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PubMed2003

EphA2 overexpression decreases estrogen dependence and tamoxifen sensitivity.

The EphA2 receptor tyrosine kinase is found at low levels on nontransformed adult breast epithelial cells but is frequently overexpressed on aggressive breast cancer cells. Recent studies have documented an inverse relationship between EphA2 and estrogen receptor expression in breast cancer cell lines. In our present study, we demonstrate that overexpression of EphA2 decreases estrogen dependence as defined using both in vitro and in vivo criteria. The EphA2-transfected cells demonstrate increased growth in vitro and form larger and more aggressive tumors in vivo. EphA2 overexpression also decreases the ability of tamoxifen to inhibit breast cancer cell growth and tumorigenesis. These effects of EphA2 overexpression can be overcome by antibody-based targeting of EphA2. In particular, certain EphA2 antibodies can resensitize EphA2-overexpressing breast tumor cells to tamoxifen. These results have important implications for understanding the molecular basis underlying estrogen dependence and provide further evidence that EphA2 may provide a much-needed therapeutic target for breast cancer.

Adenocarcinoma↗
PubMed2002

Ultrasonographic assessment of endometrial thickness: a review.

Measurement of endometrial thickness with ultrasonography is a modality commonly used today. Its clinical importance and applications extend throughout the phases of the reproductive lives of women. In premenopausal women, endometrial thickness is used to monitor infertility treatment, while in postmenopausal women with abnormal uterine bleeding it is useful as an initial investigation for endometrial hyperplasia or cancer. Moreover, endometrial thickness can vary with the menstrual cycle and with the use of hormone replacement therapy or selective estrogen receptor modulators. In this review, the use of ultrasound to measure both the premenopausal and postmenopausal endometrium is discussed.

Biopsy↗
PubMed1996

Time-dependent changes in biochemical bone markers and serum cholesterol in ovariectomized rats: effects of raloxifene HCl, tamoxifen, estrogen, and alendronate.

Bone loss associated with postmenopausal osteoporosis can be reduced by treatment with antiresorptive agents such as estrogen or bisphosphonates. Whereas bisphosphonates primarily affect bone loss, estrogens have an advantage of also lowering serum cholesterol levels, although they have a detrimental effect in the uterus. Recently, raloxifene HCl, a selective estrogen receptor modulator (SERM), has been shown to decrease both bone loss and cholesterol levels without the negative uterine effects. These antiresorptive agents reduce bone turnover, which can be evaluated by measuring bone turnover markers. To compare the effects of estrogen, two SERMs (raloxifene HCl and tamoxifen), and alendronate, a bisphosphonate that inhibits bone loss by an estrogen-independent pathway, on metabolic bone markers and cholesterol levels, rats were ovariectomized 2 weeks prior to 3 weeks of daily oral treatment with raloxifene HCl (3 mg/kg), ethynyl estradiol (0.1 mg/kg), tamoxifen (3 mg/kg), or alendronate (3 mg/kg). Raloxifene HCl, tamoxifen, and ethynyl estradiol reduced serum cholesterol to levels below control values within 4 days after initiation of treatment, whereas alendronate had no effect. After 3 weeks of treatment, serum cholesterol values in ethynyl estradiol treated animals, although still below the control value, had risen 6.4-fold; raloxifene HCl and tamoxifen values rose by only 1.4-1.5-fold. Therefore, compared with estrogen, SERMs may have a longer-term suppressive effect on serum cholesterol. At 4 days of treatment, ovariectomized rats had a 1.4-fold increase in serum osteocalcin level compared with controls. Ethynyl estradiol lowered this level within 1 week of treatment by 18%, with a more pronounced reduction of 34% at 3 weeks. In contrast, raloxifene HCl, tamoxifen, or alendronate had very little effect after the first week (6% to 13% reduction), although there was an 18% to 25% reduction by 3 weeks. Urinary pyridinoline levels, elevated 1.4-fold in the ovariectomized rat compared with controls 2 weeks after surgery, were reduced to control values after 2 weeks of treatment with raloxifene HCl, ethynyl estradiol, tamoxifen, or alendronate. These data support the concept that estrogen, raloxifene HCl, tamoxifen, and alendronate inhibit bone loss in the ovariectomized animal by reducing bone resorption. The results also indicate that for treatment of postmenopausal osteoporosis, raloxifene HCl may have an advantage over the other antiresorptives studied in having both non-uterotrophic and hypocholesterolemic effects in addition to its ability to inhibit bone resorption.

