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PubMed2004

Reducing breast cancer incidence in familial breast cancer: overlooking the present panorama.

Familial breast cancer, whether associated or not with particular other breast cancer features (male, early onset, bilateral breast cancer), determines a wide and variable risk of developing breast cancer in the 'unpatients' (unaffected individuals) of these families, particularly in those harboring a genetic predisposition. The antiestrogen tamoxifen has been proposed in different trials to prevent breast cancer in women at risk. The NSABP-P1 study demonstrated that tamoxifen drastically reduced (by approximately 50%) the incidence of breast cancer in women at risk selected according to the Gail score. The preventive effect was particularly consistent in postmenopausal women and in those showing familial breast cancer (three or more affected patients). BRCA1/BRCA2 (BRCA1/2) gene analysis in women accrued in the NSABP-P1 trial who developed breast cancer showed that tamoxifen chemoprevention reduced breast cancer incidence in BRCA2 carriers. Different chemoprevention trials are ongoing to compare different selective estrogen receptor modulators and aromatase inhibitors with tamoxifen. The Italian Consortium of Hereditary Breast Ovarian Cancer recently developed the Aromasin Prevention Study, a multicenter, double-blind, randomized, placebo-controlled phase III study evaluating the effect of the aromatase inhibitor exemestane for chemoprevention in postmenopausal women carriers of BRCA1/2 genetic predisposition. Women who are postmenopausal unaffected carriers of BRCA1/2 mutations will be selected by participating institutions and randomly assigned to receive either oral exemestane or oral placebo every day for 3 years in order to reduce the incidence of breast cancer. Genetic counseling and the detection of predisposing BRCA1/2 mutations are mandatory before accrual into the study. Signed informed consents for the performing of BRCA1 and BRCA2 genetic analysis and for enrollment into the study are required. Eligible women will be followed thereafter in order to evaluate the efficacy of exemestane in reducing the incidental rate of breast cancer in unaffected postmenopausal carriers of BRCA1/2 mutations.

Anticarcinogenic Agents↗
PubMed2004

Cloning and functional characterization of PELP1/MNAR promoter.

Proline-, glutamic acid- and leucine-rich protein 1 (PELP1)/modulator of nongenomic activity of estrogen receptor (MNAR), a novel coactivator of estrogen receptors (ERs; ERalpha and ERbeta), modulates the genomic and nongenomic functions of the ERs. PELP1 expression is developmentally regulated in mammary glands and overexpressed in breast tumors. However, little is known about the regulation of PELP1. In this study, we examined whether PELP1 expression is modulated by steroid hormone 17beta-estradiol (E2)-ER pathway. We found that in MCF-7 breast cancer cells, E2 upregulated PELP1 expression threefold and that this upregulation was reduced by antiestrogen. We also found that E2 modulated PELP1 levels in an actinomycin-D-sensitive manner, suggesting transcriptional regulation. Cloning and analysis of the 2-kb PELP1 promoter region revealed two estrogen-responsive element (ERE) half sites in the PELP1 promoter region. In transient transfection assays, E2 upregulated PELP1 promoter activity in breast, endometrial and osteosarcoma model cancer cell lines in an ICI 182,780-sensitive manner. We demonstrated the recruitment of ER to the PELP1 promoter in vitro using EMSA assays and in vivo using a chromatin immunoprecipitation assay. The PELP1 promoter was similarly upregulated by both ERalpha and ERbeta and differentially regulated by selective estrogen receptor modulators in a cell line-dependent manner. Our results suggest that PELP1 expression is modulated by the E2-ER pathway and that PELP1 is an ER target gene.

Base Sequence↗
PubMed2003

Both N- and C-terminal transactivation functions of DNA-bound ERalpha are blocked by a novel synthetic estrogen ligand.

Estrogen receptors (ERs) play a central role in the diverse actions of estrogen. A number of synthetic ER ligands have been generated that can modulate various ER functions. Here we show that TAS-108, representing a novel class of synthetic ER ligands, blocked both ER transactivation functions without inhibiting DNA-binding activity. A transient expression assay showed that similar to ICI182,780, TAS-108 exhibited pure antagonistic activity as it blocked both the N-terminal AF-1 and C-terminal AF-2 transactivation functions. However, unlike ICI182,780, TAS-108 promoted the recruitment of the SMRT co-repressor that abolished ER transactivation function without inhibition of the ability of ERalpha to bind to its target DNA. Both TAS-108 and ICI182,780 acted as antagonists for the transactivation functions of the D351Y mutant, derived from tamoxifen-resistant breast cancer cells, while estrogen and known selective estrogen receptor modulators (SERMs), 4-OH tamoxifen and raloxifene, stimulated D351Y-mediated transcription. Thus, our findings indicated that TAS-108 acts as a novel estrogen antagonist that recruits co-repressors to ERs without AF-1 activation or prevention of DNA binding. Therefore, TAS-108 may be effective against tamoxifen-resistant breast cancer via a different mechanism than that for ICI182,780.

