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)

Gynecologists use either oral or parenteral progestogens either alone or in combination with estrogens to treat various conditions. Parenteral routes of progestogen delivery are intramuscular injections, intravaginal pessaries, subcutaneous implants, and vaginal rings. Progestogens treat dysfunctional uterine bleeding by first controlling the acute bleeding episode and then by establishing normal ovulatory cycles. 1-2 tablets of medroxyprogesterone acetate (MPA)/day or 1-3 tablets of norethindrone/day should stop uterine bleeding in 72 hours. If not, 25 mg intravenous premarin should control it in 6-24 hours. Cyclical progestational (e.g., MPA) therapy for 3-6 cycles should establish normal ovulatory cycles. After appropriate laparoscopic staging by double puncture technique, progestogens can be used to treat mild-moderate endometriosis. Gynecologists should consider the following criteria when selecting the ideal progestin for hormone replacement therapy: adjustment of dosage of progestin and estrogen over 3-6 months to maintain the beneficial effects of the estrogen and to minimize the adverse effects of the progestin, progestin dosage sufficient to protect against endometrial hyperplasia and cancer, economical progestin, and minimization of weight gain, depression, oral intolerance, and androgenic action. Hydrogesterone and MPA meet these criteria. Oral contraceptives with a progestin and the smallest possible dose of estrogen are well-tolerated, cause no break-through bleeding, produce minimal side effects, and protect against pregnancy (99% contraceptive effectiveness rate). They also protect against endometrial cancer, endometriosis, premenstrual tension, dysmenorrhea, and irregular cycles. Intramuscular injections of progestins (MPA, NET-EN), subcutaneous levonorgestrel implant, and the levonorgestrel IUD are new contraceptive developments and provide a high degree of contraceptive efficacy. MPA at very high doses cause remission of breast endometrial lesions.
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PMID:Progestogens in gynaecological practice. 1217 92

Progestin-only injectables are among the most effective and safe of all contraceptives, yet they are not widely used in many countries. This limited use is in part due to a lack of accurate information about health concerns, inadequate counseling for users about managing side effects, and their limited availability. Where they are available, progestin-only injectables rapidly become one of the preferred methods. Depot-medroxyprogesterone acetate (DMPA) and norethindrone enanthate (NET-EN) are the two progestin-only injectables in use worldwide. The former drug is sold under the brand name Depo-Provera, and the latter as Noristerat. DMPA is delivered in a water-based, crystalline suspension and absorbed gradually by the body. The normal injection of 150 mg is intended to be administered every three months, but contraceptive protection continues for an additional two weeks to provide a grace period for women who are late receiving their next injection. NET-EN is an oily solution which requires a larger needle than DMPA for injection. A 200 mg injection of NET-EN is usually administered every two months. Both of these safe, highly effective drugs are injected in either the upper arm or buttocks. DMPA and NET-EN can be distributed easily in nonclinical settings where nonphysicians can provide them to clients. The main disadvantage of the method is the disruption of the menstrual cycle, but that is generally not a serious medical problem. Focusing mainly upon DMPA, this article includes discussion of menstrual irregularity, the reduced risk of endometrial cancer among DMPA users, and method availability.
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PMID:Progestin-only injectables offer many advantages. 1228 28

