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PubMedDate not supplied

Management of osteoporosis in postmenopausal women: 2006 position statement of The North American Menopause Society.

OBJECTIVE: To update the evidence-based position statement published by The North American Menopause Society (NAMS) in 2002 regarding the management of osteoporosis in postmenopausal women. DESIGN: NAMS followed the general principles established for evidence-based guidelines to create this updated document. A panel of clinicians and researchers expert in the field of metabolic bone diseases and/or women's health were enlisted to review the 2002 NAMS position statement, compile supporting statements, and reach consensus on recommendations. The panel's recommendations were reviewed and approved by the NAMS Board of Trustees. RESULTS: Osteoporosis, whose prevalence is especially high among elderly postmenopausal women, increases the risk of fractures. Hip and spine fractures are associated with particularly high morbidity and mortality in this population. Given the health implications of osteoporotic fractures, the primary goal of osteoporosis therapy is to prevent fractures, which is accomplished by slowing or stopping bone loss, maintaining bone strength, and minimizing or eliminating factors that may contribute to fractures. The evaluation of postmenopausal women for osteoporosis risk requires a medical history, physical examination, and diagnostic tests. Major risk factors for postmenopausal osteoporosis (as defined by bone mineral density) include advanced age, genetics, lifestyle factors (such as low calcium and vitamin D intake, smoking), thinness, and menopause status. The most common risk factors for osteoporotic fracture are advanced age, low bone mineral density, and previous fracture as an adult. Management focuses first on nonpharmacologic measures, such as a balanced diet, adequate calcium and vitamin D intake, adequate exercise, smoking cessation, avoidance of excessive alcohol intake, and fall prevention. If pharmacologic therapy is indicated, government-approved options are bisphosphonates, a selective estrogen-receptor modulator, parathyroid hormone, estrogens, and calcitonin. CONCLUSIONS: Management strategies for postmenopausal women involve identifying those at risk of low bone density and fracture, followed by instituting measures that focus on reducing modifiable risk factors through lifestyle changes and, if indicated, pharmacologic therapy.

Evidence-Based Medicine↗
PubMed2005

Emerging concepts in osteoporosis and bone strength.

OBJECTIVE: Osteoporosis is a systemic skeletal disorder characterized by compromised bone strength and increased fracture risk. The factors that contribute to bone strength include bone mineral density (BMD) and bone quality, which encompasses factors such as bone turnover, microarchitecture, mineralization, and geometry. The objective of this paper was to review the factors that contribute to bone strength and osteoporosis. RESEARCH DESIGN: A MEDLINE search of English language journals between 1 January 1995 and 1 March 2005 was conducted using the term 'osteoporosis' combined with 'bone strength' or 'bone quality'. Reference lists of pivotal studies and reviews were also examined. Studies were otherwise not excluded on the basis of quality or size, the aim being to present an overview of research conducted to date on osteoporosis and bone strength. RESULTS: While there is a relationship between BMD and fracture risk, evidence suggests that BMD measurements reflect only 1 component of bone strength. For example, small changes in BMD produced by osteoporosis treatments do not fully explain the reductions in fracture risk observed after initiation of therapy, and substantial fracture risk reduction is observed before peak increases in BMD are achieved. In addition to their effects on BMD, anti-resorptive therapies for osteoporosis (i.e., bisphosphonates, selective estrogen receptor modulators, calcitonin, and estrogen) produce positive effects on bone turnover, microarchitecture, and/or mineralization, all of which can contribute to the reductions in fracture risk observed with these agents. Anabolic agents such as teriparatide also appear to have beneficial effects on bone strength independent of bone mass. New, non-invasive, high-resolution imaging methods, such as magnetic resonance imaging and computed tomography, may offer a comprehensive assessment of bone quality in the future. CONCLUSIONS: The development of clinical tools that assess bone quality independent of BMD will be essential to advance our assessment of fracture risk and response to osteoporosis treatment.

