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PubMed2000

Hormone replacement therapy (estrogen and progesterone): is it necessary for heart disease prevention?

This is a brief review of the rationale for estrogen replacement as prevention of coronary artery disease. Epidemiological data suggest that Premarin (0.625 mg) together with medroxyprogesterone acetate (2.5 mg) can prevent or delay the onset of coronary artery disease in postmenopausal women. The major effects of estrogens are: improving the lipid profile by lowering low-density lipoprotein and raising high-density lipoprotein; acting on vessel walls to reduce intimal damage and plaque formation; dilating vessels by both an endothelial dependent and an independent pathway; and acting as an antioxidant, thereby reducing the oxidation of low density lipoprotein and increasing the production of nitric oxide locally in the blood vessel. Oral estrogens and transdermal estrogens may act differently on coagulation factors and lipids. The role of specific estrogen receptor modulators as possible treatment for postmenopausal women in part will depend on the effect of these drugs in preventing coronary artery disease. The specific estrogen receptor modulators decrease low-density lipoprotein and prevent triglyceride increases but it is unknown if they have estrogenic effects on blood vessel walls. Better compliance with estrogen replacement therapy will depend on educating women about their risk of getting coronary artery disease, and assisting them in decision making, as well as reducing side effects. The Heart and Estrogen/Progestin Replacement Study provides evidence that Prempro (Premarin/ medroxyprogesterone acetate) should not be given to someone who already has heart disease without careful monitoring. (c) 2000 by CHF, Inc.

Journal Article↗
PubMed2001

Alternatives for women through menopause.

Today, 42% of Americans use alternative nonprescription therapies to treat medical conditions; 46% of nonprescription alternative use for principal medical conditions is done without consulting either a medical doctor or a nonphysician practitioner of alternative therapy. Many nontraditional alternatives are used to treat the hot flashes and somatic complaints of menopause, for which options such as hormone replacement therapy and other prescription and over-the-counter drugs are also available. To date, no one agent treats all menopausal symptoms as effectively as estrogen. Selective estrogen-receptor modulators can help prevent osteoporosis but do not relieve menopausal symptoms. However, some women are unwilling or unable to take hormone replacement therapy, and some decide to discontinue therapy. Evidence supporting the use of some nonprescription alternatives for conditions related to menopause is limited. Patients need to be aware of the potential for drug interactions when these alternative therapies are used concomitantly with prescription drugs. The current evidence to support use of hormone replacement therapy, selective estrogen-receptor modulators, and nontraditional alternatives is reviewed here.

Female↗
PubMed1997

Opiate receptors modulate estrogen-induced cholecystokinin and tachykinin but not enkephalin messenger RNA levels in the limbic system and hypothalamus.

Cholecystokinin, substance P and methionine enkephalin all regulate the display of reproductive behaviour. Their expression is exquisitely regulated by estrogen in the limbic-hypothalamic circuit, a circuit that regulates the display of estrogen-sensitive female reproductive behavior. Relatively little is known, however, about the interaction of endogenous opioid peptides with cholecystokinin and substance P in the limbic-hypothalamic circuit. Opiates antagonize the release of cholecystokinin and substance P in the hypothalamus and periaqueductal gray and stimulate cholecystokinin messenger RNA levels in the amygdala. To determine the effect of endogenous opioid input on estrogen-induced cholecystokinin, enkephalin and substance P expression, in situ hybridization histochemistry was used to examine estrogen-induced messenger RNA levels of these neuropeptides in specific nuclei of the limbic system and hypothalamus in the presence of opiate receptor antagonists. Estrogen treatment of ovariectomized rats significantly elevated cholecystokinin messenger RNA levels in the central portion of the medial preoptic nucleus, the encapsulated portion of the bed nucleus of the stria terminalis and the posterodorsal medial amygdala, as well as increased preproenkephalin and preprotachykinin messenger RNA levels in the ventromedial hypothalamic nucleus and the posterodorsal medial amygdala. The universal opiate receptor antagonist naltrexone and the delta-opiate receptor antagonist naltrindole each potentiated the estrogen-induced increase and elevated cholecystokinin messenger RNA levels an additional 1.9- to 2.8-fold depending on the nucleus examined, but had no effect on the estrogen-induced expression of either preproenkephalin or preprotachykinin messenger RNA. beta-Funaltrexamine, a mu-opiate receptor antagonist, had no effect on the medial preoptic or medial amygdaloid cholecystokinin messenger RNA levels or on the estrogen-induced expression of preproenkephalin messenger RNA but did cause a decrease in estrogen-induced cholecystokinin messenger RNA levels in the bed nucleus of the stria terminalis and a decrease in the preprotachykinin messenger RNA levels in the ventromedial hypothalamic nucleus. These results indicate that endogenous opioids, acting on the delta-opiate receptor within nuclei of the limbic-hypothalamic circuit, restrain the estrogen-induced increase of cholecystokinin messenger RNA expression. Activation of the mu-opiate receptor, however, may facilitate cholecystokinin messenger RNA expression in the bed nucleus of the stria terminalis and preprotachykinin messenger RNA expression in the ventromedial hypothalamic nucleus. Thus, endogenous opioid peptides may act in a site- and receptor-specific manner to modulate estrogen-induced neuropeptide levels in the limbic system and hypothalamus.

