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PubMed2001

Raloxifene-mediated increase in matrix metalloproteinase-1 production by activated monocytes.

Matrix metalloproteinases (MMPs), proteolytic enzymes produced by monocytes, may contribute to atherosclerotic arterial wall remodeling and to plaque rupture. Because estrogen influences the synthesis of MMPs, we examined the effect of raloxifene, a selective estrogen receptor modulator, on monocyte MMP production. Human primary blood monocytes treated with raloxifene (10 micromol/L) in the presence of lipopolysaccharide (LPS) or tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor induced a 2- to 3-fold increase in MMP-1 production by monocytes. The enhancement of MMP-1 production by raloxifene in LPS-activated monocytes occurred through a cyclooxygenase-2- and prostaglandin E(2)-independent mechanism. Additionally, compared with monocytes acquired during the placebo phase, peripheral blood monocytes from 5 of 6 healthy postmenopausal women treated with raloxifene (60 mg daily for 1 month) in a clinical trial produced significantly higher levels of MMP-1 when the monocytes were activated with LPS. Furthermore, serum obtained during the raloxifene phase from 4 of these subjects, when added to control monocytes, significantly enhanced LPS-induced MMP-1 production compared with that from serum obtained during the placebo phase. In summary, raloxifene increases the production of MMP-1 in activated monocytes; this effect may be favorable in atherosclerotic arterial wall remodeling but unfavorable for plaque stability.

Arteriosclerosis↗
PubMed2004

Potent inhibition of human liver aldehyde oxidase by raloxifene.

The selective estrogen receptor modulator, raloxifene, has been demonstrated as a potent uncompetitive inhibitor of human liver aldehyde oxidase-catalyzed oxidation of phthalazine, vanillin, and nicotine-Delta1'(5')-iminium ion, with K(i) values of 0.87 to 1.4 nM. Inhibition was not time-dependent. Raloxifene has also been shown to be a noncompetitive inhibitor of an aldehyde oxidase-catalyzed reduction reaction of a hydroxamic acid-containing compound, with a K(i) of 51 nM. However, raloxifene had only small effects on xanthine oxidase, an enzyme related to aldehyde oxidase. In addition, several other compounds of the same therapeutic class as raloxifene were examined for their potential to inhibit aldehyde oxidase. However, none were as potent as raloxifene, since IC(50) values were orders of magnitude higher and ranged from 0.29 to 57 micro M. In an examination of analogs of raloxifene, it was shown that the bisphenol structure with a hydrophobic group on the 3-position of the benzthiophene ring system was the most important element that imparts inhibitory potency. The relevance of these data to the mechanistic understanding of aldehyde oxidase catalysis, as well as to the potential for raloxifene to cause drug interactions with agents for which aldehyde oxidase-mediated metabolism is important, such as zaleplon or famciclovir, is discussed.

Aldehyde Oxidase↗
PubMed2002

Estrogen receptor downregulators: new antihormonal therapy for advanced breast cancer.

BACKGROUND: Fulvestrant is the first agent in the new class of estrogen receptor (ER) downregulators to be evaluated in clinical studies. The binding of ER downregulators to ERs inhibits the activation functions of the receptors (AF-1 and AF-2). ER downregulators also disrupt the dimerization and nuclear localization of ERs. In contrast to ER downregulators, when selective estrogen receptor modulators (SERMs) bind to ERs, only AF-2 is inhibited; AF-1 remains active. Therefore, with SERMs, AF-1 can still recruit coactivators, which results in a partially inactivated transcription and a reduced rate of tumor cell division. Consistent with its mechanism of action, animal models have shown that fulvestrant demonstrates a longer suppression of tumor growth than does tamoxifen, and it has antitumor activity in tamoxifen-resistant tumors. Two Phase III trials have been conducted comparing fulvestrant (250 mg IM monthly) with anastrozole (1 mg oral tablet daily) in postmenopausal patients with advanced breast cancer progressing after prior endocrine therapy. Objective response in fulvestrant-treated patients in the 2 studies ranged from 17.5% to 20.7% compared with 15.7% to 17.5% for anastrozole-treated patients, and the median duration of response ranged from 14.3 to 19.3 months in the fulvestrant group compared with 10.5 to 14.0 months in the anastrozole group. No statistically significant differences were demonstrated for any of the predefined end points. In both studies, fulvestrant was as well tolerated as anastrozole. OBJECTIVE: This review describes the pharmacology, clinical activity, safety, dosing, and pharmacokinetic profile of fulvestrant. CONCLUSIONS: Based on evidence to date, fulvestrant will likely be an important agent in the treatment of tamoxifen-resistant metastatic breast cancer.

