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PubMed2004

[Additional effect of SERM: mammary gland].

One of selective estrogen receptor modulators (SERMs), tamoxifen, has been widely used for prevention of breast cancer, postoperative adjuvant therapy and treatment of advanced breast cancer. The relation of a long-term administration of tamoxifen and its adverse effects have been extensively investigated. Favorable effects of tamoxifen are:the reduction in the risk of contralateral breast cancer, gain in bone density in postmenopausal women and decrease in serum low-density lipoprotein cholesterol. Unfavorable effects are: gynecologic problems and the increase in the risk of endometrial cancer and thromboembolism. In contrast, another SERM, raloxifene, has reported to have similar favorable adverse effects but no unfavorable effect on endometrium.

Animals↗
PubMed2005

HPLC analysis of raloxifene hydrochloride and its application to drug quality control studies.

Raloxifene hydrochloride is a selective estrogen receptor modulator and is currently being used for prevention of osteoporosis in postmenopausal women. In this article, a high performance liquid chromatography (HPLC) method for detection of raloxifene hydrochloride was developed and validated using an ultraviolet (UV) and coulometric detectors. Limit of quantification (LOQ) was 0.336 and 0.610 mg L(-1) for coulometric and ultraviolet detectors, respectively. Acceptable accuracy (93.1-100.3%) as well as intra- and inter-day precision (CV<or=2.38% and CV<or=7.93%, respectively) was demonstrated in the range of 0.5-10 mg L(-1) for both detectors. The presented method was applied without any interference of excipients to the determination of raloxifene hydrochloride content in tablets and to the in vitro dissolution studies. The proposed method could be used for routine quality control. Moreover, due to its low LOQ, excellent accuracy, precision and selectivity, the coulometric detection could be applied to in vitro metabolism experiments such as microsome or hepatocyte preparations and for studies of transport of raloxifene hydrochloride across biological membranes.

Chromatography, High Pressure Liquid↗
PubMed2003

Extragonadal synthesis of sex steroids: intracrinology.

All androgens and estrogens in post-menopausal women are synthesized locally in peripheral target tissues by tissue-specific steroidogenic enzymes according to the intracrine process. The importance of the intracrine or peripheral formation of sex steroids is illustrated by the success of aromatase inhibitors and antiestrogens in the prevention and treatment of breast cancer in post-menopausal women. On the other hand, a large series of problems are associated with the deficiency of sex steroids accompanying menopause and the decreased secretion of DHEA, osteoporosis being the best defined example. In this context, an important observation is that women at menopause are not only deprived from ovarian estrogens but are also lacking androgens due to the marked decrease of DHEA. In order to achieve a more physiological and tissue-specific hormone replacement therapy, DHEA, in combination with a SERM (selective estrogen receptor modulator) having pure antiestrogenic activity in the mammary gland and uterus could possibly meet the most important needs of women at menopause, namely control of hot flushes and, most importantly, prevent breast cancer, uterine cancer, ovarian cancer and osteoporosis with a potential improvement of cognitive functions and memory and prevention of Alzheimer's disease.

Adult↗
PubMed2003

[SERMs and uterus].

The uterus is one of the target organs of sexual steroids synthesized in the ovary. Estrogen is known to stimulate cell proliferation in the endometrium while progesterone has an anti-estrogenic secretory effect on this tissue. Renewed interest in the action of new anti-estrogenic agents on the uterus has arisen over the last decade, but not simply in order to achieve new therapeutic strategies for the prevention or cure of uterine tumors. New compounds were developed for their action on other tissues such as the breast, but it rapidly became clear that they were a source of uterine disease. A clear example is tamoxifen which has a powerful anti-estrogenic effect on breast tissue. It was hoped however that this compound, which behaves either like an antagonist or an agonist, depending on the target tissue, could have an anti-estrogenic effect on the uterus and on the contrary an agonistic estrogenic protective effect on bony and vascular tissue. This approach progressively led to the development of SERMs (Selective Estrogen Receptor Modulators), non-steroidal compounds modulating the action of estrogens. The first member of this new pharmaceutical class was raloxifen, marketed in France under the brand name Evista, which has an estrogenic effect on vertebral bone, warranting its authorization for use in patients with vertebral osteoporosis with or without fracture. Raloxifen thus has a beneficial estrogenic effect, at least on trabecular bone, and an anti-estrogenic effect on the uterus and breast. The goal today is to continue the development of new compounds in the SERM family with well targeted, and well understood, agonistic and/or antagonistic actions on different body tissues.

