UMLS:C0476089 - FACTA Search

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Query: UMLS:C0476089 (endometrial cancer)
11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of luteinizing hormone-releasing hormone (LHRH) and its receptors has been demonstrated in a number of human malignant tumors, including cancers of the breast, ovary, endometrium and prostate. These findings suggest the presence of an autocrine regulatory system based on LHRH. Recent studies in our laboratory have demonstrated that the function of LHRH produced by ovarian cancer cells is the inhibition of their proliferation. Dose-dependent antiproliferative effects of LHRH-agonists have been observed by several laboratories in cell lines derived from the above cancers. Interestingly, also LHRH-antagonists have marked antiproliferative activity in most of the ovarian, breast and endometrial cancer cell lines tested so far, indicating that the dichotomy of LHRH-agonists/LHRH-antagonists is not valid for the LHRH-system in cancer cells. In addition, our data suggest that the classical LHRH receptor signal transduction mechanisms known from the pituitary (phospholipase-C, protein kinase C, adenylyl cyclase) are not involved in the mediation of LHRH effects in cancer cells. Data obtained by several groups, including ours, rather suggest that LHRH analogs interfere with the signal transduction of growth-factor receptors and related oncogene products associated with tyrosine-kinase activity. The mechanism of action is probably an LHRH-induced activation of a phosphotyrosine phosphatase, counteracting the effects of receptor associated tyrosine kinase. In our hands, LHRH analogs virtually blocked the EGF-induced MAP-kinase activity of ovarian and endometrial cancer cells. The pharmacological exploitation of this mechanism might provide promising new therapies for these cancers.
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PMID:Effects of LHRH-analogues on mitogenic signal transduction in cancer cells. 969 74

Progestogen suppresses the progression of endometrial cancer and has an important effect on the secretory change of human endometrium. We characterized the progestogen-induced alterations of gene expression in a human endometrial-cancer cell line using a mRNA differential-display reverse-transcriptase-polymerase-chain-reaction (DDRT-PCR) method. After 5-day incubation of Ishikawa endometrial-cancer cells, with or without 100 nM medroxyprogesterone acetate (M PA), total RNA was isolated from confluent cells. We identified 8 candidate genes by mRNA differential display by screening up to approximately 3,000 mRNA species. Among these, 2 genes named T21A and T21B showed a decrease in mRNA by MPA treatment when analyzed by Northern blot. Nucleotide sequence showed that clone T21A was part of human mitochondrial short-chain enoyl-CoA hydratase cDNA. The other clone, T21B, showed no homology with any known nucleotide sequences. Northern-blot analysis using T21A and T21B clones as probes showed a decrease in mRNA in human endometrium from the luteal stage, with high serum estradiol and progesterone levels, as compared with that from the early follicular stage, with low serum estradiol and progesterone levels, and that from the pre-ovulatory stage with high serum estradiol and low progesterone levels. These findings suggest that mRNA DDRT-PCR could be used to identify the candidate genes regulated by progestogen in human endometrial cancer and in normal human endometrium.
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PMID:Messenger RNA differential display reverse-transcriptase-polymerase-chain-reaction analysis of a progestogen-suppressive gene in a human endometrial-cancer cell line. 972 4

Estrogens are important for both normal cell growth and malignant proliferation in the mammary gland as well as in the endometrium. Tamoxifen is a non-steroidal anti-estrogen widely used in breast cancer treatment. In recent years reports have been made of an increased risk of endometrial carcinoma during tamoxifen treatment. We used surgically menopausal cynomolgus macaques to study proliferation and p53 expression during hormonal replacement therapy (HRT) and tamoxifen treatment. Animals were treated continuously for 35 months with either conjugated equine estrogens (CEE; n = 20); medroxyprogesterone acetate (MPA; n = 17); the combination of CEE + MPA (n = 13); or tamoxifen (n = 17) for 35 months. We found an increased expression of p53 in normal breast and endometrial tissue linked to CEE but not tamoxifen treatment. In the breast alveoli there was an association between proliferation measured by morphometry and p53 expression in all groups. However, in the endometrium CEE induced significantly more p53 positivity than tamoxifen, 9/20 vs. 3/17 in glands and 9/19 vs. 0/17 in stroma, respectively. If indeed long-term treatment with tamoxifen as in the present study could inactivate the tumor-suppressive function of p53, endometrial cells might thereby become more susceptible to genetic lesions associated with carcinogenesis.
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PMID:p53 expression in breast and endometrium during estrogen and tamoxifen treatment of surgically postmenopausal cynomolgus macaques. 1020 73

