Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Estrogen Receptor Modulators”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,171 records · Page 65Linked to original sources
PubMed2006

The environmental estrogen, 4-nonylphenol modulates brain estrogen-receptor- and aromatase (CYP19) isoforms gene expression patterns in Atlantic salmon (Salmo salar).

The modulations of reproductive biomarker responses, such as vitellogenin (Vtg) and zona radiata protein (Zr-protein) by xenoestrogens are mediated through the estrogen receptors (ERs). The ERalpha and ERbeta belong to the nuclear receptor (NR) superfamily of ligand activated transcription factors that modulate specific gene expression. By interacting with estrogen and estrogen like molecules (including estrogen mimics), the ERs exert a diverse array of biological effects. In addition to their effect as direct agonist to the ERs, the endocrine-disrupting effects of environmental chemicals are sometimes interpreted as interference with steroidogenesis through the aromatase enzyme (CYP19 or P450arom). The aim of this study was to investigate the effects of nonylphenol on the expression patterns of ER and aromatase (P450arom) isoform genes in the brain as sensitive molecular biomarker of response to endocrine disrupting chemicals. Immature Atlantic salmon were exposed to continuous nominal waterborne nonylphenol at 15 microg/L. Brain samples were collected after 7 days exposure. A quantitative RT-PCR method was used to analyze mRNA expression patterns. Nonylphenol caused a significant induction of P450arom and ER isoform patterns in the brain and represent quantitative gene expression biomarkers of exposure to endocrine disrupting chemicals in the environment.

Animals↗
PubMed2004

17-Beta estradiol enhances prostaglandin E2 production in human U937-derived macrophages.

Prostaglandins (PGs) are potent eicosanoid lipid mediators that have been implicated in numerous homeostatic functions and inflammation. Estrogens have been shown to regulate the expression of genes in lipid metabolism in many cellular systems. In this study, the activation of macrophages and the modulation of PG release by estrogens were examined. The effects of 17-alpha and 17-beta estradiols, phytoestrogen Genistein and several selective estrogen receptor modulators on the release of PGE2 were investigated in human U937-derived macrophages. 17-Beta estradiol caused an enhancement of PGE2 production in a time- and dose-dependent manner. Treatment of macrophages with 17-beta estradiol elicited an increased arachidonic acid (AA) release and an up-regulation of both cyclooxygenesis-1 and cyclooxygenesis-2 enzymes at both the transcript and protein levels. In addition, immunostaining of nuclear estrogen receptor alpha and the observation of ICI182 780 blockade of PGE2 production indicated that 17-beta estradiol-induced PGE2 release was mainly through nuclear estrogen receptor alpha.

Arachidonic Acid↗
PubMed2005

Deficiencies in estrogen-mediated regulation of cerebrovascular homeostasis may contribute to an increased risk of cerebral aneurysm pathogenesis and rupture in menopausal and postmenopausal women.