Animals↗
PubMed2002

Bone histomorphometric and biochemical marker results of a 2-year placebo-controlled trial of raloxifene in postmenopausal women.

Raloxifene is a selective estrogen receptor modulator that has been shown to increase bone density. The purpose of this study was to examine the effects of raloxifene on bone tissue by studying bone biopsy specimens before and after 2 years of raloxifene or placebo therapy. The women in this study were participants of the double-blind, placebo-controlled, multicenter study, the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Subjects from two U.S. sites and two European sites were included if they consented to a bone biopsy. Iliac crest bone biopsies were performed at baseline and after 2 years. Tetracycline labeling preceded each biopsy. A total of 65 paired biopsy specimens were evaluated with 25, 22, and 18 patients in the placebo, raloxifene HCl (60 mg) and raloxifene HCl (120 mg) treatment groups, respectively. They were analyzed using standard histomorphometry. None of the biopsy specimens showed evidence of toxic effects on bone or bone cells or met criteria for osteomalacia. Biopsy specimens in the placebo and raloxifene groups had the appearance of normal bone, with no evidence of marrow fibrosis or increases in the amount of woven bone or numbers of empty osteocyte lacunae. Compared with the baseline, the bone formation rate (BFR) decreased significantly in both raloxifene groups. The change in BFR in the group treated with 120 mg of raloxifene was -62.3%, which was significantly lower than the change in the placebo group of -21.0% (p = 0.03). No change in resorption parameters could be measured by histomorphometry, but there was a decrease in urinary type I collagen excretion. The results from this study suggest that raloxifene has actions on bone tissue that are similar to those observed with estrogen. The depressive effects on bone remodeling are less marked than the effects seen with alendronate.

Aged↗
PubMed2001

Adenomyosis--a result of disordered stromal differentiation.

Adenomyosis is a fairly frequent disorder in adult women characterized by the haphazard location of endometrial glands and stroma deep within the myometrium of the uterus. This study compared the effects on uterine development of the selective estrogen receptor modulators, tamoxifen, toremifene, and raloxifene with estradiol when given orally to female mice on days 2 to 5 after birth. Uterine adenomyosis was found in all (14 of 14) mice dosed with tamoxifen and most mice (12 of 14) treated with toremifene, but in none of the vehicle-dosed controls, in only one animal treated with raloxifene at 42 and 90 days after dosing and in none of the mice treated with estradiol at 42 days. At 6 days, the uterus in the groups that developed a high incidence of adenomyosis showed histological evidence of disturbed differentiation of the myometrium. Gene-expression XY-scatterplots using Clontech mouse 1.2 Atlas mouse cDNA expression arrays analyzing total uterine RNA showed nerve growth factor-alpha, preadipocyte factor-1, and insulin-like growth factor-2 were key genes differentially modified by tamoxifen or toremifene treatment, relative to the controls. As these genes may play an important role in regulating differentiation and development of the myometrium, these data suggest that adenomyosis may be caused primarily by defects in the formation of the myometrium.

Administration, Oral↗
PubMed2004

[Additional effect of SERM: central nervous system].

Raloxifene is a selective estrogen-receptor modulator recently launched in Japan as a new medicine for treatment of postmenopausal osteoporosis. Raloxifene stimulates neurite outgrowth in cultured cells and increases hippocampal cholineacethyl trasferase activity and serotonin receptor in the brain of ovariectomized rats. As a part of the Multiple Outcomes of Raloxifene Evaluation trial, 7,478 postmenopausal women with osteoporosis were studied by using six tests of cognitive function. There was some evidence that Raloxifene may lower the risk of a decline in memory and attention. It is expected that novel SERM, which has more specific efficacy improving cognitive function will be developed.

