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PubMed2001

Estrogens, selective estrogen receptor modulators, and dementia: what is the evidence?

At least 10% of people aged 65 or older have some form of cognitive impairment, increasing to around 50% by age 85. Several studies have suggested that estrogen may improve cognitive function or prevent the development of dementia, but other studies have not shown a benefit, and results from large randomized trials are lacking. Fortunately, further trials are currently being conducted. With the recognition that selective estrogen receptor modulators (SERMs) have differential tissue-dependent effects on estrogen receptor function, there is recent interest in the effects of raloxifene, tamoxifen, and other SERMs on cognition. In this paper, the current state of knowledge of the role of estrogen for preventing dementia in postmenopausal women will be reviewed. In addition, the status of ongoing and recently completed trials of estrogen and SERMs on cognitive function or on Alzheimer's disease severity will be summarized.

Aged↗

PubMedDate not supplied

"Non-hypercalcemic" analogs of 1alpha,25 dihydroxy vitamin D augment the induction of creatine kinase B by estrogen and selective estrogen receptor modulators (SERMS) in osteoblast-like cells and rat skeletal organs.

We have demonstrated previously that daily treatments for 3 days with the so-called "non-hypercalcemic" analogs of 1alpha,25 dihydroxy vitamin D in ROS 17/2.8 osteoblast-like cells, stimulate the specific activity of creatine kinase BB (CK), and that such treatment with these analogs followed by a single treatment with gonadal steroids, upregulates responsiveness and sensitivity to estradiol 17beta (E(2)) for the induction of CK. This study was designed to determine if these same "non-hypercalcemic" vitamin D analogs could upregulate in vivo the response to E(2) and whether substitution of selective estrogen receptor modulators (SERMS) for E(2) would result in the same upregulation. We found that one week or 2 weeks pretreatment of prepubertal rats with vitamin D analogs led to increased induction of CK by E(2) and by the SERMS tamoxifen, tamoxifen methiodide and raloxifene, in epiphysis and diaphysis of the femur but not in the uterus. However, in contrast to their antiestrogenic activity in the uterus, there was no inhibition of E(2) action by the SERMS in skeletal tissues. The induction of mRNA for ckb in ROS 17/2.8 cells by E(2) or SERMS was demonstrated only after vitamin D pretreatment; there was no inhibition of E(2) induction by SERMS. Antagonists of vitamin D dependent calcium transport (transcaltachia) did not inhibit stimulation by vitamin D analogs. These results support the involvement of a nuclear mechanism in the upregulation of induction of CK by E(2), which may be due, in part, to the ability of vitamin D to increase estrogen receptor(s).

Animals↗

PubMed2001

The role of selective estrogen receptor modulators in the prevention and treatment of osteoporosis.

Osteoporosis can affect almost everyone in the population, and although clinical outcome of fracture is manifested in late life, the disease process begins in the early postmenopausal years in women. The pharmacologic agents currently available for osteoporosis prevention and treatment act by inhibiting bone resorption, and include estrogen or hormone replacement therapy (estrogen with progestin), bisphosphonates, salmon calcitonin nasal spray, and selective estrogen receptor modulators (SERMs). Raloxifene is a benzothiophene SERM that has estrogen against effects in bone and on serum lipid metabolism and estrogen antagonist effects on breast and uterine tissue. This article summarizes the effects of these antiresorptive agents, as measured by changes in bone mineral density, biochemical markers of bone turnover, and incident fractures in postmenopausal osteoporosis.

Aged↗

PubMed2002

Protective effects of estrogen and selective estrogen receptor modulators in the brain.

