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Results for “Selective Estrogen Receptor Modulators”

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PubMed2004

Recruitment of distinct chromatin-modifying complexes by tamoxifen-complexed estrogen receptor at natural target gene promoters in vivo.

Tamoxifen, a breast cancer therapeutic, is a tissue-selective estrogen receptor modulator (SERM), which acts as an antiestrogen in the mammary tissue and displays estrogenic activity in other tissues such as bone and uterus. In order to understand the mechanisms underlying the antiestrogenic effect of this prototype SERM, we performed an analysis of the cofactors that interact with ER complexed with 4-hydroxytamoxifen (OHT) at natural target genes in a human breast tumor cell line MCF-7. Employing chromatin immunoprecipitation (ChIP), we observed that treatment with OHT rapidly induces the binding of ERalpha to the E-responsive promoter regions of pS2 and c-myc genes. Promoter-bound OHT-complexed ERa coordinately recruited the components of a multiprotein complex containing the corepressor NCoR, histone deacetylase 3 (HDAC3), and a WD40-repeat protein TBL1. Surprisingly, the OHT-complexed ERalpha also recruited a chromatin-remodeling NuRD complex in which histone deacetylase 1 (HDAC1) is associated with several polypeptides including metastasis-associated protein 1/2 (MTA1/2), and SWI2/SNF2-related ATPase Mi2. Kinetic studies revealed that following OHT addition the recruitment of these HDAC complexes to pS2 or the c-myc promoter occurs in a sequential manner; the NCoR-HDAC3 complex is recruited earlier than the NuRD complex. Serial ChIP experiments indicated that the ER-NCoR-HDAC3 and ER-NuRD complexes are distinct, and they do not occupy the target gene promoter simultaneously. We also established a close temporal link between the appearance of the HDAC complexes at the E-responsive regions of pS2 and c-myc promoters, local hypoacetylation of specific lysine residues in N-terminal tails of histones H3 and H4, and disappearance of RNA polymerase II from the target gene loci. Collectively, our studies indicated that transcriptional repression by tamoxifen-bound ER at E-regulated gene promoters involves a dynamic interplay of multiple distinct chromatin-modifying/remodeling complexes.

Cell Line, Tumor↗

PubMed2001

Constructive interactions among nutrients and bone-active pharmacologic agents with principal emphasis on calcium, phosphorus, vitamin D and protein.

Current and emerging bone active pharmacologic agents are capable of producing substantial gains in bone mass. However, nutrition must be adequate if this potential is to be realized. Calcium and vitamin D supplementation, for example, have both been demonstrated to augment substantially the skeletal response to estrogen therapy in postmenopausal women. The bisphosphonates and selective estrogen receptor modulator (SERMs) have all been tested only in the context of supplemental calcium and vitamin D. Therefore, it cannot be assumed that these bone active agents would be effective in the absence of these nutrients. Adequate protein intake has also been demonstrated to protect bone mass in the elderly and to improve recovery from osteoporotic fractures. Phosphorus intake, less extensively studied, may be more important than currently recognized, particularly in elderly individuals living alone, eating little meat, and receiving anti-osteoporosis treatment agents.

Adaptation, Physiological↗

PubMed2005

Adjuvant therapy of breast cancer.

The treatment of early-stage breast cancer includes the use of chemotherapeutic and hormonal agents. Both chemotherapy and hormonal therapy have been shown by large, randomized trials to offer a survival advantage. The most commonly used chemotherapeutic agents used in the United States are doxorubicin and cyclophosphamide (AC). However, 3 studies have suggested that there may be an advantage in the use of taxanes in the adjuvant treatment of breast cancer. Furthermore the use of dose dense chemotherapy, incorporating AC and paclitaxel, has shown very promising results. It is well established that tamoxifen, a selective estrogen receptor modulator (SERM), improves overall survival (OS) in women with hormone receptor (HR) positive breast cancer. However, the results from large multicenter, randomized trials, suggest the potential superiority of aromatase inhibitors, compared to tamoxifen or an advantage of sequencing tamoxifen followed by an aromatase inhibitor (AI). The role of ovarian suppression is still being investigated in patients who have received prior chemotherapy. Newer agents, such as the monoclonal antibody against the HER2/neu receptor, trastuzumab, are now being studied as adjuvant therapy in early-stage breast cancer. In the next few years, with the completion of several large randomized trials, we will be able to answer several questions, including the optimal way of incorporating AIs into adjuvant therapy, the long-term sequella of using trastuzumab in the adjuvant treatment of breast cancer and the role of ovarian suppression combined with an aromatse inhibitor in premenopausal women with breast cancer.

