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

Six patients who took oral contraceptive agents for 5 to 18 years developed endometrial neoplasia. Endometrial adenocarcinoma occurred in 4 of these patients and severe adenomatous hyperplasia occured in 2. Five of the 6 patients took sequential agents; 1 patient used a combined agent. An additional patient who took Premarin and Provera sequentially developed adenocarcinoma of the endometrium. Eighteen cases of endometrial adenocarcinoma and 7 cases of adenomatous hyperplasia in patients with long-term sequential oral contraceptive use have previously been reported by others. Progestogens may not be completely protective against the endometrial cancer-causing potential of the estrogens, especially in the sequential regimens.
 ...
PMID:Endometrial carcinoma and oral contraceptive agents. 19 73

Because of adverse publicity regarding increased risk of endometrial cancer in women receiving estrogen therapy, a 2-year prospective study was conducted in 1976 to determine the incidence of endometrial cancer in postmenopausal women. A retrospective study for the year 1975 was also added. A postmenopausal survey card for each patient recorded the patient's visit and clinical data, as well as hormone therapies (estrogen, progestogen, androgen). Postmenopausal women never treated with hormones were also provided survey cards. A total of 2088 patient-years of estrogen use was recorded during the combined 3-year study period (1975-77). 8 of the estrogen users had a diagnosis of adenocarcinoma of the endometrium for an annual incidence rate of 3.8/1000 women. 2 endometrial cancers were detected in the estrogen-progestogen users for a cancer incidence rate of 0.5/1000 (3792 patient-years of observation); this finding suggests that progestogen provides better protection against endometrial cancer compared to estrogens. This difference between estrogen users and estrogen-progestogen users was statistically significant (p ? 0.01). 1 endometrial malignancy occurred among estrogen vaginal cream users, giving an incidence of 1.7/1000. The patient used Premarin vaginal cream (1 gm thrice weekly) for 7 months before the cancer was diagnosed. No endometrial cancer was diagnosed in both the progestogen and androgen groups. Overall, 14 endometrial cancers out of 8170 years of observation were diagnosed in this clinic; annual incidence rate for the study period was 1.7/1000. 199 women with endometrial hyperplasia (a precancerous lesion) were treated with progestogens for 3 to 6 months. The hyperplastic endometrium returned to normal in 96.5%. It was suggested that all postmenopausal women with intact uterus be given the Progestogen Challenge Test and that progestogens be given to the women each month as long as bleeding follows. This should prevent the development of endometrial cancer in most women.
 ...
PMID:Reduced incidence of endometrial cancer among postmenopausal women treated with progestogens. 46 50

The side effects of using estrogen treatments to relieve menopausal symptoms in women are presented. Estrogens are effective in relieving headaches, vertigo, palpitations, and nervous symptoms such as depression, as well as degeneration and atrophy of the genital organs. In Norway, 2.5% of women over 45 as compared with 50% in the U.S. use estrogens to relieve menopausal symptoms. The incidence of endometrial cancer has risen from 9.2/100,000 in 1955 to 15.4 in 1974. Increased susceptibility to endometrial cancer has been linked to long-term use of estrogens, obesity, hypertension, diabetes, and nulliparity. In American studies, Premarin has been associated with increased risk of cancer related to the chemical equilinine, which has a long half-life. After menopause, the need for estrogen is met by the conversion of androstenedione, which is produced by the adrenal gland. When estrogens are taken, it may result in an overstimulation of the endometrium, which could cause cancer. Estrogens have bene found useful and safe for short-term relief of menopausal symptoms, and any patient using estrogens should be under routine observation to prevent development of cancer.
 ...
PMID:[From the Adverse Drug Reaction Committee. Can long-term estrogen treatment induce uterine neoplasms in post-climacteric women?]. 125 36

Two groups of postmenopausal women were seen at monthly intervals during a 6-month trial of cyclic therapy with conjugated equine oestrogens ('Premarin'). the seven women in the first group were taking premarin alone and the six women in the second group were taking premarin plus a progestagen, norethisterone acetate. On each visit, serum unconjugated oestrogens were measured by radioimmunoassay. Mean concentrations for the first group were 393 (+/- 203, SD) pmol/l for 17 beta-oestradiol, 599 (+/- 180) pmol/l for oestrone, and 6840 (+/- 5130) pmol/l for equilin. Corresponding levels for the second group were 342 (+/- 112) pmol/l, 564 (+/- 279) pmol/l, and 8840 (+/- 4020) pmol/l. 3 months after completion of therapy, the oestrone and 17 beta-oestradiol concentrations had returned to pre-treatment levels in both groups, but equilin was detected in 3 out of 3 women in the first group at a mean level of 532 (+/- 267) pmol/l and in 2 out of 4 women in the second group at 1170 (+/- 870) pmol/l. In view of the prolonged presence of equilin and the possible association between treatment with conjugated equine oestrogens and endometrial cancer, it is suggested that equilin-containing compounds should not be given for more than 12 months.
 ...
PMID:Serum equilin, oestrone, and oestradiol levels in postmenopausal women receiving conjugated equine oestrogens ('Premarin'). 610 54

