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PubMed2001

Cardiovascular effects of raloxifene hydrochloride.

Raloxifene hydrochloride binds to the estrogen receptor and shows tissue-selective effects; thus, it belongs to a class of drugs recently described as selective estrogen receptor modulators (SERMs). Tissue selectivity of raloxifene may be achieved through several mechanisms: the ligand structure, interaction of the ligand with different receptor subtypes in various tissues, and intracellular events after ligand binding. Raloxifene has estrogen-agonist effects on bone and lipids and estrogen antagonist effects on the breast and uterus. In addition to its well established effects on osteoporosis, recent preclinical and clinical findings suggest that raloxifene also possesses beneficial effects on the cardiovascular system. These findings indicated that raloxifene may have cardioprotective properties without an increased risk of cancer or other side effects. Raloxifene has been shown to reduce total and low-density lipoprotein cholesterol concentrations in plasma, an effect similar to that produced by estrogens. Unlike estrogens, however, raloxifene does not increase high-density lipoprotein cholesterol and triglyceride levels in plasma. Endothelium is thought to play an important role in the genesis of atherosclerosis. Several lines of evidence suggest that an intervention with endothelial function might influence the progression of coronary disease and the incidence of cardiovascular events. Raloxifene increases the nitric oxide/endothelin-1 ratio, and improves endothelium-dependent vasomotion in post-menopausal women to the same extent as estrogens. Furthermore, in two randomized trials on post-menopausal women raloxifene reduced homocysteine levels, another independent risk factor for the development of cardiovascular disease. Although estrogens remain the drugs of choice in the hormonal therapy of most postmenopausal women, raloxifene may represent and alternative in women who are at risk of coronary artery disease.

Animals↗
PubMed2005

Phytoestrogens derived from red clover: an alternative to estrogen replacement therapy?

The benefits of plant extracts from soy and red clover as alternatives to conventional hormone replacement therapy (HRT) have been debated in the past. Here, an attempt has been made to summarize the biochemical and pharmacological data in the light of clinical aspects. Red clover and soy extracts contain isoflavones, which have a high affinity to estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), progesterone receptor (PR) and androgen receptor (AR). The higher affinity to ERbeta compared to ERalpha has been used as an explanation why red clover extracts function as food additives to treat menopausal disorders and may reduce risk of breast cancer. Biochemical analysis shows that these representatives of phytoestrogens have multiple actions beside selective estrogen receptor modulator (SERM)-activity. They act as selective estrogen enzyme modulators (SEEMs), have antioxidant activity and interact with transcription factors such as NF-kappaB. Furthermore, it is indicated that they have protective effects on osteoporosis and the cardiovascular system. Currently 40-50mg of isoflavones (biochanin A, daidzein, formononetin and genistein) are recommended as daily dose. This recommendation is based on the daily intake of phytoestrogens in a traditional Japanese diet.

Animals↗
PubMedDate not supplied

Suppression of elevated cartilage turnover in postmenopausal women and in ovariectomized rats by estrogen and a selective estrogen-receptor modulator (SERM).

OBJECTIVE: Several observational studies indicate that estrogen deficiency increases the incidence of osteoarthritis in postmenopausal women. To validate this observation, we investigated the effects of ovariectomy (OVX) on cartilage erosion in rats using histology and an established bio-assay of cartilage-specific collagen type II degradation products (CTX-II). Furthermore, we investigated whether estrogen and levormeloxifene, a selective estrogen-receptor modulator (SERM), can prevent the OVX-induced changes in cartilage degradation. The clinical relevance was assessed in postmenopausal women by measuring the changes in CTX-II during 12-month treatment with levormeloxifene versus placebo. DESIGN: Sixty 6-month-old rats were divided in five groups. One group was subjected to sham and the others to OVX, followed by treatment with vehicle alone, estradiol or 0.2 mg/kg/day or 5 mg/kg/day of levormeloxifene. The rats were treated for 9 weeks with biweekly blood and urine sampling for measurement of bone resorption and cartilage turnover. After study termination, hind knees were removed for histological analysis of erosions. The effect of levormeloxifene in post-menopausal women was assessed by measuring CTX-II in samples from 301 women who were participating in a phase II study of this SERM. RESULTS: OVX rats showed significant increases in the urinary excretion of CTX-II. After 9 weeks this was manifested as increased surface erosion of knee articular cartilage compared with sham-operated rats. Treatment with estrogen or levormeloxifene prevented the OVX-induced changes. There was a significant correlation between the 4-week changes in CTX-II and cartilage erosion at week 9 (r = 0.64, P < 0.001). In postmenopausal women treated with levormeloxifene, the urinary excretion of CTX-II was decreased by approximately 50% and restored CTX-II levels to the premenopausal range. CONCLUSIONS: This study is the first to demonstrate that a SERM suppresses cartilage degradation in both rodents and humans, suggesting potential therapeutical benefits in the prevention of destructive joint diseases such as osteoarthritis.