Bone Density↗
PubMed2004

Activity and safety of the antiestrogen EM-800, the orally active precursor of acolbifene, in tamoxifen-resistant breast cancer.

PURPOSE: To determine the efficacy and safety of EM-800 (SCH-57050), the precursor of acolbifene, a new, highly potent, orally active, pure antiestrogen in the mammary gland and endometrium, for the treatment of tamoxifen-resistant breast cancer. PATIENTS AND METHODS: Forty-three post menopausal/ovariectomized women with breast cancer who had received tamoxifen, either for metastatic disease or as adjuvant to surgery for > or = 1 year, and had relapsed were treated in a prospective, multicenter, phase II study with EM-800 (20 mg/d [n = 21] or 40 mg/d [n = 22] orally). Results Thirty-seven patients had estrogen receptor (ER)-positive tumors (>10 fmol/mg; mean, 146 fmol/mg cytosolic protein), three patients had ER-negative/progesterone receptor-positive tumors, and three patients had undetermined ER status. The objective response rate to EM-800 was 12%, with one complete response and four partial responses. Ten patients (23%) had stable disease for > or = 3 months, and 7 patients (16%) had stable disease for > or = 6 months. With a median follow-up of 29 months, median duration of response was 8 months (range, 7 to 71+ months). Treatment with EM-800 was well tolerated. No significant adverse events related to the study drug were observed clinically or biochemically. CONCLUSION: EM-800 produced responses in a significant proportion of patients with tamoxifen-resistant breast cancer, thus showing that this highly potent, selective estrogen receptor modulator, which lacks estrogenic activity in the mammary gland and endometrium, has incomplete cross-resistance with tamoxifen, thus suggesting additional benefits in the treatment of breast cancer.

Administration, Oral↗
PubMed2004

Raloxifene and its role in breast cancer prevention.

Raloxifene (Evista, Eli Lilly), a selective estrogen receptor modulator (SERM) and ligand for the estrogen receptor (ER), competes with endogenous estrogen for ER binding. Raloxifene is approved for the prevention and treatment of osteoporosis, and shows promise as a breast cancer prevention drug. Raloxifene may be a preferred agent over tamoxifen due to its side-effect profile; in particular, it does not stimulate the endometrium and is not associated with endometrial cancer. The mechanisms for the differential tissue effects of raloxifene compared with other SERMs are not completely understood; the roles of ERalpha and -beta, classic and alternative signaling pathways, and drug conformation are discussed in this review. The utility of raloxifene will depend on the outcome of trials that are now underway, as well as acceptance by high-risk women and their healthcare practitioners.

Breast Neoplasms↗
PubMed2004

Phytoestrogens: implications in neurovascular research.

The early discontinuation of the Women's Health Initiative trial evaluating the effects of estrogen plus progestin due to concerns about the risk-benefit ratio of this steroid combination therapy emphasizes the need to examine alternative methods of estrogen replacement. One such alternative is isoflavone consumption of soy-derived dietary phytoestrogens that have received prevalent usage due to their ability to decrease age related disease (cardiovascular and osteoporosis), hormone-dependent cancers (breast and prostate), and peri- and postmenopausal symptoms. Differences in dietary phytoestrogen consumption result in large variations in somatic phytoestrogen content. These molecules affect estrogen and estrogen receptor function in several ways, including having both agonist and antagonist effects on estrogen receptors, as well as functioning like natural selective estrogen receptor modulators. Similar to estrogens, dietary phytoestrogens appear to affect certain aspects of vascular, neuroendocrine, and cognitive function. This article reviews health effects of estrogen, isoflavones and their hormonal mechanism of action, brain penetration by isoflavones, heath effects of isoflavones, and effects of isoflavones on vascular, neuroendocrine, and cognitive function. Because of their diverse health effects and widespread availability in soy foods, dietary phytoestrogens merit continued research into their effects on human health and cognitive function.

Animals↗
PubMed2007

New agents in development for breast cancer.

