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PubMed2001

Induction of the progesterone receptor gene in estrogen target cells monitored by branched DNA signal amplification.

Estrogens have multiple effects on the growth and development of cells in their target tissues, including the uterus, ovary, breast, bone marrow and brain. The hormone regulates the transcription of diverse genes in these tissues via the estrogen receptor, a nuclear transcription factor. Naturally occurring estrogens and estrogen analogs including selective estrogen receptor modulators (SERMs), constitute important therapies for breast cancer and osteoporosis, and are major components of oral contraceptives. The in vitro biologic activities of pharmaceutical estrogen agonists and antagonists have frequently been monitored by cotransfection assay, where exogenous estrogen receptor and reporter genes are transiently inserted into a heterologous, non receptor-containing cell line, such as those derived from kidney cells. Here we describe an alternative to this method, where induction of an endogenous estrogen-responsive gene, the progesterone receptor gene, is monitored by branched DNA signal amplification. Assays are performed with cultured cells derived from estrogen-responsive tissues; namely, breast, uterine endothelium and bone. Hormonal induction occurs via the endogenous estrogen receptor of these cells. Our data show that SERMs, which are estrogen agonists on bone in vivo, antagonize estrogen-dependent target gene induction in conditionally immortalized osteoblast-like cells.

Alkaline Phosphatase↗
PubMed2001

In vitro and in vivo biologic effects of Ospemifene (FC-1271a) in breast cancer.

Ospemifene (FC-1271a) is a novel selective estrogen receptor modulator under development for osteoporosis prevention. In the present paper, we examine both the in vitro and in vivo effects of FC-1271a in breast cancer models. In vitro, the growth inhibitory effects of FC-1271a and its main metabolite are investigated in MCF-7 and MDA-MB-231 human breast cancer cells at doses ranging from 0.1 to 10 microM. Modulation of pS2 expression, an indicator of estrogen activity, was also examined in all experiments using reverse transcription-polymerase chain reaction. In vivo, the effects of treatment with 10, 25, 50, or 100 mg/kg FC-1271a on MCF-7 and MDA-MB-231 human tumor xenografts in athymic, ovariectomized mice were determined. For MCF-7 cells, FC-1271a and its main metabolite, toremifene VI (TOR VI) displayed anti-estrogenic effects in vitro as shown through growth inhibition and decreased expression of pS2. Treatment with FC-1271a in vivo inhibited MCF-7 tumor growth, compared with control (P< or =0.05). FC-1271a and TOR VI did not inhibit the growth of MDA-MB-231 cells in vitro, and no clear effects of FC-1271a treatment were seen on MDA-MB-231 tumor growth in vivo. In conclusion, FC-1271a appears to exert anti-estrogenic effects dependent on estrogen receptor positivity in vitro and in vivo on the growth of MCF-7 cells.

Animals↗
PubMed2005

Discovery of novel quinoline-based estrogen receptor ligands using peptide interaction profiling.

Traditional approaches to discovery of selective estrogen receptor modulators (SERMs) have relied on ER binding and cell-based estrogen response element-driven assays to identify compounds that are osteoprotective but nonproliferative in breast and uterine tissues. To discover new classes of potential SERMs, we have employed a cell-free microsphere-based binding assay to rapidly characterize ERalpha interactions with conformation-sensing cofactor or phage display peptides. Peptide profiles of constrained triarenes were compared to known proliferative and nonproliferative ER ligands to discover potent quinoline-based ligands with minimal Ishikawa cell stimulation.

Alkaline Phosphatase↗
PubMedDate not supplied

Risk-reducing strategies for breast cancer--a review of recent literature.

