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PubMed2003

Origin and characteristics of adverse events in aromatase inhibition therapy for breast cancer.

Estrogen is critical in the progression and probably also in the initiation of breast tumors. Two classes of pharmacologic agents currently used in the treatment of estrogen receptor-positive breast tumors are the selective estrogen receptor modulators such as tamoxifen that block the interaction of estrogen with its cognate receptor, and the aromatase inhibitors (AIs) that block the final enzymatic step in the estrogen biosynthetic pathway. Recent data from first-line phase III trials in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer suggest that AIs are at least equivalent to or more effective than tamoxifen in this setting. As a result AIs are being evaluated in the adjuvant setting and may eventually displace tamoxifen as the endocrine therapy of choice for postmenopausal patients with breast cancer. Among the side effects of therapy that were observed in metastatic trials, AIs have shown less vascular and uterine adverse events than tamoxifen. Some concern exists, however, regarding their effect on lipid metabolism and bone turnover. To be acceptable for adjuvant treatment, AIs will have to show not only an advantage in efficacy, but also that any concerns from potential side effects may be managed appropriately. This article reviews the safety profile of AIs, discussing events related to their chemical structure, their specificity, and the effects of estrogen deprivation on target organs.

Antineoplastic Agents, Hormonal↗

PubMed2002

Estrogen receptor downregulators: new antihormonal therapy for advanced breast cancer.

BACKGROUND: Fulvestrant is the first agent in the new class of estrogen receptor (ER) downregulators to be evaluated in clinical studies. The binding of ER downregulators to ERs inhibits the activation functions of the receptors (AF-1 and AF-2). ER downregulators also disrupt the dimerization and nuclear localization of ERs. In contrast to ER downregulators, when selective estrogen receptor modulators (SERMs) bind to ERs, only AF-2 is inhibited; AF-1 remains active. Therefore, with SERMs, AF-1 can still recruit coactivators, which results in a partially inactivated transcription and a reduced rate of tumor cell division. Consistent with its mechanism of action, animal models have shown that fulvestrant demonstrates a longer suppression of tumor growth than does tamoxifen, and it has antitumor activity in tamoxifen-resistant tumors. Two Phase III trials have been conducted comparing fulvestrant (250 mg IM monthly) with anastrozole (1 mg oral tablet daily) in postmenopausal patients with advanced breast cancer progressing after prior endocrine therapy. Objective response in fulvestrant-treated patients in the 2 studies ranged from 17.5% to 20.7% compared with 15.7% to 17.5% for anastrozole-treated patients, and the median duration of response ranged from 14.3 to 19.3 months in the fulvestrant group compared with 10.5 to 14.0 months in the anastrozole group. No statistically significant differences were demonstrated for any of the predefined end points. In both studies, fulvestrant was as well tolerated as anastrozole. OBJECTIVE: This review describes the pharmacology, clinical activity, safety, dosing, and pharmacokinetic profile of fulvestrant. CONCLUSIONS: Based on evidence to date, fulvestrant will likely be an important agent in the treatment of tamoxifen-resistant metastatic breast cancer.

Animals↗

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↗

PubMed2002

The impact of hormonal treatments on quality of life of patients with metastatic breast cancer.

