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PubMed2000

The effect of raloxifene on coronary arteries in aged ovariectomized ewes.

BACKGROUND: Ovariectomized sheep are a useful model of postmenopausal osteoporosis and other postmenopausal conditions. Estrogen may have a protective effect on the coronary arteries in postmenopausal women. The effects of raloxifene, a selective estrogen receptor modulator, on coronary arteries in aged ovariectomized ewes was investigated. METHODS AND RESULTS: Forty eight aged ewes were randomly assigned to undergo sham surgery (Sham, n = 7), ovariectomy (OVX, n = 10), ovariectomy with estradiol supplementation (OVXE, n = 8), ovariectomy with raloxifene supplementation, 0.02 mg/kg per day (RAL1, n = 10), or ovariectomy with raloxifene supplementation, 0.10 mg/kg per day (RAL2, n = 13). Contrast coronary angiography was performed 6 months after intervention. Diameters of the right main and left anterior descending coronary arteries in the RAL1, RAL2 and Sham groups were not different from each other, but were significantly greater than the OVX and OVXE groups. Intracoronary nitroglycerin did not affect the relationships of the diameters in any group. There were no differences in vascular remodeling between the groups. CONCLUSIONS: The results indicate that raloxifene in this sheep model allows greater dilation of coronary arteries than estrogen. Raloxifene may provide a significant protective functional effect on coronary arteries in postmenopausal heart disease.

Animals↗
PubMed2001

Evidence for an estrogen-like action of raloxifene upon the hypothalamic-pituitary unit: raloxifene inhibits luteinizing hormone secretion and stimulates prolactin secretion in ovariectomized female rats.

Selective estrogen receptor modulators (SERMs) constitute a new family of drugs with growing interest in the management of estrogen-associated pathology. Raloxifene is a SERM that is used to treat and prevent osteoporosis in postmenopausal women. The actions of raloxifene on bone, breast, uterus and serum cholesterol have been widely analyzed, but very few studies have been carried out to evaluate whether raloxifene has an estrogenic activity upon the hypothalamic-pituitary axis in the rat. For this purpose, adult female rats were ovariectomized or sham ovariectomized. One week later, the rats were implanted with intracardiac canullae and 24 h after injected daily with raloxifene (500 microg/rat/day) or vehicle for 5 days. One hour after the last injection, blood samples were obtained at 5 min intervals for a 3 h. period (10:00-13:00 h). Our results indicate that raloxifene inhibits the pulsatile nature of the post-ovariectomy hypersecretion of luteinizing hormone (LH) and increases prolactin (PRL) secretion in ovariectomized animals. These effects are suggestive of an estrogenic activity of raloxifene on LH and PRL secretion in ovariectomized females.

Animals↗
PubMed2004

[Safety profile of raloxifene].

Selective estrogen receptor modulators (SERMs) are a diverse group of non-steroidal (non hormonal) compounds developed to offer the postmenopausal women many of the advantages of estrogen therapy (ET) while avoiding undesired effects on reproductive and other tissues. Tamoxifen and toremifene, first generation SERMs are used for the adjuvant treatment of breast cancer worldwide, but their stimulatory effect on the uterus prevents their widespread use in other indications. A second generation SERM, raloxifene hydrochloride, a benzothiophene SERM is fully safe for the uterus and significantly reduces the risk of vertebral fractures in postmenopausal women with osteoporosis. The safety and efficacy of raloxifene in postmenopausal women have been studied extensively in more than 40,000 women over 50 clinical trials in 30 countries. The majority of the trials have been large double-blind placebo-controlled trials, including Asia and Japan. Raloxifene is well tolerated, with the only common side effects significantly higher than placebo being hot flushes and minor leg cramps. Venous thromboembolism was the only adverse events of clinical significance but rare associated with raloxifene in Caucasian women, but was not observed so far in Asian countries.

Asian People↗
PubMed2003

Mortality and morbidity associated with osteoporosis drug treatment following hip fracture.

