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Results for “Selective Estrogen Receptor Modulators”

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PubMed2005

[Hormone resistance and its modulation in breast cancer].

Acquired hormone resistance is a reversible adaptative change of hormone-sensitive breast tumors promoting survival by changes in the balance and communication between estrogen receptor and growth factor signaling. The mechanisms of hormone resistance induced by various hormone therapies are different, however, their common feature is the dominance of growth factor signaling with the consequences of enhanced proliferation and decreased apoptosis. In case of tamoxifen or selective estrogen receptor modulator resistance, the agents' enhanced agonistic activity occurs. The increased expression of certain estrogen receptor coactivators may play an important role. The essential of hormone resistance after estrogen deprivation is estrogen hypersensitivity, which is a consequence of the enhanced activity of the membrane-associated estrogen receptor and its influence on the growth factor signaling. The integration of cell surface growth factor receptor or growth factor signal transduction blocking agents like tyrosine kinase, MAPK, mTOR, PI3K or farnesyl transferase inhibitors into hormone therapies may prevent or treat hormone resistance. The other possibility is to use the hormone therapies sequentially. A new promising agent is the pure antiestrogen fulvestrant which targets the estrogen receptor located in both the membrane or the nucleus. Also, estrogen therapy may revert hormone resistance. The use of predictive markers may promote treatment choice and indicate application of targeted therapies.

Breast Neoplasms↗
PubMed2001

Capitalizing on the complexities of estrogen receptor pharmacology in the quest for the perfect SERM.

The term Selective Estrogen Receptor Modulators (SERMs) has been used of late to describe a group of pharmaceuticals that manifest estrogen receptor (ER) agonist activity in some tissues, but that oppose estrogen action in others. Whereas the name describing this class of drugs is new, the concept is not. Indeed, compounds exhibiting tissue-selective ER agonist/antagonist properties have been around for nearly 40 years. What is new is the idea that it may be possible to capitalize on the paradoxical activities of these drugs and develop them as treatments for estrogenopathies where it is desirable to direct therapy to a specific estrogen-responsive target organ. This realization has provided the impetus for research in this area and has pushed the development and clinical use of this class of drugs. The objective of this review is to describe how the medical need for SERMs arose and how recent studies of the mechanism of action of the currently available drugs are paving the way for the development of novel drugs with improved selectivity.

Amino Acid Sequence↗
PubMed2000

Breast cancer chemoprevention.

Chemoprevention of breast cancer is a rapidly growing field. Chemoprevention was initiated with the development of the antiestrogen tamoxifen. A major clinical trial in the United States found that tamoxifen reduced the incidence of breast cancer by almost 50% in women at an increased risk for the disease. Although two European trials did not confirm these findings, the Food and Drug Administration found the American studies significant enough to approve tamoxifen for the delaying of breast cancer in women at high risk for the disease. However, adverse effects associated with tamoxifen include a minimally increased rate of endometrial cancer, cataracts, and strokes. Newer classes of antiestrogens, called selective estrogen receptor modulators (SERMs), are being investigated as potential chemopreventive agents. These SERMS, such as raloxifene, will hopefully provide some of the benefits of estrogen without its inherent risks. In addition, naturally occurring compounds and their analogues are also under investigation.

Adult↗
PubMed2001

Raloxifene for the treatment and prevention of breast cancer?

Raloxifene is a member of a family of drugs known as selective estrogen receptor modulators (SERMs). Raloxifene is currently approved by the FDA for the prevention and treatment of osteoporosis in postmenopausal women. SERMs hold the potential to treat and prevent breast cancer, osteoporosis and coronary heart disease. Ongoing clinical trials are in place to address the role of raloxifene and SERMs in each of these areas. We review the pharmacology, clinical utility, safety and tolerability of raloxifene and speculate on what the future holds for SERMs and their use in breast cancer.

Breast Neoplasms↗
PubMed2001

Raloxifene: risks and benefits.

Raloxifene, a selective estrogen receptor modulator (SERM), was designed to have the expected benefits of long-term estrogen replacement therapy without the risks. This paper reviews the clinical trial evidence for raloxifene benefits and risks, and how they compare with those of hormone replacement therapy (HRT) and relate to the choices of postmenopausal women.

Breast Neoplasms↗
PubMed2006

The role of xenoestrogenic compounds in the development of breast cancer.

