Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0600142 (hot flushes)
 1,242 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Raloxifene is a selective estrogen receptor modulator that produces both estrogen-agonistic effects on bone and lipid metabolism and estrogen-antagonistic effects on uterine endometrium and breast tissue. Because of its tissue selectivity, raloxifene may have fewer side effects than are typically observed with estrogen therapy. The most common adverse effects of raloxifene are hot flushes and leg cramps. The drug is also associated with an increased risk of thromboembolic events. The beneficial estrogenic activities of raloxifene include a lowering of total and low-density lipoprotein cholesterol levels and an augmentation of bone mineral density. Raloxifene has been labeled by the U.S. Food and Drug Administration for the prevention of osteoporosis. However, its effects on fracture risk and its ability to protect against cardiovascular disease have yet to be determined. Studies are also being conducted to determine its impact on breast and endometrial cancer reduction.
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PMID:Raloxifene: a selective estrogen receptor modulator. 1050 39

Hormone replacement therapy (HRT) is a highly cost-effective treatment for symptoms of the menopause such as hot flushes (flashes). A number of economic evaluations have indicated that it may also be a cost-effective therapy for the prevention of cardiovascular disease and osteoporosis. However, these evaluations are based on the premise that HRT will reduce cardiovascular disease by 30 to 50%. Recent evidence casts doubt on its effectiveness at preventing cardiovascular disease, certainly as a secondary preventive therapy. Furthermore, HRT is likely to increase the incidence of breast cancer. If the effect of HRT on the cardiovascular system is slight or nonexistent, but its effect on breast cancer is modest or strong, then HRT is unlikely to be a cost-effective treatment for asymptomatic women at low risk of osteoporosis. However, the unwanted effects of HRT on the breast may be significantly reduced by targeting therapy to those women with low bone mass and who have other risk factors for fracture. Such a strategy is likely to be more cost effective than a strategy which allows asymptomatic women with low fracture risk to take HRT in the long term. As selective estrogen receptor modulators (SERMs) aggravate menopausal symptoms they are not likely to be an alternative for most perimenopausal women. Therefore, SERMs are more likely to be a competitor to existing and forthcoming bisphosphonates rather than HRT.
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PMID:The pharmacoeconomics of hormone replacement therapy. 1053 25

Ever since the discovery of estradiol and the elucidation of its chemical structure, there has been a great deal of interest in its mechanism of action and its potential therapeutic value. It is now well established that estrogens have many different functions in many different cell-types. With respect to the potential use of estrogens as therapeutics, there is an interest in controlling reproductive function, bone metabolism, cardiovascular disease, as well as in the prevention of hot flushes, mood changes and Alzheimer s disease. For over a decade, it was believed that estrogens signal through a a single estrogen receptor, now referred to as ERalpha, which belongs to a family of ligand-activated transcription factors. More recently, however, a second estrogen receptor ERbeta was identified. The current review describes similarities as well as differences between these two distinct estrogen receptors. Both ERalpha and ERbeta bind 17beta-estradiol with high affinity and they bind to classical estrogen response elements in a similar if not identical fashion. However, there are also major differences between ERalpha and ERbeta for instance with respect to their tissue distribution, the phenotype of the corresponding knock-out mice and their transcriptional activities. It is anticipated that a better understanding of these two receptors will eventually lead to more selective ways of modulating physiological processes which are influenced by estrogens. For this purpose, the development of ERalpha and ERbeta specific ligands, both agonists as well as antagonists, will be of great importance.
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PMID:Estrogen receptors alpha and beta: two receptors of a kind? 1070 25

Third-generation aromatase inhibitors are able to reduce circulating plasma estrogen concentrations in postmenopausal women to below detectable limits and significantly inhibit aromatase, the enzyme responsible for estrogen synthesis, in normal breast tissue and breast tumors. Their role in the treatment of advanced breast cancer is well established and their use in adjuvant therapy is currently being explored. On the basis of these trials, evaluation of these inhibitors in the prevention of breast cancer may be appropriate. Aromatase inhibitors have non-specific toxic side effects including (but not limited to): asthenia, headache, nausea, peripheral edema, fatigue, vomiting and dyspepsia. In addition, certain endocrinological side effects in postmenopausal women are notable, namely hot flushes and vaginal dryness. In advanced breast cancer, these side effects result in treatment withdrawal in few (<4%) women. Of concern, however, are the potential long-term endocrinological side effects in women receiving treatment as first-line adjuvant therapy or in sequence or combination with tamoxifen or other selective estrogen receptor modulators (SERMs). Current studies of adjuvant treatments for breast cancer in healthy women are carefully evaluating, in addition to general toxicities, the effects on bone, lipid metabolism, cardiovascular risk, quality of life and menopausal symptoms. Careful evaluation of all-cause morbidity and mortality is necessary to plan trials and justify long-term use of aromatase inhibitors in the treatment or prevention of breast cancer in healthy women.
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PMID:Risks versus benefits in the clinical application of aromatase inhibitors. 1073 Nov 26