Animals↗
PubMed2004

Soy isoflavone phyto-pharmaceuticals in interleukin-6 affections. Multi-purpose nutraceuticals at the crossroad of hormone replacement, anti-cancer and anti-inflammatory therapy.

Interleukin-6 is a pleiotropic cytokine which plays a crucial role in immune physiology and is tightly controlled by hormonal feedback mechanisms. After menopause or andropause, loss of the normally inhibiting sex steroids (estrogen, testosterone) results in elevated IL6 levels that are further progressively increasing with age. Interestingly, excessive IL6 production promotes tumorigenesis (breast, prostate, lung, colon, ovarian), and accounts for several disease-associated pathologies and phenotypical changes of advanced age, such as osteoporosis, rheumatoid arthritis, multiple myeloma, neurodegenerative diseases and frailty. In this respect, pharmacological modulation of IL6 gene expression levels may have therapeutical benefit in preventing cancer progression, ageing discomforts and restoring immune homeostasis. Although "plant extracts" are used in folk medicine within living memory, it is only since the 20th century that numerous scientific investigations have been performed to discover potential health-protective food compounds or "nutraceuticals" which might prevent cancer and ageing diseases. About 2000 years ago, Hippocrates already highlighted "Let food be your medicine and medicine be your food". Various nutrients in the diet play a crucial role in maintaining an "optimal" immune response, such that deficient or excessive intakes can have negative consequences on the organism's immune status and susceptibility to a variety of pathologies. Over the last few decades, various immune-modulating nutrients have been identified, which interfere with IL6 gene expression. Currently, a broad range of phyto-pharmaceuticals with a claimed hormonal activity, called "phyto-estrogens", is recommended for prevention of various diseases related to a disturbed hormonal balance (i.e. menopausal ailments and/or prostate/breast cancer). In this respect, there is a renewed interest in soy isoflavones (genistein, daidzein, biochanin) as potential superior alternatives to the synthetic selective estrogen receptor modulators (SERMs), which are currently applied in hormone replacement therapy (HRT). As phyto-chemicals integrate hormonal ligand activities and interference with signaling cascades, therapeutic use may not be restricted to hormonal ailments only, but may have applications in cancer chemoprevention and/or NF-kappaB-related inflammatory disorders as well.

Animals↗
PubMed2002

Climacteric: concept, consequence and care.

Climacteric is the period of life starting from the decline in ovarian activity until after the end of ovarian function. According to the definition, the period includes peri-menopause, menopause and post-menopause. Climacteric is considered to be a natural change of life which may be accompanied by various health consequences i.e., menopausal symptoms, osteoporosis, coronary heart disease, or Alzheimer's disease. The key concept is that women enter menopause with different menopausal status for instances, natural menopause, surgical menopause, early menopause or even premature ovarian failure. Women may experience various health consequences due to the difference in genetic and environmental interaction. The prevalence and incidence of menopausal problems vary according to ethnic groups. For instance, Asian women seem to have less problems after menopause than their occidental counterparts. Nevertheless, the problems do exist and seem to be increasing due to the longer life expectancy and lifestyle changes of people in the region. Clinical decision in menopausal therapy can be determined according to health risk stratification. Appropriated menopausal therapeutic strategies include medical and non-medical modalities. The non-medical modalities are mainly focussed on lifestyle modification, while the medical modalities are classified as hormone replacement therapy (HRT) and non-HRT. Those in the high risk group will probably benefit most from medication besides lifestyle modification. There are various types, doses, routes and regimens of medication which need to be appropriately matched with the proper women's characteristics. Those who have contraindications to HRT or can not tolerate its side effects may choose other alternatives eg, selective estrogen receptor modulators, bisphosphonates, calcitonin or calcium and vitamin D. The success of menopausal therapy is to give an appropriate therapeutic option to the right woman. The future direction of research will remain focussing on the development in diagnosis and menopausal therapy particularly the main three areas of health promotion, disease prevention and treatment. The trend of research and development will probably be concentrated on new pharmaceutical agents with more specific action and high selectivity in an attempt to maximize its efficacy and safety. Attention may be paid more on the convenience of drug administration to increase its compliance. Alternative medicine and appropriated technologies are also the fields of special interest of which research is underway.