Aged↗
PubMed2002

Idoxifene causes endothelium-dependent, nitric oxide-mediated vasorelaxation in male rats.

Selective estrogen receptor modulators are estrogen-like compounds that lack the deleterious effects of estrogen. The present study was designed to determine whether idoxifene, a new selective estrogen receptor modulator, may have a vasodilatory effect on aortic vessels from male animals, and if so, to investigate the mechanism (i.e., endothelium-independent, direct vasorelaxation vs. endothelium-dependent, nitric oxide mediated vasorelaxation) by which idoxifene may exert its vasodilatory effect. Superior mesenteric arterial rings from adult male Sprague-Dawley rats were suspended in Krebs-Henseleit ring baths. Rings were contracted with 50 nM U-46619 (9,11-epoxymethano-PGH(2)), a thromboxane A(2) mimetic. Cumulative dose-response vasorelaxation to idoxifene (0.01 to 3 microM) was studied in the presence and absence of 200 microM N(omega)-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase (NOS) inhibitor). The results obtained from idoxifene were compared with those from 17beta-estradiol. Our experimental results demonstrated that addition of idoxifene to superior mesenteric arterial rings isolated from male rats resulted in a dose-dependent vasorelaxation in the range of 0.1 microM (minimal vasodilatory concentration) to 3 microM (maximal vasodilatory concentration). Pre-treatment with L-NAME to block nitric oxide (NO) production virtually abolished idoxifene-induced vasodilatation, indicating that idoxifene caused an NO-mediated vasorelaxation in vessels from male animals. Addition of 17beta-estradiol also resulted in an endothelium-dependent vasorelaxation in aortic rings from male rats. However, these vessels were 30-fold less sensitive to 17beta-estradiol than to idoxifene in their vasorelaxation responses. Taken together, these results demonstrate that selective estrogen receptor modulators are superior to traditional estrogen in their vascular protection and may thus have potential therapeutic use in protection against cardiovascular disease, especially in male patients.

Animals↗
PubMed2002

Regulation of estrogen target genes and growth by selective estrogen-receptor modulators in endometrial cancer cells.

OBJECTIVE: Tamoxifen has mixed agonist/antagonist activities, leading to tissue-specific estrogen-like actions and endometrial cancer. The purpose of this study was to evaluate the effects of antiestrogens on the growth of estrogen receptor (ER)-positive ECC-1 endometrial cancer cells in vitro and in vivo. METHODS: We performed growth studies and luciferase assays using ERE-tK and AP-1 reporters. ERalpha protein expression was measured by Western blot after antiestrogen treatments. We investigated the actions of antiestrogens on the transcription of the pS2 gene in situ measured by Northern blot and the actions of antiestrogens on the VEGF protein secreted by ELISA. ERalpha, ERbeta, EGFR, and HER2/neu mRNAs were determined by RT-PCR. Last, ECC-1 tumors were developed by inoculation of cells into ovariectomized athymic mice and treated with estradiol (E2), tamoxifen, raloxifene, and a combination. RESULTS: E2 induced cell proliferation while antiestrogens did not. E2 and raloxifene down regulated ERalpha protein; in contrast, 4OHT did not. ICI182,780 completely degraded the receptor. ECC-1 cells express ERbeta at insignificant levels. Luciferase assays did not show any induction in ERE- nor AP-1-mediated transcription by antiestrogens. E2 caused a concentration-dependent increase in pS2 mRNA but antiestrogens did not. E2 increased VEGF expression in a dose-dependent manner and antiestrogens blocked E2 action. E2 down regulated HER2/neu while 4OHT and raloxifene did not change HER2/neu levels compared to control. In addition, EGFR mRNA was down regulated by E2 but raloxifene did not change it. Tamoxifen and raloxifene did not promote tumor growth in vivo. However, raloxifene (1.5 mg daily) only partially blocked E2-stimulated growth. CONCLUSION: Tamoxifen and raloxifene are antiproliferative agents and antiestrogens in ECC-1 endometrial cells in vitro and in vivo. The observation that selective estrogen-receptor modulators do not down regulate EGFR and HER2/neu mRNA may provide a potential role for these oncogenes in the development of raloxifene- or tamoxifen-stimulated endometrial cancer. The ECC-1 cell line could provide important new clues about the evolution of drug resistance to tamoxifen and raloxifene.

