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PubMed2006

Ovarian steroids enhance object recognition in naturally cycling and ovariectomized, hormone-primed rats.

Learning and memory processes may be influenced by fluctuations in steroid hormones, such as estrogens and progestins. In this study, we have used an animal model to investigate the effects of endogenous fluctuations in ovarian steroids in intact female rats and effects of administration of ovarian steroids to ovariectomized rats for non-spatial, working memory using the object recognition task. Performance in this task relies on cortical and hippocampal function. As such, serum, cortical, and hippocampal concentrations of estradiol (E2), progesterone (P4), and P4's metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), were measured by radioimmunoassay. Experiment 1: Rats in behavioral estrus, compared to those in diestrus or estrus, spent a greater percentage of time exploring a novel object concomitant with increases in serum E2, P4, and 3alpha,5alpha-THP levels. Regression analyses revealed that there was a significant positive relationship between E2 levels in the hippocampus and 3alpha,5alpha-THP levels in the hippocampus and cortex and performance in this task. Experiment 2: Administration of E2 and/or P4 immediately post-training increased the percentage of time spent exploring the novel object and produced levels of E2, P4, and 3alpha,5alpha-THP akin to that of rats in behavioral estrus. Experiment 3: Post-training administration of selective estrogen receptor modulators, including 17beta-E2, propyl pyrazole triol, and diarylpropionitrile increased the percentage of time spent exploring the novel object compared to vehicle-administration. Experiment 4: Post-training P4 or 3alpha,5alpha-THP administration, compared to vehicle, increased the percentage of time spent exploring the novel object and produced P4 and/or 3alpha,5alpha-THP levels within the physiological range typically observed for rats in behavioral estrus. Experiment 5: If post-training administration of E2 and/or P4 was delayed one hour, no enhancement in object recognition was observed. Together, these results suggest that E2 and progestins can have mnemonic effects through actions in the cortex and/or hippocampus.

Analysis of Variance↗

PubMed2005

The color appearance of stimuli detected via short-wavelength-sensitive cones for breast cancer survivors using tamoxifen.

This study compared color appearance data for two populations of middle-aged women: (1) women using the selective estrogen receptor modulator tamoxifen as adjuvant therapy following successful treatment for early-stage breast cancer, and (2) healthy amenorrheic (peri- or post-menopausal) control subjects not using any hormonally acting medications. A 3-alternative forced-response paradigm (with "blue", "lavender", or "white" as the allowable responses) was used for assessing the perceived color of 440-nm foveal test stimuli superimposed on a larger 3.6 log td 580-nm background. In contrast to the control subjects, the majority of tamoxifen users described the test stimuli as "white", whether at threshold or slightly suprathreshold. Threshold-sensitivity measurements themselves appeared less effective for distinguishing between subject groups. The results show that a simple color-naming procedure can reveal alterations of foveal short-wavelength-sensitive cone-mediated visual function that are common among tamoxifen users.

Adult↗

PubMed2003

Acute effects of toremifene on the vasculature of intact and menopause-induced rats.

Clinical studies have shown that cardiovascular performance in postmenopausal women could be modified by treatment with selective estrogen receptor modulators (SERM). However, the mechanisms by which these drugs act on the cardiovascular system have not been elucidated. This work evaluates the effect of toremifene, a new member of the SERM family, on the vasculature of intact and ovariectomized adult Sprague-Dawley rats. The responsiveness of rings from the thoracic aorta to norepinephrine, potassium chloride, acetylcholine and sodium nitroprusside was assessed before and after 15 min of incubation with 1.0-microM toremifene. Toremifene displaced the concentration-response curve for norepinephrine-induced contractions to the right in both groups of animals. Moreover, the EC(50) values for the curves increased from 154+/-31 to 754+/-162 nM (P<.05) in intact rats and from 88+/-11 to 230+/-71 nM (P<.05) in ovariectomized rats. Toremifene also reduced contractile responses to potassium chloride (10-120 mM), displacing the entire curve to the right in both groups of animals without modifying the EC(50) values. The drug shifted the concentration-response curve for the acetylcholine-induced relaxation to the left and significantly increased E(max) values (18% for ovariectomized rats vs. 16% for controls) without affecting EC(50) values in either group tested. In addition, toremifene potentiated the relaxing responses to physiological doses (0.1-1.0 nM) of sodium nitroprusside in both groups, suggesting a direct effect at the level of the vascular smooth muscle. Acute toremifene incubation increased basal relaxation in aortic rings from both intact and ovariectomized rats. These results suggest that toremifene, by improving the functional status of the endothelium-smooth muscle unit, may have a beneficial effect on the cardiovascular status of menopause-induced rats.