BACKGROUND: The concept of quality of life (QOL) increasingly has been used to assess health-related outcomes associated with a specific disease or its treatment, especially in patients with incurable tumors, such as metastatic breast cancer (MBC). Hormonal therapy (HT) is often used to treat hormone receptor-positive MBC, with the primary treatment goal of reducing both disease burden and patient suffering. OBJECTIVE: This article reviews the instruments used to assess QOL in patients with breast cancer, the adverse effects of HTs, and the clinical trials that assess QOL in patients with MBC receiving various HTs. METHODS: Articles were identified for inclusion in this manuscript 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 abstacts (2001 and 2002). The following search terms were used: quality of life, breast cancer, hormonal therapies, tamoxifen, toremifene, letrozole, anastrozole, exemestane, and megestrol acetate. CONCLUSIONS: QOL assessment following MBC treatment has become an important indicator of treatment effectiveness, and numerous clinical trials have studied the impact of HT on QOL. In general, the older HTs, such as the progestins and selective estrogen receptor modulators (SERMs), produce more adverse effects than do the newer HTs, such as the aromatase inhibitors (AIs) and estrogen receptor (ER) antagonists. QOL data regarding tamoxifen, a SERM associated with a high incidence of vasomotor symptoms and vaginal discharge, are limited, although tamoxifen has not been associated with significant psychological distress when administered as a chemopreventive or adjuvant MBC therapy in clinical trials. QOL studies comparing the third-generation AIs with tamoxifen or megestrol acetate show that the AIs produce a more favorable QOL, probably because these agents target the aromatase enzyme, which results in a lower incidence of thromboembolism and vaginal bleeding. Although QOL studies of the ER antagonist fulvestrant have not been conducted, several attributes of this new HT may contribute to the retention of a good QOL in patients with MBC. A variety of QOL-assessment tools to measure the impact of HTs on patients with MBC are available. Clinical trial data regarding QOL in patients with MBC receiving HT will be useful for both clinicians and patients in evaluating treatment options and developing treatment strategies.

Antineoplastic Agents, Hormonal↗

PubMed2002

Tamoxifen enhances choline acetyltransferase mRNA expression in rat basal forebrain cholinergic neurons.

Novel estrogen-like molecules known as SERMs (selective estrogen receptor modulators) produce many of the beneficial estrogen-like actions without the detrimental side-effects. The SERM, tamoxifen, an estrogen-like molecule with both agonist and antagonist properties, is widely prescribed for the treatment of breast cancer. While the effects of tamoxifen are being evaluated in many peripheral tissues, its effects in the central nervous system (CNS) have been largely ignored. In the present study, we begin to evaluate the effects of tamoxifen in the rat basal forebrain, a region known to be highly responsive to estrogen. We compared the effects of short-term (24 h) tamoxifen treatment to that of estrogen on ChAT mRNA expression in cholinergic neurons. In addition, we examined the effect of tamoxifen in the presence and absence of estrogen. Our results indicate that tamoxifen enhances ChAT expression in a manner similar to that of estrogen in several basal forebrain regions. In contrast, tamoxifen exhibits antagonist properties with respect to estrogen-induction of progesterone receptor mRNA in the medial preoptic nucleus. These results indicate tamoxifen has estrogenic properties with respect to cholinergic neurons, suggesting a previously unidentified effect of this agent in the CNS.

Animals↗

PubMed1999

Pharmacokinetics of raloxifene and its clinical application.

Hormone replacement therapy (HRT) administered to postmenopausal women relieves climacteric symptoms, prevents loss of bone mass, and counteracts the development of coronary artery disease. However, whereas all the benefits associated with HRT are achieved only following long-term therapy, the long-term compliance to the regimen is poor. The most common reasons for discontinuance are uterine bleeding, breast pains, and a fear of breast cancer. Long-term HRT may be associated with an increased risk of breast cancer. Consequently, there is a need for an "ideal estrogen", designed to pinpoint desired target tissues for estrogen, such as the bone and liver, while acting as an antiestrogen in uterus and breast tissues. Raloxifene belongs to a new class of compounds, selective estrogen receptor modulators (SERMs). It binds to and interacts with estrogen receptors, acting as an estrogen agonist in bone and liver, but as an estrogen antagonist in breast and uterus. Therefore, raloxifene represents a potentially important alternative to HRT in postmenopausal women for the prevention and treatment of osteoporosis and cardiovascular disease. Clinical studies regarding the drug's long term benefits are still required.

Adult↗

PubMed1999

Clinical efficacy of raloxifene in postmenopausal women.

