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The number of anterior cruciate ligament injuries in female athletes exceeds that in male athletes at similar competitive levels. This difference has been attributed by some authors to hormone-mediated alteration in knee laxity in women.
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The current study investigated the estrogen agonist-antagonist properties of the selective estrogen receptor modulator, raloxifene (Ral), on neuroprotection and neuronal markers of memory function. Low concentrations of raloxifene significantly reduced basal markers of membrane damage and had no deleterious effect on neuronal survival. However, high concentrations of raloxifene (1000-5000 ng/ml) induced a significant increase in markers of membrane damage and a significant decrease in neuronal survival. At subtoxic concentrations, raloxifene induced significant neuroprotection against beta amyloid(25-35)-, hydrogen peroxide- and glutamate-induced toxicity. Results of analyses to determine whether raloxifene acted competitively or synergistically with 17 beta-estradiol revealed that a postmenopausal level of 17 beta-estradiol exerted a significantly greater increase in neuronal survival against beta-amyloid- and glutamate-induced toxicity compared to 50 ng/ml raloxifene. The combined presence of raloxifene and 17 beta-estradiol was significantly neuroprotective against beta amyloid(25-35)- and glutamate-induced excitotoxicity but was significantly lower than 17 beta-estradiol alone while not significantly different than raloxifene alone. Morphologic analyses demonstrated that raloxifene significantly increased neuronal outgrowth of hippocampal neurons within a narrow dose range that was blocked by a glutamate NMDA receptor antagonist. Raloxifene did not promote the outgrowth of basal forebrain or cortical neurons. Results of this study indicate that raloxifene exerted partial estrogen agonist action in the absence of 17 beta-estradiol whereas in the presence of 17 beta-estradiol, raloxifene exerted a mixed estrogen agonist-antagonist effect.
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A 55-yr-old post-menopausal woman with osteopenia and no history of breast disease is presented. She was placed on raloxifene HCl 60 mg and soon after developed severe breast pain. The follow-up mammogram, performed prematurely at 6 months, showed a marked increase in breast density. Therapy was accordingly stopped and mastodynia subsided. The patient's mammogram regressed to pre-treatment status after 6 months off-therapy.
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The sodium iodide symporter (NIS) mediates active iodide uptake in lactating breast tissue, and when its levels are enhanced by all-trans retinoic acid (atRA), NIS has been proposed as a target for the imaging and radiotherapy of breast cancer. Importantly, the estrogen receptor α (ERα) is an important regulator of atRA induced NIS gene expression in breast cancer cells. In this study, we investigated the effect of an ER agonist (17β-estradiol, E(2)) or antagonist [trans-hydroxytamoxifen (TOT) or raloxifene (RAL)] treatment on the regulation of NIS gene expression and iodide uptake in an ERα-positive breast cancer (MCF-7) model.
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In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis, defined by low bone mineral density and/or prevalent vertebral fractures (VF), were randomized to placebo or raloxifene (60 or 120 mg/day). All women received daily calcium (500 mg) and vitamin D (400-600 IU) supplements. Our previous analyses found that changes in BMD and biochemical markers of bone turnover are poorly predictive of the reduction in VF risk observed with raloxifene. This present study evaluated the effects of raloxifene on type I procollagen N-terminal propeptide (PINP), a new marker of bone turnover. Logistic regression analysis models evaluated the relationships between the changes at 1 year in PINP, serum osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), and urinary excretion of type I collagen C-telopeptide fragments normalized to creatinine (CTx/Cr), and the risk of new VF at 3 years for placebo and pooled raloxifene. A subset of 967 women (mean age = 68 years) from the MORE cohort had PINP, OC, BSAP, and CTx evaluated at baseline. Both doses of raloxifene significantly decreased (P < 0.001) all biochemical markers of bone turnover from baseline. Compared to baseline, PINP levels were decreased by medians of 11.0% and 40.8% in the placebo and pooled raloxifene groups, respectively. In addition, the placebo and pooled raloxifene groups decreased serum OC by 8.5% and 31.8%, BSAP by 15.8% and 34.6%, and urinary CTx/Cr excretion by 5.6% and 46.5%, respectively, from baseline. In the pooled raloxifene group, the logistic regression relationship between 3-year VF risk and 1-year percentage change for each biochemical marker was statistically significant with PINP (slope estimate = 0.0085, P = 0.009), OC (slope estimate = 0.0068, P = 0.035), and BSAP (slope estimate = 0.0056, P = 0.039), but not with CTx/Cr (slope estimate = 0.0027, P = 0.192). Furthermore, the percent decrease in PINP at 1 year could account for 28% of the total reduction in vertebral fracture risk. In conclusion, a 1-year decrease in PINP, BSAP, or OC, but not CTx/Cr, may be predictive of the 3-year VF risk reduction with raloxifene therapy in this subset of postmenopausal women with osteoporosis.
