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)

Different subcellular fractions (purity checked by electron microscopy and respective marker enzymes) were incubated with 0.1 muCi 14C-progesterone (10 muM) in 0.15 M phosphate buffer at pH 7.4 and 37 C under air for varying periods of time in the presence of NAD(P)H (500 muM). By the preparation of chromic acid oxidation products and acetates, thin-layer chromatography, and crystallisation to constant specific activity, the following metabolites were identified: 20alpha-hydroxypregn-4-en-3-one, 20alpha-hydroxy-5alpha-pregnan-3-one, 20alpha-hydroxy-5beta-pregnan-3-one, 5alpha-pregnane-3,20-dione, and 5beta-pregnane-3,20-dione, indicating the presence of a 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) and 5alpha- and 5beta-reductases. Most of the 20alpha-HSD activity was located in mitochondria (associated mainly with outer membranes) and microsomes. Purified nuclei and cytosol contained 1/6 to 1/18 of the activity of mitochondria and microsomes, respectively. SUBFRACTIONS OF ENDOMETRIAL CELLS ONLY CONTAINED EITHER 5ALPHA- OR 5BETA-REDUCTASE ACTIVITY. 5alpha-reductase activity was mainly associated with microsomes, 5beta-reductase activity was found only in the cytosol. While in normal endometrium specific enzyme activities in subcellular fractions depended on the phase of the cycle, in endometrial carcinoma it depended on the degree of tumour differentiation. The highest values of 5alpha-reductase activity were found in the early proliferative phase. 20alpha-HSD activity was highest in the middle of the secretory phase. The specific activity of the 5alpha-reductase increased with decreasing differentiation of the tumour while the specific activity of the 20alpha-HSD decreased. Kinetic parameters (Km-values, coenzyme requirements and maximum velocities) were determined. The Km-value for progesterone of the 20alpha-HSD in proliferative endometrium was significantly higher than in secretory endometrium, while the Km-values of the 5alpha- and 5beta-reductases were considerably lower during the proliferative than secretory phase.
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PMID:Progesterone metabolism in normal human endometrium during the menstrual cycle and in endometrial carcinoma. 24 Aug 67

Kinetics of estradiol dehydrogenase (E2DH) activity and the in vitro effects of progesterone (P) and synthetic steroids on E2DH activity were investigated in human normal endometrium and endometrial carcinoma. In proliferative and secretory endometrium and endometrial carcinoma, E2DH activities were 1.5 +/- 0.2, 10.1 +/- 1.1 and 1.2 +/- 0.1 nmol/mg protein/h (mean +/- SEM), Km was 2.3 microM, and Vmax were 0.20, 1.7 and 0.14 nmol/mg protein/10 min, respectively. Culturing proliferative endometria with progestogens resulted in a time- and dose-dependent stimulation of E2DH activity up to 72 h and 10(-6) M, respectively. Medroxyprogesterone acetate had the highest effect to stimulate E2DH activity among the steroids investigated. Chlormadinone acetate, norethindrone, P and R2323 were also effective. However, danazol, lynestrenol and E2 had negligible effect. Histological examination showed that progestogens caused early secretory change in the proliferative endometrium. These results indicate that the progestational activity is responsible for the elevation of E2DH activity in proliferative endometrium and that the extent to which each steroid increases E2DH activity may correlate with its local progestational activity. In the endometrial carcinoma, progestogens also stimulated E2DH activity in seven cases out of nine during culture for 48 h, but the elevation was lower than that in the proliferative endometrium.
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PMID:[Studies on estradiol dehydrogenase activity in the human uterine endometrium]. 296 May 69

Entry into menopause is associated with a severe diminution of ovarian estrogen and progesterone secretion and a reduction of circulating androgens, although, in the presence of ovaries, a degree of testosterone secretion persists. Menopause is associated to a varying degree and severity, with hot flashes--a disorder of central thermoregulation--progressive sex tissue atrophy, and accelerated bone mineral loss that eventually leads to a substantial prevalence of osteoporosis, with spine, hip, and radial fractures, particularly in thin, inactive smokers with low calcium intake. Treatment with estrogens eliminates hot flashes and sex tissue atrophy and prevents osteoporosis. Unfortunately, oral estrogen therapy results in overstimulation of the liver, producing secreted proteins and an increased risk of endometrial carcinoma and gallbladder disease. The addition of a progestogen will diminish the risk of endometrial carcinoma, presumably by reducing estrogen-receptor concentration and increasing estradiol dehydrogenase activity but will usually result in vaginal bleeding in women with uteri. The use of estrogen therapy with or without a progestin should be an informed joint decision of physician and patient that must be reevaluated regularly as new information becomes available.
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PMID:Menopausal endocrinology and management. 704 70