This study examined post-fracture osteoporosis drug treatment in hip fracture patients and the association of treatment with mortality and morbidity. Pre- and post-fracture demographic/health information was collected on a cohort of hip fracture patients aged 65+ years. Post-fracture administrative data on prescription drug use and health care utilization was linked to the cohort data. Five classes of osteoporosis drugs were available during the study period: hormone replacement therapy (HRT), bisphosphonates (BSP), calcitonin, selective estrogen receptor modulators (SERMs) and vitamin D(3) (Rocaltrol). Pre-fracture, 38 of 449 patients (8%) were on osteoporosis medications. Post-fracture, 81 of 356 patients (23%) were treated; 63 of these patients were untreated prior to fracture. Both treated and untreated patients had similar rates of subsequent hip fracture (6% and 4%, respectively) and Colles fracture (2%). Regardless of treatment status, patients were also equally likely to be hospitalized, both in the short-term (28% in treated, 27% in untreated) and in the long-term (43% versus 37%). However, mortality was significantly lower in the treated group. The lower mortality in the treated group, combined with the knowledge that antiresorptive drugs reduce fractures and increase bone density, merit undertaking a randomized trial to confirm our findings that antiresorptive therapy should be considered in all patients post-hip fracture.

Aged↗
PubMed2002

Hormone replacement therapy in women with a history of breast cancer.

Health care professionals in modern Western societies will meet an increasing number of women surviving breast cancer. How the menopause of these women should be treated is still an open question. Use of hormone replacement therapy (HRT) may, at least in theory, increase the risk for recurrence of cancer, but its categoric refusal is a double-edged sword because it also denies these women all the undisputable health benefits HRT provides. This refusal is not, however, supported by the observational data available so far on this question, because HRT has not increased the risk for breast cancer recurrence. In fact, it is well established that HRT abolishes hot flushes and improves significantly these patients' quality of life. At present, we have no effective nonhormonal alternatives for the control of vasomotor symptoms, and the efficacy of phytoestrogens in the treatment of menopausal symptoms is unproven. Selective estrogen receptor modulators (SERMs) which protect against osteoporosis and perhaps also against breast cancer, and which may have beneficial effects on the cardiovascular system, aggravate hot flushes and are therefore not useful, at least in the first postmenopausal years. In some countries, progestins are often prescribed for the control of such patients' vasomotor symptoms, but their safety has never been assessed in clinical trials, and in theory they can be harmful. Randomized clinical trials (RCT) on the use of HRT in breast cancer survivors are underway, but their completion will take years, and even these may be open to criticism. Tibolone may appear to be an appealing alternative for HRT, but it should also be studied with RCTs in this indication. At present, a patient with a history of breast cancer must be given balanced information as to the possible benefits and risks of HRT, and she herself must make the decision whether or not to start HRT.

Breast Neoplasms↗
PubMedDate not supplied

[Large clinical trials for osteoporosis].

The prevention and treatment of osteoporosis are now a necessary goal because of the aging of the population and the social and economic costs of fracture complications. The publication of guidelines by registration agencies during the last 10 years has provided precise rules for evaluating new drugs designed for the prevention and treatment of postmenopausal osteoporosis. The benefit of combination treatment with calcium and vitamin D in osteoporotic patients has clearly been proven, especially among the oldest patients, but results of prospective studies designed for the prevention of fracture risk are conflicting. In the Fracture Intervention Trial (FIT), treatment with alendronate 10 mg/day reduces the risk of vertebral fracture by 48% and increases bone mineral density (BMD) in patients with vertebral fractures. In the Vertebral Efficacy with Risedronate Therapy Multi-National (VERT-MN) and VERT-NA (North America) studies, treatment with risedronate 5 mg/day reduces the risk of vertebral fracture by 49% and 41%, respectively. Risedronate 5 mg daly for 3 years leads to an increase in BMD. The Prevent Recurrence Of Osteoporotic Fractures (PROOF) study has shown a significant decrease in the risk of vertebral fracture in patients treated with calcitonin 200 IU. However, numerous criticisms of the methodology of this study design have been identified. Selective estrogen receptor modulators could act as agonists or antagonists of estrogens, depending on the target tissue. In the Multiple Outcomes of Raloxifene Evaluation (MORE) study, treatment with raloxifene reduces the risk of vertebral fracture by 50% in patients without prevalent vertebral fracture and by 30% in patients with prevalent vertebral fracture. PTH treatment leads to an increase in BMD and reduces the risk of vertebral fracture by 65%. Strontium ranelate has a novel mechanism of action (stimulation of bone synthesis and decrease in bone resorption), and administration of 2 g daily has a proven positive effect, leading to an increase in bone mass among women with osteoporosis. This effect was especially evident in the Spinal Osteoporosis Therapeutic Intervention phase III (SOTI) study, in which a significant decrease in the incidence of vertebral fracture of 41% over 3 years has been shown. Thus, effective therapeutic strategies now enable improved treatment of postmenopausal osteoporosis. However, this condition is still poorly diagnosed and not all patients are correctly treated. Preventing the occurrence of the first fracture should remain the prime concern.

