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Effects of estrogen and raloxifene on neuroglia number and morphology in the hippocampus of aged female mice.

Lei DL, Long JM, Hengemihle J, O'Neill J, Manaye KF, Ingram DK, Mouton PR.

Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, NIH, Baltimore, MD 21224, USA.

Hormone replacement therapy with the gonadal steroid estrogen or synthetic agents such as raloxifene, a selective estrogen receptor modulator, may affect cellular function in brains of postmenopausal women. In vitro studies suggest that 17beta estradiol and raloxifene can alter the microglial and astrocyte expression of immuno-neuronal modulators, such as cytokines, complement factors, chemokines, and other molecules involved in neuroinflammation and neurodegeneration. To directly test whether exogenous 17beta estradiol and raloxifene affect the number of glial cells in brain, C57BL/6NIA female mice aged 20-24 months received bilateral ovariectomy followed by s.c. placement of a 60-day release pellet containing 17beta estradiol (1.7 mg), raloxifene (10 mg), or placebo (cholesterol). After 60 days, numbers of microglia and astrocytes were quantified in dentate gyrus and CA1 regions of the hippocampal formation using immunocytochemistry and design-based stereology. The results show that long-term 17beta estradiol treatment in aged female mice significantly lowered the numbers of astrocytes and microglial cells in dentate gyrus and CA1 regions compared with placebo. After long-term treatment with raloxifene, a similar reduction was observed in numbers of astrocytes and microglial cells in the hippocampal formation. These findings indicate that estrogen and selective estrogen receptor modulators can influence glial-mediated inflammatory pathways and possibly protect against age- and disease-related neuropathology.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14568026&dopt=Abstract raloxifene Evista



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beta-estradiol influences differentiation of hippocampal neurons in vitro through an estrogen receptor-mediated process.

Audesirk T, Cabell L, Kern M, Audesirk G.

Biology Department, University of Colorado at Denver, PO Box 173364, Denver, CO 80217-3364, USA. taudesir carbon.cudenver.edu

We utilized morphometric analysis of 3 day cultures of hippocampal neurons to determine the effects of both estradiol and the synthetic estrogen receptor modulator raloxifene on several parameters of neuronal growth and differentiation. These measurements included survival, neurite production, dendrite number, and axon and dendrite length and branching. 17 beta-Estradiol (10 nM) selectively stimulated dendrite branching; this effect was neither mimicked by alpha-estradiol, nor blocked by the estrogen receptor antagonist ICI 182780. The selective estrogen receptor modulator raloxifene (100 nM) neither mimicked nor reversed the effects of estradiol on dendritic branching. Western immunoblotting for the alpha and beta subtypes of estrogen receptor revealed the presence of alpha, but not beta, estrogen receptors in our hippocampal cultures. There is growing recognition of the effects of 17 beta-estradiol on neuronal development and physiology, with implications for brain sexual dimorphism, plasticity, cognition, and the maintenance of cognitive function during aging. The role of estradiol in hippocampal neuronal differentiation and function has particular implications for learning and memory. These data support the hypothesis that 17 beta-estradiol is acting via alpha estrogen receptors in influencing hippocampal development in vitro. Raloxifene, prescribed to combat osteoporosis in post-menopausal women, is a selective estrogen receptor modulator with tissue-specific agonist/antagonist properties. Because raloxifene had no effect on dendritic branching, we hypothesize that it does not interact with the alpha estrogen receptor in this experimental paradigm.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14580943&dopt=Abstract raloxifene Evista



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Apoptotic action of 17beta-estradiol in raloxifene-resistant MCF-7 cells in vitro and in vivo.

Liu H, Lee ES, Gajdos C, Pearce ST, Chen B, Osipo C, Loweth J, McKian K, De Los Reyes A, Wing L, Jordan VC.

Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

BACKGROUND: Resistance to tamoxifen, a selective estrogen receptor modulator (SERM), involves changes that prevent apoptosis and enhance cell proliferation and survival. Paradoxically, estrogen treatment inhibits the growth of long-term tamoxifen-treated breast tumors. Because of the increasing use of raloxifene, another SERM, to prevent osteoporosis and potentially reduce breast cancer risk, some women will develop raloxifene-resistant breast cancer. We developed a raloxifene-resistant MCF-7 cell model (MCF-7/Ral) and investigated the nature of raloxifene-resistant breast cancer and its response to estradiol. METHODS: Raloxifene resistance and hormone responsiveness were assessed by proliferation assays and cell cycle analysis in parental MCF-7 and MCF-7/Ral cells. Nuclear factor kappaB (NF-kappaB) activity was investigated with a transient transfection assay. Apoptosis was investigated by annexin V staining, mRNA was measured by real-time polymerase chain reaction, and protein was measured by western blotting. Tumorigenesis was studied by injecting MCF-7 or MCF-7/Ral cells into ovariectomized athymic mice (10 per group) and monitoring tumor size weekly. All statistical tests were two-sided. RESULTS: Basal NF-kappaB activity was higher in MCF-7/Ral cells (1.6 U, 95% confidence interval [CI] = 1.2 to 2.0 U) than in MCF-7 cells (0.8 U, 95% CI = 0.4 to 1.1 U; P =.004). When cultured with 1 microM raloxifene, MCF-7/Ral cells grew statistically significantly (P<.001) faster than MCF-7 cells. Estradiol treatment of MCF-7/Ral cells arrested cells in G(2)/M phase of the cell cycle, decreased NF-kappaB activity (0.2 U, 95% CI = 0.2 to 0.3 U; P<.001), increased expression of Fas protein and mRNA (4.5-fold, 95% CI = 2.8- to 6.3-fold versus 0.5-fold, 95% CI = 0.3- to 0.8-fold for control treatment; P<.001), and induced apoptosis. Treatment with either raloxifene or tamoxifen stimulated MCF-7/Ral tumor growth, suggesting that such tumors were resistant to both drugs. When a 9-week raloxifene or tamoxifen treatment was followed by a 5-week estradiol treatment, estradiol statistically significantly reduced the size of tumors stimulated by raloxifene or tamoxifen (at week 14, P =.004 for raloxifene and P<.001 for tamoxifen). CONCLUSIONS: Growth of raloxifene-resistant MCF-7/Ral cells in vitro and in vivo is repressed by estradiol treatment by a mechanism involving G2/M-phase arrest, decreased NF-kappaB activity, and increased Fas expression to induce apoptosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14600091&dopt=Abstract raloxifene Evista



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Treatment of desmoids and mesenteric fibromatosis in familial adenomatous polyposis with raloxifene.

Tonelli F, Ficari F, Valanzano R, Brandi ML.

Department of Clinical Physiopathology, University of Florence, Italy.

BACKGROUND: Among the great variety of extracolonic manifestations of familial adenomatous polyposis, the most serious are desmoids and fibromatosis of the abdominal cavity. These may be a danger to the patient and a concern to the clinician. Pharmacological management of this relentless problem is favored by surgical intervention. At present, however, beneficial actions of medical therapy are not separable from undesirable side effects. METHODS: We studied the effects of 120 mg daily of raloxifene, a non-steroidal benzothiophene, on progressive desmoid tumors and mesenteric fibromatosis by evaluation of lesion size and symptoms in 13 patients with familial adenomatous polyposis, selected on the basis of intra-abdominal localization of the lesion, on refractoriness to other medical treatments, and on estrogen receptor-alpha expression. RESULTS: The patients had a significant response to raloxifene therapy, with complete remission in 8 cases and partial response in 5 cases, evaluated by regression of symptoms and tumor size. Serum biochemical parameters did not show any significant changes. Side effects were never observed. CONCLUSIONS: Although the number of patients included in the study is limited and in spite of some limitations, the available results support that, in the evaluation of response, daily therapy with raloxifene decreases desmoid tumor and mesenteric fibromatosis size and symptoms and does not cause side effects. These findings offer a novel option in the pharmacological treatment of desmoids, leading to medical therapy of these neoplastic lesions in familial adenomatous polyposis patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14606641&dopt=Abstract raloxifene Evista



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Modeling the annual costs of postmenopausal prevention therapy: raloxifene, alendronate, or estrogen-progestin therapy.

Mullins CD, Ohsfeldt RL.