The incidence of newly diagnosed breast cancer cases world-wide is expected to double by 2020. Risk-reducing strategies for breast cancer include lifestyle modifications, chemoprevention and surgery (bilateral mastectomy and/or oophorectomy). Lifestyle modifications include avoidance of postmenopausal obesity and hormone replacement therapy (HRT), regular physical activity, and restriction of alcohol and animal fat intake. Tamoxifen is a selective estrogen receptor modulator (SERM) shown in randomized controlled trials to reduce the incidence of estrogen receptor (ER)-positive breast cancer in high-risk healthy women. However, its routine use cannot be recommended for breast cancer prevention in healthy women due to its significant adverse effects, specifically in terms of endometrial carcinoma and thromboembolism. On the other hand, tamoxifen may be used for chemoprevention in women at high risk of developing ER-positive breast cancer and at low risk of developing complications. Raloxifene, another SERM, also appears to be effective in reducing breast cancer risk, and lacks the unwanted stimulatory effect on the uterus. Other promising chemopreventive agents currently under investigation include cyclo-oxygenase 2 (COX-2) inhibitors, fenretinide, aromatase inhibitors, and goserelin. Prophylactic mastectomy can reduce breast cancer risk by 90% in high-risk women. Bilateral oophorectomy has the potential of reducing the risk of both breast and gynecologic cancer in women carrying BRCA-1 or BRCA-2 mutations. Further research is required to identify novel strategies to prevent ER-negative breast cancer, minimize the adverse effects of tamoxifen and other SERMs, and evaluate the role of mammary ductal lavage and ductoscopy in guiding risk-reducing strategies.

Breast Neoplasms↗
PubMed2000

Characterization of hot flashes reported by healthy postmenopausal women receiving raloxifene or placebo during osteoporosis prevention trials.

OBJECTIVE: Raloxifene, a selective estrogen receptor modulator, is estrogen-like in the skeleton and cardiovascular system and antiestrogenic in reproductive tissues. In contrast to estrogens, raloxifene is not indicated for the treatment of hot flashes. This study was designed to examine the characteristics of hot flashes among healthy postmenopausal women participating in osteoporosis prevention trials who were receiving raloxifene or placebo. METHODS: Adverse event data from three randomized, double-blind trials (N = 876) comparing raloxifene 60 mg/day with placebo for 30 months were integrated and analyzed. Two of the three trials (one European, two North American) were identically designed and were open to healthy postmenopausal women ages 45 through 60 without regard to prior hysterectomy. The third trial was multinational, was open to women ages 40 through 60, and all enrollees had prior hysterectomy at baseline. Women were questioned in general terms about the occurrence of adverse events at 3-6-month intervals. Treatment-emergent adverse events pertaining to hot flashes were included in the current study. RESULTS: At baseline, 12% of women randomly assigned to placebo and 13% assigned to raloxifene reported prevalent hot flashes. After 30 months, the cumulative incidence of hot flashes was 21% for placebo and 28% for raloxifene (P = 0.022), with the difference in incidence rate confined to the first 6 months of therapy. There was no difference between placebo and raloxifene in reported maximum severity of or early discontinuations as a result of hot flashes (< or = 3% per group for both outcomes). Among women whose hot flashes had stopped completely during the 30-month study period, the median total duration of the event prior to becoming symptom-free was 246 days for placebo and 205 days for raloxifene. Among all women reporting a hot flash, the extrapolated total duration of hot flashes was the same for women treated with either raloxifene or placebo. No subgroup-by-therapy interactions were detected. Multivariable regression analysis revealed several factors that were independently weakly predictive of hot flashes. CONCLUSIONS: Raloxifene slightly affects the incidence but not the natural history of hot flashes in healthy postmenopausal women seeking prevention therapy.

Adult↗
PubMed1999

[Results of international clinical trials with raloxifene].

