Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women.
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Endometrium↗
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Results for “Selective Estrogen Receptor Modulators”
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Selective estrogen receptor modulators: tissue actions and potential for CNS protection.
Significant physiologic changes occur during menopause. Evidence exists to suggest that estrogen may be neuroprotective under specific conditions. However, there are limitations in the neuroprotection afforded by standard hormone therapy. Accordingly, alternative agents with selected estrogenic effects may hold even greater promise rather than conventional hormone replacement therapy for the prevention and treatment of CNS injury. Recently, a variety of selective estrogen receptor modulators (SERMs) have been developed to retain the favorable and minimize the adverse side effects of estrogens. This review focuses on the CNS and known neuroprotective effects of two specific SERMs, raloxifene and arzoxifene. Recent studies hint that raloxifene and arzoxifene are neuroprotective and may preserve some elements of cognitive function. However, the mechanism of action is not well described and it is unclear if the beneficial effects of SERMs rely on activation of estrogen receptors.
Animals↗
ERbeta-selective estrogen receptor modulators produce antianxiety behavior when administered systemically to ovariectomized rats.
17beta-Estradiol (E2) may influence anxiety behavior; however, its effects and mechanisms are not well understood. To determine whether E2's effects on anxiety behavior may involve actions at intracellular estrogen receptor (ER) alpha or beta isoforms, selective ER modulators (SERMs) were administered (10 microg; s.c.) to ovariectomized rats 48 h before testing for anxiety behavior. Rats received sesame oil vehicle, 17beta-E2, which has a high affinity for ERalpha and ERbeta, or SERMs that vary in their activity at ERalpha and beta. ERalpha-selective SERMs were propyl pyrazole triol (PPT), which has more selective effects at ERalpha, than does the other ERalpha SERM utilized, 17alpha-E2, which also binds ERbeta. ERbeta-selective SERMs were diarylpropionitrile (DPN) and 7,12-dihydrocoumestan (coumestrol). DPN is more selective at ERbeta than coumestrol, which also binds ERalpha. 17beta-E2 and ERbeta-selective SERMs (DPN, coumestrol) produced clear antianxiety behavior in the open field, elevated plus maze, emergence, light-dark transition, defensive freezing, and Vogel punished drinking tasks. Anxiety behavior of rats administered ERalpha-selective SERMs (PPT, 17alpha-E2) was not different from vehicle; however, PPT and 17alpha-E2 enhanced sexual receptivity in a manner similar to 17beta-E2. Coadministration of tamoxifen (10 mg/kg) blocked the antianxiety behavior produced by 17beta-E2, DPN, or coumestrol. Together, these data suggest that actions at ERbeta may underlie some of E2's antianxiety effects.
Animals↗
Antidepressant effects of ERbeta-selective estrogen receptor modulators in the forced swim test.
Estradiol (E2) may influence depressive symptomology of women and decrease depressive behavior among rodents. The mechanism(s) for E2's antidepressant effects are not well understood. To determine whether antidepressant effects of E2 may involve actions at intracellular estrogen receptor (ER) alpha or beta isoforms, selective ER modulators (SERMs) were administered (10 microg sc) to ovariectomized rats 48 h before testing in the forced swim test, an animal model of depression, and the horizontal crossing task. Rats received sesame oil vehicle, 17beta-E2, which has a high affinity for ERalpha and ERbeta, SERMs that vary in their activity at ERalpha and beta, or a tricyclic antidepressant (desipramine; 30 mg/kg ip), as a positive control. ERalpha-selective SERMs were propyl pyrazole triol (PPT) and 17alpha-E2. PPT has more selective effects at ERalpha than does 17alpha-E2, which also binds ERbeta. ERbeta-selective SERMs were diarylpropionitrile (DPN) and 7,12-dihydrocoumestan (coumestrol). DPN is more selective at ERbeta than coumestrol, which also binds ERalpha. 17beta-E2, ERbeta-selective SERMs (DPN, coumestrol), and desipramine administration produced antidepressive behavior (decreased immobility, increased struggling and swimming). ERalpha-selective SERMs (PPT, 17alpha-E2) were not different from vehicle. There were no differences among groups in the number of beam breaks made in the horizontal crossing task. These data suggest that E2's antidepressive effects may involve actions at ERbeta.
Animals↗
Ovulation induction is not the same as superovulation: the effect of selective estrogen receptor modulators and aromatase inhibitors.
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Aromatase Inhibitors↗
Selective estrogen receptor modulators: raloxifene.