Despite the catastrophic consequence of ruptured intracranial aneurysms, very little is understood regarding their pathogenesis, and there are no reliable predictive markers for identifying at-risk individuals. Few studies have addressed the molecular pathological basis and mechanisms of intracranial aneurysm formation, growth, and rupture. The pathogenesis and rupture of cerebral aneurysms have been associated with inflammatory processes, and these have been implicated in the digestion and breakdown of vascular wall matrix. Epidemiological data indicate that the risk of cerebral aneurysm pathogenesis and rupture in women rises during and after menopause as compared to premenopausal women, and has been attributed to hormonal factors. Moreover, experimental evidence supports a role for estrogen in the modulation of each phase of the inflammatory response implicated in cerebral aneurysm pathogenesis and rupture. While the risk of aneurysm rupture in men also increases with age, this increased risk has been attributed to other recognized risk factors including cigarette smoking, use of alcohol, and history of hypertension, all of which are more common in men than women. We hypothesize, therefore, that decreases in both circulating estrogen levels and cerebrovascular estrogen receptor density may contribute to an increased risk of cerebral aneurysm pathogenesis and rupture in women during and after menopause. To test our hypothesis, experiments are needed to identify genes regulated by estrogen and to evaluate gene expression and intracellular mechanisms in cells/tissues exposed to varying concentrations and duration of treatment with estrogen, metabolites of estrogen, and selective estrogen receptor modulators (SERMs). Furthermore, it is not likely that the regulation of cerebrovascular homeostasis is due to the actions of estrogen alone, but rather the interplay of estrogen and other hormones and their associated receptor expression. The potential interactions of these hormones in the maintenance of normal cerebrovascular tone need to be elucidated. Additional studies are needed to define the role that estrogen and other sex hormones may play in the cerebrovascular circulation and the pathogenesis and rupture of cerebral aneurysms. Efforts directed at understanding the basic pathophysiological mechanisms of aneurysm pathogenesis and rupture promise to yield dividends that may have important therapeutic and clinical implications. The development of non-invasive tools such as molecular MRI for the detection of specific cells, molecular markers, and tissues may facilitate early diagnosis of initial pathophysiological changes that are undetectable by clinical examination or other diagnostic tools, and can also be used to evaluate the state of activity of cerebral aneurysm pathogenesis before, during, and after treatment.

Brain↗
PubMed1987

Two high-affinity ligand binding states of uterine estrogen receptor distinguished by modulation of hydrophobic environment.

The steroid binding function of soluble (cytosolic) estrogen receptors from calf uteri was evaluated under conditions known to modify the extent of hydrophobic interaction with receptor-associated proteins. Receptor preparations were equilibrated into 6 M urea (+/- 0.4 M KCl) buffers and control buffers (+/- 0.4 M KCl) by chromatography through small columns of Sephadex G-25 or by dialysis at 0-6 degrees C. Equilibrium dissociation constants (Kd) and binding capacities (n) of experimental and control receptor preparations were determined by 13-point Scatchard analyses using concentrations of 17 beta-[3H]estradiol from 0.05 to 10 nM. Nonspecific binding was determined at each concentration by parallel incubations with a 200-fold molar excess of the receptor-specific competitor diethylstilbestrol. The control receptor population was consistently found to be a single class of binding sites with a high affinity for estradiol (Kd = 0.36 +/- 0.09 nM, n = 14) which was unaffected by G-25 chromatography, by dialysis, by dilution, or by the presence of 0.4 M KCl. However, equilibration into 6 M urea induced a discrete (10-fold) reduction in receptor affinity (Kd = 3.45 +/- 0.86 nM, n = 6) to reveal a second, thermodynamically stable, high-affinity binding state. The presence of 0.4 M KCl did not significantly influence the discrete change in receptor affinity induced by urea. However, KCl did help prevent the reduction in binding capacity induced by urea. The effects of urea on both receptor affinity and binding capacity were reversible, suggesting a lack of covalent modification.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Treatment of menopause-related mood disturbances.

More than 1.7 million American women are expected to reach menopause each year. Recent Canadian statistics show that a 50-year-old woman can now expect to live until her mid-80s, which implies living at least one-third of her life after menopause. The menopausal transition is typically marked by intense hormonal fluctuations, accompanied by vasomotor symptoms (eg, hot flashes, night sweats), sleeps disturbance, and changes in sexual function, as well as increased risk for osteoporosis, cardiovascular disease, and cognitive decline. More importantly, recent studies have demonstrated a significant association between menopausal transition and a higher risk for developing depression. In the post-Women's Health Initiative Study era, physicians and patients are questioning the safety and efficacy of long-term hormone therapy use. This article reviews the current literature on the benefits and risks of using hormone therapy for the treatment of menopause-related mood disturbances and alternate strategies currently available for the management of menopause-related problems, including antidepressants, complementary and alternative medicine, and selective estrogen receptor modulators.