Attention↗
PubMed2004

Comparative vascular effects of hormone replacement therapy and raloxifene in women at increased cardiovascular risk.

Hormone replacement therapy (HRT) improves endothelial function in postmenopausal women while the effects of raloxifene, a selective estrogen receptor modulator, are still under debate. The aim of this study was to evaluate endothelium-dependent flow-mediated vasodilatation in the brachial artery and plasma levels of nitrite, nitrate and endothelin-1 in 20 postmenopausal women with increased cardiovascular risk treated with either HRT or raloxifene for 4 weeks in a randomized double-blind single cross-over study. Patients had an endothelium-dependent flow-mediated dilatation of 4% prior to initiation of the study. Treatment with HRT resulted in a 67% increase in dilatation compared with baseline (from a 7.4% increase to a 12.4% increase, p < 0.01). Raloxifene treatment resulted in no change in vasodilatation from baseline. Endothelium-dependent dilatation was significantly improved by HRT compared with raloxifene treatment (12.4+/-0.6% vs. 6.1+/-2.0%; p < 0.01). Compared with baseline values, nitrate plus nitrite levels increased significantly (p < 0.05) with HRT but not with raloxifene. Similarly, endothelin-1 decreased from baseline with both treatments, but only the HRT-induced decrease was statistically significant (p < 0.05). In conclusion, HRT improved endothelial function and reduced plasma levels of endothelin-1 in postmenopausal women at risk of coronary artery disease. These beneficial effects were not shared by raloxifene.

Aged↗
PubMed2006

Administration of raloxifene reduces sensorimotor and working memory deficits following traumatic brain injury.

Hormonal differences between males and females have surfaced as a crucial component in the search for effective treatments after experimental models of traumatic brain injury (TBI). Recent findings have shown that selective estrogen receptor modulators (SERMs) may have therapeutic benefit. The present study examined the effects of raloxifene, a SERM, on functional recovery after bilateral cortical contusion injury (bCCI) or sham procedure. Male rats received injections of raloxifene (3.0mg/kg, i.p.) or vehicle (1.0 ml/kg, i.p.) 15 min, 24, 48, 72, and 96 h after bCCI or sham procedure. Rats were tested on both sensorimotor (bilateral tactile removal and locomotor placing tests) and cognitive tests (reference and working memory in the Morris water maze). Raloxifene-treated animals showed a significant reduction in the initial magnitude of the deficit and facilitated the rate of recovery for the bilateral tactile removal test, compared to vehicle-treated animals. The raloxifene-treated animals also showed a significant improvement in the acquisition of working memory compared to vehicle-treated animals. However, raloxifene did not significantly improve the acquisition of reference memory or locomotor placing ability. Raloxifene treatment also did not result in a significant reduction in the size of the lesion cavity. Thus, the task-dependent improvements seen following raloxifene treatment do not appear to be the result of cortical neuroprotection. However, these results suggest that raloxifene improves functional outcome following bCCI and may present an interesting avenue for future research.

Analysis of Variance↗
PubMedDate not supplied

Raloxifene is a better antioxidant of low-density lipoprotein than estradiol or tamoxifen in postmenopausal women in vitro.

