UMLS:C0432222 - FACTA Search

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Query: UMLS:C0432222 (SEM)
47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate whether a tumour-directed gradient in androgen levels in fatty tissue can account for the maintenance of intra-tissue oestradiol levels, androstenedione (Adione), dehydroepiandrosterone (DHEA), testosterone (Testo) and androstenediol (Adiol) were assayed in breast tumour tissues and in fatty tissue taken at different distances from the tumour. The concentration of Adione was significantly lower in tumour tissue (5.6 +/- 1.5 pmol/g tissue; mean +/- SEM; n = 14) than in the adjacent fatty tissue (20.4 +/- 2.2; P less than 0.005). Testo, by contrast, occurred in equal concentrations in tumour (0.80 +/- 0.11) and in adjacent fatty tissue (0.70 +/- 0.07). Adione levels tended to be lower after the menopause only in fatty tissue, not in the tumour tissue; for Testo no differences were observed between samples from pre- and postmenopausal patients. Tumour DHEA levels (57 +/- 12 pmol/g tissue) were lower than those in fatty tissue (117 +/- 17; P less than 0.02). As with Adione, fatty tissue DHEA concentrations tended to be higher in pre- than in postmenopausal patients. Adiol showed a similar pattern as Testo. For none of the aromatase substrates nor their precursors a tumour-directed gradient was observed. The concentration of Adione in breast cancer tissue is much lower than the reported Km of the aromatase system for Adione. We have concluded, therefore, that the maintenance of oestradiol concentrations in tumour tissues is not substrate-driven.
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PMID:Tissue androgens and the endocrine autonomy of breast cancer. 138 49

Mutant forms of aromatase cytochrome P-450 bearing modifications of amino acid residues Pro308 and Asp309 and expressed in transfected Chinese hamster ovary cells were subjected to kinetic analysis and inhibition studies. The Km for androstenedione for expressed wild type (11.0 +/- 0.3 nM SEM, n = 3) increased 4-, 25- and 31-fold for mutants Pro308Phe, Asp309Asn and Asp309Ala, respectively. There were significant differences in sensitivity among wild type and mutants to highly selective inhibitors of estrogen biosynthesis. 4-Hydroxyandrostenedione (4-OHA) a strong inhibitor of wild type aromatase activity (IC50 = 21 nM and Ki = 10 nM), was even more effective against mutant Pro308Phe (IC50 = 13 nM and Ki = 2.8 nM), but inhibition of mutants Asp309Asn and Asp309Ala was considerably less (IC50 = 345 and 330 nM and Ki = 55 and 79 nM, respectively). Expressed wild type aromatase and Pro308Phe aromatase were strongly inhibited by CGS 16949A (IC50 = 4.0 and 4.6 nM, respectively) whereas mutants Asp309Asn and Asp309Ala were markedly less sensitive (IC50 = 140 and 150 nM, respectively). CGS 18320B produced similar inhibition. Kinetic analyses produced Ki = 0.4 nM for CGS 16949A inhibition of wild type versus 1.1, 37 and 58 nM, respectively, against Pro308Phe, Asp309Asn and Asp309Ala. The results demonstrate significant changes in function resulting from single amino acid modifications of the aromatase enzyme. Our data indicate that mutation in Asp309 creates a major distortion in the substrate binding site, rendering the enzyme much less efficient for androstenedione aromatization. The substitution of Pro308 with Phe produces weaker affinity for androstenedione in the substrate pocket, but this alteration favors 4-OHA binding. Similarly, mutant Pro308Phe exhibits a slightly greater sensitivity to inhibition by CGS 18320B than does the wild type. These results indicate that residues Pro308 and Asp309 play critical roles in determining substrate specificity and catalytic capability in aromatase.
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PMID:Kinetic properties of aromatase mutants Pro308Phe, Asp309Asn, and Asp309Ala and their interactions with aromatase inhibitors. 147 61

Events in the normal menstrual cycle of the endangered Sulawesi Crested Black Macaque (Macaca nigra) were characterized. Daily blood samples were obtained during 10 menstrual cycles from five M. nigra demonstrating regular cycles. The amount of perineal tumescence was scored daily. Serum levels of estradiol and progesterone were determined by RIA, serum LH levels were determined by the mouse Leydig cell bioassay, and serum FSH levels were determined by the rat granulosa cell aromatase bioassay. Cycle length was 39.8 +/- 1.0 days (mean +/- SEM) with an LH surge occurring 25 +/- 1.5 days from the onset of menses. After menses, both LH and estradiol were initially depressed, with estradiol first exceeding 50 pg/ml 8 days before the LH surge. In five cycles, peak estradiol levels (340 +/- 44 pg/ml) occurred on the day of the LH surge (637 +/- 58 ng/ml) and in the other five cycles, on the day before the LH surge. There was a broad increase of FSH in midcycle without a well-defined surge corresponding to the LH surge. Progesterone began increasing on the day of the LH surge and reached peak levels (6.8 +/- 0.96 ng/ml) 8 days later. Maximal perineal tumescence was generally associated with the time of the LH surge, but variation between animals made it impossible to predict accurately the day of the LH surge by perineal tumescence scores alone.
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PMID:The Sulawesi Crested Black Macaque (Macaca nigra) menstrual cycle: changes in perineal tumescence and serum estradiol, progesterone, follicle-stimulating hormone, and luteinizing hormone levels. 159 42

