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Development of clinical practice guidelines for prevention and treatment of osteoporosis.

Clinical practice guidelines should be written for the physician who sees patients who already have or are at high risk for osteoporosis. They should also guide the physician in distinguishing between those at high and low risk and provide general guidelines for prevention of osteoporosis for the low-risk patient. Patients at high risk may require intervention to prevent further bone loss. The guidelines should be based on the strongest evidence available and be easy to comprehend and apply. Methods to identify individuals at high risk for osteoporosis must be described. Effective interventions also should be described, as should their benefits and risks. Elderly individuals who have a poor diet and little sun exposure may be vitamin D deficient unless a supplement is given. Factors that may be deleterious to the skeleton should be avoided. Weight-bearing exercise is important throughout life. Assessment of fracture risk is important in choosing candidates for intervention, especially interventions aimed at preventing osteoporosis. Measuring bone mass at any skeletal site is the necessary initial step for most individuals; measurement at the hip may best assess the risk of hip fracture. Some risk factors independent of bone mass may also aid in patient selection. The WHO has defined osteoporosis as a bone mass at least 2.5 standard deviations (SDs) below the mean of young normal. Such individuals and those with bone mass from 1 to 2.5 SDs below the mean of young normal may also be considered for intervention. The decision will depend on assessments of the risks, the costs of treatment, the desire of the patient, and the presence of other independent risk factors. The patient with an acute fracture may require an orthopedic intervention and should receive adequate analgesia. Physical therapy is an important adjunct that aids recovery. A number of therapeutic interventions, including adequate calcium intake throughout life and an adequate vitamin D intake, are available to high-risk individuals. These interventions may be recommended generally and do not require a diagnosis of osteoporosis. Similarly, a safe weight-bearing exercise program that helps to maintain muscle strength can be recommended to older patients. Other forms of therapy include hormone replacement, bisphosphonates, and calcitonin. Vitamin D analogs and selective estrogen receptor modulators may be helpful in the future. The risks and costs of each therapy should be weighed against its benefit in slowing bone loss or increasing bone mass and reducing fractures.

Female↗

Hydrolysis of black soybean isoflavone glycosides by Bacillus subtilis natto.

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

Bacillus subtilis↗

Clinical significance of estrogen receptor beta in breast cancer.

Ever since the estrogen receptor (ER) beta was discovered in 1996, we have been trying to determine its value as a prognostic and/or predictive factor in breast cancer and its potential as a novel target for pharmacological intervention. Recent progress in cellular experiments has shown that ERbeta works as counter partner of ERalpha through inhibition of the transactivating function of ERalpha by heterodimerization, distinct regulation on several specific promoters by ERalpha or ERbeta, and ERbeta-specific regulated genes which are probably related to its anti-proliferative properties. Accumulated data from protein studies in breast cancer tissues indicate that positive expression of ERbeta appears to correlate with a favorable prognosis. Although the number of studies is small, a positive response to tamoxifen treatment is observed in both ERalpha- and ERbeta-positive populations. The significance of ERbeta2/cx, a splicing variant of ERbeta, remains controversial and needs to be analyzed in further studies. We postulate that a combined evaluation of ERbetacx with progesterone receptor may help the stratification of ERalpha-positive breast cancer. Epidemiological studies of hormone replacement therapy and isoflavone (genistein) consumption indicate the possible contribution of ERbeta-specific signaling in breast cancer prevention. A selective estrogen receptor modulator, which works as an antagonist of ERalpha and an agonist of ERbeta, may be a promising chemo-preventive treatment.

Breast Neoplasms↗

[Risk of thromboembolism and arteriosclerosis in women].

Young women are at a 3-fold higher risk of experiencing venous thromboembolism compared to young men. This risk is further increased by oral contraceptives, smoking, hereditary thrombophilia and/or low socioeconomic status. There are also hints for gender-specific differences in the arterial system. Coronary heart disease which is particularly important, develops in women 10-15 years later than in men. However, the clinical course in women is often more complicated. In women, thrombophilic predispositions play a more important role before menopause and metabolic risk factors after menopause compared to men. Thrombus formation needs to be initiated by disturbances of at least one element of the Virchow trias. There is principally no difference between men and women. However, all three elements are influenced by estrogen, resulting in gender-specific differences. There is a favorable influence on blood flow by the inhibition of atherogenesis and on the endothelial function by increased NO release, and the unfavorable influence on hemostasis resulting in hypercoagibility. Thus, particularly non-selective hormone replacement therapy for the inhibition of atherogenesis may be questionable due to increased thrombogenicity. The solution may be more selective estrogen receptor modulators. Clinical trials are still needed for both hormone replacement therapy and the therapy of venous and arterial thromboembolism, which have been studied in predominantly male patient cohorts so far.