Estrogen Replacement Therapy↗
PubMed2000

Characterization of androgen receptors in a well-differentiated endometrial adenocarcinoma cell line (Ishikawa).

Androgen receptors (AR) have been identified in the human endometrium, but their role in endometrial function and development towards endometrial receptivity remains poorly understood. In an effort to study the regulation and possible function in endometrial epithelium, we utilized the well-differentiated endometrial adenocarcinoma cell line, Ishikawa, as a model system. This cell line has proven to be stable, hormonally responsive, contains both estrogen and progesterone receptors, and has been shown to express endometrial proteins in a hormone responsive manner. In the present study, we demonstrate that Ishikawa cells also express AR, based on immunohistochemical staining, radioactive binding studies, RT-PCR and Northern blot analysis. The expression of AR is induced in Ishikawa cells by estrogens, similar to that reported for normal endometrium. Further, using an estrogen-responsive gene that has been characterized in this cell line, alkaline phosphatase, we show that androgens act as antiestrogens in diethylstilbestrol (DES) treated cells, inhibiting enzymatic activity in a dose-dependent manner. These data support a physiologic role for AR in the endometrium. Elevations in endometrial AR in certain clinical situations such as polycystic ovarian syndrome (PCOS) may amplify the effects of androgens on the endometrium leading to suspected defects in uterine receptivity, higher than expected infertility and high miscarriage rates observed in patients with this disorder.

Adenocarcinoma↗
PubMed2005

Effects of resveratrol, raloxifene, tibolone and conjugated equine estrogen on vaginal squamous cell maturation of ovariectomized rats.

OBJECTIVE: The effects of estrogen replacement therapy, selective estrogen receptor modulators, or tibolone on vaginal squamous cell maturation in postmenopausal women are not well established. Resveratrol (3,5,4'-trans-trihydroxystilbene) has been shown to bind the estrogen receptor in rat uteri. The aim of this study was to cytologically evaluate vaginal smears from ovariectomized rats treated with resveratrol, raloxifene, tibolone and conjugated equine estrogen, and to compare each drug with regard to vaginal epithelial maturation. MATERIAL AND METHODS: Forty-two bilaterally ovariectomized Wistar albino rats were equally randomized into 6 groups: (1) control sham-operated rats; (2) ovariectomized rats administered 0.1% ethanol; (3) ovariectomized rats administered resveratrol at a dose of 5 mg/kg/day p.o.; (4) ovariectomized rats administered conjugated equine estrogen (CEE) at a dose of 0.1 mg/kg/day p.o.; (5) ovariectomized rats administered tibolone at a dose of 0.25 mg/kg/day p.o., and (6) ovariectomized rats administered raloxifen at a dose of 1 mg/kg/day p.o. Administration of drugs started 5 days after bilateral ovariectomy and continued for 35 days. After 35 days of treatment a vaginal smear was obtained from each rat. Smears were stained with the usual Papanicolaou method, and observed with a light microscope by an experienced cytopathologist. Cytological grading was made according to the extent of parabasal, intermediate, superficial and anuclear squamous cells. RESULTS: Ovariectomized rats had lower scores for superficial and anuclear cells when compared to sham-operated rats (p < 0.05). The CEE group had higher scores for superficial and anuclear cells than those of the ovariectomized, raloxifene and tibolone groups (p < 0.05). The resveratrol-treated rats had higher scores for superficial cells but lower scores for parabasal cells than ovariectomized rats (p < 0.05). The raloxifene and tibolone groups had the same scores for intermediate, superficial and anuclear cells but lower scores for parabasal cells compared to ovariectomized rats. CONCLUSION: The results of our study suggest that resveratrol offsets the reduction in vaginal stratification generally observed after oophorectomy.

Animals↗
PubMed2006

Prenatal estrogen and progesterone deprivation impairs alveolar formation and fluid clearance in newborn piglets.

