DOCSLIB.ORG

Bazedoxifene: a New Selective Estrogen-Receptor Modulator for Postmenopausal Osteoporosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Bazedoxifene: a New Selective Estrogen-Receptor Modulator for Postmenopausal Osteoporosis DRUG EVALUATION Bazedoxifene: a new selective estrogen-receptor modulator for postmenopausal osteoporosis Bazedoxifene acetate (WAY-140424; TSE-424) is an oral, nonsteroidal, indole-based selective estrogen- receptor modulator that is being clinically evaluated as a monotherapy for the prevention and treatment of osteoporosis and in combination with conjugated estrogens for the treatment of menopausal symptoms and prevention of osteoporosis. Developed by Wyeth (now Pfizer) Pharmaceuticals (NJ, USA), it is undergoing regulatory review for clinical use under the trade name Viviant™ by the US FDA. Bazedoxifene is currently marketed in Switzerland, Spain, Italy, Germany, Ireland and Japan. Its brand names in the EU and Japan are Conbriza® and Viviant™, respectively. In the EU, Conbriza is indicated for the treatment of postmenopausal osteoporosis in women at increased risk of fracture. Bazedoxifene reduces vertebral fractures in postmenopausal osteoporotic women, and nonvertebral fractures in a subgroup of postmenopausal osteoporotic women at higher risk. This review describes the mechanism of action and summarizes the clinical experience with bazedoxifene. Current evidence indicates that bazedoxifene is effective and safe for the treatment of postmenopausal osteoporosis. KEYW ORDS: bazedoxifene n fracture n osteoporosis n sSERM Annie Kung Department of Medicine, University of Hong Kong, China [email protected] Osteoporosis is a global public health problem estrogen–progestin therapy, namely hormone that is estimated to affect more than 200 mil- replacement therapy, has been used extensively in lion people worldwide. The disease affects one post menopausal women for both prevention and in three postmenopausal women and one in treatment of osteoporosis. However, the signifi- five men aged above 65 years. According to the cant increase in incidences of breast cancer, stroke, WHO, osteoporosis is the cause of over 8.9 mil- heart attack and venous thromboembolism with lion fractures globally each year [1] . The com- estrogen–progestin therapy and the significant bined lifetime risk for hip, spine and forearm increase in the incidence of stroke with estrogen fracture has been estimated to be approximately therapy outweighed the benefit of fracture risk 40%, similar to that for coronary artery disease. reduction in older postmenopausal women [2]. By 2050, the cost of treating hip fracture alone Although other treatments for osteoporosis are in the USA is projected to be US$130 billion. available (bisphosphonates, RANKL inhibitor, In addition to this major burden on the health parathyroid hormone, calcitonin and strontium economy, hip fracture is associated with a mor- ranelate), the development of agents that can tality rate of 20–50% within the first year of mimic the action of estrogens in decreasing the occurrence. Although the age-adjusted fracture rate of bone turnover and preserve or increase rates have leveled off in North America and bone mass without the side effects of h ormone Europe, there is a rising trend in most parts of replacement therapy would be preferable. Asia. Rapid aging and changing lifestyle habits Selective estrogen-receptor modulators of the population mean that most fractures in (SERMs) are nonsteroidal estrogen-like molecules Asia are expected to occur in 50 years’ time. In that bind to the estrogen receptor (ER) a and b. view of the major consequence of osteoporotic Each SERM presents diverse clinical effects in fractures, early prevention and treatment of response to the conformational changes