Adult↗

[The osteoporosis patient with renal insufficiency: what has to be taken into account in the selection and administration of antiosteoporosis medication?].

The incidence of osteoporosis and renal insufficiency increases with age, the use of antiosteoporotic drugs approved for long-term administration in patients with inadequate renal function is therefore a cause for concern. In the dose approved for the treatment of osteoporosis oral bisphosphonates and i.v. ibandronate (3 mg every 12 weeks) have a secure antifracture efficacy, and their use is considered safe in patients with glomerular filtration rate (GFR) > 30 mI/min. Treatment with strontium ranelate and the osteoanabolic substance teriparatide is not altered by impaired renal function until GFR falls below 30 ml/min. Efficiancy of the selective estrogen receptor modulator (SERM) raloxifene is not altered by renal function.

Administration, Oral↗

Effects of an isopropanolic extract of Cimicifuga racemosa on urinary crosslinks and other parameters of bone quality in an ovariectomized rat model of osteoporosis.

A potential bone-sparing effect of Rhizoma actaeae (= cimicifugae) racemosae (black cohosh) was evaluated in ovariectomized Sprague-Dawley rats. The rats were ovariectomized at 12 weeks of age (body weight, 219-226 g) and placed on a soy-free diet 6 days after surgery. Animals were randomly assigned the following groups: control (n = 10), soy-free diet only; RAL (n = 10), soy-free diet plus raloxifene 3 mg/kg intragastrically; and REM (n = 10), soy-free diet supplemented with an isopropanolic black cohosh extract (Remifemin) with a daily intake of 4500 micro g triterpeneglycosides. Urinary levels of pyridinoline (PYR) and deoxypyridinoline (DPY), specific markers for bone loss, were measured at baseline and at weekly intervals. At the end of the study, the animals were killed and bone loss was determined by volumetric bone mineral density (BMD) measurements and peripheral quantitative computed tomography (pQCT). Mechanical resistance to fracture was also determined. Results demonstrated that an isopropanolic extract of black cohosh significantly diminished the urinary content of PYR and DPY and the morphometric correlates of bone loss associated with ovariectomy in rats. Reversal of the effects of ovariectomy on bone loss began 2-5 weeks after the start of treatment and continued through at least 7 weeks. Results similar in quality and magnitude were obtained in the group treated with raloxifene, a known selective estrogen receptor modulator (SERM). Because extracts of black cohosh are already recognized as safe and effective in the treatment of certain gynecological disorders, a longer-term clinical trial of this herbal remedy for the treatment of osteoporosis is warranted.

2-Propanol↗

Effects of ospemifene and raloxifene on biochemical markers of bone turnover in postmenopausal women.

Ospemifene is a novel selective estrogen receptor modulator (SERM) that is initially being developed for the treatment of vaginal atrophy in postmenopausal women. However, it also shows promise in the prevention and treatment of osteoporosis. As a part of a phase II trial, we compared the effects of ospemifene and raloxifene on bone turnover in postmenopausal women. The study was conducted as a randomized, double-blind study in which 118 healthy postmenopausal women received 30 (n = 29), 60 (n = 30), or 90 mg (n = 30) ospemifene or 60 mg (n = 29) raloxifene for 3 months. Bone resorption was assessed by measuring the urinary outputs of N- and C-terminal cross-linking telopeptides of type I collagen (NTX and CTX, respectively). Bone formation was assessed by measuring bone-specific alkaline phosphatase (bone ALP), osteocalcin (OC), procollagen type I N propeptide (PINP), and procollagen type I C propeptide (PICP) in serum. All markers were studied before and at 3 months and 2-4 weeks after cessation of the medication. Urine NTX outputs decreased in all study groups, and the only statistically significant difference in NTX was observed between raloxifene and 30 mg ospemifene, which was reduced more in the raloxifene group. The output of CTX decreased most clearly in 60- and 90-mg ospemifene groups, but no significant differences between study groups emerged. A significant difference was found between the 90-mg ospemifene group and raloxifene in PINP in favor of ospemifene. No other differences in bone formation markers emerged between ospemifene and raloxifene. The study confirms the bone-restoring activity of ospemifene, which is comparable to that of raloxifene.