A new drug class called Selective Estrogen Receptor Modulators (SERM) could combine ideal properties for a product designed for menopausal women. The most widely studied member of this class is raloxifene which is currently marketed in several countries for the prevention of osteoporosis in menopaused women. This product is a nonsteroidal derivative of benzothiophene which, like estrogens, has a preventive effect against bone loss involving the spine and peripheral skeleton and a cholesterol lowering effect, both in the ovariectomized rat and in menopausal women. Unlike estrogens, raloxifene does not stimulate breast or uterine tissue. These interesting properties make raloxifene a possible preventive treatment for osteoporosis and other menopause-related risks for menopausal women of all ages. Multicenter studies have been conducted in recently menopausal women who received either raloxifene at the doses of 30, 60, or 150 mg/day or a placebo in a randomized protocol. All subjects were also given calcium supplementation. Bone density was measured twice a year for 36 months by dual X-rays absorptiometry and showed a significant decrease at all sites in the placebo group while there was a significant increase in the spine, the hip and the overall skeleton for all three raloxifen groups. After 24 months of treatment, mean increase over placebo was 2.4% for 60 mg raloxifene measured on the spine and total hip and 2% for the overall skeleton. Markers of bone formation (serum osteocalcin and bone alkaline phasphatase) and resorption (urinary CrossLaps) decreased significantly reaching, after 3 to 6 months of treatment, the levels observed in non menopausal women. In addition, total serum cholesterol as well as LDL-cholesterol decreased significantly in a dose-dependent fashion in all groups treated with raloxifene. Serum HDL-cholesterol and triglycerides did not very significantly during treatment. Hot flashes were the most frequently observed undesirable effect, at a frequency slightly higher in the raloxifene group (25%) than in the placebo group (18%). This undesirable effect was of low intensity and generally occurred during the first months of treatment. It did not cause a higher drop out rate (raloxifen 1.5%; placebo 2.1%). The preliminary data at two years follow-up suggest that raloxifene is not associated with an increased risk of breast cancer. In conclusion, raloxifene is a particularly interesting drug for menopausal women showing very promising efficacy and clinical tolerance.

Animals↗
PubMed2001

What would be the properties of an ideal SERM?

Selective estrogen receptor modulators (SERMs) are drugs that bind to the estrogen receptor (ER); in some tissues they act like estrogen (agonists), while in other tissues they oppose the action of estrogen (antagonists). The SERM tamoxifen acts as an estrogen antagonist in the breast in that it prevents and treats breast cancer, but it acts as an estrogen agonist in the endometrium, where it can induce cancer. Estrogen, and to a lesser extent SERMs, are effective in preventing and treating osteoporosis. Contrary to the prevalent hypothesis that estrogen provides benefit to women with regard to secondary prevention of coronary heart disease (CHD), randomized clinical trials have demonstrated that estrogen is associated with an increased risk of CHD in this population of women. Conflicting results have been reported on the effect of estrogens on cognitive function. The latest and largest randomized clinical trials have demonstrated a beneficial role in short-term memory in nondemented women, in contrast to the absence of such benefit in improving symptoms in women with Alzheimer's disease. Although estrogens have been used successfully to treat some menopausal symptoms such as hot flashes, the SERMs tamoxifen and raloxifene actually induce or increase hot flashes. Data on the beneficial and adverse effects of estrogen and SERMs are reported along with an elaboration of the constellation of properties that would characterize an ideal SERM working through the ER.

Breast Neoplasms↗
PubMed2006

Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure.

Over 6 billion pounds per year of the estrogenic monomer bisphenol A (BPA) are used to manufacture polycarbonate plastic products, in resins lining metal cans, in dental sealants, and in blends with other types of plastic products. The ester bond linking BPA molecules in polycarbonate and resins undergoes hydrolysis, resulting in the release of free BPA into food, beverages, and the environment, and numerous monitoring studies now show almost ubiquitous human exposure to biologically active levels of this chemical. BPA exerts estrogenic effects through the classical nuclear estrogen receptors, and BPA acts as a selective estrogen receptor modulator. However, BPA also initiates rapid responses via estrogen receptors presumably associated with the plasma membrane. Similar to estradiol, BPA causes changes in some cell functions at concentrations between 1 pM and 1 nM, and the mean and median range of unconjugated BPA measured by multiple techniques in human pregnant maternal, fetal, and adult blood and other tissues exceeds these levels. In contrast to these published findings, BPA manufacturers persist in describing BPA as a weak estrogen and insist there is little concern with human exposure levels. Our concern with human exposure to BPA derives from 1) identification of molecular mechanisms mediating effects in human and animal tissues at very low doses, 2) in vivo effects in experimental animals caused by low doses within the range of human exposure, and 3) widespread human exposure to levels of BPA that cause adverse effects in animals.

Animals↗
PubMed1999

Treatment of postmenopausal women with osteoporosis or low bone density with raloxifene. Raloxifene Study Group.