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At the beginning of the study, the chronological ages, menopausal ages, years of amenorrhea, weights, body mass indexes, and blood pressures were not significantly different between groups (P < 0.05). RAL treatment caused a significant decrease on serum IL-4 concentration (P < 0.001). Although HRT caused a 14% decrease in serum IL-4 concentration, this decrease was not statistically significant (P > 0.05). Serum TGF-beta1 concentrations were significantly decreased by HRT when compared to basal value (P < 0.001), and to control (P < 0.05). RAL treatment has no significant effect on serum TGF-beta1 concentration (P > 0.05).
Tamoxifen had an oestrogen receptor dependent, direct, inhibitory effect on human osteoclast differentiation and bone resorption, whereas ospemifene and raloxifene required osteoblastic cells to achieve a similar inhibition. The effects of ospemifene and raloxifene were mediated by oestrogen receptors by a mechanism involving paracrine induction of osteoprotegerin in cultures with osteoblast derived osteosarcoma cells.
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Proteasome-mediated protein degradation has been implicated in playing a role in nuclear receptor-mediated gene expression; inhibition of the proteasome impairs the transcriptional activity of estrogen receptor alpha (ERalpha) and most other nuclear receptors. This coincides with blockage of agonist-dependent degradation of the receptor and elevation of the steady-state levels of SRC family coactivators and CBP. Here, we examined the effects that different ERalpha ligands have on coactivator protein steady-state levels and demonstrate that the selective ER modulators (SERMs) 4-hydroxytamoxifen (4HT) and raloxifene are able to elevate SRC-1 and SRC-3 protein levels. Using the HeLa cell line, we show that this effect is ERalpha dependent. Consistent with the observed increase in coactivator protein levels, we were also able to observe an increase in the transcriptional activity of other nuclear receptors in SERM-treated cells. Information presented here demonstrates an unexpected consequence of SERM treatment, which could help further define the complex tissue responses to 4HT and raloxifene, and suggests that these ligands can have a broad biological action, stimulating the transcriptional activity of other nuclear receptors.
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Female Wistar rats were OVX or subjected to sham surgery and received vehicle or RLX by gavage for 90 days. The treatment groups were as follows: sham surgery and treated with vehicle (SHAM-veh), OVX and treated with vehicle (OVX-veh), and OVX and treated with RLX (OVX-RLX). During treatment, the pulp of lower first molar was exposed to the oral environment for induction of periapical lesion that was analyzed 7 or 30 days after procedure. Blood samples were taken from jugular vein for measurement of estradiol, and the mandibles were removed and prepared for radiographic, histopathologic, histometric, and immunohistochemical analysis.
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The primary endpoint in MORE was incidence of vertebral fracture, and the difference between the raloxifene and placebo groups for this endpoint widened during 4 years of therapy, with the relative risk reduction during the fourth year of the study being similar to the relative risk reduction during years 0 to 3 of the study. Continued raloxifene treatment is necessary to preserve bone mineral density (BMD). In MORE, raloxifene lowered markers of bone turnover to a premenopausal reference interval. Biopsies from three patients treated with raloxifene for 8 years showed normal bone and bone cells and double label in all specimens. Invasive breast cancer risk is a clinical consideration in postmenopausal women with osteoporosis, and invasive breast cancer risk reduction was the primary endpoint in CORE. In MORE and CORE, the benefit of raloxifene versus placebo in incidence of invasive breast cancer increased with greater duration of therapy up to 8 years.