Lifetime exposure to endogenous steroidal estrogens is an established risk factor for breast cancer, and exposures to other estrogenic and antiestrogenic compounds might also modify the risk of breast cancer. It has been hypothesized that synthetic estrogenic industrial pollutants such as organochlorine compounds and plant-derived estrogenic compounds also modify breast cancer risks; however, recent studies show that levels of organochlorine pollutants are similar in breast cancer patients and controls. There is evidence that synthetic and plant-derived estrogens are selective estrogen receptor modulators, which implies that these compounds can induce tissue-specific, time- and dose-dependent estrogenic or antiestrogenic responses. Therefore, the effects of synthetic or plant-derived estrogens on the incidence of breast cancer depend on both the levels and the timing of exposure to these compounds, particularly during stages of mammary gland development that are extremely sensitive to hormone levels.

Breast Neoplasms↗
PubMed2003

Mechanisms of action of antiresorptive therapies of postmenopausal osteoporosis.

In the treatment of osteoporosis, the aim of the antiresorptive therapy is to restore bone density by decreasing bone remodeling. The process of bone remodeling plays a role in plasma calcium homeostasis and serves to modify bone architecture in order to meet changing mechanical needs, to maintain osteocyte viability, and to repair microdamage in bone matrix. Estrogen deficiency results in a number of detrimental effects on bone, including suppression of osteocyte survival as well as impairment of osteoblast response to mechanical stimuli and repair of ageing bone. In this review, effects of available antiresorptive therapies on endocrine regulations of bone metabolism in postmenopausal osteoporosis are compared. The aim of antiresorptive treatment is to ensure adequate bone remodeling, reparation of microdamage of bone, and increased bone strength. Ideally, this effect should be maintained long-term. Several agents are approved for the treatment of osteoporosis. Calcitonin transiently inhibits osteoclast activity without decreasing osteoblast collagen synthesis. Aminobisphosphonates decrease bone remodeling by decreasing osteoclast activity and by inducing osteoclast apoptosis. This allows more time for secondary mineralization to proceed to completion in the existing bone tissue mass, so increasing the mechanical resistance of bone to loading. Estrogens and raloxifene (a selective estrogen receptor modulator that acts as an estrogen agonist in bone) suppress bone remodeling to the premenopausal range, maintaining the function of osteoblasts and osteocytes. In the placebo-controlled osteoporosis treatment trials, all the above treatments reduced the risk of fractures. Raloxifene therapy was also associated with a favorable or neutral effect in the cardiovascular system, and a reduced incidence of breast cancer. Selection of appropriate drug for treatment of postmenopausal osteoporosis should take into account the long-term effect of the antiresorptive agent on bone. Moreover, the effects on other tissues ++should also be considered, and this encompasses both safety concerns, as well as the potentially beneficial effects on other tissues. Further investigation is needed to evaluate the different modes of action of these agents, and their long-term effects on bone and other tissues.

Alendronate↗
PubMed2005

Acteoside and martynoside exhibit estrogenic/antiestrogenic properties.

Acteoside and martynoside are plant phenylpropanoid glycosides exhibiting anticancer, cytotoxic and antimetastatic activities. We investigated their potential to activate estrogen receptor isoforms ERalpha and ERbeta in HeLa cells transfected with an estrogen response element (ERE)-driven luciferase (Luc) reporter gene and an ERalpha or ERbeta expression vector. Their estrogenic/antiestrogenic effects were also assessed in breast cancer cells (MCF7), endometrial cancer cells (Ishikawa) and osteoblasts (KS483), by measuring IGFBP3 levels, cell viability and number of mineralized nodules, respectively, seeking for a natural selective estrogen receptor modulator (SERM). Acteoside and martynoside antagonized both ERalpha and ERbeta (p<0.001), whereas they reversed the effect of E(2) mainly via ERalpha (p<0.001). Martynoside was a potent antiestrogen in MCF-7 cells, increasing, like ICI182780, IGFBP3 levels via the ER-pathway. In osteoblasts, martynoside induced nodule mineralization, which was abolished by ICI182780, implicating an ER-mediated mechanism. Furthermore, its antiproliferative effect on endometrial cells suggests that martynoside may be an important natural SERM. Acteoside was an antiestrogen in breast cancer cells and osteoblasts, without any effect on endometrial cells. Our study suggests that the nature is rich in selective ERalpha and ERbeta ligands, the discovery of which may lead to the development of novel neutraceutical agents.