Both animal experimental work and epidemiological, clinical, and laboratory research on the effects of endogenous hormones in the human have made it clear that some influence of administered female sex hormones on the risk of certain cancers would be anticipated, and this has turned out to be the case. This review focuses on the administration of hormones during pregnancy, around the time of the menopause, and to prevent pregnancy. In the daughters who were exposed in utero to stilbestrol during the 1950s and 1960s, the most important effect is the development of clear cell adenocarcinoma of the vagina or cervix. Few cases of this disease have been reported before puberty, but the cumulative risk thereafter up to the age of 24 years is estimated to be between 1.4 and 4/10,000 exposed. Much less attention has been paid to the mothers who actually took the stilbestrol than to their daughters, but the published data fail to provide any convincing evidence of an increased risk of either breast or reporductive cancer among them. Regarding the administration of hormones around the time of menopause, it is well established that unopposed estrogen therapy in menopausal women can cause endometrial cancer. This has been demonstrated in a large number of case control studies reported since 1975. Most of these studies were conducted in the US and most concern the drup Premarin (conjugated equine estrogens). Some cohort studies also have been reported, and they largely support the results of the case control studies. There is now little doubt that combined oral contraceptives (OCs) protect against both epithelial ovarian cancer and endometrial cancer. Preliminary findings in the major cohort studies concerned with the longterm effects of OC use also are encouraging. A series of large case control studies conducted during the 1970s showed clearly that there is no general association between oral contraceptive use and breast cancer risk, but these large studies included few women with appreciable OC use at an early age and accordingly the publication by Pike et al. in 1981 caused much concern. Pike's study involved 163 women in Los Angeles County in whom breast cancer has been diagnosed at age 32 or less, together with a like number of neighborhood controls. Vessey et al. (1982) and the Centers for Disease control subsequently published results which did not support the California findings. Preliminary results from a new case control study conducted in Oxford and in London since 1980 suggest an increased risk of breast cancer in young women who have prolonged OC use before 1st pregnancy. The situation is very confusing and it may be some time before there is a conclusive answer. In a large cohort study conducted in Los Angeles, rates of progression from cervical dysplasia to carcinoma in situ were much higher in women using Ovulen than in women using IUDs.
 ...
PMID:Exogenous hormones in the aetiology of cancer in women. 637 76

This review of the connection between unopposed estrogen therapy for climacteric symptoms and the development of endometrial hyperplasia briefly outlines the history of the association, and then concentrates on clinical classification problems which muddy the attempts to come to a clear understanding of the relationship between estrogen replacement therapy (ERT) and endometrial cancer. Little agreement exists about the definition of endometrial pathology and of the malignant potentials of different types of hyperplasia. This paper classifies 4 types of hyperplasia: 1) cystic hyperplasia, which has the risk of malignant change of less than 2%; 2) adenomatous hyperplasia, which has a risk of malignant change from 12-25%; 3) atypical hyperplasia, which has a malignancy potential of 45%; and 4) carcinoma in situ, which is malignant. The following conditions are discussed as they are associated with endometrial hyperplasia and adenocarcinoma: 1) obesity; 2) anovulation; 3) late menopause; 4) Stein-Leventhal syndrome; 5) functioning ovarian tumors; and 6) diabetes history. In addition hypertension and cancers of the breast and ovary occur more often with endometrial cancer than would be expected by chance. The remainder of the paper discusses the administration of exogenous estrogens unopposed, exogenous progestins, and their concurrent use, especially in controlling menopausal symptoms. Prevention, diagnosis, and treatment of hyperplasia are discussed. In terms of prevention, a study showed that low-dose cyclical Premarin (.625 mg) resulted in an incidence of hyperplasia of 7% and with higher doses (1.25 mg) rose to 15%. The addition of d-norgestrel for 7 days to the high dose of Premarin reduced incidences to 3%, whereas estrogen plus low-dose norethindrone resulted in 0% incidence of cystic hyperplasia. It is recommended that the unopposed use of estrogens be avoided if possible, although short-term therapy up to 6 months is probably safe. Longer term therapy must have added progestogen, and endometrial sampling in the form of Vabra curettage should be performed every year in patients taking unopposed estrogens and every 3 years in patients taking combined estrogen therapy.
 ...
PMID:Oestrogens and endometrial hyperplasia. 699 95

Equilin and equilenin make up approximately 20% of Premarin which is currently the most popular estrogen replacement therapy. Although there are numerous health benefits of estrogen replacement therapy, there are concerns over the link between estrogen replacement therapy and breast and endometrial cancer risk. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2- and 4-hydroxylated catechols which are further oxidized to electrophilic/redox active o-quinones which have the potential to both initiate and promote the carcinogenic process. In this investigation, we have synthesized potential metabolites of equilin and equilenin, 2-hydroxyequilin and 2-hydroxyequilenin, respectively, as well as their methyl ether metabolites. These compounds were synthesized from commercially available optically pure equilin via a practical and efficient approach; five steps gave 2-methoxyequilin from which 2-hydroxyequilin was prepared by BBr3-catalyzed demethylation in one step. Similarly, treating 2-methoxyequilin with SeO2 followed by demethylation with BBr3 produced 2-hydroxyequilenin. The structures of the catechols as well as those of their methoxy ethers were unambiguously characterized by one-dimensional and two-dimensional NMR experiments, including 1H, 13C, APT, COSY, HMBC, and HMQC as well as mass spectrometry.
 ...
PMID:Synthesis of the equine estrogen metabolites 2-hydroxyequilin and 2-hydroxyequilenin. 1002 99