Within the last few years, there has been a growing interest in the neuroprotective effects of estrogen and the possible beneficial effects of estrogen in neurodegenerative diseases such as stroke, Alzheimer disease, and Parkinson disease. Here, we review the progress in this field, with a particular focus upon estrogen-induced protection from stroke-induced ischemic damage. The important issue of whether clinically relevant selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene and estrogen replacement therapy can exert neuroprotection is also addressed. Although the mechanism of estrogen and SERM neuroprotection is not clearly resolved, we summarize the leading possibilities, including 1) a genomic estrogen receptor-mediated pathway that involves gene transcription, 2) a nongenomic signaling pathway involving activation of cell signalers such as mitogen-activated protein kinases and/or phosphatidylinositol-3-kinase /protein kinase B, and 3) a nonreceptor antioxidant free-radical scavenging pathway that is primarily observed with pharmacological doses of estrogen. The role of other potential mediatory factors such as growth factors and the possibility of an astrocyte role in neuroprotection is also discussed.

Animals↗

PubMed2006

Emerging selective estrogen receptor modulators: special focus on effects on coronary heart disease in postmenopausal women.

Menopause, regardless of age at onset, is associated with a marked increase in coronary heart disease (CHD) risk. On the basis of epidemiological studies that demonstrated mainly positive effects of postmenopausal hormone therapy on CHD as well as on risk markers of CHD, it has been suggested that CHD could be prevented in postmenopausal women with long-term hormone therapy. However, since the publications of the Heart and Estrogen/progestin Replacement Study and the Women's Health Initiative trial, prescription of hormone therapy for the prevention of CHD has become controversial. Major efforts have been made to identify alternatives for hormone therapy. Compounds suggested have included selective estrogen receptor modulators (SERMs), which represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This pharmacological profile may offer the opportunity to dissociate favourable estrogenic effects on the bone and cardiovascular system from unfavourable stimulatory effects on the breast and endometrium. Two SERMs presently on the market are tamoxifen and raloxifene. The only data available regarding the effects of tamoxifen on cardiovascular events in postmenopausal women are from breast cancer trials. These trials found fewer fatal myocardial events in women randomly assigned to tamoxifen compared with women assigned to placebo. Raloxifene is a second-generation SERM that has been shown to prevent osteoporotic fractures, is safe for the endometrium and holds high promise for the prevention of breast cancer. The effect of raloxifene on CHD is still uncertain. On the basis of the MORE (Multiple Outcomes of Raloxifene Evaluation) trial, raloxifene may offer some protection to women with CHD or to those who are at high risk of CHD. Proof that raloxifene reduces the risk of CHD requires a clinical trial with hard clinical endpoints. Such a study is currently underway. Next-generation SERMs taken into clinical development include idoxifene, droloxifene, ospemifene, arzoxifene, acolbifene/EM-800, levormeloxifene, lasofoxifene, bazedoxifene and HMR 3339. The aim is to find a compound with the ideal profile, that is, alleviation of climacteric symptoms and prevention of osteoporotic fractures, but without an adverse effect on the breast and endometrium, and no negative effect or even a beneficial effect on the cardiovascular system and the brain. Currently, limited data are available with regard to these next-generation SERMs and CHD. Nevertheless, some of these novel agents provide arguments for continuing the search for an ideal SERM.

Animals↗

PubMed2000

Molecular mechanisms of selective estrogen receptor modulator (SERM) action.

In females, estrogens play a key role in reproduction and have beneficial effects on the skeletal, cardiovascular, and central nervous systems. Most estrogenic responses are mediated by estrogen receptors (ERs), either ER alpha or ER beta, which are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues act like estrogens, but block estrogen action in others. Thus, SERMs may exhibit an agonistic or antagonistic biocharacter depending on the context in which their activity is examined. For example, the SERMs tamoxifen and raloxifene both exhibit ER antagonist activity in breast and agonist activity in bone, but only tamoxifen manifests agonist activity in the uterus. Numerous studies have examined the molecular basis for SERM selectivity. Collectively they indicate that different ER ligands induce distinct structural changes in the receptor that influence its ability to interact with other proteins (e.g., coactivators or corepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and of its target gene promoter affect SERM biocharacter. Taken together, SERM selectivity reflects the diversity of ER forms and coregulators, cell type differences in their expression, and the diversity of ER target genes. This model provides a basis for understanding the molecular mechanisms of SERM action, and should help identify new SERMs with enhanced tissue or target gene selectivity.