Antineoplastic Agents↗

PubMed2004

Management of anovulatory infertility associated with polycystic ovary syndrome: tamoxifen citrate an effective alternative compound to clomiphene citrate.

Clomiphene citrate (CC) is widely used as first-line treatment for ovulation induction in anovulatory women with polycystic ovary syndrome (PCOS). Tamoxifen citrate (TMX), another non-steroidal selective estrogen receptor modulator, may also be effective on the resumption of ovulation in these women. The aim of this controlled observational study was to compare the efficacy and safety of ovulation induction with TMX versus CC in anovulatory infertile women with PCOS. A total of 102 consecutive women (mean age+/-SD: 31+/-3.6 years; range: 26-38) with PCOS were studied. Following a spontaneous or progesterone-induced withdrawal bleed, women received either 50 mg daily of CC (days 2-6) or 20 mg daily of TMX (days 2-5). In case ovulation failed to occur, the dose was sequentially increased to 100 mg daily of CC and 40 mg daily of TMX, respectively. Serum progesterone levels were measured on cycle day 21 to monitor the ovulation pattern. The overall ovulation rate was significantly higher in women who received TMX compared with those who received CC (61/98, 62.2% vs. 60/127, 47.2%, p=0.03). Although not statistically significant, the pregnancy rate per ovulatory cycle was higher in the TMX group compared to the CC group (14/61, 22.9% vs. 11/60, 18.3%, respectively). All pregnancies were single and there were no side-effects in either group of treatment. Collectively, these data demonstrate that TMX is a safe and effective agent, and a suitable alternative to CC for anovulatory infertility in women with PCOS.

Adult↗

PubMed2000

Chemoprevention of breast cancer by tamoxifen: risks and opportunities.

The antiestrogen tamoxifen is widely used in the adjuvant therapy of breast cancers in women and helps to prevent the occurrence of breast tumors in healthy women. However, epidemiological studies have shown tamoxifen treatment to be associated with a 2- to 5-fold increased risk of endometrial cancer. In rats but not in mice, long-term administration of tamoxifen results in an increase in hepatocellular carcinomas. Mechanistically, this occurs through metabolic activation of the drug, mainly by the CYP3A family, to an electrophilic species, that causes DNA damage in target tissues, and subsequently leads to gene mutations. It is controversial whether low levels of DNA damage occur in human uterine tissues, and there is no evidence that this can be causally related to the mechanisms of carcinogenesis. In healthy women, the risk:benefits for the use of tamoxifen is in part related to the risk of developing breast cancer. The results from the carcinogenicity studies in rats do not predict the likelihood that women will develop liver cancer or indeed cancers in other organs. The mechanism of endometrial cancer in women remains unresolved, but the experience with tamoxifen has highlighted the potential problems that need to be addressed in the assessment of future generations of selective estrogen receptor modulators.

Animals↗

PubMed2006

Homocysteine, estrogen and cognitive decline.

BACKGROUND: Factors that contribute to cognitive decline in women from midlife remain poorly understood. There are circumstantial data indicating a positive association between homocysteine and cognitive decline and that endogenous and exogenous estrogen may influence homocysteine levels. The aim of this review was to establish what is known of the relationships between cognitive change and homocysteine levels, and the impact of the menopause transition and exogenous estrogen on homocysteine levels. METHODS: We reviewed the recent published literature from 1993 to 2005 pertaining to the current understanding of the relationship(s) between plasma homocysteine levels and cognitive functioning and endogenous hormone levels and exogenous estrogen use in women. RESULTS: Hyperhomocysteinemia is consistently associated with cognitive decline. Dietary supplementation with vitamins may assist in normalizing homocysteine levels; however, there is no evidence that this results in favorable effects on cognition. Changes in endogenous estrogen levels are inversely associated with changes in serum homocysteine. Consistent with this, estrogen therapy is associated with reductions in plasma homocysteine, with the greatest effects reported in women with higher levels of homocysteine at baseline. Limited data indicate that tibolone is associated with little change in homocysteine. The use of raloxifene, the most studied selective estrogen receptor modulator, is associated with a modest reduction in homocysteine. CONCLUSIONS: There are data to suggest an underlying link between homocysteine levels and cognitive decline. There is also evidence for a link between both the menopause transition and use of exogenous estrogen therapy and homocysteine levels. Clinical data do not support a role for exogenous estrogen in the prevention of dementia in older women; however, the 'window of opportunity' theory suggests that there is a need for randomized controlled trials to evaluate the role of estrogen in the early postmenopausal years to protect against cognitive decline in later life.