Exposure to high levels of estradiol (E2) and progesterone (P) derived from the fetoplacentomaternal unit during the last trimester of pregnancy may play a crucial role in prenatal lung development and immediate postnatal alveolar fluid clearance (AFC). To measure prenatal alveolar formation and postnatal amiloride-sensitive AFC after pharmacological deprivation of E2 and P in utero, fetuses from five sows received an intramuscular depot injection of the E2 receptor blocker ICI 182.780 (ICI) and the P receptor blocker RTI 3021-022 (RTI) and fetuses of five other sows received a placebo injection (control group) during a laparotomy at 90 d of gestation (term gestation, 115 d). Piglets were delivered by cesarean section on d 114 of gestation. Of 95 live-born piglets, 35 were mechanically ventilated. The airways of the right lower lobe were isolated by a balloon catheter wedged in the bronchus and 5% albumin in 0.9% NaCl with or without 1 mmol/L amiloride was instilled. Amiloride-sensitive AFC was calculated from the protein concentration changes in fluid recovered after 120 min as the percentage of absorbed fluid. Lungs were removed under standardized conditions to perform alveolar counts. Prenatal treatment with ICI and RTI resulted in a significantly lower amiloride-sensitive AFC (median, 31%; min-max, -4-58) than placebo (74%, 18-231). Median alveolar counts per visual field were significantly lower in piglets that were exposed to ICI and RTI (38, 21-78) compared with placebo (56, 32-113). We conclude that prenatal E2 and P deprivation significantly impaired alveolar formation and amiloride-sensitive AFC.

Amiloride↗
PubMed2006

Raloxifen prevents bone loss in castrated male mice.

Raloxifen is a selective estrogen receptor modulator which prevents bone loss in ovariectomized female mice in a fashion similar to estrogens. Since testosterone-deficient male mice also lose bone mass, we were interested in testing the effects of raloxifen on bones in intact and castrated male mice. Bone density was significantly reduced in castrated animals (1.36+/-0.04 g/ml) as compared to intact animals (1.42+/-0.03 g/ml) (p<0.01). When castrated mice with extraordinarily low concentrations of testosterone and with reduced weight of seminal vesicles were treated with raloxifen, the changes in bone density and bone minerals resulting from castration (1.36+/-0.04 g/ml) were entirely prevented (1.40+/-0.01 g/ml). Cortical bone was lost in orchidectomized mice, and this decrease in cortical thickness of the femur was prevented by raloxifen administration. Raloxifen in a dose used in humans for treatment of osteoporosis decreased the weight of seminal vesicles, an organ which is highly sensitive to the androgenic effect, decreased the concentration of testosterone (12.5+/-2.8 micromol/l) (p<0.01) but not to the same level as in the case of castrated animals (0.6+/-0.3 micromol/l), and did not have any effect on bone density or mineral content in intact mice. The results of the present study may thus be interpreted as supporting the hypothesis that raloxifen is an effective agent against the deleterious effects of castration-induced osteopenia in male mice and also support the hypothesis that estrogens may have physiological skeletal effects in male mice.

Animals↗
PubMed2001

Aromatase (Cyp19) expression is up-regulated by targeted disruption of Dax1.

DAX-1 [dosage-sensitive sex reversal, adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1] is an orphan nuclear receptor that represses transcription by steroidogenic factor-1 (SF-1), a factor that regulates expression of multiple steroidogenic enzymes and other genes involved in reproduction. Mutations in the human DAX1 gene (also known as AHC) cause the X-linked syndrome AHC, a disorder that is associated with hypogonadotropic hypogonadism also. Characterization of Dax1-deficient male mice revealed primary testicular defects that included Leydig cell hyperplasia (LCH) and progressive degeneration of the germinal epithelium, leading to infertility. In this study, we investigated the effect of Dax1 disruption on the expression profile of various steroidogenic enzyme genes in Leydig cells isolated from Dax1-deficient male mice. Expression of the aromatase (Cyp19) gene, which encodes the enzyme that converts testosterone to estradiol, was increased significantly in the Leydig cells isolated from mutant mice, whereas the expression of other proteins (e.g., StAR and Cyp11a) was not altered. In in vitro transfection studies, DAX-1 repressed the SF-1-mediated transactivation of the Cyp19 promoter but did not inhibit the StAR or Cyp11a promoters. Elevated Cyp19 expression was accompanied by increased intratesticular levels of estradiol. Administration of tamoxifen, a selective estrogen-receptor modulator, restored fertility to the Dax1-deficient male mice and partially corrected LCH, suggesting that estrogen excess contributes to LCH and infertility. Based on these in vivo and in vitro analyses, aromatase seems to be a physiologic target of Dax-1 in Leydig cells, and increased Cyp19 expression may account, in part, for the infertility and LCH in Dax1-deficient mice.