OBJECTIVE: The oxidation of low-density lipoprotein (LDL) is an important factor in the development of atherosclerosis. The antioxidant activity of some compounds buffers the free radicals generated either endogenously or exogenously, thus decreasing the potential damage mediated by oxidation. Estrogens are potent antioxidants of LDL, in vitro and in vivo, a mechanism that could probably influence the cardioprotection associated with hormone replacement therapy in postmenopause. We conducted an in vitro study of the antioxidant effect on LDL of two selective estrogen receptor modulators, raloxifene (RLX) and tamoxifen (TMX), comparing them with the known antioxidant effect of estradiol (E2 ). DESIGN: LDL was isolated by ultracentrifugation from plasma obtained from 12 healthy, untreated, postmenopausal women. Aliquots containing 0.5 mg of LDL protein were incubated for 4 h with CuSO4 (15 micro M) to induce oxidative stress and with one of the three compounds studied: RLX, TMX, or E2 at doses of 0, 1, 2, 3, 5, 15, 50, and 500 micro M, and 1 and 2 mM. Malonaldehyde (MDA, nmol/mg protein) was measured as a marker of LDL oxidation. RESULTS: E2 induced a dose-dependent decrease in MDA concentration. MDA values decreased significantly, as compared with baseline, starting at a concentration of 2 micro M for RLX and 3 micro M for both, TMX, or E2. The dose necessary to reduce the generation of MDA by 50% was significantly lower for RLX (3.3 micro M, < 0.001) than for E2 (24.6 micro M ) or TMX (35.3 micro M). The area under the curve also showed a higher antioxidant activity for RLX compared with TMX or E2 ( < 0.001). CONCLUSIONS: The in vitro antioxidant activity of RLX is substantially more potent than TMX or E2. This finding, added to the other beneficial effects of the drug in the cardiovascular system, could imply some cardioprotector effect.

Antioxidants↗
PubMed2005

Investigations on the effects of basic side chains on the hormonal profile of (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines.

Basic side chains determine the pharmacology of selective estrogen receptor modulators such as tamoxifen or raloxifene. In this study we tried to turn the hormonal profile of (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines from agonistic to antagonistic by introduction of a dimethylaminoethane, a piperidin-1-ylethane, or a pyrrolidin-1-ylethane side chain into one of the 4-hydroxyphenyl rings. The compounds were tested for agonistic and antagonistic activity on hormone sensitive, ERalpha-positive MCF7-2a cells, stably transfected with the plasmid ERE(wtc)luc and on U-2 OS cells transiently transfected with plasmids encoding for ERalpha (pSG5-ERalpha) or ERbeta (pSG5-ERbeta FL) as well as the reporter plasmid (ERE)(2)luc(+). Despite the presence of a basic side chain, the majority of the 4,5-diaryl-2-imidazolines showed agonistic effects. The most active compound, (4R,5S)/(4S,5R)-4-(2-chloro-4-(2-piperidin-1-ylethoxy)phenyl)-5-(2,6-dichloro-4-hydroxyphenyl)-2-imidazoline (5a), achieved at ERalpha an EC(50) value of 0.085 microM and at ERbeta an EC(50) = 0.40 microM. High antagonistic properties only possessed the C2 ethyl substituted compounds 2a and 4a. (4R,5S)/(4S,5R)-2-Ethyl-4-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-ylethoxy)phenyl)-2-imidazoline (2a) reduced the effect of estradiol at ERalpha strongly with IC(50) = 0.038 microM, while its antagonistic properties at ERbeta were distinctly lower (IC(50) = 9.00 microM), probably due to the partial agonistic effects (EC(50) = 0.50 microM).

Cell Line, Tumor↗
PubMed2002

Dietary soy isoflavones and bone mineral density: results from the study of women's health across the nation.

Isoflavones are naturally occurring selective estrogen receptor modulators, with potential bone protective effects. To study the relation between soy isoflavone intake and bone mineral density (BMD), the authors analyzed baseline data from the Study of Women's Health Across the Nation, a US community-based cohort study of women aged 42-52 years. Their 1996-1997 analysis included African-American (n = 497), Caucasian (n = 1,003), Chinese (n = 200), and Japanese (n = 227) participants. Genistein and daidzein intakes were highly correlated (r = 0.98); therefore, analyses were conducted by using genistein. Median intakes of genistein (measured in micrograms/day) by African Americans and Caucasians were too low to pursue relational analyses further. For Chinese and Japanese women, median genistein intakes were 3,511 and 7,151 microg/day, respectively. Ethnic-specific, linear models were used to predict BMD as a function of energy-adjusted tertile of intake, controlled for relevant covariates. For Chinese women, no association between genistein and BMD was found. Premenopausal, but not perimenopausal, Japanese women whose intakes were greater had higher spine and femoral neck BMD. Adjusted mean spinal BMD of those in the highest tertile of intake was 7.7% greater than that of women in the lowest tertile (p = 0.02); femoral neck BMD was 12% greater in the highest versus the lowest tertile (p < 0.0001).