Acetylcholine↗

PubMed2003

Chronic effects of toremifene on the vasculature of menopause-induced rats.

During menopause, women have a higher propensity for developing cardiovascular diseases. Recent studies have shown that treatment with selective estrogen receptor modulators (SERMs) improves cardiovascular status in menopausal women. The mechanisms involved, however, have not been elucidated. The present study evaluates the effect of toremifene (10 mg/kg/day), a new member of SERM family, on the vasculature of ovariectomized (Ovx) Sprague-Dawley rats that have been treated with the drug for a 4-week period. Age-matched sham, Ovx-untreated, and Ovx 17beta-estradiol-treated rats were used as controls. Aortic rings from treated and untreated animals were used to determine vascular responses to norepinephrine, acetylcholine, and sodium nitroprusside. Systolic blood pressure (SBP), plasmatic nitric oxide (NO) concentration, estrogen levels, aortic wall thickness, and cholesterol profiles were also determined. Toremifene displaces the concentration-response curve (CRC) for the acetylcholine-induced relaxation to the left and increases the Emax by 34% (from 59.2 +/- 4.2% in Ovx-untreated to 90.2 +/- 3.1% in Ovx-treated rats, n = 9, P < .05). Toremifene increases the Emax (by 22%) without modifying the EC5o for the NE-induced contraction. In addition, toremifene amplifies the relaxing responses to sodium nitroprusside compared to Ovx-untreated group (P < .05). SBP was significantly reduced in the Ovx toremifene-treated group when compared to the Ovx-untreated group (124 +/- 3.5 mm Hg for Ovx toremifene-treated vs. 161 +/- 4.3 mm Hg for Ovx-untreated, n = 10, P < .05). Rats treated chronically with toremifene also exhibited a significantly higher plasmatic NO levels, and a decrease in basal resting tension and aortic wall thickness. The drug, however, did not affect the plasmatic high-density lipoprotein (HDL)/total cholesterol ratio. These results suggest that chronic administration of toremifene improves cardiovascular performance in menopause-induced rats by reversing endothelial dysfunction and decreasing vascular resting tone. Thus, use of toremifene may help to diminish total peripheral resistance and improve cardiovascular status in Ovx rats.

Animals↗

PubMed2004

A soy supplement and tamoxifen inhibit sexual behavior in female rats.

In addition to displaying proceptive (hopping and darting) and receptive (lordosis) behaviors during a sexual encounter with a male, female rodents will regulate the timing of the encounter by engaging in a series of approaches and withdrawals from the male, a behavior termed paced mating behavior. Proceptive, receptive, and paced mating behaviors are all regulated by, and sensitive to, estrogen and progesterone, suggesting that compounds capable of disrupting these critical hormones may also perturb the display of female sexual behavior. The present experiments examined the impact of the selective estrogen receptor modulator (SERM) tamoxifen and a popular soy phytoestrogen dietary supplement on female sexual behavior in rats. Ovariectomized female rats were given either tamoxifen (TAMOX) by implant or the soy supplement through the diet then injected with estradiol benzoate (EB, 10 microg) or oil followed 48 h later with an injection of progesterone (P, 500 microg). Animals were then tested for sexual behavior 4 h after the P injection. Neither compound had any effect on sexual behavior when administered in conjunction with P alone; however, both significantly diminished receptive behavior, as measured by the lordosis quotient (LQ), in animals primed with both EB and P. Similarly, the hopping and darting rate was also significantly depressed in both the soy- and TAMOX-treated animals, compared to the EB- and P-treated controls, with the soy-treated animals showing significantly less proceptive behavior than the TAMOX-treated animals. Finally, soy but not TAMOX significantly attenuated paced mating behavior in animals compared to the EB- and P-treated controls. These results demonstrate that both the soy supplement and TAMOX act as estrogen antagonists on both proceptive and receptive behavior in female rats.