Raloxifene, a selective estrogen receptor modulator (SERM), has been shown to improved bone mineral density (BMD) and serum lipid profiles in healthy postmenopausal women. The objective of this study was to examine the effects of raloxifene on BMD, biochemical markers of bone metabolism and serum lipids in postmenopausal women with low bone density or osteoporosis. This Phase II, multicenter, 24-month, double-masked study assessed the efficacy and safety of raloxifene in 129 postmenopausal women (mean age +/- SD: 60.2 +/- 6.7 years) with osteoporosis or low bone density (baseline mean lumbar spine BMD T-score: -2.8). Women were randomly assigned to one of three treatment groups: placebo, 60 mg/day raloxifene-HCl (RLX 60) or 150 mg/day raloxifene-HCL (RLX 150) and concomitantly received 1000 mg/day calcium and 300 U/day vitamin D3. At 24 months, BMD was significantly increased in the lumbar spine (+3.2%), femoral neck (+2.1%), trochanter (+2.7%) and total hip (+1.6%) in the RLX 60 group compared with the placebo group (p < 0.05). The RLX 150 group had increases in BMD similar to those observed with RLX 60. A greater percentage of raloxifene-treated patients, compared with those receiving placebo, had increased BMD (p < 0.05). Serum bone-specific alkaline phosphatase activity, serum osteocalcin, and urinary type I collagen:creatinine ratio were significantly decreased in the RLX-treated groups, compared with the placebo group (p < 0.01). RLX 60 treatment significantly decreased serum levels of triglycerides, and total- and LDL-cholesterol levels (p < 0.01). The rates of patient discontinuation and adverse events were not significantly different among groups. In this study, raloxifene increased bone density, decreased bone turnover, and improved the serum lipid profile with minimal adverse events, and may be a safe and effective treatment for postmenopausal women with osteoporosis or low bone density.

Aged↗
PubMed2004

A molecular docking study of estrogenically active compounds with 1,2-diarylethane and 1,2-diarylethene pharmacophores.

Numerous selective estrogen receptor modulators (SERMs) have been synthesized and assayed in recent years. The focus of this study is to apply coarse-grain molecular docking procedures coupled with fine-grain all-atom force field optimization strategies to shed light on the binding mechanisms of currently available estrogen receptor-active compounds. Although the mechanics of ligand binding in estrogen receptors is generally well understood, there is room for surprises. In this paper computational evidence corroborating the experimentally observed type I agonistic binding mode for estradiol (E2) and diethylstilbesterol (DES) and the type II antagonistic binding mode for 4-hydroxytamoxifen and raloxifen is presented. Included in this type I agonistic mode are the DES derivatives, transstilbene and 1,2-diaryldiaminoethane. In addition, a novel 'type II agonistic' binding mode for 2,3-diarylimidazolines, 4,5-diarylimidazoles, 2,3-diarylpiperazines is introduced. This mode is stabilized by suggesting alternative hydrogen bond anchor points in the ligand binding domain as potential leads for future drug design.

Computer Simulation↗
PubMed2001

Differential effects of raloxifene and continuous combined hormone replacement therapy on biochemical markers of cardiovascular risk: results from the Euralox 1 study.

OBJECTIVE: To compare the effects of the selective estrogen receptor modulator (SERM) raloxifene (Evista) and a continuous combined hormone replacement therapy (ccHRT) formulation containing estradiol and norethisterone acetate (Kliogest) on lipid and fibrinogen levels of postmenopausal women. METHODS: Euralox 1 was a prospective, randomized, double-blind trial. After a placebo wash-out, healthy postmenopausal women (n = 1008, average age 56.1 +/- 4.9 years) with a health risk profile that suggested a potential benefit from either treatment were randomly assigned to either 60 mg raloxifene or ccHRT consisting of 2 mg estradiol and 1 mg norethisterone acetate (NETA) per day for 6 months. MEASUREMENTS: Total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol with its fractions HDL2 and HDL3, the LDL/HDL ratio, triglycerides and fibrinogen were assessed at baseline and after 6 months or on early drop-out. RESULTS: Baseline values were comparable between the two groups. Blood samples of 841 women (83.4%) were available at baseline and endpoint. Total and LDL cholesterol decreased statistically significantly from baseline to endpoint in both treatment arms (by 7.2% and 3.8% with raloxifene and by 13.0% and 8.9% with ccHRT, respectively). Raloxifene produced a statistically significant increase in HDL cholesterol by 4.2%, while ccHRT induced a decline by 9.5%. Triglycerides were moderately suppressed with raloxifene and ccHRT, by 3.6 and 5.4%, respectively. Fibrinogen fell by 7.0% with raloxifene and rose by 3.6% with ccHRT. CONCLUSIONS: Continuous combined HRT was associated with decreases in total cholesterol and LDL cholesterol about twice as large as with raloxifene, but also with a decrease in HDL cholesterol. The smaller decreases in total cholesterol and LDL cholesterol associated with raloxifene were accompanied by an increase in HDL cholesterol and a decrease in fibrinogen. In conclusion, raloxifene affects fibrinogen concentrations and the overall cholesterol profile more favorably than ccHRT; these differences may have important implications for the reduction of cardiovascular disease.