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Effect of ormeloxifene, a multifunctional selective estrogen receptor modulator, on prevention of ovariectomy-induced bone resorption in retired breeder female rats, osteoclastogenesis using bone marrow cells from adult Balb/c mice cultured in presence of M-CSF and RANKL, osteoclast apoptosis using terminal deoxynucleotidyl transferase fragment end labeling and TGF beta-3 expression were investigated. Raloxifene, a benzothiophene reported to mimic effects of estrogen in bone, and estradiol were used for comparison. Ormeloxifene (10(-6) and 10(-8)M) significantly inhibited osteoclastogenesis (P<0.001 versus vehicle control) as evidenced by lower number of TRAP-positive osteoclasts in bone marrow cultures and caused apoptosis of osteoclasts. The effect was almost equivalent to that observed in presence of estradiol-17 beta, except that significant number of cells undergoing apoptosis was evident even at 10(-9)M concentration of estradiol-17 beta (P<0.001). Raloxifene, though inhibited osteoclastogenesis at much lower concentrations (10(-8) to 10(-12)M; P<0.001), failed to cause apoptosis of osteoclasts at any of the concentrations used. While ormeloxifene, raloxifene and ethynylestradiol significantly prevented ovariectomy-induced bone loss in vivo in retired breeder female rats, prevention of ovariectomy-induced decrease in BMD and trabecular network of proximal tibia, calcium and phosphorus levels in femur and tibia and prevention of ovariectomy-induced down-regulation of TGF beta-3 expression in lumbar vertebrae was of lower order in raloxifene- than ormeloxifene- or ethynylestradiol-supplemented females. Both the SERMs, however, produced considerable estrogenic effects at the uterine level as evidenced by increase in weight, total and endometrial area and luminal epithelial cell height; the effect being generally greater in raloxifene- than ormeloxifene-treated rats. Findings demonstrate that inhibition of estrogen-deficiency osteoporosis by ormeloxifene, as in case of estradiol, was mediated via inhibition of osteoclastogenesis, apoptosis of osteoclasts and up-regulation of TGF beta-3 expression. Raloxifene, though effective in inhibiting osteoclastogenesis in vitro at much lower concentrations, was not only less potent in preventing ovariectomy-induced bone loss in retired breeder female rats in vivo but also appeared to have a different mechanism of action than ormeloxifene and estradiol.
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Raloxifene reduces myocardial infarct size and the incidence of ventricular fibrillations by NO- and the opening of KCa channels-dependent mechanisms in canine hearts.
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Our results suggest that tamoxifen has more of an estrogenic effect on the gynecologic reproductive organs. These effects should be considered in counseling women on options for breast cancer prevention.
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Given raloxifene's mechanism of action and the preclinical evidence for its role in breast cancer prevention, a clinically favorable effect seems feasible. Results of ongoing clinical studies will provide evidence to support or refute the clinical findings of MORE and thus raloxifene's role in the breast cancer prevention.
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Large bladders with urinary retention developed in ERαWT and ERβWT litter mates treated with testosterone plus 17β-estradiol but such bladders did not develop in ERαKO mice treated with testosterone plus 17β-estradiol. ERβKO mice treated with testosterone plus 17β-estradiol had large bladders with urinary retention and increased bladder mass. Cotreatment with the estrogen receptor-α antagonist raloxifene resulted in decreased bladder mass compared to that in wild-type mice treated with testosterone plus 17β-estradiol. Bladders in mice treated with the estrogen receptor-β antagonist R,R-THC were similar to those in testosterone plus 17β-estradiol treated mice.
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Laparoscopic excision of lesions, including recording of lesion characteristics and surgical impression of the lesions.
Raloxifene is approved for the treatment and prevention of postmenopausal osteoporosis. Previous studies have described a raloxifene-associated increase in hot flushes, reported as adverse events. This study was undertaken to provide a detailed evaluation of the potential of raloxifene to induce or exacerbate hot flushes in postmenopausal women.