PURPOSE OF REVIEW: This review summarizes the continuing value of some therapeutic drugs and new agents under development for the treatment of breast cancer. RECENT FINDINGS: Overexpression and activation of various growth factor receptors occurs frequently in human breast cancer. Therapeutic approaches mainly involve the epidermal growth factor receptor family, insulin-like growth factor receptor and vascular endothelial growth factor receptor. Therapeutic agents targeting these receptors include the monoclonal antibodies trastuzumab and pertuzumab, and the small-molecule inhibitors gefitinib and erlotinib. Other small-molecule and dual inhibitors are in development, some of which have been demonstrated to have higher efficacy in the treatment of breast cancer. The selective estrogen receptor modulators and aromatase inhibitors continue to be valuable in the endocrine therapy of breast cancer. These drugs have been shown to have higher efficacy than conventional therapy agents, and to have extensive potential, especially in the treatment of postmenopausal women with advanced breast cancer. SUMMARY: Approved agents including epidermal growth factor receptor-targeted inhibitor, selective estrogen receptor modulators and aromatase inhibitors continue to be valuable in treating breast cancer. To overcome the acquired resistance caused by these agents and to enhance the therapy effect, the development of new and specific dual inhibitors targeting various growth factor receptors will be important in the future.

Antibodies, Monoclonal↗
PubMed2003

Estrogens and Parkinson disease: neuroprotective, symptomatic, neither, or both?

Parkinson disease is a neurodegenerative disorder caused by substantia nigra dopamine cell death and is characterized by bradykinesia, rigidity, rest tremor, and postural instability. Epidemiologic and clinical studies have suggested that gender and estrogen play a role in modulating Parkinson disease. The etiology of the estrogenic effect is unclear-it may be neuroprotective, symptomatic, or both. Retrospective studies suggest a possible neuroprotective role. Interventional studies have suggested a positive modulatory role or no role at all. While it is difficult to establish whether there is a true neuroprotective benefit of estrogen in the setting of even mild symptomatic benefit, laboratory data suggest such a neuroprotective role. Estrogen may act as an antiapoptotic agent, an antioxidant, or a neurotrophic modulating agent, promoting crosstalk with neurotrophic factors. The selective estrogen receptor modulators (SERMs) may also confer neuroprotection. However, prior to establishing the role of estrogen in Parkinson disease, additional study, including of the SERMs, is warranted.

Dementia↗
PubMed2003

Mechanisms of action of antiresorptive therapies of postmenopausal osteoporosis.

In the treatment of osteoporosis, the aim of the antiresorptive therapy is to restore bone density by decreasing bone remodeling. The process of bone remodeling plays a role in plasma calcium homeostasis and serves to modify bone architecture in order to meet changing mechanical needs, to maintain osteocyte viability, and to repair microdamage in bone matrix. Estrogen deficiency results in a number of detrimental effects on bone, including suppression of osteocyte survival as well as impairment of osteoblast response to mechanical stimuli and repair of ageing bone. In this review, effects of available antiresorptive therapies on endocrine regulations of bone metabolism in postmenopausal osteoporosis are compared. The aim of antiresorptive treatment is to ensure adequate bone remodeling, reparation of microdamage of bone, and increased bone strength. Ideally, this effect should be maintained long-term. Several agents are approved for the treatment of osteoporosis. Calcitonin transiently inhibits osteoclast activity without decreasing osteoblast collagen synthesis. Aminobisphosphonates decrease bone remodeling by decreasing osteoclast activity and by inducing osteoclast apoptosis. This allows more time for secondary mineralization to proceed to completion in the existing bone tissue mass, so increasing the mechanical resistance of bone to loading. Estrogens and raloxifene (a selective estrogen receptor modulator that acts as an estrogen agonist in bone) suppress bone remodeling to the premenopausal range, maintaining the function of osteoblasts and osteocytes. In the placebo-controlled osteoporosis treatment trials, all the above treatments reduced the risk of fractures. Raloxifene therapy was also associated with a favorable or neutral effect in the cardiovascular system, and a reduced incidence of breast cancer. Selection of appropriate drug for treatment of postmenopausal osteoporosis should take into account the long-term effect of the antiresorptive agent on bone. Moreover, the effects on other tissues ++should also be considered, and this encompasses both safety concerns, as well as the potentially beneficial effects on other tissues. Further investigation is needed to evaluate the different modes of action of these agents, and their long-term effects on bone and other tissues.