Alendronate↗
PubMed2002

Organochlorine pesticides directly regulate gonadotropin-releasing hormone gene expression and biosynthesis in the GT1-7 hypothalamic cell line.

Environmental toxicants profoundly affect growth and developmental processes. In the present study, we hypothesized that hypothalamic gonadotropin-releasing hormone (GnRH) neurons, which regulate the reproductive axis, are targets of environmental endocrine disrupting chemicals. Two organochlorine pesticides (methoxychlor and chlorpyrifos) were tested for their effects on GnRH gene expression and biosynthesis in the immortalized hypothalamic GT1-7 cells, which synthesize and secrete GnRH. GT1-7 cells were treated with methoxychlor or chlorpyrifos for 24 h in dose-response experiments, and GnRH gene expression and peptide levels were quantified. In order to examine whether these pesticides affect GnRH biosynthesis through the estrogen receptor (ER), in other experiments their effects were compared to those of estrogen, or they were co-administered with the ER antagonist, ICI 182,780 (ICI). Both methoxychlor and chlorpyrifos had significant effects on GnRH gene transcription and GnRH mRNA levels. These effects were not consistently blocked by ICI, nor did the effects of these pesticides consistently mimic those of estrogen, suggesting a mechanism independent of the ER. Chlorpyrifos and methoxychlor slightly stimulated peptide levels, and this effect was blocked by ICI, suggesting that the ER may mediate effects of pesticides on GnRH release. These results indicate that chlorpyrifos and methoxychlor alter GnRH biosynthesis in this hypothalamic cell line in vitro, suggesting that they may have endocrine disrupting effects on GnRH neurons in vivo.

Animals↗
PubMed1999

Biologic agents and innovative interventional approaches in the management of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a difficult disease to study, having a variable disease course characterized by exacerbations and remissions. A variety of biologic agents are under investigation as potential treatments for SLE. These products are designed to specifically interfere with the following immunologic processes: T cell activation/T cell-B cell collaboration, production of anti-double-stranded DNA antibodies, deposition of anti-double-stranded DNA antibody complexes, complement activation, and immune complex deposition and cytokine activation and modulation. More aggressive interventions include gene therapy and stem cell transplantation. Immunomodulatory agents recently examined in patients with SLE include: thalidomide, AS101, 2' chlordeoxyadenosine, mycophenolate mofetil, and bindarit. Additional innovative pharmaceutical treatments include the mild androgen dehydroepiandrosterone, selective estrogen receptor modulators, and the prolactin inhibitor, bromocriptine. A variety of these biologic and pharmaceutical agents offer promise as potential therapies. Active participation in clinical trial efforts to develop international consensus regarding trial methodology and outcome measures are crucial to the development of these innovative therapies.

Animals↗
PubMed2006

Hydrolysis of black soybean isoflavone glycosides by Bacillus subtilis natto.

Hydrolysis of isoflavone glycosides by Bacillus subtilis natto NTU-18 in black soymilk is reported. At the concentration of 3-5% (w/v), black soymilk in flask cultures, the isoflavones, daidzin, and genistin were highly deglycosylated within 24 h. Deglycosylation of isoflavones was further carried out in a 7-l fermenter with 5% black soymilk. During the fermentation, viable cells increased from 10(3) to 10(9) CFU ml(-1) in 15 h, and the activity of beta-glucosidase appeared at 8 h after inoculation and reached a maximum (3.3 U/ml) at 12 h, then decreased rapidly. Deglycosylation of isoflavone glycosides was observed at the same period, the deglycosylation rate of daidzin and genistin at 24 h was 100 and 75%, respectively. It is significantly higher than the previous reports of fermentation with lactic acid bacteria. In accordance with the deglycosylation of isoflavone glycosides, the estrogenic activity of the 24 h fermented black soymilk for ERbeta estrogen receptor increased to threefold; meanwhile, the fermented broth activated ERalpha estrogen receptor to a less extent than ERbeta. These results suggest that this fermentation effectively hydrolyzed the glycosides from isoflavone in black soymilk and the fermented black soymilk has the potential to be applied to selective estrogen receptor modulator products.