Adenocarcinoma↗
PubMed2002

Role of antiestrogens and aromatase inhibitors in breast cancer treatment.

This review explores the recent experience with, and the basis for, the use of selective estrogen receptor modulators to treat and prevent breast cancer. As new agents are unveiled, they will continue to be tested against tamoxifen. A number of new selective estrogen receptor modulators are in clinical development in an attempt to decrease the unwanted effects of tamoxifen. Raloxifene holds the promise of treating osteoporosis with the beneficial side effect of breast cancer prevention. Additionally, two different classes of hormonal agents, the aromatase inhibitors and estrogen receptor down-regulators, which have no estrogen-like properties at any site, appear to be promising new treatments for advanced breast cancer.

Aromatase Inhibitors↗
PubMed2003

DT56a (Tofupill/Femarelle) selectively stimulates creatine kinase specific activity in skeletal tissues of rats but not in the uterus.

The novel natural product DT56a (Tofupill/Femarelle), derived from soybean, has been shown to relieve menopausal vasomotor symptoms and to increase bone mineral density with no effect on sex steroid hormone levels or endometrial thickness. In the present study, we compared the effects of DT56a and estradiol-17beta (E2) on bone and cartilage (Ep) of immature or ovariectomized female rats, by measuring the changes in the specific activity of the BB isozyme of creatine kinase (CK). Single short-term injection of high doses of DT56a induced estrogenic activity in bones and uterus similar to that of E2. When administered in multiple oral doses, DT56a stimulated skeletal tissues similarly to E2, but whereas E2 increased CK specific activity in the uterus, DT56a did not. The selective estrogen receptor modulator (SERM) raloxifene (Ral) blocked the stimulation of CK by either DT56a or by E2 in all tissues tested. Our findings suggest that DT56a acts as a selective estrogen receptor modulator stimulating skeletal tissues without affecting the uterus. The effect of DT56a on other systems, such as the vascular and the central nervous system, are currently under investigation.

Animals↗
PubMed2005

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands.

Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ERalpha and ERbeta. The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17beta-estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ERalpha-selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ERbeta-selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139-151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ERbeta agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ERalpha-selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.

Adoptive Transfer↗
PubMed2004

Differential regulation of K+ and Ca2+ channel gene expression by chronic treatment with estrogen and tamoxifen in rat aorta.

The beneficial effect of estrogen on the vascular system is partly associated with its ability to reduce vascular contractility. Estrogen acutely activates large-conductance Ca(2+)-activated K(+) channel (BK(Ca)) and inhibits L-type voltage-gated Ca(2+) channel (VGCC) in vascular smooth muscle cells. However, a long-term influence of estrogen, estrogen deficiency, or selective estrogen receptor modulators on gene expression of these ion channels is unclear. This study was therefore aimed to determine the relative mRNA expression levels of alpha- and beta-subunits of BK(Ca), K(V)1.5 subtype of delayed rectifier K(+) channel (K(V)), and alpha(1C) subunit of L-type VGCC in endothelium-denuded aortas from female rats by a semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis. Rats were divided into four experimental groups: (i) sham-operated control, (ii) ovariectomized, (iii) ovariectomized with 17 beta-estradiol treatment and (iv) ovariectomized with tamoxifen treatment. The results showed that ovariectomy decreased the mRNA expression of K(V)1.5 while it increased the mRNA expression of alpha(1C) subunit of L-type VGCC. Ovariectomy-induced modulation of gene expression of these ion channels was completely prevented in ovariectomized rats receiving chronic treatment with estrogen or tamoxifen. In contrast, the expression levels of genes encoding both alpha- and beta-subunits of BK(Ca) remained the same in the four animal groups. The present study has provided the first line of evidence suggesting the long-term beneficial effects of estrogen and tamoxifen therapy on vascular ion channel expressions, which may be an important mechanism by which the favorable modulation of vessel tone by estrogen or selective estrogen receptor modulators is mediated.