Breast cancer is the most frequent cancer in women while it is the second cause of cancer death. Estrogens are well recognized to play the predominant role in breast cancer development and growth and much efforts have been devoted to the blockade of estrogen formation and action. The most widely used therapy of breast cancer which has shown benefits at all stages of the disease is the use of the antiestrogen Tamoxifen. This compound, however, possesses mixed agonist and antagonist activity and major efforts have been devoted to the development of compounds having pure antiestrogenic activity in the mammary gland and endometrium. Such a compound would avoid the problem of stimulation of the endometrium and the risk of endometrial carcinoma. We have thus synthesized an orally active non-steroidal antiestrogen, EM-652 (SCH 57068) and the prodrug EM-800 (SCH57050) which are the most potent of the known antiestrogens. EM-652 is the compound having the highest affinity for the estrogen receptor, including estradiol. It has higher affinity for the ER than ICI 182780, hydroxytamoxifen, raloxifene, droloxifene and hydroxytoremifene. EM-652 has the most potent inhibitory activity on both ER alpha and ER beta compared to any of the other antiestrogens tested. An important aspect of EM-652 is that it inhibits both the AF1 and AF2 functions of both ER alpha and ER beta while the inhibitory action of hydroxytamoxifen is limited to AF2, the ligand-dependent function of the estrogen receptors. AF1 activity is constitutive, ligand-independent and is responsible for mediation of the activity of growth factors and of the ras oncogene and MAP-kinase pathway. EM-652 inhibits Ras-induced transcriptional activity of ER alpha and ER beta and blocks SRC-1-stimulated activity of the two receptors. EM-652 was also found to block the recruitment of SRC-1 at AF1 of ER beta, this ligand-independent activation of AF1 being closely related to phosphorylation of the steroid receptors by protein kinase. Most importantly, the antiestrogen hydroxytamoxifen has no inhibitory effect on the SRC-1-induced ER beta activity while the pure antiestrogen EM-652 completely abolishes this effect, thus strengthening the need to use pure antiestrogens in breast cancer therapy in order to control all known aspects of ER-regulated gene expression. In fact, the absence of blockade of AF2 by hydroxytamoxifen could explain why the benefits of tamoxifen observed up to 5 years become negative at longer time intervals and why resistance develops to tamoxifen. EM-800, the prodrug of EM-652, has been shown to prevent the development of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat, a well-recognized model of human breast cancer. It is of interest that the addition of dehydroepiandrosterone, a precursor of androgens, to EM-800, led to complete inhibition of tumor development in this model. Not only the development, but also the growth of established DMBA-induced mammary carcinoma was inhibited by treatment with EM-800. An inhibitory effect was also observed when medroxyprogesterone was added to treatment with EM-800. Uterine size was reduced to castration levels in the groups of animals treated with EM-800. An almost complete disappearance of estrogen receptors was observed in the uterus, vaginum and tumors in nude mice treated with EM-800. EM-652 was the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro when compared with ICI 182780, ICI 164384, hydroxytamoxifen, and droloxifene. Moreover, EM-652 and EM-800 have no stimulatory effect on the basal levels of cell proliferation in the absence of E2 while hydroxytamoxifen and droloxifene had a stimulatory effect on the basal growth of T-47D and ZR-75-1 cells. EM-652 was also the most potent inhibitor of the percentage of cycling cancer cells. (ABSTRACT TRUNCATED)
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PMID:EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium. 1041 81

This study presents a review of current clinical evidence on the usefulness of Depo Provera (medroxyprogesterone acetate, DMPA), a long-term method of reversible contraception. It is taken as an intramuscular long-acting agent (150 mg every 12 calendar weeks). The user failure rate approaches the method failure rate, which varies considerably with age. In terms of metabolic effects, it did not show changes in cholesterol or triglycerides and had no significant effect on hemostasis, which impairs the oral glucose tolerance test (OGTT) glucose response and increases insulin response. There were no significant adverse effects on long term growth and development in DMPA exposed children and no delays in return to fertility. For cancers, controlled surveillance of DMPA users found no overall increased risk of ovarian, liver or cervical cancer and even found a prolonged protective effect in reducing the risk of endometrial cancer. However, increased risk of breast cancer in recent users was observed; this could be due to enhanced detection of breast tumors of women using DMPA. The main DMPA disadvantages are menstrual disturbance and weight gain after 1 year. Bone mineral density (BMD) is found to be significantly lower. DMPA patients' sociodemographic characteristics and behavior placed then at higher risk for adverse pregnancy outcome in low infant birth weight and also possibly in polysyndactyl and chromosomal defects. Thus, for injectable progestogen, the data is again less conclusive. Risks may be similar to POP (progestogen-only contraceptive pill), but did not reach significance in the meta-analysis.
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PMID:Depo Provera. Position paper on clinical use, effectiveness and side effects. 1089 62

