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PubMed2005

Osteoporosis: diagnostic testing, interpretation, and correlations with oral health--implications for dentistry.

Osteoporosis affects over 10 million Americans, including over 2 million men. Dentistry is in a position to work alongside medicine to assist the population in preventing and coping with this condition. This article provides an overview of osteoporosis, including its causes, assessment, prevention, and treatment. Various pharmacologic agents are reviewed, including bisphosphonates, selective estrogen receptor modulators, calcitonin, anabolic agents, and fluoride. The article also discusses the dentist's role in prevention, risk assessment, diagnosis, nutrition counseling, and evaluating the impact of the disease and its treatment on dental management and treatment planning. As dental implants become more in demand, the prognosis for and potential complications of implant therapy in patients with osteoporosis are a matter of intense interest.

Aged↗
PubMed2004

Prevention of breast cancer by recapitulation of pregnancy hormone levels.

At the present time, the only approved method of breast cancer prevention is use of the selective estrogen receptor modulator (SERM) tamoxifen. Many breast cancers are driven to grow by estrogen, and tamoxifen exploits this by blocking estrogen action at the estrogen receptor. A counter-intuitive and controversial approach to breast cancer prevention is administration of estrogen and progestin at an early age to achieve pregnancy levels. This approach is supported by the fact that breast cancer incidence is halved by early (< or = 20 years of age) full-term pregnancy. Moreover, it has been demonstrated in rodent models that mimicking the hormonal milieu can effectively prevent carcinogen-induced mammary cancer. In this issue of Breast Cancer Research Rajkumar and colleagues use the rodent model to further define the timing and type of hormonal therapy that is effective in preventing mammary carcinogenesis. Clearly, application of this approach in humans may be difficult, but the potential benefit is intriguing.

Animals↗
PubMed2003

Repeated estradiol treatment prevents MPTP-induced dopamine depletion in male mice.

Epidemiological data suggest that the steroid hormone 17beta-estradiol plays an important role in protecting the brain from neurodegenerative processes, including that causing the loss of dopamine (DA) neurons in Parkinson's disease. Determining the mechanisms of neuroprotection in experimental systems may facilitate the development of estrogenic therapies for these diseases. The present study sought to further investigate the mechanism of the neuroprotective effect of 17beta-estradiol in a murine model of Parkinson's disease, i.e. 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal DA depletion. Consistent with previous findings, 17beta-estradiol was found to inhibit MPTP-induced DA depletion under a dosing regimen (repeated daily administration) that mimicked physiological levels of the steroid. However, high doses of the steroid administered repeatedly or acutely failed to inhibit toxicity, as did 17alpha-estradiol. These data suggest that the neuroprotective effect of 17beta-estradiol was mediated through an interaction with one of the nuclear estrogen receptors, and is not the result of an antioxidant action. In order to realize the therapeutic potential of the neuroprotective effect of 17beta-estradiol for Parkinson's disease, it will be necessary to identify synthetic estrogen receptor modulators that lack the activity of the steroid on peripheral tissue. In this study, raloxifene failed to mimic the neuroprotective effect of 17beta-estradiol against MPTP toxicity. Thus, exploration of new compounds with different pharmacological and/or physiochemical properties is warranted.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

[Hormone therapy and breast cancer: a review].

PURPOSE: Tamoxifen as adjuvant hormonal therapy after hormonosensitive-breast cancer surgery is well established nowadays, as well as its efficacy in first-line therapy of advanced hormonosensitive breast cancers. Research of drugs which could be effective, with little toxicity, and having a positive impact on cardiovascular disease or bone is an important issue. CURRENT KNOWLEDGE AND KEY POINTS: New drugs are in development or will soon be on the market to permit second or third lines of treatment with respect to effectiveness and quality of life, such as new anti-estrogens or selective estrogen receptors modulators or aromatase inhibitors. Their principal characteristics are reviewed through recent data. FUTURE PROSPECTS AND PROJECTS: Prevention of breast cancer is a pertinent question and major publications are presented. Finally, the controversy about the possible reintroduction of replacement hormonal therapy after breast cancer will be questioned through trials.

Adolescent↗
PubMed2001

Sex steroids and bone.