Analysis of Variance↗

PubMed2004

Estrogen and regulation of heat shock protein expression in female cardiomyocytes: cross-talk with NF kappa B signaling.

UNLABELLED: Estrogen is associated with increased heat shock protein (HSP)72 and protection during hypoxia-reoxygenation in cardiomyocytes from adult male rats, as previously reported. We have also reported that female rats have more cardiac HSP72 than males. We hypothesized that, despite higher endogenous estrogen levels and higher baseline HSP72, 17 beta-estradiol treatment would still result in increased HSP72 and protection during hypoxia-reoxygenation in cardiomyocytes from females. METHODS/RESULTS: Cardiac cells isolated from adult female rats were treated for 12 hr with 17 beta-estradiol (0.1, 10, or 50 microM), tamoxifen, (10 or 25 microM; estrogen receptor agonist/antagonist), geldanamycin (2, 5, or 10 microg/ml; inactivates HSP90, preventing interaction with HSF1), or vehicle. Western blot analyses revealed that treatment with 17 beta-estradiol (10 or 50 microM), tamoxifen (25 microM), and geldanamycin (all doses) resulted in significant increases in HSP72. Electromobility shift assays revealed activation of HSF1 by 2 to 3 hr, and NF kappa B activation by 15 min. HSP72 induction via HSF1 activation was confirmed using transcription factor decoys containing the heat shock element, which prevented the estrogen-related HSP72 induction. Estrogen pretreatment resulted in decreased LDH release during 24 hr hypoxia. This protective effect persisted despite decoy-mediated blockade of nuclear HSF1 binding. However, transfection with an NF?B decoy not only prevented an estrogen-associated increase in HSP72, but also abolished the estrogen-related protection during hypoxia. CONCLUSIONS: Despite higher endogenous estrogen, 17 beta-estradiol and the selective estrogen receptor modulator, tamoxifen, upregulate HSP72 in cardiomyocytes from adult females, and provide cytoprotection during hypoxia, independent of HSP induction. NF kappa B activation is necessary for the increase in HSP72, suggesting that estrogen treatment activates NF kappa B, with subsequent HSF1 activation. NF kappa B activation is critical for estrogen-associated HSP induction, and protection during hypoxia in female cardiocytes. Treatment with 17 beta-estradiol and tamoxifen may provide a novel means of protecting both male and female cardiac myocytes against hypoxia-induced damage. Further studies are needed to define the cross-talk between HSF1 and NF kappa B signaling pathways.

Animals↗

PubMed1997

Effects of raloxifene hydrochloride on the endometrium of postmenopausal women.

OBJECTIVE: We evaluated subtle endometrial morphologic changes in postmenopausal women assigned to placebo, raloxifene hydrochloride 200 or 600 mg/day, or conjugated estrogens (Premarin 0.625 mg/day) according to a new estrogenicity scoring system. Raloxifene, a new selective estrogen receptor modulator, was not expected to stimulate the endometrium. STUDY DESIGN: Baseline and end point endometrial biopsies were performed during this double-blind, placebo-controlled 8-week study. A scoring system that was based on standard glandular and stromal morphologic criteria was used to quantitate estrogen-induced effects. Baseline, end point, and baseline-to-end point changes were analyzed for treatment differences. RESULTS: Treatment groups were similar at baseline with most women showing no estrogenic effects. At end point, statistically significant moderate and marked estrogenic effects were noted in 77% of estrogen-treated women versus 15% of placebo-treated women versus 0% of raloxifene-treated women. CONCLUSIONS: As expected, estrogen treatment stimulated postmenopausal endometrium. In contrast, raloxifene did not induce histopathologic evidence of endometrial stimulation in healthy postmenopausal women.