Animals↗
PubMed2006

Effects of memantine on estrogen-dependent acute tolerance to the morphine analgesia in female rats.

Both human and animal studies suggest that there are sex differences in responding to noxious stimulation as well as in effects of opiate analgesic drugs. Development and/or expression of tolerance to opiate analgesia are also affected by the hormonal status of the experimental subjects. The present study aimed to compare acute tolerance to morphine in cycling and ovariectomized female rats and to evaluate the effects of N-methyl-D-aspartate (NMDA) receptor channel blocker memantine as well as 17-beta-estradiol on tolerance development using the tail-flick test. Acute tolerance to morphine analgesia was observed as a substantial reduction in the response to a test dose of morphine (10 mg/kg) given 6 h after the tolerance-inducing dose (10 mg/kg). Significant acute tolerance was observed in proestrous female rats and was prevented by memantine (3 or 10 mg/kg) treatment. Ovariectomized rats did not demonstrate tolerance to morphine analgesic effects but chronic estradiol administration (5 microg/day, 5 days) reinstated induction of tolerance. Both estrogen receptor modulator tamoxifen (5 mg/kg/day, 5 days) and memantine (3 mg/kg/day, 5 days) prevented estradiol-induced tolerance in ovariectomized rats. Thus, estrogens were found to play a key role in induction of acute tolerance to morphine antinociception. Estradiol-induced acute morphine tolerance may have NMDA receptor-dependent mechanisms.

Analgesics, Opioid↗
PubMed1996

Effects of melatonin on estrogen receptor expression in the forebrain of outbred (Lak.LVG) golden hamsters.

Studies have shown that the pineal gland via its hormone, melatonin, induces the involution of male and female reproductive systems in seasonally reproducing animals. Melatonin has direct inhibitory effects on both hypothalamic and pituitary functions, which are also exquisitely sensitive to the feedback effects of estradiol. Since melatonin can modulate estrogen receptor (ER) expression in other tissues, immunocytochemical and ribonuclease protection analyses were used to examine the effects of 12 weeks of daily late afternoon injections of melatonin on ER protein and mRNA levels in the hypothalamus of Lak.LVG golden hamsters. Significant decreases in ER-immunoreactivity were noted in the medial preoptic area (MPOA) and bed nucleus of the stria terminalis (BNST) in response to melatonin, while other hypothalamic areas which express ER, e.g. the anterior hypothalamus, showed less dramatic changes. Hypothalamic ER mRNA was decreased in response to melatonin in both intact and ovariectomized animals by 25%. In intact, cycling female hamsters, there was a significant reduction in uterine weight after melatonin treatment. These results suggest that melatonin exerts its anti-reproductive effects in hamsters by modulating ER levels in neurons of the MPOA and BNST, thereby influencing steroid feedback mechanisms.

Animals↗
PubMed2005

Female sexual dysfunction and use of hormone therapy in postmenopausal women.