follow- individuals at risk remains an important goal ing formation of a distinct ER–SERM ligand throughout the world in the management of complex. They demonstrate variable agonist osteoporosis. and antagonist activity that is dependent on the genes being regulated and occurs on a tissue-by- Overview of the market tissue basis (i.e., a tissue-selective response). An Bone loss in postmenopausal women occurs as ideal SERM would possess agonistic ER action a result of lost estrogenic inhibition of osteo- on bone with an associated reduced fracture risk clastic bone resorption. Estrogen therapy or and beneficial effects on lipoprotein cholesterols 10.2217/IJR.12.47 © 2012 Future Medicine Ltd Int. J. Clin. Rheumatol. (2012) 7(6), 583–590 ISSN 1758-4272 583 DRUG EVALUATION Kung Bazedoxifene & postmenopausal osteoporosis DRUG EVALUATION with decreased cardiovascular risks. It would have bioavailability of both tablet and capsule formula- no stimulatory action on uterine endometrium tions is the same at approximately 6.2%, threefold or breast tissue. Positive effects in the CNS and higher than that of raloxifene [4]. To determine vagina, with fewer hot flushes and the mainte- the pharmacokinetics, multiple oral doses of 5, nance of vaginal secretion, would p rovide further 20 and 40 mg were administered to postmeno- benefits. pausal women in a crossover manner for 14 days. At present, two SERMs are available for clini- The maximum plasma concentration of bazedoxi- cal use: tamoxifen, a triphenylethylene approved fene was achieved 1–2 h following administra- for the treatment of breast cancer, and raloxifene, tion. The elimination half-life was 28 h without a benzothiophene approved for the prevention accumulation. More than 99% of the compound and treatment of postmenopausal osteoporosis was protein bound and a steady-state plasma con- and the prevention of breast cancer. centration was achieved by day 7 of oral admin- istration. When administration was extended to Introduction to the compound 30 days at various doses from 1 to 80 mg, plasma Bazedoxifene acetate (WAY-140424; TSE-424) concentration increased in a linear fashion with is an oral, nonsteroidal, indole-based SERM steady-state achieved by day 14 [5]. being developed for the prevention and treat- The metabolic disposition of bazedoxifene ment of osteoporosis. It is classified as a third- was evaluated in six healthy postmenopausal generation SERM and has the chemical name women by evaluation of blood, urine and feces 1H-indo-5-ol,1-[[4-[2(hexahydro-1H-azepin- following administration of a single 20-mg oral 1-yl)ethoxy]methyl]2-(-4-hydroxyphenyl)-3- dose of 14C-bazedoxifene [6]. Bazedoxifene was methyl] acetic acid [3]. The core binding domain mainly excreted in the feces (84.7%), with only consists of a 2-phenyl-3-methyl indole and a a minute amount excreted in the urine (0.81%). h examethylenamine ring at the side chain affecter Glucuronidation is the major metabolic path- region. way, as the major metabolite is bazedoxifene- Preclinical studies with bazedoxifene have 5-glucuronide. Little or no CYP450-mediated demonstrated estrogen agonist effects on the m etabolism was found. skeleton and lipid metabolism but not on breast and uterine endometrium. Phase III clinical stud- Preclinical data ies have shown favorable effects on the skeleton n Uterus without stimulation of endometrium and breast: E2 stimulates the uterine endometrium and causes bone loss in postmenopausal women without endometrial hyperplasia and cancer. The action of osteoporosis is prevented and vertebral fractures bazedoxifene on the uterus was evaluated with in women with postmenopausal osteoporosis an immature rat model by assessing uterine wet reduced. In women at high risk of fracture with weight [7,8]. At a dose of 0.5 mg/kg, bazedoxifene