Adult↗
PubMed2002

The hemorheological effects of raloxifene in postmenopausal women with osteoporosis. Results of a 3-year placebo-controlled clinical trial.

Raloxifene, the prototype of the selective estrogen receptor modulators, has been associated with an increased risk of venous thromboembolism. As hemorheological factors may be involved in thrombus formation this placebo-controlled study investigated whether raloxifene was associated with changes in determinants of blood viscosity. Fifty-seven post-menopausal women were randomly assigned to receive placebo, raloxifene 60 mg/day, or raloxifene 120 mg/day for 36 months. Venous blood samples were collected at baseline and at 12-monthly intervals and used to measure hematocrit, whole blood and plasma viscosity and plasma fibrinogen concentration. Time- and treatment-related changes in the grouped and pooled data was analysed using ANOVA with repeated measures and correlation matrices. The mean values of all the hemorheological indices showed small inconsistent changes within the normal reference range over the 36-month period of the study. There was a small but significant decrease over time in high shear rate blood viscosity and plasma viscosity in raloxifene-treated subjects compared to those receiving placebo (p<0.05). Correlation analyses showed the anticipated relationships between blood viscosity and hematocrit and plasma viscosity levels and also between plasma viscosity and plasma fibrinogen concentration. No subject developed a thromboembolic vascular event during the study. These results show that compared with placebo treated-subjects, long-term raloxifene treatment in post-menopausal women, at a dose of either 60 or 120 mg daily, was not associated with adverse changes in hemorheological factors that may contribute to venous thromboembolism.

Aged↗
PubMed2004

Inhibition of low-density lipoprotein and high-density lipoprotein oxidation by raloxifene.

BACKGROUND: Raloxifene (RX), a selective estrogen receptor modulator (SERM), has demonstrated hypolipidemic and in vitro antioxidant properties. In the pathogenesis of atherosclerosis, the oxidative modification of low-density lipoprotein (LDL) is implicated to play a crucial role. METHODS: In this study, we investigated the antioxidant properties of RX during in vitro LDL and high-density lipoprotein (HDL) oxidation. The concentrations of RX, chosen ranged from 5.1 to 5100 nM. Isolated lipoproteins were supplemented with RX, and copper-mediated oxidation was monitored via the formation of conjugated dienes (CD), and oxidation resistance (lag time) was calculated. The formation of thiobarbituric acid-reactive substances (TBARS) was measured after 90, 120, 210, and 300 minutes of oxidation. RESULTS: We found a dose-dependent inhibition of LDL and HDL oxidation in terms of both increased lag time and decreased formation of TBARS. Differences in lag time became significant at 51 nM RX added to LDL and HDL, respectively. TBARS formation in LDL was significantly reduced after 120 minutes incubation with 510 and 5100 nM RX and also after 300 minutes with 51 nM RX added. In HDL, significant reduction in TBARS formation was observed after 90 minutes by the addition of 51, 510, and 5100 nM RX. CONCLUSIONS: These results confirm data from previous studies concerning inhibition of in vitro oxidation of LDL by RX and additionally show that RX efficiently inhibits in vitro oxidation of HDL in a broad concentration range.

Adult↗
PubMedDate not supplied

Effects of ospemifene, a novel SERM, on vascular markers and function in healthy, postmenopausal women.