Bacillus subtilis↗
PubMed2004

[Right or wrong of the hormone replacement therapy involving osteoporosis].

Hormone Replacement Therapy (HRT) is replacement of depleted endogenous estrogen for postmenopausal women. Usually progestin is used in combination to avoid endometrial proliferation. As for bone metabolism, estrogens exert bone protective effect through inhibition of bone absorption. HRT has been shown to improve bone mineral density and to lower the risk of osteoporotic bone fracture. However, recent clinical studies proved that HRT not only raise the risk of breast cancer, but also increase the incidence of atherosclerotic cardiovascular diseases. Other than the treatment of postmenopausal vasomotor symptoms, the benefit of HRT is thought to be hard to outweigh its risk. To resolve this problem, low dose HRT and SERM (Selective Estrogen Receptor Modulator) regimens are under investigation. The evidences of androgen replacement for aged men are not accumulated enough to verify its effects and long term safety.

Estrogen Replacement Therapy↗
PubMed2003

New findings about endocrine therapy for breast cancer.

For over a decade, the selective estrogen receptor modulator, tamoxifen, has been the primary agent for adjuvant endocrine therapy for steroid receptor-positive breast cancer. New data over the last 2 years now suggest that its primacy may be challenged by strategies that lower circulating and/or intratumoral estrogens. Recent trials support the use of ovarian suppression approaches with or without tamoxifen in place of chemotherapy in premenopausal women. A large randomized trial has also established the short-term efficacy and safety of the aromatase inhibitor, anastrozole, in postmenopausal women. How and when to integrate these new approaches into standard practice are topics of debate. Ongoing research is focused on choice of endocrine approach, duration and sequencing of endocrine treatment, identification of better predictive markers for hormone response, and assessment of long-term risks and benefits.

Anastrozole↗
PubMed2006

Development and therapeutic options for the treatment of raloxifene-stimulated breast cancer in athymic mice.

PURPOSE: Selective estrogen receptor modulators (SERM) are used for the treatment and prevention of breast cancer (tamoxifen) and osteoporosis (raloxifene). Mechanisms of tamoxifen-resistance in breast cancer are incompletely understood but current research is focused on crosstalk between growth factor receptors and the estrogen receptor alpha (ERalpha) pathway. There is increasing clinical use of raloxifene for the treatment of osteoporosis, but the widespread use of this SERM will have consequences for the treatment of breast cancer in raloxifene-exposed women. EXPERIMENTAL DESIGN: We took the strategic step of developing a raloxifene-resistant tumor (MCF-7RALT) model in vivo and investigating the mechanisms responsible for resistance. RESULTS: MCF-7RALT tumors exhibited phase I SERM resistance, growing in response to SERMs and 17beta-estradiol. Epidermal growth factor receptor/HER1 and HER2/neu mRNAs were increased in MCF-7RALT tumors. The HER2/neu blocker, trastuzumab, but not the epidermal growth factor receptor blocker, gefitinib, decreased the growth of MCF-7RALT tumors in vivo. Consequently, trastuzumab decreased prosurvival/proliferative proteins: phospho-HER2/neu, total HER2/neu, phospho-Akt (protein kinase B), glycogen synthetase kinase-3, cyclin D1, and the antiapoptotic protein X chromosome-linked inhibitor of apoptosis, whereas increasing the proapoptotic protein, caspase-7, in raloxifene-treated MCF-7RALT tumors. Interestingly, ERalpha protein was overexpressed in untreated MCF-7RALT tumors and hyperactivated in cells derived from these tumors. Only fulvestrant completely inhibited the growth and ERalpha activity of MCF-7RALT tumors. The coactivator of ERalpha, amplified in breast cancer-1 protein was modestly increased in the raloxifene-treated MCF-7RALT tumors and increased both basal and estradiol-induced activity of ERalpha in cells derived from the MCF-7RALT tumors. CONCLUSIONS: These results suggest that overexpression and increased activity of HER2/neu might be responsible for the development of raloxifene-resistant breast cancer. The results also suggest that increased expression of basal activity of ERalpha could contribute to the hypersensitivity of MCF-7RALT tumors in response to estradiol because only fulvestrant blocked growth and ERalpha activity.