The role of progestins in breast tissue is less well defined than in the endometrium. Although in vitro studies have shown that progestins induce a similar decrease in both estrogen and progesterone receptors and an increase in 17beta-estradiol dehydrogenase in the breast as in the endometrium, epidemiologic studies have suggested that progestins prevent endometrial cancer, but do not reverse the estrogen-related increase in breast cancer risk in long-term hormone-replacement therapy (HRT). Other studies have also suggested a protective effect for progestins on breast tissue. The dual effect of progesterone and progestins on the cell cycle has been demonstrated, suggesting that according to the duration of administration, the same steroid can induce cells to enter the multiplication phase or to enter a resting state. Progestins exert different effects according to the steroid from which they are derived, e.g. pregnanes derived from progesterone, estranes or gonanes derived from testosterone. Some estrane derivatives are able to stimulate breast cell multiplication in vitro through an estrogen receptor-mediated pathway. Most pregnanes do not exert such an effect. Also, some pregnane derivatives stimulate apoptosis, leading to cell death. However, it is well established that high doses of progestins have been successfully used in the treatment of advanced breast cancer as second-line endocrine therapy. Finally, striking differences have been observed in progestin use in Europe and in the USA. In France, where the rate of progestin use per head is higher than in the USA, the rate of breast cancer has not increased as sharply as observed in North America. Although cancer genesis is multifactorial, it may be concluded that progestins do protect endometrial tissue against the proliferative action of estrogen and if they do not protect breast tissue, at least they do not stimulate its proliferation. Also, they are useful agents as a second-line therapy for breast cancer, when used at high doses.
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PMID:Progestins and cancer. 1222 96

Endometrial cancer is the most common malignancy of the female genital tract. Its incidence correlates with prolonged estrogen stimulation unopposed by progesterone or synthetic progestins. Estrogen and progestin action is regulated at the pre-receptor level, by interconversion of active hormones (estradiol (E2), progesterone (P)) with their inactive counterparts (estrone (E1), 20alpha-hydroxyprogesterone (20alpha-OHP)) in target tissues. Expression of enzymes that control the ratio of E2 and P may thus play role in the disease process. We first confirmed that AKR1C1 (human 20alpha-hydroxysteroid dehydrogenase) in a cellular context inactivates P by forming 20alpha-OHP but does not catalyze the reverse reaction. We next examined the expression of AKR1C1 and AKR1C3 (type 5 17beta-hydroxysteroid dehydrogenase) in 16 paired specimens of endometrial cancer and adjacent normal endometrium. Quantification by isoform specific real-time PCR revealed higher expression of AKR1C1 in nine specimens and higher expression of AKR1C3 in four specimens of endometrial cancer. Importantly, upregulation of both enzymes in the same specimen was observed. Since AKR1C1 inactivates P its elevated expression in diseased endometrium may contribute to diminished protection by P, while elevated expression of AKR1C3 which forms E2 in vivo, may contribute to the enhanced estrogen action. It is suggested that the expression of AKR1C1 and AKR1C3 in endometrial cancer will govern the ratio of P:E2.
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PMID:AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer. 1633 60

20alpha-hydroxysteroid dehydrogenase (AKR1C1) plays a key role in the metabolism of progesterone and other steroid hormones, thereby regulating their action at the pre-receptor level. AKR1C1 is implicated in neurological and psychiatric conditions such as catamenial epilepsy and depressive disorders. Increased activity of AKR1C1 is associated with termination of pregnancy and the development of breast cancer, endometriosis and endometrial cancer. Inhibition of the undesired activity of AKR1C1 will help reduce risks of premature birth, neurological disorders and the development of cancer. In order to identify potential leads for new inhibitors of AKR1C1 we adopted a virtual screening-based approach using the automated DOCK program. Approximately 250,000 compounds from the NCI database were screened for potential ligands based on their chemical complementarity and steric fit within the active site of AKR1C1. Kinetic analysis revealed 3,5-diiodosalicylic acid, an analogue of salicylic acid, as a potent competitive inhibitor with respect to the substrate 5beta-pregnane-3alpha,20alpha-diol with a K(i) of 9 nM. Aspirin, which is a well known salicylic acid-based drug, was also found to inhibit AKR1C1 activity. This is the first report to show aspirin (IC(50)=21 microM) and its metabolite salicylic acid (IC(50)=7.8 microM) as inhibitors of AKR1C1.
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PMID:A salicylic acid-based analogue discovered from virtual screening as a potent inhibitor of human 20alpha-hydroxysteroid dehydrogenase. 1804 4

Endometrial cancer is related to estrogen stimulation not opposed by progesterone. We have examined expression of the pre-receptor regulatory enzymes aromatase, 17beta-hydroxysteroid dehydrogenases (17beta-HSDs), 20alpha-hydroxysteroid dehydrogenases (20alpha-HSDs), sulfatase and sulfotransferase, and estrogen (ERs) and progesterone (PRs) receptors in samples of endometrial cancer and adjacent normal endometrium. No significant gene up-regulation was seen, although aromatase, AKR1C3, a 17beta-HSD and 20alpha-HSD, and AKR1C1, the major 20alpha-HSD, were up-regulated in 50% of samples. Significant down-regulation was seen for 17beta-HSD types 1 and 7, sulfotransferase, ERalpha, ERbeta, PR-AB. Western blotting revealed higher levels of AKR1C3 and PR-B and lower levels of ERalpha in cancerous endometrium, and immunohistochemistry confirmed expression of AKR1C3, PR-B and ERalpha at the cellular level. Up-regulation of aromatase in concert with AKR1C3 can lead to increased levels of estradiol, which acts via ERalpha. Up-regulation of AKR1C1 and AKR1C3 can result in lower levels of the protective progesterone, which acts mainly via PR-B.
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PMID:Aberrant pre-receptor regulation of estrogen and progesterone action in endometrial cancer. 1893 Jul 84