Alendronate↗
PubMed2002

Effects of oral estrogen, raloxifene and arzoxifene on gene expression in serotonin neurons of macaques.

The serotonin neural system contributes to cognition and affect, both of which exhibit pathologies with gender bias. We previously showed that estrogen (E) treatment of female macaques via Silastic implant alters gene expression for tryptophan hydroxylase (TPH), the serotonin reuptake transporter (SERT) and the 5HT1A autoreceptor. In addition, we have found that serotonin neurons of macaques express ER beta (ER beta). Together these studies suggest that the serotonin neural system could transduce the action of estrogen via ER beta on aspects of mood and cognition. However, estrogen replacement therapy can increase the risk for breast and uterine cancer. Therefore, we questioned whether the selective estrogen receptor modulators, raloxifene and arzoxifene, act in a manner similar to E on gene expression in serotonin neurons of a nonhuman primate model. Female rhesus macaques were ovariectomized and orally dosed with vehicle, estradiol 17beta, raloxifene or arzoxifene once per day by sipper bottles for 30 days. The animals were then euthanized and the midbrains were prepared for in situ hybridization for TPH, SERT and 5HT1A receptor mRNAs followed by densitometric analysis. There was a significant increase in TPH total signal (positive pixelsxOD) with E, raloxifene and arzoxifene, respectively. There was a significant decrease in SERT mRNA optical density with all treatments. 5HT1A autoreceptor mRNA did not change with any treatment. If these changes in gene expression are reflected by similar changes in the functional proteins, then raloxifene or arzoxifene could increase serotonin neurotransmission with little or no negative action in peripheral tissues. In conclusion, the selective estrogen receptor modulators, raloxifene and arzoxifene, act in a manner similar to natural E on TPH and SERT mRNA expression in serotonin neurons. This suggests that raloxifene and arzoxifene are agonists at ER beta in the context of the serotonin neuron. However, the responses to E were more variable and less robust with the oral dosing paradigm compared to a chronic implant paradigm.

Animals↗
PubMed2001

Raloxifene.

Raloxifene is a selective estrogen receptor modulator, a compound that has estrogen agonist activity at some sites and antagonist activity at others. In investigations in animals and in rigorously conducted trials in humans, raloxifene treatment is associated with a 30%-40% reduction in risk of one or more spine fractures using the 60 mg dose. This reduction in risk is found in women with or without baseline fractures, in women with bone mineral density (BMD) in the lower, middle, or upper third of the low range (all had BMD reduced by more than 2.5 SD) and in women aged less than 65 years, between 65-70 years, and greater than 70 years. A reduction in ankle fractures, but not hip or wrist fractures, was found. Raloxifene treatment also is associated with a 60%-70% reduction in risk for breast cancer and is associated with reduced total and LDL cholesterol, lower fibrinogen, and no rise in triglyceride. Reduced aortic wall cholesterol content is reported in animal studies. These are surrogate endpoints of cardioprotection. There is no evidence that raloxifene reduces the incidence of myocardial or cerebrovascular events. Raloxifene does not induce breast tenderness, endometrial hyperplasia, menstrual bleeding, or endometrial cancer, but may be associated with an increased risk of thromboembolic disease (1/1000 cases per year), leg cramps in 2%-4% of cases and hot flushes in 4%-6% of cases, usually in first 6 months.

Animals↗
PubMedDate not supplied

Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years.