Biopsy↗

PubMed1998

Effects of LY-117018 HCl on bone remodeling and mineral density in the oophorectomized rat.

OBJECTIVE: LY-117018 HCl is a recently developed, selective estrogen receptor modulator and an analog of raloxifene. Its mode of action on the skeleton is similar to that of estrogens, although it does not have the same side effects. The aim of the current study was to compare the effects produced by the administration of 17alpha-ethinyl estradiol (0.1 mg/kg/day) and LY-117018 HCl (1 mg/kg/day) on bone remodeling, bone mineral density, and body and uterus weight in sham-operated and oophorectomized rats (experimental model of postmenopausal osteoporosis). STUDY DESIGN: Twelve-week-old female Wistar rats were used. Treatment was given for 3 months after oophorectomy or sham operation. Bone mineral density was determined in the lumbar spine (L2, L3, and L4) and in the left femur with use of a Hologic QDR 1000 (S/N 277) densitometer. Bone remodeling was estimated with use of the formation markers osteocalcin (bone gla protein) and alkaline phosphatase and the resorption markers type I collagen carboxyterminal telopeptide and tartrate-resistant acid phosphatase. RESULTS AND CONCLUSIONS: The newly developed derivative of raloxifene, LY-117018 HCl, offsets the reduction in bone mineral density and the accompanying increase in bone remodeling markers observed in oophorectomized rats compared with control animals. 17Alpha-ethinyl estradiol also prevents the loss of bone mass attributed to oophorectomy, but this is accompanied by an increase in body mass and a greater increase in uterus weight than that observed after treatment with LY-117018 HCl.

Acid Phosphatase↗

PubMed2003

Molecular assay to generate expression profile of eight estrogen receptor alpha isoform mRNA copy numbers in picogram amounts of total RNA from breast cancer tissues.

The presence of estrogen receptor alpha (ERalpha) is the basis for treating breast cancer patients with targeted molecular therapies that block estrogen stimulation of breast cancer cell division. Currently, the ERalpha presence is determined by microscopically scoring the slides subjected to immunohistochemistry. This method is not quantitative, cannot distinguish between all the known ERalpha isoforms, and requires large amounts of tumor tissue. We describe here a real-time PCR-based molecular approach that can be applied to determine mRNA copies of eight ERalpha isoforms in picogram amounts of total RNA from clinical samples. Each isoform mRNA is quantified using a specific primer pair and a 5'FAM- and 3'TAMARA-labeled probe in comparison with a standard curve constructed with known copy numbers of its respective reverse-transcribed cRNA. Seven alternatively spliced isoforms were quantified using splice-targeted primers. The cRNAs for eight isoforms were generated by in vitro transcription of their respective coding sequences. The sensitivity of detection with reverse-transcribed cRNAs is as low as 100 copies. The devised assays can detect ERalpha cDNAs reverse transcribed from as low as 50-100 pg of total RNA from breast cancer tissues. The applicability of the devised assays for profiling eight ERalpha isoform mRNAs is demonstrated using 6 breast cancer cell lines and 10 breast cancer tissues. It is expected that these assays could be applied to profile ERalpha isoforms in any estrogen-responsive tissues. In addition, these methods could highly facilitate the design of tissue-specific selective estrogen receptor modulators to treat breast cancers and other estrogen-related abnormalities.

Alternative Splicing↗

PubMed2001

Transcriptional activities of estrogen receptor alpha and beta in yeast properties of raloxifene.