Animals↗
PubMed2001

Estrogen-like activity of glabrene and other constituents isolated from licorice root.

Licorice root extract and its major isoflavan, glabridin, exhibited varying degrees of estrogen receptor (ER) agonism in different tissues in vitro and in vivo. Animals fed with licorice extract, compared with estradiol and glabridin, showed an increase in creatine kinase (CK) activity, a known marker for estrogen responsive genes, which was higher than expected from the levels of glabridin in the extract. This led us to test for other components that may contribute to this strong estrogen agonist activity. Results indicated that glabrene and isoliquiritigenin, (2',4',4-three hydroxy chalcone) (ILC) in the licorice extract can bind to the human ER with higher affinity (IC50, 1 and 0.5 microM) than glabridin (IC50, 5 microM). The stimulatory effects of glabrene in vivo were tissue specific and similar to those of estradiol. The effect of increasing concentrations of glabrene and ILC on the growth of breast tumor cell were biphasic. Both showed an ER-dependent growth-promoting effect at low concentrations (10 nM-10 microM), and ER-independent antiproliferative activity at concentrations >15 microM. This is the first study to indicate that glabrene, an isoflavene exerted varying degrees of ER agonism in different tissues.

Animals↗
PubMed2002

Estrogenicity of organophosphorus and pyrethroid pesticides.

Although organophosphorus and pyrethroid pesticides are considered environmental contaminants, their estrogenic potentials are still ubiquitous and unclear. The present study was undertaken to evaluate the estrogenic activities of nine pesticides (phoxim, malathion, monocrotophos, dimethoate, opunal, fenvalerate, cypermethrin, permethrin, and deltamethrin) using three in vitro methods [E-Screen assay, estrogen receptor (ER) competitive binding assay, and pS2 expression assay]. All the pyrethroid pesticides tested induced MCF-7 cell proliferation significantly, while organophosphorus pesticides did not. The estrogenic potency were ranked as permethrin > fenvalerate > cypermethrin > deltamethrin. The proliferation induced by cypermethrin, permethrin, and deltamethrin was blocked by ICI 182.780, while fenvalerate only partly inhibited it. In addition, pyrethroid pesticides inhibited the binding of [3H]estradiol to ER, while the organophosphorus failed to do so. Fenvalerate, permethrin, and cypermethrin induced pS2 mRNA expression with varying potency, while there were no significant effects in deltamethrin-treated groups. Our findings provide evidence to support the idea that pyrethroid pesticides tested produce an ER-specific, agonist response. Fenvalerate induced MCF-7 cell proliferation by a mechanism not involving ER-mediated pathway. Organophosphorus pesticides tested showed no estrogenic potential. Compared with the pS2 expression assay, E-Screen was a more sensitive and useful assay for screening of the xenoestrogenic chemicals.

Animals↗
PubMed2006

Homocysteine, estrogen and cognitive decline.