A new class of compounds known as selective estrogen receptor modulators (SERMs) may possess the optimal combination of characteristics desirable in a drug designed for use in postmenopausal women. Among this class of compounds, raloxifene is the most studied and is currently available for clinical use in some countries for the prevention of osteoporosis in post-menopausal women. Raloxifene is a non-steroidal benzotiophene derivative shown to prevent bone loss at axial and appendicular sites and reduce serum cholesterol, like estrogen, in oophorectomized rats and in postmenopausal women. In animal models, unlike estrogen, raloxifene does not stimulate breast or uterine tissues. These appealing attributes make raloxifene a potential treatment for osteoporosis and other menopause related risks in middle aged and elderly women. Multicenter studies have been performed in early postmenopausal women, randomly assigned to receive raloxifene 30, 60, or 150 mg/day or placebo. All subjects received a calcium supplement. Bone mineral density, which was measured twice a year over 24 months by dual X-ray absorptiometry, decreased significantly at all skeletal sites with placebo, and significantly increased with raloxifene at the spine, hip, and total body at the three doses. At 24 months, the mean increase with raloxifene 60 mg compared with placebo was 2.4% at the lumbar spine and at the total hip, and 2% at the total body. Markers of bone formation (serum osteocalcin and bone specific alkaline phosphatase) and of resorption (urinary CrossLaps) decreased significantly to the premenopausal range within 3-6 months of treatment with raloxifene. In addition, total serum and low-density lipoprotein cholesterol decreased significantly in all raloxifene therapy groups in a dose-related fashion. Serum HDL-cholesterol and triglycerides were not significantly changed by therapy. The most commonly observed side-effect was hot flushes, with patients taking raloxifene reporting a slightly higher rate of flushes (25%) than those on placebo (18%). This adverse event usually occurred within the first few months of therapy, was generally mild, and did not result in excess study dropout (raloxifene 1.5%, placebo 2.1%). Preliminary 2-year data indicated that raloxifene is not associated with an increased risk of breast cancer. In summary, the clinical efficacy and safety of raloxifene is very promising and this compound will offer a particularly attractive choice for postmenopausal women.

Cardiovascular Diseases↗

PubMed2000

Modeling of signaling pathways for endocrine disruptors.

The so called endocrine disruptors have become an important working hypothesis for a wide range of toxicology researchers. This hypothesis has also attracted those who have worked on designer estrogens or selective estrogen receptor modulators. Already numbers of substances have been identified as such chemicals, but there remain a large number of chemicals waiting to be tested for their endocrine modulating capabilities. Because of the time and costs required for wet lab tests, it is unrealistic to apply these kinds of tests to all such suspicious or probable chemicals. Thus some theoretical methods must be developed for this purpose. However the conventional QSAR (quantitative structure activity relationships) approach is of limited relevance to this problem, because these methods do not take detailed mechanisms of molecular interactions in biological systems into account. Thus we have developed a database complex system that enables one to trace molecular interactions triggered by interaction of receptors with xenobiotic chemicals. The main components of this database complex are a potential endocrine disruptor database, a receptor database, a cell signaling networks database, a transcription factor database, and an affinity binding database based on modes of actions.

Database Management Systems↗

PubMed2002

Raloxifene effects upon the neuronal system controlling sexual receptivity in female rats.

Selective estrogen receptor modulators (SERMs) constitute a new family of drugs with growing interest in the management of estrogen-associated pathology. Raloxifene is a SERM that mimics estrogen action on bone and blood lipid concentration but whether it acts as estrogen in the central nervous system remains to be fully established. In the present communication, we aimed at evaluating the estrogenic/antiestrogenic effects of raloxifene upon organization and activation of sexual receptivity, an estrogen-dependent event, in female rats. To this end, the effects of raloxifene, administered during the neonatal period, were compared with those of estrogen in terms of disruption of sexual receptivity in estrogen-progesterone-primed ovariectomized (OVX) female rats. In addition, the ability of raloxifene to induce sexual receptivity in progesterone-primed OVX females was analyzed. Similarly, the effects of the combined administration of estrogen and raloxifene were studied. Our results suggest that raloxifene does not act as estrogen upon the organization of the neuronal system involved in the control of sexual receptivity in female rats and exerted an antiestrogenic action in adult OVX estrogen-primed female rats.