Humans↗

PubMedDate not supplied

Hormone therapy and selective estrogen receptor modulators for prevention of coronary heart disease in postmenopausal women estrogen replacement from the cardiologist's perspective.

Coronary heart disease is the leading cause of morbidity and mortality in women older than the age of 50 in the United States today. Traditional cardiovascular risk factors (hyperlipidemia, glucose intolerance, and hypertension) are more clearly associated with significant cardiovascular risk after menopause. The increased incidence of cardiovascular events in postmenopausal women and the evidence that cardiovascular disease on average manifests a decade later in women compared with men suggests that estrogen deficiency may predispose women to a higher cardiovascular risk. Numerous biologic mechanisms have been proposed that relate use of hormone therapy (HT) to improved lipid profiles, insulin sensitivity, and vascular reactivity. Early observational trials in the last 2 decades showed a significant decrease in cardiovascular events. Recently published randomized clinical trial results, however, have led to uncertainty about the earlier established cardiovascular benefits of HT. To complicate issues further, alternative estrogenlike compounds, selective estrogen receptor modulators, are being introduced that appear to convey similar cardiovascular benefit and notably less cancer risk than HT. The newly released randomized trials on hormone and nonhormonal agents are reviewed.

Coronary Disease↗

PubMed2002

Responsiveness of endometrial genes Connexin26, Connexin43, C3 and clusterin to primary estrogen, selective estrogen receptor modulators, phyto- and xenoestrogens.

Phytohormones and chemical compounds revealing estrogenic effects are of increasing interest for their possible influence on the physiology of the reproductive tract. The gap junction connexin (Cx) genes Cx26 and Cx43, the plasma glycoprotein clusterin gene and the complement C3 gene are highly regulated by estrogen in rat endometrium. To test the value of these genes as markers for estrogenic responsiveness we analyzed the effects of estradiol, diethylstilbestrol, the selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen, the phytoestrogens genistein and daidzein, and the industrial compounds DDT (1,1,1-trichloro-2-(2-chlorophenyl)-2-(4-chlorophenyl) ethane) and polychlorinated biphenyl (PCB) on the transcription of these genes in rat endometrium in vivo. Enhancement of Cx26 and decrease of clusterin transcripts expression by estradiol was observed at 0.03 micro g/250 g body weight (BW), and induction of C3 expression was observed at 0.05 micro g/250 g BW. A comparable effect was obtained by a tenfold higher concentration of diethylstilbestrol. Tamoxifen had a regulatory effect on this set of genes at about a 300-fold higher concentration, while raloxifen revealed much weaker estrogenic activity. No effect on Cx43 transcripts was observed with any of the compounds at the concentrations used. An effect of genistein was observed only on Cx26 expression, while PCB decreased clusterin transcripts. These results show that Cx26, C3 and clusterin reveal a comparable sensitivity to estrogens and SERMs. With respect to the phytoestrogen genistein, however, Cx26 seems to be the most sensitive gene. The analysis of clusters of estrogen-sensitive endometrial genes could help to identify estrogenic substances, assess their potency, and elucidate their mechanism of action.

Animals↗

PubMed2007

The risk for cardiovascular disease in women: from estrogens to selective estrogen receptor modulators.

Cardiovascular disease, a generic denomination including coronary heart disease (CHD), stroke, and venous thromboembolic disease (VTED), has shown sensitivity to estrogens. The relative protection of women as compared with men has nourished a debate about a possible protective role for estrogens, but the prejudicial effects detected in clinical trials has created confusion on the risk/benefit ratio induced by hormone administration. The hypothesis that agonists distinct to estrogens might improve the effects associated with estrogens is at the base of the increasing interest on the role of selective estrogen receptor modulators (SERMs). There is a lack of definitive clearcut clinical data on the effects of SERMs in CVD, although the available information suggests a neutral balance on CHD and stroke and an increase in risk similar to estrogens for VTED. Research on pathogenetic mechanisms concentrates in atherosclerosis as the main determinant of the arterial forms of the disease and in hypercoagulability as the counterpart for venous disease. The different experimental models used up to the present moment suggest that, compared with estrogens, SERMs play a less active protection against atherogenesis but do not increase vulnerability of unstable plaques. There is not a clear notion on the mechanisms promoted by SERMs to increase risk for VTED.