University of Maryland School of Pharmacy, 515 W. Lombard St., Room 262, Baltimore, MD 21201-1563, USA. dmullins rx.umaryland.edu

OBJECTIVE: To estimate the annual cost and outcome impacts attributable to raloxifene, alendronate, and estrogen-progestin therapy as prevention therapies among postmenopausal women over the first 7 years of hormone replacement therapy (HRT). METHODS: A budget-impact model was devised to compare the costs, benefits, and costs per event avoided for various postmenopausal therapies (raloxifene, alendronate, or estrogen-progestin combination therapy), compared to no intervention, taking into account the persistency rates. Net costs are direct medical costs attributable to treatments relative to no intervention. Net benefits are defined as the number of events avoided as a result of therapy. The main outcome measures are annual total net costs, net benefits, and costs per event avoided compared to no intervention among postmenopausal white women with intact uteri and normal baseline risks for osteoporotic hip or vertebral fractures, fatal or nonfatal myocardial infarction, and breast cancer. Data and model assumptions are based on clinical trial data and published retrospective studies. RESULTS: The average annual net cost of therapy declines after the first year of therapy for all interventions, primarily due to discontinuation, and continues to decline over time due to savings in medical costs for events avoided. Net events avoided are greater for raloxifene than alendronate, but HRT use results in net harm. The cost per event avoided is lower for raloxifene than alendronate. Improved persistence improves the cost-effectiveness for both interventions. Sensitivity analyses indicate the model results are most sensitive to the assumed impact of raloxifene on coronary heart disease and breast cancer risk. Alendronate as a prevention intervention is dominated by raloxifene under almost all model scenarios. CONCLUSION: The annual cost of long-term postmenopausal prevention therapy is highest during the first few years of therapy. Long-term prevention does not provide a return on investment in fewer than 3 years, but savings in medical costs partially offset intervention costs after 2 years. For postmenopausal women, pharmacologic interventions with multiple prevention benefits tend to be more cost effective than interventions with a single source of health benefit.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14613344&dopt=Abstract raloxifene Evista



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Raloxifene inhibits cholesterol aortic content but not atherosclerotic plaque size in oophorectomised cholesterol-fed rabbits.

Castelo-Branco C, Sanjuan A, Casals E, Ascaso C, Colodron M, Vicente JJ, Mercader I, Escaramis G, Blumel JE, Ordi J, Vanrell JA.

Menopause Clinic, Department of Gynecology and Obstetrics, Public Health Department, Hospital Clinic Provincial, University of Barcelona, Spain. castelo medicina.ub.es

Raloxifene, a selective oestrogen receptor modulator, is effective in the treatment of osteoporosis without stimulating the breast and the endometrium. Although it is associated with a decrease of cardiovascular risk markers the effect of these changes on atherogenesis, is not clear. In this study, we aimed to investigate the effect of raloxifene on aorta atherogenesis. A total of 32 cholesterol-fed New Zealand white rabbits were studied for 4 months. Twenty-four rabbits underwent bilateral ovariectomy; of these eight received raloxifene (group OR), eight received oestradiol valerate (group OE) and eight received placebo after sterilisation (group OP). Finally, another eight were sham-operated (non-ovariectomised) and received placebo with a hypercholesterolaemic diet (group SP). After the diet, total levels of cholesterol increased in group SP from 111.25 +/- 34.8 mg/dl to 1112.25 +/- 364.2, in group OP from 122.62 +/- 27.7 mg/dl to 1367.37 +/- 348.4, in group OE from 65.25 +/- 17.01 to 1710.5 +/- 356.2 and in group OR from 108.88 +/- 15.54 mg/dl to 1407.86 +/- 397.7 (no significant differences). At 4 months, in both treated and untreated rabbits, the cholesterol-rich diet caused atherosclerotic lesions affecting 24.51 +/- 16.1% for group SP, 30.47 +/- 12.2% for group OP, 30.31 +/- 18.07% for group OR and 17.91 +/- 10.19 for group OE (P<0.05) of the aortic surface, respectively. Aortic cholesterol expressed as mg of cholesterol/mg aortic weight was found to decrease in raloxifene-treated rabbits: 3.82 +/- 2.14 mg col/aortic mg versus 8.55 +/- 4.63 (group OP) and 11.97 +/- 11.33 (group SP). P<0.001. Raloxifene reduced aortic cholesterol content but not the atherosclerotic plaque extension in cholesterol-fed ovariectomised rabbits.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14675981&dopt=Abstract raloxifene Evista