Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence for breast and other female-hormone-related neoplasms levels off after menopause. The relative risk (RR) of breast cancer is moderately elevated in current and recent users of hormone replacement therapy (HRT) and increases by about 2.3% per year with longer duration of use, but the effect drops after cessation. Unopposed oestrogen use is strongly related to endometrial cancer risk but cyclic combined oestrogen-progestin treatment appears to reduce this side-effect. However, combined HRT may be associated with higher risk of breast cancer as compared to unopposed oestrogens. Ovarian cancer may also be unfavourably influenced by the use of HRT. HRT has been related to decreased risk of colorectal cancer, the overall RR being about 0.8. Tamoxifen and other selective oestrogen receptor modulators (SERMs) may have a favourable effect on the risk of breast cancer but their risk-benefit profile requires further quantification. The potential effect of 'natural' SERMs (phytoestrogens) on cancer risk remains undefined.
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PMID:Cancer risk in menopausal women. 1209 64

Given the rapidly increasing number of women above 50 it is of pivotal importance to consider health issues related to gonadal hormone deficiency. The possibility of alleviating such symptoms by hormone replacement therapy (HRT) should be recognized by all physicians, not merely by gynaecologists. But which women should be given what therapy, and for how long? Due to the increased risk of endometrial cancer and bleeding problems when using oestrogen monotherapy, only women who have undergone hysterectomy could use this regimen unless treatment is aimed at amelioration of urogenital symptomatology only. In this case a vaginal administration of low-dose oestrogens is possible as such doses do not induce endometrial proliferation. In all other cases a combination of an oestrogen and a progestogen must be used. There are several options for doing so. During the early phase of the climacteric period when irregular and/or heavy vaginal bleeds are part of the symptomatology a cyclical therapy will often combat these problems. As women pass into the menopause a sequential regimen is often preferred until 1-3 years have elapsed since menopause. With advancing time since menopause women become more and more reluctant to experience monthly bleeds. In such cases a continuous combined regimen may be offered even though it cannot guarantee a bleed-free remedy.Non-oral, particularly transdermal, therapy is an alternative in women with co-existing morbidity such as migraine, diabetes, malfunction of the gastrointestinal tract and liver disease. Oral therapy is preferred particularly in women with elevated plasma levels of LDL-cholesterol, lipoprotein(a) or homocysteine. Oral therapy induces liver protein synthesis. This could be an advantage in cases with low plasma levels of sex hormone-binding globulin (SHBG) as low levels of SHBG may promote androgenic stigmata such as hirsutism and a lowering of the voice. However, in cases with too low an androgen influence the use of a non-oral therapy may counteract symtoms such as low libido.Tibolone could be used for the prevention (and treatment?) of osteoporosis but it will also mitigate the typical climacteric symptoms. Raloxifene is a fairly new type of drug which is classified as a selective oestrogen receptor modulator (SERM). It will reduce vertebral fractures to the same extent as bisphosphonates, albeit the increase in bone density is less. Raloxifene has no effect on climacteric symptoms. Its greatest benefit is a clear reduction of breast cancer in women, which is in contrast to HRT/ERT.There are insufficent data on tibolone and the incidence of breast cancer. Experimental data, however, are intriguing in suggesting less impact on the breast than conventional HRT/ERT.
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PMID:The role of ERT/HRT. 1209 68