Animals↗

PubMed2001

[Hormone replacement and selective estrogen receptor modulators (SERMS) in the prevention and treatment of postmenopausal osteoporosis].

For many years, hormone replacement therapy (HRT) has been regarded as one of the most reliable means of prophylaxis and treatment for postmenopausal osteoporosis. As HRT ameliorates menopausal symptoms, it is widely prescribed among early postmenopausal women. A variety of different modes of replacement that suit each individual requirement are available in terms of schedule (cyclic or combined application of gestagens) and route of application (oral or transdermal). HRT effectively prevents spinal bone loss and delays bone loss at the hip up to a very old age. With continued use after menopause, HRT might theoretically halve the incidence of vertebral and hip fractures. However, long-term use or use of HRT in old age is rarely practiced, and the actual benefit of a transient use for future fracture prevention remains unclear. Raloxifene is the first member of the novel class of selective estrogen receptor modulators (SERMs) that has been approved for the prophylaxis and treatment of postmenopausal osteoporosis. It combines the positive effects of estrogen on the skeleton with estrogen-antagonistic effects on sex tissues. Thus, raloxifene maintains bone mass and decreases the incidence of vertebral fractures in osteoporotic women, but avoids many of the side effects that are responsible for the poor long-term compliance to HRT such as resumption or continuation of regular menses, breast tenderness, or breast cancer. It even markedly reduces the risk of breast cancer. Both estrogen and raloxifene are characterized by a large number of extraskeletal effects that have to be taken into account when counseling postmenopausal women on the use of these agents for the prevention or treatment of osteoporosis.

Administration, Oral↗

PubMed2000

[Estrogens and selective estrogen receptor modulators in the treatment of osteoporosis].

Estrogen deficiency is the major determinant of bone loss, not only in the first years postmenopause, but also throughout the entire life and in the elderly. Major progress in the knowledge of cellular actions of estrogens has been made leading to a better understanding of the underlying mechanisms of different estrogen-deficiency related diseases such as osteoporosis, atherosclerosis and also maybe cerebral aging. Estrogen replacement therapy remains the first choice treatment in the prevention of postmenopausal osteoporosis, but the continuous aging process of the female population raises the question of a better strategy of action in a more efficient prevention of hip fractures. Moreover, the potential gynecological effects of estrogens are likely to limit their indications or long-term use. The development of new compounds, called SERMs (selective estrogen receptor modulators), with both agonist and antagonist estrogen actions, in particular with no negative effects on the uterus and the breast opens new therapeutical insights into the prevention of postmenopausal osteoporosis.

Age Factors↗

PubMed2003

Estrogen and selective estrogen receptor modulators: neuroprotection in the Women's Health Initiative era.

Estrogen has been comprehensively studied as a neuroprotective agent in women, animals, and a variety of in vitro models of neural injury and degeneration. Most data suggest that estrogen can benefit the ischemic brain and reduce cell death. However, recent data from the Women's Health Initiative have raised concerns about the utility and safety of chronic estrogen use in women. While estrogen is a potent and reproducible neuroprotectant in animals and in vitro, its current administration in women has had unanticipated and paradoxical effects. Nonetheless, estrogen's diverse actions make it an ideal prototype for developing new neuroprotectants such as selective estrogen receptor modulators (SERMs). SERMs represent a class of drugs with mixed estrogen agonistic and antagonistic activity. Experimental and clinical data suggest a neuroprotective role for SERMs in normal and injured brain. The discrepancy among observational studies, preclinical data, and clinical trials emphasizes the need for further study of the mechanisms leading to the increased incidence of stroke observed in postmenopausal women. Research is still needed to optimize combined or estrogen alone hormone replacement therapy options as well as the prevention/management of cerebrovascular/ central nervous system disorders. This review critiques estrogen and SERMs' neuroprotective potential in experimental and clinical studies of stroke and cerebrovascular disease.