OBJECTIVE: Raloxifene hydrochloride (60 mg/day) is a selective estrogen receptor modulator indicated for the prevention and treatment of postmenopausal osteoporosis. Raloxifene treatment for 3 years increases bone mineral density (BMD) and, unlike tamoxifen (a triphenylethylene selective estrogen receptor modulator), does not stimulate the endometrium in healthy postmenopausal women. The effect of longer duration of treatment with raloxifene is not known. Therefore, the main objectives of these analyses are (1) to compare the effect of 5 years of treatment with raloxifene (60 mg/day) with placebo in terms of the likelihood of developing osteoporosis and (2) to evaluate the effect of 5 years of raloxifene treatment on the endometrium and incidence of vaginal bleeding. DESIGN: The current analyses include integrated data from two identically designed, prospective, double-blinded trials including postmenopausal women (mean age, 55 years) randomly assigned to either placebo (n = 143) or raloxifene (60 mg/day; n = 185). Osteoporosis and osteopenia were diagnosed according to World Health Organization criteria, using the manufacturer's database for the lumbar spine and the National Health and Nutrition Examination Survey's 1998 reference base for the hip. Endometrial thickness was determined using transvaginal ultrasonography. Clinical diagnoses of endometrial hyperplasia or endometrial cancer were confirmed by blinded review of histopathology reports. RESULTS: Compared with the case of placebo, raloxifene treatment for 5 years reduced bone turnover markers (osteocalcin: -10.9%, P < 0.001; bone-specific alkaline phosphatase: -7.2%, P = 0.042; urinary C-telopeptide: -11.1%, P = 0.034) and was associated with increased BMD in the lumbar spine (2.8%; P < 0.001) and total hip BMD (2.6%; P < 0.001). Women taking raloxifene were less likely to develop osteoporosis (relative risk [RR] for raloxifene v placebo: 0.13; 95% CI: 0.00, 0.37; P = 0.001) or osteopenia (RR: 0.23; 95% CI: 0.00, 0.81; P = 0.038) at the lumbar spine and were more likely to convert to normal BMD status at the lumbar spine (RR: 4.01; 95% CI: 1.34, 11.23; P = 0.043) and total hip (RR: 3.92; 95% CI: 1.12,14.27; P = 0.011) at 5 years, compared with the case of placebo. Raloxifene also significantly reduced total cholesterol (-5.5%; P < 0.001) and low-density lipoprotein cholesterol (-8.7%; P < 0.001), compared with the case of placebo. No significant changes in high-density lipoprotein cholesterol (P = 0.257) or triglycerides (P = 0.620) were detected. Incidence of hot flashes was higher among women taking raloxifene compared with those taking placebo [raloxifene, 47 (28.8%); placebo, 21 (16.8%); P = 0.017]. Women taking placebo or raloxifene reported a similar incidence of vaginal bleeding (P = 0.999) or of mean endometrial thickness of more than 5 mm at baseline and at each visit, up to the 5-year endpoint (P >/= 0.349). No diagnoses of endometrial hyperplasia or endometrial cancer were made in either treatment group. CONCLUSIONS: Five years of raloxifene treatment in healthy postmenopausal women preserves BMD, significantly reduces the likelihood of development of osteoporosis, and was not associated with an increased rate of vaginal bleeding, endometrial hyperplasia, or endometrial carcinoma, compared with the case of placebo.

Bone Density↗
PubMedDate not supplied

Molecular mechanisms of estrogen actions on the vasculature.

In summary, clinical and animal studies demonstrate that the effects of estrogen in the cardiovascular system protect against the development of histologic and clinical atherosclerosis. However, because estrogen affects so many cellular processes (Figure 4), there are many known adverse effects, including oncogenic and potential negative consequences on the vasculature, including procoagulant and plaque-destabilizing effects. Selective estrogen receptor modulators may allow us to target specific pathways that selectively and favorably effect beneficial responses. However, we must first gain a better understanding of the molecular mechanisms by which estrogen induces cellular signals, both genomic and nongenomic, before we can take full advantage of selective estrogen receptor modulators. As our ability to selectively modulate vascular responses to injury improves, it will be imperative that we have the ability to assess vascular structure, function and pathology with more practical, logistically accessible and biologically targeted approaches than those currently available. Such tools will allow us to test a broad spectrum of agents aimed at pharmacologic therapy for vascular disease.