Biomarkers↗

The 1999 James Ewing Lecture: in pursuit of molecules of oncogenesis and neoplastic therapy.

Breast cancer is a progressive, phenotypic, genetic and epigenetic alteration, induced by various stimulants of which the principal steroid hormone, estrogen, initiates and promotes neoplastic transformation of normal ductal mammary epithelium to acquire distinct biochemical and molecular characteristics. The molecular events that characterize oncogenesis with dysregulated physiologic states represent an area of intense translational research. The progress of the last century suggests that the targeted responses initiated by this steroid hormone can be attenuated and modified with anti-estrogen therapies or through applied intervention with selective estrogen receptor modulation. New pharmacological, genetic, and biological agents will undoubtedly afford clinical investigators of the next millennium the opportunity to provide major impact on the disease progression of this neoplasm, through these targeted endocrine responses for estrogen.

Antineoplastic Agents↗

Effects of toremifene (TOR) and tamoxifen (TAM) on serum lipids in postmenopausal patients with breast cancer.

This study clarified the difference in the effects on serum lipids between toremifene (TOR) and tamoxifen (TAM). To remove influencing factors, we investigated adjuvant therapy for hormone receptor-positive patients with breast cancer without lymph node metastasis. The subjects were 65 patients who were enrolled in a multicenter randomized comparative study between April 1997 and March 2001. As adjuvant therapy, 20 mg of TAM or 40 mg of TOR was administered for 1 year. The levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-1 (Apo A-1), apolipoprotein A(Apo B), and lipoprotein a (Lp(a)) were measured prior to administration and 3, 6, and 12 months after the start of administration. TC, LDL-C, Lp(a) and Apo B significantly decreased from the third month of administration compared with values before the start of administration in both the TOR and TAM groups. HDL-C significantly increased from the third month only in the TOR group. TG significantly increased in the TAM group but significantly decreased in the TOR group in the 12th month of administration. When these two groups were compared, HDL-C was significantly higher (p < 0.01) and TG was significantly lower (p < 0.01) in the TOR group in the 12th month. Improvement of abnormal values of TG, HDL-C and LDL-C was better in the TOR group than in the TAM group after administration for 12 months. The effect on lipid metabolism showed different profiles between the two selective estrogen receptor modulators (SERMs), and TOR gave better results than TAM.

Adult↗

Pharmacologic resistance in prolactinoma patients.

Pharmacologic resistance to dopamine agonists is defined here as failure to normalize PRL levels and failure to decrease macroprolactinoma size by >or=50%. Failure to normalize PRL levels is found in about one-quarter of patients treated with bromocriptine and 10-15% of those treated with pergolide or cabergoline. Failure to achieve at least a 50% reduction in tumor size occurs in about one-third of those treated with bromocriptine and 10-15% of those treated with pergolide or cabergoline. The cause of dopamine resistance is primarily a decrease in D(2) receptors but the receptors have normal affinity for dopamine. Treatment approaches for patients resistant to dopamine agonists include changing to another dopamine agonist and increasing the dose of the drug as long as there is continued response to the dose increases and no adverse effects with higher doses. Transsphenoidal surgery is also an option. Clomiphene, gonadotropins, and GnRH can be used if fertility is desired. For those not desiring fertility, estrogen replacement may be used unless there is a macroadenoma, in which case control of tumor growth is also an issue and dopamine agonists are generally necessary. In many patients modest or even no reduction in tumor size may be acceptable as long as there is not tumor growth. Hormone replacement (estrogen or testosterone) may cause a decrease in efficacy of the dopamine agonist so that it must be carried out cautiously. Reduction of endogenous estrogen, use of selective estrogen receptor modulators, and aromatase inhibitors are potential experimental approaches.

Bromocriptine↗

Complete and selective estrogenic effects on lipids and cardiovascular disease.

Observational studies have shown a protective effect of estrogen replacement on risk of cardiovascular disease in postmenopausal women. The estrogen protection is thought to be mediated by mechanisms acting at different levels, including a beneficial effect on plasma lipid concentrations. Selective estrogen receptor modulators (SERM) share with estrogen the ability to reduce plasma levels of atherogenic lipoproteins like low-density lipoproteins and lipoprotein(a). The recent publication of the first randomized, placebo-controlled trial of estrogen/progestin replacement (HERS), which failed to show a reduced number of cardiovascular events in women randomized to estrogen treatment as compared with placebo, has cast some doubts on the protective role of estrogen. Other large randomized studies on the effect of estrogen and other compounds with estrogenic activity (eg, SERM) on cardiovascular disease risk are currently underway and will provide more definite answers to both clinicians and postmenopausal women.