BACKGROUND: Factors that contribute to cognitive decline in women from midlife remain poorly understood. There are circumstantial data indicating a positive association between homocysteine and cognitive decline and that endogenous and exogenous estrogen may influence homocysteine levels. The aim of this review was to establish what is known of the relationships between cognitive change and homocysteine levels, and the impact of the menopause transition and exogenous estrogen on homocysteine levels. METHODS: We reviewed the recent published literature from 1993 to 2005 pertaining to the current understanding of the relationship(s) between plasma homocysteine levels and cognitive functioning and endogenous hormone levels and exogenous estrogen use in women. RESULTS: Hyperhomocysteinemia is consistently associated with cognitive decline. Dietary supplementation with vitamins may assist in normalizing homocysteine levels; however, there is no evidence that this results in favorable effects on cognition. Changes in endogenous estrogen levels are inversely associated with changes in serum homocysteine. Consistent with this, estrogen therapy is associated with reductions in plasma homocysteine, with the greatest effects reported in women with higher levels of homocysteine at baseline. Limited data indicate that tibolone is associated with little change in homocysteine. The use of raloxifene, the most studied selective estrogen receptor modulator, is associated with a modest reduction in homocysteine. CONCLUSIONS: There are data to suggest an underlying link between homocysteine levels and cognitive decline. There is also evidence for a link between both the menopause transition and use of exogenous estrogen therapy and homocysteine levels. Clinical data do not support a role for exogenous estrogen in the prevention of dementia in older women; however, the 'window of opportunity' theory suggests that there is a need for randomized controlled trials to evaluate the role of estrogen in the early postmenopausal years to protect against cognitive decline in later life.

Cognition↗
PubMed1999

Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy postmenopausal women: A 2-year, placebo-controlled study.

Currently raloxifene, a selective estrogen receptor modulator, is being investigated as a potential alternative for postmenopausal hormone replacement to prevent osteoporosis and cardiovascular disease. We compared the 2-year effects of raloxifene on a wide range of cardiovascular risk factors with those of placebo and conjugated equine estrogens (CEEs). Analyses were based on 56 hysterectomized but otherwise healthy postmenopausal women aged 54. 8+/-3.5 (mean+/-SD) years who entered this double-blind study and who were randomly assigned to raloxifene hydrochloride 60 mg/d (n=15) or 150 mg/d (n=13), placebo (n=13), or CEEs 0.625 mg/d (n=15). At baseline and after 6, 12, and 24 months of treatment, we assessed serum lipids, blood pressure, glucose metabolism, C-reactive protein, and various hemostatic parameters. Compared with placebo, both raloxifene and CEEs lowered the level of low density lipoprotein cholesterol by 0.53 to 0.79 mmol/L (all P<0.04) and lowered, at 24 months, the level of fibrinogen by 0.71 to 0.86 g/L (all P<0.05). The effects of raloxifene and CEEs did not differ significantly. In contrast to raloxifene, from 6 months on CEEs increased high density lipoprotein cholesterol by 0.25 to 0.29 mmol/L and reduced plasminogen activator inhibitor-1 antigen by 30.6 to 48.6 ng/mL (all P<0.02 versus both placebo and raloxifene). CEEs transiently increased C-reactive protein by 1.0 mg/L at 6 months (P<0.05 versus placebo) and prothrombin-derived fragment F1+2 by 0. 79 nmol/L at 12 months (P<0.001 versus placebo). Finally, from 12 months on, CEEs increased triglycerides by 0.33 to 0.56 mmol/L (all P<0.05 versus both placebo and raloxifene). Our findings suggest that in healthy postmenopausal women, raloxifene and estrogen monotherapy have similar beneficial effects on low density lipoprotein cholesterol and fibrinogen levels. These treatments differ, however, in their effects on high density lipoprotein cholesterol, triglycerides, and plasminogen activator inhibitor-1 and possibly in their effects on prothrombin fragment F1+2 and C-reactive protein.

Biomarkers↗
PubMed2000

Hormone replacement therapy and coronary heart disease. A new debate.

Hormone replacement therapy is extensively used in the United States, especially for the possible prevention of heart disease, osteoporotic fractures, and, more recently, dementia. The results of recent clinical trials have raised new questions about the risk and benefits of estrogen or estrogen/progesterone therapy to prevent heart attacks, the choice of specific drug therapy such as specialized estrogen receptor modulation (SERM). The change in risk factors, especially weight gain or obesity, may determine the risks and benefits of hormone replacement therapy.

