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Results for “Selective Estrogen Receptor Modulators”

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PubMed2003

Neuroprotection by estrogen in animal models of global and focal ischemia.

Estrogen has been demonstrated to protect against brain injury, neurodegeneration, and cognitive decline. Furthermore, estrogen seems to specifically protect cortical and hippocampal neurons from ischemic injury. Here our data evaluating the neuroprotective effects of estrogens, the selective estrogen receptor modulators (SERMs), and estrogen receptor alpha- and beta-selective ligands in animal models of ischemic injury are discussed. In rats and mice, the middle cerebral artery occlusion (MCAO) model was used as models representing cerebrovascular stroke, while in gerbils the two-vessel occlusion model, resenting acute heart attack, was used. Using focal ischemia in ovariectomized ERalphaKO, ERbetaKO, and wild-type mice, we clearly established that the ERalpha subtype is the critical ER-mediating neuroprotection in mouse focal ischemia. Because of the characteristic blood supply of the gerbil, the gerbil global ischemia model was used to evaluate the neuroprotective effects of estrogen, SERMs, and ERalpha- and ERbeta-selective compounds in the hippocampus. Analysis of neurogranin mRNA, a marker of viability of hippocampal neurons, with in situ hybridization, revealed that estrogen treatment resulted in a complete protection in the CA1 regions not only when administered before, but also when given 1 hour after occlusion. Our in vivo binding studies with (125)I-estrogen in gerbils revealed the presence of nuclear estrogen binding sites primarily in CA1 neurons, but not in the CA3 region, as we saw in rats and mice. Together, these observations demonstrate that estrogen protects from ischemic injury in both the focal and global ischemia models by acting primarily via classical nuclear receptors.

Animals↗
PubMed2006

Neuroprotection by ovarian hormones in animal models of neurological disease.

Ovarian hormones can protect against brain injury, neurodegeneration, and cognitive decline. Most attention has focused on estrogens and accumulating data demonstrate that estrogen seems to specifically protect cortical and hippocampal neurons from ischemic injury and from damage due to severe seizures. Although multiple studies demonstrate protection by estrogen, in only a few instances is the issue of how the steroid confers protection known. Here, we first review data evaluating the neuroprotective effects of estrogens, a selective estrogen receptor modulator (SERM), and estrogen receptor alpha- and beta-selective ligands in animal models of focal and global ischemia. Using focal ischemia in ovariectomized ERalphaKO, ERbetaKO, and wild-type mice, we clearly established that the ERalpha subtype is the critical ER mediating neuroprotection in mouse focal ischemia. In rats and mice, the middle cerebral artery occlusion (MCAO) model was used to represent cerebrovascular stroke, while in gerbils the two-vessel occlusion model, representing global ischemia, was used. The gerbil global ischemia model was used to evaluate the neuroprotective effects of estrogen, SERMs, and ERalpha- and ERbeta-selective compounds in the hippocampus. Analysis of neurogranin mRNA, a marker of viability of hippocampal neurons, with in situ hybridization, revealed that estrogen treatment protected the dorsal CA1 regions not only when administered before, but also when given 1 h after occlusion. Estrogen rarely is secreted alone and studies of neuroprotection have been less extensive for a second key ovarian hormone progesterone. In the second half of this review, we present data on neuroprotection by estrogen and progesterone in animal model of epilepsy followed by exploration into ovarian steroid effects on neuronal damage in models of multiple sclerosis and traumatic brain injury.

Animals↗
PubMed2005

Malignant mixed mullerian tumor of the uterus in a patient taking raloxifene.

BACKGROUND: Uterine malignant mixed mesodermal tumor is a rare variant of uterine cancer. Data suggest that tamoxifen is involved in the pathogenesis. We report a case of a women in whom a malignant mixed mesodermal tumor was diagnosed while she was taking raloxifene, which is also a selective estrogen receptor modulator. CASE: A malignant mixed mesodermal tumor was diagnosed in a 64-year-old woman with a bicornuate uterus while she was taking raloxifene for osteoporosis prevention. Diagnosis had been delayed secondary to sampling of the other uterine horn. CONCLUSION: There may be an association between raloxifene and the development of malignant mixed mesodermal tumor. Special attention should be paid when attempting to sample the endometrium in patients with mullerian abnormalities.