Cognition↗

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↗

PubMed2002

Contemporary management of hyperlipidemia in women.

OBJECTIVE: The objective of this paper is to review prospective, large-scale studies of lipid-lowering therapy and hormone replacement therapy, and to provide clinical recommendations for the management of hyperlipidemia in women within the context of the revised National Cholesterol Education Program (NCEP) guidelines. METHODS: Recent English language literature derived from a MEDLINE search (January 1990-July 2001) and bibliographies of relevant papers were reviewed, and data were abstracted from identified papers. RESULTS: Hyperlipidemia is largely undertreated in women. Previously, hormone replacement therapy (HRT) was considered first-line treatment for the management of hypercholesterolemia to prevent coronary artery disease (CAD) in women. Recent studies, however, show no benefit of HRT for secondary prevention of coronary events, despite its beneficial effects on lipids. Large-scale, controlled clinical trials indicate that women, even those with only moderately elevated cholesterol, benefit from the lipid-lowering effects of statins for both high-risk primary and secondary prevention of CAD. Based on this evidence, the recently revised NCEP guidelines recommend statins as first-line therapy for women with hyperlipidemia, an approach that is supported by the American Heart Association and the American College of Cardiology. With its emphasis on aggressive intervention for persons with multiple risk factors, the new guidelines substantially increase the number of women eligible for pharmacological therapy. CONCLUSIONS: All women with hyperlipidemia should receive counseling regarding lifestyle approaches for lowering cholesterol. The decision to use HRT should be made in the context of other conditions hormones may affect. Alternative hormonal regimens for lipid management may include selective estrogen receptor modulators and phytoestrogens, but results of randomized clinical trials are necessary before firm recommendations can be made regarding their clinical value in preventing CAD.

Aged↗

PubMed1999

Healthcare use among U.S. women aged 45 and older: total costs and costs for selected postmenopausal health risks.

The purpose of this study is to estimate the level of healthcare use and costs incurred by postmenopausal women overall and for these selected conditions: cardiovascular disease, osteoporosis, breast cancer, and gynecological cancers. National healthcare survey and discharge data were used to estimate healthcare use by women aged 45 and older. Clinical Classification for Health Policy Research (CCHPR) codes were used to identify patients whose primary diagnosis or procedure corresponded with the selected conditions. National weights were used to estimate resource use. Treatment costs were estimated using cost/charge ratios or the Medicare fee schedule to calculate costs for each individual procedure. Estimated total annual medical care treatment costs for women 45 and older were about $186 billion in 1997 dollars, including about $60.4 billion for cardiovascular disease, $12.9 billion for osteoporosis, and $5.0 billion for breast and gynecological cancers. For each condition, estimated resource use and costs are reported for hospitalization, outpatient, nursing home, and home healthcare services. Resource use and costs are also reported by age and expected source of payment. The economic burden of disease for conditions commonly affecting postmenopausal women is substantial. Prior research establishes that hormone replacement therapy (HRT) may be effective in reducing the burden of disease among women who continue preventive therapy for many years, but few at-risk women do so. New alternatives for prevention, such as selective estrogen receptor modulators (SERMs), may be effective in reducing the burden of disease among postmenopausal women.

Aged↗

PubMed1999

Osteoporosis and African American women.

The incidence of osteoporosis and related fractures in African American women is half that of Caucasian women. African American women who sustain osteoporosis-related fractures have increased disability and decreased survival. Given the exponential increase in hip fracture rate among African American women over the age of 70 years, the risk of osteoporosis among this population may be underestimated. This review focuses on racial differences in women's bone mineral density (BMD) and bone metabolism and on various explanations for these observed differences. Environmental risk factors for osteoporosis and related fractures among African American women and modalities for prevention and treatment of osteoporosis are discussed. African American women begin menopause with higher BMD and have lower rates of women's bone loss after menopause, which account for their decreased incidence of osteoporosis and related fractures. The risk factors for osteoporosis among African American women are similar to those found in Caucasian women. Lifestyle interventions, such as calcium and vitamin D supplementation, smoking cessation, and increased physical activity, should be encouraged to enhance peak bone mass and to decrease bone loss. These interventions and other treatment modalities, such as hormone replacement therapy, bisphosphonates, and selective estrogen receptor modulators, should be studied further in African American women.