Sexual dysfunction is a common problem for women of all ages and remains an important aspect of women's health following menopause. For postmenopausal women, the evaluation and management of sexual dysfunction differs from that of younger women because the etiology is often linked to the diminished levels of sex hormones. Female sexual function is highly complex and deeply influenced by nonhormonal factors such as emotional intimacy and culture. Our understanding of this important area of women's health remains inadequate, and much more research needs to be performed before definitive conclusions can be made. Existing data allow for some preliminary observations. It appears that lack of estrogen may lead to sexual dysfunction primarily by causing vaginal atrophy and dyspareunia. These symptoms may be treated by systemic or local estrogen therapy. Conversely, androgen deficiency appears to be most strongly linked to diminished sexual desire. Growing evidence indicates that administration of androgens may be beneficial in such situations. Other agents that use sex hormone receptors, such as selective estrogen receptor modulators and tibolone, also may affect sexual function.

Androgens↗
PubMed2003

Alternate options to hormone replacement therapy for osteoporosis.

This presentation, developed from a symposium lecture at the 40th Annual Convention of the American College of Osteopathic Family Physicians on March 22, 2003, in Nashville, Tenn, highlights three pivotal studies that have altered the preferred option for the treatment and prevention of osteoporosis in post-menopausal women. The Heart Estrogen/progestin Replacement Study (HERS), the HERS II, and the Women's Health Initiative provide evidence that the benefits (fewer colorectal cancers and hip fractures) of using hormone replacement therapy--conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) specifically--did not outweigh the risks (more CHD-related deaths, strokes, venous thromboembolisms, and invasive breast cancer). Treatment and prevention options for osteoporosis now include modification of risk factors, calcium and vitamin D supplementation, third-generation bisphosphonates (alendronate sodium and risedronate sodium), selective estrogen receptor modulators, and synthetic parathyroid hormone.

Estrogen Replacement Therapy↗
PubMedDate not supplied

An estrogen receptor basis for raloxifene action in bone.

Although controversy remains regarding direct effects of estrogen on bone, in vivo data clearly show that estrogens suppress bone turnover, resulting in decreased bone resorption and formation activity. Selective estrogen receptor modulators (SERMs), such as raloxifene, produce effects on bone which are very similar to those of estrogen. In vitro, both raloxifene and estrogen inhibit mammalian osteoclast differentiation and bone resorption activity, but only in the presence of IL-6. Data from a number of ovariectomized rat model manipulations (i.e. hypophysectomy, low calcium diet and drug combinations) demonstrate a strong parallel between the antiosteopenic effects of raloxifene and estrogen. A characteristic action of estrogens on the skeleton is inhibition of longitudinal bone growth, an effect which is not observed with other resorption inhibitors, including calcitonin and bisphosphonates. Consistent with an estrogen-like mechanism on bone, raloxifene inhibits longitudinal bone growth in growing rats. In addition to the overall similarity of the bone activity profile in animals, estrogen and raloxifene also produce similar effects on various signaling pathways relative to the antiosteopenic effect of these two agents. For example, IL-6, a cytokine involved in high turnover bone resorption following estrogen deficiency in rats, is suppressed by both raloxifene and estrogen. Raloxifene and estrogen also produce a similar activation of TGF-beta3 (a cytokine associated with inhibition of osteoclast differentiation and activity) in ovariectomized rats. Like 17beta-estradiol, raloxifene binds with high affinity to both estrogen receptor-alpha (ER alpha) and estrogen receptor-beta (ER beta). Crystal structure analyses have shown that 17beta-estradiol and raloxifene bind to ER alpha with small, but important, differences in three dimensional structure. These subtle differences in the conformation of the ligand:receptor complex are likely the basis for the key pharmacological differences between estrogens and the various SERMs (i.e. raloxifene vs tamoxifen). Raloxifene also produces estrogen-like effects on serum cholesterol metabolism and the vasculature. Thus, while raloxifene exhibits a complete estrogen antagonist in mammary tissue and the uterus, it produces beneficial effects on the cardiovascular system and prevents bone loss via an estrogen receptor mediated mechanism.