Raloxifene represents a potent compound for the prevention and treatment of osteoporosis and cardiovascular disease in postmenopausal women. Raloxifene exhibits targeted antiestrogenicity in breast and uterus, but acts as an agonist in bone and liver. This synthetic selective estrogen receptor modulator binds both estrogen receptors alpha and beta. The molecular mechanisms by which raloxifene exerts agonistic or antagonistic activity are still not resolved. Therefore, the binding behavior of raloxifene to estrogen receptors and its effects on DNA binding and transactivation were studied. The equilibrium binding affinity of raloxifene by displacing radiolabeled 17beta-estradiol exhibited a similar affinity behavior to that of its natural ligand. Using BIACORE technology with an immobilized estrogen response element, we showed that 17beta-estradiol and raloxifene increased the binding of estrogen receptor alpha to the DNA, suggesting a ligand-dependent dimerization. The influence of the ligands to the binding of estrogen receptor beta was lower. We may conclude that unliganded estrogen receptor alpha binds as a monomer whereas in the presence of 10(-8) M 17beta-estradiol or higher, homodimers are formed that interact with the estrogen response element. Transactivation studies in a yeast reporter system in a ligand-dependent manner resulted in a similar potency of raloxifene to estrogen receptor beta compared to the control testosterone. Subeffective doses of raloxifene combined with 17beta-estradiol did not shift the efficiency, whereas saturating concentrations of 17beta-estradiol combined with increasing concentrations of raloxifene altered the response induced by 17beta-estradiol. In this pure system, the antagonistic activity of raloxifene could not be detected as was expected by the results from ligand competition analysis.

Estrogen Antagonists↗

PubMed2002

Estrogen blocks 3-nitropropionic acid-induced Ca2+i increase and cell damage in cultured rat cerebral endothelial cells.

Systemic administration of 3-nitropropionic acid (3-NPA, a mycotoxin) induces brain damage accompanied by disturbance in the blood-brain barrier (BBB). Since the endothelial cells are important components of the BBB and the first target of a systemic intoxication, in the present study, the effect of 3-NPA on primary cultured rat brain endothelial cells (rBECs) was examined by studying intracellular Ca(2+) ([Ca(2+)](i)) response using imaging techniques with fura-2. rBECs were prepared using a method of Kis et al. [Eur. J. Pharmacol. 368 (1999) 35-42] and Szabo et al. [Neurobiology 5 (1997) 1-16]. Almost all cells were immunoreactive to antibody against the factor VIII-related antigen (von-Willebrand factor). They showed a typical dose-dependent increase of [Ca(2+)](i) in response to ATP or bradykinin. Low concentrations of 3-NPA (1.7 mM, 3.4 mM) caused no changes, and a medium concentration (6.8 mM) increased the [Ca(2+)](i) gradually and progressively, and the increase was reversed incompletely back to the resting level after washing. A high concentration (13.6 mM) increased the [Ca(2+)](i) irreversibly. These elevations of [Ca(2+)](i) were absent in a Ca(2+)-free medium. In endothelial cells treated with 17beta-estradiol (above 10(-5) M) or with a selective estrogen receptor modulator, tamoxifen (5 x 10(-7) M), no elevation of [Ca(2+)](i) was observed with 3-NPA treatment. The response to ATP was impaired after application of 3-NPA, but it was preserved by cotreatment with 17beta-estradiol or tamoxifen. An estrogen receptor antagonist ICI 182,780 inhibited these effects by 17beta-estradiol or tamoxifen. Lysosomal neutral red uptake and TUNEL experiments revealed the necrotic but not apoptotic cell death at least in this acute stage. Data indicate that a medium to high concentration of 3-NPA induces damage on rBECs as revealed by an accumulation of [Ca(2+)](i), but the damage was protected by cotreatment with 17beta-estradiol or tamoxifen, suggesting that estrogen may be protective for the brain vascular damage via estrogen receptor.

Adenosine Triphosphate↗

PubMed2003

Immediate and residual effects of tamoxifen and ethynylestradiol in the female rat hypothalamus.