Animals↗

PubMed2003

Cellular environment of metabolites and a metabonomic study of tamoxifen in endometrial cells using gradient high resolution magic angle spinning 1H NMR spectroscopy.

High resolution magic angle spinning (HRMAS) 1H NMR spectroscopy was used to metabolically characterise Ishikawa cells, a human cell line derived from endometrial adenocarcinoma. The spectra obtained had well-resolved resonances from the nucleotide derivatives of uridine and adenosine. Using a combination of diffusion- and relaxation-weighted spectroscopy, the cellular environment of key metabolites previously identified as related to cell growth was also investigated. As Ishikawa cells are hormone-responsive, the metabolic action of tamoxifen, a selective estrogen receptor modulator (SERM), was also investigated. Cells were exposed to 5, 1 and 0.1 microM tamoxifen. Using the statistical regression technique of prediction to latent structures by partial least squares, a predictive model was built modelling the metabolic profile of the cells against exposure to tamoxifen. These spectral changes were characterised by increased resonance intensities from ethanolamine (3.26 ppm), glucose (3.34-3.94 ppm), glutamate (2.14, 2.32 ppm), tyrosine (7.24 ppm), uridine (7.85 ppm) and adenosine (8.20 ppm), and a relative decrease in contributions from myo-inositol resonances (3.30, 3.62, 3.55 ppm). The nucleotide changes suggest that tamoxifen affects RNA transcription, while the changes in ethanolamine and myo-inositol concentrations are indicative of cell membrane turnover.

Adenocarcinoma↗

PubMed2001

Breast cancer: hormones and other risk factors.

UNLABELLED: In North America and Northern Europe, breast cancer incidence rates begin increasing in the early reproductive years and continue climbing into the late seventies, whereas rates plateau after menopause in japan and less developed countries. Female gender, age and country of birth are the strongest determinants of disease risk. Family history and mutations in the BRCA1 and BRCA2 genes are important correlates of lifetime risk. Genetic polymorphisms associated with estrogen synthesis and metabolism are currently under study. Atypical hyperplasia and molecular alterations in benign breast lesions appear to be involved in the pathogenesis of invasive carcinoma. In postmenopausal women, increased breast density on mammograms increases risk. Bone density and breast cancer are associated, presumably through the mechanism of endogenous estrogen levels. Serum estrogen levels are higher in breast cancer cases than controls. Many established risk factors for breast cancer may function through and endocrine mechanism. Current use of oral contraceptives and prolonged, current or recent use of hormone replacement therapy moderately increase risk. Tamoxifen and possibly other selective estrogen receptor modulators reduce breast cancer risk in high risk women. Relationships between various dietary micro and macronutrients and breast cancer have been suggested but require evaluation in clinical trials. Whereas alcohol consumption is associated with increased risk, most environmental factors, including polychlorinated compounds and electromagnetic fields, are not. CONCLUSION: Breast cancer etiology is becoming clearer through the study of molecular alterations in germline and somatic cell genes, and the interaction of these genes with steroid hormones and relevant growth factors. This knowledge should be useful for breast cancer prevention.

Breast Neoplasms↗

PubMed2002

Effects of ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index, and hormonal status in healthy postmenopausal women.