Arteriosclerosis↗

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

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

Alendronate↗

Effect of raloxifene on cardiovascular adverse events in postmenopausal women with osteoporosis.

The impact of selective estrogen receptor modulators on cardiovascular disease outcomes in postmenopausal women remains unclear. This analysis assessed the effect of raloxifene on the incidence of cardiovascular adverse events in postmenopausal women followed for < or =8 years as participants in a 4-year osteoporosis treatment trial and a subsequent 4-year follow-up trial. The Continuing Outcomes Relevant to Evista (CORE) trial, designed to determine the effect of raloxifene on the incidence of invasive breast cancer, was a 4-year follow-up study to the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial. Of the 7,705 participants originally enrolled in MORE, 4,011 were enrolled in CORE and thus participated in both trials (MORE-CORE participants). The incidence of serious cardiovascular (i.e., coronary and cerebrovascular) adverse events during 8 years, confirmed by external adjudication in the 2 trials, was compared between treatment groups using Cox proportional hazards models. The 8-year incidence of serious cardiovascular adverse events did not differ significantly between the raloxifene (5.5%) and placebo (4.7%) groups (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.86 to 1.56). Similar results were obtained when coronary (HR 1.22, 95% CI 0.82 to 1.83) or cerebrovascular (HR 1.19, 95% CI 0.78 to 1.84) events were analyzed separately, and when cardiovascular events were analyzed in the 459 MORE-CORE participants who were at increased risk of cardiovascular events by previously established criteria (HR 1.03, 95% CI 0.58 to 1.82). In conclusion, we found no evidence of a beneficial or harmful effect of raloxifene on the incidence of cardiovascular events overall, or coronary or cerebrovascular events, in postmenopausal osteoporotic women at relatively low risk of cardiovascular events.

Aged↗

Estradiol and endocrine disrupting compounds adversely affect development of sea urchin embryos at environmentally relevant concentrations.

Environmental endocrine disrupting compounds (EDCs) are a wide variety of chemicals that typically exert effects, either directly or indirectly, through receptor-mediated processes, thus mimicking endogenous hormones and/or inhibiting normal hormone activities and metabolism. Little is known about the effects of EDCs on echinoderm physiology, reproduction and development. We exposed developing sea urchin embryos (Strongylocentrotus purpuratus and Lytechinus anamesus) to two known EDCs (4-octylphenol (OCT), bisphenol A (BisA)) and to natural and synthetic reproductive hormones (17beta-estradiol (E2), estrone (E1), estriol (E3), progesterone (P4) and 17alpha-ethynylestradiol (EE2)). In addition, we studied two non-estrogenic EDCs, tributyltin (TBT) and o,p-DDD. Successful development to the pluteus larval stage (96 h post-fertilization) was used to define EDC concentration-response relationships. The order of compound potency based on EC50 values for a reduction in normal development was as follows: TBT(L. anamesus)>OCT>TBT(S. purpuratus)>>E2>EE2>DDD>>BisA>P4>E1>>E3. The effect of TBT was pronounced even at concentrations substantially lower than those commonly reported in heavily contaminated areas, but the response was significantly different in the two model species. Sea urchin embryos were generally more sensitive to estrogenic EDCs and TBT than most other invertebrate larvae. Stage-specific exposure experiments were conducted to determine the most sensitive developmental periods using blastula, gastrula and post-gastrula (pluteus) stages. The stage most sensitive to E2, OCT and TBT was the blastula stage with less overall sensitivity in the gastrula stage, regardless of concentration. Selective estrogen receptor modulators (SERMs) were added to the experiments individually and in combination with estrogenic EDCs to interfere with potential receptor-mediated actions. Tamoxifen, a partial ER agonist, alone inhibited development at concentrations as low as 0.02 ng/ml and was effective at this concentration in decreasing the sensitivities of the embryos to estradiol and estrogenic EDCs. The complete antagonist ICI 182,780 inhibited development at concentrations as low as 0.03 ng/ml but increased embryo sensitivity to estradiol and estrogenic EDCs. Estradiol and estrogenic EDCs all cause developmental toxicity in sea urchins through a TAM-sensitive but an ICI-insensitive mechanism. It remains to be demonstrated whether this mechanism involves an estrogen-responsive nuclear receptor (NR), a membrane receptor (NR or non-NR-related) or a completely different mechanism of toxicity. However, early embryo sensitivity and the differential response to SERM co-incubation further suggests more than one mode of EDC action in the developing sea urchin embryo.