Raloxifene belongs to the group of selective estrogen receptor modulators (SERMs). It interacts with both estrogen receptor alpha and beta, but the postreceptor responses differ from those of estrogens. Raloxifene exerts tissue specific responses that differ from estrogens. The drug increases bone mass by 2-3% and inhibits the risk of subsequent vertebral fractures by 30-50%. Raloxifene reduces the risk of breast cancer by 76% after treatment for four years and builds an atrophic endometrium without any bleedings. Furthermore, the risk of endometrial cancer is not increased. The drug exerts positive effects on plasma lipids, but the effects of these changes on subsequent risk of myocardial infarction and cardiovascular death are still unknown. The main side effects are leg cramps, increases in hot flushes and peripheral oedema. Like estrogen, the drug increases the relative risk for venous thrombosis by a factor three.
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PMID:[Raloxifene]. 1096 34

Three hundred and one healthy women between 45 and 65 yr of age and at least 1 yr postmenopausal were randomly assigned to 12-month double-blind therapy with levormeloxifene [1.25 (n = 51), 5, 10, or 20 mg/day], low dose continuous combined hormone replacement therapy [HRT; 1 mg 17 beta-estradiol and 0.5 mg norethisterone acetate/day], or placebo (all n = 50). All of the women were also given a daily supplement of calcium (500 mg). Serum CrossLaps decreased by about 50% in the levormeloxifene groups, with no dose-response effect. The group receiving HRT decreased more (>60%), and the placebo group (500 mg calcium alone) decreased by about 10%. The pattern was similar for bone alkaline phosphatase, except that the decreases were smaller, about 30% for the levormeloxifene groups and 50% for the HRT group. Serum osteocalcin also showed highly significant decreases, of the same magnitude in the levormeloxifene and HRT groups. Spinal bone mineral density (BMD) decreased by less than 1% in the placebo group and increased by about 2% in the levormeloxifene groups and by almost 5% in the HRT group (P < 0.001 for the difference between levormeloxifene and HRT vs. placebo). BMD of the total hip and total body changed in the same direction, although differences between groups were not as pronounced as those for BMD spine. Total cholesterol decreased by about 13--20% during levormeloxifene therapy, whereas daily doses of 1 mg estradiol and 0.5 mg norethisterone acetate produced a decrease of only about 8%. Levormeloxifene decreased low density lipoprotein cholesterol by about 22-30% compared with about 12% in the low dose HRT group. High density lipoprotein cholesterol was unchanged in all groups. Endometrial thickness increased both clinically and statistically significantly in the levormeloxifene groups independently of the dose; the difference from the placebo and HRT groups was significant (P < 0.001). There was no significant difference between the HRT and placebo groups. Other adverse events of interest include hot flushes, which did not occur more frequently in the levormeloxifene than the placebo groups, but occurred significantly less frequently in the HRT group (P < 0.05). Breast tenderness was much more common in the HRT group (<0.001) than in all other groups. In conclusion, the study shows that levormeloxifene, a new selective estrogen receptor modulator, has positive effects on BMD and bone turnover and apparently strong estrogenic effects on the serum concentrations of different cholesterol subfractions. Levormeloxifene at the doses tested had an estrogen-like effect on endometrium and no effect on hot flushes. The study was unable to differentiate between the effects of the different doses of levormeloxifene.
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PMID:Efficacy of levormeloxifene in the prevention of postmenopausal bone loss and on the lipid profile compared to low dose hormone replacement therapy. 1115 42

Raloxifene is a selective estrogen receptor modulator, a compound that has estrogen agonist activity at some sites and antagonist activity at others. In investigations in animals and in rigorously conducted trials in humans, raloxifene treatment is associated with a 30%-40% reduction in risk of one or more spine fractures using the 60 mg dose. This reduction in risk is found in women with or without baseline fractures, in women with bone mineral density (BMD) in the lower, middle, or upper third of the low range (all had BMD reduced by more than 2.5 SD) and in women aged less than 65 years, between 65-70 years, and greater than 70 years. A reduction in ankle fractures, but not hip or wrist fractures, was found. Raloxifene treatment also is associated with a 60%-70% reduction in risk for breast cancer and is associated with reduced total and LDL cholesterol, lower fibrinogen, and no rise in triglyceride. Reduced aortic wall cholesterol content is reported in animal studies. These are surrogate endpoints of cardioprotection. There is no evidence that raloxifene reduces the incidence of myocardial or cerebrovascular events. Raloxifene does not induce breast tenderness, endometrial hyperplasia, menstrual bleeding, or endometrial cancer, but may be associated with an increased risk of thromboembolic disease (1/1000 cases per year), leg cramps in 2%-4% of cases and hot flushes in 4%-6% of cases, usually in first 6 months.
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PMID:Raloxifene. 1128 Nov 62