Calcitonin↗
PubMed2006

Arzoxifene: the development and clinical outcome of an ideal SERM.

Hormone-sensitive tumours are among the most common cancers in women. Specific inhibition of the estrogen receptor by selective estrogen receptor downregulators or selective estrogen receptor modulators (SERMs) is effective for the treatment of breast and endometrial cancers and may be used for the prevention of breast cancer. Due to differential recruitment of co-activators and corepressors, SERMs are tissue specific and may have antiestrogenic effects in some tissues, with estrogen agonist activity in others. The ideal SERM would have antiestrogenic effects on the breast and endometrium, but pro-estrogenic effects on bone and lipids. The SERM, arzoxifene (LY-353381.HCl) meets all of these criteria. This review summarises the development, preclinical studies and the clinical outcome of arzoxifene and places it in context with other modalities in the treatment of hormone receptor-positive tumours.

Animals↗
PubMed2005

Tamoxifen fails to affect central serotonergic tone but increases indices of anxiety in female rhesus macaques.

The selective estrogen receptor modulator (SERM), tamoxifen, effectively slows the progression of estrogen-positive breast cancer and aids in the prevention of cancer in at-risk women. Tamoxifen is well characterized with regards to its effects on breast cancer, but its effects on other estrogen-related systems, particularly neural circuits regulating brain function and mood, are poorly understood. Using ovariectomized rhesus monkeys, we examined the effects of tamoxifen, with and without estrogen replacement therapy (ERT), on social behavior and central serotonin (5HT) systems thought to influence these behaviors. Relative to placebo treatments, estrogen treatment increased serotonergic tone, based on response in prolactin and cortisol to fenfluramine, a 5HT releasing agent. Tamoxifen neither blocked nor enhanced this effect, indicating it to be neither an antagonist nor an agonist on serotonergic activity. In contrast, CSF measures of the 5HT metabolite, 5HIAA, were not significantly affected by treatment. Tamoxifen-treated animals showed increases in measures of anxiety, compared with ERT-treated animals, suggesting that this SERM may be anxiogenic. Co-treatment with estrogen attenuated the anxiogenic properties of tamoxifen. These data show that tamoxifen administration increased anxiety levels, but the affect was not associated with differences in central levels of the serotonin tone.

Affect↗
PubMed2002

Novel therapeutic options for osteoporosis.

Osteoporosis remains a significant clinical problem despite effective therapies. Many patients cannot or will not take currently available therapies. For this reason, research continues in search of more effective and more tolerable agents. Arzoxifene and TSE-424 are investigational selective estrogen receptor modulators that have been shown to be effective in animal studies and are now in clinical studies. Tibolone is a tissue-specific steroid that is currently used in Europe for the prevention and treatment of osteoporosis. Multiple studies have shown efficacy in improving bone mineral density, but no fracture studies have been conducted to date. Although studies of the effect of isoflavones on bone mineral density have been encouraging, a large multicenter study in Europe recently showed no effect of isoflavones on fractures. The investigational bisphosphonates ibandronate and zoledronic acid may offer the advantage of less frequent dosing. The newly described agent osteoprotegerin has been shown in early studies to inhibit bone turnover. Finally, the issue of efficacy of statins in bone continues to be debated with no prospective, randomized studies yet to confirm the suggestion of benefit seen in epidemiologic studies.

Animals↗
PubMed2000

Estrogen receptor pathways to AP-1.