Biopsy, Needle↗
PubMed2006

Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy.

Deregulation of the estrogen axis in humans prompts a series of tissue-specific events. In the breast and prostate, alterations in estrogen signalling lead to genotypic and phenotypic molecular alterations that result in dysplastic cellular appearance, deregulated cell growth and carcinoma. In bone, decreased estrogen leads to increased osteoclastogenesis and bone resorption, decreased bone mineral density and a significant fracture risk. Toremifene is a selective estrogen receptor modulator that exerts pharmacological activity in the breast, bone and prostate. An intense interest in developing this agent for prostate cancer chemoprevention is based on the reduction of premalignant and malignant prostate lesions in a transgenic model of prostate cancer. Biological and clinical activity was demonstrated in Phase II trials by the prevention of progression to prostate cancer in men with high-grade prostate intraepithelial neoplasia and through suppression of bone turnover biomarkers and increased bone mineral density in men on androgen deprivation therapy for prostate cancer.

Androgen Antagonists↗
PubMed2004

Benzothiophene and naphthalene derived constrained SERMs.

For selective estrogen receptor modulators (SERMs), the orientation of the basic side chain relative to the SERM core has a significant impact on function. The synthesis and biological evaluation of two series of SERMs are disclosed, where the ligand side chain is constrained to adopt a defined orientation. Compounds where the side chain is forced into the plane of the SERM core have a different profile compared to those compounds where the side chain is pseudo-orthogonal, particularly with regard to antagonism of estradiol action on an Ishikawa uterine cell line.

Animals↗
PubMed2001

Homocysteine in postmenopausal women and the importance of hormone replacement therapy.

Homocysteine (Hcy) has been shown to damage the vascular endothelial cells, contributing to atherothrombosis. The increase in plasma Hcy levels with natural menopause suggests a close relationship between Hcy metabolism and estrogen status and proposes one of the mechanisms through which menopause unfavorably affects cardiovascular disease risk in women. In addition to the prevention of osteoporosis, hormone replacement therapy (HRT) lowers Hcy levels in postmenopausal women. The first report by van der Mooren et al., demonstrated in an uncontrolled study a significant reduction (11%) in fasting serum Hcy level after 6 months of treatment with sequentially combined estradiol-dydrogesterone therapy in 21 healthy postmenopausal women. This effect was particularly evident in women with initially elevated baseline serum Hcy concentrations. Similar results were found in other studies in which women were treated with various transdermal as well as oral HRT regimens, although two studies could not confirm these findings. All these studies were uncontrolled, and three of them consisted of a relatively small number of participants. Therefore, they remained inconclusive. Three randomized controlled trials on HRT and Hcy were published to date, confirming that postmenopausal HRT reduces circulating levels of Hcy. Current and recent HRT use is associated with a slight increased risk of breast cancer. As a result of this, research has centered on finding compounds that can prevent the consequences of estrogen deficiency, without the potential risk of HRT. Raloxifene, referred to as a Selective Estrogen Receptor Modulator (SERM), has the potential as a viable alternative to HRT. Recently, two randomized controlled trials demonstrated that raloxifene lowers plasma Hcy levels in postmenopausal women, similar to the reduction obtained with HRT. Little is known about the mechanisms underlying the HRT-associated lowering of plasma Hcy. Proposed mechanisms relate to an increase in kidney methionine synthase activity or may be related to the transamination of methionine. We conclude that HRT decreases plasma Hcy levels in postmenopausal women and that the strongest reductions can be achieved in women with the highest concentrations.

Cardiovascular Diseases↗
PubMed1999

Pharmacotherapy of dyslipidemia in postmenopausal women: weighing the evidence.