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Clinical Trials as Topic↗
Selective estrogen receptor modulators: an alternative to hormone replacement therapy.
Estrogen is a key regulatory hormone, which in addition to its role in reproduction, affects a number of physiological systems, including the skeleton and cardiovascular system. The important role of estrogen in various tissues is perhaps most evident in postmenopausal women who, in addition to menopausal symptoms, experience increases in osteoporosis and coronary heart disease as their estrogen levels decline. Estrogen replacement, while effective against osteoporosis and heart disease, produces a number of side effects associated with the breast and uterus which limits compliance. Selective estrogen receptor modulators (SERMs), such as raloxifene and tamoxifen, produce beneficial estrogen-like effects on bone and lipid metabolism, while antagonizing estrogen in reproductive tissue. SERMs can be distinguished from each other in reproductive tissue, particularly the uterus, by their activity profile. For example, while triphenylethylenes like tamoxifen behave as partial agonists, raloxifene (a benzothiophene) behaves as a complete antagonist in the uterus. The SERM profile is distinct from that of full estrogens (ie. 17beta-estradiol or 17alpha-dihydroequilenin) which behave as estrogen agonists in all tissues and pure estrogen antagonists (i.e. ICI-164,384) which exhibit only an estrogen antagonist profile in a battery of tissue types. The precise mechanism by which SERMs produce this tissue-selective pharmacology remains a question. It is clear, however, that for raloxifene, both the estrogen agonist effects on bone and cholesterol metabolism as well as the estrogen antagonist effects in uterine and mammary tissue involve high affinity interaction with the estrogen receptor. The estrogen antagonist activity is mediated via classical pharmacological competition for estrogen receptor binding. The estrogen agonist activity, in bone for example, appears to involve novel post-receptor pathways and non-classical estrogen response element(s) which are activated by SERMs. These novel response elements may represent natural pathways which respond to estrogen metabolites in vivo.
Bone Resorption↗
A new selective estrogen receptor modulator, CHF 4227.01, preserves bone mass and microarchitecture in ovariectomized rats.
UNLABELLED: A new SERM, CHF 4227.01, given to 6-month-old female rats immediately after ovariectomy, preserved bone mass and bone microarchitecture without affecting uterus weight. It also decreased serum cholesterol and fat mass in estrogen-deficient rats. INTRODUCTION: We tested the effect of a new benzopyran derivative, CHF 4227.01, with selective estrogen receptor modulator (SERM) activity on bone mass and biomechanics in ovariectomized (OVX) female rats in comparison with 17alpha-ethinylestradiol (EST), raloxifene (RLX), and lasofoxifene (LFX). MATERIALS AND METHODS: Four doses of CHF 4227.01 (0.001, 0.01, 0.1, and 1 mg/kg body weight [bw]/day) were administered in OVX animals daily by gavage 5 days/week for 4 months. EST was administered at a dose of 0.1 mg/kg bw/day, whereas RLX and LSX were administered at doses of 1 and 0.1 mg/kg bw/day, respectively, by gavage. In one group (Sham), rats were operated but the ovaries not removed; another OVX group was treated only with placebo. RESULTS AND CONCLUSIONS: Treatment with CHF 4227.01 (1.0 and 0.1 mg/kg bw), EST (0.1 mg/kg bw), LFX (0.1 mg/kg bw), or RLX (1.0 mg/kg bw) prevented bone loss on the lumbar spine and the proximal femur assessed in vivo by DXA. Volumetric BMD obtained by pQCT ex vivo confirmed protection from bone loss in the spine and proximal femur among rats treated with CHF 4227.01. This effect was associated with strong inhibition of bone resorption both histologically and biochemically. Furthermore, CHF 4227.01 preserved trabecular microarchitecture, analyzed by muCT, and maintained biomechanical indices of bone strength in the spine and proximal femur, effects also observed for RLX, whereas LSX was less protective of microarchitecture. CHF 4227.01 treatment did not affect uterine weight, prevented the increase in body weight and fat mass seen in OVX animals, and decreased serum cholesterol to below the average of intact animals. In conclusion, CHF 4227.01 exhibits a promising therapeutic and safety profile as a new SERM on both skeletal and extraskeletal outcomes.
Absorptiometry, Photon↗
Nongenomic mechanisms of endothelial nitric oxide synthase activation by the selective estrogen receptor modulator raloxifene.