Very little is known about the impact of selective estrogen receptor modulators (SERMs) on the brain. We examined the effects of tamoxifen (TAMOX) and the synthetic estrogen 17alpha-ethynylestradiol (EE) on estrogen-dependent gene expression and receptor binding in the female rat brain. Both immediate and residual effects were examined in both the presence and absence of 17beta-estradiol. Two groups of adult, ovariectomized, female rats (n=30 per group) were injected with TAMOX (5 mg/kg), EE (0.1 mg/kg), or sesame oil daily for 14 days. Animals from the first group were implanted with blank or 17beta-estradiol Silastic capsules concurrently with the last three SERM injections (immediate, group 1). Animals from the second group received either blank or 17beta-estradiol implants 2 weeks after the last injection (residual, group 2). All animals were sacrificed 72 h after implantation. TAMOX increased uterine weight in the absence of estrogen, but inhibited uterine weight gain in the presence of estrogen in both groups 1 and 2. TAMOX and EE increased oxytocin receptor binding in the ventromedial nucleus of the hypothalamus (VMN) in the absence of estrogen in both groups 1 and 2. The estrogen-dependent induction of PR mRNA expression in the VMN was significantly attenuated by TAMOX in group 1. Finally, TAMOX and EE had opposite effects on ERbeta mRNA expression in the paraventricular nucleus in the absence of 17beta-estradiol in group 1. Neither had any effect in group 2 when 17beta-estradiol was present. These results suggest that TAMOX has mixed agonist/antagonist effects in the female rat brain, many of which persist at least 2 weeks after the administration ceases.

Animals↗

PubMed2002

Evaluation of interaction potential of certain concurrently administered drugs with pharmacological and pharmacokinetic profile of centchroman in rats.

Centchroman (Ormeloxifene) is a nonsteroidal, selective estrogen receptor modulator, oral contraceptive and anticancer agent, and is intended for long-term use by women. In view of its vast clinical application and the interaction of steroidal oral contraceptives with certain commonly used therapeutic agents, evaluation of interaction of certain concomitantly administered therapeutic agents (ibuprofen, rifampicin, diazepam, salbutamol, nifedipine, paracetamol, haloperidol, and tetracycline), in terms of both the postcoital contraceptive efficacy and pharmacokinetic profile, with centchroman was undertaken in female Sprague-Dawley rats. Among the representatives from each commonly used therapeutic category, interaction (pharmacokinetic) was observed with ibuprofen (60 mg/kg, twice daily), haloperidol (0.7 mg/kg, twice daily), and tetracycline (140 mg/kg, twice daily) coadministration on Days 1 through 5 postcoitum. Of these three therapeutic agents, only tetracycline interfered with the contraceptive efficacy of centchroman. It reduced the bioavailability of centchroman and its active metabolite by increasing their excretion through bile and feces. Increased metabolite excretion on tetracycline coadministration indicates the enterohepatic recirculation of the metabolite, not the parent drug. However, the effect of tetracycline was negated by the inclusion of lactic acid bacillus spores in the regimen.

Animals↗

PubMed1998

A medical method of early pregnancy termination using tamoxifen and misoprostol.