Animals↗
PubMed2006

Different effects of raloxifene and estrogen on interleukin-1beta and interleukin-1 receptor antagonist production using in vitro and ex vivo studies.

The increase in lumbar spine BMD in response to Raloxifene (RLX), a selective estrogen receptor modulator, is smaller in magnitude compared to the response to treatment with estradiol (E2). The reasons for this observation are unclear. Estrogen has a potent effect on the production of proinflammatory cytokines which support osteoclastogenic and bone resorption. Therefore the different response to RLX may relate, at least in part, to a difference in the ability of RLX to modulate the production of proinflammatory cytokines which are abundant in the red marrow of the vertebrae. The aim of this study was to determine the effect of RLX and E2 both in vitro and ex vivo on the production of the pro-resorptive cytokine interleukin-1beta (IL-1beta) and its antagonist, interleukin-1 receptor antagonist (IL-1ra). We obtained samples of peripheral blood from (a) 10 untreated postmenopausal women with osteopenia (ages 53 to 72 years, mean 61 years), (b) 15 postmenopausal women (ages 52 to 72 years, mean 63 years) at baseline and after 6 months of RLX therapy (60 mg/day) and (c) 10 postmenopausal women (ages 60 to 75 years, mean 64 years) at baseline and 6 months after a single E2 implant (25 mg). Cultures of whole blood from the untreated women were incubated with RLX or 17beta-E2 at 1 pM, 100 pM, 10 nM and 1 microM concentrations. LPS-stimulated whole blood cultures from the raloxifene- and estradiol-treated women were prepared at baseline and at 6 months. IL-1beta and IL-1ra were measured by ELISA in the conditioned media. In vitro there was a significant dose-dependent decrease in IL-1beta and IL-1ra in response to 17beta-E2 (both P<0.0001) which was not apparent in response to RLX (both P>0.05). In ex vivo cultures from women receiving 6 months treatment with E2 implants, there was a significant decrease in IL-1beta (-36+/-8%, P=0.01) but no significant change in IL-1ra (+29+/-20%, P=0.3). There was no significant change in either IL-1beta or IL-1ra after 6 months RLX therapy (+20+/-14% and +12+/-10%, both P>0.05). We conclude that treatment with RLX, unlike estradiol does not modulate the production of the proinflammatory cytokines IL-1beta and IL-1ra using in vitro or ex vivo whole blood culture methods. This may account, at least in part for the reduced efficacy of RLX therapy compared to estrogen which has been observed in vivo on bone mineral density, bone turnover and reduction in fracture risk.

Aged↗
PubMed1998

Raloxifene effects on vasomotor and other climacteric symptoms in postmenopausal women.

