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At least 919 records · Page 51Linked to original sources
PubMed2005

Progressive pigmentary purpura related to raloxifene.

Progressive pigmentary purpura is a rare condition characterized by lymphocytic capillaritis histologically causing various clinical entities which are also named as persistent pigmented purpuric dermatoses. It is generally idiopathic; however, rare cases secondary to drugs and various diseases have been reported. In this report we describe a case of progressive pigmentary purpura induced by raloxifene, a selective estrogen receptor modulator which is primarily used in the treatment and prevention of postmenopausal osteoporosis. As far as we know, no case of progressive pigmentary purpura has previously been reported as an adverse effect of raloxifene.

Disease Progression↗
PubMed2006

Strategies for the prevention and treatment of osteoporosis during early postmenopause.

During the perimenopause, both the quantity and quality of bone decline rapidly, resulting in a dramatic increase in the risk of fracture in postmenopausal women. Although many factors are known to be associated with osteoporotic fractures, measures to identify and treat women at risk are underused in clinical practice. Consequently, osteoporosis is frequently not detected until a fracture occurs. Identification of postmenopausal women at high risk of fracture therefore is a priority and is especially important for women in early postmenopause who can benefit from early intervention to maintain or to increase bone mass and, thus, reduce the risk of fracture. Most authorities recommend risk-factor assessment for all postmenopausal women, followed by bone mineral density measurements for women at highest risk (ie, all women aged > or =65 years, postmenopausal women aged <65 years with > or =1 additional risk factors for osteoporosis, and postmenopausal women with fragility fractures). All postmenopausal women can benefit from nonpharmacologic interventions to reduce the risk of fracture, including a balanced diet with adequate intake of calcium and vitamin D, regular exercise, measures to prevent falls or to minimize their impact, smoking cessation, and moderation of alcohol intake. Several pharmacologic agents, including the bisphosphonates (eg, alendronate, risedronate, and ibandronate) and the selective estrogen receptor modulator, raloxifene, have been shown to increase bone mass, to reduce fracture risk, and to have acceptable side-effect profiles. Women who have discontinued hormone therapy are in particular need of monitoring for fracture risk, in light of the accelerated bone loss and increased risk of fracture that occurs after withdrawal of estrogen treatment.

Accidental Falls↗
PubMed2005

Raloxifene exposure enhances brain activation during memory performance in healthy elderly males; its possible relevance to behavior.

Raloxifene is a selective estrogen receptor modulator (SERM) that is prescribed in females only, but its use in male subjects is increasingly considered. With a growing number of patients having potential benefit from raloxifene, the need for an assessment of its effects on brain function is growing. Effects of estrogens on brain function are very subtle and difficult to detect by neuropsychological assessment. Functional imaging techniques, however, have been relatively successful in detecting such changes. This study used functional magnetic resonance imaging (fMRI) to examine effects of raloxifene treatment on memory function. Healthy elderly males (n = 28; mean age 63.6 years, SD 2.4) were scanned during performance on a face encoding paradigm. Scans were made at baseline and after 3 months of treatment with either raloxifene (n = 14) or placebo (n = 14). Treatment effects were analyzed using mixed-effects statistical analysis (FSL). Activation during task performance involved bilateral parietal and prefrontal areas, anterior cingulate gyrus, and inferior prefrontal, occipital, and mediotemporal areas bilaterally. When compared to placebo, raloxifene treatment significantly enhanced activation in these structures (Z > 3.1), except for mediotemporal areas. Task performance accuracy diminished in the placebo group (P = 0.02), but remained constant in the raloxifene group (P = 0.60). In conclusion, raloxifene treatment enhanced brain activation in areas spanning a number of different cognitive domains, suggesting an effect on cortical arousal. Such effects may translate into small effects on behavior, including effects on attention and working memory performance, executive functions, verbal skills, and episodic memory. Further neuropsychological assessment is necessary to test the validity of these predictions.

Aged↗
PubMed2001

Prospects for prevention and treatment of cancer with selective PPARgamma modulators (SPARMs).

Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor and transcription factor that regulates the expression of many genes relevant to carcinogenesis, is now an important target for development of new drugs for the prevention and treatment of cancer. Deficient expression of PPARgamma can be a significant risk factor for carcinogenesis, although in some cases overexpression enhances carcinogenesis. Ligands for PPARgamma suppress breast carcinogenesis in experimental models and induce differentiation of human liposarcoma cells. By analogy to the selective estrogen receptor modulator (SERM) concept, it is suggested that selective PPARgamma modulators (SPARMs), designed to have desired effects on specific genes and target tissues without undesirable effects on others, will be clinically important in the future for chemoprevention and chemotherapy of cancer.