OBJECTIVE: Selective estrogen receptor modulators (SERMs) are drugs that exhibit both estrogen agonistic and antagonistic effects that are tissue-specific. Ospemifene (FC-1271a) is a novel SERM compound, which has been shown in animal models to have estrogen-like effects on bone and the cardiovascular system, while having antiestrogen-like effects in uterus and breast. In this study, we investigated the effects of ospemifene on the uterine endometrium, vaginal maturation index and hormonal status in healthy postmenopausal women. METHODS: The study was conducted as a double-blind, placebo-controlled phase I study, where 40 healthy postmenopausal women volunteers were randomized to receive daily oral doses of ospemifene either 25, 50, 100 or 200 mg or placebo for 12 weeks. Vaginal ultrasonography and endometrial biopsy were performed and vaginal maturation index determined at baseline and at 12 weeks' visit. Serum concentrations of estradiol, luteinizing hormone, follicle stimulating hormone (FSH), sex-hormone binding globulin (SHBG), parathyroid hormone and prolactin were determined from samples taken at baseline, at 4 days and at 4, 12, and 16 weeks' visits. Climacteric symptoms were assessed using 12 visual analogue scales (VAS) at baseline and at the end of the study. RESULTS: No clinically significant changes were seen in endometrial thickness at any dose level. Ospemifene exerted a very weak estrogenic effect on endometrial histology. On the other hand, it induced a clear estrogenic effect on vaginal epithelium. Among the endocrine parameters only FSH and SHBG showed significant dose dependent changes; FSH decreased and SHBG increased during the treatment. In general, ospemifene was well tolerated. The 25 and 50 mg doses tended to reduce climacteric symptoms, but no statistically significant differences were observed between different doses of ospemifene and placebo. The highest dose level (200 mg) induced more subjective adverse reactions, especially hot flushes, than lower doses. CONCLUSION: Our study suggests that a safe and well tolerated dose of ospemifene for potential clinical use may be between 25 and 100 mg. Further studies are needed to substantiate the results of this Phase I pilot study.

Administration, Oral↗

PubMed2003

Pharmacology of Cimicifuga racemosa extract BNO 1055 in rats: bone, fat and uterus.

OBJECTIVES: Hormone replacement therapy (HRT) has therapeutic effects on climacteric complaints and prevents osteoporosis. Owing to the increased risks of breast cancer and cardiovascular diseases, patients look for alternatives. Cimicifuga racemosa (CR) preparations might be an alternative, because they proved to reduce climacteric complaints as efficiently as conjugated estrogens without exerting estrogenic effects in the uterus. Whether CR has positive effects on bone and in fat tissue is currently unknown. Therefore, osteoprotective effects of the CR extract BNO 1055 and an influence on fat tissue were studied in ovariectomized rats. METHODS: Bone mineral density (BMD) of the tibia of ovariectomized (ovx) rats was determined by computer-assisted tomography (CT). CT scans of fat depots were perimetrically quantified. Bone turnover (osteocalcin, crosslaps) and lipocyte activity (leptin) were also determined. Uterine weights were measured and gene expression of estrogen-regulated uterine genes (IGF-1, ERbeta) was determined by RT-PCR. RESULTS: Treatment of the ovx rats over a period of 3 months with E(2) and the CR extract BNO 1055 showed osteoprotective effects; both significantly reduced the loss of BMD in tibia. Serum osteocalcin levels were significantly reduced by both treatments, whereas only E(2), but not BNO 1055, reduced serum crosslaps. A paratibial fat depot and serum leptin concentration were also significantly reduced. In contrast to E(2), the CR extract showed no effect on uterine weight and gene expression of E(2)-regulated genes. CONCLUSION: The CR extract BNO 1055 exerted estrogenic effects in the bone (particularly in osteoblasts) and in fat tissue, but not in the uterus of ovx rats. The extract appears to contain rat organ-specific selective estrogen receptor modulators (SERMs), and if these findings can be approved in human it may be an alternative to HRT.

Adipose Tissue↗

PubMed2003

The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers.