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This article reviews lasofoxifene, a new-generation selective estrogen receptor modulator (SERM) that is currently in Phase III development for the prevention and treatment of osteoporosis in postmenopausal women. This compound selectively binds to both of the estrogen receptors with a high affinity and a median inhibitory concentration that is similar to that seen with estradiol and > or = 10-fold higher than those reported for other SERMs (raloxifene and tamoxifen). Lasofoxifene has a remarkably improved oral bioavailability with respect to other SERMs due to increased resistance to intestinal wall glucuronidation. In both preclinical and short-term studies, the compound showed a favourable safety profile and demonstrated a proven efficacy in preventing bone loss and lowering cholesterol levels. Dose modelling from Phase II studies allowed the selection of lasofoxifene 0.25 mg/day as the lowest fully effective dose.
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Experimental animal model.
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The risk of vertebral fractures was lower in women treated with raloxifene, regardless of prior HT use, but there was a suggestion that the effect was greater in women who had used HT. Women randomized to receive raloxifene exhibited a decreased incidence of invasive breast cancer, compared with women receiving placebo. No change occurred in the incidence of cardiovascular events, regardless of prior HT use.
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Overall, raloxifene use was associated with an increased VTE risk (HR 1.44, 95% CI 1.06-1.95) vs. placebo. Most women (72%) reported using aspirin, and 14.2% reported using nonaspirin antiplatelet agents during the study period. Users of antiplatelet agents were older, more likely to have CHD, and more likely to be hyperlipidemic. They had a higher VTE risk than nonusers. No difference in VTE risk was observed in women who used raloxifene alone vs. those who used raloxifene with antiplatelet agents during the study. The increase in VTE risk with raloxifene compared with placebo was not different between women who used antiplatelet agents at baseline (HR 1.44, 95% CI 0.98, 2.10) and those who did not use antiplatelet agents (HR 1.37, 95% CI 0.83, 2.27) (interaction p = 0.88). Similar conclusions were noted for aspirin and nonaspirin antiplatelet use.
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Cell culture for different incubation times.
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Ten healthy postmenopausal women and ten healthy men were randomized to 2-wk sequential treatment with tamoxifen (10 and 20 mg/d) and raloxifene (60 and 120 mg/d) with a washout of 2 wk between treatments.
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The UDP glucuronosyltransferase (UGT) 1A gene cluster encodes nine UGT1A family members via splicing of individual first exons to common exons 2 through 5. Each of these nine UGT1As can also undergo alternative splicing at their 3' ends by using an alternate exon 5, resulting in 27 different UGT1A mRNA species with each UGT1A gene encoding three different combinations of 5A and 5B UGT1A exons. To examine the importance of UGT1A exon 5 splice variants on overall UGT1A activity, a nested quantitative polymerase chain reaction assay was developed to accurately assess the combined expression of exon 5 splice variants (termed v2/v3) versus the expression of wild-type (termed v1) for each specific UGT1A. v1 expression was 16-, 17-, 57- and 29-fold higher than that observed for the levels of v2/v3 for UGTs 1A1, 1A4, 1A6, and 1A9, respectively, in normal human liver specimens. In a series of 58 normal human liver specimens, the expression of both UGT1A1 v1 and v2/v3 mRNAs was positively correlated with raloxifene glucuronidation activity in corresponding microsomes prepared from the same specimens (p < 0.0001, r² = 0.720; p = 0.0002, r² = 0.241, respectively), with expression of both variants lower in individuals homozygous for the UGT1A1*28 allele (42% for v1, p = 0.041; 53% for v2/v3, p = 0.0075). The expression of UGT1A1 v2/v3 was 1.6-fold higher than v1 (p = 0.03) in HepG2 cells, and short interfering RNA knockdown of HepG2 v2/v3 increased raloxifene glucuronidation activity by 83%. Together, these data suggest that hepatic UGT1A v2/v3 mRNA species are minor form variants in human livers from most individuals.
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Compared with continuous combined hormone replacement therapy, 6 and 12 months of raloxifene treatment do not lead to vaginal bleeding/spotting, are not associated with increased endometrial thickness or uterine volume and result in a significantly lower rate of early treatment discontinuations in asymptomatic women receiving treatment to prevent long term postmenopausal health risks.