Cholesterol↗
PubMed2003

Ligand-induced regulation of ERalpha and ERbeta is indicative of human breast cancer cell proliferation.

Two estrogen receptors (ER), ERalpha and ERbeta, are expressed in breast cancer but their role in treatment response is unclear. The overall objective of this study was to determine if the presence of ERbeta protein in breast cancer cell lines is an indicator of a poor prognosis based on cell proliferation. In addition, we determined the effect of estradiol (E2) and selective estrogen receptor modulators (SERMs), such as tamoxifen and genistein, on ERalpha and ERbeta protein regulation, to help in the understanding of the mechanism behind their role in modulating cell proliferation. Using western blot and immunofluorescence analysis, the ER positive cell lines, MCF-7 and T47D, were found to contain both ERalpha and ERbeta, and thus were used as model systems. E2 and genistein, which increased cell proliferation in both cell lines, induced an up regulation of ERbeta in both cell lines. This suggests that an estrogenic response in breast cancer cells is indicated by an increase in ERbeta expression. Tamoxifen decreased cell proliferation in both cell lines, while up regulating ERalpha in both cell lines, suggesting that antiestrogenic response is indicated by an increase in ERalpha expression. Although a change in the ERalpha/ERbeta ratio may play a role in the effect seen in cell proliferation, this study indicates that ERbeta is a poor prognosticator of cell proliferation in breast cancer and that ERalpha is a positive prognosticator of responsiveness to antiestrogen treatment.

Antineoplastic Agents↗
PubMed2005

Apoptosis and proliferation in breast cancer cells, cultured in vitro: effects of SERMs.

OBJECTIVE: Selective estrogen receptor modulators (SERMs) decrease the risk of developing breast cancer. As an antagonistic effect, SERMs may aggravate or induce climacteric symptoms. Hormone therapy (HT) would be able to alleviate these symptoms. The present in vitro study tries to elucidate the effects of several HT preparations combined with SERMs on estrogen receptor-positive (ER +) (i.e. MCF-7 and T-47D) and -negative (ER-) (i.e. MDA-MB-231) human breast cancer cells in vitro. METHODS: We performed experiments with various HT preparations (estradiol (E2)/E2 + progesterone/E2 + dihydrodydrogesterone /E2 + norethisterone acetate/E2 + medroxyprogesterone acetate/tibolone) in the concentration of 10(-6) mol/l together with SERMs (raloxifene or tamoxifen) added to different breast cancer cell lines in vitro. After an incubation period of 144 h, proliferation and apoptosis were measured. The first was measured by quantification of the expression of cyclin D1 mRNA, the latter by the Nicoletti method. RESULTS: This in vitro study clearly demonstrates differences in results if various HT preparations, combined with SERMs, are added to ER + and ER- breast cancer cell lines. CONCLUSIONS: Adding estradiol/progestogens in combination with a SERM to estrogen receptor-positive breast cancer cell lines does not obligatorily lead to proliferation of tumor cells. Not all progestogens act equally.

Apoptosis↗
PubMed2002

Tamoxifen, raloxifene and the prevention of breast cancer.