Injectable hormonal contraception with 2 longacting steroidal preparations--norethisterone enanthate (NET-EN) and depot medroxyprogesterone acetate (DMPA)--provides an effective means of fertility regulation and has become an important method of family planning. DMPA and NET-EN have several advantages which make them particularly appropriate for some women and acceptable in family planning programs. A single injection can provide highly effective contraception for 2 or more months, delivery is simple, independent of coitus, and ensures periodic contact with medical or other trained health personnel. Currently, DMPA is registered as a therapeutic agent in nearly all countries and as a contraceptive agent in over 80 developed and developing countries. NET-EN is registered as a contraceptive in 40 countries. Administered by intramuscular injection in an aqueous microcrystalline suspension, DMPA exerts its contraceptive effect primarily by suppression of ovulation, but its effects on the endometrium, the uterine tubes, and the production of cervical mucus may also play a role in reducing fertility. DMPA as a contraceptive agent is generally given at a dosage of 150 mg every 90 days. NET-EN when administered as an intramuscular injection of an oil preparation at a dose of 200 mg inhibits ovulation. It should be administered at 8 weekly intervals for the 1st 6 months of use, then at intervals of 8 or 12 weeks. Longterm animal studies with DMPA have been completed mainly on beagle bitches and rhesus monkeys, and similar studies with NET-EN are nearing completion. None of the findings in beagles is considered applicable to human populations because the beagle responds differently than humans to steroidal hormones. None of the deaths among rhesus monkeys was attributable to effects of the drug. Endometrial carcinoma was found in 2 of the replacement monkeys but the number of animals was too small for statistically significant studies, and it is not possible to conclude whether DMPA or NET-EN caused these cancers or instead failed to prevent them. Despite more than 18 years of use and an estimated 13 million women who have ever used DMPA or NET-EN, no case has been recorded of an endometrial malignancy in women so exposed. There is no evidence at this stage of a causal association, either anecdotal or scientific. No evidence of an increased risk of malignant and premalignant disease of the uterine cervix has been found in DMPA users. There is sufficient evidence from investigations in several countries that DMPA and NET-EN may increase both milk production and the duration of lactation. The only clinical metabolic effect attributed to DMPA is weight gain. NET-EN and DMPA are associated with disruption of the menstrual cycle and irregular bleeding.
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PMID:Statement on injectable contraception. 1233 11

Depot medroxyprogesterone acetate (DMPA, Depo-Provera) is used for contraception by 8-9 million women in more than 90 countries, including the US, as of January 1993. Pharmacologically active levels of DMPA persist for 3-4 months following injection. A 150 mg dose is used most often for high contraceptive efficacy every 3 months. Norethindrone enanthate (NET-EN, Noristerat) is somewhat less widely used and is not marketed in the US. Injectables act primarily by inhibiting ovulation, lowering the levels of follicle-stimulating hormone and luteinizing hormone. Approximately 50% of women using DMPA for 1 year report amenorrhea whose occurrence is less frequent with NET-EN. Menstrual changes are the most frequent causes of discontinuation of injectables. In cases of heavy bleeding it is appropriate to undergo gynecological examination to rule out unrelated conditions, such as vaginitis, cervicitis, or cervical lesions. The use of conjugated estrogen (12.5-2.5 mg daily) for 10-21 days will minimize bleeding. Some women using injectables experience headache, dizziness, bloating of the abdomen or breast, and mood changes. Long-term use of DMPA or NET-EN can often result in 1-3 kg weight gain. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives was launched in 1979 to examine cancer risks with the use of DMPA in Thailand, Mexico, and Kenya. The relative risk of breast cancer was 1.21, which was statistically not significant. In women diagnosed with breast cancer under age 35, short-term exposure to DMPA was associated with a slightly increased breast cancer risk, which, however, was not associated with duration of use. DMPA dramatically lowers the risk of endometrial cancer for at least eight years following discontinuation of its use. DMPA did not alter the risk of cervical cancer. Fertility returns in 70% of former users within 12 months; it is suitable for postpartum and lactating women, and provides other noncontraceptive benefits.
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PMID:Injectable contraception: the USA perspective. 1234 20

Fibroblast growth factors (FGFs) exert diverse effects resulting from their interaction with cognate receptors on target cells. Our current study was designed to examine the local production and action of two specific stromal-epithelial cell mediatory factors, keratinocyte growth factor (KGF) and FGF-10, in human endometrial carcinoma cells. The RT-PCR method was used to determine gene expression of KGF, FGF-10, and KGF receptor in human endometrial carcinoma cells (HEC-1) and human endometrial stromal cells. KGF mRNAs were expressed in both of these cell types. On the other hand, FGF-10 mRNA was detected only in the endometrial stromal cells, and KGF receptor mRNA was observed in the HEC-1 cells. The novel finding of the present study is that KGF is expressed in carcinoma cells and FGF-10 is expressed in human endometrial stromal cells. The distinct phosphorylation of ERK-1 and -2 (ERK1/2), which are members of the MAPK family, was observed when HEC-1 cells were treated with KGF or FGF-10. KGF and FGF-10 could induce the prompt phosphorylation of ERK1/2 and consequently stimulate DNA synthesis. KGF and FGF-10 did not activate the phosphorylation of Akt, protein kinase C, or signal transducer and activator of transcription-3. Blocking the MAPK pathway with the specific methyl ethyl ketone 1/2 inhibitor (U0126) completely neutralized the enhancement of cell proliferation induced by KGF and FGF-10. In addition, KGF and FGF-10 activated expressions of downstream nuclear transcription factors, such as Elk-1 and c-myc, but not c-fos. These results demonstrate for the first time that KGF and FGF-10 are capable of stimulating the growth of endometrial carcinoma cells via activating MAPK pathway through autocrine/paracrine fashion.
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PMID:Activation of mitogen-activated protein kinase pathway by keratinocyte growth factor or fibroblast growth factor-10 promotes cell proliferation in human endometrial carcinoma cells. 1257 12