Estrogen Antagonists↗
PubMed2006

Strategies for the prevention and treatment of osteoporosis during early postmenopause.

During the perimenopause, both the quantity and quality of bone decline rapidly, resulting in a dramatic increase in the risk of fracture in postmenopausal women. Although many factors are known to be associated with osteoporotic fractures, measures to identify and treat women at risk are underused in clinical practice. Consequently, osteoporosis is frequently not detected until a fracture occurs. Identification of postmenopausal women at high risk of fracture therefore is a priority and is especially important for women in early postmenopause who can benefit from early intervention to maintain or to increase bone mass and, thus, reduce the risk of fracture. Most authorities recommend risk-factor assessment for all postmenopausal women, followed by bone mineral density measurements for women at highest risk (ie, all women aged > or =65 years, postmenopausal women aged <65 years with > or =1 additional risk factors for osteoporosis, and postmenopausal women with fragility fractures). All postmenopausal women can benefit from nonpharmacologic interventions to reduce the risk of fracture, including a balanced diet with adequate intake of calcium and vitamin D, regular exercise, measures to prevent falls or to minimize their impact, smoking cessation, and moderation of alcohol intake. Several pharmacologic agents, including the bisphosphonates (eg, alendronate, risedronate, and ibandronate) and the selective estrogen receptor modulator, raloxifene, have been shown to increase bone mass, to reduce fracture risk, and to have acceptable side-effect profiles. Women who have discontinued hormone therapy are in particular need of monitoring for fracture risk, in light of the accelerated bone loss and increased risk of fracture that occurs after withdrawal of estrogen treatment.

Accidental Falls↗
PubMed2002

[Hormone replacement therapy in peri- and postmenopause. Routine use is not indicated].

Hormone replacement therapy (HRT) with estrogens (in non-hysterectomized women with estrogens and progestins) during the peri- and postmenopausal period has been widely applied for many years. On the basis of new data, HRT is currently being critically reviewed. HRT administered for up to 5 years to treat climacteric hot flashes, mood changes and sleep disturbances continues to be advocated and is largely safe. When HRT is used for longer periods, as required for the prevention of osteoporosis, a possible increase in the relative risk for breast cancer must be considered. Correctly applied in combination with an adequate dose of progestins, HRT can avoid an increase in the endometrial cancer risk. HRT is no longer recommended for secondary prevention of cardiovascular disease, and its use in primary prevention has not been convincingly demonstrated. The hoped-for efficacy of HRT in the prevention of Alzheimer's disease has not been confirmed by the data. Selective estrogen receptor modulators (e.g. Raloxifene) and biphosphonates are efficacious drugs for the prevention and treatment of osteoporosis. For women at risk of developing cardiovascular disease, changes in lifestyle, lipid-lowering drugs (statins), blood pressure control, use of acetylsalicylic acid, among others, have well-documented efficacy in primary and secondary prevention.

Alzheimer Disease↗
PubMed2003

An approach to postmenopausal osteoporosis treatment: a case study review.

PURPOSE: To review and discuss the clinical evaluation and therapeutic options for a postmenopausal woman with osteoporosis. DATA SOURCES: Review of scientific literature, practice guidelines, and a case study. CONCLUSIONS: To prevent and treat postmenopausal osteoporosis, women should be encouraged to perform weight-bearing exercise, to not smoke, and to optimize calcium and vitamin D intake through diet and supplements. Drug regimens are effective and well tolerated in postmenopausal women with osteoporosis. IMPLICATIONS FOR PRACTICE: Drugs currently approved by the U.S. Food and Drug Administration for the treatment of postmenopausal osteoporosis include the bisphosphonates risedronate and alendronate; the selective estrogen receptor modulator, raloxifene; and intranasal calcitonin-salmon spray. Bisphosphonates have demonstrated the most impressive fracture risk reduction in prospective clinical trials of women with postmenopausal osteoporosis. Risedronate has consistently demonstrated significant reductions in vertebral fracture risk at 1 year and in vertebral and nonvertebral fracture risk at 3 years. Alendronate has demonstrated significant reductions in vertebral and nonvertebral fracture risk after 3 years.