Sex steroids are essential for skeletal development and the maintenance of bone health throughout adult life, and estrogen deficiency at menopause is a major pathogenetic factor in the development of osteoporosis in postmenopausal women. The mechanisms by which the skeletal effects of sex steroids are mediated remain incompletely understood, but in recent years there have been considerable advances in our knowledge of how estrogens and, to a lesser extent androgens, influence bone modeling and remodeling in health and disease. New insights into estrogen receptor structure and function, recent discoveries about the development and activity of osteoclasts, and lessons learned from human and animal genetic mutations have all contributed to increased understanding of the skeletal effects of estrogen, both in males and females. Studies of untreated and treated osteoporosis in postmenopausal women have also contributed to this knowledge and have provided unequivocal evidence for the potential of high-dose estrogen therapy to have anabolic skeletal effects. The development of selective estrogen receptor modulators has provided a new approach to the prevention of osteoporosis and other major diseases of menopause and has implications for the therapeutic use of other steroid hormones, including androgens. Further elucidation of the mechanisms by which sex steroids affect bone thus has the potential to improve the clinical management not only of osteoporosis, both in men and women, but also of a number of other diseases related to sex hormone status.

Androgens↗
PubMed2005

Efficient access to 2-aryl-3-substituted benzo[b]thiophenes.

[reaction: see text] Benzo[b]thiophene derivatives are important in part because of their use as selective estrogen receptor modulators. They are usually synthesized by intramolecular cyclization. Here, we propose a method for the synthesis of 2-arylbenzo[b]thiophenes with heteroatoms at the 3-positions directly from the benzo[b]thiophene core by using an aromatic nucleophilic substitution reaction and Heck-type coupling. This methodology provides 2-aryl-3-amino or phenoxybenzo[b]thiophenes in about 35% overall yield in 5 steps.

Cyclization↗
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

Effects of ospemifene, a novel SERM, on hormones, genital tract, climacteric symptoms, and quality of life in postmenopausal women: a double-blind, randomized trial.

OBJECTIVE: Ospemifene, a novel selective estrogen receptor modulator, shows a potential for prevention and treatment of osteoporosis in postmenopausal women. We studied the effects of ospemifene on hormone levels, genital tract organs, climacteric symptoms, and quality of life. DESIGN: A double-blinded study in which 160 postmenopausal women were randomly allocated to receive either ospemifene at three different daily doses (30, 60, or 90 mg) or placebo for 3 months. RESULTS: No significant differences were observed among the study groups in clinical characteristics or parameters reflecting estrogen action at baseline. Ospemifene reduced follicle-stimulating hormone and insulin-like growth factor I levels, whereas estradiol failed to change at all, and luteinizing hormone was reduced only in the 90-mg group of ospemifene. In the vast majority of participants, the endometrium remained atrophic after 3 months of treatment with ospemifene. Although the rate of proliferative endometrium slightly increased in all groups, including placebo, no hyperplasia or bleeding occurred in any participant. Ospemifene had no effect on the appearance of proliferation marker Ki-67 in the endometrium as compared with placebo, and endometrial thickness increased by mean 0.4 to 0.6 mm (P < 0.01, P < 0.05 and P < 0.05 for 30, 60 and 90 mg ospemifene, respectively). Uterine volume slightly increased (8.4%-14.7%) in the ospemifene groups (P > 0.05), perhaps as a result of increased uterine blood flow. The most conspicuous finding was the significant estrogenic effect on vaginal epithelium, as evidenced by an increase in intermediate and superficial cells in repeat Pap smears. Ospemifene was not observed to aggravate climacteric symptoms or cause adverse events, nor did it suppress climacteric symptoms. CONCLUSIONS: Ospemifene at daily doses of 30 to 90 mg did not stimulate endometrium or aggravate hot flashes but clearly had a rather strong estrogenic effect on the vaginal epithelium during a 3-month treatment period. Such effects would be advantageous if ospemifene were found to be effective in the long-term prevention of osteoporosis.

Aged↗
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↗
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↗
PubMed2000

Future possibilities in the prevention of breast cancer: role of genetic variation in breast cancer prevention.

Risk factors for breast cancer are related to endogenous hormones and reproductive events. As such, traditional cancer prevention strategies are not easily applicable. Tamoxifen and other selective estrogen receptor modulators (SERMs) offer a new preventive strategy for some high-risk women, but have not yet been shown to be efficacious for all women. New tools to identify high-risk women are needed. One such tool is the development of a multigenic model of breast cancer susceptibility that can be used to screen women in order to identify those who carry a combination of alleles that puts them at significantly increased risk.