Introduction and Objectives: Raloxifene, a novel selective estrogen receptor modulator (SERM), is under investigation for the prevention of osteoporosis in postmenopausal women. Like traditional estrogen replacement therapy, raloxifene has beneficial effects on bone and on serum lipids whereas, in contrast to estrogen's adverse effects in the breast and uterus, raloxifene is an estrogen antagonist in the breast and is nonstimulatory in the uterus. This study examines the effects of raloxifene 60 mg/day compared with placebo on: 1) the incidence of vasomotor symptoms: hot flashes (flushing) and sweating (including night sweats), 2) the severity and time course of hot flashes, and 3) the relation of hot flashes to baseline subject characteristics and study discontinuations. Additionally, the study explores the effects of raloxifene 60 mg/day compared with placebo on other climacteric symptoms that affect the quality of life of postmenopausal women, such as depression, insomnia, mood lability and genitourinary complaints.Methods: Integrated data from five randomized, placebo-controlled studies involving 1,165 healthy, postmenopausal women, with up to 30 months of study drug exposure, were analyzed. The incidence and severity of hot flashes and other climacteric symptoms were compared in patients treated with placebo or raloxifene (60 mg/day) via open-ended, non-directed subject self-assessment questionnaires. Data were analyzed for subgroup-by-therapy interactions using many baseline subject characteristics such as age, body mass index, smoking, alcohol, and years post-menopause, as well as preexisting conditions such as hot flashes, sweating, insomnia, depression, and history of hysterectomy. The overall incidence of other climacteric symptoms were reported as adverse events.Results: The increase in overall incidence of hot flashes in raloxifene-treated (24.6%) and placebo-treated (18.3%) subjects was modest, but statistically significant. However, this difference was significant only during the first 6 months of therapy, raloxifene (20.1%) compared with placebo (14.4%). After 6 months of treatment, there was no statistically significant difference in the incidence of hot flashes between the two treatment groups. The majority of hot flashes in raloxifene-treated subjects were subject-assessed as "mild-to-moderate" in severity (89%). The incidence of hot flashes reported as "severe" did not differ significantly in raloxifene- or placebo-treated subjects. Subgroup analyses revealed the overall incidence of hot flashes to be highest for both raloxifene and placebo-treated subjects, in younger (age < 55 years) women (P =.004), in women who had previously experienced hot flashes (P =.031), and in women having had hysterectomies (P <.001). Within each of these subgroups, there was no statistical difference in the incidence of hot flashes between the raloxifene and placebo groups. Between the two treatment groups, there was no difference in the overall incidence of subject discontinuations from study due to hot flashes. The occurrence of the other common vasomotor symptom, sweating (which includes night sweats), was not statistically different for the raloxifene- or placebo-treated subjects.Genitourinary complaints are often symptoms related to vaginal dryness, such as dyspareunia and decreased libido, as well as other symptoms of vaginitis and leukorrhea. No statistically significant differences occurred for raloxifene- or placebo-treated subjects in reports of these genitourinary symptoms. Similarly, for the other common climacteric symptoms; depression, insomnia, and mood lability, no significant differences in incidence between the raloxifene and placebo treatment groups were observed.Conclusions: Raloxifene (60 mg/day) treatment modestly increased the incidence of hot flashes compared with placebo, however, this difference was only statistically significant during the first 6 months of treatment. There were no differences in the severity of hot flashes between treatment groups, and this symptom did not adversely affect subjects' study participation. In both the raloxifene and placebo treatment groups, young postmenopausal women (age < 55), those with baseline hot flashes, and those with histories of hysterectomy were most likely to experience hot flashes. Raloxifene therapy did not affect the occurrence of other climacteric symptoms commonly affecting the quality of life of women after menopause.

Journal Article↗
PubMed2005

Sex hormones in the regulation of bone and cartilage metabolism: an old paradigm and a new challenge.

The effects of estrogen on tissues such as bone, endometrium and breast have been extensively studied, and the pleitropic effects of the female sex hormone are well established. Cartilage is not generally viewed as an estrogen responsive tissue. However, several epidemiological studies, and a few recent intervention studies supports that estrogen may have a role in osteoarthritis (OA), and recent animal studies further suggests that estrogen may be involved in regulation of cartilage turnover. Accordingly the issue of chondroprotrective properties of estrogen has received increased attention in recent scientific publications. In this review, we summarize current studies indicating a role for estrogen in the regulation of cartilage turnover and development of joint diseases. We report results from in vitro and animal studies where the effects of ovariectomy and treatment with estrogen and selective estrogen receptor modulators (SERM) on cartilage erosion have been evaluated. Furthermore, we report results from assessment of the effects of estrogen and SERM in postmenopausal women which shed new light on the interactions between estrogen and joint tissues. It still remains to be established whether estrogen or SERM could find a role in prophylaxis and/or treatment of OA, and much work lies ahead. Current data reviewed in this manuscript can be considered encouraging and they raise the hope that new treatment options for OA may become available based on estrogen and, in particular, compounds acting through the estrogen receptor. However, at present hormone replacement therapy and SERMs available in clinical practice, cannot be recommended as a therapy for arthritic disease.

Bone and Bones↗