OBJECTIVE: Ospemifene, a novel selective estrogen receptor modulator (SERM), shows promise for bone preservation in postmenopausal women. This study examined the effects of ospemifene on different vascular surrogate markers. DESIGN: A double-blinded study was conducted in 160 healthy, postmenopausal women who used, in a randomized order, ospemifene (at daily doses of 30, 60, or 90 mg) or placebo for 3 months. RESULTS: Although ospemifene caused falls from basal levels in total cholesterol, low-density lipoprotein cholesterol, oxidized low-density lipoprotein cholesterol, and a rise in high-density lipoprotein cholesterol, the only statistically significant difference between ospemifene and placebo was an increase of triglyceride levels (11.3%) in the 90-mg group. Ospemifene caused no significant effect on endothelial markers or homocysteine. Of the markers reflecting coagulation and fibrinolysis, plasma fibrinogen was significantly reduced in the 60- and 90-mg groups of ospemifene (8.7% and 8.5%, respectively) when compared with the placebo group. No changes were seen in generation of thrombin or degradation of crosslinked fibrin D-dimer. The uterine or carotid arteries and 24-h ambulatory blood pressure were not affected by ospemifene. Ospemifene caused no changes in basal insulin or in a 2-h glucose tolerance test, suggesting unaltered insulin sensitivity. CONCLUSIONS: Neutral effects of short-term use of ospemifene on vascular surrogate markers imply no effect for ospemifene on the risk for cardiovascular disorders in healthy, postmenopausal women.

Aged↗
PubMed2026

Differential Effectiveness of Adjuvant Endocrine Therapy According to Menopausal Status, Body Mass Index, and Molecular Subtype in Hormone Receptor-Positive Breast Cancer.

The effectiveness of adjuvant endocrine therapy for hormone receptor-positive (HR+) breast cancer (BC) varies according to menopausal status, body mass index (BMI), and tumor biology. We evaluated the association between selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and BC-specific mortality according to menopausal status, BMI, and molecular subtype in a nationwide Korean cohort. We analyzed data from 31,030 patients with HR+ BC who were registered in the Korean Breast Cancer Society Registry, diagnosed between 2000 and 2008, and followed through 2013. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for BC-specific mortality after adjusting for demographic and clinical factors. Of the 31,030 patients, 19,634 received SERM therapy, and 3,354 received AI therapy. SERM use was associated with lower BC-specific mortality in premenopausal women (HR, 0.75; 95% CI, 0.63-0.91), whereas AI therapy was more strongly associated with lower BC-specific mortality among postmenopausal women (HR, 0.76; 95% CI, 0.61-0.94). Lower BC-specific mortality was observed among patients with a BMI &#x2265; 23 kg/m&#xb2; who received SERM (HR, 0.84; 95% CI, 0.72-0.98) or AI therapy (HR, 0.78; 95% CI, 0.62-0.99). The strongest association with lower BC-specific mortality was observed in postmenopausal women with luminal B tumors (HR, 0.59; 95% CI, 0.42-0.83). The association between adjuvant endocrine therapy and BC-specific mortality differed according to menopausal status, BMI, and molecular subtype. These findings suggest that menopausal status, BMI, and molecular subtype are important considerations when evaluating endocrine treatment strategies.

Aromatase Inhibitors↗
PubMed2003

Randomized, double-blind, multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients.

BACKGROUND: This randomized, double-blind, phase II study assessed two doses of the selective estrogen receptor modulator arzoxifene in women with advanced breast cancer. The primary end point was to choose the best of two doses of arzoxifene based on the response rate or the clinical benefit rate (CBR). Pharmacokinetics and toxicities were also assessed. PATIENTS AND METHODS: Ninety-two patients with advanced breast cancer received arzoxifene 20 or 50 mg/day. Tumor response was assessed using World Health Organization criteria. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) system. Pharmacokinetic data were analyzed using the NONMEM software program (GloboMax, Hanover, MD, USA). RESULTS: Response rates in the 20 mg arm were numerically higher than the 50-mg arm according to the investigator (40.5% versus 36.4%) and the independent review panel (42.9% versus 27.3%). CBR was higher in the 20 mg arm according to the investigator (64.3% versus 61.4%) and the independent review panel (59.5% versus 47.7%). Arzoxifene was well tolerated. There were no study drug-related deaths. Mean observed steady-state plasma concentrations of arzoxifene were 3.62 and 7.48 ng/ml for the 20 and 50 mg doses, respectively. CONCLUSIONS: There were no significant differences in efficacy or safety between 20 and 50 mg of arzoxifene. Accordingly, arzoxifene 20 mg/day was selected for further study in patients with breast cancer.