This is the first report in the English literature of a composite endometrial tumor composed of papillary serous carcinoma and small cell carcinoma. A 79-year-old woman underwent total abdominal hysterectomy and left salpingo-oophorectomy due to endometrial carcinoma. Grossly, the uterus was enlarged with an irregular and nodular serosal surface, thickened myometrium, and irregular endometrium. Microscopic examination revealed an endometrial carcinoma composed of papillary serous carcinoma and small cell carcinoma. There was a differential immunoreactivity between the two components: the cells of the papillary serous carcinoma were positive for cytokeratin, CA-125, CEA, and HER-2/Neu, whereas these markers were negative in the small cell carcinoma. Various neuroendocrine markers were positive in the small cell carcinoma and negative in the papillary serous carcinoma. Fluorescence in situ hybridization analysis using 4, 8, and 10 centromeric probes revealed hyperploidy (6-8 signals) in the small cell carcinoma cells. Most of the serous carcinoma cells were euploid, with scattered trisomies and tetrasomies of these chromosomes. The patient died of progressive disease 5 months after surgery. We suggest that the small cell carcinoma may have arisen from the endometrial papillary serous carcinoma undergoing tumor progression with neuroendocrine differentiation.
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PMID:An unusual composite endometrial tumor combining papillary serous carcinoma and small cell carcinoma. 1525 20

Identification of genes that are expressed in a cancer cell-specific manner can provide markers for detection, diagnosis, and disease progression. We have previously reported that receptor tyrosine kinase ligands in concert with ligation of alphavbeta5 integrin induce expression of Mig-7 restricted to carcinoma cells. Because of this highly specific expression, we hypothesized that Mig-7 could be used as a marker of occult tumor cells. The objective of this study was to begin to test this hypothesis by generating Mig-7 specific antisera and RT-PCR methods for detection of Mig-7 expression in tissues and blood from cancer patients as compared to those from normal subjects. By immunohistochemistry and by RT-PCR, we detected Mig-7 mRNA in lymph nodes from 7 out of 9 (77.8%) endometrial carcinoma xenograft mice but not from any of the 5 negative control animals. Mig-7 expression was more specific than Met expression, the RTK that binds Scatter factor and is used as a marker of poor progression, in endometrial carcinoma as compared to normal endometrial tissue samples. In 87.3% of tumors from various tissues including breast, lung, colon and ovary, we detected Mig-7 expression. Blood samples from untreated metastatic cancer patients also displayed Mig-7 mRNA in contrast to a lack of expression in chemotherapy treated or normal individuals. In conclusion, we report the first immunohistochemical and RT-PCR assays for Mig-7 and discuss its highly specific localization to cancer cells in contrast to an absence in normal cells. Our preliminary data indicate that Mig-7 may be a potential early marker of migrating and circulating carcinoma cells.
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PMID:Carcinoma cell-specific Mig-7: a new potential marker for circulating and migrating cancer cells. 1558 99

