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)

Tamoxifen is reported to increase the risk of endometrial cancers mostly in postmenopausal women. In the Royal Marsden chemoprevention programme, we noted that premenopausal women at the start of tamoxifen/placebo who developed amenorrhea may be at special risk of endometrial cancer. The aim of this report was to investigate recently amenorrheic women by measuring plasma estradiol (E2), follicular stimulating hormone (FSH), and endometrial thickness (ET) by transvaginal ultrasound (TVUS). ET readings and E2 levels were available in the same proportion of women on tamoxifen or placebo. Women on placebo developed amenorrhea with upper limit of E2 readings of 450 pmol/L. In both postmenopausal women and recently amenorrheic women with low E2 (< or = 450 pmol/L), tamoxifen significantly increased endometrial thickening (p < 0.0001 and < 0.005 respectively). Conversely, tamoxifen did not result in endometrial thickening in women with high E2 (> 450 pmol/L), with a trend to lower ET readings (p = 0.07). Finally, all five women who developed endometrial cancer were premenopausal at the start of tamoxifen/placebo. Two of these five women were asymptomatic with increased ET readings (17 mm and 17 mm) and low E2 levels (32 and 51 pmol/L). These results indicate that women who develop amenorrhea on tamoxifen may be at special risk of endometrial cancer. Tamoxifen causes endometrial thickening in amenorrheic women with low E2 but has an opposite antiestrogenic effect in women with high E2. We recommend that women who develop amenorrhea on tamoxifen especially in the presence of endometrial thickening, low E2 levels, and/or gynaecological symptoms warrant further investigations.
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PMID:Variation in endometrial thickening in women with amenorrhea on tamoxifen. 954 Nov 92

Tamoxifen is by far the most clinically tested antiestrogenic drug currently used as adjuvant therapy for breast cancer and it continues to provide considerable benefit in this setting. The balance from clinical trials indicates a strong association between the use of tamoxifen and an increase in uterine tumors (three to sixfold). In rats, tamoxifen is a mutagenic, genotoxic hepatocarcinogen. These actions are not related to its estrogen antagonist activity but have been shown to be as a result of metabolic activation of this drug by cytochrome P450 enzymes, resulting in irreversible binding to cellular DNA. The mechanism of endometrial cancer associated with tamoxifen treatment is unclear, although there are two plausible hypotheses: (1), tamoxifen causes damage and mutation to DNA in uterine cells or (2), it promotes the development of endometrial tumors through its estrogen agonist activity. The evidence for a genotoxic effect of tamoxifen in the uterus is highly contentious and, on balance, we have concluded that it is more likely that the estrogenic effects of tamoxifen promote tumor development.
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PMID:Antiestrogen therapy: uncertainties and risk assessment. 955 86

Worldwide, 7 million women are taking tamoxifen for breast cancer. The beneficial effects of tamoxifen on patient survival have been clearly demonstrated. Tamoxifen has few adverse effects and severe complications are very uncommon. An higher risk of endometrial cancer at the 20 mg/d dosage has been discussed and if it does exist, is minimal (RR x 2 instead of 1.3). Patient monitoring is basically clinical with an annual examination of the lower limbs and genital organs and an ophthalmological examination. Further explorations are needed in cases with specific symptoms, especially metrorrhage. There has been no proof that systematic endometrial cytology or ultrasound explorations are useful.
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PMID:[Monitoring women on tamoxifen ]. 964 6