Animals↗
PubMed2004

A new series of estrogen receptor modulators: effect of alkyl substituents on receptor-binding affinity.

New types of selective estrogen receptor modulators (SERMs) were synthesized and evaluated for their binding affinity and biological effect on reproductive cells. A proposed lead structure (B) was derivatized to provide compounds 30 and 44, which showed good estrogen-receptor binding affinity (K(i) values: 6.3 and 10 nM, respectively), as well as minimal impact on mammary and uterine carcinoma cells. Introduction of an alkyl group in the core structure considerably enhanced receptor-binding affinity of the compounds tested. Synthesis and structure-activity relationships of these compounds are described.

Alkaline Phosphatase↗
PubMed2006

Non-steroidal anti-estrogens in the treatment of breast cancer.

The non-steroidal selective estrogen receptor modulator (SERM) tamoxifen has been used as standard first-line therapy for postmenopausal breast cancer since the 1970s, during which time over 400,000 lives have been saved. Nevertheless, much attention has been paid to the side effect profile of tamoxifen, particularly in terms of cardiovascular and endometrial abnormalities. Third generation non-steroidal aromatase inhibitors, such as anastrozole and letrozole, have been approved as an alternative, although it is still too early to judge what long-term adverse effects might be associated with prolonged restriction of the supply of estrogen. Novel SERMs have demonstrated improved characteristics over tamoxifen, reducing or eliminating certain adverse events while retaining breast tumor-reducing efficacy. Thus, these agents could provide a direct substitute for tamoxifen. In addition, other estrogen receptor (ER) subtype-selective modulators are under investigation, and the importance of ERbeta as a positive prognostic indicator may open up further therapeutic opportunities. Resistance to hormonal therapies is still a major problem and identifiying the onset of the development of resistance, together with earlier intervention with inhibitors of growth-factor driven cell survival pathways, in combination or sequentially, requires more intense study.

Animals↗
PubMed2004

Selective estrogen-receptor modulators (SERMs) in the cyclopentadienylrhenium tricarbonyl series: synthesis and biological behaviour.

A series of organometallic antiestrogens based on the OH-tamoxifen (OH-Tam) skeleton and bearing the (eta(5)-C(5)H(4))Re(I)(CO)(3) unit has been prepared by using McMurry coupling for the purpose of studying their biological behaviour. The cyclopentadienylrhenium tricarbonyl moiety is indeed stable in biological media, compact, lipophilic and easy to handle. Furthermore, this study allowed us to select the best candidates for subsequent use as radiopharmaceuticals either for imaging or therapy by using appropriate radionucleides, namely (99m)Tc and (188)Re. In these molecules the beta-phenyl group of OH-Tam has been replaced by the (eta(5)-C(5)H(4))Re(CO)(3) moiety, and the length of the dimethylamino side chain --O(CH(2))(n)N(CH(3))(2) was varied (n=2, 3, 4, 5 and 8). The compounds 7 a-7 e were obtained as mixtures of their Z and E isomers, which could be separated by semipreparative HPLC. Unlike their ferrocene homologues, the compounds do not isomerise in solution. Structural identification was carried out with NMR spectroscopy by using the HMBC and NOE techniques and was confirmed by the X-ray structural determination of (E)-7 a (n=2). These molecules were more lipophilic than OH-Tam (log P(o/w)=4.5-6.3) and they were all reasonably well recognized by the two forms of the estrogen receptor (ERalpha and ERbeta). For example, (Z)-7 b (n=3) has high relative binding affinity (RBA) values of 31 % for ERalpha and 16.8 % for ERbeta. The antiproliferative effects of two pairs of isomers, (Z)- and (E)-7 b (n=3) and (Z)- and (E)-7 d (n=5), were studied at a molarity of 1 microM on two breast-cancer cell lines, MCF7 (ERalpha positive) and MDA-MB231 (ERalpha negative). These molecules had an antiproliferative effect on MCF7 cells slightly higher than that of OH-Tam and no effect on MDA-MB231 cells. Thus, the antiproliferative effect observed on the MCF7 cells seemed essentially to be linked to an antiestrogenic effect. Molecular modelling studies have allowed us to rationalise these effects and select the best compounds for future development of a radioactive series.