Aged↗
PubMed2000

Ovarian steroids and raloxifene prevent MPTP-induced dopamine depletion in mice.

The activity of steroids was studied in 1-methyl-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned retired breeder C57BL/6 male mice as a model of Parkinson's disease. Steroids were injected daily for 5 days before MPTP (4 injections, 15 mg/kg i.p., at 2 h intervals) and hormonal treatment continued for 5 more days. Mice that received 17beta-estradiol or progesterone or raloxifene (a selective estrogen receptor modulator) and MPTP had striatal concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) similar to those in control animals, whereas mice that received MPTP alone or with 17alpha-estradiol (the isomer with weak estrogenic activity) had an extensive decrease of DA and its metabolites. These results suggest stereospecific prevention of MPTP-induced dopamine loss by 17beta-estradiol, which is also observed with progesterone and raloxifene.

Animals↗
PubMedDate not supplied

Designer estrogen vs. hormone replacement therapy: the menopausal woman's dilemma.

Although hormone replacement therapy (HRT) has many proven health benefits for postmenopausal women, relatively few women are taking advantage of this option. A major reason for this is lack of understanding by women of the benefits and risks of using HRT. Additionally, many women are uninformed about "designer estrogens," more correctly known as Selective Estrogen Receptor Modulators (SERMs), as an alternative approach to the use of esrogen. One of the major challenges of contemporary nursing is to help women maintain optimum health and enjoy a high quality of life after menopause. One aspect of managing menopausal health is an understanding of the hormonal options available to women. The purpose of this article is to present a synthesis of information comparing HRT and SERMs so that the reader can help his/her clients make informed choices about replacement therapy.

Education, Continuing↗
PubMedDate not supplied

Antiestrogens: clinical applications of pharmacology.

Selective estrogen receptor modulators (SERMs) appear to reduce the incidence of breast cancer in high-risk women. Five years of tamoxifen administration after the diagnosis of breast cancer results in a 50% reduction in the incidence of contralateral breast cancer. This reduction is maintained for 5 years after therapy is discontinued. The Study of Tamoxifen And Raloxifene (STAR), presently ongoing, will address the questions of breast cancer prevention, risk of endometrial cancer, the incidence of bone fractures, and coronary artery disease in women treated with these SERMs.

Breast Neoplasms↗
PubMed1999

Activation of transcription by estrogen receptor alpha and beta is cell type- and promoter-dependent.

Tamoxifen acts as a strong estrogen antagonist in human breast but as an estrogen agonist in the uterus. The action of tamoxifen is mediated through estrogen receptors (ERalpha and ERbeta), which bind to a variety of responsive elements, to activate transcription. To examine the role of these varied elements in the response to antiestrogens, we studied the activation of a panel of differing promoters, by these compounds, in human breast, bone, and endometrial derived cell lines. No agonistic activity was observed in breast cells, whereas all antiestrogens, particularly tamoxifen, exhibited agonistic effects in uterine cell lines. All antiestrogens studied were agonistic in co-transfections of a collagenase reporter gene and ERbeta, but tamoxifen alone was agonistic with ERalpha in (uterine) HEC-1-A cells. The ERalpha mediated, agonism of tamoxifen was not observed in primary cultures of human uterine stromal cells, whereas the ERbeta-mediated agonism of all selective estrogen receptor modulators was present. This suggests that the two receptors operate by distinct pathways and that the response of cells to antiestrogens is dependent on the ER subtypes expressed.

Blotting, Western↗
PubMed2001

Tamoxifen to raloxifene and beyond.