Adult↗
PubMed2004

Estradiol and endocrine disrupting compounds adversely affect development of sea urchin embryos at environmentally relevant concentrations.

Environmental endocrine disrupting compounds (EDCs) are a wide variety of chemicals that typically exert effects, either directly or indirectly, through receptor-mediated processes, thus mimicking endogenous hormones and/or inhibiting normal hormone activities and metabolism. Little is known about the effects of EDCs on echinoderm physiology, reproduction and development. We exposed developing sea urchin embryos (Strongylocentrotus purpuratus and Lytechinus anamesus) to two known EDCs (4-octylphenol (OCT), bisphenol A (BisA)) and to natural and synthetic reproductive hormones (17beta-estradiol (E2), estrone (E1), estriol (E3), progesterone (P4) and 17alpha-ethynylestradiol (EE2)). In addition, we studied two non-estrogenic EDCs, tributyltin (TBT) and o,p-DDD. Successful development to the pluteus larval stage (96 h post-fertilization) was used to define EDC concentration-response relationships. The order of compound potency based on EC50 values for a reduction in normal development was as follows: TBT(L. anamesus)>OCT>TBT(S. purpuratus)>>E2>EE2>DDD>>BisA>P4>E1>>E3. The effect of TBT was pronounced even at concentrations substantially lower than those commonly reported in heavily contaminated areas, but the response was significantly different in the two model species. Sea urchin embryos were generally more sensitive to estrogenic EDCs and TBT than most other invertebrate larvae. Stage-specific exposure experiments were conducted to determine the most sensitive developmental periods using blastula, gastrula and post-gastrula (pluteus) stages. The stage most sensitive to E2, OCT and TBT was the blastula stage with less overall sensitivity in the gastrula stage, regardless of concentration. Selective estrogen receptor modulators (SERMs) were added to the experiments individually and in combination with estrogenic EDCs to interfere with potential receptor-mediated actions. Tamoxifen, a partial ER agonist, alone inhibited development at concentrations as low as 0.02 ng/ml and was effective at this concentration in decreasing the sensitivities of the embryos to estradiol and estrogenic EDCs. The complete antagonist ICI 182,780 inhibited development at concentrations as low as 0.03 ng/ml but increased embryo sensitivity to estradiol and estrogenic EDCs. Estradiol and estrogenic EDCs all cause developmental toxicity in sea urchins through a TAM-sensitive but an ICI-insensitive mechanism. It remains to be demonstrated whether this mechanism involves an estrogen-responsive nuclear receptor (NR), a membrane receptor (NR or non-NR-related) or a completely different mechanism of toxicity. However, early embryo sensitivity and the differential response to SERM co-incubation further suggests more than one mode of EDC action in the developing sea urchin embryo.

Age Factors↗
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↗
PubMed2001

Raloxifene for the treatment and prevention of breast cancer?

Raloxifene is a member of a family of drugs known as selective estrogen receptor modulators (SERMs). Raloxifene is currently approved by the FDA for the prevention and treatment of osteoporosis in postmenopausal women. SERMs hold the potential to treat and prevent breast cancer, osteoporosis and coronary heart disease. Ongoing clinical trials are in place to address the role of raloxifene and SERMs in each of these areas. We review the pharmacology, clinical utility, safety and tolerability of raloxifene and speculate on what the future holds for SERMs and their use in breast cancer.

Breast Neoplasms↗
PubMed2005

Effects of oestrogen receptor-active compounds on lipid metabolism.

Selective estrogen receptor modulators (SERMs) have been used successfully in the treatment of breast cancer and osteoporosis while Tibolone has been used extensively in Europe for the treatment of menopausal symptoms. Limited data is available on the effect of these agents on the cardiovascular system. Traditional and novel lipid markers are valuable in determining patients at increased cardiovascular risk. The purpose of this article is to discuss the mechanism of action of Tamoxifen, Raloxifene and Tibolone and their effects on lipid metabolism.

Antineoplastic Agents↗
PubMed2003

Endothelial function and menopause: effects of raloxifene administration.