BACKGROUND: Nontranscriptional signaling through estrogen receptors (ERs) is important in the cardiovascular system. In particular, estrogen stimulates endothelial NO synthase (eNOS) via the phosphatidylinositol 3-kinase (PI3K) pathway. The selective estrogen receptor modulator (SERM) raloxifene is effective for the treatment of postmenopausal osteoporosis, but its ability to activate eNOS via PI3K is unknown. METHODS AND RESULTS: Human umbilical vein endothelial cells were cultured in estrogen-deprived, phenol red-free medium. Raloxifene stimulated eNOS in a concentration- and time-dependent manner. Activation of eNOS by raloxifene was blocked by the PI3K inhibitor wortmannin and by the ER antagonist ICI 182,780 but not by transcriptional or translational inhibitors. Coimmunoprecipitation studies demonstrated that, in a ligand-dependent manner, raloxifene increased ERalpha-associated p85alpha, p110alpha, and PI3K activity. This correlated temporally with increases in the serine and threonine phosphorylation and activation of protein kinase Akt. CONCLUSIONS: Our findings indicate that nongenomic ER signaling triggered by a SERM leads to a rapid activation of NO synthesis in human endothelial cells. The ability of raloxifene to facilitate ERalpha-PI3K interaction may provide additional insight into the structure-function relationship of specific SERMs, which promote the nontranscriptional effects of ER.
Cells, Cultured↗
Raloxifene, a new selective estrogen receptor modulator.
There is evidence from observational studies that estrogen replacement therapy in postmenopausal women can reduce the rates of morbidity and mortality of atherosclerotic heart disease. The mechanism of this cardiovascular protective effect is not yet established, but favorable actions of hormone therapy on plasma lipids and vascular endothelial function have been proposed. Estrogens can also increase the risk of breast and uterine carcinoma. The new selective estrogen receptor modulator (SERM) raloxifene appears to have benefits similar to estrogen on plasma lipids and osteoporosis, but it does not affect the rate of uterine carcinoma as does tamoxifen and estrogen. Animal studies suggest an anti-atherosclerotic action of raloxifene, but this needs to be confirmed in long-term human studies.
Animals↗
Plant 2-arylobenzofurans demonstrate a selective estrogen receptor modulator profile.
We have isolated from the plant Onobrychis ebenoides three novel arylobenzofurans with binding affinity for the estrogen receptor. In this study, we evaluated these arylobenzofurans, namely ebenfuran I, ebenfuran II and ebenfuran III for their potential selective estrogen receptor modulator (SERM)-like properties. We examined their ability, (1) to induce the insulin growth factor binding protein-3 (IGFBP-3) in MCF-7 breast cancer cells, (2) to stimulate differentiation and mineralization of osteoblastic cell culture by histochemical staining for alkaline phosphatase, Alizarin Red-S staining and calcium levels in the supernatants and (3) to inhibit cell proliferation of cervical adenocarcinoma (Hela) cells by use of the MTT assay. An estrogen receptor mediated effect was investigated by carrying out chloramphenicol acetyl transferase (CAT) assay on transient MCF-7 transfectants. Estradiol and the "pure" antiestrogen ICI 182780 were included to serve as control samples of the estrogenic and antiestrogenic effect respectively. Our data reveal that ebenfuran II is a highly potent SERM, exhibiting antiestrogenic activity in breast cancer cells via the estrogen receptor, estrogenic effect on osteoblasts and no stimulatory effect on cervix adenocarcinoma cells. In conclusion, our study is the first to demonstrate that plant derived arylobenzofurans show a SERM profile and may be considered for the prevention and treatment of diseases such as breast cancer, cervical cancer and osteoporosis.
Adenocarcinoma↗
LY353381.HCl, a selective estrogen receptor modulator, and experimental stroke.