The recognition of a new group of drugs, now named selective estrogen receptor modulators (SERMs) has revolutionized prospects for the prevention of breast cancer. New agents will continue to be tested against tamoxifen, the first SERM and an established treatment of ER positive breast cancer. Raloxifene a related SERM is used to treat and prevent osteoporosis with the potential beneficial side effect of preventing breast cancer. The Study of Tamoxifen and Raloxifene (STAR) trial will establish whether raloxifene is an improvement over tamoxifen. Most importantly, emerging information about the molecular pharmacology of SERMs will be used to decipher the mechanism of action at specific target sites around a woman's body. This knowledge can be used to design new SERMs and advance the prospects for multifunctional medicine to prevent breast cancer, osteoporosis and coronary heart disease.

Adult↗
PubMed2004

Effects of raloxifene hydrochloride on endometrial cancer cells in vitro.

OBJECTIVE: Determine effects of raloxifene hydrochloride, a selective estrogen receptor modulator (SERM), on growth and proliferation of an estrogen-responsive endometrial cancer cell line in vitro. MATERIALS AND METHODS: Studies were performed with Ishikawa endometrial adenocarcinoma cells, a well-differentiated cancer that expresses estrogen receptors and progesterone receptors. Raloxifene was purified as the hydrochloride salt. The four arms of the study were cells grown (1) without any further addition (control), (2) with estradiol only, (3) with raloxifene only, or (4) with estradiol and raloxifene. Three concentrations of estradiol (10, 100, 1000 pg/ml) and raloxifene (1, 10, 100 ng/ml) were used. After 1 week of culturing, the number of living cells for each experimental group was determined and expressed as a percentage of the control group. RESULTS: Cells treated with raloxifene 10 or 100 ng/ml alone grew significantly faster than control cells: 10 ng/ml [115.25%; SD, 11.05; 95% confidence interval (CI), 107.35-123.16; P = 0.002] and 100 ng/ml (111.14%; SD, 14.19; 95% CI, 100.98-121.29; P = 0.03). Estradiol 10 or 100 pg/ml did not stimulate cell growth, whereas cells treated with 1000 pg/ml grew significantly faster than control cells (114.69%; SD, 16.84; 95% CI, 102.65-126.74; P = 0.02). Raloxifene and estradiol together in any concentration did not affect cell growth. CONCLUSIONS: Raloxifene did not inhibit the growth of endometrial cancer cells in vitro. High concentrations even promoted cell growth. Estradiol in physiologic concentrations did not stimulate the growth of endometrial cancer cells in vitro.

Adenocarcinoma↗
PubMedDate not supplied

The reversible effects of raloxifene on luteinizing hormone levels and ovarian morphology in mice.

Raloxifene is a selective estrogen receptor modulator that has estrogen agonist effects on bone and serum lipids and estrogen antagonist effects on breast and uterine tissues. This study assessed the effects of raloxifene hydrochloride (HCl) treatment on circulating luteinizing hormone (LH) levels and ovarian morphology in sexually mature, 15-week-old, female CD-1 mice. Mice were maintained on diets providing average daily doses of 0 or 233 mg/kg raloxifene for 2 weeks (Study 1) or 0, 7.9, or 236 mg/kg raloxifene for 4 weeks (Study 2). At the end of the treatment period, blood samples were collected every 2 hours for 24 h in Study 1 (5 mice per group) and at 10:00 a.m. and 10:00 p.m. in Study 2 (8 mice per group). Serum LH levels were measured by radioimmunoassay. Ovarian histomorphology was evaluated in the 10 mice per group (Study 1) and the 8 mice per group (Study 2). For the reversibility phase (Study 2), mice were fed untreated diets for 3 weeks; serum LH levels and ovarian histomorphology were then assessed. Raloxifene treatment at 233 mg/kg/day for 2 weeks (Study 1) significantly elevated circulating LH levels by 4- to 7-fold compared with control. Raloxifene-treated mice had elevated LH levels sustained over the 24-h sampling period and did not exhibit the preovulatory LH surge evident in some control mice at the 4:00 p.m., 6:00 p.m., and 8:00 p. m. time points. Mice treated with 236 mg/day raloxifene for 4 weeks (Study 2) had elevated LH levels (4.4-fold compared to control), whereas mice exposed to 7.9 mg/kg/day raloxifene had a slight, nonsignificant increase in LH (2-fold compared to control). In both dose groups, LH levels were indistinguishable from controls 3 weeks after raloxifene treatment was discontinued. The ovaries in six of the eight mice treated with 7.9 mg/kg/day raloxifene had dilated and/or anovulatory follicles. One mouse in this group had a single hemorrhagic follicle; however, corpora lutea distribution was normal, indicating that ovulation was occurring. Raloxifene-treated mice in Study 1 and mice treated with a comparable raloxifene dose (236 mg/day) in Study 2 had histomorphological changes in the ovary indicative of arrested follicular maturation, including anovulatory hemorrhagic follicles, some developing follicles, and very few corpora lutea. At the end of the reversibility phase, hemorrhagic follicles were no longer evident and follicular maturation and corpora lutea distribution were normal. Raloxifene treatment in mice produces a dose-dependent, sustained elevation in serum LH levels and is associated with changes in ovarian follicular morphology. These changes are reversible upon discontinuation of raloxifene treatment.