While tamoxifen use is associated with clear benefits in the treatment of hormone-sensitive breast cancer, it also exhibits partial oestrogen agonist activity that is associated with adverse events, including endometrial cancer. Fulvestrant ("Faslodex") is a new oestrogen receptor antagonist that downregulates the oestrogen receptor and has no known agonist effect. This single-centre, double-blind, randomised, parallel-group trial was conducted to determine the direct effects of fulvestrant on the female endometrium when given alone and in combination with the oestrogen, ethinyloestradiol. Following a 14-day, pretrial screening period, 30 eligible postmenopausal volunteers were randomised to receive fulvestrant 250 mg, fulvestrant 125 mg or matched placebo administered as a single intramuscular injection. Two weeks postinjection, volunteers received 2-weeks concurrent exposure to ethinyloestradiol 20 microg day(-1). Endometrial thickness was measured before and after the 14-day screening period with further measurements predose (to confirm a return to baseline) and on days 14, 28 and 42 post-treatment with fulvestrant. Pharmacokinetic and safety assessments were performed throughout the trial. Fulvestrant at a dose of 250 mg significantly (P=0.0001) inhibited the oestrogen-stimulated thickening of the endometrium compared with placebo. Neither the 125 mg nor 250 mg doses of fulvestrant demonstrated oestrogenic effects on the endometrium over the initial 14-day assessment period. Fulvestrant was well tolerated and reduced the incidence of ethinyloestradiol-related side effects. At the same dose level that is being evaluated in clinical trials of postmenopausal women with advanced breast cancer, fulvestrant (250 mg) is an antioestrogen with no evidence of agonist activity in the endometrium of healthy postmenopausal women.
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PMID:A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers. 1245 61

Oestrogen receptors mediate the cellular response to oestrogens and related compounds and promote a wide range of effects on haemopoiesis. Polymorphisms of the oestrogen receptor genes have previously been associated with variation in bone mineral density, likelihood of fractures, risk of developing Alzheimer's disease, endometrial cancer and response to hormone replacement therapy. We examined the polymorphisms in both ERalpha and ERbeta genes in 108 patients receiving a bone marrow transplant from an HLA-matched sibling donor, and compared ER genotype with outcomes of occurrence of graft-versus-host disease (GVHD) and survival using logistic regression analysis. Polymorphism of ERalpha (presence of the PX haplotype (PvuII-XbaI RFLP) of intron 1), but not ERbeta, in the patient genotype associates with occurrence of acute GVHD and with lower overall survival, following correction for known clinical and genotypic risk features. Analysis of ER genotype prior to transplant might therefore inform on a patient's likelihood of developing post-transplant complications. Variation in transplant performance because of ER genotype suggests an underlying role for oestrogens in the pathophysiology of transplant-related complications, and suggests that oestrogen-related therapy may offer a new modality of post-transplant support.
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PMID:Oestrogen receptor alpha gene polymorphism associates with occurrence of graft-versus-host disease and reduced survival in HLA-matched sib-allo BMT. 1281 77

The current recommended adjuvant therapy for oestrogen receptor-positive breast cancer typically includes 20 mg/day tamoxifen (Nolvadex) for 5 years post-operatively. This regimen has been found to reduce the incidence of contralateral breast cancer in breast cancer survivors by 47%, and, when used prophylactically, to reduce new breast cancers in high risk women by 49%. However, epidemiological evidence links tamoxifen therapy to increases in endometrial cancer and thromboembolic events in breast cancer patients. In addition, in tamoxifen-exposed rats dose-related increases in hepatic tamoxifen-DNA adduct formation and liver tumour incidence occur through a classic genotoxic mechanism. In women, endometrial cancers may be the result of genotoxicity, hormonally induced signal transduction and/or other mechanisms. If genotoxicity is relevant to tamoxifen-induced endometrial cancer it may be possible to identify women at risk through detection of tamoxifen-DNA adducts. The aim of this one day conference was to examine the most recent evidence for the occurrence of tamoxifen-induced genotoxicity in women receiving tamoxifen therapy. There were significant experimental differences, as some participants presented evidence for a genotoxic mechanism, while others reported finding insufficient evidence to support a genotoxic mechanism. The discussion was wide ranging and the outcome underscored the need for further investigations, access to more human tissue samples, shared tamoxifen-DNA standards for methodological comparisons and inter-laboratory exchange of human tissue samples.
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PMID:The genotoxicity of tamoxifen: extent and consequences, Kona, Hawaii, January 23, 2003. 1284 Jan 14