Cell Line, Tumor↗
PubMed2001

Osteoporosis therapies for rheumatoid arthritis patients: minimizing gastrointestinal side effects.

OBJECTIVE: This manuscript identifies characteristics that put people with rheumatoid arthritis (RA) at high risk for osteoporosis or gastrointestinal (GI) disturbances. The manuscript then reviews therapies available for osteoporosis in the United States and makes recommendations about choosing therapies that minimize GI adverse effects in RA patients at high risk for such events. DATA SOURCES: References identified through MEDLINE, abstracts, and prescribing information for individual drugs. DATA EXTRACTION: Characteristics that predispose patients to osteoporosis and GI problems were identified. Data on individual osteoporosis therapies were assessed by risk-benefit analysis and appropriateness for use in patients at risk for GI disturbances. DATA SYNTHESIS: High risk of osteoporosis in people with RA is caused by disease activity, medication effects, physical inactivity, and standard risk factors such as postmenopausal status and increased age. Patients with RA are frequently at high GI risk if they are receiving nonsteroidal anti-inflammatory drugs or corticosteroids. Because of the high potential for erosive esophagitis and other upper GI disorders with alendronate, caution is warranted in prescribing alendronate to RA patients with high GI risk. In such patients, estrogen replacement therapy, selective estrogen receptor modulators, or calcitonin should be considered for treatment, and either estrogen replacement therapy or selective estrogen receptor modulators should be considered for osteoporosis prevention. CONCLUSIONS: Assessment of GI risk is important in patients with RA and osteoporosis. Risk factors should be considered when choosing osteoporosis therapies.

Alendronate↗
PubMed2003

Selective estrogen-receptor modulators.

Tamoxifen is useful for adjuvant treatment of breast cancer and in some women for the prevention of breast cancer. The risk-benefit ratio in regard to the skeleton and perhaps other organ systems may very well be different for postmenopausal versus premenopausal women. In postmenopausal women, tamoxifen (20 mg/d) increased BMD in the spine and perhaps the hip; however, the effect on fracture risk is unclear. Therefore, for postmenopausal women with osteoporosis, consideration should be given to the addition of an agent that is shown to have efficacy against fractures (such as bisphosphonates), even while these women are on tamoxifen. For women at only modest or moderate risk, with bone density above the osteoporosis range (T score above -2.5) and no major fracture history, tamoxifen is probably adequate for 5 years of use. Potentially serious adverse effects include venous thromboembolism, uterine cancer, benign uterine disease, and cataracts. Raloxifene (60 mg/d) protects against vertebral fractures over 4 years in women with osteoporosis, produces small increases in bone mass of the spine, hip, and total body, and reduces bone turnover in postmenopausal women with or without osteoporosis. No significant effect has yet been demonstrated on nonvertebral fractures after 4 years of treatment. Raloxifene has the additional benefit of substantially reducing the risk of ER-positive invasive breast cancer and does not increase the risk of uterine disease. Raloxifene increases the risk of venous thromboembolic disease to the same degree as tamoxifen and estrogen. Therefore, SERMS and estrogens are generally contraindicated in women with a previous history of venous thromboembolism or those who are at significantly increased risk. Raloxifene is probably most useful in women who have osteoporosis (T score = -2.5) or who are at risk (T score less than -1.5 with clinical risk factors) in the middle menopausal period (age 55-65) or in the early menopausal period in women who have no significant hot flashes. At this stage in life, vertebral fractures are common, but hip fractures are not. Therefore, women who take raloxifene can expect a reduction in the likelihood of having a vertebral fracture, and possibly breast cancer. The lack of definitive efficacy against hip fracture is not a major deterrent to use of this agent in this age group because hip fracture risk is very low. Raloxifene might not be the treatment of choice for elderly women who are at particularly high risk of hip fracture.

Female↗