatment for metastatic prostate cancer. Corticosteroids and estrogens are also useful agents in castration-resistant prostate cancer (CRPC). However, oral estrogens are associated with thromboembolic events, which limits their use, and transdermal estrogens may offer a safer alternative. This study was carried out to determine the safety and effectiveness of transdermal estrogens in CRPC. PATIENTS AND METHODS Forty-one patients with CRPC and steroid-resistant prostate cancer were eligible for this dose-escalation study of transdermal estradiol. A starting dose of 50 mcg/24 hours was applied and increased if prostate-specific antigen (PSA) rose > 5 ng/mL in steps to 300 mcg/24 hours. The primary endpoint was PSA response, and secondary outcomes included incidence of thromboembolic events and progression-free survival. Patients who progressed were offered diethylstilbestrol. RESULTS Five (13%) of 40 patients had > 50% PSA reduction for at least 1 month at any transdermal estradiol dose. No venous-thromboembolic events were observed, and responses plateaued at 200 mcg/24 hours. A correlation between PSA response and rising sex hormone binding globulin was seen. Fifty percent of patients subsequently responded to low-dose diethylstilbestrol. CONCLUSION Transdermal estradiol appears to be a low toxicity treatment option to control CRPC after failure of steroid therapy. Modulation of sex hormone binding globulin by transdermal estradiol may be one mechanism of action of estrogens on CRPC. Oral estrogens remain effective after the use of transdermal estradiol.