Black or African American↗

PubMed1998

Hormone and nonhormone therapy for the maintenance of postmenopausal health: the need for randomized controlled trials of estrogen and raloxifene.

Multiple health benefits have been postulated for the long-term use of hormone therapy in postmenopausal women, most notably for prevention of osteoporotic fractures and coronary heart disease, as well as several risks, including cancer of the breast and uterus and venous thromboembolism. Cardiovascular disease is the most common cause of death among postmenopausal women. If real, the reduction in risk of coronary heart disease by hormone use suggested by observational studies would likely outweigh the risks. The decision to initiate and maintain hormone therapy is complicated by uncertainties about estrogen's true benefits and risks. Raloxifene, a selective estrogen receptor modulator (SERM), appears to have many of the benefits of estrogen without the cancer risks. It is not known if SERMs can provide significant cardiovascular protection. This article reviews the relation of use of postmenopausal hormones and raloxifene to women's health and addresses the need for large randomized trials to quantify the effect of both postmenopausal estrogen and raloxifene on cardiovascular health.

Cardiovascular Diseases↗

PubMed2006

Osteoporosis management in a Medicaid population after the Women's Health Initiative study.

OBJECTIVE: Publication of the Women's Health Initiative (WHI) study has changed our understanding on the effects of hormone replacement therapy. This study was designed to evaluate patterns of antiosteoporosis medication (AOM) use in a Medicaid population before and after the release of the WHI study results. METHODS: A descriptive time series analysis was conducted among women 50 years of age and older who were enrolled in the Pennsylvania Medicaid program from December 1, 2001, through December 31, 2002. All AOMs were identified, including estrogens, bisphosphonates, selective estrogen receptor modulators (SERMs), and calcitonin. The monthly prevalence of each AOM and drug class was estimated. Comparisons between pre-WHI (December 1, 2001-July 30, 2002) and post-WHI (August 1, 2002-December 31, 2002) study periods were made for overall AOM use by AOM drug class as well as by recipient characteristics. RESULTS: The overall prevalence of AOM did not change between pre-WHI and post-WHI study publication. However, there were significant changes in the prevalence of certain AOM drug classes. Estrogen use decreased significantly after the WHI study release for all age and racial groups. The prevalence for bisphosphonates and SERM increased significantly in the post-WHI period. CONCLUSIONS: The WHI study influenced patterns of use of all types of AOM, decreasing estrogen and increasing nonestrogen use among postmenopausal women in a Medicaid program. These results suggest that the WHI study affected patterns of use of bone protective pharmacotherapy, with a shift in bone protection therapy use from estrogen to nonestrogen AOMs.

Aged↗

PubMed2005

Uterine cancer after use of clomiphene citrate to induce ovulation.

Clomiphene citrate, a selective estrogen receptor modulator, increases estradiol levels and consequently may increase risk of cancer of the uterine corpus. The authors conducted a retrospective cohort study of 8,431 US women (145,876 woman-years) evaluated for infertility during 1965-1988. Through 1999, 39 uterine cancers were ascertained by questionnaire or cancer and death registries. Poisson regression estimated adjusted rate ratios. Study results suggest that clomiphene may increase uterine cancer risk (rate ratio (RR) = 1.79, 95% confidence interval (CI): 0.9, 3.4) and present evidence of a dose response (p(trend) = 0.07) and latency effect (p(trend) = 0.04). Uterine cancer risk increased with clomiphene dose (RR = 1.93, 95% CI: 0.9, 4.0 for >900 mg), menstrual cycles of use (RR = 2.16, 95% CI: 0.9, 5.2 for >or=6 cycles), and time elapsed since initial use (RR = 2.50, 95% CI: 0.9, 7.2 for women followed for >or=20 years). Risk was more strongly associated with clomiphene among nulligravid (RR = 3.49, 95% CI: 1.3, 9.3) and obese (RR = 6.02, 95% CI: 1.2, 30.0) women, with risk substantially elevated among women who were both obese and nulligravid (RR = 12.52, 95% CI: 1.5, 108.0). Clomiphene may increase uterine cancer risk, with higher doses leading to higher risk. Long-term follow-up of infertility cohorts is necessary to clarify the association between clomiphene use and uterine cancer.