multiple risk factors, bazedoxifene reduces non- increased uterine wet weight by 35%; nonetheless, vertebral fracture risk in post hoc ana lysis. Clinical a dose of 5 mg/kg resulted in no significant differ- trials with bazedoxifene have shown beneficial ence in weight compared with placebo. Although effects on bone mineral density and bone turn- the 0.5 mg/kg dose of bazedoxifene increased uter- over markers with little or no stimulation of breast ine wet weight, which is consistent with that seen and endometrium. with raloxifene, no luminal epithelial cell hyper- trophy or hyperplasia, myometrial hypertrophy, or Pharmacodynamics, luminal distention was noted. These results show pharmacokinetics & metabolism that the increased uterine weight was not accom- Bazedoxifene binds to both ERa and ERb, with panied by hypertrophy or hyperplasia. Overall, a slightly higher affinity for ERa. The dissocia- bazedoxifene exhibits a small stimulatory effect tion constant for ERa is approximately equal to (at low doses) on rat uterine wet weight without 0.1 nM and for ERb is 0.3 nM. The IC50 (i.e., detectable histological changes. inhibitory concentration required to compete 50% of 17b -estradiol [E2] off the estrogen receptor) for nBreast bazedoxifene is 23 ± 15 and 85 ± 59 nM for ERa E2 stimulates the breast, exhibited by increased and ERb, respectively, compared with 4 ± 3 and ductal branching with minimal end-bud cell 43 ± 13 nM, respectively, for raloxifene [3]. proliferation, but has been associated with an The oral bioavailability of bazedoxifene has increased risk of breast cancer. Bazedoxifene has been evaluated in 18 healthy postmenopausal no stimulatory effect on MCF-7 human breast women under fasting conditions. The absolute tumor cell line proliferation [8,9]. In the presence 584 Int. J. Clin. Rheumatol. (2012) 7(6) future science group DRUG EVALUATION Kung Bazedoxifene & postmenopausal osteoporosis DRUG EVALUATION of E2, bazedoxifene dose-dependently inhibited the preclinical data indicate that bazedoxifene E2-induced MCF-7 cellular proliferation with may represent a promising new therapy for post- an IC50 value of 3.7 ± 1.6 nM [7]. In an in vivo
Load more

Recommended publications
  • Cryptorchidism and Endocrine Disrupting Chemicals ⇑ Helena E
    Molecular and Cellular Endocrinology 355 (2012) 208–220 Contents lists available at SciVerse ScienceDirect Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce Review Cryptorchidism and endocrine disrupting chemicals ⇑ Helena E. Virtanen , Annika Adamsson Department of Physiology, University of Turku, Finland article info abstract Article history: Prospective clinical studies have suggested that the rate of congenital cryptorchidism has increased since Available online 25 November 2011 the 1950s. It has been hypothesized that this may be related to environmental factors. Testicular descent occurs in two phases controlled by Leydig cell-derived hormones insulin-like peptide 3 (INSL3) and tes- Keywords: tosterone. Disorders in fetal androgen production/action or suppression of Insl3 are mechanisms causing Cryptorchidism cryptorchidism in rodents. In humans, prenatal exposure to potent estrogen diethylstilbestrol (DES) has Testis been associated with increased risk of cryptorchidism. In addition, epidemiological studies have sug- Endocrine disrupting chemical gested that exposure to pesticides may also be associated with cryptorchidism. Some case–control stud- ies analyzing environmental chemical levels in maternal breast milk samples have reported associations between cryptorchidism and chemical levels. Furthermore, it has been suggested that exposure levels of some chemicals may be associated with infant reproductive hormone levels. Ó 2011 Elsevier Ireland Ltd. All rights reserved. Contents 1. Background.