Animals↗
PubMed2003

Prevention of breast cancer using SERMs and aromatase inhibitors.

Breast cancer is one of the most common cancers of women in the Western world. Despite modest achievements in the treatment of this disease, there is a substantial unmet medical need to reduce the occurrence of new breast cancers. In several prospective, placebo-controlled trials, the antiestrogen tamoxifen has been shown to reduce the incidence of both invasive cancer and preinvasive breast lesions. Meanwhile, numerous other selective estrogen receptor modulators (SERMs) are being developed and trials comparing tamoxifen to these agents are ongoing. The goal of these studies is not only to show superior chemopreventive efficacy of the newer SERMs, but also an improved side-effect profile. The proof-of-principle demonstrated with tamoxifen suggests that strategies inhibiting estrogen are a logical way forward in breast cancer prevention. Aromatase inhibitors, which antagonize estrogen by blocking its synthesis from androgens, offer an alternative way of preventing the effects of estrogen and its metabolites on the breast. In this paper, the available data on SERMs including tamoxifen and raloxifene in breast cancer prevention and the data pointing to the efficacy of aromatase inhibitors in this setting are outlined.

Aromatase Inhibitors↗
PubMed2003

Biosynthesis of MUC1 mucin in human endometrial adenocarcinoma is modulated by estradiol and tamoxifen.

Polymorphic epithelial mucin MUC1 is expressed by most epithelial cancers, although free natural MUC1 antibodies are present in the circulation of healthy subjects as well as in that of cancer patients. The role of MUC1 mucin molecules in cancer cells of endometrium is not precisely known. The results reported here demonstrate that MUC1 biosynthesis in human endometrial adenocarcinoma cells (Ishikawa line) is stimulated by estradiol hormone and inhibited by tamoxifen, which was measured by [(14)C]threonine or [(3)H]glucosamine incorporation into MUC1 protein. Tamoxifen applied in combination with estradiol also inhibited this process, but pre-incubation of cells with estradiol resulted in a decrease in the inhibitory effect of tamoxifen. Electroblotting and reactions with antibodies against MUC1 core protein epitopes confirmed the presence of MUC1 in cell lysates and culture media of Ishikawa cells. Reactions with lectins showed the presence of oligosaccharide structures demonstrating antigen-T activity and the presence of sialic acid residues. The results confirm that there is downregulation of MUC1 expression in cancer culture cells treated with selective estrogen receptor modulators, which may be essential for reducing the migration of cancer cells and the metastatic properties of tumor cells.

Adenocarcinoma↗
PubMedDate not supplied

Management of postmenopausal osteoporosis: position statement of the North American Menopause Society.

OBJECTIVE: The North American Menopause Society (NAMS) established a goal to create an evidence-based position statement regarding the management of postmenopausal osteoporosis. DESIGN: NAMS followed the general principles established for evidence-based guidelines to create this document. A MEDLINE search was conducted. Clinicians and researchers acknowledged to be experts in the field of osteoporosis were enlisted to review the evidence. The NAMS Board of Trustees reviewed and approved the final document. RESULTS: Osteoporosis, which has its highest rate of occurrence in postmenopausal women, increases the risk for fractures, including hip and spine fractures. These injuries are often associated with particularly high morbidity and mortality. Given the health implications of osteoporotic fractures, the primary goal of osteoporosis therapy is to prevent fractures by slowing or preventing bone loss, maintaining bone strength, and minimizing or eliminating factors that may contribute to falls. The evaluation of postmenopausal women for osteoporosis risk requires the recording of a medical history, a physical examination, and diagnostic tests. Major risk factors for osteoporosis are age, genetics, lifestyle (especially nutrition), and menopausal status. Management focuses first on nonpharmacologic measures, such as a balanced diet including adequate calcium and vitamin D intakes, appropriate exercise, smoking cessation, avoidance of excessive alcohol intake, and fall prevention. If pharmacologic therapy is indicated, FDA-approved options are estrogens (prevention only), bisphosphonates and selective estrogen-receptor modulators (prevention and treatment), and calcitonin (treatment only). CONCLUSIONS: Management of postmenopausal osteoporosis involves identifying the potential risk for osteoporosis and osteoporotic fracture, followed by measures that focus on reducing modifiable risk factors through lifestyle changes and, if indicated, pharmacologic therapy.