Animals↗
PubMed2000

Drugs with estrogen-like potency and brain activity: potential therapeutic application for the CNS.

Numerous reports, ranging from molecular investigations to clinical studies, demonstrate the potency of estrogens to modulate brain function and their implications in schizophrenia and depression. Alterations of dopaminergic, cholinergic, GABAergic, glutamatergic and serotonergic neurotransmission through estrogen-mediated mechanisms have been consistently established. Moreover, studies using in vivo and in vitro models as well as epidemiological data suggest that estrogens provide neuroprotection of central nervous system (CNS) cells implicated in the etiology of neurodegenerative disorders such as Alzheimer s (AD) and Parkinson s (PD) diseases. Numerous genomic or non-genomic mechanisms of actions of estrogens in the brain have been documented implicating classical nuclear estrogen receptors as well as possible estrogen membrane receptors, antioxidant activity of steroids, their effect on fluidity as well as on antiapoptotic proteins and growth factors. Selective estrogen receptor modulators (SERMs) have estrogenic and/or antiestrogenic activity depending on the target tissue. Hence, SERMs have the same beneficial effect as estrogen in skeleton and cardiovascular systems but act as antagonists in breast and uterus. The finding of beneficial side effects of SERMs in the CNS might improve their risk-benefit ratio in traditional indications. In this review, we will survey schizophrenia and depression as examples of mental diseases and AD and PD as neurodegenerative diseases. We will review brain effects of estrogens, steroids possibly acting as pro-drugs of estrogens such as testosterone and dehydroepiandrosterone (DHEA) and present novel findings with SERMs. Drugs with estrogen activity in the brain may have therapeutic potential either by modulating brain neurotransmitter transmission or through neuroprotective activity.

Alzheimer Disease↗
PubMed1998

Estrogen response elements function as allosteric modulators of estrogen receptor conformation.

The estrogen receptor (ER) is a ligand-dependent transcription factor that regulates the expression of estrogen-responsive genes. ER-mediated transcriptional changes are brought about by interaction of the ER with the estrogen response element (ERE). In this study, we examined the interaction of the Xenopus laevis ER DNA binding domain (DBD) and the intact ER with the X. laevis vitellogenin A2 ERE and the human pS2 ERE. Using gel mobility shift, DNase I footprinting, and methylation interference assays, we demonstrated that the DBD bound only as a dimer to the A2 ERE. However, the DBD bound as a monomer to the consensus pS2 ERE half site at lower DBD concentrations and then as a homodimer to the consensus and imperfect pS2 ERE half site at higher DBD concentrations. Antibody supershift experiments carried out with partially purified, yeast-expressed full-length ER demonstrated that three ER-specific antibodies interacted differentially with A2 and pS2 ERE-bound ER, indicating that receptor epitopes were differentially exposed. Furthermore, partial digestion of the A2 and pS2 ERE-bound ER with chymotrypsin or trypsin produced distinct protease cleavage patterns. Taken together, these data provide evidence that differential interaction of the DBD with the A2 and pS2 EREs brings about global changes in ER conformation. The conformational changes in ER induced by individual ERE sequences could lead to association of the receptor with different transcription factors and assist in the differential modulation of estrogen-responsive genes in target cells.