Aged↗
PubMedDate not supplied

A one-year follow-up on the effects of raloxifene on thyroid function in postmenopausal women.

OBJECTIVE: Estrogens increase serum thyroxine-binding globulin (TBG) and total thyroxine (TT4) concentrations. Serum free thyroxine (FT4) concentrations, however, remain normal. Raloxifene (RAL) is a selective estrogen receptor modulator used to treat postmenopausal osteoporosis. Data on the long-term effects of RAL on thyroid physiology are scanty. We evaluated the effects of RAL administration for 1 year on thyroid function in osteopenic, postmenopausal women. DESIGN: Fifty osteopenic, postmenopausal women were randomly assigned to receive either RAL (60 mg/day, n = 25) or placebo (PL, n = 25) for 1 year, in a double-blind study. Measurements of serum TBG, TT4, FT4, thyroid-stimulating hormone (TSH), thyroid hormone-binding ratio (THBR), FT4 index (FT4-I) and TT4/TBG ratio were carried out at baseline and after 4 and 12 months of therapy. RESULTS: Baseline values were similar in both treatment groups. Serum TBG concentrations were increased during RAL treatment from baseline values of 29.60 +/- 0.9 microg/mL to 31.45 +/- 1.33 and 32.34 +/- 1.37 microg/mL at 4 months and 1 year, respectively (P < 0.05, baseline v 1-year values) but were unchanged during PL treatment. A small, insignificant increase in TT4 and TSH concentrations occurred in the RAL group and no changes in the PL group. All other values were unchanged during either treatment. CONCLUSIONS: These results demonstrate that RAL significantly increased serum TBG levels, but the changes were small and not accompanied by changes in FT4-I, FT4, or TSH concentrations, suggesting that long-term RAL treatment is unlikely to clinically affect the thyroid status in euthyroid, postmenopausal women.

Double-Blind Method↗
PubMed2000

Effects of the estrogen antagonist EM-652.HCl on energy balance and lipid metabolism in ovariectomized rats.

OBJECTIVE: The estrogen antagonist EM-652.HCl behaves as a highly potent and pure antiestrogen in human breast and uterine cancer cells. Because of its pure antiestrogenic activity in these cells, and because its prodrug, EM-800, reduces bone loss and decreases serum cholesterol and triglycerides in the rat, EM-652.HCl can be classified as a pure selective estrogen receptor modulator (SERM). This study was conducted to assess the ability of EM-652.HCl to prevent obesity and abnormalities of lipid metabolism induced by ovariectomy in a rat model. DESIGN: Female rats were left intact or ovariectomized (OVX), and OVX rats were treated with placebo, estradiol (E2), or EM-652.HCl for 20 days. At the end of the treatment period, parameters of energy balance and determinants of lipid metabolism were assessed. RESULTS: As expected, OVX increased energy intake, which in turn was accompanied by an increased energy, fat and protein gain and higher food efficiency. OVX also increased the triglyceride content of the liver and produced hypercholesterolemia and hyperinsulinemia. The weight of representative white adipose depots was higher in OVX than in intact rats. Lipoprotein lipase activity was higher in white adipose tissues of OVX rats than in those of intact animals, whereas its activity was lower in oxidative tissues (brown adipose and soleus muscle). Replacement therapy with a physiological dose of E2 prevented most of the abnormalities in energy and lipid metabolism brought about by OVX, although its orexigenic effect was only partially corrected. In contrast, treatment of OVX rats with EM-652. HCl completely abolished OVX-induced obesity and its related abnormalities in lipid metabolism and glucose/insulin homeostasis. CONCLUSION: These findings demonstrate that EM-652.HCl can be considered as an effective agent to prevent OVX-induced obesity. The present study also shows that EM-652.HCl reduces cardiovascular risk factors associated with obesity such as hyperlipidemia and insulin resistance.

Animals↗