    [Show full text]
  • And Active-Controlled Phase 3 Study of Postmenopausal Women with Osteoporosis
    Christiansen et al. BMC Musculoskeletal Disorders 2010, 11:130 http://www.biomedcentral.com/1471-2474/11/130 RESEARCH ARTICLE Open Access SafetyResearch article of bazedoxifene in a randomized, double-blind, placebo- and active-controlled phase 3 study of postmenopausal women with osteoporosis Claus Christiansen*1, Charles H Chesnut III2, Jonathan D Adachi3, Jacques P Brown4, César E Fernandes5, Annie WC Kung6, Santiago Palacios7, Amy B Levine8, Arkadi A Chines8 and Ginger D Constantine8 Abstract Background: We report the safety findings from a 3-year phase 3 study (NCT00205777) of bazedoxifene, a novel selective estrogen receptor modulator under development for the prevention and treatment of postmenopausal osteoporosis. Methods: Healthy postmenopausal osteoporotic women (N = 7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. Safety and tolerability were assessed by adverse event (AE) reporting and routine physical, gynecologic, and breast examination. Results: Overall, the incidence of AEs, serious AEs, and discontinuations due to AEs in the bazedoxifene groups was not different from that seen in the placebo group. The incidence of hot flushes and leg cramps was higher with bazedoxifene or raloxifene compared with placebo. The rates of cardiac disorders and cerebrovascular events were low and evenly distributed among groups. Venous thromboembolic events, primarily deep vein thromboses, were more frequently reported in the active treatment groups compared with the placebo group; rates were similar with bazedoxifene and raloxifene. Bazedoxifene showed a neutral effect on the breast and an excellent endometrial safety profile. The incidence of fibrocystic breast disease was lower with bazedoxifene 20 and 40 mg versus raloxifene or placebo.
    [Show full text]
  • Critical Role of Oxidative Stress in Estrogen-Induced Carcinogenesis
    Critical role of oxidative stress in estrogen-induced carcinogenesis Hari K. Bhat*†, Gloria Calaf‡, Tom K. Hei*‡, Theresa Loya§, and Jaydutt V. Vadgama¶ *Department of Environmental Health Sciences, Mailman School of Public Health, 60 Haven Avenue-B1, Columbia University, New York, NY 10032; ‡Center for Radiological Research, Columbia University, New York, NY 10032; and Departments of §Pathology and ¶Medicine, Charles Drew University, Los Angeles, CA 90059 Communicated by Donald C. Malins, Pacific Northwest Research Institute, Seattle, WA, December 27, 2002 (received for review August 22, 2002) Mechanisms of estrogen-induced tumorigenesis in the target quinones generates oxidative stress and potentially harmful free organ are not well understood. It has been suggested that oxida- radicals that are postulated to be required for the carcinogenic tive stress resulting from metabolic activation of carcinogenic process, and analogous to the metabolic activation of hydrocar- estrogens plays a critical role in estrogen-induced carcinogenesis. bons and other nonsteroidal estrogen carcinogens (9, 19–22). We We tested this hypothesis by using an estrogen-induced hamster have investigated the role of oxidative stress in estrogen carci- renal tumor model, a well established animal model of hormonal nogenesis by using a well established hamster renal tumor model carcinogenesis. Hamsters were implanted with 17␤-estradiol (␤E2), that shares several characteristics with human breast and uterine 17␣-estradiol (␣E2), 17␣-ethinylestradiol (␣EE), menadione, a com- cancers, pointing to a common mechanistic origin (6, 9, 23). bination of ␣E2 and ␣EE, or a combination of ␣EE and menadione Different estrogens used in the present study differ in their for 7 months.
    [Show full text]
  • Selective Estrogen Receptor Modulators Enhance CNS Remyelination Independent of Estrogen Receptors
    This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Cellular/Molecular Selective estrogen receptor modulators enhance CNS remyelination independent of estrogen receptors Kelsey A. Rankin1, Feng Mei1, Kicheol Kim1, Yun-An A. Shen1, Sonia R. Mayoral1, Caroline Desponts2, Daniel S. Lorrain2, Ari J. Green1, Sergio E. Baranzini1, Jonah R. Chan1 and Riley Bove1 1University of California, San Francisco, Weill Institute for Neurosciences, Department of Neurology 2Inception Sciences, San Diego, CA https://doi.org/10.1523/JNEUROSCI.1530-18.2019 Received: 11 June 2018 Revised: 17 January 2019 Accepted: 20 January 2019 Published: 29 January 2019 Author contributions: K.R., Y.-A.A.S., A.J.G., J.R.C., and R.B. designed research; K.R., F.M., K.K., Y.- A.A.S., S.R.M., C.D., D.S.L., and S.B. performed research; K.R. analyzed data; K.R. wrote the first draft of the paper; K.R., J.R.C., and R.B. edited the paper; K.R. wrote the paper; F.M. and J.R.C. contributed unpublished reagents/analytic tools. Conflict of Interest: The authors declare no competing financial interests. We would like to thank the Innovation Program for Remyelination and Repair at the Weill Institute for Neurosciences at the University of California, San Francisco (UCSF). This work was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01NS062796, R01NS097428, R01NS095889, R01NS088155], the National Multiple Sclerosis Society [RG5203A4], The Adelson Medical Research Foundation: ANDP (A130141), the Heidrich Family and Friends and the Rachleff Family Endowments.