Animals↗
PubMed2003

Current approaches to the prevention and treatment of postmenopausal osteoporosis.

Current approaches to the prevention, detection, treatment, and monitoring of postmenopausal osteoporosis are discussed. In the United States, 44 million men and women ages 50 years or older have low bone mass or osteoporosis. The most devastating consequence of this disease is fractures. The assessment of osteoporosis risk includes determining risk factors, conducting laboratory and physical examinations, and measuring bone density and bone-turnover markers. Once risk has been established, nonpharmacologic strategies, such as exercise, appropriate dietary habits, and discontinuing tobacco and alcohol use, are helpful. Fall prevention and adequate intake of calcium and vitamin D are critical. When pharmacologic therapy is warranted, bisphosphonates have shown the greatest benefit in preventing bone loss and lowering fracture rates. Selective estrogen-receptor modulators and calcitonin are also options for prevention or treatment of osteoporosis. Estrogen should not be used for the sole purpose of osteoporosis prevention; however, short-term use is acceptable for women with vasomotor symptoms or in whom the benefits outweigh the risks. Parathyroid hormone may offer another treatment alternative. A variety of pharmacologic options are available for patients with osteoporosis in whom lifestyle modifications have proven insufficient. Bisphosphonates are the mainstay of drug therapy.

Accidental Falls↗
PubMed2005

Tamoxifen blocks estrogen-induced B cell maturation but not survival.

Estrogen treatment has been shown not only to exacerbate disease activity and accelerate death in spontaneous murine models of lupus but also to induce a lupus-like phenotype in non-spontaneously autoimmune mice. In mice transgenic for the H chain of an anti-DNA Ab, estrogen rescues naive autoreactive B cells that normally are deleted and causes them to mature to a marginal zone phenotype. Estrogen further leads to the activation of this population causing an elevation of serum anti-DNA Ab titers and renal disease. This study was designed to evaluate the therapeutic potential of tamoxifen, a selective estrogen receptor modulator, on estrogen-induced lupus. Mice treated with both estradiol and tamoxifen showed no elevation in anti-DNA Ab titers and consequently no glomerular IgG. The DNA-reactive B cell population that is rescued by estrogen was present in an anergic state in mice treated with both estradiol and tamoxifen. Estradiol enhances transitional B cell resistance to apoptosis and expands the population of marginal zone B cells; tamoxifen did not impede the enhanced resistance to apoptosis, but prevented the development of autoreactive cells as marginal zone B cells. Thus, estrogen-induced autoimmunity proceeds through two distinct molecular pathways, one affecting survival and the other maturation. Activation, but not survival, of autoreactive B cells can be abrogated by tamoxifen. Drugs that modulate even some of the effects of estrogen may be beneficial in patients with lupus. Eventually, understanding the pathways involved in survival and activation of autoreactive B cells will permit the development of therapeutics that target all relevant pathways.

Animals↗
PubMed2003

Update on clinical role of tamoxifen.

PURPOSE OF REVIEW: Breast cancer is the most common malignancy amongst women in the United States and decreased mortality over the past decade has been attributed to a combination of screening and adjuvant therapies. There has been a resurgence of interest in hormonal therapies and this article discusses the clinical status of tamoxifen in the context of emerging alternative agents for treatment and prevention of breast cancer. RECENT FINDINGS: Tamoxifen has served as a prototype for the development of selective estrogen receptor modulators at the laboratory-clinical interface. Molecular technologies have permitted elucidation of mechanisms for tissue specific action and led to newer selective estrogen receptor modulators with potentially greater antitumour efficacy and attenuated uterotrophic profile. Publications over the past 12 months have emphasized the risks of thromboembolism and endometrial carcinoma associated with tamoxifen use which has accelerated application of other hormonal agents for treatment of advanced disease and as neoadjuvant therapy. This article reviews the current role of tamoxifen in the treatment of early and advanced breast cancer together with its potential for chemoprevention. Models for quantitative risk assessment are being developed to identify women for whom chemoprotection is justified. SUMMARY: Recent data showing a survival advantage for the aromatase inhibitor letrozole compared with tamoxifen in the advanced setting and improvement in disease-free survival for the aromatase inhibitor anastrozole versus tamoxifen as adjuvant treatment may herald a major shift in standard first-line endocrine therapies for both advanced and early disease and ultimately chemoprevention of breast cancer. Other agents including newer SERMs and pure antiestrogens are undergoing phase III clinical trials and future endocrine and biological therapies are likely to include more selective and targeted therapies, which may be efficacious in both hormone-sensitive and receptor-negative disease.