Adult↗

PubMed2003

Idoxifene versus tamoxifen: a randomized comparison in postmenopausal patients with metastatic breast cancer.

BACKGROUND: More efficacious and safer hormonal agents are needed for breast cancer treatment and prevention. Idoxifene is a novel selective estrogen receptor modulator (SERM) that, in preclinical models, has greater antiestrogenic but lower estrogenic activity than tamoxifen. PATIENTS AND METHODS: Three hundred and twenty-one postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer were randomized to receive either tamoxifen or idoxifene as initial endocrine therapy for advanced disease. Data were analyzed based on intention to treat and all the responses were subject to independent review. RESULTS: At the time of a second planned interim analysis, the trial was stopped for economic considerations, not for reasons related to safety or efficacy. Complete data for the 219 patients included in the second interim analysis are fully available and reported here. Median age was 59.1 years for idoxifene patients and 59.9 years for tamoxifen patients. Complete response (CR) plus partial response (PR) rates were as follows: tamoxifen, 9%; idoxifene, 13% (P = 0.39). Clinical benefit rate [CR + PR + stable disease (SD) >or=6 months] was 34.3% for idoxifene and 38.7% for tamoxifen (P = 0.31). Median time to progression and duration of response were 140 days and 151.5 days, respectively, for tamoxifen compared with 166 days and 218 days for idoxifene. None of these endpoints was significantly different for the two drugs, nor was survival. Adverse events (lethal, serious but not lethal and important but not life threatening) were similar in the two arms. CONCLUSIONS: Idoxifene was both active and well tolerated in postmenopausal women with metastatic breast cancer. Idoxifene had similar efficacy and toxicity to tamoxifen in this randomized comparison.

Administration, Oral↗

PubMed2003

Characterization and chromosomal instability of novel derived cell lines from a wt-erbB-2 transgenic mouse model.

Amplification and overexpression of the erbB-2 (HER-2/neu) proto-oncogene and exposure to the cell cycle mitogenic hormone estrogen (E2) have been associated with mammary tumorigenesis. Phytoestrogens found in soy act as selective estrogen receptor modulators and may also modify mammary carcinogenesis. We have used the wt-erbB-2 transgenic mouse model to study the effects of estrogen and dietary phytoestrogens on erbB-2-associated mammary tumorigenesis. Transgenic mice were treated with short-term E2 or placebo pellets during the early reproductive period and fed a casein or soy diet for life. Mammary tumors from the different treatment groups were used for the derivation of novel cell lines. Comparative genomic hybridization (CGH), flow cytometry, assays of cell proliferation and soft agar cloning were performed to study genomic instability and in vitro characteristics. CGH data were compared with corresponding parental tumors. Mammary tumors exhibited significantly fewer genetic changes than cell lines by CGH. Cell lines from soy-fed animals (that developed tumors with a longer latency) demonstrated the greatest frequency of chromosomal gain and loss. The E2-treated, casein-fed animals (that developed tumors with the shortest latency) had the fewest genetic changes in derived lines by CGH. Nonetheless, E2-associated tumors in vivo and lines in vitro had the most aggressive phenotypes. In addition, over 40% of all derived cell lines, and both tumors from the placebo-treated casein-fed mice, exhibited loss of chromosome 4 by CGH. In aggregate, our data suggest that estrogenic signaling influences mammary tumor development in this transgenic mouse model bearing the rat wt-erbB-2 gene. Once induced, tumors and derived lines demonstrate persistent phenotypic characteristics, including tumor aggression and shortened latency in E2-treated mice. Loss of chromosome 4 was commonly identified in derived lines and may have facilitated immortalization or passage in culture.

Animals↗

PubMedDate not supplied

Sex steroids and bone: current perspectives.