Adaptation, Physiological↗
PubMedDate not supplied

New possibilities for diagnosis and treatment of osteoporosis.

Postmenopausal osteoporosis is preventable and treatable. Women need not lose bone mineral density (BMD) after the menopause. Without intervention, all women lose bone after menopause, regardless of the amount of calcium, vitamin D, and exercise they undertake. Postmenopausal women need estrogen replacement, a selective estrogen receptor modulator (SERM), or a bisphosphonate to prevent bone loss. Alendronate, risedronate (bisphosphonates) and raloxifene (SERM) are approved for the prevention of bone loss. The diagnosis of at-risk postmenopausal women can best be accomplished by measuring BMD in all postmenopausal women age 65 years and older regardless of their risk profile and in all postmenopausal women under 65 years with one or more risk factors. Treatment guidelines direct physicians to treat postmenopausal women with T-scores lower than -2.0 SD regardless of their risk profile and postmenopausal women with T-scores lower than -1.5 SD with one or more risk factors. The lower the BMD, the greater the fracture risk, particularly in individuals with increased age, existing fragility fractures, or high bone turnover. The best intervention for a patient should be individually selected, based on careful clinical assessment. Although calcitonin is not approved for prevention, it is approved for treatment. The labeling of estrogens has been modified to state that they may be used to "manage" osteoporosis. The lack of efficacy of calcitonin to prevent bone loss during the first 5 years after menopause, and the lack of prospective fracture reduction data for estrogen, have resulted in these labeling restrictions. Alendronate, risedronate, and raloxifene are currently approved for the treatment of osteoporosis. Both of these compounds have been shown to increase BMD and decrease fracture risk. Monitoring of a patient's response to treatment may be accomplished using serial BMD testing and biomarkers of bone turnover.

Aged↗
PubMed2001

Toxicology of environmental estrogens.

It has been hypothesized that environmental contaminants that modulate endocrine signaling pathways may be causally linked to adverse health effects in humans. There has been particular concern regarding synthetic estrogens and their role in disrupting normal development of the male reproductive tract. Most estrogenic industrial compounds, such as bisphenol A (BPA) and nonylphenol, typically bind estrogen receptors alpha (ERalpha) and beta (ERbeta) and induce transactivation of estrogen-responsive genes/reporter genes, but their potencies are usually > or = 1,000-fold lower than observed for 17beta-estradiol (E2). Selective estrogen receptor modulators (SERMs) represent another class of synthetic estrogens that are being developed for treatment of hormone-dependent problems. The SERMs differentially activate wild-type ERalpha and variant forms expressing activation function 1 (ER-AF1) and AF2 (ER-AF2) in human HepG2 hepatoma cells transfected with a pC3-luciferase construct, and these in vitro differences reflect their unique in vivo biologies. The HepG2 cell assay has also been used in our laboratories to investigate the estrogenic activities of the following structurally diverse synthetic and phytoestrogens: 4'-hydroxytamoxifen; BPA; 2',4',6'-trichloro-4-biphenylol; 2',3',4',5'-tetrachloro-4-biphenylol; p-t-octylphenol; p-nonylphenol; naringenin; kepone; resveratrol; and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). The results show that synthetic and phytoestrogens induce distinct patterns of gene activation in HepG2 and U2 osteogenic sarcoma cells, suggesting that these compounds will induce tissue-specific in vivo ER agonist or antagonist activities. The predicted differences between these compounds, based on results of the in vitro bioassay, have been confirmed. For example, BPA inhibits E2-induced responses in the rodent uterus, and HPTE and structurally related compounds are ERalpha agonists and ERbeta antagonists in assays carried out in HepG2 and other cancer cell lines.

Animals↗
PubMed2000

The importance of patient education in improving compliance.