Animals↗
PubMed2002

The effect of raloxifene on glyco-insulinemic homeostasis in healthy postmenopausal women: a randomized placebo-controlled study.

The effect of raloxifene, a selective estrogen receptor modulator recently approved as a therapeutic agent for menopause, on glyco-insulinemic metabolism was investigated in 40 healthy postmenopausal women. At the baseline and after 12 wk of raloxifene (60 mg/d) or placebo administration, all aspects of glucose metabolism were evaluated in each subject using both an oral glucose tolerance test (OGTT; 75 g) and a hyperinsulinemic euglycemic clamp to assess peripheral insulin sensitivity. Glucose, insulin, and C-peptide, measured in fasting conditions, as well as glucose and insulin responses to OGTT [expressed as area under curve (AUC)] were not modified by raloxifene, whereas C-peptide-AUC increased significantly (P < 0.05). Furthermore, a trend toward an improvement of peripheral insulin sensitivity and hepatic clearance of the hormone (fractional hepatic insulin extraction) was observed in the raloxifene-treated women with respect to the control patients. When the subjects were studied in relation to their insulin secretion in response to the glucose load, the patients, classified as hyperinsulinemic, showed the most significant response to the raloxifene treatment. In these women, the selective estrogen receptor modulator was able to induce a significant reduction of insulin circulating plasma values (P < 0.01) through both an increase of fractional hepatic insulin extraction (P < 0.01) and an improvement of the peripheral insulin sensitivity (P < 0.05). On the contrary, no net change of insulin dynamics was observed in normoinsulinemic and placebo-treated women. The present data indicate that raloxifene does not negatively influence glyco-insulinemic metabolism in unselected postmenopausal women and may indeed improve the excessive insulin responsiveness to OGTT in a selected population of hyperinsulinemic postmenopausal women.

Androgens↗
PubMed2000

Is thyroid hormone a modulator of estrogen receptor in porcine follicular cells?

OBJECTIVE: To examine whether the action of triiodothyronine on aromatase activity in porcine follicular cells is related to the modulation of estradiol receptor. METHODS: Medium and large preovulatory follicles were incubated in Parker medium (M199) supplemented with 5 % of calf serum as a control medium or with addition of triiodothyronine (T3; 10 -9 M), tamoxifen (TMX; 0.1 mM ) or T3+TMX. The media were collected after 48 h, and assayed for progesterone (P4) and estradiol (E2) secretion by RIA. RESULTS: T3 added to the medium decreased E2 secretion by both medium and large preovulatory follicles (119.7 % and 123.8 %, respectively; P<0.05). In contrast, T3 increased the secretion of P4 by medium (136 %; P<0. 05), while decreased the P4 secretion by large preovulatory follicles (123 %; P<0.05). The effect of TMX added alone was also dependent on follicular development. Estradiol secretion by medium follicles was 2.5 fold higher (p<0.01) than in control and 2.9 fold higher (P<0.01) than in T3 treated cells. In preovulatory follicles basal E2 secretion was not affected by TMX, while 1.2 fold higher (P<0.05) secretion compared to T3 treated cells was noted. On the other hand, TMX suppressed basal P4 secretion in medium and preovulatory follicles 1.5 fold (P<0.01) and 1.3 fold (P<0.05), respectively. The same phenomenon was observed in T3 treated cells. TMX added to the culture media decreased P4 secretion by medium follicles 1.8 fold (P<0.01) and that by preovulatory follicles 1.3 fold (P<0.05). CONCLUSIONS: The reversed T3 action on estradiol secretion by both medium (P<0.05) and large preovulatory (P<0.01) follicles in TMX treated follicles suggests the up-regulation of ER by triidothyronine.