    [Show full text]
  • Bazedoxifene–Conjugated Estrogens for Treating Endometriosis Endometriosis: Nina S
    Endometriosis: Case Report Bazedoxifene–Conjugated Estrogens Teaching Points for Treating Endometriosis 1. The estrogen receptor (ER) is a definitive down- stream target in endometriosis. As an endometrial ER antagonist, bazedoxifene assures not only block- Valerie A. Flores, MD, ade of estrogen binding, but it also has the ability to Nina S. Stachenfeld, PhD, degrade the receptor. This unique property of baze- and Hugh S. Taylor, MD doxifene blocks estrogen action and makes it an attractive treatment option for endometriosis. 2. Conjugated estrogens paired with bazedoxifene do BACKGROUND: Endometriosis is a gynecologic disorder not require a progestin to block endometrial affecting 6–10% of reproductive-aged women. First-line growth, thus avoiding the side effects associated therapies are progestin-based regimens; however, failure with progestin-based regimens. 08/19/2018 on BhDMf5ePHKbH4TTImqenVGLGjjqParD6K7Nl5tTGGFqgjMmLRmuIlIgbkUbgVXoQ by http://journals.lww.com/greenjournal from Downloaded rates are high, often requiring alternative hormonal agents, each with unfavorable side effects. Bazedoxifene with con- ’ 1 Downloaded that can have a significant effect on patients lives. jugated estrogens is approved for treatment of menopausal Treatment consists of agents that induce atrophy of symptoms, and use in animal studies has demonstrated from regression of endometriotic lesions. As such, it represents endometriotic lesions. There is tremendous need for http://journals.lww.com/greenjournal a potential treatment option for endometriosis. therapies that are effective, have favorable side effect profiles, and can be used long term in women with CASE: A patient with stage III endometriosis referred for symptomatic endometriosis, especially for those not management of dysmenorrhea and cyclic pelvic pain was treated with 20 mg bazedoxifene and 0.45 mg conjugated responding to progestin-based regimens.
    [Show full text]
  • Bazedoxifene Plus Conjugated Oestrogens (Duavive®) the East of England Priorities Advisory Committee a Function Of
    PAC - Bazedoxifene plus conjugated oestrogens (Duavive®) The East of England Priorities Advisory Committee A function of FULL EVIDENCE REVIEW Bazedoxifene plus conjugated oestrogens (Duavive®) for post-menopausal symptoms in women with a uterus Recommendations on the use of bazedoxifene plus conjugated oestrogens (Duavive ®) for the treatment of post-menopausal symptoms in women with a uterus Routine commissioning of bazedoxifene plus conjugated oestrogens (Duavive®) for the treatment of post-menopausal symptoms in women with a uterus is currently NOT recommended because: • There is insufficient evidence to quantify the risks and benefits compared to current alternative treatments • There are no long term safety data. • Information on cost effectiveness and cost impact is not currently available. Recommendations will be reviewed in the light of new national guidance, new evidence and information on cost effectiveness. Medicine Bazedoxifene (BZA) plus conjugated oestrogens (CE), Duavive® Proposed sector of prescribing Primary and secondary care Key points/Evidence level Key points • Bazedoxifene acetate is a third generation selective oestrogen receptor modulator (SERM), similar to raloxifene, and has oestrogen-receptor agonist effects on bone, and antagonist effects on uterine and breast tissue. • When a SERM is paired with an oestrogen, it forms a tissue-selective estrogen complex (TSEC); a novel class of therapeutic agents, which achieve an optimal blend of estrogen receptor agonist and antagonist effects for the treatment of menopausal symptoms and prevention of osteoporosis. • Bazedoxifene combined with conjugated estrogens has recently been approved by the Food & Drug Administration (FDA) in the United States (US) for treatment of moderate-to- severe vasomotor symptoms associated with menopause and prevention of postmenopausal osteoporosis in women with a uterus as Duavee® and in the European Union (EU), as Duavive®, for the treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus.