Tamoxifen (tam) is used extensively for treatment of patients with breast cancer and is being evaluated for chemoprevention in healthy women. It has, however, been reported to increase the risk of endometrial cancer in post-menopausal women, probably by an oestrogenic effect on the endometrium. It also causes endometrial cysts and polyps. The aims of this study were to identify the incidence of endometrial thickening, polyps and cysts by transvaginal ultrasound (TVUS) screening of a population of post-menopausal healthy women in the Royal Marsden tamoxifen chemoprevention trial and to evaluate the possible benefit from the use of intermittent norethisterone (NE) in women with persistent changes. Since 1990, we have undertaken regular TVUS, using an endovaginal B mode probe, of the 463 post-menopausal women in the trial randomized to tam (20 mg day(-1)) or placebo (plac), without breaking the randomization code. Endometrial thickening (ET) was defined as > or = 8 mm at the widest point across the myometrial cavity in the longitudinal plane, including any stromal changes. Cystic changes were defined as more than one hypoechogenic area > 1 mm. Polyps were identified using saline hydrosonography. Oral NE (2.5 mg day(-1)) was used for 21 days out of 28 for three consecutive cycles by women with persistent endometrium > or = 8 mm, including cystic and polypoid changes. TVUS was repeated after the three courses to evaluate any change caused by NE and endometrial biopsies, including hysteroscopy, was performed on those women with persistent abnormalities. A persistent ET > or = 8 mm was identified in 56 (24%) of the 235 women on tamoxifen compared with only 5 (2%) of 228 women on placebo (P <0.0005). Stromal changes, including cysts, were detected in 36 (15%) and polyps in 26 (11%) of the women on tamoxifen compared with only two (< 1%) of the women on placebo (P << 0.0005). After 3 months of cyclical norethisterone, 39 of 47 women (83%) on tamoxifen had persistent ultrasound changes. However, 45 (96%) had a progesterone withdrawal bleed. Hysteroscopy was performed in 39 women on tamoxifen (28 endometrial biopsy, 15 polypectomy), five of whom had histological evidence of a proliferative endometrium and a further three had an atypical hyperplastic endometrium (one of whom had a focus of invasive carcinoma). The cysts and polyps which were detected in women on tam could not be reversed by NE and were presumably stromal and not of malignant risk. However, 96% of the women had withdrawal NE bleeding, indicating an oestrogenically primed endometrium which could be a mechanism for an increased risk of endometrial cancer. Further studies are required to ascertain whether a progestin would protect against this risk. As in other studies, these results indicate that any increased risk of endometrial cancer caused by tamoxifen is low, and that TVUS screening is probably not justified for asymptomatic women on tamoxifen.
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PMID:The effects of norethisterone on endometrial abnormalities identified by transvaginal ultrasound screening of healthy post-menopausal women on tamoxifen or placebo. 1036 26

Tamoxifen is currently established as the endocrine treatment of choice in breast cancer. In advanced breast cancer, response rates of up to 60% in women with oestrogen receptor (ER)-positive tumours have been reported. In early breast cancer, tamoxifen can produce significant benefits, both statistically and clinically, in terms of reduction in relative risk of relapse or death in all patient subgroups (i.e. ER status, aged < or > 50 years) except premenopausal women with ER-negative tumours. The major benefit, however, is seen in women over 50 years old with ER-positive tumours. The results of randomized trials suggest that the optimum duration of tamoxifen therapy is at least 5 years. Two large pragmatic trials (aTTom and ATLAS) are under way to determine whether additional benefit can be gained from continuing tamoxifen treatment beyond 5 years. Recent data also suggest possible synergism between tamoxifen and chemotherapy in the treatment of early breast cancer in post-menopausal women. Other benefits of tamoxifen treatment include reduction in the risk of developing contralateral breast cancer. Included among the non-breast cancer benefits of tamoxifen are reduced risk of cardiovascular disease and protection against bone loss in post-menopausal women. These benefits must be weighed against the possible increased incidence of endometrial cancer. Notwithstanding its undoubted success, there is a need for agents to improve upon tamoxifen. Newer agents, such as the luteinizing hormone-releasing hormone analogue goserelin and the new-generation aromatase inhibitors, such as anastrozole, will add new life to the search for an improved endocrine therapy for early breast cancer.
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PMID:Tamoxifen--the treatment of choice. Why look for alternatives? 974 80

Tamoxifen offers protection against the development or recurrence of breast cancer in a range of clinical circumstances, while simultaneously helping to prevent osteoporosis and perhaps coronary heart disease. The most serious side effects of this antiestrogen are thromboembolism and accelerated development of endometrial carcinoma; they occur primarily in postmenopausal women.
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PMID:Preventing breast cancer with tamoxifen. 975 May 54