It is self-evident that the benefits of hormone replacement therapy will not be realized if women do not continue taking the therapy for long enough. All surveys show very disappointing levels of compliance or continuance, with typically about 25% of women stopping within 6 months and very few remaining on therapy for more than 1 or 2 years. The main reasons for stopping include unexpected or unacceptable side-effects, bleeding, fears of cancer, ignorance of the effects of hormone replacement therapy and the potential benefits, inappropriate expectations and poor support from medical advisers. With the ever-increasing options for prescribing hormone replacement therapy, including different routes of administration, combinations of hormones and variable dosages, it should be possible to find a regimen of hormone replacement therapy to suit most women. In the long term, poor continuation of hormone replacement therapy is strongly influenced by the presence of bleeding. Continuous combined estrogen/progestogen regimens, which avoid cyclical bleeding, are more acceptable, particularly for the older postmenopausal woman. However, the initial counselling has a most important impact and time taken to explain and to involve the woman in the decision process will encourage greater confidence in the merits of the therapy. The use of informative literature, videos and telephone help-lines, together with regular and close follow-up until a regimen is satisfactorily established, allows reassurance about initial side-effects or worries and adjustment of therapy. Recent developments of lower-dose combination therapy, selective estrogen receptor modulators and intrauterine progestogen-releasing systems should further improve compliance, but the key to continuation with hormone replacement therapy is a well-informed and confident patient.

Aged↗
PubMed1999

Sonographic assessment of the endometrium in osteopenic postmenopausal women treated with idoxifene.

Idoxifene is a novel selective estrogen receptor modulator that has shown beneficial effects on bone turnover and lipid metabolism in clinical studies. Preclinical studies have demonstrated that idoxifene has estrogen antagonist activities on the endometrium. This paper describes the results of a double-blind, placebo-controlled, and dose ranging study involving 331 osteopenic postmenopausal women who were treated with either placebo or idoxifene (2.5, 5, or 10 mg/day) for 12 weeks. In these women, endometrial assessment was carried out by transvaginal sonography and endometrial biopsy on selected patients at baseline and on all women at the end of treatment. Women with an endometrial thickness greater than 10 mm were excluded from the study. Aspiration endometrial biopsy was performed on women with an endometrial thickness between 6 and 10 mm at baseline and on all women after treatment. Of the 298 biopsies performed in the subjects at the end of treatment, 99% of the women were reported to have either a benign or atrophic endometrium (85%) or insufficient tissue for diagnosis (14%). Proliferative histologic features were reported in two cases (1%) (2.5 mg idoxifene) and atypical hyperplasia in one placebo patient. Even though idoxifene use was associated with a dose related increase in endometrial thickness as evaluated by transvaginal sonography, no relationship was established between endometrial histologic features and change in endometrial thickness. On histologic analysis, the increase in endometrial thickness seen on transvaginal sonography was not associated with proliferative or hyperplastic change in the epithelial (glandular) endometrial tissue. In 48 patients (16% of total) transvaginal sonography showed endometrial thickening of 5 mm or more over the study period. The endometrial histologic features were benign in all these patients. Nineteen percent of women developed intraluminal fluid, even though endometrial thickness was normal and unchanged and histologic features were normal. Our data show that after 3 months of treatment, no significant pathologic changes of the endometrium were observed. Our data indicate that measurements of endometrial thickness by transvaginal sonography may falsely suggest the presence of endometrial pathologic changes in some postmenopausal women treated with idoxifene. Additional testing using saline infusion sonohysterography is an important part of the transvaginal sonography protocol in equivocal or abnormal cases to exclude focal lesions such as polyps. In addition, our data indicate that pathologic changes of the endometrium are extremely rare in the treated group, indicative of its short term safety. Continued investigation such as this will be needed to establish long term safety.

Aged↗
PubMed2003

Endocrine therapy of advanced disease: analysis and implications of the existing data.

Endocrine therapy remains an important approach to the treatment of metastatic breast cancer because of its effectiveness and excellent tolerability. In the last 10 years, a number of new endocrine therapies have been introduced. These include the luteinizing hormone-releasing hormone agonists, which produce menopausal changes in premenopausal women; the aromatase inhibitors, which prevent production of estrogen in postmenopausal women; and the estrogen receptor down-regulator fulvestrant (Faslodex), which is effective in postmenopausal women whose tumors have progressed following response to other selective estrogen receptor modulators. The endocrine cascade for the treatment of premenopausal women with metastatic disease now involves the concurrent or sequential combination of a luteinizing hormone-releasing hormone analogue and tamoxifen, whereas the cascade for the treatment of postmenopausal women can begin with tamoxifen followed by an aromatase inhibitor or with an aromatase inhibitor followed by tamoxifen. The optimal cascade following the use of an aromatase inhibitor and tamoxifen in postmenopausal women remains unclear, but fulvestrant and megestrol acetate or the use of an aromatase inactivator (exemestane) following an aromatase inhibitor are all available options with some activity. Over the next few years, clinical trials will clarify the optimal sequence of endocrine therapy for postmenopausal women. The use of estrogen and progesterone receptor status to select for endocrine therapy is undeniably crucial. HER2/neu overexpression may also predict response to endocrine therapy, but this remains controversial.