Postmenopausal women have more severe endothelial dysfunction than premenopausal women. In the present study, we evaluated the possible beneficial effect of raloxifene administration, a selective estrogen receptor modulator, on endothelial regulation in postmenopausal women. In a double-blind, randomized vs. placebo trial, 60 healthy postmenopausal women were treated with raloxifene (60 mg/d) or placebo for 4 months to evaluate the effect of raloxifene treatment on endothelial function. Furthermore, in raloxifene-treated subjects (n = 30), the effect of raloxifene was also assessed during the intraarterial infusion of N(G)-monomethyl-L-arginine (4 micromol/min). Raloxifene administration vs. placebo was associated with a decrease in plasma low-density lipoprotein cholesterol (P < 0.01), triglyceride (P < 0.05), thiobarbituric acid-reactive substance (P < 0.01), vascular cell adhesion molecule-1 (P < 0.05), intercellular adhesion molecule-1 (P < 0.001), and E-selectin (P < 0.001) levels and with an increase in plasma Trolox equivalent antioxidant capacity (P < 0.001) levels. Indeed, raloxifene treatment was also associated with a significant improvement in endothelial-dependent vasodilatation assessed by brachial reactivity technique. Raloxifene administration had no impact on endothelial-independent vasodilatation. Furthermore, intraarterial infusion of N(G)-monomethyl-L-arginine inhibited the significant effect of raloxifene on endothelium-mediated brachial arterial diameter and flow. In conclusion, our results demonstrate that raloxifene administration is associated with a positive modulation of endothelial-dependent vasodilatation likely due to a reduction of risk factors for endothelial damage.

Adult↗
PubMed2004

Inhibition of estrogen receptor alpha-mediated transcription by antiestrogenic 1,1-dichloro-2,2,3-triarylcyclopropanes.

A novel class of pure antiestrogens, 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs), lack estrogenic activity in a mouse uterotrophic assay and inhibit the growth of estrogen-sensitive MCF-7 breast cancer cells (Day et al., 1991). Here, reporter assays were used to evaluate the effects of the DTACs on estrogen receptor alpha (ERalpha)-mediated transcription from either classic estrogen-response elements (EREs) or nonclassic AP-1 elements. Among the DTACs tested, only the compounds with smaller aromatic substituents, BDRM72 and BDRM81, displayed weak agonist activity on EREs. Their activity was less than that observed for the ER partial agonist, 4-hydroxytamoxifen (ZOHT). In competition experiments, the DTACs blocked estradiol-stimulated transcription from an ERE in a dose-dependent manner and were more effective inhibitors than ZOHT. Each of the DTACs was significantly less active than ZOHT or the pure antiestrogen ICI 182,780 (faslodex) in stimulating transcription from nonclassic AP-1 elements in the presence of ERalpha. DTACs did not modulate either basal or TPA (12-O-tetradecanoylphorbol-13-acetate)-stimulated transcription from an AP-1 element in the absence of ERalpha, indicating that they are not nonspecific inhibitors of transcription and that ERalpha is the drug target. Glutathione S-transferase pull-down assays were used to examine whether DTACs alter the interaction between ERalpha and the p160 coactivator, GRIP1. BDRM35, which has the same dimethylaminomethoxy and phenolic moieties as ZOHT, reduced binding by more than 50%. Thus, disruption of p160 coactivator recruitment by ERalpha may represent one mechanism by which DTACs function as antiestrogens. BDRM35 also suppresses estradiol induction of endogenous target genes c-myc and cyclin D1 in MCF-7 breast cancer cells.

Animals↗
PubMed2002

Breast cancer risk reduction: strategies for women at increased risk.

Breast cancer risk reduction now represents an achievable medical objective. Current interventions include selective estrogen receptor modulators (SERMs), prophylactic surgery, and lifestyle change. For SERMs, current evidence supports tamoxifen use for breast cancer risk reduction whereas raloxifene requires further study. Prophylactic mastectomy and prophylactic oophorectomy, effective in retrospective clinical experiences, should be considered only for women at substantial risk willing to accept the irreversible consequences of these procedures. Although dietary fat intake is under clinical trial evaluation, lifestyle change, including weight loss, dietary change, and increased physical activity, can be recommended based on other health considerations. Use of any intervention requires careful breast cancer risk assessment, risk-benefit calculations, and informed decision making with full patient participation. Future breast cancer risk assessment may incorporate additional biologic measures of estrogen exposure and/or analyses of collected breast cells. Under active evaluation are novel SERMs, aromatase inhibitors/inactivators, gonadotrophin-releasing hormone agonists, retinoids, statins, and tyrosine kinase and cyclooxygenase-2 inhibitors.

Breast Neoplasms↗