The purpose of this study was to analyze follicular fluid (FF) samples for steroid levels from stimulated and unstimulated cycles triggered with human chorionic gonadotropin (hCG) and to assess the influence of controlled ovarian hyperstimulation and luteinizing hormone/hCG on these levels. Spontaneous ovulatory cycles were monitored with serial ultrasound examinations, and hCG 10,000 IU was given when the lead follicle was mature. Fourteen FF samples yielding fertilizable oocytes were compared with 13 FF samples from controlled ovarian hyperstimulation cycles. Progesterone (P) was higher in controlled ovarian hyperstimulation than in unstimulated cycles (9.0 +/- 1.2 micrograms/mL versus 4.4 +/- 0.6 microgram/mL; mean +/- SEM), whereas estradiol (E2) was lower (0.8 +/- 0.1 microgram/mL versus 1.3 +/- 0.2 microgram/mL), resulting in a higher P:E2 ratio (15.5 +/- 3.3 versus 4.4 +/- 0.7). Androstenedione (A), testosterone (T), and T:E2 ratios were all higher in unstimulated than controlled ovarian hyperstimulation cycles. We conclude that controlled ovarian hyperstimulation is associated with increased FF P, decreased FF E2, T, and A levels, and decreased T:E2 ratios, suggesting altered steroidogenesis and enhanced follicular aromatase activity.
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PMID:Preovulatory follicular fluid steroid levels in stimulated and unstimulated cycles triggered with human chorionic gonadotropin. 198 71

R 76713 (6-[(4-chlorophenyl)(1-H-1,2,4-trizol-1-yl)methyl]1-H benzotriazole) is a highly potent and selective inhibitor of the aromatase enzyme both in vitro and in vivo. The ability of R 76713 to inhibit peripheral aromatization of androstenedione (A) to estrone (E1) in vivo was studied in male cynomolgus monkeys (Macaca fascicularis). Peripheral aromatization was measured using a primed constant infusion of [3H] A and [14C]E1 for 3.5 h. Blood samples, collected during the final hour of infusion, were analyzed for plasma radioactivity as infused and product steroids. MCRs, conversion ratios (CR), and percent conversion of A to E1 were calculated. R 76713 (0.03-10 microgram/kg) or vehicle (10% hydroxypropyl-beta-cyclodextrin) were administered iv 90 min before beginning the infusion of radiolabeled steroids. In vehicle-treated monkeys, the aromatization of A (mean +/- SEM, 1.35 +/- 0.11%) was similar to that previously reported for cynomolgus and rhesus monkeys, baboons, and humans. Aromatization of A, measured 4-5 h after injection of R 76713, was dose-dependently decreased from the control value by 87 +/- 3%, 85 +/- 2%, 61 +/- 5%, and 33 +/- 8% (all P less than 0.05) at doses of 10.0, 3.0, 0.3, and 0.03 micrograms/kg, respectively, with an ID50 of 0.13 microgram/kg, iv (95% confidence interval, 0.06-0.21). When measured 15-16 h after iv administration of 3.0 micrograms/kg R 76713, aromatization (0.55 +/- 0.13%) was significantly inhibited by 53 +/- 11% compared to that in control monkeys (1.16 +/- 0.18%). The CRs between androgens, the CRs between estrogens, and the MCRs of A and E1 were not significantly altered by R 76713 compared to those after vehicle treatment. R 76713 potently decreased peripheral conversion of androgen to estrogen in vivo in male cynomolgus monkeys and may be a useful therapeutic agent in treating estrogen-dependent diseases, including post-menopausal breast cancer.
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PMID:Inhibition of peripheral aromatization in the male cynomolgus monkey by a novel nonsteroidal aromatase inhibitor (R 76713). 200