Estrogen receptor (ER) binds to estrogen response elements in target genes and recruits a coactivator complex of CBP-pl60 that mediates stimulation of transcription. ER also activates transcription at AP-1 sites that bind the Jun/Fos transcription factors, but not ER. We review the evidence regarding mechanisms whereby ER increases the activity of Jun/Fos and propose two pathways of ER action depending on the ER (alpha or beta) and on the ligand. We propose that estrogen-ERalpha complexes use their activation functions (AF-1 and AF-2) to bind to the p 160 component of the coactivator complex recruited by Jun/Fos and trigger the coactivator to a higher state of activity. We propose that selective estrogen receptor modulator (SERM) complexes with ERbeta and with truncated ERalpha derivatives use their DNA binding domain to titrate histone deacetylase (HDAC)-repressor complexes away from the Jun/Fos coactivator complex, thereby allowing unfettered activity of the coactivators. Finally, we consider the possible physiological significance of ER action at AP-1 sites.

Animals↗
PubMed2005

Prevention of hormone-related cancers: breast cancer.

Carcinogenesis in the breast is a hormonally dependent process. Evidence implicating estrogen as a key breast carcinogen comes from various lines of investigation. Traditional epidemiologic studies demonstrate associations between estrogen exposure, both exogenous and endogenous, and increased breast cancer risk. Ongoing genetic epidemiologic studies also show associations between specific polymorphisms in estrogen-metabolizing genes and risk, albeit inconsistently. The application of these findings to the treatment and, more recently, the prevention of breast cancer has led to the development of agents that either (1) inhibit estrogen action at the estrogen receptor (selective estrogen receptor modulators (SERMs]); or (2) inhibit estrogen-synthesizing enzymes, thereby abrogating synthesis of this hormone (aromatase inhibitors). Large phase III trials have evaluated the ability of such agents to reduce the incidence of breast cancer in women at increased risk of the disease. The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1: Breast Cancer Prevention Trial (BCPT) demonstrated the superiority of the SERM tamoxifen to placebo in reducing breast cancer risk, leading to the Food and Drug Administration approval of tamoxifen for risk reduction. The implementation of tamoxifen for this indication has not become widespread in clinical practice, however, for a variety of reasons that we discuss. Results from the NSABP Study of Tamoxifen and Raloxifene, which compares the risk-reducing efficacy as well as toxicity of these two SERMs in a similar high-risk population, will be available in the near future. Based on promising data involving reduction of contralateral breast cancer risk in adjuvant studies, several aromatase inhibitors, including letrozole, anastrozole, and exemestane, are being incorporated into trials evaluating their efficacy as preventive agents in women at increased risk.

Antineoplastic Agents, Hormonal↗
PubMed2003

Effect of estrogen and antiestrogens on the estrogen receptor content in the cochlea of ovariectomized rats.

Older women in the normal population tend to develop less severe hearing loss as compared to males in the same age. In Turner syndrome (45,X), estrogen deficiency is one of the predominant problems. Ear and hearing problems are common among these patients. Does estrogen have an impact on the hearing organ? Twenty-four rats were ovariectomized and treated with vehicle (controls), estradiol or selective estrogen receptor modulators such as tamoxifen and ICI182780, in order to study the effects on the estrogen receptor levels and distribution in the inner ear. The cochleas were stained immunohistochemically using antibodies against estrogen receptor alpha and beta. No major difference in estrogen receptor content in the cochleas was observed among groups. There was however a potential down regulation of estrogen receptor alpha in the marginal cells of stria vascularis in the rats that were substituted with ICI182780 (pure antiestrogen) as compared to those given estradiol or tamoxifen. When investigating the tissues with light microscopy no change in inner ear anatomy could be observed.

Animals↗
PubMed2003

Discovery and preclinical characterization of (+)-3-[4-(1- piperidinoethoxy)phenyl]spiro[indene- 1,1'-indane]-5,5'-diol hydrochloride: a promising nonsteroidal estrogen receptor agonist for hot flush.