Adult↗
PubMed2002

Estrogen replacement therapy, atherosclerosis, and vascular function.

There is strong evidence from both human and nonhuman primate studies supporting the conclusion that estrogen deficiency increases the progression of atherosclerosis. More controversial is the conclusion that postmenopausal estrogen replacement inhibits the progression of atherosclerosis. Estrogen treatment of older women (>65 years) with pre-existing coronary artery atherosclerosis had no beneficial effects. In contrast, estrogen treatment of younger postmenopausal women or monkeys in the early stages of atherosclerosis progression has marked beneficial effects. Whether progestogens attenuate the cardiovascular benefits of estrogen replacement therapy has been controversial for more than a decade. Current evidence from studies of both monkeys and women suggest little or no attenuation of estrogen benefits for coronary artery atherosclerosis. Lack of compliance with estrogen replacement therapy, usually because of fear of breast cancer, remains a major problem. Future regimens may overcome that fear by the co-administration of a breast cancer preventive agent (i.e., selective estrogen receptor modulators, phytoestrogens) with low dose estrogen.

Aged↗
PubMed2006

Effects of tamoxifen on vaginal blood flow and epithelial morphology in the rat.

BACKGROUND: Tamoxifen, a selective estrogen receptor modulator with both estrogenic and anti-estrogenic activity, is widely used as adjuvant therapy in breast cancer patients. Treatment with tamoxifen is associated with sexual side effects, such as increased vaginal dryness and pain/discomfort during sexual activity. There have been limited investigations of the effect of tamoxifen on estrogen-dependent peripheral genital arousal responses. The objective of this study was to investigate the effects of tamoxifen on vaginal physiology in the rat. METHODS: Female Sprague-Dawley rats were subjected to sham surgery or bilateral ovariectomy. After 2 weeks, sham-operated rats were implanted with subcutaneous osmotic infusion pumps containing vehicle (control) or tamoxifen (150 microg/day). Ovariectomized rats were similarly infused with vehicle. After an additional 2 weeks, vaginal blood flow responses to pelvic nerve stimulation were measured by laser Doppler flowmetry and vaginal tissue was collected for histological and biochemical assay. RESULTS: Tamoxifen treatment did not change plasma estradiol concentrations relative to control animals, while ovariectomized rats exhibited a 60% decrease in plasma estradiol. Tamoxifen treatment caused a significant decrease in mean uterine weight, but did not alter mean vaginal weight. Vaginal blood flow was significantly decreased in tamoxifen-infused rats compared to controls. Similar to ovariectomized animals, estrogen receptor binding was increased and arginase enzyme activity was decreased in tamoxifen-infused rats. However, different from control and ovariectomized animals, the vaginal epithelium in tamoxifen-infused rats appeared highly mucified. Periodic acid-Schiff staining confirmed a greater production of carbohydrate-rich compounds (e.g. mucin, glycogen) by the vaginal epithelium of tamoxifen-infused rats. CONCLUSION: The observations suggest that tamoxifen exerts both anti-estrogenic and pro-estrogenic effects in the vagina. These physiological alterations may eventually lead to vaginal atrophy and compromise sexual function.

Journal Article↗
PubMed2003

Tamoxifen is an estrogen antagonist on gonadotropin secretion and responsiveness of the hypothalamic-pituitary- adrenal axis in female monkeys.