Gonadotroph adenomas may exhibit qualitative and quantitative defects in gonadotropin biosynthesis and secretion. Hypersecretion of immunoreactive FSH dimers by these adenomas occurs frequently; however, it has not been known whether this FSH is biologically active. Using the granulosa cell aromatase bioassay and a highly specific immunoradiometric assay for FSH, we studied the serum bioactivity and bio- to immunoactivity (B/I) ratios of 14 men with FSH-secreting adenomas and compared these values to those of 11 age-matched normal men. In addition, three adenoma patients received TRH (400 micrograms, iv). The mean basal serum FSH level (international units per L), as measured by both bio- and immunoassays, and the FSH B/I ratios were significantly higher (P less than 0.02, by Kolmogorov-Smirnov test) in the adenoma patients than in normal men (mean +/- SEM; adenoma patients: bioactivity, 68.8 +/- 10.4; immunoreactivity, 34.8 +/- 13.7; B/I ratio, 3.4 +/- 0.6; normal men: bioactivity, 5.8 +/- 1.2; immunoreactivity, 6.4 +/- 0.8; B/I ratio, 0.90 +/- 0.1). Both bio- and immunoactive FSH rose after TRH injection, resulting in maintenance of the B/I (mean +/- SEM; pre-TRH: bio-FSH, 63.7 +/- 22.4; immuno-FSH, 28.0 +/- 14.1; B/I ratio, 2.8 +/- 1.2; post-TRH: bio-FSH, 125.6 +/- 42.7; immuno-FSH, 45.8 +/- 21.8; B/I ratio, 3.5 +/- 1.6). When gonadotroph adenoma cells from three separate patients were cultured and their conditioned media (n = 3) studied, relatively large amounts of both bio- and immuno-FSH were detected. Furthermore, the major isoelectric profile of bio-FSH (pH 4.9-3.0) in the conditioned medium from two such adenomas was shown by chromatofocusing to be comparable to that of purified human pituitary FSH (pH 5.2-3.6). We conclude that gonadotroph adenomas in men secrete FSH that is biologically active, both basally and in response to TRH.
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PMID:Gonadotroph adenomas in men produce biologically active follicle-stimulating hormone. 211 91

Chronic administration of LHRH agonist analogs to humans reduces gonadal function through pituitary desensitization. Serum immunoreactive gonadotropin levels are modestly reduced, whereas serum bioactive LH levels are drastically suppressed. The effects on bioactive FSH levels, however, are not known. In this study, serum bioactive FSH was measured using an in vitro granulosa cell aromatase bioassay in four normal men given a LHRH agonist, [D-Trp6,Pro9-NEt]LHRH (LHRHA; 500 micrograms/day for 16 weeks), by sc infusion and testosterone enanthate (TE; 100 mg, im every 2 weeks) and in five men given 500 micrograms/day LHRHA by daily sc injection for 20 weeks and TE (100 mg every 2 weeks) from weeks 10 through 20. During the first study, serum immunoreactive FSH levels (IR-FSH) decreased by 56.5 +/- 4.8% (+/- SEM), and serum bioactive FSH (Bio-FSH) level decreased by 57.6 +/- 6.4%. The ratio of Bio-FSH to IR-FSH did not change. During the second study, both serum IR-FSH and Bio-FSH levels followed a triphasic pattern, decreasing slightly but not significantly immediately after initiation of LHRHA administration, progressively increasing to a peak (P less than 0.5 vs, baseline) at week 10, and then, after addition of TE to this regimen, decreasing slightly again. The Bio-FSH to IR-FSH ratio, as in the first study, did not change. When serum obtained at week 10 during the second study, just before initiation of TE, was chromatographed on a Sephadex G-100 column, IR-LH eluted in two distinct peaks, while IR-FSH eluted as a single peak. These results demonstrate that in normal men chronic LHRHA administration alone for up to 10 weeks or LHRHA plus TE for up to 16 weeks does not alter the qualitative characteristics of secreted FSH, since there was no dissociation between serum IR- and Bio-FSH levels.
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PMID:Maintenance of the ratio of bioactive to immunoreactive follicle-stimulating hormone in normal men during chronic luteinizing hormone-releasing hormone agonist administration. 283 9