Fulvestrant is a 7alpha-alkylsulphinyl analogue of estradiol that competes with endogenous estrogen for binding to the estrogen receptor. Once bound to the receptor, fulvestrant attenuates receptor dimerisation, effecting a rapid degradation of the estrogen receptor protein and inhibition of transcription. Fulvestrant is a potent inhibitor of the growth of human breast cancer cells in vitro and in vivo. It has demonstrated pure anti-estrogenic activity in animal systems. Intramuscular fulvestrant 250 mg once a month was as effective as the oral aromatase inhibitor anastrozole 1 mg/day in 2 phase III trials in postmenopausal women with advanced breast cancer who had received prior endocrine therapy. Median time to disease progression (the primary end-point) with fulvestrant and anastrozole was 5.4 and 3.4 months (North American trial) and 5.5 and 5.1 months (European trial). The median duration of response was 19.3 and 10.5 months (North American trial) and 14.3 and 14.0 months (European trial). The most common adverse events with fulvestrant are gastrointestinal disturbances and hot flushes. Fulvestrant showed similar tolerability to anastrozole in 2 phase III trials.
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PMID:Fulvestrant. 1139 12

The objective of this paper is to review the published and unpublished knowledge of the effect of selective estrogen receptor modulators on reproductive tissues other than endometrium. Pharmaceutical companies developing or marketing selective estrogen receptor modulators (SERMs) were identified. The investigators at each company responsible for the conduct of investigational trials were contacted and queried about reports of adverse events in any ongoing or completed trials involving SERMs produced by their company. Levormeloxifene and idoxifene trials noted a higher proportion of surgery for pelvic organ prolapse in treated versus untreated women. The development of these pharmaceutical agents was discontinued, primarily for endometrial concerns. However, pelvic organ prolapse was reported to the FDA as an adverse event associated with both drugs. Study weaknesses preclude a definitive association between the agents and pelvic organ prolapse. The treated groups were not necessarily similar for confounding factors such as age, parity, obesity, cigarette smoking, and other risk factors for pelvic organ prolapse. Tamoxifen and raloxifene increase hot flash intensity and frequency. Ovarian cyst formation and uterine fibroid growth have also been reported with some SERMs. The identification and assessment of the impact of current and future SERMs on the pelvic floor and other genital tissues will be important to understanding their potential long-term application in disease treatment and prevention.
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PMID:Effect of selective estrogen receptor modulators on reproductive tissues other than endometrium. 1179 59

Estrogens are known as important modulators of development, growth and maintenance of primary sexual physiology. The medical field has also grown increasingly appreciative of the effects of estrogens on non-traditional target tissues such as bone, cardiovascular tissue and the CNS. Postmenopausal women have been the beneficiaries of estrogen supplementation regimes, but the proliferative actions of estrogens on uterine and breast tissue have raised concerns. Combining estrogens with progestins (HRT) has succeeded in blunting the uterine effects of estrogen but not the effects of estrogens on breast tissue, and breakthrough bleeding induced by HRT regimes continues to present compliance issues. The discovery by Jordan and coworkers in 1987 that the "antiestrogens" tamoxifen and raloxifene showed estrogenic effects in preventing bone loss in ovariectomized rats revolutionized the way we have come to the think of nuclear receptor functioning. Since that time, broad insights have been garnered into both the mechanisms involved in the primary, ligand activated nuclear transcription pathway as well as other, non-traditional pathways via which estrogens may exert their effects. The recent discovery of a second estrogen receptor ERbeta has provided additional possibilities for investigation and therapeutic intervention. Even though raloxifene (Evista) has been approved for the treatment and prevention of osteoporosis in postmenopausal women, there is room for improvement. For example, normal HRT alleviates hot flush and urogenital complaints; raloxifene does neither. In addition raloxifene does not raise overall HDL (while HRT does) but does increase venous thromboembolisms. The ideal SERM will maximize all of the positive estrogen attributes while minimizing the negatives, and to that end, there has been considerable activity in the medicinal chemistry community dedicated towards the modification of the SERM structure to achieve compounds with preferable profiles. What we have witnessed, so far, is an evolutionary march of compounds with potential clinical benefit over raloxifene, although the ideal SERM remains to be realized.
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PMID:SERMs: evolutionary chemistry, revolutionary biology. 1217 20


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