The selective estrogen receptor modulator, tamoxifen, effectively slows the progression of estrogen-positive breast cancer and reduces the possibility of this cancer developing in women at high risk. Despite the widespread acceptance of tamoxifen as a therapeutic agent for this disease, its effects on other estrogen-dependent pathways, particularly on neural circuits regulating brain function and peripheral hormone secretion, are poorly understood. The present study, using previously ovariectomized rhesus monkeys, examined the effects of tamoxifen, in both the presence and absence of estradiol replacement, on the reproductive and hypo-thalamic-pituitary-adrenal (HPA) axes. In Experiment 1, monkeys randomly assigned to three groups (n = 8 each) were treated with placebo and either two doses of estradiol, two doses of tamoxifen alone, or two doses of tamoxifen plus high-dose estradiol to assess the effects on negative feedback suppression of luteinizing hormone (LH). Both doses of tamoxifen effectively antagonized the negative feedback efficacy of estradiol on LH secretion. In contrast, neither the low- or high-dose tamoxifen alone had any effect on LH secretion, as concentrations during tamoxifen treatments were indistinguishable from those during placebo. In Experiment 2, females were randomly assigned to one of four treatment groups (placebo, n = 6; estradiol, n = 5; tamoxifen only, n = 5; or tamoxifen plus estradiol, n = 6) to assess the effects on glucocorticoid negative feedback and pituitary and adrenal responsiveness to exogenous corticotropin- releasing hormone (CRH). Tamoxifen also antagonized the facilitating effects of estradiol on basal and CRH-induced ACTH and cortisol secretion. However, this antagonism produced basal and CRH-stimulated cortisol and ACTH concentrations that were lower than placebo-treated females. Interestingly, tamoxifen in the absence of estradiol produced a similar diminution in ACTH and cortisol response. These data suggest that, in the presence of estradiol, tamoxifen not only antagonized estrogenic facilitation of HPA responsivity but also actually attenuated the response compared with the placebo-treatment condition. Taken together, these data indicate that tamoxifen acts as an estrogen antagonist on the neural circuits controlling the neuroendocrine regulation of the hypothalamic-pituitary-ovarian and adrenal axes in ovariectomized macaque females.

Adrenocorticotropic Hormone↗
PubMed2004

Ovariectomized rats as a model of postmenopausal osteoarthritis: validation and application.

We aimed to assess the effect of ovariectomy on cartilage turnover and degradation, to evaluate whether ovariectomized (OVX) rats could form an experimental model of postmenopausal osteoarthritis. The effect of ovariectomy on cartilage was studied using two cohorts of female Sprague-Dawley rats, aged 5 and 7 months. In a third cohort, the effect of exogenous estrogen and a selective estrogen receptor modulator was analyzed. Knee joints were assessed by histological analysis of the articular cartilage after 9 weeks. Cartilage turnover was measured in urine by an immunoassay specific for collagen type II degradation products (CTX-II), and bone resorption was quantified in serum using an assay for bone collagen type I fragments (CTX-I). Surface erosion in the cartilage of the knee was more severe in OVX rats than in sham-operated animals, particularly in the 7-month-old cohort (P = 0.008). Ovariectomy also significant increased CTX-I and CTX-II. Both the absolute levels of CTX-II and the relative changes from baseline seen at week 4 correlated strongly with the severity of cartilage surface erosion at termination (r = 0.74, P < 0.01). Both estrogen and the selective estrogen receptor modulator inhibited the ovariectomy-induced acceleration of cartilage and bone turnover and significantly suppressed cartilage degradation and erosion seen in vehicle-treated OVX rats. The study indicates that estrogen deficiency accelerates cartilage turnover and increases cartilage surface erosion. OVX rats provide a useful experimental model for the evaluation of the chondroprotective effects of estrogens and estrogen-like substances and the model may be an in vivo representation of osteoarthritis in postmenopausal women.

Aging↗
PubMed2005

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↗
PubMed2005

Interaction between estrogen receptor alpha, ionizing radiation and (anti-) estrogens in breast cancer cells.