Breast Neoplasms↗
PubMed2005

Benefit-risk assessment of raloxifene in postmenopausal osteoporosis.

Raloxifene, a nonsteroidal benzothiophene, is a second-generation selective estrogen receptor modulator (SERM) that is an antiresorptive agent. Raloxifene is a non-hormonal agent that binds to the estrogen receptor and results in estrogen agonist effects on bone and the cardiovascular system and estrogen antagonist effects on endometrial and breast tissue. Raloxifene has diverse pharmacodynamic properties due to its differential interactions with the estrogen receptor and tissue selectivity. Raloxifene was the first SERM to be approved for the prevention and treatment of postmenopausal osteoporosis. In this review, we conducted a systematic search of the literature for trials that evaluated the following outcomes: bone density, fractures, quality of life, cardiovascular outcomes, safety and adverse events. Raloxifene at the approved dosage of 60 mg/day increased lumbar spine bone density by 2.5% relative to control after 2 years of therapy. A large fracture prevention trial confirmed that treatment with raloxifene 60 mg/day for 3 years decreased the relative risk of incident vertebral fractures by 30-50% in women with prevalent fractures or osteoporosis. Extraskeletal effects of raloxifene include a reduction in total cholesterol and low density lipoprotein cholesterol levels. Assessment of the safety profile revealed that raloxifene was not associated with endometrial hyperplasia and that there was a 72% reduction in the incidence of invasive breast cancer in raloxifene-treated postmenopausal women with osteoporosis. Adverse events associated with raloxifene included an increase in the absolute risk of venous thromboembolism and an increase in the risk of hot flashes and leg cramps. In comparison to other osteoporosis therapies, raloxifene has a lesser impact on bone mineral density, a similar effect on the occurrence of vertebral fractures, but no effect on the frequency of non-vertebral fractures. Raloxifene can be recommended for the prevention of vertebral fractures in women with osteopenia/osteoporosis who are not at high risk of non-vertebral fractures and who do not have a past history of venous thromboembolism.

Bone Density↗
PubMed2003

Comparing therapies for postmenopausal osteoporosis prevention and treatment.

OBJECTIVE: To review the literature concerning the efficacy of calcium, hormone replacement therapy (HRT), bisphosphonates, selective estrogen receptor modulators, and calcitonin in the prevention and treatment of postmenopausal osteoporosis. DATA SOURCES: Articles were identified through searches of the MEDLINE (1966-July 2002), EMBASE (1980-July 2002), and International Pharmaceutical Abstracts (1970-July 2002) databases using the key words osteoporosis, postmenopausal, fracture, calcium, vitamin D, hormone replacement therapy, bisphosphonates, alendronate, risedronate, raloxifene, and calcitonin. Additional references were located through review of the bibliographies of the articles cited. Searches were not limited by time restriction, language, or human subject. STUDY SELECTION AND DATA EXTRACTION: Experimental and observational studies of the use of calcium and antiresorptive therapies for the prevention and treatment of postmenopausal osteoporosis were selected. Articles evaluating bone mineral density (BMD) or fracture efficacy were included in this review. DATA SYNTHESIS: HRT, bisphosphonates, raloxifene, and calcitonin have demonstrated stabilization of and improvement in BMD. Randomized clinical trials have shown fracture risk reduction with bisphosphonates, raloxifene, HRT, calcium, and calcitonin. The largest risk reductions have been reported with use of bisphosphonates in several trials. CONCLUSIONS: Several therapeutic options with well-documented improvements in BMD and reductions in fracture risk are available to women for the prevention and treatment of postmenopausal osteoporosis.

Calcitonin↗
PubMed2006

What role of estrogens in ovarian stimulation.