Calcitonin↗
PubMed2005

Raloxifene: bone and cardiovascular effects.

Raloxifene (RLX), a selective estrogen receptor modulator (SERM), is currently indicated for the prevention and treatment of post-menopausal osteoporosis. At present, RLX is evaluated in other areas of study that include the reduction of the risk of breast cancer and cardiovascular (CV) disease in post-menopausal women. This SERM acts as an estrogen agonist in the skeleton, on serum lipid metabolism and on a number of coagulation factors, while it is an estrogen antagonist in the breast and uterus. Although our current data are incomplete, RLX has a favourable risk-benefit safety profile and is one of the most promising medical agents not only for the prevention of osteoporosis, but also for a large number of other disorders in post-menopausal women.

Aged↗
PubMed2005

SERMs in chemoprevention of breast cancer.

Selective estrogen receptor modulators (SERMs) play a key role in breast cancer chemoprevention. Tamoxifen has been shown to reduce breast cancer incidence by 30-40% in at-risk subjects in large phase III trials. However, toxicity may be a limiting factor. Thus, different strategies are being pursued to improve the risk: benefit ratio of using these compounds in chemoprevention. Firstly, the second generation SERM raloxifene is currently undergoing evaluation in comparison with tamoxifen in a large phase III trial. Also, lower doses of tamoxifen are being assessed in phase II-III trials. In addition, the combination of hormone replacement therapy (HRT) or aromatase inhibitors and tamoxifen at low doses may reduce the risks while retaining the benefits of either agents. Finally, new agents that interfere with the onset of ER-negative breast cancer are being sought for combination chemoprevention since almost a third of breast cancers will not be sensitive to hormonal modulation.

Anticarcinogenic Agents↗
PubMed2006

Bone protection by estrens occurs through non-tissue-selective activation of the androgen receptor.

The use of estrogens and androgens to prevent bone loss is limited by their unwanted side effects, especially in reproductive organs and breast. Selective estrogen receptor modulators (SERMs) partially avoid such unwanted effects, but their efficacy on bone is only moderate compared with that of estradiol or androgens. Estrens have been suggested to not only prevent bone loss but also exert anabolic effects on bone while avoiding unwanted effects on reproductive organs. In this study, we compared the effects of a SERM (PSK3471) and 2 estrens (estren-alpha and estren-beta) on bone and reproductive organs to determine whether estrens are safe and act via the estrogen receptors and/or the androgen receptor (AR). Estrens and PSK3471 prevented gonadectomy-induced bone loss in male and female mice, but none showed true anabolic effects. Unlike SERMs, the estrens induced reproductive organ hypertrophy in both male and female mice and enhanced MCF-7 cell proliferation in vitro. Estrens directly activated transcription in several cell lines, albeit at much higher concentrations than estradiol or the SERM, and acted for the most part through the AR. We conclude that the estrens act mostly through the AR and, in mice, do not fulfill the preclinical efficacy or safety criteria required for the treatment or prevention of osteoporosis.

Animals↗
PubMed2002

Tamoxifen enhances choline acetyltransferase mRNA expression in rat basal forebrain cholinergic neurons.

Novel estrogen-like molecules known as SERMs (selective estrogen receptor modulators) produce many of the beneficial estrogen-like actions without the detrimental side-effects. The SERM, tamoxifen, an estrogen-like molecule with both agonist and antagonist properties, is widely prescribed for the treatment of breast cancer. While the effects of tamoxifen are being evaluated in many peripheral tissues, its effects in the central nervous system (CNS) have been largely ignored. In the present study, we begin to evaluate the effects of tamoxifen in the rat basal forebrain, a region known to be highly responsive to estrogen. We compared the effects of short-term (24 h) tamoxifen treatment to that of estrogen on ChAT mRNA expression in cholinergic neurons. In addition, we examined the effect of tamoxifen in the presence and absence of estrogen. Our results indicate that tamoxifen enhances ChAT expression in a manner similar to that of estrogen in several basal forebrain regions. In contrast, tamoxifen exhibits antagonist properties with respect to estrogen-induction of progesterone receptor mRNA in the medial preoptic nucleus. These results indicate tamoxifen has estrogenic properties with respect to cholinergic neurons, suggesting a previously unidentified effect of this agent in the CNS.

Animals↗
PubMed2006

Emerging principles for the development of resistance to antihormonal therapy: implications for the clinical utility of fulvestrant.