BACKGROUND AND PURPOSE: The impact of postmenopausal estrogen replacement therapy on stroke prevention and stroke severity remains controversial. Previously we have shown that cerebral tissue infarction volume sustained after middle cerebral artery (MCA) occlusion is smaller in female than in male animals. This protection is lost after ovariectomy but is restored by 17ss-estradiol replacement. However, the therapeutic range for estradiol is suboptimal, since only doses resulting in a narrow range of plasma levels are protective in brain. The present study tested the hypothesis that a benzothiophene analogue and selective estrogen receptor modulator, LY353381.HCl (LY), reduces tissue infarction after MCA occlusion in estrogen-deficient, ovariectomized female rats. METHODS: Ovariectomized female Wistar rats received LY 10 mg/kg (n=16) or an equivalent volume of vehicle (n=14) by gavage for 5 to 8 days. Subsequently, each animal was anesthetized with halothane (1.2%) and treated with 2 hours of MCA occlusion by the intraluminal filament technique and 22 hours of recovery. Infarction volumes in the cerebral cortex and caudoputamen were determined by 2, 3,5-triphenyltetrazolium chloride staining and digital image analysis. End-ischemic regional cerebral blood flow (CBF) was measured in separate animal cohorts by quantitative [(14)C]iodoantipyrine autoradiography. RESULTS: Caudoputamen infarction was reduced by LY treatment (49+/-6% versus 64+/-4% of ipsilateral caudoputamen in LY and vehicle groups, respectively; P:<0.05). Cerebral cortical infarction was not different in the LY compared with vehicle group (7+/-3% versus 13+/-4% of ipsilateral cerebral cortex, respectively). Intra-ischemic blood pressure, arterial blood gases, and temporalis muscle temperature were controlled and equivalent between treatment groups. Averaged laser-Doppler flow during MCA occlusion was 36+/-3% of baseline in the LY group versus 29%+/-2% in the vehicle group. However, end-ischemic CBF or blood flow distribution within the MCA territory was not altered by LY treatment. Cortical or caudoputamen tissue volumes with end-ischemic CBF <20 mL/100 g per minute were similar in both groups. CONCLUSIONS: We conclude that LY confers neuroprotection from focal cerebral ischemia in caudoputamen in ovariectomized female rats. The mechanism of protection is not linked to preservation of ischemic cerebral blood flow, as determined by end-occlusion quantitative autoradiography.
Animals↗
[Selective estrogen receptor modulators as a new concept in preventing health risks of menopause].
Long-term estrogen deficiency after menopause is responsible for different disorders, which not only make the quality of life in the older age worse but also are the major causes of women's mortality. It is especially the case for cardiovascular disease, osteoporosis and dementia. The risk for these disorders can significantly be reduced by hormone replacement therapy (HRT). Unfortunately, the mean duration of the postmenopausal administration of HRT is too short to demonstrate its efficacy in preventing the mentioned diseases. In this review the new therapeutic possibilities are discussed, called selective estrogen receptor modulators (SERMs). These structurally heterogeneous compounds interact with estrogen receptors and act as either estrogen-agonists or--antagonists according to the type of organ and physiological context (i.e., dose, target tissue and hormone concentration in the tissue). The evaluation of the effects of these compounds led to the better understanding of both antiestrogens and the whole steroid signaling system. The research of the clinical properties of SERM showed their potential benefit in the long-term care of the women in their non-reproductive period of life and demonstrated the possibility to overcome some drawbacks of HRT.
Cardiovascular Diseases↗
Treatment of estrogen deficiency symptoms in women surviving breast cancer. Part 5: Selective estrogen receptor modulators and hormone replacement therapy. Proceedings of a conference. Charlottesville, Virginia, USA. September 21-23, 1997.
There are several million breast cancer survivors worldwide. In the United States, 180,000 women were diagnosed with breast cancer in 1997, and approximately 97,000 of these women have an extremely low chance of suffering a recurrence of their cancer. With an average age at diagnosis of 60 years and a 25-year expected duration of survival, the current number of breast cancer survivors in the United States may approach 2.5 million women. Since breast cancer is now being detected at an earlier stage than previously and since adjuvant chemotherapy may cause ovarian failure, an increasing number of women are becoming postmenopausal at a younger age after breast cancer treatment. This conference was convened in September 1997 to consider how menopausal breast cancer survivors should be treated at the present time and what future studies are needed to develop improved therapeutic strategies. A total of 47 breast cancer experts and 13 patient advocates participated. The proceedings of the conference are being published in six installments in successive issues of ONCOLOGY. This fifth part examines the potential role of antiestrogens and selective estrogen receptor modulators (SERMs) in breast cancer patients being treated for estrogen deficiency symptoms.
Antineoplastic Agents↗
Selective estrogen receptor modulators to prevent treatment-related osteoporosis.