OBJECTIVES: In the present study, therapeutic effects of the Cimicifuga racemosa preparation CR BNO 1055 (Klimadynon/Menofem) on climacteric complaints, bone metabolism and endometrium will be compared with those of conjugated estrogens (CE) and placebo. The question whether CR BNO 1055 contains substances with selective estrogen receptor modulator (SERM) activity will be investigated. METHODS: Sixty-two evaluable postmenopausal women were included in the double-blind, randomized, multicentre study, and treated either with CR BNO 1055 (daily dose corresponding to 40 mg herbal drug), 0.6 mg CE, or matching placebo, for 3 months. Menopausal symptoms were assessed by the menopause rating scale (MRS) and a diary. Levels of CrossLaps (marker of bone degradation) were determined by ELECSYS system and bone-specific alkaline phosphatase (marker of bone formation) by an enzymatic assay. Endometrial thickness was measured via transvaginal ultrasound; vaginal cytology was also studied. The primary efficacy criterion was the change from baseline to end point in the MRS. Change from baseline was analyzed for the secondary variables too. RESULTS: CR BNO 1055 proved to be equipotent to CE and superior to placebo in reducing climacteric complaints. Under both verum preparations, beneficial effects on bone metabolism have been observed in the serum. CR BNO 1055 had no effect on endometrial thickness, which was significantly increased by CE. Vaginal superficial cells were increased under CE and CR BNO 1055 treatment. CONCLUSION: The results concerning climacteric complaints and on bone metabolism indicate an equipotent effect of CR BNO 1055 in comparison to 0.6 mg CE per day. It is proposed that CR BNO 1055 contains substances with SERM activity, i.e. with desired effects in the brain/hypothalamus, in the bone and in the vagina, but without exerting uterotrophic effects.

Administration, Oral↗

PubMed1998

The effect of estrogens and antiestrogens in a rat model for hot flush.

The present studies evaluated the effect of estrogens and the selective estrogen receptor modulator (SERM) tamoxifen and raloxifene in a rat model for hot flush. In this model, ovariectomized rats were treated for 8 or 9 days either sc or po. Rats were dependent to morphine by implanting a morphine pellet (75 mg each) sc on days 3 and 5 of treatment. On the last day of treatment, a thermistor, connected to a data acquisition system, was placed on the tail of each animal and morphine addiction was withdrawn by naloxone injection (1.0 mg/kg, sc). Temperature measurements were taken for 1 h under ketamine (80 mg/kg, im) anesthesia. In general, vehicle treated rats showed a 5-6 degrees C elevation of their tail skin temperature with the peak occurring about 15 min after naloxone injection. 17 alpha-Ethinyl estradiol (EE) was evaluated both sc and po using a broad range of doses. The IC50 for inhibition of tail skin temperature rise was approximately 0.1 mg/kg, sc and 0.2 mg/kg, po. 17 beta-Estradiol and 17 alpha-estradiol were also active in this model whereas non-estrogenic steroids were inactive. Raloxifene and tamoxifen were tested for estrogen agonist and antagonist activity administered sc and po. Raloxifene did not demonstrate reproducible estrogen agonist activity at doses up to 10 mg/kg, whereas it demonstrated significant antagonistic activity at the 10 mg/kg dose regardless of the route of administration. Tamoxifen exhibited significant estrogen agonist activity at all doses tested (0.1-10.0 mg/kg) and was a significant antagonist of EE at the 1.0 mg/kg dose. Our results demonstrate the potential utility of this model to evaluate and discriminate among classes of compounds with varying degrees of estrogen agonist and antagonist activity.

Animals↗

PubMed1998

Osteoporosis: intervention options.