We seek to evaluate the clinical consequences of resistance to antihormonal therapy by studying analogous animal xenograft models. Two approaches were taken: (1) MCF-7 tumors were serially transplanted into selective estrogen receptor modulator (SERM)-treated immunocompromised mice to mimic 5 years of SERM treatment. The studies in vivo were designed to replicate the development of acquired resistance to SERMs over years of clinical exposure. (2) MCF-7 cells were cultured long-term under SERM-treated or estrogen withdrawn conditions (to mimic aromatase inhibitors), and then injected into mice to generate endocrine-resistant xenografts. These tumor models have allowed us to define Phase I and Phase II antihormonal resistance according to their responses to E(2) and fulvestrant. Phase I SERM-resistant tumors were growth stimulated in response to estradiol (E(2)), but paradoxically, Phase II SERM and estrogen withdrawn-resistant tumors were growth inhibited by E(2). Fulvestrant did not support growth of Phases I and II SERM-resistant tumors, but did allow growth of Phase II estrogen withdrawn-resistant tumors. Importantly, fulvestrant plus E(2) in Phase II antihormone-resistant tumors reversed the E(2)-induced inhibition and instead resulted in growth stimulation. These data have important clinical implications. Based on these and prior laboratory findings, we propose a clinical strategy for optimal third-line therapy: patients who have responded to and then failed at least two antihormonal treatments may respond favorably to short-term low-dose estrogen due to E(2)-induced apoptosis, followed by treatment with fulvestrant plus an aromatase inhibitor to maintain low tumor burden and avoid a negative interaction between physiologic E(2) and fulvestrant.

Animals↗
PubMed2003

Cell proliferation, apoptosis, and expression of cyclin D1 and cyclin E as potential biomarkers in tamoxifen-treated mammary tumors.

Tamoxifen has been widely used for treatment, and more recently, for the prevention of breast cancer. Since breast carcinomas are composed of heterogeneous populations of estrogen receptor-positive (ER+) cells, we hypothesized that tamoxifen may suppress tumor growth by differentially affecting cell proliferation and apoptosis. ER+ mammary tumors were induced in Sprague-Dawley rats by N-methyl-N-nitrosourea (MNU) and when they became palpable, the animals were treated for 5, 10, or 20 days with tamoxifen, 1.0 mg/kg body weight. Tamoxifen induced a time-dependent decrease in proliferating (BrdU-labeled) cells, arrested the cells in G1/0 phase, and differentially decreased the cyclin E and cyclin D1 expression at mRNA and protein levels. In the same tumors, apoptotic cells increased during the first 10 days of treatment, but their number remained unchanged with extension of the treatment to 20 days. Thus, we provide data that tamoxifen may differentially affect cell proliferation and apoptosis in mammary tumors and that the expression levels of cyclin D1 and cyclin E might also be considered potential intermediate biomarkers of response of mammary tumors to tamoxifen and possibly to other selective estrogen receptor modulators (SERMs).

Animals↗
PubMed2004

Raloxifene and hormone replacement therapy increase arachidonic acid and docosahexaenoic acid levels in postmenopausal women.

Estrogens may affect the essential n-6 and n-3 fatty acids arachidonic acid (AA; C20:4n-6) and docosahexaenoic acid (DHA; C22:6n-3). Therefore, we investigated the long-term effects of hormone replacement therapy and raloxifene, a selective estrogen-receptor modulator, in two randomized, double-blind, placebo-controlled studies. In study I, 95 healthy, non-hysterectomized, early postmenopausal women (age range 47-59 years) received one of the following treatments: daily raloxifene 60 mg (n=24), daily raloxifene 150 mg (n=23), 0.625 mg conjugated equine estrogens (CEE) plus 2.5 mg medroxyprogesterone acetate (MPA; n=24), or placebo (n=24). In study II, 30 men (age range 60-69 years) received daily 120 mg raloxifene (n=15) or placebo (n=15). In study I, plasma cholesteryl ester fatty acids were measured at baseline and after 6, 12, and 24 months in 83 (drop out rate 13%), 73 (23%), and 70 (25%) women respectively. In study II, fatty acids were measured at baseline and after 3 months in 29 men (drop out rate 3%). In postmenopausal women, administration of 150 mg raloxifene increased AA by a mean of +6.1% (P=0.055, not significant). Administration of CEE plus MPA increased AA by +14.1% (P<0.0005). Mean changes in DHA were +22.1% (P=0.003) and +14.9% (P=0.047) respectively, as compared with placebo. In men, 120 mg raloxifene for 3 months did not significantly affect AA (-5.2%; P=0.342) or DHA (+4.0%; P=0.755), but it increased testosterone levels by +19.8% (P=0.006). Administration of raloxifene 150 mg/day as well as CEE plus MPA to postmenopausal women increases the proportion of AA and DHA in plasma cholesteryl esters during a follow-up of 2 years. Short term administration of raloxifene in elderly men did not affect AA or DHA. The synthesis of AA and DHA from precursors may be enhanced through an estrogen receptor-dependent pathway.