In our studies of the development of a novel class of selective estrogen receptor modulators, (+)-3-[4-(1-piperidinoethoxy)phenyl]spiro[indene-1,1'-indane]-5,5'-diol hydrochloride (1) was found to be an estrogen receptor ligand with beneficial effects in rat models for human hot flush. Moreover, 1 was found to have beneficial effects on lipid and bone metabolism while maintaining marginal effects on the uterus and breasts. These findings suggest that 1 would provide a new treatment for hot flush.

Animals↗
PubMed2002

Osteoporosis: a review and its dental implications.

Osteoporosis is a disease that affects primarily women, but can also occur in men. It is characterized by a loss of bone mineral density (BMD), and often culminates in a fracture of the hip, wrist, and/or vertebrae. The diagnosis of osteoporosis is often made by using bone density measurements. They are often expressed in relative terms (T-scores and Z-scores); the Z-score is the number of standard deviations from the age-matched average value of healthy women. A low Z-score indicates the bone density is lower than it should be for a patient's age and sex. Osteoporosis is defined as a BMD loss of 2.5 standard deviations or more below the established mean. Osteoporosis can be treated by a variety of methods, the most common being the use of estrogen, with or without progestin or progesterone. The use of estrogen alone is referred to as estrogen replacement therapy (ERT), and the combination hormone replacement therapy (HRT). Other drugs used in the treatment of osteoporosis are the selective estrogen receptor modulators (SERMs) and the bisphosphonates. The SERMs appear to offer many of the positive benefits of estrogen with fewer adverse effects on the breast or uterus. Recently, a randomized, double blind study of nearly 3,000 women found no overall benefit in reducing heart disease for those taking estrogen. In fact, in the first year of estrogen use, heart disease was higher in this group than in those taking placebo. The relationship between systemic BMD and periodontal status has been investigated. In some patients, there is a correlation between a decrease of mandibular bone mass and tooth loss. In others, there is no such correlation. Those postmenopausal women taking HRT had greater tooth retention and a reduced likelihood of edentulism. A recent study has found no correlation between clinical attachment levels and the BMD of the lumbar spine. Many possible factors contribute to the development of osteoporosis and periodontal diseases. It is difficult to establish a direct correlation between tooth loss, bone loss, and loss of attachment resulting from periodontitis and decreased BMD associated with osteoporosis, but studies are ongoing.

Aged↗
PubMed2006

Estrogen receptor-alpha (ER-alpha) and defects in uterine receptivity in women.

Endometriosis is a disorder that affects 5% of the normal population but is present in up to 40% of women with pelvic pain and/or infertility. Recent evidence suggests that the endometrium of women with endometriosis exhibits progesterone insensitivity. One endometrial protein that fluctuates in response to progesterone is the estrogen receptor-alpha (ER alpha), being down-regulated at the time of peak progesterone secretion during the window of implantation. Here we demonstrate that the biomarker of uterine receptivity, beta 3 integrin subunit, is reduced or absent in some women with endometriosis and that such defects are accompanied by inappropriate over-expression of ER alpha during the mid-secretory phase. Using a well-differentiated endometrial cell line we showed that the beta 3 integrin protein is negatively regulated by estrogen and positively regulated by epidermal growth factor (EGF). By competing against estrogen with various selective estrogen receptor modulators (SERMs) and estrogen receptor agonists and antagonists, inhibition of expression of the beta 3 integrin by estrogen can be mitigated. In conclusion, we hypothesize that certain types of uterine receptivity defects may be caused by the loss of appropriate ER alpha down-regulation in the mid-secretory phase, leading to defects in uterine receptivity. Such changes might be effectively treated by timely administration of the appropriate anti-estrogens to artificially block ER alpha and restore normal patterns of gene expression. Such treatments will require further clinical studies.

Cells, Cultured↗
PubMedDate not supplied

Estradiol, but not raloxifene, improves aspects of spatial working memory in aged ovariectomized rhesus monkeys.