Tamoxifen, a selective estrogen receptor modulator (SERM), is the treatment of choice for all stages of hormone-responsive breast cancer and has been shown to prevent breast cancer in high-risk women. Despite acting as an antiestrogen on the breast, tamoxifen has partial estrogenic effects on other target tissues. These partial estrogen agonistic actions produce beneficial effects on bones and the lipid profile in postmenopausal women. However, tamoxifen is associated with an increase in endometrial cancer. Additionally, its antiestrogenic effects in the central nervous system result in hot flashes in postmenopausal women. Raloxifene is another SERM approved for the prevention of osteoporosis in postmenopausal women. Like tamoxifen, raloxifene appears to prevent breast cancer in high-risk women and has not, to date, been noted to increase the incidence of endometrial cancer. The Study of Tamoxifen and Raloxifene will compare the effects of the two agents on breast cancer prevention and endometrial cancer risk. A number of new agents are being developed for breast cancer treatment and prevention and osteoporosis prevention. These include other SERMs, selective estrogen receptor downregulators (SERDs), and aromatase inhibitors. It is hoped that one of these new agents will be the ideal agent, acting as an antiestrogen on breast and endometrium while having estrogenic effects on bones, the lipid profile, and the central nervous system. Semin Oncol 28:260-273.

Aromatase Inhibitors↗
PubMed2001

Effect of physicians opinion on patients' choice of treatment.

BACKGROUND: While it is obvious that patients should be involved in the decision making process, questions arise as to whether it is feasible to inform them objectively. OBJECTIVE: To assess the impact of the physician's opinion, on the choice of treatment, to the patient. SETTING: We imagined a hypothetical case of a 55-years-old woman with a high risk of osteoporosis. Two patient information letters were written, containing valid scientific information, but reflecting two diverging physicians' opinions, giving the choice between two available medications for osteoporosis prevention: hormone replacement therapy (HRT) and a selective estrogen receptor modulator (SERM), raloxifene. SUBJECTS: We submitted one of the letters (by lottery) to 58 nurses. They were asked to act as this potential patient, and to choose which treatment they preferred to have prescribed. RESULTS: 23/30 women receiving the version favouring the use of HRT, preferred HRT, 26/28 receiving the version favouring SERM preferred this treatment (Chi-Square Pearson 37.3; P<0.001). CONCLUSION: The content of the information provided and its wording have a great influence on the patients' decision.

Estrogen Replacement Therapy↗
PubMed2000

Drugs for the gynecologist to prescribe in the prevention of breast cancer: current status and future trends.

Tamoxifen was approved for breast cancer prevention in October 1998. Thus, for the first time, we as gynecologists are being asked to prescribe this drug to healthy women. In the past each one of us has cared for women with breast cancer who have been treated with tamoxifen by oncologists or breast surgeons for the malignancy. Effects of tamoxifen on the uterus resulting in carcinomas, hyperplasia, and polyps are well known. Furthermore, tamoxifen has estrogenic properties in the venous system, increasing the incidence of deep vein thrombosis and pulmonary emboli. A new SERM (selective estrogen receptor modulator), raloxifene, has been approved for prevention and treatment of osteoporosis in postmenopausal women. It does not have stimulatory effects on the endometrium; however, it is estrogenic in the venous system. Preclinical data, as well as the breast cancer incidence reported in studies of the skeleton, seem to indicate that its effects in the breast are similar to those of tamoxifen. This article reviews tamoxifen and the new SERM, raloxifene, in an attempt to help gynecologists better understand each compound and what data are currently known, what we hope to learn from future studies, and what currently makes sense for clinical practice.

Breast Neoplasms↗
PubMed2001

A review of cancer chemopreventive agents.