Clinical Trials as Topic↗
PubMed2000

Differential estrogen receptor binding of estrogenic substances: a species comparison.

The study investigated the ability of 34 natural and synthetic chemicals to compete with [3H]17beta-estradiol (E2) for binding to bacterially expressed glutathione-S-transferase (GST)-estrogen receptors (ER) fusion proteins from five different species. Fusion proteins consisted of the ER D, E and F domains of human alpha (GST-hERalphadef), mouse alpha (GST-mERalphadef), chicken (GST-cERdef), green anole (GST-aERdef) and rainbow trout ERs (GST-rtERdef). All five fusion proteins displayed high affinity for E2 with dissociation constants (K(d)) ranging from 0.3 to 0.9 nM. Although, the fusion proteins exhibited similar binding preferences and binding affinities for many of the chemicals, several differences were observed. For example, alpha-zearalenol bound with greater affinity to GST-rtERdef than E2, which was in contrast to other GST-ERdef fusion proteins examined. Coumestrol, genistein and naringenin bound with higher affinity to the GST-aERdef, than to the other GST-ERdef fusion proteins. Many of the industrial chemicals examined preferentially bound to GST-rtERdef. Bisphenol A, 4-t-octylphenol and o,p' DDT bound with approximately a ten-fold greater affinity to GST-rtERdef than to other GST-ERdefs. Methoxychlor, p,p'-DDT, o,p'-DDE, p,p'-DDE, alpha-endosulfan and dieldrin weakly bound to the ERs from the human, mouse, chicken and green anole. In contrast, these compounds completely displaced [3H]E2 from GST-rtERdef. These results demonstrate that ERs from different species exhibit differential ligand preferences and relative binding affinities for estrogenic compounds and that these differences may be due to the variability in the amino acid sequence within their respective ER ligand binding domains.

Amino Acid Sequence↗
PubMed1992

Estrogen receptor messenger ribonucleic acid in female rat brain during the estrous cycle: a comparison with ovariectomized females and intact males.

Variations in levels of estrogen receptor mRNA were investigated in the medial preoptic nucleus, arcuate nucleus, and ventromedial nucleus of the hypothalamus throughout the phases of the female estrous cycle and compared with those in ovariectomized female and intact male rats. Female Wistar rats were killed during estrus, metestrus, diestrus, or proestrus or 72 h after ovariectomy as were a group of intact male rats. Brains were removed and frozen, and 20-microns cryostat sections were thaw-mounted onto slides and hybridized with a 35S-labeled antisense estrogen receptor probe. Section-mounted slides were processed, apposed to x-ray film, then dipped in liquid emulsion, and quantified. After exposure, estrogen receptor mRNA was detected in several brain regions, including the medial preoptic nucleus, arcuate nucleus, and ventromedial nucleus of the hypothalamus. Estrogen receptor mRNA levels in the medial preoptic nucleus were highest during estrus and metestrus, attenuated at diestrus, and low during proestrus. In contrast, the hybridization signal in the arcuate and ventromedial nuclei was low during estrus and then gradually increased throughout the cycle until it peaked during proestrus. Ovariectomized females exhibited an elevated level of estrogen receptor mRNA in all brain regions investigated. Hybridization signal in male medial preoptic nucleus and ventromedial nucleus was reduced compared with those in both intact and ovariectomized females. Estrogen receptor mRNA levels in the arcuate nucleus were similar to those in intact females, but less than those in ovariectomized animals. The results of these studies demonstrate that estrogen receptor mRNA levels are sexually dimorphic, vary during the estrous cycle, and increase after ovariectomy. Furthermore, these results indicate that the magnitude and direction of change observed during the estrous cycle are region specific and suggest that factors other than endogenous estrogen levels differentially modulate estrogen receptor mRNA expression in the hypothalamus.

Animals↗
PubMed2000

Antiproliferative effects of idoxifene in a placebo-controlled trial in primary human breast cancer.