Antineoplastic Agents, Hormonal↗
PubMed2000

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

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

Alzheimer Disease↗
PubMed2002

Endocrine modulation and the fragile balance of homeostasis--an overview.

Endocrine modulation by natural and synthetic chemicals and the eventually resulting beneficial or adverse effects for human and animal health are controversially debated not only among scientists but particularly in the public. Most information is available on so-called environmental estrogens, however the amount of information on substances interfering with other hormonal axes steadily increases, particularly on those exhibiting (anti)androgenic activities. The aim of this paper is to summarize existing data and to give an overview on the potential pathways leading to interferences of environmental hormones with homeostasis and eventually resulting health effects. Experimental evidence suggests the hypothesis that fetal and neonatal organisms may be at risk if exposed to environmental estrogens. In contrary, it appears as if phytoestrogens, particularly those with selective estrogen receptor modulator- (SERM-)like activities have the potential to be useful in medical application, both as dietary means and as pharmaceuticals. Lacking valid information about the detailed analysis of the molecular mode of action for environmental estrogens, the possibility for an ultimate classification of environmental estrogens in "dangerous endocrine disruptors" and phytoestrogens in "useful pharmaceuticals" cannot be supported conclusively. Nevertheless both activities are likely.

Aging↗
PubMed2005

Deficiencies in estrogen-mediated regulation of cerebrovascular homeostasis may contribute to an increased risk of cerebral aneurysm pathogenesis and rupture in menopausal and postmenopausal women.

Despite the catastrophic consequence of ruptured intracranial aneurysms, very little is understood regarding their pathogenesis, and there are no reliable predictive markers for identifying at-risk individuals. Few studies have addressed the molecular pathological basis and mechanisms of intracranial aneurysm formation, growth, and rupture. The pathogenesis and rupture of cerebral aneurysms have been associated with inflammatory processes, and these have been implicated in the digestion and breakdown of vascular wall matrix. Epidemiological data indicate that the risk of cerebral aneurysm pathogenesis and rupture in women rises during and after menopause as compared to premenopausal women, and has been attributed to hormonal factors. Moreover, experimental evidence supports a role for estrogen in the modulation of each phase of the inflammatory response implicated in cerebral aneurysm pathogenesis and rupture. While the risk of aneurysm rupture in men also increases with age, this increased risk has been attributed to other recognized risk factors including cigarette smoking, use of alcohol, and history of hypertension, all of which are more common in men than women. We hypothesize, therefore, that decreases in both circulating estrogen levels and cerebrovascular estrogen receptor density may contribute to an increased risk of cerebral aneurysm pathogenesis and rupture in women during and after menopause. To test our hypothesis, experiments are needed to identify genes regulated by estrogen and to evaluate gene expression and intracellular mechanisms in cells/tissues exposed to varying concentrations and duration of treatment with estrogen, metabolites of estrogen, and selective estrogen receptor modulators (SERMs). Furthermore, it is not likely that the regulation of cerebrovascular homeostasis is due to the actions of estrogen alone, but rather the interplay of estrogen and other hormones and their associated receptor expression. The potential interactions of these hormones in the maintenance of normal cerebrovascular tone need to be elucidated. Additional studies are needed to define the role that estrogen and other sex hormones may play in the cerebrovascular circulation and the pathogenesis and rupture of cerebral aneurysms. Efforts directed at understanding the basic pathophysiological mechanisms of aneurysm pathogenesis and rupture promise to yield dividends that may have important therapeutic and clinical implications. The development of non-invasive tools such as molecular MRI for the detection of specific cells, molecular markers, and tissues may facilitate early diagnosis of initial pathophysiological changes that are undetectable by clinical examination or other diagnostic tools, and can also be used to evaluate the state of activity of cerebral aneurysm pathogenesis before, during, and after treatment.