Animals↗
PubMed1999

Raloxifene acutely relaxes rabbit coronary arteries in vitro by an estrogen receptor-dependent and nitric oxide-dependent mechanism.

BACKGROUND: Selective estrogen receptor modulators (SERMs) have been defined as compounds that display tissue specificity with regard to estrogenic effects. They appear to share the beneficial effects of estrogen on bone and lipids but are not associated with an increased risk of breast or uterine carcinoma. Estrogen relaxes coronary arteries and has long-term protective effects on the vascular system. The effect of SERMs on the coronary vasculature is unknown. We therefore investigated the effects of the SERM raloxifene on isolated rabbit coronary arteries. METHODS AND RESULTS: Rings of coronary artery from adult male and nonpregnant female New Zealand White rabbits were suspended in organ baths containing Krebs solution; isometric tension was then measured. Raloxifene induced coronary arterial relaxation in male and female coronary arteries by an endothelium-dependent and estrogen receptor-dependent mechanism involving nitric oxide. Raloxifene also had a direct calcium antagonistic effect on the coronary myocyte. Estrogen, however, induced only endothelium-independent coronary arterial relaxation. The endothelium-dependent component of relaxation induced by raloxifene 10(-6) mol/L resulted in almost 100% (79+/-7% versus 43+/-3%, P<0.001) more relaxation than that induced by estrogen 10(-6) mol/L. CONCLUSIONS: These data demonstrate that raloxifene has vascular relaxing properties. The surprising finding is that the receptor-dependent effects via the endothelium are observed in coronary arteries from both male and female animals.

Animals↗
PubMed2005

Exercise and pharmacological countermeasures for bone loss during long-duration space flight.

Bone loss in the lower extremities and lumbar spine is an established consequence of long-duration human space flight. Astronauts typically lose as much bone mass in the proximal femur in 1 month as postmenopausal women on Earth lose in 1 year. Pharmacological interventions have not been routinely used in space, and countermeasure programs have depended solely upon exercise. However, it is clear that the osteogenic stimulus from exercise has been inadequate to maintain bone mass, due to insufficient load or duration. Attention has therefore been focused on several pharmacological interventions that have been successful in preventing or attenuating osteoporosis on Earth. Anti-resorptives are the class of drugs most commonly used to treat osteoporosis in postmenopausal women, notably alendronate sodium, risedronate sodium, zoledronic acid, and selective estrogen receptor modulators, such as raloxifene. There has also been considerable recent interest in anabolic agents such as parathyroid hormone (PTH) and teriparatide (rhPTH [1-34]). Vitamin D and calcium supplementation have also been used. Recent studies of kindreds with abnormally high bone mineral density have provided insight into the genetic regulation of bone mass. This has led to potential therapeutic interventions based on the LRP5, Wnt and BMP2 pathways. Another target is the RANK-L/osteoprotegerin signaling pathway, which influences bone turnover by regulating osteoclast formation and maturation. Trials using such therapies in space are being planned. Among the factors to be considered are dose-response relationships, bone quality, post-use recovery, and combination therapies--all of which may have unique characteristics when the drugs are used in space.

Aerospace Medicine↗