Osteoporosis is a systemic progressive disease with important clinical complications because of the fractures that arise and cause major morbidity in especially the aging postmenopausal women. Because of the relative not complex procedure of diagnosis and prediction the most important question to answer: is treatment possible? There are now a variety of treatments available for the management of osteoporosis. The inhibitors of bone resorption, which include calcium, the vitamin Ds, bisphosphonates, calcitonins and gonadal steroids have been variously shown to prevent bone loss or to reduce fractures. On the other hand bone formation stimulating agents as fluorides and in the near future parathyroid hormone and analogues must be considered also. However, randomized clinical trials with fractures as clinical endpoints are only few in number and not present for every suggested treatment. During the last 3 years it has become clear that besides estrogen, bisphosphonates and now perhaps the selective estrogen receptor modulators also show a good alternative as intervention option of postmenopausal osteoporosis. At this moment sodium fluoride is not the first choice in treatment of osteoporosis in general practice.

Calcitonin↗

PubMed1998

Post-menopausal women and osteoporosis: available choices for maintenance of skeletal health.

OBJECTIVE: To briefly summarize the therapeutic choices for osteoporosis prevention which are currently available to post-menopausal women. METHODS: Results of randomized clinical trials and epidemiological studies in postmenopausal women, and pre-clinical studies in ovariectomized rats were summarized. RESULTS: Estrogen combined with progestogen in hormone replacement therapy (HRT) is effective in relieving perimenopausal symptoms and maintaining bone mineral density. However, the increased breast cancer risk associated with long-term HRT use makes it a less desirable option for many women. Selective estrogen receptor modulators (SERMs), such as raloxifene, are also effective in maintaining bone density, without stimulating the breast or uterus. However, SERMs do not relieve perimenopausal hot flashes. CONCLUSION: HRT is effective for acute relief of perimenopausal symptoms, but for women who are unwilling or unable to take HRT long-term, SERMs such as raloxifene are a useful therapy for the prevention of osteoporosis.

Animals↗

PubMed1999

Hormone replacement therapy: the perspectives for the 21st century.

UNLABELLED: Nowadays different lines of evidence demonstrate the benefits of postmenopausal hormone replacement therapy (HRT). HRT is extremely effective in treating subjective symptoms and can really improve the quality of life of climacteric women. HRT and dementia: Estrogens are potentially relevant to the pathogenesis and treatment of Alzheimer's disease. The effects of different progestogens on cognitive functions and Alzheimer's disease are largely unknown. The prevention of Alzheimer disease might be a major indication to long term HRT. Large prospective, randomized trials will confirm these preliminary data. HRT and osteoporosis: HRT has been strongly correlated with higher bone mineral density and lower fracture incidence. Definite answers in terms of minimum effective dosages, timing and duration of HRT for fracture prevention are needed. HRT and cardiovascular disease: Different lines of evidence suggest that HRT can exert cardioprotective effects with substantial reduction of morbidity and mortality for cardiovascular disease in postmenopausal women. The effects and the role of progestogens in cardiovascular disease prevention are still debated. Prospective, randomized, controlled studies are needed to assess the impact of different HRT regimens on cardiovascular events. HRT and cancer: The major issue in the relationship between HRT and cancer is breast cancer. Long-term and current HRT use are followed by a slight, though significant increase in the risk of breast cancer. Progestogens can modify the cellular response of normal as well as cancer breasts. The possible protective effect of continuous progestogen addition is very interesting and needs further investigation. Alternative to classical HRT: Selective estrogen receptor modulators (SERM). SERMs such as raloxifene (RAL) are a new class of drugs that exert site specific estrogenic or antiestrogenic effects in different target tissues. RAL prevents bone loss and reduces serum cholesterol in postmenopausal women. In contrast to estrogen RAL does not stimulate breast or uterine tissues. In vitro RAL is highly effective at inhibiting the growth of estrogen-dependent breast adenocarcinoma cells. SERMs are expected to represent a major breakthrough for postmenopausal health. CONCLUSION: HRT can be offered either as a preventive tool or as individualized care on the basis of personal needs. New therapeutic options like the SERMs will offer a substantial medical advancement for the treatment of postmenopausal women.

Adult↗