Brain↗
PubMed2002

Estrogenic modulation of brain activity: implications for schizophrenia and Parkinson's disease.

Evidence suggests the estrogens may play a role in various mental and neurodegenerative diseases. We review the evidence implicating estradiol in schizophrenia and Parkinson's disease. Epidemiologic and clinical studies on the effects of estrogens in schizophrenia are surveyed, and animal studies and in vitro models of the modulatory effects of estrogens on neurotransmitters associated with schizophrenia (i.e., dopamine, serotonin, glutamate) are reviewed. Epidemiologic and clinical data suggesting a role for estrogens in Parkinson's disease and in vivo and in vitro models demonstrating neuroprotective effects of estrogens are then examined. Despite the numerous animal studies on the effects of estrogens in the brain, clinical data are sparse and often contradictory. Compounds with more specific and potent estrogenic activity in the brain are required to further research efforts in this area. Possible candidates are the selective estrogen receptor modulators (SERMs), whose agonist or antagonist properties depend on the target tissue. The effects of various SERMs in the brain are reviewed, and our novel findings on the effects of SERMs on 5-HT2A receptors in the rat cortex and nucleus accumbens are presented. We suggest that drugs with estrogenic activity in the brain may have therapeutic potential, either by modulating brain neurotransmission or through neuroprotective activity.

Animals↗
PubMed2003

New markers for cardiovascular disease risk in women: impact of endogenous estrogen status and exogenous postmenopausal hormone therapy.

The role of estrogen in altering cardiovascular disease risk in women is contentious. Menopause is associated with increased risk for ischemic heart disease and cerebrovascular disease, which collectively are the main causes of morbidity and mortality in women of developed nations. Observational studies suggest a protective role of estrogen, whereas recent randomized controlled trials report a negative role for oral estrogen in primary and secondary prevention of cardiovascular events. Inflammatory mechanisms underlie the process of arterial thrombus formation following atheromatous plaque rupture, and as such modulation of the inflammatory process may be a potential means of reducing cardiovascular risk. Sex steroids may influence inflammatory processes and hence modify cardiovascular risk. The objective of the study was to review the current understanding of the relationships between C-reactive protein (CRP), homocysteine, IL-6, and lipoprotein (a) [Lp(a)] and endogenous estrogen status, exogenous estrogen treatment, and cardiovascular disease risk. The design was a review of all relevant published, peer- reviewed studies. Raised levels of CRP, homocysteine, Lp(a), IL-6, and CRP are each independently associated with increased risk for cardiovascular events in women. Changes in these parameters across the menopausal transition cannot clearly be attributed to hormonal changes. With respect to the effects of exogenous postmenopausal therapy, oral estrogen use is consistently associated with elevations in CRP, no change or a reduction in homocysteine, varied effects on IL-6, and a consistent reduction in Lp(a). Transdermal estradiol overall has no significant effect on any of these parameters. Progestin use appears to attenuate the effect of oral estrogen on CRP and is associated with a reduction in Lp(a). Like oral estrogen, tibolone use is associated with a rise in CRP, with no change in homocysteine and consistent lowering of Lp(a). Selective estrogen receptor modulators modestly lower homocysteine and Lp(a), have varied effects on CRP, and have no reported effects on IL-6. Despite these varied effects of postmenopausal hormone treatment on inflammatory markers, homocysteine, and Lp(a), there is no evidence that change in these markers results in modification of cardiovascular risk. Further studies are required to specifically investigate whether treatments that increase or decrease these markers in fact modulate the risk of cardiovascular events in women.

Biomarkers↗
PubMed2005

Extended adjuvant endocrine therapy of early breast cancer.

Women who are diagnosed with early breast cancer remain at considerable risk of recurrence over the next several decades, even if their tumors were small and lymph nodes were negative, and despite receiving standard adjuvant therapy. A majority of breast cancers are hormone (estrogen) receptor-positive and amenable to endocrine therapy, and for those women five years of the selective estrogen receptor modulator tamoxifen is standard therapy. Longer treatment of node-negative patients with tamoxifen may reduce survival benefits, however, possibly due to tamoxifen resistance and emerging receptor agonist activity of that drug. Aromatase inhibitors, which indirectly prevent estrogen stimulation of breast cancer by suppressing whole-body estrogen synthesis in post-menopausal women, are being investigated as alternative, or complementary, therapy to adjuvant tamoxifen in those women: as an alternative to five years of tamoxifen, sequenced with two to three years of tamoxifen, or following five years of tamoxifen. The strategy to extend the benefits of adjuvant therapy beyond a standard course of tamoxifen, using the aromatase inhibitor letrozole, was explored in a large trial, MA.17. Compared with women who received placebo, those who were treated with letrozole experienced a significant 43% reduction in their residual risk of recurrence. This effect was seen regardless of nodal status. Based on the long-term risk of most women with early breast cancer and the MA.17 trial results, the extended adjuvant letrozole may benefit many of those women who are disease-free after five years of tamoxifen. This review is based on a literature search of databases including MEDLINE/PubMed, San Antonio Breast Cancer Symposium, and the Annual Meeting of the American Society of Clinical Oncology, up to and including August 2005, with information selected for its relevance to adjuvant therapy of breast cancer with endocrine therapy only.