Animals↗
PubMed2001

Chemoprevention with aromatase inhibitors--trial strategies.

Estrogen and its catechol metabolites from both the circulation and synthesized within the breast are important in the pathogenesis of breast cancer. Blocking estrogen's effects on the breast with selective estrogen receptor modulators (SERMS) is an ongoing strategy. Thus, tamoxifen and raloxifene reduce risk as monotherapy. Aromatase (estrogen synthetase) inhibitors are a logical alternative to SERMS. To date, SERMS have demonstrated reduction only in estrogen-progesterone receptor positive cancers without reduction in receptor negative tumors. By inhibiting the parent estrogens and their catechol metabolites, true prevention of cancer initiation might occur and reduction not only in the receptor positive but also negative tumors might result. Ongoing adjuvant breast cancer trials are exploring aromatase inhibitors as alternatives to tamoxifen, or in sequence or in combination with tamoxifen. Relative efficacies including reduction in contralateral breast cancer, toxicities and end-organ effects and impact on quality of life, are being explored. Data from these trials will help to guide future chemoprevention strategies. Proof of principal trials in 'high risk' cohorts such as premalignant breast lesions, dense screening mammograms, high plasma estradiol levels or increased bone density are already ongoing. Issues such as dose, schedule, therapeutic index and mono versus combination therapy are important to define.

Animals↗
PubMed2001

Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma no concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women.

The endothelium is thought to play an important role in the genesis of atherosclerosis, and several lines of evidence suggest that the effect of an intervention on endothelial function might predict its involvement in coronary disease progression and in the rate of cardiovascular events. Estrogen has direct effects on the blood vessel wall, indicating that vascular endothelium may play a key role in the cardiovascular protective effects of hormone replacement therapy (HRT). Raloxifene relaxes coronary arteries in vitro by an estrogen receptor-dependent and NO-dependent mechanism, thus suggesting that this selective estrogen receptor modulator could also have beneficial effects on endothelial function. This study compared the effects of HRT and raloxifene on NO products, endothelin-1 plasma levels, and endothelium-dependent vasodilatation in postmenopausal women. Healthy postmenopausal women (n=90) were enrolled in a double-blind, randomized, placebo-controlled, 6-month trial. Women were randomly assigned to receive continuous HRT (1 mg 17beta-estradiol combined with 0.5 mg norethisterone acetate), raloxifene (60 mg/d), or placebo for 6 months. Flow-mediated endothelium-dependent vasodilation of the brachial artery, plasma NO concentrations, and endothelin levels were measured at baseline and after 6 months of therapy. The mean baseline level of NO breakdown products was 26.5+/-10.7 micromol/L and increased to 36.3+/-11.4 micromol/L after 6 months of treatment with raloxifene. The mean baseline plasma endothelin level was 17.3+/-8.9 pg/mL and decreased to 11.5+/-2.1 pg/mL after 6 months of treatment with the selective estrogen receptor modulator. The mean baseline ratio of NO (breakdown products) to endothelin was also significantly increased at the end of treatment with raloxifene. Postmenopausal women treated with HRT had similar changes in plasma nitrites/nitrates and endothelin levels as well as in the ratio of NO to endothelin. In contrast, these markers of endothelial function did not change in the placebo-treated women. Flow-mediated endothelium-dependent vasodilation of the brachial artery was 8.3+/-2.1% at baseline and increased to 12.3+/-2.1% after 6 months of treatment with raloxifene. HRT also caused a significant and similar increase in flow-mediated endothelium-dependent vasodilation. No change in flow-mediated vasodilation was observed in the participants treated with placebo. We conclude that raloxifene therapy and HRT influence endothelial function and improve flow-mediated endothelium-dependent vasodilation to a comparable extent in healthy postmenopausal women at least after a 6-month treatment period. However, further investigation is warranted to enhance our understanding of the mechanisms of the effect of raloxifene on vascular function and to determine whether its effect on endothelial function may contribute to the reduction in cardiovascular-related morbidity and mortality.