In the United States, coronary heart disease (CHD) is the leading cause of death in women. The incidence of CHD rises dramatically in women following menopause, which can be partially attributed to a more atherogenic lipoprotein profile. For years, observational and epidemiological data have suggested that estrogen and progesterone therapy reduced CHD end points. However, the first prospective trial that evaluated hormone replacement therapy (HRT) for secondary CHD prevention demonstrated no positive cardiovascular benefit of HRT compared with placebo. In interventional studies, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase inhibitors significantly reduced CHD outcomes in postmenopausal women, and these agents have emerged as the drugs of choice for primary and secondary CHD prevention. The selective estrogen receptor modulators (SERMs) may have a role in CHD prevention, but long-term clinical trials evaluating end points are needed. An evidence-based approach is necessary when deciding the appropriate pharmacotherapy of dyslipidemia in postmenopausal women.

Aged↗
PubMed2000

Raloxifene: a new choice for treating and preventing osteoporosis.

Selective estrogen receptor modulators (SERMs) are a new class of drugs that provide a new option for addressing the health challenges of postmenopausal women. This review discusses the proposed mechanism of action of SERMs and describes clinical findings on raloxifene, a SERM now available for treating and preventing osteoporosis.

Aged↗
PubMed2005

Chronic estrogenic drug treatment increases preproenkephalin mRNA levels in the rat striatum and nucleus accumbens.

Estrogens modulate the expression of preproenkephalin (PPE) in the hypothalamus but little is known for other brain regions. The present study investigated the effect of hormonal withdrawal and replacement therapy on PPE expression in the striatum, nucleus accumbens and cortex. Ovariectomized Sprague-Dawley rats were treated for 2 weeks with estradiol, a specific ligand for estrogen receptor alpha (ERalpha), 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and estrogen receptor beta (ERbeta) 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), or the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene. Brain PPE mRNA levels, measured by in situ hybridization, were high in the striatum and nucleus accumbens compared to the low expression in the cortex. Ovariectomy decreased uterine weights compared to intact uterus, which was corrected by estradiol and PPT. Tamoxifen and raloxifene partially stimulated uterine weights while DPN left it unchanged. In the anterior, median and posterior striatum and in the core and shell of the nucleus accumbens, ovariectomy decreased PPE mRNA levels compared to intact rats, this was corrected by estradiol treatment except for the posterior striatum. PPT, DPN, tamoxifen and raloxifene reproduced the estradiol effect. In the prefrontal and cingulate cortices, neither ovariectomy nor treatments changed PPE mRNA levels. These results show for the first time that estradiol increases PPE mRNA in the striatum and nucleus accumbens. This effect is observed also with estrogen receptor agonists for the ERalpha and ERbeta as well as with SERMs.

Analysis of Variance↗
PubMedDate not supplied

Sequencing of hormonal therapy in breast cancer.

Hormonal therapy plays an integral role in the management of the majority of women with breast cancer who can be considered to have hormone-dependent breast cancer because of the presence of the molecular predictive markers, estrogen receptor and progesterone receptor. Numerous hormonal agents are available from multiple classes of drugs, including selective estrogen receptor modulators, aromatase inhibitors, progestins, androgens, and luteinizing hormone-releasing hormone analogues. Multiple clinical trials involving these agents have been conducted which permit an evidence-based approach to the development of a sequencing strategy for treatment of women with breast cancer.

Aged↗
PubMed2006

[Present development of new drugs for osteoporosis].

Bisphosphonates are widely used, though gastrointestinal tolerance is a problem on daily administration. Alendronate 35 mg administered once weekly is as effective at increasing bone mineral density (BMD) as 5 mg/day in the treatment of osteoporosis. Once weekly regimen will be soon available in Japan and can reduce adverse events. Injection therapies may also circumvent this, although this introduces the smaller problem of acute phase reactions. New generation bisphosphonates (milodronate, ibandronate and zoledronate) along with anti-receptor activator of nuclear factor-kappaB ligand (RANKL) antibody are promising and eagerly developed for the treatment of osteoporosis. Raloxifene appears to have a superior safety profile to hormone replacement therapy (HRT), though its efficacy on bone may be limited, so that various new generation of selective estrogen receptor modulator (SERMs) is now underdeveloped. Anabolic agents such as teriparatide and strontium ranelate have marked effects on BMD and subsequent reduction on fracture risk. While none of these options is suitable for everyone, the range of future available therapies does mean that most patients can find an intervention that is effective and acceptable.