A study was undertaken to determine whether ingestion of the selective estrogen receptor modulator tamoxifen followed by vaginal administration of the prostaglandin misoprostol would be an effective medical method of elective termination of early pregnancy. A clinical trial was conducted with a study group of 100 healthy women with pregnancies of 56 days gestational age or less who desired elective pregnancy termination. Each subject ingested 20 mg of tamoxifen once daily for 4 days followed 4 days later by intravaginal placement of four 200 micrograms tablets of misoprostol. If abortion did not occur within the next 24 h a second dose of 800 micrograms of misoprostol was given. The main outcome measures were incidence of complete abortion, hemoglobin levels, duration of vaginal bleeding, and incidence of side effects. Complete abortion occurred in 92 (92%, 95% CI 86.7, 97.3%) of 100 subjects. Of these 92 women, four aborted after ingesting tamoxifen without use of misoprostol, 84 within 24 h after receiving a single dose of misoprostol, one 21 days following a single dose of misoprostol, and three after a second dose of misoprostol was administered. There were six (6.0%) complete treatment failures and two (2%) incomplete abortions that required a dilatation and curettage. The mean duration of uterine bleeding was 8.1 days (range 1-34 days) and there was a median decrease in hemoglobin level of 0.50 g/dL (+2.2 to -4.7 g/dL). Vomiting occurred in 28% of subjects and diarrhea in 8%. These initial data suggest that ingestion of tamoxifen followed by intravaginal misoprostol may be an effective, easily administered, and inexpensive method to electively induce complete abortion in pregnancies of 56 days gestational age or less. Additional studies are necessary to determine whether the addition of tamoxifen increases the success rate compared with that obtained with the use of vaginally administered misoprostol by itself.

Abortifacient Agents, Nonsteroidal↗

PubMed2003

Effects of raloxifene on carotid blood flow resistance and endothelium-dependent vasodilation in postmenopausal women.

Raloxifene is one of the most important selective estrogen receptor modulators currently employed for the treatment of postmenopausal osteoporosis. However, it has also been suggested that this compound affects the vascular system. We evaluated both carotid blood flow resistance and endothelium-dependent vasodilation in 50 healthy postmenopausal women randomly assigned to receive, in a double blind design, either raloxifene (60 mg per day; N=25 subjects) or placebo (N=25 subjects) for 4 months. Indices of carotid blood flow resistance, such as the pulsatility index (PI) and resistance index (RI), as well as the flow-mediated brachial artery dilation were measured both at baseline and at the end of treatment. Changes in PI were -1.86+/-2.24 and -2.15+/-2.22% after placebo and raloxifene treatment, respectively, with no significant differences between groups. Changes in RI were -0.77+/-1.72 and -1.81+/-1.54% after placebo and raloxifene treatment, respectively, with no significant differences between groups. At the end of the treatment period, the increments in artery diameter measured after the flow stimulus were 10.79+/-2.39 and 6.70+/-1.23% for placebo and raloxifene, respectively, with no significant differences between groups. These results demonstrate no significant effects of raloxifene on either carotid blood flow resistance or brachial artery flow-mediated dilation in postmenopausal women.

Aged↗

PubMed2003

Uncoupling of 5-HT1A receptors in the brain by estrogens: regional variations in antagonism by ICI 182,780.

Previously we have shown that 17beta-estradiol (in vivo and in vitro) rapidly decreases the function of serotonin(1A) (5-HT(1A)) receptors, allowing us to hypothesize that 17beta-estradiol accomplished this via activation of a membrane estrogen receptor. Hippocampus and frontal cortex obtained from ovariectomized rats were incubated with 17beta-estradiol or bovine serum albumin (BSA)-estradiol in the presence or absence of the estrogen receptor (ER) antagonist ICI 182,780. Membranes were prepared to measure R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding (a measure of 5-HT(1A) receptor coupling and function). In both hippocampus and frontal cortex, 17beta-estradiol and BSA-estradiol (50 nM) decreased R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. ICI 182,780 blocked the effect of both the estrogens in hippocampus, but only the effect of 17beta-estradiol in frontal cortex. Due to the inability of ICI 182,780 to block the effects of BSA-estradiol in frontal cortex, similar experiments were performed using the selective estrogen receptor modulator tamoxifen as the agonist. Tamoxifen (100 nM and 1 microM) decreased R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. ICI 182,780 (1 microM) blocked the ability of tamoxifen to decrease 5-HT(1A) receptor coupling in the hippocampus, but not in the frontal cortex. Taken together, these data support the existence of a pharmacologically distinct ER in hippocampus vs. frontal cortex that might be responsible for rapid uncoupling of 5-HT(1A) receptors.