The estradiol (E2) to estriol (E3) ratio during human pregnancy depends on fetal liver hydroxylation of fetal adrenal dehydroepiandrosterone sulfate (DHEAS) and conversion by the trophoblast of DHEAS and 16 alpha-hydroxy-DHEAS (16 OH-DHEAS) to estrone (E1), estradiol (E2), and estriol (E3), respectively. It is not known whether the conversion of DHEAS into E1 and E2 influence the conversion of 16OH-DHEAS into E3 and vice versa. To examine this question, we studied these interactions in human choriocarcinoma JEG-3 cells. In serum-free medium (Dulbecco's Modified Eagle's Medium), JEG-3 cells secreted hCG [27 +/- 3 (+/- SEM) ng/mg cellular protein X 24 h] and progesterone (22 +/- 2.5), but neither C-19 nor C-18 steroids. The addition of DHEAS resulted in secretion of E1 and E2; at a concentration of 500 ng DHEAS/ml, the secretion of E1 (1 +/- 0.16) and E2 (11 +/- 3.1) was maximal, while E3 remained undetectable. The addition of 1000 ng 16 OH-DHEAS/ml resulted in maximum E3 secretion (13 +/- 1.8), while E1 and E2 remained undetectable. The addition of increasing concentrations of DHEAS to cultures exposed to 1000 ng 16OH-DHEAS/ml caused a decrease in E3 secretion and increased secretion of E1 and E2. Conversely, addition of increasing concentrations of 16OH-DHEAS in cultures exposed to 500 ng DHEAS/ml resulted in inhibition of E1 and E2 secretion and increased E3 secretion. A concentration of 16OH-DHEAS that inhibited the conversion of DHEAS into E1 and E2 neither altered the intracellular to extracellular steroid ratios (approximately 0.1) nor reduced the secretion of DHEA, androstenedione, and testosterone. The inhibitory effect of 16OH-DHEAS was minimal at low DHEAS concentrations (favoring the secretion of E1 and E2) and was greatly enhanced at concentrations of DHEAS that induced maximum E1 and E2 secretions. The results indicate that in trophoblastic cells, the metabolism of DHEAS can modulate E3 secretion, and the metabolism of 16OH-DHEAS can modulate the secretion of E1 and E2; and this regulatory mechanism appears to take place at the level of the aromatase system.
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PMID:Competitive studies with dehydroepiandrosterone sulfate and 16 alpha-hydroxydehydroepiandrosterone sulfate in cultured human choriocarcinoma JEG-3 cells: effect on estrone, 17 beta-estradiol, and estriol secretion. 294 57

In order to study the regulation of aromatase activity by androgens in cultured fibroblasts derived from genital skin of normal prepubertal boys, aromatase activity was evaluated in the presence of various concentrations of non-aromatizable androgen DHT(5 alpha-dihydrotestosterone). The estrogen formation was assayed by an enzymatic method, after 24 h incubation of the cells with 10(-6) M androstenedione. Aromatase activity was stimulated 3- to 20-fold by DHT at concentrations 10(-10) and 10(-9) M. It was necessary to preincubate the cells with DHT for 48 h in order to bring about this stimulation. The stimulatory effect was not significant after preincubation for only 24 h. The basal value of aromatase activity was in the range of 8 +/- 1.2 pmol/mg protein/day (mean +/- SEM), while the maximal stimulation 1043 +/- 46 pmol/mg protein/day was obtained at the concentration of 10(-8) M DHT. This stimulation was partially blocked with cyproterone acetate at level of 20 +/- 4 pmol/mg protein/day; stimulation of aromatase activity by DHT could thus be mediated by the androgen receptor. This stimulatory effect was prevented by incubation of the cells with cycloheximide or actinomycin D, suggesting that DHT acts to increase aromatase activity in cultured fibroblasts by inducing the synthesis of new proteinaceous material. In vitro regulation of aromatase activity by androgens could contribute to a new approach to the extraglandular formation of estrogen.
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PMID:Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts. 294 41

In addition to the histology of epithelial and stromal elements of prostates from intact dogs (group 0) and castrated dogs (group I), the latter of which were treated with androstenedione (group II), androstenedione plus the aromatase inhibitor 1-methyl-1,4-androstadiene-3,17-dione (group III), or androstenedione plus aromatase inhibitor and cyproterone acetate (group IV) (Habenicht and El Etreby: The Prostate 11:133-143, 1987) it was of interest to study the influence of such in vivo treatment on the prostatic 5 alpha-reductase, which is responsible for the cellular conversion of testosterone to 5 alpha-dihydrotestosterone. Michaelis constants (KM) and maximal activities (Vmax) of 5 alpha-reductase were determined under optimized incubation conditions in mechanically separated epithelium and stroma. The metabolites were separated by high-performance liquid chromatography and determined radiometrically. The main results were: 1) The mean KM (nM +/- SEM) was significantly (P less than .001) higher in epithelium (892 +/- 132) than stroma (70 +/- 11). The same was true concerning the Vmax (pmol.mg protein-1.h-1 +/- SEM) in epithelium (54.6 +/- 5.8) as compared to stroma (13.0 +/- 2.0). 2) No specific in vivo or in vitro effect of the aromatase inhibitor on the KM and Vmax data was found. 3) In prostates of intact dogs and dogs of group II the proportion of epithelial 5 alpha-reductase exceeded distinctly that of stromal 5 alpha-reductase. 4) In groups I, III, and IV the proportion of epithelial 5 alpha-reductase was rather low. These data were discussed in the light of the histological findings.
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PMID:5 alpha-reductase activity in epithelium and stroma of prostates from intact and castrated dogs treated with androstenedione, the aromatase inhibitor 1-methyl-1,4-androstadiene-3,17-dione, and cyproterone acetate. 296 68

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