Antibodies↗
PubMed2003

Endothelial function and menopause: effects of raloxifene administration.

Postmenopausal women have more severe endothelial dysfunction than premenopausal women. In the present study, we evaluated the possible beneficial effect of raloxifene administration, a selective estrogen receptor modulator, on endothelial regulation in postmenopausal women. In a double-blind, randomized vs. placebo trial, 60 healthy postmenopausal women were treated with raloxifene (60 mg/d) or placebo for 4 months to evaluate the effect of raloxifene treatment on endothelial function. Furthermore, in raloxifene-treated subjects (n = 30), the effect of raloxifene was also assessed during the intraarterial infusion of N(G)-monomethyl-L-arginine (4 micromol/min). Raloxifene administration vs. placebo was associated with a decrease in plasma low-density lipoprotein cholesterol (P < 0.01), triglyceride (P < 0.05), thiobarbituric acid-reactive substance (P < 0.01), vascular cell adhesion molecule-1 (P < 0.05), intercellular adhesion molecule-1 (P < 0.001), and E-selectin (P < 0.001) levels and with an increase in plasma Trolox equivalent antioxidant capacity (P < 0.001) levels. Indeed, raloxifene treatment was also associated with a significant improvement in endothelial-dependent vasodilatation assessed by brachial reactivity technique. Raloxifene administration had no impact on endothelial-independent vasodilatation. Furthermore, intraarterial infusion of N(G)-monomethyl-L-arginine inhibited the significant effect of raloxifene on endothelium-mediated brachial arterial diameter and flow. In conclusion, our results demonstrate that raloxifene administration is associated with a positive modulation of endothelial-dependent vasodilatation likely due to a reduction of risk factors for endothelial damage.

Adult↗
PubMed1999

[New developments in the hormonal treatment of breast cancer in postmenopausal women].

Nowadays the role of the hormonotherapy in the treatment of breast cancer in postmenopausal women is well established. The benefit of tamoxifen is demonstrated in the adjuvant setting as well as in the treatment of advanced breast cancer. After tamoxifen failure the hormonosensitive patients can be offered a second and a third hormonal treatment. The developments of new hormonotherapies recently or shortly put at the disposal of oncologists, such as new antiestrogens or selective estrogen receptors modulators (SERM), new steroidal and nonsteroidal aromatase inhibitors and antiprogestins are reviewed as well as the recent data on the use of tamoxifen in the primary prevention of breast cancer. The principal characteristics and the potential therapeutic uses of these agents are reviewed in the treatment and prevention of breast cancer in postmenopausal patients.

Anticarcinogenic Agents↗
PubMed2005

HPLC analysis of raloxifene hydrochloride and its application to drug quality control studies.

Raloxifene hydrochloride is a selective estrogen receptor modulator and is currently being used for prevention of osteoporosis in postmenopausal women. In this article, a high performance liquid chromatography (HPLC) method for detection of raloxifene hydrochloride was developed and validated using an ultraviolet (UV) and coulometric detectors. Limit of quantification (LOQ) was 0.336 and 0.610 mg L(-1) for coulometric and ultraviolet detectors, respectively. Acceptable accuracy (93.1-100.3%) as well as intra- and inter-day precision (CV<or=2.38% and CV<or=7.93%, respectively) was demonstrated in the range of 0.5-10 mg L(-1) for both detectors. The presented method was applied without any interference of excipients to the determination of raloxifene hydrochloride content in tablets and to the in vitro dissolution studies. The proposed method could be used for routine quality control. Moreover, due to its low LOQ, excellent accuracy, precision and selectivity, the coulometric detection could be applied to in vitro metabolism experiments such as microsome or hepatocyte preparations and for studies of transport of raloxifene hydrochloride across biological membranes.

