Showing papers on "Aromatase published in 1978"
TL;DR: In vitro studies demonstrated that aminoglutethimide (AG), a drug previously used as an adrenal steroidogenesis inhibitor, is also a potent aromatase blocker, and in vivo effects of AG on the rate of aromatization of δ4-A to E1 by direct radioisotopic kinetic methods were examined.
Abstract: Extraglandular aromatization of androstenedione (δ4-A) to estrone (E1) provides the primary source of estrogen production in spontaneously postmenopausal or surgically castrate women. Estrogens produced by this enzymatic reaction in peripheral tissues can be biologically important, particularly in women with metastatic breast carcinoma. In such patients, an aromatase inhibitor would have potential usefulness clinically. In vitro studies demonstrated that aminoglutethimide (AG), a drug previously used as an adrenal steroidogenesis inhibitor, is also a potent aromatase blocker. A similar in vivo effect of AG was suggested by clinical observations of suppressed plasma E1 without concomitant reductions in δ4-A concentrations in postmenopausal women given this drug. Based upon these considerations, we examined the in vivo effects of AG on the rate of aromatization of δ4-A to E1 by direct radioisotopic kinetic methods. AG inhibited the fractional conversion of δ4-A to E1 in blood from 1.65 ± 0.28% (se) before t...
342 citations
TL;DR: The role of FSH in the activation of aromatase enzymes in granulosa cells was studied by using immature, hypophysectomized, estrogen-primed rats as a model system and enzyme activity was comparable to that found in granULosa cells of adult preovulatory follicles.
Abstract: The role of FSH in the activation of aromatase enzymes in granulosa cells was studied by using immature, hypophysectomized, estrogen-primed rats as a model system. After twice daily injections of ovine FSH, aromatase activity was induced in granulosa cells after a 24-h lag period. Continued FSH treatment caused a further increase in aromatase activity. After 48 h, the enzyme activity was comparable to that found in granulosa cells of adult preovulatory follicles. The effects of enzyme substrate (androstenedione) as well as purified FSH and LH upon aromatase activity were investigated in vitro by culturing granulosa cells for 2 days in a chemically defined medium containing these hormones. In the absence of aromatase substrate, no significant stimulation of estrogen secretion was observed in control and gonadotropin-treated cultures. However, in the presence of enzyme substrate (10-7 M androstenedione), highly purified FSH (200 ng/ml), but not LH (200 ng/ml), stimulated estrogen production 8.8- and 40-fold...
287 citations
TL;DR: Results indicate that the glucocorticoids exert a selective inhibition of the FSH-induction of aromatase activity in rat granulosa cells by a mechanism other than directly interfering with the aromatization reaction.
220 citations
TL;DR: Comparative studies together with autoradiographic, physiological, and behavioral data in mammals and selected nonmammalian species support the view that metabolism in situ is an important component of androgen action and a general characteristic of the vertebrate brain.
Abstract: Aromatase activity has been detected in the central nervous system (CNS) of representatives of each major vertebrate group with the exception of the Agnatha. 5a-reductase and 17/3-oxidoreductase are also present in brain tissues of many vertebrates and in the cerebral ganglion of the lobster. These comparative studies together with autoradiographic, physiological, and behavioral data in mammals and selected nonmammalian species support the view that metabolism in situ is an important component of androgen action and a general characteristic of the vertebrate brain.
154 citations
TL;DR: The synthesis and biochemical evaluation of various C19-steroidal derivatives as inhibitors of estrogen biosynthesis are described and several 7alpha-substituted androst-4-ene-3,17-diones were effective competitive inhibitors.
Abstract: The synthesis and biochemical evaluation of various C19-steroidal derivatives as inhibitors of estrogen biosynthesis are described. Steroids with substitutions on the A or B ring were synthesized by Michael addition of various thiol reagents to appropriate dienone intermediates. An in vitro assay employing the microsomal fraction isolated from human term placenta was used to evaluate aromatase inhibitory properties. Agents exhibiting high inhibitory activity were further evaluated in inital velocity studies (low product formation) to determine apparent Ki values. Several 7alpha-substituted androst-4-ene-3,17-diones were effective competitive inhibitors and have apparent Ki values equal to or less than the apparent Km of 0.063 microM for the substrate androstenedione.
115 citations
TL;DR: The findings indicate the potential importance of the forebrain as a source of estrogens during embryogenesis, and when projected to the whole organ, the capacity of the diencephalon for aromatization exceeds thecapacity of the fetal ovary approximately 9-fold.
Abstract: The formation of 17β-[3H]estradiol from [l,2,6,7-3H]testosterone was assessed in placenta and central nervous system tissues from rabbit embryos that varied in age from 13–28 days of gestation. In the fetal brain, significant rates of aromatase activity were limited exclusively to the forebrain, and the highest rates of activity (approximately 0.5 pmol/h/mg protein) were found in the diencephalon of both male and female embryos between days 19 and 25 of gestation. These rates of aromatase activity are second only to the fetal ovary when expressed per mg protein; moreover, forebrain is the only tissue in the male embryo capable of synthesizing significant amounts of estrogens in vitro. When projected to the whole organ, the capacity of the diencephalon for aromatization exceeds the capacity of the fetal ovary approximately 9-fold. Placenta! aromatase activity was high (2.1 pmol/h/mg protein) on day 13 but fell to a level approximately 20-fold lower by day 19 of gestation. These findings indicate the potent...
57 citations
TL;DR: The experiments reported here indicate that the conversion of androgen to estrogen and other neutral metabolites by the brain is a primitive tetrapod characteristic and suggest that metabolism is an integral component of brain-steroid interactions which has been conserved during the evolution of vertebrates.
45 citations
TL;DR: The results suggest that the increased aromatase specific activity in dbT-stimulated cells results from an increase in amount of active enzyme, rather than from a increase in affinity of the enzyme for its substrate.
42 citations
TL;DR: The aromatase system associated with the mitochondrial fraction of human term placenta, present at 35--50% the specific activity of the microsomal enzyme, is substantially the same as the microSomal enzyme as determined by the following.
30 citations
TL;DR: The microsomal fraction of term placenta was incubated with a range of concentrations of several bile acids and non-ionic detergents and inhibited aromatase activity in themicrosomal homogenate in a concentration-dependent manner that roughly paralleled the concentration- dependent depletion of aromat enzyme activity from the pellet.
22 citations
TL;DR: Luteinized bovine granulosa cells in tissue culture contained an active 19-hydroxylase aromatase enzyme system which converted exogenous androstenedione and testosterone to oestradiol-17beta; no oestrone was detected.
Abstract: Luteinized bovine granulosa cells in tissue culture contained an active 19-hydroxylase aromatase enzyme system which converted exogenous androstenedione and testosterone to oestradiol-17beta; no oestrone was detected. In the absence of exogenous androgens, the cells failed to synthesize oestrogens due to a limited capacity to synthesize androgen precursor. Theca-lutein cells, present in those CL which synthesize oestrogens, may provide androgen precursor for aromatization by the granulosa-lutein cells.
TL;DR: The data described here suggest that this increased aromatase activity is due to an increase in the concentration of only one component of the mono-oxygenase system, cytochrome P-450.