Two women with endometrial carcinoma who wished to preserve their childbearing ability received conservative treatment by medroxyprogesterone acetate (MPA, 600 mg/day for 22 weeks and 29 weeks, respectively). Following regression of endometrial lesions, their infertility was treated by inducing ovulation. Intact pregnancy was diagnosed 13 months and 11 months after completion of the MPA treatment, respectively. One patient had a twin pregnancy and delivered two infants at 35 weeks of gestational age. The other patient delivered a full-term baby. They had no evidence of recurrence 60 months and 31 months after the conservative treatment, respectively. We believe this conservative treatment with progestin may be safely performed for young patients with endometrial cancer who wish to preserve their fertility.
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PMID:Successful conservative treatment of endometrial carcinoma permitting subsequent pregnancy: report of two cases. 1084 66

Medroxyprogesterone acetate (MPA) is a drug commonly used in endocrine therapy for advanced or recurrent breast cancer and endometrial cancer. The drug is extensively metabolized in the intestinal mucosa and in the liver. Cytochrome P450s (CYPs) involved in the metabolism of MPA were identified by using human liver microsomes and recombinant human CYPs. In this study, the overall metabolism of MPA was determined as the disappearance of the parent drug from an incubation mixture. The disappearance of MPA in human liver microsomes varied 2.6-fold among the 18 samples studied. The disappearance of MPA in the same panel of 18 human liver microsomes was significantly correlated with triazolam alpha-hydroxylase activity, a marker activity of CYP3A (r = 0.764; P < 0.001). Ketoconazole, an inhibitor of CYP3A4, potently inhibited the disappearance of MPA in 18 human liver microsomes. Anti-CYP3A antibody also inhibited 86% of the disappearance of MPA in human liver microsomes. Although sulfaphenazole (an inhibitor of CYP2C9) and S-mephenytoin (an inhibitor of CYP2C19) partially inhibited the disappearance of MPA, no effect of the anti-CYP2C antibody was observed. The disappearance of MPA did not correlate with either the activity metabolized via CYP2C9 (diclofenac 4'-hydroxylase activity) or the activity metabolized via CYP2C19 (S-mephenytoin 4'-hydroxylase activity). Among the 12 recombinant human CYPs (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5) studied, only CYP3A4 showed metabolic activity of MPA. These results suggest that CYP3A4 is mainly involved in the overall metabolism of MPA in human liver microsomes.
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PMID:Role of human cytochrome P450 3A4 in metabolism of medroxyprogesterone acetate. 1095 16

BACKGROUND: Postoperative adjuvant tamoxifen (TAM) therapy in breast cancer patients may lead, albeit rarely, to endometrial cancer. Preventive measures are urgently needed. METHODS: The study subjects were postmenopausal women who had undergone surgery for breast cancer. The control group (n=10) received no further therapy. Patients who had completed adjuvant TAM therapy were assigned to a medroxyprogesterone acetate (MPA;400 mg/day orally for 4 weeks) group (n =15) or no MPA treatment group (no MPA group)(n=15). Uterine cervix cytodiagnosis was performed after completing the TAM therapy(initial), and 4(4-week)and 16(16-week)weeks later. The serum 17beta-estradiol (E2) and progesterone concentrations were measured initially and at 4 weeks. The karyopyknotic index (KPI), eosinophilic index (EI) and maturation index (MI) were calculated from Papanicolaou-stained specimens. RESULTS: The background parameters showed no biases. There were no differences in the PKI or El between the no MPA and MPA groups. However, regarding the MI, after 4 weeks in the MPA group, the intermediate cells were significantly increased, while the superficial cells tended to be significantly decreased. Regarding the percent change from the initial value, after 4 weeks in the MPA group, the KPI and superficial cells were significantly decreased, and the intermediate cells were significantly increased. The estrogen activity level and the progesterone concentration were significantly lower in the MPA group compared with the no MPA group. CONCKLUSIONS: The MPA administration clearly lowered the estrogenic activity, indicating that MPA therapy should be effective in reducing the risk of TAM-associated endometrial cancer.
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PMID:Suppression of Estrogenic Activity by Medroxyprogesterone Acetate in Tamoxifen-treated Patients after Surgery for Breast Cancer to Reduce the Risk of Endometrial Cancer Development. 1109 50