Estrogen and progestin combination in hormone replacement therapy (HRT) increases the incidence of breast cancer, but decreases the endometrial cancer risk of unopposed estrogen. Therefore, a SERM such as Tibolone, that delivers the beneficial, but not the adverse side effects, of steroid hormones would be clinically advantageous. However, data from the Million Women Study suggests that Tibolone increases the risk of both breast and endometrial cancer. Herein, we assessed the estrogenic and progestagenic actions of Tibolone using transvaginal sonography studies and an in vitro model of breast (ZR-75, MCF7) and endometrial cancer (Ishikawa). The known cancer associated proteins (ER, EGFR, STATS, tissue factor and Bcl-xL) were selected for study. Transvaginal sonography demonstrated that postmenopausal women treated with Tibolone displayed a thinner endometrium than in the late proliferative phase, but had a phenotype characteristic of the secretory phase, thus demonstrating the estrogenic and progestagenic actions of this SERM. In vitro, Tibolone acted as an estrogen in downregulating ER and upregulating Bcl-xL, yet as progesterone, increasing STAT5 and tissue factor in breast cancer cells. The increase in tissue factor by Tibolone correlated with its coagulative potential. Interestingly, EGFR was up-regulated by progesterone in the breast and by estrogen in endometrial cells, while Tibolone increased protein levels in both cell types. In conclusion, this study further demonstrates the estrogenic and progestagenic nature of Tibolone. The pattern of regulation of known oncogenes in cells of breast and endometrial origin dictates caution and vigilance in the prescription of Tibolone and subsequent patient monitoring.
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PMID:In vivo and in vitro estrogenic and progestagenic actions of Tibolone. 1623 3

To understand how type I and II endometrial tumors uniquely respond to tyrosine kinase inhibitor treatments, we evaluated the signaling pathways of epidermal growth factor (EGF) receptor (EGFR) under the effects of EGF and Iressa (ZD1839, gefitinib) using Ishikawa H and Hec50co cells that model type I and II endometrial carcinomas, respectively. The cells were assayed for the expression of EGFR and both cell lines express an average of 100,000 EGFR per cell; however, Ishikawa H cells express higher levels of HER-2/neu compared with Hec50co cells (1.38 x 10(5) compared with 2.04 x 10(4), respectively). Using the Kinetworks multi-immunoblotting approach, which profiles 31 signaling phosphoproteins, the most striking result was that Hec50co cells show a higher number of basal phosphorylated sites compared with Ishikawa H cells. Furthermore, we identified targets of Iressa treatment in both cell lines. Iressa, at a dose of 1 micromol/L, blocked the autophosphorylation of EGFR in Ishikawa H and Hec50co cells with some distinctive effects on downstream effectors. Nevertheless, in both cell lines, EGF stimulated and Iressa blocked the major EGFR target mitogen-activated protein kinases extracellular signal-regulated kinase 1 and 2 equally. The high basal phosphorylation of numerous signaling molecules in Hec50co cells that were not inhibited by Iressa indicates that other growth factor pathways are active in addition to EGFR. We conclude that endometrial cancer cells that model type I and II carcinomas have the capacity to respond to EGFR inhibition as a therapeutic strategy; however, the response of the more aggressive type II tumors may be limited by the constitutive activation of other signaling pathways.
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PMID:Regulation of signaling phosphoproteins by epidermal growth factor and Iressa (ZD1839) in human endometrial cancer cells that model type I and II tumors. 1637 4

The fact that the genetic alterations of PTEN are frequently found in hormone-dependent cancers, such as endometrial, breast, and prostate cancers, might suggest the involvement of PTEN in the hormone-dependent cell growth of such tumors. Estrogen promotes the cell growth of the tumors by inducing peptide growth factors in part. We analyzed the possible involvement of PTEN in peptide-growth factor-dependent cell growth in endometrial carcinoma cells. PTEN-null Ishikawa cells were efficiently infected with recombinant adenovirus at 20 MOI (multiplicity of infection) to express PTEN protein. In PTEN-IK cells, phospho-Akt/PKB was down-regulated regardless of the consistent expression of Akt/PKB. The cell growth of parental IK cells was significantly stimulated by EGF and IGF-I, and PTEN-IK cells were further sensitized to the EGF-or IGF-I-growth stimulation. EGFR antibody could completely compromise the stimulatory effects of EGF in both cell lines. Wortmannin, a PI3K inhibitor, or UO126, a MAPK inhibitor, partly suppressed EGF-mediated cell growth stimulation in both cell lines. EGF augmented the level of phospho-Akt/PKB of PTEN-IK cells more effectively than that of parental IK cells. These results imply that the dysfunction of PTEN leads cells into a less-sensitive phenotype to peptide growth factors by constitutive activation of the PI3K/Akt/PKB signaling pathway in endometrial carcinoma.
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PMID:PTEN sensitizes epidermal growth factor-mediated proliferation in endometrial carcinoma cells. 1652 71


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