The intended therapeutic effect of gonadotropin-releasing hormone (GnRH) agonists is hypogonadism, which is a leading cause of osteoporosis in men. Consistent with this observation, GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. GnRH agonists markedly decrease serum levels of both testosterone and estrogen. Estrogens play a central role in homeostasis of the normal male skeleton, and the available evidence suggests that estrogen deficiency rather than testosterone deficiency accounts for the adverse skeletal effects of GnRH agonists. The central role of estrogens in male bone metabolism provides a strong rationale to evaluate selective estrogen receptor modulators for prevention of treatment-related osteoporosis in men with prostate cancer. Preliminary evidence suggests that both raloxifene and toremifene increase bone mineral density in GnRH agonist-treated men. An ongoing pivotal study will evaluate the effects of toremifene on fractures and other complications of GnRH agonists in men with prostate cancer.
Journal Article↗
Selective estrogen receptor modulators (SERMs).
Naturally occurring estrogens, such as 17 beta-estradiol and estrone, have traditionally been thought to play a central role in the development and maintenance of the female reproductive system and secondary sexual characteristics. In recent years, their beneficial effects on the skeleton, the cardiovascular system, and the central nervous system, as well as the cancer risks associated with long term exposure have also been recognized. The widespread use of "antiestrogens" such as tamoxifen for the prevention and treatment of breast cancer has revealed that such compounds, while functioning as estrogen antagonists in mammary tissue, actually mimic the effects of estrogen in other tissues. The search for more selective agents has led to the development of raloxifene, a Selective Estrogen Receptor Modulator, which functions as an estrogen antagonist in the breast and uterus and as an estrogen agonist in the skeleton and cardiovascular system. Recent progress in the development of SERMs is the subject of this review, with an emphasis on structure activity relationships and on their effects in non-traditional target tissues.
Animals↗
The combination of a novel selective estrogen receptor modulator with an estrogen protects the mammary gland and uterus in a rodent model: the future of postmenopausal women's health?
The Women's Health Initiative Study and other reports have created major uncertainty among postmenopausal women and physicians concerning hormone replacement therapy. We have thus investigated the possibility of replacing the progestin in hormone replacement therapy by a novel selective estrogen receptor (ER) modulator having potent and pure antiestrogenic activity in the mammary gland and uterus. As measured by changes in histology and Cdc47 labeling in the rat model, the present study shows that the stimulatory effect of estradiol in the mammary gland and uterus is efficiently blocked by simultaneous administration of the novel selective ER modulator EM-652, but bone mineral density is preserved and serum cholesterol is decreased. After the administration of 14C-labeled EM-652, we observed that there is no detectable radioactivity in the brain. Moreover, ER alpha immunoreactivity remained constant in the hypothalamus after EM-652 treatment, whereas ER alpha became almost undetectable in the mammary gland and uterus. The present data show the poor or absent access of EM-652 to the brain, whereas the effects of estrogens are efficiently neutralized in the mammary gland and uterus. Such data support the exciting possibility of a novel approach that could meet most of the needs of women's health at menopause, namely control of hot flushes and prevention of breast, uterine, and ovarian cancer as well as osteoporosis and potentially helping brain function and preventing Alzheimer's disease with no identifiable risk or negative effect.
Animals↗
Comparative effects of the selective estrogen receptor modulators (-)-, (+)- and (+/-)-Z bisdehydrodoisynolic acids on metabolic and reproductive parameters in male and female rats.
Doisynolic acids are non-steroidal estrogenic compounds originally obtained from alkali fusion of estrone and equilenin. Z-bisdehydrodoisynolic acids (Z-BDDA) exhibit a low binding affinity accompanied by a disproportionately high biologic activity. Two experiments were designed to investigate the chronic effects of (+)-, (-)- and (+/-)-Z-BDDA and (+)-17beta-estradiol (E2) in male and female rats. The (+)-, (-)- and (+/-)-forms Z-BDDA were prepared and injected, daily for four to six weeks into male and female rats and changes in body weight, food intake, metabolic parameters, and reproductive parameters were investigated. Results from both experiments demonstrate that in male and female rats, (+)- and (+/-)-Z-BDDA had similar estrogenic effects on reproductive organ weight. Surprisingly, (-)-Z-BDDA did not induce the increase in uterine weight observed with (+)- and (+/-)-Z-BDDA and E2, demonstrating selective estrogen receptor modulation (SERM). Beneficial metabolic effects, although compound- and gender-specific, included a significant weight repression, reduction in cholesterol, reduction in blood glucose, and positive alterations in body fat distribution. Future research defining the optimal dosages of (-)-Z-BDDA that will maximize beneficial effects and minimize undesirable effects on reproductive tissues will lead to more efficacious treatment options for endocrine-responsive conditions in males and females.
Animals↗