Although the process of bone remodelling or its control has not yet been fully elucidated there is, at present, sufficient information available to conclude that ovarian steroids (estrogens, androgens, progesterone) play an essential role in skeletal homeostasis. The mechanism of action of sex steroids on the skeleton is still not entirely clear, but it has traditionally included indirect effects on systemic hormones that regulate calcium balance and a direct receptor-mediated action. More recently, changes in cytokine production within the bone marrow, as well as pro-apoptotic and anti-apoptotic effects in the osteoblastic cells, have been proposed as new perspectives on the cellular and molecular mechanisms by which sex steroids influence adult bone homeostasis. Mechanical loading, when combined with estrogens or androgens, results in a greater osteogenic response than either condition separately. Women are especially at risk for osteoporosis if they have had a premature or surgical menopause and have not received hormone replacement therapy (HRT). Other reproductive factors that can help to identify women with osteopenia and emphasize the role of sex steroids in preserving bone mass in premenopausal women include: age at menarche, menstrual history and irregularities (including those associated with excessive exercise), age at menopause, previous hysterectomy, hyperprolactinaemia, anorexia nervosa, scoliosis, ovarian dysgenesis, pregnancy and lactation, and pharmacological ovarian suppression. The prevention of osteoporosis starts with the onset of the menarche. A combination of exercise, appropriate nutrition and a healthy lifestyle all maximize bone mineral accrual and result in optimal peak bone mass; normal ovarian function is essential to this process. Unfortunately, many women actually become aware of the need for osteoporosis prevention much later in life, usually after they have already become menopausal. HRT, however, has important limitations for prevention of fractures in post-menopausal women. Future perspectives for treatment of osteoporosis include androgen therapy and anabolic agents. Specifically, synthetic ligands of the estrogen receptor that can evoke the non-genotrophic but not the genotrophic signal of the receptor may be bone anabolic agents, as opposed to natural estrogens or selective estrogen receptor modulators that are anti-resorptive agents. The same ligands may circumvent the side effects associated with conventional HRT.

Bone Diseases, Metabolic↗

PubMed2000

Advances in the development of retinoids as chemopreventive agents.

With the inclusion of brief discussions of retinoid drug development in animal carcinogenesis models (e.g., skin, breast, oral cavity, lung, prostate or bladder) and clinical trials (e.g., head and neck or cervix), this review will focus on recent advances in retinoid molecular targeting studies designed primarily to develop retinoids with reduced toxicity, while maintaining or enhancing activity in the context of chemoprevention. Major current retinoid molecular targets include the six known nuclear retinoid receptors (RAR and RXR). Receptor numbers, distinct functions, tissue-expression patterns, ligand specificities, functional redundancy and regulation of multiple pathways make retinoid signaling highly complex. Development of receptor-selective synthetic retinoids is a major focus of molecular retinoid development. RAR heterodimerize with RXR and mediate classic retinoid activity/toxicity. RXR are more promiscuous, heterodimerizing with several other members of the steroid receptor superfamily [e.g., peroxisome proliferator-activated receptors (PPAR) or vitamin D receptors]. RXR-selective ligands are less toxic and more active in animal breast cancer prevention studies and less toxic than RAR ligands in clinical trials. Other new avenues of retinoid molecular drug development include newly identified retinoid-regulated genes, orphan-receptor ligands/functions, novel retinoid mechanisms involving potent receptor-independent apoptosis-inducing activity (e.g., 4-HPR or anhydroretinol), synergistic combinations [e.g., RXR agonists plus selective estrogen receptor modulators (SERM)], activity in other diseases and novel delivery systems.

Chemoprevention↗

PubMed2002

The health consequences of early soy consumption.

Infants fed soy formula are the segment of the U. S. population that consumes the most soy. Before birth and after weaning, most Americans are not exposed to appreciable levels of soyfoods other than foods that have small amounts of processed soy components. The opposite scenario occurs in Asia, because Asians are more likely to consume relatively high levels of soyfoods throughout life, except between birth and weaning, when breastfeeding or milk-based formula are common. Soy formula is made with soy protein isolate containing isoflavones (SPI+) and supports normal growth and development in term infants. Recent data suggest that there are no long-term adverse effects of early exposure to soy formula through young adulthood. It is as yet unknown whether soy formula consumption by infants will result in health problems or benefits upon aging, but multigenerational animal studies with diets made with SPI+ have not revealed any problems. Soy isoflavones can function as estrogen agonists, antagonists or selective estrogen receptor modulators, depending on the conditions, and much research has focused on health effects of purified isoflavones. Results from several studies suggest that the effects of diets made with SPI+ differ significantly from those of diets to which purified soy isoflavones are added. Furthermore, it seems that soy protein processed to contain lower levels of isoflavones also provides significant health benefits. Further research is needed to confirm the results of the few studies that have been conducted and new studies are needed to investigate the more subtle effects that could occur during development or that could surface later in life.

Animals↗