Animals↗

PubMed2002

Effects of selective estrogen receptor modulators (SERMs) on coactivator nuclear receptor (NR) box binding to estrogen receptors.

Coactivators are required for activation of target genes by nuclear receptors. A well-studied class of coactivators, the p160 proteins, use short nuclear receptor interaction domains (NR boxes) to bind to the activated ligand-binding domain of a nuclear receptor. To investigate how selective estrogen receptor modulators (SERMs) affect NR box recruitment, we compared the recruitment of p160 NR box peptides to the estrogen receptor (ER)alpha and ER beta in the presence of 17beta-estradiol (E2), 4-OH tamoxifen (4-OH Tam), LY 117018 (a raloxifene analog), and ICI 182780 (ICI, an ER antagonist). Our coactivator interaction assay utilizes time-resolved fluorescence technology to assess the binding of the 10 NR boxes derived from the three known p160 coactivators (SRC-1, -2, -3) to the ER subtypes in the presence of each ligand. The SERMs we studied did not increase NR box binding to either ER alpha or ER beta, but instead were potent antagonists decreasing estradiol-dependent NR box binding. We also demonstrated inverse agonism for all of the SERMs tested as they dose-dependently decreased hormone-independent NR box binding to ER beta. Therefore, the SERMs studied behave as antagonists of ER alpha and ER beta NR box binding and do not increase coactivator NR box binding to either ER subtype. In addition, we examined the preference of E2-bound ER alpha and ER beta for various naturally occurring NR boxes including the 10 SRC boxes as well as the motifs from PGC-1, TRBP, TRAP220, and CBP. Interestingly, a clear preferential pattern of interaction was noted that was receptor specific.

Amino Acid Sequence↗

PubMed2005

Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance.

Despite the beneficial effects of estrogens in women's health, there is a plethora of evidence that suggest an important role for these hormones, particularly 17beta-estradiol (E(2)), in the development and progression of breast cancer. Most estrogenic responses are mediated by estrogen receptors (ERs), either ERalpha or ERbeta, which are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues (i.e. bone and cardiovascular system) act like estrogens but block estrogen action in others. Tamoxifen is the first SERM that has been successfully tested for the prevention of breast cancer in high-risk women and is currently approved for the endocrine treatment of all stages of ER-positive breast cancer. Raloxifene, a newer SERM originally developed for osteoporosis, also appears to have preventive effect on breast cancer incidence. Numerous studies have examined the molecular mechanisms for the tissue selective action of SERMs, and collectively they indicate that different ER ligands induce distinct conformational changes in the receptor that influence its ability to interact with coregulatory proteins (i.e. coactivators and corepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and its target gene promoter also affect SERM biocharacter. This review summarizes the therapeutic application of SERMs in medicine; particularly breast cancer, and highlights the emerging understanding of the mechanism of action of SERMs in select target tissues, and the inevitable development of resistance.

Animals↗

PubMed2001

Selective estrogen receptor modulators: the ideal estrogen replacement?(2)(2).

The ultimate estrogen for replacement therapy should exert beneficial actions upon the skeletal, cardiovascular, and central nervous systems while displaying minimal side effects in the uterus and breast. Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, have recently been studied to achieve these aims. Not only are these agents potentially effective in reducing a patient's risk of breast carcinoma but they have also been shown to increase bone mineral density and prevent osteoporosis. Displaying favorable effects on lipid metabolism, SERMs also may be protective against coronary heart disease and myocardial infarction. Tamoxifen's adverse side effects on the uterus have not been noted with raloxifene, because the latter behaves as an estrogen antagonist in the endometrium. Ongoing studies, such as the Study of Tamoxifen and Raloxifene and the Raloxifene Use for the Heart trials, may help to further determine whether SERMs are the ideal estrogen for the postmenopausal female patient.

Journal Article↗

PubMed2006

Selective estrogen receptor modulators: A possible new treatment of osteoporosis in males.