In the late 20(th) century, the treatment of cancer began to include its prevention. Today, compounds exist that will lower the risk of developing certain types of cancer. This has been demonstrated in studies where chemically induced tumor growth has been slowed or reversed. Anti-inflammatory compounds having chemopreventive activity are piroxicam, sulindac, aspirin, celecoxib and curcumin. The selective estrogen receptor modulators, tamoxifen and raloxifene, are beneficial in the prevention of estrogen dependent tumors. Retinoids, vitamin A derivatives, such as targretin and fenretinide are useful in the prevention of tumors. Compounds containing sulfur, such as sulforaphane and oltipraz, are even useful as radioprotective agents. The steroid dehydroepiandosterone can inhibit experimental carcinogenesis. All of these chemical classes provide a start for the medicinal chemist to design more effective chemopreventive agents. The biomarkers used to determine the chemopreventive activity of new compounds are quite often activities of enzymes. The identification of those individuals at high risk is still in its infancy and presents a troubling dilemma.

Animals↗
PubMed2003

Prevention of breast cancer using SERMs and aromatase inhibitors.

Breast cancer is one of the most common cancers of women in the Western world. Despite modest achievements in the treatment of this disease, there is a substantial unmet medical need to reduce the occurrence of new breast cancers. In several prospective, placebo-controlled trials, the antiestrogen tamoxifen has been shown to reduce the incidence of both invasive cancer and preinvasive breast lesions. Meanwhile, numerous other selective estrogen receptor modulators (SERMs) are being developed and trials comparing tamoxifen to these agents are ongoing. The goal of these studies is not only to show superior chemopreventive efficacy of the newer SERMs, but also an improved side-effect profile. The proof-of-principle demonstrated with tamoxifen suggests that strategies inhibiting estrogen are a logical way forward in breast cancer prevention. Aromatase inhibitors, which antagonize estrogen by blocking its synthesis from androgens, offer an alternative way of preventing the effects of estrogen and its metabolites on the breast. In this paper, the available data on SERMs including tamoxifen and raloxifene in breast cancer prevention and the data pointing to the efficacy of aromatase inhibitors in this setting are outlined.

Aromatase Inhibitors↗
PubMed2003

SP500263, a novel SERM, blocks osteoclastogenesis in a human bone cell model: role of IL-6 and GM-CSF.

Bone metabolism requires tightly coupled activities exhibited by two unique cell populations, the bone-resorbing osteoclasts and the bone-forming osteoblasts. Imbalance in the function of these two cell types can result in osteoporosis, a condition characterized by loss in bone integrity and of bone mass. We developed a human bone cell culture model that allows the in vitro study of bone formation and osteoclastogenesis and employed this bone model for the screening and pharmacological analyses of protein and small molecule therapeutics. The cytokines, interleukin-6 (IL-6) and granulocyte macrophage colony stimulating factor (GM-CSF), play an intricate role in osteoclastogenesis in this system. Neutralizing antibodies to IL-6 and GM-CSF decreased the formation of osteoclast-like cells. SP500263, an early lead compound from a novel class of selective estrogen receptor modulators (SERMs), was more efficacious than estrogen and comparable to raloxifene in blocking cytokine production and formation of osteoclast-like cells. Our research demonstrates the usefulness of the in vitro co-culture model in the dissection of molecular events relevant to bone metabolism and provides greater insight into a potential novel role for cytokines in bone resorption. Furthermore, representatives of the SP500263 family of SERMs may be effective as therapeutics for the treatment of osteoporosis.

Biomarkers↗
PubMed2002

[Antiestrogen therapy in the treatment of breast neoplasms].

During recent years the development of hormone therapy for the treatment breast neoplasms has seen, in addition to classic aspecific antiestrogens (AE) like tamoxifen (TAM) and to a lesser extent toremifen, a major development of new molecules divided into two groups: the first is the so-called selective estrogen receptor modulators (SERMs), the most important of which is Raloxifen, which mediate estrogen-agonist effects in some tissues and estrogen-antagonist effects in others; the second group includes the aromatase inhibitors (AI), important enzymes for peripheral estrogen conversion. Some studies compare or associate classic AE with the new SERMs and AI, both in adjuvant therapy and in treatment for advanced forms. Other trials assess the anti-osteoporotic activity of some SERMs which present concomitant inhibitory activity on the breast and endometrium.

Adult↗