Estrogen replacement therapy (ERT) alleviates many postmenopausal symptoms but whether it also benefits cognitive function remains controversial. Further, since estrogen increases the risk of breast and uterine cancers, a new class of compounds, called selective estrogen receptor modulators (SERMs) is being considered as possible alternative to ERT. The SERM raloxifene is particularly interesting because, like estrogen, it improves lipid metabolism and reduces bone loss, without adverse effects on the breast or uterus. Little is known, however, about its effect upon cognitive function. We used a rhesus monkey model of human menopause to examine the effects of ERT and raloxifene on cognitive function. We tested 5 aged females (21-24 years old) ovariectomized long-term (10-16 years) on a battery of age-sensitive tasks, including the Delayed Response (DR), the Delayed Non-Matching-to-Sample-10 min (DNMS-10 min) and the spatial-Delayed Recognition Span Test (DRST). Monkeys were tested 5 days a week on each task for 9 consecutive months, while undergoing treatments with placebo, ethinyl estradiol (EE(2)), and raloxifene in alternating 28-days blocks. EE(2) transiently enhanced the working memory component of the spatial-DRST, but did not affect performance on the other tasks of the battery. Raloxifene had no effect on cognitive performance. These findings indicate that estradiol is able to enhance some aspects of spatial working memory in aged monkeys despite many years of estrogenic deprivation. Further, they suggest that raloxifene does not affect cognitive function after long-term ovarian hormone deprivation.

Aging↗
PubMed2004

Drug targeting of estrogen receptor signaling in the cardiovascular system: preclinical and clinical studies.

Atherosclerosis and associated coronary heart disease events have lower prevalence in women than in men, especially during young adult years. Although multiple lines of evidence suggest that estrogens contribute to this difference, the efficacy of hormone replacement therapy for the prevention of cardiovascular disease in postmenopausal women is controversial. The protective action of estrogen in the cardiovascular system appears to be mediated indirectly by an effect on serum lipoprotein and triglyceride profiles and on the expression of coagulant and fibrinolytic proteins, and by a direct effect on the vessel wall itself. Estrogen has both rapid effects involving alteration of membrane ionic permeability and activation of membrane-bound enzymes and increases in endothelial cell nitric oxide synthase activity, as well as longer-term effects on gene expression that are mediated, at least in part, by the ligand-activated transcription factors, estrogen receptor alpha and beta. Compounds with pure antiestrogenic activity and selective estrogen receptor modulators that regulate estrogen receptor function in a tissue-specific manner have been developed in an attempt to achieve the cardioprotective effects of estrogens while minimizing the undesirable risks associated with hormone replacement therapy (e.g., endometrial and breast cancer). In this review, we will discuss recent developments on the mechanisms of estrogen action in the cardiovascular system. The results of clinical trials testing the long-term efficacy of hormone replacement therapy for the treatment of cardiovascular disease will also be discussed.

Animals↗
PubMed2001

Soy for breast cancer survivors: a critical review of the literature.

A variety of health benefits, including protection against breast cancer, have been attributed to soy food consumption, primarily because of the soybean isoflavones (genistein, daidzein, glycitein). Isoflavones are considered to be possible selective estrogen receptor modulators but possess nonhormonal properties that also may contribute to their effects. Concern has arisen over a possible detrimental effect of soy in breast cancer patients because of the estrogen-like effects of isoflavones. Genistein exhibits a biphasic effect on the growth of MCF-7 cells in vitro, stimulating proliferation at low concentrations but inhibiting it at high concentrations. In ovariectomized athymic mice implanted with MCF-7 cells, both genistein and soy protein stimulate tumor growth in a dose-dependent manner. In contrast, in intact mice fed estrogen, genistein inhibits tumor growth. Although two studies in premenopausal women suggested that soy exerts estrogenic-like effects on breast tissue, recently conducted year-long studies indicated that isoflavone supplements do not affect breast tissue density in premenopausal women and may decrease density in postmenopausal women. These latter effects are opposite to those of hormone replacement therapy (HRT). Importantly, substantial data suggest that the progestogen, not the estrogen, component of HRT increases risk of developing breast cancer. Furthermore, recently conducted studies have failed to find that even HRT reduces survival in breast cancer patients. Overall, the data are not impressive that the adult consumption of soy affects the risk of developing breast cancer or that soy consumption affects the survival of breast cancer patients. Consequently, if breast cancer patients enjoy soy products, it seems reasonable for them to continue to use them.

Animals↗