Tamoxifen has been used as an adjuvant therapy for breast cancer for nearly two decades. The benefits of adjuvant tamoxifen therapy in prolonging disease-free and overall survival have been shown in randomized clinical trials. Despite this, some developing evidence suggests that tamoxifen causes a 2- to 3-fold increase in endometrial cancer. This paper reviews the reports of endometrial carcinoma in tamoxifen-treated patients. Two hundred fifty cases of endometrial carcinoma are reported, but only one case is identified in a premenopausal woman. When documented, 77% (n=127) of the cases are good-grade (grade 1 or 2) and 80% (n=125) are stage-I disease. Since the distribution of good grade (79%) and stage I (74%) from the Surveillance, Epidemiology and End Results (SEER) data are comparable, concerns about more aggressive or late-stage disease appear to be unwarranted. The modest increase in the incidence of early-stage, good-grade endometrial carcinoma described during tamoxifen therapy suggests that it would be unreasonable to institute an aggressive detection strategy of endometrial biopsies. This approach would only lead to further detection bias and would not be cost-effective. Physicians should ensure that patients do not have pre-existing endometrial cancer prior to adjuvant tamoxifen therapy for breast cancer and, furthermore, they should educate patients about signs and symptoms of early endometrial carcinoma and when reported these should be followed up with a gynecologic examination.
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PMID:Gynecologic effects of tamoxifen and the association with endometrial carcinoma. 976 62

Tamoxifen increases the risk of human endometrial cancer and is a potent carcinogen in rat liver, in which it produces DNA adducts and cytogenetic damage. Nevertheless its prophylactic use against breast cancer in healthy women is under investigation in several large trials. To investigate whether rat hepatocarcinogenicity predicts human hepatocarcinogenicity we used genetically engineered bacterial and mammalian target cells to investigate how alpha-hydroxy-tamoxifen, a major phase I metabolite of tamoxifen, is further metabolised by rat and human phase II enzymes, sulfotransferases, to mutagenic and DNA-adduct-forming species. We expressed rat hydroxysteroid sulfotransferase a, a liver-specific enzyme, and corresponding human sulfotransferase in bacteria (Salmonella typhimurium) and in a mammalian cell line (Chinese hamster V79 cells) and tested alpha-hydroxytamoxifen for DNA adduct formation and mutagenicity in these systems, using unmodified cells as controls. In cells that expressed rat hydroxysteroid sulfotransferase, alpha-hydroxytamoxifen was mutagenic and formed the same pattern of DNA adducts as that found in the liver of tamoxifen-treated rats. Alpha-hydroxytamoxifen was not activated, or was at least 20 times less active in cells expressing human hydroxysteroid sulfotransferase. All the other six known human xenobiotic-metabolising sulfotransferases were also expressed in S. typhimurium. None activated alpha-hydroxytamoxifen to a mutagen. These results suggest that the risk of DNA adduct formation, and cancer, in the human liver is low and explain why tamoxifen is a powerful carcinogen to the rat liver, and why standard short-term tests fail to detect its mutagenicity.
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PMID:Rat, but not human, sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture. 980 49

We present a case of endometrial carcinoma accompanied with mucinous cystadenoma in a 70-year-old postmenopausal woman treated with tamoxifen for breast cancer demonstrated by MR imaging. Tamoxifen therapy (20 mg/day) had been carried out for more than 11 years since the surgical procedure for the primary tumor. MR images showed a markedly enlarged uterus containing endometrial carcinoma, cystic atrophy of the endometrium, and a right adnexal mass with multicystic components of various signal intensities.
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PMID:MR appearance of endometrial carcinoma and mucinous cystadenoma in a postmenopausal patient treated with tamoxifen for breast cancer. 981 31

Tamoxifen is associated with an increased incidence of endometrial cancer in women. It is also a potent carcinogen in rat liver and forms covalent DNA adducts in this tissue. A previous study exploring DNA adducts in human endometria, utilizing thin layer chromatography 32P-postlabelling, found no evidence for adducts in tamoxifen-treated women [Carmichael,P.L., Ugwumadu,A.H.N., Neven,P., Hewer,A.J., Poon,G.K. and Phillips,D.H. (1996) Cancer Res., 56, 1475-1479]. However, subsequent work utilizing HPLC 32P-post-labelling [Hemminki,K., Ranjaniemi,H., Lindahl,B. and Moberger,B. (1996) Cancer Res., 56, 4374-4377] suggested that very low levels could be detected. We have sought to investigate this question further by reproducing the HPLC methodology at two centres, and analysing endometrial DNA from 20 patients treated with 20 mg/day tamoxifen for between 22 and 65 months. Liver DNA isolated from tamoxifen-treated rats was used as a positive control. We found no convincing evidence for tamoxifen-derived DNA adducts in human endometrium. HPLC elution profiles of post-labelled DNA from tamoxifen-treated women were indistinguishable from those obtained with DNA from 14 untreated women and from six women taking toremifene, an analogue of tamoxifen.
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PMID:Lack of evidence from HPLC 32P-post-labelling for tamoxifen-DNA adducts in the human endometrium. 1006 74


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