Aged↗
PubMed2003

A novel pure SERM achieves complete regression of the majority of human breast cancer tumors in nude mice.

BACKGROUND: The objective was to determine if EM-652, a novel selective estrogen receptor modulator (SERM) having highly potent and pure antiestrogenic activity in the mammary gland could cause complete regression of the majority of human breast cancer xenografts in nude mice. METHODS: Human breast cancer ZR-75-1 xenografts were used as model in nude mice. RESULTS: EM-652 not only prevented estrogen-induced tumor growth but it reduced tumor size to 20% of the pretreatment value. Complete disappearance of the tumors was observed in 65% (106/163) of tumors. No tumor progressed. Most importantly, 93% of the tumors which had become undetectable under EM-652 treatment did not reappear when exposed to estrogen challenge for 12 weeks, thus achieving an overall 61% cure rate. CONCLUSIONS: The present data demonstrate that EM-652 is strongly cytotoxic or tumorocidal and not only cytostatic or tumorostatic in estrogen-sensitive breast cancer, thus changing the paradigm of a tumorostatic role of estrogen blockade established with tamoxifen. These findings support the use of such a compound for more efficient breast cancer prevention and therapy.

Analysis of Variance↗
PubMed2006

Tamoxifen improved final height prediction in a girl with McCune-Albright syndrome: patient report and literature review.

McCune-Albright syndrome (MAS) is characterized by gonadotropin-independent precocious puberty, café-au-lait spots on the skin and polyostotic fibrous dysplasia of bones. Treatment of precocious puberty (PP) in MAS should be considered in patients with poor predicted adult height (PAH). Treatment of gonadotropin-independent PP in MAS with ketoconazole, cyproterone acetate or testolactone, an aromatase inhibitor, does not appear to be always effective in slowing bon. maturation. We report here a Thai girl with MAS who received tamoxifen, one of the selective estrogen receptor modulators, for the management of advanced puberty and rapid bone maturation. Her pubertal progression, vaginal bleeding, growth rate and PAH improved during treatment with tamoxifen despite persistently elevated serum estradiol levels and an enlarged ovarian cyst.

Body Height↗
PubMed2003

Synthesis and binding affinities of fluoroalkylated raloxifenes.

Three fluoroalkylated derivatives (1-3) of the selective estrogen receptor modulator (SERM), raloxifene, have been synthesized. The key step in the synthesis is the C-C bond formation of benzo[b]thiophene and a substituted phenyl group (ring C) using a Stille reaction. The in vitro binding affinities of the substituted raloxifenes 1-3 are 45, 60, 89%, respectively, relative to the affinity of estradiol, which is higher than the affinity of raloxifene itself (25%). When labeled with the positron-emitting radionuclide, these compounds might be useful as PET imaging agents for estrogen receptor-positive breast tumors.

Fluorocarbons↗
PubMed2000

Anti-estrogenic activity of diesel exhaust particles.

Estrogenic and anti-estrogenic activities of diesel exhaust particles (DEP) were evaluated using yeast cells expressing the human estrogen receptor and the responsive element regulating the expression of the receptor gene for beta-galactosidase (Routledge and Sumpter, 1996). It was found that a suspension of whole DEP suspension is not estrogenic but that this preparation possesses the ability to reduce the estrogen-dependent reporter activity. DEP were serially extracted with hexane, benzene, dichloromethane, methanol, and 1 M ammonia, and the estrogenic and anti-estrogenic activities of these preparations were determined. None of the extracts of DEP were estrogenic, but the extracts of benzene, dichloromethane and methanol possessed anti-estrogenic activity, and the activity of estrogen in the presence of hexane extract was slightly decreased. These results indicated that DEP contain heterologous compounds having anti-estrogenic activity. It is thought that those compounds in DEP can modulate the activity of estrogen, leading to the distruption of balance between estrogen and androgen. In this paper, the environmental effects of DEP in relation to the endocrine disrupting effect of organic compounds in DEP are discussed.

Air Pollutants↗