    [Show full text]
  • Estrogen Actions Throughout the Brain
    Estrogen Actions Throughout the Brain BRUCE MCEWEN Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10021 ABSTRACT Besides affecting the hypothalamus and other brain areas related to reproduction, ovarian steroids have widespread effects throughout the brain, on serotonin pathways, catecholaminergic neurons, and the basal forebrain cholinergic system as well as the hippocampal formation, a brain region involved in spatial and declarative memory. Thus, ovarian steroids have measurable effects on affective state as well as cognition, with implications for dementia. Two actions are discussed in this review; both appear to involve a combination of genomic and nongenomic actions of ovarian hormones. First, regulation of the serotonergic system appears to be linked to the presence of estrogen- and progestin-sensitive neurons in the midbrain raphe as well as possibly nongenomic actions in brain areas to which serotonin neurons project their axons. Second, ovarian hormones regulate synapse turnover in the CA1 region of the hippocampus during the 4- to 5-day estrous cycle of the female rat. Formation of new excitatory synapses is induced by estradiol and involves N-methyl-D-aspartate (NMDA) receptors, whereas downregulation of these synapses involves intracellular progestin receptors. A new, rapid method of radioimmunocytochemistry has made possible the demonstration of synapse formation by labeling and quantifying the specific synaptic and dendritic molecules involved. Although NMDA receptor activation is required for synapse formation, inhibitory interneurons may play a pivotal role as they express nuclear estrogen receptor-alpha (ER␣). It is also likely that estrogens may locally regulate events at the sites of synaptic contact in the excitatory pyramidal neurons where the synapses form.
    [Show full text]
  • Interactions of Putative Estrogens with the Intracellular Receptor Complex in Mouse Leydig Cells: Relationship to Preneoplastic Hyperplasia R
    [CANCER RESEARCH 48, 14-18, January 1, 1988) Interactions of Putative Estrogens with the Intracellular Receptor Complex in Mouse Leydig Cells: Relationship to Preneoplastic Hyperplasia R. Lloyd Juriansz,1 Robert A. Huseby, and R. Bruce Wilcox2 Department of Biochemistry, Loma Linda University, Loma Linda, California 92350 ABSTRACT (3), the initial spurt of DNA synthesis occurs independent of pituitary function (6). Actual tumor induction, however, results The interaction of 14 steroidal and nonsteroidal estrogen agonists and from action of unmetabolized estrogen directly upon the Leydig antagonists with the intracellular estrogen receptor system was examined cells (7). These cells in both a susceptible and a nonsusceptible in cell suspensions prepared from the testes of mice that develop malig strain of mouse contain an ER3 complex. The cells from the nant Leydig cell tumors after prolonged estrogen administration. The ability of these substances to stimulate DNA synthesis in short-term (3- two strains differ significantly in that nuclei from susceptible day) studies and to provoke Leydig cell hyperplasia with prolonged (3- animals bind more estrogen, and the proportion of the nuclear mo) administration was also measured. Our data were consistent with ER that remains fixed to the nuclear matrix in solutions of the proposal that, in Leydig cells, the carcinogenic effects of estrogens high salt concentration is greater in the tumor-susceptible ani are mediated through the intracellular receptor complex that results in a mals (8). Furthermore this fraction of the ER increases in localization of hormone bound to chromâtin and nuclear matrix. All tested compounds displaced 170-[3H]estradiol from the cytosolic amount per Leydig cell as estrogen treatment of susceptible mice continues over a 3-mo period and hyperplasia is initiated estrogen receptor, but to varying degrees; and there was no discernible (9).