PURPOSE: Estrogen receptor alpha (ERalpha) plays a major role in breast cancer development. It acts as ligand-inducible transcription factor which determines growth, survival and differentiation of breast cancer cells. The aim of this study is to evaluate the potential interference between radiotherapy and estrogen receptor responsiveness. Materials and methods. The effect of ionizing radiation was assessed on the estrogen receptor alpha status, growth (proliferation and apoptosis) and sensitivity of MCF-7 breast cancer cells to estrogenic (17beta-estradiol (E2)), selective estrogen receptor modulator (SERM) and anti-estrogenic compounds. Results. We have observed a ligand-independent decrease in ERalpha expression after radiation, resulting from a specific reduction in mRNA level and protein synthesis. This ERalpha disappearance occurred 72 h post-irradiation at 8 Gy and decreased the transcriptional activity in ERalpha of these cells. On the other hand, E2 impedes the growth inhibitory effects (essentially on proliferation) of ionizing radiation in MCF-7 cells, which potentially decreases radiosensitivity of these cells. This effect was totally blocked by SERM and anti-estrogenic treatments. Moreover, this growth effect of concurrent anti-estrogenic drugs and ionizing radiation appeared to be strongly synergistic. CONCLUSIONS: This study may increase general comprehension of ERalpha modulation by radiotherapy and improve adjuvant therapeutic approaches based on co-administration of radiation and endocrine therapy.

Analysis of Variance↗
PubMed2006

Physiologic estrogen receptor alpha signaling in non-tumorigenic human mammary epithelial cells.

Currently, a number of breast cancer cell lines exist that serve as models for both estrogen receptor alpha (ERalpha) positive and ERalpha negative disease. Models are also available for pre-neoplastic breast epithelial cells that do not express ERalpha; however, there are no ideal systems for studying pre-neoplastic cells that are ERalpha positive. This has been largely due to the inability to establish an estrogen growth stimulated, non-tumorigenic breast epithelial cell line, as most human breast epithelial cells engineered to overexpress ERalpha have been found to be growth inhibited by estrogens. We have developed independently derived clones from the non-cancerous MCF-10A human breast cell line that express ERalpha and are growth stimulated by 17-beta-estradiol (E2) in the absence of epidermal growth factor (EGF), a cytokine normally required for MCF-10A cell proliferation. This effect is blocked by the selective estrogen receptor modulator (SERM), Tamoxifen and the selective estrogen receptor downregulator, ICI 182,780 (Faslodex, Fulvestrant). Exposure of these cells to EGF and E2 results in a growth inhibitory phenotype similar to previous reports. These data present a reconciling explanation for the previously described paradoxical effects of ERalpha overexpression, and provide a model for examining the carcinogenic effects of estrogens in non-tumorigenic human breast epithelial cells.

Breast↗
PubMed2002

Evolving uses of hormonal agents for breast cancer therapy.

BACKGROUND: During the past decade, a number of new hormonal therapies (HTs) have been developed, including the selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and estrogen receptor (ER) antagonists. Their uses in breast cancer are continually evolving as new clinical trial results become available. Although tamoxifen, the most widely used HT for breast cancer, was originally approved for and used in the treatment of metastatic breast cancer (MBC), its effectiveness as MBC therapy led to its subsequent assessment and use as adjuvant and risk-reduction therapy for breast cancer. However, tamoxifen is not universally effective in these settings and is associated with infrequent known toxicities such as increased risk of thromboembolism and endometrial cancer; therefore, a search for more effective and more tolerable HTs has evolved. OBJECTIVE: This article reviews the data supporting the use of newer HTs as initial treatment of MBC and their potential use as adjuvant, neoadjuvant, and chemopreventive therapies. METHODS: Articles for inclusion in this manuscript were identified through the following searches, limited to English-language publications: MEDLINE (mid 1960s to January 2002), American Society of Oncology abstracts (1997-2001), and San Antonio Breast Cancer Symposium abstracts (2001 and 2002). The following search terms were used: breast cancer, breast cancer guidelines, hormonal therapies, tamoxifen, toremifine, letrozole, anastrozole, exemestane, megestrol acetate, fulvestrant, and ICI 182,780. RESULTS: Recent studies have focused on newer agents as initial and subsequent treatment of MBC, adjuvant or neoadjuvant treatments of breast cancer, and chemopreventive agents in both healthy women and women with a history of ductal carcinoma in situ (DCIS). Results of clinical trials comparing AIs with tamoxifen as first-line MBC treatment show that AIs are as effective as, or more effective than, tamoxifen and are associated with fewer serious adverse events. Tamoxifen remains the gold standard for adjuvant therapy. However, preliminary results of ongoing clinical trials comparing tamoxifen with anastrozole suggest that anastrozole may be the superior agent. Both tamoxifen and the AIs have been shown to be active in the neoadjuvant treatment of breast cancer. Trial results have shown that tamoxifen is effective for breast cancer prevention in patients at high risk of developing breast cancer but who are otherwise healthy, patients with a history of DCIS, and patients with lobular carcinoma in situ. CONCLUSIONS: Although tamoxifen has been the gold standard of HT for breast cancer, results of ongoing trials assessing the newer HTs as initial, neoadjuvant, adjuvant, and chemopreventive therapies may substantially change our current clinical practice patterns.