Idoxifene is a novel selective estrogen receptor modulator. It has reduced agonist activity on breast and uterine cells compared with tamoxifen and antiproliferative effects in tamoxifen-resistant breast cancer cells. Previous studies have shown that a short course of treatment with other antiestrogens prior to surgery caused a significant reduction of the growth fraction when measured by immunohistological staining using the mouse monoclonal antibody Ki67. In this study, we assessed the effect of idoxifene on biological markers of cell proliferation (Ki67) and apoptosis (TdT-mediated dUTP-biotin nick end labeling), and estrogen and progesterone receptor (ER/PR) expression was also evaluated. Core-cut biopsies were obtained in 77 postmenopausal patients with primary breast cancer at diagnosis. Patients were randomized to 40 mg/day idoxifene or placebo for 14-21 days prior to obtaining a second biopsy sample at surgical resection. The percentage of Ki67-positive cells fell from a mean 19.7 +/- 2.7% (SE) to 13.4 +/- 3.4% in idoxifene-treated ER-positive tumors (n = 30; P = 0.0043), but there was no significant effect in placebo-treated ER-positive tumors (n = 27). No effect was seen on ER-negative tumors in either group. Idoxifene had no significant effect on apoptotic index but produced a statistically significant fall in idoxifene-treated ER immunohistochemical score and a small increase in PR that did not reach statistical significance (0.05 < P < 0.10). Idoxifene was well tolerated in all patients. Idoxifene has an antiproliferative effect in ER-positive but not ER-negative breast cancers, and no significant effect on apoptosis in the short-term.

Aged↗
PubMed2000

Prevention of bone loss by EM-800 and raloxifene in the ovariectomized rat.

Some undesirable effects are associated with chronic estrogen and progestin administration used to prevent bone loss in postmenopausal women, thus leading to poor compliance and the need for improved therapeutic and preventive agents. We have thus studied the ability of the new antiestrogen EM-800 (SCH 57050) to prevent bone loss and lower serum cholesterol levels and compared its effects with those of raloxifene. Ovariectomized (OVX) female rats were treated by oral gavage for 37 weeks with increasing daily doses (0.01, 0.03, 0.1, 0. 3 or 1 mg/kg) of EM-800 or raloxifene. At 35 weeks after OVX, lumbar spine bone mineral density (BMD) was 19% lower than in intact animals (P<0.01), while the OVX animals given EM-800 or raloxifene had 90-93 and 85-90%, respectively, of the BMD values observed in intact rats. Similar effects were observed on femoral BMD. Bone histomorphometry measurements were performed on proximal tibia. At the 0.01 mg/kg dose, EM-800 prevented the effect of OVX on TBV by 34% (P<0.01), while raloxifene had no detectable effect. Treatment with 1 mg/kg EM-800 and raloxifene resulted in, respectively, 68% (P<0.01) and 64% (P<0.01) prevention of the OVX-induced decrease in TBV. In addition, the administration of 0.01 and 0.03 mg/kg EM-800 caused, respectively, 54% (P<0.01) and 56% (P<0.01) inhibitions of serum cholesterol levels, while raloxifene administered at the same doses caused, respectively, 24% (P<0.01) and 41% (P<0.01) decreases of the value of the same parameter. At the highest doses used (0.1-1 mg/kg), both compounds lowered serum cholesterol levels by approximately 65% (P<0.01). No stimulatory effect of EM-800 was observed on the endometrial epithelial cells at doses up to 1 mg/kg, while hypertrophy of uterine epithelium was observed with raloxifene. EM-800 and raloxifene achieve the same degree of effectiveness on bone and serum cholesterol at higher doses, but EM-800 is at least three to ten times more potent than raloxifene at lower concentrations and has no stimulatory effect on uterine epithelium. The present data show the potent effect of EM-800 preventing bone loss and lower serum cholesterol levels without the negative effect on the endometrium, thus suggesting the particular interest of this new fully tissue-specific selective estrogen receptor modulator.

Administration, Oral↗