Aromatase Inhibitors↗
PubMedDate not supplied

Paradoxical interactions among estrogen receptors, estrogens and SERMS: mutual annihilation and synergy.

The phenomenon of mutual annihilation of action between 17beta estradiol (E(2)) and a selective estrogen receptor modulator (SERM), previously described in prepubertal rat diaphysis, epiphysis and uterus, has been investigated in ROS 17/2.8 rat osteoblastic cells and in transiently co-transfected cells in culture. In ROS 17/2.8 cells, the estrogen-induced marker enzyme creatine kinase B (CKB) was stimulated by raloxifene, tamoxifen and tamoxifen methiodide to a specific activity equal to or greater than that induced by 10 nM E(2). However, when a fully inhibitory dose of any of these SERMS was given simultaneously with E(2), no stimulation of CK activity resulted. Therefore, SERMS can be full agonists when acting alone, but complete antagonists to a super-physiological dose of estrogen. It is expected that excess tamoxifen would prevent the action of a SERM, but that the agonist activity of a SERM is abolished by 1000-fold less estrogen is a phenomenon without obvious explanation by classical pharmacology of competitive inhibition. To probe the mechanism of this interaction further, a ckb-CAT reporter plasmid, plus the human receptor expression plasmid, HEO, was transfected transiently into several cell types. In MCF-7 cells, a 1:10 ratio of E(2) to tamoxifen produced mutual annihilation, but the same ratio in ROS 17/2.8 or HeLa cells led to synergistic stimulation. In HeLa cells, co-transfected with the more efficient wild-type estrogen receptor plasmid, HEGO, synergy was demonstrated only at sub-saturation levels of HEGO. We speculate that, in the presence of estradiol and a SERM, not only active homodimers would be formed, but also hetero-dimers of estrogen-liganded and tamoxifen-liganded receptor monomers, depending on the molar ratio of their ligands and their relative affinities. The resulting hetero-dimer conformation would change the specific receptor surface for interactions with the growing number of co-activators and co-repressors, structural changes which could help to explain the mutual annihilation and synergy phenomena and their cell selectivity.

Antineoplastic Agents, Hormonal↗
PubMed2006

Improvement in dermatomyositis rash associated with the use of antiestrogen medication.

BACKGROUND: Dermatomyositis (DM) is an autoimmune disorder that occurs more often in women than men and causes highly symptomatic and inflammatory cutaneous and proximal muscle disease. Corticosteroids have been the treatment of choice for myositis in DM, and antimalarial agents for the skin disease of DM, with methotrexate sodium, azathioprine, mycophenolate mofetil, cyclosporine, and intravenous immunoglobulin used as steroid-sparing agents. Recently, reports supporting a role for anti-tumor necrosis factor alpha (TNF-alpha) therapy in the treatment of DM have emerged. OBSERVATIONS: We describe 2 women who experienced an improvement in their DM-associated skin eruptions while taking antiestrogen medication. The first patient was taking tamoxifen, a selective estrogen receptor modulator that has been found to have anti-TNF-alpha properties. The second was taking anastrozole, an aromatase inhibitor. When tamoxifen therapy was discontinued after 4 years of use in the first patient, her DM rash worsened and remained difficult to control with conventional immunosuppressant medication. CONCLUSIONS: With the limited number of therapies available to manage DM skin eruptions, the discovery of novel agents effective in treating this disease is vital. Using antiestrogen medication in women with DM may result in a significant improvement in their rash, possibly via the inhibition of TNF-alpha production by immune or other cells. Further investigation into the use of antiestrogen therapy in DM is merited to evaluate long-term risks and benefits.

Adult↗