Breast cancer remains the most common malignancy in women worldwide. Oestrogen levels appear to be associated with an increased risk for the development of breast cancer. The Early Breast Cancer Trialists' Cooperative Group reported in a 1998 meta-analysis of 37000 breast cancer patients in 55 randomized adjuvant trials that tamoxifen, a selective oestrogen receptor modulator, reduced the incidence of contralateral breast cancers by 47% at 5 years. Tamoxifen has been shown in numerous prevention studies to decrease the incidence of breast cancer in high-risk women. Overall, the tamoxifen prevention trials showed a 38% reduction in the incidence of breast cancer (95% CI 28-46; P<0.0001). In the largest risk-reduction trial, the Breast Cancer Prevention Trial conducted by the National Surgical Adjuvant Breast and Bowel Project, tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<0.00001), and non-invasive breast cancer by 50% (P<0.002). The occurrence of oestrogen receptor-(OR)-positive tumours decreased by 69%. Tamoxifen reduces the risk of developing oestrogen receptor-positive tumours, but OR-negative tumours are not affected. Rare but life-threatening side-effects of tamoxifen include endometrial carcinoma, thromboembolic events and cerebrovascular events. Less serious side-effects include cataracts, vasomotor instability, nausea and vaginal discharge. Raloxifene, a second-generation selective oestrogen receptor modulator, is approved for treatment of osteoporosis in post-menopausal women in the USA but it is not currently approved for breast cancer prevention outside of a clinical trial. Prevention studies involving raloxifene and aromatase inhibitors are currently being conducted.
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PMID:Endocrine prevention of breast cancer using selective oestrogen receptor modulators (SORMs). 1468

Tamoxifen is an effective and relatively non-toxic compound used in palliative and adjuvant treatment of breast cancer. More recently its preventive role in breast cancer has also been demonstrated. However, tamoxifen use is related to some increase in the risk of endometrial cancer and to a significant rise in the incidence of benign endometrial pathologies. The activity of tamoxifen against breast cancer is mainly achieved by blocking the oestrogen receptor, whereas the effect of this compound on the female genital tract is mostly related to its agonistic properties. Despite numerous studies no effective methods of tamoxifen-user surveillance have been developed and currently no active screening for endometrial cancer, apart from yearly gynaecological examination, is recommended in these patients. In other parts of the genital tract, tamoxifen increases the risk of some benign conditions and may cause difficulties in the interpretation of cervical smears. Further studies are warranted to develop more effective surveillance and methods decreasing the detrimental effects of tamoxifen on the female genital tract.
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PMID:The effects of tamoxifen on the female genital tract. 1505 52

Large epidemiological studies have proved that the risk of coronary heart disease in postmenopausal women can be decreased by oestrogen replacement therapy. The effect is triggered by metabolic processes in the liver (decrease of LDL-cholesterol, increase of HDL-cholesterol) as well as by direct impact on the arterial wall (anti-oxidation, relaxation, anti-proliferation). The therapeutical usage of oestrogens is limited by an increased incidence of breast and endometrial cancer. Cyclic application of progestogens virtually eliminates the risk. Unfortunately, progestogens may antagonise the atheroprotective effect of oestrogens. Structurally modified oestrogens as well as selective oestrogen receptor modulators were investigated in clinical trials. They might provide the desired atheroprotective effects of oestrogen without negative side effects on the mammary gland or the endometrium. In this respect isoflavones also known as phytoestrogens, were analysed. They are widespread and occur naturally in many plants, especially in soy products. Cell culture and animal experiments as well as clinical studies revealed that phytoestrogens such as genistein and daidzein act atheroprotectively in the same way as oestrogen. Effects on the mammary gland or the endometrium could not be detected, but positive side effects on the bone metabolism and the decrease of certain types of cancer could be observed. In total, the therapeutical application of phytoestrogens in postmenopausal women seems to be of real and great benefit. We conclude that in women the risk of death from coronary heart disease increases after the onset of menopause. Recently discovered properties of phyto-oestrogens seem to be of great benefit as they do not seem to have any side effects on the mammary gland and the endometrium which are limiting factors for oestrogen replacement therapy.
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PMID:The value of phytoestrogens as a possible therapeutic option in postmenopausal women with coronary heart disease. 1551 63