Anastrozole↗
PubMed2001

Divergent effects of raloxifene HCI on the pharmacokinetics and pharmacodynamics of warfarin.

PURPOSE: Evista (raloxifene HCl) is a nonsteroidal selective estrogen receptor modulator that displays estrogen agonist effects on bone and lipid metabolism but estrogen antagonist effects on the breast and endometrium. The potential for drug-drug interaction between raloxifene and warfarin was assessed in 15 healthy postmenopausal women. METHODS: Single doses of warfarin (20 mg) were administered prior to and during 2 weeks of dosing with raloxifene 120 mg/day. Each warfarin dose was followed by pharmacokinetic sampling and prothrombin time measurements. RESULTS: Raloxifene administration resulted in 7.1% and 14.1% decreases in the clearance (CLp/F) and 7.4% and 9.8% decreases in the volume of distribution (Vss/F) of R- and S-warfarin, respectively (all p < or = 0.05). In contrast to the slightly higher plasma concentrations of R- and S-warfarin, raloxifene reduced the maximum prothrombin time (PTmax) by 10% and the area under the PT versus time curve from 0-120 h (AUCPT) by 8% (p < 0.01). CONCLUSIONS: Raloxifene administration may result in a small increase in systemic warfarin exposure that is associated with a diminution, not augmentation, of the pharmacodynamic effect. Due to the small magnitude of this effect, concomitant administration of raloxifene and warfarin is not likely to result in clinically significant drug-drug interaction.

Administration, Oral↗
PubMed2003

Efficacy of soyfoods and soybean isoflavone supplements for alleviating menopausal symptoms is positively related to initial hot flush frequency.

Soy has received attention as an alternative to conventional hormone replacement therapy (HRT) largely because it is a unique dietary source of isoflavones. Isoflavones are diphenolic compounds that have both hormonal and nonhormonal properties and are considered to be selective estrogen receptor modulators. The estrogen-like effects of isoflavones in combination with the low reported frequency of hot flushes in Japan has prompted investigation of the effect of soy on menopausal symptoms. The purpose of this review is to evaluate the efficacy of soyfoods and isoflavone supplements for the alleviation of hot flushes. Nineteen trials (13 using a parallel design) involving more than 1,700 women were identified. Six trials were excluded from analysis: two that involved breast cancer patients, two that reported data on severity but not hot flush frequency, one that was not blinded, and one that did not include a control group. Based on a simple regression analysis of the remaining data set (13 trials), there was a statistically significant relationship (P =.01) between initial hot flush frequency and treatment efficacy. Initial hot flush frequency explained about 46% of the treatment effects, and hot flush frequency decreased by about 5% (above placebo or control effects) for every additional initial hot flush per day in women whose initial hot flush frequency was five or more per day. Although conclusions based on this analysis should be considered tentative, the available data justify the recommendation that patients with frequent hot flushes consider trying soyfoods or isoflavone supplements for the alleviation of their symptoms.

Adult↗