More recently, osteoporosis in men has been recognized as an important public health problem. Bone loss begins in mid life and is associated with the decline of the sex steroids production. Although there is no equivalent of the menopause, gonadal function in men is affected in a slow progressive way leading to hypogonadism. Testosterone, the major androgen in men, exerts its effect on bone by local conversion to 5alpha-dihydrotestosterone or by aromatization to estrogens. Several studies have found that estrogen, rather than testosterone, levels are more closely correlated with BMD in elderly men. Selective estrogen receptor modulator (SERM) raloxifene binds to estrogen receptors and exhibit estrogenic effect in bone, but, contrary to estrogen, without feminizing effect. There are limited numbers of studies investigating the effects of SERMs in males. Animal studies demonstrated that SERMs inhibit bone turnover and prevent bone loss in orchidectomised adult male rats. Raloxifene has been shown to increase bone mineral density of the hip in men receiving androgen deprivation therapy for prostate cancer. Moreover, experimental data demonstrated dramatic increase in cell death in human prostate cancer cell lines after the treatment with raloxifene. All these observations suggest that SERMs may be useful for the prevention and treatment of osteoporosis not only in postmenopausal women but also in elderly men. However, our hypothesis should be tested in a proper designed clinical trial. Several important issues have to be addressed. Does the same drug dose that has been shown to be effective in postmenopausal women should be used in men, too? Does treatment with SERMs reduce the fracture risk in men and is it comparable to that observed in women? Does treatment with SERMs have any beneficial effect on cardiovascular system and prostate cancer? And finally, do men experience adverse events other than women treated with SERMs? Answering to these questions will have great impact in getting the decision of possible SERMs usage in the treatment of osteoporosis in elderly males.

Aged↗

PubMed2003

[Cardiovascular effects of selective estrogen receptor modulators. Current perspectives].

The use of hormone replacement therapy (HRT) after the menopause for the prevention of the long-term complications of estrogen deprivation has recently been questioned after the publication of large clinical trials that failed to show benefits for postmenopausal women. Although these trials risk to dump the widespread opinion of the cardioprotective effects of long-term estrogen use, they have many pitfalls that prevent a direct clinical application of these negative results. Furthermore, the large amount of epidemiological and experimental evidence indicating estrogens as protective on the vascular system cannot be ignored, and efforts should be devoted to understand the reasons for the discrepancy of results of these recent large trials. In the meanwhile, different molecules should be studied in depth as for the actions on the cardiovascular system, and their specific mechanisms of actions should be elucidated. Selective estrogen receptor modulators (SERM) are a promising family of molecules and some of these compounds have positive effects on cardiovascular risk parameters as well as on vascular cells. Large trials are ongoing to study the impact of these substances on cardiovascular risk, and the near future should provide us with answers on the possible use of SERM as possible safer alternatives to HRT for the long-term prevention of cardiovascular disease in postmenopausal women.

Aged↗

PubMed2000

Mechanism of action of estrogens and selective estrogen receptor modulators.

Estrogen, one of several sex steroid hormones, mediates its actions through the estrogen receptor. The estrogen receptor (ER) has two subtypes, ER alpha and ER beta, each of which predominates in specific tissues and organs. Cofactor proteins interact with the ER to maximize ligand-dependent transactivation of target-gene promoters. The estrogen response element is the final step in estrogen-mediated gene regulation, and current research is focused on alternate response elements. The resulting biologic action can vary according to the specific type of ER, cofactor milieu, response element, and ligand. Selective estrogen receptor modulators (SERMs) exhibit tissue-specific estrogen agonist or antagonist activity. The SERM raloxifene, which binds to ER and targets a distinct DNA element, may distinguish agonist vs antagonist activity by ER subtype and has unique activity among other SERMs because of its molecular conformation. Phytoestrogens, a potential alternative to hormone replacement therapy and for cancer prevention, do not consistently mimic estrogen's activity. Different types of phytoestrogens have different potencies, and taking high-dose supplements after menopause may not emulate the apparent benefits of lifelong consumption of phytoestrogen-rich diets. In conclusion, the complexity of estrogen action--through different ER subtypes, with various cofactors, on alternate response element--is further enhanced by ligands with selective estrogen activity. Additional research is needed to elucidate these pathways and the resulting biological effects.

Estrogens↗