Aged↗
PubMed2006

[Interactions between radiation and hormonal therapy in breast cancer: simultaneous or sequential treatment].

BACKGROUND: Combining radiation and hormone therapy (administration of selective estrogen receptor modulators) has become common clinical practice in recent years for receptor positive breast cancer. Little is known about a possible interaction of both treatment modalities if they are given simultaneously. Tamoxifen (antiestrogen molecule, triphenylethylene derivative) may theoretically render cancer cells less responsive to radiotherapy arresting hormone-receptor-positive cells in G0/G1 phase and increase the risk of breast and lung fibrosis stimulating the secretion of transforming growth factor beta in human fibroblasts. PURPOSE: This article reviews the published data to assess the impact of sequencing of hormonal and radiation therapy on outcomes in breast cancer. METHODS: Computerised searches for publications debating the sequencing of hormonal therapy relative to radiation therapy were done using MEDLINE data. RESULTS: Results of tamoxifen experiments with cell culture regarding radioprotection of tumour clonogens are conflicting. In contrast to in vitro results, in animal studies no protective effect of tamoxifen was observed. In one in vitro study, letrozole (non-steroid selective aromatase inhibitor) had a radiosensitizing effect on breast-cancer lines. No randomised clinical trials to date have studied sequencing of tamoxifen or other selective estrogen receptor modulators and radiotherapy. Results from retrospective clinical studies which included treatment arms with and without tamoxifen showed reduction in tumour recurrence with tamoxifen. Some of these studies have noted increased risk of lung and breast fibrosis with tamoxifen with radiotherapy. Results of three articles examined the effect of tamoxifen sequence showed no adverse effect on local control or survival in sequential versus concurrent tamoxifen and radiation patients. One of the three studies also assessed the risk of complications with respect to the timing of tamoxifen with radiotherapy. There was no difference in the rates of complications between the two groups. The association of radiation and selective aromatase inhibitors or aromatase inactivators has not been addressed in clinical studies. CONCLUSIONS: Combined application of tamoxifen and radiotherapy improves survival and local control in breast cancer. Available clinical studies do not indicate that the simultaneous application of tamoxifen and radiotherapy is disadvantageous, as was suggested by some of the in vitro studies. The risk of subcutaneous breast and lung fibrosis might be slightly increased if tamoxifen is given simultaneously with radiotherapy. Both treatment modalities should be started early after surgery. There is no sufficient evidence to withhold tamoxifen administration during irradiation of breast cancer. The issue of optimal sequencing of hormonal and radiotherapy should be addressed in randomised clinical trials.

Animals↗
PubMed2000

Progress in the prevention of breast cancer: concept to reality.

In 1936, Professor Antoine Lacassagne suggested that breast cancer could be prevented by developing drugs to block estrogen action in the breast. Jensen discovered the physiologic target, the estrogen receptor, that regulates estrogen action in its target tissues and Lerner discovered the first nonsteroidal antiestrogen MER25. However, the success of tamoxifen as a treatment of breast cancer opened the door for the testing of the worth of tamoxifen to reduce breast cancer incidence in high-risk women. In 1998, Fisher showed that tamoxifen could reduce breast cancer incidence by 50%. Nevertheless, only half the women who develop breast cancer have risk factors other than age, so what can be done for women without risk factors? The recognition that nonsteroidal antiestrogens have the ability to modulate estrogen action selectively has advanced the design and development of new drug for multiple diseases. Tamoxifen and raloxifene maintain bone density and raloxifene is now used to prevent osteoporosis and is being tested as a preventive for coronary heart disease and breast cancer. The drug group is now known as selective estrogen receptor modulators (SERMs) and the challenge is to design new agents for multiple applications. If the 20th century was the era of chemotherapy, the 21st century will be the era of chemoprevention.

Bone Density↗