    [Show full text]
  • Menopausal Hormone Therapy
    GYNAECOLOGY ENDOCRINOLOGY Menopausal hormone therapy: where are we now? Menopausal hormone therapy (MHT) is an effective treatment for symptoms associated with menopause, such as hot flushes, night sweats, mood changes, sleep disturbances and changes in sexual function. While the evidence around MHT has changed over the years, there is now international consensus that the benefits of MHT are likely to outweigh the risks for most women aged < 60 years or within ten years of menopause, for whom menopausal symptoms are affecting their quality of life. KEY PRACTICE POINTS: Every woman’s experience of menopause is different, and Among the oestrogen and progestogen formulations perceptions of menopause vary across cultures. Most available, transdermal oestrogen (funded) and micronised women will experience some menopause symptoms, progesterone (not funded) are associated with the lowest however, only some will seek treatment. risk of adverse effects Menopausal hormone therapy (MHT) is likely to offer overall There is no specific recommended duration for MHT. The benefit to women with menopausal symptoms affecting decision to continue treatment should be reviewed on their quality of life if they are aged < 60 years or within ten an annual basis, taking into account any changes in the years of menopause patient’s risk factors, adverse effects and extent of benefit. Adverse outcomes associated with MHT include breast If women primarily seek assistance for urogenital symptoms cancer, stroke and venous thromboembolism (VTE). of menopause, vaginal products are recommended instead However, the risk of these outcomes depends on factors of MHT. This includes moisturisers, lubricants or a vaginal such as the age or time since menopause when MHT oestrogen cream or pessary.
    [Show full text]
  • Identification and Confirmation of the Environmental Risks of Emerging Pollutants in Surface Waters and Sediments
    Identification and confirmation of the environmental risks of emerging pollutants in surface waters and sediments Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der RWTH Aachen University zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigte Dissertation Vorgelegt von Shangbo Zhou, Master of engineering aus Gansu, China Berichter: Univ.-Prof. Dr. rer. nat. Henner Hollert Univ.-Prof. Dr. rer. nat. Andreas Schäffer Tag der mündlichen Prüfung: 24.09.2019 Diese Dissertation ist auf den Internetseiten der Universitätsbibliothek online verfügbar. Your teacher can open the door but you must enter by yourself. – Chinese verb Abstract Although the occurrence, the fate and the toxicology of emerging pollutants in the aquatic environment have been widely studied, there is still a lack in the correlation of the levels of pollutants with the possible adverse effects in wildlife. The shortcomings of traditional methods for risk assessment have been observed, and the contributions of the identified compounds to the observed risks are rarely confirmed. Therefore, the main purpose of this thesis was to develop reasonable methods for risk identification of single compounds and mixtures, and to identify and confirm environmental risks caused by non-specific and mechanism-specific toxicity in aquatic systems. In this thesis, optimized methods for risk identification of single compounds and mixtures were developed. For screening-level risk assessment of single compounds, an optimized risk quotient that considers not only toxicological data but also the frequency with which the detected concentrations exceeded predicted no-effect concentrations was used to screen candidate priority pollutants in European surface waters. Results showed that 45 of the 477 analyzed compounds indicated potential risks for European surface waters.