Chromatography, High Pressure Liquid↗
PubMed2003

Extragonadal synthesis of sex steroids: intracrinology.

All androgens and estrogens in post-menopausal women are synthesized locally in peripheral target tissues by tissue-specific steroidogenic enzymes according to the intracrine process. The importance of the intracrine or peripheral formation of sex steroids is illustrated by the success of aromatase inhibitors and antiestrogens in the prevention and treatment of breast cancer in post-menopausal women. On the other hand, a large series of problems are associated with the deficiency of sex steroids accompanying menopause and the decreased secretion of DHEA, osteoporosis being the best defined example. In this context, an important observation is that women at menopause are not only deprived from ovarian estrogens but are also lacking androgens due to the marked decrease of DHEA. In order to achieve a more physiological and tissue-specific hormone replacement therapy, DHEA, in combination with a SERM (selective estrogen receptor modulator) having pure antiestrogenic activity in the mammary gland and uterus could possibly meet the most important needs of women at menopause, namely control of hot flushes and, most importantly, prevent breast cancer, uterine cancer, ovarian cancer and osteoporosis with a potential improvement of cognitive functions and memory and prevention of Alzheimer's disease.

Adult↗
PubMed2003

[SERMs and uterus].

The uterus is one of the target organs of sexual steroids synthesized in the ovary. Estrogen is known to stimulate cell proliferation in the endometrium while progesterone has an anti-estrogenic secretory effect on this tissue. Renewed interest in the action of new anti-estrogenic agents on the uterus has arisen over the last decade, but not simply in order to achieve new therapeutic strategies for the prevention or cure of uterine tumors. New compounds were developed for their action on other tissues such as the breast, but it rapidly became clear that they were a source of uterine disease. A clear example is tamoxifen which has a powerful anti-estrogenic effect on breast tissue. It was hoped however that this compound, which behaves either like an antagonist or an agonist, depending on the target tissue, could have an anti-estrogenic effect on the uterus and on the contrary an agonistic estrogenic protective effect on bony and vascular tissue. This approach progressively led to the development of SERMs (Selective Estrogen Receptor Modulators), non-steroidal compounds modulating the action of estrogens. The first member of this new pharmaceutical class was raloxifen, marketed in France under the brand name Evista, which has an estrogenic effect on vertebral bone, warranting its authorization for use in patients with vertebral osteoporosis with or without fracture. Raloxifen thus has a beneficial estrogenic effect, at least on trabecular bone, and an anti-estrogenic effect on the uterus and breast. The goal today is to continue the development of new compounds in the SERM family with well targeted, and well understood, agonistic and/or antagonistic actions on different body tissues.

Estrogen Antagonists↗
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↗
PubMed2002

[Hormone replacement therapy in peri- and postmenopause. Routine use is not indicated].

Hormone replacement therapy (HRT) with estrogens (in non-hysterectomized women with estrogens and progestins) during the peri- and postmenopausal period has been widely applied for many years. On the basis of new data, HRT is currently being critically reviewed. HRT administered for up to 5 years to treat climacteric hot flashes, mood changes and sleep disturbances continues to be advocated and is largely safe. When HRT is used for longer periods, as required for the prevention of osteoporosis, a possible increase in the relative risk for breast cancer must be considered. Correctly applied in combination with an adequate dose of progestins, HRT can avoid an increase in the endometrial cancer risk. HRT is no longer recommended for secondary prevention of cardiovascular disease, and its use in primary prevention has not been convincingly demonstrated. The hoped-for efficacy of HRT in the prevention of Alzheimer's disease has not been confirmed by the data. Selective estrogen receptor modulators (e.g. Raloxifene) and biphosphonates are efficacious drugs for the prevention and treatment of osteoporosis. For women at risk of developing cardiovascular disease, changes in lifestyle, lipid-lowering drugs (statins), blood pressure control, use of acetylsalicylic acid, among others, have well-documented efficacy in primary and secondary prevention.

Alzheimer Disease↗