Estrogens and progesterone represent the key ovarian hormones produced by the developing ovulatory follicle. Serum concentrations start to rise from the mid-follicular phase onwards, coinciding with the development of the dominant follicle. Androgens are converted into estrogens by aromatase activity of the granulosa cells and secreted into the follicular fluid compartment. Their significance for oocyte maturation and fertilizing potential remains unknown. Paradoxically, serum estrogen levels are within the normal range in the majority of patients presenting with cycle abnormalities due to ovarian dysfunction. Similarly, the distribution of estradiol (E2) and follicle-stimulating hormone (FSH) levels within the normal range is comparable between normo-ovulatory controls and normogonadotropic anovulatory women. Moreover, E2 levels are only moderately correlated with luteïnizing hormone (LH), testosterone (T), androstenedione (A), sex hormone binding globulin (SHBG), the free androgen index (FAI) and finally ovarian volume as measured by ultrasound. No correlations could be found between E2 and age, body weight and cycle history and FSH. Androgen concentrations and cycle history--but not E2--were the most prominent predictors of ovarian response tot the conventional ovulation induction. Anti-estrogenic compounds like clomiphene citrate and tamoxifen have remained the first-line treatment of choice for anovulation. Certainly, CC and to a lesser extent tamoxifen have demonstrated to exhibit undesired anti-estrogenic properties at the uterine level however. However, large follow-up studies demonstrate cumulative ovulation rates around 75%, and the overall pregnancy rates of around 50%. Aromatase inhibitors, another way to interfere with estrogen feedback, represent a feasible option. This claim should, however, be substantiated by further sufficiently powered, controlled studies, and the possibility of embryo toxicity remains a major concern. In retrospect, CC and tamoxifen represent the first generation of selective estrogen receptor modulators (SERMs), and many new compounds have recently been introduced into the clinic or are currently under investigation. The major focuses of these compounds are bone density, the cardiovascular system and breast cancer. No studies have been reported in the area of ovarian stimulation.

Anovulation↗
PubMed2002

Tissue-specific estrogenic response and molecular mechanisms.

Estrogens exert profound effects on growth, differentiation, and function of many reproductive tissues. They also affect other tissues, including bone, liver, cardiovascular system, and brain. In the last few years it has been demonstrated that several synthetic estrogens can act in a tissue-specific manner. The first example of such a selective estrogen receptor modulator (SERM) was tamoxifen, for which an estrogen agonist-like activity in the endometrium and bone was seen to occur simultaneously with an estrogen antagonist activity in the breast. The mechanisms by which the same compound can exert tissue-specific agonist and antagonist actions are still being investigated. Important aspects include the interaction of the ligand with the two estrogen receptor subtypes and the interaction of these ligand-receptor complexes with effectors, which include different DNA response elements and important coregulator proteins. In addition to well-documented effects on gene transcription, there is evidence that estrogen receptors and other estrogen binding proteins are involved in some rapid, non-genomic effects of estrogens in target cells. For these reasons it is important to point out that a toxicological evaluation of endocrine modulators should include an analysis of potential SERM-like properties.

Animals↗
PubMed2000

[Menopause and hormone replacement therapy].

Due to the improving life expectancy of women spend third of their active life after the menopause. Estrogen deficiency can be caused by both natural and artificial menopause. The lack of estrogen can directly worsen the quality of life and epidemiological evidence suggests association with development of certain diseased states. Hormone replacement with natural estrogens has been proven to be successful for various indications: it reduces the menopausal vasomotor and psychological symptoms thus improving quality of life. It can also be used to prevent harmful effects of estrogen deficiency in various organs. Literature review supports the role of estrogen in atherosclerosis and osteoporosis prevention. Further evidence required establishing the role of estrogens in secondary prevention of coronary artery disease. Also needs to be explained why the beneficial effects of estrogen therapy in osteoporosis seem to disappear soon after cessation of therapy. Currently the relative risk increase of breast cancer during long-term hormone replacement therapy cannot be exactly measured. Nevertheless, substantial reduction of mortality in estrogen receptor positive breast cancer can also be seen with women on hormone replacement as compared to controls. Some data support the negative correlation of residual but still detectable, endogen estrogen and atherosclerosis and similarly to osteoporosis. The same residual estrogen levels seem to correlate positively with breast cancer. The recognition (and further acceptance) of the role of the residual estrogens might have influence on the indication, choice and dosage of preparation and duration of hormone replacement therapy. Overall evidence is in favor of the need medical attention for menopause: which ranges from preventive screening to long term hormone replacement therapy. The decision to treat requires the risks and benefits taken into consideration. This highly specialized care is provided in menopause clinics in Hungary. New oestrogen like agents are being developed like the selective estrogen receptor modulators, the tibolone and the phyto-estrogens. They provide tissue-specific effect acting as estrogen agonistics, sustaining the beneficial preventive and therapeutic effects of the estrogens, but in the breast and endometrial tissue they behave like estrogen antagonists avoiding the side effects of the current used oestrogens. They might play a significant role in the treatment of menopause in the future.

Breast Neoplasms↗
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↗
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↗