    [Show full text]
  • Effects of Diethylstilbestrol on the Proliferation and Tyrosinase Activity of Cultured Human Melanocytes
    BIOMEDICAL REPORTS 3: 499-502, 2015 Effects of diethylstilbestrol on the proliferation and tyrosinase activity of cultured human melanocytes JIANBING TANG, QIN LI, BIAO CHENG, CHONG HUANG and KUI CHEN Department of Plastic Surgery, The Key Laboratory of Trauma Treatment and Tissue Repair of Tropical Area, People's Liberation Army, HuaBo BioPharmaceutical Institute of Guangzhou, General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China Received March 13, 2015; Accepted April 24, 2015 DOI: 10.3892/br.2015.472 Abstract. The aim of the present study was to observe the with estrogen. The pigmented spot becomes more severe and effects of different exogenous estrogen diethylstilbestrol (DES) malignant melanoma proceeds rapidly during an abnormal concentrations on the human melanocyte proliferation and menstruation or pregnancy. There are changes in the estrogen tyrosinase activity. Skin specimens were obtained following level in these physiological processes. Therefore, estrogen blepharoplasty, and the melanocytes were primary cultured is considered an important factor that affects pigmented and passaged to the third generation. The melanocytes were diseases (1). Diethylstilbestrol (DES) is a synthetic nonsteroidal seeded in 96-well plates, each well had 5x103 cells. The medium estrogen that can produce the same pharmacological effects as was changed after 24 h, and contained 10-4-10 -8 M DES. After natural estrogen (2). In order to explore the mechanism, the the melanocytes were incubated, the proliferation and tyrosi- excess skin following eyelid blepharoplasty was collected for nase activity were detected by the MTT assay and L-DOPA melanocyte culture and different DES concentrations were reaction. DES (10-8-10 -6 M) enhanced the proliferation of used to detect the effect on the proliferation and tyrosinase cultured melanocytes.
    [Show full text]
  • Endocrine Disruptors and Their Influence in the Origin of Breast Neoplasm and Other Breast Pathologies
    REVIEW ARTICLE DOI: 10.29289/2594539420180000294 ENDOCRINE DISRUPTORS AND THEIR INFLUENCE IN THE ORIGIN OF BREAST NEOPLASM AND OTHER BREAST PATHOLOGIES Disruptores endócrinos e o seu papel na gênese das neoplasias e de outras patologias das mamas Mauri José Piazza1*, Almir Antônio Urbanetz1, Cicero Urban2 ABSTRACT A higher occurrence of early breast cancer in women has created the need to identify possible etiologic agents characterized as direct co-responsible. The motivation for this review is the relevance of detecting potential endocrine disruptors responsible for harmful effects on breast tissue and, consequently, its damage. KEYWORDS: Breast; breast cancer; breast neoplasms. RESUMO Uma maior ocorrência no surgimento precoce das neoplasias das mamas em mulheres tem gerado a necessidade da descoberta dos possíveis agentes etiológicos caracterizados como corresponsáveis diretos. A relevância da detecção dos possíveis disruptores endócrinos responsáveis por exercer efeitos danosos nos tecidos mamários e, consequentemente, o seu comprometimento é a motivação da presente revisão. PALAVRAS-CHAVE: Mama; câncer de mama; neoplasias da mama. Study conducted at Universidade Federal do Paraná – Curitiba (PR), Brazil. 1Department of Obstetrics and Gynecology, Universidade Federal do Paraná – Curitiba (PR), Brazil. 2Universidade Positivo – Curitiba (PR), Brazil. *Corresponding author: [email protected] Conflict of interests: nothing to declare. Received on: 11/16/2017. Accepted on: 02/05/2018. Mastology, 2018;28(4):257-67 257 Piazza MJ, Urbanetz AA, Urban C INTRODUCTION 2. Phthalates (Figure 2): phthalates and phthalate esters are also In recent decades, a higher incidence of hormone-dependent neo- commonly used in the plastic and toys industries, in cosmet- plasms has been observed in body parts such as breasts, endo- ics, and in medical tubing manufacturing.
    [Show full text]