The early termination of the two arms of the Women's Health Initiative Trials has led to an increased interest and demand for selective oestrogen receptor modulators because of their potential to retain the benefits of hormone replacement therapy (oestrogen plus a gestagen) and at the same time avoid most of its severe adverse events. Selective oestrogen receptor modulators are a class of oestrogen receptor binding, small organic molecules that take advantage of the plasticity of the oestrogen receptors (alpha and beta, respectively), modulating the surface conformation of the oestrogen receptors upon binding in the respective ligand binding cavity. By doing so they affect the binding of various co-factors to the surface of the oestrogen receptors that, at least in part, explains why selective oestrogen receptor modulators may mimic the activity of oestrogen in some tissues where so desired, while opposing its activity in tissues where oestrogen-like activity is undesirable. Although selective oestrogen receptor modulators have many properties in common they also display unique activities including oestrogen receptor surface modulation and regulation of target gene expression. Selective oestrogen receptor modulators therefore offer the opportunity to develop pharmaceuticals with very distinct pharmacology and mechanism of action. Furthermore, these modulators offer the advantage of decreased risk for the development of breast and endometrial cancer and circumvent the need for combination with a gestagen. Most selective oestrogen receptor modulators in development bind with roughly equal affinity to both oestrogen receptor alpha and beta (balanced) and our view is that it is unlikely that a balanced selective oestrogen receptor modulator will inherit all desired effects of oestrogen (e.g. 17beta-oestradiol) and at the same time be devoid of all undesired effects. We therefore propose that the development of oestrogen receptor-subtype (alpha and beta, respectively) selective pharmaceuticals for specific applications (designer drugs) would better provide the benefits of hormone replacement therapy without its associated risks.
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PMID:Oestrogen receptors and selective oestrogen receptor modulators: molecular and cellular pharmacology. 1566 91

Accelerated bone loss secondary to loss of ovarian function at menopause is well recognised as a major risk factor for osteoporotic fractures in postmenopausal women. Postmenopausal bone loss can be prevented or arrested by oestrogen replacement therapy (ERT). It has also been reported that ERT protects against cardiovascular disease by improving the serum lipid profile, however there are mixed reports concerning these benefits. Unopposed ERT causes an unacceptable increase in the risk of endometrial cancer and proliferative effects in mammary tissue resulting in an increased risk of breast cancer. While this can be counteracted by combining ERT with a low-dose of a progestin, withdrawal bleeding and the continuing uncertainty about the effect of oestrogen on the risk of breast cancer contribute to poor compliance for long-term use. Because of the known and suspected risks of oestrogen therapy it has been estimated that in the US < 40% of women on ERT will continue treatment beyond one year. An ideal therapy would retain the desirable skeletal and cardiovascular effects of oestrogen, lack oestrogenic activity on the endometrium and reduce the incidence of breast cancer. The concept of selective oestrogen receptor modulation (SERM) has been demonstrated for a number of compounds including tamoxifen, raloxifene, droloxifene, GW-5638 and levormeloxifene. However, the clinical utility of these agents will depend on the profile of tissue-specific effects and the extent to which they are translated into in vivo efficacy. A SERM is defined as a compound that has oestrogen agonism on one or more of the desired target tissues, such as bone or liver, and has antagonism and/or minimal agonism (i.e., clinically insignificant) in reproductive tissue, such as the breast or uterus. Although tamoxifen acts as a SERM, it is also associated with an increased incidence (4% gynaecological symptoms greater than placebo control) of endometrial cancer. Indeed, there have been a number of mechanistic-based studies to explain the increased incidence of endometrial carcinomas in tamoxifen treated patients, which provide an in vitro insight into the adverse clinical observations in vivo. Attempts to improve on the pharmacological profile of tamoxifen have resulted in compounds that differ in their oestrogen agonist/antagonist characteristics, including the pure oestrogen antagonists. This suggests that it may be possible to develop a molecule with a desired profile of tissue-specific agonist/antagonist activities by establishing bone and cardiovascular protective effects but having no effects (or even behaving as an antagonist) in the reproductive tissues.
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PMID:Therapeutic potential of oestrogen receptor ligands in development for osteoporosis. 1598 1


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