Age Factors↗

Sodium nitroprusside-induced osteoblast apoptosis is mediated by long chain ceramide and is decreased by raloxifene.

Release of high levels of nitric oxide (NO) is associated with osteoblastic cell death. The mechanisms of NO-induced cytotoxicity are not well documented and it is presently not known if estrogenic compounds prevent this effect. We studied the role of ceramides in cell death induced by the NO donor sodium nitroprusside (SNP) and we tested the possibility that 17beta-estradiol, the anti-estrogen ICI 182.780 and two selective estrogen receptor modulators raloxifene and tamoxifen modify osteoblastic cell apoptosis. SNP dose-dependently decreased MC3T3-E1 osteoblast viability, increased NO production in the culture media and enhanced the release of intracellular ceramides C22 and C24. Cell death induced by SNP was partially inhibited when MC3T3-E1 cells were pretreated with raloxifene and tamoxifen but was not modified when the cells were pretreated with 17beta-estradiol or ICI 182.780. Cell death induced by SNP resulted from apoptosis as demonstrated by Annexin-V and propidium iodide labeling and a reduction of SNP-induced MC3T3-E1 apoptosis was confirmed in the presence of raloxifene and tamoxifen. SNP induction of C22 and C24 production was inhibited by a pretreatment with raloxifene but not with 17beta-estradiol. Moreover, the synthetic ceramide C24 (0.75 and 1microM) decreased MC3T3-E1 cell viability and osteoblast cell death induced by C24 was partially decreased by raloxifene and to a lesser extent by 17beta-estradiol. These data demonstrate that SNP-induced cell death is mediated by the long chain ceramides C22 and C24 and that raloxifene protected osteoblast from apoptosis induced by SNP, an effect that might be relevant to its pharmacological properties on bone remodeling.

Animals↗

In vitro evaluation of the anti-estrogenic activity of hydroxyl substituted diphenylnaphthyl alkene ligands for the estrogen receptor.

There is still a need for additional scaffolds to further explore tissue selectivity and improving efficacy of selective estrogen receptor modulators (SERMs). A series of hydroxyl substituted diphenylnaphthyl alkene ligands for the two estrogen receptors are described that arose from an initial de novo designed diphenylnaphthyl propylene ligand 1. All compounds gave K(i)s under 10 nM when assayed in the presence of ERalpha. Generally these compounds had very high affinity for both ER isotypes. Moving the hydroxyl group on naphthalene from the 6- to the 5-position of the alpha-naphthalene attached compounds (6b and 6e vs 6c and 6f) had little affect on ER binding nor did altering the position of the naphthalene attachment (alpha or beta) to the alkene moiety. In transfection assays none of the compounds displayed agonistic activity in the absence of E(2). In MCF-7 proliferation assays 6a-d, 6f and 12a-c successfully abrogated E(2) stimulation and resulted in greater than 50% inhibition at 1 microM, a level of efficacy similar to that obtained when the cells were treated with raloxifene. Our results show that this new class of SERMs are good candidates for further study as therapeutic agents for the treatment of breast cancer and osteoporosis.

Alkenes↗

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↗

Phytoestrogens: hormonal action and brain plasticity.

Because of their protective effects in age-related diseases and hormone-dependent cancers, the use of phytoestrogens (isoflavones) as 'natural' remedies has gained prominence. Isoflavones are estrogen mimics that bind estrogen receptors and act like natural selective estrogen receptors modulators. However, limited data exists regarding the influence of soy-derived dietary isoflavones in brain. This brief review will address these topics and examine the influence of dietary isoflavones on sexually dimorphic hypothalamic nuclei. We have observed that altering the isoflavone content within diet significantly affects both the sexually dimorphic nucleus of the preoptic area (a structure that is larger in males than in females) and the anteroventral periventricular nucleus (a structure that is larger in females than in males). Specifically, when animals were switched from phytoestrogen-rich to a phytoestrogen-free diet the volume of the sexually dimorphic nucleus of the preoptic area was decreased in males (no alterations were detected in females). Conversely, when the anteroventral periventricular nucleus was examined, volume changes were recorded in males and females opposite to the patterns observed for the sexually dimorphic nucleus of the preoptic area. Given the practical limitations of examining the effects of dietary phytoestrogens in the human brain, it is important to establish comparative data sets to elucidate phytoestrogen's hormone action and potentially its beneficial brain health effects.

Animals↗