Animals↗

PubMed2002

17beta-Estradiol and the phytoestrogen genistein attenuate neuronal apoptosis induced by the endoplasmic reticulum calcium-ATPase inhibitor thapsigargin.

Estrogenic compounds have been shown to protect neurons from a variety of toxic stimuli in vitro and in vivo and depletion of estrogen at menopause has been associated with increased risk of neurodegenerative diseases. Genistein is an isoflavone soy derivative that binds to estrogen receptors with selective estrogen receptor modulator (SERM) properties. Recent FDA recommendations of soy intake for cholesterol reduction have prompted investigation into the potentially estrogenic role of dietary soy phytochemicals in the brain. In this study, we have shown that 50nM genistein significantly reduces neuronal apoptosis in an estrogen receptor-dependent manner. The importance of apoptosis in the brain has been recognized with regard to organization of the developing brain as well as degeneration in response to disease or stroke; however, the effects of estrogenic compounds on neuronal apoptosis have not been thoroughly examined. We developed a model of apoptotic toxicity in primary cortical neurons by using the endoplasmic reticulum (ER) calcium-ATPase inhibitor, thapsigargin, to test potential anti-apoptotic effects of 17beta-estradiol and genistein. Estrogen receptor beta, but not estrogen receptor alpha, was detected in our primary neuron cultures. Thapsigargin-induced apoptosis was confirmed by loss of mitochondrial function, DNA laddering, nuclear condensation and fragmentation, and caspase activation. Both 17beta-estradiol and genistein reduced the number of apoptotic neurons and reduced the number of neurons containing active caspase-3. This effect was blocked by co-addition of ICI 182780. Our results demonstrate that genistein and 17beta-estradiol have comparable anti-apoptotic properties in primary cortical neurons and that these properties are mediated through estrogen receptors.

Animals↗

PubMed2002

Bone growth stimulators. New tools for treating bone loss and mending fractures.

In the new millennium, humans will be traveling to Mars and eventually beyond with skeletons that respond to microgravity by self-destructing. Meanwhile in Earth's aging populations growing numbers of men and many more women are suffering from crippling bone loss. During the first decade after menopause all women suffer an accelerating loss of bone, which in some of them is severe enough to result in "spontaneous" crushing of vertebrae and fracturing of hips by ordinary body movements. This is osteoporosis, which all too often requires prolonged and expensive care, the physical and mental stress of which may even kill the patient. Osteoporosis in postmenopausal women is caused by the loss of estrogen. The slower development of osteoporosis in aging men is also due at least in part to a loss of the estrogen made in ever smaller amounts in bone cells from the declining level of circulating testosterone and is needed for bone maintenance as it is in women. The loss of estrogen increases the generation, longevity, and activity of bone-resorbing osteoclasts. The destructive osteoclast surge can be blocked by estrogens and selective estrogen receptor modulators (SERMs) as well as antiosteoclast agents such as bisphosphonates and calcitonin. But these agents stimulate only a limited amount of bone growth as the unaffected osteoblasts fill in the holes that were dug by the now suppressed osteoclasts. They do not stimulate osteoblasts to make bone--they are antiresorptives not bone anabolic agents. (However, certain estrogen analogs and bisphosphates may stimulate bone growth to some extent by lengthening osteoblast working lives.) To grow new bone and restore bone strength lost in space and on Earth we must know what controls bone growth and destruction. Here we discuss the newest bone controllers and how they might operate. These include leptin from adipocytes and osteoblasts and the statins that are widely used to reduce blood cholesterol and cardiovascular damage. But the main focus of this article is necessarily the currently most promising of the anabolic agents, the potent parathyroid hormone (PTH) and certain of its 31- to 38-aminoacid fragments, which are either in or about to be in clinical trial or in the case of Lilly's Forteo [hPTH-(1-34)] tentatively approved by the Food and Drug Administration for treating osteoporosis and mending fractures.

Animals↗