Estrogen replacement therapy has been correlated with an increased risk of developing breast or endometrial cancer. 4-Hydroxyequilenin (4-OHEN) is a catechol metabolite of equilenin which is a minor component of the estrogen replacement formulation marketed under the name of Premarin (Wyeth-Ayerst). Previously, we showed that 4-OHEN autoxidizes to quinoids which can consume reducing equivalents and molecular oxygen, are potent cytotoxins, and cause a variety of damage to DNA, including formation of bulky stable adducts, apurinic sites, and oxidation of the phosphate-sugar backbone and purine/pyrimidine bases [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S. (1998) Chem. Res. Toxicol. 11, 1113-1127]. All of these deleterious effects could contribute to the cytotoxic and genotoxic effects of equilenin in vivo. In the study presented here, we examined the relative toxicity of 4-OHEN in estrogen receptor (ER) positive cells (MCF-7 and S30) compared to that in breast cancer cells without the estrogen receptor (MDA-MB-231). The data showed that 4-OHEN was 4-fold more toxic to MCF-7 cells (LC(50) = 6.0 +/- 0. 2 microM) and 6-fold more toxic to S30 cells (LC(50) = 4.0 +/- 0.1 microM) than to MDA-MB-231 cells (LC(50) = 24 +/- 0.3 microM). Using the single-cell gel electrophoresis assay (comet assay) to assess DNA damage, we found that 4-OHEN causes concentration-dependent DNA single-strand cleavage in all three cell lines, and this effect could be enhanced by agents which catalyze redox cycling (NADH) or deplete cellular GSH (diethyl maleate). In addition, the ER(+) cell lines (MCF-7 and S30) were considerably more sensitive to induction of DNA damage by 4-OHEN than the ER(-) cells (MDA-MB-231). 4-OHEN also caused a concentration-dependent increase in the amount of mutagenic lesion 8-oxo-dG in the S30 cells as determined by LC/MS-MS. Cell morphology assays showed that 4-OHEN induces apoptosis in these cell lines. As observed with the toxicity assay and the comet assay, the ER(+) cells were more sensitive to induction of apoptosis by 4-OHEN than MDA-MB-231 cells. Finally, the endogenous catechol estrogen metabolite 4-hydroxyestrone (4-OHE) was considerably less effective at inducing DNA damage and apoptosis in breast cancer cell lines than 4-OHEN. Our data suggest that the cytotoxic effects of 4-OHEN may be related to its ability to induce DNA damage and apoptosis in hormone sensitive cells in vivo, and these effects may be potentiated by the estrogen receptor.
 ...
PMID:A metabolite of equine estrogens, 4-hydroxyequilenin, induces DNA damage and apoptosis in breast cancer cell lines. 1081 50

The US Food and Drug Administration (FDA) approved marketing of diethylstilbestrol in 1941 and conjugated equine estrogens (CEE) in 1942 for treatment of menopausal symptoms. Estrogen sales doubled and tripled in the mid-1960s to mid-1970s, until 1975, when reports of increased endometrial cancer in estrogen users resulted in a dramatic decline. Estrogen use increased again, with evidence of protective effects of progestins on estrogen-induced endometrial changes, combined with a 1982 report that Premarin (conjugated estrogen tablets; Wyeth Pharmaceuticals, Philadelphia, PA) retained bone mass and a 1984 National Institutes of Health (NIH) Consensus Conference on Osteoporosis statement that estrogens were the most effective means for preventing bone loss. Despite conflicting reports in 1985 regarding the relation between estrogens and coronary heart disease (CHD), many published observations of reduced CHD risk in estrogen users--reinforced by clinical trial findings in 1995 of favorable lipoprotein changes in women assigned to CEE with or without a progestin--promoted increased use through the 1990s. By 2001, approximately 15 million US women were using estrogen therapy, with or without progestins. The 2002 Women's Health Initiative (WHI) report of greater harm than benefit of combined CEE plus a progestin resulted in a precipitous decrease in estrogen and progestin use and a serious reevaluation of menopausal hormone therapy, as well as increased interest in alternative approaches to managing menopausal symptoms, including use of "bioidentical" hormones. FDA guidelines regarding treatment indications for vasomotor symptoms, vaginal atrophy, and osteoporosis prevention have resulted in approval of several estrogen (and progestin) formulations, doses, and routes of administration, thereby providing many options for women who seek conventional therapy.
 ...
PMID:Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration. 1641 29