Estrogen replacement therapy (ERT) increases a woman's risk of developing endometrial cancer approximately 120% for each 5 years of use. ERT increases a woman's risk of developing breast cancer approximately 10% for each 5 years of use. To reduce the greatly increased endometrial cancer risk, progestins have been added to ERT (estrogen-progestin replacement therapy; EPRT) for between 5 and 15 days (usually 7 or 10 days) per month in a sequential fashion (sequential EPRT; SEPRT) or with each dose of ERT (continuous-combined EPRT; CEPRT). We conducted two large case-control studies in postmenopausal women in Los Angeles to evaluate the effects of these changes on endometrial and breast cancer risks. As expected CEPRT was not associated with any increased risk of endometrial cancer. SEPRT with the progestin being given for 10 days per month also did not increase endometrial cancer risk. SEPRT with the progestin being given for 7 days per month did increase endometrial cancer risk with only a relatively slight reduction in risk compared to ERT effectively proportional to the reduction in the number of days of unopposed estrogen. The sharp contrast between the effects of 7 days and 10 days of progestin in SEPRT suggests that the extent of endometrial sloughing or of 'terminal' differentiation at the completion of the progestin phase may play a critical role in determining endometrial cancer risk. This may provide an explanation of why endometrial cancer risk increases so sharply with age in young women even in countries where obesity-associated anovulation is very uncommon; extended periods of unopposed estrogen is not an explanation but less than 10 days of an 'adequate' progesterone level may be. EPRT significantly increased the risk of breast cancer. EPRT was associated with an approximately 24% increase in risk for each 5 years of use; the effect was some 212-fold greater than the effect of ERT, which we had previously predicted on theoretical grounds. This effect could also be predicted from the results on mammographic densities seen in the PEPI randomized trial of different forms of hormone replacement therapy (HRT). In the PEPI trial EPRT increased mammographic densities to a much greater extent than ERT. Progestins need to be given to protect the endometrium. They need to be delivered to the endometrium in a manner that will have the least effect on the breast. This can be carried out by using a vaginal or direct endometrial route of administration. The vaginal route will provide adequate endometrial progestin levels with low blood levels so that the effects of the progestin on the breast should be small; with the direct endometrial route the blood progestin levels are even lower, and the effects of the progestin on the breast will be effectively zero. If this is unacceptable to a woman, then giving progestins by mouth (or transdermally) for 10 days every 3 to 4 months should provide satisfactory protection of the endometrium when used with standard-dose conjugated estrogen (CE). This regimen has much less effect on the breast than monthly SEPRT or CEPRT. Two clinical trials of 10 mg per day of MPA for 14 days every 3 months and 0.625 mg/day of CE have been published. Both studies suggest that this approach may be satisfactory in that the extent of hyperplasia was minimal. More studies of this approach are urgently needed.
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PMID:Progestins and menopause: epidemiological studies of risks of endometrial and breast cancer. 1110 73

Fifteen cases of endometrial cancer were administered daily doses of 600 mg of MPA after surgery to prevent the recurrence of cancer. The initiation times of coagulation (time necessary for fibrin network formation) were measured with a highly sensitive damped oscillation rheometer and compared with those of 15 control patients who were not administered MPA. Biochemical studies of blood coagulation and fibrinolysis were also done. The initiation times of coagulation were 19.0+/-1.8 minutes (min mean +/- standard deviation) after 3-6 months and 16.0+/-2.0 min after 9-12 months of MPA administration, both times being significantly shorter compared with the controls (24.0+/-2.5 min). Hematocrit values, platelet counts and fibrinogen levels were similar between the two groups. Activated partial thromboplastin time (APTT) was significantly decreased and antithrombin III activity (AT III), thrombin-antithrombin complex (TAT), plasminogen level, plasmin-alpha(2) plasmin inhibitor complex level (PIC) and the fibrin degradation product level (FDP) were significantly increased in the MPA group compared with the control group. Accelerated coagulation of blood was definitely induced by high-dose MPA but antithrombin and fibrinolytic activities were also induced, and, thus, thromboembolic complications were prevented.
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PMID:Effect of high-dose progestogen on hemostatic properties of blood in patients with endometrial cancer. 1138 Nov 84

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